Jun 2011

PNN Quarterly File—Second Quarter 2011

PNN Pharmacotherapy Line
Apr. 1, 2011 * Vol. 18, No. 63
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Apr. issue of Pharmacotherapy (2011; 31).
Dabigatran’s Place in Therapy: An editorialist pokes fun at the names of the several dabigatran trials whose acronyms begin with “RE-” while providing this perspective on this agent (pp. 335–7): “When defining the ‘ideal’ anticoagulant, warfarin meets four of the 13 criteria, whereas dabigatran meets five and ximelagatran meets six. However, because the criteria met by dabigatran may be considered to be more clinically relevant, a strong argument exists for most patients and providers, and especially those with no formal warfarin training, that dabigatran REPRESENTS a step in the right direction. Use of dabigatran will result in more patients with nonvalvular atrial fibrillation being anticoagulated than those previously treated with warfarin.
“Warfarin will become RE-DUNDANT. It may take a while, but without a doubt, dabigatran will hasten the inevitable. There is room for improvement with warfarin therapy, and with continued study and diligence, we may eventually see the ideal oral anticoagulant—and that RE-ALITY will be RE-FRESHING.” (J. G. Gums,
jgums@ufl.edu)
Outcomes in Trauma Patients with Ventilator-Associated Pneumonia: Despite empiric use of inadequate antibiotics, trauma patients with Stenotrophomonas maltophilia ventilator-associated pneumonia (VAP) responded well to therapy, researchers report (pp. 338–45). Among 101 patients who developed VAP caused by this organism in a level I trauma ICU in 1997–2007, these outcomes were noted: “The study population had higher injury severity scores and a higher rate of traumatic brain injury than is typically observed in the study’s intensive care unit. The median time to diagnosis of S. maltophilia VAP was 15 days (interquartile range 11–24 days). Stenotrophomonas maltophilia was the sole organism isolated in 34% of patients; the other patients had polymicrobial VAP. Despite inadequate empiric antibiotic therapy being administered to 97% of the patients, the overall clinical success rate was 87%. The microbiologic plus clinical success rate was 82%. The most common treatments for S. maltophilia VAP were trimethoprim–sulfamethoxazole (77 patients received monotherapy, 9 received combination therapy) and ciprofloxacin (6 patients received monotherapy, 8 received combination therapy); all-cause and VAP-related mortality rates were 13% and 7%, respectively.” (Q. A. Czosnowski, q.czosnowski@usp.edu)
Drug Renal Alert Pharmacy Program: For 15 target medications, a Drug Renal Alert Pharmacy (DRAP) program reduced errors in patients with renal insufficiency, and the improvements were sustained after the study was completed, according to a report from an integrated health system (pp. 346–56). Conducted in 2003–05, the trial randomized nearly 33,000 adult health plan members with estimated creatinine clearance less than 50 mL/min and who were not on dialysis to intervention and usual-care groups. For those in the intervention group, pharmacists were alerted by the DRAP computerized tool of possible errors in drug product selection and dosing, with these results: “Among the 6,125 patients who received a target drug, no significant differences were noted in age, sex, creatinine clearance, comorbid conditions, and number of target drugs between groups at baseline. Over the 15-month intervention period, the proportion of medication errors was significantly lower in the intervention group than the usual care group (33% vs 49%, p < 0.001). After the study period, when the intervention was expanded to both groups, a 20% reduction in errors was sustained in the combined groups over the subsequent 7 months.” (B. Bhardwaja, bharati.bhardwaja@kp.org)
OTC Oral Contraceptives?: If sold where pharmacists are on duty and exemptions are in place for Medicaid coverage, oral contraceptives should have nonprescription status, argues the ACCP Women’s Health Practice and Research Network (pp. 424–37): “Existing data indicate that oral contraceptives meet safety criteria required of OTC products. Available literature demonstrates that women can self-screen for contraindications to oral contraceptives and can do this as well as clinicians, and experience with OTC emergency contraception suggests that OTC oral contraceptives would not increase sexual risk-taking behavior. Women support OTC access to oral contraceptives, but express an interest in accessing pharmacist counseling.” (J. McIntosh, j.mcintosh@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 4, 2011 * Vol. 18, No. 64
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2011; 342).
Cost-Effectiveness with Primary-Prevention Statins: Even when available generically, statins are not cost-effective for primary prevention in patients with low risks of vascular diseases, according to an analysis of data from the Netherlands (d1672). In a hypothetical population of adults aged 45–75 years, a Markov model analysis showed these patterns in quality-adjusted life–years (QALYs), costs, and incremental cost-effectiveness ratios for varying risks of myocardial infarction and stroke: “Over a 10-year period, statin treatment cost 35,000 euros (£30,000, $49,000) per QALY gained for men aged 55 years with a 10-year vascular risk of 10%. The incremental cost-effectiveness ratio improved as risk for vascular disease increased. The cost per QALY ranged from approximately 5,000 to 125,000 euros when the 10-year vascular risk for men aged 55 years was varied from 25% to 5%. The incremental cost-effectiveness ratio slightly decreased with age after the level of vascular risk was specified. Results were sensitive to the costs of statin treatment, statin effectiveness, non-adherence, disutility of taking medication daily, and the time horizon of the model.” (J. P. Greving, J.P.Greving@umcutrecht.nl)
TMP-SMX for Malarial Prophylaxis: In 203 breastfeeding, HIV-exposed infants, trimethoprim–sulfamethoxazole was moderately protective against malaria, researchers report (d1617). In a nonblinded trial conducted in Uganda, antibiotic treatment was continued until breastfeeding stopped and HIV-negative status was confirmed. Infants were then randomized to stop or continue co-trimoxazole until age 2 years, with these results: “The incidence of malaria and prevalence of genotypic mutations associated with antifolate resistance were high throughout the study. Among the 98 infants randomised to continue co-trimoxazole, 299 malaria cases occurred in 92.28 person years (incidence 3.24 cases/person year). Among the 87 infants randomised to stop co-trimoxazole, 400 malaria cases occurred in 71.81 person years (5.57 cases/person year). Co-trimoxazole prophylaxis yielded a 39% reduction in malaria incidence, after adjustment for age at randomisation (incidence rate ratio 0.61 (95% CI 0.46 to 0.81), P = 0.001). There were no significant differences in the incidence of complicated malaria, diarrhoea, pneumonia, hospitalisations, or deaths between the two treatment arms.” (T. Sandison, tgsand@u.washington.edu)
Barriers in Acute Care to Transition to Palliative Care: A number of “significant barriers” are identified by 58 health professionals in moving patients from acute to palliative care in the U.K. health system (d1773): “Participants identified that a structured transition to a palliative care approach of the type advocated in UK policy guidance is seldom evident in acute hospital settings. In particular they reported that prognosis is not routinely discussed with inpatients. Achieving consensus among the clinical team about transition to palliative care was seen as fundamental to the transition being effected; however, this was thought to be insufficiently achieved in practice. Secondary care professionals reported that discussions about adopting a palliative care approach to patient management were not often held with patients; primary care professionals confirmed that patients were often discharged from hospital with ‘false hope’ of cure because this information had not been conveyed. Key barriers to ensuring a smooth transition to palliative care included the difficulty of ‘standing back’ in an acute hospital situation, professional hierarchies that limited the ability of junior medical and nursing staff to input into decisions on care, and poor communication.” (M. Gott, m.gott@auckland.ac.nz)

>>>PNN JournalWatch
* Chronic Pancreatitis, in Lancet, 2011; 377: 1184–97. (J. M. Braganza, jenny.parr@manchester.ac.uk)
* Beyond the Monofilament for the Insensate Diabetic Foot: A Systematic Review of Randomized Trials to Prevent the Occurrence of Plantar Foot Ulcers in Patients with Diabetes, in
Diabetes Care, 2011; 34: 1041–6. (Y. Arad, yadonarad@gmail.com)
* Coinfection with Human Immunodeficiency Virus and Hepatitis C Virus: Challenges and Therapeutic Advances—Insights from the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2011; 31: 357–68. (P. Deming, pdeming@salud.unm.edu)
* Solid-Organ Transplantation in Childhood: Transitioning to Adult Health Care, in
Pediatrics, 2011; 127: 742–53. (C. LaRosa)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 5, 2011 * Vol. 18, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 5 issue of the Annals of Internal Medicine (2011; 154).
Optimizing HIV Therapy: A once-daily ritonavir-boosted protease inhibitor regimen performed similarly to once-daily efavirenz-based treatments in antiretroviral-naive patients with HIV-1 infections, researchers report (pp. 445–56; released early—see PNN, Feb. 15). Adverse effects were fewer when ritonavir was combined with abacavir–lamivudine than with tenofovir disoproxil fumarate (DF)–emtricitabine, the investigators noted, adding these details about patients at 59 AIDS Clinical Trials Group sites in the U.S. and Puerto Rico: “463 eligible patients were randomly assigned to receive atazanavir plus ritonavir and 465 were assigned to receive efavirenz, both with abacavir–lamivudine; 322 (70%) and 324 (70%), respectively, completed follow-up. The respective numbers of participants in each group who received tenofovir DF–emtricitabine were 465 and 464; 342 (74%) and 343 (74%) completed follow-up. Primary efficacy was similar in the group that received atazanavir plus ritonavir and the group that received efavirenz and did not differ according to whether abacavir–lamivudine or tenofovir DF–emtricitabine was also given. Hazard ratios for time to virologic failure were 1.13 (95% CI, 0.82 to 1.56) and 1.01 (CI, 0.70 to 1.46), respectively, although CIs did not meet prespecified criteria for equivalence. The time to safety (P = 0.048) and tolerability (P < 0.001) events was longer in persons given atazanavir plus ritonavir than in those given efavirenz with abacavir–lamivudine but not with tenofovir DF–emtricitabine.” (E. S. Daar, EDaar@LABioMed.org)
Patient Self-Management of Anticoagulation: In selected, motivated adult patients on long-term anticoagulation with vitamin K antagonists, patient self-testing (PST), with or without patient self-management (PSM), is linked to fewer deaths and thromboembolic events, report authors of a meta-analysis of available trials (pp. 472–82). While only five high-quality trials were available and two studies were conducted in the U.S., the investigators found these patterns among all available studies: “Twenty-two trials, with a total of 8,413 patients, were included. In one half of the trials, fewer than 50% of potentially eligible persons successfully completed the training and agreed to be randomly assigned. Patients randomly assigned to PST or PSM had lower total mortality (Peto odds ratio [OR], 0.74 [95% CI, 0.63 to 0.87]), lower risk for major thromboembolism (Peto OR, 0.58 [CI, 0.45 to 0.75]), and no increased risk for a major bleeding event (Peto OR, 0.89 [CI, 0.75 to 1.05]). The strength of evidence was moderate for the bleeding and thromboembolism outcomes but low for mortality. Eight of 11 trials reported that patient satisfaction, quality of life, or both was better with PST or PSM than with usual care.” (H. E. Bloomfield, hanna.bloomfield@va.gov)
Commenting on the advent of patient self-directed care using handheld technology, editorialists write (
pp. 500–1): “In some ways, self-directed care provides a glimpse into the future, with greater reliance on newer technologies and on the patient’s ability to measure specific chemical or biological variables and instantly communicate these to their provider electronically. Such capabilities as diabetic glucose monitoring, insulin management, diuretic management based on changes in volume status, and wireless or telephonic monitoring of pacemakers and internal cardiac defibrillators already exist. With wider utilization of electronic health records, the prevalence and continued evolution of smart phones and pocket computers, and the application of genetic-based medicine, it is likely that self-care capabilities will become more common. Should the clinical benefits of home INR testing and management reported in this meta-analysis continue to be realized, it is likely that this technology will soon join the ranks of other current self-directed care strategies.” (D. J. Moliterno, moliterno@uky.edu)

>>>PNN NewsWatch
* A consumer-friendly website providing information on product recalls was launched yesterday by FDA. The new presentation of this information was mandated under the FDA Food Safety Modernization Act, signed into law in Jan. by Pres. Obama. It also gives FDA authority to mandate recalls of foods and feed products; previously, the agency could act only for infant nutrition.
* House Republicans today will unveil their ideas for
reform of the Medicare and Medicaid systems, Kaiser Health News 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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 6, 2011 * Vol. 18, No. 66
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 6 issue of JAMA (2011; 305).
Outcomes in Women After Estrogen Cessation: In participants receiving conjugated equine estrogens (CEE) in the Women’s Health Initiative Estrogen-Alone Trial, the risks of cardiovascular and other events dropped to placebo-group levels after hormone therapy was stopped in 2002, but the protection against breast cancer persisted, researchers report (pp. 1305–14). The study, stopped after a mean of 7.1 years because of an increased stroke risk, included 10,739 postmenopausal women who received either CEE 0.625 mg/d or placebo.
Follow-up with 78% of participants over a mean of 10.7 years showed these outcomes for coronary heart disease (CHD) and invasive breast cancer: “The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75–1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51–1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84–1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64–1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41–0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88–1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62–0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction).” (A. Z. LaCroix,
alacroix@whi.org)
Questions remain about short-term use of hormone therapy (HT), editorialists write (
pp. 1354–5): “There may still be a role for short-term use of unopposed estrogen for treating some women with menopausal symptoms, but this role may be vanishing as existing and emerging data continue to be better understood in terms of application to patients. In the meantime, the symptoms of menopause can be significant and require thoughtful management. This would include careful consideration and discussion of the long-term risks and short-term benefits of HT as well as thorough discussion of other treatment strategies and optimization of lifestyle to ensure the best outcomes for women in the many years they should enjoy postmenopause.” (G. A. Colditz, colditzg@wustl.edu)
Opioid Prescribing & Deaths: Patients on higher opioid doses are at increased risk of dying from those drugs, according to a 2004–08 VA case–cohort study (pp. 1315–21). Researchers compared 750 people who died from unintentional prescription opioid overdoses with nearly 155,000 other patients. Results showed: “The frequency of fatal overdose over the study period among individuals treated with opioids was estimated to be 0.04%.The risk of overdose death was directly related to the maximum prescribed daily dose of opioid medication. The adjusted hazard ratios (HRs) associated with a maximum prescribed dose of 100 mg/d or more, compared with the dose category 1 mg/d to less than 20 mg/d, were as follows: among those with substance use disorders, adjusted HR = 4.54 (95% confidence interval [CI], 2.46–8.37; absolute risk difference approximation [ARDA] = 0.14%); among those with chronic pain, adjusted HR = 7.18 (95% CI, 4.85–10.65; ARDA = 0.25%); among those with acute pain, adjusted HR = 6.64 (95% CI, 3.31–13.31; ARDA = 0.23%); and among those with cancer, adjusted HR = 11.99 (95% CI, 4.42–32.56; ARDA = 0.45%). Receiving both as-needed and regularly scheduled doses was not associated with overdose risk after adjustment.” (A. S. B. Bohnert, amybohne@med.umich.edu)
“Better initial training of physicians, dentists, nurses, and pharmacists in pain management, opioid pharmacology, and principles of abuse and addiction” is needed, write authors of a Commentary (
pp. 1346–7), along with more guidance for practitioners. (N. D. Volkow, nvolkow@nida.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 7, 2011 * Vol. 18, No. 67
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 7 issue of the New England Journal of Medicine (2011; 364).
Dalteparin v. Heparin in Critically Ill Patients: The early-release article (see PNN, Mar. 22) showing that dalteparin was not superior to unfractionated heparin for prevention of deep-vein thrombosis is printed in this issue (pp. 1305–14; D. Cook, debcook@mcmaster.ca).
Investigational Yellow Fever Vaccine: An inactivated cell-culture vaccine against yellow fever may be a safer alternative to the live attenuated 17D vaccine, according to a Phase I, placebo-controlled trial (pp. 1326–33). In 60 healthy adults ages 18–49 years, XRX-001 purified whole-virus, beta-propiolactone–inactivated yellow fever vaccine produced in Vero cell cultures and adsorbed to aluminum hydroxide (alum) adjuvant was administered on days 0 and 21 in two antigen doses, with these results: “The vaccine induced the development of neutralizing antibodies in 100% of subjects receiving 4.8 µg of antigen in each injection and in 88% of subjects receiving 0.48 µg of antigen in each injection. Antibody levels increased by day 10 after the second injection, at which time levels were significantly higher with the 4.8-µg formulation than with the 0.48-µg formulation (geometric mean titer, 146 vs. 39; P < 0.001). Three adverse events occurred at a higher incidence in the two vaccine groups than in the placebo group: mild pain, tenderness, and (much less frequently) itching at the injection site. One case of urticaria was observed on day 3 after the second dose of 4.8 µg of vaccine.” (T. P. Monath, tmonath@kpcb.com)
NICE Out, Value In: The U.K. National Health Services is switching to value-based pricing of pharmaceuticals in 2014, a move that will strip the National Institute for Health and Clinical Excellence (NICE) of its role in determining what pharmaceuticals are provided based on comparative clinical effectiveness and cost-effectiveness, authors of a Perspective article report (pp. 1289–91). The move has implications in the U.S. as health care reform moves forward, the article explains: “NICE’s history and the British government’s new turn demonstrate that, as a political if not a moral matter, the value of health care cannot be defined solely in terms of comparative clinical effectiveness or health outcomes. But clearly it is hard, politically and technically, to define value, even for an organization that has pioneered approaches to expanding the meaning of value in health care. As Britain’s value-based pricing proposal unfolds, the United States would do well to watch carefully how the ‘burden of illness’ and ‘wider societal benefits’ come to affect pharmaceutical pricing, decision making, and sources of influence over the interpretation of societal value.” (R. R. Faden)
Losing Money with ACOs: As providers scramble to evaluate the proposed regulations released recently defining accountable care organizations (ACOs), Perspective authors write that most ACOs will lose money for the first 3 years of their participation in the new value-based payment model (e27; T. T. Haywood)

>>>PNN NewsWatch
* Vandetanib (AstraZeneca), a kinase inhibitor, was approved yesterday by FDA for treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Approval was based on the ZETA study, which included 331 patients with late-stage medullary thyroid cancer. Patients treated with vandetanib 300 mg had median progression-free survival of at least 22.6 months, compared with 16.4 months in the placebo group. A Risk Evaluation and Mitigation Strategy (REMS) is required for vandetanib because of the risks of QT prolongation, torsades de pointes, and sudden death. The most common adverse reactions (>20%) seen in the ZETA trial with vandetanib were diarrhea (57%), rash (53%), acne (35%), nausea (33%), hypertension (33%), headache (26%), fatigue (24%), decreased appetite (21%), and abdominal pain (21%).
* Impact of a
government shutdown on pharmacy and health care continues to be unclear, even as a Friday deadline approaches for Congress and the President. In an article posted on pharmacist.com before the Mar. 4 deadline, FDA and CMS referred inquiries to HHS officials, who would say only that the Office of Management and Budget would give them “instructions … if this situation occurs.”

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 8, 2011 * Vol. 18, No. 68
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Apr. issue of Pediatrics (2011; 127).
Pediatric Medical Home: About half of American children are cared for in practices that meet the criteria for the “medical home,” a study shows (pp. 604–11). Using data from the National Survey of Children’s Health, investigators found these patterns among 83,448 children aged 1–17 years whose providers had any of several medical home characteristics (having a usual source of care; having a personal physician or nurse; receiving all needed referrals for specialty care; receiving help as needed in coordinating health and health-related care; and receiving family-centered care): “In 2007, 56.9% of US children aged 1 to 17 years received care in medical homes. Younger children were more likely to have a medical home than their older counterparts. Substantial racial/ethnic, socioeconomic, and health-related disparities were present. Children who received care in medical homes were less likely to have unmet medical and dental needs and were more likely to have annual preventive medical visits.” (B. B. Strickland)
IVIg for Neonatal Rhesus Hemolytic Disease: The need for exchange transfusions and occurrence of other adverse neonatal outcomes were not reduced by provision of intravenous immunoglobulin, researchers report (pp. 680–6). IVIg 0.75 g/kg or placebo (5% glucose) administered to neonates yielded these outcomes: “Eighty infants were included in the study, 53 of whom (66%) were treated with intrauterine transfusion(s). There was no difference in the rate of exchange transfusions between the IVIg and placebo groups (7 of 41 [17%] vs 6 of 39 [15%]; P = .99) and in the number of exchange transfusions per patient (median [range]: 0 [0–2] vs 0 [0–2]; P = .90) or in duration of phototherapy (4.7 [1.8] vs 5.1 [2.1] days; P = .34), maximum bilirubin levels (14.8 [4.7] vs 14.1 [4.9] mg/dL; P = .52), and proportion of neonates who required top-up red-cell transfusions (34 of 41 [83%] vs 34 of 39 [87%]; P = .76).” (V. E. H. J. Smits–Wintjens)
Alternative Medicine for Infantile Colic: Fennel extract, mixed herbal tea, and sugar solutions may have positive effects on infants with colic, found authors of a systematic review of nutritional supplements and other complementary medicines (pp. 720–33): “Fifteen randomized clinical trials met the inclusion criteria and were included. Thirteen studies were placebo controlled. Eight were of good methodological quality. Eleven trials indicated a significant result in favor of complementary and alternative medicines. However, none of these randomized clinical trials were without flaws. Independent replications were missing for most modalities.
“Some encouraging results exist for fennel extract, mixed herbal tea, and sugar solutions, although it has to be stressed that all trials have major limitations. Thus, the notion that any form of complementary and alternative medicine is effective for infantile colic currently is not supported from the evidence from the included randomized clinical trials. Additional replications are needed before firm conclusions can be drawn.” (R. Perry)

>>>PNN NewsWatch
* FDA has issued two safety communications, both about topical benzocaine. The agency said it continues to receive reports of rare but serious methemoglobinemia associated with use of benzocaine sprays for numbing the mouth and throat during medical procedures. Similar problems could occur with OTC benzocaine liquids, gels, lozenges, and spray solutions, FDA added. Those products are used for pain relief in teething, canker sores, and mouth and gum irritation. FDA cautioned that such products should not be used in children younger than 2 years and that adults using the products should follow recommendations on product labeling.
* Urgent action is needed “to preserve the last lines of defense against” a variety of pathogens,
CDC warned yesterday. Director Thomas R. Frieden, MD, MPH, said, “People assume that antibiotics will always be there to fight the worst infections, but antimicrobial resistance is robbing us of that certainty and new drug-resistant pathogens are emerging. It’s not enough to hope that we’ll have effective drugs to combat these infections. We must all act now to safeguard this important resource.” CDC, working with FDA and NIH, recently released an 11-point public health action plan focusing on antimicrobial resistance.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 11, 2011 * Vol. 18, No. 69
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 9 issue of Lancet (2011; 377).
CMV Vaccine in Transplant Recipients: In a Phase II trial of 140 patients awaiting kidney or liver transplantation, a cytomegalovirus vaccine produced an immune response, one that was inversely correlated with CMV viremia after transplant, researchers report (pp. 1256–63). In patients receiving either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, these results were noted: “Glycoprotein-B antibody titres were significantly increased in both seronegative [geometric mean titre 12,537 (95% CI 6,593–23,840) versus 86 (63–118) in recipients of placebo recipients; p < 0.0001] and seropositive (118,395; 64,503–217,272) versus 24,682 (17,909–34,017); p < 0.0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p = 0.0022). In the seronegative patients with seropositive donors, the duration of viraemia (p = 0.0480) and number of days of ganciclovir treatment (p = 0.0287) were reduced in vaccine recipients.” (P. D. Griffiths, p.griffiths@medsch.ucl.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2011; 342).
Statins & Pneumonia Mortality: Clinical trials of statins for reducing pneumonia-related mortality are warranted, authors argue, based on positive results from a cohort study (d1642). Using data from the U.K. Health Improvement Network, investigators matched 129,288 people who began statins in 1995–2006 with up to five nonstatin users (600,241 controls in all), with these results among 9,073 patients with a recorded diagnosis of pneumonia (1,398 of these patients were statin users): “Among users and non-users of statins with comparable propensity scores, 95/942 users and 686/3,615 non-users died on the day that pneumonia was diagnosed. In the following six month period, 109/847 statin users died compared with 578/2,927 non-users, giving an adjusted hazard ratio of 0.67 (0.49 to 0.91). If these observed benefits translated into clinical practice, 15 patients would need to be treated with a statin for six months after pneumonia to prevent one death.” (I. Douglas, ian.douglas@lshtm.ac.uk)
Treatment of Acute Bronchiolitis in Young Children: In infants and children younger than 2 years, use of epinephrine with or without dexamethasone is supported by evidence, conclude authors of a systematic review and meta-analysis (d1714). These findings were extracted from 48 trials of 4,897 patients: “Risk of bias was low in 17% (n = 8), unclear in 52% (n = 25), and high in 31% (n = 15). Only adrenaline (epinephrine) reduced admissions on day 1 (compared with placebo: pooled risk ratio 0.67, 95% confidence interval 0.50 to 0.89; number needed to treat 15, 95% confidence interval 10 to 45 for a baseline risk of 20%; 920 patients). Unadjusted results from a single large trial with low risk of bias showed that combined dexamethasone and adrenaline reduced admissions on day 7 (risk ratio 0.65, 0.44 to 0.95; number needed to treat 11, 7 to 76 for a baseline risk of 26%; 400 patients). A mixed treatment comparison supported adrenaline alone or combined with steroids as the preferred treatments for outpatients (probability of being the best treatment based on admissions at day 1 were 45% and 39%, respectively). The incidence of reported harms did not differ. None of the interventions examined showed clear efficacy for length of stay among inpatients.” (L. Hartling, hartling@ualberta.ca)

>>>PNN NewsWatch
* FDA is looking into the possibility of increased risk of new malignancies with lenalidomide (Revlimid, Celgene), an agent indicated for treatment of multiple myeloma, the agency said on Friday.

>>>PNN JournalWatch
* Dabigatran Etexilate: A New Oral Thrombin Inhibitor, in Circulation, 2011; 123: 1436–50. (G. J. Hankey, gjhankey@cyllene.uwa.edu.au)
* Guidelines for the Prevention of Intravascular Catheter-Related Infections, in
Clinical Infectious Diseases, 2011; 52: e162–93. (N. P. O’Grady, nogrady@mail.cc.nih.gov)
* Stinging Insect Hypersensitivity: A Practice Parameter Update 2011, in
Journal of Allergy and Clinical Immunology, 2011; 127: 852–54.e23. (Joint Council of Allergy, Asthma and Immunology)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 12, 2011 * Vol. 18, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 11 issue of the Archives of Internal Medicine (2011; 171).
Mortality with Opioids for Nonmalignant Pain: Daily dose of opioids being used to treat nonmalignant pain is strongly associated with opioid-related mortality, according to a population-based, nested, case–control study of patients in Ontario (pp. 686–91). The findings are similar to a study reported last week in JAMA (see PNN, Apr. 6) that showed increased overdose-related deaths among patients taking opioids for a variety of conditions. In the new report, investigators found these outcomes among patients on publicly funded prescription drugs who had received an opioid in 1997–2006: “Among 607,156 people aged 15 to 64 years prescribed an opioid over the study period, we identified 498 eligible patients whose deaths were related to opioids and 1,714 matched controls. After extensive multivariable adjustment, we found that an average daily dose of 200 mg or more of morphine (or equivalent), was associated with a nearly 3-fold increase in the risk of opioid-related mortality (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.79–4.63) relative to low daily doses (<20 mg of morphine, or equivalent). We found significant but attenuated increases in opioid-related mortality with intermediate doses of opioids (50–99 mg/d of morphine: OR, 1.92; 95% CI, 1.30–2.85; 100–199 mg/d of morphine: OR, 2.04; 95% CI, 1.28–3.24).” (T. Gomes, tara.gomes@ices.on.ca)
“The findings of Gomes et al are consistent with [the] adverse selection hypothesis,” writes an editorialist (
pp. 691–3). “Opioid-related deaths generally occurred as part of a polydrug overdose in higher-risk patients. Because opioid dose was closely related to these patient risk characteristics, with cases consistently showing greater risk than controls, clearly distinguishing between risks associated with high-dose opioids and risks associated with the patients receiving these doses is difficult. It is likely that both dose and patient characteristics contribute to risk, possibly in greater than additive fashion. However, the clinical lesson seems clear: it is important for patient safety to avoid pairing high-dose therapy with high-risk patients.” (M. D. Sullivan, sullimar@uw.edu)

