PNN Pharmacotherapy Line
July 1, 2009 * Vol. 16, No. 125
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: July 1 issue of JAMA (2009; 302).
Genetics of CRP, CHD: Comparing the presence of genotypes that affect C-reactive protein levels with occurrence of coronary heart disease, investigators find that the “lack of concordance … argues against a causal association of CRP with coronary heart disease” (pp. 37–48). In genomewide association and replication studies involving more than 30,000 patients, researchers looked for single-nucleotide polymorphisms associated with the CRP locus and investigated the association of CRP variants with coronary heart disease: “Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (–14.8%; 95% confidence interval [CI], –17.6% to –12.0%; P = 6.2 x 10–22), rs4537545 in IL6R (–11.5%; 95% CI, –14.4% to –8.5%; P = 1.3 x 10–12), rs7553007 in the CRP locus (–20.7%; 95% CI, –23.4% to –17.9%; P = 1.3 x 10–38), rs1183910 in HNF1A (–13.8%; 95% CI, –16.6% to –10.9%; P = 1.9 x 10–18), and rs4420638 in APOE-CI-CII (–21.8%; 95% CI, –25.3% to –18.1%; P = 8.1 x 10–26). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, –3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.” (P. Elliott, p.elliott@imperial.ac.uk)
Management of Shingles: The case of a 70-year-old woman with shingles is discussed in relatino to management of shingles (pp. 73–80): “Ms A would not benefit from continued antiviral therapy. Because of her age and pain at presentation, the likelihood of her developing [postherpetic neuralgia] exceeded 75%. She and her physician may want to consider adding an analgesic to the gabapentin, in addition to the plan of increasing the gabapentin dose over the next several weeks to allow acclimation to the sedating effects of the medication. This approach likely will help control her pain but will require careful titration. Of note, the Advisory Committee on Immunization Practices recommends administration of herpes zoster vaccine to those who have had shingles but does not specify at what interval it should be given after infection.” (R. J. Whitley, rwhitley@peds.uab.edu)

>>>PNN NewsWatch
* FDA advisors yesterday voted overwhelmingly in favor of a black-box warning and new restrictions on use of acetaminophen, both in prescription and nonprescription products containing the analgesic/antipyretic. On the prescription side, advisors voted 20–17 in favor of a ban on opioid–acetaminophen combinations such as Percocet and Vicodin, according to the Washington Post, and favored a black-box warning (36–1) for any products remaining on the market. The members of Drug Safety and Risk Management, Nonprescription Drugs, and Anesthetic and Life Support Drugs Advisory Committees also advocated reducing the maximum OTC strength of single-ingredient acetaminophen products to 650 mg, making products with higher amount available only by prescription. Panelists stopped short of removing multi-ingredient acetaminophen products from the OTC market, voting 24–13 against a proposal that would have affected most cough-and-cold products and headache remedies such as Excedrin. Some observers found the recommendations to pull Rx combination products from the market while leaving OTC ones inconsistent. In a close vote of 21–16, panelists recommended that the maximum daily dosage of acetaminophen be lowered from its current 4 g/d. In Europe, the maximum recommended amount is 3 g/d. Only one concentration of acetaminophen liquid should be available, the panelists overwhelmingly voted, 36–1. The group favored unit-of-use packaging (27–10) but did not recommend a package size limit (17–20) that some believe has reduced accidental and deliberate overdoses in countries with such limits.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 2, 2009 * Vol. 16, No. 126
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: July 2 issue of the New England Journal of Medicine (2009; 361).
Effects of Angiotensin Blockade in Type 1 Diabetes: Blockade of the renin–angiotensin system in patients with type 1 diabetes was beneficial in slowing progression of retinopathy but failed to stem the pace of nephropathy, a research study shows (pp. 40–51). Losartan 100 mg daily, enalapril 20 mg daily, or placebo produced these results over a 5-year period: “A total of 90% and 82% of patients had complete renal-biopsy and retinopathy data, respectively. Change in mesangial fractional volume per glomerulus over the 5-year period did not differ significantly between the placebo group (0.016 units) and the enalapril group (0.005, P = 0.38) or the losartan group (0.026, P = 0.26), nor were there significant treatment benefits for other biopsy-assessed renal structural variables. The 5-year cumulative incidence of microalbuminuria was 6% in the placebo group; the incidence was higher with losartan (17%, P = 0.01 by the log-rank test) but not with enalapril (4%, P = 0.96 by the log-rank test). As compared with placebo, the odds of retinopathy progression by two steps or more was reduced by 65% with enalapril (odds ratio, 0.35; 95% confidence interval [CI], 0.14 to 0.85) and by 70% with losartan (odds ratio, 0.30; 95% CI, 0.12 to 0.73), independently of changes in blood pressure. There were three biopsy-related serious adverse events that completely resolved. Chronic cough occurred in 12 patients receiving enalapril, 6 receiving losartan, and 4 receiving placebo.” (M. Mauer, mauer002@umn.edu)
Editorialists add (pp. 83–5): “From a risk–benefit perspective, the subgroup of patients less likely to benefit from inhibition of the renin–angiotensin system must be identified, including, for example, those with the best glycemic control or those with more advanced stages of retinopathy. Determining these thresholds and the logistical framework for standardized, accurate, and timely reporting of retinal findings between eye specialists and diabetes care providers requires active research—these are not trivial tasks.” (B. A. Perkins)
Part D Drug Spend: Spending on Part D medications for Medicare beneficiaries without prior drug coverage or with minimal coverage was offset by reductions in other medical spending, a study shows, but for those who already had generous coverage, costs of both medications and other medical interventions increased (pp. 52–61). In particular, lipid-lowering and antidiabetic medication use increased among those with prior poor/no coverage. (J. M. Donohue, jdonohue@pitt.edu)

>>>PNN NewsWatch
* Psychiatric boxed warnings and Medication Guides are coming for the smoking cessation aids varenicline (Chantix, Pfizer) and bupropion (Zyban, GlaxoSmithKline; and generics) as well as bupropion products (Wellbutrin, GlaxoSmithKline; and generics) indicated for treatment of depression and seasonal affective disorder. Observed symptoms include changes in behavior, hostility, agitation, depressed mood, suicidal thoughts and behavior, and attempted suicide.
* Three of four recent studies have associated use of insulin glargine (Lantus) with cancer in patients with diabetes, and FDA said yesterday it has launched a review of safety data on the product. In the interim, the agency advises patients to not stop taking their insulin therapy without consulting a physician.
* Thomas E. Menighan, BPharm, MBA, became APhA’s 26th executive yesterday, taking over from 20-year veteran John A. Gans, PharmD. Menighan becomes Executive Vice President and Chief Executive Officer at a point when APhA is completing its move into a new 6-story headquarters annex behind its historic building on the National Mall in Washington. In a blog launched yesterday, Menighan emphasized the opportunities offered by health care reform in noting, “We’ve all heard the phrase, ‘Today is the first day of the rest of your life.’ Those words are especially fitting today both for me and for our profession as I assume the role of APhA’s CEO at a critical juncture in pharmacy history. It is a privilege and honor to serve, especially in this time of exciting possibilities for pharmacists.”
* PNN will not be published on Fri., July 3, Independence Day (observed).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 6, 2009 * Vol. 16, No. 127
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: July 4 issue of Lancet (2009; 374).
Rivaroxaban in ACS: In a Phase II trial of 3,491 patients stabilized after an acute coronary syndrome, the oral factor Xa inhibitor rivaroxaban may have reduced major ischemic outcomes, and its effects on bleeding risk were directly related to dose, making episodes easier to predict and identify (pp. 29–38). Investigators at 297 sites could elect to manage patients with aspirin alone (stratum 1; n = 761) or aspirin plus a thienopyridine (stratum 2; n =2,730), and those in the latter arm received either placebo or rivaroxaban 5—20 mg given once daily or the same total daily dose given twice daily. Results showed: “Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25–3.91] for 5 mg, 3.35 [2.31–4.87] for 10 mg, 3.60 [2.32–5.58] for 15 mg, and 5.06 [3.45–7.42] for 20 mg doses; p < 0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2,331) for rivaroxaban versus 7.0% (79/1,160) for placebo (HR 0.79 [0.60–1.05], p = 0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2,331 [3.9%] vs 62/1,160 [5.5%]; HR 0.69, [95% CI 0.50–0.96], p = 0.0270). The most common adverse event in both groups was chest pain (248/2,309 [10.7%] vs 118/1,153 [10.2%]).” (J. L. Mega, jmega@partners.org)
Liraglutide v. Exenatide in Type 2 Diabetes: Liraglutide 1.8 mg once daily significantly improved glycemic control, compared with exenatide 10 mcg twice daily, and was generally better tolerated, researchers report (pp. 39–47). The 26-week, open-label trial included 464 patients with inadequately controlled type 2 diabetes, and treatment showed these effects on glycosylated hemoglobin levels: “Mean baseline HbA1c for the study population was 8.2%. Liraglutide reduced mean HbA1c significantly more than did exenatide (–1.12% [SE 0.08] vs –0.79% [0.08]; estimated treatment difference −0.33; 95% CI –0.47 to –0.18; p < 0.0001) and more patients achieved a HbA1c value of less than 7% (54% vs 43%, respectively; odds ratio 2.02; 95% CI 1.31 to 3.11; p = 0.0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (–1.61 mmol/L [SE 0.20] vs –0.60 mmol/L [0.20]; estimated treatment difference –1.01 mmol/L; 95% CI –1.37 to –0.65; p < 0.0001) but postprandial glucose control was less effective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide –3.24 kg vs exenatide –2.87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0.448, p < 0.0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1.93 vs 2.60 events per patient per year; rate ratio 0.55; 95% CI 0.34 to 0.88; p = 0.0131; 25.5% vs 33.6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode.” (J. B. Buse, jbuse@med.unc.edu)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 338).
Statin Benefits in Primary Prevention: Significantly improved survival and reduced cardiovascular risk is evident among patients treated with statins for primary prevention, authors of a meta-analysis conclude (b2376). Based on analysis of studies in which patients had cardiovascular risk factors but no established disease, the investigators found: “10 trials enrolled a total of 70,388 people, of whom 23,681 (34%) were women and 16,078 (23%) had diabetes mellitus. Mean follow-up was 4.1 years. Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to 0.81), and major cerebrovascular events (0.81, 0.71 to 0.93). No evidence of an increased risk of cancer was observed. There was no significant heterogeneity of the treatment effect in clinical subgroups.” (J. .J Brugts, j.brugts@erasmusmc.nl)

