Jun 2012

PNN April–June 2012

PNN Pharmacotherapy Line
Apr. 2, 2012 * Vol. 19, No. 63
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 31 issue of Lancet (2012; 379).
Interleukin-6 in Coronary Disease: In two reports, the IL6R Genetics Consortium Emerging Risk Factors Collaboration provides evidence that interleukin-6 receptor pathways are involved in downstream regulation of inflammatory processes that play a role in coronary heart disease.
In a collaborative meta-analysis, the researchers report that “large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease” (
pp. 1205–13). A genetic variant known to be involved in IL6R signaling, Asp358Ala (rs2228145), occurred at a frequency of 39% in 125,222 participants. The authors found, “For every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4–38.2) and of interleukin 6 by 14.6% (10.7–18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9–9.1) and of fibrinogen by 1.0% (0.7–1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8–5.0).”
“IL6R blockade could provide a novel therapeutic approach to prevention of coronary heart disease that warrants testing in suitably powered randomised trials,” collaboration investigators concluded in a second article (
pp. 1214–24). Applying the mendelian randomization principle, the researchers used single nucleotide polymorphisms (SNPs) in the gene IL6R to “evaluate the likely efficacy and safety of IL6R inhibition for primary prevention of coronary heart disease,” with these results: “In 40 studies including up to 133,449 individuals, an IL6R SNP (rs7529229) marking a non-synonymous IL6R variant (rs8192284; p.Asp358Ala) was associated with increased circulating log interleukin-6 concentration (increase per allele 9.45%, 95% CI 8.34–10.57) as well as reduced C-reactive protein (decrease per allele 8.35%, 95% CI 7.31–9.38) and fibrinogen concentrations (decrease per allele 0.85%, 95% CI 0.60–1.10). This pattern of effects was consistent with IL6R blockade from infusions of tocilizumab (4–8 mg/kg every 4 weeks) in patients with rheumatoid arthritis studied in randomised trials. In 25,458 coronary heart disease cases and 100,740 controls, the IL6R rs7529229 SNP was associated with a decreased odds of coronary heart disease events (per allele odds ratio 0.95, 95% CI 0.93–0.97, p = 1.53×10−5).”

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
CV Risks Following Post-MI Discontinuation of HRT: Based on equivocal results obtained in nationwide cohort study of 3,322 women in Denmark, investigators conclude that the possible cardiovascular risk of hormone-replacement therapy (HRT) must be balanced against the need to treat menopausal symptoms in women surviving myocardial infarction (e1802). During 1997–2008, all women in Denmark aged 40 years or older who survived for at least 30 days after MI were analyzed. Results showed: “A total of 282 (8.5%) women had a reinfarction, 218 (6.6%) died of cardiovascular causes, and 357 (10.7%) died of any cause during follow-up. Women who discontinued overall hormone replacement therapy in the first year after myocardial infarction did not have a significantly different risk of reinfarction (hazard ratio 0.90, 95% confidence interval 0.68 to 1.19), cardiovascular mortality (1.21, 0.90 to 1.62), or all cause mortality (1.22, 0.97 to 1.53) than women who continued use. However, discontinuation of vaginal oestrogen was associated with a lower risk of reinfarction (hazard ratio 0.54, 0.34 to 0.86).” (D-M Bretler, dimabr01@geh.regionh.dk)

>>>PNN JournalWatch
* Fish Consumption, Dietary Long-Chain n-3 Fatty Acids, and Risk of Type 2 Diabetes: Systematic Review and Meta-analysis of Prospective Studies, in
Diabetes Care, 2012; 35: 918–29. (A. Wolk, alicja.wolk@ki.se)
* Fish Consumption and Incidence of Diabetes: Meta-analysis of Data from 438,000 Individuals in 12 Independent Prospective Cohorts with an Average 11-Year Follow-up, in
Diabetes Care, 2012; 35: 930–8. (K. He, kahe@unc.edu)
* Vitamin D Supplementation: What’s Known, What to Do, and What’s Needed, in
Pharmacotherapy, 2012; 32: 354–82. (S. T. Haines, shaines@rx.umaryland.edu)
* Everolimus: Targeted Therapy on the Horizon for the Treatment of Breast Cancer, in
Pharmacotherapy, 2012; 32: 383–96. (C. M. Barnett, cmbarnet@mdanderson.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 3, 2012 * Vol. 19, No. 64
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Apr. 3 issue of the Annals of Internal Medicine (2012; 156).
Health Care–Associated Hepatitis C Infections & Narcotic Diversion: Drug diversion and narcotic tampering by a health care worker led to five cases of infection with hepatitis C virus over a 3–4-year period at an acute care hospital and affiliated clinic, researchers report (pp. 477–82). Based on employee work and narcotic dispensing records, the investigators made these findings while seeking to uncover the reasons for HCV infections in 3 patients: “21 employees were recorded as being at work or as retrieving a narcotic from an automated dispensing cabinet in an area where a narcotic was administered to each of the 3 case patients; all employees provided blood samples for HCV testing. One employee was infected with HCV that had more than 95% NS5B sequence homology with the HCV strains of the 3 case patients. Quasi-species analysis showed close genetic relatedness with variants from each of the case patients and more than 97.9% nucleotide identity. The employee acknowledged parenteral opiate diversion. An investigation identified 6,132 patients at risk for exposure to HCV because of the drug diversion. Of the 3,929 living patients, 3,444 (87.7%) were screened for infection. Two additional cases of genetically related HCV infection attributable to the employee were identified.” (W. C. Hellinger, helling@mayo.edu)
Diagnosing & Treating Influenza: Two review articles detail the accuracy of rapid influenza diagnostic tests (pp. 500–11) and use of medications for treatment of the viral infection (pp. 512–24). RIDTs are good for ruling in but not ruling out influenza, authors conclude. “The pooled sensitivity and specificity were 62.3% (95% CI, 57.9% to 66.6%) and 98.2% (CI, 97.5% to 98.7%), respectively,” the authors write. “The positive and negative likelihood ratios were 34.5 (CI, 23.8 to 45.2) and 0.38 (CI, 0.34 to 0.43), respectively.” (M. Pai, madhukar.pai@mcgill.ca)
Authors of the antiviral paper summarized evidence from 74 studies: “Meta-analyses of the few studies providing effects with adjustment for confounders suggest that, in high-risk populations, oral oseltamivir may reduce mortality (odds ratio, 0.23 [95% CI, 0.13 to 0.43]; low-quality evidence), hospitalization (odds ratio, 0.75 [CI, 0.66 to 0.89]; low-quality evidence), and duration of symptoms (33 hours [CI, 21 to 45 hours]; very low–quality evidence) compared with no treatment. Earlier treatment with oseltamivir was generally associated with better outcomes. Inhaled zanamivir may lead to shorter symptom duration (23 hours [CI, 17 to 28 hours]; moderate-quality evidence) and fewer hospitalizations (odds ratio, 0.66 [CI, 0.37 to 1.18]) but more complications than no treatment. Direct comparison of oral oseltamivir and inhaled zanamivir suggests no important differences in key outcomes. Data from 1 study suggest that oral amantadine may reduce mortality and pneumonia associated with influenza A. No included study evaluated rimantadine.” (H. J. Schünemann,
schuneh@mcmaster.ca)
Economics of ACA: In an opinion article that argues that the Affordable Care Act is constitutional, Harvard economists provide this economic assessment of the health care reform law (early release): “At the heart of the ACA is a ‘three-legged stool’ designed to solve two of the most important failures in insurance markets in the United States today: Not everyone can afford insurance, and insurers can discriminate against the sick by excluding preexisting conditions, denying or dropping coverage, and basing insurance prices on health. The first leg of the stool is insurance market reform—ending the ability of insurance companies to discriminate against the sick. No longer will people be one bad gene or one chronic condition away from being uninsured. The second is the individual mandate, which requires individuals to purchase coverage as long as it is affordable (defined as costing less than 8% of income). The mandate is fundamental; without it, sick people will disproportionately buy insurance, many healthy people will not, and prices to the sick will increase accordingly. The third leg of the stool is extensive subsidies that will make health insurance affordable for those who cannot afford it. Thus, everyone will be able to access the insurance system.” (D. Cutler, dcutler@harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 4, 2012 * Vol. 19, No. 65
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 4 issue of JAMA (2012; 307).
Cetuximab in Colon Cancer: Added to the modified sixth version of the FOLFOX regimen (mFOLFOX6), cetuximab provided no added benefit in terms of disease-free survival in a trial of 2,686 adults with resected stage III colon cancer (pp. 1383–93). Participants received 12 biweekly cycles of leucovorin, fluorouracil, and oxaliplatin with or without cetuximab. The trial was stopped early when a planned interim analysis showed a low probability that disease-free survival rates in the cetuximab group could surpass those in the mFOLFOX6-only group: “Median (range) follow-up was 28 (0–68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98–1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86–1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1–2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4–1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older.” (S. R. Alberts, alberts.steven@mayo.edu)
Antitumor activity in metastatic disease does not necessarily equate to efficacy in adjuvant care, an editorialist reminds clinicians (
pp. 1431–2): “The implications of the discordant results observed between trials of agents in unresectable stage IV vs stage III colon cancer are clear; the way chemotherapy kills tumor cells in macrometastases differs from how adjuvant therapy accomplishes this in micrometastases. The epithelial-mesenchymal transformation, in which metastasizing cells assume mesenchymal, stem cell–like characteristics while transiting through basement membranes and through the circulation, and thereby become more chemo-resistant, has been suggested as a possible mechanism to explain this phenomenon. However, that would not explain why some agents, such as fluorouracil and oxaliplatin, are effective in the adjuvant or micrometastatic setting, whereas irinotecan, bevacizumab, and now cetuximab are not.” (L. B. Saltz, saltzl@mskcc.org)
Oral Fluoroquinolones & Retinal Detachment: Patients on oral fluoroquinolones have a slightly increased risk of retinal detachment, according to a nested case–control study of British Columbians (pp. 1414–9). Patients visited ophthalmologists in 2000–07 for procedures coded as retinal repair surgery within 14 days of visits coded for physician services. Results showed: “From a cohort of 989,591 patients, 4,384 cases of retinal detachment and 43,840 controls were identified. Current use of fluoroquinolones was associated with a higher risk of developing a retinal detachment (3.3% of cases vs 0.6% of controls; adjusted rate ratio [ARR], 4.50 [95% CI, 3.56–5.70]). Neither recent use (0.3% of cases vs 0.2% of controls; ARR, 0.92 [95% CI, 0.45–1.87]) nor past use (6.6% of cases vs 6.1% of controls; ARR, 1.03 [95% CI, 0.89–1.19]) was associated with a retinal detachment. The absolute increase in the risk of a retinal detachment was 4 per 10,000 person–years (number needed to harm = 2,500 computed for any use of fluoroquinolones). There was no evidence of an association between development of a retinal detachment and beta-lactam antibiotics (ARR, 0.74 [95% CI, 0.35–1.57]) or short-acting beta-agonists (ARR, 0.95 [95% CI, 0.68–1.33]).” (M. Etminan, metminan@popi.ubc.ca)
Patient Satisfaction & Drug Abuse: When patients visit physicians with the intent of obtaining prescriptions for abusable drugs, patient satisfaction is not the best metric for judging the doctor’s performance, a Viewpoint author writes (pp. 1377-8): “Physicians who comply with unreasonable requests may find themselves in the role of ‘customer service’ providers rather than medical professionals or healers; physicians who do not comply with patient requests may be the recipients of poor ratings on patient satisfaction scores, possibly resulting in emotional, financial, and professional penalties. These issues may be inadvertent but powerful disincentives for physicians to provide medically correct care and may contribute to the erosion of trust needed in a healthy patient–physician relationship.” (A. Zgierska, aleksandra.zgierska@fammed.wisc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 5, 2012 * Vol. 19, No. 66
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 5 issue of the New England Journal of Medicine (2012; 366).
Immunogenicity of HIV-1 Vaccine: Analysis of data from an efficacy trial of an HIV-1 vaccine sheds light on which responding antibodies were helpful and which may have “mitigated the effects of protective antibodies” (pp. 1275–86). Six antibodies were chosen from 17 identified in pilot studies, and these were assessed to determine the roles of T-cell, IgG antibody, and IgA antibody responses in the modulation of infection risk. Based on assays of samples from 41 infected and 205 uninfected vaccinees, the investigators determined: “Of six primary variables, two correlated significantly with infection risk: the binding of IgG antibodies to variable regions 1 and 2 (V1V2) of HIV-1 envelope proteins (Env) correlated inversely with the rate of HIV-1 infection (estimated odds ratio, 0.57 per 1-SD increase; P = 0.02; q = 0.08), and the binding of plasma IgA antibodies to Env correlated directly with the rate of infection (estimated odds ratio, 1.54 per 1-SD increase; P = 0.03; q = 0.08). Neither low levels of V1V2 antibodies nor high levels of Env-specific IgA antibodies were associated with higher rates of infection than were found in the placebo group. Secondary analyses suggested that Env-specific IgA antibodies may mitigate the effects of potentially protective antibodies.” (B. F. Haynes, hayne002@mc.duke.edu)
Correlates of infection such as those identified in this study “may shortcut the road to a clinically viable vaccine,” editorialists write (
pp. 1343–4): “Because of the efficacy observed in the trial, new hypotheses to advance the investigation of HIV candidate vaccines can now be generated, as the authors suggest. These hypotheses should be tested in an iterative manner both in the experimental nonhuman primate model and in clinical trials. Many intriguing questions emerge. How do we better understand the protective response—or, more likely, the interplay of immune responses—that affords protection? Do the immune responses in peripheral blood correlate with responses in important compartments such as the mucosa? Which components of the vaccine regimen are responsible for the protection observed? The findings of correlates reported by Haynes and colleagues suggest that certain antibody responses may be responsible for the protective effect and, thus, that the envelope protein may be central to that effect. Can the protective effect be enhanced or prolonged by the administration of booster doses of the vaccine? Can immunogens be designed to stimulate antibody responses to the V1V2 region without inducing potentially interfering Env-specific IgA responses?” (L. R. Baden)
Rivaroxaban in Symptomatic Pulmonary Embolism: In 4,832 patients with acute symptomatic pulmonary embolism with or without deep-vein thrombosis, fixed-dose oral rivaroxaban was noninferior to standard therapies, report EINSTEIN–PE investigators (pp. 1287–97). Study participants received oral rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily or enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months, with these results: “Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P = 0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). [Major or clinically relevant nonmajor bleeding] occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P = 0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P = 0.003). Rates of other adverse events were similar in the two groups.” (H. R. Büller, h.r.buller@amc.uva.nl)
Malaria Treatments: In 1,271 patients from Asia and Africa, fixed-dose pyronaridine 180 mg plus artesunate 60 mg was efficacious for treatment of uncomplicated Plasmodium falciparum malaria, researchers report (pp. 1298–309). The open-label Phase III trial compared those agents with mefloquine 250 mg plus artesunate 100 mg. Efficacy rates were 99.2% with the pyronaridine regimen, compared with 97.8% when mefloquine was used, establishing noninferiority of the new combination. (I. Borghini-Fuhrer, borghinii@mmv.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 6, 2012 * Vol. 19, No. 67
Providing news and information about medications and their proper use

>>>Pediatrics Report
Source:
Apr. issue of Pediatrics (2012; 129).
Pharmacy Communication About Emergency Contraceptives: While most pharmacies stock products indicated for emergency contraception (EC), staff members often give inaccurate information about who can take EC and at what age the products are available without a prescription, researchers report (pp. 624–9). Using standardized scripts, female callers telephoned 943 pharmacies in five U.S. cities and posed as 17-year-old adolescents or as physicians calling about 17-year-old patients. Results showed: “Seven hundred fifty-nine pharmacies (80%) indicated to adolescent callers, and 766 (81%) to physician callers, that EC was available on the day of the call. However, 145 pharmacies (19%) incorrectly told the adolescent callers that it would be impossible to obtain EC under any circumstances, compared with 23 pharmacies (3%) for physician callers. Pharmacies conveyed the correct age to dispense EC without a prescription in 431 adolescent calls (57%) and 466 physician calls (61%). Compared with physician callers, adolescent callers were put on hold more often (54% vs 26%) and spoke to self-identified pharmacists less often (3% vs 12%, P < .0001). When EC was not available, 36% and 33% of pharmacies called by adolescents and physicians respectively offered no additional suggestions on how to obtain it.” (T. A. Wilkinson)
Nurse-Initiated Steroids in Asthma: In the pediatric emergency department (ED), nurse-initiated oral corticosteroids in children with moderate to severe acute asthma exacerbations reduced times to clinical improvement and discharge and reduced admission rates compared with physician care, a study shows (pp. 671–80). Chart review of 644 patients aged 2–17 years showed these patterns in a time-series controlled trial of physician- and nurse- (before physician assessment and based on Pediatric Respiratory Assessment Measure scores) initiated bronchodilator therapy: “Nurse-initiated phase children improved earlier compared to physician-initiated phase (median difference: 24 minutes; 95% confidence interval [CI]: 1–50; P = .04). Admission was less likely if children received steroids at triage (odds ratio = 0.56; 95% CI: 0.36–0.87). Efficiency gains were made in time to steroid receipt (median difference: 44 minutes; 95% CI: 39–50; P < .001), time to mild status (median difference: 51 minutes; 95% CI: 17–84; P = .04), and time to discharge (median difference: 44 minutes; 95% CI: 17–68; P = .02). No differences were found in return visit rate or subsequent admission.” (R. Zemek)

>>>Cardiology Highlights
Source:
Apr. 10 issue of the Journal of the American College of Cardiology (2012; 59).
Endothelial Shear Stress Testing in Stent Restenosis and Thrombosis: Personalized care of patients with coronary stents could be enhanced using endothelial shear stress (ESS) profiling, according to authors of a review article (pp. 1337–49): “Local hemodynamic factors, low … ESS in particular, are long known to critically affect the natural history of atherosclerosis. Increasing evidence now suggests that ESS may also contribute to the development of restenosis and thrombosis upon stenting of atherosclerotic plaques, in conjunction with well-appreciated risk factors. In this review, we present in vivo and mechanistic evidence associating ESS with the localization and progression of neointimal hyperplasia and in-stent clotting. Clinical studies have associated stent design features with the risk of restenosis. Importantly, computational simulations extend these observations by directly linking specific stent geometry and positioning characteristics with the post-stenting hemodynamic milieu and with the stent’s thrombogenicity and pro-restenotic potential, thereby indicating ways to clinical translation. An enhanced understanding of the pathophysiologic role of ESS in restenosis and thrombosis might dictate hemodynamically favorable stent designs and deployment configurations to reduce the potential for late lumen loss and thrombotic obstruction. Recent methodologies for in vivo ESS profiling at a clinical level might allow for early identification of patients at high risk for the development of restenosis or thrombosis and might thereby guide individualized, risk-tailored treatment strategies to prevent devastating complications of endovascular interventions.” (G. D. Giannoglou, yan@med.auth.gr)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 9, 2012 * Vol. 19, No. 68
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 7 issue of Lancet (2012; 379).
Hepatic Veno-occlusive Prophylaxis with Defibrotide: In pediatric patients undergoing hematopoietic stem-cell transplantation (HSCT), defibrotide therapy provides protection against hepatic veno-occlusive disease, researchers report (pp. 1301–9). In an open-label, Phase III trial at 28 European facilities, patients younger than 18 years of age received either intravenous defibrotide prophylaxis or no treatment, with these results: “Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference –7.7%, 95% CI –15.3 to –0.1; Z test for competing risk analysis p = 0.0488; log-rank test p = 0.0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls.” (S. Corbacioglu, selim.corbacioglu@klinik.uni-regensburg.de)
Pharmacist-Led Information Technology Intervention for Medication Errors: In an article released early (see PNN, Feb. 21), a pharmacist-led information technology intervention (PINCER) that used feedback, educational outreach, and dedicated support was superior to computer-generated simple feedback for reducing a range of medication errors (pp. 1310–9). Implemented in the primary care setting in the U.K., the system relied on computerized systems in general practices to permit pharmacists to review patients’ medical records. Interventions included discussions with family doctors to decide on actions to be taken; invitation of patients to be reviewed or to have blood tests; and working with members of the practice team to improve local safety systems. Results showed: “72 general practices with a combined list size of 480,942 patients were randomised. At 6 months’ follow-up, patients in the PINCER group were significantly less likely to have been prescribed a non-selective NSAID if they had a history of peptic ulcer without gastroprotection (OR 0.58, 95% CI 0.38–0.89); a beta blocker if they had asthma (0.73, 0.58—0.91); or an ACE inhibitor or loop diuretic without appropriate monitoring (0.51, 0.34–0.78). PINCER has a 95% probability of being cost effective if the decision-maker’s ceiling willingness to pay reaches £75 per error avoided at 6 months.” (A. J. Avery, tony.avery@nottingham.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Antibiotics v. Appendectomy for Appendicitis: For acute uncomplicated appendicitis, antibiotics provide safe, effective primary treatment, according to a meta-analysis of randomized controlled trials (e2156): “Four randomised controlled trials with a total of 900 patients (470 antibiotic treatment, 430 appendicectomy) met the inclusion criteria. Antibiotic treatment was associated with a 63% (277/438) success rate at one year. Meta-analysis of complications showed a relative risk reduction of 31% for antibiotic treatment compared with appendicectomy (risk ratio (Mantel–Haenszel, fixed) 0.69 (95% confidence interval 0.54 to 0.89); I2 = 0%; P = 0.004). A secondary analysis, excluding the study with crossover of patients between the two interventions after randomisation, showed a significant relative risk reduction of 39% for antibiotic therapy (risk ratio 0.61 (0.40 to 0.92); I2 = 0%; P = 0.02). Of the 65 (20%) patients who had appendicectomy after readmission, nine had perforated appendicitis and four had gangrenous appendicitis. No significant differences were seen for treatment efficacy, length of stay, or risk of developing complicated appendicitis.” (D. N. Lobo, ileep.Lobo@nottingham.ac.uk">Dileep.Lobo@nottingham.ac.uk)

>>>PNN JournalWatch
* Hypercalcemia in Children Receiving Pharmacologic Doses of Vitamin D [case report], in
Pediatrics, 2012; 129: e1060–3. (M. B. Vanstone)
* Medical Therapy for the Patient with Obesity, in
Circulation, 2012; 125: 1695–703. (G. Bray, George.Bray@pbrc.edu)
* Caring for the Whole Patient: The Science of Psychosocial Care [overview of special series that includes articles on evidence-based treatment of depression, anxiety, and delirium in patients with cancer], in
Journal of Clinical Oncology, 2012; 30: 1151–3. (P. Jacobsen, paul.jacobsen@moffitt.org)
* A New Perspective on Anhedonia in Schizophrenia, in
American Journal of Psychiatry, 2012; 169: 364–73. (G. P. Strauss, gstrauss@mprc.umaryland.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 10, 2012 * Vol. 19, No. 69
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Apr. 9 issue of the Archives of Internal Medicine (2012; 172).
Influenza Vaccine Effectiveness in Hemodialysis: In patients on hemodialysis for end-stage renal disease (ESRD), the effectiveness of influenza vaccine may be less than previously thought, researchers report (pp. 548–54). Vaccine effectiveness (VE) was estimated using the U.S. Renal Data System; vaccinated patients were compared for years when the influenza vaccine matched the circulating virus (1998, 1999, 2001) versus a mismatched year (1997). Cox proportional hazards model results showed the following: “Vaccination rates were less than 50% each year. Conventional analysis comparing vaccinated with unvaccinated patients produced average VE estimates of 13%, 16%, and 30% for influenza-like illness, influenza/pneumonia hospitalization, and mortality, respectively. When restricted to the preinfluenza period, results were even stronger, indicating bias. The pooled ratio of hazard ratios comparing matched seasons with a placebo season resulted in a VE of 0% (95% CI, –3% to 2%) for influenza-like illness, 2% (–2% to 5%) for hospitalization, and 0% (–3% to 3%) for death.”
These results led the authors to conclude, “Our analysis suggests that the potential health benefits of the current influenza vaccine may be small to negligible in the dialysis population. Conventional analyses comparing vaccinated with unvaccinated groups are prone to bias. Although it is premature to discontinue vaccinating high-risk patients, alternate vaccination strategies should be investigated in patients with ESRD to achieve better health outcomes.” (M. A. Brookhart,
mabrook@email.unc.edu)
B Vitamin/Fatty Acid Supplementation & Cancer: Among 2,501 middle-aged and older adults, low doses of B vitamins and/or omega-3 fatty acids had no effects on cancer outcomes, according to the Supplementation With Folate, Vitamins B6 and B12 and/or Omega-3 Fatty Acids (SU.FOL.OM3) secondary prevention trial (pp. 540–7). Conducted in France in 2003–09, the study assigned patients to one of four supplement groups: 5-methyltetrahydrofolate 0.56 mg, pyridoxine hydrochloride 3 mg, and cyanocobalamin 0.02 mg; eicosapentaenoic and docosahexaenoic acid 600 mg in a 2:1 ratio; B vitamins and omega-3 fatty acids; or placebo, with these results: “After 5 years of supplementation, incident cancer was validated in 7.0% of the sample (145 events in men and 29 in women), and death from cancer occurred in 2.3% of the sample. There was no association between cancer outcomes and supplementation with B vitamins (HR, 1.15 [95% CI, 0.85–1.55]) and/or omega-3 fatty acids (HR, 1.17 [95% CI, 0.87–1.58]). There was a statistically significant interaction of treatment by sex, with no effect of treatment on cancer risk among men and increased cancer risk among women for omega-3 fatty acid supplementation (HR, 3.02 [95% CI, 1.33–6.89]).” (V. A. Andreeva, v.andreeva@uren.smbh.univ-paris13.fr)
Omega-3 Fatty Acids in the Secondary CVD Prevention: Supplements of omega-3 fatty acids do not prevent cardiovascular events in patients with histories of cardiovascular disease (CVD), a meta-analysis of 14 studies shows (doi: 10.1001/archinternmed.2012.262). A small reduction (relative risk, 0.91; 0.84–0.99) “disappeared when [the authors] excluded a study with major methodological problems,” and the overall relative risk was 0.99 (0.89–1.09). (S-K Myung, msk@ncc.re.kr)
Lack of Fenofibrate Generic Competition: Pharmacists could help in achieving more competition among branded and generic formulations of fenofibrate, authors write (doi: 10.1001/archinternmed.2012.187). Abbott’s ability to maintain market share for its expensive branded product costs the U.S. health care system $700 million annually, the authors note, adding: “The inability of pharmacists to switch patients with prescriptions for the new reformulations to generics prevented meaningful uptake of these less expensive drugs. Although Abbott conducted bioequivalence trials showing that its reformulations had the same effects as Tricor-1, pharmacists were unable to switch patients because of dose differences between each of the Tricor formulations. Revising the language of generic substitution statutes to allow switching between bioequivalent drug formulations (including those at different doses) could prevent the recurrence of similar switching strategies.” (H. M. Krumholz, harlan.krumholz@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 11, 2012 * Vol. 19, No. 70
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 11 issue of JAMA (2012; 307).
Mortality with ARBs in Heart Failure: A study of losartan and candesartan does not support the hypothesis of differential effects of ARBs in patients with heart failure (pp. 1506–12). Lower losartan doses were associated with increased mortality risk when compared with higher candesartan doses, but mortality risks were similar with the highest doses of the two drugs. The analysis, which relied on data from the Danish registry-based cohort study, included patients aged 45 years or older with first-time hospitalizations for heart failure in 1998–2008. New users of losartan and candesartan had these mortality risks: “Among 4,397 users of losartan, 1,212 deaths occurred during 11,347 person–years of follow-up (unadjusted incidence rate [IR]/100 person–years, 10.7; 95% CI, 10.1–11.3) compared with 330 deaths during 3,675 person–years among 2,082 users of candesartan (unadjusted IR/100 person–years, 9.0; 95% CI, 8.1–10.0). Compared with candesartan, losartan was not associated with increased all-cause mortality (adjusted hazard ratio [HR], 1.10; 95% CI, 0.96–1.25) or cardiovascular mortality (adjusted HR, 1.14; 95% CI, 0.96–1.36). Compared with high doses of candesartan (16–32 mg), low-dose (12.5 mg) and medium-dose losartan (50 mg) were associated with increased mortality (HR, 2.79; 95% CI, 2.19–3.55 and HR, 1.39; 95% CI, 1.11–1.73, respectively); use of high-dose losartan (100 mg) was similar in risk (HR, 0.71; 95% CI, 0.50–1.00).” (H. Svanström, htr@ssi.dk)
Statins in Healthy Men: A new JAMA feature, “dueling” Viewpoints, debuts in this issue with a debate over use of statins for primary prevention of coronary heart disease (CHD) in men. The question posed to two sets of authors was: “Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 250 mg/dL, and no family history of premature CHD be treated with a statin?”
Yes, responds the first group (
pp. 1489–90): “Assuming a high-density lipoprotein cholesterol (HDL-C) level of about 40 mg/dL, the patient in this common clinical scenario would have an ‘intermediate’ 10-year risk for developing CHD (approximately 10%) based on the Framingham Risk Score. As always, lifestyle change is the first-line therapy. However, if this patient’s cholesterol level remains abnormal, despite sustained attempts at lifestyle optimization, statin therapy should be considered with the goal of reducing CHD risk. Current guidelines suggest an LDL-C goal of less than 130 mg/dL with an optional target of less than 100 mg/dL. In the shared decision-making process, the clinician should explicitly inform this patient that a statin is likely to reduce the chance of a first CHD event and reduce the chance of stroke and may offer a survival benefit that is likely to become more evident over a lifetime.” (R. S. Blumenthal, rblument@jhmi.edu)
No, counters the second set of authors, who maintain that the risks of statin therapy exceed potential benefits (
pp. 1491–2): “For the 55-year-old man in this scenario, his risk of myocardial infarction in the next 10 years based on the Framingham Risk Score varies from 10% to 20%. His risk is driven mostly by his age rather than by his cholesterol level. Increasing age has a much larger influence on risk for cardiovascular disease than do increasing levels of cholesterol. Recent data on increased risk of diabetes, cognitive dysfunction, and muscle pain associated with statins suggest that there is risk with no evidence of benefit. Advising healthy patients to take a drug that does not offer the possibility to feel better or live longer and has significant adverse effects with potential decrement in quality of life is not in their interest.” (R. F. Redberg, redberg@medicine.ucsf.edu)
Reducing Waste in Health Care: Six categories of waste in health care (overtreatment, failures of care coordination, failures in execution of care processes, administrative complexity, pricing failures, and fraud and abuse) account for 20% of expenses, according to an article coauthored by former CMS head Don Berwick (pp. 1513–6): “The savings potentially achievable from systematic, comprehensive, and cooperative pursuit of even a fractional reduction in waste are far higher than from more direct and blunter cuts in care and coverage. The potential economic dislocations, however, are severe and require mitigation through careful transition strategies.” (D. M. Berwick, donberwick1@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 12, 2012 * Vol. 19, No. 71
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 12 issue of the New England Journal of Medicine (2012; 366).
Outcomes Following Induction Failure in Childhood ALL: In the small percentage of children and adolescents with acute lymphoblastic leukemia (ALL) whose remission-induction fails, those with T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, researchers report (pp. 1371–81). Patients with precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy, the authors add, based on 1,041 cases of failure among 44,017 patients treated for newly diagnosed ALL in studies conducted in 1985–2000: “Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (± SE) was estimated at only 32 ± 1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72 ± 5% when treated with chemotherapy only.” (C-H Pui, ching-hon.pui@stjude.org)
An editorialist considers what is needed to attack “remaining challenges in childhood leukemia” (
pp. 1445–6): “Although induction failure occurred disproportionately among ‘high risk’ patients, it is remarkable that in one quarter of the cases, it occurred in one of the ‘best risk’ groups. A final challenge is to develop therapeutic strategies to combat the poor outcomes associated with clinically defined subgroups that lack any known adverse molecular features—namely, male sex, older age, and hyperleukocytosis. Despite our increasingly sophisticated molecular characterization of ALL, these clinical risk factors stubbornly persist as independent predictors of poor prognosis, both within induction failure and in ALL overall. Identifying molecular therapies that effectively target mutated genes is difficult enough, but for these clinically defined groups, identifying molecular targets remains an even greater challenge.” (K. R. Rabin)
Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer: Among 265 patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer, the oral poly-ADP–ribose) polymerase inhibitor olaparib significantly improved progression-free survival when used as maintenance therapy (pp. 1382–92). The Phase II trial tested olaparib 400 mg twice daily against placebo, using a primary end point of progression-free survival according to the Response Evaluation Criteria in Solid Tumors guidelines. Results showed: “Progression-free survival was significantly longer with olaparib than with placebo (median, 8.4 months vs. 4.8 months from randomization on completion of chemotherapy; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.25 to 0.49; P < 0.001). Subgroup analyses of progression-free survival showed that, regardless of subgroup, patients in the olaparib group had a lower risk of progression. Adverse events more commonly reported in the olaparib group than in the placebo group (by more than 10% of patients) were nausea (68% vs. 35%), fatigue (49% vs. 38%), vomiting (32% vs. 14%), and anemia (17% vs. 5%); the majority of adverse events were grade 1 or 2. An interim analysis of overall survival (38% maturity, meaning that 38% of the patients had died) showed no significant difference between groups (hazard ratio with olaparib, 0.94; 95% CI, 0.63 to 1.39; P = 0.75).” (J. Ledermann, j.ledermann@ctc.ucl.ac.uk)
Rectal Indomethacin in Pancreatitis: Indomethacin administered rectally reduced the incidence of pancreatitis among 602 patients at high risk following endoscopic retrograde cholangiopancreatography, a study shows (pp. 1414–22; B. J. Elmunzer, badihe@umich.edu).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 13, 2012 * Vol. 19, No. 72
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Apr. issue of Chest (2012; 141).
Fetal Smoke Exposure & Childhood Wheezing: Preschool children whose mothers smoked during the second and third trimesters of pregnancy have increased risks of wheezing, a study shows (pp. 876–85). Paternal smoking may also contribute to the problem, authors add based on a population-based prospective cohort study that used parental smoking questionnaires, registries that identified children with wheezing and those who were born small for gestational age. Among 4,574 children aged 1–4 years, these results were noted: “Maternal smoking during the first trimester only was not associated with wheezing. Continued maternal smoking in pregnancy was associated with the risk of wheezing at 1 to 4 years (P for trends < .05). The strongest effect estimates were observed for frequent wheezing (four or more episodes of wheezing per year) until age 3 years (OR [95% CI]: age 1,1.64 [1.12–2.40]; age 2, 1.64 [1.01–2.64]; age 3, 2.19 [1.24–3.86]). Among children of nonsmoking mothers, fetal exposure to paternal smoking was not consistently associated with the risks of wheezing. The associations of continued maternal smoking during pregnancy with wheezing symptoms were independent of postnatal smoke exposure or small for gestational age at birth.” (L. Duijts, l.duijts@erasmusmc.nl)
Pediatric Obesity-Associated Asthma: Children with obesity and asthma have a different pathologic mechanisms at work than those in children with atopic asthma, researchers report (pp. 895–905). Pediatric obesity-associated asthma is characterized by involvement of the T helper (Th) 1 cell rather than the Th2 cells implicated in atopic asthma, according to these findings in 120 children: “Obese asthmatic children had significantly higher Th1 responses to [phorbol 12-myristate 13-acetate (PMA)] (P < .01) and tetanus toxoid (P < .05) and lower Th2 responses to PMA (P < .05) and [Dermatophagoides farinae] (P < .01) compared with nonobese asthmatic children. Th-cell patterns did not differ between obese asthmatic children and obese nonasthmatic children. Obese asthmatic children had lower FEV1/FVC (P < .01) and residual volume/total lung capacity ratios (P < .005) compared with the other study groups, which negatively correlated with serum interferon-inducible protein 10 and IFN-gamma levels, respectively. PFTs, however, did not correlate with BMI z score or waist to hip ratio.” (D. Rastogi, drastogi@montefiore.org)