>>>Chest Highlights
Source:
Apr. issue of Chest (2011; 139).
Probiotics & Lung Diseases: After reviewing relatively positive effects on probiotics on the respiratory system in animal models, an author provides this assessment of clinical data (pp. 901–8): “Despite progress in basic research, clinical trials of probiotics in allergy/asthma and respiratory infection have been highly variable at best, leading to an undermining of confidence in this potential therapeutic strategy. It is clear that there is still much to learn regarding the determinants of the diverse immune responses elicited by different bacterial strains. A deeper knowledge of the interactions between administered probiotics and the existing microbiota, together with an understanding of how the dialogue between microbes and the innate immune system is translated into beneficial/protective responses, will be required before we can achieve clinically effective bacteria-based strategies that maintain and promote respiratory health.” (P. Forsythe, forsytp@mcmaster.ca)
Iatrogenic Septicemia on ICU Admission: About 20% of patients with bloodstream infections (BSIs) on admission to intensive-care units have health-care–associated pathogens, and these should be treated as potentially drug-resistant pathogens until culture data are available, researchers report (pp. 810–5). At 27 Spanish hospitals and an Argentine facility, BSIs were categorized as community-acquired BSI (CAB), health-care-associated BSI (HCAB), or hospital-acquired BSI (HAB), with these results: “Of 726 BSIs, 343 (47.2%) were CABs, 252 (34.7%) were HABs, and 131 (18.0%) were HCABs. Potentially antibiotic-resistant pathogens were more frequently isolated in HABs (34.8%) and HCABs (27.6%) than in CABs (10.3%) (P < .001). Logistic regression analysis revealed that HABs (OR, 4.6; 95% CI, 2.9–7.3), HCABs (OR, 3.1; 95% CI, 1.8–5.4), and BSIs of unknown origin (OR, 1.7; 95% CI, 1.0–2.8) were independently associated with the isolation of potentially antibiotic-resistant pathogens. The incidence of inappropriate treatment was significantly higher in HABs (OR, 3.4; 95% CI, 2.1–5.3) and in HCABs (OR, 1.8; 95% CI, 1.0–3.2) than in CABs.” (J. Vallés, jvalles@tauli.cat)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 13, 2011 * Vol. 18, No. 71
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 13 issue of JAMA, a theme issue on infectious diseases and immunology (2011; 305).
Fixed-Dose, 4-Drug Combination for TB: Administration of 4 antitubercular agents in a single fixed-dose combination (FDC) formulation should be preferred over administration of the agents separately, authors of a noninferiority study write (pp. 1415–23). Conducted in Africa, Asia, and Latin America, the trial included 1,585 patients who had just been diagnosed with smear-positive pulmonary tuberculosis. They received rifampicin, isoniazid, pyrazinamide, and ethambutol given as an FDC or separately. In intention-to-treat subanalyses, model 1 classified all changes in treatment or refusal to continue therapy as unfavorable, while model 2 classified these according to an 18-month bacteriological outcome, when that was available.
Using a noninferiority margin of 4%, the investigators found that the FDC was noninferior in two of three analyses: “In the per-protocol analysis, 555 of 591 patients (93.9%) had a favorable outcome in the FDC group vs 548 of 579 (94.6%) in the separate-drugs group (risk difference, −0.7% [90% confidence interval {CI}, −3.0% to 1.5%]). In the model 1 analysis, 570 of 684 patients (83.3%) had a favorable outcome in the FDC group vs 563 of 664 (84.8%) in the separate-drugs group (risk difference, −1.5% [90% CI, −4.7% to 1.8%]). In the post hoc model 2 analysis, 591 of 658 patients (89.8%) in the FDC group and 589 of 647 (91.0%) in the separate-drugs group had a favorable outcome (risk difference, −1.2% [90% CI, −3.9% to 1.5%]). Adverse events related to trial drugs were similarly distributed among treatment groups.” (C. Lienhardt,
lienhardtc@who.int)
Alternative Schedules for HPV Vaccine: Stretching the 3-dose, 6-month schedule for human papillomavirus vaccine to 9 or 12 months results in acceptable antibody concentrations, researchers report, but the compensating for missed doses up to 24 months is not feasible (pp. 1424–31). In Vietnam, four schedules were tested in 903 adolescent girls—the standard schedule of 0, 2, and 6 months and 3 alternative schedules of 0, 3, and 9 months; 0, 6, and 12 months; and 0, 12, and 24 months. Lower bounds of confidence intervals of geometric mean titers (GMT) were used to assess effectiveness, with these results: “Noninferiority criteria were met for the alternative schedule groups that received doses at 0, 3, and 9 months (HPV-16 GMT ratio: 0.92 [95% CI, 0.71–1.20]; HPV-18 GMT ratio: 0.87 [95% CI, 0.68–1.11]) and at 0, 6, and 12 months (HPV-16 GMT ratio: 0.98 [95% CI, 0.75–1.29]; HPV-18 GMT ratio: 0.91 [95% CI, 0.71–1.17]). Prespecified noninferiority criteria were not met for the alternative schedule group that received doses at 0, 12, and 24 months (HPV-16 GMT ratio: 0.64 [95% CI, 0.48–0.84]; HPV-18 GMT ratio: 0.77 [95% CI, 0.62–0.96]). Pain at the injection site was the most common adverse event.” (K. M. Neuzil, kneuzil@path.org)
Hepatitis B Vaccine in Patients with HIV: Alternative schedules for hepatitis B virus vaccine administration improved serological responses in patients with HIV-1 infection, an open-label study shows (pp. 1432–40). Regimens tested were the standard intramuscular 20-mcg dose of recombinant HBV vaccine (IM20) at 0, 4, and 24 weeks; 4 intramuscular double doses (IM40) at 0, 4, 8, and 24 weeks; and 4 intradermal low dose (4 mcg; ID4) injections at 0, 4, 8, and 24 weeks. Results showed: “A total of 437 patients were randomized to the 3 study groups, of whom 11 did not receive any vaccine. Of these, 396 had available anti-HBs titers at week 28. The percentage of responders at week 28 was 65% (95% confidence interval [CI], 56%–72%) in the IM20 × 3 group (n = 91), 82% (95% CI, 77%–88%) in the IM40 × 4 group (n = 119) (P < .001 vs IM20 × 3 group), and 77% (95% CI, 69%–84%) in the ID4 × 4 group (n = 108) (P = .02 vs IM20 × 3 group). No safety signal and no effect on CD4 cell count or viral load were observed.” (O. Launay, dile.launay@cch.aphp.fr">odile.launay@cch.aphp.fr)

>>>PNN NewsWatch
* “Partnership for Patients: Better Care, Lower Costs” is a public–private program announced yesterday by HHS that “brings together leaders of major hospitals, employers, physicians, nurses, and patient advocates along with state and federal governments in a shared effort to make hospital care safer, more reliable, and less costly.”

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 14, 2011 * Vol. 18, No. 72
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 14 issue of the New England Journal of Medicine (2011; 364).
Preventing Nosocomial Bacterial Infections: Two research studies and an editorial report on efforts to stop the spread of resistant bacteria in health care settings.
Surveillance and expanded use of barrier precautions failed to reduce transmission of multidrug-resistant bacteria in intensive-care units, authors of the first study report (
pp. 1407–18). Transmission patterns of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) were as follows in this cluster-randomized trial: “During a 6-month intervention period, there were 5,434 admissions to 10 intervention ICUs, and 3,705 admissions to 8 control ICUs. Patients who were colonized or infected with MRSA or VRE were assigned to barrier precautions more frequently in intervention ICUs than in control ICUs (a median of 92% of ICU days with either contact precautions or universal gloving [51% with contact precautions and 43% with universal gloving] in intervention ICUs vs. a median of 38% of ICU days with contact precautions in control ICUs, P < 0.001). In intervention ICUs, health care providers used clean gloves, gowns, and hand hygiene less frequently than required for contacts with patients assigned to barrier precautions; when contact precautions were specified, gloves were used for a median of 82% of contacts, gowns for 77% of contacts, and hand hygiene after 69% of contacts, and when universal gloving was specified, gloves were used for a median of 72% of contacts and hand hygiene after 62% of contacts. The mean (± SE) ICU-level incidence of events of colonization or infection with MRSA or VRE per 1,000 patient–days at risk, adjusted for baseline incidence, did not differ significantly between the intervention and control ICUs (40.4 ± 3.3 and 35.6 ± 3.7 in the two groups, respectively; P = 0.35).” (W. C. Huskins, huskins.charles@mayo.edu)
A “MRSA bundle” was more successfully implemented in VA hospitals nationwide, according to the second study (
pp. 1419–30). “Universal nasal surveillance for MRSA, contact precautions for patients colonized or infected with MRSA, hand hygiene, and a change in the institutional culture whereby infection control would become the responsibility of everyone who had contact with patients” produced these outcomes: “From October 2007, when the bundle was fully implemented, through June 2010, there were 1,934,598 admissions to or transfers or discharges from intensive care units (ICUs) and non-ICUs (ICUs, 365,139; non-ICUs, 1,569,459) and 8,318,675 patient–days (ICUs, 1,312,840; and non-ICUs, 7,005,835). During this period, the percentage of patients who were screened at admission increased from 82% to 96%, and the percentage who were screened at transfer or discharge increased from 72% to 93%. The mean (± SD) prevalence of MRSA colonization or infection at the time of hospital admission was 13.6 ± 3.7%. The rates of health care–associated MRSA infections in ICUs had not changed in the 2 years before October 2007 (P = 0.50 for trend) but declined with implementation of the bundle, from 1.64 infections per 1,000 patient–days in October 2007 to 0.62 per 1,000 patient–days in June 2010, a decrease of 62% (P < 0.001 for trend). During this same period, the rates of health care–associated MRSA infections in non-ICUs fell from 0.47 per 1,000 patient–days to 0.26 per 1,000 patient–days, a decrease of 45% (P < 0.001 for trend).” (M. E. Evans, martin.evans@va.gov)
Asking whether it’s time for “culture change” in health care, an editorialist writes (
pp. 1464–5): “These studies … illustrate the larger challenge we confront in knowing whether health care practices produce the results we expect. Better evidence of effectiveness will require practice-based evaluation of treatments, tests, technologies, systems of care, and payment systems. The Institute of Medicine’s Roundtable on Value and Science-Driven Health Care and its Clinical Effectiveness Innovation Collaborative identify the development of evidence as an essential element of the Learning Healthcare System, articulating both general principles and specific policies and programs. These include, among others, rethinking the relationship between clinical practice and research, streamlining research oversight, and evaluating innovations in normal practice settings. Ongoing developments in information technology and analytic methods will facilitate these evaluations.” (R. Platt)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 15, 2011 * Vol. 18, No. 73
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Apr. issue of the American Journal of Psychiatry (2011; 168).
Nicotine Replacement in Agitation/Schizophrenia: Smoking status should be a part of the work-up of patients with schizophrenia who present with agitation and aggression, researchers conclude (pp. 395–9). In a study of 40 adult smokers who were admitted to a Swiss psychiatric emergency service with a diagnosis of schizophrenia, screening for agitation and nicotine dependence followed by assignment to nicotine-replacement therapy or placebo showed the following: “At baseline, participants were at least moderately agitated, and 28% reported aggressive behavior in the previous week. The mean Agitated Behavior Scale score for the nicotine replacement group was 33% lower at 4 hours and 23% lower at 24 hours than for the placebo group. Participants with lower levels of nicotine dependence responded better than those with higher levels of dependence.” (M. H. Allen, michael.allen@ucdenver.edu)
An editorialist writes that implications of this study likely go beyond schizophrenia (
pp. 347–9): “Allen and colleagues have made a significant contribution by bringing our attention to a frequently neglected aspect of emergency department and psychiatric practice. While their focus is on smokers with schizophrenia, one would expect that proactive treatment with nicotine replacement could lower levels of agitation in smokers with other psychiatric and substance use disorders as well. In addition, the benefits of nicotine replacement therapy for psychiatric patients who smoke are likely to go beyond measurable changes in agitation. Smokers who are not craving cigarettes and having physical manifestations of nicotine withdrawal are very likely to feel better. This improvement in patient experience, in addition to being an important end in itself, may have implications for the treatment alliance and for adherence with other recommended treatments.” (M. A. Schechter, mschechter@partners.org)

>>>Oncology Report
Source:
Apr. 10 issue of the Journal of Clinical Oncology (2011; 29).
Fosaprepitant for Preventing Nausea/Vomiting: A single dose of intravenous fosaprepitant 150 mg was noninferior for preventing chemotherapy-induced nausea and vomiting (CINV) to standard 3-day oral aprepitant in 2,247 patients (pp. 1495–501). The patients, all receiving cisplatin for the first time, were given ondansetron and dexamethasone along with either aprepitant 125 mg on day 1 and 80 mg on days 2 and 3 or the single dose of i.v. fosaprepitant, with these results based on an expected complete response in 67.7% of patients and a margin of noninferiority of minus 7 percentage points: “Antiemetic protection with aprepitant and fosaprepitant was equivalent within predefined bounds for noninferiority. Both regimens were well tolerated, although more frequent infusion site pain/erythema/thrombophlebitis was seen with fosaprepitant relative to aprepitant (2.7% v 0.3%, respectively).” (S. Grunberg, steven.grunberg@uvm.edu)
Asking Patients with Cancer About Other Medication Use: Reporting the cases of three patients with advanced hepatocellular carcinoma (HCC), authors emphasize the importance of asking, “And what other medications are you taking?” (pp. e288–91): “Although the three patients presented here took a variety of [complementary and alternative medicines (CAM)], all used Ling Zhi, also known as Reishi, prepared from the edible mushroom Ganoderma lucidum (G. lucidum). G. lucidum has been shown to have anticancer activity in vitro and in mouse models of cancer. A number of antineoplastic activities have been described for G. lucidum, including nuclear factor kappa-B and protein kinase C inhibition, immune modulation, and direct cytotoxicity.… These cases underscore the need for oncologists to be aware of CAM agents such as Ling Zhi, not only because they may be active against HCC, but also because concurrent use of these agents with chemotherapy, as in our first patient, might confound the attribution of results in clinical trials.” (J. D. Gordan)

>>>PNN NewsWatch
* In two drug-safety–related announcements yesterday, FDA said that benefits of olmesartan (Benicar, Daiichi Sankyo) continue to outweigh its cardiovascular risks and it has received more reports associating TNF blocker use with hepatosplenic T-cell lymphomas in adolescents and young adults.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 18, 2011 * Vol. 18, No. 74
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 16 issue of Lancet (2011; 377).
Phentermine, Topiramate for Weight Control: With lifestyle, phentermine plus topiramate offers a potentially “valuable treatment for obesity that can be provided by family doctors,” based on a 56-week Phase III trial (pp. 1341–52). Among 2,487 patients, all overweight or obese adults (BMI, 27–45 kg/m2) with two or more comorbidities, these results were recorded: “At 56 weeks, change in bodyweight was –1.4 kg (least-squares mean –1.2%, 95% CI –1.8 to –0.7), –8.1 kg (–7.8%, –8.5 to –7.1; p < 0.0001), and –10.2 kg (–9.8%, –10.4 to –9.3; p < 0.0001) in the patients assigned to placebo, phentermine 7.5 mg plus topiramate 46.0 mg, and phentermine 15.0 mg plus topiramate 92.0 mg, respectively. 204 (21%) patients achieved at least 5% weight loss with placebo, 303 (62%; odds ratio 6.3, 95% CI 4.9 to 8.0; p < 0.0001) with phentermine 7.5 mg plus topiramate 46.0 mg, and 687 (70%; 9.0, 7.3 to 11.1; p < 0.0001) with phentermine 15.0 mg plus topiramate 92.0 mg; for ≥10% weight loss, the corresponding numbers were 72 (7%), 182 (37%; 7.6, 5.6 to 10.2; p < 0.0001), and 467 (48%; 11.7, 8.9 to 15.4; p < 0.0001). The most common adverse events were dry mouth (24 [2%], 67 [13%], and 207 [21%] in the groups assigned to placebo, phentermine 7.5 mg plus topiramate 46.0 mg, and phentermine 15.0 mg plus topiramate 92.0 mg, respectively), paraesthesia (20 [2%], 68 [14%], and 204 [21%], respectively), constipation (59 [6%], 75 [15%], and 173 [17%], respectively), insomnia (47 [5%], 29 [6%], and 102 [10%], respectively), dizziness (31 [3%], 36 [7%], 99 [10%], respectively), and dysgeusia (11 [1%], 37 [7%], and 103 [10%], respectively). 38 (4%) patients assigned to placebo, 19 (4%) to phentermine 7.5 mg plus topiramate 46.0 mg, and 73 (7%) to phentermine 15.0 mg plus topiramate 92.0 mg had depression-related adverse events; and 28 (3%), 24 (5%), and 77 (8%), respectively, had anxiety-related adverse events.” (K. M. Gadde, gadde001@mc.duke.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
Artificial Pancreas in Type 1 Diabetes: An overnight closed-loop insulin-delivery system showed promise as a form of artificial pancreas in two small crossover trials, researchers report (d1855). Using conventional insulin pump therapy with glucose sensor measurements in 24 adults with type 1 diabetes, these results were noted: “For the eating in scenario, overnight closed loop delivery of insulin increased the time plasma glucose levels were in target by a median 15% (interquartile range 3–35%), P = 0.002. For the eating out scenario, closed loop delivery increased the time plasma glucose levels were in target by a median 28% (2–39%), P = 0.01. Analysis of pooled data showed that the overall time plasma glucose was in target increased by a median 22% (3–37%) with closed loop delivery (P < 0.001). Closed loop delivery reduced overnight time spent hypoglycaemic (plasma glucose ≤3.9 mmol/L) by a median 3% (0–20%), P = 0.04, and eliminated plasma glucose concentrations below 3.0 mmol/L after midnight.” (R. Hovorka, rh347@cam.ac.uk)

>>>PNN NewsWatch
* FDA on Friday approved tocilizumab (Actemra, Genentech) for treatment, either alone or in combination with methotrexate, of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older. The product is the first approved for SJIA, which is the rarest form of systemic juvenile arthritis and has the worst long-term prognosis of the types of childhood arthritis. Approval was based on data from a Phase III study, TENDER. It showed that 85% (64/75) of children with SJIA receiving tocilizumab experienced a 30% improvement in the signs and symptoms of SJIA and an absence of fever after 12 weeks of therapy, significantly more than the 24% (9/37) of children receiving placebo. Common adverse effects of tocilizumab, a humanized IL-6 receptor-inhibiting monoclonal antibody approved last year (see PNN, Jan. 12, 2010), include upper respiratory tract infections, headache, and hypertension. A boxed warning details serious infections in patients receiving the agent, including tuberculosis.

>>>PNN JournalWatch
* The Efficacy of Proton Pump Inhibitors for the Treatment of Asthma in Adults: A Meta-analysis, in
Archives of Internal Medicine, 2011; 171: 620–9. (W. W. Chan, wwchan@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 19, 2011 * Vol. 18, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 19 issue of the Annals of Internal Medicine (2011; 154).
Initiation Point for Antiretroviral Therapy: A CD4 threshold of 0.500 × 109 cells/L for initiation of combined antiretroviral therapy (cART) is supported by results of an analysis of prospective observational data from the U.S. and Europe (pp. 509–15). Most clinical guidelines in developed countries recommend starting cART at CD4 cell counts below 0.350 × 109 cells/L. Data from 20,971 HIV-infected, therapy-naive persons with baseline CD4 cell counts at or above 0.500 × 109 cells/L and no previous AIDS-defining illnesses, including 8,392 patients with a CD4 cell count that had decreased into the range of 0.200 to 0.499 × 109 cells/L, showed these patterns during treatment: “Compared with initiating cART at the CD4 cell count threshold of 0.500 × 109 cells/L, the mortality hazard ratio was 1.01 (95% CI, 0.84 to 1.22) for the 0.350 threshold and 1.20 (CI, 0.97 to 1.48) for the 0.200 threshold. The corresponding hazard ratios were 1.38 (CI, 1.23 to 1.56) and 1.90 (CI, 1.67 to 2.15), respectively, for the combined end point of AIDS-defining illness or death.” (L. E. Cain, lcain@hsph.harvard.edu)
Deciding whether to use cART in the above CD4 cell count ranges is difficult, given that treatment is already essentially rationed, an editorialist writes (
pp. 563–5): “Expanded use of cART could substantially curtail the future HIV epidemic. The HIV-CAUSAL Collaboration study is a robust, carefully performed analysis that supports the presence of a graded benefit of cART even when risk for AIDS is low, but uncertainty remains regarding the cumulative benefits, in absolute terms, of treating everyone with HIV infection. Investment in well-conceived clinical studies is often met with resistance because of the up-front costs, particularly in current times, but the continuing HIV epidemic and tightening resources requires that we clarify the absolute benefits, risks, and costs of expanding the indications for cART. Improved care for our patients with HIV infection in an era of fiscal constraint is a goal we can achieve, as long as we have sound data to inform both individual treatment and public policy decisions.” (K. Henry, keithh6680@aol.com)
Off-Label Hospital Use of Recombinant Factor VIIa: The off-label use of recombinant factor VIIa in U.S. hospitals dwarfs use of the agent for FDA-approved indications, a study shows (pp. 516–22). Using the Premier Perspectives database, investigators found these results during 12,644 hospitalizations at both academic and nonacademic hospitals: “From 2000 to 2008, off-label use of rFVIIa in hospitals increased more than 140-fold, such that in 2008, 97% (95% CI, 96% to 98%) of 18,311 in-hospital uses were off-label. In contrast, in-hospital use for hemophilia increased less than 4-fold and accounted for 2.7% (CI, 1.9% to 3.5%) of use in 2008. Adult and pediatric cardiovascular surgery (29% [CI, 21% to 33%]), body and brain trauma (29% [CI, 19% to 38%]), and intracranial hemorrhage (11% [CI, 7.7% to 14%]) were the most common indications for rFVIIa use. Across all indications, in-hospital mortality was 27% (CI, 19% to 34%) and 43% (CI, 26% to 59%) of patients were discharged to home.” (R. S. Stafford, rstafford@stanford.edu)
Discussing the above article and a related systematic review of the benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications (
pp. 529–40; V. Yank, vyank@stanford.edu), editorialists write of “a hemorrhage of off-label use” (pp. 566–7): “With such compelling data in place about the runaway use, uselessness, and risk for this expensive treatment, what can be done to reduce it? First, if evidence should emerge that the manufacturer played a role in building a market for the unauthorized and increasingly implausible prescribing of its product, both civil and criminal responses will probably be brought to bear, as has occurred for many other instances of corporate-sponsored drug misuse. Second, rFVIIa is used in hospitals, which should be providing organizational oversight to protect patients, as well as the institutions’ own pharmacy budgets. In hospitals where such use continues, existing quality assurance, patient safety, and risk-management groups will surely want to look hard at these practices. Although off-label prescribing by physicians is not illegal, physicians who persist in such use in the face of clear evidence of inutility and harm could be subject to civil action by the affected patients or their heirs.” (J. Avorn, javorn@medsoc.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 20, 2011 * Vol. 18, No. 76
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 20 issue of JAMA (2011; 305).
Cystatin C as Renal Biomarker: Commenting on studies that support addition of cystatin C to creatinine/albumin-to-creatinine ratio identification of patients with chronic kidney disease (pp. 1545–52; C. A. Peralta, carmenalicia.peralta@ucsf.edu) and use of other noncreatinine-based indicators of renal function (pp. 1553–9; N. Tangri, ntangri@tuftsmedicalcenter.org), editorialists write about the challenges of incorporating these findings into clinical practice (pp. 1593–5): “Developing optimal risk prediction tools is only part of the challenge ahead. Data are urgently needed to clarify how better prognostic information can be incorporated into routine care to improve patient outcomes rather than simply increasing physician workload, the costs of laboratory testing, and the complexity of risk instruments. This seems particularly important given studies showing that routine estimated [glomerular filtration rate] reporting increased the likelihood of specialist referrals but did not improve outcomes. Achieving this objective will require studies that use other metrics besides discrimination and calibration—such as assessing the acceptability of risk stratification schemes to primary care physicians and the feasibility of implementation in diverse clinical settings—and will require studies that demonstrate that using better risk prediction tools will lead to clinically meaningful benefit for patients.” (M. Tonelli, mtonelli@ualberta.ca)
Whole-Genome Sequencing in Oncology: The promise of whole-genome sequencing in the delivery of personalized medicine is being realized first in oncology, as shown in two studies and described in an editorial.
One new research study shows that whole-genome sequencing can be used to “identify novel, cryptic variants in cancer susceptibility genes in addition to providing unbiased information on the spectrum of mutations in a cancer genome” (
pp. 1568–76; R. K. Wilson, rwilson@wustl.edu). The other investigation successfully used the technique to “identify cytogenetically invisible oncogenes in a clinically relevant time frame” in a difficult diagnostic case of acute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase fluorescence in situ hybridization (pp. 1577–84; R. K. Wilson, rwilson@wustl.edu).
The editorialists write (
pp. 1596–7): “It is clear that the first test bed for implementation of personalized genomic medicine is being established in oncology, where its use can have an immediate effect on patient care. There is also a great potential for the use of similar approaches for unbiased discovery of genetic features associated with sensitivity and resistance to a given therapy. Hence, recent advances in genomics are likely to change the molecular characterization of cancer rapidly and provide a path for the personalized treatment of patients with cancer.” (B. Pasche)

>>>PNN NewsWatch
* The White House yesterday took aim at the nation’s growing epidemic of prescription drug abuse, which it said is now the leading cause of injury death in 17 states and second only to motor vehicle fatalities nationally. In an event at the National Press Club in Washington, Gil Kerlikowske, White House Director of National Drug Control Policy; Assistant Secretary for Health and Human Services Howard Koh, MD; FDA Commissioner Margaret A. Hamburg, MD; and DEA Administrator Michele M. Leonhart released the Obama administration’s “Epidemic: Responding to America’s Prescription Drug Abuse Crisis.” It provides a national framework for reducing prescription drug diversion and abuse by supporting the expansion of state-based prescription drug monitoring programs, recommending more convenient and environmentally responsible disposal methods to remove unused medications from the home, supporting education for patients and health care providers, and reducing the prevalence of pill mills and doctor shopping through enforcement efforts. FDA specifically announced new Risk Evaluation and Mitigation Strategy education for practitioners regarding all extended-release and long-acting opioid medications, including those containing hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 21, 2011 * Vol. 18, No. 77
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 21 issue of the New England Journal of Medicine (2011; 364).
PR0051 in Duchenne’s Muscular Dystrophy: Weekly abdominal injections of the antisense oligonucleotide PR0051 (Prosensa Therapeutics) showed dose-dependent molecular efficacy in 12 patients with Duchenne’s muscular dystrophy, researchers report (pp. 1513–22). PR0051 induces the skipping of exon 51 of the dystrophin gene during pre-messenger RNA splicing, thereby correcting a reading-frame error that produces the deficiency of dystrophin and continued fiber degeneration that is the hallmark of Duchenne’s. In this Phase I/IIa trial, the agent was administered subcutaneously at one of five doses for 5 weeks, followed by an open-label, 12-week extension phase in which PR0051 was given at 6 mg/kg/wk, with these safety results and effects on RNA splicing and protein levels in the tibialis anterior muscle: “The most common adverse events were irritation at the administration site and, during the extension phase, mild and variable proteinuria and increased urinary alpha-1-microglobulin levels; there were no serious adverse events. The mean terminal half-life of PRO051 in the circulation was 29 days. PRO051 induced detectable, specific exon-51 skipping at doses of 2.0 mg or more per kilogram. New dystrophin expression was observed between approximately 60% and 100% of muscle fibers in 10 of the 12 patients, as measured on post-treatment biopsy, which increased in a dose-dependent manner to up to 15.6% of the expression in healthy muscle. After the 12-week extension phase, there was a mean (± SD) improvement of 35.2 ± 28.7 m (from the baseline of 384 ± 121 m) on the 6-minute walk test.” (J. C. van Deutekom, j.vandeutekom@prosensa.nl)
Novel Bunyavirus in China: Investigators looking into the cause of severe fever with thrombocytopenia syndrome (SFTS) in patients in six Chinese provinces have identified a novel, pathogenic bunyavirus (pp. 1523–32). Blood samples yielded the following clues whan analyzed using electron microscopy, nucleic acid sequencing, enzyme-linked immunosorbent assay, and other tests: “We isolated a novel virus, designated SFTS bunyavirus, from patients who presented with fever, thrombocytopenia, leukocytopenia, and multiorgan dysfunction. RNA sequence analysis revealed that the virus was a newly identified member of the genus phlebovirus in the Bunyaviridae family. Electron-microscopical examination revealed virions with the morphologic characteristics of a bunyavirus. The presence of the virus was confirmed in 171 patients with SFTS from six provinces by detection of viral RNA, specific antibodies to the virus in blood, or both. Serologic assays showed a virus-specific immune response in all 35 pairs of serum samples collected from patients during the acute and convalescent phases of the illness.” (D-X Li, lidx@chinacdc.cn)
“Nowadays, diagnostic capacity in developed countries should not (but sometimes still does) pose a real problem in the context of an outbreak investigation for routine organisms, but pathogen discovery still largely relies on traditional isolation attempts,” an editorialist writes (
pp. 1561–3). “However, such efforts often do not detect pathogens that are neither cytolytic in cell culture nor virulent in animals. There is a boom in the development of promising high-tech diagnostic approaches that have increased sensitivity and specificity, as well as being faster and more successful. For example, metagenomics can provide complete molecular characterization of a virus in a certain microenvironment, such as blood, within a day’s time. This process does not fulfill Koch’s postulates but will have a rapid effect on the treatment of patients, intervention therapy, and public health response.” (H. Feldmann)

>>>PNN NewsWatch
* Manufacturers of hand sanitizers and other OTC drug products that claim to prevent infection from methicillin-resistant Staphylococcus aureus (MRSA) have received warning letters, FDA said yesterday. The companies—Tec Laboratories, JD Nelson and Associates, Dr. G. H. Tichenor Antiseptic Co., and Oh So Clean—have 15 days to correct the alleged violations regarding Staphaseptic First Aid Antiseptic/Pain Relieving Gel, Safe4Hours Sanitizing Lotion and First Aid Antiseptic Skin Protectant, Dr. Tichenor’s Antiseptic Gel, and several CleanWell products.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 22, 2011 * Vol. 18, No. 78
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Apr. Journal of the American Geriatrics Society (2011; 59).
Treatment of Depression in Patients with Comorbid Dementia: Antidepressants may work for treating depression in people who also have dementia, but the published evidence of efficacy is lacking, according to a systematic review and meta-analysis of seven trials of 330 participants (pp. 577–85): “The odds ratio (OR) for six trials reporting response rates with antidepressant and placebo was 2.12 (95% confidence interval (CI)=0.95–4.70; Z = 1.84, P = .07). The OR for five trials reporting remission rates was 1.97 (95% CI = 0.85–4.55; Z = 1.59, P = .11). Both analyses demonstrated heterogeneity. The standardized mean difference in trials was 0.29 (95% CI = 0.02–0.60, Z = 1.86, P = .06). This analysis did not demonstrate significant heterogeneity. Adverse event discontinuation rates (9.0%) were not significantly higher with drug than placebo (6.0%), and were low.” (J. C. Nelson, craign@lppi.ucsf.edu)
Pharmaceutical Care in Northern Ireland Nursing Homes: Pharmaceutical care was cost-effective in the Fleetwood Northern Ireland Study of 22 nursing homes (pp. 586–93). “The proportions of residents receiving inappropriate psychoactive medication at 12 months in the intervention and control group were 19.5% and 50.4%, respectively. The mean cost of healthcare resources used per resident per year was $4,923 (95% confidence interval (CI)=$4,206–5,640) for the intervention group and $5,053 (95% CI = $4,328–5,779) for the control group. The probability of the intervention being cost-effective was high, even at low levels of willingness to pay to avoid a resident receiving inappropriately prescribed psychoactive medication.” (C. Hughes, c.hughes@qub.ac.uk)