>>>PNN JournalWatch
* Ethnicity Matters in the Assessment and Treatment of Children’s Pain, in Pediatrics, 2009; 124: 378–80. (M. A. Fortier, mfortier@choc.org)
* Exploring the Convergence of Posttraumatic Stress Disorder and Mild Traumatic Brain Injury, in American Journal of Psychiatry, 2009; 166: 768–76. (M. B. Stein, mstein@ucsd.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 7, 2009 * Vol. 16, No. 128
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and July 7 issue of the Annals of Internal Medicine (2009; 151).
Stepwise Dosing for Neuropsychiatric Events Caused by Efavirenz: Initial stepwise dosing over the first 2 weeks of treatment can reduce the frequency of efavirenz-related neuropsychiatric adverse events (NPAEs) while maintaining efficacy of the antiretroviral agents, according to a study of 114 patients in Spain (early release). Eligible patients were randomized to efavirenz 200 mg/d on days 1 through 6, 400 mg/d on days 7 through 13, and 600 mg/d on day 14 and after, or to efavirenz 600 mg/d from day 1 plus two nucleoside or nucleotide reverse transcriptase inhibitors, with these results: “Compared with the stepped-dose group, the full-dose group presented higher incidence and severity of dizziness (66.0% vs. 32.8%; P = 0.001), hangover (45.8% vs. 20.7%; P = 0.008), impaired concentration (22.9% vs. 8.9%; P = 0.038), and hallucinations (6.1% vs. 0%; P = 0.056) during the first week. From week 2, the incidence of efavirenz-related NPAEs was similar in both groups, although the severity was higher in the full-dose group. Virologic and immunologic efficacy seemed similar in both groups.” (L. F. López-Cortés, lflopez@telefonica.net)
Travel-Related VTE Risk: Long-distance travel is associated with a 3-fold increase in risk of venous thromboembolism, a review article concludes, with a dose–response relationship of 26% higher risk for each 2-h increase in air travel duration (early release). Seeking to clarify the contradictory findings of prior studies, the authors excluded from their analysis studies with control participants having different VTE risks than case patients, finding: “Of 1,560 identified abstracts, 14 studies (11 case–control, 2 cohort, and 1 case–crossover) met inclusion and exclusion criteria, including 4,055 cases of VTE. Compared with nontravelers, the overall pooled relative risk for VTE in travelers was 2.0 (95% CI, 1.5 to 2.7). Significant heterogeneity was present because of the method for selecting control participants (P = 0.008): Whether the studies used control participants who had been referred for VTE evaluation or nonreferred control participants. Excluding the studies that used referred control participants, the pooled relative risk for VTE in travelers was 2.8 (CI, 2.2 to 3.7), without significant heterogeneity. A dose–response relationship was identified, with an 18% higher risk for VTE for each 2-hour increase in duration of travel by any mode (P = 0.010) and a 26% higher risk for every 2 hours of air travel (P = 0.005).” (D. Chandra, dchandra@hsph.harvard.edu)
Lessons from H1N1 Influenza Outbreaks: Lessons learned during the current outbreak of a new H1N1 triple-reassortant “swine” influenza virus are compared with those of prior pandemics involving this strain (pp. 59–62): “Unlike the 1957 and 1968 pandemics, which were caused by reassortment between avian and human strains, the pandemic in 1918 was most likely caused by an avian virus that accumulated mutations and, subsequently, evolved and adapted to humans. Thus, at least 2 mechanisms could explain zoonotic outbreaks. In addition, analysis of amino acid substitution rates in the 1918 virus suggest that genes of avian origin could have been circulating in human influenza viruses as early as 1900, which points toward the possibility of detecting sequence modifications years before zoonotic pathogens cause human epidemics. The sequence of the current H1N1 strain will probably provide clues about how this virus emerged and what factors enabled animal-to-human and then human-to-human transmission. We must learn, from all the zoonotic pathogens that have afflicted humankind, the particular circumstances that facilitated each outbreak. If we can integrate this information successfully, we will understand what makes us vulnerable to pathogens that cross species barriers.” (R. A. Stein, ras2@princeton.edu)

>>>PNN NewsWatch
* Dronedarone (Multaq, Sanofi Aventis) has been approved by FDA, indicated for reducing the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted. Because of mortality concerns, the drug’s label will contain a boxed warning stating that the drug should not be used in those with severe heart failure.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 8, 2009 * Vol. 16, No. 129
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: July 8 issue of JAMA (2009; 302).
Reduced-Dose PCV-7 Schedules: Reduced-dose schedules of 7-valent pneumococcal conjugate vaccine (PCV-7) significantly lowered carriage of vaccine serotype pneumococci in the second year of live, compared with no vaccine, researchers report (pp. 159–67). In the Netherlands, 1,003 healthy newborns received either a 2-dose or 2 + 1-dose PCV-7 schedule, or no vaccine, with this impact on nasopharyngeal pneumococcal carriage: “At 12 months, vaccine serotype pneumococcal carriage was significantly decreased after both PCV-7 schedules, with vaccine serotype pneumococcal carriage rates of 25% (95% confidence interval [CI], 20%–30%) and 20% (95% CI, 16%–25%) in the 2-dose and 2 + 1-dose schedule groups, respectively, vs 38% (95% CI, 33%–44%) in the control group (both P < .001). At 18 months, in the 2 + 1-dose schedule group, vaccine serotype pneumococcal carriage had further decreased to 16% (95% CI, 12%–20%) and, at 24 months, to 14% (95% CI, 11%–18%; both P < .001); whereas in the 2-dose schedule group, vaccine serotype pneumococcal carriage had remained stable at 18 months (24%; 95% CI, 20%–29%), but at 24 months had further decreased to 15% (95% CI, 11%–19%; both P < .001). In the control group, vaccine serotype pneumococcal carriage remained around 36% to 38% until 24 months.” (E. A. M. Sanders, l.sanders@umcutrecht.nl)
Adiponectin Levels & Diabetes Risk: Patients with higher levels of adiponectin have lower risk of developing type 2 diabetes, conclude authors of a systematic review and meta-analysis (pp. 179–88). Secretion of adiponectin by adipose tissue is down-regulated with increasing adiposity, decreasing the availability of a factor known to have anti-inflammatory and insulin-sensitizing properties. Based on analysis of data from 13 prospective studies involving 14,598 participants, the investigators found: “Higher adiponectin levels were monotonically associated with a lower risk of type 2 diabetes. The relative risk of type 2 diabetes was 0.72 (95% confidence interval, 0.67–0.78) per 1-log µg/mL increment in adiponectin levels. This inverse association was consistently observed in whites, East Asians, Asian Indians, African Americans, and Native Americans and did not differ by adiponectin assay, method of diabetes ascertainment, duration of follow-up, or proportion of women. The estimated absolute risk difference (cases per 1,000 person–years) per 1-log µg/mL increment in adiponectin levels was 3.9 for elderly Americans and 30.8 for Americans with impaired glucose tolerance.” (R. M. van Dam, rvandam@hsph.harvard.edu)
FDA Performance Goals: The linkage of FDA user fees with performance goals is problematic and unnecessary, argues the author of a Commentary article (pp. 189–91): “In 2008, Carpenter et al reported … that drugs approved within 2 months before the performance goal deadline for that drug were significantly more likely to have postapproval safety issues, with odds ratios ranging from 2.1 to 3.6. The authors concluded that ‘it appears to be the deadline, not the speed of approval, that explains the difference in the risk of such problems.’ The observation that the deadline is the problem is consistent with the FDA’s own … guidance, in which the FDA notes the potential for ‘errors associated with crisis-style management dealing with unresolved issues at the end of the review cycle.’ Crisis-style management of drugs and biologics, driven by the performance goals, is not consistent with public health.” (J. D. Miller, jdmiller@jhsph.edu)

>>>PNN NewsWatch
* FDA yesterday began requiring a boxed warning and Medication Guide for products containing propoxyphene. The agency also mandated a new safety study to assess the effects of the narcotic analgesic on the heart and said that it would work with CMS and the VA to study how often the elderly are prescribed propoxyphene instead of other pain relievers and the difference in the safety profiles of propoxyphene compared with other drugs. FDA also yesterday denied a citizen petition from Public Citizen requesting a phased withdrawal of propoxyphene. The agency said in its response that despite its serious concerns about propoxyphene, the benefits of using the medication for pain relief at recommended doses outweighs safety risks at this time.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 9, 2009 * Vol. 16, No. 130
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Early-release article and July 9 issue of the New England Journal of Medicine (2009; 361).
Hearing Improvement with Bevacizumab in Neurofibromatosis Type 2: In a retrospective study of 10 consecutive patients with neurofibromatosis type 2, blockade of vascular endothelial growth factor (VEGF) with bevacizumab improved hearing in some patients (10.1056/NEJMoa0902579). The genetic condition is associated with bilateral, previously untreatable vestibular schwannomas, benign tumors arising in the eighth cranial nerve that produce hearing impairment. Based on an imaging response of at least 20% decrease in tumor volume, the investigators found these effects of bevacizumab: “VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2.” (S. R. Plotkin, splotkin@partners.org)
Raxibacumab for Inhalational Anthrax: In rabbits and monkeys with symptomatic inhalational anthrax, the IgG1-delta monoclonal antibody raxibacumab improved survival after a single dose, and the drug produced presumed therapeutic concentrations in human volunteers (pp. 135–44). The agent, which targets the protective antigen component of anthrax toxin, was administered to 333 healthy humans in a safety study and to rabbits and monkeys who had been exposed to Bacillus anthracis spores, with these effects on 14-day (rabbits) and 28-day (monkeys) survival rates: “In both rabbits and monkeys, the time to detection of protective antigen correlated with the time to bacteremia (r = 0.9, P < 0.001). In the therapeutic-intervention studies, the survival rate was significantly higher among rabbits that received raxibacumab at a dose of 40 mg per kilogram (44% [8 of 18]) than among rabbits that received placebo (0% [0 of 18]; P = 0.003). Raxibacumab treatment also significantly increased survival in monkeys (64% [9 of 14], vs. 0% [0 of 12] with placebo; P < 0.001). In human subjects, intravenous raxibacumab at a dose of 40 mg per kilogram had a half-life of 20 to 22 days and provided a maximum concentration of the drug in excess of levels that are protective in animals. Concentrations of raxibacumab provide a surrogate end point that should be predictive of clinical benefit.” (T-S Migone, thi_migone@hgsi.com)
An editorialist uses this study to describe procedures in place for biodefense research (pp. 191–3): “Raxibacumab could become one of the first biologic interventions licensed under the animal rule. On the basis of two relevant animal models, with the use of both preventive and therapeutic challenges, a minimum threshold value for treatment has been established, and phase 2 safety studies suggest that the therapeutic levels of the antibody that can be achieved in humans are equal to or greater than those that provide protection in the animal models. The animal rule allows for licensure of a new therapeutic drug when several criteria are met. The rule can be invoked when there is a well-understood pathophysiology of toxicity and inactivation of the substance can be achieved through the use of the therapeutic agent. It is recommended that the therapy be tested in more than one animal when infection in these animals is relevant to the human infection or in a single animal species if it is the optimal model for predicting the human response. The study end point must be clearly related to the clinical benefit desired in humans, and the pharmacodynamics of the product must be such that the effective dose in animals is also achievable and therapeutic in humans.” (G. J. Nabel)