>>>Allergy/Immunology Report
Source:
Apr. issue of the Journal of Allergy and Clinical Immunology (2012; 129).
Pertussis & Asthma: Changes in vaccine policy may be needed, based on results of a population-based case–control study showing increased prevalence of pertussis among patients with asthma (pp. 957–63). The investigators suggest replacing the every-10-year tetanus–diphtheria booster with tetanus, diphtheria, and acellular pertussis vaccine in adolescents and adults with asthma. In 2004–05, PCR-confirmed cases of pertussis showed these patterns as compared with matched controls: “Of the 223 subjects, 164 were eligible for the study, and 328 matched control subjects (1:2 matching) were enrolled. Of these 164 subjects, 50% were male, and 82% were white. The median age at the index date of pertussis was 14 years. Sixty-two (38%) of the 164 cases had asthma before the index date of pertussis compared with 85 (26%) of the 328 control subjects (odds ratio, 1.73; 95% CI, 1.12–2.67; P = .013). The population attributable risk percentage of asthma for risk of pertussis was 17%.” (Y. J. Juhn, juhn.young@mayo.edu)
Omalizumab & Malignancy: No relationship between omalizumab use and malignancy was found in a pooled analysis of 67 clinical trials of 11,459 unique patients (pp. 983–9.e6): “The primary analysis identified malignancies in 25 patients…: 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient–years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26–6.94) and 4.45 (95% CI, 2.22–7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39–2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified.” (W. Busse, wwb@medicine.wisc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 16, 2012 * Vol. 19, No. 73
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 14 issue of Lancet (2012; 379).
TAK-875 in Type 2 Diabetes: Activation of the free fatty acid receptor 1 (FFAR1) can significantly improve glycemic control in patients with type 2 diabetes mellitus, according to findings from a Phase II study of the FFAR1 activator TAK-875 (Takeda) (pp. 1403–11). In 426 outpatients with type 2 diabetes, these changes in hemoglobin A1c were noted during treatment with TAK-875 at five different doses, glimepiride 4 mg once daily, or placebo for 12 weeks: “At week 12, significant least-squares mean reductions in HbA1c from baseline occurred in all TAK-875 (ranging from –1.12% [SE 0.113] with 50 mg to –0.65% [0.114] with 6.25 mg) and glimepiride (–1.05% [SE 0.111]) groups versus placebo (–0.13% [SE 0.115]; p value range 0.001 to <0.0001). Treatment-emergent hypoglycaemic events were similar in the TAK-875 and placebo groups (2% [n = 7, all TAK-875 groups] vs 3% [n = 2]); significantly higher rates were reported in the glimepiride group (19% [n = 12]; p value range 0.010–0.002 vs all TAK-875 groups). Incidence of treatment-emergent adverse events was similar in the TAK-875 overall (49%; n = 147, all TAK-875 groups) and placebo groups (48%, n = 29) and was lower than in the glimepiride group (61%, n = 38).” (C. F. Burant, burantc@umich.edu)
Pneumonia & Vitamin D: In infants at high risk, quarterly bolus doses of vitamin D did not prevent pneumonia, researchers report (pp. 1419–27). In Kabul, Afghanistan, children aged 1–11 months were given vitamin D3 100,000 IU or placebo every 3 months by fieldworkers, with these effects on first or only episodes of radiologically confirmed pneumonia: “1,524 children were assigned to receive vitamin D3 and 1,522 placebo. There was no significant difference between the incidence of first or only pneumonia between the vitamin D (0.145 per child per year, 95% CI 0.129–0.164) and the placebo group (0.137, 0.121–0.155); the incidence rate ratio was 1.06 (95% CI 0.89–1.27). From 652 children during five separate periods of testing serum calcifediol, only one child in each of two testing periods had results greater than 375 nmol/L in the intervention group—a toxic level.” (S. Manaseki–Holland, s.manasekiholland@bham.ac.uk)
While this study has several strengths, an editorialist writes that pharmacokinetics of vitamin D is one of several reasons why “investigation of a different dosing regimen of vitamin D in a different population might yet yield a positive result” (
pp. 1373–5): “Quarterly administration of large bolus doses of vitamin D to infants … resulted in a rapid increase in circulating calcifediol concentrations—to supraphysiological concentrations in some cases—with a subsequent slow decline to concentrations similar to those recorded in unsupplemented children. Such peaks and troughs could have potentially deleterious effects on the immune response: concentrations of calcifediol greater than 140 nmol/L have been associated with impaired immunity to infection, possibly related to the fact that vitamin D can suppress adaptive responses to infection as well as boosting innate responses. Moreover, chronic exposure to falling calcifediol concentrations has been postulated to cause an imbalance between the activity of enzymes that synthesise and catabolise calcitriol in extra-renal tissues, resulting in reduced concentrations of this active metabolite at sites of disease. Either or both of these events could have contributed to the excess of recurrent pneumonia recorded in the intervention group of the study. Giving lower doses of vitamin D more often could induce sustained elevation of calcifediol concentrations into the physiological range; this might have more favourable effects on immune function.” (A. R. Martineau a.martineau@qmul.ac.uk)

>>>PNN JournalWatch
* Cluster Headache, in
BMJ, 2012; 344: e2407. (P. J. Goadsby, pgoadsby@headache.ucsf.edu)
* American College Of Rheumatology 2012 Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the Hand, Hip, and Knee, in
Arthritis Care & Research, 2012; 64: 465–74. (M. C. Hochberg, mhochber@umaryland.edu)
* 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis, in
Arthritis Care & Research, 2012; 64: 625–39. (J. A. Singh, Jasvinder.md@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 17, 2012 * Vol. 19, No. 74
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Apr. 17 issue of the Annals of Internal Medicine (2012; 156).
Cost-Effectiveness of Preexposure HIV Prophylaxis: Among men who have sex with men (MSM) and are at high risk of acquiring HIV, daily oral preexposure chemoprophylaxis (PrEP) could prevent substantial numbers of new cases of HIV but at a societal cost of $4 billion, researchers report (pp. 541–50). Assuming a target population of MSM aged 13–64 years in the U.S., the investigators make these calculations based on a 44% reduction in HIV risk using PrEP: “Initiating PrEP in 20% of MSM in the United States would reduce new HIV infections by an estimated 13% and result in a gain of 550,166 [discounted quality-adjusted life–years (QALYs)] over 20 years at a cost of $172,091 per QALY gained. Initiating PrEP in a larger proportion of MSM would prevent more infections but at an increasing cost per QALY gained (up to $216,480 if all MSM receive PrEP). Preexposure chemoprophylaxis in only high-risk MSM can improve cost-effectiveness. For MSM with an average of 5 partners per year, PrEP costs approximately $50,000 per QALY gained. Providing PrEP to all high-risk MSM for 20 years would cost $75 billion more in health care–related costs than the status quo and $600,000 per HIV infection prevented, compared with incremental costs of $95 billion and $2 million per infection prevented for 20% coverage of all MSM.” (J. L. Juusola)
Fibrates & Renal Function: New use of fibrates is associated with increased serum creatinine levels and an absolute increase in hospitalizations and nephrologist consults in older adults over the following 90 days, according to a population-based cohort study from Ontario (pp. 560–9): “Compared with ezetimibe users (n = 61,831), fibrate users (n = 19,072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1,110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease.” (Y. Y. Zhao)
Urgency Urinary Incontinence in Women: Drugs used for treatment of urgency urinary incontinence (UI) in women lack evidence of long-term adherence and safety, and more attention should be paid to possible harms, according to systematic review of 94 randomized controlled trials (early release): “Pooled analyses showed that among drugs for urgency UI, per 1,000 treated, continence was achieved in 130 with fesoterodine (CI, 58 to 202), 85 with tolterodine (CI, 40 to 129), 114 with oxybutynin (CI, 64 to 163), 107 with solifenacin (CI, 58 to 156), and 114 with trospium (CI, 83 to 144). Rates of treatment discontinuation due to adverse effects were 31 per 1,000 treated with fesoterodine (CI, 10 to 56), 63 with oxybutynin (CI, 12 to 127), 18 with trospium (CI, 4 to 33), and 13 with solifenacin (CI, 1 to 26). The studies’ inconsistent definitions of improvement in UI and quality of life hampered synthesis of evidence.” (T. Shamliyan)
Obesity Drugs: Reflecting on and FDA advisory panel’s recommendation for approval of Qnexa, a phentermine–topiramate combinatin under review for obesity, one of the panelists who voted negatively uses the analogy of some cars being “lemons” and others “peaches” to reach (early release): “People assume that observations seen in small samples automatically translate to correct inferences about the general universe. We cannot assume that an absence of excess cardiovascular events in small trials—trials that yielded only 12 outcome events—means that we can confidently conclude that Qnexa is safe.…
“We can resolve the information asymmetry by insisting on a large-scale,
preapproval cardiovascular outcomes trial of Qnexa. It would be too risky to rely on postapproval surveillance or to hope that a rigorous trial could be conducted in a timely manner. If Qnexa prevents cardiovascular events, or at least doesn’t increase the risk for them, in a preapproval trial, then we will all know that we have the peach we’ve been waiting for.” (M. S. Lauer)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 18, 2012 * Vol. 19, No. 75
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 18 issue of JAMA, a theme issue on comparative effectiveness research (2012; 307).
Bevacizumab in Older Patients with Advanced Non–Small Cell Lung Cancer: Among Medicare patients with advanced non–small cell lung cancer (NSCLC), addition of bevacizumab to carboplatin and paclitaxel chemotherapy did not improve survival rates, a study shows (pp. 1593–601). Participants in the retrospective cohort study were 4,168 Medicare beneficiaries aged 65 years or older with stage IIIB or stage IV non−squamous cell NSCLC. Participants were analyzed in three groups based on diagnosis year (2002–05 or 2006–07) and initial chemotherapy regimen (carboplatin–paclitaxel with or without bevacizumab). Results showed: “The median survival estimates were 9.7 (interquartile range [IQR], 4.4–18.6) months for bevacizumab–carboplatin–paclitaxel, 8.9 (IQR, 3.5–19.3) months for carboplatin–paclitaxel in 2006–2007, and 8.0 (IQR, 3.7–17.2) months for carboplatin–paclitaxel in 2002–2005. One-year survival probabilities were 39.6% (95% CI, 34.6%–45.4%) for bevacizumab–carboplatin–paclitaxel vs 40.1% (95% CI, 37.4%–43.0%) for carboplatin–paclitaxel in 2006–2007 and 35.6% (95% CI, 33.8%–37.5%) for carboplatin–paclitaxel in 2002–2005. Neither multivariable nor propensity score–adjusted Cox models demonstrated a survival advantage for bevacizumab–carboplatin–paclitaxel compared with carboplatin–paclitaxel cohorts. In propensity score–stratified models, the hazard ratio for overall survival for bevacizumab–carboplatin–paclitaxel compared with carboplatin–paclitaxel in 2006–2007 was 1.01 (95% CI, 0.89–1.16; P = .85) and compared with carboplatin–paclitaxel in 2002–2005 was 0.93 (95% CI, 0.83–1.06; P = .28). The propensity score–weighted model and propensity score–matching model similarly failed to demonstrate a statistically significant superiority for bevacizumab–carboplatin–paclitaxel. Subgroup and sensitivity analyses for key variables did not change these findings.” (D. Schrag, deb_schrag@dfci.harvard.edu)
Commenting on these and other CER articles in this issue, an editorialist writes that it’s time to go beyond evidence-based medicine (EBM) and its reliance on randomized controlled trials (RCTs) (
pp. 1641–3): “In EBM practice, validity (whether the study found the correct answer internally) is evaluated first and may be based largely on type of research design. Generalizability (how well the results apply externally) is then assessed, with consideration given to how study populations, interventions, or end points differ across studies, and compare with the general population. This approach may be reflected in statements that even though observational studies of a problem have suggested one conclusion, an RCT shows that a different conclusion is actually true. In reality, RCTs can have limited clinical relevance, whether evaluating treatments for lung cancer, prostate cancer, or other topics.
“In a medicine-based evidence approach, the primary emphasis is on clinically relevant issues of who and where were the patients, what and why were the treatments, and when and how were the outcomes assessed—as well as an assessment of validity and generalizability considered together and denoted as accuracy. Thus, in contrast to an emphasis in EBM on hierarchies of research design, medicine-based evidence is both rigorous and patient-centered.” (J. Concato,
john.cancato@yale.edu)
PCORI’s Perspective: The Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI)—created under the health care reform law now before the U.S. Supreme Court—provides an overview of the “rigorous methodological standards [needed] to ensure that medical research produces information that is valid and generalizable, and [that] are essential in patient-centered outcomes research (pp. 1636–40): “The Methodology Committee recognizes the unique opportunity afforded by the Patient Protection and Affordable Care Act to enhance and expand methodological approaches for designing and implementing high-quality medical research. Methods for prioritizing research questions, using appropriate study designs and analyses, incorporating patient perspectives, and fostering efficient dissemination and implementation of results will drive future Methodology Committee activities and guide PCORI’s funding announcements.” (E. Basch, ebasch@mskcc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 19, 2012 * Vol. 19, No. 76
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 19 New England Journal of Medicine (2012; 366).
Chemotherapy in Muscle-Invasive Bladder Cancer: Addition of chemotherapy to radiotherapy significantly improved local and regional control of bladder cancer, according to a multicenter, Phase III trial of 360 patients with muscle-invasive bladder cancer (pp. 1477–88). Participants were randomly assigned to radiotherapy alone or radiotherapy plus fluorouracil 500 mg/sq m/d during fractions 1–5 and 16–20 of radiotherapy and mitomycin C 12 mg/sq m on day 1. The investigators found: “At 2 years, rates of locoregional disease–free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P = 0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P = 0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P = 0.07) but not during follow-up (8.3% vs. 15.7%, P = 0.07).” (N. D. James, n.d.james@bham.ac.uk)
Old drugs such as these will be combined with contemporary medical advances to aid in “bladder cancer turning a corner,” editorialists write (
pp. 1540–1): “Ultimately, the decision whether to use chemoradiotherapy—and if so, which drugs to choose—will be made by pretreatment molecular analysis of tumor tissue. A recent report indicates that high expression of MRE11 protein, which is active in the cellular response to radiotherapy, predicted increased eradication rates for bladder tumors and improved cancer-specific survival after radiotherapy but did not predict a difference in cancer-specific survival after cystectomy. A protocol evaluating the pretreatment levels of MRE11 expression and subsequent response to chemoradiotherapy with fluorouracil and mitomycin C is under development through the National Cancer Institute Bladder Cancer Task Force. In addition, retrospective validation with the use of specimens from the BC2001 trial is planned in the United Kingdom.” (W. U. Shipley)
Albendazole & Enteric Parasites in Refugees: The prevalence of intestinal nematodes in refugees arriving in the U.S. from Africa and Southeast Asia decreased following institution of a program of presumptive albendazole therapy administered overseas, a study shows (pp. 1498–507). Stool specimens collected on resettlement in Minnesota in 1993–2007 showed these patterns: “Among 4,370 untreated refugees, 20.8% had at least one stool nematode, most commonly hookworm (in 9.2%). Among 22,586 albendazole-treated refugees, only 4.7% had one or more nematodes, most commonly trichuris (in 3.9%).… Schistosoma ova were identified exclusively among African refugees and were less prevalent among those treated with albendazole (prevalence ratio, 0.60). After implementation of the albendazole protocol, the most common pathogens among 17,011 African refugees were giardia (in 5.7%), trichuris (in 5.0%), and schistosoma (in 1.8%); among 5,575 Southeast Asian refugees, only giardia remained highly prevalent (present in 17.2%).” (S. J. Swanson, stephen.swanson@hcmed.org)

>>>PNN NewsWatch
* Based on 26 cases of death and hospitalization of children over the past 15 years, FDA yesterday issued a reminder to the public about proper storage, use, application, and disposal of fentanyl patches. Young children are at particular risk of accidental exposure to fentanyl patches, FDA said, noting that 16 of the cases were in children aged 2 or younger. “Their mobility and curiosity provide opportunities for them to find lost patches, take improperly discarded patches from the trash, or find improperly stored patches, all of which may result in patches being placed in their mouths or sticking to their skin,” FDA cautioned.
*
FDA reminds consumers of its strong ties to the Institute for Safe Medication Practices and their collective commitment to preventing medication errors. ISMP collects reports from health professionals through its Medication Errors Reporting Program and from consumers through a separate website. All reports are shared with FDA’s MedWatch system.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 20, 2012 * Vol. 19, No. 77
Providing news and information about medications and their proper use

>>>Geriatrics Highlights

Source: Apr. Journal of the American Geriatrics Society (2012; 60).

2012 Beers Criteria: With support of the American Geriatrics Society, a panel of 11 experts in geriatric care and pharmacotherapy has compiled an updated list of potentially inappropriate medications (PIMs) whose use should be avoided in older adults (pp. 616–31). Five of the 11 voting panelists were pharmacists, and two others were among nonvoting participants: Todd Semla (cochair) of the VA National Pharmacy Benefits Management Services and Northwestern U., Judith Beizer of St. Johns U., Nicole Brandt of U. Maryland, Joseph Hanlon of U. Pittsburgh and Pittsburgh VA, Sunny Linnebur of U. Colorado, Robert Dombrowski (nonvoting) of CMS, and David Nau (nonvoting) of the Pharmacy Quality Alliance. Using a modified Delphi method to systematically review and grade medications and reach consensus, the panel produced the 2012 AGS Beers Criteria: “Fifty-three medications or medication classes encompass the final updated Criteria, which are divided into three categories: potentially inappropriate medications and classes to avoid in older adults, potentially inappropriate medications and classes to avoid in older adults with certain diseases and syndromes that the drugs listed can exacerbate, and finally medications to be used with caution in older adults. This update has much strength, including the use of an evidence-based approach using the Institute of Medicine standards and the development of a partnership to regularly update the Criteria. Thoughtful application of the Criteria will allow for (a) closer monitoring of drug use, (b) application of real-time e-prescribing and interventions to decrease ADEs in older adults, and (c) better patient outcomes.” (C. M. Campanelli, ccampanelli@americangeriatrics.org)
In accompanying article, a writer points out improvements in the methodology used for this version of the Beers criteria (
pp. 612–3): “The interdisciplinary panel followed an evidence-based approach that the Institute of Medicine recommended in its 2011 report on developing practice guidelines. The new criteria also include ratings of the quality of the evidence supporting the panel’s recommendations and the panel’s assessment of the strength of these recommendations.” (B. Resnick)
A second commentary (
pp. 614–5) advises future research to “consider partnerships to create an improved database that will support updating the criteria more frequently so that they become less static and more of a real-time decision support tool. Future updates, as did this one, should include in-depth discussion of the specific language used for the lists of drugs to avoid and use with caution, careful consideration of the number and expertise of panelists participating in the update, the inclusion of drug–drug interactions, and development of a list of medications that could be used as alternatives to those to avoid. The panel recognizes the increasingly loud plea from the front-line clinicians for such a list of alternatives to pair with the Beers Criteria and agrees that it is needed.” (D. Fick, T. Semla [panel cochairs])

>>>Infectious Disease Report
Source:
May 1 issue of Clinical Infectious Diseases (2012; 54).
Pneumonia During Pandemic Influenza: During the 2009 pandemic, hospitalization of infected patients with pneumonia was common, and new research shows those patients had increased risk of severe outcomes, including acute respiratory distress syndrome (ARDS), sepsis, and death (pp. 1221–9). Antiviral treatment of these patients was often delayed, according to data from two national case series conducted during spring and fall of the 2009 pandemic influenza A H1N1 (pH1N1) in the U.S.: “Of 451 patients with chest radiographs performed, 195 (43%) had pneumonia (spring, 106 of 237 [45%]; fall, 89 of 214 [42%]). Compared with 256 patients without pneumonia, these 195 patients with pneumonia were more likely to be admitted to the intensive care unit (52% vs 16%), have ARDS (26% vs 2%), have sepsis (18% vs 3%), and die (17% vs 2%; P < .0001). One hundred eighteen (61%) of the patients with pneumonia had ≥1 underlying condition. Bacterial infections were reported in 13 patients with pneumonia and 2 patients without pneumonia. Patients with pneumonia, when compared with patients without pneumonia, were equally likely to receive influenza antiviral agents (78% vs 79%) but less likely to receive antiviral agents within ≤2 days of illness onset (28% vs 50%; P < .0001).” (S. Jain, bwc8@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 23, 2012 * Vol. 19, No. 78
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 21 issue of Lancet (2012; 379).
Insulin Degludec in Type 2 Diabetes: Two Phase III trials compare the ultra-long-acting basal agent insulin degludec with insulin glargine in patients with type 1 diabetes (pp. 1489–97; S. Heller, s.heller@sheffield.ac.uk) and type 2 diabetes (pp. 1498–507; A. J. Garber, agarber@bcm.tmc.edu). The latter study, the noninferiority BEGIN Basal–Bolus Type 2 trial conducted at 123 sites in 12 countries, included 1,006 participants with type 2 diabetes mellitus and a glycosylated hemoglobin level of 7–10% after 3 months or more of any insulin regimen with or without oral antidiabetic agents. Participants were assigned to once-daily subcutaneous insulin degludec or glargine titrated based on glucose levels before breakfast and used insulin aspart at mealtimes. Results were as follows: “744 (99%) of 755 participants randomly allocated degludec and 248 (99%) of 251 allocated glargine were included in the full analysis set (mean age 58.9 years [SD 9.3], diabetes duration 13.5 years [7.3], HbA1c 8.3% [0.8], and fasting plasma glucose 9.2 mmol/L [3.1]); 618 (82%) and 211 (84%) participants completed the trial. After 1 year, HbA1c decreased by 1.1% in the degludec group and 1.2% in the glargine group (estimated treatment difference [degludec–glargine] 0.08%, 95% CI –0.05 to 0.21), confirming non-inferiority. Rates of overall confirmed hypoglycaemia (plasma glucose <3.1 mmol/L or severe episodes requiring assistance) were lower with degludec than glargine (11.1 vs 13.6 episodes per patient–year of exposure; estimated rate ratio 0.82, 95% CI 0.69 to 0.99; p = 0.0359), as were rates of nocturnal confirmed hypoglycaemia (1.4 vs 1.8 episodes per patient–year of exposure; 0.75, 0.58 to 0.99; p = 0.0399). Rates of severe hypoglycaemia seemed similar (0.06 vs 0.05 episodes per patient–year of exposure for degludec and glargine) but were too low for assessment of differences. Rates of other adverse events did not differ between groups.”

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Cardiovascular Outcomes with Metformin & Insulin in Type 2 Diabetes: All-cause mortality and cardiovascular mortality are not improved when metformin is used in addition to insulin in patients with type 2 diabetes, according to a systematic review of 26 randomized trials of 2,286 patients (e1771). Interpretation of study results was hampered by a “severe lack of data” on patient-relevant outcomes and poor bias control, the authors noted, adding these observations: “Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced HbA1c, weight gain, and insulin dose, compared with insulin alone; trial sequential analyses showed sufficient evidence for a HbA1c reduction of 0.5%, lower weight gain of 1 kg, and lower insulin dose of 5 U/day.” (B. Hemmingsen, bh@ctu.rh.dk)

>>>PNN NewsWatch
* Aliskiren-containing ACE and ARB combinations should not be used in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia, FDA said on Friday. Such products should also be avoided in those with moderate to severe renal impairment (GFRs < 60 mL/min).

