Sep 2012

PNN July–September 2012

PNN Pharmacotherapy Line
July 2, 2012 * Vol. 19, No. 127
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 30 issue of Lancet (2012; 379).
Coformulated Antiretroviral Regimens: A single-tablet, integrase inhibitor approach to initial treatment of HIV is examined in two research articles.
In a Phase III noninferiority trial, an HIV integrase strand inhibitor–based regimen coformulated in a single tablet was not inferior to a ritonavir-boosted (RTV) protease inhibitor regimen, the GS-236-0103 study team reports (
pp. 2429–38). Elvitegravir (EVG) was coformulated with the CYP3A4 inhibitor cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF). Patients were assigned to once-daily doses of this product or to atazanavir (ATV)/RTV+FTC/TDF once daily, with these effects on a primary outcome of HIV RNA concentration of 50 copies per mL or less after 48 weeks (12% noninferiority margin): “1,017 patients were screened, 715 were enrolled, and 708 were treated (353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome (316 patients [89.5%] vs 308 patients [86.8%], adjusted difference 3.0%, 95% CI –1.9% to 7.8%). Both regimens had favourable safety and tolerability; 13 (3.7%) versus 18 (5.1%) patients discontinued treatment because of adverse events. Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration (90 µmol/L vs 260 µmol/L, p = 0.006). Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2; they generally stabilised by week 8 and did not change up to week 48 (median change 11 µmol/L vs 7 µmol/L).” (B. P. Kearney, bkearney@gilead.com)
In a second Phase III trial from the same research group, EVG/COBI/FTC/TDF was noninferior to standard of care coformulated efavirenz (EFV)/FTC/TDF as initial treatment for HIV infection (
pp. 2439–48). “If regulatory approval is given, EVG/COBI/FTC/TDF would be the only single-tablet, once-daily, integrase-inhibitor-based regimen for initial treatment of HIV infection,” the authors conclude, based on these findings: “700 patients were randomly assigned and treated (348 with EVG/COBI/FTC/TDF, 352 with EFV/FTC/TDF). EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF; 305/348 (87.6%) versus 296/352 (84.1%) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 (difference 3.6%, 95% CI −1.6% to 8.8%). Proportions of patients discontinuing drugs for adverse events did not differ substantially (13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group). Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF (72/348 vs 48/352) and dizziness (23/348 vs 86/352), abnormal dreams (53/348 vs 95/352), insomnia (30/348 vs 49/352), and rash (22/348 vs 43/352) were less common. Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (median 13 µmol/L, IQR 5 to 20 vs 1 µmol/L, −6 to 8; p < 0.001).” (P. E. Sax, psax@partners.org)

>>>PNN NewsWatch
* Patients with kidney impairment are at risk for nonconvulsive status epilepticus if they receive doses of cefepime that are not renally adjusted, FDA warns.
* A single 32-mg dose of
ondansetron can affect QT interval prolongation and place patients at risk for torsades de pointes, according to FDA. GlaxoSmithKline is removing the 32-mg dose from product labeling; ondansetron can continue to be used in adults and children with chemotherapy-induced nausea and vomiting at a lower intravenous dose.

>>>PNN JournalWatch
* Effect of Fructose on Glycemic Control in Diabetes: A Systematic Review and Meta-analysis of Controlled Feeding Trials, in
Diabetes Care, 2012; 35: 1611–20. (J. L. Sievenpiper, john.sievenpiper@medportal.ca)
* Optimizing Care for Patients With CKD, in
American Journal of Kidney Diseases, 2012; 60: 133–8. (B. R. Hemmelgarn, brenda.hemmelgarn@albertahealthservices.ca)
* Ergocalciferol and Cholecalciferol in CKD, in
American Journal of Kidney Diseases, 2012; 60: 139–56. (R. Thadhani, rthadhani@partners.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, 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
July 3, 2012 * Vol. 19, No. 128
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 3 issue of the Annals of Internal Medicine (2012; 157).
Pharmacists & Med Errors After Discharge: An intensive pharmacist intervention in hospitalized adults with acute coronary syndromes or acute decompensated heart failure failed to reduce postdischarge medication errors, a study shows (pp. 1–10). At two tertiary-care academic hospitals, the PILL-CVD (Pharmacist Intervention for Low Literacy in Cardiovascular Disease) Study Group compared standard care with an intervention that included pharmacist-assisted medication reconciliation, inpatient pharmacist counseling, low-literacy adherence aids, and individualized telephone follow-up after discharge. Results showed that clinically important medication errors occurred in about one half of patients: “Among 851 participants, 432 (50.8%) had 1 or more clinically important medication errors; 22.9% of such errors were judged to be serious and 1.8% life-threatening. Adverse drug events occurred in 258 patients (30.3%) and potential ADEs in 253 patients (29.7%). The intervention did not significantly alter the per-patient number of clinically important medication errors (unadjusted incidence rate ratio, 0.92 [95% CI, 0.77 to 1.10]) or ADEs (unadjusted incidence rate ratio, 1.09 [CI, 0.86 to 1.39]). Patients in the intervention group tended to have fewer potential ADEs (unadjusted incidence rate ratio, 0.80 [CI, 0.61 to 1.04]).” (S. Kripalani, sunil.kripalani@vanderbilt.edu)
30-Day Rehospitalizations After MI: A number of factors are associated with rehospitalization within 30 days among patients with acute myocardial infarction, but many of these events appear unrelated to the initial MI, researchers report (pp. 11–8). A retrospective cohort study using a population-based registry in a Minnesota county shows these patterns using Cox proportional hazards regression models: “Among 3,010 patients (mean age, 67 years; 40.5% female) with incident MI (31.2% ST-segment elevation), 643 rehospitalizations occurred within 30 days in 561 (18.6%) patients. Overall, 30.2% of rehospitalizations were unrelated to the incident MI and 42.6% were related; the relationship was unclear in 27.2% of rehospitalizations. Angiography was performed in 153 (23.8%) rehospitalizations. Revascularization was performed in 103 (16.0%) rehospitalizations, of which 46 (44.7%) had no revascularization during the index hospitalization. After adjustment for potential confounders, diabetes, chronic obstructive pulmonary disease, anemia, higher Killip class, longer length of stay during the index hospitalization, and a complication of angiography or reperfusion or revascularization were associated with increased rehospitalization risk. The 30-day incidence of rehospitalization was 35.3% in patients who experienced a complication of angiography during the index MI hospitalization and 31.6% in those who experienced a complication of reperfusion or revascularization during the index MI hospitalization, compared with 16.8% in patients who had reperfusion or revascularization without complications.” (V. L. Roger, roger.veronique@mayo.edu)
Impact of Clinical Decision-Support Systems: Clinical decision support systems (CDSS) improve health care process measures, authors of a systematic review report, but their effects on hard clinical, economic, workload, and efficiency outcomes remain unproven (pp. 29–43): “148 randomized, controlled trials were included. A total of 128 (86%) assessed health care process measures, 29 (20%) assessed clinical outcomes, and 22 (15%) measured costs. Both commercially and locally developed CDSSs improved health care process measures related to performing preventive services (n = 25; odds ratio [OR], 1.42 [95% CI, 1.27 to 1.58]), ordering clinical studies (n = 20; OR, 1.72 [CI, 1.47 to 2.00]), and prescribing therapies (n = 46; OR, 1.57 [CI, 1.35 to 1.82]). Few studies measured potential unintended consequences or adverse effects.” (G. D. Sanders, gillian.sanders@duke.edu)
Thoughts on Dabigatran: An author recounts “emerging reports of dabigatran-related adverse events, including bleeding and thromboembolic events, and unanticipated safety risks” in an opinion article (pp. 66–8), urging “physicians considering dabigatran for individual patients to be conservative in considering whether it is an appropriate replacement for warfarin.” (R. P. Radecki, Ryan.P.Radecki@uth.tmc.edu)

>>>PNN NewsWatch
* PNN will not be published on July 4, Independence Day.

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
July 5, 2012 * Vol. 19, No. 129
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 4 issue of JAMA (2012; 308).
Herpes Zoster Vaccine & Risk of Shingles: In Medicare beneficiaries with immune-mediated diseases, receipt of the herpes zoster (HZ) vaccine did not produce short-term increases in incidence of the disease but was linked to decreased HZ incidence over a median of 2 years’ follow-up, researchers report (pp. 43–9). A lack of sound data is the basis for a contraindication of the vaccine in patients taking anti–tumor necrosis factor therapies and other biologics. This retrospective cohort study used claims data for 463,541 Medicare beneficiaries 60 years and older to assess the risk of HZ immunization during treatment for rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, or inflammatory bowel disease. Results showed: “Median duration of follow-up was 2.0 years (interquartile range, 0.8–3.0); 4.0% of patients received HZ vaccine. The overall crude HZ incidence rate was 7.8 cases per 1,000 person–years (95% CI, 3.7–16.5) within 42 days after vaccination. The rate among the unvaccinated was 11.6 cases per 1,000 person–years (95% CI, 11.4–11.9). Among 633 patients exposed to biologics at the time of vaccination or within the subsequent 42 days, no case of HZ or varicella occurred. After multivariable adjustment, HZ vaccination was associated with a hazard ratio of 0.61 (95% CI, 0.52–0.71) for HZ risk after 42 days.” (J. R. Curtis, jcurtis@uab.edu)

>>>NEJM Highlights
Source:
July 5 issue of the New England Journal of Medicine (2012; 367).
Eltrombopag in Refractory Aplastic Anemia: In some patients with refractory aplastic anemia, multilineage clinical responses were observed in a Phase II study of the oral thrombopoietin mimetic eltrombopag (pp. 11–9). Approved by FDA under the trade name Promacta for treatment of chronic immune thrombocytopenic purpura, eltrombopag was administered over a 12-week period in doses of 50–150 mg daily to 25 patients with aplastic anemia that was refractory to immunosuppression, with these results: “Eleven of 25 patients (44%) had a hematologic response in at least one lineage at 12 weeks, with minimal toxic effects. Nine patients no longer needed platelet transfusions (median increase in platelet count, 44,000 per cubic millimeter). Six patients had improved hemoglobin levels (median increase, 4.4 g per deciliter); 3 of them were previously dependent on red-cell transfusions and no longer needed transfusions. Nine patients had increased neutrophil counts (median increase, 1350 per cubic millimeter). Serial bone marrow biopsies showed normalization of trilineage hematopoiesis in patients who had a response, without increased fibrosis. Monitoring of immune function revealed no consistent changes.” (C. E. Dunbar, dunbarc@nhlbi.nih.gov)
“If confirmed, the implication of these intriguing results is that in many patients with aplastic anemia, the hematopoietic stem cells and their progenitor-cell progeny may have acquired defective MPL receptors that are unresponsive to thrombopoietin but remain able to be activated by eltrombopag,” writes an editorialist (
pp. 74–5). “Of particular interest is a recent study in which patients with familial aplastic anemia were shown to have nonsense mutations in the MPL gene. Time will tell whether the hematopoietic cells in other patients with aplastic anemia will also prove to have defective MPL signaling.” (D. Metcalf)
Vitamin D Doses in Fracture Prevention: Daily doses of 800 IU or more of vitamin D are associated with greater prevention of hip fracture and any nonvertebral fracture in patients aged 65 or older, an analysis of pooled data from 11 trials of 31,022 people shows (pp. 40–9): “Participants who were randomly assigned to receive vitamin D, as compared with those assigned to control groups, had a nonsignificant 10% reduction in the risk of hip fracture (hazard ratio, 0.90; 95% confidence interval [CI], 0.80 to 1.01) and a 7% reduction in the risk of nonvertebral fracture (hazard ratio, 0.93; 95% CI, 0.87 to 0.99). By quartiles of actual intake, reduction in the risk of fracture was shown only at the highest intake level (median, 800 IU daily; range, 792 to 2000), with a 30% reduction in the risk of hip fracture (hazard ratio, 0.70; 95% CI, 0.58 to 0.86) and a 14% reduction in the risk of any nonvertebral fracture (hazard ratio, 0.86; 95% CI, 0.76 to 0.96).” (H. A. Bischoff–Ferrari)

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
July 6, 2012 * Vol. 19, No. 130
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
July issue of Pharmacotherapy (2012; 32).
Retracted Drug Studies: Practitioners should monitor retractions of drug therapy articles in the biomedical literature and adjust recommendations for patient management accordingly, according to authors who assessed problems with articles published since 2000 (pp. 586–95). Trends and factors associated with retracted publications in the drug therapy literature included the following: “A total of 742 retractions were identified from 2000–2011 in the general biomedical literature, and 102 drug studies met our inclusion criteria. Of these, 73 articles (72%) were retracted for a reason classified as scientific misconduct, whereas 29 articles (28%) were retracted for error. Among the 73 articles classified as scientific misconduct, those classified as unethical author conduct (32 articles [44%]) and data fabrication (24 articles [33%]) constituted the majority. The median time from publication of the original article to retraction was 31 months (range 1–130). Fifty percent of retracted articles did not state a funding source, whereas pharmaceutical manufacturer funding accounted for only 13 articles (13%) analyzed. Many retractions were due to repeat offenses by a small number of authors, with nearly 40% of the retracted studies associated with two individuals. We found that a greater proportion of drug therapy articles were retracted for reasons of misconduct and fraud compared with other biomedical studies.” (A. S. Pickard, pickard1@uic.edu)
Plerixafor in Autologous Stem Cell Mobilization: “Plerixafor plus filgrastim could be a viable first-line option in patients with multiple myeloma,” investigators in a 33-patient study conclude, adding that the drug “was comparable to second-line therapy in patients with non-Hodgkin’s lymphoma” (pp. 596–603). A retrospective medical record review for 2008–09 looked for use of plerixafor plus filgrastim as the initial peripheral blood stem cell (PBSC) mobilization (first-line strategy) and as rescue therapy after failure with filgrastim plus cyclophosphamide (second-line strategy), with these results: “Mobilization with plerixafor plus filgrastim resulted in a median yield of 8.95 × 106 and 2.45 × 106 CD34+ cells/kg in patients with multiple myeloma or non-Hodgkin’s lymphoma, respectively. As rescue mobilization, plerixafor plus filgrastim successfully mobilized CD34+ cells in 16 (84%) of 19 patients. When comparing first-line plerixafor plus filgrastim therapy with second-line therapy, we found an increase in CD34+ yield and 1 less apheresis day in patients with multiple myeloma, but no difference in patients with non-Hodgkin’s lymphoma.” (K. W. Lor, kloricacid@gmail.com)
Amiodarone Sensitivity in Iodine-Sensitive Patients: Among 234 hospitalized patients with allergies to iodine and/or iodinated radiocontrast agents, fewer than 1% had hypersensitivity reactions while taking amiodarone, researchers report (pp. 618–22). “Allergy to iodine and iodinated contrast agents may not be a valid absolute contraindication to amiodarone administration in the inpatient setting,” the authors conclude based on these retrospective data: “Mean ± SD age was 69 ± 12 years, and 51% were male. Of the 234 patients, 167 (71%) had a listed previous allergy to iodinated contrast agents, 55 (24%) to iodine, and 12 (5%) to both. Patients received an average inpatient total dose of 2.9 ± 3.2 g of either oral (106 patients [45%]), intravenous (39 patients [17%]), or both oral and intravenous (89 patients [38%]) amiodarone. Only 1 (0.4%) of the 234 patients was identified as having a probable allergic reaction to amiodarone (score of 6 on the Naranjo adverse drug reaction probability scale). One additional patient receiving intravenous amiodarone experienced a rash that was determined to be caused by an antibiotic. All other patients received amiodarone without any identifiable allergic reactions.” (J. E. Marine, jmarine2@jhmi.edu)

>>>PNN NewsWatch
* In a Federal Register notice yesterday, FDA instructed companies to stop manufacturing and distributing certain unapproved oxycodone products. The agency said its action affects companies that manufacture and distribute unapproved single-ingredient, immediate-release oxycodone drug products in oral dosage forms, including tablets, capsules, and oral solutions. FDA recommended that health professionals use Drugs@FDA or the NDC Directory to determine whether a drug product is approved.

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
July 9, 2012 * Vol. 19, No. 131
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Adverse Events with Intravitreal Bevacizumab, Ranibizumab: Intravitreal injections of vascular endothelial growth factor inhibitors was not associated with increased risks of several serious adverse events, researchers report, including ischemic stroke, acute myocardial infarction, congestive heart failure, and venous thromboembolism (e4203). In a population-based, nested case–control study, 91,378 older adults with retinal disease were identified. A comparison of those who had the above cardiovascular events and matched controls showed the following: “After adjustment for potential confounders, participants who had ischaemic stroke, acute myocardial infarction, congestive heart failure, or venous thromboembolism were not more likely than control participants to have been exposed to either bevacizumab (adjusted odds ratios of 0.95 (95% confidence interval 0.68 to 1.34) for ischaemic stroke, 1.04 (0.77 to 1.39) for acute myocardial infarction, 0.81 (0.49 to 1.34) for venous thromboembolism, and 1.21 (0.91 to 1.62) for congestive heart failure) or ranibizumab (adjusted odds ratios 0.87 (0.68 to 1.10) for ischaemic stroke, 0.90 (0.72 to 1.11) for acute myocardial infarction, 0.88 (0.67 to 1.16) for venous thromboembolism, and 0.87 (0.70 to 1.07) for congestive heart failure). Similarly, a secondary analysis of exclusive users of bevacizumab or ranibizumab showed no differences in risk between the two drugs (adjusted odds ratios for bevacizumab relative to ranibizumab of 1.03 (0.67 to 1.60) for ischaemic stroke, 1.23 (0.85 to 1.77) for acute myocardial infarction, 0.92 (0.51 to 1.69) for venous thromboembolism, and 1.35 (0.93 to 1.95) for congestive heart failure). These findings were consistent for all but one outcome in subgroup analyses.” (R. J. Campbell, rob.campbell@queensu.ca)

>>>Lancet Highlights
Source:
July 7 issue of Lancet (2012; 380).
Monoclonal Antibody for LDL Cholesterol: In patients with heterozygous familial hypercholesterolemia, addition of the monoclonal antibody REGN727 to high-dose statins with or without ezetimibe increased the reductions in LDL cholesterol levels, a Phase II study shows (pp. 29–36). The monoclonal antibody inhibits proprotein convertase subtilisin/kexin type 9 serine protease (PCSK9). At 16 lipid clinics in the U.S. and Canada, patients received REGN727 in doses of 150, 200, or 300 mg every 4 weeks, or 150 mg every 2 weeks, or placebo every 2 weeks, with these results: “Least-squares (LS) mean LDL-C reduction from baseline to week 12 was 28.9% (SE 5.08) for 150 mg every 4 weeks (p = 0.0113), 31.54% (4.91) for 200 mg every 4 weeks (p = 0.0035), 42.53% (5.09) for 300 mg every 4 weeks (p < 0.0001), and 67.90% (4.85) for 150 mg every 2 weeks (p < 0.0001), compared with 10.65% (5.04) with placebo. One serious adverse event was reported with placebo and none with REGN727. No increases of more than three times the upper limit of normal were reported for hepatic transaminases or creatinine kinase. The most common adverse event was injection-site reaction with one patient in the group of 300 mg REGN727 terminating treatment.” (E. A. Stein, steinmrl@aol.com)

>>>PNN NewsWatch
* FDA on Friday approved the first genetic test for determining if cetuximab (Erbitux; Bristol-Myers Squibb, Lilly) would be effective based on genetics of a patient’s colorectal cancer. The therascreen KRAS RGQ PCR Kit identifies presence of the KRAS gene mutation in patients with metastatic cases; cetuximab is not effective in those with the mutation.
*
Cancer therapies are beginning to focus more on specific genes rather than types of cancers, according to “Genetic Gamble,” a series of articles that began yesterday in the New York Times.

>>>PNN JournalWatch
* Screening, Brief Intervention, and Referral for Alcohol Use in Adolescents: A Systematic Review, in
Pediatrics, 2012; 130: 115–22. (P. J. Yuma-Guerrero)
* Use of an Integrated Therapy With Prolonged Exposure to Treat PTSD and Comorbid Alcohol Dependence in an Iraq Veteran, in
American Journal of Psychiatry, 2012; 169: 688–91. (S. E. Back, backs@musc.edu)
* Drug Testing in the Workplace, in
Pharmacotherapy, 2012; 32: 649–56. (H. M. Phan, hieu.phan@tu.edu)
* iPhones, iPads, and Medical Applications for Antimicrobial Stewardship, in
Pharmacotherapy, 2012; 32: 657–61. (D. A. Goff, ebbie.goff@osumc.edu">Debbie.goff@osumc.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
July 10, 2012 * Vol. 19, No. 132
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 9 issue of the Archives of Internal Medicine (2012; 172).
Cranberry Products for UTIs: While study results vary considerably, a systematic review and meta-analysis indicates that cranberry-containing products can help prevent urinary-tract infections in susceptible patients (pp. 988–96). Based on a review of available literature through Nov. 2011, investigators found: “Thirteen trials, including 1,616 subjects, were identified for qualitative synthesis from 414 potentially relevant references; 10 of these trials, including a total of 1,494 subjects, were further analyzed in quantitative synthesis. The random-effects pooled risk ratio (RR) for cranberry users vs nonusers was 0.62 (95% CI, 0.49–0.80), with a moderate degree of heterogeneity (I2 = 43%) after the exclusion of 1 outlier study. On subgroup analysis, cranberry-containing products seemed to be more effective in several subgroups, including women with recurrent UTIs (RR, 0.53; 95% CI, 0.33–0.83) (I2 = 0%), female populations (RR, 0.49; 95% CI, 0.34–0.73) (I2 = 34%), children (RR, 0.33; 95% CI, 0.16–0.69) (I2 = 0%), cranberry juice drinkers (RR, 0.47; 95% CI, 0.30–0.72) (I2 = 2%), and subjects using cranberry-containing products more than twice daily (RR, 0.58; 95% CI, 0.40–0.84) (I2 = 18%).” (C-C Lee, cclee100@gmail.com)
DMAA as Dietary Supplement: Despite paltry evidence of any natural origins, the amphetamine derivative 1,3-dimethylamylamine (DMAA) currently is widely available as a dietary supplement, an author writes in a Research Letter (pp. 1038–9). Originally introduced in 1948 as a treatment for rhinitis, DMAA has been banned by Health Canada and removed from exchanges by the U.S. military. FDA in April asked for evidence of safety from 10 DMAA manufacturers but has taken no other action, the writer notes, adding this warning: “Given its wide availability, physicians should understand DMAA’s potential health effects. Supplements containing DMAA have been implicated as potentially contributing agents in multiple serious adverse events, including panic attacks, seizures, stress-induced cardiomyopathy, and 2 deaths. In Europe and New Zealand, DMAA use as a party drug has been implicated in at least 1 hemorrhagic stroke. Causality has yet to be proven, but these adverse effects are consistent with DMAA’s known pharmacologic actions. In The Dispensatory of the United States of America 1950 Edition, DMAA’s systemic toxic effects in animals was described as ‘greater than that of ephedrine and less than that of amphetamine,’ and the authors counseled that if DMAA’s use as a nasal inhaler ‘produces side effects such as headache, nervousness, mental stimulation, or tremors, the drug should be discontinued.’ Small trials have also demonstrated that DMAA-containing supplements increase blood pressure and heart rate.” (P. A. Cohen, pcohen@challiance.org)
Editorialists write that this is another example of “the consequences of ineffective regulation of dietary supplements” (
pp. 1035–6): “The consequences of DSHEA for consumers include the expenditure of tens of billions of dollars annually on ineffective and potentially dangerous dietary supplements. Internists and other health care professionals have paid insufficient attention to problems that may affect the 18% of the population that uses nonvitamin, nonmineral supplements.” (D. M. Marcus, dmarcus@bcm.tmc.edu)

>>>PNN NewsWatch
* FDA yesterday approved a risk evaluation and mitigation strategy (REMS) for extended-release (ER) and long-acting (LA) opioids. FDA said the REMS introduces new safety measures designed to reduce risks and improve the safe use of ER/LA opioids while ensuring access to needed medications for patients in pain. The new ER/LA opioid REMS will affect more than 20 companies that manufacture these opioid analgesics. The companies will be required to make education programs available to prescribers based on an FDA Blueprint. It is expected that companies will meet this obligation by providing educational grants to continuing education providers, who will develop and deliver the training. The REMS also will require companies to make available FDA-approved patient education materials on the safe use of these drugs.
* Pres. Obama yesterday signed PDUFA, the
FDA reauthorization bill, which grants the agency the authority to begin charging user fees for generic drugs and biosimilars.

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
July 11, 2012 * Vol. 19, No. 133
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 11 issue of JAMA (2012; 308).
Adverse Event Risk with Pandemic Influenza Vaccine: Articles examine the risks associated with administration of the pandemic influenza A(H1N1) vaccine.
An AS03-adjuvanted influenza A(H1N1)pdm09 vaccine was not associated with adverse fetal outcomes when given during pregnancy in a cohort analysis of the Danish Medical Birth Register (
pp. 165–74): “From a cohort of 53,432 infants (6,989 [13.1%] exposed to the influenza A[H1N1]pdm09 vaccine during pregnancy [345 in the first trimester and 6,644 in the second or third trimester]), 660 (330 exposed) were included in propensity score–matched analyses of adverse fetal outcomes associated with first-trimester exposure. For analysis of small size for gestational age after second- or third-trimester exposure, 13,284 (6,642 exposed) were included; for analyses of preterm birth, 12,909 (6,543 exposed) were included. A major birth defect was diagnosed in 18 of 330 infants (5.5%) exposed to the vaccine in the first trimester, compared with 15 of 330 unexposed infants (4.5%) (POR, 1.21; 95% CI, 0.60–2.45). Preterm birth occurred in 31 of 330 infants (9.4%) exposed in the first trimester, compared with 24 of 330 unexposed infants (7.3%) (POR, 1.32; 95% CI, 0.76–2.31), and in 302 of 6,543 infants (4.6%) with second- or third-trimester exposure, compared with 295 of 6,366 unexposed infants (4.6%) (POR, 1.00; 95% CI, 0.84–1.17). Small size for gestational age was observed in 25 of 330 infants (7.6%) with first-trimester exposure compared with 31 of 330 unexposed infants (9.4%) (POR, 0.79; 95% CI, 0.46–1.37), and in 641 of 6,642 infants (9.7%) with second- or third-trimester exposure, compared with 657 of 6,642 unexposed infants (9.9%) (POR, 0.97; 95% CI, 0.87–1.09).” (B. Pasternak, bjp@ssi.dk)
“Pandemic influenza has increased the attention of scientists, the public, and policy makers to influenza vaccine and its use in pregnancy,” editorialists write (
pp. 184–5). “The hope is that such increased attention will translate into support for approaches to assessing the details of the altered immunology of pregnancy and of the pathophysiology of antenatal influenza infection, leading to effective prevention and treatment strategies for pregnant women and their infants.” (M. C. Steinhoff, m.steinhoff@gmail.com)
The risk of Guillain-Barré syndrome (GBS) increased slightly after administration of the 2009 pandemic influenza vaccine in Quebec, researchers report (
pp. 175–81). A population-based cohort study of all acute care hospitals and neurology clinics showed these patterns when linked to an immunization registry: “Over a 6-month period, 83 confirmed GBS cases were identified, including 71 Brighton level 1 through 3 cases. Twenty-five confirmed cases had been vaccinated against 2009 influenza A(H1N1) 8 or fewer weeks before disease onset, with most (19/25) vaccinated 4 or fewer weeks before onset. In the Poisson model, the age- and sex-adjusted relative risk was 1.80 (95% CI, 1.12–2.87) for all confirmed cases during the 8-week postvaccination period and was 2.75 (95% CI, 1.63–4.62) during the 4-week postvaccination period. Using the self-controlled case-series method, relative risk estimates during the 4-week postvaccination period were 3.02 (95% CI, 1.64–5.56) for all confirmed cases (n = 42) and 2.33 (95% CI, 1.19–4.57) for Brighton level 1 through 3 cases (n = 36). The number of GBS cases attributable to vaccination was approximately 2 per 1 million doses. There was no indication of an excess risk in persons younger than 50 years.” (P. De Wals, Philippe.De.Wals@ssss.gouv.qc.ca)
Chemotherapy in Resected Periampullary Adenocarcinoma: Multivariate analysis revealed a survival advantage among 428 patients receiving fluorouracil or gemcitabine following resection of periampullary adenocarcinoma (pp. 147–56): “In the observation group, the median survival was 35.2 months (95%% CI, 27.2–43.0 months) and was 43.1 (95%, CI, 34.0–56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66–1.11; chi square = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57–0.98; Wald chi square = 4.53, P = .03).” (J. P. Neoptolemos, j.p.neoptolemos@liverpool.ac.uk)