>>>Allergy/Immunology Report
Source:
Apr. Journal of Allergy and Clinical Immunology (2011; 127).
Oxymetazoline plus Fluticasone in Perennial Allergic Rhinitis: Rhinitis medicamentosa was not a significant problem in a 60-patient study of the addition of oxymetazoline to fluticasone furoate treatment of perennial allergic rhinitis, researchers report (pp. 927–34). Concluding that this intervention should be explored in a large clinical trial, the investigators reported these 4-week results with once-nightly administration of fluticasone furoate, oxymetazoline hydrochloride, the combination, or placebo: “The total nasal symptom score over the 4 weeks of treatment was lower with the combination (median, 143; range, 30–316) compared with treatment with placebo (262; 116–358) and oxymetazoline alone (219; 78–385; ANOVA, P = .04). When acoustic rhinometry was compared between the groups at the end of 4 weeks of treatment, the combination resulted in significantly higher nasal volume (mean + SEM, 15.8 + 1.1 mL; P < .03) compared with both placebo (12.1 + 0.9 mL) and oxymetazoline (12.4 + 0.8 mL) alone. The quality of life data showed no significant differences among the groups. Peak flow showed a nonsignificant improvement with the groups on fluticasone furoate. There was no evidence of rhinitis medicamentosa.” (R. M. Naclerio, rnacleri@surgery.bsd.uchicago.edu)

>>>Neurology Highlights
Source:
Apr. 19 issue of Neurology (2011; 76).
Efavirenz & Cognitive Disorders: Efavirenz may be neurotoxic, according to a study showing HIV-associated neurocognitive disorders (HAND) among many patients on the drug (pp. 1403–9). Recommending neuropsychological examinations that can identify “mild but clinically relevant” manifestations of HAND, the researchers found these relationships in 146 HIV-positive patients: “129 (88.4%) [patients] were on [combination antiretroviral therapy] and 59.6% of them were on current regimen from ≥1 year. Sixty-nine patients (47%) were classified as cognitively impaired (35.6% asymptomatic and 11.6% mild neurocognitive impairment). In the multivariate analysis, efavirenz use (odds ratio [OR] = 4.00; p = 0.008) and non–Italian nationality (OR = 3.46; p = 0.035) were associated with increased risk of cognitive impairment, whereas higher education was associated with a lower risk (OR = 0.85; p = 0.002). Furthermore, efavirenz use and age ≥65 years independently predicted worse performance on the double barrage and the Stroop test (time). No association between [CNS penetration effectiveness] rank and cognitive impairment was observed.” (N. Ciccarelli, nicoletta.ciccarelli@rm.unicatt.it)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 25, 2011 * Vol. 18, No. 79
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2011; 342).
Venous Thromboembolism with Drospirenone: Venous thromboembolism in women on oral contraceptives occurs more often with drospirenone, two studies show, compared with levonorgestrel.
In a nested case–control and cohort analysis of information from PharMetrics since 2002, these patterns were observed among U.S. women aged 15–44 years (
d2151): “186 newly diagnosed, idiopathic cases of venous thromboembolism were identified in the study population and matched with 681 controls. In the case–control analysis, the conditional odds ratio for venous thromboembolism comparing use of oral contraceptives containing drospirenone with use of those containing levonorgestrel was 2.3 (95% confidence interval 1.6 to 3.2). The incidence rates for venous thromboembolism in the study population were 30.8 (95% confidence interval 25.6 to 36.8) per 100,000 woman years among users of oral contraceptives containing drospirenone and 12.5 (9.61 to 15.9) per 100,000 woman years among users of oral contraceptives containing levonorgestrel. The age adjusted incidence rate ratio for venous thromboembolism for current use of oral contraceptives containing drospirenone compared with those containing levonorgestrel was 2.8 (2.1 to 3.8).” (S. S. Jick, sjick@bu.edu)
Similar findings come from the U.K. General Practice Research Database, where women in the 15–44 range showed these risks in 2002–09 (
d2139): “61 cases of idiopathic venous thromboembolism and 215 matched controls were identified. In the case–control analysis, current use of the drospirenone contraceptive was associated with a threefold higher risk of non-fatal idiopathic venous thromboembolism compared with levonorgestrel use; the odds ratio adjusted for body mass index was 3.3 (95% confidence interval 1.4 to 7.6). Subanalyses suggested that referral, diagnostic, first time user, duration of use, and switching biases were unlikely explanations for this finding. The crude incidence rate was 23.0 (95% confidence interval 13.4 to 36.9) per 100,000 woman years in current users of drospirenone and 9.1 (6.6 to 12.2) per 100,000 woman years in current users of levonorgestrel oral contraceptives. The age adjusted incidence rate ratio was 2.7 (1.5 to 4.7).” (S. S. Jick, sjick@bu.edu)
Calcium Supplements & CVD Risks: Administered with or without vitamin D, calcium supplements are associated with an increased risk of cardiovascular events, according to a reanalysis of data from the Women’s Health Initiative Calcium/Vitamin D Supplementation Study (WHI CaD Study) (d2040). Among 26,282 community-dwelling postmenopausal women studied over 7 years, investigators found an interaction between personal use of calcium and events in those allocated to calcium 1 g and vitamin D 400 IU daily. “In the 16,718 women (46%) who were not taking personal calcium supplements at randomisation the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P = 0.05 for clinical myocardial infarction or stroke, P = 0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D. In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (95% confidence interval 1.01 to 1.44), P = 0.04), stroke (1.20 (1.00 to 1.43), P = 0.05), and the composite of myocardial infarction or stroke (1.16 (1.02 to 1.32), P = 0.02). In meta-analyses of placebo controlled trials of calcium or calcium and vitamin D, complete trial-level data were available for 28,072 participants from eight trials of calcium supplements and the WHI CaD participants not taking personal calcium supplements. In total 1,384 individuals had an incident myocardial infarction or stroke. Calcium or calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.24 (1.07 to 1.45), P = 0.004) and the composite of myocardial infarction or stroke (1.15 (1.03 to 1.27), P = 0.009).” (I. R. Reid, i.reid@auckland.ac.nz)

>>>PNN JournalWatch
* Gastrointestinal Stromal Tumors: Disease and Treatment Update, in Gastroenterology, 2011; 140: 1372–6.e2. (C. D. Blanke, cblanke@bccancer.bc.ca)
* An Early Status Report on the Beacon Communities’ Plans for Transformation via Health Information Technology, in
Health Affairs, 2011; 30: 782–8. (A. McKethan, aaron.mckethan@hhs.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 26, 2011 * Vol. 18, No. 80
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 25 issue of the Archives of Internal Medicine (2011; 171).
Varenicline Preloading in Smoking Cessation: Administration of varenicline for 4 weeks before a target quit date (TQD) can reduce ad lib smoking and ultimately improve 12-week quit rates, reserchers report (pp. 770–7). Before the TQD at a smoking cessation clinic in London, 101 smokers received varenicline for 4 weeks or placebo for 3 weeks and varenicline for 1 week, with these effects on smoking satisfaction and smoke intake before quitting, urges to smoke and withdrawal discomfort after quitting, and sustained abstinence from the TQD to 3 months: “Varenicline preloading reduced prequit enjoyment of smoking (P = .004) and smoke intake (P < .001), with 36.7% of participants reducing their cotinine concentrations by more than 50% (reducers). Varenicline preloading did not affect postquit withdrawal symptoms, but it increased 12-week abstinence rates (47.2% in the varenicline arm vs 20.8% in the placebo arm, P = .005). The effect was particularly strong among the reducers in the varenicline arm (66.7% in reducers vs 22.6% in nonreducers, P = .002). Varenicline preloading was well tolerated.” (H. J. McRobbie, h.j.mcrobbie@qmul.ac.uk)
Beta-Blockers in Thick Melanoma: As reflected in decreased mortality rates, beta-blocker therapy for 1 or more years reduced the risk of progression of thick malignant melonoma in a case series of 749 patients seen at a dermatology department in Florence, Italy (pp. 779–81). Among 121 patients analyzed for this report, 30 were treated with beta-blockers for 1 year or more, with these effects on disease-free survival (DFS) in comparison with 91 untreated patients: “When the time to progression was analyzed, the log-rank test showed that DFS was significantly greater in the treated group (P = .002). After adjusting for age and Breslow thickness, the Cox model indicated that treatment with beta-blockers was inversely associated with recurrence (hazard ratio, 0.03; 95% confidence interval [CI], 0.01–0.28; P = .01). Furthermore, consistent results were obtained when we considered duration of treatment: a 36% reduction (95% CI, 11%–54%) in the risk of relapse for each year of beta-blocker use was determined by the Cox model (P = .002). Finally, and most important, although no deaths unrelated to melanoma occurred during the study period in either group, all 24 patients who died of melanoma during the follow-up period were in the untreated group (P < .001).” (V. De Giorgi, vincenzo.degiorgi@unifi.it)
Tai Chi in Chronic Heart Failure: In a study of 100 outpatients with systolic heart failure, a tai chi exercise program improved quality of life, mood, and exercise self-efficacy (pp. 750–7). The 12-week program, conducted in patients with mean left ventricular ejection fraction of 29%, produced little change in physical parameters but improved emotional measures. (G. Y. Yeh, gyeh@bidmc.harvard.edu)

>>>PNN NewsWatch
* Infants as young as 9 months can now receive FDA-licensed meningococcal vaccine, the agency announced on Friday. Extending the lower end of the previously approved age range of 2 to 55 years, FDA said the safety of Menactra (Sanofi Pasteur)—which protects against invasive meningococcal disease caused by Neisseria meningitidis serogroups A, C, Y and W-135—in children as young as 9 months was evaluated in four clinical studies in which more than 3,700 participants received the vaccine. The most common adverse events reported in children who received Menactra at 9 months and 12 months of age were injection-site tenderness and irritability. Occurrence of fever was comparable with other vaccines routinely recommended for young children. Menactra is given as a two-dose series beginning at 9 months, 3 months apart. The study results showed the vaccine produces serum antibodies protective against the disease.
* The product labeling for
natalizumab (Tysabri, Elan) now summarizes the risk of progressive multifocal leukoencephalopathy (PML) in those being treated for multiple sclerosis and Crohn’s disease, FDA said on Friday. The labeling also says patients who took immunosuppressants such as mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate before taking natalizumab have been shown to be at an increased risk for developing PML.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 27, 2011 * Vol. 18, No. 81
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 27 issue of JAMA (2011; 305).
Vitamin E v. Metformin for Pediatric Nonalcoholic Fatty Liver Disease: In children and adolescents with nonalcoholic fatty liver disease (NAFLD), neither vitamin E nor metformin was superior to placebo, as measured by reduction in ALT levels, researchers report (pp. 1659–68). In the Treatment of NAFLD in Children (TONIC) trial, 173 patients aged 8–17 years received daily vitamin E 800 IU, metformin 1000 mg, or placebo for 96 weeks, with these effects on reduction in ALT levels to 50% of baseline or by 40 IU: “Sustained reduction in ALT level was similar to placebo (10/58; 17%; 95% CI, 9% to 29%) in both the vitamin E (15/58; 26%; 95% CI, 15% to 39%; P = .26) and metformin treatment groups (9/57; 16%; 95% CI, 7% to 28%; P = .83). The mean change in ALT level from baseline to 96 weeks was −35.2 U/L (95% CI, −56.9 to −13.5) with placebo vs −48.3 U/L (95% CI, −66.8 to −29.8) with vitamin E (P = .07) and −41.7 U/L (95% CI, −62.9 to −20.5) with metformin (P = .40). The mean change at 96 weeks in hepatocellular ballooning scores was 0.1 with placebo (95% CI, −0.2 to 0.3) vs −0.5 with vitamin E (95% CI, −0.8 to −0.3; P = .006) and −0.3 with metformin (95% CI, −0.6 to −0.0; P = .04); and in NAFLD activity score, −0.7 with placebo (95% CI, −1.3 to −0.2) vs −1.8 with vitamin E (95% CI, −2.4 to −1.2; P = .02) and −1.1 with metformin (95% CI, −1.7 to −0.5; P = .25). Among children with [nonalcoholic steatohepatitis], the proportion who resolved at 96 weeks was 28% with placebo (95% CI, 15% to 45%; 11/39) vs 58% with vitamin E (95% CI, 42% to 73%; 25/43; P = .006) and 41% with metformin (95% CI, 26% to 58%; 16/39; P = .23). Compared with placebo, neither therapy demonstrated significant improvements in other histological features.” (J. E. Lavine, jl3553@columbia.edu)
Nonadherence to Antiepileptic Drug Therapy in Newly Diagnosed Children: In a longitudinal, prospective, observational study of 124 children newly diagnosed with epilepsy, five “trajectory patterns” of medication nonadherence were identified (pp. 1669–76). At the Cincinnati Children’s Hosp. Med. Ctr., patients recruited in 2006–09 showed these patterns of adherence as measured by electronic monitors: “Fifty-eight percent of children with newly diagnosed epilepsy demonstrated persistent nonadherence during the first 6 months of therapy. Group-based trajectory models identified 5 differential adherence patterns (Bayesian information criterion = −23611.8): severe early nonadherence (13%; 95% confidence interval [CI], 8%-20%), severe delayed nonadherence (7%; 95% CI, 3%–12%), moderate nonadherence (13%; 95% CI, 8%–20%), mild nonadherence (26%; 95% CI, 19%–34%), and near-perfect adherence (42%; 95% CI, 33%–50%). The adherence pattern of most patients was established by the first month of therapy. Socioeconomic status was the sole predictor of adherence trajectory group status (chi square-4 = 19.3 [n = 115]; P < .001; partial r2 = 0.25), with lower socioeconomic status associated with higher nonadherence.” (A. C. Modi, avani.modi@cchmc.org)
Health Literacy & Mortality in Heart Failure: Patients with heart failure had significantly higher all-cause mortality when their health literacy was low, a study shows (pp. 1695–701). At Kaiser Permanente Colorado, outpatients with heart failure were retrospectively identified for the 2001–08 period, surveyed by mail, and followed for a median of 1.2 years. Health literacy, measured using three “established screening questions” and categorized as adequate or low, was related to mortality as follows: “Of the 2,156 patients surveyed, 1,547 responded (72% response rate). Of 1,494 included responders, 262 (17.5%) had low health literacy. Patients with low health literacy were older, of lower socioeconomic status, less likely to have at least a high school education, and had higher rates of coexisting illnesses. In multivariable Cox regression, low health literacy was independently associated with higher mortality (unadjusted rate, 17.6% vs 6.3%; adjusted hazard ratio, 1.97 [95% confidence interval, 1.3–2.97]; P = .001) but not hospitalization (unadjusted rate, 30.5% vs 23.2%; adjusted hazard ratio, 1.05 [95% confidence interval, 0.8–1.37]; P = .73).” (P. N. Peterson, pamela.peterson@ucdenver.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 28, 2011 * Vol. 18, No. 82
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 28 issue of the New England Journal of Medicine (2011; 364).
Sirolimus in Lymphangioleiomyomatosis: Women with the progressive cystic lung disease lymphangioleiomyomatosis (LAM) responded to treatment with sirolimus, a study shows (pp. 1595-606). LAM is associated with inappropriate activation of mammalian target of rapamycin (mTOR) signaling. Since sirolimus acts through mTOR inhibition, it was tested for 12 months in 89 women with lung impairment, with these results: “During the treatment period, the FEV1 slope was −12 ± 2 ml per month in the placebo group (43 patients) and 1 ± 2 ml per month in the sirolimus group (46 patients) (P < 0.001). The absolute between-group difference in the mean change in FEV1 during the treatment period was 153 ml, or approximately 11% of the mean FEV1 at enrollment. As compared with the placebo group, the sirolimus group had improvement from baseline to 12 months in measures of forced vital capacity, functional residual capacity, serum vascular endothelial growth factor D (VEGF-D), and quality of life and functional performance. There was no significant between-group difference in this interval in the change in 6-minute walk distance or diffusing capacity of the lung for carbon monoxide. After discontinuation of sirolimus, the decline in lung function resumed in the sirolimus group and paralleled that in the placebo group. Adverse events were more common with sirolimus, but the frequency of serious adverse events did not differ significantly between the groups.” (F. X. McCormack, frank.mccormack@uc.edu)
Reflecting on the role of patient organizations in research on rare diseases such as LAM, editorialists write (
pp. 1670–1): “LAM is not the only medical condition in which patient groups have sponsored both clinical and basic research, have located patients to participate in trials, and have enlisted the help of expert clinicians and investigators. Other examples are cystic fibrosis, Huntington’s disease, Waldenström’s macroglobulinemia, oxalosis and primary hyperoxaluria, cystinosis, autosomal recessive polycystic kidney disease, and Duchenne’s muscular dystrophy, to name just a few. In each case, patients have formed groups to drive research aimed at understanding and treating their particular illness. The key to success for such groups has been to support basic research that is held to the highest scientific standards. When appropriate, they can take the results of the basic work forward to test hypotheses in patients. Trials involving patients with the disease will help illuminate whether the investigators are headed in the right direction and will lead to more focused basic research and better ideas to test in patients. This is true ‘bench to bedside and back’ research that fits the Pareto principle of factor sparsity—in which the affected patients are the vital few and those caring for them work together with professional researchers to advance the field. It is a good model to emulate.” (J. R. Ingelfinger)
Leprosy & Armadillos: In Louisiana, Texas, and other southern states, armadillos likely represent a natural reservoir of Mycobacterium leprae and are likely responsible for zoonotic transmission of the pathogen, researchers report (pp. 1626–33). Looking for an explanation for development of leprosy in native-born Americans without any history of foreign exposure, the investigators conducted whole-genome resequencing on M. leprae from one wild armadillo and three U.S. patients and compared these with strains from Asia and Brazil. After identifying and genotyping 51 single nucleotide polymorphisms and an insertion–deletion at 11-bp, the investigators analyzed M. leprae strains from 33 wild armadillos from five southern states, 50 U.S. outpatients in Louisiana, and 64 Venezuelan patients. Results showed: “The M. leprae genotype of patients with foreign exposure generally reflected their country of origin or travel history. However, a unique M. leprae genotype (3I-2-v1) was found in 28 of the 33 wild armadillos and 25 of the 39 U.S. patients who resided in areas where exposure to armadillo-borne M. leprae was possible. This genotype has not been reported elsewhere in the world.” (R. W. Truman, rtruman@hrsa.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Apr. 29, 2011 * Vol. 18, No. 83
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May issue of Diabetes Care (2011; 34).
Vitamin D Levels & Mortality in Type 1 Diabetes: Among 227 patients who were followed from the onset of type 1 diabetes in 1979–84, severe vitamin D deficiency was independently associated with increased risk of all-cause mortality, a study shows (pp. 1081–5). Whether vitamin D supplementation can improve this prognosis remains to be proven, the authors note, adding these study details: “Median (range) vitamin D was 44.6 (1.7–161.7) nmol/L. Vitamin D level was not associated with age, sex, urinary albumin excretion rate (UAER), or blood pressure. During follow-up, 44 (18%) patients died. In a Cox proportional hazards model, the hazard ratio for mortality in subjects with severe vitamin D deficiency was 2.7 (1.1–6.7), P = 0.03, after adjustment for UAER, HbA1c, and conventional cardiovascular risk factors (age, sex, blood pressure, cholesterol, smoking). Of the 220 patients, 81 (37%) developed microalbuminuria and 27 (12%) of these progressed to macroalbuminuria. Furthermore, 192 (87%) patients developed background retinopathy, whereas 34 (15%) progressed to proliferative retinopathy. Severe vitamin D deficiency at baseline did not predict the development of these microvascular complications.” (C. Joergensen, cijq@steno.dk)
Emphasizing that “vitamin D deficiency is not good for you,” editorialists make these points (
pp. 1245–6): “Vitamin D deficiency is associated with increased mortality in type 1 diabetic patients.… Being aware of populations at risk and screening for vitamin D deficiency with appropriate methods is therefore essential. Cutoff levels for deficiency and sufficiency are under discussion, but levels below 10 ng/mL (25 nmol/L) are considered severely deficient and should certainly be avoided and supplemented. Guidelines suggest supplements of vitamin D of 600 IU per day in all and 800 IU in elderly (age >70 years). Many voices shout for higher doses, but only demonstrating these claims by hard clinical data will move the field forward from hype to science.” (C. Mathieu, chantal.mathieu@uzleuven.be)
Herbal Products in Obesity: Neither beta-cell function nor insulin sensitivity (IS) was improved in overweight or obese patients by use of ginseng or its active component, gingenoside Re (pp. 1071–6). All study participants had impaired glucose tolerance or were newly diagnosed with type 2 diabetes when they were randomized to 30 days of treatment with ginseng root extract 8 g/d, ginsenoside Re 250–500 mg/d, or placebo. Results showed: “Values for [disposition index (DI)] and IS after therapy (Post) were not different from values before therapy (Pre) in the placebo (DI: Pre, 5.8 ± 0.9 × 10−3 and Post, 5.8 ± 0.8 × 10−3, P = 0.99; IS: Pre, 165 ± 29% and Post, 185 ± 24%, P = 0.34), ginseng (DI: Pre, 7.7 ± 2.0 × 10−3 and Post, 6.0 ± 0.8 × 10−3, P = 0.29; IS: Pre, 171 ± 72% and Post,137 ± 59%, P = 0.88), and ginsenoside Re (DI: Pre, 7.4 ± 3.0 × 10−3 and Post, 5.9 ± 1.1 × 10−3, P = 0.50; IS: Pre, 117 ± 31% and Post, 134 ± 34%, P = 0.44) groups. Ginsenosides Re, Rb1, and Rb2 were not detectable in plasma after treatment with ginseng root extract or ginsenoside Re.” (S. Klein, sklein@dom.wustl.edu)
Diet & Diabetes: The effectiveness of the 2005 Dietary Guidelines for Americans (DGA) needs to be reassessed, researchers conclude, especially in ethnic minority populations (pp. 1183–5). Among 4,381 black and white young adults who were examined repeatedly from 1985 to 2005, rating of diets using the 2005 Diet Quality Index (DQI) showed these results: “Overall, we found no association between DQI score and diabetes risk using Cox models adjusted for potential confounders. Higher DQI scores were associated with favorable changes in HDL cholesterol and blood pressure overall (P for trend <0.05), but with increased insulin resistance among blacks (P for trend <0.01).” (B. M. Popkin, popkin@unc.edu)

>>>PNN NewsWatch
* “Got Drugs?” is the theme of DEA’s second National Prescription Drug Take-Back Day. On Saturday from 10 a.m. to 2 p.m. local time at more than 5,300 sites nationwide, consumers can safely dispose of expired, unused, and unwanted prescription drugs that are potentially dangerous if left in the family’s medicine cabinet.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 2, 2011 * Vol. 18, No. 84
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 30 issue of Lancet (2011; 377).
Depot Naltrexone for Opioid Dependence: Once-monthly injections of a depot naltrexone product offer a new potential treatment option for patients with opioid dependence, researchers report (pp. 1506–13). Combined with psychosocial counseling, an extended-release formulation of naltrexone (XR-NTX) produced these effects in a 24-week trial: “Between July 3, 2008, and Oct 5, 2009, 250 patients were randomly assigned to XR-NTX (n = 126) or placebo (n = 124). The median proportion of weeks of confirmed abstinence was 90.0% (95% CI 69.9–92.4) in the XR-NTX group compared with 35.0% (11.4–63.8) in the placebo group (p = 0.0002). Patients in the XR-NTX group self-reported a median of 99.2% (range 89.1–99.4) opioid-free days compared with 60.4% (46.2–94.0) for the placebo group (p = 0.0004). The mean change in craving was −10.1 (95% CI −12.3 to −7.8) in the XR-NTX group compared with 0.7 (−3.1 to 4.4) in the placebo group (p < 0.0001). Median retention was over 168 days in the XR-NTX group compared with 96 days (95% CI 63–165) in the placebo group (p = 0.0042). Naloxone challenge confirmed relapse to physiological opioid dependence in 17 patients in the placebo group compared with one in the XR-NTX group (p < 0.0001). XR-NTX was well tolerated. Two patients in each group discontinued owing to adverse events. No XR-NTX-treated patients died, overdosed, or discontinued owing to severe adverse events.” (E. Krupitsky, kruenator@gmail.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
Levothyroxine Dose & Fracture Risk in Older Adults: Levothyroxine is significantly associated with increased risk of fractures in adults older than 70, a study shows, and that relationship is strongly related to dose (d2238). Population health databases from Ontario show the following in 2002–07: “Of 213,511 prevalent levothyroxine users identified, 22,236 (10.4%) experienced a fracture over a mean 3.8 years of follow-up, 18,108 (88%) of whom were women. Compared with remote levothyroxine use, current use was associated with a significantly higher risk of fracture (adjusted odds ratio 1.88, 95% confidence interval 1.71 to 2.05), despite adjustment for numerous risk factors. Among current users, high and medium cumulative doses (>0.093 mg/day and 0.044–0.093 mg/day) were associated with a significantly increased risk of fracture compared with low cumulative doses (<0.044 mg/day): 3.45 (3.27 to 3.65) and 2.62 (2.50 to 2.76), respectively.” (L. L. Lipscombe, lorraine.lipscombe@wchospital.ca)

>>>PNN NewsWatch
* FDA has approved abiraterone acetate (Zytiga, Centocor) for use in combination with prednisone for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel. The oral, once-daily agent inhibits production of testosterone by cytochrome P450 17A1. FDA approved the drug under its priority review program based on a results of a Phase III study of 1,195 men in which mortality risk was reduced by 35% (median overall survival of 14.8 versus 10.9 months). The most commonly reported adverse reactions (occurring in 5% or more patients) reported in the clinical study were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection.
*
PNN, first published 17 years ago today, has kept pharmacists informed about the latest clinical news and information on 4,233 business days since then.

>>>PNN JournalWatch
* Angiotensin Receptor Blockers and Risk of Myocardial Infarction: Meta-Analyses and Trial Sequential Analyses of 147,020 Patients from Randomised Trials, in BMJ, 2011; 342: d2234. (S. Bangalore, sripalbangalore@gmail.com)
* Effects of Denosumab on Bone Mineral Density and Bone Turnover in Postmenopausal Women, in
Pharmacotherapy, 2011; 31: 510–23. (T. M. Wensel, twensel@samford.edu)
* Strategies for Developing Pharmacy Residents as Educators, in
Pharmacotherapy, 2011; 31: 526.
* Diabetic Retinopathy Predicts All-Cause Mortality and Cardiovascular Events in Both Type 1 and 2 Diabetes: Meta-analysis of Observational Studies, in
Diabetes Care, 2011; 34: 1238–44. (C. K. Kramer, carolinekkramer@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 3, 2011 * Vol. 18, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 3 issue of the Annals of Internal Medicine (2011; 154).
Omalizumab in Severe Allergic Asthma: In patients poorly controlled on standard medications for asthma, omalizumab provides a useful addition to therapy, according to a study of 850 adolescents and adults in the U.S. and Canada (pp. 573–82). Participants in the trial were inadequately controlled on high-dose inhaled corticosteroids and long-acting beta-2 agonists, with or without controller medications. These results were recorded in those receiving added omalizumab or placebo using the Asthma Quality of Life Questionnaire (AQLQ[S]) and other measures: “During 48 weeks, the rate of protocol-defined asthma exacerbations was significantly reduced for omalizumab compared with placebo (0.66 vs. 0.88 per patient; P = 0.006), representing a 25% relative reduction (incidence rate ratio, 0.75 [95% CI, 0.61 to 0.92]). Omalizumab improved mean AQLQ(S) scores (0.29 point [CI, 0.15 to 0.43]), reduced mean daily albuterol puffs (−0.27 puff/d [CI, −0.49 to −0.04 puff/d]), and decreased mean asthma symptom score (−0.26 [CI, −0.42 to −0.10]) compared with placebo during the 48-week study period. The incidence of adverse events (80.4% vs. 79.5%) and serious adverse events (9.3% vs. 10.5%) were similar in the omalizumab and placebo groups, respectively.” (M. D. Eisner, eisner.mark@gene.com)
Managing COPD: In older adults with chronic obstructive pulmonary disease, lower mortality was observed in patients who were initially treated with long-acting inhaled beta-agonists rather than long-acting anticholinergic agents, researchers report (pp. 583–92). A retrospective, population-based cohort study in Ontario provides these trends in patients 66 years or older with COPD: “A total of 46,403 patients with COPD (mean age, 77 years; 49% women) were included. Overall mortality was 38.2%. Mortality was higher in patients initially prescribed a long-acting anticholinergic than in those initially prescribed a long-acting inhaled beta-agonist (adjusted hazard ratio, 1.14 [95% CI, 1.09 to 1.19]). Rates of hospitalizations and emergency department visits were also higher in those initially prescribed a long-acting anticholinergic.” (A. Gershon, andrea.gershon@ices.on.ca)
Individualized Hypertension Therapy: An analysis of longitudinal data from the Atherosclerosis Risk in Communities (ARIC) study demonstrates how use of individualized guidelines can increase the quality and reduce the cost of antihypertensive care (pp. 627–34). Investigators included study participants aged 45–64 years who had no preexisting cardiovascular disease in this analysis, which found these patterns for myocardial infarctions, strokes, and medical costs: “Compared with treating people according to random care, individualized guidelines could prevent the same number of MIs and strokes as JNC 7 guidelines at savings that are 67% greater than using JNC 7 guidelines, or it could prevent 43% more MIs and strokes for the same cost as treatment according to JNC 7 guidelines. The superiority of individualized guidelines was not sensitive to a wide range of assumptions about costs, treatment effectiveness, level of risk for cardiovascular disease in the population, or effects on workflow. The degree of superiority was sensitive to the accuracy of the method used to rank patients and to its span (the proportion of the population for whom all of the outcomes of interest can be calculated).” (D. M. Eddy, author@archimedesmodel.com)
An editorialist offers this advice (
pp. 638–9): “Guideline developers try to strike a balance between recommendations that are simple enough to be useable but specific enough to provide useful guidance. To the extent that they can further tailor recommendations to specific patient circumstances and maintain the usability of the guideline, developers of guidelines have an important opportunity to make guidelines more helpful to clinicians and to improve outcomes for patients.” (D. K. Owens, wens@stanford.edu">owens@stanford.edu)