>>>PNN NewsWatch
* Francis S. Collins, MD, PhD, a physician–geneticist who spoke earlier this year at APhA2009, has been nominated by President Obama as director of the National Institutes of Health.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 10, 2009 * Vol. 16, No. 131
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source: July issue of Pharmacotherapy (2009; 29).
Pharmacists’ Impact in ICUs: Reduced mortality, improved clinical and economic outcomes, and fewer bleeding complications occurred among patients in intensive care units that had dedicated clinical pharmacists during 2004, researchers find in an analysis of Medicare data from that year (pp. 761–8). The study focused on patients with thromboembolic or infarction-related events (TIE), finding the following: “We identified 141,079 patients with TIE, of whom 7,987 also had bleeding complications. In hospitals with ICU clinical pharmacy services, mortality rates in patients with TIE only and TIE with bleeding complications were higher by 37% (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.36–1.46) and 31% (OR 1.35, 95% CI 1.13–1.61), respectively, than in ICUs with clinical pharmacy services. Lengths of ICU stay were longer by 14.8% (mean ± SD 7.28 ± 8.17 vs 6.34 ± 7.80 days, p < 0.0001) and 15.8% (12.4 ± 13.28 vs 10.71 ± 9.53 days, p = 0.008), respectively. The lack of clinical pharmacist participation in a patient’s care was associated with extra Medicare charges of $215,397,354 (p < 0.001) and $63,175,725 (p < 0.0001) and extra drug charges of $26,363,674 (p < 0.0001) and $2,610,750 (p < 0.001) for TIE only and TIE with bleeding complications, respectively. Without clinical pharmacy services, bleeding complications increased by 49% (OR 1.53, 95% CI 1.46–1.60), resulting in 39% more patients requiring transfusions (OR 1.47, 95% CI 1.28–1.69); these patients also received more blood products (mean ± SD 6.8 ± 10.4 vs 3.1 ± 2.6 units/patient, p = 0.006).” (R. MacLaren, rob.maclaren@uchsc.edu)
Antiepileptic Drug Substitutions: Recent antiepileptic drug substitutions are associated with increased risk of acute events requiring ambulance service, emergency department visit, or hospitalization, according to an a case–control analysis of PharMetrics data from 2005–06 (pp. 769–74). Among 991 patients requiring acute care (cases) and 2,973 matched controls, the researchers found: “Using discordant pairs analysis, we calculated the odds ratio of an epileptic event that required acute care occurring in patients whose antiepileptic drug underwent substitution to an A-rated (therapeutically equivalent) alternative (switch from branded product to generic, generic to branded, or generic to generic) versus those whose drugs were not substituted. For matched data, 109 (11.0%) of 991 cases had an A-rated antiepileptic drug substitution in the 6 months before the event, whereas only 186 (6.3%) of 2,973 controls had a substitution (odds ratio 1.84, 95% confidence interval 1.44–2.36). Our results were similar to those of a previous study involving a different patient database, which showed substitution rates of 11.3% for cases versus 6.5% for controls (odds ratio 1.81, 95% confidence interval 1.25–2.63). Our sensitivity analyses were robust, and we found a temporal relationship in that numerous substitutions occurred in the month before the acute event.” (K. L. Rascati, krascati@mail.utexas.edu)
Statins & Cognitive Function: Patients with statin-associated memory or other cognitive problems have variable onset and recovery courses, researchers report, and statin potency is clearly related to effects and the adverse drug reactions have a significantly negative impact on quality of life (pp. 800–11). Those and other patterns were observed in 171 patients reporting altered cognition during a statin study: “128 patients (75%) experienced cognitive ADRs determined to be probably or definitely related to statin therapy. Of 143 patients (84%) who reported stopping statin therapy, 128 (90%) reported improvement in cognitive problems, sometimes within days of statin discontinuation (median time to first-noted recovery 2.5 wks). Of interest, in some patients, a diagnosis of dementia or Alzheimer’s disease reportedly was reversed. Nineteen patients whose symptoms improved or resolved after they discontinued statin therapy and who underwent rechallenge with a statin exhibited cognitive problems again (multiple times in some). Within this vulnerable group, a powerful relationship was observed between potency of the statin and fraction of trials with that agent resulting in cognitive ADRs (p < 0.00001). Quality of life was significantly adversely affected for each of the seven assessed domains (all p < 0.00000001).” (B. A. Golomb, bgolomb@ucsd.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 13, 2009 * Vol. 16, No. 132
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: July 11 issue of Lancet (2009; 374).
Famotidine Use in Patients Taking Low-Dose Aspirin: Among 404 patients taking cardioprotective aspirin doses, famotidine prevented gastric and duodenal ulcers and erosive esophagitis, according to the Famotidine for the Prevention of Peptic Ulcers in Users of Low-dose Aspirin (FAMOUS) study (pp. 119–25). Baseline and 12-week endoscopy studies revealed these patterns for those taking placebo or famotidine 20 mg twice daily while using aspirin in doses of 75–325 mg daily: “82 patients (famotidine, n = 33; placebo, n = 49) did not have the final endoscopic examination and were assumed to have had normal findings; the main reason for participant withdrawal was refusal to continue. At 12 weeks, comparing patients assigned to famotidine with patients assigned to placebo, gastric ulcers had developed in seven (3.4%) of 204 patients compared with 30 (15.0%) of 200 patients (odds ratio [OR] 0.20, 95% CI 0.09–0.47; p = 0.0002); duodenal ulcers had developed in one (0.5%) patient compared with 17 (8.5%; OR 0.05, 0.01—0.40; p = 0.0045); and erosive oesophagitis in nine (4.4%) compared with 38 (19.0%; OR 0.20, 0.09—0.42; p < 0.0001), respectively. There were fewer adverse events in the famotidine group than in the placebo group (nine vs 15); four patients in the placebo group were admitted to hospital with upper gastrointestinal haemorrhage. The other most common adverse event was angina (famotidine, n = 2; placebo, n = 4).” (A. S. Taha, ali.taha1@btinternet.com)
Aleglitazar & Cardiovascular Risk in Type 2 Diabetes: The peroxisome proliferator-activated receptor (PPAR) agonist aleglitazar was safe and effective for reducing cardiovascular risk in the Phase II SYNCHRONY trial of 332 patients with type 2 diabetes (pp. 126–35). Patients received 16 weeks’ treatment with aleglitazar 50, 150, 300, or 600 mcg once daily, matching placebo, or open-label pioglitazone 45 mg once daily, with these results: “The efficacy analysis excluded six patients (n = 0 in pioglitazone group; n = 1 in each of placebo, 50 mcg, 150 mcg, and 600 mcg aleglitazar groups; and n = 2 in 300 mcg aleglitazar group). Aleglitazar significantly reduced baseline HbA1c versus placebo in a dose-dependent manner, from −0.36% (95% CI 0.00 to −0.70, p = 0.048) with 50 mcg to −1.35% (−0.99 to −1.70, p < 0.0001) with 600 mcg. The trend of changes over time suggests that the maximum effect of aleglitazar on HbA1c concentration was not yet reached after 16 weeks of treatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 mcg, no patients had congestive heart failure, frequency of oedema was similar to placebo (one case at 50 mcg, two at 150 mcg, and three with placebo) and less than with pioglitazone (four cases), and body-weight gain was less than with pioglitazone (0.52 kg at 150 mcg vs 1.06 kg).” (R. R. Henry, rrhenry@ucsd.edu)

>>>PNN NewsWatch
* FDA has approved prasugrel (Effient; Lilly, Daiichi Sankyo) for reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndromes who are managed with percutaneous coronary intervention (PCI). The agency is requiring a black-box warning about potentially fatal bleeding in patients using the orally active thienopyridine platelet inhibitor, which should not be used in patients with active pathological bleeding, a history of transient ischemic attacks or stroke, or urgent need for surgery, including coronary artery bypass graft surgery.

>>>PNN JournalWatch
* Filaggrin Gene Defects and Risk of Developing Allergic Sensitisation and Allergic Disorders: Systematic Review and Meta-analysis, in BMJ, 2009; 339: b2433. (A. Sheikh, Aziz.Sheikh@ed.ac.uk)
* Probiotics and Prebiotics for Severe Acute Malnutrition (Pronut Study): A Double-Blind Efficacy Randomised Controlled Trial in Malawi, in Lancet, 2009; 374: 136–44. (M. Kerac, marko.kerac@gmail.com)
* The 50-Year History, Controversy, and Clinical Implications of Left Ventricular Outflow Tract Obstruction in Hypertrophic Cardiomyopathy, in Journal of the American College of Cardiology, 2009; 54: 191–200. (B. J. Maron, hcm.maron@mhif.org)
* Lipid Treatment Assessment Project 2: A Multinational Survey to Evaluate the Proportion of Patients Achieving Low-Density Lipoprotein Cholesterol Goals, in Circulation, 2009; 120: 28–34. (D. D. Waters, dwaters@medsfgh.ucsf.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 14, 2009 * Vol. 16, No. 133
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: July 13 issue of the Archives of Internal Medicine (2009; 170).
ACE Inhibitors & Cognitive Decline: Some ACE inhibitors may be associated with cognitive decline in older adults with hypertension, according to the Cardiovascular Health Study Cognition Substudy (pp. 1195–202). Findings that accrued during 6 years of follow-up among 1,054 patients with a mean age of 75 showed these results with respect to incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs): “Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88–1.15), difference in 3MSE scores (–0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99–1.14). Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00–1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03–1.30 per year of exposure) compared with other anti-HTN drugs.” (K.M. Sink, kmsink@wfubmc.edu)
Optimal Oral Anticoagulant Therapy: In future clinical trials, target international normalized ratios of 3.0 and 3.5 are recommended for patients with mechanical heart valve prostheses/atrial fibrillation and myocardial infarction, respectively (pp. 1203–9). A study conducted at the Netherlands’ Leiden Anticoagulation Clinic from 1994 to 1998 included 4,202 patients with 7,788 patient–years of therapy and showed these outcomes: “A total of 3,226 hospital admissions were reported, 306 owing to an untoward event. Incidence rates of untoward events were around 4% per year for all indications: 4.3 (95% confidence interval [CI], 3.1–5.6) for patients with mechanical heart valve prostheses, 4.3 (95% CI, 3.7–5.1) for patients with atrial fibrillation, and 3.6 per year (95% CI, 3.0–4.4) for patients treated after a myocardial infarction. The optimal intensity of anticoagulation for patients with mechanical heart valve prostheses was an … INR of 2.5 to 2.9; for patients with atrial fibrillation, an INR of 3.0 to 3.4; and for patients after myocardial infarction, an INR of 3.5 to 3.9.” (F. R. Rosendaal, f.r.rosendaal@lumc.nl)
Directly Observed Antiretroviral Therapy: Among treatment-naive patients with HIV infection, modified directly observed therapy (mDOT) cannot be recommended routinely, according to an open-label, 24-week trial (pp. 1224–32). Conducted at 23 AIDS Clinical Trials Group (ACTG) sites in the U.S. and 1 site in South Africa in 2002–06, the study provided mDOT on Monday through Friday to 82 participants, and results were compared with those in 161 self-administering patients: “Over 24 weeks, mDOT had greater virologic success (0.91; 95% confidence interval [CI], 0.81 to 0.95) than self-administered therapy (0.84; 95% CI, 0.77 to 0.89), but the difference (0.07; lower bound 95% CI, –0.01) did not reach the prespecified threshold of 0.075. Over 48 weeks, virologic success was not significantly different between mDOT (0.72; 95% CI, 0.61 to 0.81) and self-administered therapy (0.78; 95% CI, 0.70 to 0.84) (difference, –0.06; 95% CI, –0.18 to 0.07 [P = .19]).” (R. Gross, grossr@mail.med.upenn.edu)
Vitamins & Vision in Aging: Vitamin therapy is no replacement for ophthalmic care among aging individuals, Commentary authors write (pp. 1180–2): “Our ability to diagnose the earliest stages of [age-related macular degeneration] has never been better. It is also important to recognize the need to refer those who are impaired to low vision specialists, who can assist those who are unresponsive to available treatment options and provide access to devices and training that would allow them to maximize their residual visual capacity. Although the benefits of antioxidant therapy with folic acid and vitamins B6 and B12 must be verified in other populations, based on our current knowledge and the burden of disease, it is important for the physician community to respond affirmatively and ensure that patients are receiving the ophthalmic surveillance and care they need.” (C. O. Phillips, chr_phi@yahoo.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 15, 2009 * Vol. 16, No. 134
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: July 15 issue of JAMA (2009; 302).
Hormone Therapy & Ovarian Cancer: In a study of all Danish women aged 50 through 79 years from 1995 through 2005, use of hormone therapy was associated with increased risk of ovarian cancer for all durations of use, formulations, estrogen doses, regimens, progestin types, and routes of administration (pp. 298–305). The nationwide prospective cohort study reported the following results: “In an average of 8.0 years of follow-up (7.3 million women–years), 3,068 incident ovarian cancers, of which 2,681 were epithelial cancers, were detected. Compared with women who never took hormone therapy, current users of hormones had incidence rate ratios for all ovarian cancers of 1.38 (95% confidence interval [CI], 1.26–1.51) and 1.44 (95% CI, 1.30–1.58) for epithelial ovarian cancer. The risk declined with years since last use: 0 to 2 years, 1.22 (95% CI, 1.02–1.46); more than 2 to 4 years, 0.98 (95% CI, 0.75–1.28); more than 4 to 6 years, 0.72 (95% CI, 0.50–1.05), and more than 6 years, 0.63 (95% CI, 0.41–0.96). For current users the risk of ovarian cancer did not differ significantly with different hormone therapies or duration of use. The incidence rates in current and never users of hormones were 0.52 and 0.40 per 1,000 years, respectively, ie, an absolute risk increase of 0.12 (95% CI, 0.01–0.17) per 1,000 years. This approximates 1 extra ovarian cancer for roughly 8,300 women taking hormone therapy each year.” (L. S. Mørch, linamorch@yahoo.dk)