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
July 12, 2012 * Vol. 19, No. 134
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles and July 12 issue of the New England Journal of Medicine (2012; 367).
Antiretroviral Prophylaxis for HIV Prevention: Three articles released in advance of print examine ways antiretroviral drugs can be used to prevent viral transmission to HIV-negative individuals.
HIV-1–negative partners in discordant couples benefited from two drug regimens in a study conducted in Kenya and Uganda (
10.1056/NEJMoa1108524). Once-daily tenofovir (TDF), combination tenofovir–emtricitabine (TDF–FTC), or matching placebo produced these outcomes in 4,747 couples: “Among HIV-1–seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person–years), 13 in the TDF–FTC group (incidence, 0.50 per 100 person–years), and 52 in the placebo group (incidence, 1.99 per 100 person–years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P < 0.001) and of 75% with TDF–FTC (95% CI, 55 to 87; P < 0.001).” (J. M. Baeten, jbaeten@uw.edu)
TDF-FTC prophylaxis failed to significantly reduce the rate of HIV infection among 2,120 African women in a study where poor adherence could not be overcome even with “substantial counseling efforts” (
10.1056/NEJMoa1202614): “HIV infections occurred in 33 women in the TDF–FTC group (incidence rate, 4.7 per 100 person–years) and in 35 in the placebo group (incidence rate, 5.0 per 100 person–years), for an estimated hazard ratio in the TDF-FTC group of 0.94 (95% confidence interval, 0.59 to 1.52; P = 0.81). The proportions of women with nausea, vomiting, or elevated alanine aminotransferase levels were significantly higher in the TDF–FTC group (P = 0.04, P < 0.001, and P = 0.03, respectively). Rates of drug discontinuation because of hepatic or renal abnormalities were higher in the TDF–FTC group (4.7%) than in the placebo group (3.0%, P = 0.051). Less than 40% of the HIV-uninfected women in the TDF–FTC group had evidence of recent pill use at visits that were matched to the HIV-infection window for women with seroconversion.” (L. Van Damme, lvandamme@fhi360.org)
Among 1,219 sexually active men and women in Botswana, daily TDF-FTC prophylaxis significantly reduced HIV transmission but with declines on bone mineral density and minor adverse effects (
10.1056/NEJMoa1110711). During 1,563 person–years of therapy, investigators found: “The TDF–FTC group had higher rates of nausea (18.5% vs. 7.1%, P < 0.001), vomiting (11.3% vs. 7.1%, P = 0.008), and dizziness (15.1% vs. 11.0%, P = 0.03) than the placebo group, but the rates of serious adverse events were similar (P = 0.90). Participants who received TDF–FTC, as compared with those who received placebo, had a significant decline in bone mineral density. K65R, M184V, and A62V resistance mutations developed in 1 participant in the TDF–FTC group who had had an unrecognized acute HIV infection at enrollment.” (M. C. Thigpen, mthigpen@cdc.gov)
MEK Inhibition in BRAF-Mutated Melanoma: In a Phase III, open-label trial of trametinib in patients who had metastatic melanoma with a BRAF V600E or V600K mutation, the oral MEK inhibitor improved rates of progression-free and overall survival, researchers report (pp. 107–14). Responses of 322 patients to trametinib 2 mg orally once daily, intravenous dacarbazine 1000 mg/sq m, or paclitaxel 175 mg/sq m every 3 weeks were as follows: “Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P < 0.001). At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P = 0.01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group and were managed with dose interruption and dose reduction; asymptomatic and reversible reduction in the cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin neoplasms were not observed.” (K. T. Flaherty, kflaherty@partners.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, 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
July 13, 2012 * Vol. 19, No. 135
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
July 17 issue of the Journal of the American College of Cardiology (2012; 60).
Ticagrelor v. Prasugrel in Acute Coronary Syndrome: In 44 patients with acute coronary syndrome (ACS) with high on-treatment platelet reactivity (HTPR) while taking clopidogrel, ticagrelor provided significantly higher platelet inhibition than did prasugrel, researchers report (pp. 193–9). The single-blind study included patients at 24 hours after percutaneous coronary intervention, with ticagrelor 90 mg twice daily or prasugrel 10 mg once daily for 15 days with crossover producing these results: “The primary endpoint of platelet reactivity at the end of the 2 treatment periods was lower for ticagrelor (32.9 platelet reactivity units [PRU], 95% confidence interval [CI]: 18.7 to 47.2) compared with prasugrel (101.3 PRU, 95% CI: 86.8 to 115.7) with a least squares mean difference of –68.3 PRU (95% CI: –88.6 to –48.1; p < 0.001). The secondary endpoint of HTPR rate was 0% for ticagrelor and 2.4% for prasugrel (1 of 42, p = 0.5). No patient exhibited a major bleeding event at either treatment group.” (D. Alexopoulos)
Beta-Blocker Dose in Heart Failure & Systolic Dysfunction: In the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial, titration of carvedilol-standardized beta-blocker (BB) doses up to 50 mg/d in ambulatory patients with heart failure (HF) with systolic dysfunction is supported by data showing an inverse relationship of BB dose and all-cause death or hospitalization (pp. 208–15). A total of 2,331 patients with New York Heart Association functional class II to IV, left ventricular ejection fraction <0.35, were randomized to exercise training or usual care for a median follow-up of 2.5 years. BB dose at baseline standardized as carvedilol equivalents showed these patterns with respect to all-cause mortality and hospitalization: “Ninety-five percent of patients were receiving a BB. There was a significant inverse relationship between BB dose and all-cause death or hospitalization but not other cardiovascular endpoints after adjustment for other predictors of outcome, with a linear benefit up to the 50-mg daily dose. There was a significant association between BB dose and change in peak VO2 at 3 months. There was no increase in bradycardia with higher doses of BB.” (M. Fiuzat)
Excessive Focus on Risk of Medications: The journal’s editor-in-chief writes that people have become too focused on “the adverse effects of drugs and devices” (pp. 233–4). Given the “outrageous medications and claims of benefits were quite prevalent in the distant past,” it is understandable that FDA is “more disposed to the sin of omission of not approving an effective modality than to the sin of commission of approving one with serious adverse effects,” the editor notes before reaching this conclusion: “Determination of the risk–benefit ratio of any medical intervention is complex at best, always challenging, and continues to be a frequently discussed in the literature. I believe that the professionals of the FDA who are charged with making these decisions are hard working and dedicated. Thank goodness that I do not have to make the judgments that are required of them. Not uncommonly they must reach verdicts in the absence of absolute certainty, and in the setting of external pressures. Society can help them in this regard by recognizing that safe does not mean without adverse events, but rather that the benefits outweigh the risks. While the occurence of significant adverse effects will almost certainly attract more attention than the absence of an effective therapy, the impact upon society of the latter may be much greater. We have to be willing to accept that a few may be injured so that many may be benefited.” (A. N. DeMaria)

>>>PNN NewsWatch
* The abuse-deterrent formulation of OxyContin has successfully reduced inappropriate use of this product but has also led patients to switch to other opioid agents, including heroin, according to a letter in yesterday’s New England Journal of Medicine (pp. 187–9). Among 2,566 patients with opioid dependence, 35.6% were using OxyContin before the release of the abuse-deterrent formulation, compared with 12.8% 21 months later. Instead, use of high-potency fentanyl and hydromorphone rose as the primary drug, from 20.1% to 32.3%, and heroin use as a “drug used to get high in the past 30-days” nearly doubled, the authors report. (T. J. Cicero, cicerot@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
July 16, 2012 * Vol. 19, No. 136
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 345).
Clopidogrel–PPI Interaction: Based on the “lack of a specific association and the discrepancy between findings of the analyses between and within people,” authors of an observational cohort study and self-controlled case series conclude that “the interaction between proton pump inhibitors and clopidogrel is clinically unimportant” (e4388). Linking of records of 24,471 patients in the U.K. General Practice Research Database with two other databases showed these patterns for a primary outcome of death or incident myocardial infarction: “Of the 24,471 patients prescribed clopidogrel and aspirin, 12,439 (50%) were also prescribed a proton pump inhibitor at some time during the study. Death or incident myocardial infarction occurred in 1,419 (11%) patients while they were receiving a proton pump inhibitor compared with 1,341 (8%) who were not receiving a proton pump inhibitor. In multivariate analysis, the hazard ratio for the association between proton pump inhibitor use and death or incident myocardial infarction was 1.37 (95% confidence interval 1.27 to 1.48). Comparable results were seen for secondary outcomes and with other 2C19 inhibitors and with non-2C19 inhibitors. With the self controlled case series design to remove the effect of differences between people, there was no association between proton pump inhibitor use and myocardial infarction, with a rate ratio of 0.75 (0.55 to 1.01). Similarly, with the self controlled case series there was no association with myocardial infarction for other 2C19 inhibitors/non-inhibitors.” (I. J. Douglas, ian.douglas@lshtm.ac.uk)
Spironolactone & Breast Cancer: A retrospective matched cohort study of 1.3 million women older than 55 years and without any history of breast cancer shows that long-term use of spironolactone does not increase their risk of developing this condition (e4447). Comparison of the exposed cohort with unexposed controls showed the following: “Index dates for study patients ranged from 1987 to 2010, and 29,491 new cases of breast cancer were recorded in the study population (incidence rate 0.35% per year). The exposed cohort of 28,032 patients and control cohort of 55,961 patients had unadjusted incidence rates of 0.39% and 0.38% per year, respectively, over a mean follow-up time of 4.1 years. Time-to-event analysis, adjusting for potential risk factors, provided no evidence of an increased incidence of breast cancer in patients exposed to spironolactone (hazard ratio 0.99, 95% confidence interval 0.87 to 1.12).” (I. S. Mackenzie, i.s.mackenzie@dundee.ac.uk)

>>>Lancet Highlights
Source:
July 14 issue of Lancet (2012; 380).
Maternal Deaths Averted by Contraceptive Use: Unwanted pregnancies and unmet contraceptive need remain high in developing countries, conclude researchers who argue for use of contraception as “a substantial and effective primary prevention strategy to reduce maternal mortality” (pp. 111–25). Data from three international databases were mined to construct two models, one that estimated maternal deaths averted by contraceptive use in 172 countries (model I) and another for estimating the effect of satisfying the unmet need for contraceptives (model II): “We estimate, using model I, that 342,203 women died of maternal causes in 2008, but that contraceptive use averted 272,040 (uncertainty interval 127 937–407,134) maternal deaths (44% reduction), so without contraceptive use, the number of maternal deaths would have been 1·8 times higher than the 2008 total. Satisfying unmet need for contraception could prevent another 104,000 maternal deaths per year (29% reduction).” (S. Ahmed, sahmed@jhsph.edu)

>>>PNN JournalWatch
* Recent Advances in Hypersensitivity Pneumonitis, in
Chest, 2012; 142:208–17. (Y. Lacasse, Yves.Lacasse@med.ulaval.ca)
* Nonatherosclerotic Arterial Disorders of the Lower Extremities, in
Circulation, 2012; 126: 213–22. (M. R. Jaff, mjaff@partners.org)
* Hepatitis C Treatment Highlights From the 2011 American Association for the Study of Liver Disease Meeting, in
Clinical Infectious Diseases, 2012; 55: 418–25. (C. L. Cooper, ccooper@ottawahospital.on.ca)
* Acute Hospital Use, Nursing Home Placement, and Mortality in a Frail Community-Dwelling Cohort Managed With Primary Integrated Interdisciplinary Elder Care at Home, in
Journal of the American Geriatrics Society, 2012; 60: 1340–6. (T. Rosenberg, trosenberg@gem-health.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
July 17, 2012 * Vol. 19, No. 137
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 17 issue of the Annals of Internal Medicine (2012; 157).
Escitalopram for Prevention of Peginterferon–Associated Depression: In 181 patients with hepatitis C virus (HCV) infection and no prior psychiatric history, escitalopram provided effective prophylaxis against pegylated interferon-alfa (IFN-alfa)–associated depression, a study shows (pp. 94–103). At 21 German hospitals, patients were enrolled in 2004–08 and given escitalopram 10 mg/d or placebo beginning 2 weeks before IFN-alfa therapy and continuing for 24–48 months, with these results: “32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a [Montgomery–Asberg Depression Rating Scale (MADRS)] score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21).” (M. Schaefer, m.schaefer@kliniken-essen-mitte.de)
Menopausal Hormone Therapy for Primary Prevention: A systematic review being published 10 years after the landmark Women’s Health Initiative (WHI) findings changed the treatment landscape finds a variety of risks increased or decreased by estrogen alone or estrogen plus progestin in menopause (pp. 104–13): “9 fair-quality trials met the inclusion criteria. The Women’s Health Initiative reported most of the results, had 11 years of follow-up, and had data most applicable to postmenopausal women in the United States. It showed that estrogen plus progestin therapy reduced fractures (46 fewer per 10,000 woman–years) and increased invasive breast cancer (8 more per 10,000 woman–years), stroke (9 more per 10,000 woman–years), deep venous thrombosis (12 more per 10,000 woman–years), pulmonary embolism (9 more per 10,000 woman–years), lung cancer death (5 more per 10,000 woman–years), gallbladder disease (20 more per 10,000 woman–years), dementia (22 more per 10,000 woman–years), and urinary incontinence (872 more per 10,000 woman–years). Estrogen-only therapy reduced fractures (56 fewer per 10,000 woman–years), invasive breast cancer (8 fewer per 10,000 woman–years), and death (2 fewer per 10,000 woman–years) and increased stroke (11 more per 10,000 woman–years), deep venous thrombosis (7 more per 10,000 woman–years), gallbladder disease (33 more per 10,000 woman–years), and urinary incontinence (1271 more per 10,000 woman–years). Outcomes did not consistently differ by age or comorbid conditions.” (H. D. Nelson, nelsonh@ohsu.edu)
Learning About the Science of Patient Safety & Quality: Authors of a commentary article discuss “the minimal investment in the science of patient safety and quality improvement and [argue] that more patient safety researchers are needed to rigorously design, implement, evaluate, and spread interventions to reduce preventable harm” (pp. 141–3). The article, citing the “many patients [who] still suffer preventable errors and harms and fail to receive recommended therapies,” calls for restoration of government funding for training of researchers and research projects directed at a safer health care system. (P. J. Pronovost, ppronovo@jhmi.edu)

>>>PNN NewsWatch
* FDA yesterday approved a fixed-dose combination of emtricitabine/tenofovir disoproxil fumarate (Truvada, Gilead), the first drug product approved to reduce the risk of HIV infection in uninfected individuals who are at high risk of HIV infection and who may engage in sexual activity with HIV-infected partners. The product must be taken daily for pre-exposure prophylaxis in combination with safer sex practices to reduce the risk of sexually acquired HIV infection in adults at high risk. In addition to use with safe-sex practices in HIV-discordant couples, Truvada could reduce the need for assisted reproductive technologies in HIV-discordant heterosexual couples who are trying to have a baby when the woman is the HIV-negative partner, NPR reports.

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
July 18, 2012 * Vol. 19, No. 138
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 18 issue of JAMA (2012; 308).
Interferon Beta in Relapsing-Remitting MS: Interferon beta did not reduce disability progression among British Columbians with relapsing-remitting multiple sclerosis in a retrospective cohort study (pp. 247–56). For the 1985–2008 period, 868 patients treated with interferon beta were compared with 829 untreated contemporary patients and 959 historical cohorts, with these effects on the Expanded Disability Status Scale (EDSS) and other measures: “The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta–treated cohort, 5.1 years (interquartile range [IQR], 3.0–7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1–6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3–14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92–1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58–1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results.” (H. Tremlett, helen.tremlett@ubc.ca)
Despite its reliance on large data sets, this study may have been underpowered, editorialists note before reaching this conclusion (
pp. 290–1): “It is likely that neurologists will continue to prescribe interferon beta and other interferons and patients with relapsing-remitting MS will continue to self-inject these agents, relying on the available evidence from controlled studies about short-term benefits, especially from studies that have included patients in the early phase of the disease. However, the rigorously collected data of Shirani and colleagues reinforce the conclusion that the associations between use of interferons and long-term disability, although plausible, remain unproven. As Shirani and colleagues suggest, more effective treatment options and better criteria that lead to more accurate selection of patients who might best respond to these treatments are needed. The relatively low progression rate in the untreated contemporary cohort is reassuring because it indicates that despite the unreliable explicit prognostic criteria, neurologists and patients in British Columbia seem to have made the right choices.” (L. Kappos, lkappos@uhbs.ch)
Milk Thistle & Liver Disease in Hepatitis C: In 154 patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy, high doses of the milk-thistle extract silymarin did not significantly reduce ALT levels, researchers report (pp. 274–82). At 14 U.S. medical centers, participants randomly received silymarin 420 or matching placebo three times per day for 24 weeks. Serum ALT levels and secondary outcome measures showed these patterns: “Only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo.” (M. W. Fried, mfried@med.unc.edu)

>>>PNN NewsWatch
* Qsymia (Vivus), a combination of phentermine and extended-release topiramate, was approved late yesterday by FDA for weight loss as an addition to reduced-calorie diet and exercise in adults with obesity or adults with overweight and at least one related condition.

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
July 19, 2012 * Vol. 19, No. 139
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online content and July 19 issue of the New England Journal of Medicine (2012; 367).
Oral Immunotherapy for Pediatric Egg Allergy: In a double-blind study of 55 children with egg allergy, desensitization and sustained unresponsiveness was achieved with oral immunotherapy (pp. 233–43). Placebo was given to 15 children, while 40 children received oral immunotherapy for 22 months. Egg-white powder and other challenges showed these patterns: “After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months.” (A. W. Burks, wburks@email.unc.edu)
Inhibition of HIV-1 Progression by HIV-2 Infection: In a study with implications for vaccine and therapy development, researchers find that concomitant HIV-2 infection inhibits the progression of HIV-1 infections (pp. 224–32). This effect in 223 participants was especially marked in those whose HIV-2 infection occurred first: “The median time to AIDS was 104 months (95% confidence interval [CI], 75 to 133) in participants with dual infection and 68 months (95% CI, 60 to 76) in participants infected with HIV-1 only (P = 0.003). CD4+ T-cell levels were higher and CD8+ T-cell levels increased at a lower rate among participants with dual infection, reflecting slower disease progression. Participants with dual infection with HIV-2 infection preceding HIV-1 infection had the longest time to AIDS and highest levels of CD4+ T-cell counts. HIV-1 genetic diversity was significantly lower in participants with dual infections than in those with HIV-1 infection alone at similar time points after infection.” (J. Esbjörnsson, joakim.esbjornsson@med.lu.se)
Roadmap to an AIDS-Free Generation: With a theme of “Turning the Tide Together,” the 19th International AIDS Conference convenes this weekend in Washington, DC, “at a moment of extraordinary optimism in the response to the human immunodeficiency virus,” write authors of a Perspective article before outlining a plan to eliminate the virus for future generations (10.1056/NEJMp1207138). “The core elements of a strategy are arguably now in hand: first, the strategic use of existing resources, including resources for accelerated research on prevention, HIV vaccines, and a cure; second, marked increases in HIV testing, counseling, and linkages to and retention in services and care; third, the eradication of mother-to-child transmission of HIV and preservation of maternal health, a goal very much within the realm of possibility with existing knowledge; and finally, expanded access to prevention services and antiretroviral treatment to reach everyone in need—which will require an end to the stigma, discrimination, legal sanctions, and human rights abuses against people at risk for or living with HIV infection. Markedly expanding high-quality treatment programs, taking new prevention tools to scale, and maximizing the potential of antiretroviral therapies for prevention will be difficult and costly, but failure to capitalize on the scientific advances of this critical period could be devastating. A future of ongoing transmission of HIV, ever-increasing numbers of people receiving or needing therapy, and further strains on overburdened health systems will not be sustainable.” (D. Havlir)
200-Year History of Drug-Risk Assessment: As part of the journal’s celebration of its bicentennial, an author reviews 200 years of progress in the “systematic approach for determining which treatments could be effective with an acceptable level of risk and which were merely toxic” (pp. 193–7): “Greater access to data and the application of modern information technology and sophisticated epidemiologic approaches are finally providing a valuable and potentially lifesaving way to balance the good that medications can do against the harm that they sometimes cause.” (J. Avorn)

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
July 20, 2012 * Vol. 19, No. 140
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
July issue of the Journal of Allergy and Clinical Immunology (2012; 130).
Whipworm “Therapy” for Allergy: The pig whipworm offers a potential therapy for immune-mediated diseases for which no therapies are currently available, according to authors of a review (pp. 3–10). The proposal is based on “the hygiene hypothesis,” which addresses low levels of immune disorders in areas where helminths are common. It proposes that the “recent increase in allergic and autoimmune diseases is due to increasing hygiene standards,” the authors write. “Numerous epidemiologic and animal studies have provided support for this hypothesis and showed that certain microorganisms, helminths in particular, have immunomodulatory effects. More recently, studies have led to the identification of some of the mechanisms underlying these immunomodulatory effects. Substances, or crude extracts, produced by worms and responsible for these effects have been analyzed. Clinical trials have been performed mainly with pig whipworm, which was chosen because it is likely to be nonpathogenic in human subjects. Eggs of the pig whipworm (Trichuris suis ova) have been shown to be safe in multiple studies. Efficacy has been demonstrated in patients with inflammatory bowel diseases and in 1 case of pecan allergy. Altogether, this information supports further investigation of T suis ova in patients with immune-mediated diseases, particularly in areas in which there is currently no therapy, such as food allergy.” (M-H Jouvin, mjouvin@bidmc.harvard.edu)
Implications of Molecular Mimicry on Hygiene Hypothesis: In a study designed to test a major glutathione-S transferase (GST) allergen of cockroach (Bla g 5) for cross-reactivity with the GST of the lymphatic filarial pathogen Wuchereria bancrofti (WbGST), investigators compare immunoglobulin levels in infected and uninfected patients and confirm that the molecular mimicry produces allergic cross-sensitization in mice (pp. 248–56.e9): “These 2 proteins are 30% identical at the amino acid level with remarkable similarity in the N-terminal region and overall structural conservation based on predicted 3-dimensional models. Filarial infection was associated with IgE, IgG, and IgG4 anti–Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST (P < .0003). Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%–70%) anti–Bla g 5 IgE, IgG, and IgG4 antibodies. IgE epitope mapping of Bla g 5 revealed that 2 linear N-terminal epitopes are highly conserved in WbGST corresponding to Bla g 5 peptides partially involved in the inhibition of WbGST binding. Finally, mice infected with Heligmosomoides bakeri developed anti-HbGST IgE and showed immediate-type skin test reactivity to Bla g 5.” (H. C. Santiago, helton.santiago@nih.gov)
After explaining that Bla g 5 also produces cross-reactivity to a GST of the house dust mite, an editorialist concludes (
pp. 257–8): “The induction of cross-reactive IgE antibodies to aeroallergens by parasitic infections in the study by Santiago et al suggests that the immune responses to parasites can induce allergic disease. Other examples in which components common to aeroallergens (chitin, glycans, and proteins) can mimic parasite exposure and induce Th2 responses have also appeared. Continued research on the innate and adaptive immune responses will help solve the fascinating puzzle of parasite-allergen relationships.” (R. K. Bush, rkb@medicine.wisc.edu)
Vitamin D with Steroids in Pediatric Asthma: Bone health could be improved through vitamin D supplementation in boys with asthma poorly controlled by oral corticosteroids OCS), a study shows (pp. 53–60.e4). Over a mean of 4.3 years, investigators found these effects of vitamin D on bone mineral accretion (BMA) in 780 participants: “In boys baseline vitamin D levels significantly modified the relationship between OCSs and BMA (vitamin D × OCS interaction, P = .023). Stratification by vitamin D levels showed a decrease in BMA with increased use of OCSs in vitamin D–insufficient boys only (P < .001). Compared with vitamin D–sufficient boys, vitamin D–insufficient boys exposed to more than 2 courses of OCSs per year had twice the decrease in BMA rate (relative to boys who were OCS unexposed).” (S. M. Tse, reszt@channing.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, 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
July 23, 2012 * Vol. 19, No. 141
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 21 issue of Lancet (2012; 380).
Morbidity, Mortality Burdens of Physical Inactivity: Some 5.3 million annual deaths could be averted worldwide if physical inactivity could be eliminated, according to an analysis of major noncommunicable diseases such as coronary heart disease, type 2 diabetes, and breast and colon cancers (pp. 219–29). Estimates of population attributable fractions (PAFs) associated with physical inactivity show these relationships with disease burden and life expectancy: “Worldwide, we estimate that physical inactivity causes 6% (ranging from 3.2% in southeast Asia to 7.8% in the eastern Mediterranean region) of the burden of disease from coronary heart disease, 7% (3.9–9.6) of type 2 diabetes, 10% (5.6–14.1) of breast cancer, and 10% (5.7–13.8) of colon cancer. Inactivity causes 9% (range 5.1–12.5) of premature mortality, or more than 5.3 million of the 57 million deaths that occurred worldwide in 2008. If inactivity were not eliminated, but decreased instead by 10% or 25%, more than 533,000 and more than 1.3 million deaths, respectively, could be averted every year. We estimated that elimination of physical inactivity would increase the life expectancy of the world’s population by 0.68 (range 0.41–0.95) years.” (I-M Lee, ilee@rics.bwh.harvard.edu)
Duration of Antiarrhythmic Drug Therapy in Atrial Fibrillation: In patients with persistent atrial fibrillation who have been cardioverted, short-term antiarrhythmic therapy is less effective than long-term treatment but can prevent most recurrences, Flec-SL researchers report (pp. 238–46). At 44 German centers, patients received placebo or flecainide 200–300 mg/d for 4 weeks and then that dose of flecainide for 6 months, with this impact on a primary outcome of persistent atrial fibrillation or death: “After assay sensitivity was established with 4-week follow-up data from 242 patients showing that flecainide was superior to no treatment (Kaplan–Meier survival 70.2% vs 52.5%; p = 0.0160), the trial continued to compare short-term versus long-term treatment. The primary outcome occurred in 120 (46%) of 261 patients receiving short-term treatment and in 103 (39%) of 263 patients receiving long-term treatment (event-free survival 48.4% [95% CI 41.9–55.0] vs 56.4% [49.1–63.6]; Kaplan–Meier estimate of difference 7.9% [–1.9 to 17.7]; p = 0.2081 for non-inferiority; margin prespecified at 12%). In a post-hoc landmark analysis of patients who had not reached the primary endpoint in the first month, long-term treatment was superior to short-term treatment (Kaplan–Meier estimate of difference 14.3% [5.1–23.6]; hazard ratio 0.31 [0.18–0.56]; p = 0.0001).” (P. Kirchhof, p.kirchhof@bham.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Cardiovascular Safety of CNS Stimulants in Pediatrics: The short-term risk of severe cardiac events is not increased in children and young people who are taking central nervous system stimulants, according to a population-based retrospective cohort study (e4627). Based on a composite endpoint of stroke, acute myocardial infarction, or sudden cardiac death, the investigators found: “A total of 66 (95 including ventricular arrhythmia) events occurred during 2,321,311 years of follow-up. The odds ratio adjusted for propensity score and antipsychotic use for current versus no stimulant use was 0.62 (95% confidence interval 0.27 to 1.44), with a corresponding adjusted incidence rate of 2.2 and 3.5 per 100,000 patient years for current stimulant and non-use, respectively. Twenty six events occurred in high risk patients (incidence rate 63 per 100,000 patient years) with an odds ratio of 1.02 (0.28 to 3.69). Odds ratios for the secondary endpoint were similar to those for the primary endpoint (0.74, 0.38 to 1.46).” (A. G. Winterstein, almut@cop.ufl.edu)

>>>PNN JournalWatch
* Update in Rheumatology: Evidence Published in 2011, in
Annals of Internal Medicine, 2012; 157: 114–9. (A. R. Bass, bassa@hss.edu)
* Effects of Acetylcholine in the Striatum: Recent Insights and Therapeutic Implications, in
Neurology, 2012; 79: 274–81. (E. E. Benarroch, benarroch.eduardo@mayo.edu)
* MicroRNAs in Pathogenesis, Diagnosis, and Treatment of Gastroesophageal Cancers, in
Gastroenterology, 2012; 143: 35–47.e2. (J. H. Song, jsong37@jhmi.edu)
* Long-term Management of CKD–Mineral and Bone Disorder, in
American Journal of Kidney Diseases, 2012; 60: 308–15. (K. J. Martin, martinkj@slu.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
July 24, 2012 * Vol. 19, No. 142
Providing news and information about medications and their proper use

>>>Internal Medicine I
Source:
Early-release article from the Annals of Internal Medicine (2012; 157).
Preexposure HIV Prophylaxis: Released in conjunction with the XIX International AIDS Conference being held this week in Washington, DC, a review provides primary care providers with what they “need to know about preexposure prophylaxis for HIV prevention” (early release): “On 16 July 2012, the FDA recommended that [oral tenofovir–emtricitabine] be approved for use as [preexposure prophylaxis (PrEP)] in high-risk persons without HIV. Patients may seek PrEP from their primary care providers, and those receiving PrEP require monitoring. Thus, primary care providers should become familiar with PrEP. This review outlines current knowledge about PrEP as it pertains to primary care, including identifying persons likely to benefit from PrEP; counseling to maximize adherence and reduce potential increases in risky behavior; and monitoring for potential drug toxicities, HIV acquisition, and antiretroviral drug resistance. Issues related to cost and insurance coverage are also discussed. Recent data suggest that PrEP, combined with other prevention strategies, holds promise in helping to curtail the HIV epidemic.” (K. H. Mayer, kmayer@fenwayhealth.org)

>>>Internal Medicine II
Source:
July 23 issue of the Archives of Internal Medicine (2012; 172).
Hospital-Based Medication Reconciliation: For reducing adverse drug events and improving clinical outcomes, medication reconciliation interventions that heavily use pharmacist staff and focus on high-risk patients have outperformed other options, according to a systematic review (pp. 1057–69): “Fifteen of 26 studies reported pharmacist-related interventions, 6 evaluated [information technology] interventions, and 5 studied other interventions. Six studies were classified as good quality. The comparison group for all the studies was usual care; no studies compared different types of interventions. Studies consistently demonstrated a reduction in medication discrepancies (17 of 17 studies), potential adverse drug events (5 of 6 studies), and adverse drug events (2 of 2 studies) but showed an inconsistent reduction in postdischarge health care utilization (improvement in 2 of 8 studies). Key aspects of successful interventions included intensive pharmacy staff involvement and targeting the intervention to a high-risk patient population.” (J. L. Schnipper, jschnipper@partners.org)

>>>PNN NewsWatch
* FDA on Friday approved the proteasome inhibitor carfilzomib (Kyprolis for Injection, Onyx) for treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of completion of the last therapy. The accelerated approval was based on results of a single-arm, multicenter clinical trial of 266 patients with multiple myeloma who had received a median of five prior regimens. Overall response was 22.9% and median response duration was 7.8 months. During the study, 37 (7%) of patients died. Causes other than disease progression included cardiac (5), end-organ failure (4), and infection (4). Adverse effects of carfilzomib occurring in more than 30% of study participants were fatigue, low blood cell count and blood platelet levels, shortness of breath, diarrhea, and fever.
*
Aclidinium bromide inhalation powder (Tudorza Pressair, Forest) was approved yesterday by FDA for long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. The long-acting anticholinergic agent is inhaled twice daily and acts on muscarinic receptors. In three pivotal trials, aclidinium bromide improved bronchodilation, as measured by change from baseline in morning predose trough FEV1 at 12 weeks compared with placebo. The most common adverse reactions with the drug were headache (6.6% vs 5.0% with placebo), nasopharyngitis (5.5% vs 3.9%), and cough (3.0% vs 2.2%). Serious adverse effects included paradoxical bronchospasm, acute narrow-angle glaucoma, and new or worsened urinary retention. Aclidinium should not be used as a rescue therapy to treat acute bronchospasm and is not recommended for people younger than 18 years.