>>>PNN NewsWatch
* Linagliptin (Boehringer Ingelheim, Lilly), a dipeptidyl peptidase-4 inhibitor that requires no dose adjustment in hepatic or renal impairment, was approved yesterday by FDA for treatment of adults with type 2 diabetes. In clinical trials, addition of linagliptin to metformin and/or sulfonylurea therapy lowered A1c levels by up to 0.6 percentage points.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 4, 2011 * Vol. 18, No. 86
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 4 issue of JAMA (2011; 305).
Structured Exercise for Patients with Diabetes: Greater reductions in glycosylated hemoglobin result from structured exercise programs in patients with type 2 diabetes, compared with advice on physical activity and diet, according to authors of a review and meta-analysis (pp. 1790–9). Based on data from available randomized controlled trials (RCTs) that recorded changes in hemoglobin A1c (HbA1c) levels, investigators determined: “Of 4,191 articles retrieved, 47 RCTs (8,538 patients) were included. Pooled mean differences in HbA1c levels between intervention and control groups were calculated using a random-effects model. Overall, structured exercise training (23 studies) was associated with a decline in HbA1c level (−0.67%; 95% confidence interval [CI], −0.84% to −0.49%; I2, 91.3%) compared with control participants. In addition, structured aerobic exercise (−0.73%; 95% CI, −1.06% to −0.40%; I2, 92.8%), structured resistance training (−0.57%; 95% CI, −1.14% to −0.01%; I2, 92.5%), and both combined (−0.51%; 95% CI, −0.79% to −0.23%; I2, 67.5%) were each associated with declines in HbA1c levels compared with control participants. Structured exercise durations of more than 150 minutes per week were associated with HbA1c reductions of 0.89%, while structured exercise durations of 150 minutes or less per week were associated with HbA1c reductions of 0.36%. Overall, interventions of physical activity advice (24 studies) were associated with lower HbA1c levels (−0.43%; 95% CI, −0.59% to −0.28%; I2, 62.9%) compared with control participants. Combined physical activity advice and dietary advice was associated with decreased HbA1c (−0.58%; 95% CI, −0.74% to −0.43%; I2, 57.5%) as compared with control participants. Physical activity advice alone was not associated with HbA1c changes.” (B. D. Schaan, beatrizschaan@gmail.com)
This article provides “solid evidence for public policy makers to consider structured exercise and physical activity programs as worthy of insurance reimbursement to promote health, especially in high-risk populations,” an editorialist writes, adding (
pp. 1808–9): “[A] cost-effectiveness analysis of 7 interventions for the public health promotion of physical activity and structured physical exercise in adults found that compared with no intervention, 6 interventions were cost-effective and had the potential to achieve gains in survival and health-related quality of life. The cost per quality-adjusted life–year (QALY) for 6 of the 7 interventions ranged from $14,000 to $47,000 and for the seventh intervention it was $69,000.‚Äč Compared with other broadly accepted preventive strategies, such interventions may offer good value for the expense. For example, it has been estimated that the cost per QALY gained of the well-accepted diabetes self-management education in the community was $40,000, which is less than the $50,000 per QALY gained conventionally used as a threshold for assessing the cost-effectiveness of an intervention.” (M. Pahor, mpahor@ufl.edu)
Comparative Efficacy Data for New Drugs at Approval: At the time of approval in the U.S., about one-half of new molecular entities (NMEs) had head-to-head comparative data available, researchers report (pp. 1786–9). Efficacy studies for NMEs approved in 2000–10 showed the following: “Of 197 NMEs identified that met eligibility criteria, 100 (51% [95% confidence interval {CI}, 44%–58%]) met criteria for having comparative efficacy data available at the time of market authorization. After excluding NMEs designated as orphan products (n = 37) and those approved for indications for which no alternative treatments existed (n = 17), this proportion increased to 70% (95% CI, 62%–77%). The proportions of NMEs with available comparative efficacy data varied widely by therapeutic area, from 33% (95% CI, 9%–67%) for hormones and contraceptives to 89% (95% CI, 56%–99%) for diabetes medications.” (J. J. Gagne, jgagne1@partners.org)

>>>PNN NewsWatch
* Lot 9H49374A of Bristol-Myers Squibb brand of warfarin (Coumadin) has been recalled because of discovery of a tablet with higher-than-labeled potency.
* Working with the Federal Trade Commission,
FDA is moving against Medavir, Herpaflor, Viruxo, C-Cure, and Never An Outbreak, products that the agency says make unproven claims about sexually transmitted diseases.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 5, 2011 * Vol. 18, No. 87
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 5 issue of the New England Journal of Medicine (2011; 364).
Leukotriene Antagonists as Asthma-Controller Therapy: In a test of “real-world effectiveness” of leukotriene-receptor antagonists (LTRAs), results at 2 months showed equivalence of an LTRA as first-line or add-on therapy, in comparison with long-acting beta-2-agonists (LABAs), but the advantages disappeared by the end of the second year of therapy (pp. 1695–707). Two parallel trials included primary care patients aged 12 to 80 years who had impaired asthma-related quality of life (Mini Asthma Quality of Life Questionnaire [MiniAQLQ] score ≤6) or inadequate asthma control (Asthma Control Questionnaire [ACQ] score ≥1). Patients were randomly assigned to an LTRA (148 patients) or an inhaled glucocorticoid (158 patients) in a first-line controller therapy trial and an LTRA (170 patients) or an LABA (182 patients) added to an inhaled glucocorticoid in an add-on therapy trial, with these results: “Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials. At 2 months, differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence (95% confidence interval [CI] for an adjusted mean difference, –0.3 to 0.3). At 2 years, mean MiniAQLQ scores approached equivalence, with an adjusted mean difference between treatment groups of –0.11 (95% CI, –0.35 to 0.13) in the first-line controller therapy trial and of –0.11 (95% CI, –0.32 to 0.11) in the add-on therapy trial. Exacerbation rates and ACQ scores did not differ significantly between the two groups.” (D. Price, david@rirl.org)
An editorialist describes these findings as “asthma treatment guidelines [meeting] the real world,” concluding that an oral therapy should be preferred over inhalations in some situations (
pp. 1769–70): “All current asthma treatments provide only symptomatic relief; they do not modify the underlying condition. Therefore, we treat patients to help them cope with their asthma today. The two studies described by Price et al. show that oral leukotriene modifiers provide an alternative treatment that may help patients pursue their activities of daily life as effectively as inhaled glucocorticoids do. The ease of taking a pill should be particularly attractive in developing parts of the world, where most patients with asthma remain untreated.” (S-E Dahlén)
Bisphosphonate Use & Atypical Femoral Fractures: In a population-based study from Sweden, women on bisphosphonates had a statistically significant but numerically small increase in risk of atypical fractures of the femur (pp. 1728–37). The analysis included 12,777 women aged 55 years or older who had femur fractures in 2008. Review of radiographs of 1,234 of 1,271 women with subtrochanteric or shaft fracture identified 59 patients with atypical fractures: “The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient–years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38).” (P. Aspenberg, per.aspenberg@liu.se)

>>>PNN NewsWatch
* FDA yesterday released its final guidance on OTC liquid drug products packaged with measuring cups, droppers, syringes, and spoons. Key recommendations in the guidance include (1) dosage delivery devices should be included for all orally ingested OTC liquid drug products; (2) devices should be marked with calibrated units of liquid measurement (e.g., teaspoon, tablespoon, or milliliter) that are the same as the units of liquid measure specified in the directions for the product, and there should not be any unnecessary markings; (3) manufacturers should ensure that dosage delivery devices are used only with the products with which they are packaged; and (4) liquid measure markings on dosage delivery devices should be clearly visible and not obscured when the liquid product is added to the device.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 6, 2011 * Vol. 18, No. 88
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
May issue of Pharmacotherapy (2011; 31).
Validation of Vancomycin Nomogram: Target trough levels of 15–20 mcg/mL were achieved for 58% of patients whose vancomycin doses were determined using a new nomogram based on weight and renal function, a study shows (pp. 441–8). Performance increased to 80% when troughs were adjusted to 13–22 mcg/mL, as assessed using data from 200 adults at five teaching hospitals: “Median patient age was 56 years (interquartile range [IQR] 49–65 yrs), median weight was 71.2 kg (IQR 63–85 kg), and median creatinine clearance was 66.5 ml/minute (IQR 52–82 ml/min). The median initial vancomycin trough concentration achieved was 17.5 mg/L (IQR 15.0–20.0 mg/L), with 116 patients (58%) achieving the initial target trough of 15–20 mg/L. The median percent error was 13.6%, and the mean ± SD error for predicted versus actual serum trough concentrations was −0.50 ± 0.021 mg/L. One hundred fifty-four patients (77%) eventually achieved the trough target concentration within a median of 2 days. One hundred forty patients (70%) achieved initial troughs of 14–21 mg/L and 160 (80%) achieved troughs of 13–22 mg/L. Nine patients (4.5%) experienced nephrotoxicity while receiving vancomycin, which occurred after a median of 8 days of therapy. The median initial vancomycin trough concentration for these patients was 18.5 mg/L (IQR 15.3–19.3 mg/L), with eight of the nine patients having trough concentrations of 15 mg/L or greater.” (M. J. Rybak, m.rybak@wayne.edu)
Beta-Agonist Bioassay Using Methacholine Challenge: In bioequivalence studies of pulmonary delivery of long-acting beta-2 agonists (LABAs), methacholine challenge provides a useful bioassay, a researcher reports (pp. 449–57). Ten adults with mild asthma received a single dose of formoterol 12 or 24 mcg, followed by performance of a methacholine challenge, with these results: “The dose–response curve for bronchodilatation was flat; the mean ± SD increase in FEV1 after formoterol 12 and 24 mcg was 14 ± 5% and 14 ± 8%, respectively (p > 0.05). In contrast, the geometric mean [provocational concentration of methacholine required to decrease FEV1 by 20%] was 7 mg/ml (2–22 mg/ml) after the 12-mcg dose and 16 mg/ml (5–45 mg/ml) after the 24-mcg dose (p < 0.001).” (L. Hendeles, hendeles@cop.ufl.edu)
Drug Interactions with Antiretroviral Therapy: In both younger and older patients with HIV infections, clinically significant drug interactions (CSDIs) occur commonly during antiretroviral drug therapy, including interactions with non-HIV agents, according to results of a retrospective chart review (pp. 480–9). These experiences of 110 patients were identified, with age 50 dividing younger versus older individuals: “At least one CSDI was present in 83.3% and 89.2% of younger and older patients, respectively (p = 0.56), with most having both antiretroviral and nonantiretroviral CSDIs. Younger and older patients, respectively, had a median of 3 and 5.5 total CSDIs/patient (p = 0.09), 2 and 3 antiretroviral CSDIs/patient (p = 0.65), and 0.5 and 2.5 nonantiretroviral CSDIs/patient (p = 0.04). The proportions of grade 2, 3, and 4 CSDIs were 74.1%, 25.0%, and 0.9%, respectively, in younger patients and 73.1%, 26.1%, and 0.7%, respectively, in older patients (p = 0.92). Younger patients had more CSDIs involving antihistamine, erectile dysfunction, and hormone or corticosteroid agents (p < 0.01), whereas older patients had more CSDIs involving antihypertensive and antidiabetic agents (p < 0.001). Management and outcomes of grades 3 and 4 antiretroviral CSDIs did not differ significantly by age. A list of frequently mismanaged interactions is provided.” (N. N. Nguyen, nnguyen1@pacific.edu)
Bleeding Risk with Ginkgo: Patients on standardized Ginkgo biloba leaf extracts are not at increased risk of bleeding, authors of a meta-analysis report (pp. 490–502). In 18 trials of 1,985 adults that reported hemostasis outcomes, blood perfusion was increased and blood viscosity decreased. But the investigators found no evidence of significant effects on ADP-induced platelet aggregation, fibrinogen concentration, or prothrombin time. A subgroup analysis showed lower activated partial thromboplastin times in studies that included only patients and no healthy volunteers and with high-dose therapy; the authors write that both findings are not “clinically relevant.” (C. Kloft)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 9, 2011 * Vol. 18, No. 89
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 7 issue of Lancet (2011; 377).
Antibiotics for Acute Appendicitis: Outcomes in patients with acute appendicitis treated with oral antibiotics were not noninferior to surgery, a study shows (pp. 1573–9). Among 239 adult patients with uncomplicated cases, amoxicillin plus clavulanic acid or appendicectomy produced these results in an open-label, noninferiority, randomized trial: “30-day postintervention peritonitis was significantly more frequent in the antibiotic group (8%, n = 9) than in the appendicectomy group (2%, n = 2; treatment difference 5.8; 95% CI 0.3–12.1). In the appendicectomy group, despite CT-scan assessment, 21 (18%) of 119 patients were unexpectedly identified at surgery to have complicated appendicitis with peritonitis. In the antibiotic group, 14 (12% [7.1–18.6]) of 120 underwent an appendicectomy during the first 30 days and 30 (29% [21.4–38.9]) of 102 underwent appendicectomy between 1 month and 1 year, 26 of whom had acute appendicitis (recurrence rate 26%; 18.0–34.7).” (C. Vons, corinne.vons@jvr.aphp.fr)
Triple-Class Virological Failure in Children with HIV: Long-term viral suppression is difficult to maintain in children infected perinatally with HIV who will require antiretroviral therapy (ART) throughout their lives, researchers report (pp. 1580–7). Triple-class virological failure showed these patterns among children started on ART in 1998–2008: “Of 1,007 children followed up for a median of 4.2 (IQR 2.4–6.5) years, 237 (24%) were triple-class exposed and 105 (10%) had triple-class virological failure, of whom 29 never had a viral-load measurement less than 500 copies per mL. Incidence of triple-class virological failure after ART initiation increased with time, and risk by 5 years after ART initiation was 12.0% (95% CI 9.4–14.6). In multivariate analysis, older age at ART initiation was associated with increased risk of failure (p = 0.02). Of 686 children starting ART with NRTIs and either a NNRTI or ritonavir-boosted protease inhibitor, the rate of failure was higher than in adults with heterosexually transmitted HIV (hazard ratio 2.2 [95% CI 1.6–3.0, p < 0.0001]).” (Pursuing Later Treatment Options II [PLATO II] project team for the Collaboration of Observational HIV Epidemiological Research Europe [COHERE])
Isoniazid Prophylaxis in Patients with HIV: Six months of isoniazid prophylaxis may not be enough to protect patients with HIV infection against tuberculosis, according to a trial that tested 36 months’ prophylaxis (pp. 1588–98). The study also showed that testing for TB exposure—not commonly done in this setting—was needed to guide prophylaxis. Adults with HIV infection treated at government-run clinics in Botswana showed these outcomes with 6 versus 36 months of isoniazid: “Between Nov 26, 2004, and July 3, 2009, we recorded 34 (3.4%) cases of incident tuberculosis in 989 participants allocated to the control group and 20 (2.0%) in 1,006 allocated to the continued isoniazid group (incidence 1.26% per year vs 0.72%; hazard ratio 0.57, 95% CI 0.33–0.99, p = 0.047). Tuberculosis incidence in those individuals receiving placebo escalated approximately 200 days after completion of open-label isoniazid. Participants who were tuberculin skin test positive (ie, ≥5 mm induration) at enrolment received a substantial benefit from continued isoniazid treatment (0.26, 0.09–0.80, p = 0.02), whereas participants who were tuberculin skin test-negative received no significant benefit (0.75, 0.38–1.46, p = 0.40). By study completion, 946 (47%) of 1,995 participants had initiated antiretroviral therapy. Tuberculosis incidence was reduced by 50% in those receiving 360 days of antiretroviral therapy compared with participants receiving no antiretroviral therapy (adjusted hazard ratio 0.50, 95% CI 0.26–0.97). Severe adverse events and death were much the same in the control and continued isoniazid groups.” (T. Samandari, tts0@cdc.gov)

>>>PNN JournalWatch
* Strategies for Reduction in Duration of Antibiotic Use in Hospitalized Patients, in Clinical Infectious Diseases, 2011; 52: 1232–40. (D. L. Paterson, david.antibiotics@gmail.com)
* Advances in Pneumococcal Disease Prevention: 13-Valent Pneumococcal Conjugate Vaccine for Infants and Children, in
Clinical Infectious Diseases, 2011; 52: 1241–7. (P. R. Paradiso, peter.paradiso@pfizer.com)
* Efficacy of Proton-Pump Inhibitors in Children with Gastroesophageal Reflux Disease: A Systematic Review, in
Pediatrics, 2011; 127: 925–35. (R. J. van der Pol)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 10, 2011 * Vol. 18, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 9 issue of the Archives of Internal Medicine (2011; 171).
Therapeutic Complexity & Cardiac Med Adherence: In addition to the number of medications a patient is taking, a number of other factors related to therapeutic complexity affects adherence, a study shows, including the number of visits to pharmacies and failure to consolidate refills (pp. 814–22). Data from CVS Caremark for 1.5 million patients show these relationships between adherence to statins and angiotensin- converting enzyme inhibitors or renin angiotensin receptor blockers (ACEI/ARB) and therapeutic complexity: “The statin cohort had a mean age of 63 years and were 49% male. On average, during the 3-month complexity assessment period, statin users filled 11.4 prescriptions for 6.3 different medications, had prescriptions written by 2 prescribers, and made 5.0 visits to the pharmacy. Results for ACEI/ARB users were similar. Greater prescribing and filling complexity was associated with lower levels of adherence. In adjusted models, patients with the least refill consolidation had adherence rates that were 8% lower over the subsequent year than patients with the greatest refill consolidation.” (N. K. Choudhry, nchoudhry@partners.org)
Responding to recommendations made by the above researchers based on their data, Dutch authors note that such interventions have been implemented in the Netherlands (
pp. 864–5). Analysis of data from that country showed the following: “We observed a statistical significant correlation between therapeutic complexity and nonpersistence for the number of visits, number of fills, number of single dispensings, number of prescribing physicians, and total number of switches within each drug class. However, odds ratios approached 1, indicating a low predictive value. For compliance, only the number of single dispensings reached statistical significance, again with a very poor predictive value.
“We were able to also link therapeutic complexity to both nonpersistence and poor compliance in the Dutch health care system, but odds ratios were too low to be clinically meaningful. We agree with Choudhry and coworkers that therapeutic complexity should be reduced, but we believe differences in health care systems have a much larger impact on both (non)persistence and (poor) compliance because we could not identify any clinical meaningful relation between therapeutic complexity and adherence. Predicting medication adherence remains an important challenge.” (E. R. Heerdink,
e.r.heerdink@uu.nl)
Authors of a Commentary article add this perspective (
pp. 822–3): “The study by Choudhry et al highlights the fragmentation of prescription management by drawing attention to the intricacies of managing a complex medication regimen. Prior research has operationalized medication complexity based largely on the number of medications, doses, or times of administration. However, such measures do not account for patients who may have multiple prescribers, shop around for lower prices by filling generic medications for $4 or $5 at retail pharmacy chains, use both mail-order and retail pharmacies, and have refills due on different dates. Each of these practical issues adds complexity to patients’ medication management, and as we learn from this study, adherence suffers.” (A. H. Kripalani, sunil.kripalani@vanderbilt.edu)

>>>PNN NewsWatch
* In a Federal Register notice posted yesterday, FDA requested input from stakeholders and the public on the development of a fee program for biosimilar and interchangeable biologic product applications. The Biologics Price Competition and Innovation Act of 2009, a provision of the Affordable Care Act, created an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to or interchangeable with an FDA-licensed biological product. the agency said. It directs the FDA to develop recommendations for a 351(k) user fee program for fiscal years 2013 through 2017. The recommendations must be presented to Congress by January 15, 2012.
* Crash carts, ambulances, and emergency departments should be stocked with
adenosine and amiodarone supplied in vials or prefilled plastic syringes, FDA cautions. Related warnings about needleless prefilled glass syringes were issued last year (see PNN, Nov. 18).

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 11, 2011 * Vol. 18, No. 91
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 11 issue of JAMA (2011; 305).
Epoetin in STEMI: Administered within 4 hours of successful reperfusion surgery, epoetin increased rates of adverse cardiovascular events without reduction in infarct size, researchers report (pp. 1863–72). The Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial included 222 patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy. Random assignment to a single dose of intravenous epoetin alfa 60,000 units or placebo within 4 hours of reperfusion produced these results: “The infarct size did not differ between groups on either the first [cardiac magnetic resonance (CMR)] scan (n = 136; 15.8% [left ventricular (LV)] mass [95% confidence interval {CI}, 13.3–18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6–17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4–12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5–12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0–25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2–16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%–9.09%) but in none of the 97 who received placebo (P = .04).” (S. S. Najjar, Samer.S.Najjar@medstar.net)
An editorialist questions whether future trials of this type can be conducted in the U.S. (
pp. 1908–9): “In the REVEAL study, more than 3 years were required to enroll 222 patients at 22 sites, which translates to approximately 1 patient enrolled per site every 3 to 4 months. While this in part may have been due to the need for CMR expertise at sites performing primary PCI, it also points to the difficulties of conducting STEMI research in the United States in the current health care environment. Concern about door-to-balloon times and public reporting of that metric have led to an exodus of STEMI trials to other countries. The concern is that the time necessary to screen patients for trial eligibility might delay the door-to-balloon time by several minutes. Although that degree of delay is unlikely to harm a patient, it can negatively skew the door-to-balloon times of an active research site. Even if patients enrolled in trials are excluded from the denominator of door-to-balloon calculations, the larger number of patients who are screened but not enrolled could still increase the average door-to-balloon time at a site. These factors have generated a great degree of skepticism about whether US sites can still perform STEMI trials.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
Genomic Prediction of Chemotherapy Response in Breast Cancer: Patients with a high probability of survival following taxane and anthracycline chemotherapy can be identified using genomics, a study shows (pp. 1873–81). Investigators looked at the association between survival after neoadjuvant chemotherapy and 310 patients’ estrogen receptor (ER) status and genomically predicted sensitivity to endocrine therapy, chemoresistance, and chemosensitivity. Results for distant relapse–free survival (DRFS) if predicted treatment sensitive and absolute risk reduction (ARR) at a median follow-up of 3 years showed the following: “Patients in the independent validation cohort (99% clinical stage II–III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%–78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%–100%), with an ARR of 18% (95% CI, 6%–28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%–100%]; ARR, 11% [95% CI, 0.1%–21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%–48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.” (W. F. Symmans, fsymmans@mdanderson.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 12, 2011 * Vol. 18, No. 92
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 12 issue of the New England Journal of Medicine (2011; 364).
FOLFIRINOX for Metastatic Pancreatic Cancer: FOLFIRINOX—a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin—increased survival but also adverse effects when used as first-line therapy among 342 patients with metastatic pancreatic cancer, compared with gemcitabine (pp. 1817–25). Six months of therapy in patients who responded provided these outcomes: “The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P < 0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P < 0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P < 0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P < 0.001).” (T. Conroy, t.conroy@nancy.fnclcc.fr)
Lung Stem Cells & Possible Lung Regeneration: Researchers have identified and characterized human lung stem cells in situ, a study reports (pp. 1795–806). Using surgical lung-tissue specimens, they found: “Human lungs contain undifferentiated human lung stem cells nested in niches in the distal airways. These cells are self-renewing, clonogenic, and multipotent in vitro. After injection into damaged mouse lung in vivo, human lung stem cells form human bronchioles, alveoli, and pulmonary vessels integrated structurally and functionally with the damaged organ. The formation of a chimeric lung was confirmed by detection of human transcripts for epithelial and vascular genes. In addition, the self-renewal and long-term proliferation of human lung stem cells was shown in serial-transplantation assays.” (P. Anversa, panversa@partners.org)
An editorialist projects potential clinical uses of lung stem cells (
pp. 1867–8): “The most provocative implication of the discovery of these cells concerns bioengineering. The field of bioengineered lung tissue sees clinical medicine on the distant horizon. But patients are living with airway transplants of devitalized tracheal matrix repopulated with their own epithelial cells. It is possible to grow well-organized rodent lung tissue beginning with an intact, devitalized lung matrix and embryonic lung cells and to observe a functional effect, if only briefly, when this tissue is implanted in live animals. Expanded, c-kit–positive lung stem cells from a patient are an appealing parent for bioengineered tissue, but [the above authors] report no evidence that the observed respiratory units integrate sufficiently with the host vasculature or airways to support perfusion or ventilation. There are reasons to anticipate that such connections will develop, but can these stem cells efficiently assemble into a permanent, fully functional unit? What are the limits of expansion of lung stem cells that can be reasonably achieved while maintaining genomic integrity and avoiding senescence? In spite of the many major uncertainties that presage translation of the current results into applications in the clinical arena, these new findings should energize the field.” (H. A. Chapman)
Republicans & ACA: Elements of consensus and conflict exist between the Republican budget plan, the Roadmap for America’s Future, and the Affordable Care Act, an author writes, providing this analysis of the controversial mandatory health insurance requirement (e40): “Both plans penalize Americans who choose to remain outside the insurance market, undermining the risk pool. The ‘individual mandate,’ which imposes a tax penalty on Americans who can afford health insurance but choose not to buy it, is one of the most controversial provisions of the ACA. The Republican tax credit, however, is offered only to Americans who purchase health insurance. An incentive available only to those who comply with a condition is the exact economic equivalent of a penalty imposed for noncompliance with the same condition. Indeed, the price of remaining uninsured imposed by the Roadmap will in most instances be greater than that under the ACA.” (T. S. Jost)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 13, 2011 * Vol. 18, No. 93
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Assoc. (2011; 51).
White Paper on REMS: For FDA’s risk evaluation and mitigation strategies (REMS) system to work, several elements will be needed, including effective patient interventions, standardized elements for patients and providers, and standardized yet flexible implementation strategies, according to a white paper published by APhA (pp. 340–58). Based on discussions of 34 stakeholders at an Oct. 2010 meeting, the white paper makes these points: “The current REMS environment presents many challenges for health care providers due to the growing number of REMS programs and the lack of standardization or similarities among various REMS programs. A standardized REMS process that focuses on maximizing patient safety and minimizing impacts on patient access and provider implementation could offset these challenges. A new process that includes effective provider interventions and standardized tools and systems for implementing REMS programs may improve patient care and overcome some of the communication issues providers and patients currently face. Metrics could be put in place to evaluate the effectiveness of REMS elements. By incorporating REMS program components into existing technologies and data infrastructures, achieving REMS implementation that is workflow neutral and minimizes administrative burden may be possible. An appropriate compensation model could ensure providers have adequate resources for patient care and REMS implementation. Overall, stakeholders should continue to work collaboratively with FDA and manufacturers to improve REMS program design and implementation issues.” (M. Bough, mbough@aphanet.org)
Product- v. Patient-Centered Pharmacists: Community pharmacists in Edmonton, Canada, view themselves as primarily “dispensers of medication” rather than patient-centered practitioners, researchers report (pp. 363–7). Among 100 community pharmacists providing usable responses in brief telephone interviews, these self-descriptions and perceptions of professional roles were identified: “The majority of pharmacists practiced in a community chain setting (76%) and within the city of Edmonton (81%). The median length of time in practice was 15 years. A total of 278 separate response items were obtained. Of these responses, 45% were categorized as product focused, 29% as patient centered, and 26% as ambiguous. The first response of 52 of the 100 pharmacists was a product-focused description of their role. Overall, in either their first or second response, 57% of the pharmacists used the term ‘dispensing’ or dispensing-related terms to describe their professional role.” (R. T. Tsuyuki, ross.tsuyuki@ualberta.ca)
Assessing Drug–Drug Interaction Software: Pharmacy drug–drug interaction (DDI) software can be evaluated for recognition of relevant DDIs using a tool described in this article (pp. 418–24). Based on a test profile and a set of orders that challenge the system with 19 drug pairs, the performance of DDI software can be evaluated: “Suggestions for improvement include determining whether the software allows for customization, creating standard policies for handling specific interactions, and ensuring that drug knowledge database updates occur frequently.” (T. L. Warholak, warholak@pharmacy.arizona.edu)
Moving Toward Pay for Performance: Using a pharmacist-run medication therapy management/lifestyle medicine program as an example, authors conclude that pharmacists “should begin to explore ways they can participate in a high-performance health care system by moving to a [pay for performance] model of reimbursement rather than fee-for-service or product-based dispensing reimbursement models.” (pp. 425–31; T. L. Lenz, tlenz@creighton.edu)

>>>PNN NewsWatch
* Five cases of gonorrhea with reduced susceptibility to azithromycin have been identified in San Diego County, CA, according to this week’s MMWR. The infections occurred in men who have sex with men who had no known connections to each other, suggesting that the strains with reduced drug susceptibility might be widespread in the community. Continued surveillance is needed, the report notes, as is development of new diagnostic and treatment strategies.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 16, 2011 * Vol. 18, No. 94
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 14 issue of Lancet (2011; 377).
Hydroxyurea for Sickle Cell in Young Children: Hydroxycarbamide (hydroxyurea) can be used in very young children with sickle cell disease, according to results of the BABY HUG trial (pp. 1663–72). Approved by FDA in adults with sickle cell disease, the agent produced these results in the Pediatric Hydroxyurea Phase III Clinical Trial when used in doses of 20 mg/kg/d in children aged 9–18 months: “96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p = 0.21; and a difference in the mean increase in [technetium 99m-labelled DTPA] glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1.73 m2, p = 0.84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p = 0.002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p < 0.0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia.” (W. C. Wang, winfred.wang@stjude.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
PPIs in Aspirin-Treated Patients After First MI: Adverse cardiovascular events—including cardiovascular death, myocardial infarction, and stroke—occur more frequently when aspirin-treated patients also receive a proton-pump inhibitor after a first MI, researchers report (d2690). The effect may be due to a drug–drug interaction, the investigators write, one in which PPIs decrease aspirin absorption by raising the intragastric pH above the pKa of acetylsalicylic acid (3.5). In a retrospective analysis of all Danish hospitals for 1997 through 2006, patients who survived 30 days after an initial MI had these outcomes: “3,366 of 19,925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P < 0.001) and for the propensity score matched model based on 8,318 patients it was 1.61 (1.45 to 1.79; P < 0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P = 0.78).” (M. Charlot, mc@heart.dk)

>>>PNN NewsWatch
* Boceprevir (Victrelis, Merck) was approved by FDA on Friday for treatment of chronic hepatitis C. The drug, used only in combination with peginterferon alfa and ribavirin, is the first approved agent in a new class, the hepatitis C virus protease inhibitors. In clinical studies of patients poorly responsive to interferon, oral boceprevir administered three times daily (every 7–9 hours) with food improved the sustained virologic response rate by threefold (up to 66%, compared with 23% with placebo). In treatment-naive patients, the SVR was also in the 66% range, compared with 38% for patients in a control group. In combination boceprevir therapy, the most commonly reported adverse reactions (greater than 35%) have been fatigue, anemia, nausea, headache, and dysgeusia.