>>>Nephrology Highlights
Source: July American Journal of Kidney Diseases (2009; 54).
GFR Estimating Equations: The Modification of Diet in Renal Disease (MDRD) Study equation performed better than the Cockcroft–Gault equation used with either actual (CG) or ideal body weight (CGIBW) in an analysis of data for 5,504 participants in 6 research studies and 4 clinical populations (pp. 33–42). Comparisons of glomerular filtration rates (GFRs) determined using iodine-125–iothalamate urinary clearance with the equations showed the following: “Concordance of kidney function estimates with measured GFR for FDA-assigned kidney function categories was 78% for the MDRD Study equation compared with 73% for the CG equation (P < 0.001) and 66% for the CGIBW equation (P < 0.001). Concordance between the MDRD Study equation and CG and CGIBW equations was 78% and 75%, respectively (P < 0.001). Concordance of kidney function estimates with measured GFR for recommended drug dosages was 88% for MDRD Study equation compared with 85% for the CG equation (P < 0.001) and 82% for the CGIBW equation (P < 0.001), with lower concordance when dosing recommendations for drugs included narrow GFR ranges. Concordance rates between the CG and CGIBW equations and MDRD Study equation were 89% and 88%, respectively (P < 0.05).” (L. A. Stevens, lstevens1@tuftsmedicalcenter.org)
Flu Vaccine Challenges in CKD: Responding to research articles in this issue on influenza vaccination in kidney transplant recipients (pp. 112–21), among patients with chronic kidney disease on long-term hemodialysis (pp. 77–85), and in dialysis clinics using standing-order policies (pp. 86–94), editorialists write (pp. 6-9): “If influenza vaccine is immunogenic, safe, and effective for the majority of patients with CKD, what needs to be done to further improve levels of vaccination in these patients and [health care professionals]? Understanding why some of these patients and many HCP are not being vaccinated is important because different reasons may require different solutions. Is vaccination simply not being recommended? If so, developing systematic ways to provide and encourage vaccinations may be useful. Are patients and staff refusing to be vaccinated? If so, educational interventions and incentives may be more important. More work is needed to understand these issues and develop and compare strategies for vaccination.” (A. J. Kallen, akallen@cdc.gov)

>>>PNN NewsWatch
* Based on reports of adverse drug events, FDA is requiring manufacturers of immunosuppressants used after renal transplant to update their labeling. Increased risk of opportunistic infections, including activation of latent infections, has been reported, including BK virus–associated nephropathy. Agents included are sirolimus, cyclosporine (original and modified), mycophenolate mofetil, and mycophenolic acid.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 16, 2009 * Vol. 16, No. 135
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: July 16 issue of the New England Journal of Medicine (2009; 361).
HPV Vaccine & Cervical Dysplasia: In a Clinical Therapeutics article, the case of a young sexually active woman with a family history of precervical cancer is used as the framework for discussing appropriate use of the human papillomavirus vaccine (pp. 271–8). The author concludes: “The young woman described in the vignette is 18 years of age and therefore an appropriate candidate for HPV immunization. I recommend that the HPV vaccine be universally administered to young women of this age, regardless of their history of sexual activity, unless there are contraindications to vaccination. In order to avoid vaccination during pregnancy, I would assess the risk of pregnancy and perform a pregnancy test, if indicated, in this sexually active young woman. I would also explain that although she may have already been exposed to HPV through sexual contact, she is unlikely to be infected with both of the cancer-associated HPV types targeted by the quadrivalent HPV vaccine, so vaccination would be expected to protect her at least partially. Finally, I would use this opportunity to reinforce the importance of both practicing safe sexual behaviors to prevent sexually transmitted infections and returning for future Pap screening, since current vaccines do not target all high-risk HPV types and the duration of efficacy is unknown.” (J. A. Kahn, jessica.kahn@cchmc.org)
Alzheimer’s Disease Genotypes: Two articles and an editorial explore use of genotyping for estimating risk of Alzheimer’s disease.
Patients who were told of their elevated risk for Alzheimer’s disease had no short-term psychological risk, researchers report (pp. 245–54). Included in the study were 162 asymptomatic adults who had a parent with Alzheimer’s disease and who underwent genotyping of their apolipoprotein E allele. Some patients chose to be told of the results, while others did not want to know whether they had the predisposing APOE episolon-4 genotype. Comparisons between the groups over the following year showed: “Test-related distress was reduced among those who learned that they were APOE-epsilon-4–negative. Persons with high levels of emotional distress before undergoing genetic testing were more likely to have emotional difficulties after disclosure.” (R. C. Green, rcgreen@bu.edu)
In a second study, investigators find that carriers of the APOE epsilon-4 gene have measurable declines in memory status before the age of 60, despite normal clinical status (pp. 255–63; R. J. Caselli, caselli.richard@mayo.edu).
Editorialists make this assessment of genotyping for APOE status (pp. 298–9): “Could any societal good or harm result from widespread, on-demand genetic testing for APOE epsilon-4? Societal benefit seems unlikely, given that it is not possible to prevent Alzheimer’s disease, and available treatments have at best a modest effect on disease progression. Societal harm from testing remains possible, given that Alzheimer’s disease is widely regarded as being singularly horrific, although persons with Alzheimer’s disease can retain their sense of humor, experience existential joy, and overcome the sum total of so-called negative behaviors that are typically measured in care settings. One hopes that the subjects in [the Green et al.] study had experiences with their affected family members that were consistent with this observation. With an increasing public familiarity with Alzheimer’s disease and improving choices in community care for those with the disease, perhaps the social effects of genetic testing will be less worrisome by the time a clinical rationale for the test becomes apparent.” (R. A. Kane)

>>>PNN NewsWatch
* FDA has approved Teva’s Plan B One-Step (levonorgestrel 1.5 mg), which provides one-dose emergency contraception. The agency also expanded OTC access by allowing OTC purchase of this product at age 17, a year earlier than with two-dose Plan B. Younger patients still require a prescription for Plan B One Step, which will be available within the next month.
* FDA has issued a draft guidance for industry on the use of inks, pigments, flavors, and other physical-chemical identifiers by manufacturers to make drug products more difficult to duplicate by counterfeiters, and to make it easier to identify the genuine version of the drug.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.


PNN Pharmacotherapy Line
July 17, 2009 * Vol. 16, No. 136
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source: Aug. 1 issue of Clinical Infectious Diseases (2009; 49).
Vancomycin Therapeutic Guidelines: New recommendations are provided for “targeting and adjustment of vancomycin therapy” in treatment of Staphylococcus aureus infection in adult patients (pp. 325–7). An expert panel convened by the Infectious Diseases Society of America, ASHP, and Society of Infectious Diseases Pharmacists provides this summary of the rationale for new guidelines: “The relationship between serum concentrations and treatment success or failure in serious Staphylococcus aureus infections has recently been established. Failure rates exceeding 60% for S. aureus displaying a vancomycin [minimum inhibitory concentration (MIC)] value of 4 mg/L prompted recommendations in 2006 from the Clinical and Laboratory Standards Institute to lower the breakpoint for susceptibility from 4 to 2 mg/L and in 2008 from the US Food and Drug Administration. Recently, a number of studies have established a relationship between vancomycin treatment failures and infections in patients with methicillin-resistant S. aureus displaying an MIC of 2 mg/L. Vancomycin displays concentration-independent activity against S. aureus, with the area under the concentration curve (AUC) divided by the MIC as the primary predictive pharmacodynamic parameter for efficacy. On the basis of in vitro, animal, and limited human data, an AUC/MIC value of 400 has been established as the pharmacokinetic–pharmacodynamic target. To achieve this target, larger vancomycin doses and high trough serum concentrations are required. Although vancomycin administration is associated with some adverse effects, the committee felt that the potential benefit of increased drug dosage was worth the risk of mostly reversible adverse events.” (M. J. Rybak, m.rybak@wayne.edu)