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
July 25, 2012 * Vol. 19, No. 143
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 25 issue of JAMA, an HIV theme issue (2012; 308).
Hydroxychloroquine in Untreated HIV-Infected Patients: In 83 patients with asymptomatic HIV infections not currently treated with antiretroviral therapy, 48 weeks of hydroxychloroquine produced a significant decline in CD4 cell count and increased viral replication, compared with placebo, researchers report (pp. 353–61). Hydroxychloroquine, used for treatment of T-cell–mediated immune diseases for its immunomodulatory and anti-inflammatory effects, did not reduce CD8 cell activation in this study: “There was no significant difference in CD8 cell activation between the 2 groups (−4.8% and −4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, −0.6%; 95% CI, −4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (−85 cells/µL vs −23 cells/µL at week 48; difference, −62 cells/µL; 95% CI, −115 to −8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03).” (N. I. Paton, nick.paton@ctu.mrc.ac.uk)
“Although the findings from this trial did not verify the concept that reducing immune activation could slow progression of HIV disease, the results do not exclude the possibility that hydroxychloroquine or other immunomodulators could reduce immune activation and inflammation in virologically suppressed patients receiving ART,” editorialists note (
pp. 405–6; J. H. Stein, jhs@medicine.wisc.edu).
Liver Disease, Antiviral Therapy, & Liver-Related Events in HIV/HCV: In a prospective cohort of 638 adults coinfected with HIV and hepatitis C virus (HCV), baseline hepatic fibrosis stage was independently associated with a composite outcome of end-stage liver disease (ESLD), hepatocellular carcinoma (HCC), or death (pp. 370–8). From an initial liver biopsy taken in 1993–2011, these patterns were observed during a median of 4.82 years of follow-up: “Patients experienced a graded increased risk in incidence of clinical outcomes based on baseline hepatic fibrosis stage…. Compared with F0, the incidence rate ratio (RR) for F2 was 2.31 (95% CI, 1.23–4.34; P = .009); F3, 3.18 (95% CI, 1.47–6.88; P = .003); and F4, 3.57 (95% CI, 2.06–6.19; P < .001). Human immunodeficiency virus treatment was associated with fewer clinical events (incidence RR, 0.27; 95% CI, 0.19–0.38; P < .001). For the 226 patients who underwent HCV treatment, the incidence of clinical events did not significantly differ between treatment nonresponders and untreated patients (incidence RR, 1.27; 95% CI, 0.86–1.86; P = .23). In contrast, no events were observed in the 51 patients with sustained virologic response (n = 36) and relapse (n = 15), including 19 with significant fibrosis.” (M. S. Sulkowski, msulkowski@jhmi.edu)
Eliminating AIDS: “The availability of combination antiretroviral therapy for prevention as well as treatment, advances in preexposure prophylaxis with oral or mucosally delivered antiretroviral medications to reduce an individual’s risk of acquiring HIV infection, together with scaling up medical male circumcision, services for pregnant HIV-infected women, condom provision, and other proven prevention tools suggest that controlling and ultimately ending the global HIV/AIDS pandemic is possible,” editorialists write in hoping that “an AIDS-free generation is indeed within reach” (pp. 343–4). “Achieving this goal, however, will require implementing a multifaceted global effort to expand testing, treatment, and prevention programs, as well as meet the scientific challenges of developing an HIV vaccine and possibly a cure.” A. S. Fauci, afauci@niaid.nih.gov)

>>>PNN NewsWatch
* Kathleen A. Johnson, PharmD, MPH, PhD, Vice Dean for Clinical Affairs and Outcomes Sciences at the U. Southern Calif. School of Pharmacy, died yesterday in France. A strong proponent for expansion of community clinical pharmacy services throughout her career, she was also the William A. Heeres and Josephine A. Heeres Professor in Community Pharmacy.

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
July 26, 2012 * Vol. 19, No. 144
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 26 New England Journal of Medicine (2012; 367).
Fish Oils & Cardiovascular Events in Diabetes: Among 12,536 patients with diabetes or prediabetes, daily n-3 fatty acid supplements had no effect on cardiovascular events, ORIGIN authors report (pp. 309–18). In a 2 X 2 factorial design, high-risk patients with diabetes, impaired fasting glucose, or impaired glucose tolerance received placebo or n-3 fatty acids 1 g (at least 90% ethyl esters), with these results: “During a median follow up of 6.2 years, the incidence of the primary outcome was not significantly decreased among patients receiving n–3 fatty acids, as compared with those receiving placebo (574 patients [9.1%] vs. 581 patients [9.3%]; hazard ratio, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P = 0.72). The use of n–3 fatty acids also had no significant effect on the rates of major vascular events (1,034 patients [16.5%] vs. 1,017 patients [16.3%]; hazard ratio, 1.01; 95% CI, 0.93 to 1.10; P = 0.81), death from any cause (951 [15.1%] vs. 964 [15.4%]; hazard ratio, 0.98; 95% CI, 0.89 to 1.07; P = 0.63), or death from arrhythmia (288 [4.6%] vs. 259 [4.1%]; hazard ratio, 1.10; 95% CI, 0.93 to 1.30; P = 0.26). Triglyceride levels were reduced by 14.5 mg per deciliter (0.16 mmol per liter) more among patients receiving n–3 fatty acids than among those receiving placebo (P < 0.001), without a significant effect on other lipids. Adverse effects were similar in the two groups.” (ORIGIN Project Office, rigin@phri.ca">origin@phri.ca)
Basal Insulin & Cardiovascular Events in Diabetes: In a second ORIGIN report, use of insulin glargine for normalizing fasting glucose levels in 12,537 patients with diabetes or prediabetes had a neutral effect on coprimary outcomes of nonfatal myocardial infarction or stroke, or cardiovascular death and those events plus revascularization or hospitalization for heart failure (pp. 319–28). Testing the hypothesis that correction of elevated fasting glucose levels could reduce their impact as an independent risk factor for cardiovascular events, the investigators used a 2 X 2 factorial design to provide insulin glargine (≤95 mg/dL target glucose level) or standard care and n–3 fatty acids or placebo: “The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person–years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P = 0.63) and 5.52 and 5.28 per 100 person–years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P = 0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1,456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P = 0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person–years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P = 0.97).” (ORIGIN Project Office, rigin@phri.ca">origin@phri.ca)
Sirolimus & Skin Cancer in Renal Transplantation: Among 120 patients with renal grafts and previous squamous-cell carcinoma, switching from calcineurin inhibitors to sirolimus provided an antitumor effect, researchers report (pp. 329–39). Patients were randomly assigned to maintain calcineurin inhibitors or change to sirolimus, with these effects on a primary end point of survival free of squamous-cell carcinoma at 2 years: “Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P = 0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups.” (S. Euvrard, sylvie.euvrard@numericable.fr)

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
July 27, 2012 * Vol. 19, No. 145
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Early-release and Aug. articles in Diabetes Care (2012; 35).
Curcumin as Diabetes Preventive: Curcumin, the principal curcuminoid in tumeric, significantly lowered the number of prediabetic patients who progressed to type 2 diabetes (T2DM), compared with placebo, in a 9-month trial (10.2337/dc12-0116). In 240 patients with prediabetes, curcumin or placebo produced these changes in beta-cell function (homeostasis model assessment [HOMA]-beta, C-peptide, and proinsulin/insulin), insulin resistance (HOMA-IR), anti-inflammatory cytokine (adiponectin), and other parameters: “After 9 months of treatment, 16.4% of subjects in the placebo group were diagnosed with T2DM, whereas none were diagnosed with T2DM in the curcumin-treated group. In addition, the curcumin-treated group showed a better overall function of beta-cells, with higher HOMA-beta (61.58 vs. 48.72; P < 0.01) and lower C-peptide (1.7 vs. 2.17; P < 0.05). The curcumin-treated group showed a lower level of HOMA-IR (3.22 vs. 4.04; P < 0.001) and higher adiponectin (22.46 vs. 18.45; P < 0.05) when compared with the placebo group.” (S. Chuengsamarn, somlukc@hotmail.com)
Gevokizumab in Type 2 Diabetes: A novel interleukin (IL)-1-beta–neutralizing antibody, gevokizumab improved glycemia and reduced inflammation in a dose-ranging study of 98 patients with type 2 diabetes, researchers report (pp. 1654–62). Results indicate that the agent may be able to be dosed on a once monthly or less frequent schedule: “The study drug was well tolerated with no serious adverse events. There was one hypoglycemic event whereupon concomitant insulin treatment had to be reduced. Clearance of gevokizumab was consistent with that for a human IgG2, with a half-life of 22 days. In the combined intermediate-dose group (single doses of 0.03 and 0.1 mg/kg), the mean placebo-corrected decrease in glycated hemoglobin was 0.11, 0.44, and 0.85% after 1, 2 (P = 0.017), and 3 (P = 0.049) months, respectively, along with enhanced C-peptide secretion, increased insulin sensitivity, and a reduction in C-reactive protein and spontaneous and inducible cytokines.” (M. Y. Donath, mdonath@uhbs.ch)
Vitamin D Levels & Diabetes: Low serum concentrations of vitamin D may be related to glycemic deterioration over the long term, a study shows, but they are not associated with development of incident diabetes after correction for confounders (pp. 1695–700). In the Inter99 study, a sample of the Copenhagen general population was analyzed, including 6,405 adults aged 30–65 years at baseline and 4,296 who were examined again 5 years later: “The risk of incident diabetes associated with a 10 nmol/L increase in 25(OH)D was odds ratio (OR) 0.91 (95% CI 0.84–0.97) in crude analyses. The association became statistically nonsignificant after adjustment for confounders, with an OR per 10 nmol/L of 0.94 (0.86–1.03). Low 25(OH)D status was significantly associated with unfavorable longitudinal changes in continuous markers of glucose homeostasis after adjustment for confounders. Fasting and 2-h glucose and insulin as well as the degree of insulin resistance increased significantly more during follow-up among those with low 25(OH)D levels compared with those with higher levels.” (L. L. N. Husemoen, lloh@glo.regionh.dk)
Health Utility Scores in Type 2 Diabetes: Decreases in health-related quality of life with type 2 diabetes complications are quantified by TRIAD investigators (10.2337/dc11-2478). Among 7,327 individuals with type 2 diabetes, the EuroQol (EQ)-5D instrument showed (1.0 indicates perfect health): “The mean EQ-5D–derived heath utility score for those individuals with diabetes was 0.80. The modeled utility score for a nonobese, non–insulin-treated, non-Asian, non-Hispanic man with type 2 diabetes, with an annual household income of more than $40,000, and with no diabetes complications, risk factors for cardiovascular disease, or comorbidities, was 0.92. Being a woman, being obese, smoking, and having a lower household income were associated with lower utility scores. Arranging complications from least to most severe according to the reduction in health utility scores resulted in the following order: peripheral vascular disease, other heart diseases, transient ischemic attack, cerebral vascular accident, nonpainful diabetic neuropathy, congestive heart failure, dialysis, hemiplegia, painful neuropathy, and amputation.” (P. Zhang, paz2@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
July 30, 2012 * Vol. 19, No. 146
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 28 issue of Lancet (2012; 380).
Citicoline in Ischemic Stroke: In the International Citicoline Trial on acUte Stroke (ICTUS) trial, citicoline was not efficacious in the treatment of moderate-to-severe acute ischemic stroke (pp. 349–57). Approved in some countries for stroke, citicoline is a choline intermediate that is also marketed as a supplement with claims of improving focus and mental energy. This trial compared placebo with citicoline 1000 mg every 12 hours for 3 days and then orally for 6 weeks, with these results: “2,298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2,298 patients who gave informed consent and underwent randomisation, 1,148 were assigned to citicoline and 1,150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2,078 patients. The final randomised analysis was based on data for 2,298 patients: 1,148 in citicoline group and 1,150 in placebo group. Global recovery was similar in both groups (odds ratio 1.03, 95% CI 0.86–1.25; p = 0.364). No significant differences were reported in the safety variables nor in the rate of adverse events.” (A. Dávalos, adavalos.germanstrias@gencat.cat)
Dabrafenib in Metastatic Melanoma: Compared with dacarbazine, the mutated-BRAF inhibitor dabrafenib improved progression-free survival among patients with BRAFV600E-mutated metastatic melanoma, according to an open-label Phase III trial (pp. 358–65). Adults with previously untreated, stage IV or unresectable stage III mutation-positive melanoma received either oral dabrafenib 150 mg twice daily or intravenous dacarbazine 1000 mg/m2 every 3 weeks. Results in 250 patients showed: “Median progression-free survival was 5.1 months for dabrafenib and 2.7 months for dacarbazine, with a hazard ratio (HR) of 0.30 (95% CI 0.18–0.51; p < 0.0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3–4 adverse events were uncommon in both groups.” (A. Hauschild, ahauschild@dermatology.uni-kiel.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Melanoma & Sunbed Use: People who use sunbeds are at significantly greater risk of developing melanoma, authors of a systematic review conclude, and the risk increases with greater use and initial use before age 35 (e4757): “Based on 27 studies ever use of sunbeds was associated with a summary relative risk of 1.20 (95% confidence interval 1.08 to 1.34). Publication bias was not evident. Restricting the analysis to cohorts and population based studies, the summary relative risk was 1.25 (1.09 to 1.43). Calculations for dose-response showed a 1.8% (95% confidence interval 0% to 3.8%) increase in risk of melanoma for each additional session of sunbed use per year. Based on 13 informative studies, first use of sunbeds before age 35 years was associated with a summary relative risk of 1.87 (1.41 to 2.48)…. “ (M. Boniol, mathieu.boniol@i-pri.org)

>>>PNN NewsWatch
* Ton Hoek, CEO and General Secretary of the International Pharmacy Federation, died on Saturday at his home in the Netherlands. Hoek served as head of FIP since 1999 and solidified key global partnerships with the World Health Organization and similar groups and incorporated FIP as a Founding Partner in the World Health Professions Alliance. FIP celebrates its 100th anniversary this Oct. in Amsterdam.

>>>PNN JournalWatch
* Nonnutritive Sweeteners: Current Use and Health Perspectives. A Scientific Statement From the American Heart Association and the American Diabetes Association, in
Diabetes Care, 2012; 35: 1798–808. (C. Gardner)
* Association of Industry Funding With the Outcome and Quality of Randomized Controlled Trials of Drug Therapy for Rheumatoid Arthritis, in
Arthritis & Rheumatism, 2012; 64: 2059–67. (N. A. Khan, nakhan@uams.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
July 31, 2012 * Vol. 19, No. 147
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
Jul/Aug issue of the Journal of the American Pharmacists Association (2012; 52).
Predicting Exenatide Responses: Patients with type 2 diabetes who had high baseline A1C levels were more likely to respond to exenatide therapy than those with low levels, a study reports, but weight loss showed no relationship to drug therapy or glycemic response (pp. 466–71). In a retrospective observational cohort study, these response patterns were noted while 100 adults (61 responders, 39 nonresponders) were on exenatide: “Responders had a mean A1C decrease of 1.57%, whereas nonresponders had a mean A1C increase of 0.23% (P < 0.001). Post hoc linear regression analysis revealed that baseline A1C was a predictor of response to exenatide (P < 0.001). Binary logistic regression analysis demonstrated that no other variables were predictors of response to exenatide (P > 0.05 for all). No correlation was found between weight loss and exenatide and glycemic response (P = 0.99).” (S. L. Anderson, sarah.anderson@ucdenver.edu)
OTC Intervention Follow-up: An offer to follow up with patients after an OTC counseling intervention in a community pharmacy was accepted by more than one third of patients and holds promise for leading to “improved patient outcomes,” authors of an Experience article report (pp. 535–40). Pharmacists and P4 student pharmacists at a Massachusetts chain provided detailed, documented counseling when patients sought nonprescription care. Point-of-care surveys and an offer to contact patients by telephone yielded these results: “Of the 207 patients offered a follow-up phone call, 83 accepted. Of these, 54 completed one call and 9 completed two calls. Of those who completed one phone call and claimed complete adherence to advice provided, 38 (82.6%) experienced great symptom relief. Three patients followed advice only partially and experienced the same level of improvement. More than 75% of patients classified the follow-up as ‘very helpful,’ felt that it led to greater symptom improvement, and would like to see this service offered all of the time.” (N. Bosse, neetaroo@aol.com)
Substance-Impaired Pharmacists’ Views on Occupational Risks: A variety of occupational risks for addiction should be addressed in education of student pharmacists and practitioners and by pharmacy managers, according to researchers who examined the views of recovering substance-impaired pharmacists in a southeastern state in 2008–09 (pp. 480–91). A total of 32 participants, three fourths of them men, from an impaired health professionals monitoring groups provided these insights: “Several occupational hazards unique to the pharmacy profession might contribute to the problem of substance use disorders among some members of this population, including increased access to potent drugs of abuse, a stressful/unpleasant working environment, a culture that unofficially condones medication diversion, lack of education related to addiction, and lack of support for individuals seeking treatment.” (L. J. Merlo, lmerlo@ufl.edu)
Quality of Pharmacy Education: Educational quality of PharmD programs has not changed during the recent period of rapid expansion of both older (those existing in 1995) and newer pharmacy colleges and schools (CS), according to an analysis conducted by AACP and ACPE (pp. 528–34). Using institutional research used by CS and ACPE in evaluating the knowledge, skills, and abilities of pharmacy graduates; scores on the North American Pharmacist Licensure Examination (NAPLEX); and survey data from CS graduates, faculty, and preceptors, the authors report: “Mean first-time NAPLEX pass rates over time are comparable for older and newer CS and for main versus branch campuses. Graduates, faculty, and preceptor survey results affirm that faculty, preceptors, and students perceive the quality of pharmacy education to be very high.” (L. L. Maine, lmaine@aacp.org)
Culture Trumps Strategy: William E. Evans, 2012 Remington Lecture Medalist, emphasizes the importance of culture in organizations as he reflects on his career at St. Jude Children’s Research Hosp. in Memphis (pp. 450–3): “Most of us … are at a stage in our professional careers where we can influence the culture of our institutions and our profession. We must take advantage of that and take steps to ensure the next generation of pharmacists finds a culture where they too can flourish and where they see beyond current boundaries.”

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
Aug. 1, 2012 * Vol. 19, No. 148
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 1 issue of JAMA (2012; 308).
Phenotypes in Familial Adenomatosis Polyposis: Researchers examine phenotypes of patients with multiple colorectal adenomas and find that pathogenic APC and MUTYH mutations vary considerably, even in patients with classic polyposis phenotype (pp. 485–92). Among 8,676 patients who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the two most common MUTYH mutations (Y179C and G396D) between 2004 and 2011, prevalences of pathogenic genes and polyps were as follows: “Colorectal adenomas were reported in 7,225 individuals; 1,457 with classic polyposis (≥100 adenomas) and 3,253 with attenuated polyposis (20–99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%–87%]) and 2 of 119 (2% [95% CI, 0.2%–6%]), respectively, among individuals with 1,000 or more adenomas, 756 of 1,338 (56% [95% CI, 54%–59%]) and 94 of 1,338 (7% [95% CI, 6%–8%]) among those with 100 to 999 adenomas, 326 of 3,253 (10% [95% CI, 9%–11%]) and 233 of 3,253 (7% [95% CI, 6%–8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%–7%]) and 37 of 970 (4% [95% CI, 3%–5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses.” (S. Syngal, ssyngal@partners.org)
Genomics is promising but must be applied cautiously, editorialists conclude (
pp. 514–5): “At this juncture, clinicians need to carefully consider the effect of a positive or negative test result on management of patient care prior to making decisions regarding genetic testing. Appropriate patient education and informed consent prior to testing is mandatory, highlighting the integral nature of genetic counseling. Until development of more robust genomic technologies for [familial adenomatosis polyposis (FAP)] detection, complementary approaches including careful assessment of family history and biomarkers may have utility. Furthermore, these considerations for FAP may serve as a model for evaluating the wider issues associated with practicing medicine at the front lines of the genomic revolution.” (H. K. Roy, h-roy@northwestern.edu)
Fractures After Cataract Surgery: The odds of having a hip fracture are lower after cataract surgery, according to a study of 1.1 million Medicare beneficiaries 65 or older (pp. 493–501). Patients with cataract diagnoses in 2002–09 showed these patterns with or without surgery: “Compared with 1-year hip fracture incidence in patients with cataract who did not have cataract surgery, adjusted OR of hip fracture within 1 year after cataract surgery was 0.84 (95% CI, 0.81–0.87) with an absolute risk difference of 0.20%. Compared with matched subgroups of patients who did not receive cataract surgery, patient subgroups that experienced lower odds of hip fracture after cataract surgery included patients with severe cataract, patients most likely to receive cataract surgery based on propensity score, patients 75 years and older, and patients with a [Charlson Comorbidity Index] score of 3 or greater.” (A. L. Coleman, colemana@ucla.edu)
Opioid REMS: “Implemented appropriately and followed correctly, [FDA’s risk evaluation and mitigation strategy (REMS)] may be an important component for addressing the opioid epidemic” in the U.S., a Viewpoint author writes (pp. 457–8). But “prescriber and patient education alone will likely prove insufficient to assuage the concerns of patients with chronic noncancer pain, who fear the reduced availability of opioid pain relievers, and public health advocates, who fear the excessive use of these drugs,” he writes in referring to plans for extended-release/long-acting (ER/LA) opioids: “Participation in this class-wide ER/LA REMS will be voluntary for health care providers. An advisory committee expressed concern that a voluntary process would not likely provide sufficient assurance of knowledge dissemination and retention and instead recommended linking certification, through mandatory testing, to renewal of a prescriber’s Drug Enforcement Administration registration. In anticipation of the final REMS by the FDA, a training website has been independently created by the drug’s sponsor that currently does not require demonstration of competency prior to self-certification.” (L. S. Nelson, lewis.nelson@nyumc.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, 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
Aug. 2, 2012 * Vol. 19, No. 149
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 2 issue of the New England Journal of Medicine (2012; 367).
Preexposure HIV Prophylaxis: Editorialists consider data from three preexposure antiretroviral prophylaxis studies released in advance of print (see PNN, Jul. 12) and make these observations about their implications in clinical practice (pp. 459–61): “Because [tenofovir disoproxil fumarate (TDF)] and [tenofovir–emtricitabine (TDF-FTC)] are readily available for clinical use, questions emerge as to how to consider these data in practice. How should preexposure prophylaxis be managed? Most anti-infective prophylactic agents are used as a bridge through an exposure window, much as antimicrobials are used at the time of surgery to prevent wound infection. If preexposure prophylaxis is started, how and when will it be stopped? What messages should the health care worker provide to the patient? And how should preexposure prophylaxis be monitored for adherence and safety? Providing a daily medication to healthy, HIV-uninfected persons demands an extraordinarily high degree of safety. There is substantial clinical experience with the TDF-FTC combination in the treatment of people with HIV infection, and no major safety concerns have been identified. However, the drugs have the potential to affect kidney and liver function and to reduce bone density. The current studies were time-limited (about 1 to 2 years), so the long-term safety of TDF-FTC in healthy persons must be monitored, because the implied use may be for many years.” (M. S. Cohen)
Anastrozole/Fulvestrant in Metastatic Breast Cancer: In postmenopausal women with previously untreated hormone-receptor–positive metastatic breast cancer, low-dose fulvestrant in combination with the aromatase inhibitor anastrozole was more effective than anastrozole alone or the two agents given sequentially (pp. 435–44). Fulvestrant, which binds and accelerates degradation of estrogen receptors, was administered intramuscularly in doses of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. Patients were assigned to anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2), with these results: “The median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P = 0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P = 0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.” (R. S. Mehta, rsmehta@uci.edu)

>>>Pediatrics Report
Source:
Aug. issue of Pediatrics (2012; 130).
Herd Immunity With HPV Vaccine: At two primary care clinics, herd immunity was evident among 777 sexually active young women 4 years after introduction of the human papillomavirus (HPV) vaccine (e249–56): “After propensity score weighting, the prevalence rate for vaccine-type HPV decreased substantially (31.7%–13.4%, P < .0001). The decrease in vaccine-type HPV not only occurred among vaccinated (31.8%–9.9%, P < .0001) but also among unvaccinated (30.2%–15.4%, P < .0001) postsurveillance study participants. Nonvaccine-type HPV increased (60.7%–75.9%, P < .0001) for vaccinated postsurveillance study participants.” (J. A. Kahn)

>>>PNN NewsWatch
* FDA announced two Class I recalls of infusion devices yesterday. Malfunctioning of the Alaris PC unit, model 8015, during start-up results in the device not being able to be programmed and delay of therapy. In the B. Braun Infusomat Space Infusion System, an anti–free-flow clip catch located inside the infusion pump door can break if inserted improperly and the door is forced closed. Both companies have been contacting hospitals with these devices.

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
Aug. 3, 2012 * Vol. 19, No. 150
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Aug. issue of Pharmacotherapy, a theme issue on antimicrobial stewardship (2012; 32).
Antibiogram-Assessed Outcomes After Stewardship: The development of hospital antimicrobial stewardship programs (ASPs) in response to national guidelines that call for improved use and extended utility of anti-infective drugs and utility of the antibiogram for assessing effectiveness are reviewed based on 8 published articles (pp. 668–76): “An often implied purpose of ASPs is to curb or reverse the emergence of resistant bacteria. Because antibiotic use causes antibiotic resistance, there is a natural tendency to link local measures of antibiotic use to local measures of bacterial resistance, and the hospital antibiogram is a readily available measure of resistance.… The antibiogram itself is neither designed nor well suited to reflect changes in hospital antimicrobial drug use. The literature on the effectiveness of ASPs in reducing resistance continues to emerge, but at this time the antibiogram bears an inconsistent relationship with changes in hospital antibiotic use and cannot be recommended to reliably evaluate an ASP intervention. Interrupted time series analysis is a superior strategy to assess the effect of an ASP intervention on bacterial resistance, but it is not widely used because of its complexity and greater data requirements. Nevertheless, before ASP efforts can be convincingly demonstrated to have a favorable impact on resistance, a more sophisticated approach that links drug use to resistance should become a priority, at least for hospitals that have sufficient resources.” (R. E. Polk, rpolk@vcu.edu)
Rapid Diagnostic Tests for Selecting Antimicrobials: Linking results of rapid molecular tests with data such as hospital antibiograms in selecting initial empiric antimicrobial agents is discussed in a review article (pp. 677–87): “Tests that provide accurate organism identification and antimicrobial susceptibility not only benefit the individual patient but also increase the effectiveness of antimicrobial stewardship programs. This review focuses on the use of molecular diagnostic methods to rapidly identify Staphylococcus species, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Clostridium difficile, and Candida species from clinical samples and summarizes studies that describe the application of rapid diagnostic tests in antimicrobial stewardship programs.” (D. A. Goff, ebbie.goff@osumc.edu">Debbie.goff@osumc.edu)
Process v. Outcome in Antimicrobial Stewardship: The focus of antimicrobial stewardship programs (ASPs) has shifted from cost reduction to improved antimicrobial use, authors write in evaluating process and outcome measures of such programs (pp. 688–706): “Study design and duration limitations … can make it difficult to measure the impact of these programs. Process measures have been validated and can evaluate quality of care; however, they do not adequately describe the clinical impact of these programs at the patient level. Outcome measures also have limitations; they are not a direct measure of quality of care. Therefore, both process and outcome measures need to be defined and assessed when evaluating an ASP to confirm that goals of the intervention are attained and clinical objectives are met. Most available well-designed studies judging the effectiveness of ASPs use process measures alone. Adding improvements in clinical outcomes to process measures would theoretically attract the attention of a broader audience and provide additional support to expand current ASPs and develop novel ASPs.” (J. Brown, jb322@buffalo.edu)
Prolonged Infusions of Beta-Lactam Antibiotics: Based on a review of data from Monte Carlo simulations, clinical outcome analyses, and pharmacoeconomic studies, authors reach this conclusion about utility of prolonged infusions of beta-lactam antibiotics (pp. 707–21): “From a clinical perspective and as part of a stewardship measure, patient outcome data evaluating both safety and efficacy are not sufficient to recommend the universal adoption of [a prolonged-infusion] dosing strategy for all beta-lactam agents. However, in the case of piperacillin–tazobactam, many institutions have switched to hospitalwide implementation of prolonged infusions, primarily because the available clinical data describe at least similar outcomes with lower total daily doses and resultant cost savings.” (J. M. George, j.george@usp.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
Aug. 6, 2012 * Vol. 19, No. 151
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 4 issue of Lancet (2012; 380).
Linagliptin in Type 2 Diabetes: The DPP-4 inhibitor linagliptin is noninferior to the sulfonylurea glimepiride for reducing A1C levels in patients with type 2 diabetes and produces fewer adverse effects, researchers report (pp. 475–83). In a 2-year trial, 1,519 patients with type 2 diabetes and A1C levels of 6.5–10% were randomized to linagliptin 5 mg or glimepiride 1–4 mg orally once daily, with these results: “Reductions in adjusted mean HbA1c (baseline 7.69% [SE 0.03] in both groups) were similar in the linagliptin (–0.16% [SE 0.03]) and glimepiride groups (–0.36% [0.03]; difference 0.20%, 97.5% CI 0.09–0.30), meeting the predefined non-inferiority criterion of 0.35%. Fewer participants had hypoglycaemia (58 [7%] of 776 vs 280 [36%] of 775 patients, p < 0.0001) or severe hypoglycaemia (1 [<1%] vs 12 [2%]) with linagliptin compared with glimepiride. Linagliptin was associated with significantly fewer cardiovascular events (12 vs 26 patients; relative risk 0.46, 95% CI 0.23—0.91, p = 0.0213).” (B. Gallwitz, baptist.gallwitz@med.uni-tuebingen.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Cardiovascular Events With Glucocorticoids in Iatrogenic Cushing’s Syndrome: Patients on glucocorticoids who have signs and symptoms of iatrogenic Cushing’s syndrome “should be aggressively targeted for early screening and management of cardiovascular risk factors,” conclude authors of a cohort study (e4928). At 424 general practices in the U.K., these outcomes were noted for 547 patients who were prescribed systemic glucocorticoids and had a diagnosis of iatrogenic Cushing’s syndrome, 3,231 patients on the drugs with no syndrome, and 3,282 patients not on the drugs: “417 cardiovascular events occurred in 341 patients. Taking into account only the first event by patient (coronary heart disease n = 177, heart failure n = 101, ischaemic stroke n = 63), the incidence rates of cardiovascular events per 100 person years at risk were 15.1 (95% confidence interval 11.8 to 18.4) in those prescribed glucocorticoids and with a diagnosis of iatrogenic Cushing’s syndrome, 6.4 (5.5 to 7.3) in those prescribed glucocorticoids without a diagnosis of iatrogenic Cushing’s syndrome, and 4.1 (3.4 to 4.8) in those not prescribed glucocorticoids. In multivariate analyses adjusted for sex, age, intensity of glucocorticoid use, underlying disease, smoking status, and use of aspirin, diabetes drugs, antihypertensive drugs, lipid lowering drugs, or oral anticoagulant drugs, the relation between iatrogenic Cushing’s syndrome and cardiovascular events was strong (adjusted hazard ratios 2.27 (95% confidence interval 1.48 to 3.47) for coronary heart disease, 3.77 (2.41 to 5.90) for heart failure, and 2.23 (0.96 to 5.17) for ischaemic cerebrovascular events). The adjusted hazard ratio for any cardiovascular event was 4.16 (2.98 to 5.82) when the group prescribed glucocorticoids and with iatrogenic Cushing’s syndrome was compared with the group not prescribed glucocorticoids.” (L. Fardet, laurence.fardet@sat.aphp.fr)

>>>PNN NewsWatch
* FDA on Friday approved ziv-aflibercept (Zaltrap, sanofi aventis) for use with a FOLFIRI (folinic acid, fluorouracil and irinotecan) chemotherapy regimen to treat adults with colorectal cancer. The angiogenesis inhibitor increased survival by 1.5 months (mean of 13.5 versus 12 months with FOLFIRI) and reduced tumor size by 20% (versus 11% with FOLFIRI). Adverse effects in patients receiving ziv-aflibercept plus FOLFIRI were leukopenia, diarrhea, stomatitis, fatigue, hypertension, proteinuria, weight loss, decreased appetite, abdominal pain, and headache.