>>>PNN JournalWatch
* Coronary Stent Implantation in Patients Committed to Long-term Oral Anticoagulation Therapy: Successfully Navigating the Treatment Options, in Chest, 2011; 139: 981–7. (A. Rubboli, andrearubboli@libero.it)
* Gut Microbiota, Probiotics, and Vitamin D: Interrelated Exposures Influencing Allergy, Asthma, and Obesity?, in
Journal of Allergy and Clinical Immunology, 2011; 127: 1087–94. (N. P. Ly, lyn@peds.ucsf.edu)
* Adipocytokines as Driving Forces in Rheumatoid Arthritis and Related Inflammatory Diseases?, in
Arthritis & Rheumatism, 2011; 63: 1159–69. (E. Neumann, e.neumann@kerckhoff-klinik.de)
* Patient-Centered Medical Homes: Primer for Pharmacists, in
Journal of the American Pharmacists Association, 2011; 51: e38–e50. (J. P. Abrons, jeanine.abrons@me.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 17, 2011 * Vol. 18, No. 95
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and May 17 issue of the Annals of Internal Medicine (2011; 154).
CER of Pain Management in Hip Fracture: Nerve blockade has the best evidence for efficacy of the available pharmacologic and nonpharmacologic interventions for management of acute pain following hip fracture, according to a comparative effectiveness research analysis (early release). While nerve blockade relieves acute pain and reduces delirium, other interventions have only “sparse data” to support their use, the authors write based on this analysis of randomized controlled trials (RCTs) and other studies listed in 25 electronic databases for the 1990 to 2010 time period: “83 unique studies (64 RCTs, 5 non-RCTs, and 14 cohort studies) that addressed the following interventions were included: nerve blockade (n = 32), spinal anesthesia (n = 30), systemic analgesia (n = 3), traction (n = 11), multimodal pain management (n = 2), neurostimulation (n = 2), rehabilitation (n = 1), and complementary and alternative medicine (n = 2). Overall, moderate evidence suggests that nerve blockades are effective for relieving acute pain and reducing delirium. Low-level evidence suggests that preoperative traction does not reduce acute pain. Evidence was insufficient about the benefits and harms of most interventions, including spinal anesthesia, systemic analgesia, multimodal pain management, acupressure, relaxation therapy, transcutaneous electrical neurostimulation, and physical therapy regimens, in managing acute pain.” (A. M. Abou-Setta, ahmedabou-setta@med.ualberta.ca)
High-Selenium Yeast & Lipids: Positive effects of selenium on plasma lipids identified in a controlled trial are not enough to justify supplementation with the element, authors conclude (pp. 656–65). At four general practices in the U.K., 501 volunteers ages 60–74 years received either selenium in doses of 100, 200, or 300 mcg/d as high-selenium yeast or placebo for 6 months, with these results: “Mean plasma selenium concentration was 88.8 ng/g (SD, 19.2) at baseline and increased statistically significantly in the treatment groups. The adjusted difference in change in total cholesterol levels for selenium compared with placebo was −0.22 mmol/L (−8.5 mg/dL) (95% CI, −0.42 to −0.03 mmol/L [−16.2 to −1.2 mg/dL]; P = 0.02) for 100 mcg of selenium per day, −0.25 mmol/L (−9.7 mg/dL) (CI, −0.44 to −0.07 mmol/L [−17.0 to −2.7 mg/dL]; P = 0.008) for 200 mcg of selenium per day, and −0.07 mmol/L (−2.7 mg/dL) (CI, −0.26 to 0.12 mmol/L [−10.1 to 4.6 mg/dL]; P = 0.46) for 300 mcg of selenium per day. Similar reductions were observed for non-HDL cholesterol levels. There was no apparent difference in change in HDL cholesterol levels with 100 and 200 mcg of selenium per day, but the difference was an adjusted 0.06 mmol/L (2.3 mg/dL) (CI, 0.00 to 0.11 mmol/L [0.0 to 4.3 mg/dL]; P = 0.045) with 300 mcg of selenium per day. The total–HDL cholesterol ratio decreased progressively with increasing selenium dose (overall P = 0.01).” (M. P. Rayman, m.rayman@surrey.ac.uk)
Choice of Third Agent in Antidiabetic Therapy: In patients with type 2 diabetes who are inadequately managed with metformin and a sulfonylurea, evidence is unclear as to which drug class should be added next, researchers report (pp. 672–9). A meta-analysis of trials at least 24 weeks in duration showed these results for adults aged 18 years or older and hemoglobin A1c levels greater than 7.0%: “Eighteen trials involving 4,535 participants that lasted a mean of 31.3 weeks (24 to 52 weeks) were included. Compared with placebo, drug classes did not differ in effect on HbA1c level (reduction ranging from −0.70% [95% credible interval {CrI}, −1.33% to −0.08%] for acarbose to −1.08% [CrI, −1.41% to −0.77%] for insulin). Weight increase was seen with insulins (2.84 kg [CrI, 1.76 to 3.90 kg]) and thiazolidinediones (4.25 kg [CrI, 2.76 to 5.66 kg]), and weight loss was seen with glucagon-like peptide-1 agonists (−1.63 kg [CrI, −2.71 to −0.60 kg]). Insulins caused twice the absolute number of severe hypoglycemic episodes than noninsulin antihyperglycemic agents.” (J. L. Gross, jorgeluizgross@gmail.com)

>>>PNN NewsWatch
* Counterfeit ExtenZe dietary supplements contain tadalafil, FDA warned last week. The products are labeled as lots 1110075 and F050899. The agency also cautioned consumers not to buy supplements marketed for antimicrobial use.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 18, 2011 * Vol. 18, No. 96
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 18 issue of JAMA (2011; 305).
Surgery v. PPIs in GERD: Both major modes of antireflux therapy—long-term PPI therapy and laparoscopic antireflux surgery (LARS)—are effective in patients with gastroesophageal reflux disease (GERD), according to results of the LOTUS (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) trial (pp. 1969–77). Conducted at academic hospitals in 11 European countries, this 5-year exploratory randomized, open, parallel-group trial included 554 patients who received esomeprazole 20–40 mg/d or LARS, with these results: “Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%–96%) in the esomeprazole group and 85% (95% CI, 81%–90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%).” (J-P Galmiche, jeanpaul.galmiche@chu-nantes.fr)
Vitamin A Supplements During Pregnancy: Correction of vitamin A deficiencies in pregnant women in rural Bangladesh did not reduce all-cause maternal, fetal, or infant mortality, researchers report (pp. 1986–95). Addressing a public health concern in the developing world, the trial provided weekly retinol 7000 mcg as retinyl palmitate or all-trans-beta-carotene 42 mg, beginning in the first trimester and continuing until 12 weeks after delivery, to married women in 596 community clusters. Results showed: “The numbers of deaths and all-cause, pregnancy-related mortality rates (per 100,000 pregnancies) were 41 and 206 (95% confidence interval [CI], 140–273) in the placebo group, 47 and 237 (95% CI, 166–309) in the vitamin A group, and 50 and 250 (95% CI, 177–323) in the beta carotene group. Relative risks for mortality in the vitamin A and beta carotene groups were 1.15 (95% CI, 0.75–1.76) and 1.21 (95% CI, 0.81–1.81), respectively. In the placebo, vitamin A, and beta carotene groups the rates of stillbirth and infant mortality were 47.9 (95% CI, 44.3–51.5), 45.6 (95% CI, 42.1–49.2), and 51.8 (95% CI, 48.0–55.6) per 1,000 births and 68.1 (95% CI, 63.7–72.5), 65.0 (95% CI, 60.7–69.4), and 69.8 (95% CI, 65.4–72.3) per 1,000 live births, respectively. Vitamin A compared with either placebo or beta carotene supplementation increased plasma retinol concentrations by end of study (1.46 [95% CI, 1.42–1.50] µmol/L vs 1.13 [95% CI, 1.09–1.17] µmol/L and 1.18 [95% CI, 1.14–1.22] µmol/L, respectively; P < .001) and reduced, but did not eliminate, gestational night blindness (7.1% for vitamin A vs 9.2% for placebo and 8.9% for beta carotene [P < .001 for both]).” (K. P. West Jr., kwest@jhsph.edu)
Major Birth Defects with Newer Antiepileptic Drugs: No increase in major birth defects was observed in women who took any of several newer antiepileptic drugs during the first trimester of pregnancy, a study shows (pp. 1996–2002). In a population-cohort study of 837,795 infants born alive in 1996–2008 in Denmark, 1,532 were exposed to newer antiepileptic drugs during the first trimester. Prevalence odds ratios (POR) showed: “49 [infants] were diagnosed with a major birth defect compared with 19,911 of the 836,263 who were not exposed to an antiepileptic drug (3.2% vs 2.4%, respectively; adjusted POR [APOR], 0.99; 95% confidence interval [CI], 0.72–1.36). A major birth defect was diagnosed in 38 of 1,019 infants (3.7%) exposed to lamotrigine during the first trimester (APOR, 1.18; 95% CI, 0.83–1.68), in 11 of 393 infants (2.8%) exposed to oxcarbazepine (APOR, 0.86; 95% CI, 0.46–1.59), and in 5 of 108 infants (4.6%) exposed to topiramate (APOR, 1.44; 95% CI, 0.58–3.58). Gabapentin (n = 59) and levetiracetam (n = 58) exposure during the first trimester was uncommon, with only 1 (1.7%) and 0 infants diagnosed with birth defects, respectively.” (D. Mølgaard-Nielsen, dnl@ssi.dk)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 19, 2011 * Vol. 18, No. 97
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 19 issue of the New England Journal of Medicine (2011; 364).
Ranibizumab v. Bevacizumab for Neovascular Age-Related Macular Degeneration: For treatment of 1,208 patients with neovascular age-related macular degeneration (AMD), the FDA-approved agent ranibizumab was as effective as the commonly used off-label and lower-cost bevacizumab, but the former drug was associated with significantly fewer hospitalizations and other serious adverse events, researchers report (pp. 1897–908). The single-blind, 1-year noninferiority Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) used a primary outcome of mean change in visual acuity at 1 year and a noninferiority limit of 5 letters on the eye chart. Results showed: “Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 µm) than in the other groups (152 to 168 µm, P = 0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P > 0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern.” (M. G. Maguire, maguirem@mail.med.upenn.edu)
An editorialist writes that the substantially lower cost of bevacizumab will continue to drive its use for AMD (
pp. 1966–7): “The CATT results, together with the totality of global experience, support the use of either bevacizumab or ranibizumab for the treatment of neovascular AMD. An as-needed regimen is an acceptable alternative to a monthly regimen, but strict compliance on the part of both the clinician and the patient is required. Health care providers and payers worldwide will now have to justify the cost of using ranibizumab.” (P. J. Rosenfeld)
Alemtuzumab Induction in Renal Transplantation: Antibody induction therapy with steroid taper in recipients of renal transplants proved more efficacious for reducing 1-year rates of biopsy-confirmed acute rejection, compared with standard therapy, in a trial of 335 low-risk and 139 high-risk patients (pp. 1909–19). In addition to tacrolimus and mycophenolate mofetil with 5-day glucocorticoid taper, high-risk patients received alemtuzumab or rabbit antithymocyte globulin, while low-risk patients were given alemtuzumab or basiliximab. Results showed: “The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P < 0.001) and 12 months (5% vs. 17%, P < 0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P = 0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P = 0.63). Adverse-event rates were similar among all four treatment groups.” (M. J. Hanaway, michael.hanaway@ccc.uab.edu)

>>>PNN NewsWatch
* FDA yesterday announced restrictions on access and distribution of products containing rosiglitazone, including Avandia, Avandemet, and Avandaryl. In addition to the previously required Medication Guide, the REMS program for rosiglitazone will now include the Avandia–Rosiglitazone Medicines Access Program. It requires enrollment of health care providers and patients and limits use of rosiglitazone-containing products to patients already being successfully treated with these medicines and those whose blood glucose cannot be controlled with other antidiabetic medicines and who, after consulting with their health care provider, do not wish to use pioglitazone-containing medicines (Actos, Actoplus Met, Actoplus Met XR, or Duetact).

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 20, 2011 * Vol. 18, No. 98
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
May issue of Chest (2011; 139).
Smoking, Warfarin Interaction: Changes in patients’ smoking habits may alter the metabolism of warfarin, requiring close monitoring, according to authors of a systematic review and meta-analysis (pp. 1130–9). Evidence identified in databases from 1966 through 2008 showed that “smoking may potentially cause significant interaction with warfarin by increasing warfarin clearance”: “Of the 1,240 studies retrieved, one experimental pharmacokinetic study and 12 cross-sectional studies were included. The pooled analyses of multivariate studies suggested that smoking was associated with a 12.13% (95% CI, 6.999–17.265; P < .001) increase in warfarin dosage requirement and an additional 2.26 mg (95% CI, 2.529–7.042; P = .355) per week compared with nonsmoking. Additional sensitivity analysis of four multivariate studies with adjustment for pharmacogenomic factors suggested that smoking was associated with a 13.21% (95% CI, 8.59%–17.83%; P < .001) increase in warfarin dosage requirement compared with nonsmokers. Results of an experimental pharmacokinetic study lend theoretical support to the findings.” (N. Chaiyakunapruk, chaiyakunapr@wisc.edu)
Antibiotic Dosing in Multiple Organ Dysfunction: Determining correct doses for early, appropriate antibiotic therapy in patients with multiple organ dysfunction syndrome (MODS) is problematic, authors report (pp. 1210–20). Review of available literature yields this analysis of best pharmacokinetic practices: “The two parameters that vary with greatest significance in critically ill patients with MODS are drug volume of distribution and clearance. Disease- and clinician-driven changes lead to an increased volume of distribution and lower-than-expected plasma drug concentrations during the first day of therapy at least. Decreased antibiotic clearance is common and can lead to drug toxicity. In summary, ‘front-loaded’ doses of antibiotic during the first 24 h of therapy should account for the likely increases in the antibiotic volume of distribution. Thereafter, maintenance dosing must be guided by drug clearance and adjusted to the degree of organ dysfunction.” (J. Rello, jrello.hj23.ics@gencat.cat)
Osteopontin in Idiopathic Pulmonary Hypertension: Circulating levels of the pleiotropic cytokine osteopontin can be used to predict survival in patients with idiopathic pulmonary hypertension (IPAH), a study shows (pp. 1010–7). Levels in patients with IPAH averaged 50 ng/mL, compared with 24 ng/mL in healthy control patients, and baseline osteopontin levels were independent predictors of mortality, with 34.5 ng/mL separating normal from elevated levels. (J. M. Lorenzen, J.M.Lorenzen@gmail.com)

>>>Cardiology Highlights
Source:
May 24 issue of the Journal of the American College of Cardiology (2011; 57).
Beta-Blockers & Beta-Agonists in HF, COPD: The “quandary” of beta-blockers and beta-agonists in the treatment of patients with heart failure and chronic obstructive pulmonary disease is analyzed in a state-of-the-art paper (pp. 2127–38): “The combination of heart failure and chronic obstructive pulmonary disease presents many therapeutic challenges. The cornerstones of therapy are beta-blockers and beta-agonists, respectively. Their pharmacological effects are diametrically opposed, and each is purported to adversely affect the alternative condition. The tolerability of beta-blockade in patients with mild and fixed airflow obstruction likely extends to those with more severe disease. However, the evidence is rudimentary. The long-term influence of beta-blockade on pulmonary function, symptoms, and quality of life is unclear. Low-dose initiation and gradual up-titration of cardioselective beta-blockers is currently recommended. Robust clinical trials are needed to provide the answers that may finally allay physicians’ mistrust of beta-blockers in patients with chronic obstructive pulmonary disease. Beta-agonists are associated with incident heart failure in patients with pulmonary disease and with increased mortality and hospitalization in those with existing heart failure. These purported adverse effects require further investigation. In the meantime, clinicians should consider carefully the etiology of dyspnea and obtain objective evidence of airflow obstruction before prescribing beta-agonists to patients with heart failure.” (N. M. Hawkins, nathawkins@hotmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 23, 2011 * Vol. 18, No. 99
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 21 issue of Lancet (2011; 377).
Chemotherapy Options in Older Patients with Metastatic Colorectal Cancer: Using reduced starting doses, clinicians can successfully include older and frail patients in randomized controlled trials, with oxaliplatin-based regimens performing best, FOCUS2 researchers report (pp. 1749–59). In an open-label, randomized, 2 x 2 factorial trial, starting doses were 80% of normal; these could be escalated to full doses at 6 weeks. Results for progression-free survival (PFS), global quality of life (QoL), and overall treatment utility (OTU) were as follows for 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D): “459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5.8 months [IQR 3.3–7.5] vs 4.5 months [2.8–6.4]; hazard ratio 0.84, 95% CI 0.69–1.01, p = 0.07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p = 0.17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p = 0.03). In multivariable analysis, fewer baseline symptoms (odds ratio 1.32, 95% CI 1.14–1.52), less widespread disease (1.51, 1.05–2.19), and use of oxaliplatin (0.57, 0.39–0.82) were predictive of better OTU.” (M. T. Seymour, m.seymour@ncrn.org.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
Arginine, Antioxidant Vitamins in Preeclampsia: Among 672 women in Mexico City at high risk of preeclampsia, use of medical foods containing L-arginine and antioxidant vitamins reduced the incidence of the condition, a study shows (d2901): “222 women were allocated to the placebo group, 228 received L-arginine plus antioxidant vitamins, and 222 received antioxidant vitamins alone. Women had 4-8 prenatal visits while receiving the bars. The incidence of pre-eclampsia was reduced significantly (chi square = 19.41; P < 0.001) in women randomised to L-arginine plus antioxidant vitamins compared with placebo (absolute risk reduction 0.17 (95% confidence interval 0.12 to 0.21). Antioxidant vitamins alone showed an observed benefit, but this effect was not statistically significant compared with placebo (chi square =3.76; P=0.052; absolute risk reduction 0.07, 0.005 to 0.15). L-arginine plus antioxidant vitamins compared with antioxidant vitamins alone resulted in a significant effect (P = 0.004; absolute risk reduction 0.09, 0.05 to 0.14).” (F. Vadillo–Ortega, felipe.vadillo@gmail.com)
>>>PNN NewsWatch
* Rilpivirine (Edurant, Tibotec Therapeutics), a nonnucleoside reverse transcriptase inhibitor, was approved by FDA on Friday for use in treatment-naive patients with HIV infection. The safety and effectiveness of the drug was evaluated in two 48-week Phase III trials of 1,368 adults with HIV infection, and from a 96-week (with extension to 192 weeks) trial. In the rilpivirine and efavirenz groups, 83% and 80% of participants, respectively, had undetectable amounts of HIV in their blood after 48 weeks of treatment. The most commonly reported adverse effects in patients taking rilpivirine included depression, insomnia, headache, and rash.

*
FDA has approved two agents this month for treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. A supplemental NDA for this use was approved on Friday for sunitinib malate (Sutent, Pfizer). Earlier in the month, FDA approved everolimus (Afinitor, Novartis) for the same indication.

>>>PNN JournalWatch
* Nitrate Therapy: New Aspects Concerning Molecular Action and Tolerance, in Circulation, 2011; 123: 2132–44. (T. Münzel, tmuenzel@uni-mainz.de)
*Evidence-Based Guideline: Treatment of Painful Diabetic Neuropathy, in
Neurology, 2011; 76: 1758–65. (American Academy of Neurology, guidelines@aan.com)
* Sudden Cardiac Death in Hemodialysis Patients: An In-Depth Review, in
American Journal of Kidney Diseases, 2011; 57: 921–9. (P. A. Kalra, philip.kalra@srft.nhs.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 24, 2011 * Vol. 18, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 23 issue of the Archives of Internal Medicine (2011; 171).
Urinary Retention with Anticholinergics in COPD: Acute urinary retention (AUR) occurs more frequently in men using inhaled anticholinergic medications (IACs) for chronic obstructive pulmonary disease, compared with those not on the drugs, a study shows (pp. 914–20). Using a database of patients with COPD in Ontario, investigators found these relationships between IAC use and AUR in a nested case–control study: “Of 565,073 individuals with COPD, 9,432 men and 1,806 women developed AUR. Men who just initiated a regimen of IACs were at increased risk for AUR compared with nonusers (adjusted odds ratio [OR], 1.42; 95% confidence interval [CI], 1.20–1.68). In men with evidence of benign prostatic hyperplasia, the risk was increased further (OR, 1.81; 95% CI, 1.46–2.24). Men using both short- and long-acting IACs had a significantly higher risk of AUR compared with monotherapy users (OR, 1.84; 95% CI, 1.25–2.71) or nonusers (2.69; 1.93–3.76). (A. Stephenson, stephensona@smh.ca)
In an invited commentary, authors describe these “implications of the accumulating evidence about serious harm associated with IAC use” (
pp. 920–2): “Physicians should inform patients with COPD about the risk of AUR associated with IACs and determine the optimal choice of therapy for their patients after eliciting patient preferences for various patient-oriented outcomes in a shared decision-making context. Clinicians need reliable, accurate, and comprehensive safety data to determine whether the increasing morbidity and mortality in COPD are due to the underlying disease or are treatment induced. Regulators ought to review safety data for all inhaled bronchodilators, with particular attention to vulnerable subgroups at the highest risk of systemic anticholinergic effects, such as older men with [benign prostatic hyperplasia] or patients with preexisting arrhythmias, who are often excluded from [randomized controlled trials] of efficacy.” (S. Singh, ssingh31@jhu.edu)
Reasons People Take, or Don’t Take, Preventive Medications: Older patients’ willingness to take medications for primary prevention of cardiovascular disease is driven more by concern over adverse reactions than by perceived benefits of the drugs, researchers report (pp. 923–8). In-person interviews of 356 community-dwelling older people elicited these responses to varying descriptions of benefits and harms associated with medication for primary prevention of myocardial infarction: “Most (88%) would take medication, providing an absolute benefit of 6 fewer persons with MI out of 100, approximating the average risk reduction of currently available medications. Of participants who would not take it, 17% changed their preference if the absolute benefit was increased to 10 fewer persons with MI, and, of participants who would take it, 82% remained willing if the absolute benefit was decreased to 3 fewer persons with MI. In contrast, large proportions (48%–69%) were unwilling or uncertain about taking medication with average benefit causing mild fatigue, nausea, or fuzzy thinking, and only 3% would take medication with adverse effects severe enough to affect functioning.” (T. R. Fried, terri.fried@yale.edu)

>>>PNN NewsWatch
* Telaprevir (Incivek, Vertex Pharmaceuticals) was approved by FDA on Monday for treatment of certain adults with genotype 1 chronic hepatitis C with compensated liver disease, including cirrhosis. It is the second hepatitis C virus protease inhibitor to reach the U.S. market, joining Merck’s recently approved boceprevir (Victrelis; see PNN, May 16). Telaprevir is approved for treatment-naive patients as well as for relapsers, partial responders, and null responders. The drug is given for 12 weeks in combination with pegylated-interferon and ribavirin, followed by continued treatment with pegylated-interferon and ribavirin alone for an additional 12 or 36 weeks. Response rates have been 60% in both treatment-naive and-experienced patients. The most common adverse effects of the drug, which is given three times daily, are itching, nausea, diarrhea, vomiting, anal or rectal problems (including hemorrhoids, discomfort or burning around or near the anus, itching around or near the anus), taste changes, and tiredness. Telaprevir is contraindicated during pregnancy.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 25, 2011 * Vol. 18, No. 101
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 25 issue of JAMA (2011; 305).
Corticosteroid Therapy for Idiopathic Sudden Sensorineural Hearing Loss: Intratympanic corticosteroid therapy is not inferior to oral doses of the drugs, according to a comparative effectiveness research study of patients with unilateral idiopathic sudden sensorineural hearing loss (pp. 2071–9). Change in hearing at 2 months was assessed in 250 patients who received either oral prednisone 60 mg/d for 14 days with a 5-day taper or 4 doses over 14 days of methylprednisolone 40 mg/mL injected into the middle ear. With noninferiority defined as less than 10-dB difference in pure tone average (PTA) hearing threshold, the results showed: “In the oral prednisone group, PTA improved by 30.7 dB compared with a 28.7-dB improvement in the intratympanic treatment group. Mean pure tone average at 2 months was 56.0 for the oral steroid treatment group and 57.6 dB for the intratympanic treatment group. Recovery of hearing on oral treatment at 2 months by intention-to-treat analysis was 2.0 dB greater than intratympanic treatment (95.21% upper confidence interval, 6.6 dB). Per-protocol analysis confirmed the intention-to-treat result. Thus, the hypothesis of inferiority of intratympanic methylprednisolone to oral prednisone for primary treatment of sudden sensorineural hearing loss was rejected.” (S. D. Rauch, steven_rauch@meei.harvard.edu)
While this trial answers some questions, others remain, an editorialist notes (
pp. 2114–5): “The finding of noninferiority of intratympanic steroids when compared to oral steroids now provides a new therapeutic option for patients with sudden hearing loss for whom oral steroids are contraindicated. The use of intratympanic steroids is moderately uncomfortable, inconvenient, and more costly than oral steroids and is associated with several relatively minor adverse effects. Nevertheless, for patients with sudden hearing loss who are thought to be at too high a risk for systemic steroid usage, this study suggests a reasonable alternative in the setting of rapid specialty referral. Additional research should focus on identifying subgroups of patients for whom steroid treatment seems especially helpful and whether combination oral and intratympanic is better than single modality alone. However, the study by Rauch et al did not answer the lingering question of whether there is any benefit of steroids for the patient with sudden sensorineural hearing loss. A better understanding of the pathophysiology of hearing loss, identification of unique prognostic subgroups, and adherence to rigorous clinical research methods are required for the proper assessment of the therapeutic benefits of existing treatments and discovery of new treatments for this disorder.” (J. F. Piccirillo, piccirilloj@ent.wustl.edu)
Mortality in Women with New-Onset AF: In initially healthy women, new-onset atrial fibrillation is a predictor of increased mortality, including greater risk of fatality from noncardiovascular causes, researchers report (pp. 2080–7). Data on 34,722 women in the Women’s Health Study showed these primary (all-cause, cardiovascular, and noncardiovascular mortality) and secondary (stroke, congestive heart failure, and myocardial infarction) outcomes: “During a median follow-up of 15.4 (IQR, 14.7–15.8) years, 1,011 women developed AF. Incidence rates per 1,000 person–years among women with and without AF were 10.8 (95% confidence interval [CI], 8.1–13.5) and 3.1 (95% CI, 2.9–3.2) for all-cause mortality, 4.3 (95% CI, 2.6–6.0) and 0.57 (95% CI, 0.5–0.6) for cardiovascular mortality, and 6.5 (95% CI, 4.4–8.6) and 2.5 (95% CI, 2.4–2.6) for noncardiovascular mortality, respectively. In multivariable models, hazard ratios (HRs) of new-onset AF for all-cause, cardiovascular, and noncardiovascular mortality were 2.14 (95% CI, 1.64–2.77), 4.18 (95% CI, 2.69–6.51), and 1.66 (95% CI, 1.19–2.30), respectively. Adjustment for nonfatal cardiovascular events potentially on the causal pathway to death attenuated these risks, but incident AF remained associated with all mortality components (all–cause: HR, 1.70 [95% CI, 1.30–2.22]; cardiovascular: HR, 2.57 [95% CI, 1.63–4.07]; and noncardiovascular: HR, 1.42 [95% CI, 1.02–1.98]). Among women with paroxysmal AF (n = 656), the increase in mortality risk was limited to cardiovascular causes (HR, 2.94; 95% CI, 1.55–5.59).” (D. Conen, conend@uhbs.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 26, 2011 * Vol. 18, No. 102
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 26 issue of the New England Journal of Medicine (2011; 364).
Abiraterone in Metastatic Prostate Cancer: Overall survival was prolonged among 1,195 men with metastatic castration-resistant prostate cancer who previously received chemotherapy when they were treated with abiraterone, an inhibitor of androgen biosynthesis (pp. 1995–2005). The study used a primary end point of overall survival to test effects of prednisone 5 mg twice daily plus abiraterone acetate 1000 mg or placebo, with these results: “After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate–prednisone group than in the placebo–prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P < 0.001). Data were unblinded at the interim analysis, since these results exceeded the preplanned criteria for study termination. All secondary end points, including time to PSA progression (10.2 vs. 6.6 months; P < 0.001), progression-free survival (5.6 months vs. 3.6 months; P < 0.001), and PSA response rate (29% vs. 6%, P < 0.001), favored the treatment group. Mineralocorticoid-related adverse events, including fluid retention, hypertension, and hypokalemia, were more frequently reported in the abiraterone acetate–prednisone group than in the placebo–prednisone group.” (J. S. de Bono, johann.de-bono@icr.ac.uk)
These results and the expanding treatment options for prostate cancer call into question efficacy measures used in clinical trials as well as continued use of placebo in them, editorialists write (
pp. 2055–8): “Is it still realistic to demand that new agents increase overall survival among patients with metastatic castration-resistant prostate cancer? Survival is likely to become harder to assess, unless we are able to control for the influence of subsequent treatments on survival. More recent trials in metastatic castration-resistant prostate cancer have used coprimary end points such as progression-free survival and overall survival in an attempt to validate progression-free survival as a clinically meaningful and more feasible end point. Furthermore, clinical, radiologic, biologic, and genomic response biomarkers should be identified and validated; these may act as surrogates of clinical benefit and may help in the selection of appropriate patients for specific therapies. In addition, the approach of regulatory agencies to consider patients who have received chemotherapy as a distinct group from those who have not may need to be rethought. Currently, a trial leading to approval of a drug for patients who have previously received chemotherapy may not lead to approval of the same drug for patients who have not received chemotherapy unless a second clinical trial involving the latter group is conducted. It is not clear that a second trial should be required. Finally, placebo-controlled trials may no longer be ethical or feasible in men with metastatic castration-resistant prostate cancer.” (E. S. Antonarakis)
Prescription Data Mining & the Courts: Journal editors write in opposition to the recent U.S. Supreme Court decision (Sorrell v. IMS Health) regarding free speech and data mining of community pharmacies’ prescription files (pp. 2053–5): “As medical journal editors committed to the open communication of medical knowledge, we are strong proponents of First Amendment protection for speakers who attempt to communicate important evidence-based health information or advocate for patients’ and physicians’ rights. But, the doctor–patient relationship is a sacred trust, and the sale of physicians’ confidential prescribing information puts patients’ highly private medical information at risk. Why should this information be sold to data-mining and drug companies as a commodity, when it offers no benefit to patients and their physicians? This undesirable practice is nothing more than commercial conduct—not speech—and it is not in the best interest of the health of the American people.” (G. D. Curfman)

>>>PNN NewsWatch
* SimplyThick, an OTC product marketed to thicken formula for babies with swallowing disorders, should not be used in premature infants, FDA warned last week. It may cause life-threatening necrotizing enterocolitis, the agency said.
*
FDA has also issued 11 warning letters to online retailers of tobacco products about their use of misleading phrases such as “light,” “less toxic,” and “safer.”