>>>Geriatrics Highlights
Source: July issue of the Journal of the American Geriatrics Society (2009; 57).
Concomitant Prescription Drug/Dietary Supplement Use: Large numbers of patients aged 75 or older combine multiple prescription drugs and multiple dietary supplements in their daily regimens, report investigators from the Ginkgo Evaluation of Memory Study (pp. 1197–205). Identification of substances brought to clinics in four states by 3,700 ambulatory patients showed the following: “Almost three-quarters (74.2%) of the cohort combined use of at least one prescription drug and one dietary supplement, with 32.5% using three or more prescription drugs and three or more supplements. The 15 most-prevalent prescription drugs exhibited substantial concomitant use with dietary supplements, ranging from 77.6% for diuretics to 93.6% for estrogen preparations. Although supplements were taken concomitantly with all classes of prescription drugs, the use of supplements was more likely in individuals using nonsteroidal anti-inflammatory drugs, thyroid drugs, and estrogens. The use of drugs for diabetes mellitus was negatively associated with the use of supplements, with most of this attributed to low use in those taking multivitamins, glucosamine and chondroitin, and echinacea.” (R. L. Nahin, nahinr@mail.nih.gov)

>>>PNN NewsWatch
* Onsolis, a Meda Pharmaceuticals product that delivers fentanyl via an absorbable film that sticks to the inside of the cheek, has been approved by FDA for treatment of breakthrough pain in patients with cancer. The product’s Risk Evaluation and Mitigation Strategy (REMS) restricts prescribing, dispensing, and distribution to registered prescribers, pharmacies, and patients. Onsolis was approved with a boxed warning stating that the medication should not be used for the management of migraines, dental pain, or postoperative pain or by patients who use opioids intermittently, or on an as-needed basis.
* Interim results from a Genentech trial has indicated a possible association between use of omalizumab (Xolair) and increased risk of heart attack, abnormal heart rhythm, heart failure, and stroke, FDA announced yesterday. The agency is conducting a safety review as a result.
* Health care reform is back on track on Capitol Hill, APhA reports, with a Senate committee passing legislation on Tuesday, a House committee starting mark-up yesterday, and the American Medical Assn. endorsing the House bill and its controversial public-option plan.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 20, 2009 * Vol. 16, No. 137
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: July 18 issue of Lancet (2009; 374).
Golimumab for Rheumatoid Arthritis: In 461 patients with active rheumatoid arthritis treated previously with tumor necrosis factor–alpha inhibitors, the TNF-alpha inhibitor golimumab reduced signs and symptoms of the disease (pp. 210–21). In the GO-AFTER (GOlimulab After Former anti-tumour necrosis factor alpha Therapy Evaluated in Rheumatoid arthritis) trial, patients received placebo or golimumab 50 or 100 mg subcutaneously every 4 weeks for 1.5 years, with these results: “Patients had discontinued previous TNF-alpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0—22.0) swollen and 26.0 (16.0—41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% CI 1.5—4.2], p = 0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6—4.7], p = 0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1—16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1—24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab.” (J. S. Smolen, josef.smolen@wienkav.at)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 339).
Cost-Effectiveness of PPIs with Cyclooxygenase Inhibition: Depending on risks of adverse effects for individual NSAIDs, concomitant therapy with proton-pump inhibitors can be cost-effective, conclude authors of a Markovian analysis of systematic review data (b2538). Evaluating the economics of treatment with licensed COX-2–selective inhibitors (celecoxib and etoricoxib) and traditional NSAIDs (diclofenac, ibuprofen, and naproxen), the researchers found: “Addition of a proton pump inhibitor to both COX 2 selective inhibitors and traditional NSAIDs was highly cost effective for all patient groups considered (incremental cost effectiveness ratio less than £1,000 (1,175 euros, $1,650)). This finding was robust across a wide range of effectiveness estimates if the cheapest proton pump inhibitor was used. In our base case analysis, adding a proton pump inhibitor to a COX 2 selective inhibitor (used at the lowest licensed dose) was a cost effective option, even for patients at low risk of gastrointestinal adverse events (incremental cost effectiveness ratio approximately £10,000). Uncertainties around relative adverse event rates meant relative cost effectiveness for individual COX 2 selective inhibitors and traditional NSAIDs was difficult to determine.” (P. G. Conaghan, p.conaghan@leeds.ac.uk)

>>>PNN NewsWatch
* Lot numbers 31305429B and 31305430B of Teva’s Propofol Injectable Emulsion 10 mg/mL 100 mL vials have been recalled because of potentially elevated endotoxin levels. Postoperative fever, chills, and other flu-like symptoms have been reported in 41 patients, according to an FDA posting.

>>>PNN JournalWatch
* Near-Total Human Face Transplantation for a Severely Disfigured Patient in the USA, in Lancet, 2009; 374: 203–9. (M. Siemionow, siemiom@ccf.org)
* Intestinal Barrier Function: Molecular Regulation and Disease Pathogenesis, in Journal of Allergy and Clinical Immunology, 2009; 124: 3–20. (S. P. Hogan, simon.hogan@cchmc.org)
* Mechanisms of Liver Development: Concepts for Understanding Liver Disorders and Design of Novel Therapies, in Gastroenterology, 2009; 137: 62–79. (F. P. Lemaigre, frederic.lemaigre@uclouvain.be)
* Vaccine Supply, Demand, and Policy: A Primer, in Journal of the American Pharmacists Assoc., 2009; 49: e87–99. (R. R. Cline, cline011@umn.edu)
* Practice Parameter Update: Management Issues for Women with Epilepsy—Focus on Pregnancy (an evidence-based review): Teratogenesis and Perinatal Outcomes, in Neurology, 2009; 73: 133–41. (American Academy of Neurology, guidelines@aan.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 21, 2009 * Vol. 16, No. 138
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and July 21 issue of the Annals of Internal Medicine (2009; 151).
Mixed Effects of Tight Glycemic Control: Evidence continues to accumulate that tight glycemic control is not the panacea once hoped for in patients with type 2 diabetes. In a systematic review, authors show that intensive glucose control reduces the risk of some cardiovascular diseases but does not affect cardiovascular mortality or all-cause mortality—but it does increase the frequency of severe hypoglycemia (early release): “5 trials involving 27,802 adults were included. Intensive glucose targets were lower in the 3 most recent trials. Summary analyses showed that compared with conventional control, intensive glucose control reduced the risk for cardiovascular disease (relative risk [RR], 0.90 [95% CI, 0.83 to 0.98]; risk difference per 1,000 patients per 5 years [RD], –15 [CI, –24 to –5]) but not cardiovascular death (RR, 0.97 [CI, 0.76 to 1.24]; RD, –3 [CI, –14 to 7]) or all-cause mortality (RR, 0.98 [CI, 0.84 to 1.15]; RD, –4 [CI, –17 to 10]) and increased the risk for severe hypoglycemia (RR, 2.03 [CI, 1.46 to 2.81]; RD, 39 [CI, 7 to 71]). As was seen in the overall analyses, pooled findings from the early and more recent trials showed that intensive glucose control reduced the risk for cardiovascular disease and increased the risk for severe hypoglycemia.” (T. N. Kelly, tkelly@tulane.edu)
Antiretroviral Initiation in Resource-Limited Settings: Cost-effectiveness analysis of simulated models shows that earlier initiation of antiretroviral therapy is likely beneficial in the resource-limited South African setting (early release). The CEA takes a modified societal perspective and uses 5-year and lifetime horizons to make these observations about the timing of ART initiation in patients with HIV infection: “If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 109 cells/L would reduce severe opportunistic diseases by 22,000 to 221,000 and deaths by 25,000 to 253,000 during the next 5 years compared with ART initiation at 0.250 x 109 cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 109 cells/L. Compared with an initiation threshold of 0.250 x 109 cells/L, a threshold of 0.350 x 109 cells/L has an incremental cost-effectiveness ratio of $1,200 per year of life saved.” (R. P. Walensky)
HIV Susceptibility Testing During Antiretroviral Therapy: HIV-1 genotypic and phenotypic susceptibility testing (GPT) improved survival among patients treated previously with highly active antiretroviral therapy, researchers report (pp. 73–84). At 10 U.S. HIV clinics, 2,699 patients with HIV infection had these outcomes based on GPT status from 1999 through 2005: “Patients were followed for a median of 3.3 years; 915 (34%) had GPT. Patients who had GPT had lower mortality rates than those who did not (2.0 vs. 2.7 deaths per 100 person–years). In standard Cox models, GPT was associated with improved survival (adjusted HR, 0.69 [95% CI, 0.51 to 0.94]; P = 0.017) after controlling for demographic characteristics, CD4+ cell count, HIV RNA level, and intensity of clinical follow-up. In subgroup analyses, GPT was associated with improved survival for the 2,107 highly active antiretroviral therapy (HAART)–experienced patients (2.2 vs. 3.2 deaths per 100 person-years for patients who had GPT vs. those who did not have GPT; adjusted HR, 0.60 [CI, 0.43 to 0.82]; P = 0.002) and for the 921 triple antiretroviral class–experienced patients (2.1 vs. 3.1 deaths per 100 person–years; adjusted HR, 0.61 [CI 0.40 to 0.93]; P = 0.022). Marginal structural models supported associations between GPT and improved survival in the overall cohort (adjusted HR, 0.54; P = 0.001) and in the HAART-experienced group (adjusted HR, 0.56; P = 0.003).” (F. J. Palella Jr., f-palella@northwestern.edu)