>>>PNN JournalWatch
* Incremental Costs Associated with Physician and Pharmacist Collaboration to Improve Blood Pressure Control, in
Pharmacotherapy, 2012; 32: 772–80. (J. M. Brooks, john-brooks@uiowa.edu)
* Comparative Effectiveness of Collaborative Chronic Care Models for Mental Health Conditions Across Primary, Specialty, and Behavioral Health Care Settings: Systematic Review and Meta-Analysis, in
American Journal of Psychiatry, 2012; 169: 790–804. (M. S. Bauer, mark.bauer@va.gov)
* USPSTF Perspective on Evidence-Based Preventive Recommendations for Children, in
Pediatrics, 2012; 130: e399–e407. (B. M. Melnyk)
* Managing HIV/AIDS: Yunnan’s Government-driven, Multi-sector Partnership Model, in
Management and Organization Review, 2012; 10.1111/j.1740-8784.2012.00307.x. (M-l Wang)

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
Aug. 7, 2012 * Vol. 19, No. 152
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 7 issue of the Annals of Internal Medicine (2012; 157).
Racial Differences in A1C-Associated Retinopathy: Even though A1C levels are consistently higher in blacks than whites, the diagnostic threshold should not be raised, authors conclude based on a study that shows retinopathy occurring at lower A1C levels in black patients (pp. 153–9). A cross-sectional study used data from the National Health and Nutrition Examination Survey from 2005 through 2008 to identify these trends in 2,804 whites and 1,008 blacks aged 40 years or older: “After adjustment for age, sex, hypertension, body mass index, family history of diabetes, and use of antidiabetes medications or insulin, the lowest HbA1c category for which the prevalence of retinopathy was significantly higher than the reference category (<5.5%) was 6.0% to 6.4% for white persons (risk difference, 4.8% [95% CI, 0.5% to 9.1%]) and 5.5% to 5.9% for black persons (risk difference, 5.3% [CI, 1.0% to 9.5%]). The restricted cubic spline models indicated that the risk for retinopathy increased at lower HbA1c levels in black persons than in white persons.” (Y. Tsugawa, ytsugawa@bidmc.harvard.edu)
Context & Antimicrobial Prescribing for Febrile Respiratory Illness: When prescribing for patients with symptoms of febrile respiratory illness (FRI), physicians’ likelihood to use antimicrobial agents is influenced by contextual factors, a study shows, including the number of patients recently seen with FRIs and epidemiologic factors such as season and pandemics (pp. 160–9). Among patients seen in a network of midwestern primary care providers, patients with FRI presenting during influenza seasons in 2006–11 showed these results: “28,301 unique patient encounters for FRI with 69 physicians in 26 practices were included. An antibiotic was prescribed in 12,795 (45.2%) cases. The range of prescribing among physicians was 17.9% to 83.7%. Antibiotics were prescribed in 47.5% of encounters during the seasonal period and 39.2% during the pandemic period (P < 0.001). After multivariable adjustment for patient and physician characteristics, antibiotic prescribing was lower in the pandemic period (odds ratio [OR], 0.72 [95% CI, 0.68 to 0.77]) than in the seasonal period. The likelihood of prescribing an antibiotic decreased as the number of FRI cases that a physician had seen in the previous week increased (OR, 0.93 [CI, 0.86 to 1.01] for 2 to 3 patients with FRI seen in the previous week; OR, 0.84 [CI, 0.77 to 0.91] for 4 to 6 patients; OR, 0.71 [CI, 0.64 to 0.78] for 7 to 11 patients; and OR, 0.57 [CI, 0.51 to 0.63] for ≥12 patients compared with the reference range of 0 to 1 patients). Pandemic season and recent personal context were also associated with antiviral prescribing.” (C. Hebert, courtney.hebert@osumc.edu)
Research such as this can help explain “exactly where and how to intervene when designing strategies to reduce unnecessary prescriptions and change the ‘culture of prescribing,’” editorialists write (
pp. 211–2): “Qualitative and mixed-methods approaches based in the social sciences have proved invaluable to this effort, particularly those including direct observation of clinical encounters. On-the-ground observations not only produce more nuanced explanations of clinical priorities and practices, they can also disentangle the complex interplay of tacit knowledge, social norms, economic pressures, and broader cultural trends—all of which shape patients’ perceptions, clinical reasoning, and prescribing decisions. To change practices, we need to understand not only which contextual factors shape them but how and why.” (R. Gonzales, ralphg@medicine.ucsf.edu)
Hyaluronic Acid in Knee Osteoarthritis: Intra-articular injection of hyaluronic acid, or viscosupplementation, in patients with symptomatic knee osteoarthritis “is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events,” authors of a systematic review and meta-analysis conclude (pp. 180–91): “Eighteen large trials with blinded outcome assessment (5,094 patients) showed a clinically irrelevant effect size of −0.11 (CI, −0.18 to −0.04). Six trials (811 patients) showed that viscosupplementation increased, although not statistically significantly, the risk for flare-ups (relative risk, 1.51 [CI, 0.84 to 2.72]). Fourteen trials (3,667 patients) showed that viscosupplementation increased the risk for serious adverse events (relative risk, 1.41 [CI, 1.02 to 1.97]).” (P. Jüni, juni@ispm.unibe.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
Aug. 8, 2012 * Vol. 19, No. 153
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 8 issue of JAMA (2012; 308).
Weight, Diabetes & Mortality: Adult patients with normal BMIs at the time of diagnosis of type 2 diabetes have higher mortality rates than overweight or obese patients, a study shows (pp. 581–90). In five longitudinal cohorts, investigators followed 2,625 participants for a total of 27,125 person–years. Trends among those older than 40 years with incident diabetes showed the following: “The proportion of adults who were normal weight at the time of incident diabetes ranged from 9% to 21% (overall 12%). During follow-up, 449 participants died: 178 from cardiovascular causes and 253 from noncardiovascular causes (18 were not classified). The rates of total, cardiovascular, and noncardiovascular mortality were higher in normal-weight participants (284.8, 99.8, and 198.1 per 10,000 person–years, respectively) than in overweight/obese participants (152.1, 67.8, and 87.9 per 10,000 person–years, respectively). After adjustment for demographic characteristics and blood pressure, lipid levels, waist circumference, and smoking status, hazard ratios comparing normal-weight participants with overweight/obese participants for total, cardiovascular, and noncardiovascular mortality were 2.08 (95% CI, 1.52–2.85), 1.52 (95% CI, 0.89–2.58), and 2.32 (95% CI, 1.55–3.48), respectively.” (M. R. Carnethon, carnethon@northwestern.edu)
Higher mortality rates in metabolically obese normal-weight (MONW) individuals who develop diabetes may indicate a greater health threat for low cardiorespiratory fitness and inactivity than obesity, editorialists write (
pp. 619–20): “This could be a wake-up call for timely prevention and management to reduce adverse outcomes in all patients with type 2 diabetes, particularly in those MONW at diagnosis, who may have a false sense of protection because they are not overweight or obese. Standards of diabetes care recommend weight loss for all overweight or obese individuals who have diabetes. Low-carbohydrate, low-fat, calorie-restricted, or Mediterranean diets may be effective weight-loss strategies in these individuals. The additional benefits of increased physical activity and behavior modification strategies may lead to the successful implementation of weight management and healthy living programs for all patients with diabetes. It is important to understand how diabetes duration relates to the benefits of intentional weight loss, as well as the clinical consequences associated with sarcopenic obesity and bone loss in older adults with or at high risk for diabetes.” (H. Florez, hflorez@med.miami.edu)

>>>Cardiology Highlights
Source:
Aug. 14 issue of the Journal of the American College of Cardiology (2012; 60).
Cardiovascular Priorities in CER: A report of a workshop “provides an overview of [cardiovascular comparative effectiveness research (CER)] methods, with an emphasis on practical clinical trials and observational treatment comparisons,” with authors reaching this conclusion about steps in the CER cycle (pp. 569–80). “The approach to actionable research outlined by workshop participants implies a cycle of research and its application. The 4 important linked steps in this cycle are: 1) the prospective articulation of research questions based on identifying gaps in knowledge about optimal patient care, incorporating input of stakeholders, including patients; 2) the development of evidence by a variety of research methods to address key evidence gaps; 3) application of the evidence in practice guidelines and standards of care; and 4) determination whether quality of care and patient outcomes are improved.” (M. A. Hlatky)

>>>PNN NewsWatch
* Physical activity is “a wonder drug,” said CDC Director Thomas R. Frieden, MD, MPH, for the half of American adults who exercise 2.5 hours or more per week. “Even if you don’t lose any weight, getting regular physical activity will decrease your risk of getting sick, it will decrease your risk of getting diabetes, it will decrease your risk of getting high blood pressure, cancer, and a host of many other conditions,” Frieden said. “I would say that there is really no single drug that can do anything like what regular physical activity does.” About 48% of Americans get 2.5 hours per week of physical activity, CDC said, and 15 million more Americans were walking in 2010 than in 2005, bringing the total to 145 million people.

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
Aug. 9, 2012 * Vol. 19, No. 154
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 9 issue of the New England Journal of Medicine (2012; 367).
Kinase Inhibition in Rheumatoid Arthritis: In two studies and an editorial, the use of the oral Janus kinase inhibitor tofacitinib is examined in patients with rheumatoid arthritis.
Tofacitinib monotherapy reduced signs and symptoms of rheumatoid arthritis and improved physical function in 611 patients with active disease, compared with placebo (
pp. 495–507). Over a 6-month period, patients were allocated to tofacitinib 5 or 10 mg twice daily or to placebo for 3 months followed by tofacitinib 5 or 10 mg twice daily. Assessed at month 3, primary end points—20% improvement in the American College of Rheumatology scale (ACR 20), change from baseline in Health Assessment Questionnaire–Disability Index (HAQ-DI) scores, and percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6—showed these patterns: “At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P < 0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (−0.50 and −0.57 points, respectively, vs. −0.19 points; P < 0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P = 0.62 and P = 0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.” (R. Fleischmann, rfleischmann@arthdocs.com)
In 717 patients with rheumatoid arthritis who were on stable methotrexate doses, tofacitinib compared favorably with adalimumab in measures of efficacy, authors of second study report (
pp. 508–19). Based on ACR20 at month 6, changes in HAQ-DI from baseline to month 3, and DAS28-4(ESR) counts at month 6, this study demonstrated these effects of oral tofacitinib 5 or 10 mg twice daily, subcutaneous adalimumab 40 mg every 2 weeks, or placebo: “At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P < 0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts.” (B. Wilkinson, bethanie.wilkinson@pfizer.com)
After reviewing potential toxicities of tofacitinib and other JAK kinase inhibitors and noting the “unexpected emergence of new autoimmune syndromes even as the rheumatoid arthritis responds to treatment” with biologic agents, an editorialist concludes (
pp. 565–7): “The clear success of JAK inhibition as a treatment for rheumatoid arthritis, if confirmed by robust long-term efficacy assessed with the use of both clinical and radiographic measures, represents an important therapeutic advance. Considering that there are currently nine biologic medications (directed at five distinct molecular targets) that are FDA-approved for use in patients with rheumatoid arthritis, along with a range of effective conventional disease-modifying drugs that generally have good side-effect profiles, the ideal clinical situations in which a kinase inhibitor should be used are not clear at present. A better understanding of the safety profile of tofacitinib will influence the consideration of when in the course of rheumatoid arthritis clinicians should consider this novel approach.” (D. A. Fox)

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
Aug. 10, 2012 * Vol. 19, No. 155
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Aug. issue of Chest (2012; 142).
Bronchodilators & Arrhythmias in COPD: Two studies and an editorial assess cardiac safety of bronchodilators in chronic obstructive pulmonary disease (COPD).
New use of ipratropium and long-acting beta-agonists (LABAs) was associated with increased risk of cardiac arrhythmias in a cohort analysis from Saskatchewan (
pp. 298–304). Among patients in the province’s health database, those with COPD and ages 55 years or older in 1990–99 were included. Based on follow-up through the end of 2003, these trends were noted in a nested case–control analysis using 20 control subjects per patient with hospitalization for or death from arrhythmias: “The cohort included 6,018 patients with COPD in whom 469 arrhythmia cases occurred, including 56 deaths, for an overall rate of 1.37 arrhythmias per 100 per year. The rate of arrhythmia was elevated with the new use of ipratropium (RR, 2.4; 95% CI, 1.4–4.0) and of … LABAs (RR, 4.5; 95% CI, 1.4–14.4). It was not elevated with new use of short-acting beta-agonists (RR, 0.9; 95% CI, 0.5–1.6) or methylxanthines (RR, 1.6; 95% CI, 0.7–3.7).” (S. Suissa, samy.suissa@mcgill.ca)
The same researchers sought to confirm these findings in a larger cohort, with the beta-agonist findings supported but not those for ipratropium (
pp. 305–11). Using Quebecois health databases for the same time periods, the group found: “The cohort included 76,661 patients with COPD, of whom 5,307 developed an arrhythmia (10.3 arrhythmias per 1,000 per year), 621 of which were fatal. The rate of cardiac arrhythmias was elevated with the new use of short-acting (RR, 1.27; 95% CI, 1.03–1.57) and long-acting (RR, 1.47; 95% CI, 1.01–2.15) beta-agonists. The rate was slightly elevated, although not statistically significantly, with new use of ipratropium bromide (RR, 1.23; 95% CI, 0.95–1.57) and methylxanthines (RR, 1.28; 95% CI, 0.93–1.77). These effects waned with longer-term use.” (S. Suissa, samy.suissa@mcgill.ca)
“What is the number needed to analyze” in drug-safety cohort studies, asks an editorialist, adding (
pp. 271–4): “Epidemiologists should lead [this] field by establishing clear guidance as to the quality of datasets, statistical methods that are generally accepted and valid, including the number needed to analyze, the importance of which is demonstrated in the present back-to-back articles featured in this issue. In the end, the somewhat uncomfortable recommendations, including those of the FDA, are correct: If drug safety is at our hearts, we need to invest in this type of research and conduct the appropriate trials.” (K. F. Rabe)

>>>Psychiatry Report
Source:
Aug. issue of the American Journal of Psychiatry (2012; 169).
NAC in Cannabis-Dependent Adolescents: The dietary supplement N-acetylcysteine (NAC) improved cessation rates in a group of cannabis-dependent patients ages 15–21 years, researchers report (pp. 805–12). In an 8-week trial, NAC 1200 mg or placebo twice daily showed these effects when used with a contingency management intervention and brief (<10 min) weekly cessation counseling: “Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio = 2.4, 95% CI = 1.1–5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events.” (K. M. Gray, graykm@musc.edu)
Given “the serious epidemic of marijuana abuse in adolescents,” all options must be considered, an editorialist writes, but serious questions remain regarding NAC use (
pp. 771–3): “While it is tempting to now think of NAC as another potential daily supplement for ‘good health,’ like its neighbors on the shelves of the vitamin/supplement section of many stores, we have more work to do in considering NAC’s place as a modality in the treatment of substance use disorders in adolescents. Does NAC work to prevent the development of substance use disorders? Does NAC work in longer-term therapy to prevent relapse? Does it work for problems with other drugs or more severe levels of substance use disorder? What are the adjunctive effects with other psychosocial treatment modalities or combinations? The last issue is particularly important as many may be tempted to use NAC as a single, individual treatment.” (O. G. Bukstein, scar.g.bukstein@uth.tmc.edu">oscar.g.bukstein@uth.tmc.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
Aug. 13, 2012 * Vol. 19, No. 156
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 11 issue of Lancet (2012; 380).
Statin CVD Benefits v. Diabetes Risk: In patients taking statins for primary prevention, cardiovascular and mortality benefits exceed diabetes risks, according to an analysis of JUPITER data (pp. 565–71). Among 17,603 patients without prior cardiovascular disease or diabetes, rosuvastatin 20 mg or placebo for up to 5 years showed these effects on a primary endpoint of myocardial infarction, stroke, admission to hospital for unstable angina, arterial revascularization, or cardiovascular death, and prespecified secondary endpoints: “Trial participants with one or more major diabetes risk factor (n=11,508) were at higher risk of developing diabetes than were those without a major risk factor (n = 6,095). In individuals with one or more risk factors, statin allocation was associated with a 39% reduction in the primary endpoint (hazard ratio [HR] 0.61, 95% CI 0.47–0.79, p = 0.0001), a 36% reduction in venous thromboembolism (0.64, 0.39–1.06, p = 0.08), a 17% reduction in total mortality (0.83, 0.64–1.07, p = 0.15), and a 28% increase in diabetes (1.28, 1.07–1.54, p = 0.01). Thus, for those with diabetes risk factors, a total of 134 vascular events or deaths were avoided for every 54 new cases of diabetes diagnosed. For trial participants with no major diabetes risk factors, statin allocation was associated with a 52% reduction in the primary endpoint (HR 0.48, 95% CI 0.33–0.68, p = 0.0001), a 53% reduction in venous thromboembolism (0.47, 0.21–1.03, p = 0.05), a 22% reduction in total mortality (0.78, 0.59–1.03, p = 0.08), and no increase in diabetes (0.99, 0.45–2.21, p = 0.99). For such individuals, a total of 86 vascular events or deaths were avoided with no new cases of diabetes diagnosed. In analysis limited to the 486 participants who developed diabetes during follow-up (270 on rosuvastatin vs 216 on placebo; HR 1.25, 95% CI 1.05–1.49, p = 0.01), the point estimate of cardiovascular risk reduction associated with statin therapy (HR 0.63, 95% CI 0.25–1.60) was consistent with that for the trial as a whole (0.56, 0.46–0.69). By comparison with placebo, statins accelerated the average time to diagnosis of diabetes by 5.4 weeks (84.3 [SD 47.8] weeks on rosuvastatin vs 89.7 [50.4] weeks on placebo).” (P. M. Ridker, pridker@partners.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Rotavirus Vaccine & Belgian Hospital Admissions: In a case–control study of 39 hospitals in Belgium, a monovalent rotavirus vaccine prevented hospital admissions for rotavirus gastroenteritis among young children, researchers report (e4752). For the 2008–10 timeframe, 215 children were compared with 276 age- and hospital-matched controls: “99 children (48%) admitted with rotavirus gastroenteritis and 244 (91%) controls had received at least one dose of any rotavirus vaccine (P < 0.001). The monovalent rotavirus vaccine accounted for 92% (n = 594) of all rotavirus vaccine doses. With hospital admission as the outcome, the unadjusted effectiveness of two doses of the monovalent rotavirus vaccine was 90% (95% confidence interval 81% to 95%) overall, 91% (75% to 97%) in children aged 3–11 months, and 90% (76% to 96%) in those aged ≥12 months. The G2P[4] genotype accounted for 52% of cases confirmed by polymerase chain reaction with eligible matched controls. Vaccine effectiveness was 85% (64% to 94%) against G2P[4] and 95% (78% to 99%) against G1P[8]. In 25% of cases confirmed by polymerase chain reaction with eligible matched controls, there was reported co-infection with adenovirus, astrovirus and/or norovirus. Vaccine effectiveness against co-infected cases was 86% (52% to 96%). Effectiveness of at least one dose of any rotavirus vaccine (intention to vaccinate analysis) was 91% (82% to 95%).” (P. Van Damme, pierre.vandamme@ua.ac.be)

>>>PNN JournalWatch
* Management of Deep Vein Thrombosis of the Upper Extremity, in
Circulation, 2012; 126: 768–73. (N. Kucher, nils.kucher@insel.ch)
* Pneumococcal Pneumonia: Mechanisms of Infection and Resolution, in
Chest, 2012; 142: 482–91. (D. H. Dockrell, d.h.dockrell@sheffield.ac.uk)
* Transmission of Infection With Human Allografts: Essential Considerations in Donor Screening, in
Clinical Infectious Diseases, 2012; 55: 720–7–. (J. A. Fishman, jfishman@partners.org)
* Evidence-Based Guideline: Pharmacologic Treatment of Chorea in Huntington Disease, in
Neurology, 2012; 79: 597–603. (American Academy of Neurology, guidelines@aan.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
Aug. 14, 2012 * Vol. 19, No. 157
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 13/27 issue of the Archives of Internal Medicine (2012; 172).
Hypertension, Frailty & Mortality in the Older Adults: Exploring the attenuated relationship between hypertension and mortality in patients aged 65 years and older, investigators determine that “walking speed could be a simple measure to identify [those] most at risk for adverse outcomes related to high [blood pressure (BP)]” (pp. 1162–8). Data from the National Health and Nutrition Examination Surveys in 1999–2000 and 2001–02 and death certificates in the National Death Index show these patterns for 6-m walking speed classified as faster (≥0.8 m/s; 1,307 patients), slower (n = 790), or incomplete (n = 243): “Among the participants, there were 589 deaths through December 31, 2006. The association between BP and mortality varied by walking speed. Among faster walkers, those with elevated systolic BP (≥140 mm Hg) had a greater adjusted risk of mortality compared with those without (hazard ratio [HR], 1.35; 95% CI, 1.03–1.77). Among slower walkers, neither elevated systolic nor diastolic BP (≥90 mm Hg) was associated with mortality. In participants who did not complete the walk test, elevated BP was strongly and independently associated with a lower risk of death: HR, 0.38; 95% CI, 0.23–0.62 (systolic); and HR, 0.10; 95% CI, 0.01–0.81 (diastolic).” (M. C. Odden, Michelle.Odden@oregonstate.edu)
This article demonstrates the utility of gait speed, writes an author of an invited commentary, noting that it “is a strong predictor of many important outcomes, including subsequent functional decline and disability, hospitalization, nursing home placement, surgical outcomes, and survival” (
pp. 1168–9). A second contribution of this work is to provide “a better understanding of the complexities of BP in old age,” the author concludes. “Geriatricians are uncomfortable using age-based guidelines because heterogeneity in all physiologic processes increases with age. There is no such thing as an ‘average octogenarian’ Despite this appreciation, we were confronted with a set of age-based findings related to hypertension in elderly adults. Odden et al suggest that a simple test—as easily accomplished as recording a temperature or BP—will allow clinicians to categorize older individuals into those in whom high BP is clearly associated with bad outcomes vs those in whom the relationship is unclear or reversed. The realization of the importance of gait speed comes at the same time as increasing calls for individualizing the approach to older patients—the realization that guideline-based care is inappropriate for octogenarians, particularly when the guidelines were developed from data generated on younger populations. Among elderly adults, gait speed may evolve to become the most important of vital signs.” (J. S. Goodwin, jsgoodwi@utmb.edu)
Effect of Statins on Energy and Fatigue With Exertion: Exertional fatigue was worse in patients on statins than in those on placebo in a 1,016-participant study of patients with LDL cholesterol levels of 115–190 mg/dL and no cardiovascular disease or diabetes (pp. 1180–2). Participants were randomized to the lipophilic simvastatin 20 mg, the hydrophilic pravastatin 40 mg, or placebo, with these effects on “EnergyFatigEx” values: “Each statin contributed [to on-treatment changes in EnergyFatigEx] (effects separately significant for simvastatin). Women were disproportionately affected. The 0.4 mean difference observed for women receiving simvastatin vs placebo would arise if 4 in 10 treated women cited worsening in either energy or exertional fatigue; 2 in 10 characterized both as ‘worse’ or either as ‘much worse’; 1 in 10 characterized both components as much worse’; or combinations of these conditions, with the fractions of subjects for which each statement holds, summing to 1. Adjusted for baseline EnergyFatigEx (via ordinal logit), effects on EnergyFatigEx were significantly unfavorable for combined statins and each statin separately.” (B. A. Golomb, bgolomb@ucsd.edu)
Rx Drug Abuse & Drug Take-Back Events: A desire to “clean out the medicine cabinet” was cited by 68% of people bringing medicines to 2009–11 drug take-back programs in Appalachia, a study shows (pp. 1186–7). Controlled substances were common, representing 9.3% of all prescription drugs brought and totaling 11,000 doses of potentially abusable agents. (N. E. Hagemeier, hagemeier@etsu.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
Aug. 15, 2012 * Vol. 19, No. 158
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 15 issue of JAMA (2012; 308).
Integrated Therapy for PTSD & Substance Dependence: Patients with posttraumatic stress disorder (PTSD) responded more to an integrated interventional approach than to usual treatment alone, researchers report (pp. 690–9). Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE) includes motivational enhancement and cognitive–behavioral therapy for substance use, psychoeducation, in vivo exposure, imaginal exposure, cognitive therapy for PTSD, and a review of treatment, devising an after-care plan, and termination of therapy. In 103 patients, COPE plus usual treatment produced these results in comparison with usual treatment alone: “From baseline to 9-month follow-up, significant reductions in PTSD symptom severity were found for both the treatment group (mean difference, −38.24 [95% CI, −47.93 to −28.54]) and the control group (mean difference, −22.14 [95% CI, −30.33 to −13.95]); however, the treatment group demonstrated a significantly greater reduction in PTSD symptom severity (mean difference, −16.09 [95% CI, −29.00 to −3.19]). No significant between-group difference was found in relation to improvement in severity of substance dependence (0.43 vs 0.52; incidence rate ratio, 0.85 [95% CI, 0.60 to 1.21), nor were there any significant between-group differences in relation to changes in substance use, depression, or anxiety.” (K. L. Mills, k.mills@unsw.edu.au)

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (2012; 130).
Budesonide/Formoterol Inhaler Safety in Blacks: In a 1-year trial conducted in 742 black patients ages 12 or older with asthma, budesonide/formoterol pressurized metered-dose inhaler (pMDI) produced a lower asthma exacerbation rate and similar safety outcomes, compared with budesonide alone (pp. 362–7.e9). Participants had moderate-to-severe asthma and had been previously treated with medium- to high-dose inhaled corticosteroids. Results showed: “Both treatments were well tolerated. Asthma exacerbation incidence and rate (per patient–treatment year) were lower with budesonide/formoterol versus budesonide (incidence, 7.7% vs 14.0% [P = .006]; rate ratio, 0.615 [P = .002]). Time to first asthma exacerbation was longer (P = .018) with budesonide/formoterol versus budesonide. The most common adverse events, regardless of study drug relationship, were headache (9.5% and 7.7%), nasopharyngitis (6.9% and 8.0%), sinusitis (4.0% and 6.3%), and viral upper respiratory tract infection (5.8% and 4.4%) for budesonide/formoterol and budesonide, respectively. Serious adverse events occurred in 12 and 15 patients, respectively; none were considered drug related. No substantial or unexpected patterns of abnormalities were observed in laboratory, electrocardiographic, or Holter monitoring assessments. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups, respectively. Pulmonary function and asthma control measures generally favored budesonide/formoterol.” (R. W. Brown, docrbrown@gmail.com)
Suicide Attempts With Pediatric Use of Leukotriene Modifiers: In children, adolescents, and young adults with asthma and being treated with leukotriene-modifying agents (LTMAs), no increase in risk of suicide attempts (SAs) was found in a nested case–control study (pp. 368–75). Using an insurance claims database, investigators identified patients ages 5–24 years who were new users of LTMAs or other drugs for asthma. Those with SAs after exposure to antiasthmatic drugs were compared with controls using a 10:1 match, with these results: “We identified 344 cases and 3,438 matched control subjects. Cases were more likely than control subjects to have risk factors for suicide. We found that current use of any LTMA was not associated with increased risk of an SA; in fact, the direction of effect was the opposite (adjusted odd ratio, 0.70; 95% CI, 0.36–1.39).” (G. T. Schumock, schumock@uic.edu)

>>>PNN NewsWatch
* FDA has approved 2012–13 formulations of influenza vaccine for all six U.S. manufacturers. Products contain the same A/H1N1 viral strain as last year’s vaccine and new A/H3N2 and B strains.