>>>PNN JournalWatch
* Role of Procalcitonin in Managing Adult Patients with Respiratory Tract Infections, in
Chest, 2012; 141: 1063–73. (P. Schuetz, Schuetzph@gmail.com)
* Pearls & Oy-sters: Treatment of Central Sleep Apnea with Topiramate, in
Neurology, 2012; 78: e97–9. (M. Vendrame, vendrame@bu.edu)
* The US Food and Drug Administration’s Risk Evaluation and Mitigation Strategy (REMS) Program in Practice: Does It Really Inform Patients and Limit Risk [editorial]?, in
American Journal of Kidney Diseases, 2012; 59: 604–6. (R. Brown, rbrown@bidmc.harvard.edu)
* Accountable Care Organizations and ESRD: The Time Has Come, in
American Journal of Kidney Diseases, 2012; 59: 724–33. (A. R. Nissenson, allen.nissenson@davita.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 24, 2012 * Vol. 19, No. 79
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Apr. 23 issue of the Archives of Internal Medicine (2012; 172).
Levothyroxine Outcomes in Subclinical Hypothyroidism: In younger patients, treatment of subclinical hypothyroidism (SCH) with levothyroxine was associated with fewer ischemic heart disease (IHD) events, but this trend was not evident among older patients in an analysis of data in the U. K. General Practitioner Research Database (doi:10.1001/archinternmed.2012.1159). Concluding that “an appropriately powered randomized controlled trial of levothyroxine in SCH examining vascular outcomes is now warranted,” the authors report these outcomes for patients aged 40–70 (younger) and older than 70 (older): “Subclinical hypothyroidism was identified in 3,093 younger and 1,642 older individuals. For a median follow-up period of 7.6 years, 52.8% and 49.9% of younger and older patients with SCH were treated with levothyroxine, respectively. There were 68 incident IHD events in 1,634 younger patients treated with levothyroxine (4.2%) vs 97 IHD events in 1,459 untreated individuals (6.6%) (multivariate-adjusted HR, 0.61; 95% CI, 0.39–0.95). In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59–1.33).” (S. Razvi, salman.razvi@ghnt.nhs.uk)
Stroke Prevention with Warfarin in Nonvalvular Atrial Fibrillation: The proportion of time patients with warfarin-treated nonvalvular atrial fibrillation (AF) spend in therapeutic anticoagulation has improved over time, a meta-analysis of 8 trials shows, and the rate of residual stroke or systemic embolism in such patients is now estimated at 1.66% per year (pp. 623–31): “Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%–1.91%). Major bleeding rates varied from 1.40% to 3.40% per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS2 (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.” (V. Menon, menonv@ccf.org)
Addressing the question of when patients with AF who are taking warfarin should be switched to newer anticoagulants, an editorialist writes (
pp. 631–3): “Patients who are comfortable with warfarin therapy and whose [time in the standard therapeutic range] is above 75% should be in no hurry to switch. They may forgo a small reduction in risk of intracranial hemorrhage, but they should benefit as we gain more experience with the novel agents. For others, the case for the use of novel anticoagulants may be more compelling, particularly if out-of-pocket costs are acceptable.…
“The novel anticoagulants appear to constitute a positive disruptive technology. However, warfarin management has also evolved, allowing safe, effective, and inexpensive anticoagulation for many patients with AF, likely slowing the ultimate transition to modern anticoagulant agents.” (D. E. Singer, dsinger@partners.org)
Antipsychotics & MI in Older Patients with Treated Dementia: Antipsychotic (AP) use in patients with dementia treated with cholinesterase inhibitors (CIs) carries “a modest and time-limited increased” risk of myocardial infarction (MI), researchers report (pp. 648–53). A retrospective review of 2000–09 prescription claims for 37,138 community-dwelling older patients shows these patterns: “Within 1 year of initiating AP treatment, 1.3% of [patients] had an incident MI. Hazard ratios for the risk of MI after initiation of AP treatment [n = 10,969] were 2.19 (95% CI, 1.11–4.32) for the first 30 days, 1.62 (95% CI, 0.99–2.65) for the first 60 days, 1.36 (95% CI, 0.89–2.08) for the first 90 days, and 1.15 (95% CI, 0.89–1.47) for the first 365 days. The self-controlled case series study conducted among 804 incident cases of MI among new AP users yielded incidence rate ratios of 1.78 (95% CI, 1.26–2.52) for the 1- to 30-day period, 1.67 (95% CI, 1.09–2.56) for the 31- to 60-day period, and 1.37 (95% CI, 0.82–2.28) for the 61- to 90-day period.” (Y. Moride, yola.moride@umontreal.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 25, 2012 * Vol. 19, No. 80
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 25 issue of JAMA (2012; 307).
TWHAB–Texting as Influenza Vaccine Intervention: A text-messaging intervention targeting low-income, urban parents was effective for getting children and adolescents vaccinated against influenza, but overall rates remained low in a study of 9,213 pediatric patients (pp. 1702–8). During the 2011–12 season at four community clinics in the U.S., parents of children assigned to the intervention received up to five weekly immunization registry–linked text messages providing education and information about Saturday clinics. Examples of messages were, “Children age 6–59 months like [child’s name] have the highest risk of getting sick from the flu and should be vaccinated” and “To avoid the flu, doctors recommend a flu shot. It is not too late!” Compared with usual care, texting yielded these benefits: “Study children and adolescents were primarily minority, 88% were publicly insured, and 58% were from Spanish-speaking families. As of March 31, 2011, a higher proportion of children and adolescents in the intervention group (43.6%; n = 1,653) compared with the usual care group (39.9%; n = 1,509) had received influenza vaccine (difference, 3.7% [95% CI, 1.5%-5.9%]; relative rate ratio [RRR], 1.09 [95% CI, 1.04–1.15]; P = .001). At the fall review date, 27.1% (n = 1026) of the intervention group compared with 22.8% (n = 864) of the usual care group had received influenza vaccine (difference, 4.3% [95% CI, 2.3%–6.3%]; RRR, 1.19 [95% CI, 1.10–1.28]; P < .001).” (M. S. Stockwell, mstockwell@columbia.edu)
While the results are modest, this study represents an approach likely to be common in a few years, writes an editorialist (
pp. 1748–9): “Modest steps are the norm when complex behaviors and systems are targeted such as receipt of preventive services. Nonetheless, these systems have substantial potential, particularly when the technologies are tailored to individual patients and families, delivered in an actionable way, and driven toward important health behaviors. There can be little doubt that in the next decade there will be an increasing use of such systems and their application to additional services. As recently as 10 years ago, e-mailing patients was considered novel and text messaging did not exist. Within the next few years, the novel findings presented in this study will also become a routine component of the complex system of health care delivery.” (W. G. Adams, badams@bu.edu)
Botulinum Toxin A for Headaches: Used for prophylaxis against headaches in adults, botulinum toxin A provides “a small to modest benefit for chronic daily headaches and chronic migraines but was not associated with fewer episodic migraine or chronic tension-type headaches per month,” wrote investigators who conducted a meta-analysis of published trials (pp. 1736–45): “Pooled analyses suggested that botulinum toxin A was associated with fewer headaches per month among patients with chronic daily headaches (1,115 patients, −2.06 headaches per month; 95% CI, −3.56 to −0.56; 3 studies) and among patients with chronic migraine headaches (n = 1508, −2.30 headaches per month; 95% CI, −3.66 to −0.94; 5 studies). There was no significant association between use of botulinum toxin A and reduction in the number of episodic migraine (n = 1,838, 0.05 headaches per month; 95% CI, −0.26 to 0.36; 9 studies) or chronic tension-type headaches (n = 675, −1.43 headaches per month; 95% CI, −3.13 to 0.27; 7 studies). In single trials, botulinum toxin A was not associated with fewer migraine headaches per month vs valproate (standardized mean difference [SMD], −0.20; 95% CI, −0.91 to 0.31), topiramate (SMD, 0.20; 95% CI, −0.36 to 0.76), or amitriptyline (SMD, 0.29; 95% CI, −0.17 to 0.76). Botulinum toxin A was associated with fewer chronic tension-type headaches per month vs methylprednisolone injections (SMD, −2.5; 95% CI, −3.5 to −1.5). Compared with placebo, botulinum toxin A was associated with a greater frequency of blepharoptosis, skin tightness, paresthesias, neck stiffness, muscle weakness, and neck pain.” (J. L. Jackson, jjackson@mcw.edu)

>>>PNN NewsWatch
* In a new FDA document, Global Engagement Report, the agency describes its efforts and strategies for transforming from a domestic to a global public health agency. FDA now regulates products originating from 150 countries, 130,000 importers, and 300,000 foreign facilities.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 26, 2012 * Vol. 19, No. 81
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online-only articles and Apr. 26 issue of the New England Journal of Medicine (2012; 366).
Insulin-Pump Therapy in Type 1 Diabetes: Based on the case of a 39-year-old man with poorly controlled type 1 diabetes, the use of insulin pump therapy is reviewed (pp. 1616–24). Authors make these recommendations: “The patient described in the vignette has been unable to achieve acceptable glycemic control with multiple daily insulin injections—despite having recently attended a diabetes education course—because of disabling, severe hypoglycemia. The hypoglycemia is probably due in part to unpredictable glycemic fluctuations, which have also prevented the lowering of glycated hemoglobin to target levels. If, after undergoing an assessment at a specialized center and discussing the options with a team that is experienced in insulin-pump therapy, the patient is willing and able to undergo a trial of such therapy, this should be arranged. It is to be expected that the frequency of severe hypoglycemia will be reduced and glycated hemoglobin levels will be lowered and that the patient’s quality of life will improve. His body-mass index may also be reduced, since there will be less need for him to eat in order to avoid hypoglycemia, and improved control may be attained with a lower dose of insulin.” (J. C. Pickup, john.pickup@kcl.ac.uk)
Bariatric Surgery for Obesity: Assessing the results of two comparative trials of bariatric surgery and medical therapy in patients with obesity and type 2 diabetes (pp. 1577–85, G. Mingrone, gmingrone@rm.unicatt.it; pp. 1567–76, P. R. Schauer, schauep@ccf.org), editorialists provide support for continued use and study of surgical approaches in selected patients (pp. 1635–6). “Is surgery, then, the universal panacea for obese patients with type 2 diabetes? We would answer, not yet. All controlled surgical studies to date have been short-term and have involved a relatively small number of patients. Will the results of bariatric surgery be as good in routine practice? The long-term benefits have yet to be proved, although there is suggestive evidence of cardiovascular benefit and prolonged improvement in glycemia on the basis of the Swedish Obese Subjects (SOS) study (ClinicalTrials.gov number, NCT01479452).
“The studies by Mingrone et al. and Schauer et al. are likely to have a major effect on future diabetes treatment. Nevertheless, more studies are needed, particularly those that may provide better prediction of success and the expected duration of remission and long-term complications. Meanwhile, the success of various types of bariatric surgery suggests that they should not be seen as a last resort. Such procedures might well be considered earlier in the treatment of obese patients with type 2 diabetes.” (P. Zimmet)
Reassessing Statin Risks: The widespread use of statins makes “overestimating their clinical benefit or underestimating their risk … of potentially major importance to public health,” writes the author of a Perspective article (10.1056/NEJMp1203020). Despite that, the writer concludes that the evidence supporting broad statin use remains quite strong: “The net cardiovascular benefit for people at high cardiovascular risk strongly favors statin use. The greatest area of uncertainty is the use of statins for primary prevention among patients with a relatively low baseline risk of major adverse cardiovascular events, but multiple cardiovascular primary prevention trials have shown reductions in mortality even in this population. We lack data showing that any specific subgroup of patients is uniquely at increased risk for statin-induced diabetes and should therefore not use statins. Rather, the risk appears to be greatest among people in whom diabetes is most likely to develop anyway—at which point they would be treated with statins as part of their routine care. Although diabetes is a serious health concern, the management of dyslipidemia with statins substantially reduces cardiovascular risk and improves survival; thus, current data do not support the discontinuation of statins when diabetes is diagnosed, and it remains prudent to target lipid levels according to established guidelines. Of course, it also remains important to recommend increased exercise, healthy food choices, and portion control and to help manage weight in patients with prediabetes levels of glycemia or metabolic syndrome.” (A. B. Goldfine)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 27, 2012 * Vol. 19, No. 82
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Early-release article from and May issue of Diabetes Care (2012; 35).
Patient-Centered Diabetes Management: In an official position statement, ADA and the European Association for the Study of Diabetes project a world where pharmacogenetics drives personalized care of patients with type 2 diabetes and comparative trials are plentiful (10.2337/dc12-0413): “For antihyperglycemic management of type 2 diabetes, the comparative evidence basis to date is relatively lean, especially beyond metformin monotherapy. There is a significant need for high-quality comparative-effectiveness research, not only regarding glycemic control, but also costs and those outcomes that matter most to patients—quality of life and the avoidance of morbid and life-limiting complications, especially [cardiovascular disease]. Another issue about which more data are needed is the concept of durability of effectiveness (often ascribed to beta-cell preservation), which would serve to stabilize metabolic control and decrease the future treatment burden for patients. Pharmacogenetics may very well inform treatment decisions in the future, guiding the clinician to recommend a therapy for an individual patient based on predictors of response and susceptibility to adverse effects. We need more clinical data on how phenotype and other patient/disease characteristics should drive drug choices. As new medications are introduced to the type 2 diabetes pharmacopeia, their benefit and safety should be demonstrated in studies versus best current treatment, substantial enough both in size and duration to provide meaningful data on meaningful outcomes. It is appreciated, however, that head-to-head comparisons of all combinations and permutations would be impossibly large. Informed judgment and the expertise of experienced clinicians will therefore always be necessary.” (S. F. Inzucchi, silvio.inzucchi@yale.edu)
Exenatide Plus Insulin Glargine in Type 2 Diabetes: Particularly in moderately obese patients and those with longer duration of type 2 diabetes, twice-daily exenatide improves glycemic control and aids weight loss when added to optimized insulin glargine therapy, researchers report (pp. 955–8). In a 30-week study comparing exenatide with placebo in 259 patients on optimized insulin glargine, these outcomes were recorded: “Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001).” (B. J. Hoogwerf, hoogwerf_byron_james@lilly.com)
Treatment Intensification & Severe Hypoglycemia: Intensification of antihyperglycemic therapy over the past decade and half has produced significantly increased episodes of severe hypoglycemia, according to a study conducted in the Lippe–Detmold area of Germany (pp. 972–5). Based on number of symptomatic events requiring treatment with intravenous glucose and confirmed by a blood glucose measurement of <50 mg/dL, the investigators determined: “Severe hypoglycemia increased considerably from 264 events in 1997–2000 to 495 events in 2007–2010, which translated into an increase in frequency of severe hypoglycemia among all emergency admissions from 0.68 to 0.83% (P = 0.015). This was mostly related to intensification of antihyperglycemic therapy, particularly in the increasingly morbid group of hypoglycemic patients with type 2 diabetes indicated by lower HbA1c, more comedication (3.3 vs. 7.7 drugs), and more concomitant diseases (3.6 vs. 4.4) (all P values <0.001).” (A. Holstein, andreas.holstein@t-online.de)

>>>PNN NewsWatch
* Boceprevir (Victrelis), a protease inhibitor indicated for treatment of hepatitis C virus, should not be used with certain ritonavir-boosted HIV protease inhibitors, FDA cautioned yesterday. The combination may reduce the effectiveness of the medicines, FDA said, permitting the viral loads of HCV or HIV to increase. Ritonavir-boosted HIV protease inhibitors include ritonavir-boosted Reyataz (atazanavir), ritonavir-boosted Prezista (darunavir), and Kaletra (lopinavir/ritonavir).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 30, 2012 * Vol. 19, No. 83
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 28 issue of Lancet (2012; 379).
Aspirin & Cancer: Two studies examine effects of aspirin on cancer.
Aspirin provides some protection against distant metastases, according to an analysis of five large trials of daily doses of 75 mg or more (
pp. 1591–601): “Of 17,285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6.5 years (SD 2.0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0.64, 95% CI 0.48–0.84, p = 0.001; adenocarcinoma, HR 0.54, 95% CI 0.38–0.77, p = 0.0007; other solid cancers, HR 0.82, 95% CI 0.53–1.28, p = 0.39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0.52, 95% CI 0.35–0.75, p = 0.0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0.69, 95% CI 0.50–0.95, p = 0.02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0.45, 95% CI 0.28–0.72, p = 0.0009), particularly in patients with colorectal cancer (HR 0.26, 95% CI 0.11–0.57, p = 0.0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0.31, 95% CI 0.15–0.62, p = 0.0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma.… Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0.65, 95% CI 0.53–0.82, p = 0.0002), but not the risk of other fatal cancers (HR 1.06, 95% CI 0.84–1.32, p = 0.64; difference, p = 0.003).…”
Evidence from 51 trials supports use of daily aspirin based on long-term reduction in risk of cancer death and decreases in risk of major extracranial bleeds with low case-fatalities (
pp. 1602–12): “Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0.85, 95% CI 0.76–0.96, p = 0.008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0.63, 95% CI 0.49–0.82, p = 0.0005), resulting in fewer non-vascular deaths overall (1,021 vs 1,173; OR 0.88, 95% CI 0.78–0.96, p = 0.003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards.… The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3.13 [95% CI 1.44–4.82] per 1,000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control.…” (P. M. Rothwell, peter.rothwell@clneuro.ox.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
ARBs & Cancer: Overall risk of cancer was not increased among patients taking angiotensin II receptor blockers, a cohort study shows (e2697). Small increases in absolute risk of breast and prostate cancer were noted by the authors, who added these details for nearly 400,000 users of ARBs or ACE inhibitors: “Follow-up ended a median of 4.6 years after the start of treatment; 20,203 cancers were observed. There was no evidence of any increase in overall risk of cancer among those ever exposed to angiotensin receptor blockers (adjusted hazard ratio 1.03, 95% confidence interval 0.99 to 1.06, P = 0.10). For specific cancers, there was some evidence of an increased risk of breast and prostate cancer (1.11, 1.01 to 1.21, P = 0.02; and 1.10, 1.00 to 1.20, P = 0.04; respectively), which in absolute terms corresponded to an estimated 0.5 and 1.1 extra cases, respectively, per 1,000 person years of follow-up among those with the highest baseline risk. Longer duration of treatment did not seem to be associated with higher risk (P > 0.15 in each case). There was a decreased risk of lung cancer (0.84, 0.75 to 0.94), but no effect on colon cancer (1.02, 0.91 to 1.16).” (K. Bhaskaran, krishnan.bhaskaran@lshtm.ac.uk)

>>>PNN JournalWatch
* Sustained Effects of a Mindfulness-Based Stress-Reduction Intervention in Type 2 Diabetic Patients, in
Diabetes Care, 2012; 35: 945–7. (M. Hartmann, mechthild.hartmann@med.uni-heidelberg.de)
* Statin Use as a Moderator of Metformin Effect on Risk for Prostate Cancer Among Type 2 Diabetic Patients, in
Diabetes Care, 2012; 35: 1002–7. (Donna M. Lehman, lehman@uthscsa.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 1, 2012 * Vol. 19, No. 84
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 1 issue of the Annals of Internal Medicine (2012; 156).
Vitamin D & Major Clinical Events in Older Adults: Among 1,621 white older adults in the Cardiovascular Health Study, risks increased for relevant clinical disease events below a threshold concentration of 50 nmol/L (20 ng/mL) of 25-hydroxyvitamin D [25-(OH)D], researchers report (pp. 627–34). Findings also support season-specific targets for 25-(OH)D concentrations, as noted in this analysis of cohort data for a composite outcome of incident hip fracture, myocardial infarction, cancer, or death: “Over a median 11-year follow-up, the composite outcome occurred in 1,018 participants (63%). Defining events included 137 hip fractures, 186 myocardial infarctions, 335 incidences of cancer, and 360 deaths. The association of low 25-(OH)D concentration with risk for the composite outcome varied by season (P = 0.057). A concentration lower than a season-specific Z score of −0.54 best discriminated risk for the composite outcome and was associated with a 24% higher risk in adjusted analyses (95% CI, 9% to 42%). Corresponding season-specific 25-(OH)D concentrations were 43, 50, 61, and 55 nmol/L (17, 20, 24, and 22 ng/mL) in winter, spring, summer, and autumn, respectively.” (I. H. de Boer)
Hospital Strategies for Reducing Mortality in AMI: Fewer than 10% of U.S. hospitals have implemented four of five promising strategies for reducing deaths among patients with acute myocardial infarctions, according to an analysis of CMS data for 2008–09 (pp. 618–26). Among acute care hospitals in the U.S. with at least 25 patients with AMI per year, these patterns were noted in 30-day risk-standardized mortality rates (RSMRs) and various hospital performance improvement strategies: “In multivariate analysis, several hospital strategies were significantly associated with lower RSMRs and in aggregate were associated with clinically important differences in RSMRs. These strategies included holding monthly meetings to review AMI cases between hospital clinicians and staff who transported patients to the hospital (RSMR lower by 0.70 percentage points), having cardiologists always on site (lower by 0.54 percentage points), fostering an organizational environment in which clinicians are encouraged to solve problems creatively (lower by 0.84 percentage points), not cross-training nurses from intensive care units for the cardiac catheterization laboratory (lower by 0.44 percentage points), and having physician and nurse champions rather than nurse champions alone (lower by 0.88 percentage points). Fewer than 10% of hospitals reported using at least 4 of these 5 strategies.” (E. H. Bradley)
Mammography Screening at Age 40: Younger women at increased risk for breast cancer may benefit from biennial mammography screening beginning at age 40, according to two studies. Currently, major organizations with mammography screening guidelines do not have a consensus on whether to routinely screen all women in their 40s.
In a comparative modeling study, women in their 40s with a 2-fold increased risk for breast cancer had similar harm–benefit ratios as did women aged 50–74 years with average risk (
pp. 609–17). Researchers used four independent models to examine what level of risk tips the balance of benefits and harms to favor screening mammography for women aged 40 to 49, finding: “The threshold RRs are higher for annual screening with digital mammography (median, 4.3 [range, 3.3 to 10]) and when false-positive findings/deaths averted is used as an outcome measure instead of false-positive findings/life-years gained. The harm–benefit ratio for film mammography is more favorable than for digital mammography because film has a lower false-positive rate.” (N. T. van Ravesteyn)
A meta-analysis of 66 studies and data from the Breast Cancer Surveillance Consortium finds that extremely dense breasts and first-degree relatives with breast cancer are associated with a 2-fold increase in breast cancer risk (
pp. 635–48). “Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk,” the authors add. (H. D. Nelson)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 2, 2012 * Vol. 19, No. 85
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and May 2 issue of JAMA (2012; 307).
Neonatal Abstinence Syndrome: The incidence of neonatal abstinence syndrome (NAS), maternal opiate use during pregnancy, and associated health care costs increased significantly over the first decade of this century, according to a retrospective analysis of data from the Kids’ Inpatient Database (KID) (10.1001/jama.2012. 3951). In 2000–09, the incidence of and national health care expenditures for NAS showed these patterns: “The separate years (2000, 2003, 2006, and 2009) of national discharge data included 2,920 to 9,674 unweighted discharges with NAS and 987 to 4,563 unweighted discharges for mothers diagnosed with antepartum opiate use, within data sets including 784,191 to 1.1 million discharges for children (KID) and 816,554 to 879,910 discharges for all ages of delivering mothers (NIS). Between 2000 and 2009, the incidence of NAS among newborns increased from 1.20 (95% CI, 1.04–1.37) to 3.39 (95% CI, 3.12–3.67) per 1,000 hospital births per year (P for trend < .001). Antepartum maternal opiate use also increased from 1.19 (95% CI, 1.01–1.35) to 5.63 (95% CI, 4.40–6.71) per 1,000 hospital births per year (P for trend < .001). In 2009, newborns with NAS were more likely than all other hospital births to have low birthweight (19.1%; SE, 0.5%; vs 7.0%; SE, 0.2%), have respiratory complications (30.9%; SE, 0.7%; vs 8.9%; SE, 0.1%), and be covered by Medicaid (78.1%; SE, 0.8%; vs 45.5%; SE, 0.7%; all P < .001). Mean hospital charges for discharges with NAS increased from $39,400 (95% CI, $33,400–$45,400) in 2000 to $53,400 (95% CI, $49,000–$57,700) in 2009 (P for trend < .001). By 2009, 77.6% of charges for NAS were attributed to state Medicaid programs.” (S. W. Patrick, stepatri@med.umich.edu)
Fish Oil & Graft Patency, Cardiovascular Events: Daily fish oil ingestion did not prevent graft patency when used for 12 months in patients with new synthetic arteriovenous grafts, although the nutrient did have positive effects on graft patency, rates of thrombosis, interventions, and other cardiovascular events (pp. 1809–16). In the Fish Oil Inhibition of Stenosis in Hemodialysis Grafts (FISH) study, 201 adults with stage 5 chronic kidney disease received fish oil capsules or matching placebo beginning on day 7 after graft creation. At 15 North American dialysis centers 2003–10, a primary outcome of the proportion of participants experiencing graft thrombosis or radiological or surgical intervention during 12 months’ follow-up showed these trends: “The risk of the primary outcome did not differ between fish oil and placebo recipients (48/99 [48%] vs 60/97 [62%], respectively; relative risk, 0.78 [95% CI, 0.60 to 1.03; P = .06]). However, the rate of graft failure was lower in the fish oil group (3.43 vs 5.95 per 1,000 access–days; incidence rate ratio [IRR], 0.58 [95% CI, 0.44 to 0.75; P < .001]). In the fish oil group, there were half as many thromboses (1.71 vs 3.41 per 1,000 access–days; IRR, 0.50 [95% CI, 0.35 to 0.72; P < .001]); fewer corrective interventions (2.89 vs 4.92 per 1,000 access–days; IRR, 0.59 [95% CI, 0.44 to 0.78; P < .001]); improved cardiovascular event–free survival (hazard ratio, 0.43 [95% CI, 0.19 to 0.96; P = .04]); and lower mean systolic blood pressure (−3.61 vs 4.49 mm Hg; difference, −8.10 [95% CI, −15.4 to −0.85]; P = .01).” (C. E. Lok, charmaine.lok@uhn.ca)

>>>PNN NewsWatch
* Taliglucerase alfa (Elelyso, Pfizer) has been approved by FDA for long-term enzyme replacement therapy in patients with Type 1 (nonneuropathic) Gaucher disease. In a 9-month trial of 31 adult patients with the condition, the orphan drug was effective in reducing spleen volume, the study’s primary endpoint, from baseline by an average of 29% and 40% in patients receiving 30 and 60 units/kg, respectively. Improvements in liver volume, blood platelet counts, and hemoglobin levels also were observed. Similar results were observed in a 9-month, open-label trial of 25 patients with Type 1 Gaucher disease who were switched from imiglucerase after at least 2 years of therapy. The most common adverse effects were infusion reactions and allergic reactions, including anaphylaxis. Other adverse effects in more than 10% of patients included upper respiratory tract infection, nasopharyngitis, arthralgia, influenza, headache, extremity pain, back pain, and urinary tract infections.
*
PNN marks its 18th anniversary today, with nearly 4,500 issues written and delivered from four continents since May 2, 1994.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 3, 2012 * Vol. 19, No. 86
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online articles from the New England Journal of Medicine (2012; 366).
Warfarin v. Aspirin in Sinus-Rhythm Heart Failure: In patients with heart failure who are in normal sinus rhythm, the choice between warfarin and aspirin should be individualized, a study concludes (10.1056/NEJMoa1202299). Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) investigators used a composite primary outcome time of ischemic stroke, intracerebral hemorrhage, or death from any cause in a group of 2,305 patients with reduced left ventricular ejection fraction (LVEF) to compare INR-optimized warfarin therapy (target range, 2.0 to 3.5) and aspirin 325 mg/d: “The rates of the primary outcome were 7.47 events per 100 patient–years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient–years vs. 1.36 per 100 patient–years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient–years in the warfarin group as compared with 0.87 in the aspirin group (P < 0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient–years with warfarin and 0.22 with aspirin, P = 0.82).” (S. Homma)
Noting that warfarin’s benefits are offset by major bleeding rates, editorialists conclude (
10.1056/NEJMe1202504): “The results of the WARCEF trial are consistent with those of three previous smaller randomized, controlled trials in showing that warfarin anticoagulant therapy, as compared with aspirin, is not associated with a reduction in mortality among patients with heart failure. The WARCEF trial provides clear evidence that anticoagulant therapy prevents stroke, probably embolic stroke, in patients with heart failure who have severe systolic dysfunction, but the rates of stroke are too low to justify the routine clinical use of warfarin in most patients with heart failure, in light of the increase in the risk of bleeding.” (J. W. Eikelboom)
Chemotherapy in Adrenocortical Carcinoma: Outcomes were improved in 304 patients with advanced adrenocortical carcinoma when they were treated with mitotane plus etoposide, doxorubicin, and cisplatin (EDP) rather than mitotane plus streptozocin (10.1056/NEJMoa1200966). Patients were switched to the alternative regimen if their disease progressed (second-line therapy). Results showed: “For first-line therapy, patients in the EDP–mitotane group had a significantly higher response rate than those in the streptozocin–mitotane group (23.2% vs. 9.2%, P < 0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P < 0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P = 0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP–mitotane group and 2.2 months in the streptozocin–mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments.” (M. Fassnacht, fassnacht_m@medizin.uni-wuerzburg.de)
Rationing v. Waste Avoidance: Health care resources are finite, notes the author of a Perspectives article, making some type of rationing or waste avoidance necessary (10.1056/NEJMp1203365): “As medical technology advances, especially with personalized genomic medicine, we will almost certainly arrive at the day when we cannot afford all potentially beneficial therapies for everyone. The ethical challenge of rationing care will have to be faced sooner or later, particularly when we confront inequitable distribution of health care resources globally.” (H. Brody)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 4, 2012 * Vol. 19, No. 87
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
May issue of the American Journal of Psychiatry (2012; 169).
Naltrexone Implant in Polydrug Dependence: The majority of drug addicts are dependent on multiple agents, and in such patients, naltrexone implant produce higher retention rates and decrease amphetamine and heroin use, researchers report (pp. 531–6). In a 10-week randomized controlled trial, 100 patients with heroin and amphetamine polydrug dependence were assigned to naltrexone or placebo implants, with these results: “At week 10, the retention rate was 52% for patients who received a naltrexone implant and 28% for those who received a placebo implant; the proportions of drug-free urine samples were 38% and 16%, respectively, for the two groups. On the [Clinical Global Impressions Scale] improvement item, 56% of the patients in the naltrexone group showed much or very much improvement, compared with 14% of those in the placebo group (number needed to treat = 3).” (J. Tiihonen, jari.tiihonen@niuva.fi)
The availability of an effective treatment for amphetamine dependence is especially important, an editorialist writes, as it is more common than the more-vilified cocaine dependence (
pp. 455–7): “The results of Tiihonen et al. are encouraging not only for showing a direct effect of naltrexone in reducing opiate and amphetamine use but also for significantly increasing ratings of functioning and retention. Studies in the field emphasize the importance of retention over a period of many weeks and months in determining a successful outcome. Retaining patients in programs where they can obtain beneficial pharmacotherapies in conjunction with behavioral and cognitive therapies may be our most effective treatment strategy for combating the difficult medical, behavioral, and societal problem of substance abuse.” (D. M. Penetar, dpenetar@mclean.harvard.edu)