>>>PNN NewsWatch
* FDA has licensed a 2009–10 seasonal influenza vaccine. It contains A/Brisbane/59/2007 (H1N1)-like virus, A/Brisbane/10/2007 (H3N2)-like virus, and B/Brisbane/60/2008-like virus. A second flu vaccine, one for novel H1N1 virus, is also being recommended, meaning that Americans will need two influenza vaccines this season.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 22, 2009 * Vol. 16, No. 139
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: July 22/29 issue of JAMA (2009; 302).
Preventing Cardiovascular Diseases: Two research studies and an editorial describe the important place of modifiable lifestyle factors in preventing heart failure in men and hypertension in women.
In a cohort of 20,900 apparently healthy men in the Physicians’ Health Study (PHS) I, a lower lifetime risk of heart failure was associated with adherence to six healthy lifestyle factors: body weight, smoking, exercise, alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables (pp. 394–400). “During a mean follow-up of 22.4 years, 1,200 men developed heart failure,” the authors write. “Overall, the lifetime risk of heart failure was 13.8% (95% confidence interval [CI], 12.9%–14.7%) at age 40 years. Lifetime risk remained constant in men who survived free of heart failure through age 70 years and reached 10.6% (95% CI, 9.4%–11.7%) at age 80 years. Lifetime risk of heart failure was higher in men with hypertension than in those without hypertension. Healthy lifestyle habits (normal body weight, not smoking, regular exercise, moderate alcohol intake, consumption of breakfast cereals, and consumption of fruits and vegetables) were individually and jointly associated with a lower lifetime risk of heart failure, with the highest risk in men adhering to none of the 6 lifestyle factors (21.2%; 95% CI, 16.8%–25.6%) and the lowest risk in men adhering to 4 or more desirable factors (10.1%; 95% CI, 7.9%–12.3%).” (L. Djoussé, ldjousse@rics.bwh.harvard.edu)
A lower risk of self-reported hypertension was evident among women adhering to low-risk dietary and lifestyle factors in the second Nurses Health Study (pp. 401–11). Used in the study were 6 low-risk factors for hypertension: body mass index (BMI) of less than 25, daily mean of 30 minutes of vigorous exercise, high score on the Dietary Approaches to Stop Hypertension (DASH) diet based on responses to a food frequency questionnaire, modest alcohol intake up to 10 g/d, use of nonnarcotic analgesics less than once per week, and intake of 400 mcg/d or more of supplemental folic acid. Results showed: “A total of 12,319 incident cases of hypertension were reported. All 6 modifiable risk factors were independently associated with the risk of developing hypertension during follow-up after also adjusting for age, race, family history of hypertension, smoking status, and use of oral contraceptives. For women who had all 6 low-risk factors (0.3% of the population), the hazard ratio for incident hypertension was 0.22 (95% confidence interval [CI], 0.10–0.51); the hypothetical [population attributable risk (PAR)] was 78% (95% CI, 49%–90%) for women who lacked these low-risk factors. The corresponding hypothetical absolute incidence rate difference (ARD) was 8.37 cases per 1,000 person–years. The PARs were 72% (95% CI, 57%–82%; ARD, 7.76 cases per 1,000 person–years) for 5 low-risk factors (0.8% of the population), 58% (95% CI, 46%-67%; ARD, 6.28 cases per 1,000 person–years) for 4 low-risk factors (1.6% of the population), and 53% (95% CI, 45%–60%; ARD, 6.02 cases per 1,000 person–years) for 3 low-risk factors (3.1% of the population). Body mass index alone was the most powerful predictor of hypertension, with a BMI of 25 or greater having an adjusted PAR of 40% (95% CI, 38%–41%) compared with a BMI of less than 25.” (J. P. Forman, jforman@partners.org)
The importance of personal action in the prevention of cardiovascular disease is of paramount important, an editorialist explains (pp. 437–9): “The national cost of treating cardiovascular diseases cannot be sustained, and prevention is urgent. Because prevention can benefit from policies aimed at creating a healthier environment, this approach must be expanded, with obvious targets being school-based meals provided to children, which still do not meet national dietary recommendations for good health, and the conceptualization and restructuring of the environment to promote physical activity. These and other public health measures should be envisioned as complementary and synergistic with clinical care, because unhealthy societal choices that lead to illness result in unsustainable strain on health care systems.” (V. L. Roger, roger.veronique@mayo.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 23, 2009 * Vol. 16, No. 140
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: July 23 issue and online content of the New England Journal of Medicine (2009; 361).
Vi Typhoid Vaccine Trial: In a Phase IV trial conducted in India, young children responded to immunization with Vi polysaccharide vaccine for typhoid fever, and unvaccinated neighbors were protected indirectly (pp. 335–44). Participants were ages 2 to 5 years, and single doses of Vi vaccine or inactivated hepatitis A vaccine produced these results over a 2-year period: “A total of 37,673 subjects received a dose of a study vaccine. The mean rate of vaccine coverage was 61% for the Vi vaccine clusters and 60% for the hepatitis A vaccine clusters. Typhoid fever was diagnosed in 96 subjects in the hepatitis A vaccine group, as compared with 34 in the Vi vaccine group, with no subject having more than one episode. The level of protective effectiveness for the Vi vaccine was 61% (95% confidence interval [CI], 41 to 75; P < 0.001 for the comparison with the hepatitis A vaccine group). Children who were vaccinated between the ages of 2 and 5 years had a level of protection of 80% (95% CI, 53 to 91). Among unvaccinated members of the Vi vaccine clusters, the level of protection was 44% (95% CI, 2 to 69). The overall level of protection among all residents of Vi vaccine clusters was 57% (95% CI, 37 to 71). No serious adverse events that were attributed to either vaccine were observed during the month after vaccination.” (J. D. Clemens, jclemens@ivi.int)
Hearing Improvement After Bevacizumab: Vascular endothelial growth factor (VEGF) blockade with bevacizumab produced hearing improvement in some but not all patients with neurofibromatosis type 2, researchers report (pp. 358–67). VEGF expression patterns were determined along with those of three of its receptors (VEGFR-2, neuropilin-1, and neuropilin-2) in schwannoma tissue samples, and 10 consecutive patients who were not candidates for standard neurofibromatosis treatment received bevacizumab, with these results: “VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2.” (S. R. Plotkin, splotkin@partners.org)
Pay for Performance in Primary Care: At 42 family practices in the U.K., pay-for-performance programs improved care of asthma and diabetes but not heart disease, and P4P was associated with declining quality of care for nonincentivized diseases and a reduced level of continuity of care (pp. 368–78). The investigators add: “The initial acceleration in the underlying rate of quality improvement after the introduction of pay for performance was not sustained.” (S. M. Campbell, stephen.campbell@manchester.ac.uk)
Need for Clinicians in Health Care Reform: Citing the experiences in the development of the National Health Service in the U.K., an author implores clinicians to get involved in the health care reform debate in this country, lest reforms be determined by bureaucrats and insurance companies (online only): “Clinicians must educate both policymakers and the wider public about appropriate levels of care. Health care systems all suffer from a disproportionately heavy focus on the treatment of acute illness and injury—the type of medical work glamorized on television—which consumes by far the most resources. But primary care accounts for most of the health care that is delivered: nearly a billion visits are made to physicians’ offices every year in the United States, but there are fewer than 40 million hospital stays. The current system of insurance and referrals can often lead to the unintended consequence of unnecessary referrals for the most expensive tests and treatments. Health problems related to lifestyle, such as obesity, smoking, and diabetes will be solved not by high-tech robotics and bigger hospitals but rather through access to family doctors, innovations in public health, and lessons from the emerging discipline of behavioral economics.” (A. Darzi)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 24, 2009 * Vol. 16, No. 141
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source: July issue of Medical Care (2009; 47).
Translating the Theory of Medical Homes into Practice: The medical home is a 1960s-era theory, authors write, that has become a centerpiece of the current health care reform debate (pp. 714–22). Defining what constitutes a medical home and translating this theory into practice will require much effort, the authors conclude: “Advocates for medical homes should be wary of overstating its short-term benefits, or of minimizing the commitment required for its implementation on the part of payers and providers. Health services researchers will need to play a critical role in identifying and refining evaluation metrics and in determining how best to interpret the findings. Tremendous opportunities exist to conduct large-scale research on the outcomes associated with [electronic health record] adoption and practice redesign. Future research can assess whether [National Committee for Quality Assurance (NCQA)] scores are correlated with patient-oriented measures such as [Consumer Assessment of Healthcare Providers and Systems] scores, and compare practices that have chosen to adopt different medical home elements with respect to quality and cost of care. The number of medical home eligibility criteria will create a series of natural experiments in which the effect of individual standards and elements can be measured. In doing so, health services researchers can answer the question: are the key elements of a medical home fundamentally different from the key elements of chronic care, or simply from high-quality [primary care]? Because such research has not preceded but rather will follow spread of the medical home concept, it may lead to a reexamination of the NCQA eligibility criteria. Providers, advocates and researchers are only at the beginning of determining what truly constitutes a medical home.” (E. Carrier, carrie02@med.nyu.edu)
Resident Duty Hours & Patient Safety: Patient safety indicators (PSIs) have been unaffected by regulations implemented in 2003 to prevent medical residents from working inordinately long duty shifts, researchers report (pp. 723–31). In VA and Medicare hospitals where some 14 million patients were cared for between 2000 and 2005, these patterns were apparent in a logistic regression analysis of PSIs and other factors: “Continuity of Care composite rates showed no significant changes postreform in hospitals of different teaching intensity in either VA or Medicare. In the VA, there were no significant changes postreform for the technical care composite. In Medicare, the odds of a Technical Care PSI event in more versus less teaching-intensive hospitals in postreform year 1 were 1.12 (95% CI; 1.01-1.25); there were no significant relative changes in postreform year 2. Other composite rates increased in VA in postreform year 2 in more versus less teaching-intensive hospitals (odds ratio, 1.63; 95% CI; 1.10-2.41), but not in Medicare in either postreform year.” (A.K. Rosen, akrosen@bu.edu)

>>>Health Affairs Report
Source: Jul/Aug issue of Health Affairs (2009; 28).
Primary Care: Reversing the decline in U.S. primary care is “essential to achieving health outcomes and health system performance comparable to those of other industrialized nations,” write authors (pp. 1136–45): “Five points [reimbursement, clinician workforce, medical education, practice infrastructure, health-system performance measurement] constitute a New Charter for Primary Care. It will take a concerted, coordinated effort advancing all five aspects nearly simultaneously to create real change. Such a charter will not be accepted or implemented without the creation of a strong political coalition capable of overcoming the advantages of inertia. Many stakeholders, however, have a common interest in promoting such a charter. Employers are recognizing that costs can be contained only with a strong primary care foundation for the health care system. Health plans and federal, state, and local governments, groaning under the weight of rising costs, would similarly benefit from the cost containment potential of primary care. Patients are currently organized chiefly into disease-specific organizations, but groups such as AARP, the Consumer Purchaser Disclosure group, and others could become active advocates of accessible, comprehensive, high-quality primary care. The formation of the Patient Centered Primary Care Coalition might prove to be an important step in creating the political force that can drive change.” (L.G. Sandy)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 27, 2009 * Vol. 16, No. 142
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: July 25 issue of Lancet (2009; 374).
Ketamine for Endotracheal Intubation: For rapid-sequence intubation of critically ill patients, ketamine provides a safe and effective alternative to etomidate and should be considered for those with sepsis, researchers conclude (pp. 293–300). In a randomized, controlled, single-blind trial of 655 patients, etomidate 0.3 mg/kg or ketamine 2 mg/kg for intubation produced these outcomes: “234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum [sequential organ failure assessment] score between the two groups did not differ significantly (10.3 [SD 3.7] for etomidate vs 9.6 [3.9] for ketamine; mean difference 0.7 [95% CI 0.0—1.4], p = 0.056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0—3] in both groups; p = 0.70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5—12.7). We recorded no serious adverse events with either study drug.” (F. Adnet, frederic.adnet@avc.aphp.fr)
HPV Vaccine & Cervical Infection/Precancers: In the Phase III randomized, double-blind, controlled PApilloma TRIal against Cancer In young Adults (PATRICIA), the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine was effective in patient cohorts that would be targeted in mass vaccination and catch-up programs (pp. 301–14). Analyzing data from an according-to-protocol cohort for efficacy (ATP-E; vaccine, n = 8,093; control, n = 8,069), the total vaccinated cohort (TVC, included all women receiving at least one vaccine dose, regardless of their baseline HPV status) and the TVC-naive cohort (no evidence of oncogenic HPV infection at baseline; represents women before sexual debut; vaccine, n = 5,822; control, n = 5,819) showed these patterns: “Mean follow-up was 34.9 months (SD 6.4) after the third dose. Vaccine efficacy against [cervical intraepithelial neoplasia 2+ (CIN2+)] associated with HPV-16/18 was 92.9% (96.1% CI 79.9—98.3) in the primary analysis and 98.1% (88.4—100) in an analysis in which probable causality to HPV type was assigned in lesions infected with multiple oncogenic types (ATP-E cohort). Vaccine efficacy against CIN2+ irrespective of HPV DNA in lesions was 30.4% (16.4—42.1) in the TVC and 70.2% (54.7—80.9) in the TVC-naive. Corresponding values against CIN3+ were 33.4% (9.1—51.5) in the TVC and 87.0% (54.9—97.7) in the TVC-naive. Vaccine efficacy against CIN2+ associated with 12 non-vaccine oncogenic types was 54.0% (34.0—68.4; ATP-E). Individual cross-protection against CIN2+ associated with HPV-31, HPV-33, and HPV-45 was seen in the TVC.” (J. Paavonen, Jorma.Paavonen@hus.fi)