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 27, 2011 * Vol. 18, No. 103
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (2011; 34).
Diet, Lifestyle, & Genes in Globalization of Diabetes: Several common factors are driving the worldwide growth in incidence of diabetes, authors write, and the disease is an economic threat, especially in developing countries (pp. 1249–57): “Fueled by rapid urbanization, nutrition transition, and increasingly sedentary lifestyles, the epidemic has grown in parallel with the worldwide rise in obesity. Asia’s large population and rapid economic development have made it an epicenter of the epidemic. Asian populations tend to develop diabetes at younger ages and lower BMI levels than Caucasians. Several factors contribute to accelerated diabetes epidemic in Asians, including the ‘normal-weight metabolically obese’ phenotype; high prevalence of smoking and heavy alcohol use; high intake of refined carbohydrates (e.g., white rice); and dramatically decreased physical activity levels. Poor nutrition in utero and in early life combined with overnutrition in later life may also play a role in Asia’s diabetes epidemic. Recent advances in genome-wide association studies have contributed substantially to our understanding of diabetes pathophysiology, but currently identified genetic loci are insufficient to explain ethnic differences in diabetes risk. Nonetheless, interactions between Westernized diet and lifestyle and genetic background may accelerate the growth of diabetes in the context of rapid nutrition transition. Epidemiologic studies and randomized clinical trials show that type 2 diabetes is largely preventable through diet and lifestyle modifications. Translating these findings into practice, however, requires fundamental changes in public policies, the food and built environments, and health systems. To curb the escalating diabetes epidemic, primary prevention through promotion of a healthy diet and lifestyle should be a global public policy priority.” (Frank B. Hu, frank.hu@channing.harvard.edu)
Rosiglitazone & Delay of Diabetes: The beneficial effects of rosiglitazone in delaying onset of diabetes end when the drug is stopped, as progression returning to placebo rates, according to investigators in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) trial (pp. 1265–9). In 3,366 participants, these trends were noted after therapy was stopped at the end of the study: “Following median (interquartile range) 71 (63–86) days drug withdrawal, overall glycemic status remained modestly improved in those allocated ramipril during the trial with an 11% increase in regression to normoglycemia, compared with placebo. In those previously allocated rosiglitazone, glycemic status remained substantially improved with a 49% reduction of new-onset diabetes or death and a 22% increase in regression to normoglycemia, compared with placebo. However, during the washout phase alone the incidence of diabetes or death was identical for those allocated previously to ramipril or placebo, or to rosiglitazone or placebo.” (DREAM Project Office, dream@cardio.on.ca)
Vitamin D Status & Type 2 Diabetes in Septuagenarians: Vitamin D sufficiency may help protect patients in their 70s against development of type 2 diabetes, researchers report (pp. 1284–8). In a cross-sectional analysis of 668 Faroese residents aged 70–74 years, having a serum vitamin D level less than 50 nmol/L doubled the adjusted risk of developing type 2 diabetes. (C. Dalgård, cdalgaard@health.sdu.dk)

>>>PNN NewsWatch
* Added to statin therapy in people with cardiovascular disease in a large clinical trial, high dose, extended-release niacin failed to reduce the risk of cardiovascular events, the National Heart, Lung, and Blood Institute said yesterday. In fact, in stopping the AIM-HIGH trial 18 months early, the NIH agency said that patients on niacin experienced “a small and unexplained increase in ischemic stroke rates,” a finding that FDA says it will review in relation to product labeling of Abbott’s Niaspan. During the 32-month follow-up period, the 3,414 AIM-HIGH participants had 28 strokes (1.6%) among those taking high dose, extended-release niacin versus 12 strokes (0.7%) in the control group. In the niacin group, 9 of the 28 strokes occurred in participants who had discontinued the drug at least 2 months and up to 4 years before their stroke.
*
PNN will not be published on Mon., May 30, Memorial 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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
May 31, 2011 * Vol. 18, No. 104
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 28 issue of Lancet (2011; 377).
Length of Antibiotic Treatment in Childhood Meningitis: Five days of ceftriaxone therapy is sufficient in nonneonatal children who have purulent bacterial meningitis, researchers conclude (pp. 1837–45). In children aged 2 months to 12 years with infections caused by Streptococcus pneumoniae, Haemophilus influenzae type B, or Neisseria meningitidis, random assignment to 5 or 10 days of therapy with ceftriaxone produced these results in a study conducted in Bangladesh, Egypt, Malawi, Pakistan, and Vietnam: “We included 1,004 of 1,027 children randomly assigned to study groups in our analyses; 496 received treatment with ceftriaxone for 5 days, and 508 for 10 days. In the 5-day treatment group, two children (one infected with HIV) had a relapse; there were no relapses in the 10-day treatment group and there were no bacteriological failures in either study group. Side-effects of antibiotic treatment were minor and similar in both groups.” (S. A. Qazi, qazis@who.int)
Bevacizumab in Advanced Non–Small-Cell Lung Cancer: In 636 patients with recurrent or refractory non-small-cell lung cancer (NSCLC), addition of bevacizumab to erlotinib had no effect on survival, a study shows (pp. 1846–54). In the Phase III trial BeTa, patients had these responses at 177 sites in 12 countries: “Median overall survival was 9.3 months (IQR 4.1–21.6) for patients in the bevacizumab group compared with 9.2 months (3.8–20.2) for controls. Progression-free survival seemed to be longer in the bevacizumab group (3.4 months [1.4–8.4]) than in the control group (1.7 months [1.3–4.1]; HR 0.62, 95% CI 0.52–0.75) and objective response rate suggested some clinical activity of bevacizumab and erlotinib. However, these secondary endpoint differences could not be defined as significant because the study prespecified that the primary endpoint had to be significant before testing of secondary endpoints could be done, to control type I error rate.” (R. S. Herbst, roy.herbst@yale.edu)

>>>PNN NewsWatch
* Fidaxomicin (Dificid, Optimer Pharmaceuticals) has been approved for treatment of Clostridium difficile–associated diarrhea (CDAD), FDA said on Friday. The macrolide antibiotic, which is taken twice daily for 10 days with or without food, was studied in two clinical trials involving 564 patients. The clinical response was similar with fidaxomicin, compared with vancomycin, in both studies. A greater number of CDAD patients treated with fidaxomicin had a sustained cure 3 weeks after treatment ended versus those patients treated with vancomycin. The most common adverse effects reported with fidaxomicin included nausea, vomiting, headache, abdominal pain, and diarrhea.
*
FDA also approved Solesta (Oceana Therapeutics), a biocompatible tissue bulking agent consisting of dextranomer microspheres and stabilized sodium hyaluronate, for treatment for fecal incontinence in adult patients who have failed conservative therapy such as dietary control. The injectable gel can be administered in an outpatient setting without anesthesia. Solesta is injected in the deep submucosal layer in the proximal part of the anal canal. While the exact mechanism of action has not been identified, Solesta injections may narrow the anal canal and thereby allow for better sphincter control. In a 6-month trial, more than one-half of 206 patients injected with Solesta had a 50% reduction in the number of fecal incontinence episodes. One-third of patients who received sham injections experienced a similar reduction. Overall, a greater proportion of patients treated with Solesta experienced improvements, indicating the gel provides benefit, FDA said. The most common adverse effects associated with Solesta include injection area pain and bleeding. Infection and inflammation of anal tissue are more serious risks, but are less common.

>>>PNN JournalWatch
* Use of Metformin in the Setting of Mild-to-Moderate Renal Insufficiency, in Diabetes Care, 2011; 34: 1431–7. (S. E. Inzucchi, silvio.inzucchi@yale.edu)
* Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials, in
Journal of Clinical Oncology, 2011; 29: 2144–9. (A. Gennari, alessandra.gennari@galliera.it)
* Discovering How Environmental Exposures Alter Genes Could Lead to New Treatments for Chronic Illnesses, in
Health Affairs, 2011; 30: 833–41. (K. Olden, kolden@hunter.cuny.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 1, 2011 * Vol. 18, No. 105
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 1 issue of JAMA (2011; 305).
Outcomes with ICU Telemedicine: Improvements in a number of positive outcomes were noted after telemedicine was implemented in seven intensive-care units at a tertiary medical center, including improved mortality risk, hospital length of stay, best practice adherence, and preventable complications (pp. 2175–83). Use of audio, video, and electronic links by remotely located intensivists and other team members had these effects on patients in tele-ICUs: “The hospital mortality rate was 13.6% (95% confidence interval [CI], 11.9%–15.4%) during the preintervention period compared with 11.8% (95% CI, 10.9%–12.8%) during the tele-ICU intervention period (adjusted odds ratio [OR], 0.40 [95% CI, 0.31–0.52]). The tele-ICU intervention period compared with the preintervention period was associated with higher rates of best clinical practice adherence for the prevention of deep vein thrombosis (99% vs 85%, respectively; OR, 15.4 [95% CI, 11.3–21.1]) and prevention of stress ulcers (96% vs 83%, respectively; OR, 4.57 [95% CI, 3.91–5.77], best practice adherence for cardiovascular protection (99% vs 80%, respectively; OR, 30.7 [95% CI, 19.3–49.2]), prevention of ventilator-associated pneumonia (52% vs 33%, respectively; OR, 2.20 [95% CI, 1.79–2.70]), lower rates of preventable complications (1.6% vs 13%, respectively, for ventilator-associated pneumonia [OR, 0.15; 95% CI, 0.09–0.23] and 0.6% vs 1.0%, respectively, for catheter-related bloodstream infection [OR, 0.50; 95% CI, 0.27–0.93]), and shorter hospital length of stay (9.8 vs 13.3 days, respectively; hazard ratio for discharge, 1.44 [95% CI, 1.33–1.56]). The results for medical, surgical, and cardiovascular ICUs were similar.” (C. M. Lilly, craig.lilly@umassmed.edu)
Noting that the intensivists in this study were reactive rather than proactive and that they “conducted real-time best-practice audits for selected evidence-based practices, reviewed care plans and daily goal sheets, and ensured adherence with the local intensivists’ plans,” an editorialist writes (
pp. 2227–8): “This view of telemedicine as just another instrument for quality improvement has a downside. It means that the question of whether ICU telemedicine is good or bad is tangential to the real issue. But the upside, as demonstrated in the study by Lilly et al, is that in the right settings and with the right goals, telemedicine can indeed be used to help improve outcomes. Yet just as with all applications of health information technology, good outcomes should not be assumed. The challenge is to not conclude from this study that ICU telemedicine always is associated with improved quality of care, but instead to continue to explore how telemedicine can be used in clinical settings in which other strategies for quality improvement have not worked. Only then will it be possible to improve the use and avoid the misuse of this complex and evolving technology.” (J. M. Kahn)
Estimating Fracture Risk in Patients with Diabetes: Compared with older patients without type 2 diabetes, those with the disease have higher fracture risks at given T or World Health Organization Fracture Risk Algorithm (FRAX) scores, a study shows (pp. 2184–92). While the investigators found the femoral neck BMD T scores and FRAX scores were associated with risk of hip and nonspine fractures, they found these more complicated patterns among patients in three prospective observational studies: “Age-adjusted hazard ratios (HRs) for 1-unit decrease in femoral neck BMD T score in women with DM were 1.88 (95% confidence interval [CI], 1.43–2.48) for hip fracture and 1.52 (95% CI, 1.31–1.75) for nonspine fracture, and in men with DM were 5.71 (95% CI, 3.42–9.53) for hip fracture and 2.17 (95% CI, 1.75–2.69) for nonspine fracture. The FRAX score was also associated with fracture risk in participants with DM (HRs for 1-unit increase in FRAX hip fracture score, 1.05; 95% CI, 1.03–1.07, for women with DM and 1.16; 95% CI, 1.07–1.27, for men with DM; HRs for 1-unit increase in FRAX osteoporotic fracture score, 1.04; 95% CI, 1.02–1.05, for women with DM and 1.09; 95% CI, 1.04–1.14, for men with DM). However, for a given T score and age or for a given FRAX score, participants with DM had a higher fracture risk than those without DM. For a similar fracture risk, participants with DM had a higher T score than participants without DM.” (A. V. Schwartz, aschwartz@psg.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 2, 2011 * Vol. 18, No. 106
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 2 issue of the New England Journal of Medicine (2011; 364).
Vaccine for Advanced Melanoma: Used with high-dose interleukin-2, a gp100 peptide vaccine increased response rates and progression-free survival in 185 patients with metastatic melanoma, according to results of a Phase III trial (pp. 2119–27). All participants had stage IV or locally advanced stage III cutaneous melanoma, expression of HLA*A0201, an absence of brain metastases, and suitability for high-dose interleukin-2 therapy. They received interleukin-2 720,000 IU/kg/dose or gp100:209-217(210M) plus incomplete Freund’s adjuvant (Montanide ISA-51) once per cycle, followed by interleukin-2, with these results: “The treatment groups were well balanced with respect to baseline characteristics and received a similar amount of interleukin-2 per cycle. The toxic effects were consistent with those expected with interleukin-2 therapy. The vaccine–interleukin-2 group, as compared with the interleukin-2–only group, had a significant improvement in centrally verified overall clinical response (16% vs. 6%, P = 0.03), as well as longer progression-free survival (2.2 months; 95% confidence interval [CI], 1.7 to 3.9 vs. 1.6 months; 95% CI, 1.5 to 1.8; P = 0.008). The median overall survival was also longer in the vaccine–interleukin-2 group than in the interleukin-2–only group (17.8 months; 95% CI, 11.9 to 25.8 vs. 11.1 months; 95% CI, 8.7 to 16.3; P = 0.06).” (D. J. Schwartzentruber, dschwart@iuhealth.org)
I.V. Thrombolytics for Stroke: The case of an 81-year-old man with speech difficulty and right-sided weakness of 75 minutes’ duration provides the basis for a discussion of i.v. thrombolytic therapy for acute ischemic stroke (pp. 2138–46). The authors reach this conclusion: “The patient described in the case vignette meets all the inclusion criteria for treatment with intravenous rt-PA. Assuming that further history taking reveals no pertinent findings, he also has no contraindications to treatment. Evidence from clinical trials does not suggest that persons older than 80 years of age do not benefit from intravenous rt-PA. He completed evaluation in the emergency department 2 hours after the onset of the stroke, which is within the FDA-approved 3-hour window, and the probability of recovery is greater the more rapidly treatment can be administered. Once consent has been obtained from his wife, I would elect to proceed with intravenous rt-PA therapy at the standard dose of 0.9 mg per kilogram, with 10% given as a bolus and the remainder infused over a 60-minute period. After the administration of intravenous rt-PA, the patient should be admitted to a specialized stroke unit for monitoring and additional workup to determine the cause of the stroke.” (L. R. Wechsler, wechslerlr@upmc.edu)
Drugs & the Incarceration Epidemic: A punitive “War on Drugs” has failed, Perspective authors write, suggesting ways drug abuse could be better addressed (pp. 2081–3): “There are tremendous medical and public health opportunities that can be created by addressing the health care needs of prisoners and former prisoners. Perhaps foremost among these is that opened up by health care reform: the Affordable Care Act will permit most former prisoners to receive health insurance coverage, which will offer them greater access to much-needed medical care. Such access could redirect many people with serious illnesses away from the revolving door of the criminal justice system, thereby improving overall public health in the communities to which prisoners return and decreasing the costs associated with reincarceration due to untreated addiction and mental illness. To achieve these gains, we will need to ensure linkages to medical homes that provide substance-use and mental health treatment for reentering populations. Partnerships between correctional facilities and community health care providers—especially community health centers and academic medical centers—can capitalize on health gains made during incarceration and improve the continuity of care for former inmates during the critical post-release period. The success of this effort will determine not only the health of released prisoners, but that of our society as a whole.” (J. D. Rich)

>>>PNN NewsWatch
* FDA is assessing the risk of blood clots with use of drospirenone in oral contraceptives, the agency said this week. Conflicting data from four studies will be analyzed.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 3, 2011 * Vol. 18, No. 107
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
June issue of Pharmacotherapy (2011; 31).
High-Dose Daptomycin for Complicated Gram-Positive Infections: In a case-series analysis of 250 patients with infections of organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE), daptomycin in dosages of 8 mg/kg/d or more was safe and effective (pp. 527–36). The patients, all adults, were not undergoing dialysis and received the high-dose antibiotic at least 72 hours when admitted in 2005–10. Results showed: “The median dose of daptomycin was 8.9 mg/kg/day (interquartile range [IQR] 8.0–10.0 mg/kg/day). The median duration of daptomycin during hospitalization for MRSA and VRE infection was 10 days (IQR 5–16 days) and 13 days (IQR 6–18 days), respectively. Among the 250 patients, high-dose daptomycin was primarily used as salvage therapy after vancomycin treatment (184 patients [73.6%]). Primary infections included complicated bacteremia (119 patients [47.6%]), endocarditis (59 [23.6%]), skin or wound (70 [28.0%]), and bone or joint (67 [26.8%]). Overall, clinical response and microbiologic success were assessed in 83.6% (209/250 patients) and 80.3% (175/218 patients), respectively. Isolates from 13 patients (5.2%) developed nonsusceptibility to daptomycin, with most of these patients having extended vancomycin exposure. Three patients (1.2%) developed an adverse event attributable to high-dose daptomycin therapy, with the event considered either mild or moderate in severity. The median end-of-therapy [creatine phosphokinase (CPK)] level was 39 U/L (IQR 26–67 U/L). No significant correlation was found between daptomycin dose and highest observed CPK level.” (M. J. Rybak, m.rybak@wayne.edu)
Risk of Fungal Infections in Lung Transplant: Routine systemic antifungal prophylaxis in patients who have undergone lung transplant appears unnecessary, based on findings at a university-affiliated lung transplant center (pp. 537–45). Retrospective analysis of the records of 242 adults without cystic fibrosis provided data that were compared with published literature: “Twenty-three cases of invasive fungal infections were identified in 22 patients, resulting in a 9.1% overall invasive fungal infection rate in our study population. Aspergillus infections were the most common type of fungal infection identified, occurring in 11 (47.8%) of the 23 cases, with an overall rate of 4.5% (11/242 patients). Invasive fungal infections in lung transplant recipients have been reported in the literature at a rate 15–35%, with rates of Aspergillus infections reported as 3–15%.” (M. F. Pinney, Marlena.Pinney@orlandohealth.com)
Economic Impact of C. difficile Infections: In the hospital setting, patients who acquire Clostridium difficile infections (CDI) have higher mean costs of care and longer lengths of stay than do matched controls, researchers report (pp. 546–51). The rise in costs is especially noticeable at the lower end of the acuity scale, measured using the All Patient Refined–Diagnosis Related Group (APR-DRG) severity of illness level. Results for administrative claims data at 45 academic medical centers showed these patterns: “The adjusted mean cost for cases was significantly higher than that for controls ($55,769 vs $28,609), and adjusted mean length of stay was twice as long (21.1 vs 10.0 days). The interaction between CDI and APR-DRG severity of illness level was significant; the effect of CDI on costs and length of stay decreased as severity of illness increased.” (A. Pakyz, apakyz@vcu.edu)

>>>PNN NewsWatch
* Angiotensin II receptor blockers are not associated with development of cancers, FDA said yesterday. A safety review, started in July of last year, used a trial-level meta-analysis of 31 studies of 156,000 patients to demonstrate no increase in risk of cancer among people taking ARBs. The rate of incident cancer events in the ARB group was 1.82 per 100 patient–years, and the rate in non–ARB comparators was 1.84 per 100 patient–years. The relative risk of incident cancer in patients taking ARBs was 0.99 (95% confidence interval 0.92 to 1.06). The comparison was prompted by a more limited meta-analysis, one involving 5 trials, that reported a small but statistically significant rise in cancers with use of the drugs.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 6, 2011 * Vol. 18, No. 108
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 4 issue of Lancet (2011; 377).
Fibroblast Growth Factor in Amputation: In a Phase III trial, the nonviral 1 fibroblast growth factor (NV1FGF) failed to reduce amputation rates and mortality among 525 patients with critical limb ischemia unsuitable for revascularization (pp. 1929–37). Participants in EFC6145/TAMARIS had ischemic ulcers in their legs or minor skin gangrene. They received NV1FGF 0.2 mg/mL or placebo on days 1, 15, 29, and 43, with these effects on a primary endpoint of time to major amputation or death at 1 year: “The mean age was 70 years (range 50–92), 365 (70%) were men, 280 (53%) had diabetes, and 248 (47%) had a history of coronary artery disease. The primary endpoint or components of the primary did not differ between treatment groups, with major amputation or death in 86 patients (33%) in the placebo group, and 96 (36%) in the active group (hazard ratio 1.11, 95% CI 0.83–1.49; p = 0.48). No significant safety issues were recorded.” (J. Belch, j.j.f.belch@dundee.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
Vitamin D Supplements in Low Birthweight Term Infants: Among 2,079 low birthweight term infants in New Dehli, weekly vitamin D supplements improved vitamin D status and bone growth, but severe morbidity and mortality were not reduced, researchers report (d2975). During their first 6 months, infants were given weekly doses of vitamin D at the recommended amount of 35 mcg, with these results, compared with placebo: “Between group differences were not significant for death or hospital admissions (92 among 1,039 infants in the vitamin D group v 99 among 1,040 infants in the placebo group; adjusted rate ratio 0.93, 95% confidence interval 0.68 to 1.29; P = 0.68), or referral to the outpatient clinic for moderate morbidity. Vitamin D supplementation resulted in better vitamin D status as assessed by plasma calcidiol levels at six months. In adjusted analyses, vitamin D treatment significantly increased standard deviation (z) scores at six months for weight, length, and arm circumference and decreased the proportion of children with stunted growth (length for age z score ≤2) or with arm circumference z scores of 2 or less.” (G. T. Kumar, geetatrilokkumar@gmail.com)

>>>PNN NewsWatch
* Articles on exemestane in breast-cancer prevention (10.1056/NEJMoa1103507) and venurafenib in metastatic melenoma (10.1056/NEJMoa1103782) were released over the weekend by the New England Journal of Medicine to coincide with presentation at the Annual Meeting of the American Society of Clinical Oncology. In 4,560 postmenopausal women who were at moderately increased risk for breast cancer, the annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo, yielding a significant hazard ratio of 0.47 (0.27–0.79, P = 0.04). Vemurafenib, a BRAF kinase inhibitor (PLX4032), produced 6-month overall survival rates of 84%, compared with 64% for dacarbazine, in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation.
*
Aidapak has recalled hundreds of drug products repackaged for hospital inpatients, FDA said on Friday. Nonpenicillin drug products may have been contaminated with beta-lactam antibiotics that were repackaged in the same facility. A 317-page list of recalled products is posted online.

>>>PNN JournalWatch
* Sports Drinks and Energy Drinks for Children and Adolescents: Are They Appropriate?, in Pediatrics, 2011; 127: 1182–9. (American Academy of Pediatrics Committee on Nutrition and the Council on Sports Medicine and Fitness)
* Principles of Pediatric Patient Safety: Reducing Harm Due to Medical Care, in
Pediatrics, 2011; 127: 1199–210. (American Academy of Pediatrics Steering Committee on Quality Improvement and Management and Committee on Hospital Care)
* Misdiagnosed Postpartum Psychosis Revealing a Late-Onset Urea Cycle Disorder, in
American Journal of Psychiatry, 2011; 168: 576–80. (T. Fassier)
* Effect of Acetaminophen on International Normalized Ratio in Patients Receiving Warfarin Therapy, in
Pharmacotherapy, 2011; 31: 591–7. (G. J. Hughes)
* Monotherapy or Combination Therapy? The
Pseudomonas aeruginosa Conundrum, in Pharmacotherapy, 2011; 31: 598–608. (J. S. Lewis, II, James.Lewis@uhs-sa.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 7, 2011 * Vol. 18, No. 109
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 7 issue of the Annals of Internal Medicine (2011; 154).
Smoking & Risk of PAD in Women: Smoking increases women’s risk of developing peripheral arterial disease, researchers report, and while cessation reduces the odds, PAD continues to occur during abstinence (pp. 719–26). Analysis of 39,825 women over a median of 12.7 years in the Women’s Health Study showed the following: “178 confirmed PAD events occurred. Across the 4 smoking categories (never, former, <15 cigarettes/d, and ≥15 cigarettes/d), age-adjusted incidence rates were 0.12, 0.34, 0.95, and 1.63 per 1000 person-years of follow-up, respectively. Multivariate adjustment had little effect on this relationship (adjusted hazard ratios [HRs], 3.14 [95% CI, 2.01 to 4.90], 8.93 [CI, 5.02 to 15.89], and 16.95 [CI, 10.77 to 26.67], respectively, vs. women who never smoked). Additional adjustment for high-sensitivity C-reactive protein and soluble intercellular adhesion molecule-1 levels among women with available blood samples (28 314 participants, 117 events) attenuated risk estimates (HR, 5.58 [CI, 2.61 to 11.93] for smoking <15 cigarettes/d and 9.52 [CI, 5.17 to 17.53] for smoking ≥15 cigarettes/d). Lifetime exposure showed a strong dose–response relationship; fully adjusted HRs for smoking abstinence of fewer than 10, 10 to 29, and 30 or more pack-years were 2.52 (CI, 1.49 to 4.25), 6.75 (CI, 4.33 to 10.52), and 11.09 (CI, 6.94 to 17.72), respectively. Compared with current smokers, the adjusted HRs for fewer than 10 years, 10 to 20 years, more than 20 years, or lifelong abstinence were 0.39 (CI, 0.24 to 0.66), 0.28 (CI, 0.17 to 0.46), 0.16 (CI, 0.10 to 0.26), and 0.08 (CI, 0.05 to 0.12), respectively.” (A. D. Pradhan, apradhan@partners.org)
Quality of VA Care: Compared with fee-for-service Medicare patients, older men with cancer receive similar or better care in the Veterans Health Administration, a study shows (pp. 727–36). Adoption of new technologies may be delayed in the VA system, the authors note, adding these details about patients diagnosed with cancer in 2001–04 and followed through 2005: “Compared with the fee-for-service Medicare population, the VHA population received diagnoses of colon (P < 0.001) and rectal (P = 0.007) cancer at earlier stages and had higher adjusted rates of curative surgery for colon cancer (92.7% vs. 90.5%; P < 0.010), standard chemotherapy for diffuse large B-cell non-Hodgkin lymphoma (71.1% vs. 59.3%; P < 0.001), and bisphosphonate therapy for multiple myeloma (62.1% vs. 50.4%; P < 0.001). The VHA population had lower adjusted rates of 3-dimensional conformal or intensity-modulated radiation therapy for prostate cancer treated with external-beam radiation therapy (61.6% vs. 86.0%; P < 0.001). Adjusted rates were similar for 9 other measures. Sensitivity analyses suggest that if patients with cancer in the VHA system have more severe comorbid illness than other patients, rates for most indicators would be higher in the VHA population than in the fee-for-service Medicare population.” (N. L. Keating, keating@hcp.med.harvard.edu)
HIV at 30: Better testing, cure of at least a proportion of infections, and prevention of new infections are three “critical elements” needed to fight HIV and AIDS, according to NIH researchers writing on the 30th anniversary of the first description of the syndrome (pp. 766–71). An HIV vaccine would be critical in the prevention aspect of three-pronged approach, the authors write: “A safe and effective HIV vaccine would be the ideal cornerstone of a potent combination prevention strategy that can draw on a growing list of interventions that have been validated or seem promising in large clinical trials. Adult male circumcision was a major advance in the arena of prevention, with a demonstrated efficacy of at least 55% that has been sustained in follow-up studies. Since 2009, we have seen 3 separate positive efficacy signals in large prevention studies, increasing from 31% with the RV144 vaccine to 39% with the CAPRISA 004 microbicide study to 44% with PrEP. A safe and effective vaccine would be an important addition to the armamentarium of combination prevention strategies. Such a vaccine optimally would show significant and durable protection from infection against all methods of sexual transmission and, if possible, against bloodborne transmission, as well.” (C. W. Dieffenbach, cdieffenba@niaid.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.