>>>Pediatrics Report
Source:
May issue of Pediatrics (2012; 129).
Publication Bias in Autism Drug-Treatment Studies: A meta-analysis finds a “small but significant effect” of serotonin receptor inhibitors (SRIs) in treatment of repetitive behaviors in autism spectrum disorders (ASD), but investigators conclude that this may represent publication bias rather than a true effect (pp. e1301–10): “Our search identified 5 published and 5 unpublished but completed trials eligible for meta-analysis. Meta-analysis of 5 published and 1 unpublished trial (which provided data) demonstrated a small but significant effect of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.22 [95% confidence interval: 0.07–0.37], z score = 2.87, P < .005). There was significant evidence of publication bias in all analyses. When Duval and Tweedie’s trim and fill method was used to adjust for the effect of publication bias, there was no longer a significant benefit of SRI for the treatment of repetitive behaviors in ASD (standardized mean difference: 0.12 [95% confidence interval: –0.02 to 0.27]). Secondary analyses demonstrated no significant effect of type of medication, patient age, method of analysis, trial design, or trial duration on reported SRI efficacy.” (M. Carrasco)
CAM Use & Asthma Medication Adherence: In pediatric patients with asthma, use of complementary and alternative medicine (CAM) “is not necessarily ‘competitive’ with conventional asthma therapies,” a study concludes (pp. e1148–54). A retrospective cohort design included telephone surveys of caregivers in 2004–07, looking for the percent missed doses per week and using a previously validated Medication Adherence Scale score. Results showed: “From our longitudinal data set of 1,322 patients, we focused on 187 children prescribed daily medications for all 3 years of our study. Patients had high rates of adherence. The mean percent missed asthma daily controller medication doses per week was 7.7% (SD = 14.2%). Medication Adherence Scale scores (range: 4–20, with lower scores reflecting higher adherence) had an overall mean of 7.5 (SD = 2.9). In multivariate analyses, controlling for demographic factors and asthma severity, initiation of CAM use was not associated with subsequent adherence (P > .05).” (J. C. Philp)
Measles Vaccines & Febrile Seizures: Children ages 4 to 6 years old are not at increased risk of febrile seizures after receiving measles-containing vaccines, according to an analysis of Vaccine Safety Datalink files (pp. 809–14; N. P. Klein).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 7, 2012 * Vol. 19, No. 88
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 5 issue of Lancet (2012; 379).
Point-of-Care Personalization of Antiplatelet Treatment: Bedside determination of gene patterns can be used to individualize doses of antiplatelet agents in patients with acute coronary syndrome or stable angina, according to a proof-of-concept study (pp. 1705–11). In 2010–11, participants undergoing percutaneous coronary intervention (PCI) were assigned to point-of-care genotyping for the CYP2C19*2 allele or to standard treatment with clopidogrel 75 mg daily. Using a primary endpoint of the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit [PRU] value of more than 234) after 1 week of dual antiplatelet treatment, the investigators found: “After randomisation, 187 patients completed follow-up (91 rapid genotyping group, 96 standard treatment). 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a PRU value of more than 234 at day 7, compared with seven (30%) given standard treatment (p = 0.0092). The point-of-care genetic test had a sensitivity of 100% (95% CI 92.3–100) and a specificity of 99.3% (96.3–100).” (D. Y. F. So, dso@ottawaheart.ca)
Treatment of Methotrexate-Refractory Early Rheumatoid Arthritis: In patients who fail initial methotrexate treatment, “add-on treatment with disease-modifying antirheumatic drugs is an appropriate treatment option,” researchers report (pp. 1712–20). In the Swedish Farmacotherapy (Swefot) trial, adult patients with rheumatoid arthritis and a symptom duration of less than 1 year were assigned to conventional or biological treatment after 3–4 months if symptoms did not improve. Results at 18 and 24 months with additional sulfasalazine/hydroxychloroquine (Group A) versus additional infliximab (B) showed the following: “Of 493 screened individuals, we enrolled 487, of whom 258 were randomly allocated to treatment. The proportion of patients in group B who received a EULAR-defined good response was non-significantly greater than it was in group A at 18 months (49 of 128 [38%] vs 38 of 130 [29%]) and at 24 months (49 of 128 [38%] vs 40 of 130 [31%]; p = 0.204). After 24 months, radiological disease progression was greater in patients in group A than it was in those in group B (mean 7.23 [SD 12.72] vs 4.00 [10.0]; p = 0.009). We recorded three serious adverse events: an extended generalised illness in group A, an extended febrile episode in group B, and a generalised illness in group B.” (R. F. van Vollenhoven, ronald.van.vollenhoven@ki.se)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Cardiovascular Events with Varenicline: A meta-analysis of available published trials found no significant increase in cardiovascular serious adverse events associated with varenicline use for tobacco cessation (e2856): “We identified 22 trials; all were double blinded and placebo controlled; two included participants with active cardiovascular disease and 11 enrolled participants with a history of cardiovascular disease. Rates of treatment emergent, cardiovascular serious adverse events were 0.63% (34/5431) in the varenicline groups and 0.47% (18/3801) in the placebo groups. The summary estimate for the risk difference, 0.27% (95% confidence interval −0.10 to 0.63; P = 0.15), based on all 22 trials, was neither clinically nor statistically significant. For comparison, the relative risk (1.40, 0.82 to 2.39; P = 0.22), Mantel–Haenszel odds ratio (1.41, 0.82 to 2.42; P = 0.22), and Peto odds ratio (1.58, 0.90 to 2.76; P = 0.11), all based on 14 trials with at least one event, also indicated a non-significant difference between varenicline and placebo groups.” (J. J. Prochaska, JProchaska@ucsf.edu)

>>>PNN JournalWatch
* Vaccination Against Pandemic A/H1N1 2009 Influenza in Pregnancy and Risk of Fetal Death: Cohort Study in Denmark, in
BMJ, 2012; 344: e2794. (B. Pasternak, bjp@ssi.dk)
* The Effect of the School Environment on the Emotional Health of Adolescents: A Systematic Review, in
Pediatrics, 2012; 129: 925–49. (J. Kidger)
* Premenstrual Dysphoric Disorder: Evidence for a New Category for DSM-5, in
American Journal of Psychiatry, 2012; 169: 465–75. (C. N. Epperson, cepp@upenn.edu)
*
Klebsiella pneumoniae Carbapenemases in Enterobacteriaceae: History, Evolution, and Microbiology Concerns, in Pharmacotherapy, 2012; 32: 399–407. (R. P. Rapp, rprapp01@email.uky.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 8, 2012 * Vol. 19, No. 89
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
May issue of Pharmacotherapy (2012; 32).
Vancomycin Dosing in Neonates: The difficulty of achieving target trough vancomycin levels in preterm and term neonates is demonstrated in a Monte Carlo simulation based on retrospective therapeutic drug monitoring data (pp. 408–19). Investigators used data from 1990 to 2007 for 134 neonates, two-thirds of them preterm, to determine the following for four dosing regimens: “The 5–15-mg/L target trough serum concentration was achieved in 34% (90% confidence interval [CI] 20–53%), 42% (90% CI 31–55%), 52% (90% CI 43–60%), and 63% (90% CI 54–72%) of patients receiving the standard dose, postmenstrual age–based dose, postmenstrual and postnatal age–based dose, and serum creatinine–based dose, respectively. Serum creatinine–based dosing produced trough concentrations predominantly in the 5–15-mg/L target range, with the smallest variability in both term and preterm neonates. As expected, when the target range was narrow and higher (15–20 mg/L), only 13–21% of patients were within the range across the four dosing regimens.” (B. Meibohm, bmeibohm@uthsc.edu)
Telehealth for MTM in Diabetes: In 103 patients with poorly controlled diabetes, use of a Care Coordination Home Telehealth (CCHT) program to provide medication therapy management (MTM) services produced better but not significantly improved 6-month outcomes than MTM alone, researchers report (pp. 420–6). In four VA primary care clinics, patients received either standard care or CCHT services, which included use of a messaging device between an initial and two follow-up visits over the following 6 months, with these results: “A statistically significant difference in mean A1C was noted in the CCHT versus the non-CCHT group at 3 months (7.2% vs 8.0%, p = 0.0002) and 6 months (6.9% vs 7.5%, p = 0.0066); however, the mean reduction in A1C from baseline to 6 months was not significant between groups (p = 0.1987). Sixty-nine percent of the CCHT group versus 36% in the non-CCHT group achieved the ADA A1C goal of less than 7% (p = 0.0011). More time was spent (p < 0.001) and more antidiabetic drug changes were made (p < 0.0001) in the CCHT group.” (M. McFarland, michael.mcfarland2@va.gov)
Pill Burden, Drug Cost & Renal Function After Transplantation: In 68 adults following kidney or kidney–pancreas transplantation in 2007, higher pill burdens and drug costs were associated with poor renal function, a study shows (pp. 427–32). Retrospective medical record review showed these data and relationships before and after transplantation: “The median pretransplantation pill burden was 15 pills/day, which increased to 25 pills/day at 1 month after transplantation and returned to 16 pills/day by 1 year after transplantation. Pretransplantation pill burden was lower than the burden at 1, 3, 6, 12, and 24 months after transplantation (p < 0.05). The mean pretransplantation drug cost of $1,918/month was lower than the cost at 1 month after transplantation ($2,564/mo, p = 0.04) but was similar thereafter. Higher pretransplantation pill burden was associated with increased serum creatinine concentration at 6 months after transplantation (r = 0.288, p = 0.017). Higher pill burdens at 1 month (r = 0.364, p= 0.002), 3 months (r = 0.332, p = 0.006), and 6 months (r = 0.374, p = 0.002) were associated with increased 3-month serum creatinine concentration. Higher drug costs were associated with increased serum creatinine concentrations throughout the study.” (K. Hardinger, hardingerk@umkc.edu)
Guiding Antihypertensive Therapy with Plasma Renin: Ambulatory measurement of plasma renin activity (PRA) can be used to guide selection of antihypertensive therapy, according to an review article that covers history of the approach and recent data on PRA use (pp. 446–55; A. Hough, Augustus.Hough@va.gov).

>>>PNN NewsWatch
* Secondary primary malignancies occur with increased frequency in patients receiving lenalidomide (Revlimid, Celgene) for newly diagnosed multiple myeloma, compared with patients receiving placebo, FDA warned yesterday. In clinical trials conducted after lenalidomide was approved, newly diagnosed patients had an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma when treated with the drug, the agency said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 9, 2012 * Vol. 19, No. 90
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and May 9 issue of JAMA (2012; 307).
Emergent Administration of Glucose-Insulin-Potassium: Out-of-hospital administration of glucose–insulin–potassium (GIK) was not effective in preventing progression to myocardial infarction (MI) in patients with acute coronary syndromes (ACS), researchers report (pp. 1925–33). Comparing intravenous GIK with a 5% glucose placebo, the investigators found these outcomes in 871 patients in the care of paramedics outside the hospital (after arrival at the hospital, the intervention was continued for 12 hours): “There was no significant difference in the rate of progression to MI among patients who received GIK (n = 200; 48.7%) vs those who received placebo (n = 242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66–1.13; P = .28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40–1.29; P = .27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27–0.85; P = .01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40–1.38; P = .34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27–1.49; P = .29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18–0.82; P = .01). Serious adverse events occurred in 6.8% (n = 28) with GIK vs 8.9% (n = 41) with placebo (P = .26).” (H. P. Selker, hselker@tuftsmedicalcenter.org)
This study illustrates the problem of properly using research methods to identify best practices outside classic inpatient and ambulatory situations (
pp. 1972–3): “Although the IMMEDIATE trial proves that creative research can be done in emergency settings, it did not generate the type of evidence needed to recommend widespread use of GIK. The problems encountered by this study highlight the pressing need to transform the clinical trials enterprise in ways that allow energy to be focused on informing critical decisions about potentially life-saving therapies.” (R. M. Califf, robert.califf@duke.edu)
Probiotics for Antibiotic-Associated Diarrhea: Probiotics are effective for prevention and treatment of antibiotic-associated diarrhea (AAD), according to a systematic review and meta-analysis of 82 randomized controlled trials (RCTs) (pp. 1959–69): “The majority [of RCTs] used Lactobacillus-based interventions alone or in combination with other genera; strains were poorly documented. The pooled relative risk in a DerSimonian–Laird random-effects meta-analysis of 63 RCTs, which included 11,811 participants, indicated a statistically significant association of probiotic administration with reduction in AAD (relative risk, 0.58; 95% CI, 0.50 to 0.68; P < .001; I2, 54%; [risk difference, −0.07; 95% CI, −0.10 to −0.05], [number needed to treat, 13; 95% CI, 10.3 to 19.1]) in trials reporting on the number of patients with AAD. This result was relatively insensitive to numerous subgroup analyses. However, there exists significant heterogeneity in pooled results and the evidence is insufficient to determine whether this association varies systematically by population, antibiotic characteristic, or probiotic preparation.” (S. Hempel, susanne_hempel@rand.org)
Product Lifecycles & FDA: The lifecycle approach to drug-product regulation, proposed in a 2007 Institute of Medicine (IOM) report, serves as the basis for a Viewpoint article on “opportunities” FDA currently has as it retools for today’s pharmaceutical world (10.1001/jama.2012.5545): “One of the report’s 23 recommendations proposes that the FDA implement a benefit and risk assessment and management plan (BRAMP) to capture in a single document and continuously update the FDA’s evaluation of the drug’s benefit–risk profile during the entire market life of the product. This plan should be first developed by the sponsor in the drug preapproval phase, discussed with FDA at the time of approval, and updated over the drug’s lifecycle at prespecified times in the postmarket setting and whenever questions arise about its benefit–risk profile. The BRAMP collates information from postmarket studies or trials about safety, efficacy, and new indications and from the Sentinel Initiative about the effects of warnings, precautions, and contraindications on approved use.” (B. M. Psaty, psaty@u.washington.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 10, 2012 * Vol. 19, No. 91
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 10 issue of the New England Journal of Medicine (2012; 366).
Lenalidomide for Newly Diagnosed Multiple Myeloma: Lenalidomide, subject of an FDA warning earlier this week (see PNN, May 8), is more effective for treatment of newly diagnosed multiple myeloma in patients ages 65–75 years than in older patients, researchers report (pp. 1759–69). In 459 participants in the MM-015 trial, nine 4-week cycles of melphalan–prednisone–lenalidomide induction followed by lenalidomide maintenance (MPR-R) until relapse or disease progression had these effects compared with MPR or melphalan–prednisone (MP) without maintenance therapy: “The median follow-up period was 30 months. The median progression-free survival was significantly longer with MPR-R (31 months) than with MPR (14 months; hazard ratio, 0.49; P < 0.001) or MP (13 months; hazard ratio, 0.40; P < 0.001). Response rates were superior with MPR-R and MPR (77% and 68%, respectively, vs. 50% with MP; P < 0.001 and P = 0.002, respectively, for the comparison with MP). The progression-free survival benefit associated with MPR-R was noted in patients 65 to 75 years of age but not in those older than 75 years of age (P = 0.001 for treatment-by-age interaction). After induction therapy, a landmark analysis showed a 66% reduction in the rate of progression with MPR-R (hazard ratio for the comparison with MPR, 0.34; P < 0.001) that was age-independent. During induction therapy, the most frequent adverse events were hematologic; grade 4 neutropenia was reported in 35%, 32%, and 8% of the patients in the MPR-R, MPR, and MP groups, respectively. The 3-year rate of second primary tumors was 7% with MPR-R, 7% with MPR, and 3% with MP.” (A. Palumbo, appalumbo@yahoo.com)
With an annual cost of $163,381 for the average patient, lenalidomide may or may be a game changer in treatment of newly diagnosed multiple myeloma, an editorialist writes (
pp. 1836–8) based on this and two other studies of the drug in this issue (use after stem-cell transplantation, pp. 1770–81, P. L. McCarthy, philip.mccarthy@roswellpark.org; maintenance use after stem-cell transplantation, pp. 1782–91, M. Attal, attal.m@chu-toulouse.fr): “The data on progression-free survival provide support for the use of lenalidomide maintenance therapy after careful assessment of the risks and benefits. However, a new congener, pomalidomide, and bortezomib are now being tested in trials of maintenance therapy, and both appear to have efficacy in patients with resistance to lenalidomide. As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life.” (A. Z. Badros)
Worldwide Measles: More small outbreaks of measles in developed countries can be expected because of poor measles control in other parts of the world, authors of a Perspective article write (pp. 1755–7): “Since 2008, the measles genie seems to have slipped out of the bottle in many regions. In Africa, measles control has deteriorated markedly, with the number of confirmed cases increasing from around 37,000 in 2008 to more than 172,000 in 2010. The distribution of cases follows the expected epidemiologic patterns: countries that had previously achieved good control report many cases in older children and adults, and countries with historically poor control, such as Nigeria, report that most cases occur in infancy and early childhood. A common feature in developing countries is the substantial proportion of cases occurring in the first year of life. The situation in Europe continues to be concerning as well, with measles incidence increasing in many industrialized countries. France alone reported over 15,000 measles cases, including 6 deaths, in 2011, according to the WHO.” (E. K. Mulholland)
HIV–HBV Coinfection: Coinfections of HIV-1 and hepatitis B virus (HBV) represent a global challenge, Perspective authors write, and “neither can be eradicated with the use of current therapies,” given challenges with antiviral resistance (pp. 1749–52): “Because each virus affects the other’s natural history and response to therapy, HIV–HBV coinfection requires dedicated research. A willingness to rapidly implement new scientific evidence is critical. Preventing transmission of both viruses to the next generation should be a priority for health policymakers.” (A. P. Kourtis)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 11, 2012 * Vol. 19, No. 92
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
May 15 issue of the Journal of the American College of Cardiology (2012; 59).
Resting Heart Rate in Heart Failure: In the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program, resting heart rate was an important predictor of outcome among patients with stable chronic heart failure (HF) without atrial fibrillation (AF), regardless of their level of left ventricular ejection fraction (LVEF) or use of beta-blockers (pp. 1785–95). The study analyzed patients based on tertiles of baseline heart rate and used Cox proportional hazard models to find these patterns: “After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001).” (S. D. Solomon, ssolomon@rics.bwh.harvard.edu)

>>>Allergy/Immunology Report
Source:
May Journal of Allergy and Clinical Immunology (2012; 129).
Combination Steroid/LABA Use & Asthma Exacerbations: Among a diverse population of patients with asthma, including some in high-risk groups, a fixed-dose combination of inhaled corticosteroids (ICS) and long-acting beta-agonist (LABA) reduced severe asthma exacerbations more than an ICS-alone regimen, researchers report (pp. 1274–9.e2). Pharmacy data for patients ages 12–56 years with asthma in a health maintenance organization were analyzed. Proportional hazard models showed these relationships among medication use and clinical outcomes: “Among the 1,828 patients who met the inclusion criteria, 37% were African American, 46% were treated with ICS therapy alone, and 54% were treated with an ICS/LABA combination. Models assessing the risk of severe asthma exacerbations among individuals using ICS treatment alone and ICS/LABA combination therapy suggested that the overall protective effect was as good or better for ICS/LABA combination therapy when compared with ICS treatment alone (hazard ratio, 0.65 vs 0.72, respectively). Analyses in several subgroups, including African American patients, showed a similar statistically significant protective association for combination therapy.” (K. E. Wells, kwells1@hfhs.org)
Enough data have been accumulated to implement these results in patients with asthma, editorialists write (
pp. 1280–1): “The US Food and Drug Administration has requested a series of very large postmarketing clinical trials to evaluate LABA/ICS combination safety, but the most serious asthma outcomes are so rare that even these studies might not be able to provide a definite conclusion. Moreover, the results from these studies will not be available until 2017 at the earliest. What should clinicians do in the meantime?
“It would be a disservice to our patients if we, in the fear of doing harm to our patients, waited for the perfect. The study by Wells et al supports that a better option would be to follow the recommendations of the asthma guidelines, which unanimously have taken the stand that there is no convincing evidence that LABA/ICS combinations administered in a single inhaler are associated with serious adverse effects. Their benefits on asthma control and reduction of asthma exacerbations outweigh their risk, and we should be careful not to let the perfect become the enemy of the good.” (S. Pedersen,
sp@spconforsk.dk)
Genes & Asthma: “Genetic determinants of longitudinal and cross-sectional lung function differ and vary by asthma status,” according to a genonewide study of 4,118 adults of European ancestry (pp. 1218–28): “The association between the height-related gene DLEU7 and FEV1 decrease suggested for nonasthmatic participants in the discovery phase was replicated (discovery, P = 4.8 × 10−6; replication, P = .03), and additional sensitivity analyses point to a relation to growth. The top ranking signal, TUSC3, which is associated with FEV1/FVC ratio decrease in asthmatic participants (P = 5.3 × 10−8), did not replicate.” (N. M. Probst-Hensch, Nicole.Probst@unibas.ch)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 14, 2012 * Vol. 19, No. 93
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 12 issue of Lancet (2012; 379).
Reduced-Intensity Chemotherapy in Hodgkin’s Lymphoma: Fewer treatment failures and less toxicity resulted when six rather than eight cycles of escalated BEACOPP were used in patients with advanced Hodgkin’s lymphoma, researchers report (pp. 1791–9). In an open-label, noninferiority trial, 2,182 newly diagnosed adult patients randomly received either eight cycles of BEACOPPescalated (8 × Besc), six cycles of BEACOPPescalated (6 × Besc), or eight cycles of BEACOPP14 (8 × B14), with these results: “Freedom from treatment failure was sequentially non-inferior for the 6 × Besc and 8 × B14 groups as compared with 8 × Besc. 5-year freedom from treatment failure rates were 84.4% (97.5% CI 81.0–87.7) for the 8 × Besc group, 89.3% (86.5–92.1) for 6 × Besc group, and 85.4% (82.1–88.7) for the 8 × B14 group (97.5% CI for difference between 6 × Besc and 8 × Besc was 0.5–9.3). Overall survival in the three groups was 91.9%, 95.3%, and 94.5% respectively, and was significantly better with 6 × Besc than with 8 × Besc (97.5% CI 0.2–6.5). The 8 × Besc group showed a higher mortality (7.5%) than the 6 × Besc (4.6%) and 8 × B14 (5.2%) groups, mainly due to differences in treatment-related events (2.1%, 0.8%, and 0.8%, respectively) and secondary malignancies (1.8%, 0.7%, and 1.1%, respectively).” (A. Engert, a.engert@uni-koeln.de)
Misoprostol in First-Term Abortions: Complications from vacuum aspirations during first-term abortions were reduced with cervical preparation using vaginal misoprostol 400 mcg, a study shows (pp. 1817–24). Administration of two 200-mcg misoprostol tablets into the vagina had these effects in this 2002–05 study: “50 (2%) of 2,427 women in the misoprostol group and 74 (3%) of 2,431 in the placebo group had one or more complication of vacuum aspiration (relative risk [RR] 0.68, 95% CI 0.47–0.96). No women in the misoprostol group had cervical tears and three had uterine perforations compared with two women in the placebo group who had cervical tears and one who had perforation. 19 (<1%) women given misoprostol and 55 (2%) on placebo had incomplete abortions (0.35, 0.21–0.58), of whom 14 (<1%) versus 48 (2%) needed uterine re-evacuation (0.29, 0.16–0.53). We noted no difference between groups in incidence of pelvic inflammatory disease (30 [1%] vs 25 [1%]; RR 1.20, 0.71–2.04) or other serious adverse events. The main side-effects of misoprostol during the 3 h treatment were abdominal pain (1,355 [55%] of 2,484 women vs 545 [22%] of 2,487 women in the placebo group) and vaginal bleeding (909 [37%] vs 167 [7%]).” (E. Bergel, bergele@who.int)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Venous Thrombosis with Nonoral Hormonal Contraception: Danish women using contraceptive transdermal patches and vaginal rings are at increased risk of venous thrombosis, compared with nonusers, according to a national registry-based cohort study (e2990). In 2001–10, these trends were noted in 1.6 million nonpregnant Danish females ages 15–49 years without prior thrombotic disease or cancer: “Within 9,429,28 woman years of observation, 5,287 first ever venous thrombosis events were recorded, of which 3,434 were confirmed. In non-users of hormonal contraception the incidence rate of confirmed events was 2.1 per 10,000 woman years. Compared with non-users of hormonal contraception, and after adjustment for age, calendar year, and education, the relative risk of confirmed venous thrombosis in users of transdermal combined contraceptive patches was 7.9 (95% confidence interval 3.5 to 17.7) and of the vaginal ring was 6.5 (4.7 to 8.9). The corresponding incidences per 10,000 exposure years were 9.7 and 7.8 events. The relative risk was increased in women who used subcutaneous implants (1.4, 0.6 to 3.4) but not in those who used the levonorgestrel intrauterine system (0.6, 0.4 to 0.8). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk of venous thrombosis in users of transdermal patches was 2.3 (1.0 to 5.2) and of the vaginal ring was 1.9 (1.3 to 2.7).” (Ø. Lidegaard, Lidegaard@rh.regionh.dk)

>>>PNN JournalWatch
* Seasonality of Tuberculosis in the United States, 1993–2008, in
Clinical Infectious Diseases, 2012; 54: 1553–60. (M. D. Willis, mwillis@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 15, 2012 * Vol. 19, No. 94
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 15 issue of the Annals of Internal Medicine (2012; 156).
Comprehensive Management of COPD: In a trial stopped prematurely, a comprehensive care management program (CCMP) increased excess mortality and failed to decrease hospitalizations among patients with severe chronic obstructive pulmonary disease (COPD) (pp. 673–83). At 20 VA clinics, study participants received usual care or COPD education in individual and group sessions, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management, with these results: “Of the eligible patients, 209 were randomly assigned to the intervention group and 217 to the usual care group. Citing serious safety concerns, the data monitoring committee terminated the intervention before the trial’s planned completion after 426 (44%) of the planned total of 960 patients were enrolled. Mean follow-up was 250 days. When the study was stopped, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention group and 24% in the usual care group (hazard ratio, 1.13 [95% CI, 0.70 to 1.80]; P = 0.62). There were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P = 0.003). Cause could be assigned in 27 (71%) deaths. Deaths due to COPD accounted for the largest difference: 10 in the intervention group versus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to 13.08]; P = 0.053).” (V. S. Fan, vincent.fan@va.gov)
An editorialist comments on the difficulties of making ethical judgments in clinical research (
pp. 746–7): “Although one can argue post hoc about how the protocol of this current trial differs from the others, nothing convincing comes to light; therefore, the possibility of chance must be considered when interpreting these data. It may be best to think of this trial as having stopped for futility—there was no hint of any beneficial effect on the primary outcome. On the other hand, the possibility that genuine harm was done by this behavioral intervention cannot be dismissed. Perhaps insufficient evidence was collected by the investigators about the detailed consequences of the educational package, thus denying us any causal insight into the excess mortality.” (S. J. Pocock, stuart.pocock@lshtm.ac.uk)