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
Aug. 16, 2012 * Vol. 19, No. 159
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 16 New England Journal of Medicine (2012; 367).
Ocriplasmin for Vitreomacular Traction & Macular Holes: Ocriplasmin, a recombinant protease, was significantly more effective than placebo for resolving vitreomacular traction and closing macular holes in patients with severe, symptomatic vitreomacular adhesion, researchers report (pp. 606–15). In Phase III trials, a single intravitreal injection of ocriplasmin 125 mcg produced these results based on resolution of vitreomacular adhesion at day 28: “Overall, 652 eyes were treated: 464 with ocriplasmin and 188 with placebo. Vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P < 0.001). Total posterior vitreous detachment was more prevalent among the eyes treated with ocriplasmin than among those injected with placebo (13.4% vs. 3.7%, P < 0.001). Nonsurgical closure of macular holes was achieved in 40.6% of ocriplasmin-injected eyes, as compared with 10.6% of placebo-injected eyes (P < 0.001). The best-corrected visual acuity was more likely to improve by a gain of at least three lines on the eye chart with ocriplasmin than with placebo. Ocular adverse events (e.g., vitreous floaters, photopsia, or injection-related eye pain—all self-reported—or conjunctival hemorrhage) occurred in 68.4% of ocriplasmin-injected eyes and in 53.5% of placebo-injected eyes (P < 0.001), and the incidence of serious ocular adverse events was similar in the two groups (P = 0.26).” (J.A. Haller, jhaller@willseye.org)
Tofacitinib in Active Ulcerative Colitis: In a dose-ranging Phase II trial of 194 adult patients with severely active ulcerative colitis, all doses except the lowest tofacitinib were more effective than placebo for improving clinical response at 8 weeks (pp. 616–24). Tofacitinib, an orally active inhibitor of Janus kinases 1, 2, and 3, was studied in patients with rheumatoid arthritis in last week’s Journal (see PNN, Aug. 9). The drug had this impact on the 8-week primary outcome of absolute decrease from baseline in the score on the Mayo scoring system for assessment of ulcerative colitis activity of 3 or more and a relative decrease from baseline of 30% or more with an accompanying decrease in the rectal bleeding subscore of 1 point or more or an absolute rectal bleeding subscore of 0 or 1: “The primary outcome, clinical response at 8 weeks, occurred in 32%, 48%, 61%, and 78% of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.39), 3 mg (P = 0.55), 10 mg (P = 0.10), and 15 mg (P < 0.001), respectively, as compared with 42% of patients receiving placebo. Clinical remission (defined as a Mayo score ≤2, with no subscore >1) at 8 weeks occurred in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (P = 0.76), 3 mg (P = 0.01), 10 mg (P < 0.001), and 15 mg (P < 0.001), respectively, as compared with 10% of patients receiving placebo. There was a dose-dependent increase in both low-density and high-density lipoprotein cholesterol. Three patients treated with tofacitinib had an absolute neutrophil count of less than 1,500.” (W. J. Sandborn, wsandborn@ucsd.edu)
PSA Screening: A study of prostate surface antigen (PSA) screening (pp. 595–605; E. A. M. Heijnsdijk, e.heijnsdijk@erasmusmc.nl) “shows the way to a resolution of the long-standing controversy about screening for prostate cancer” and “is a model for developing the evidence base for practice guidelines,” an editorialist writes (pp. 669–71): “[This study] says that the net effect of prostate-cancer screening can be a loss or a gain, depending on patients’ utilities for their potential future health states. It is tempting to speculate that most patients will gain, since the range of net benefit is larger for gains (0 to 97.1 life-years) than for losses (0 to −20.7 years). These data do not support that conclusion, because we do not know the number of patients with low utilities for the health states, as compared with the number with higher utilities. If we knew that all patients have utilities consistent with a gain in quality-adjusted life–years, we could recommend universal screening. Until we know the distribution of utilities for these health states, guidelines should avoid recommending for or against PSA screening [in favor of shared decision making].” (H. C. Sox)

>>>PNN NewsWatch
* FDA yesterday warned of 3 deaths and 1 case of life-threatening respiratory depression with usual doses codeine in children after tonsillectomy and adenoidectomy.

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
Aug. 17, 2012 * Vol. 19, No. 160
Providing news and information about medications and their proper use

>>>Oncology Report
Source:
Aug. 10 issue of the Journal of Clinical Oncology (2012; 30).
Diabetes, Metformin & Breast Cancer: Used in postmenopausal women with diabetes, metformin may reduce the risk of invasive breast cancer, researchers report (pp. 2844–52). Based on data from the Women’s Health Initiative for 68,019 postmenopausal women, the study finds these patterns in the 3,401 patients with diabetes when observed over a mean of 11.8 years: “Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2.” (R. T. Chlebowski, rowanchlebowski@gmail.com)
“These findings from the WHI clinical trials, together with the results of the two recent population-based studies, challenge the current wisdom that breast cancer risk is increased after a diagnosis of diabetes,” editorialists write (
pp. 2812–4). They conclude: “Are we making progress in understanding the relationships between diabetes, its treatment, and breast cancer? Absolutely. Do we have sufficient evidence to change clinical practice in relation to either diabetes or breast cancer? Not yet. Understanding these relationships is a work in progress that, like the French lilac from which the biguanides originated, will continue to blossom.” (P. J. Goodwin, pgoodwin@mtsinai.on.ca)

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (2012; 60).
Part D Coverage Gap & Health Outcomes: Medicare Part D beneficiaries did not have increased numbers of adverse cardiovascular outcomes when they lacked financial assistance while in the “doughnut hole,” a study shows (pp. 1408–17). Long-term health consequences were not studied, the authors note. In the prospective cohort study, 9,436 “exposed” patients were admitted to the study when they reached the Part D coverage gap and followed until catastrophic coverage began or the year ended, with these results when compared with 9,436 “unexposed” patients: “In [propensity score]-matched analyses, exposed beneficiaries had higher, albeit not significantly so, hazard of death (hazard ratio (HR) = 1.25, 95% confidence interval (CI) = 0.98–1.59) and [acute coronary syndrome with revascularization] (HR = 1.16, 95% CI = 0.83–1.62) than unexposed beneficiaries. [High-dimensional propensity score]-matched analyses minimized residual confounding and confirmed results (death: HR = 0.99, 95% CI = 0.78–1.24; ACS: HR = 1.07, 95% CI = 0.81–1.41). Exposed beneficiaries were no more or less likely to experience other outcomes than were those who were unexposed.” (J. M. Polinski, jpolinski@partners.org)

>>>Nephrology Report
Source:
Sept. issue of the American Journal of Kidney Diseases (2012; 60).
Theophylline Prophylaxis of Contrast-Induced Acute Kidney Injury: Adenosine receptor antagonists such as theophylline significantly reduce the incidence of acute kidney injury (AKI) secondary to use of contrast media, according to a meta-analysis of 16 trials of 1,412 participants (pp. 360–70). Studies compared adenosine antagonists with or without N-acetylcysteine versus control with or without N-acetylcysteine, finding the following: “Theophylline significantly decreased the risk of contrast-induced AKI (13 trials, 1,222 patients; risk ratio, 0.48; 95% CI, 0.26-0.89; P = 0.02; I2 = 45%) and had a protective effect on the absolute change in serum creatinine concentration (13 trials, 1,170 patients; standardized mean difference, −0.31 mg/dL; 95% CI, −0.50 to −0.11; P = 0.002; I2 = 60%). Meta-regression showed a significant relation between the relative risk of contrast nephropathy and baseline serum creatinine level or Jadad score. No clear effects of treatment on risk of dialysis and in-hospital mortality were identified.” (J. Zhang, zhangjiayou@medmail.com.cn)

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
Aug. 20, 2012 * Vol. 19, No. 161
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 18 issue of Lancet (2012; 380).
Mepolizumab for Severe Eosinophilic Asthma: In 621 patients with severe eosinophilic asthma, the interleukin-5 inhibitor mepolizumab was effective for reducing risk of asthma exacerbations and well tolerated, researchers report (pp. 651–9). Adults and adolescents received one of three doses of i.v. mepolizumab (75, 250, or 750 mg) or placebo during 13 infusions over 4 weeks, with these outcomes: “776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2.40 per patient per year in the placebo group, 1.24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31–61%; p < 0.0001), 1.46 in the 250 mg mepolizumab group (39% reduction, 19–54%; p = 0.0005), and 1.15 in the 750 mg mepolizumab group (52% reduction, 36–64%; p < 0.0001). Three patients died during the study, but the deaths were not deemed to be related to treatment.” (I. D. Pavord, ian.pavord@uhl-tr.nhs.uk)
Azithromycin Prophylaxis Against Non–Cystic Fibrosis Bronchiectasis: In 141 patients with histories of at least one non–cystic fibrosis bronchiectasis exacerbation in the prior year, azithromycin provided a “new option for prevention,” a study concludes (pp. 660–7). At three centers in New Zealand in 2008–09, adults randomly received azithromycin 500 mg or placebo three times a week for 6 months. Effects on coprimary endpoints of rate of event-based exacerbations in the 6-month treatment period, change in FEV1 before bronchodilation, and change in total score on St. George’s respiratory questionnaire (SGRQ) were as follows: “The rate of event-based exacerbations was 0.59 per patient in the azithromycin group and 1.57 per patient in the placebo group in the 6-month treatment period (rate ratio 0.38, 95% CI 0.26–0.54; p < 0.0001). Prebronchodilator FEV1 did not change from baseline in the azithromycin group and decreased by 0.04 L in the placebo group, but the difference was not significant (0.04 L, 95% CI −0.03 to 0.12; p = 0.251). Additionally, change in SGRQ total score did not differ between the azithromycin (–5.17 units) and placebo groups (–1.92 units; difference −3.25, 95% CI −7.21 to 0.72; p = 0.108).” (C. Wong, cawong@middlemore.co.nz)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Monoclonal Antibodies in Diabetic Macular Edema: Bevacizumab and ranibizumab—monoclonal antibodies that target vascular endothelial growth factor but at widely different costs—performed similarly in clinical trials of patients with diabetic macular edema, according to a systematic review and indirect comparison (e5182). LogMAR units were used for assessing best corrected visual acuity, with these results: “Five randomised controlled trials with follow-up of 6–12 months and a common comparator (multiple laser treatment) were sufficiently similar to be included in the indirect comparison. Generally studies were small, resulting in wide credible intervals. The proportions of patients with an improvement in best corrected visual acuity of >2 lines were 21/77 participants (27%) for bevacizumab and 60/152 participants (39%) for ranibizumab (odds ratio 0.95 (95% credible interval 0.23 to 4.32)). The wide credible intervals cannot exclude a greater improvement, or worse outcome, for either drug. The mean change in best corrected visual acuity non-significantly favoured bevacizumab (treatment effect −0.08 logMAR units (−0.19 to 0.04)). The difference in mean change in central macular thickness was not statistically significant between ranibizumab and bevacizumab (treatment effect −6.9 µm (−88.5 to 65.4)).” (J. A. Ford, john.ford@uea.ac.uk)

>>>PNN JournalWatch
* Pathogenesis, and Clinical Approaches, in
Gastroenterology, 2012; 143: 307–20. (E. Seki, ekseki@ucsd.edu)
* Insulin Use in Elderly Adults: Risk of Hypoglycemia and Strategies for Care, in
Journal of the American Geriatrics Society, 2012; 60: 1564–70. (R. J. Ligthelm, rjligthe@xs4all.nl)
* “Tight Control” in Geriatrics: The Emperor Wears a Thong, in
Journal of the American Geriatrics Society, 2012; 60: 1571–5. (T. E. Finucane, tfinucan@jhmi.edu)
* Diagnosis and Management of Early Asthma in Preschool-Aged Children, in
Journal of Allergy and Clinical Immunology, 2012; 130: 287–96. (L. B. Bacharier, bacharier_L@kids.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
Aug. 21, 2012 * Vol. 19, No. 162
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Aug. 21 issue of the Annals of Internal Medicine (2012; 172).
Lead Exposure & Gout: Among patients with blood lead levels (BLLs) in the currently acceptable range, prevalence of gout and hyperuricemia is higher than among patients with lower BLLs, according to a population-based cross-sectional analysis of data from the National Health and Nutrition Examination Survey for 2005–08 (pp. 233–41). Included were 6,153 civilians aged 40 years or older with glomerular filtration rates greater than 10 mL/min per 1.73 sq m, whose data yielded these insights: “The prevalence of gout was 6.05% (95% CI, 4.49% to 7.62%) among patients in the highest BLL quartile (mean, 0.19 µmol/L [3.95 µg/dL]) compared with 1.76% (CI, 1.10% to 2.42%) among those in the lowest quartile (mean, 0.04 µmol/L [0.89 µg/dL]). Each doubling of BLL was associated with an unadjusted odds ratio of 1.74 (CI, 1.47 to 2.05) for gout and 1.25 (CI, 1.12 to 1.40) for hyperuricemia. After adjustment for renal function, diabetes, diuretic use, hypertension, race, body mass index, income, and education level, the highest BLL quartile was associated with a 3.6-fold higher risk for gout and a 1.9-fold higher risk for hyperuricemia compared with the lowest quartile.” (E. Krishnan)
Lipid-Lowering Therapy in Chronic Kidney Disease: In patients with chronic kidney disease (CKD), lipid-lowering therapy lowers rates of cardiac death and atherosclerosis-mediated cardiovascular events, according to a systematic review and meta-analysis of 18 randomized controlled trials (RCTs) (pp. 251–62): “Five RCTs involved CKD populations, and 13 were CKD subgroup analyses from trials in the general population. Sixteen RCTs examined statins, and 2 examined statins plus ezetimibe. Lipid-lowering therapy does not improve kidney outcomes but decreases the risk for cardiac mortality (pooled risk ratio [RR] from 6 trials, 0.82 [95% CI, 0.74 to 0.91]; P < 0.001), cardiovascular events (including revascularization) (pooled RR from 9 trials, 0.78 [CI, 0.71 to 0.86]; P < 0.001), and myocardial infarction (pooled RR from 9 trials, 0.74 [CI, 0.67 to 0.81]; P < 0.001). Significant benefit was also seen for all-cause mortality but was limited by a high degree of heterogeneity. No benefit was found for other cardiovascular outcomes. Rates of adverse events were similar between intervention and comparator groups.” (A. Upadhyay, ashishu@bu.edu)
Statin Therapy in Chronic Kidney Disease: Statins are beneficial in patients with a wide range of chronic kidney disease (CKD), but effects are minimal in those on dialysis and uncertain in patients with kidney transplants, according to a systematic review and meta-analysis of 80 trials with 51,099 participants (pp. 263–75): “Moderate- to high-quality evidence indicated that statins reduced all-cause mortality (relative risk [RR], 0.81 [95% CI, 0.74 to 0.88]), cardiovascular mortality (RR, 0.78 [CI, 0.68 to 0.89]), and cardiovascular events (RR, 0.76 [CI, 0.73 to 0.80]) in persons not receiving dialysis. Moderate- to high-quality evidence indicated that statins had little or no effect on all-cause mortality (RR, 0.96 [CI, 0.88 to 1.04]), cardiovascular mortality (RR, 0.94 [CI, 0.82 to 1.07]), or cardiovascular events (RR, 0.95 [CI, 0.87 to 1.03]) in persons receiving dialysis. Effects of statins in kidney transplant recipients were uncertain. Statins had little or no effect on cancer, myalgia, liver function, or withdrawal from treatment, although adverse events were evaluated systematically in fewer than half of the trials.” (G. F. M. Strippoli, strippoli@negrisud.it)
First- v. Second-Generation Antipsychotics: “Clear benefits” of second-generation agents (SGAs) over first-generation antipsychotics (FGAs) remain unproven, a systematic review and meta-analysis of 114 studies concludes (online first): “Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine for improving positive symptoms, but the benefit was scale-dependent.… Moderate-strength evidence showed a clinically important benefit of olanzapine over haloperidol in improving negative symptoms when the [Positive and Negative Syndrome Scale] and the Scale for the Assessment of Negative Symptoms were used.… Evidence was insufficient to draw conclusions for diabetes mellitus.” (L. Hartling, hartling@ualberta.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, 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
Aug. 22, 2012 * Vol. 19, No. 163
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 22/29 issue of JAMA (2012; 308).
Statins & Pancreatitis: In patients with normal or mildly elevated triglyceride levels, statin therapy is associated with a lower risk of pancreatitis, according to a meta-analysis (pp. 804–11): “In 16 placebo- and standard care–controlled statin trials with 113,800 participants conducted over a weighted mean follow-up of 4.1 (SD, 1.5) years, 309 participants developed pancreatitis (134 assigned to statin, 175 assigned to control) (RR, 0.77 [95% CI, 0.62–0.97; P = .03; I2 = 0%]). In 5 dose-comparison statin trials with 39,614 participants conducted over 4.8 (SD, 1.7) years, 156 participants developed pancreatitis (70 assigned to intensive dose, 86 assigned to moderate dose) (RR, 0.82 [95% CI, 0.59–1.12; P = .21; I2 = 0%]). Combined results for all 21 statin trials provided RR 0.79 (95% CI, 0.65–0.95; P = .01; I2 = 0%). In 7 fibrate trials with 40,162 participants conducted over 5.3 (SD, 0.5) years, 144 participants developed pancreatitis (84 assigned to fibrate therapy, 60 assigned to placebo) (RR, 1.39 [95% CI, 1.00–1.95; P = .053; I2 = 0%]).” (D. Preiss, david.preiss@glasgow.ac.uk)
Cardiovascular Risk Assessment: Two studies and an editorial explore “cardiovascular risk assessment in the 21st century.”
For intermediate-risk patients, coronary artery calcium, ankle-brachial index, high-sensitivity C-reactive protein, and family history are important predictors of incident coronary heart disease (CHD) and cardiovascular disease (CVD), researchers report (
pp. 788–95). Data from the Multi-Ethnic Study of Atherosclerosis (MESA) for 6,814 participants were mined to identify 1,330 patients with intermediate risk, no diabetes mellitus, and complete information on six markers. The above predictors were more common in those who had 94 CHD and 123 CVD events than in others. (J. Yeboah, jyeboah@wakehealth.edu)
In 14 population-based cohorts and 45,838 individuals, “addition of common [carotid intima-media thickness (CIMT)] measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke,” but the improvement is probably not clinically relevant (
pp. 796–803): “During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749–0.764; and 0.759; 95% CI, 0.752–0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%–1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%–4.6%) and no differences between men and women.” (H. M. Den Ruijter, hruijte2@umcutrecht.nl)
Editorialists provide “a few simple questions” for assessing a patient’s overall vascular risk (
pp. 816–7): “First, does the patient have known cardiovascular disease? If the answer is yes, there is not really any need to use a risk calculator because these individuals are at sufficiently high enough risk to warrant aggressive management. If the answer is no, a risk calculator is useful. Second, does the patient have diabetes mellitus? If the answer is yes, more aggressive management of cardiovascular disease risk factors should be considered, especially because the long-term burden of cardiovascular disease in diabetic patients is so high. Third, if the simple risk calculator, such as [Framingham Risk Score] or Adult Treatment Panel calculators, identifies patients at low risk (<5% over 10 years), or high risk (>20% over 10 years), then risk refinement is not as informative. For patients at intermediate risk (ie, 5% to <20% estimated risk over 10 years), clinicians may be in a position to refine the risk estimate with a [[coronary artery calcium (CAC)] scan. Another possibility is repeating a risk assessment in a few months, and that strategy deserves further study. Coronary artery calcium score appears to augment the risk assessment process but may have limited utility in terms of tracking an individual patient’s vascular risk because it is unlikely that CAC imaging will be tracked over time. This limitation might change in the future as non-ionizing imaging methods are developed to quantify the atherosclerotic burden.” (J. M. Gaziano, jmgaziano@partners.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, 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
Aug. 23, 2012 * Vol. 19, No. 164
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 23 issue of the New England Journal of Medicine (2012; 367).
Preprocedural Eltrombopag in Cirrhosis and Thrombocytopenia: An oral thrombopoietin agonist reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing invasive elective procedures, but eltrombopag produced higher rates of portal-vein thrombosis, compared with placebo (pp. 716–24). In the Eltrombopag Evaluated for Its Ability to Overcome Thrombocytopenia and Enable Procedures (ELEVATE) study, 292 patients received placebo or eltrombopag 75 mg daily for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose, with these results: “A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P<0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups.” (N. H. Afdhal, nafdhal@bidmc.harvard.edu)
AIDS-Like Condition in Asian Adults: In adults in Thailand and Taiwan, neutralizing autoantibodies to interferon-gamma were detected in 88% of patients with multiple opportunistic infections, researchers report (pp. 725–34). Comparing the condition to advanced HIV infection, investigators made these observations about five groups of patients (52 with disseminated, rapidly or slowly growing, nontuberculous mycobacterial infection [group 1)]; 45 with another opportunistic infection, with or without nontuberculous mycobacterial infection [group 2)]; 9 with disseminated tuberculosis [group 3)]; 49 with pulmonary tuberculosis [group 4)]; and 48 healthy controls [group 5)]: “Patients in groups 1 and 2 had CD4+ T-lymphocyte counts that were similar to those in patients in groups 4 and 5, and they were not infected with the human immunodeficiency virus (HIV). Washed cells obtained from patients in groups 1 and 2 had intact cytokine production and a response to cytokine stimulation. In contrast, plasma obtained from these patients inhibited the activity of interferon-gamma in normal cells. High-titer anti–interferon-gamma autoantibodies were detected in 81% of patients in group 1, 96% of patients in group 2, 11% of patients in group 3, 2% of patients in group 4, and 2% of controls (group 5). Forty other anticytokine autoantibodies were assayed. One patient with cryptococcal meningitis had autoantibodies only against granulocyte–macrophage colony-stimulating factor. No other anticytokine autoantibodies or genetic defects correlated with infections. There was no familial clustering.” (S. K. Browne, brownesa@niaid.nih.gov)
Bariatric Surgery for Diabetes Prevention: In 1,658 Swedish patients with obesity who underwent bariatric surgery, the procedure was “markedly more efficient than usual care in the prevention of type 2 diabetes,” a study shows (pp. 695–704). Those receiving bariatric surgery were 37–60 years of age and had BMIs of 34 or more in men or 38 or more in women. Compared with 1,771 matched controls with obesity, the rates of incident type diabetes were determined as follows after 15 years of follow-up for about two-thirds of the study populations: “During the follow-up period, type 2 diabetes developed in 392 participants in the control group and in 110 in the bariatric-surgery group, corresponding to incidence rates of 28.4 cases per 1,000 person–years and 6.8 cases per 1,000 person–years, respectively (adjusted hazard ratio with bariatric surgery, 0.17; 95% confidence interval, 0.13 to 0.21; P < 0.001). The effect of bariatric surgery was influenced by the presence or absence of impaired fasting glucose (P = 0.002 for the interaction) but not by BMI (P = 0.54). Sensitivity analyses, including end-point imputations, did not change the overall conclusions. The postoperative mortality was 0.2%, and 2.8% of patients who underwent bariatric surgery required reoperation within 90 days owing to complications.” (L. Sjöström, lars.v.sjostrom@medfak.gu.se)

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
Aug. 24, 2012 * Vol. 19, No. 165
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (2012; 35).
Diabetes & Cause-Specific Mortality: In 1 million U.S. adults, those with diabetes had higher risks of death from many diseases, including cancers, report investigators who analyzed histories of those who enrolled in the Cancer Prevention Study-II in 1982 and were followed until 2008 (pp. 1835–44): “During 26 years of follow-up, 243,051 men and 222,109 women died. In multivariable models that controlled for age, BMI, and other variables, diabetes was associated with higher risk of all-cause mortality (women RR 1.90 [95% CI 1.87–1.93]; men 1.73 [1.70–1.75]). Among women, diabetes was associated with higher risk of death from cancers of the liver (1.40 [1.05–1.86]), pancreas (1.31 [1.14–1.51]), endometrium (1.33 [1.08–1.65]), colon (1.18 [1.04–1.33]), and breast (1.16 [1.03–1.29]). Among men, diabetes was associated with risk of death from cancers of the breast (4.20 [2.20–8.04]), liver (2.26 [1.89–2.70]), oral cavity and pharynx (1.44 [1.07–1.94]), pancreas (1.40 [1.23–1.59]), bladder (1.22 [1.01–1.47]), colon (1.15 [1.03–1.29]), and (inversely) prostate (0.88 [0.79–0.97]). Diabetes was also associated with higher risks of death involving the circulatory system, respiratory system, digestive system, genitourinary system, and external causes/accidental deaths.” (P. T. Campbell, peter.campbell@cancer.org)
Mortality, Diabetes & Severe Hypoglycemia: In a study of 1,013 adults with diabetes, self-reports of severe hypoglycemia were associated with a 3.4-fold increase in mortality risk (pp. 1897–901). Participants were seen in a specialty diabetes clinic in 2005–06; medical records checked 5 years later showed the following when stratified by self-reports of severe hypoglycemia at baseline: “In total, 1,013 patients with type 1 (21.3%) and type 2 (78.7%) diabetes were questioned about hypoglycemia. Among these, 625 (61.7%) reported any hypoglycemia, and 76 (7.5%) reported severe hypoglycemia. After 5 years, patients who reported severe hypoglycemia had 3.4-fold higher mortality (95% CI 1.5–7.4; P = 0.005) compared with those who reported mild/no hypoglycemia.” (S. A. Smith, smith.steven@mayo.edu)

>>>Rheumatology Report
Source:
Aug. issue of Arthritis & Rheumatism (2012; 64).
Golimumab in Psoriatic Arthritis: In a 1-year study of 405 patients with active psoriatic arthritis (PsA), golimumab treatment inhibited structural damage progression was effective and safe throughout the trial, researchers report (pp. 2504–17). Participants were adults with 3 or more swollen and 3 or more tender joints. They received subcutaneous placebo, golimumab 50 or 100 mg every 4 weeks through week 20, with these changes from baseline to week 24 in PsA-modified Sharp/van der Heijde score (SHS): “Mean changes in PsA-modified SHS from baseline to week 24 for the combined golimumab 50 mg and 100 mg group (−0.09) and the golimumab 50 mg group (−0.16) were significantly different versus placebo (0.27) (P = 0.015 and P = 0.011, respectively). Radiographic benefit was maintained through week 52 with golimumab. Clinical efficacy, including improvement in joint and skin responses and physical function, was maintained through 1 year. The frequency/types of adverse events were similar to those reported through week 24.” (A. Kavanaugh, akavanaugh@ucsd.edu)
Gastroprotection During Coxib Therapy: Patients at high risk of upper gastrointestinal (UGI) tract complications who do not adhere to gastroprotective agents (GPAs) during treatment with cyclooxygenase-2 inhibitors (coxibs) have increased rates of UGI events, a study shows (pp. 2792–802). Three primary-care databases yielded this information when analyzed in a case–control fashion for 31,000 patients 50 years and older: “Most patients were treated with coxibs for <30 days. Seventy-four patients had a UGI tract event during or shortly after a coxib treatment interval in which a GPA was coprescribed, with an incidence rate of 11.9 (95% CI 9.4–14.8) per 1,000 years of coxib treatment. The risk of UGI tract events was 1.97 (95% CI 0.84–4.60) for patients with <20% adherence to GPAs compared to patients with >80% adherence to GPAs. For every 10% decrease in GPA adherence, the risk of UGI tract events increased by 9% (OR 1.09 [95% CI 1.00–1.18]).” (V. E. Valkhoff, v.valkhoff@erasmusmc.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
Aug. 27, 2012 * Vol. 19, No. 166
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 25 issue of Lancet (2012; 380).
I.V. Aspirin With Alteplase in Acute Ischemic Stroke: Three-month outcomes were not improved and intracranial bleeding was worse when aspirin was administered intravenously in alteplase-treated patients with ischemic stroke, the ARTIS trial shows (pp. 731–7). In this open-label study, patients with acute ischemic stroke received i.v. aspirin 300 mg within 90 minutes of the start of alteplase treatment or no additional treatment, with this impact on modified Rankin scale scores at 3 months: “Between July 29, 2008, and April 20, 2011, 642 patients (322 patients aspirin, 320 patients standard treatment) of the targeted 800 patients were enrolled. At that time, the trial was terminated prematurely because of an excess of symptomatic intracranial haemorrhage (SICH) and no evidence of benefit in the aspirin group. At 3 months, 174 (54.0%) patients in the aspirin group versus 183 (57.2%) patients in the standard treatment group had a favourable outcome (absolute difference −3.2%, 95% CI –10.8 to 4.2; crude relative risk 0.94, 0.82 to 1.09, p = 0.42). Adjusted odds ratio was 0.91 (95% CI 0.66–1.26, p = 0.58). SICH occurred more often in the aspirin group (14 [4.3%] patients) than in the standard treatment group (five [1.6%]; absolute difference 2.8%, 95% CI 0.2–5.4; p = 0.04). SICH was more often the cause of poor outcome in the aspirin group compared with the standard treatment group (11 vs 1, p = 0.006).” (Y. B. Roos, y.b.roos@amc.uva.nl)
Apremilast for Psoriasis: Apremilast was effective and safe in a study of moderate to severe plaque psoriasis (pp. 738–46). The phosphodiesterase-4 inhibitor was given in doses of 10, 20, or 30 mg twice daily at sites in the U.S. and Canada. After 16 weeks of concealed treatment, those on placebo could be switched to active therapy for 8 weeks with doses blinded. A primary endpoint of proportion of patients achieving 75% reduction from baseline psoriasis area and severity index (PASI-75) at week 16 showed: “At week 16, PASI-75 was achieved in five patients (6%) assigned placebo, ten (11%) assigned apremilast 10 mg, 25 (29%) assigned 20 mg, and 36 (41%) assigned 30 mg. Apremilast 10 mg did not differ significantly from placebo in achievement of the endpoint (odds ratio 2.10; 95% CI 0.69–6.42); for both apremilast 20 mg (6.69; 2.43–18.5; p < 0.0001) and apremilast 30 mg (11.5; 4.24–31.2; p < 0.0001), the differences from placebo were significant. Most adverse events (96%) were mild or moderate; at least 5% of patients had nausea, upper respiratory tract infection, diarrhoea, nasopharyngitis, headache, arthralgia (placebo), gastroenteritis, or dyspepsia. Eight serious adverse events occurred (three each, placebo and apremilast 20 mg; two, apremilast 30 mg); none were judged to be related to apremilast. Apremilast had no apparent effect on the results of haematological, urinalysis, immunological or inflammation, serum chemistry, or electrocardiographic tests.” (K. Papp, kapapp@probitymedical.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Trends in HIV Drug Resistance: In the U.K., time trends show a stablization of prevalence of transmitted drug resistance in HIV-1 isolates (e5253). Among 14,584 patients first tested in 2002–09, 1,654 had resistant strains: “Prevalence was found to decline from 15.5% in 2002 to 9.6% in 2007, followed by a slight increase to 10.9% in 2009 (P = 0.21). This later rise was mainly a result of increases in resistance to nucleos(t)ide reverse transcriptase inhibitors (from 5.4% in 2007 to 6.6% in 2009, P = 0.24) and protease inhibitors (1.5% to 2.1%, P = 0.12). Thymidine analogue mutations, including T215 revertants, remained the most frequent mutations associated with nucleos(t)ide reverse transcriptase inhibitors, despite a considerable fall in stavudine and zidovudine use between 2002 and 2009 (from 29.4% of drug regimens in 2002 to 0.8% in 2009, from 47.9% to 8.8%, respectively).” (D. Dolling, avid.dolling@ctu.mrc.ac.uk">David.dolling@ctu.mrc.ac.uk)