PNN Pharmacotherapy Line
June 8, 2011 * Vol. 18, No. 110
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 8 issue of JAMA, a theme issue on cancer (2011; 305).
Cancer Risk in Lynch Syndrome: Colorectal and other cancers occur commonly in families with Lynch syndrome, and a new study identifies the specific mutations associated with that increased risk (pp. 2304–10). At 40 French cancer genetics clinics, investigators with the ERISCAM (Estimation des Risques de Cancer chez les porteurs de mutation des gènes MMR) study analyzed 537 families with segregating mutated genes (248 with MLH1; 256 with MSH2; and 33 with MSH6). Results showed: “Significant differences in estimated cumulative cancer risk were found between the 3 mutated genes (P = .01). The estimated cumulative risks of colorectal cancer by age 70 years were 41% (95% confidence intervals [CI], 25%–70%) for MLH1 mutation carriers, 48% (95% CI, 30%–77%) for MSH2, and 12% (95% CI, 8%–22%) for MSH6. For endometrial cancer, corresponding risks were 54% (95% CI, 20%–80%), 21% (95% CI, 8%–77%), and 16% (95% CI, 8%-32%). For ovarian cancer, they were 20% (95% CI, 1%–65%), 24% (95% CI, 3%–52%), and 1% (95% CI, 0%–3%). The estimated cumulative risks by age 40 years did not exceed 2% (95% CI, 0%–7%) for endometrial cancer nor 1% (95% CI, 0%–3%) for ovarian cancer, irrespective of the gene. The estimated lifetime risks for other tumor types did not exceed 3% with any of the gene mutations.” (C. Lasset, lasset@lyon.fnclcc.fr)
Evidence on Orphan Cancer Drugs: Compared with pivotal trials for nonorphan cancer drugs, orphan cancer agents have a much weaker body of evidence to support their safety and efficacy, a study shows (pp. 2320–6). An assessment of those agents approved in 2004–10 showed that trials for orphan cancer drugs were more likely to smaller in size and to use nonrandomized, unblinded trial designs and surrogate end points, as follows: “Fifteen orphan and 12 nonorphan drugs were approved between January 1, 2004, and December 31, 2010. Pivotal trials of orphan drugs had smaller participant numbers (median, 96 [interquartile range {IQR}, 66–152] vs 290 [IQR, 185-394] patients exposed to th; P < .001) and were less likely to be randomized (30% vs 80%; P = .007). Orphan and nonorphan pivotal trials varied in their blinding (P = .04), with orphan trials less likely to be double-blind (4% vs 33%). Primary study outcomes also varied (P = .04), with orphan trials more likely to assess disease response (68% vs 27%) rather than overall survival (8% vs 27%). More treated patients had serious adverse events in trials of orphan drugs vs trials of nonorphan drugs (48% vs 36%; odds ratio, 1.72; 95% confidence interval, 1.02–2.92; P = .04).” (A. S. Kesselheim, akesselheim@partners.org)
Adjuvant Chemotherapy Timing & Survival: A meta-analysis supports earlier use of adjuvant chemotherapy (AC) to improve survival among patients with resected colorectal cancer, researchers report (pp. 2335–42). Literature from 1975 through Jan. 2011 showed the following: “We identified 10 eligible studies involving 15,410 patients (7 published articles, 3 abstracts). Nine of the studies were cohort or population based and 1 was a secondary analysis from a randomized trial of chemotherapy. Six studies reported time to AC as a binary variable and 4 as 3 or more categories. Meta-analysis demonstrated that a 4-week increase in time to AC was associated with a significant decrease in both overall survival (HR, 1.14; 95% confidence interval [CI], 1.10–1.17) and disease-free survival (HR, 1.14; 95% CI, 1.10–1.18). There was no significant heterogeneity among included studies. Results remained significant after adjustment for potential publication bias and when the analysis was repeated to exclude studies of largest weight.” (J. J. Biagi, jim.biagi@krcc.on.ca)

>>>PNN NewsWatch
* At FDA’s request, U.S. Marshals yesterday seized probiotic products from UAS Laboratories because they were being marketed as drugs, the agency said. The seized products include DDS Acidophilus, DDS Plus, Probioplus DDS, DDS Junior, and Cran-Gyn DDS, in capsule, powder, and tablet forms. FDA said it had warned UAS Laboratories that its products were in violation of federal law. During a March 2011 inspection, the agency said it discovered that the company continued to make disease claims for the products.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 9, 2011 * Vol. 18, No. 111
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 9 issue of the New England Journal of Medicine (2011; 364).
Hepatitis C Outcomes with Specially Trained Primary Care Providers: An educational program delivered by videoconference can improve outcomes in patients with hepatitis C virus (HCV) infection when managed by primary care providers, researchers report (pp. 2199–207). The Extension for Community Healthcare Outcomes (ECHO) model was used train primary care providers in 21 rural areas to manage complex diseases, and results were compared with care at the University of New Mexico (UNM) HCV clinic. For 407 patients with HCV infection, these outcomes were noted: “A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, −9.2 to 10.7; P = 0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P = 0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites.” (S. Arora, sarora@salud.unm.edu)

>>>Cardiology Report
Source:
June 14 issue of the Journal of the American College of Cardiology (2011; 57).
Teamwork, Leadership During Codes: The complex but critical interactions among team members during cardiopulmonary resuscitation are dissected in a state-of-the-art paper (pp. 2381–8). The authors note that decades of efforts to educate health care workers about treatment algorithms have failed to improve the poor outcomes with CPR and that teams often deviate from these algorithms: “Emerging evidence suggests that in addition to technical skills of individual rescuers, human factors such as teamwork and leadership affect adherence to algorithms and hence the outcome of CPR.… Because logistical barriers make controlled measurement of team interaction in the earliest moments of real-life resuscitations challenging, our review focuses mainly on high-fidelity human simulator studies. This technique allows in-depth investigation of complex human interactions using precise and reproducible methods. It also removes variability in the clinical parameters of resuscitation, thus letting researchers study human factors and team interactions without confounding by clinical variability from resuscitation to resuscitation. Research has shown that a prolonged process of team building and poor leadership behavior are associated with significant shortcomings in CPR. Teamwork and leadership training have been shown to improve subsequent team performance during resuscitation and have recently been included in guidelines for advanced life support courses. We propose that further studies on the effects of team interactions on performance of complex medical emergency interventions such as resuscitation are needed. Future efforts to better understand the influence of team factors (e.g., team member status, team hierarchy, handling of human errors), individual factors (e.g., sex differences, perceived stress), and external factors (e.g., equipment, algorithms, institutional characteristics) on team performance in resuscitation situations are critical to improve CPR performance and medical outcomes of patients.” (S. Hunziker, HunikerS@post.harvard.edu)

>>>PNN NewsWatch
* Simvastatin dosage restrictions were announced by FDA yesterday, along additional contraindications concerning use of the drug with certain other medications or above certain doses with other drugs. Simvastatin 80 mg should be used only in patients who have been taking this dose for 12 months or more without evidence of myopathy, FDA said. Simvastatin 80 mg should not be started in new patients, including patients already taking lower doses of the drug, the agency added. FDA said simvastatin should never be used with posaconazole, and it moved three drugs from a “do not exceed simvastatin 10 mg” category to an absolute contraindication (gemfibrozil, cyclosporine, and danazol). Dosing limits for simvastatin were lowered for amiodarone, verapamil, and diltiazem (now 10 mg daily) and added for amlodipine and ranolazine (20 mg daily).

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 10, 2011 * Vol. 18, No. 112
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
June issue of Chest (2011; 139).
Nonphysicians in ICUs: Daytime use of nonphysician providers is safe and effective in intensive-care units, a study shows (pp. 1347–53). In two medical ICUs in one hospital, care provided in one unit by nurse practitioners and physician assistants (MICU-NP/PA) was compared with outcomes from a unit staffed by medical residents (MICU-RES). Retrospective results for 590 daytime admissions showed the following: “Mortality probability model III (MPM0-III) predicted mortality was similar (P = .14). There was no significant difference in hospital mortality (32.1% for MICU-NP/PA vs 32.3% for MICU-RES, P = .96), MICU [length of stay (LOS)] (4.22 ± 2.51 days for MICU-NP/PA vs 4.44 ± 3.10 days for MICU-RES, P = .59), or hospital LOS (14.01 ± 2.92 days for MICU-NP/PA vs 13.74 ± 2.94 days for MICU-RES, P = .86). Discharge to a skilled care facility (vs home) was similar (37.1% for MICU-NP/PA vs 32.5% for MICU-RES, P = .34). After multivariate adjustment, MICU staffing type was not associated with hospital mortality (P = .26), MICU LOS (P = .29), hospital LOS (P = .19), or posthospital discharge destination (P = .90).” (H. B. Gershengorn, hgershengorn@chpnet.org)
Rapid Response Teams for Codes: At an academic hospital, implementation of rapid response teams (RRTs) did not alter code rates or outcomes in the ensuing 27 months, researchers report (pp. 1361–7). Results of a retrospective cohort study showed: “We analyzed 16,244 nonobstetrics hospital admissions and 70,208 patient days in the control period and 45,145 nonobstetrics hospital admissions and 161,097 patient days after the RRT was implemented. The RRT was activated 1,206 times (7.7 calls per 1,000 patient days). There was no difference in the code rate (0.83 vs 0.98 per 1,000 patient days, P = .3). There was a modest but nonsustained improvement in nonobstetrics hospital mortality during the study period (2.40% vs 2.15%; P = .05), which could not be explained by the RRT effect on code rates. The mortality was 2.40% in the control group and 2.06%, 1.94%, and 2.46%, respectively, during the next three consecutive 9-month intervals.” (G. Sharma, gulshan.sharma@utmb.edu)

>>>Nephrology Report
Source:
June issue of the American Journal of Kidney Diseases (2011; 57).
Biomarkers for Acute Kidney Injury: Finding a better marker than serum creatinine for acute kidney injury (AKI) remains a challenge, according to authors of a review article (pp. 930–40): “As a marker for changing kidney function rather than frank kidney injury, creatinine level lacks sensitivity and specificity for the diagnosis of AKI and shows significant lag time before increasing after injury. It has been unclear whether the failure to translate promising results from animal studies in AKI into successful human trials has been caused by lack of therapeutic efficacy or inappropriately delayed application of the intervention. Multiple novel biomarkers with the potential to revolutionize the timing and accuracy of the diagnosis of AKI currently are under investigation. We have chosen to use one of these biomarkers, interleukin 18 (IL-18), to show the ways in which biomarkers at present can supplement the conventional management of AKI. IL-18 is well suited for this analysis because it is both a mediator of and marker for AKI. We describe 2 cases in which reliance on serum creatinine level for the diagnosis of AKI led to diagnostic and management uncertainty. In the context of these cases, we discuss how IL-18 and other biomarkers can facilitate earlier detection, enhance the differential diagnosis, and allow more prescient prognosis. Additionally, we describe the potential role for biomarkers in prospective trial design and discuss the utility of biomarkers in facilitating adequate powering of trials through more accurate characterization of cases and controls.” (C. R. Parikh, chirag.parikh@yale.edu)

>>>PNN NewsWatch
* Finasteride and dutasteride increase men’s risk of developing high-grade prostate cancer, FDA cautioned yesterday. After analyzing Prostate Cancer Prevention Trial (PCPT) and Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial findings, FDA added new safety information to the Warnings and Precautions sections of labeling for the 5-alpha reductase inhibitors.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 13, 2011 * Vol. 18, No. 113
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 11 issue of Lancet (2011; 377).
Terutroban in Cerebral Ischemic Events: In a noninferiority trial, terutroban and aspirin had similar efficacy outcomes in patients with ischemic stroke in the past 3 months or transient ischemic attacks (TIAs) in the past 8 days (pp. 2013–22). The new agent, a selective thromboxane-prostaglandin receptor antagonist, showed increased minor bleeding. Compared in the PERFORM trial, terutroban 30 mg/d and aspirin 100 mg/d yielded these results based on a primary efficacy composite endpoint of fatal or nonfatal ischemic stroke, fatal or nonfatal myocardial infarction, or other vascular death (excluding hemorrhagic death): “9,562 patients were assigned to terutroban (9,556 analysed) and 9,558 to aspirin (9,544 analysed); mean follow-up was 28.3 months (SD 7.7). The primary endpoint occurred in 1,091 (11%) patients receiving terutroban and 1,062 (11%) receiving aspirin (hazard ratio [HR] 1.02, 95% CI 0.94–1.12). There was no evidence of a difference between terutroban and aspirin for the secondary or tertiary endpoints. We recorded some increase in minor bleedings with terutroban compared with aspirin (1,147 [12%] vs 1,045 [11%]; HR 1.11, 95% CI 1.02–1.21), but no significant differences in other safety endpoints.” (M-G Bousser, mg.bousser@lrb.aphp.fr)
Dexamethasone & Hospital LOS in Community-Acquired Pneumonia: Added to antibiotic treatment in nonimmunocompromized patients with community-acquired pneumonia, dexamethasone significantly lowers hospital length of stay (LOS), researchers report (pp. 2023–30). Adults with community-acquired pneumonia who presented to two Dutch emergency departments received intravenous dexamethasone 5 mg or placebo once daily for 4 days, beginning on admission, with these results: “Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4–5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6.5 days (IQR 5.0–9.0) in the dexamethasone group compared with 7.5 days (5.3–11.5) in the placebo group (95% CI of difference in medians 0–2 days; p = 0.0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p < 0.0001).” (S. C. A. Meijvis, s.meijvis@antoniusziekenhuis.nl)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
Salicylic Acid v. Cryotherapy for Plantar Warts: In 240 adolescents and adults, salicylic acid and cryotherapy were equally effective in clearing plantar warts, an open-label trial shows (d3271). At clinics in the U.K., cryotherapy using liquid nitrogen administered by professionals in up to four treatments 2–3 weeks apart was compared with patient-administered 50% salicylic acid, with these results: “There was no evidence of a difference between the salicylic acid and cryotherapy groups in the proportions of participants with complete clearance of all plantar warts at 12 weeks (17/119 (14%) v 15/110 (14%), difference 0.65% (95% CI –8.33 to 9.63), P = 0.89). The results did not change when the analysis was repeated but with adjustment for age, whether the wart had been treated previously, and type of plantar wart or for patients’ preferences at baseline. There was no evidence of a difference between the salicylic acid and cryotherapy groups in self reported clearance of plantar warts at six months (29/95 (31%) v 33/98 (34%), difference –3.15% (–16.31 to 10.02), P = 0.64) or in time to clearance (hazard ratio 0.80 (95% CI 0.51 to 1.25), P = 0.33). There was also no evidence of a difference in the number of plantar warts at 12 weeks (incident rate ratio 1.08 (0.81 to 1.43), P = 0.62).” (S. Cockayne, sarah.cockayne@york.ac.uk)

>>>PNN JournalWatch
* Estimated Economic Benefits During the ‘Decade Of Vaccines’ Include Treatment Savings, Gains in Labor Productivity, in Health Affairs, 2011; 30: 1021–8. (M. L. Stack, mstack@jhsph.edu)
* Country-to-Country Transfer of Patients and the Risk of Multi-Resistant Bacterial Infection, in
Clinical Infectious Diseases, 2011; 53: 49–56. (B. Rogers, benrogers@uq.edu.au)

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.


PNN Pharmacotherapy Line
June 14, 2011 * Vol. 18, No. 114
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 13 issue of Archives of Internal Medicine (2011; 171).
Acid Suppression & GI Bleeding in Noncritically Ill Patients: The number needed to treat is relatively high for preventing gastrointestinal bleeding through use of acid-suppressing medications in hospitalized patients who are not critically ill, according to a study that also found nosocomial GI bleeding rare outside intensive care settings (pp. 991–7). At an academic medical center, a pharmacoepidemiological study examined adult patients admitted in 2004–07 and hospitalized for 3 days or more. Proton-pump inhibitor or histamine-2-receptor antagonist use showed these effects on nosocomial GI bleeding: “The final cohort included 78,394 admissions (median age, 56 years; 41% men). Acid-suppressive medication was ordered in 59% of admissions, and nosocomial GI bleeding occurred in 224 admissions (0.29%). After matching on the propensity score, the adjusted odds ratio for nosocomial GI bleeding in the group exposed to acid-suppressive medication relative to the unexposed group was 0.63 (95% confidence interval, 0.42–0.93). The number needed to treat to prevent 1 episode of nosocomial GI bleeding was 770.” (S. J. Herzig, sherzig@bidmc.harvard.edu)
PPI–Alendronate Interaction: Patients lose the bone-protecting effects of alendronate when on concurrent proton-pump inhibitors, according to results of a register-based, open cohort study (pp. 998–1004) that was released in advance of print publication (see PNN, Feb. 15). While not designed to infer causality, the research provides these correlations in 38,088 new users of alendronate during a mean of 3.5 years of follow-up: “For hip fractures, there was statistically significant interaction with alendronate for PPI use (P < .05). The treatment response associated with complete refill compliance to alendronate was a 39% risk reduction (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.52–0.71; P < .001) in patients who were not PPI users, while the risk reduction in concurrent PPI users was not significant (19%; HR, 0.81; 95% CI, 0.64–1.01; P = .06). The attenuation of the risk reduction was dose and age dependent. In contrast, there was no significant impact of concurrent use of histamine H2 receptor blockers.” (B. Abrahamsen, b.abrahamsen@physician.dk)
Test of Tool for Preventing Adverse Drug Events in Older Hospitalized Patients: Avoidable adverse drug events (ADEs) that cause or contribute to hospitalization can be identified through use of the new STOPP (Screening Tool of Older Persons’ potentially inappropriate Prescriptions) criteria, researchers report (pp. 1013–9). While previous studies have shown that the popular Beers’ criteria have not consistently linked potentially inappropriate medicines (PIMs) with avoidable ADEs, the STOPP criteria showed these effects in 600 consecutive patients aged 65 years or older who were admitted to a university hospital over a 4-month interval: “A total of 329 ADEs were detected in 158 of 600 patients (26.3%); 219 of 329 ADEs (66.6%) were considered causal or contributory to admission. Of the 219 ADEs, 151 (68.9%) considered causal or contributory to admission were avoidable or potentially avoidable. After adjusting for age, sex, comorbidity, dementia, baseline activities of daily living function, and number of medications, the likelihood of a serious avoidable ADE increased significantly when STOPP PIMs were prescribed (odds ratio, 1.847; 95% confidence interval [CI], 1.506–2.264; P < .001); prescription of Beers criteria PIMs did not significantly increase ADE risk (odds ratio, 1.276; 95% CI, 0.945–1.722; P = .11).” (D. O’Mahony, enis.OMahony@hse.ie">Denis.OMahony@hse.ie)

>>>PNN NewsWatch
* FDA has approved ezogabine (Potiga, Valeant Pharmaceuticals and GlaxoSmithKline) for adjunct treatment of partial seizures in adults. The drug is the first neuronal potassium channel opener developed for the treatment of epilepsy, FDA said. Ezogabine has been associated with urinary retention and several neuropsychiatric adverse effects. Its most common adverse effects include dizziness, fatigue, confusion, vertigo, tremor, problems with coordination, double vision, problems paying attention, memory impairment, lack of strength, and double vision.
* FDA has warned of medication errors caused by confusion between
risperidone and ropinirole. The agency also announced new labeling for Merck OTC products designed to improve readability.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 15, 2011 * Vol. 18, No. 115
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 15 issue of JAMA (2011; 305).
Malpractice Claims: Lessons for medicine are evident in an analysis of paid claims for malpractice in inpatient and outpatient settings (pp. 2427–31). Claims paid on behalf of physicians were analyzed retrospectively using data from the National Practitioner Data Bank: “In 2009, there were 10,739 malpractice claims paid on behalf of physicians. Of these paid claims, 4,910 (47.6%; 95% confidence interval [CI], 46.6%–48.5%) were for events in the inpatient setting, 4,448 (43.1%; 95% CI, 42.1%–44.0%) were for events in the outpatient setting, and 966 (9.4%; 95% CI, 8.8%–9.9%) involved events in both settings. The proportion of payments for events in the outpatient setting increased by a small but statistically significant amount, from 41.7% (95% CI, 40.9%–42.6%) in 2005 to 43.1% (95% CI, 42.1%–44.0%) in 2009 (P < .001 for trend across years). In the outpatient setting, the most common reason for a paid claim was diagnostic (45.9%; 95% CI, 44.4%–47.4%), whereas in the inpatient setting the most common reason was surgical (34.1%; 95% CI, 32.8%–35.4%). Major injury and death were the 2 most common outcomes in both settings. Mean payment amount for events in the inpatient setting was significantly higher than in the outpatient setting ($362,965; 95% CI, $348,192–$377,738 vs $290,111; 95% CI, $278,289–$301,934; P < .001).” (T. F. Bishop, tlfernan@med.cornell.edu)
Writing that malpractice in ambulatory settings is “an increasing and underrecognized problem,” editorialists call for more study of this trend (
pp. 2464–5): “In the end, much remains to be learned about malpractice risk in the ambulatory setting and it is likely that with the continued shift to care delivery in ambulatory settings, the medical home, and the growth of hospital-based ambulatory networks, the risk of malpractice in the ambulatory setting will continue to increase. The findings by Bishop et al should prompt additional research and discussion about what an effective ambulatory risk management program should look like at both local and national levels. Analysis of malpractice claims is one piece of this process and will help provide a unique window into opportunities to make patient care safer for everyone.” (G. Zuccotti, gzuccotti@partners.org)
Ambulance Diversion & MI Survival: In four populous counties in California, diversion of ambulances to different emergency departments (EDs) was associated with increased 30-day, 90-day, 9-month, and 1-year mortality among Medicare patients with acute myocardial infarction (pp. 2440–7). The situation arises when an ED has to temporarily close ambulance traffic because of factors such as excessive number of patients already awaiting care; the study showed this happened for a mean of 7.9 ± 6.2 hours per day in these counties. When diversion reached 12 hours, MI survival rates declined. (Y-C Shen, yshen@nps.edu)

>>>PNN NewsWatch
* Changes are on the way for labeling of sunscreens, FDA said yesterday. “Broad spectrum” protection against both ultraviolet A and UVB will be afforded by products with sun protection factor (SPF) values of 15 or higher. Products with SPF values of more than 50 will be labeled as “SPF 50+” rather than with a specific number, as FDA says evidence does not support any additional protection with values above 50, compared with those with SPF ratings of 50.
* Meeting in Denver, the
ASHP House of Delegates has finalized policies on a number of topics, including research on medical use of marijuana, agricultural use of hormone and pro-hormone therapies, direct-to-consumer clinical genetic tests, pharmacogenomics, safe and effective use of IV promethazine, pain management, quality of pharmacy education and expansion of colleges of pharmacy, residency equivalency (with clinical experience), pharmacy internships, state-specific requirements for pharmacist continuing education, innovative residency models, and professional socialization. Daniel M. Ashby of Johns Hopkins Hospital received the 2011 Harvey A. K. Whiteny Lecture Award at a banquet last night, addressing the topic, “Permission Granted” and calling for emergence of an “attending pharmacist” in the integrated practice model envisioned in the Society’s Pharmacy Practice Model Initiative. The ASHP meeting closes today.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 16, 2011 * Vol. 18, No. 116
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 16 issue of the New England Journal of Medicine (2011; 364).
Intussusception & Rotavirus Vaccination: Deaths and hospitalizations averted through use of the new monovalent rotavirus vaccine (RV1) far exceed cases of iatrogenic intussusception, according to data from Mexico and Brazil (pp. 2283–92). Case-series and case–control analysis at 69 hospitals in the two countries showed the following: “We enrolled 615 case patients (285 in Mexico and 330 in Brazil) and 2,050 controls. An increased risk of intussusception 1 to 7 days after the first dose of RV1 was identified among infants in Mexico with the use of both the case-series method (incidence ratio, 5.3; 95% confidence interval [CI], 3.0 to 9.3) and the case–control method (odds ratio, 5.8; 95% CI, 2.6 to 13.0). No significant risk was found after the first dose among infants in Brazil, but an increased risk, albeit smaller than that seen after the first dose in Mexico—an increase by a factor of 1.9 to 2.6—was seen 1 to 7 days after the second dose. A combined annual excess of 96 cases of intussusception in Mexico (approximately 1 per 51,000 infants) and in Brazil (approximately 1 per 68,000 infants) and of 5 deaths due to intussusception was attributable to RV1. However, RV1 prevented approximately 80,000 hospitalizations and 1,300 deaths from diarrhea each year in these two countries.” (M. M. Patel, mpatel@cdc.gov)
An editorialist calls for increased efforts to demonstrate to the public that benefits of vaccines far outweigh their adverse effects (
pp. 2354–5): “It is crucial that the medical community in general, and the vaccine establishment in particular, work to better educate the public to the fact that virtually all beneficial interventions, including vaccination, come with some risk and that the key issue is to ensure that the ratio of benefit to risk is most favorable.… Rotavirus infection is now a rare cause of death in the United States but remains a very common cause of hospitalization and physician visits. Intussusception is also a rare cause of death in the United States and other developed countries. Given the low rates of intussusception associated with rotavirus vaccine that were observed in Mexico and Brazil, as well as the possibility that rotavirus vaccination might actually reduce the absolute rate of intussusception, it seems both appropriate and advisable to continue to recommend the rotavirus vaccine for children in both the developed and the developing world, on the basis of the increasingly well documented and substantial benefits.” (H. B. Greenberg)
Vaccine-Derived Poliomyelitis: A case of vaccine-related poliomyelitis occurring 12 years after exposure is presented (pp. 2316–23): “A 44-year-old woman with long-standing common variable immunodeficiency who was receiving intravenous immune globulin suddenly had paralysis of all four limbs and the respiratory muscles, resulting in death. Type 2 vaccine-derived poliovirus was isolated from stool. The viral capsid protein VP1 region had diverged from the vaccine strain at 12.3% of nucleotide positions, and the two attenuating substitutions had reverted to the wild-type sequence. Infection probably occurred 11.9 years earlier (95% confidence interval [CI], 10.9 to 13.2), when her child received the oral poliovirus vaccine. No secondary cases were identified among close contacts or 2,038 screened health care workers. Patients with common variable immunodeficiency can be chronically infected with poliovirus, and poliomyelitis can develop despite treatment with intravenous immune globulin.” (A. S. DeVries, aaron.devries@state.mn.us)

>>>PNN NewsWatch
* Pioglitazone used for more than 1 year may be associated with an increased risk of bladder cancer, FDA said yesterday. The implicating data come from a 5-year interim analysis of an ongoing 10-year epidemiologic study. While the 5-year results showed no overall increased risk of bladder cancer with pioglitazone use, FDA said an increased risk of bladder cancer was noted among patients with the longest exposure to pioglitazone and in those exposed to the highest cumulative dose of pioglitazone. Information about this risk will be added to the Warnings and Precautions section of the label for pioglitazone-containing medicines. The patient Medication Guide for these medicines will also be revised.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 17, 2011 * Vol. 18, No. 117
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
June issue of Arthritis & Rheumatism (2011; 63).
Risks with Early Anti-TNF Therapy in RA: In contrast to previously reported increases in risk of serious infections and malignancy in patients with rheumatoid arthritis treated with anti–tumor necrosis factor (anti-TNF) therapy, a meta-analysis shows those drugs are safer in treatment-naive patients with early disease (pp. 1479–85). Literature through summer 2009 showed these results in studies of patients with early RA who had not received prior therapy with disease-modifying antirheumatic drugs (DMARDs) or methotrexate (MTX): “A pooled odds ratio (OR) … was calculated for serious infections (requiring hospitalization) and malignancies, comparing anti-TNF therapy to MTX control. The pooled OR for serious infections was 1.28 (95% confidence interval [95% CI] 0.82–2.00) and that for malignancies was 1.08 (95% CI 0.50–2.32). There was no significant difference in either the rate of serious infections or the rate of malignancies between the anti-TNF therapy group and the control group.” (A. E. Thompson, andy.thompson@sjhc.london.on.ca)
Effects of RA Drugs on Response to Influenza Vaccine: Two doses of influenza vaccine are needed to achieve adequate immunologic responses to influenza vaccine in patients with rheumatoid arthritis, spondylarthritis, and other inflammatory rheumatic diseases who are receiving synthetic or biologic disease-modifying antirheumatic drugs, a study shows (pp. 1486–96). In 138 control participants and 173 patients with rheumatic diseases, one or two doses, respectively, of adjuvanted influenza A/09/H1N1 vaccine produced these results: “Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the [geometric mean titers (GMTs)] and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P < 0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease-modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor alpha antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity.” (C. Gabay, cem.gabay@hcuge.ch)

>>>PNN NewsWatch
* Belatacept (Nulojix, Bristol-Myers Squibb), the first selective T-cell costimulation blocker, has been approved by FDA for the prophylaxis of organ rejection in adult patients receiving a kidney transplant, in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids.In two open-label randomized, Phase III studies of more than 1,200 patients, belatacept was safe and effective for prevention of acute organ rejection. The drug carries a boxed warning about increased risk of post-transplant lymphoproliferative disorder (PTLD). Because the risk of PTLD is higher in transplant patients who have never been exposed to Epstein–Barr virus (EBV), patients should be tested for EBV and should only receive belatacept if the test is positive. Patients on belatacept also have an increased risk of serious infections and other cancers similar to that seen with other immunosuppressants. Common adverse reactions with belatacept include anemia, constipation, kidney or bladder infection, and swollen legs, ankles, or feet. All transplant patients should limit the amount of time spent in sunlight because of the risk of skin cancer and should not receive live vaccines because of the risk of infection.
*
Varenicline (Chantix, Pfizer) use may be associated with a small increased risk of certain cardiovascular adverse events in patients who have cardiovascular disease, FDA said yesterday. A revised medication guide will warn of this risk. FDA said a randomized clinical trial of 700 smokers with cardiovascular disease showed cardiovascular adverse events to be infrequent overall. But certain events, including myocardial infarction, were reported more frequently in patients treated with varenicline than in patients treated with placebo.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 20, 2011 * Vol. 18, No. 118
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 18 issue of Lancet (2011; 377).
Cervical Abnormalities After HPV Vaccination: In Victoria, Australia, the incidence of high-grade cervical abnormalities (HGAs) declined in the 3 years after implementation of populationwide human papillomavirus (HPV) vaccination of girls and women, researchers report (HGAs (pp. 2085–92). Assessing the incidence of HGAs and low-grade cytological abnormalities (LGAs) in girls and women aged 12–26 years old between 2003 and 2009, the investigators found these patterns before and during the HPV program in 2007–09: “After the introduction of the vaccination programme, we recorded a decrease in the incidence of HGAs by 0.38% (95% CI 0.61–0.16) in girls younger than 18 years. This decrease was progressive and significantly different to the linear trend in incidence before introduction of the vaccination (incident rate ratio 1.14, 1.00–1.30, p = 0.05). No similar temporal decline was recorded for LGAs or in older age groups.” (J. M. L. Brotherton, jbrother@vcs.org.au)
Cetuximab in Advanced Colorectal Cancer: Limited benefits were identified when cetuximab was added to oxaliplatin-based chemotherapy in 1,630 patients with first-line treatment of advanced colorectal cancer, a study shows (pp. 2103–14). Overall survival in patients with KRAS wild-type tumors showed these results for oxaliplatin and fluoropyrimidine chemotherapy without (arm A) and with (arm B) cetuximab: “Tumour samples from 1,316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n = 367; arm B, n = 362), overall survival did not differ between treatment groups (median survival 17.9 months [IQR 10.3–29.2] in the control group vs 17.0 months [9.4–30.1] in the cetuximab group; HR 1.04, 95% CI 0.87–1.23, p = 0.67). Similarly, there was no effect on progression-free survival (8.6 months [IQR 5.0–12.5] in the control group vs 8.6 months [5.1–13.8] in the cetuximab group; HR 0.96, 0.82–1.12, p = 0.60). Overall response rate increased from 57% (n = 209) with chemotherapy alone to 64% (n = 232) with addition of cetuximab (p = 0.049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: KRAS mutant, 8.8 months (IQR 4.5–27.4); KRAS mutant, 14.4 months (8.5–24.0); all wild-type, 20.1 months (11.5–31.7).” (R. Kaplan, rk@ctu.mrc.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 342).
Ticagrelor v. Clopidogrel in Acute Coronary Syndromes: PLATO results showing a benefit of ticagrelor over clopidogrel in patients with acute coronary syndrome being managed noninvasively are confirmed in a study of 5,216 patients in 43 countries (d3527): “2,183 (41.9%) patients had coronary angiography during their initial hospital admission, 1,065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3,143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point [composite end point of cardiovascular death, myocardial infarction, and stroke] was lower with ticagrelor than with clopidogrel (12.0% (n = 295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P = 0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P = 0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P = 0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P = 0.10) was numerically higher with ticagrelor than with clopidogrel.” (S. James, Stefan.James@ucr.uu.se)