Internal Medicine Report
Source:
May 14 issue of Archives of Internal Medicine (2012; 172).
Avoiding Generic Fenofibrate Competition: The use of reformulated branded drug products to avoid generic competition is reviewed (pp. 724–30): “Abbott Laboratories maintained its dominance of the fenofibrate market in part through a complex switching strategy involving the sequential launch of branded reformulations that had not been shown to be superior to the first-generation product and patent litigation that delayed the approval of generic formulations. The small differences in dose of the newer branded formulations prevented their substitution with generics of older-generation products. As soon as direct generic competition seemed likely at the new dose level, where substitution would be allowed, Abbott would launch another reformulation, and the cycle would repeat. Based on the fenofibrate example, our objective is to describe how current policy can allow pharmaceutical companies to maintain market share using reformulations of branded medications, without demonstrating the superiority of next-generation products.” (H. M. Krumholz, harlan.krumholz@yale.edu)
Lactobacilli for UTIs: Compared with trimethoprim–sulfamethoxazole, lactobacilli do not meet noninferiority criteria for prevention of urinary tract infections (UTIs), but the preparations do avoid development of bacterial resistance to antibiotics, researchers report (pp. 704–12). In 2005–07, 252 postmenopausal women with recurrent UTIs received 12 months of prophylaxis with antibiotic once daily or Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily. Results showed that the prior mean annual number of symptomatic UTIs (7.0) was reduced to 2.9 and 3.3 by the antibiotics and lactobacilli, respectively. The 0.4 difference was outside the study’s margin of noninferiority. Overall, 69.3% and 79.1% of women in the two groups had at least one symptomatic UTI during the trial. (S. E. Geerlings, S.E.Geerlings@amc.uva.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 16, 2012 * Vol. 19, No. 95
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 16 issue of JAMA (2012; 307).
Multifaceted ACS Educational Intervention: Educational efforts directed at clinicians in Brazil resulted in significantly better management of patients with acute coronary syndromes (ACS), according to results of the BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes) trial (pp. 2041–9). The multifaceted quality improvement intervention included educational materials, reminders, algorithms, and case manager training. Using cluster randomization with concealed allocation, 1,150 patients at 34 public hospitals (clusters) had these outcomes in Nov. 11 through Jan. 12: “Mean age of the patients enrolled was 62 (SD, 13) years; 68.6% were men, and 40% presented with ST-segment elevation myocardial infarction, 35.6% with non–ST-segment elevation myocardial infarction, and 23.6% with unstable angina. The randomized clusters included 79.5% teaching hospitals, all from major urban areas and 41.2% with 24-hour percutaneous coronary intervention capabilities. Among eligible patients (923/1,150 [80.3%]), 67.9% in the intervention vs 49.5% in the control group received all eligible acute therapies (population average odds ratio [ORPA], 2.64 [95% CI, 1.28–5.45]). Similarly, among eligible patients (801/1,150 [69.7%]), those in the intervention group were more likely to receive all eligible acute and discharge medications (50.9% vs 31.9%; ORPA, 2.49 [95% CI, 1.08–5.74]). Overall composite adherence scores were higher in the intervention clusters (89% vs 81.4%; mean difference, 8.6% [95% CI, 2.2%–15.0%]). In-hospital cardiovascular event rates were 5.5% in the intervention group vs 7.0% in the control group (ORPA, 0.72 [95% CI, 0.36–1.43]); 30-day all-cause mortality was 7.0% vs 8.4% (ORPA, 0.79 [95% CI, 0.46–1.34]).” (O. Berwanger, berwanger@hcor.com.br">oberwanger@hcor.com.br)
Former CMS head Don Berwick comments on research into quality improvement in a related editorial (
pp. 2093–4): “I think it is a disservice to the sciences of improvement to reify the term ‘quality improvement’ as if it were a device or even a stable methodology. Making patient care better is always a good idea, and there is no harm at all in using the term ‘improvement’ to describe that quest. However, treating the pursuit of improvement (no initial caps) by searching for a boxable, boundable formula, let alone canonizing it with a proper-noun label—’Quality Improvement’ (initial caps)—is misleading. The ways in which people and organizations try to overcome the destructive forces of entropy in complex systems and to continually improve the work that they do on behalf of patients are numerous and, thank goodness, will forever evolve.” (D. M. Berwick, donberwick1@gmail.com)

>>>Chest Highlights
Source:
May issue of Chest (2012; 141).
Macrolides in Acute Lung Injury: In a secondary analysis of randomized controlled data from the Acute Respiratory Distress Syndrome Network Lisofylline and Respiratory Management of Acute Lung Injury Trial, patients with acute lung injury (ALI) who received macrolide antibiotics within 24 h of trial enrollment had significantly improved outcomes, researchers report (pp. 1153–9): “Forty-seven of 235 participants (20%) received a macrolide antibiotic within 24 h of trial enrollment. Among patients who received a macrolide, erythromycin was the most common (57%), followed by azithromycin (40%). The median duration of macrolide use after study enrollment was 4 days (interquartile range, 2–8 days). Eleven of the 47 (23%) patients who received macrolides died, compared with 67 of the 188 (36%) who did not receive a macrolide (P = .11). Participants administered macrolides were more likely to have pneumonia as an ALI risk factor, were less likely to have nonpulmonary sepsis or to be randomized to low tidal volume ventilation, and had a shorter length of stay prior to trial enrollment. After adjusting for potentially confounding covariates, use of macrolide was associated with lower 180-day mortality (hazard ratio [HR], 0.46; 95% CI, 0.23–0.92; P = .028) and shorter time to successful discontinuation of mechanical ventilation (HR, 1.93; 95% CI, 1.18–3.17; P = .009). In contrast, fluoroquinolone (n = 90) and cephalosporin antibiotics (n = 93) were not associated with improved outcomes.” (A. J. Walkey, alwalkey@bu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 17, 2012 * Vol. 19, No. 96
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 17 issue of the New England Journal of Medicine (2012; 366).
Progressive Multifocal Leukoencephalopathy with Natalizumab: Patients taking natalizumab are at higher risk of developing progressive multifocal leukoencephalopathy (PML) if they have anti–JC virus antibodies, have previously used immunosuppressants, and have longer durations of natalizumab treatment, a study shows (pp. 1870–80). Based on postmarketing data on natalizumab use along with clinical studies and a Swedish registry, investigators determined: “As of February 29, 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1,000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti–JC virus antibodies. When the risk of PML was stratified according to three risk factors, the risk of PML was lowest among the patients who were negative for anti–JC virus antibodies, with the incidence estimated to be 0.09 cases or less per 1,000 patients (95% confidence interval [CI], 0 to 0.48). Patients who were positive for anti–JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk (incidence, 11.1 cases per 1,000 patients [95% CI, 8.3 to 14.5]).” (G. Bloomgren, gary.bloomgren@biogenidec.com)
Describing “fascinating clinical and biologic dimensions [of] the natalizumab–PML story,” an editorialist writes (
pp. 1938–9): “Natalizumab may reactivate the JC virus without causing symptoms or lesions on MRI. When the JC virus transits from the urinary tract to the brain, it also undergoes mutations in its capsid protein. These alterations change the virus’s receptor binding to neurons in a manner that favors the emergence of PML; whether natalizumab affects the emergence of the mutation is not known. Finally, plasma exchange may be used to remove the drug and restore lymphocyte trafficking adequately to induce an immune reconstitution inflammatory response (IRIS), much the same as happens in patients with AIDS during antiretroviral treatment. Under these circumstances, patients with PML can survive with varying degrees of disability, although preventing the disease by attending to the risk factors is certainly preferable.” (A. H. Ropper)
Azithromycin & Cardiovascular Death: During azithromycin therapy in Tennessee Medicaid patients, the risk of cardiovascular deaths was increased, especially among those with prior elevated risk of cardiovascular disease, researchers report (pp. 1881–90). The cohort study included patients who received 347,795 prescriptions for courses of azithromycin, propensity-score–matched patients who did not receive antibiotics during 1.4 million control periods, and patients who received 1.7 million prescriptions for other antibiotics. Results showed: “During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P < 0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P = 0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P = 0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P = 0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.” (W. A. Ray, cindy.naron@vanderbilt.edu)
Coffee & Mortality: In the NIH–AARP Diet and Health Study, those aged 50–71 years at baseline had lower mortality rates with higher coffee consumption (pp. 1891–904). After adjusting for greater smoking exposure among coffee drinkers, those consuming 6 or more cups of coffee daily had 10% (men) or 15% (women) lower risk of mortality during 1995–2008. (N. D. Freedman, freedmanne@mail.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 18, 2012 * Vol. 19, No. 97
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
June 1 issue of Clinical Infectious Diseases (2012; 54).
Rapid Treatment of Toxoplasma gondii in Pregnancy: Rapid treatment of pregnant women who are infected with Toxoplasma gondii can reduce placental transfer of the parasite to the fetus, according to a retrospective analysis of 685 women (pp. 1545–52). Treatment of Toxoplasma gondii infecion varies among countries, the authors explain, adding: “In Germany, spiramycin is given until the 16th week of pregnancy, followed by at least 4 weeks of combination therapy with pyrimethamine, sulfadiazine, and folinic acid independent of the infection stage of the fetus. If infection of the fetus is confirmed by polymerase chain reaction or if fetal ultrasound indicates severe symptoms (hydrocephalus, ventricular dilation), treatment is continued until delivery with regular monitoring of pyrimethamine and sulfadiazine concentration in maternal blood and observation of possible adverse effects. In other European countries, such as France, only spiramycin is given unless infection of the fetus is proven.”
Among the patients whose care and outcomes were analyzed, the investigators found “an increased transmission rate to the fetus with increased time in gestation and a decreased risk of clinical manifestations. In comparison with studies performed in other countries, the overall transmission rate (4.8%) and the rate of clinical manifestations in newborns (1.6%) were lower.” (U. Groß,
ugross@gwdg.de)
Antimicrobial Stewardship in CAP: Stewardship interventions reduced the duration of antibiotic therapy for community-acquired pneumonia, according to a study from Johns Hopkins (pp. 1581–7). In a prospective study, management of patients with CAP before and after a stewardship intervention showed the following trends based on a primary outcome measure of antibiotic therapy duration: “There were 62 patients in the preintervention period and 65 patients in the intervention period. The duration of antibiotic therapy decreased from a median of 10 to 7 days (P < .001), with 148 fewer days of antibiotic therapy. The median lengths of stay were similar in the 2 groups (4 vs 5 days). A causative pathogen was identified less frequently during the intervention period (14% vs 34%); however, antibiotics were more frequently narrowed or modified on the basis of susceptibility results during the intervention period (67% vs 19%). Fewer patients received duplicate therapy within 24 hours in the intervention period (90% vs 55%).” (E. Avdic, eavdic1@jhmi.edu)

>>>Oncology Highlights
Source:
May issue of the Journal of Clinical Oncology (2012; 30).
Survival in Pediatric ALL: Survival rates among children and adolescents with acute lymphoblastic leukemia (ALL) improved in 1990–2005, researchers report, and 36% of deaths occurred among children with risk factors identified by the National Cancer Institute (pp. 1663–9). The authors conclude that efforts to continue improvements in survival should focus on both high-risk subsets of patients and those who have excellent chances for cure: “Five-year survival rates increased from 83.7% in 1990–1994 to 90.4% in 2000–2005 (P < .001). Survival improved significantly in all subgroups (except for infants age ≤ 1 year), including males and females; those age 1 to 9 years, 10+ years, or 15+ years; in whites, blacks, and other races; in Hispanics, non-Hispanics, and patients of unknown ethnicity; in those with B-cell or T-cell immunophenotype; and in those with … NCI standard- or high-risk clinical features. Survival rates for infants changed little, but death following relapse/disease progression decreased and death related to toxicity increased.” (S. P. Hunger, stephen.hunger@childrenscolorado.org)

>>>PNN NewsWatch
* Based on the azithromycin study in yesterday’s NEJM (see yesterday’s PNN), FDA said it was studying the problem and issued this recommendation: “Patients taking azithromycin should not stop taking their medicine without talking to their health care professional. Health care professionals should be aware of the potential for QT interval prolongation and heart arrhythmias when prescribing or administering macrolides.”
* Earlier in the week,
FDA updated its Dec. 20 advice on cardiovascular monitoring and use of fingolimod (Gilenya, Novartis) in patients with multiple sclerosis.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 21, 2012 * Vol. 19, No. 98
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 19 issue of Lancet (2012; 379).
Pazopanib for Metastatic Soft-Tissue Sarcoma: The multitargeted tyrosine kinase inhibitor pazopanib increased progression-free but not overall survival in patients with advanced nonadipocytic soft-tissue sarcoma in the PALETTE trial (pp. 1879–86). At 72 institutions in 13 countries, the Phase III trial produced these outcomes for pazopanib 800 mg once daily versus placebo: “372 patients were registered and 369 were randomly assigned to receive pazopanib (n = 246) or placebo (n = 123). Median progression-free survival was 4.6 months (95% CI 3.7–4.8) for pazopanib compared with 1.6 months (0.9–1.8) for placebo (hazard ratio [HR] 0.31, 95% CI 0.24–0.40; p < 0.0001). Overall survival was 12.5 months (10.6–14.8) with pazopanib versus 10.7 months (8.7–12.8) with placebo (HR 0.86, 0.67–1.11; p = 0.25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib.” (W. T. A. van der Graaf, w.vandergraaf@onco.umcn.nl)
Dabrafenib for Solid Tumors: In Phase I and Phase II trials of patients with melanoma, brain metastases, and other solid tumors, dabrafenib proved to be safe and an active inhibitor of BRAF kinase selective for mutant BRAF (pp. 1893–901): “We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51.9–83.7) and confirmed responses in 18 (50%, 32.9–67.1). 21 (78%, 57.7–91.4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35.3–74.5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer.” (G. S. Falchook, gfalchoo@mdanderson.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Tranexamic Acid & Surgical Bleeding: While the “evidence is strong that tranexamic acid reduces blood transfusion in surgery … [and] further trials … are unlikely to add useful new information,” authors of a systematic review and cumulative meta-analysis conclude that the drug’s has “uncertain” effects on thromboembolic events and mortality (e3054). “Surgical patients should be made aware of this evidence so that they can make an informed choice,” the group concludes. (K. Ker, katharine.ker@lshtm.ac.uk)

>>>PNN JournalWatch
* Circulating MicroRNA in Digestive Tract Cancers, in
Gastroenterology, 2012; 142: 1074–8.e1. (D. Ichikawa, ichikawa@koto.kpu-m.ac.jp)
* Summary Report from the Human Immunodeficiency Virus and Aging Consensus Project: Treatment Strategies for Clinicians Managing Older Individuals with the Human Immunodeficiency Virus, in
Journal of the American Geriatrics Society, 2012; 60: 974–9. (W. C. McCormick, mccorm@uw.edu)
* Despite 2007 Law Requiring FDA Hotline To Be Included in Print Drug Ads, Reporting of Adverse Events by Consumers Still Low, in
Health Affairs, 2012; 31: 1022–9. (D. “Tony” Du, dongyi.du@fda.hhs.gov)
* Taking Aim at America’s Number One Killer–One Key Heart Disease Risk Factor at a Time, in
Health Affairs, 2012; 31: 895–8. (H. Meyer)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 22, 2012 * Vol. 19, No. 99
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
June issue of Medical Care (2012; 50).
Medication Packaging & MTM: Among Medicaid patients, specialized medication packaging combined with medication therapy management services increased adherence over levels seen with usual care in a retrospective cohort study but had no significant effect on resource utilization or nonpharmacy costs (pp. 485–93). Outcomes in 1,007 patients who voluntarily enrolled in the program were compared with 13,614 control patients, with these effects identified based on medication adherence at 12 months, hospital admissions and emergency department visits at 6 and 12 months, and total paid claim costs at 6 and 12 months: “Measures of medication adherence were significantly improved in the program cohort compared with the usual care cohort. At 6 months, adjusted all-cause hospitalization was marginally less in the program cohort compared with the usual care cohort [odds ratio = 0.73, 95% confidence interval (CI), 0.54–1.0, P = 0.05]. No statistically significant differences were observed between the 2 cohorts for any of the other adjusted utilization endpoints at 6 or 12 months. Adjusted total cost at 6 and 12 months were higher in the program cohort (6-month cost ratio = 1.76, 95% CI,1.65–1.89; 12-month cost ratio = 1.84, 95% CI,1.72–1.97), primarily because of an increase in prescription costs. Emergency department visits and hospitalization costs did not differ between groups.” (A. J. Zillich)
FDA Drug Risk Communications: FDA warnings and other communications about drug risks have had inconsistent effects on health care utilization and behaviors, according to a systematic review of 49 studies published in 1990–2010 (pp. 466–78): “These studies covered 16 medicines or therapeutic classes; one third examined communications regarding antidepressants. Most used medical or pharmacy claims and a few rigorously examined patient–provider communication, decision making, or risk perceptions. Advisories recommending increased clinical or laboratory monitoring generally led to decreased drug use, but only modest, short-term increases in monitoring. Communications targeting specific subpopulations often spilled over to other groups. Repeated or sequential advisories tended to have larger but delayed effects and decreased incident more than prevalent use. Drug-specific warnings were associated with particularly large decreases in utilization, although the magnitude of substitution within therapeutic classes varied across clinical contexts.” (S. B Dusetzina)
FDA Ezetimibe Warning: After an FDA warning expressing concern about efficacy of ezetimibe that provided no clear clinical guidance, many patients stopped taking the medication but only a few made a “clinically appropriate switch after discontinuation,” researchers report (pp. 479–84). Data from a national pharmacy benefits manager in 2006–08 showed these patterns of cholesterol-lowering medication use before and after the FDA announcement: “Among 867,027 new ezetimibe users, 407,006 (46.9%) were nonpersistent in the first year. After the FDA communication, the monthly level of ezetimibe nonpersistence increased by 5.7 percentage points (P < 0.0001). Younger patients, those who lived in low-income zip codes, and female patients were less likely to discontinue therapy (P < 0.0001 for all). Among nonpersistent patients, rates of clinically appropriate switching increased from 10.8% before to 16.5% after the FDA warning (P = 0.004).” (W. H. Shrank)

>>>Nephrology Report
Source:
June issue of the American Journal of Kidney Diseases (2012; 59).
Dietary Amino Acids & Blood Pressure: The amount of four amino acids consumed in the diet may affect blood pressure, according to data from an observational cohort study (pp. 803–9). Methionine and alanine were linked to higher blood pressures, while values were lower in those taking in more threonine and histidine. (K. R. Tuttle, katherinetuttle@providence.org)

>>>PNN NewsWatch
* Recommendations against routine PSA screening of men by the U.S. Preventive Services Task Force are published online in the Annals of Internal Medicine along with a point (O. W. Brawley)–counterpoint (W. J. Catalona et al.) exchange.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 23, 2012 * Vol. 19, No. 100
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 23/30 issue of JAMA (2012; 307).
Sleep Apnea & Hypertension: Editorialists commenting on two research studies (pp. 2161–8, F. Barbé, fbarbe@arnau.scs.es; pp. 2169–76, J. M. Marin, jmmarint@unizar.es) on the relationship between obstructive sleep apnea (OSA) and hypertension make these points (pp. 2197–8): “Despite … questions, considerable evidence supports the role of identification and treatment of OSA to improve symptoms, quality of life, and cardiovascular end points. More specifically, data generally support a causal link with hypertension. Treatment may not only reduce blood pressure (although modestly on average), but if confirmed by future studies also may prevent hypertension in at-risk patients. Thus, OSA deserves attention in patients with or at risk of developing hypertension as a potentially treatable cause of hypertension as well as other clinically important outcomes.” (E. M. Weaver, eweaver@uw.edu)
Perioperative Management of Hip Fracture: Medications are important in the care of patients during and following surgery for hip fracture, authors of a Clinician’s Corner review write (pp. 2185–94). “Perioperative care should include prophylaxis with antibiotics, chemoprophylaxis for venous thromboembolism, and correction of major clinical abnormalities prior to surgery. Pain control, delirium, and pressure ulcer prevention are important inpatient care elements. Multidisciplinary models incorporating these care elements can decrease complications during inpatient stay. Rehabilitation strategies should be tailored to patient needs; early mobilization followed by rehabilitation exercises in institutional, home, and group settings should be considered to maximize restoration of locomotive abilities. Attention to care transitions is necessary and treatment for osteoporosis should be considered. The road to recovery for hip fracture patients is long and most patients may not regain their prefracture functional status. Understanding and anticipating issues that may arise in the older patient with hip fracture, while delivering evidence-based care components, is necessary to maximize patient recovery.” (W. W. Hung, william.hung@mssm.edu)
Medical Clinics in Retail Settings: Medical clinics in pharmacies and other retail settings may fill important long-term needs in the U.S. health care system with regard to access and cost, an author writes, if they can successfully coordinate chronic care with other health providers (pp. 2151–2): “What would it take for the retail clinic to have a greater role as an access point and coordinator of care in the fragmented US health care system? First, the exchange of health information among medical specialists, hospitals, and perhaps accountable care organizations with the retail clinic will be critical. In this era of increasing aspirations for health information exchange this ought to be possible—and appears to be beginning to take shape. Second, retail clinics need to become more ubiquitous. Almost every person in the United States could have a health care practitioner within just a few miles. If that practitioner could have access to that patient’s information through health information technology connectivity, full information about every patient could be available at every encounter to every relevant clinician.
“There are challenges, but this is happening already. The question is whether this phenomenon will grow and flourish in the ways described here or whether 20th-century attitudes about physician and hospital dominance in health care will prevent market-based solutions to the health care access and cost crisis. This model is a challenge to medical and hospital leadership, as well as to leaders in the retail health clinic industry, as they pursue the potential opportunities and benefits for the American people.” (C. K. Cassel,
ccassel@abim.org)

>>>PNN NewsWatch
* In a just-published article in AIDS, (early release; M. Norcross, michael.norcross@fda.hhs.gov) a research team led by FDA scientists describe “a model of drug-induced autoimmunity in which abacavir alters the quantity and quality of self-peptide loading into HLA-B*57:01.” Such drug-induced loading of novel self-peptides “generates an array of neoantigen peptides that drive polyclonal T-cell autoimmune responses and multi-organ systemic toxicity,” the authors conclude. This mechanism of drug-induced adverse reactions may also be applicable in autoimmune disorders.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 24, 2012 * Vol. 19, No. 101
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 24 New England Journal of Medicine (2012; 366).
Aspirin & Venous Thromboembolism: Aspirin 100 mg daily, given to patients with first-ever unprovoked venous thromboembolism following 6–18 months of oral anticoagulation, reduced the risk of recurrence, according to results of the Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) study (pp. 1959–67). Compared with placebo over a 2-year period, aspirin therapy had these effects on a primary efficacy outcome of recurrence of venous thromboembolism and a primary safety outcome of major bleeding: “Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups.” (C. Becattini, cecilia.becattini@unipg.it)
These results “are compelling and may signal an important step in the evolution of care” of venous thromboembolism, an editorialist writes (
pp. 2028–30): “However, confirmatory studies will be required to establish a role in daily clinical practice for the use of aspirin among patients who are at high risk for bleeding due to anticoagulant therapy or for whom ongoing investigations identify and subsequently validate a clinical or biomarker-based profile associated with a low risk of recurring venous thromboembolism. The ongoing Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study … has recruited 822 patients with a first unprovoked event, as documented by means of objective testing, who have received warfarin anticoagulant therapy for 3 to 6 months (but not longer than 12 months). Patients have been randomly assigned to either aspirin (100 mg daily) or placebo for a median of 3 years and are being followed for a first occurrence of symptomatic and objectively confirmed deep-vein thrombosis or nonfatal or fatal pulmonary embolism with the use of an intention-to-treat approach. Results of this study are expected during 2012. A prospectively planned combined analysis of the ASPIRE and WARFASA trials … may provide more reliable evidence of the effect of aspirin in patients with first unprovoked venous thromboembolism.” (R. C. Becker)
Treatment of Pulmonary Fibrosis: A widely used but unproven regimen for idiopathic pulmonary fibrosis— prednisone, azathioprine, and N-acetylcysteine (NAC)—increased risks of death and hospitalization in a comparison with placebo (pp. 1968–77). Longitudinal measurements of forced vital capacity over 60 weeks of treatment showed these patterns for patients on combination therapy, NAC alone, and placebo: “When approximately 50% of data had been collected (with 77 patients in the combination-therapy group and 78 in the placebo group), a planned interim analysis revealed that patients in the combination-therapy group, as compared with the placebo group, had an increased rate of death (8 vs. 1, P = 0.01) and hospitalization (23 vs. 7, P < 0.001). These observations, coupled with no evidence of physiological or clinical benefit for combination therapy, prompted the independent data and safety monitoring board to recommend termination of the combination-therapy group at a mean follow-up of 32 weeks.” (F. J. Martinez, fmartine@umich.edu)
Long-Acting Reversible Contraception: Studied in prospective cohorts, intrauterine devices and implants were significantly more effective than contraceptive pills, patches, or rings (pp. 1998–2007). Based on 334 unintended pregnancies in 7,486 participants, investigators found: “The contraceptive failure rate among participants using pills, patch, or ring was 4.55 per 100 participant–years, as compared with 0.27 among participants using long-acting reversible contraception (hazard ratio after adjustment for age, educational level, and history with respect to unintended pregnancy, 21.8; 95% confidence interval, 13.7 to 34.9). Among participants who used pills, patch, or ring, those who were less than 21 years of age had a risk of unintended pregnancy that was almost twice as high as the risk among older participants.” (J. F. Peipert, peipertj@wustl.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 25, 2012 * Vol. 19, No. 102
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Association (2012; 52).
Assessing Patient Opinions About Ambulatory Pharmacy Services: A tool for obtaining patient assessments of ambulatory pharmacy services proved reliable and valid in a study of 895 consumers obtaining prescription medications at participating pharmacies in 2006–07 (pp. 324–32). Following factor analysis, standard psychometric methods were used to assess the reliability and construct validity of three potential composite and three global-item measures derived from items in the Consumer Assessment of Pharmacy Services survey: “Confirmatory factor analysis indicated that a subset of 15 items measuring three aspects of pharmacy services (General Staff Communication, Health- and Medication-Focused Communication, and Clarity of Written Information about Medications) provided excellent fit to the data. Cronbach’s alphas for these scales were greater than 0.80. The three scales and corresponding three global ratings of quality reliably described differences among providers of pharmacy services.” (S. J. Blalock, s_blalock@unc.edu)
Patient Involvement in Medication Treatment Decisions: Identification of patients who want to be involved in medication treatment decisions could be useful to pharmacists in promoting medication therapy management services, researchers report (pp. 333–41). In a cross-sectional survey of 465 patients aged 45 years or older who were taking at least one prescription medication for chronic health problems, the following attitudes were identified with regard to usefulness of, satisfaction with, and intention to use medication-related services: “Respondents wanted to be highly involved in treatment decisions but found medication information they received to be moderately useful and satisfactory. Medication-related services fell into three groups based on reported intention to use: therapy advice, cost advice, and medication organization. Desire to be involved in treatment decisions was a key factor in predicting reported intention to use therapy advice and cost advice services. The perceived affordability of medications was another important factor in patients’ intention to use cost advice and medication organization services. Age, chronic conditions, number of prescription drugs, and the cost of therapy were not important in predicting the intention to use medication-related services in this population.” (S. N. Kucukarslan, skucukar@umich.edu)
Contraceptive Availability & Pharmacists as Information Sources: The ability of pharmacists at 282 Iowa community pharmacies to act as sources of information about contraceptive products was associated with availability of such products in their practice setting, according to a 2008 cross-sectional survey (pp. 342–8): “Significant positive relationships between the pharmacist information source score and product accessibility, product availability, and total access were observed. The relationship appeared to be driven primarily by product availability, and all were significantly influenced by pharmacy type. Significant negative relationships were found between product accessibility and independent/small chain pharmacies and mass merchandiser/grocery store pharmacies relative to large chain pharmacies. A significant negative relationship was found between independent/small chain pharmacies and the product availability score.” (E. A. Cook, elizabeth-cook@uiowa.edu)
Contraceptive Access After Health Care Reform in Massachusetts: Low-income women had better access to prescription contraceptive products following implementation of health care reform in Massachusetts, a study shows (pp. 349–57). In 2008–09, family planning staff (n = 16) and low-income women (n = 52) provided information in interviews and focus groups: “After reform, family planning staff reported providing more prescriptions for contraception versus providing contraception on site. Many focus group participants and family planning providers felt pharmacy provision of contraception enhanced access as a result of the convenient location of pharmacies. New barriers to obtaining contraception included an inability to obtain more than 1 month of contraception at a time and lack of coverage for over-the-counter methods. Findings about changes in the affordability of contraception postreform were mixed.” (J. McIntosh, j.mcintosh@jhsph.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 29, 2012 * Vol. 19, No. 103
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 28 issue of Archives of Internal Medicine (2012; 172).
Off-Label Prescribing in Primary Care: Drug, patient, and physician characteristics associated with off-label prescribing are explored through an analysis of the Health Canada database for Quebec in 2005–09 (pp. 781–8): “The prevalence of off-label use was 11.0%; of the off-label prescriptions, 79.0% lacked strong scientific evidence. Off-label use was highest for central nervous system drugs (26.3%), including anticonvulsants (66.6%), antipsychotics (43.8%), and antidepressants (33.4%). Drugs with 3 or 4 approved indications were associated with less off-label use compared with drugs with 1 or 2 approved indications (6.7% vs 15.7%; adjusted odds ratio [AOR], 0.44; 95% CI, 0.41–0.48). Drugs approved after 1995 were prescribed off-label less often than were drugs approved before 1981 (8.0% vs 17.0%; AOR, 0.46; 95% CI, 0.42–0.50). Patients with a Charlson Comorbidity Index of 1 or higher had lower off-label use than did patients with an index of 0 (9.6% vs 11.7%; AOR, 0.94; 95% CI, 0.91–0.97). Physicians with evidence-based orientation were less likely to prescribe off-label (AOR, 0.93; 95% CI, 0.88–0.99), a 7% reduction per 5 points in the evidence section of the Evidence-Practicality-Conformity Scale.” (T. Eguale, tewodros.eguale@mail.mcgill.ca)
CV Events with Levothyroxine Treatment of Subclinical Hypothyroidism: In younger patients, levothyroxine therapy of subclinical hypothyroidism (SCH) was associated with fewer ischemic heart disease (IHD) events, according to an analysis of the U.K. General Practitioner Research Database (pp. 811–7). In 2001–09, hazard ratios were as follows in 3,093 younger (40–70 years) and 1,642 older (>70 years) individuals with new SCH levels: “For a median follow-up period of 7.6 years, 52.8% and 49.9% of younger and older patients with SCH were treated with levothyroxine, respectively. There were 68 incident IHD events in 1,634 younger patients treated with levothyroxine (4.2%) vs 97 IHD events in 1,459 untreated individuals (6.6%) (multivariate-adjusted HR, 0.61; 95% CI, 0.39–0.95). In contrast, in the older group there were 104 events in 819 treated patients (12.7%) vs 88 events in 823 untreated individuals (10.7%) (HR, 0.99; 95% CI, 0.59–1.33).” (S. Razvi, salman.razvi@ghnt.nhs.uk)