>>>PNN JournalWatch
* Clinical Implications for Cannabinoid Use in the Rheumatic Diseases: Potential for Help or Harm?, in
Arthritis & Rheumatism, 2012; 64: 2417–25. (M-A Fitzcharles, mary-ann.fitzcharles@muhc.mcgill.ca)
* Visits to Retail Clinics Grew Fourfold From 2007 to 2009, Although Their Share of Overall Outpatient Visits Remains Low, in
Health Affairs, 2012; 10.1377/hlthaff.2011.1128. (A. Mehrotra, mehrotra@rand.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, 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
Aug. 28, 2012 * Vol. 19, No. 167
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Aug. 27 issue of the Archives of Internal Medicine (2012; 172).
CER of Beta-Blockers in Hypertension: Negative clinical trial data for atenolol when used for preventing cardiovascular (CV) events in patients after myocardial infarction (MI) or with heart failure (HF) may also apply to other beta-blockers, researchers report (10.1001/archinternmed.2012.4276). An analysis of data from the Cardiovascular Research Network Hypertension Registry (CVRN) shows these patterns for new users of beta-blockers in 2000–09: “During follow-up (median, 5.2 years), there were 3,517 incident MI, 3,272 incident HF, and 3,664 incident stroke events. Hazard ratios for MI, HF, and stroke in metoprolol tartrate users were 0.99 (95% CI, 0.97–1.02), 0.99 (95% CI, 0.96-1.01), and 0.99 (95% CI, 0.97–1.02), respectively. An alternative approach using propensity score matching yielded similar results in 11,176 new metoprolol tartrate users, who were similar to 11,176 new atenolol users with regard to demographic and clinical characteristics.” (E. D. Parker, Emily.D.Parker@Healthpartners.com)
Given the lack of efficacy of beta-blockers in this setting, the “current question of primary interest is whether health outcomes associated with the use of hydrochlorothiazide and chlorthalidone may differ,” authors write in an invited commentary (
10.1001/archinternmed.2012.4306). “Low-dose thiazide-type diuretics are the first-line therapy for the treatment of uncomplicated hypertension, and recent evidence suggests the possibility that chlorthalidone may provide better control of blood pressure and a lower risk of cardiovascular events than thiazides. However, in the United States chlorthalidone is not widely used, and such a comparison may not have been possible in the CVRN. Reliable and valid comparisons between hydrochlorothiazide and chlorthalidone will require a large, long-term clinical trial.” (J. S. Floyd, jfloyd@uw.edu)
Discontinuation of LABAs in Asthma: Discontinuing long-acting beta-2-agonist (LABA) therapy in adults and older children with asthma controlled with a combination of inhaled corticosteroids (ICSs) and LABAs may be associated with increased asthma-related impairment, according to a review of five clinical trials (10.1001/archinternmed.2012.3250): “Results did not favor the LABA step-off approach compared with no change in treatment. The LABA step-off regimen increased asthma impairment, with worse Asthma Quality of Life Questionnaire score (mean difference [95% CI], 0.32 [0.14–0.51] points lower); worse Asthma Control Questionnaire score (0.24 [0.13–0.35] points higher); fewer symptom-free days (9.15% [1.62%–16.69%] less); and greater risk of withdrawal from study resulting from lack of efficacy or loss of asthma control (risk ratio, 3.27 [2.16–4.96]). Risk of exacerbations and deaths after LABA step-off were not evaluable because of the small number of events and short duration of follow-up.” (T. B. Casale, tbcasale@creighton.edu)

>>>PNN NewsWatch
* FDA yesterday approved the first once-daily combination product for use in treatment-naive adults with HIV infection. Stribild (Gilead) contains elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate. The safety and effectiveness of the combination product was evaluated in 1,408 adult patients not previously treated for HIV in two double-blind clinical trials. Patients were randomly assigned to receive Stribild or Atripla, which contains Truvada and efavirenz, once daily in the first trial; and Stribild or Truvada plus atazanavir and ritonavir once daily in the second trial. Results showed that 88% to 90% of patients treated with Stribild had an undetectable amount of HIV in their blood, compared with 84% treated with Atripla and 87% treated with Truvada plus atazanavir and ritonavir. Common adverse effects in clinical trials included nausea and diarrhea. Serious adverse effects included new or worsening kidney problems, decreased bone mineral density, fat redistribution and changes in the immune system (immune reconstitution syndrome). Patients should be monitored for kidney or bone adverse effects, FDA 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, 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
Aug. 29, 2012 * Vol. 19, No. 168
Providing news and information about medications and their proper use

>>>Medical Care Report
Source:
Aug. and Sept. issues of Medical Care (2012; 50).
Pharmacy Effects on Medication Adherence: Patients’ adherence to medication therapy varies according to which pharmacy they use, a study shows (pp. 685–91). Future studies should identify underlying reasons for this effect and contributing pharmacy characteristics and practice style differences, the authors conclude. The study retrospectively analyzed cross-sectional design and insurance claims data for adults aged 18–64 who had employer-sponsored private health plans, finding: “We estimated models with and without covariates. In both models, pharmacy cluster effect was statistically significant (P < 0.001). In the model without covariates, pharmacy cluster effect accounted for 12.8% (95% confidence interval, 12.4%–13.1%) of total variance in adherence, whereas in the model with covariates pharmacies accounted for 12.1% (95% confidence interval, 11.6%–12.4%) of total variance. Covariates associated significantly with adherence were age, sex, mail order pharmacy, and prescription drug copay.” (K. P. Sharma)
Health Promotion in the Workplace: An evaluation of two health promotions at the U. Minnesota shows reduced health care expenditures in a disease-management program’s third year of operation (pp. 772–8). Health care expenditure and absenteeism data for 2004–08 were gathered along with participation data for Minnesota’s 10,000 Steps walking program and Miavita self-help programs. The authors, looking for reasons why such a third-year effect has been previously identified, report: “The study finds that a 1.76 return on investment occurs in the third year of operation that is generated solely by the effect of disease management program participation in reducing health care expenditures. However, neither of the explanations for a third-year effect we tested seemed to be able to explain this phenomenon.” (J. A. Nyman)

>>>Health Affairs Highlights
Source:
Aug. issue of Health Affairs (2012; 31).
ACOs for Vulnerable Populations: Special attention is needed to ensure that clinically at-risk patients and the socially disadvantaged enjoy the benefits of accountable care organizations (ACOs), report authors who provide “a framework to use in considering challenges for both vulnerable patients and health systems on the path to accountable care” (pp. 1777–85). The group concludes: “Notably, because clinically vulnerable populations are geographically dispersed and use a good deal of clinical care, these patients are most susceptible to problems within a given ACO. In contrast, socially disadvantaged groups are geographically concentrated and receive a disproportionate amount of care in low-performing health care systems. They face barriers to care largely at the level of communities or health care organizations.
“ACOs offer sizable potential benefits to each of these groups: the promise of improved care coordination and care management for the clinically vulnerable; and the promise of overall improved quality of care and coordination with social services for the socially disadvantaged. Obstacles to receiving accountable care involve access, quality, and cost. We must carefully design ACO programs and policies so that all Americans may experience the intended benefits of these organizations.” (V. A. Lewis,
Valerie.A.Lewis@Dartmouth.edu)
Post-Katrina Medical Homes in New Orleans: As Hurricane Isaac dumps rain on New Orleans on the seventh anniversary of Katrina’s landfall, an article recounts the conversion of clinics into medical homes as the city rebuilt after that 2005 storm destroyed much of the city’s health care infrastructure (pp. 1729–38). Surveys of clinic leaders and analysis of administrative data yielded these insights: “Clinics made substantial progress in implementing new clinical processes to improve access, quality and safety, and care coordination and integration. But there was wide variation, with some clinics making only minimal progress. Because the transformation was closely tied to the receipt of federal grants and bonus payments, we observed declines in performance toward the end of the study, when clinics faced diminished federal funding and refocused their priorities on survival. Now that federal funds have dried up, moreover, clinics may be losing ground in sustaining their practice changes.” (D. R. Rittenhouse, Rittenhouse@fcm.ucsf.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
Aug. 30, 2012 * Vol. 19, No. 169
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 30 issue of the New England Journal of Medicine (2012; 367).
Predictive Markers in Inherited Alzheimer’s Disease: Pathophysiologic changes in patients with autosomal dominant Alzheimer’s disease include biochemical markers in the cerebrospinal fluid (CSF), brain amyloid deposition, changes in brain metabolism, and progressive cognitive impairment, according to results of the Dominantly Inherited Alzheimer Network (DIAN) study of 128 participants (pp. 795–804): “Concentrations of amyloid-beta (AßWinking42 in the CSF appeared to decline 25 years before expected symptom onset. Aß deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini–Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.” (R. J. Bateman, batemanr@wustl.edu)
With markers changing years before symptom onset in this study, an editorialist imagines possible long-term management of patients at risk for inherited Alzheimer’s disease (
pp. 864–6): “Should we begin to think of lifelong control of Aß metabolism in the same way that we now think of lifelong control of cholesterol metabolism? The lesson of the DIAN study and of [a 2011] study on the protective [Aß precursor protein (APP)] mutation is that reduction of the risk of late-life dementia requires a long-term and possibly lifelong effort. What is also clear—regardless of whether, in light of the protective APP mutation, one considers the ‘amyloid hypothesis of Alzheimer’s disease’ as proven or not — is that any comprehensive strategy aimed at reduction of late-life dementia risk will almost certainly include monitoring and immunopharmacologic or neuropharmacologic control of Aß metabolism.” (S. Gandy)
Clopidogrel Added to Aspirin in Recent Lacunar Stroke: Among 3,020 patients with recent stroke in small cerebral blood vessels, addition of clopidogrel to aspirin did not improve risks of recurrent stroke, but risks of bleeding and death were higher, researchers report (pp. 817–25). In the SPS3 trial, patients had recent lacunar infarcts when they randomly received aspirin 325 mg daily plus clopidogrel 75 mg or placebo, with these results: “After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P < 0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P = 0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone).” (O. R. Benavente, scar.benavente@ubc.ca">oscar.benavente@ubc.ca)

>>>PNN NewsWatch
* FDA yesterday approved everolimus tablets for oral suspension (Afinitor Disperz, Novartis), a new pediatric dosage form indicated for treatment of subependymal giant cell astrocytoma in patients 1 year of age or older. The agency also approved Sicor Biotech’s tbo-filgrastim to reduce the time in neutropenia in adults on myelosuppressive regimens for nonmyeloid malignancies. This short-acting form of G-CSF will be available in Nov. 2013 in accordance with a settlement between Teva and Amgen.

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
Aug. 31, 2012 * Vol. 19, No. 170
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Sept. 15 issue of Clinical Infectious Diseases (2012; 55).
Asymptomatic Bacteriuria in Recurrent UTIs: In young women with recurrent urinary tract infection (UTIs), asymptomatic bacteriuria (AB) should not be treated because it “may play a protective role in preventing symptomatic recurrence,” authors conclude (pp. 771–7). In 673 consecutive asymptomatic young women with demonstrated bacteriuria seen from 2005 to 2009, those not treated (group A, n = 312) and treated (group B, n = 361) had these clinical and microbiological outcomes at 3, 6, and 12 months: “At baseline, the 2 most commonly isolated pathogens were Escherichia coli (group A, 38.4%; group B, 39.3%) and Enterococcus faecalis (group A, 32.7%; group B, 33.2%). At the first follow-up visit, there was no difference between the 2 groups (relative risk [RR], 1.05; 95% confidence interval [CI], 1.01–1.10), whereas after 6 months, 23 (7.6%) in group A and 98 (29.7%) in group B showed recurrence with a statistically significant difference (RR, 1.31; 95% CI, 1.21–1.42; P < .0001). At the last follow-up, 41 (13.1%) in group A and 169 (46.8%) in group B showed recurrence (RR, 3.17; 95% CI, 2.55–3.90; P < .0001). One patient in group A and 2 patients in group B were found to have pyelonephritis.” (T. Cai, ktommy@libero.it)
Piperacillin MIC & Pneumococcal Outcomes: Recent lowering of the piperacillin susceptibility breakpoint from 64 to 16 mcg/mL is supported by clinical data from a retrospective cohort study of children with Pseudomonas aeruginosa bacteremia in 2001–10 (pp. 799–806). The Clinical and Laboratory Standards Institute made the adjustment based largely on pharmacokinetic–pharmacodynamic (PK–PD) modeling studies, the authors note. Their clinical data found these patterns in 30-day mortality outcomes in children whose infecting organisms had piperacillin minimum inhibitory concentrations (MICs) of ≤16 mcg/mL and of 32–64 mcg/mL: “There were 170 children with P. aeruginosa bacteremia receiving piperacillin therapy who met inclusion criteria. One hundred twenty-four (72%) children had piperacillin MICs of ≤16 mcg/mL and 46 (28%) children had piperacillin MICs of 32–64 mcg/mL. There was no significant difference in baseline characteristics between the 2 groups. Thirty-day mortality was 9% and 24% in children with a piperacillin MIC of ≤16 mcg/mL and of 32–64 mcg/mL, respectively. Using multivariable logistic regression, children with elevated MICs had increased odds of mortality compared with children with lower MICs (odds ratio, 3.21; 95% confidence interval, 1.26–8.16).” (P. D. Tamma, ptamma1@jhmi.edu)
Vaccine Administration Decision Making: A study of vaccine providers shows that targeted information about yellow fever disease and serious risks of the yellow fever vaccine was “necessary but insufficient” to enable providers to “apply evidence, overcome cognitive decision-making errors, and involve patients in vaccine decisions” (pp. 837–43). More than one third of providers making one or more incorrect initial decisions did not change their advice after being presented with risk–benefit information. (B. A. Lown, blown@mah.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday approved linaclotide (Linzess, Ironwood Pharmaceuticals and Forest) for treatment of adult men and women with chronic idiopathic constipation (CIC) or irritable bowel syndrome with constipation (IBS-C). A first-in-class guanylate cyclase-C agonist, linaclotide acts locally in the intestine to reduce intestinal pain and increase gastrointestinal transit. The safety and effectiveness of linaclotide for management of IBS-C were established in two, double-blind studies. In Phase III trials of more than 2,800 adults, linaclotide was more effective in reducing the amount of abdominal pain in patients with IBS-C and increasing the number of complete spontaneous bowel movements in patients with either IBS-C or CIC, compared with placebo. For those with CIC, two doses are approved: 145 or 290 mcg once daily. The 290-mcg dose is not approved for chronic constipation because studies indicated it was no more effective than the 145-mcg dose. Linaclotide is approved with a boxed warning that the drug should not be used in patients 17 years of age and younger. The most common adverse effects of linaclotide during clinical studies were diarrhea, abdominal pain, flatulence, and abdominal distension.
*
PNN will not be published on Mon. Sept. 3, Labor Day.

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
Sept. 4, 2012 * Vol. 19, No. 171
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 4 issue of the Annals of Internal Medicine (2012; 157).
Immune Reconstitution Inflammatory Syndrome After HIV/TB Therapy: Immune reconstitution inflammatory syndrome (IRIS) presents several challenges when antiretroviral therapy (ART) is started during early phases of treatment for tuberculosis, a study shows (pp. 313–24). At an outpatient clinic in South Africa, secondary analysis of data from the SAPiT (Starting Antiretroviral Therapy at Three Points in Tuberculosis) trial showed these patterns in 642 patients randomly assigned to initiate ART within 4 weeks of either tuberculosis treatment initiation (early integrated treatment group), completion of the intensive phase of tuberculosis treatment (late integrated treatment group), or completion of tuberculosis therapy (sequential treatment group): “Incidence of IRIS was 19.5 (n = 43), 7.5 (n = 18), and 8.1 (n = 19) per 100 person–years in the early integrated, late integrated, and sequential treatment groups, respectively. Among patients with a baseline CD4+ count less than 0.050 × 109 cells/L, IRIS incidence was 45.5, 9.7, and 19.7 per 100 person–years in the early integrated, late integrated, and sequential treatment groups, respectively. Incidence of IRIS was higher in the early integrated treatment group than in the late integrated (incidence rate ratio, 2.6 [95% CI, 1.5 to 4.8]; P < 0.001) or sequential (incidence rate ratio, 2.4 [CI, 1.4 to 4.4]; P < 0.001) treatment groups. More severe IRIS cases occurred in the early integrated treatment group than in the other 2 groups (35% vs. 19%; P = 0.179), and patients in the early integrated treatment group had significantly higher hospitalization rates (42% vs. 14%; P = 0.007) and longer time to resolution (70.5 vs. 29.0 days; P = 0.001) than patients in the other 2 groups.” (K. Naidoo)
Insulin Delivery, Glucose Monitoring in Diabetes: In a comparative effectiveness and safety systematic review and meta-analysis, technology-driven means of administering insulin and monitoring glucose were generally superior to methods that depended on patients, researchers report (pp. 336–47). Analysis of data from 33 randomized controlled trials of children and adults showed these patterns for multiple daily injections (MDI), rapid-acting analogue–based continuous subcutaneous insulin infusion (CSII), self-monitoring of blood glucose (SMBG), and real-time continuous glucose monitoring (rt-CGM): “MDI and CSII showed similar effects on hemoglobin A1c (HbA1c) levels and severe hypoglycemia in children or adults with type 1 diabetes mellitus and adults with type 2 diabetes mellitus. In adults with type 1 diabetes mellitus, HbA1c levels decreased more with CSII than with MDI, but 1 study heavily influenced these results. Compared with SMBG, rt-CGM achieved a lower HbA1c level (between-group difference of change, −0.26% [95% CI, −0.33% to −0.19%]) without any difference in severe hypoglycemia. Sensor-augmented insulin pump use decreased HbA1c levels more than MDI and SMBG did in persons with type 1 diabetes mellitus (between-group difference of change, −0.68% [CI, −0.81% to −0.54%]). Little evidence was available on other outcomes.” (S. Hill Golden, sahill@jhmi.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Systemic Steroids After Tonsillectomy: Because of an increased need for surgical management of bleeding, systemic steroids should be used cautiously in patients undergoing tonsillectomy, according to authors of a systematic review and meta-analysis (e5389): “Of 1,387 citations identified, 29 randomised controlled trials (n = 2,674) met all eligibility criteria. Seven studies presented a low risk of bias, but none was specifically designed to systematically identify postoperative bleeding. Administration of systemic steroids did not significantly increase the incidence of post-tonsillectomy bleeding (29 studies, n = 2,674 patients, odds ratio 0.96 (95% confidence interval 0.66 to 1.40), I2 = 0%). We observed a significant increase in the incidence of operative reinterventions for bleeding episodes in patients who received systemic steroids (12, n = 1,178, 2.27 (1.03 to 4.99), I2 = 0%). No deaths were reported. Sensitivity analyses were consistent with the findings.” (A. F. Turgeon, alexis.turgeon@fmed.ulaval.ca)

>>>PNN JournalWatch
* Identification of New Susceptibility Loci for Osteoarthritis (arcOGEN): A Genome-wide Association Study, in
Lancet, 2012; 380: 815–23. (arcOGEN Consortium)

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
Sept. 5, 2012 * Vol. 19, No. 172
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 5 issue of JAMA (2012; 308).
Clopidogrel & Adverse Events in Diabetes: Possibly because of higher platelet reactivity, clopidogrel produces lower reductions in mortality in patients with diabetes than in those without the disease, a study shows (pp. 882–9). Danish nationwide registries for 2002–09 were examined for patients who survived for 30 days after being hospitalized for incident myocardial infarction (MI) and who had not undergone coronary artery bypass surgery. Patterns for up to 1 year later showed the following: “Of the 58,851 patients included in the study, 7,247 (12%) had diabetes and 35,380 (60%) received clopidogrel. In total, 1,790 patients (25%) with diabetes and 7,931 patients (15%) without diabetes met the composite end point. Of these, 1,225 (17%) with and 5,377 (10%) without diabetes died. In total, 978 patients (80%) with and 4,100 patients (76%) without diabetes died of events of cardiovascular origin. For patients with diabetes who were treated with clopidogrel, the unadjusted mortality rates (events/100 person–years) were 13.4 (95% CI, 12.8–14.0) vs 29.3 (95% CI, 28.3–30.4) for those not treated. For patients without diabetes who were treated with clopidogrel, the unadjusted mortality rates were 6.4 (95% CI, 6.3–6.6) vs 21.3 (95% CI, 21.0–21.7) for those not treated. However, among patients with diabetes vs those without diabetes, clopidogrel was associated with less effectiveness for all-cause mortality (HR, 0.89 [95% CI, 0.79–1.00] vs 0.75 [95% CI, 0.70–0.80]; P for interaction, .001) and for cardiovascular mortality (HR, 0.93 [95% CI, 0.81–1.06] vs 0.77 [95% CI, 0.72–0.83]; P for interaction, .01) but not for the composite end point (HR, 1.00 [95% CI, 0.91–1.10] vs 0.91 [95% CI, 0.87–0.96]; P for interaction, .08). Propensity score−matched models gave similar results.” (C. Andersson, ca@heart.dk)
An editorialist discusses bleeding risk differentials between patients with and without diabetes and examines use of aspirin in those with diabetes (
pp. 921–2). He concludes: “The study by Andersson et al highlights the elevated risk of recurrent MI and cardiovascular mortality among patients with diabetes following MI. More needs to be done to reduce these risks among such patients. At least a portion of this excess risk appears due to platelet activity and function and to the effects of antiplatelet medications in patients with diabetes. Therefore, in appropriately selected patients, intensification of the antiplatelet regimen may be one method by which their outcomes might be markedly improved.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
Malignancies During Biologic Treatment of Rheumatoid Arthritis: Compared with other disease-modifying antirheumatic drugs or placebo, biologic response modifiers (BRMs) do not increase the risk of malignancies during treatment of rheumatoid arthritis (RA), according to a systematic review and meta-analysis of 63 randomized controlled trials (pp. 898–908): “Of the 29,423 patients, 211 developed a malignancy during the trial (118 solid tumors, 48 skin cancers, 14 lymphomas, 5 hematologic nonlymphomas, and 26 not specified). The incidence rate for any malignancy during the first year of therapy was very low in the BRM plus methotrexate group (0.77%; 95% CI, 0.65%–0.92%), the BRM monotherapy group (0.64%; 95% CI, 0.42%–0.95%), and the controls (0.66%; 95% CI, 0.52%–0.84%). Anakinra plus methotrexate showed lower odds compared with methotrexate alone (Peto odds ratio, 0.11; 95% CI, 0.03–0.45). No statistically significant risk was observed for specific cancer sites, although the Peto odds ratio for lymphoma was 2.1 (95% CI, 0.55–8.4) in patients receiving tumor necrosis factor inhibitors compared with controls.” (M. E. Suarez–Almazor, msalmazor@mdanderson.org)

>>>PNN NewsWatch
* An orphan drug indicated for treatment of chronic myelogenous leukemia (CML), bosutinib (Bosulif, Pfizer), was approved yesterday by FDA. Most of the 5,400 Americans diagnosed with CML annually carry the Philadelphia chromosome. In a clinical trial of 546 patients with CML, 34% of those treated with bosutinib had a major cytogenetic response (MCyR) within the first 24 weeks. Of those who had an MCyR at any time, 52.8% had responses that lasted 18 months. Common adverse effects of the drug include diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, fever, and fatigue.

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
Sept. 6, 2012 * Vol. 19, No. 173
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 6 issue of the New England Journal of Medicine (2012; 367).
Intermittent Androgen Suppression After Radiotherapy: In a noninferiority trial of men with rising PSA levels after radiotherapy for localized prostate cancer, intermittent androgen suppression was noninferior to continuous androgen therapy and improved some quality-of-life factors, researchers report (pp. 895–903). Patients enrolled in the study had PSA levels of more than 3 ng/mL more than 1 year after primary or salvage therapy. Androgen therapy was provided continuously (n = 696) or in intermittent 8-month cycles (n = 690), with these effects on a primary end point of overall survival: “Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P = 0.24).” (J. M. Crook, jcrook@bccancer.bc.ca)
A third option—no therapy—should be considered in men in this clinical situation, an editorialist writes (
pp. 945–6): “As compared with the Huggins era [1941], we now appreciate many more adverse effects of androgen-deprivation therapy (e.g., diabetes, osteoporosis, and sarcopenia). In Huggins’s day, treatments provided palliation for symptoms. Today, androgen-deprivation therapy is typically used to treat asymptomatic men. The risk–benefit ratio for treating symptomatic men is very different from that for treating asymptomatic men. How many patients in the trial by Crook et al. were unnecessarily exposed to the side effects and expense of androgen-deprivation therapy? In addition to knowing little about which men in this population would benefit from treatment as compared with no treatment, we know little regarding the best possible timing of androgen-deprivation therapy for those clearly in need of treatment. Does early androgen-deprivation therapy in asymptomatic men with rising PSA levels provide more benefit than treatment in symptomatic men with metastases? This question bedevils our field, and we are no closer to an answer now than we were before.” (O. Sartor)
Childhood Inhaled Steroids & Adult Height: Children with initially decreased heights from inhaled corticosteroids are likely to see this persist into adulthood, a study shows (pp. 904–12). However, these height decrements are neither progressive nor cumulative, researchers add based on these data on 943 participants in the Childhood Asthma Management Program whose adult heights were measured at an average of 25 years of age: “Mean adult height was 1.2 cm lower (95% confidence interval [CI], −1.9 to −0.5) in the budesonide group than in the placebo group (P = 0.001) and was 0.2 cm lower (95% CI, −0.9 to 0.5) in the nedocromil group than in the placebo group (P = 0.61). A larger daily dose of inhaled glucocorticoid in the first 2 years was associated with a lower adult height (−0.1 cm for each microgram per kilogram of body weight) (P = 0.007). The reduction in adult height in the budesonide group as compared with the placebo group was similar to that seen after 2 years of treatment (−1.3 cm; 95% CI, −1.7 to −0.9). During the first 2 years, decreased growth velocity in the budesonide group occurred primarily in prepubertal participants.” (H. W. Kelly, hwkelly@salud.unm.edu)

>>>PNN NewsWatch
* In a webinar yesterday, U.S. Surgeon General Regina Benjamin, MD, MBA, and Janet Wright, MD, executive director of the Million Hearts initiative, launched a new pharmacy-centered HHS project, Team Up, Pressure Down. They were joined by officials from several pharmacy groups. The initiative calls on pharmacists to emphasize medication adherence and hypertension control as two critical components of cardiovascular disease prevention.