>>>PNN NewsWatch
* Widespread or regional activity involving novel H1N1 influenza virus is evident in 20 American states currently, CDC said on Friday. As schools begin reopening next week, the rapid spread of the virus in summer camps in the U.S. could portend greater problems. “It’s very unusual for that kind of illness to be occurring at this time of the year,” explained Anne Schuchat, MD, director of the National Center for Immunization and Respiratory Diseases. “The Novel H1N1 viruses are making up 98% of all the subtyped viruses we have, subtype influenza A viruses, and we’re seeing them dominate here in the U.S.” In the Southern Hemisphere, where seasonal influenza is occurring, novel H1N1 has been found in many countries, Schuchat explained, adding, “This virus is capable of causing a range of illness. Severe life-threatening disease that requires intensive care unit and mechanical ventilation and also milder illness that gets better on its own. And this is really important for people to know this virus is out there, it’s circulating, it causes a range of illness and we in the United States have to get ready for the fall.”
* In other influenza-related developments, CDC on Friday released recommendations for seasonal influenza vaccine and FDA approved an additional diagnostic test for the 2009 H1N1 influenza virus.

>>>PNN JournalWatch
* Sleep in the ICU: Potential Mechanisms and Clinical Implications, in Chest, 2009; 136: 284–94. (K. A. Hardin, kahardin@ucdavis.edu)
* Impact of Androgen Deprivation Therapy on Cardiovascular Disease and Diabetes, in Journal of Clinical Oncology, 2009; 27: 3452–8. (S. M. H. Alibhai, shabbir.alibhai@uhn.on.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 28, 2009 * Vol. 16, No. 143
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: July 27 issue of the Archives of Internal Medicine (2009; 170).
Quality of Care & Drugs-to-Avoid Criteria: Drugs-to-avoid criteria are not accurate enough to be used as stand-alone measures of prescribing quality, write authors who had a physician–pharmacist team review the therapy of 256 Iowa City VA outpatients aged 65 years or older and taking 5 or more medications (pp. 1326–32). The study team’s assessment of each patient, as compared with the lists of Beers et al. and Zhan et al., showed these patterns: “In the study cohort, 256 patients were using 3,678 medications. The physician–pharmacist team identified 563 drugs (15%) as problematic, while 214 drugs (6%) were flagged as potentially inappropriate by the Beers criteria and 91 drugs (2.5%) were flagged as potentially inappropriate using the Zhan criteria. The kappa statistics for concordance between drugs-to-avoid criteria and expert assessments were 0.10 to 0.14, indicating slight agreement between these measures. Sixty-one percent of drugs identified as potentially inappropriate by the Beers criteria and 49% of drugs flagged by the Zhan criteria were not judged to be problematic by the expert reviewers. Correspondence between drugs-to-avoid criteria and expert assessment varied widely across different types of drugs.” (M. A. Steinman, mike.steinman@ucsf.edu)
A commentary author describes current approaches to evaluating drug therapy (pp. 1332–4): “The [Agency for Healthcare Research and Quality’s National Healthcare Quality Report] has included measures of adverse events from anticoagulants and hypoglycemic agents, and HEDIS has included a process measure of annual monitoring of persistent medications, including digoxin. The development and implementation of these measures is encouraging and hopefully will mark a trend away from measures based on potential errors by physicians with weak evidence of patient harm and toward measures directly linked by a strong evidence base to patient harm.” (D. S. Budnitz, dbudnitz@cdc.gov)
Antipsychotic Drugs & Hyperglycemia: Patients aged 66 years and older with diabetes are at increased risk of hospitalization for hyperglycemia during antipsychotic therapy, concludes a nested case–control study of health databases (pp. 1282–9). Concluding that the risk is particularly high during the initial course of treatment and with all first- and second-generation agents, the researchers report of 2002–06 Ontario data: “Of 13,817 patients studied, 1,515 (11.0%) were hospitalized for hyperglycemia. Current antipsychotic treatment was associated with a higher risk of hyperglycemia compared with remote antipsychotic use [discontinued more than 180 days previously] in all diabetes treatment groups (overall adjusted rate ratio, 1.50; 95% confidence interval, 1.29–1.74). The risk was increased among patients who were treated with atypical and typical antipsychotic agents and was extremely high among patients who were just starting treatment (only 1 prescription before event).” (L. L. Lipscombe, Lorraine.Lipscombe@wchospital.ca)
Anticholinergic Therapy & Cognitive Function: Older French patients were at significantly increased risk of cognitive decline and dementia when exposed to anticholinergic drugs, a study of 4,128 women and 2,784 men shows (pp. 1317–24): “A total of 7.5% of the participants reported anticholinergic drug use at baseline. Multivariate-adjusted logistic regression indicated that women reporting use of anticholinergic drugs at baseline showed greater decline over 4 years in verbal fluency scores (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.11–1.79) and in global cognitive functioning (OR, 1.22; 95% CI, 0.96–1.55) than women not using anticholinergic drugs. In men, an association was found with decline in visual memory (OR, 1.63; 95% CI, 1.08–2.47) and to a lesser extent in executive function (OR, 1.47; 95% CI, 0.89–2.44). Notable interactions were observed in women between anticholinergic use and age, apolipoprotein E, or hormone therapy. A 1.4- to 2-fold higher risk of cognitive decline was observed for those who continuously used anticholinergic drugs but not for those who had discontinued use. The risk of incident dementia over the 4-year follow-up period was also increased in continuous users (hazard ratio [HR], 1.65; 95% CI, 1.00–2.73) but not in those who discontinued the use of anticholinergic drugs (HR, 1.28; 95% CI, 0.59–2.76).” (M-L Ancelin, marie-laure.ancelin@inserm.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 29, 2009 * Vol. 16, No. 144
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source: Aug. issue of Pharmacotherapy (2009; 29).
Beta-1 Selectivity of Metoprolol with Increasing Doses: In 25 patients with American College of Cardiology Stage C heart failure, a dose-ranging study of beta-blockers shows that carvedilol is nonselective at all clinically relevant doses, but metoprolol succinate is beta-1 selective at low doses and progressively nonselective at higher doses (pp. 883–90). Initial doses were doubled every 2 weeks to maximum tolerated doses or a goal doses of carvedilol 25 mg twice daily and metoprolol 200 mg daily. Beta-2 selectivity tests with terbutaline before dose titration revealed: “As assessed by glucose [median area under the concentration-time curve (AUC)], there was no significant difference in the degree of beta-2-blockade between metoprolol 200 mg and carvedilol 25 mg. In contrast to these data, the degree of beta-2-blockade as assessed by potassium AUC was greater for carvedilol compared with metoprolol across all doses.” (M. Munger, mmunger@hsc.utah.edu)
Meta-analysis of COPD Drugs: In traditional and mixed-treatment comparison (MTC) meta-analyses of 43 trials of 31,020 patients with chronic obstructive pulmonary disease, combination inhaled corticosteroid–long-acting beta-2-agonist therapy had the greatest positive effect on outcomes, while tiotropium performed the best of the bronchodilator monotherapies (pp. 891–905). The authors report: “With MTC analysis, long-acting beta-2-agonists, tiotropium, inhaled corticosteroids, and combination inhaled corticosteroid–long-acting beta-2-agonist therapy each decreased the odds of having an exacerbation by 16%, 31%, 15%, and 24%, respectively, compared with placebo. Moreover, tiotropium use reduced the odds of having at least one exacerbation by 18% compared with long-acting beta-2-agonists and by 19% compared with inhaled corticosteroids alone. Each of the four drug classes was associated with significant odds reductions in patient withdrawals (26–41%) compared with placebo, and both tiotropium and combination therapy significantly decreased the odds of patient withdrawals compared with long-acting beta-2-agonists or inhaled corticosteroids alone. Only combination therapy was associated with a mortality benefit, showing a 29% reduction compared with placebo and a 25% reduction compared with long-acting beta-2-agonists alone. Compared with combination therapy, tiotropium use reduced exacerbations by 9% and increased mortality by only 4%. These findings did not demonstrate significant changes in the sensitivity or subgroup analyses, which were performed to evaluate the effect of heterogeneity among the included studies.” (C. I. Coleman, ccolema@harthosp.org)
Warfarin Interaction with Pomegranate Juice: A potential interaction between warfarin and pomegranate juice, as evidenced by subtherapeutic warfarin activity occurring when a patient stopped drinking the juice, should be investigated further, an author recommends (pp. 1002–6): “This case report describes a 64-year-old Caucasian woman who was treated with warfarin for recurrent deep vein thrombosis. She had been receiving a relatively stable dosage of warfarin 4 mg/day for several months, with stable international normalized ratios (INRs). During that time, the patient was consuming pomegranate juice 2–3 times/week. She stopped drinking the juice, and her INRs became subtherapeutic. Her dosage of warfarin was increased to maintain therapeutic anticoagulation. No rechallenge with pomegranate juice was performed. Use of the Drug Interaction Probability Scale indicated a possible relationship between the patient’s subtherapeutic INR and the pomegranate juice.” (K. E. Komperda, kkompe@midwestern.edu)

>>>PNN NewsWatch
* NIH announced yesterday that it has stopped a clinical trial, walk-PHaSST, testing sildenafil (Revatio, Pfizer) for treatment of pulmonary hypertension in adults with sickle cell disease nearly 1 year early because of safety concerns. An interim review of safety data from 33 participants who completed 16 weeks of treatment showed that those taking sildenafil were significantly more likely to have serious medical problems, including severe pain secondary to sickle cell crises, compared with those in the placebo arm.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 30, 2009 * Vol. 16, No. 145
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: July 30 issue of the New England Journal of Medicine (2009; 361).
Resistance to Artemisinin: Plasmodium falciparum is becoming resistant to first-line antimalarial artemisinin in western Cambodia, historically an area where such resistance has emerged (pp. 455–67). Two open-label, randomized trials compared oral artesunate with artesunate followed by mefloquine at two centers, one in Pailin, western Cambodia, and the other in Wang Pha, northwestern Thailand, with these results: “We studied 40 patients in each of the two locations. The overall median parasite clearance times were 84 hours (interquartile range, 60 to 96) in Pailin and 48 hours (interquartile range, 36 to 66) in Wang Pha (P < 0.001). Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients (30%) receiving artesunate monotherapy and 1 of 20 (5%) receiving artesunate–mefloquine therapy in Pailin, as compared with 2 of 20 (10%) and 1 of 20 (5%), respectively, in Wang Pha (P = 0.31). These markedly different parasitologic responses were not explained by differences in age, artesunate or dihydroartemisinin pharmacokinetics, results of isotopic in vitro sensitivity tests, or putative molecular correlates of P. falciparum drug resistance (mutations or amplifications of the gene encoding a multidrug resistance protein [PfMDR1] or mutations in the gene encoding sarco–endoplasmic reticulum calcium ATPase6 [PfSERCA]). Adverse events were mild and did not differ significantly between the two treatment groups.” (A. M. Dondorp, arjen@tropmedres.ac)
An editorialist writes of progress in development of malaria vaccines (pp. 522–3): “Malaria vaccines are moving from the laboratory into the real world. The vaccines that make it through testing and licensing will be deployed as part of malaria-control programs that distribute insecticide-treated bed nets and as an adjunct to control measures. Vaccines that can prevent, not just delay, the onset of infection would be a major plus in the endgame with falciparum transmission.…
“The coming 5 years will be decisive. Will there be a sustained commitment to deploying lifesaving interventions to reach a majority of persons at risk for malaria? Will national leaders and global financing agencies balance near-term success with longer-term programs and ensure that investment in research and development of new technologies remains a priority? The answer must be yes. The question is how. Millions of African children await the answer.” (C. C. Campbell)