>>>Lancet Highlights
Source:
May 26 issue of Lancet (2012; 379).
Artemisinin-Resistant Malaria: Based on genetic analysis of artemisinin resistance in Plasmodium falciparum along the Thailand–Myanmar border over the past 8 years, resistance will reach the high rates reported in western Cambodia within 2–6 years, researchers report (pp. 1960–6). Parasite counts every 6 hours in patients with uncomplicated hyperparasitemic falciparum malaria treated with various oral artesunate-containing regimens since 2001 showed these patterns: “3,202 patients were studied between 2001 and 2010. Parasite clearance half-lives lengthened from a geometric mean of 2.6 h (95% CI 2.5–2.7) in 2001, to 3.7 h (3.6–3.8) in 2010, compared with a mean of 5.5 h (5.2–5.9) in 119 patients in western Cambodia measured between 2007 and 2010. The proportion of slow-clearing infections (half-life ≥6.2 h) increased from 0.6% in 2001, to 20% in 2010, compared with 42% in western Cambodia between 2007 and 2010. Of 1,583 infections genotyped, 148 multilocus parasite genotypes were identified, each of which infected between two and 13 patients. The proportion of variation in parasite clearance attributable to parasite genetics increased from 30% between 2001 and 2004, to 66% between 2007 and 2010.” (F. Nosten, francois@tropmedres.ac)

>>>PNN JournalWatch
* Role of Intensive Glucose Control in Development of Renal End Points in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis [with invited commentaries], in
Archives of Internal Medicine, 2012; 172: 761–9. (S. G. Coca, steven.coca@yale.edu)
* Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach, in
Diabetes Care, 2012; 35: 1364–79. (S. E. Inzucchi, silvio.inzucchi@yale.edu)
* OTC Polyethylene Glycol 3350 and Pharmacists’ Role in Managing Constipation, in
Journal of the American Pharmacists Association, 2012; 52: 372–80. (J. R. Horn, jrhorn@u.washington.edu)
* Doctor and Pharmacy Shopping for Controlled Substances, in
Medical Care, 2012; 50: 494–500. (G. L. Peirce)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 30, 2012 * Vol. 19, No. 104
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (2012; 35).
Patient-Centered Diabetes Care: Maintaining that “due diligence was conducted” in the formulation of patient-centered guidelines for diabetes care (see PNN, Apr. 27; pp. 1364–79; S. E. Inzucchi, silvio.inzucchi@yale.edu), an editorialist writes (pp. 1201–3): “The most attractive aspect of the new position statement is that, more than any other previously reported guidelines to date, it clearly emphasizes that ‘one size does not fit all.’ As stated, the recommendations were ‘less prescriptive than and not as algorithmic as prior guidelines.’ Given the varied phenotype, genotype, stage of the patient in the natural history of the disease, and current metabolic state of the patient, we, as providers, fully understand that concept. However, if you are a provider, member of a medical care facility, or representative of a health plan and your goal is to address glycemic control issues in your patient population based on an algorithm approach that provided guidance for every step in management, you would certainly not endorse the approach taken by the writing group. Instead, we are provided with recommendations for treatment based on a knowledge and understanding of many patient and clinical factors as required before deciding to implement an individualized treatment plan. The need to pursue ‘individualized’ therapy was clearly accelerated from the findings of the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT) studies when evaluating cardiovascular end points. As described, not every subject benefited from intensive glycemic management, although there were suggestions that subsets of patients did benefit.” (W. T. Cefalu, william.cefalu@pbrc.edu)
Treatment Adherence During Transition to Adolescence: Declining treatment adherence is particularly detrimental in youths with type 1 diabetes during early adolescence, researchers report, and reinforcement of blood glucose monitoring frequency (BGMF) may be needed to detect and correct nonadherence during the transition (pp. 1219–24). Among 225 youths who entered the study on the cusp of adolescence (9–11 years), these adherence patterns with observed: “HbA1c increased from 8.2 to 8.6% (P < 0.001) and BGMF decreased from 4.9 to 4.5 checks per day (P < 0.02) during the 2-year period. Changes in the BGMF slope predicted changes in HbA1c. A change (increase) in HbA1c was associated with a change (decrease) in BGMF of 1.26 (P < 0.001) after controlling for covariates.” (D. Drotar, dennis.drotar@cchmc.org)
Lixisenatide Efficacy & Safety: A new GLP-1 receptor agonist, lixisenatide, was safe and effective in a trial of 361 patients with type 2 diabetes (pp. 1225–31). The 12-week trial included patients with HbA1c levels of 7–10% while not on any glucose-lowering therapy. Addition of once-daily subcutaneous lixisenatide or placebo produced these results when given in 1 step (10 mcg daily for 1 week, then 20 mcg) or 2 steps (10 mcg daily for 1 week, 15 mcg for 1 week, then 20 mcg): “Once-daily lixisenatide significantly improved HbA1c (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: −0.54% for 2-step, −0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA1c <7.0% (52.2% 2-step, 46.5% 1-step) and ≤6.5% (31.9% 2-step, 25.4% 1-step) versus placebo (26.8% and 12.5%, respectively; P < 0.01). Lixisenatide led to marked significant improvements of 2-h postprandial glucose levels and blood glucose excursions measured during a standardized breakfast test. A significant decrease in fasting plasma glucose was observed in both lixisenatide groups versus placebo. Mean decreases in body weight (~2 kg) were observed in all groups. The most common adverse events were gastrointestinal—nausea was the most frequent (lixisenatide 23% overall, placebo 4.1%). Symptomatic hypoglycemia occurred in 1.7% of lixisenatide and 1.6% of placebo patients, with no severe episodes. Safety/tolerability was similar for the two dose regimens.” (V. A. Fonseca, vfonseca@tulane.edu)

>>>PNN NewsWatch
* A counterfeit version of Teva’s Adderall product is being sold on the Internet, FDA warned consumers yesterday.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 31, 2012 * Vol. 19, No. 105
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 31 issue of the New England Journal of Medicine (2012; 366).
Drotrecogin Alfa (Activated) in Septic Shock: In the PROWESS-SHOCK study, drotrecogin alfa (activated) (DrotAA) failed to reduce 28- and 90-day mortality, compared with placebo (pp. 2055–64). On admission, study participants had infection, systemic inflammation, and shock and were receiving fluids and vasopressors above a threshold dose for 4 hours when they were assigned to DrotAA 24 mcg/kg/h or placebo for 96 hours, with these results: “At 28 days, 223 of 846 patients (26.4%) in the DrotAA group and 202 of 834 (24.2%) in the placebo group had died (relative risk in the DrotAA group, 1.09; 95% confidence interval [CI], 0.92 to 1.28; P = 0.31). At 90 days, 287 of 842 patients (34.1%) in the DrotAA group and 269 of 822 (32.7%) in the placebo group had died (relative risk, 1.04; 95% CI, 0.90 to 1.19; P = 0.56). Among patients with severe protein C deficiency at baseline, 98 of 342 (28.7%) in the DrotAA group had died at 28 days, as compared with 102 of 331 (30.8%) in the placebo group (risk ratio, 0.93; 95% CI, 0.74 to 1.17; P = 0.54). Similarly, rates of death at 28 and 90 days were not significantly different in other predefined subgroups, including patients at increased risk for death. Serious bleeding during the treatment period occurred in 10 patients in the DrotAA group and 8 in the placebo group (P = 0.81).” (B. T. Thompson, tthompson1@partners.org)
Editorialists take this position on “another failed treatment” for septic shock (
pp. 2122–4): “Despite its limitations, [this] large and well-conducted study … should end any further pursuit of a niche for DrotAA in the treatment of sepsis. The investigators’ findings provide a sad chapter in the noble quest for a truly effective adjunct for the treatment of septic shock. This setback should inspire a redoubling of efforts to seek new approaches to treatment that are based on a more crystalline view of the biology of sepsis.” (R. P. Wenzel)
Preoperative Chemoradiotherapy in Upper GI Cancer: In patients with potentially curable esophageal or esophagogastric-junction cancer, preoperative chemoradiotherapy improved survival with an acceptable adverse-event profile, researchers report (pp. 2074–84). Results showed these effects of surgery alone or weekly carboplatin titrated to achieve an area under the curve of 2 mg/mL/min and paclitaxel 50 mg/sq m for 5 weeks, with concurrent radiotherapy and followed by surgery: “275 [patients] (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy–surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in the surgery group (P < 0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy–surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy–surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P = 0.003).” (A. van der Gaast, a.vandergaast@erasmusmc.nl)
Health Care Reform & Undocumented Immigrants: “The [Affordable Care Act (ACA)] is emblematic of the nation’s lack of will to provide a means for the undocumented to meet their health care needs,” writes the author of a Perspectives article on the health care reform law (pp. 2045–7). “Market-based arrangements developed around the needs of individual patients may provide the best hope for meeting the basic health care needs of the United States’ 11 million undocumented immigrants— and may conceivably end up producing examples of ways to provide more efficient and cost-effective primary health care than centrally managed systems can.” (J. O. Breen)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 1, 2012 * Vol. 19, No. 106
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
June 5 issue of the Journal of the American College of Cardiology (2012; 59).
Niacin, Statins & HDL-C: Authors of a Viewpoint/Commentary present evidence from imaging trials and place them in context of the failed AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial of niacin/simvastatin versus simvastatin alone (pp. 2058–64): “Although low HDL-C remains a marker of residual risk even among statin-treated individuals treated to reach aggressive lipid goals, after AIM-HIGH, there likely will be less enthusiasm for starting niacin therapy in patients with low HDL-C who have well-controlled LDL-C (<70 mg/dl). This does not necessarily mean that niacin lacks a role in lipid-modifying therapy. Pending different conclusions from the upcoming HPS2-THRIVE [Treatment of HDL to Reduce the Incidence of Vascular Events], there may remain a place for niacin in high-risk patients who cannot reach the LDL-C goal of <70 mg/dl despite maximally tolerated statin therapy or in statin-intolerant patients. At this time, there is no clear indication to withdraw niacin in patients receiving this therapy if further LDL-C reduction is needed.” (E. D. Michos, edonnell@jhmi.edu)

>>>Circulation Report
Source:
May 29 issue of Circulation (2012; 125).
Cardiovascular Health Behavior & Factor Changes: Goals of the American Heart Assoc. for “improving cardiovascular health by 20% by 2020 will not be met if current trends continue,” according to an analysis of data from the National Health and Nutrition Examination Survey 1988–2008 (pp. 2595–602). Among 35,059 adults free of cardiovascular disease, these trends were detected in four health behaviors (smoking, diet, physical activity, body mass) and three health factors (plasma glucose, cholesterol, blood pressure): “Prevalence of current and former smoking, hypercholesterolemia, and hypertension declined, whereas prevalence of obesity and dysglycemia increased through 2008. Physical activity levels and low diet quality scores changed minimally. Projections to 2020 suggest that obesity and impaired fasting glucose/diabetes mellitus could increase to affect 43% and 77% of US men and 42% and 53% of US women, respectively. Overall, population-level cardiovascular health is projected to improve by 6% overall by 2020 if current trends continue. Individual-level Cardiovascular Health Score projections to 2020 (men = 7.4 [95% confidence interval, 5.7–9.1]; women = 8.8 [95% confidence interval, 7.6–9.9]) fall well below the level needed to achieve a 20% improvement (men = 9.4; women = 10.1).” (D. M. Lloyd-Jones, dlj@northwestern.edu)

>>>Neurology Highlights
Source:
May 29 issue of Neurology (2012; 78).
Anti-JC Virus Antibodies in Natalizumab-Treated Patients: Serology testing for anti-JC virus (JCV) antibodies before natalizumab therapy in patients with multiple sclerosis could be useful for stratifying the risk of iatrogenic progressive multifocal leukoencephalopathy (PML), researchers report (pp. 1736–42). In a blinded, retrospective, longitudinal analysis of 2,782 blood samples during routine testing of 2,253 German patients with multiple sclerosis, these patterns in PML risk were observed relative to baseline anti-JCV antibodies: “Of the natalizumab-treated patients with MS, 58.8% tested positive for anti-JCV antibodies. The rate of seropositivity was higher in males and increased with age, with a plateau between age intervals 20–29 and 30–39 years. In longitudinal analyses, 19 of 194 (9.8%) patients converted from anti-JCV antibody-negative to seropositive status over 7.7 months; 4.7% reverted from antibody-positive to seronegative status over 7.9 months. Antibody levels, especially in the latter group, were low, indicating fluctuations around the lower cut point of the assay. Neither anti-JCV serostatus nor antibody levels were associated with immunosuppressive pretreatment, duration of natalizumab treatment, or anti-natalizumab antibodies. All samples obtained from 10 patients who developed PML were seropositive (13 samples before PML diagnosis [2.0–37.6 months]; 2 samples at diagnosis). Antibody levels in these samples were higher than those in samples from seropositive patients who did not develop PML.” (A. Chan, andrew.chan@rub.de)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 4, 2012 * Vol. 19, No. 107
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 2 issue of Lancet (2012; 379).
Antipsychotic Drugs & Relapse Prevention in Schizophrenia: Compared with placebo, maintenance therapy of schizophrenia with antipsychotic agents reduces the risk of relapse at year 1 by about 60%, yielding a number needed to treat of just 3, according to a systematic review and meta-analysis of 65 trials of 6,493 patients (pp. 2063–71): “Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27% vs placebo 64%; risk ratio [RR] 0.40, 95% CI 0.33–0.49; number needed to treat to benefit [NNTB] 3, 95% CI 2–3). Fewer patients given antipsychotic drugs than placebo were readmitted (10% vs 26%; RR 0.38, 95% CI 0.27–0.55; NNTB 5, 4–9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference −0.62, 95% CI −1.15 to −0.09) and fewer aggressive acts (2% vs 12%; RR 0.27, 95% CI 0.15–0.52; NNTB 11, 6–100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10% vs 6%; RR 2.07, 95% CI 2.31–3.25), had movement disorders (16% vs 9%; 1.55, 1.25–1.93), and experienced sedation (13% vs 9%; 1.50, 1.22–1.84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0.31, 95% CI 0.21–0.41) more than did oral drugs (0.46, 0.37–0.57; p = 0.03); depot haloperidol (RR 0.14, 95% CI 0.04–0.55) and fluphenazine (0.23, 0.14–0.39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0.26, 0.17–0.39) than in most blinded studies (0.42, 0.35–0.51; p= 0.03). In a meta-regression, the difference between drug and placebo decreased with study length.” (S. Leucht, stefan.leucht@lrz.tum.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Pioglitazone & Bladder Cancer: People with type 2 diabetes who are taking pioglitazone have an increased risk of incident bladder cancer, researchers report (e3645). In a retrospective cohort study with a nested case–control design, these bladder cancer rates were observed among 115,727 new users of oral hypoglycemic drugs: “470 [cohort] patients diagnosed as having bladder cancer during follow-up (rate 89.4 per 100,000 person–years). The 376 cases of bladder cancer that were diagnosed beyond one year of follow-up were matched to 6,699 controls. Overall, ever use of pioglitazone was associated with an increased rate of bladder cancer (rate ratio 1.83, 95% confidence interval 1.10 to 3.05). The rate increased as a function of duration of use, with the highest rate observed in patients exposed for more than 24 months (1.99, 1.14 to 3.45) and in those with a cumulative dosage greater than 28,000 mg (2.54, 1.05 to 6.14).” (L. Azoulay, laurent.azoulay@mcgill.ca)

>>>PNN JournalWatch
* The Effectiveness and Cost Effectiveness of Dark Chocolate Consumption as Prevention Therapy in People at High Risk of Cardiovascular Disease: Best Case Scenario Analysis Using a Markov Model, in
BMJ, 2012; 344: e3657. (C. M. Reid, Chris.Reid@monash.edu)
* Antithrombotic Therapy in Patients with Chronic Kidney Disease, in
Circulation, 2012; 125: 2649–61. (D. J. Angiolillo, dominick.angiolillo@jax.ufl.edu)
* Thrombolytic Therapy of Acute Stroke, in
Circulation, 2012; 125: 2662–6. (S. K. Feske, sfeske@partners.org)
* Meta-analysis of Long-Chain Polyunsaturated Fatty Acid Supplementation of Formula and Infant Cognition, in
Pediatrics, 2012; 129: 1141–9. (A. Qawasmi)
* The Impact of Genomics on Pediatric Research and Medicine, in
Pediatrics, 2012; 129: 1150–60. (J. J. Connolly)
* Antifactor Xa Levels versus Activated Partial Thromboplastin Time for Monitoring Unfractionated Heparin, in
Pharmacotherapy, 2012; 32: 546–58. (T. G. Vondracek, vondracekt@exempla.org)
* Clinical and Economic Evidence for Intravenous Acetaminophen, in
Pharmacotherapy, 2012; 32: 559–79. (Y-C Yeh, yyeh@partners.org)
* An Outbreak of Tuberculosis Among Adults with Mental Illness, in
American Journal of Psychiatry, 2012; 169: 569–75. (J. S. Cavanaugh, hgi7@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 5, 2012 * Vol. 19, No. 108
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 5 issue of the Annals of Internal Medicine (2012; 156).
Part D Coverage Gap & Med Use: Patients without coverage for the Medicare Part D “doughnut hole” used less medication for hypertension and hypercholesterolemia while in the gap, researchers report (pp. 776-84). Using Medicare claims for 2005–06 for a 5% sample of Medicare beneficiaries, investigators used a pre–post design and contemporaneous control group to determine the following: “Patients with no gap coverage had a decrease in monthly antihypertensive and lipid-lowering drug prescriptions during the coverage gap. Nonadherence also increased in this group (antihypertensives: odds ratio [OR], 1.60 [95% CI, 1.50 to 1.71]; lipid-lowering drugs: OR, 1.59 [CI, 1.50 to 1.68]). The proportion of patients with no gap coverage who had continuous medication gaps in lipid-lowering medication use and antihypertensive use increased by an absolute 7.3% (OR, 1.38 [CI, 1.29 to 1.46]) and 3.2% (OR, 1.35 [CI, 1.25 to 1.45]), respectively, because of the coverage gap. Decreases in use were smaller for pain relievers and antidepressants and larger for acid suppressants in patients with no gap coverage. Patients with generic-only coverage had decreased use of cardiovascular medications but no change in use of drugs for symptomatic conditions. No measures changed in the brand-name and generic coverage groups. Results of sensitivity analyses were consistent with the main findings.” (P. Li)
GFR Estimation in Creatinine Standardization Era: Use of a single equation for estimating glomerular filtration rate (GFR) “requires a tradeoff to optimize performance at either higher or lower GFR ranges,” a review article concludes (pp. 785–95). Based on analysis of data from cross-sectional studies in adults that compared two or more GFR estimating equations, the authors found: “Eligible studies compared the MDRD (Modification of Diet in Renal Disease) Study and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations or modifications thereof. In 12 studies in North America, Europe, and Australia, the CKD-EPI equation performed better at higher GFRs (approximately >60 mL/min per 1.73 m2) and the MDRD Study equation performed better at lower GFRs. In 5 of 8 studies in Asia and Africa, the equations were modified to improve their performance by adding a coefficient derived in the local population or removing a coefficient.” (A. Earley)
Recommendations on Antiretroviral Adherence: Based on 325 randomized controlled trials of adherence to antiretroviral therapy (ART) that had at least one biological or behavioral end point, a panel of the International Association of Physicians in AIDS Care has made recommendations on how to retain patients in care and maximize their adherence (pp. 817–33): “Recommendations are provided for monitoring entry into and retention in care, interventions to improve entry and retention, and monitoring of and interventions to improve ART adherence. Recommendations cover ART strategies, adherence tools, education and counseling, and health system and service delivery interventions. In addition, they cover specific issues pertaining to pregnant women, incarcerated individuals, homeless and marginally housed individuals, and children and adolescents, as well as substance use and mental health disorders. Recommendations for future research in all areas are also provided.” (M. A. Thompson)
Secondary GI Cancer After Pediatric Cancer: Abdominal radiation of childhood cancers increases risk of secondary gastrointestinal cancers, a study of 14,358 survivors shows (pp. 757–66). Based on their data, the authors recommend earlier surveillance for secondary cancers for those surviving childhood cancers: “The risk for gastrointestinal [subsequent malignant neoplasms (SMNs)] was 4.6-fold higher in childhood cancer survivors than in the general population (95% CI, 3.4 to 6.1). The [standardized incidence ratios (SIR)] for colorectal cancer was 4.2 (CI, 2.8 to 6.3). The highest risk for gastrointestinal SMNs was associated with abdominal radiation (SIR, 11.2 [CI, 7.6 to 16.4]). However, survivors not exposed to radiation had a significantly increased risk (SIR, 2.4 [CI, 1.4 to 3.9]).” (T. O. Henderson)

>>>PNN NewsWatch
* Reumofan Plus, a “natural” dietary supplement for pain relief and other serious conditions, contains unlabeled active pharmaceutical ingredients, FDA has warned.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 6, 2012 * Vol. 19, No. 109
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 6 issue of JAMA (2012; 307).
Inhaled Hypertonic Saline in Cystic Fibrosis: Among 321 children younger than 6 years, use of inhaled hypertonic saline was no better than isotonic saline for reducing pulmonary exacerbations of cystic fibrosis, according to results of the Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS) (pp. 2269–77). At 30 cystic fibrosis centers in the U.S. and Canada, these outcomes were noted for those on twice-daily nebulized doses of 7% hypertonic saline and 0.9% isotonic saline: “The mean pulmonary exacerbation rate (events per person–year) was 2.3 (95% CI, 2.0–2.5) in the active treatment group and 2.3 (95% CI, 2.1–2.6) in the control group; the adjusted rate ratio was 0.98 (95% CI, 0.84–1.15). Among participants with pulmonary exacerbations, the mean number of total antibiotic treatment days for a pulmonary exacerbation was 60 (95% CI, 49–70) in the active treatment group and 52 (95% CI, 43–61) in the control group. There was no significant difference in secondary end points including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Infant pulmonary function testing performed as an exploratory outcome in a subgroup (n = 73, with acceptable measurements at 2 visits in 45 participants) did not demonstrate significant differences between groups except for the mean change in forced expiratory volume in 0.5 seconds, which was 38 mL (95% CI, 1–76) greater in the active treatment group. Adherence determined by returned study drug ampoules was at least 75% in each group. Adverse event profiles were also similar, with the most common adverse event of moderate or severe severity in each group being cough (39% of active treatment group, 38% of control group).” (M. Rosenfeld, margaret.rosenfeld@seattlechildrens.org)
CBT for Improving Adherence in Depression: Mixed findings resulted from a comparison of face-to-face and telephonic (T) cognitive behavioral therapy (CBT) directed at reducing attrition and improving outcomes in patients with major depressive disorder (pp. 2278–85). With a primary outcome of completion of a 18 sessions of CBT and secondary outcomes of masked interviewer-rated depression with the Hamilton Depression Rating Scale (Ham-D) and self-reported depression with the Patient Health Questionnaire–9 (PHQ-9), the investigators found: “Significantly fewer participants discontinued T-CBT (n = 34; 20.9%) compared with face-to-face CBT (n = 53; 32.7%; P = .02). Patients showed significant improvement in depression across both treatments (P < .001). There were no significant treatment differences at posttreatment between T-CBT and face-to-face CBT on the Ham-D (P = .22) or the PHQ-9 (P = .89). The intention-to-treat posttreatment effect size on the Ham-D was d = 0.14 (90% CI, −0.05 to 0.33), and for the PHQ-9 it was d = −0.02 (90% CI, −0.20 to 0.17). Both results were within the inferiority margin of d = 0.41, indicating that T-CBT was not inferior to face-to-face CBT. Although participants remained significantly less depressed at 6-month follow-up relative to baseline (P < .001), participants receiving face-to-face CBT were significantly less depressed than those receiving T-CBT on the Ham-D (difference, 2.91; 95% CI, 1.20–4.63; P < .001) and the PHQ-9 (difference, 2.12; 95% CI, 0.68–3.56; P = .004).” (D. C. Mohr, d-mohr@northwestern.edu)
Aspirin & Major Bleeding in Diabetes: Low-dose aspirin is associated with increased risks of major gastrointestinal and cerebral bleeding in patients of all types, an Italian population cohort study shows, but those with diabetes had a “high rate of bleeding that was not independently associated with aspirin use” (pp. 2286–94): “There were 186,425 individuals being treated with low-dose aspirin and 186,425 matched controls without aspirin use. During a median follow-up of 5.7 years, the overall incidence rate of hemorrhagic events was 5.58 (95% CI, 5.3–-5.77) per 1,000 person–years for aspirin users and 3.60 (95% CI, 3.48–3.72) per 1,000 person–years for those without aspirin use (incidence rate ratio [IRR], 1.55; 95% CI, 1.48–1.63). The use of aspirin was associated with a greater risk of major bleeding in most of the subgroups investigated but not in individuals with diabetes (IRR, 1.09; 95% CI, 0.97-1.22). Irrespective of aspirin use, diabetes was independently associated with an increased risk of major bleeding episodes (IRR, 1.36; 95% CI, 1.28–1.44).” (A. Nicolucci, nicolucci@negrisud.it)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 7, 2012 * Vol. 19, No. 110
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 7 issue of the New England Journal of Medicine (2012; 366).
Delamanid for Multidrug-Resistant TB: Compared with placebo, the investigational antitubercular medication delamanid increased sputum-culture conversions at 2 months among 481 patients with multidrug-resistant pulmonary tuberculosis, researchers report (pp. 2151–60). Study participants, all HIV negative, received delamanid 100 or 200 mg twice daily or placebo for 2 months in combination with a background drug regimen, with these results: “Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P = 0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P = 0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid.” (L. J. Geiter, lawrence.geiter@otsuka-us.com)
Commenting on this and another article in this issue detailing an epidemic of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in China (
pp. 2161–70; Y. Wang, awangyu@chinacdc.cn), editorialists write that diagnosis and treatment of this pathogen “is a monumental task but one that cannot be avoided if tuberculosis is to be contained” (pp. 2223–4): “Regimens containing two or more agents that are known to be effective offer the greatest hope for ‘turning back the clock’ on MDR tuberculosis. Both delamanid and [a second investigational drug, bedaquiline,] enhance the activity of second-line regimens, but how should we use these drugs going forward? Unfortunately, neither study provides an answer. The drug-development process requires companies to show the independent effects of their candidate agents; however, to treat tuberculosis, clinicians need to know what combination regimens to use, in what configuration, and for what duration. Delamanid and bedaquiline may receive regulatory approval soon, yet we don’t know whether they can be used together safely and effectively. Despite the obvious need, most sponsors are (understandably) reluctant to combine novel agents, citing proprietary, safety, and regulatory concerns. It is important to accelerate research to identify the best regimens of new and existing drugs and guide clinicians in the most effective application of these drugs. Regulatory agencies should consider this imperative in their guidance to prospective sponsors and in their review of applications for the registration of new agents.” (R. E. Chaisson)
Hedgehog Pathway Inhibition in Advanced Basal-Cell Carcinoma: Two clinical studies examine use of vismodegib, the low-molecular-weight systemic inhibitor of the hedgehog signaling pathway approved earlier this year by FDA, in patient with basal-cell carcinoma (pp. 2171–9; A. Sekulic, sekulic.aleksandar@mayo.edu) or basal-cell nevus syndrome (pp. 2180–8; E. H. Epstein, Jr., eepstein@chori.org). In an accompanying editorial, a writer adds this perspective (pp. 2225–6): “A number of other hedgehog-pathway inhibitors are under investigation, and it will be interesting to see what differences emerge. The development of intermittent-dosing therapy protocols, particularly for patients with the basal-cell nevus syndrome, might allow more patients to benefit, since it would be of great therapeutic value to prevent new lesions. In patients who have locally advanced basal-cell carcinoma with large, symptomatic lesions, the usefulness of local control in improving quality of life should not be underestimated. Another question of interest is whether vismodegib and similar agents can alter the natural history of the basal-cell nevus syndrome if they are used early in the course of the disease, although there is concern about their effects on fertility.” (J. T. Lear)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 8, 2012 * Vol. 19, No. 111
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
June issue of Pharmacotherapy (2012; 32).
PPI Costs in U.K. v. U.S.: Following up on a recent study showing that prescription drug costs are 400% higher in the U.S. private-insurance system than in the U.K. National Health Service (see PNN, Jan. 20), investigators find that the costs that the cost of a year’s treatment with proton-pump inhibitors can be nearly 4 times higher in the U.S. (pp. 489–92). The study included more than 1 million patients in the U.K. General Practice Research Database who received at least one prescription drug in 2005 and matched patients in the U.S. who were in the MarketScan Commercial Claims and Encounter Database. Among the 27,230 U.S. and 22,560 U.K. patients who received a PPI prescription, 11,292 and 9,923 patients, respectively, received a single PPI product continuously. Random sampling of annual drug costs showed the following: “The estimated annual cost/patient in the U.S. ranged from $901 for generic omeprazole to $1,485 for lansoprazole. In the U.K., the annual costs were similar, approximately $400 for each PPI, irrespective of whether the agents were available in generic formulation. The total estimated annual cost of PPIs for 2005 in this study group was $14 million in the U.S. compared with $4.1 million in the U.K.” (H. Jick, hjick@bu.edu)
Chromogenic Factor X in Argatroban–Warfarin Transition: Based on a retrospective medical record review for 2006–10 at a medical center, authors recommend measurement of chromogenic Factor X levels before patients on argatroban are transitioned to warfarin therapy (pp. 493–501). Based on the following results, the researchers also suggest at least 5 days of overlap with warfarin and that patients have a chromogenic Factor X level of 45% or less before argatroban is discontinued: “Patients received an average of 4.4 doses of warfarin before argatroban was discontinued. In 60 patients (43.2%), chromogenic factor X levels were subtherapeutic at the time of argatroban discontinuation. Chromogenic factor X levels could predict a therapeutic INR with a sensitivity of 63.2%, a specificity of 80%, a positive predictive value of 93.5, and a negative predictive value of 32.3. In patients who received 5 or more days of warfarin overlap with argatroban, the sensitivity of chromogenic factor X levels to predict an INR greater than 2.0 was 78.2%, with a specificity of 77.8%, a positive predictive value of 95.6, and a negative predictive value of 36.8. The correlation of chromogenic factor X levels and a therapeutic INR was 18.1%; however, this poor correlation may have been due to increases in the INR values of the patients who received less than 5 days of warfarin overlap with argatroban. During the transition period, nine patients developed thrombi and eight patients experienced clinically significant bleeding.” (C. A. Paciullo, Christopher.paciullo@emoryhealthcare.org)
Pharmacist-Managed Hypertension: In the Study of Cardiovascular Risk Intervention by Pharmacists—Hypertension (SCRIP-HTN) study, patients with diabetes and hypertension had lower systolic blood pressures, decreased costs, and improved outcomes when they received pharmacist interventions (pp. 527–37). The analysis combined a mean 5.6-mm Hg reduction in systolic blood pressure over 6 months of pharmacist care with meta-analytic data on cardiovascular risks, costs, and outcomes to estimate the impact of 6 and 12 months of care: “Annual estimated cost savings (in 2011 Canadian dollars) from avoided cardiovascular events were $265/patient (95% confidence interval [CI] $63–467) if the program lasted 1 year or $221/patient (95%CI $72–371) if pharmacist care ceased after 6 months with an assumed loss of effect afterward. Estimated pharmacist costs were $90/patient for 6 months or $150/patient for 1 year, suggesting that pharmacist-managed programs are cost saving, with the annual net total cost savings/patient estimated to be $131 for a program lasting 6 months or $115 for a program lasting 1 year.” (R. T. Tsuyuki, ross.tsuyuki@ualberta.ca)
The “R” Word: Pharmacotherapy Editor-in-Chief Richard T. Scheife announces his retirement with characteristic humor and aplomb (pp. 487–8): “It is clear to me that an awful lot of whether you are satisfied and enjoy your work (and your life) is anchored in the attitude of your soul. I have been called a ‘pathologic optimist’ by more than a few people. I must say that I wholeheartedly embrace that moniker! Life is far too short to work hard at a career for which you have no passion.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 11, 2012 * Vol. 19, No. 112
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release articles from Lancet (2012; 379).
Exenatide After Metformin Failure in Type 2 Diabetes: Exenatide provided better control of glycemic deterioration than glipmepiride in 977 patients with type 2 diabetes who were inadequately managed by first-line metformin, according to a study released early in conjunction with the American Diabetes Assoc. meeting now under way in Philadelphia (doi: 10.1016/S0140-6736(12)60479-6). In 2006–11 in 14 countries, patients received open-label exenatide twice daily or glimeperide once daily as add-on therapy to metformin, with these results: “203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12.4 [95% CI 6.2–18.6], hazard ratio 0.748 [0.623–0.899]; p = 0.002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA1c concentration of less than 7% (p < 0.0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6.5% and less (p = 0.0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p < 0.0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p < 0.0001), nocturnal (p = 0.007), and non-nocturnal (p < 0.0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p = 0.0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter.” (B. Gallwitz, baptist.gallwitz@med.uni-tuebingen.de)
Insulin Glargline After Metformin Failure in Type 2 Diabetes: Compared with sitagliptin, insulin glargine proved a better option for glycemic management in 515 patients with type 2 diabetes and obesity, report authors of a second early-release study (doi: 10.1016/S0140-6736(12)60439-5). In an open-label comparison conducted in 17 countries, patients in whose hemoglobin A1c levels were initially 7–11% had these outcomes following titrated insulin glargine or sitagliptin 100 mg daily: “At study end, adjusted mean reduction in HbA1c was greater for patients on insulin glargine (n = 227; –1.72%, SE 0.06) than for those on sitagliptin (n = 253; –1.13%, SE 0.06) with a mean difference of −0.59% (95% CI –0.77 to –0.42, p < 0.0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4.21 [SE 0.54] vs 0.50 [SE 0.09] events per patient–year; p < 0.0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event.” (P. Aschner, paschner@cable.net.co)