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
Sept. 7, 2012 * Vol. 19, No. 174
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Sept. issue of Pharmacotherapy (2012; 32).
Acetaminophen, Ethanol & Liver Function: In patients on acetaminophen doses up to 4 g/d, ethanol consumption has no effect on serum alanine aminotransferase (ALT) levels at day 4, according to a systematic review of six trials of 551 acetaminophen and 350 placebo recipients (pp. 784–91). Even though five of the six studies were conducted in alcohol detoxification centers where patients were moderate-to-heavy drinkers, the authors “found that the difference in mean change from baseline ALT levels between the acetaminophen and placebo groups on day 4 was 0.0 U/L (95% confidence interval −0.2–0.1 U/L). There were no reports of liver dysfunction, liver failure, or death in any of the trials.”
The authors conclude, “4 g/day of acetaminophen has minimal effects on serum ALT levels in drinkers, including recently abstinent alcoholics, when measured on study day 4. No cases of hepatic failure or death were observed in any published prospective trials of moderate-to-heavy drinkers, even when acetaminophen was used during the theoretically most vulnerable period, based on CYP2E1 activity and glutathione regeneration. The significance of small, transient rises in serum ALT levels during the second week of continuous therapy, including shortly after acetaminophen was discontinued, remains unclear but appears to be similar to the changes observed in nondrinkers.” (K. Heard,
Kennon.heard@rmpdc.org)
LMWHs in Orthopedic Surgery: Compared with unfractionated heparin (UFH) in patients undergoing orthopedic surgeries, low-molecular-weight heparins (LMWHs) provide greater benefits with less harm, according to a systematic review and meta-analysis of 37 randomized controlled trials (pp. 799–808). Other comparisons showed that direct thrombin inhibitors (DTIs) and factor Xa inhibitors had favorable benefit–risk ratios, compared with LMWHs, in those undergoing total hip replacement, total knee replacement, or hip fracture surgery, and the LMWHs may not be sufficiently more effective than vitamin K antagonists (VKAs) to overcome an increased risk of bleeding: “Compared with patients who received … UFH, patients who received LMWHs had fewer pulmonary embolism, total deep vein thrombosis (DVT), major bleeding, and heparin-induced thrombocytopenia events. Compared with patients who received … VKAs, patients who received LMWHs had fewer total DVT and distal DVT events but reported increased major bleeding, minor bleeding, and surgical site bleeding events. Major efficacy end points such as symptomatic venous thromboembolism, pulmonary embolism, and nonfatal pulmonary embolism showed similar benefits of therapy with LMWHs and VKAs. Compared with patients receiving factor Xa inhibitors, patients who received LMWHs had more major venous thromboembolism, pulmonary embolism, total DVT, asymptomatic DVT, proximal DVT, and distal DVT events but fewer major bleeding events. Compared with patients receiving … DTIs, patients who received LMWHs had more major venous thromboembolism, total DVT, and proximal DVT events without significantly negatively affecting bleeding. However, patients who received LMWHs had fewer distal DVT events versus those who received DTIs. Subgroup analyses indicated differences based on the surgical procedure and individual drug within certain pharmacologic classes.” (C. M. White, cmwhite@harthosp.org)
Health Literacy & Drug Adherence: In patients with heart failure, pharmacists can improve medication adherence among those with inadequate health literacy, researchers report (pp. 819–26). In a 9-month study, 314 patients aged 50 years or older were studied, with some receiving pharmacist intervention and other usual care: “In the usual care group, taking adherence was greater among patients with adequate (69.4%) than those with inadequate (54.2%) health literacy (p = 0.001). In the intervention group, the difference in taking adherence among patients with adequate (77.3%) and inadequate (65.3%) health literacy was not statistically significant (p = 0.06). Among patients with inadequate health literacy, the intervention increased adherence (65%, 95% confidence interval [CI] 54–77%) by an order of magnitude similar to that of the baseline adherence of patients with adequate health literacy (69%, 95% CI 65–74%).” (M. D. Murray, mmurray@regenstrief.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, 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
Sept. 10, 2012 * Vol. 19, No. 175
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 8 issue of Lancet (2012; 380).
ART Task Shifting to Nurses: In the South African Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) program, initiation of antiretroviral therapy (ART) and maintenance care were safely shifted from physicians to nurses, but time to ART and mortality were not significantly improved (pp. 889–98). At 31 primary-care ART clinics, investigators implemented the STRETCH program (educational outreach to nurses and decentralized care) at some clinics and continued with standard care at others. In adults with CD4 counts < 350 cells/µL not on ART (cohort 1), a primary outcome of time to death was used to determine whether the STRETCH program was superior to standard care. In patients already on ART (cohort 2), an equivalence analysis used a primary outcome of undetectable viral loads (less than 400 copied/mL) at 12 months.
Results showed: “5,390 patients in cohort 1 and 3,029 in cohort 2 were in the intervention group, and 3,862 in cohort 1 and 3,202 in cohort 2 were in the control group. Median follow-up was 16.3 months (IQR 12.2–18.0) in cohort 1 and 18.0 months (18.0–18.0) in cohort 2. In cohort 1, 997 (20%) of 4,943 patients analysed in the intervention group and 747 (19%) of 3,862 in the control group with known vital status at the end of the trial had died. Time to death did not differ (hazard ratio [HR] 0.94, 95% CI 0.76–1.15). In a preplanned subgroup analysis of patients with baseline CD4 counts of 201–350 cells per µL, mortality was slightly lower in the intervention group than in the control group (0.73, 0.54–1.00; p = 0.052), but it did not differ between groups in patients with baseline CD4 of 200 cells per µL or less (0.94, 0.76–1.15; p = 0.577). In cohort 2, viral load suppression 12 months after enrolment was equivalent in intervention (2,156 [71%] of 3,029 patients) and control groups (2,230 [70%] of 3,202; risk difference 1.1%, 95% CI –2.4 to 4.6).” (M. O. Bachmann,
m.bachmann@uea.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Managing Patients With Multimorbidity: Management of patients with multimorbidity in the primary care and community settings is poorly studied, according to a systematic review of 10 studies of 3,407 patients (e5205). “A need exists to clearly identify patients with multimorbidity and to develop cost effective and specifically targeted interventions that can improve health outcomes,” the authors conclude based on these findings: “Consideration of the impact of socioeconomic deprivation was minimal. All studies involved complex interventions with multiple components. In six of the 10 studies the predominant component was a change to the organisation of care delivery, usually through case management or enhanced multidisciplinary team work. In the remaining four studies, intervention components were predominantly patient oriented. Overall the results were mixed, with a trend towards improved prescribing and drug adherence. The results indicated that it is difficult to improve outcomes in this population but that interventions focusing on particular risk factors in comorbid conditions or functional difficulties in multimorbidity may be more effective. No economic analyses were included, although the improvements in prescribing and risk factor management in some studies could provide potentially important cost savings.” (S. M. Smith, susansmith@rcsi.ie)

>>>PNN JournalWatch
* Mammalian Target of Rapamycin Inhibitors in Organ Transplantation: An Unkept Promise, in
Chest, 2012; 142: 734–7. (A. J. Langone)
* Use and Safety of Unfractionated Heparin for Anticoagulation During Maintenance Hemodialysis, in
American Journal of Kidney Diseases, 2012; 60: 473–86. (J. I. Shen, jishen@stanford.edu)
* Every Year Is an Influenza Pandemic for Children: Can We Stop Them [commentary]?, in
Pediatrics, 2012; 130: 554–6. (P. V. Effler)
* Vitamin D Deficiency in Critically Ill Children: A Roadmap to Interventional Research [commentary], in
Pediatrics, 2012; 130: 557–8. (S. A. Abrams)
* Atypical Antipsychotic Use in Patients With Dementia: Managing Safety Concerns, in
American Journal of Psychiatry, 2012; 169: 900–6. (M. Steinberg, martins@jhmi.edu)
* Inflammation-Associated Cancer Development in Digestive Organs: Mechanisms and Roles for Genetic and Epigenetic Modulation, in
Gastroenterology, 2012; 143: 550–63. (T. Chiba, chiba@kuhp.kyoto-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
Sept. 11, 2012 * Vol. 19, No. 176
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 10 issue of Archives of Internal Medicine (2012; 172).
AMI After Orthopedic Surgery: Risk of acute myocardial infarction (AMI) is increased by 25-fold and 31-fold in the first 2 weeks after total hip replacement (THR) and total knee replacement (TKR) surgery, respectively, according to data from Danish national registries (pp. 1229–35). In a retrospective cohort analysis of patients in Denmark having their first THR or TKR surgery in 1998–2007, investigators found these disease- and medication history–adjusted hazard ratios: “During the first 2 postoperative weeks, the risk of AMI was substantially increased in THR patients compared with controls (adjusted HR, 25.5; 95% CI, 17.1–37.9). The risk remained elevated for 2 to 6 weeks after surgery (adjusted HR, 5.05; 95% CI, 3.58–7.13) and then decreased to baseline levels. For TKR patients, AMI risk was also increased during the first 2 weeks (adjusted HR, 30.9; 95% CI, 11.1–85.5) but did not differ from controls after the first 2 weeks. The absolute 6-week risk of AMI was 0.51% in THR patients and 0.21% in TKR patients.” (F. de Vries, f.devries@uu.nl)
Calling on physicians to “actively work to reduce perioperative risk” among orthopedic surgery patients, an editorialist writes (
pp. 1235–6): “The appropriate use of preoperative beta-blockers, clonidine, statins, and aspirin reduces perioperative cardiac risk. There is a high risk of discontinuation of therapy with anti-ischemic agents in the perioperative period, despite level I evidence for continuation, with significant cardiac morbidity from discontinuation. Physicians must carefully review perioperative medications and ensure they are appropriately managed in this critical perioperative period of high cardiac risk. It is important for physicians caring for patients in the perioperative period to recognize the potential for cardiac morbidity and mortality and then appropriately use the armamentarium of medical therapies we now have to reduce cardiac risk, prevent perioperative MIs, and prevent cardiac deaths. In their present study, Lalmohamed et al clearly reinforce the importance and significance of the cardiac risk and the need to prevent perioperative cardiac morbidity and mortality.” (A. W. Wallace, art.wallace@va.gov)
Photosensitizing Hypotensives & Lip Cancer: In non–Hispanic whites on long-term treatment of hypertension, use of the photosensitizing agents hydrochlorothiazide and nifedipine is associated with increased risk of lip cancer, researchers report (pp. 1246–51). For the 1994–2008 period in a comprehensive medical program, patients developing lip cancer (n = 712) were compared with matched control patients (n = 22,904). Odds ratios of lip cancer (compared with no use) were as follows when patients had received at least a 5-year supply of various antihypertensive agents: hydrochlorothiazide, 4.22 (2.82–6.31); hydrochlorothiazide–triamterene, 2.82 (1.74–4.55); lisinopril, 1.42 (0.95–2.13); nifedipine, 2.50 (1.29–4.84); and atenolol, 1.93 (1.29–2.91). (G. D. Friedman)
“[These] findings are important because simple interventions, such as lip protector, sunscreen, large-brim hats, rash guard swim shirts, and avoiding times of the day when the sun is most intense, are likely to decrease the harmful effects of the sun for everyone, regardless of whether they are receiving a photosensitizing agent,” an editorialist notes (
p. 1251). “When initiating use of photosensitizing agents for our patients, we need to remind them of these simple measures to avoid sun exposure.” (M. H. Katz)
Patient Satisfaction in Safety-Net Hospitals: Safety-net hospitals (SNHs) have lower scores on patient-reported experience metrics, a study of 3,096 hospitals shows (pp. 1204–10): “Patients in SNHs were less likely to rate the hospital a 9 or 10 on a 10-point scale compared with patients in non-SNHs (63.9% vs 69.5%; P < .001). Gaps were also sizeable for the proportion of patients who reported receiving discharge information (2.6 percentage point difference; P < .001) and who thought they always communicated well with physicians (2.2 percentage point difference; P < .001). Although both groups of hospitals improved from 2007 through 2010, the gap between SNHs and non-SNHs increased (3.8% in 2007 vs 5.6% in 2010; P = .08). Finally, SNHs had a 60% lower odds of meeting [value-based purchasing] performance benchmarks for hospital payments (odds ratio, 0.4; 95% CI, 0.3–0.5; P < .001) compared with non-SNHs.” (A. K. Jha, ajha@hsph.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, 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
Sept. 12, 2012 * Vol. 19, No. 177
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 12 issue of JAMA (2012; 308).
Adjusting Inhaled Steroids in Adult Asthma: In the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial, biomarker- or symptom-based adjustment of low-dose inhaled corticosteroid therapy was no better than physician-adjusted doses in adults with mild to moderate persistent asthma, researchers report (pp. 987–97). BASALT included 342 participants at 10 U.S. academic medical centers in 2007–10. Comparison of physician-, biomarker- (exhaled nitric oxide), and symptom-based assessments showed: “There were no significant differences in time to treatment failure. The 9-month Kaplan–Meier failure rates were 22% (97.5% CI, 14%–33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%–30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%–25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6–2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8–3.3).” (W. J. Calhoun, william.calhoun@utmb.edu)
Editorialists provide this perspective on use of inhaled corticosteroid (ICS) therapy in patients with asthma (
pp. 1036–7): “Although there is controversy regarding intermittent vs daily ICS dosing for mild persistent asthma, the most recent (from 2007) version of the [National Asthma Education and Prevention Program (NAEPP)] guidelines indicated that there were as yet insufficient data to recommend treatment with intermittent symptom-guided controller medication for patients in this category. Because the BASALT trial and previous ACRN [Asthma Clinical Research Network] trial were not designed as equivalence trials, and the European trial of combination albuterol–beclomethasone was not powered to demonstrate equivalence of asthma exacerbation rates, the caution urged by the NAEPP guidelines remains warranted. Dose adjustment based on exhaled nitric oxide measurements has not been shown to improve outcomes in routine asthma management. Thus, there is no compelling rationale to alter the current approach to ICS dosing for mild or mild to moderate persistent asthma. Further research, including adequately powered equivalence trials, could change this in the future.” (G. T. O’Connor, goconnor@bu.edu)
Omega-3 Fatty Acids & Cardiovascular Events: Use of supplements of omega-3 polyunsaturated fatty acids (PUFAs) does not lower patients’ risk of major cardiovascular events, according to a systematic review and meta-analysis (pp. 1024–33): “Of the 3,635 citations retrieved, 20 studies of 68,680 patients were included, reporting 7,044 deaths, 3,993 cardiac deaths, 1,150 sudden deaths, 1,837 myocardial infarctions, and 1,490 strokes. No statistically significant association was observed with all-cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; risk reduction [RD] −0.004, 95% CI, −0.01 to 0.02), cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; RD, −0.01; 95% CI, −0.02 to 0.00), sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; RD, −0.003; 95% CI, −0.012 to 0.006), myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; RD, −0.002; 95% CI, −0.007 to 0.002), and stroke (RR, 1.05; 95% CI, 0.93 to 1.18; RD, 0.001; 95% CI, −0.002 to 0.004) when all supplement studies were considered.” (M. S. Elisaf, egepi@cc.uoi.gr)
Accountable Care Organizations: As the Affordable Care Act is implemented and health care reform proceeds in the U.S., accountable care organizations (ACOs) represent a “promise, not [a] panacea,” writes former CMS head Don Berwick (pp. 1038–9). He concludes: “It is essential to keep perspective. The United States is—and it had better be—on a great expedition to find the care the nation needs—seamless, safe, reliable, patient centered, and much, much less costly, all at the same time. No single change will suffice. The transition to new care will require many new ‘forms, habits, and environments’ to be tested, tried, and spread. Accountable care organizations deserve energy, investment, discipline, and good faith; they can help. But, whether encouraged or discouraged by the [CMS Physician Group Practice Demonstration] experience, a lot more innovations than ACOs alone will be needed to emerge successfully from this fraught time.” (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, 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
Sept. 13, 2012 * Vol. 19, No. 178
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 13 issue of the New England Journal of Medicine (2012; 367).
Waning Pertussis Vaccine Protection: Children who received five doses of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine had declining protection against pertussis in the following 5 years, a study shows (pp. 1012–9). A case–control study from Kaiser Permanente Northern California for children receiving their fifth doses of DTaP from 2006 to 2011 showed these patterns for those with positive results on a polymerase-chain-reaction (PCR) assay for pertussis (cases), those negative on PCR tests, and other closely matched controls: “We compared 277 children, 4 to 12 years of age, who were PCR-positive for pertussis with 3,318 PCR-negative controls and 6,086 matched controls. PCR-positive children were more likely to have received the fifth DTaP dose earlier than PCR-negative controls (P < 0.001) or matched controls (P = 0.005). Comparison with PCR-negative controls yielded an odds ratio of 1.42 (95% confidence interval, 1.21 to 1.66), indicating that after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year.” (N. P. Klein, nicola.klein@kp.org)
PTEN Mutations, Insulin Sensitivity & Obesity: In a study of 15 patients with Cowden syndrome, who lack a functional copy of the gene for tumor-suppressor phosphatase and tensin homologue (PTEN), researchers demonstrate that lack of this enzyme “is a monogenic cause of profound constitutive insulin sensitization that is apparently obesogenic” (pp. 1002–11). PTEN mutations have “apparently divergent” effects, with increased risks of obesity and cancer but decreased risk of type 2 diabetes secondary to insulin sensitization. Comparing Cowden patients and matched controls, the investigators found: “Measures of insulin resistance were lower in the patients with a PTEN mutation than in controls (e.g., mean fasting plasma insulin level, 29 pmol per liter [range, 9 to 99] vs. 74 pmol per liter [range, 22 to 185]; P = 0.001). This finding was confirmed with the use of hyperinsulinemic euglycemic clamping, showing a glucose infusion rate among carriers 2 times that among controls (P = 0.009). The patients’ insulin sensitivity could be explained by the presence of enhanced insulin signaling through the PI3K-AKT pathway, as evidenced by increased AKT phosphorylation. The PTEN mutation carriers were obese as compared with population-based controls (mean body-mass index …, 32 [range, 23 to 42] vs. 26 [range, 15 to 48]; P < 0.001). This increased body mass in the patients was due to augmented adiposity without corresponding changes in fat distribution.” (A. L. Gloyn, anna.gloyn@drl.ox.ac.uk)
Noting that “the characteristics of the research participants were surprising and inconsistent with reports of experiments in animals,” an editorialist writes that this study “raises questions about the effects of PTEN” (
pp. 1061–3): “We need to know more about the role and complex regulation of PTEN activity in insulin-resistant states in humans. [These] findings … further underscore concerns that therapeutic approaches aimed at increasing PTEN activity will effect a decrease in insulin sensitivity and will increase the risk of type 2 diabetes.” (U. Smith)
Reduced Adult Mortality After Medicaid Expansion: Increased state coverage of low-income adults through the Medicaid program reduced mortality and improved coverage, access to care, and self-reported health, according to an analysis of data from New York, Maine, and Arizona (pp. 1025–34). Compared with neighboring states that did not expand Medicaid coverage since 2000, data from those three states shows: “Medicaid expansions were associated with a significant reduction in adjusted all-cause mortality (by 19.6 deaths per 100,000 adults, for a relative reduction of 6.1%; P = 0.001). Mortality reductions were greatest among older adults, nonwhites, and residents of poorer counties. Expansions increased Medicaid coverage (by 2.2 percentage points, for a relative increase of 24.7%; P = 0.01), decreased rates of uninsurance (by 3.2 percentage points, for a relative reduction of 14.7%; P < 0.001), decreased rates of delayed care because of costs (by 2.9 percentage points, for a relative reduction of 21.3%; P = 0.002), and increased rates of self-reported health status of ‘excellent’ or ‘very good’ (by 2.2 percentage points, for a relative increase of 3.4%; P = 0.04).” (B. D. Sommers, bsommers@hsph.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, 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
Sept. 14, 2012 * Vol. 19, No. 179
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Sept. issue of Chest (2012; 142).
Vasopressin v. Norepinephrine in Septic Shock: In the Vasopressin and Septic Shock Trial, vasopressin produced significantly lower heart rates in patients with septic shock compared with norepinephrine, but other parameters were similar with the two drugs (pp. 593–605). In a subset of 241 adult patients managed with pulmonary artery catheters, blood pressures (BPs) and other measures were as follows: “Equal BPs were maintained in both treatment groups, with a significant reduction in norepinephrine requirements in the patients treated with vasopressin. The major hemodynamic difference between the two groups was a significant reduction in heart rate in the patients treated with vasopressin (P < .0001), and this was most pronounced in the less severe shock stratum (treatment × shock stratum interaction, P = .03). There were no other major cardiopulmonary differences between treatment groups, including no difference in cardiac index or stroke volume index between patients treated with vasopressin and those treated with norepinephrine. There was significantly greater use of inotropic drugs in the vasopressin group than in the norepinephrine group.” (A. C. Gordon, anthony.gordon@imperial.ac.uk)
Cyclophosphamide in Scleroderma Interstitial Lung Disease: Cyclophosphamide (CYC) treatment of scleroderma interstitial lung disease (SSc-ILD) lowers the frequency of cough, but the symptom returns to baseline within 1 year after drug discontinuation, researchers report (pp. 614–21). In 156 patients in the Scleroderma Lung Study, cough responses to CYC and placebo (PLA) were as follows: “Patients with cough at baseline had significantly lower diffusing capacity of the lung for carbon monoxide, dyspnea, the quality-of-life physical component summary, and the maximal fibrosis score on high-resolution CT imaging compared with those without cough at baseline. Cough severity and frequency correlated with FVC % predicted. After 12 months of treatment, cough frequency decreased in the CYC group compared with the PLA group and was significantly different from the PLA group at 18 months (6 months after discontinuation of CYC). However, the decreases in cough frequency did not correlate with the changes in FVC or diffusing capacity of the lung for carbon monoxide observed in the CYC group. Treatment-related improvements in cough frequency, as well as in FVC, were no longer apparent 12 months after discontinuation of CYC.” (A. C. Theodore, atheodor@bu.edu)

>>>Circulation Report
Source:
Sept. 11 issue of Circulation (2012; 126).
Cardioprotective Medications in Lower-Extremity Peripheral Artery Disease: Despite improvements since 2000, patients with lower-extremity peripheral artery disease (PAD) “alone remain less likely than those with [coronary artery disease (CAD)] alone to” be prescribed cardioprotective medications, authors write (pp. 1345–54). Danish national registries show these patterns for 34,160 patients with PAD alone and 154,183 patients with CAD alone: “Use of medications improved temporally among both groups: for PAD alone, any antiplatelet use increased from 29% to 59% from 2000 to 2007 (P < 0.0001), whereas statin use increased 6-fold (9%–56%; P < 0.0001). However, use of these therapies by 18 months after incident diagnosis for both PAD groups remained modest and lower in comparison with CAD alone (any antiplatelet, 53% versus 66%; statins, 40% versus 52%; angiotensin-converting enzyme inhibitors, 20% versus 29%). Relative to CAD alone, patients with PAD alone were less likely to use any antiplatelet (adjusted odds ratio, 0.50; 95% confidence interval, 0.49–0.52), statins (adjusted odds ratio, 0.50; 95% confidence interval, 0.48–0.52), or angiotensin-converting enzyme inhibitors (adjusted odds ratio, 0.51; 95% confidence interval, 0.49–0.53) by 18 months.” (M. R. Patel, manesh.patel@duke.edu)

>>>PNN NewsWatch
* FDA on Wednesday approved teriflunomide (Aubagio, Sanofi), the second orally active agent approved for treating adults with relapsing forms of multiple sclerosis. Dosed once daily, the drug reduced symptoms in clinical trials by 30%, compared with placebo. Adverse effects included diarrhea, abnormal liver tests, nausea, and hair loss.

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
Sept. 17, 2012 * Vol. 19, No. 180
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 15 issue of Lancet (2012; 380).
Spray Cell Therapy for Leg Ulcers: A spray formulation of allogeneic neonatal keratinocytes and fibroblasts was used effectively for treating chronic venous leg ulcers in 205 adult outpatient participants in a multicenter study in the U.S. and Canada, researchers report (pp. 977–85). The Phase II trial compared two concentrations of cells with vehicle only and tested every 7- or every 14- day therapy: “The primary outcome analysis showed significantly greater mean reduction in wound area associated with active treatment compared with vehicle (p = 0.0446), with the [lower] dose of 0.5 ×106 cells/mL every 14 days showing the largest improvement compared with vehicle (15.98%, 95% CI 5.56–26.41, p = 0.0028). Adverse events were much the same across all groups, with only new skin ulcers and cellulitis occurring in more than 5% of patients.” (H. B. Slade, bert.slade@healthpoint.com)
Regimens for Early Bactericidal Activity in TB: A three-drug antitubercular regimen—PA-824, moxifloxacin, and pyrazinamide— may be useful in treating both drug-sensitive and multidrug-resistant tuberculosis, shows a study that also demonstrates the value in achieving early bactericidal activity (EBA) in patients with this disease (pp. 986–93). In South Africa in 2010–11, patients received bedaquiline, bedaquiline–pyrazinamide, PA-824–pyrazinamide, bedaquiline–PA-824, PA-824–moxifloxacin–pyrazinamide, or unmasked standard antituberculosis treatment, with these results: “The mean 14-day EBA of PA-824–moxifloxacin–pyrazinamide (n=13; 0.233 [SD 0.128]) was significantly higher than that of bedaquiline (14; 0.061 [0.068]), bedaquiline–pyrazinamide (15; 0.131 [0.102]), bedaquiline–PA-824 (14; 0.114 [0.050]), but not PA-824–pyrazinamide (14; 0.154 [0.040]), and comparable with that of standard treatment (10; 0.140 [0.094]). Treatments were well tolerated and appeared safe. One patient on PA-824–moxifloxacin–pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol.” (A. H. Diacon, ahd@sun.ac.za)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Antifibrinolytics in Cardiac Surgery: Evidence on use of aprotinin in cardiac surgery are “inconclusive” about the drug’s safety, a network meta-analysis shows, but inclusion of observational data suggests that concerns remain (e5798). Data from 106 randomized controlled trials and 11 observational studies, with 43,270 patients in all, shows this about antifibrinolytic therapies in cardiac surgery: “Based on the results from analysis of randomised controlled trials, tranexamic acid was associated on average with a reduced risk of death compared with aprotinin (odds ratio 0.64, 95% credible interval 0.41 to 0.99). When observational data were incorporated, comparisons showed an increased risk of mortality with aprotinin on average relative to tranexamic acid (odds ratio 0.71, 95% credible interval 0.50 to 0.98) and epsilon-aminocaproic acid (0.60, 0.43 to 0.87), and an increased risk of renal failure or dysfunction on average relative to all comparators: odds ratio 0.66 (95% credible interval 0.45 to 0.88) compared with no treatment, 0.66 (0.48 to 0.91) versus tranexamic acid, and 0.65 (0.45 to 0.88) versus epsilon-aminocaproic acid.” (B. Hutton, bhutton@ohri.ca)