>>>PNN JournalWatch
* Improving Disposition Outcomes for Patients in a Geriatric Skilled Nursing Facility, in Journal of the American Geriatrics Society, 2011; 59: 1130–6. (R. Berkowitz, rberkowitz@hsl.harvard.edu)
* Gene Therapy for Primary Immunodeficiencies: Looking Ahead, Toward Gene Correction, in
Journal of Allergy and Clinical Immunology, 2011; 127: 1344–50. (L. D. Notarangelo, luigi.notarangelo@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 21, 2011 * Vol. 18, No. 119
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 21 issue of the Annals of Internal Medicine (2011; 154).
Lung Function with Sirolimus in Lymphangioleiomyomatosis: Sirolimus therapy is associated with pulmonary benefits in women with lymphangioleiomyomatosis (LAM), a condition that causes cystic lung destruction, chylous effusions, lymphangioleiomyomas, and angiomyolipomas, a study shows (pp. 797–805). In 19 patients with LAM, lung function and size of chylous effusions and lymphangioleiomyomas were assessed before and during sirolimus therapy, with these results: “Over a mean of 2.5 years before beginning sirolimus therapy, the mean (± SE) FEV1 decreased by 2.8% ± 0.8% predicted and diffusing capacity of the lung for carbon monoxide (DLCO) decreased by 4.8% ± 0.9% predicted per year. In contrast, over a mean of 2.6 years of sirolimus therapy, the mean (± SE) FEV1 increased by 1.8% ± 0.5% predicted and DLCO increased by 0.8% ± 0.5% predicted per year (P < 0.001). After beginning sirolimus therapy, 12 patients with chylous effusions and 11 patients with lymphangioleiomyomas experienced almost complete resolution of these conditions. In 2 of the 12 patients, sirolimus therapy enabled discontinuation of pleural fluid drainage.” (A. M. Taveira-DaSilva, dasilvaa@nhlbi.nih.gov)
Discussing this and a related article on tuberous sclerosis complex (TSC;
pp. 806–13; T. N. Darling, tdarling@usuhs.mil), an editorialist notes progress but writes that research is nowhere near the ultimate goal for LAM and TSC (pp. 840–1): “Critical knowledge gaps in the pathogenesis of LAM include the possibility that other genes and signaling networks are involved and the uncertain role of estrogen-mediated events. Research in these areas is likely to reveal additional targets for the therapy of both sporadic and TSC-associated LAM. Therefore, while celebrating remarkable recent progress in therapy for LAM and TSC, we must immediately turn our attention to the next advances. To paraphrase Robert Frost, we have miles to go and promises to keep to persons with these devastating diseases.” (E. Henske, ehenske@partners.org)
Thiopurine S-Methyltransferase Activity During Thiopurine Therapy: While confirming leukopenia and myelotoxicity in patients with reduced thiopurine S-methyltransferase (TPMT) enzymatic activity or variant genotype, a systematic review fails to document effectiveness of TPMT pretesting before thiopurine-based treatment in patients with chronic inflammatory diseases (pp. 814–23). Looking at the literature on both adults and children, the investigators found: “54 observational studies and 1 randomized, controlled trial were included. Insufficient evidence addressed the effectiveness of pretesting. Genotyping sensitivity to identify patients with low and intermediate TPMT enzymatic activity ranged from 70.33% to 86.15% (lower-bound 95% CI, 54.52% to 70.88%; upper-bound CI, 78.50% to 96.33%). Sparse data precluded estimation of genotype sensitivity to identify patients with low to absent enzymatic activity. Genotyping specificity approached 100%. Compared with noncarriers, heterozygous and homozygous genotypes were both associated with leukopenia (odds ratios, 4.29 [CI, 2.67 to 6.89] and 20.84 [CI, 3.42 to 126.89], respectively). Compared with intermediate or normal activity, low TPMT enzymatic activity was significantly associated with myelotoxicity and leukopenia.” (M. T. Ansari, moansari@ohri.ca)
Enhancing Rx Drug Innovation, Adoption: Five ways of improving prescription drug innovation and hastening the adoption of new therapies in the U.S. are discussed (pp. 833–7): “These changes range from increasing the evidence required for U.S. Food and Drug Administration approval to modifying the structure of drug reimbursement. Despite the challenges of policy implementation, the United States has a long history of successfully improving the societal value and safe use of prescription medicines.” (G. C. Alexander, galexand@uchicago.edu)

>>>PNN NewsWatch
* FDA yesterday approved the first generic versions of levofloxacin, said that it was examining ways of improving consumer understanding of ads for prescription drugs, issued a draft guidance for an early version of an artificial pancreas system, and unveiled a new global strategy for ensuring the safety and quality of imported drug products.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 22, 2011 * Vol. 18, No. 120
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 22 issue of JAMA (2011; 305).
Diabetes & RA/Psoriasis Meds: Certain medications used commonly for rheumatoid arthritis (RA) or psoriasis may help prevent development of insulin resistance and diabetes, researchers report (pp. 2525–31). In a retrospective cohort study of 121,280 patients with a diagnosis of RA or psoriasis, these patterns were observed with respect to treatment with disease-modifying antirheumatic drugs (DMARDs), tumor necrosis factor (TNF) inhibitors, methotrexate, and hydroxychloroquine: “The study cohort consisted of 13,905 participants with 22,493 treatment episodes starting 1 of the categories of DMARD regimens between January 1996 and June 2008. New diabetes cases and respective incidence rates per 1,000 person–years were: other nonbiologic DMARDs (55 cases among 3,993 treatment episodes; rate, 50.2; 95% confidence interval [CI], 47.3–53.2); TNF inhibitors (80 cases among 4,623 treatment episodes; rate, 19.7; 95% CI, 19.1–20.3); methotrexate (82 cases among 8,195 treatment episodes; rate, 23.8; 95% CI, 23.0–24.6); and hydroxychloroquine (50 cases among 5,682 treatment episodes; rate, 22.2; 95% CI, 21.3–23.1). The multivariate adjusted hazard ratios for DM were 0.62 (95% CI, 0.42–0.91) for TNF inhibitors, 0.77 (95% CI, 0.53–1.13) for methotrexate, and 0.54 (95% CI, 0.36–0.80) for hydroxychloroquine compared with other nonbiologic DMARDS.” (D. H. Solomon, dsolomon@partners.org)
The possibility that hydroxychloroquine and anti-TNF agents may have dual effects is discussed by editorialists (
pp. 2573–4): “Prospective trials are needed to confirm the observational data and clarify which patients may benefit from these possible pleiotropic effects of specific anti-inflammatories. If hydroxychloroquine and anti-TNF agents should truly enable 2 complex disease processes to be addressed with a single intervention, it will be crucial to investigate how much of their potential antidiabetic effects would add to good disease control, the durability of these effects, and the timing of treatment. Because even if treatment of chronic inflammatory disease can reduce the risk of diabetes, clinicians still will have to learn how to use specific anti-inflammatory agents to achieve optimal outcomes for both conditions.” (T. Bongartz, bongartz.tim@mayo.edu)
Diabetes & Statin Therapy: Intensive lipids therapy with high doses of statins is associated with increased risk of new-onset diabetes, compared with moderate or low doses of the drugs, according to a systematic review and meta-analysis (pp. 2556–64): “In 5 statin trials with 32,752 participants without diabetes at baseline, 2,749 developed diabetes (1,449 assigned intensive-dose therapy, 1,300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1,000 patient–years) and 6,684 experienced cardiovascular events (3,134 and 3,550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1,000 patient–years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04–1.22; I2 = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75–0.94; I2 = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events.” (D. Preiss, david.preiss@glasgow.ac.uk)
Smoking & Prostate Cancer: Men who are smokers at the time of diagnosis of prostate cancer have significantly higher overall and cardiovascular mortality rates, a study shows, while those who have stopped smoking for 10 years or more have mortality rates similar to men who have never smoked (pp. 2548–55). The prospective observational Health Professionals Follow-Up Study included 5,366 men diagnosed with prostate cancer in 1986–2006. Based on 524 deaths due to prostate cancer and 416 deaths from cardiovascular disease among these men, the investigators found hazard ratios of 1.61 for prostate cancer mortality, 2.13 for cardiovascular mortality, and 2.28 for total mortality in current versus never smokers. Biochemical recurrence was also greater in current smokers, with an HR of 1.47. (S. A. Kenfield, skenfiel@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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 23, 2011 * Vol. 18, No. 121
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 23 New England Journal of Medicine (2011; 364).
Exemestane & Breast-Cancer Prevention: Compared with placebo in postmenopausal women with moderate risks of breast cancer, exemestane significantly reduced invasive breast cancers over a median of nearly 3 years, researchers report (pp. 2381–91). In a trial designed to detect a 65% relative risk reduction in invasive breast cancer, postmenopausal women aged 35 years or older were included if they had at least one risk factor. Results showed: “A total of 4,560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P = 0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P = 0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = 0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. Minimal quality-of-life differences were observed.” (P. E. Goss, pgoss@partners.org)
Editorialists write that these results make exemestane a viable third choice (with tamoxifen and raloxifene) for chemoprevention of breast cancer (
pp. 2463–4): “Women and practitioners now have three options for breast cancer chemoprevention.… Breast cancer is the second most common cause of death from cancer and one of the most feared diagnoses for women in the United States. We have the knowledge and tools to reduce its incidence today. We have run out of excuses. What are we waiting for?” (N. E. Davidson)
Telaprevir & HCV Infection: Phase III trial results are reported for the recently approved hepatitis C virus (HCV) protease inhibitor telaprevir (see PNN, May 24).
Telaprevir improved virologic response rates in 1,088 patients with treatment-naive HCV infection (
pp. 2405–16). In the T12PR group, patients received telaprevir with peginterferon alfa-2a and ribavirin for 12 weeks. Comparisons were made with telaprevir with peginterferon–ribavirin for 8 weeks and placebo with peginterferon–ribavirin for 4 weeks (T8PR group) and placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks of peginterferon–ribavirin (PR group): “Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P < 0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon–ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group.” (I. M. Jacobson, imj2001@med.cornell.edu)
In patients with previously treated HCV infection, telaprevir plus peginterferon and ribavirin significantly improved rates of sustained virologic response (
pp. 2417–28). The Phase III trial included a T12PR48 group (telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks), T12PR48 group (4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks), and control group PR48 (peginterferon plus ribavirin for 48 weeks): “Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%).” (S. Zeuzem, zeuzem@em.uni-frankfurt.de)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 24, 2011 * Vol. 18, No. 122
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
July 15 issue of Clinical Infectious Diseases (2011; 53).
Vancomycin Dose Calculator in Hemodialysis: A vancomycin dose calculator designed to achieve trough levels of 15–20 mcg/mL provided accurate vancomycin maintenance doses in nearly 80% of patients based on their predialysis trough level, dry body weight, and time to next dialysis session, researchers report (pp. 124–9). A multivariate model, the vancomycin dose calculator (VDC), identified those three variables as accounting for 94.6% of the observed variance, the authors note, adding: “Maintenance dosing was accurate in 77.9% of patients, whereas major over- and underdosing were avoided in the remaining patients. The mean measured trough level of 16.5 mcg/mL was 5.6% lower than the mean predicted trough level of 17.5 mcg/mL. With regard to loading doses, a fixed loading dose of 20 mg/kg led to subtherapeutic trough levels in one-half of patients.” (S. J. Vandecasteele, stefaan.vandecasteele@azsintjan.be)
A second article reports use of weight-based loading doses of vancomycin and resulting initial predialysis concentrations in patients on hemodialysis (
pp. 164–6; H. P. Schlecht, hans.schlecht@drexelmed.edu)
Pneumococcal Disease Following Vaccine Introduction: Despite geographic variance in rates of invasive pneumococcal disease (IPD), introduction of the pneumococcal conjugate vaccine (PCV7) led to consistent disease reduction in the U.S., a study shows (pp. 137–43). IPD caused by serotypes not included in PCV7 were variable, according to data from 8 geographic areas that were under continuous surveillance in 1998–2009: “Reductions in rates of IPD ranged, by site, from 19 to 29.9 cases per 100,000 population during 1998–1999 to 11.2–18.0 cases per 100,000 population during 2009 (rate reduction, 5.1–15.3 cases per 100,000 population). Reductions in IPD rates among children aged <5 years ranged from 35.7 to 117.2 cases per 100,000 population across the sites. Reductions in rates of IPD due to PCV7 serotypes were seen in all age groups at all sites, ranging from 12 to 21.4 cases per 100,000 population during 1998–1999 to <2 cases per 100,000 population during 2009 (92%–98% reductions). Serotype 19A rates ranged from 0.4 to 1.5 cases per 100,000 population during 1998–1999 to 1.3 to 3.4 cases per 100,000 population during 2009 (rate difference, 0.9–2.8 cases per 100,000 population); modest increases were observed for most age groups across the sites. Rates of IPD due to all other serotypes ranged from 6.3 to 10.3 cases per 100,000 population during 1998–1999 to 8.3–13.6 cases per 100,000 population during 2009 (rate difference, −0.4 to 5.7 cases per 100,000 population). Across the sites, the greatest rate increases were seen in the 50–64 and >65 year age groups.” (J. Rosen, jrosen4@health.nyc.gov)

>>>Oncology Highlights
Source:
June 20 issue of the Journal of Clinical Oncology (2011; 29).
Copayments & Hormonal Adherence in Breast Cancer: Pharmacy and medical claims in the Medco database show an association between higher copayment amounts and poorer adherence and persistence with adjuvant aromatase inhibitors in women older than 50 with resected breast cancer (pp. 2534–42). Nonpersistence was a prescription supply gap of more than 45 days, while nonadherence was a medication possession ratio of less than 80% of eligible days. The relationship was strongest in older women, the authors explain, adding these details about the 2007–08 data: “Of 8,110 women younger than age 65 years, 1,721 (21.1%) were nonpersistent and 863 (10.6%) were nonadherent. Among 14,050 women age 65 years or older, 3,476 (24.7%) were nonpersistent and 1,248 (8.9%) were nonadherent. In a multivariate analysis, nonpersistence (ever/never) in both age groups was associated with older age, having a non-oncologist write the prescription, and having a higher number of other prescriptions. Compared with a co-payment of less than $30, a co-payment of $30 to $89.99 for a 90-day prescription was associated with less persistence in women age 65 years or older (odds ratio [OR], 0.69; 95% CI, 0.62 to 0.75) but not among women younger than age 65, although a co-payment of more than $90 was associated with less persistence both in women younger than age 65 (OR, 0.82; 95% CI, 0.72 to 0.94) and those age 65 years or older (OR, 0.72; 95% CI, 0.65 to 0.80). Similar results were seen with nonadherence.” (A. I. Neugut, ain1@columbia.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 27, 2011 * Vol. 18, No. 123
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 25 issue of Lancet (2011; 377).
Simvastatin/Ezetimibe in Chronic Kidney Disease: In 9,270 patients with chronic kidney disease, simvastatin 20 mg plus ezetimibe 10 mg daily reduced the incidence of major atherosclerotic events, report researchers in the Study of Heart and Renal Protection (pp. 2181–92). Based on a prespecified outcome of first major atherosclerotic event (nonfatal myocardial infarction or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure). the investigators found: “Allocation to simvastatin plus ezetimibe … produced a 17% proportional reduction in major atherosclerotic events (526 [11.3%] simvastatin plus ezetimibe vs 619 [13.4%] placebo; rate ratio [RR] 0.83, 95% CI 0.74–0.94; log-rank p = 0.0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4.6%] vs 230 [5.0%]; RR 0.92, 95% CI 0.76–1.11; p = 0.37) and there were significant reductions in non-haemorrhagic stroke (131 [2.8%] vs 174 [3.8%]; RR 0.75, 95% CI 0.60–0.94; p = 0.01) and arterial revascularisation procedures (284 [6.1%] vs 352 [7.6%]; RR 0.79, 95% CI 0.68–0.93; p = 0.0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10,000 patients per year of treatment with this combination (9 [0.2%] vs 5 [0.1%]). There was no evidence of excess risks of hepatitis (21 [0.5%] vs 18 [0.4%]), gallstones (106 [2.3%] vs 106 [2.3%]), or cancer (438 [9.4%] vs 439 [9.5%], p = 0.89) and there was no significant excess of death from any non-vascular cause (668 [14.4%] vs 612 [13.2%], p = 0.13).” (C. Baigent, sharpclinical@ctsu.ox.ac.uk)
Bivalirudin After PCI: In the HORIZONS-AMI trial, the effectiveness and safety of bivalirudin monotherapy were sustained for 3 years in patients with ST-segment elevation myocardial infarction who had percutaneous coronary intervention (pp. 2193–204): “Compared with 1,802 patients allocated to receive heparin plus a GPI, 1,800 patients allocated to bivalirudin monotherapy had lower rates of all-cause mortality (5.9% vs 7.7%, difference −1.9% [−3.5 to −0.2], HR 0.75 [0.58–0.97]; p = 0.03), cardiac mortality (2.9% vs 5.1%, −2.2% [−3.5 to −0.9], 0.56 [0.40–0.80]; p = 0.001), reinfarction (6.2% vs 8.2%, −1.9% [−3.7 to −0.2], 0.76 [0.59–0.99]; p = 0.04), and major bleeding not related to bypass graft surgery (6.9% vs 10.5%, −3.6% [−5.5 to −1.7], 0.64 [0.51–0.80]; p = 0.0001) at 3 years, with no significant differences in ischaemia-driven target vessel revascularisation, stent thrombosis, or composite adverse events. Compared with 749 patients who received a bare-metal stent, 2,257 patients who received a paclitaxel-eluting stent had lower rates of ischaemia-driven target lesion revascularisation (9.4% vs 15.1%, −5.7% [−8.6 to −2.7], 0.60 [0.48–0.76]; p < 0.0001) after 3 years, with no significant differences in the rates of death, reinfarction, stroke or stent thrombosis. Stent thrombosis was high (≥4.5%) in both groups.” (G. W. Stone, gs2184@columbia.edu)

>>>PNN NewsWatch
* More conservative dosing of erythropoietin-stimulating agents (ESAs) in patients with chronic kidney disease (CKD) is now in labeling for epoetin alfa and darbepoetin alfa, FDA said. ESAs dosed to hemoglobin levels greater than 11 g/dL in patients with CKD have been associated with increased risk of death, adverse cardiovascular reactions, and stroke, the label says, and a safe target hemoglobin level has not been identified. The ESA labels recommend starting treatment in CKD when hemoglobin levels are less than 10 g/dL, but no advice is given on how much lower levels should be when therapy is started or about target hemoglobin levels.

>>>PNN JournalWatch
* Components of a Cardioprotective Diet: New Insights, in Circulation, 2011; 123: 2870–91. (D. Mozaffarian, dmozaffa@hsph.harvard.edu)
* Coffee Consumption Is Associated with Response to Peginterferon and Ribavirin Therapy in Patients with Chronic Hepatitis C, in
Gastroenterology, 2011; 140: 1961–9. (N. D. Freedman, freedmanne@mail.nih.gov)
* Problem Neurology Residents: A National Survey, in
Neurology, 2011; 76: 2119–23. (D. S. Tabby, avid.Tabby@drexelmed.edu">David.Tabby@drexelmed.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 28, 2011 * Vol. 18, No. 124
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 27 issue of Archives of Internal Medicine (2011; 171).
Bupropion for Smoking Cessation in ACS: Bupropion support along with intensive nurse counseling failed to reduce smoking over the following year among 151 patients hospitalized for acute coronary syndromes (pp. 1055–60). Smoking abstinence showed these patterns in this double-blind, randomized trial of slow-release bupropion or placebo: “Abstinence rates at 3 months were 45% and 44% in the bupropion SR and placebo groups, respectively (P = .99); 37% vs 42% (P = .61) at 6 months; and 31% vs 33% (P = .86) at 1 year. On multivariate analysis, an invasive procedure performed during index hospitalization was an independent predictor for smoking abstinence at 1 year (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.22–14.19). Presence of adverse effects attributed to treatment was a negative predictor for smoking cessation (OR, 0.23; 95% CI, 0.07–0.78). Treatment with bupropion SR was not associated with an increase in clinical events or change in blood pressure or body mass index, but dizziness was more common compared with placebo (14% vs 1.4%; P = .005).” (D. Planer)
Dietary Fiber & Mortality: Could simply eating more fiber-rich foods increase longevity? Yes, according to an analysis of data from the NIH–AARP Diet and Health Study (pp. 1061–8). Using a baseline food-frequency questionnaire combined with mortality figures during 9 years of follow-up, investigators found: “We identified 20,126 deaths in men and 11,330 deaths in women. Dietary fiber intake was associated with a significantly lowered risk of total death in both men and women (multivariate relative risk comparing the highest with the lowest quintile, 0.78 [95% CI, 0.73–0.82; P for trend, <.001] in men and 0.78 [95% CI, 0.73–0.85; P for trend, <.001] in women). Dietary fiber intake also lowered the risk of death from cardiovascular, infectious, and respiratory diseases by 24% to 56% in men and by 34% to 59% in women. Inverse association between dietary fiber intake and cancer death was observed in men but not in women. Dietary fiber from grains, but not from other sources, was significantly inversely related to total and cause-specific death in both men and women. (Y. Park, parkyik@mail.nih.gov)
Editorialists make a distinction between fiber per se and intact whole grains (
pp. 1069–70): “While the hypothesis that whole grains reduce disease severity and respiratory and infectious disease mortality via reduced inflammation is intriguing, it requires testing in randomized trials. It is also important to distinguish between the effects of dietary fiber and those of whole grains. While fiber is clearly a component of whole grains, the reverse is not true. Fiber isolates probably do not provide the same benefits as intact, whole grains. The appropriate public health recommendation should therefore be to increase consumption of whole grains at the expense of refined grains. Substituting whole grains for refined grains would provide benefits not only from fiber but also from other unique health-promoting components of whole grains.” (F. B. Hu, frank.hu@channing.harvard.edu)
Impact of Hospital Abscess Guideline: Implementation of a guideline for management of cellulitis and cutaneous abscess in inpatients led to shorter durations of more targeted antibiotic therapy and decreased use of resources, researchers report (pp. 1072–9). Clinical outcomes did not suffer, the authors add, noting these details about the before (2007) and after (2009) time periods: “A total of 169 patients (66 with cellulitis, 103 with abscess) were included in the baseline cohort, and 175 (82 with cellulitis, 93 with abscess) were included in the intervention cohort. The intervention led to a significant decrease in use of microbiological cultures (80% vs 66%; P = .003) and fewer requests for inpatient consultations (46% vs 30%; P = .004). The median duration of antibiotic therapy decreased from 13 days (interquartile range [IQR], 10–15 days) to 10 days (IQR, 9–12 days) (P < .001). Fewer patients received antimicrobial agents with broad aerobic gram-negative activity (66% vs 36%; P < .001), antipseudomonal activity (28% vs 18%; P = .02), or broad anaerobic activity (76% vs 49%; P < .001). Clinical failure occurred in 7.7% and 7.4% of cases (P = .93), respectively.” (T. C. Jenkins, timothy.jenkins@dhha.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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 29, 2011 * Vol. 18, No. 125
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from JAMA (2011; 305).
Sunscreen Use & Melanoma: A brief Commentary describes the evidence supporting regular sunscreen use in prevention of melanoma (10.1001/jama.2011.990): “Sun protection counseling is relevant for individuals at risk for developing melanoma, which include the 68,130 new patients with melanomas diagnosed in the United States during 2010 (about 38,870 in men and 29,260 in women) and their families. Risk factors for developing melanoma include a lifestyle of frequent sun exposure, inherited traits such as fair skin and red hair, and heritable gene mutation, or a combination of factors. Regular use of sunscreen can effectively reduce the risk of developing melanoma for at-risk individuals.”
The authors advise counseling at-risk patients to use “two coats or about 1 full teaspoon of sunscreen [on] each body part prior to going outside: head, neck, and ears; front of trunk; back of trunk; each arm, dorsum of hand, and shoulder; and each lower leg, upper leg, and dorsum of foot. The leg needs to be divided into upper and lower segments with each getting 1 teaspoon.” (J. K. Robinson,
june-robinson@northwestern.edu)

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (2011; 34).
Insulin Doses with Luraglutide Therapy: In 29 patients with type 1 diabetes, liraglutide treatment reduced insulin doses over a 4-week period, researchers report (pp. 1463–8). Patients who were C-peptide positive (n = 10) received liraglutide plus insulin, while C-peptide–negative patients (n = 19) received either liraglutide plus insulin or insulin montherapy, with these results: “Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P < 0.001) in C-peptide–positive patients and from 0.72 ± 0.08 to 0.59 ± 0.06 units/kg per day (P < 0.01) in C-peptide–negative patients treated with liraglutide but did not change with insulin monotherapy. HbA1c decreased in both liraglutide-treated groups. The percent reduction in daily insulin dose was positively correlated with beta-cell function at baseline, and two patients discontinued insulin treatment. In C-peptide–positive patients, time spent with blood glucose <3.9 mmol/L decreased from 3.0 to 1.0 h (P = 0.03). A total of 18 of 19 patients treated with liraglutide lost weight during treatment (mean [range] −2.3 ± 0.3 kg [−0.5 to −5.1]; P < 0.001). Transient gastrointestinal adverse effects occurred in almost all patients treated with liraglutide.” (U. Kielgast, urd.kielgast@hvh.regionh.dk)
Metformin & Exercise: A study of exercise in 10 patients with type 2 diabetes shows that by increasing heart rate, metformin “could lead to the prescription of lower exercise workloads,” and that exercise may interfere “with the glucose-lowering effect of metformin” (pp. 1469–74). Participants received either metformin or placebo for 28 days in crossover fashion. Exercise on the last 2 days of each intervention yielded these findings: “Metformin increased heart rate and plasma lactate during exercise (both P ≤ 0.01) but lowered respiratory exchange ratio (P = 0.03) without affecting total energy expenditure, which suggests increased fat oxidation. Metformin plasma concentrations were greater at several, but not all, time points on the exercise day compared with the nonexercise day. The glycemic response to a standardized meal was reduced by metformin, but the reduction was attenuated when exercise was added (metformin × exercise interaction, P = 0.05). Glucagon levels were highest in the combined exercise and metformin condition.” (N. G. Boulé, nboule@ualberta.ca)

>>>PNN NewsWatch
* The APhA Foundation presented its 2011 Pinnacle Awards on Monday evening at the group’s headquarters in Washington, DC. Melvin Baron of the U. Southern California received the individual award for career achievement. His work with fotonovelas in the Latino community of Los Angeles was highlighted. The health-systems award went to the Ohio State University Medical Center and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute for its Medication Assistance Program. In the government agency category, the Patient Safety and Clinical Pharmacy Services Collaborative, a program of the Health Resources and Services Administration, was honored.

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 © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
June 30, 2011 * Vol. 18, No. 126
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and June 30 issue of the New England Journal of Medicine (2011; 364).
Parenteral Nutrition in Critically Ill Adults: In a study that supports North American practices over those used in Europe, critically ill patients had better outcomes when provision of parenteral nutrition was delayed (10.1056/NEJMoa1102662). In a randomized, multicenter trial of 2,312 patients, parenteral nutrition was initiated either within 48 hours of ICU admission or on day 8 or later, with these results: “Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P = 0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P = 0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P = 0.008) and a lower incidence of cholestasis (P < 0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P = 0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P = 0.008), and a mean reduction in health care costs of 1,110 euros (about $1,600) (P = 0.04).” (G. Van den Berghe, greet.vandenberghe@med.kuleuven.be)
An editorialist says the study clearly shows “that the early initiation of parenteral nutrition to achieve caloric goals of approximately 25 to 30 kcal per kilogram of body weight per day is associated with worse clinical outcomes than those in patients in whom initiation was delayed for a week,“ but he remains cautious (
10.1056/NEJMe1106612): “However, these data should not be overinterpreted, since between-group differences in outcome were small, rates of death in the two groups were similar, approximately 80% of the patients were not seriously malnourished at entry (nutrition risk score, ≤4), and 60% were admitted to the ICU after cardiac surgery. Also, patients who were readmitted to the ICU and those who were seriously malnourished or were receiving established enteral or parenteral nutrition at the time of ICU admission were excluded.” (T. R. Ziegler)
Vemurafenib in Melanoma: In 675 patients with previously untreated melanoma and who had the BRAF V600E mutation, vemurafenib improved rates of overall and progression-free survival, researchers report (pp. 2507–16). The drug, a BRAF kinase inhibitor also known as PLX4032, was used in doses of 960 mg orally twice daily in combination with dacarbazine. Results showed: “At 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P < 0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.” (P. B. Chapman, chapmanp@mskcc.org)
Ipilimumab in Metastatic Melanoma: Ipilimumab, which blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), improved overall survival in 502 patients with previously untreated metastatic melanoma (pp. 2517–26). Used with dacarbazine, ipilimumab produced these results: “Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab–dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001).” (J. D. Wolchok, wolchokj@mskcc.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2011, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.