>>>PNN NewsWatch
* FDA on Friday approved pertuzumab (Perjeta, Genentech), an anti-HER2 therapy, to treat patients with HER2-positive late-stage (metastatic) breast cancer in combination with trastuzumab and docetaxel. Pertuzumab is believed to target a different part of the HER-protein than trastuzumab, resulting in further reduction in growth and survival of HER2-positive breast cancer cells. Because of production issues that potentially could affect the long-term supply of the drug, FDA limited its approval to drug product that has not been affected by those issues. Genentech has committed to take steps designed to resolve these production issues in a timely manner, FDA said. In a clinical trial of 808 patients, those treated with the pertuzumab combination had a median progression-free survival of 18.5 months, compared with 12.4 months with placebo. The most common adverse effects observed in patients receiving pertuzumab in combination with trastuzumab and docetaxel were diarrhea, hair loss, decreased white blood cells, nausea, fatigue, rash, and peripheral sensory neuropathy. Pregnancy status must confirmed before treatment because of serious risk to the fetus.

>>>PNN JournalWatch
* Effect of Pre-diabetes on Future Risk of Stroke: Meta-analysis, in
BMJ, 2012; 344: e3564. (B. Ovbiagele, vibes@ucsd.edu">ovibes@ucsd.edu)
* Local Allergic Rhinitis: Concept, Pathophysiology, and Management, in
Journal of Allergy and Clinical Immunology, 2012; 129: 1460–7. (C. Rondón, carmenrs61@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 12, 2012 * Vol. 19, No. 113
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and June 11 issue of the Archives of Internal Medicine (2012; 172).
Thiazolidinedione & Macular Edema: In patients with type 2 diabetes, the risk of diabetic macular edema (DME) is increased at 1 and 10 years with use of thiazolidinediones, according to a retrospective cohort study of 103,368 patients in The Health Improvement Network (THIN) database (doi: 10.1001/archinternmed.2012.1938). Those included in the cohort had type 2 diabetes but not DME in 2000, and their experiences through 2009 showed these patterns: “At 1 year, the incidence of DME was 1.3% (n = 41) and 0.2% (n = 227) among thiazolidinedione users (n = 3,227) and nonusers (n = 100,141), respectively (odds ratio [OR], 5.7 [95% CI, 4.1–7.9]). After Cox multiple regression analysis (adjusted for age; systolic blood pressure; levels of lipids and hemoglobin A1c; and use of aspirin, fibrates, insulin, oral antidiabetic drugs, or renin–angiotensin system blockers), multiple imputation analysis to adjust for missing values, and propensity score analysis to exclude for any selection bias, thiazolidinedione use was associated with an increased risk of DME at 1-year follow-up (OR, 2.3 [95% CI, 1.5–3.6]) and 10-year follow-up (hazard ratio [HR], 2.3; [95% CI, 1.7–3.0]). The effect was similar for pioglitazone and rosiglitazone. Combination therapy with insulin plus a thiazolidinedione was associated with a higher risk of DME after propensity score adjustment (HR, 3.0 [95% CI, 1.5–5.9]), while aspirin use (HR, 0.6 [95% CI, 0.4–0.9]) and angiotensin-converting enzyme inhibitor use (HR, 0.4 [95% CI, 0.2–0.7]) were associated with a reduced risk of DME.” (I. Idris, iidris@aol.com)
Premature Death Among Older Smokers: Smoking increases the risk of premature mortality in all age groups, including those older than 80, report authors of a systematic literature review and meta-analysis (pp. 837–44): “We identified 17 studies from 7 countries. Current smoking was associated with increased all-cause mortality in all studies. Relative mortality (RM) compared with never smokers ranged from 1.2 to 3.4 across studies and was 1.83 (95% CI, 1.65–2.03) in the meta-analysis. A decrease of RM of current smokers with increasing age was observed, but mortality remained increased up to the highest ages. Furthermore, a dose–response relationship of the amount of smoked cigarettes and premature death was observed. Former smokers likewise had an increased mortality (meta-analysis: RM, 1.34; 95% CI, 1.28–1.40), but excess mortality compared with never smokers clearly decreased with duration of cessation. Benefits of smoking cessation were evident in all age groups, including subjects 80 years and older.” (H. Brenner, h.brenner@dkfz.de)
“One in two smokers will be killed by smoking,” adds an editorialist (
pp. 845–6): “Most smokers grossly underestimate their own risks. Many older smokers misbelieve that they are too old to quit or too old to benefit from quitting. Because of reverse causality and from seeing deaths of old friends who had quit recently, some misbelieve that quitting could be harmful. A simple, direct, strong, and evidence-based warning is needed. Clinically, brief interventions (1 to <20 minutes) by health care professionals, though effective, are not practicable in busy service settings. The absolute risk warning of 1 in 2 deaths only takes a few seconds, but evidence of its effectiveness is lacking. Randomized controlled trials of minimal (<1 minute) intervention based on the absolute risk warning are warranted.” (T. H. Lam, hrmrlth@hku.hk)
Acupuncture for COPD: In a randomized controlled trial of 68 patients, acupuncture reduced dyspnea on exertion (DOE) in chronic obstructive pulmonary disease (COPD), compared with placebo needling (pp. 878–86). Patients were receiving standard medications for COPD in 2006–09, when once-weekly treatments showed: “After 12 weeks, the Borg scale score after the 6-minute walk test was significantly better in the real acupuncture group compared with the placebo acupuncture group (mean [SD] difference from baseline by analysis of covariance, −3.6 [1.9] vs 0.4 [1.2]; mean difference between groups by analysis of covariance, −3.58; 95% CI, −4.27 to −2.90). Patients with COPD who received real acupuncture also experienced improvement in the 6-minute walk distance during exercise, indicating better exercise tolerance and reduced DOE.” (M. Suzuki, masuzuki@meiji-u.ac.jp)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 13, 2012 * Vol. 19, No. 114
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 13 issue of JAMA (2012; 307).
Moxifloxacin in Severe Sepsis: For reducing organ failure among patients with severe sepsis, moxifloxacin added no benefit to treatment with meropenem, researchers report (pp. 2390–9). At 44 intensive-care units in Germany, patients received open-label i.v. meropenem 1 g every 8 h with or without moxifloxacin 400 mg every 24 h, with these results: “Among 551 evaluable patients, there was no statistically significant difference in mean [Sequential Organ Failure Assessment] score between the meropenem and moxifloxacin group (8.3 points; 95% CI, 7.8–8.8 points) and the meropenem alone group (7.9 points; 95% CI, 7.5–8.4 points) (P = .36). The rates for 28-day and 90-day mortality also were not statistically significantly different. By day 28, there were 66 deaths (23.9%; 95% CI, 19.0%–29.4%) in the combination therapy group compared with 59 deaths (21.9%; 95% CI, 17.1%–27.4%) in the monotherapy group (P = .58). By day 90, there were 96 deaths (35.3%; 95% CI, 29.6%–41.3%) in the combination therapy group compared with 84 deaths (32.1%; 95% CI, 26.5%–38.1%) in the monotherapy group (P = .43).” (T. Welte, welte.tobias@mh-hannover.de)
Safety of Diagnostic Imaging: Two studies and an editorial (pp. 2434–5; G. T. O’Connor, goconnor@bu.edu) look at the number and impact of diagnostic imaging studies being conducted in the U.S.
The rate of advanced diagnostic imaging and associated radiation exposure increased greatly between 1996 and 2010, according to a retrospective analysis of electronic records of six large integrated health systems in four different U.S. regions (
pp. 2400–9). Results extend previous studies of fee-for-service patients, the authors explain, adding these details about 1–2 million patients examined for each year in the study period: “Enrollees underwent a total of 30.9 million imaging examinations (25.8 million person–years), reflecting 1.18 tests (95% CI, 1.17–1.19) per person per year, of which 35% were for advanced diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MRI], nuclear medicine, and ultrasound). Use of advanced diagnostic imaging increased from 1996 to 2010; CT examinations increased from 52 per 1,000 enrollees in 1996 to 149 per 1,000 in 2010, 7.8% annual increase (95% CI, 5.8%–9.8%); MRI use increased from 17 to 65 per 1,000 enrollees, 10% annual growth (95% CI, 3.3%–16.5%); and ultrasound rates increased from 134 to 230 per 1,000 enrollees, 3.9% annual growth (95% CI, 3.0%–4.9%). Although nuclear medicine use decreased from 32 to 21 per 1,000 enrollees, 3% annual decline (95% CI, 7.7% decline to 1.3% increase), PET imaging rates increased after 2004 from 0.24 to 3.6 per 1,000 enrollees, 57% annual growth.” (R. Smith–Bindman, rebecca.smith-bindman@ucsf.edu)
Low-dose computed tomography (LDCT) for lung cancer screening may be beneficial in high-risk individuals, a systematic review shows, but overall potential harm and generalizability of results are unclear (
pp. 2418–29): “Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53,454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 274 vs 309 events per 100,000 person–years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73–0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare.” (P. B. Bach)

>>>PNN NewsWatch
* Using the Institute of Medicine model to analyze pharmacists’ contributions to patients’ health, Rita Shane, PharmD, accepted the 2012 Harvey A. K. Whitney Lecture Award last night during the ASHP Summer Meeting in Baltimore. Shane is director of pharmacy services at Cedars–Sinai Medical Center in Los Angeles.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 14, 2012 * Vol. 19, No. 115
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 14 New England Journal of Medicine (2012; 366).
Glycemic Control in Youth with Type 2 Diabetes: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, metformin monotherapy was effective for achieving durable glycemic control—defined as a glycated hemoglobin level less than 8% for 6 months (pp. 2247–56). Rosiglitazone was better add-on therapy than was a lifestyle-intervention program that focused on weight loss through eating and activity behaviors. Based on a primary outcome of loss of glycemic control or sustained metabolic decompensation requiring insulin, the researchers found the following among participants ages 10–17 years: “Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P = 0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-Hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants.” (K. Hirst, khirst@bsc.gwu.edu)
Describing the TODAY study as “a stark glimpse of tomorrow,” an editorialist writes (
pp. 2315–6): “Illness from childhood overnutrition is a societal and cultural problem that current medicines treat but cannot resolve. For a substantial proportion of those millions of children at risk for largely preventable type 2 diabetes, the findings of the TODAY study reinforce the idea that medications and even procedures will not stave off a lifetime of illness. Furthermore, lifestyle changes for youth are undermined by immersion in an obesogenic world, in which personal responsibility appears to be invalidated by the limits of willpower with respect to overnutrition. The stark message from the TODAY study is that, tomorrow and beyond, public-policy approaches—sufficient economic incentives to produce and purchase healthy foods and to build safe environments that require physical movement—and not simply the prescription of more and better pills will be necessary to stem the epidemic of type 2 diabetes and its associated morbidity.” (D. B. Allen)
Hormonal Contraception & Stroke, MI: The absolute risks of thrombotic stroke and myocardial infarction in women using hormonal contraception are low but real, according to a 15-year Danish historical cohort study (pp. 2257–66). Risks differed by estrogen dose and progestin type, as reflected in these data: “A total of 1,626,158 women contributed 14,251,063 person–years of observation, during which 3,311 thrombotic strokes (21.4 per 100,000 person–years) and 1,725 myocardial infarctions (10.1 per 100,000 person–years) occurred. As compared with nonuse, current use of oral contraceptives that included ethinyl estradiol at a dose of 30 to 40 µg was associated with the following relative risks (and 95% confidence intervals) for thrombotic stroke and myocardial infarction, according to progestin type: norethindrone, 2.2 (1.5 to 3.2) and 2.3 (1.3 to 3.9); levonorgestrel, 1.7 (1.4 to 2.0) and 2.0 (1.6 to 2.5); norgestimate, 1.5 (1.2 to 1.9) and 1.3 (0.9 to 1.9); desogestrel, 2.2 (1.8 to 2.7) and 2.1 (1.5 to 2.8); gestodene, 1.8 (1.6 to 2.0) and 1.9 (1.6 to 2.3); and drospirenone, 1.6 (1.2 to 2.2) and 1.7 (1.0 to 2.6), respectively. With ethinyl estradiol at a dose of 20 mcg, the corresponding relative risks according to progestin type were as follows: desogestrel, 1.5 (1.3 to 1.9) and 1.6 (1.1 to 2.1); gestodene, 1.7 (1.4 to 2.1) and 1.2 (0.8 to 1.9); and drospirenone, 0.9 (0.2 to 3.5) and 0.0. For transdermal patches, the corresponding relative risks were 3.2 (0.8 to 12.6) and 0.0, and for a vaginal ring, 2.5 (1.4 to 4.4) and 2.1 (0.7 to 6.5).” (Ø. Lidegaard, lidegaard@rh.regionh.dk)
Hormonal contraception is “not risk-free but safe enough,” maintains an editorialist, adding (
pp. 2316–8): “The research shows that the small risk could be minimized and perhaps eliminated by abstinence from smoking and by checking blood pressure, with avoidance of hormonal contraceptive use if blood pressure is raised.” (D. B. Petitti)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 15, 2012 * Vol. 19, No. 116
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
June issue of Chest (2012; 141).
Pulmonary Effects of E-Cigarettes: Adverse pulmonary effects are evident after just 5 minutes of use of electronic cigarettes, researchers report (pp. 1400–6). In a laboratory study of 30 healthy smokers aged 19–56 years, ad lib use of e-cigarettes with (experimental group, n = 30) or without (control group, n = 10) the cartridge showed these effects on pulmonary function tests and fraction of exhaled nitric oxide (Feno): “Using an e-cigarette for 5 min led to an immediate decrease in Feno within the experimental group by 2.14 ppb (P = .005) but not in the control group (P = .859). Total respiratory impedance at 5 Hz in the experimental group was found to also increase by 0.033 kPa/(L/s) (P < .001), and flow respiratory resistance at 5 Hz, 10 Hz, and 20 Hz also statistically increased. Regression analyses controlling for baseline measurements indicated a statistically significant decrease in Feno and an increase in impedance by 0.04 kPa/(L/s) (P = .003), respiratory resistance at 5 Hz by 0.04 kPa/(L/s) (P = .003), at 10 Hz by 0.034 kPa/(L/s) (P = .008), at 20 Hz by 0.043 kPa/(L/s) (P = .007), and overall peripheral airway resistance (beta, 0.042 kPa/[L/s]; P = .024), after using an e-cigarette.” (C. I. Vardavas, vardavas@hsph.harvard.edu)
Genomics & Platinum-Based Chemotherapy in NSCLC: In patients with advanced non-small cell lung cancer (NSCLC), presence of the rs430397 AA genotype of the gene for glucose-regulated protein 78 (GRP78) is associated with reduced survival and higher prevalence of early relapses, a study shows (pp. 1466–72). Analysis of blood samples from 2001–06 were genotyped for rs430397 and tested for other markers known to be associated with overall survival (OS), progression-free survival (PFS), and other clinical outcomes: “The AA genotype is significantly associated with platinum-based chemoresistance (P = .019) and NSCLC-related death (P = .022). OS, NSCLC-related survival, and PFS of the AA genotype group are decreased compared with the GG and AG genotype groups (log-rank P < .05, respectively). The AA group showed a higher prevalence of early NSCLC relapses than the AG and GG group (P = .030). In addition, the AA genotype showed a significantly increased risk for OS (hazard ratio, 1.95) and PFS (hazard ratio, 1.80) compared with the GG group. Functional analysis showed that NSCLC tissues with genotype AA have higher GRP78 RNA and protein expression compared with those carrying GG at rs430397.” (D. Li, lidp@mail.sysu.edu.cn)

>>>Circulation Report
Source:
June 12 issue of Circulation (2012; 125).
Pharmacists’ Impact on BP Control in Diabetes: In the Adherence and Intensification of Medications (AIM) program in two high-performing health systems, pharmacist-led interventions resulted in more rapid lowering of systolic blood pressures (SBPs) in patients with diabetes mellitus, but results were no different from what control patients achieved at 6 months (pp. 2863–72). “These findings show the importance of evaluating in different real-life clinical settings programs found in efficacy trials to be effective before urging their widespread adoption in all settings,” the authors conclude based on results in 1,797 intervention and 2,303 control team patients who had persistent hypertension and poor refill adherence or insufficient medication intensification: “The mean SBP decrease from 6 months before to 6 months after the intervention period was ≈9 mm Hg in both arms. Mean SBPs of eligible intervention patients were 2.4 mm Hg lower (95% CI: −3.4 to −1.5; P < 0.001) immediately after the intervention than those achieved by control patients.” (M. Heisler, mheisler@umich.edu)

>>>PNN NewsWatch
* FDA yesterday licensed Menhibrix (GlaxoSmithKline Biologics), a combination vaccine for infants and children ages 6 weeks through 18 months, for prevention of invasive disease caused by Neisseria meningitidis serogroups C and Y and Haemophilus influenzae type b. Menhibrix is given as a four-dose series at 2, 4, 6, and 12 through 15 months of age. The first dose may be given as early as 6 weeks of age. The fourth dose may be given as late as 18 months of age. In clinical trials of 7,500 infants and toddlers, adverse reactions reported after Menhibrix administration were pain, redness and swelling at the injection site, irritability, and fever.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 18, 2012 * Vol. 19, No. 117
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 16 issue of Lancet (2012; 379).
Preventing Diabetes: Both lifestyle and drug interventions that return patients with prediabetes to normal glucose regulation are effective for diabetes prevention, according to an analysis of data from the Diabetes Prevention Program Outcomes Study (DPPOS) (pp. 2243–51). An ongoing observational extension of the Diabetes Prevention Program, DPPOS includes 1,990 participants who have received intensive lifestyle interventions, metformin, or placebo, with these results: “Diabetes risk during DPPOS was 56% lower for participants who had returned to normal glucose regulation versus those who consistently had prediabetes (hazard ratio [HR] 0.44, 95% CI 0.37–0.55, p < 0.0001) and was unaffected by previous group assignment (interaction test for normal glucose regulation and lifestyle intervention, p = 0.1722; normal glucose regulation and metformin, p = 0.3304).… [P]revious achievement of normal glucose regulation (odds ratio [OR] 3.18, 95% CI 2.71–3.72, p < 0.0001), increased beta-cell function (OR 1.28; 95% CI 1.18–1.39, p < 0.0001), and insulin sensitivity (OR 1.16, 95% CI 1.08–1.25, p < 0.0001) were associated with normal glucose regulation in DPPOS, whereas the opposite was true for prediction of diabetes, with increased beta-cell function (HR 0.80, 95% CI 0.71–0.89, p < 0.0001) and insulin sensitivity (HR 0.83, 95% CI 0.74–0.94, p = 0.0001) having a protective effect. Among participants who did not return to normal glucose regulation in DPP, those assigned to the intensive lifestyle intervention had a higher diabetes risk (HR 1.31, 95% CI 1.03–1.68, p = 0.0304) and lower chance of normal glucose regulation (OR 0.59, 95% CI 0.42–0.82, p = 0.0014) than did the placebo group in DPPOS.” (L. Perreault)
Quality-Improvement Strategeis in Diabetes Management: For quality improvement (QI) of diabetes management, strategies that target health professionals only are not as effective as patient-mediated ones, a systematic review and meta-analysis of 138 trials shows (pp. 2252–61). “In random effects meta-analysis, the QI strategies reduced HbA1c by a mean difference of 0.37% (95% CI 0.28–0.45; 120 trials), LDL cholesterol by 0.10 mmol/L (0.05–0.14; 47 trials), systolic blood pressure by 3.13 mm Hg (2.19–4.06, 65 trials), and diastolic blood pressure by 1.55 mm Hg (0.95–2.15, 61 trials) versus usual care. We noted larger effects when baseline concentrations were greater than 8.0% for HbA1c, 2.59 mmol/L for LDL cholesterol, and 80 mm Hg for diastolic and 140 mm Hg for systolic blood pressure. The effectiveness of QI strategies varied depending on baseline HbA1c control. QI strategies increased the likelihood that patients received aspirin (11 trials; relative risk [RR] 1.33, 95% CI 1.21–1.45), antihypertensive drugs (ten trials; RR 1.17, 1.01–1.37), and screening for retinopathy (23 trials; RR 1.22, 1.13–1.32), renal function (14 trials; RR 128, 1.13–1.44), and foot abnormalities (22 trials; RR 1.27, 1.16–1.39). However, statin use (ten trials; RR 1.12, 0.99–1.28), hypertension control (18 trials; RR 1.01, 0.96–1.07), and smoking cessation (13 trials; RR 1.13, 0.99–1.29) were not significantly increased.” (A. C. Tricco, triccoa@smh.ca)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Anticoagulation After Total Hip/Knee Replacement: Used for prophylaxis in patients following total knee or hip replacement, newer oral anticoagulants are associated with greater efficacy but also more bleeding, according to a systematic review and meta-analysis (e3675): “Results 16 trials in 38,747 patients were included. Compared with enoxaparin, the risk of symptomatic venous thromboembolism was lower with rivaroxaban (relative risk 0.48, 95% confidence interval 0.31 to 0.75) and similar with dabigatran (0.71, 0.23 to 2.12) and apixaban (0.82, 0.41 to 1.64). Compared with enoxaparin, the relative risk of clinically relevant bleeding was higher with rivaroxaban (1.25, 1.05 to 1.49), similar with dabigatran (1.12, 0.94 to 1.35), and lower with apixaban (0.82, 0.69 to 0.98). The treatments did not differ on the net clinical endpoint in direct or indirect comparisons.” (A. Gómez-Outes, agomezo@aemps.es)