>>>PNN JournalWatch
* Effect of Tranexamic Acid on Mortality in Patients With Traumatic Bleeding: Prespecified Analysis of Data from Randomised Controlled Trial, in
BMJ, 2012; 345: e5839. (I. Roberts, ian.roberts@lshtm.ac.uk)
* Nosocomial Diarrhea: Evaluation and Treatment of Causes Other Than
Clostridium difficile, in Clinical Infectious Diseases, 2012; 55: 982–9. (C. R. Polage, christopher.polage@ucdmc.ucdavis.edu)
* Ocular Toxicity of Targeted Therapies, in
Journal of Clinical Oncology, 2012; 30: 3277–86. (P. L. Bedard, philippe.bedard@uhn.ca)
* Novel Targeted Therapies for Eosinophilic Disorders, in
Journal of Allergy and Clinical Immunology, 2012; 130: 563–71. (M. E. Wechsler, mikewechsler@gmail.com)
* Anaphylaxis During Pregnancy, in
Journal of Allergy and Clinical Immunology, 2012; 130: 597–606. (F. E. R. Simons, lmcniven@hsc.mb.ca)
* Expanding Role of Mineralocorticoid Receptor Antagonists in the Treatment of Heart Failure, in
Pharmacotherapy, 2012; 32: 827–37. (S. L. Chow, schow@westernu.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
Sept. 18, 2012 * Vol. 19, No. 181
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 18 issue of the Annals of Internal Medicine (2012; 157).
Thalidomide for Cough in Idiopathic Pulmonary Fibrosis: In a study of 98 patients with cough from idiopathic pulmonary fibrosis (IPF), thalidomide improved symptoms and respiratory quality of life (pp. 398–406). Concluding that further study of this use of thalidomide is warranted, the authors report these findings from the placebo-controlled trial: “[Cough Quality of Life Questionnaire] scores significantly improved with thalidomide (mean difference vs. placebo, −11.4 [95% CI, −15.7 to −7.0]; P < 0.001). Thalidomide also significantly improved scores on the visual analogue scale of cough (mean difference vs. placebo, −31.2 [CI, −45.2 to −17.2]; P < 0.001). In participants receiving thalidomide, scores from the total [St. George’s Respiratory Questionnaire (SGRQ)], SGRQ symptom domain, and SGRQ impact domain improved compared with those of participants receiving placebo. Adverse events were reported in 74% of patients receiving thalidomide and 22% receiving placebo; constipation, dizziness, and malaise were more frequent with thalidomide.” (M. R. Horton, mhorton2@jhmi.edu)
Improving Transitions of Care: Interventions aimed at improving “handovers between hospital and primary care providers at hospital discharge” improve care, a systematic review shows, but the “literature does not permit firm conclusions about which interventions have these effects” (pp. 417–28): “Of the 36 included studies, 25 (69.4%) had statistically significant effects in favor of the intervention group and 34 (94.4%) described multicomponent interventions. Effective interventions included medication reconciliation; electronic tools to facilitate quick, clear, and structured summary generation; discharge planning; shared involvement in follow-up by hospital and community care providers; use of electronic discharge notifications; and Web-based access to discharge information for general practitioners. Statistically significant effects were mostly found in reducing hospital use (for example, rehospitalizations), improvement of continuity of care (for example, accurate discharge information), and improvement of patient status after discharge (for example, satisfaction).” (G. Hesselink, g.hesselink@iq.umcn.nl)
Noting that “26 of the 36 interventions required transition managers,” an editorialist explores ways of “focusing on patient-centered outcomes and simplicity” (
pp. 448–9): “Are transition managers a key, affordable part of the medical team? Transition managers are part of the care team and are focused on coordination of care and patient education. They perform assessments of the educational, social, and functional needs of patients and may focus on communicating with community providers. The Patient Protection and Affordable Care Act includes incentives ‘to prevent hospital readmissions through a comprehensive program for hospital discharge that includes patient-centered education and counseling, comprehensive discharge planning, and post discharge reinforcement by an appropriate health care professional.’ This goal may be well-supported by transition managers to focus on patient discharge needs and postdischarge success. Physician education may also improve transitional care but will require ongoing curricula, time, and cost.” (S. T. Bray-Hall, Susan.Bray-Hall@ucdenver.edu)
Transitional Care After Stroke or MI: “Hospital-initiated transitional care can improve some outcomes in adults hospitalized for stroke or [myocardial infarction (MI)],” report authors who conducted a systematic review of literature on this topic (pp. 407–16). “Finding additional transitional care interventions that improve functional outcomes and prevent rehospitalizations and adverse events is a high priority for the growing population of patients who have an MI or a stroke,” the authors conclude based on this analysis of 62 articles: “Four intervention types were studied: hospital-initiated support (n = 14), patient and family education (n = 7), community-based support (n = 20), and chronic disease management (n = 3). Most studies (68%) were of fair quality. Overall, moderate-strength evidence showed that hospital-initiated support reduced length of stay for patients who had a stroke, and low-strength evidence showed that it reduced mortality for patients who had an MI. Evidence about benefits of other interventions and harms from transitional care services was insufficient.” (J. P. Bettger, janet.bettger@duke.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
Sept. 19, 2012 * Vol. 19, No. 182
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 19 issue of JAMA, a theme issue on obesity (2012; 308).
Exercise Dose & Diabetes Risk in Sedentary Children: Recruited from public schools in Augusta, GA, 222 children with overweight or obesity had lower markers of diabetes risk after 13 weeks of 20 or 40 minutes of aerobic training on 5 days per week, researchers report (pp. 1103–12). The exercise doses “of aerobic training improved fitness and demonstrated dose–response benefits for insulin resistance and general and visceral adiposity in sedentary overweight or obese children, regardless of sex or race,” the authors concluded. (C. L. Davis, cadavis@georgiahealth.edu)
Sustained Health Benefits of Gastric Bypass Surgery: The clinical benefits of Roux-en-Y gastric bypass (RYGB) surgery are sustained for 6 years, according to a prospective Utah-based study of 1,156 severely obese adults (pp. 1122–31). A total of 418 patients sought and received RYGB surgery, 417 sought surgery but did not receive it (control group 1), and 321 other participants were randomly selected from a population-based sample not having weight-loss surgery (control group 2). Results after 6 years showed: “Patients who received RYGB surgery (with 92.6% follow-up) lost 27.7% (95% CI, 26.6%-28.9%) of their initial body weight compared with 0.2% (95% CI, −1.1% to 1.4%) gain in control group 1 and 0% (95% CI, −1.2% to 1.2%) in control group 2. Weight loss maintenance was superior in patients who received RYGB surgery, with 94% (95% CI, 92%–96%) and 76% (95% CI, 72%–81%) of patients receiving RYGB surgery maintaining at least 20% weight loss 2 and 6 years after surgery, respectively. Diabetes remission rates 6 years after surgery were 62% (95% CI, 49%–75%) in the RYGB surgery group, 8% (95% CI, 0%–16%) in control group 1, and 6% (95% CI, 0%–13%) in control group 2, with remission odds ratios (ORs) of 16.5 (95% CI, 4.7–57.6; P < .001) vs control group 1 and 21.5 (95% CI, 5.4–85.6; P < .001) vs control group 2. The incidence of diabetes throughout the course of the study was reduced after RYGB surgery (2%; 95% CI, 0%–4%; vs 17%; 95% CI, 10%–24%; OR, 0.11; 95% CI, 0.04–0.34 compared with control group 1 and 15%; 95% CI, 9%–21%; OR, 0.21; 95% CI, 0.06–0.67 compared with control group 2; both P < .001). The numbers of participants with bariatric surgery–related hospitalizations were 33 (7.9%), 13 (3.9%), and 6 (2.0%) for the RYGB surgery group and 2 control groups, respectively.” (T. D. Adams, ted.adams@utah.edu)
Health Care Use After Bariatric Surgery: While higher for the first 6 years after bariatric surgery for patients with obesity, overall health care and drug costs are lower in postoperative years 7 through 20 (pp. 1132–41). In the Swedish Obese Subjects study, researchers found these patterns for patients treated with surgical or conventional therapies for obesity: “In the 20 years following their bariatric procedure, surgery patients used a total of 54 mean cumulative hospital days compared with 40 used by those in the control group (adjusted difference, 15; 95% CI, 2–27; P = .03). During the years 2 through 6, surgery patients had an accumulated annual mean of 1.7 hospital days vs 1.2 days among control patients (adjusted difference, 0.5; 95% CI, 0.2 to 0.7; P < .001). From year 7 to 20, both groups had a mean annual 1.8 hospital days (adjusted difference, 0.0; 95% CI, −0.3 to 0.3; P = .95). Surgery patients had a mean annual 1.3 nonprimary care outpatient visits during the years 2 through 6 vs 1.1 among the controls (adjusted difference, 0.3; 95% CI, 0.1 to 0.4; P = .003), but from year 7, the 2 groups did not differ (1.8 vs 1.9 mean annual visits; adjusted difference, −0.2; 95% CI, −0.4 to 0.1; P = .12). From year 7 to 20, the surgery group incurred a mean annual drug cost of US $930; the control patients, $1,123 (adjusted difference, −$228; 95% CI, −$335 to −$121; P < .001).” (M. Neovius, martin.neovius@ki.se)
“It is tempting to look at an issue [of
JAMA] devoted to obesity research and think solutions to such an intractable problem must be near,” editorialists write (pp. 1162–4). “While the snapshot of obesity research presented in this issue suggests areas in which progress is being made, it also reveals that key areas in understanding, preventing, and treating obesity are elusive. Many challenges lie ahead, but research such as that presented in this and recent JAMA issues provides reason for optimism.” (E. H. Livingston)

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
Sept. 20, 2012 * Vol. 19, No. 183
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 20 issue of the New England Journal of Medicine (2012; 367).
Dimethyl Fumarate in MS: Two studies and an editorial examine use of dimethyl fumarate (BG-12) in patients with multiple sclerosis.
BG-12 produced similar outcomes as glatiramer acetate in a Phase III comparison with placebo (
pp. 1087–97). Over 2 years, patients received oral BG-12 240 mg two or three times daily, the active comparator glatiramer acetate 20 mg daily subcutaneously, or placebo, with these effects on the annualized relapse rate: “At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P < 0.001; thrice-daily BG-12, 51%, P < 0.001; glatiramer acetate, 29%, P = 0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T2-weighted hyperintense lesions (all P < 0.001) and new T1-weighted hypointense lesions (P < 0.001, P < 0.001, and P = 0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T2-weighted hyperintense lesions (both BG-12 doses), and new T1-weighted hypointense lesions (thrice-daily BG-12) (nominal P < 0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.” (R. J. Fox, foxr@ccf.org)
Relapses, annualized relapse rate, rate of disability progression, and number of lesions on MRI were significantly reduced in patients on BG-12, compared with placebo, in a second Phase III trial (
pp. 1098–107). With oral 240-mg doses of BG-12 two or three times daily or placebo, these outcomes were noted in the 2-year study: “The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P < 0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P < 0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P = 0.005) and 34% with BG-12 thrice daily (P = 0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T2-weighted hyperintense lesions (P < 0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.” (R. Gold, ralf.gold@ruhr-uni-bochum.de)
Noting dimethyl fumarate’s history in “poison chairs” that produced eczematous burns in people whose skin came in contact with the fungicide and desiccant, an editorialist is cautious (
pp. 1149–50): “It is not clear at the moment how to advise patients about the new oral drugs, but the overall benefit-to-risk assessment, as of this month, may favor fumarate. And beware— if treatment for multiple sclerosis becomes too trouble-free, there could be a loosening of standards for diagnosis and for the initiation of treatment.” (A. H. Ropper)

>>>PNN NewsWatch
* Consumers should not use the El Salvadoran product Intestinomicina, FDA warned this week. Sold primarily in international grocery stores, the tablets and suspension contain chloramphenicol. Oral formulations of the drug were withdrawn in the U.S. in July 2012.

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
Sept. 21, 2012 * Vol. 19, No. 184
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Oct. 15 issue of Clinical Infectious Diseases (2012; 55).
Trials of Antibacterial Agents: Superiority and organism-specific trials of antibacterial agents could lead to “establishment of a Limited Population Antibacterial Drug (LPAD) approval pathway,” argues a white paper from the Infectious Diseases Society of America (pp. 1031–46). “LPAD [would create] conditions to protect approved drugs from overuse,” the group concludes, adding: “There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper’s drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents.” (R. J. Guidos, rguidos@idsociety.org)
TDM for Voriconazole: Routine therapeutic drug monitoring (TDM) of blood voriconazole concentrations can reduce drug discontinuation secondary to adverse events and improve treatment responses, according to a study from Korea (pp. 1080–7). In a randomized, assessor-blinded trial, 110 adult patients were assigned to TDM (voriconazole level target range, 1.0–5.5 mg/L) and non-TDM (fixed standard dose) groups, with these results: “Baseline characteristics including the CYP2C19 genotype were comparable between the two groups. While the incidence of adverse events was not different between the TDM group and the non-TDM group (both 42%; P = .97), the proportion of voriconazole discontinuation due to adverse events was significantly lower in the TDM group than in the non-TDM group (4% vs 17%; P = .02). A complete or partial response was observed in 81% (30 of 37) of patients in the TDM group compared to 57% (20 of 34) in the non-TDM group (P = .04).” (K-S Yu, ksyu@snu.ac.kr)

>>>Geriatrics Highlights
Source:
Sept. Journal of the American Geriatrics Society (2012; 60).
Physician Management of Prolonged INRs with Warfarin: An experience article from a community hospital in Israel concludes that “primary care physicians can safely maintain warfarin treatment in elderly adults, even in those with a history of hospitalization for high INR, using frequent INR measurements” (pp. 1713–7). Data were compiled for all 253 patients admitted to the internal medicine service with INRs of greater than 4 and categorized by age— 80 years or younger (group I) and older than 80 (group II): “Atrial fibrillation was the most common indication for warfarin therapy. Its incidence was higher in the older group (88% vs 73%, P = .004). More elderly participants lived in nursing homes (23% vs 9.4%. P = .004) or received in-home assistance (38.9% vs 20.5%, P = .002). There was no difference in INR upon admission, duration of warfarin treatment, or frequency of INR tests before admission. The incidence of bleeding events was 18.1% in Group I and 12.7% in Group II (P = .30). Major bleeding events occurred in 1.6% of Group I and none of Group II (P = .50). During follow-up after the first admission, the incidence of INR greater than 4 was higher in Group II (87.3% vs 70%, P = .02), without a difference in the number of additional admissions or bleeding events.” (M. Bergman, bermanm@clalit.org.il)

>>>PNN NewsWatch
* Patients taking pramipexole (Mirapex, Boehringer-Ingelheim) may be at increased risk of heart failure, FDA warns. Use of the antiparkinsonian drug was associated with new-onset heart failure in a pooled analysis of clinical trials and in two epidemiologic studies.
*
Patient visits to retail clinics grew 4-fold from 2007 to 2009, reports the Sept. Health Affairs, a theme issue on payment reform. Nearly half (44.4%) of the visits occurred at times “when physician offices are typically closed.”

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
Sept. 24, 2012 * Vol. 19, No. 185
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 22 issue of Lancet (2012; 380).
Peripheral IV Catheter Replacement: Switching from routine to clinically indicated replacement of peripheral intravenous catheters could “avoid millions of catheter insertions, associated discomfort, and substantial costs in both equipment and staff workload,” according to a study conducted at three hospitals in Australia (pp. 1066–74). In 2008–09, patients were assigned to clinically indicated replacement or every-third-day routine replacement in nonblinded fashion, with these results: “All 3,283 patients randomised (5,907 catheters) were included in our analysis (1,593 clinically indicated; 1,690 routine replacement). Mean dwell time for catheters in situ on day 3 was 99 h (SD 54) when replaced as clinically indicated and 70 h (13) when routinely replaced. Phlebitis occurred in 114 of 1,593 (7%) patients in the clinically indicated group and in 114 of 1,690 (7%) patients in the routine replacement group, an absolute risk difference of 0.41% (95% CI –1.33 to 2.15%), which was within the prespecified 3% equivalence margin. No serious adverse events related to study interventions occurred.” (C. M. Rickard, c.rickard@griffith.edu.au)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 345).
Assessing Vaccine Risks Using Background Disease Rates: The assessment of vaccine safety could be strengthened through incorporation of exact background rates of various conditions that occur infrequently during infancy and childhood, researchers report (e5823). In a nationwide population-based cohort study conducted in Denmark, the number of events for a hypothetical vaccine cohort of 1 million people was determined using follow-up periods of 182 days: “The study included 2,300,227 liveborn infants, yielding 37,262,404 person years of follow-up; median follow-up was 16.8 person years. Incidence of outcome diagnoses spanned from 0.32 per 100,000 patient years for autoimmune thrombocytopenia to 189.82 per 100,000 patient years for seizure. Seasonal differences were most pronounced for anaphylactic shock, seizure, and multiple sclerosis. Even for rare outcomes, numerous events were predicted in the hypothetical vaccine cohort. We predicted that 20 cases of type 1 diabetes mellitus, 19 of juvenile or rheumatoid arthritis, eight of facial nerve palsy, and five of multiple sclerosis per 1,000,000 children would occur within 42 days after vaccination. (T. A. Rasmussen, thomrasm@rm.dk)
Predicting Development of Type 2 Diabetes: Models for predicting whether patients will develop type 2 diabetes are generally accurate within a time frame of 5–10 years, report European Prospective Investigation into Cancer and Nutrition cohort study (EPIC-NL) researchers (e5900). A systematic review of 16 studies of 25 prediction models (12 “basic” ones that included variables that can be assessed noninvasively and 13 “extended” models that also included conventional biomarkers such as glucose concentration): “During a median follow-up of 10.2 years there were 924 cases in the full EPIC-NL cohort and 79 in the random subcohort. The C statistic for the basic models ranged from 0.74 (95% confidence interval 0.73 to 0.75) to 0.84 (0.82 to 0.85) for risk at 7.5 years. For prediction models including biomarkers the C statistic ranged from 0.81 (0.80 to 0.83) to 0.93 (0.92 to 0.94). Most prediction models overestimated the observed risk of diabetes, particularly at higher observed risks. After adjustment for differences in incidence of diabetes, calibration improved considerably.” (A. Abbasi, a.abbasi@umcg.nl)

>>>PNN JournalWatch
* Individualizing Targets and Tactics for High-Risk Patients With Type 2 Diabetes: Practical Lessons from ACCORD and Other Cardiovascular Trials, in
Diabetes Care, 2012; 35: 2100–7. (M. C. Riddle, riddlem@ohsu.edu)
* A Randomized Comparative Effectiveness Study of Oral Triple Therapy Versus Etanercept Plus Methotrexate in Early Aggressive Rheumatoid Arthritis: The Treatment of Early Aggressive Rheumatoid Arthritis Trial, in
Arthritis & Rheumatism, 2012; 64: 2824–35. (L. W. Moreland, lwm5@pitt.edu)
* Membrane Trafficking and Transport: Overview and Neurologic Implications, in
Neurology, 2012; 79: 1288–95. (E. E. Benarroch, benarroch.eduardo@mayo.edu)
* Pharmacist Education in the Era of Genomic Medicine, in
Journal of the American Pharmacists Association, 2012; 52: e113–21. (J. F. Jenkins, jean.jenkins@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
Sept. 25, 2012 * Vol. 19, No. 186
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 24 issue of Archives of Internal Medicine (2012; 172).
Pharmacist Medication Review at Hospital Discharge: Drug-related problems (DRPs) were significantly reduced when patients older than 60 had their discharge regimens reviewed by 24 community pharmacists in the Netherlands, compared with no intervention, researchers report (pp. 1346–7). Using a checklist developed by clinical pharmacologists and categorizing DRPs for medication analyses and patient interviews using the Pharmaceutical Care Network Europe score forms, investigators obtained these results for 340 patients: “The total number of DRPs at baseline and at follow-up were 253 and 437, respectively, in the control group and 271 and 689, respectively, in the intervention group. The mean number of DRPs identified with the medication analysis decreased from baseline to follow-up in the intervention group from 1.51 to 1.37. In the control group, the number of DRPs increased from 1.58 (baseline) to 1.62 (follow-up). The mean number of DRPs identified with the patient interview in the intervention group decreased from 3.88 (baseline) to 2.33 (follow-up). In the control group, the mean number of DRPs increased from 2.73 (baseline) to 2.80 (follow-up).…
“The proportion of patients with an increased, unchanged, or decreased number of DRPs after follow-up (compared with baseline) in the intervention group was significantly different from the control group. This effect was also significant for the specific DRPs ‘clear indication but no medication’ [in the medication analysis] and ‘fear of adverse effects’ [in the patient interview].” (A. Ahmad,
a.ahmad@vumc.nl)
Initial ART Choices: Based on a wide variety of initial drug choices for treatment-naive patients beginning combination antiretroviral therapy (cART), investigators conclude that “evidence-based data [are needed] for determining the best initial regimen for different HIV-infected persons” (pp. 1313–21). Among 1,957 participants in the Swiss HIV Cohort Study who started cART in 2005–09, these patterns were noted: “Tenofovir-emtricitabine (TDF-FTC)–efavirenz was the most frequently prescribed cART (29.9%), followed by TDF-FTC-lopinavir/r (16.9%), TDF-FTC-atazanavir/r (12.9%), zidovudine-lamivudine (ZDV-3TC)–lopinavir/r (12.8%), and abacavir/lamivudine (ABC-3TC)–efavirenz (5.7%). Differences in prescription were noted among different Swiss HIV Cohort Study sites (P < .001). In multivariate analysis, compared with TDF-FTC-efavirenz, starting TDF-FTC-lopinavir/r was associated with prior AIDS (relative risk ratio, 2.78; 95% CI, 1.78–4.35), HIV-RNA greater than 100,000 copies/mL (1.53; 1.07–2.18), and CD4 greater than 350 cells/µL (1.67; 1.04–2.70); TDF-FTC-atazanavir/r with a depressive disorder (1.77; 1.04–3.01), HIV-RNA greater than 100,000 copies/mL (1.54; 1.05–2.25), and an opiate substitution program (2.76; 1.09–7.00); and ZDV-3TC-lopinavir/r with female sex (3.89; 2.39–6.31) and CD4 cell counts greater than 350 cells/µL (4.50; 2.58–7.86). At 12 months, 1,715 patients (87.6%) achieved viral load less than 50 copies/mL and CD4 cell counts increased by a median (interquartile range) of 173 (89–269) cells/µL. Virologic suppression was more likely with TDF-FTC-efavirenz, and CD4 increase was higher with ZDV-3TC-lopinavir/r. No differences in outcome were observed among Swiss HIV Cohort Study sites.” (M. Battegay, mbattegay@uhbs.ch)
Opioid Dependence v. Addiction: Citing experiences from Washington State, an author maintains that the differences between opioid dependence and addiction following long-term pain therapy may make little difference clinically (pp. 1342–3): “Dependence on opioid pain treatment is not, as we once believed, easily reversible; it is a complex physical and psychological state that may require therapy similar to addiction treatment, consisting of structure, monitoring, and counseling, and possibly continued prescription of opioid agonists.” (J. C. Ballantyne, jcb12@uw.edu)

>>>PNN NewsWatch
* FDA has formed an internal task force that will support development of new antibacterial drugs. The Antibacterial Drug Development Task Force will assist in developing and revising guidance related to antibacterial drug development, as required by the Generating Antibiotic Incentives Now (GAIN) portion of the recently enacted FDA Safety and Innovation Act.

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
Sept. 26, 2012 * Vol. 19, No. 187
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 26 issue of JAMA (2012; 308).
Dexamethasone & Bleeding During Tonsillectomy: In a randomized controlled trial of perioperative dexamethasone in 314 children undergoing tonsillectomy, level II and III bleeding events were not increased significantly, compared with placebo (pp. 1221–6). However, based on a noninferiority threshold of 5%, the possibility of increased numbers of subjective (level I) episodes could not be ruled out, as the threshold was crossed. Patients received a single perioperative dose of dexamethasone 0.5 mg/kg in 0.9% sodium chloride or placebo, with these results: “One hundred fifty-seven children (median [interquartile range] age, 6 [4-8] years) were randomized into each study group, with 17 patients (10.8%) in the dexamethasone group and 13 patients (8.2%) in the placebo group reporting bleeding events. In an intention-to-treat analysis, the rates of level I bleeding were 7.0% (n = 11) in the dexamethasone group and 4.5% (n = 7) in the placebo group (difference, 2.6%; upper limit 97.5% CI, 7.7%; P for noninferiority = .17); rates of level II bleeding were 1.9% (n = 3) and 3.2% (n = 5), respectively (difference, −1.3%; upper limit 97.5% CI, 2.2%; P for noninferiority < .001); and rates of level III bleeding were 1.9% (n = 3) and 0.6% (n = 1), respectively (difference, 1.3%; upper limit 97.5% CI, 3.8%; P for noninferiority = .002).” (C. J. Hartnick, christopher_hartnick@meei.harvard.edu)
Management of COPD: The case of an 81-year-old man hospitalized for severe dyspnea and respiratory failure is used to detail care of the patient with chronic obstructive pulmonary disease (COPD) (pp. 1254–63): “COPD, a common disease in elderly patients, is characterized by high symptom burden, health care utilization, mortality, and unmet needs of patients and caregivers. Respiratory failure and dyspnea may be exacerbated by heart failure, pulmonary embolism, and anxiety; by medication effects; and by other conditions, including deconditioning and malnutrition. Randomized controlled trials, which provide the strongest evidence for guideline recommendations, may underestimate the risk of adverse effects of interventions for older patients with COPD. The focus of guidelines on disease-modifying therapies may not address the full spectrum of patient and caregiver needs, particularly the high rates of bothersome symptoms, risk of functional and cognitive decline, and need for end-of-life care planning. Meeting the many needs of older patients with COPD and their families requires that clinicians supplement guideline-recommended care with treatment decision making that takes into account older persons’ comorbid conditions, recognizes the trade-offs engendered by the increased risk of adverse events, focuses on symptom relief and function, and prepares patients and their loved ones for further declines in the patient’s health and their end-of-life care.” (T. R. Fried, terri.fried@yale.edu)
Interpreting Multiple Treatment Comparison Meta-analysis: A users’ guide and the case of a 45-year-old patient being treated for generalized anxiety disorder with the SSRI paroxetine provide the framework of an article on multiple treatment comparison (MTC) meta-analysis and how readers can address study validity, interpret results, and apply findings to patient scenarios (pp. 1246–53). “MTC meta-analysis uses both direct (head-to-head) randomized clinical trial (RCT) evidence as well as indirect evidence from RCTs to compare the relative effectiveness of all included interventions. The methodological quality of MTCs may be difficult for clinicians to interpret because the number of interventions evaluated may be large and the methodological approaches may be complex. Clinicians and others evaluating an MTC should be aware of the potential biases that can affect the interpretation of these analyses. Readers should consider whether the primary studies are sufficiently homogeneous to combine; whether the different interventions are sufficiently similar in their populations, study designs, and outcomes; and whether the direct evidence is sufficiently similar to the indirect evidence to consider combining.” (E. J. Mills, edward.mills@uottawa.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, 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
Sept. 27, 2012 * Vol. 19, No. 188
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 27 issue of the New England Journal of Medicine (2012; 367).
Post-Chemotherapy Enzalutamide in Prostate Cancer: In men with metastatic castration-resistant prostate cancer after chemotherapy, survival was significantly prolonged in those who received enzalutamide rather than placebo in the AFFIRM study (pp. 1187–97). The Phase III trial included 1,199 men with castration-resistant prostate cancer after chemotherapy and used the Eastern Cooperative Oncology Group performance-status score and pain intensity to identify these results: “The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P < 0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P < 0.001), the soft-tissue response rate (29% vs. 4%, P < 0.001), the quality-of-life response rate (43% vs. 18%, P < 0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P < 0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P < 0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P < 0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.” (H. I. Scher, scherh@mskcc.org)
“Enzalutamide, a new, highly effective, and safe nonsteroidal antiandrogen, extends survival and will become widely used in patients with metastatic castration-resistant prostate cancer,” writes an editorialist (
pp. 1256–7). “It will be used sequentially with other active agents, such as docetaxel, abiraterone, cabazitaxel, radium-223, and immunotherapy. It will be studied much earlier in the disease course. In addition, it is likely to supplant bicalutamide in combined androgen blockade after appropriate phase 3 trials have been completed.” (N. J. Vogelzang)
Tiotropium in Poorly Controlled Asthma: Tiotropium is a useful addition to therapy in patients with asthma poorly controlled on inhaled glucocorticoids and long-acting beta-agonists (LABAs), researchers report (pp. 1198–207). In two replicate randomized controlled trials, 912 patients received tiotropium 5 mcg or placebo mist inhaler once daily with these results: “The patients had a mean baseline FEV1 of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV1 from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86 ± 34 ml in trial 1 (P = 0.01) and 154 ± 32 ml in trial 2 (P < 0.001). The predose (trough) FEV1 also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88 ± 31 ml (P = 0.01) and 111 ± 30 ml (P < 0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P = 0.03). No deaths occurred; adverse events were similar in the two groups.” (H. A. M. Kerstjens, h.a.m.kerstjens@umcg.nl)
Glycemic Control After Pediatric Cardiac Surgery: While safe, institution of tight glycemic control failed to change significantly a number of efficacy variables in a study of children undergoing cardiopulmonary bypass (pp. 1208–19): “A total of 444 of the 490 children assigned to tight glycemic control (91%) received insulin versus 9 of 490 children assigned to standard care (2%). Although normoglycemia was achieved earlier with tight glycemic control than with standard care (6 hours vs. 16 hours, P < 0.001) and was maintained for a greater proportion of the critical illness period (50% vs. 33%, P < 0.001), tight glycemic control was not associated with a significantly decreased rate of health care–associated infections (8.6 vs. 9.9 per 1000 patient–days, P = 0.67). Secondary outcomes did not differ significantly between groups, and tight glycemic control did not benefit high-risk subgroups. Only 3% of the patients assigned to tight glycemic control had severe hypoglycemia (blood glucose <40 mg per deciliter [2.2 mmol per liter]).” (M. S. D. Agus, michael.agus@childrens.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, 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
Sept. 28, 2012 * Vol. 19, No. 189
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (2012; 35).
Lower Doses of Insulin Glargine and Glulisine During Hospitalizations: Hospitalized patients had 50% fewer hypoglycemic events without compromised control of hyperglycemia when lower weight-based doses of insulin glargine and glulisine were used in a study of 107 patients with type 2 diabetes and chronic renal failure (pp. 1970–4). Once-daily glargine and three-times-daily glulisine were administered in doses of 0.5 and 0.25 units/kg/d, with these effects on blood glucose (BG): “Mean BG on the first day was 196 ± 71 mg/dL in the group receiving 0.5 units/kg (0.5 group) and 197 ± 55 mg/dL in the group receiving 0.25 units/kg (0.25 group; P = 0.94). On days 2 to 6, mean BG was 174 ± 52 mg/dL in the 0.5 group and 174 ± 46 mg/dL in the 0.25 group (P = 0.96). There were no significant differences between groups in the percentage of BG values within the target range of 100 to 180 mg/dL on any of the 6 study days. In the 0.5 group, 30% experienced hypoglycemia (BG <70 mg/dL) compared with 15.8% of the 0.25 group (P = 0.08).” (D. Baldwin, david_baldwin@rush.edu)
Switching From Sitagliptin to Liraglutide: In adults with type 2 diabetes being treated with metformin, a number of effectiveness indicators—glycemic control, weight, and treatment satisfaction—improved after a switch from the DPP-4 inhibitor sitagliptin to the GLP-1 analog liraglutide, but patients reported increased numbers of gastrointestinal reactions with liraglutide (pp. 1986–93). Study participants were randomized to liraglutide 1.2 or 1.8 mg/d or sitagliptin 100 mg/d for 52 weeks. They continued therapy for an additional 26 weeks in an open-label extension, with those on sitagliptin being randomly allocated to one of the two doses of liraglutide and those on liraglutide continuing on their original dose. Results showed: “Although 52 weeks of sitagliptin changed glycosylated hemoglobin (HbA1c) by −0.9% from baseline, additional decreases occurred after switching to liraglutide (1.2 mg/day, −0.2%, P = 0.006; 1.8 mg/day, −0.5%, P = 0.0001). Conversion to liraglutide was associated with reductions in fasting plasma glucose (FPG) (1.2 mg/day, −0.8 mmol/L, P = 0.0004; 1.8 mg/day, −1.4 mmol/L, P < 0.0001) and body weight (1.2 mg/day, −1.6 kg; 1.8 mg/day, −2.5 kg; both P < 0.0001) and with an increased proportion of patients reaching HbA1c <7% (from ~30% to ~50%). Overall treatment satisfaction, assessed by the Diabetes Treatment Satisfaction Questionnaire, improved after switching to liraglutide (pooled 1.2 and 1.8 mg/day, 1.3; P = 0.0189). After switching, mostly transient nausea occurred in 21% of participants, and minor hypoglycemia remained low (3–4% of participants). Continuing liraglutide treatment at 1.2 mg/day and 1.8 mg/day for 78 weeks reduced HbA1c (baseline 8.3 and 8.4%, respectively) by −0.9 and −1.3%, respectively; FPG by −1.3 and −1.7 mmol/L, respectively; and weight by −2.6 and −3.1 kg, respectively, with 9–10% of participants reporting minor hypoglycemia.” (R. E. Pratley, richard.pratley@flhosp.org)

>>>PNN NewsWatch
* Regorafenib (Stivarga, Bayer), a multikinase inhibitor, has been approved by FDA for treatment of patients with previously treated metastatic colorectal cancer. In a single clinical study of 760 such patients, median survival in those treated with regorafenib plus best supportive care (BSC) was 6.4 months compared with 5 months in patients treated with placebo plus BSC. Progression-free survival was also longer in patients on active treatment, 2.0 versus 1.7 months. Regorafenib product labeling carries a boxed warning concerning severe and fatal liver toxicity in patients treated with regorafenib during clinical studies. The most common adverse effects reported in patients treated with regorafenib included weakness or fatigue, loss of appetite, palmar–plantar erythrodysesthesia (hand–foot syndrome), diarrhea, mucositis, weight loss, infection, high blood pressure, and dysphonia.
*
FDA today launches a national campaign to raise public awareness about the prevalence of fraudulent Internet pharmacies. BeSafeRx–Know Your Online Pharmacy provides resources for patients and caregivers who might purchase medication online so they will better understand who they are buying from and that the medication they buy matches what their physician prescribed.

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.