>PNN JournalWatch
* Choosing the Best Trastuzumab-Based Adjuvant Chemotherapy Regimen: Should We Abandon Anthracyclines?, in
Journal of Clinical Oncology, 2012; 30: 2179–82. (H. J. Burstein, hburstein@partners.org)
* Neurocognitive Impairment in Obstructive Sleep Apnea, in
Chest, 2012; 141: 1601–10. (C. Lal, chitra_lal@hotmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 19, 2012 * Vol. 19, No. 118
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 19 issue of the Annals of Internal Medicine (2012; 156).
Acute Liver Injury from Medical Food: Flavocoxid, a prescription medical food used to treat osteoarthritis, can cause reversible but clinically significant liver injury, according to a case series of four adults reported to the Drug-Induced Liver Injury Network Prospective Study (pp. 857–60): “Among 877 patients enrolled in the prospective study, 4 had liver injury suspected to have been caused by flavocoxid. All were women; ages ranged from 57 to 68 years. All developed symptoms and signs of liver injury within 1 to 3 months after initiating flavocoxid. Liver injury was characterized by marked elevations in levels of alanine aminotransferase (mean peak, 1,268 U/L; range, 741 to 1,540 U/L), alkaline phosphatase (mean peak, 510 U/L; range, 286 to 770 U/L), and serum bilirubin (mean peak, 160.7 µmol/L [9.4 mg/dL]; range, 34.2 to 356 µmol/L [2.0 to 20.8 mg/dL]). Liver biochemistry values decreased to the normal range within 3 to 12 weeks after flavocoxid was stopped, and all patients recovered without experiencing acute liver failure or chronic liver injury. Causality was adjudicated as highly likely in 3 patients and as possible in 1 patient.” (N. Chalasani, nchalasa@iupui.edu)
Medical foods and food supplements are “not always as safe as generally assumed,” writes an editorialist (
pp. 894–5): “In the United States, medical food and food supplements have to meet the standards specified in the Dietary Supplement Health and Education Act of 1994. Manufacturers of food supplements and medical food are not required to seek approval for their products or to register them with the U.S. Food and Drug Administration. The responsibility for ensuring safety is with the manufacturers, and there is no requirement to address effectiveness. [FDA] is responsible for taking action against any unsafe product only after it reaches the market. However, to understand the effectiveness and safety of any health care intervention— drug, medical device, food supplement, or medical food—clinical evidence from well-designed randomized trials and observational studies will always be necessary. Given the widespread use and potential harm of medical food and food supplements, the policy of marketing these products in the absence of clinical evidence may need to be reconsidered.” (P. Jüni, juni@ispm.unibe.ch)
Need for Delirium Prevention in AD: Following hospitalization for delirium, 1 in 8 patients with Alzheimer disease (AD) will have at least one serious adverse outcome such as death, institutionalization, or cognitive decline, researchers report (pp. 848–56). Results of a study of 771 community-based patients aged 65 years or older with AD points to the importance of delirium prevention in this population, the authors conclude: “Of 771 participants with AD, 367 (48%) were hospitalized and 194 (25%) developed delirium. Hospitalized patients who did not have delirium had an increased risk for death (adjusted RR, 4.7 [95% CI, 1.9 to 11.6]) and institutionalization (adjusted RR, 6.9 [CI, 4.0 to 11.7]). With delirium, risk for death (adjusted RR, 5.4 [CI, 2.3 to 12.5]) and institutionalization (adjusted RR, 9.3 [CI, 5.5 to 15.7]) increased further. With hospitalization and delirium, the adjusted RR for cognitive decline for patients with AD was 1.6 (CI, 1.2 to 2.3). Among hospitalized patients with AD, 21% of the incidences of cognitive decline, 15% of institutionalization, and 6% of deaths were associated with delirium.” (T. G. Fong, tfong@bidmc.harvard.edu)
Urgency Urinary Incontinence in Women: Authors of a review of 94 randomized controlled trials conclude that most drugs provide little benefit in women with urgency urinary incontinence (UI) and that “evidence for long-term adherence and safety of treatments is lacking” (pp. 861–74): “Pooled analyses showed that among drugs for urgency UI, per 1,000 treated women, continence was restored in 130 with fesoterodine (CI, 58 to 202), 85 with tolterodine (CI, 40 to 129), 114 with oxybutynin (CI, 64 to 163), 107 with solifenacin (CI, 58 to 156), and 114 with trospium (CI, 83 to 144). Rates of treatment discontinuation due to adverse effects were 31 per 1,000 treated with fesoterodine (CI, 10 to 56), 63 with oxybutynin (CI, 12 to 127), 18 with trospium (CI, 4 to 33), and 13 with solifenacin (CI, 1 to 26). The studies’ inconsistent definitions of reduction in UI and quality of life hampered synthesis of evidence.” (T. Shamliyan, shaml005@umn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 20, 2012 * Vol. 19, No. 119
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 20 issue of JAMA (2012; 307).
Lipid Markers for Improving CVD Prediction: Slight improvements in prediction of cardiovascular disease (CVD) resulted when emerging lipid-related markers were used in patients without known CVD, report researchers from The Emerging Risk Factors Collaboration (pp. 2499–506). Among 165,544 participants recruited into 37 prospective cohorts in 1968–2007, apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 were tested in addition to total cholesterol and HDL cholesterol (HDL-C), with these results: “The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model’s discrimination: C-index change, 0.0006 (95% CI, 0.0002–0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009–0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010–0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.” (J. Danesh, erfc@medschl.cam.ac.uk)
The utility of the arbitrary CVD risk categories of low, intermediate, and high has been reduced by availability of low-cost generic statins, writes an editorialist who concludes (
pp. 2540–2): “The need for reevaluation of statin treatment recommendations for primary prevention is made clear by a recent report from the Cholesterol Treatment Trialists’ Collaborators. This report argues that a sizable portion of patients previously identified as low-risk by multiple-risk-factor algorithms could now be considered candidates for cost-effective statin therapy. These algorithms probably are of less value in selection of patients for drug therapy than in the past. More promising approaches for the future risk assessment may be either testing for early, subclinical atherosclerosis by imaging methods or by simple, qualitative risk projection based on age, sex, low-density lipoprotein levels, and perhaps another major risk factor.” (S. M. Grundy, Scott.Grundy@UTSouthwestern.edu)
Alcohol Use Disorders & Bariatric Surgery: Patients undergoing bariatric surgery, especially the Roux-en-Y gastric bypass procedure, are at higher risk of alcohol use disorder (AUD) in their second postoperative year, according to the Longitudinal Assessment of Bariatric Surgery-2 (pp. 2516–25). Male sex and younger age, along with preoperative lifestyle and social factors, are linked to greater postoperative risk of AUD, according to these data from 2,458 participants in the trial: “The prevalence of AUD symptoms did not significantly differ from 1 year before to 1 year after bariatric surgery (7.6% vs 7.3%; P = .98), but was significantly higher in the second postoperative year (9.6%; P = .01). The following preoperative variables were independently related to an increased odds of AUD after bariatric surgery: male sex (adjusted odds ratio [AOR], 2.14 [95% CI, 1.51–3.01]; P < .001), younger age (age per 10 years younger with preoperative AUD: AOR, 1.31 [95% CI, 1.03–1.68], P = .03; age per 10 years younger without preoperative AUD: AOR, 1.95 [95% CI, 1.65–2.30], P < .001), smoking (AOR, 2.58 [95% CI, 1.19–5.58]; P = .02), regular alcohol consumption (≥ 2 drinks/week: AOR, 6.37 [95% CI, 4.17–9.72]; P < .001), AUD (eg, at age 45, AOR, 11.14 [95% CI, 7.71–16.10]; P < .001), recreational drug use (AOR, 2.38 [95% CI, 1.37–4.14]; P = .01), lower sense of belonging (12-item Interpersonal Support Evaluation List score per 1 point lower: AOR, 1.09 [95% CI, 1.04–1.15]; P = .01), and undergoing a Roux-en-Y gastric bypass procedure (AOR, 2.07 [95% CI, 1.40–3.08]; P < .001; reference category: laparoscopic adjustable gastric band procedure).” (W. C. King, kingw@edc.pitt.edu)
Lifecycle Approach at FDA: A Viewpoint article proposes changes in the FDA regulatory process based on a recent Institute of Medicine report (pp. 2491–2; B. M. Psaty, psaty@u.washington.edu).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 21, 2012 * Vol. 19, No. 120
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 21 issue of the New England Journal of Medicine (2012; 366).
Postpartum Antiretroviral Regimens in Infants: For preventing HIV infection in neonates exposed during delivery without antiretroviral prophylaxis, a postpartum regimen with two or three drugs is more effective than zidovudine alone, researchers report (pp. 2368–79). The 1,684 infants in the study received one of three regimens within 48 hours after birth: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). Results showed that the two-drug regimen had less toxicity than the three-drug option: “The overall rate of in utero transmission of HIV-1 on the basis of Kaplan–Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intrapartum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P = 0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P = 0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P = 0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P < 0.001 for both comparisons with the other groups).” (K. Nielsen-Saines, knielsen@mednet.ucla.edu)
Ritonavir-Boosted Lopinavir in HIV-Infected Children: In a study whose findings “present policymakers with difficult choices,” ritonavir-boosted lopinavir is shown to produce superior outcomes in HIV-infected children, compared with nevirapine alone (pp. 2380–9). In Africa and India, 288 nevirapine-naive children aged 2–36 months received either nevirapine or ritonavir-boosted lopinavir, with these results: “The median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log10 copies per milliliter. The percentage of children who reached the primary end point [of virologic failure or discontinuation of treatment by study week 24] was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P < 0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P = 0.04), as was the time to death (P = 0.06).” (P. Palumbo, paul.e.palumbo@dartmouth.edu)
Med Rec for Controlled Substances: State-based prescription-drug monitoring programs (PDMPs) provide a useful tool in dealing with the paradoxical pressures on clinicians “to increase opioid prescribing for the benefit of individual patients and to reduce it for the sake of public health,” write authors of a Perspective article (pp. 2341–3). “Clinicians are facing the challenges of caring for an increasing number of patients with chronic pain. Safety measures, including the expanded use of well-designed PDMPs, must be instituted to address the issues of opioid prescribing in this growing population. PDMPs are no panacea; a multimodal approach is required. Cultural change related to the expectations of patients and providers, new medications and formulations, and extensive education at many levels can contribute to a reduction in opioid misuse, even as appropriate access to this pharmacotherapy is maintained. As the number of deaths associated with prescription-drug use surpasses the number of fatalities from motor vehicle crashes in many states, we can learn from the success of auto-safety innovations that have mitigated mortality despite increased automobile use over the past three decades. We should initiate active safety measures to address the growing rates of illness and death associated with the pharmaceuticalization of the 21st century.” (J. Perrone)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 22, 2012 * Vol. 19, No. 121
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Early-release article from and June issue of Health Affairs (2012; 31).
Unintended ACA Consequences: A key provision of the Affordable Care Act affecting pharmacists—reducing hospital readmissions—is one of three “unintended consequences” of the law that “may threaten care of vulnerable older adults,” according to an early-release article (10.1377/hlthaff.2012.0110). Along with the National Pilot Program on Payment Bundling and the Community-Based Care Transitions Program, the Hospital Readmissions Reduction Program was “designed to enhance care transitions for the broader population of adults coping with chronic illness,” the authors write. “We found that these provisions inadequately address the unique needs of vulnerable subgroup members who require long-term services and supports and, in some instances, could produce unintended consequences that would contribute to avoidable poor outcomes. We recommend that policy makers anticipate such unintended consequences and advance payment policies that integrate care. They should also prepare the delivery system to keep up with new requirements under the Affordable Care Act, by supporting providers in implementing evidence-based transitional care practices, recrafting strategic and operational plans, developing educational and other resources for frail older adults and their family caregivers, and integrating measurement and reporting requirements into performance systems.” (M. D. Naylor, naylor@nursing.upenn.edu)
Coordinated Care & Reduced Hospital Admissions: A study identifies characteristics of coordinated-care programs that reduce readmission of high-risk patients to hospitals, finding that such programs work but save little money overall (pp. 1156–66): “Four of eleven programs that were part of the Medicare Coordinated Care Demonstration reduced hospitalizations by 8–33 percent among enrollees who had a high risk of near-term hospitalization. The six approaches practiced by care coordinators in at least three of the four programs were as follows: supplementing telephone calls to patients with frequent in-person meetings; occasionally meeting in person with providers; acting as a communications hub for providers; delivering evidence-based education to patients; providing strong medication management; and providing timely and comprehensive transitional care after hospitalizations. When care management fees were included, the programs were essentially cost-neutral, but none of these programs generated net savings to Medicare. Our results suggest that incorporating these approaches into medical homes, accountable care organizations, and other policy initiatives could reduce hospitalizations and improve patients’ lives. However, the approaches would save money only if care coordination fees were modest and organizations found cost-effective ways to deliver the interventions.” (R. S. Brown, RBrown@mathematica-mpr.com)

>>>Medical Care Highlights
Source:
July issue of Medical Care (2012; 50).
State Mandates & Consistent Contraceptive Use: In the one-half of states that mandate contraceptive coverage by health insurers, privately insured women use the drugs more consistently than in states without mandates, researchers report (pp. 562–8). In the National Survey of Family Growth (2006–08), use of contraception among 2,276 privately insured women showed these associations: “18% reported a ≥1-month gap in contraceptive use. Compared with women living in states with no mandates, those in states with comprehensive mandates had increased odds of consistent contraceptive use among privately insured women [adjusted odds ratio (aOR), 1.64; 95% confidence interval (CI), 1.08–2.50], but not uninsured women (aOR, 0.77; 95% CI, 0.38–1.55). Partial mandates were not associated with consistent contraceptive use.” (B. M. Magnusson)

>>>PNN NewsWatch
* Pregabalin (Lyrica) has been approved for an additional indication, management of neuropathic pain associated with spinal cord injury, Pfizer announced yesterday.
* Final Congressional approval of the
Prescription Drug User Fee Act (PDUFA) is nearing, according to the National Association of Chain Drug Stores. Required every 5 years, the FDA reauthorization bill addresses counterfeit drugs, prescription drug monitoring programs, and the Sentinel Initiative.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 25, 2012 * Vol. 19, No. 122
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 23 issue of Lancet (2012; 379).
Thrombolysis in Older Patients with Stroke: Functional outcomes at 6 months were improved in patients older than 80 years when acute ischemic stroke was treated with recombinant tissue plasminogen activator (rt-PA) within 6 hours, according to the third International Stroke Trial (IST-3) (pp. 2352–63). Using an outcome of the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0–2 at 6 months, investigators observed these effects of rt-PA 0.9 mg/kg versus control: “3,035 patients were enrolled by 156 hospitals in 12 countries. All of these patients were included in the analyses (1,515 in the rt-PA group vs 1,520 in the control group), of whom 1,617 (53%) were older than 80 years of age. At 6 months, 554 (37%) patients in the rt-PA group versus 534 (35%) in the control group were alive and independent (OHS 0–2; adjusted odds ratio [OR] 1.13, 95% CI 0.95–1.35, p = 0.181; a non-significant absolute increase of 14/1000, 95% CI −20 to 48). An ordinal analysis showed a significant shift in OHS scores; common OR 1.27 (95% CI 1.10–1.47, p = 0.001). Fatal or non-fatal symptomatic intracranial haemorrhage within 7 days occurred in 104 (7%) patients in the rt-PA group versus 16 (1%) in the control group (adjusted OR 6.94, 95% CI 4.07–11.8; absolute excess 58/1,000, 95% CI 44–72). More deaths occurred within 7 days in the rt-PA group (163 [11%]) than in the control group (107 [7%], adjusted OR 1.60, 95% CI 1.22–2.08, p = 0.001; absolute increase 37/1,000, 95% CI 17–57), but between 7 days and 6 months there were fewer deaths in the rt-PA group than in the control group, so that by 6 months, similar numbers, in total, had died (408 [27%] in the rt-PA group vs 407 [27%] in the control group).” (IST-3 Collaborative Group)
Thrombolysis After Ischemic Stroke: A systematic review and meta-analysis confirms effectiveness of recombinant tissue plasminogen activator (rt-PA) when used as soon as possible after acute ischemic stroke and for up to 6 hours after onset in some patients (pp. 2364–72): “In up to 12 trials (7,012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1,611/3,483 [46.3%] vs 1,434/3,404 [42.1%], OR 1.17, 95% CI 1.06–1.29; p = 0.001), absolute increase of 42 (19–66) per 1000 people treated, and favourable outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1,000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0–2, 365/896 [40.7%] vs 280/883 [31.7%], 1.53, 1.26–1.86, p < 0.0001), absolute benefit of 90 (46–135) per 1,000 people treated, and mRS 0–1 (283/896 [31.6%] vs 202/883 [22.9%], 1.61, 1.30–1.90; p < 0.0001), absolute benefit 87 (46–128) per 1,000 treated. Numbers of deaths within 7 days were increased (250/2,807 [8.9%] vs 174/2728 [6.4%], 1.44, 1.18–1.76; p = 0.0003), but by final follow-up the excess was no longer significant (679/3,548 [19.1%] vs 640/3,464 [18.5%], 1.06, 0.94–1.20; p = 0.33). Symptomatic intracranial haemorrhage (272/3548 [7.7%] vs 63/3,463 [1.8%], 3.72, 2.98–4.64; p < 0.0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early.” (J. M. Wardlaw, joanna.wardlaw@ed.ac.uk)

>>>PNN NewsWatch
* The Supreme Court decision on the health care reform law is expected to be handed down this morning at 10 am Eastern time. The Court’s current term ends this Friday, but today is the last regularly scheduled day for issuing decisions.

>>>PNN JournalWatch
* Evidence-Based Guideline Update: Medical Treatment of Infantile Spasms, in
Neurology, 2012; 78: 1974–80. (American Academy of Neurology, guidelines@aan.com)
* Osteoarthritis: A Disease of the Joint as an Organ, in
Arthritis & Rheumatism, 2012; 64: 1697–707. (R. F. Loeser, rloeser@wakehealth.edu)
* The Use of Clinical Decision-Support Tools to Facilitate Geriatric Education, in
Journal of the American Geriatrics Society, 2012; 60: 1145–9. (C. B. Litvin, litvincb@musc.edu)
* National Health Expenditure Projections: Modest Annual Growth Until Coverage Expands and Economic Growth Accelerates, in
Health Affairs, 2012; 10.1377/hlthaff.2012.0404. (S. P. Keehan, Sean.Keehan@cms.hhs.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 26, 2012 * Vol. 19, No. 123
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 25 issue of the Archives of Internal Medicine (2012; 172).
Statin Efficacy in Women: Do statins work as well in women as in men? The answer is not clear based on a meta-analysis showing efficacy in women for secondary prevention but not for stroke prevention and reduction of all-cause mortality (pp. 909–19). Investigators found these results from their systematic review and meta-analysis: “Eleven trials representing 43,193 patients were included in the analysis. Overall, statin therapy was associated with a reduced risk of cardiovascular events in all outcomes for women (relative risk [RR], 0.81 [95% CI, 0.74–0.89]) and men (RR, 0.82 [95% CI, 0.78–0.85]). However, they did not reduce all-cause mortality in women vs men (RR, 0.92 [95% CI, 0.76–1.13] vs RR, 0.79 [95% CI, 0.72–0.87]) or stroke (RR, 0.92 [95% CI, 0.76–1.10] vs RR, 0.81 [95% CI, 0.72–0.92]).” (J. Gutierrez, jg3233@columbia.edu)
Citing similar efficacy of statins for LDL cholesterol reduction in men and women, editorialists point out that this meta-analysis is not definitive (
pp. 919–20): “Focusing on a lack of statistical significance in the findings for women is misleading. The real issue is not significance but whether the effect size in women is materially different from the effect size in men. Overinterpretation of imprecisely estimated effects is a serious problem in meta-analyses and in primary studies. In the study by Gutierrez et al, the effect on stroke and all-cause mortality in women is consistent with the effect in men. If a statistical test is wanted, the appropriate P value is for the sex interaction for the outcome by sex. We suggest that statins work just as well in women as in men.” (F. Taylor, Fiona.Taylor@lshtm.ac.uk)
Critical Pathway for Reducing Antibiotic Use: A 3-step critical pathway for managing community-acquired pneumonia (CAP) was useful in reducing antibiotic duration of therapy and patients’ length of stay (LOS) while achieving similar clinical outcomes, researchers report (pp. 922–8). In 401 adults with CAP, clinicians applied the 3 steps— early mobilization and use of objective criteria for switching to oral antibiotic therapy and for deciding on hospital discharge or usual care—with these results: “Median LOS was 3.9 days in the 3-step group and 6.0 days in the usual care group (difference, −2.1 days; 95% CI, −2.7 to −1.7; P < .001). Median duration of intravenous antibiotic therapy was 2.0 days in the 3-step group and 4.0 days in the usual care group (difference, −2.0 days; 95% CI, −2.0 to −1.0; P < .001). More patients assigned to usual care experienced adverse drug reactions (4.5% vs 15.9% [difference, −11.4 percentage points; 95% CI, −17.2 to −5.6 percentage points; P < .001]). No significant differences were observed regarding subsequent readmissions, case fatality rate, and patients’ satisfaction with care.” (J. Carratalà, jcarratala@ub.edu)
Femoral Fractures with Bisphosphonates: Patients aged 50 years or older taking bisphosphonates, especially those who have been taking the drugs for longer time periods, are at increased risk of atypical femoral fractures, according to an analysis (pp. 930–6). In 1999–2010, 477 older patients hospitalized with subtrochanteric or femoral shaft fracture at a university medical center had these clinical characteristics and fracture risks: “Thirty-nine patients with atypical fractures and 438 patients with classic fractures were identified. Of the patients with atypical fractures, 32 (82.1%) had been treated with bisphosphonates compared with 28 (6.4%) in the classic fractures group (odds ratios [OR], 66.9; 95% CI, 27.1–165.1) and 11.5% in the group without fracture (OR, 35.2; 95% CI, 13.9–88.8). Bisphosphonate use was associated with a 47% reduction in risk of classic fracture (OR, 0.5; 95% CI, 0.3–0.9). Considering the duration of use, the ORs (95% CIs) for atypical fractures were 35.1 (10.0–123.6) for less than 2 years, 46.9 (14.2–154.4) for 2 to 5 years, 117.1 (34.2–401.7) for 5 to 9 years, and 175.7 (30.0–1027.6) for more than 9 years compared with no use. A contralateral fracture occurred in 28.2% of atypical cases and in 0.9% of classic cases (OR, 42.6; 95% CI, 12.8–142.4). The incidence rate of atypical fractures was low (32 cases per million person–years) and increased by 10.7% per year on average.” (R. P. H. Meier, Raphael.Meier@hcuge.ch)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 27, 2012 * Vol. 19, No. 124
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 27 issue of JAMA (2012; 307).
Stroke Risk with Warfarin + tPA: In warfarin-treated patients who experience ischemic stroke while INRs are below 1.7, tissue plasminogen activator (tPA) can be used without increased risk of symptomatic intracranial hemorrhage (sICH), researchers report (pp. 2600–8). Findings from an observational study of 23,437 patients support recommendations in current guidelines: “Overall, 1,802 (7.7%) patients with stroke treated with tPA were receiving warfarin (median INR, 1.20; interquartile range [IQR], 1.07–1.40). Warfarin-treated patients were older, had more comorbid conditions, and had more severe strokes. The unadjusted sICH rate in warfarin-treated patients was higher than in non–warfarin-treated patients (5.7% vs 4.6%, P < .001), but these differences were not significantly different after adjustment for baseline clinical factors (adjusted odds ratio [OR], 1.01 [95% CI, 0.82–1.25]). Similarly, there were no significant differences between warfarin-treated and non–warfarin-treated patients for serious systemic hemorrhage (0.9% vs 0.9%; adjusted OR, 0.78 [95% CI, 0.49–1.24]), any tPA complications (10.6% vs 8.4%; adjusted OR, 1.09 [95% CI, 0.93–1.29]), or in-hospital mortality (11.4% vs 7.9%; adjusted OR, 0.94 [95% CI, 0.79–1.13]). Among warfarin-treated patients with INRs of 1.7 or lower, the degree of anticoagulation was not statistically significantly associated with sICH risk (adjusted OR, 1.10 per 0.1-unit increase in INR [95% CI, 1.00–1.20]; P = .06).” (E. D. Peterson, peter016@mc.duke.edu)
The real risk in warfarin-treated patients with ischemic stroke lies in not treating, writes an editorialist (
pp. 2637–9): “Considering that intravenous tPA remains substantially underutilized in the United States for patients with stroke, with few if any alternate therapies, medical professionals should ensure that eligible patients receive this important therapy. [This] study … is a positive step in that direction, providing evidence that patients taking warfarin and with INRs of 1.7 or lower can be treated without experiencing a significantly increased risk of sICH. The real risk is in not treating otherwise eligible patients, who may then have prolonged morbidity from their stroke.
“To paraphrase some surgical colleagues, ‘A chance to treat is a chance to cure.’ The results of the current study provide another chance to treat a serious and potentially disabling disease that has very few effective medical therapies.” (M. J. Alberts, m-
alberts@northwestern.edu)
Weight Loss Strategies: In an 18-month comparison, a stepped-care weight loss intervention (STEP) was less effective but also less expensive than a standard behavioral weight loss intervention (SBWI) in 363 overweight and obese adults (pp. 2617–26). All participants received diet, exercise, and group counseling interventions; those in the SBWI group were placed on a fixed program, while programs in the STEP group were modified every 3 months based on actual versus goal weight loss. Results showed: “Of the 363 participants randomized, 260 (71.6%) provided a measure of mean change in weight over 18 months. The 18-month intervention resulted in weight decreasing from 93.1 kg (95% CI, 91.0 to 95.2 kg) to 85.6 kg (95% CI, 83.4 to 87.7 kg) (P < .001) in the SBWI group and from 92.7 kg (95% CI, 90.8 to 94.6 kg) to 86.4 kg (95% CI, 84.5 to 88.4 kg) in the STEP group (P < .001). The percentage change in weight from baseline to 18 months was −8.1% (95% CI, −9.4% to −6.9%) in the SBWI group (P < .001) compared with −6.9% (95% CI, −8.0% to −5.8%) in the STEP group (P < .001). Although the between-group difference in 18-month weight loss was not statistically different (−1.3 kg [95% CI, −2.8 to 0.2 kg]; P = .09), there was a significant group × time interaction effect (P = .03). The cost per participant was $1,357 (95% CI, $1272 to $1,442) for the SBWI group vs $785 (95% CI, $739 to $830) for the STEP group (P < .001). Both groups had significant and comparable improvements in resting heart rate, blood pressure level, and fitness.” (J. M. Jakicic, jjakicic@pitt.edu)

>>>PNN NewsWatch
* An FDA reauthorization bill passed yesterday by Congress allows for the first time collection of user fees from the generic drug industry, including makers of biosimilars, the Washington Post reports. The bill also includes provisions related to drug shortages, according to ASHP. Pres. Obama is expected to sign the bill within days.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 28, 2012 * Vol. 19, No. 125
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 28 issue of the New England Journal of Medicine (2012; 366).
Anti–PD-1 Antibody in Cancer: Two articles and an editorial examine blockade of PD-1 activity in tumor cells of patients with cancer.
BMS-936558, an antibody that blocks PD-1, produced objective responses in 20–25% of patients with non–small-cell lung cancer, melanoma, or renal-cell cancer, and “preliminary data suggest a relationship between PD-L1 expression on tumor cells and” these responses, researchers report (
pp. 2443–54). Study participants had advanced melanoma, non–small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer, and their responses to anti–PD-1 antibody was as follows: “A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006).” (S. L. Topalian, stopali1@jhmi.edu)
Similar activity was noted in a Phase I trial of patients with advanced cancers who received dose-ranging amounts of anti–PD-1 antibody (
pp. 2455–65): “As of February 24, 2012, a total of 207 patients—75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer—had received anti–PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non–small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up.” (J. R. Brahmer)
Personalization of cancer therapy using selectable markers to induce “a high frequency of long-lasting tumor response” is “the next frontier in the treatment of cancer,” an editorialist writes (
pp. 2517–9): “Inhibition of PD-1 may meet these expectations in selected cancers. The immune system remembers what it targets, so once the system is correctly activated, it may mediate a durable tumor response, as demonstrated previously in clinical trials of high-dose interleukin-2 and anti–CTLA-4 antibodies. The durability of the tumor response to anti–PD-1 and anti–PD-L1 antibodies in a great majority of patients who had objective tumor regressions in the studies by Topalian et al. and Brahmer et al. predicts that these antibodies unleash a memory immune response to cancer. The use of PD-1 blockade—with its reduced rate of toxic effects and potential ability to further select patients who have an increased likelihood of tumor response—may well have a major effect on cancer treatment.” (A. Ribas)

>>>PNN NewsWatch
* Lorcaserin (Belviq; Arena Pharmaceuticals, Eisai), a serotonin agonist, was approved yesterday by FDA for as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients with obesity (BMI of 30 kg/m2) or overweight (27 kg/m2) in the presence of at least one weight-related comorbid condition such as diabetes, hyperlipidemia, or hypertension.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
June 29, 2012 * Vol. 19, No. 126
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (2012; 35).
Intensive Blood Pressure Treatment in Obesity & Diabetes: Cardiovascular disease (CVD) outcomes were not improved by intensive treatment of hypertension in patients who also had diabetes (pp. 1401–5). Most measures also did not vary in patients who had central obesity, according to this analysis of data on 4,687 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Blood Pressure Trial: “There was no evidence that the effect of intensively lowering blood pressure differed by quartile of waist-to-height ratio for any of the four outcomes (P > 0.25 in all cases). Controlling for waist-to-height quartile had no significant impact on previously published results for intensive blood pressure therapy. Waist-to-height ratio was significantly related to CVD mortality (hazard ratio 2.32 [95% CI 1.40–3.83], P = 0.0009 comparing the heaviest to lightest quartiles), but not to the other outcomes (P > 0.09 in all cases).” (J. I. Barzilay, joshua.barzilay@kp.org)
Beta-Cell Function After Intensive Diabetes Therapy: Early intensive therapy for type 2 diabetes with either insulin plus metformin or triple oral therapy can preserve beta-cell function for up to 3.5 years, a study of 58 patients shows (pp. 1406–12). Following a 3-month treatment period with insulin and metformin, newly diagnosed patients received insulin plus metformin (INS) or triple oral therapy (TOT) with metformin, glyburide, and pioglitazone, with these results: “Completion rates at 3.5 years were 83% in the insulin group and 72% in the TOT group, with good compliance in both groups (87 ± 20% in the INS group vs. 90 ± 15% in the TOT group). Beta-cell function was preserved at 3.5 years after diagnosis, with no significant change from baseline or difference between the two groups as measured by area under the curve (AUC) of C-peptide (P = 0.14) or the ratio of C-peptide to glucose AUC (P = 0.7). Excellent glycemic control was maintained in both groups (end-of-study HbA1c 6.35 ± 0.84% in the INS group vs. 6.59 ± 1.94% in the TOT group). Weight increased in both groups over time (from 102.2 ± 24.9 kg to 106.2 ± 31.7 kg in the INS group and from 100.9 ± 23.0 kg to 110.5 ± 31.8 kg in the TOT group), with no significant difference between groups (P = 0.35). Hypoglycemic events decreased significantly over time (P = 0.01) but did not differ between groups (P = 0.83).” (I. Lingvay, ildiko.lingvay@utsouthwestern.edu)
Patient Disclosure of Self-care: About 30% of 316 patients with diabetes were reluctant to discuss self-care measures with physicians, and they more frequently had depressive symptoms, a study shows (pp. 1466–72): “Patients who reported elevated depressive symptoms, although not necessarily major depression, were more likely to be reluctant to discuss self-care (odds ratio [OR] 1.66 for 10-point change in t score; P < 0.001), whereas patients who were older (OR 0.78 for 10-year change; P = 0.05) and those who used more self-controlled coping styles (OR 0.78 for 10-point change; P = 0.007) were less likely to be reluctant.” (K. Weinger, katie.weinger@joslin.harvard.edu)

>>>PNN NewsWatch
* Yesterday’s 5–4 U.S. Supreme Court ruling upholding the Affordable Care Act means that pharmacy-friendly provisions in the health care reform law remain in force, APhA says in a pharmacist.com news article. The “ruling means that important elements of the law will stand, including closure of the doughnut hole and opportunities for pharmacist inclusion as members of the health care team in medical homes and accountable care organizations,” said Thomas E. Menighan, APhA Executive Vice President and CEO.
*
FDA yesterday approved mirabegron (Myrbetriq, Astellas Pharma) for treatment of overactive bladder, including urinary frequency, urgency, and urge incontinence. In clinical trials of 4,116 patients with overactive bladder, mirabegron 25 mg and 50 mg reduced the number of times a patient urinated and the number of times a patient had wetting accidents during a 24-hour period. Patients taking mirabegron 50 mg also expelled a greater amount of urine, demonstrating the drug’s effectiveness in improving the storage capacity of the bladder, FDA said. Adverse effects of the once-daily oral beta-3 adrenergic agonist include hypertension, nasopharyngitis, urinary tract infection, and headache.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.