>>>JAPhA Highlights
Source: Early-release article from and Jul/Aug issue of the Journal of the American Pharmacists Assoc. (2009; 29).
Pharmacist-Developed Protocol for Methadone Monitoring: Involvement of a pharmacist in implementation of a monitoring protocol proved more important than the protocol itself, researchers report (e102–9). In an academic family medicine setting from 2005 to 2008, a pharmacist-developed protocol calling for electrocardiographic monitoring of patients taking methadone was implemented in all clinics, including a chronic pain management clinic (PMC) where pharmacists practice. Results showed: “A 19% absolute (136% relative) increase occurred in the proportion of high-risk patients who had an ECG performed (P = 0.02). The proportion of high-risk patients from the PMC who had an ECG increased by 20% (absolute; 27% relative; P = 0.005), with no significant change in the other clinics.” (E. Weidman-Evans, eevans@lsuhsc.edu)
Sustaining In-Pharmacy Immunizations: Factors leading to sustainability of in-house pharmacy vaccination programs are identified through a survey of 104 Washington State pharmacies in 2006 (pp. 500–8). “Compatibility, which was defined as the fit between in-house immunization services and the host pharmacy, was the key to sustainability of immunization services. To enhance compatibility between in-house services and the host pharmacy, two pathways were found. First, in-house services underwent formal evaluations and subsequent modifications were made to the services. The second pathway bypassed the adaptation process. Through the second pathway, an operational champion implemented in-house services in a way that was already compatible with the host pharmacy.” (S. C. Westrick, westrsc@auburn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
July 31, 2009 * Vol. 16, No. 146
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source: Aug. issue of Diabetes Care (2009; 32).
Diet & Diabetes: Salt supplementation can affect patient’s renal response to telmisartan therapy, a study shows (pp. 1398–403), while a second paper reports that the DASH diet may help prevent type 2 diabetes (pp. 1434–6). In the 32-patient telmisartan study, those consuming low amounts of sodium chloride saw their antialbuminuric response decline with higher amounts of salt, both with and without concomitant hydrochlorothiazide therapy (E. I. Ekinci, eekinci2002@yahoo.com.au). Adherence to the DASH diet—rich in vegetables, fruit, and low-fat dairy products—was inversely proportional to incidence of type 2 diabetes among 862 participants in the Insulin Resistance Atherosclerosis Study (IRAS; A. D. Liese, liese@sc.edu).
Continuous Intraperitoneal Insulin: In 24 patients with type 1 diabetes, an open-label, crossover trial showed improved glycemic control but no significant reduction in hypoglycemic events over a 16-month period with continuous intraperitoneal insulin infusion (CIPII) with an implantable pump, compared with subcutaneous insulin (pp. 1372–7): “The incidence of grade 1 hypoglycemic events was 4.0 ± 2.6 per week with subcutaneous insulin compared with 3.5 ± 2.3 per week during CIPII (P = 0.13). The absolute mean difference in A1C with CIPII compared with subcutaneous treatment was −0.76% (95% CI −1.41 to −0.11) (P = 0.03). Baseline time spent in euglycemia was 45.2 ± 12.6% and increased 10.9% (4.6–17.3) with CIPII compared with subcutaneous treatment (absolute value; P = 0.003). There were no differences in the occurrence rate for severe hypoglycemic events, daily insulin use, or BMI. No pump or catheter malfunction was observed during the study.” (S. Logtenberg, s.j.j.logtenberg@isala.nl)
Continuous Glucose Monitoring: In 129 adults and children with type 1 diabetes that was treated intensively, continuous glucose monitoring produced better outcomes than did standard glucose monitoring (pp. 1378–83). “CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%,” the group concludes. (R. W. Beck, rbeck@jaeb.org)

>>>PNN NewsWatch
* The CDC’s Advisory Committee on Immunization Practices (ACIP) has named target groups for novel H1N1 influenza vaccination. Elderly patients—a primary target group for seasonal vaccine—were not included, as they have been relatively unaffected by the pandemic thus far. Their exclusion creates an education challenge, one of convincing the elderly and other target groups to receive the seasonal influenza vaccine and then encouraging overlapping but different target groups to return—perhaps for two doses—of the novel H1N1 influenza vaccine when it is ready later in the fall. Pharmacies are primary locations where CDC expects patients to receive both vaccines. The five target groups named by ACIP for novel H1N1 influenza vaccine are: (1) pregnant women, (2) people who live with or care for children younger than 6 months of age, (3) health care and emergency services personnel, (4) persons between the ages of 6 months and 24 years, and (5) people from ages 25 through 64 years who are at higher risk for novel H1N1 because of chronic health disorders or compromised immune systems. ACIP also provided guidance on prioritization in the event that supplies of the novel H1N1 vaccine are insufficient initially or not adequate in local situations.
* FDA yesterday announced approval of colchicine (Colcrys, Mutual Pharmaceutical) for treatment of acute flares in patients with gout and patients with familial Mediterranean fever (FMF). To assess the historical but unapproved use of hourly colchicine for acute gout flares until symptoms subside or GI symptoms become intolerable, FDA mandated a dosing study. It showed that one dose initially and a single additional dose after 1 hour was just as effective and less toxic as continued hourly dosing for acute gout flares. As a result, the drug is being approved for acute gout flares with this lower recommended dosing regimen. Physicians have also prescribed off-label colchicine for FMF for many years based on studies showing that it reduced the frequency of attacks. With this approval, colchicine becomes the first drug approved to treat FMF, the most common of the hereditary periodic fever syndromes.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 3, 2009 * Vol. 16, No. 147
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Aug. 1 issue of Lancet (2009; 374).
Resection in Stage III Non-Small-Cell Lung Cancer: In patients with stage IIIA non-small-cell lung cancer (N2) treated with chemotherapy plus radiotherapy, resection, preferably lobectomy, should be added when feasible, researchers conclude (pp. 379–86). Seeking to address the controversy over surgery after standard-of-care bimodal therapy for this condition, the investigators treated all patients with cisplatin/etoposide plus radiotherapy, followed by random allocation to resection (group 1) or continued radiotherapy (group 2), with these effects on overall survival (OS): “202 patients (median age 59 years, range 31—77) were assigned to group 1 and 194 (61 years, 32—78) to group 2. Median OS was 23.6 months (IQR 9.0—not reached) in group 1 versus 22.2 months (9.4—52.7) in group 2 (hazard ratio [HR] 0.87 [0.70—1.10]; p = 0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36—1.10]; p = 0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7—not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3—42.2) vs 10.5 months (4.8—20.6), HR 0.77 [0.62—0.96]; p = 0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy.” (K. S. Albain, kalbain@lumc.edu)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 339).
Patient Education in Respiratory Tract Infection: Antibiotic prescribing was reduced without adversely affecting parent/patient satisfaction with care through use of an educational booklet that explained, “After one week, more than three-quarters of those with a sore throat will be better whether they take antibiotics or not. Most (13 out of 14) who take antibiotics will get better just as quickly as if they had not taken them.” (b2885). Among 558 children seen at 61 U.K. general practices, these results were recorded: “Reconsultation occurred in 12.9% of children in the intervention group and 16.2% in the control group (absolute risk reduction 3.3%, 95% confidence interval –2.7% to 9.3%, P = 0.29). Using multilevel modelling (at the practice and individual level) to account for clustering, no significant difference in reconsulting was noted (odds ratio 0.75; 0.41 to 1.38). Antibiotics were prescribed at the index consultation to 19.5% of children in the intervention group and 40.8% of children in the control group (absolute risk reduction 21.3%, 95% confidence interval 13.7 to 28.9), P < 0.001). A significant difference was still present after adjusting for clustering (odds ratio 0.29; 0.14 to 0.60). There was also a significant difference in the proportion of parents who said they would consult in the future if their child developed a similar illness (odds ratio 0.34; 0.20 to 0.57). Satisfaction, reassurance, and parental enablement scores were not significantly different between the two groups.” (N. Francis, francisna@cf.ac.uk)

>>>PNN NewsWatch
* Saxagliptin (Onglyza, Bristol-Myers Squibb and AstraZeneca) has been approved by FDA as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The drug is the second dipeptidyl peptidase-4 inhibitor approved in the U.S., joining Merck’s sitagliptin (Januvia).

>>>PNN JournalWatch
* Advances in the Medical Treatment of Diabetic Retinopathy, in Diabetes Care, 2009; 32: 1556–62. (R. Simó, rsimo@ir.vhebron.net)
* Pregabalin: A New Approach to Treatment of the Dysautonomic Crisis, in Pediatrics, 2009; 124: 743–6. (F. B. Axelrod, felicia.axelrod@nyumc.org)
* Frequency and Severity of Harm of Medication Errors Related to the Parenteral Nutrition Process in a Large University Teaching Hospital, in Pharmacotherpay, 2009; 29: 966–74. (G. S. Sacks, gss0005@auburn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 4, 2009 * Vol. 16, No. 148
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release articles from and Aug. 4 issue of the Annals of Internal Medicine (2009; 151).
Hygiene in Influenza Transmission: In households where individuals have influenza, use of facemasks and hand hygiene reduces viral transmission, suggesting that such “nonpharmaceutical interventions are important for mitigation of pandemic and interpandemic influenza,” researchers report (early release). In Hong Kong, 749 household contacts of 407 patients who were positive for influenza A or B virus received either lifestyle education (control), hand hygiene, or surgical facemasks plus hand hygiene, with these results: “Sixty (8%) household contacts in the 259 households had [reverse transcription polymerase chain reaction (RT-PCR)]–confirmed influenza virus infection in the 7 days after intervention. Hand hygiene without or with facemasks seemed to reduce influenza transmission, but the differences in transmission compared with the control group were not statistically significant. In 154 households in which interventions were implemented within 36 hours of symptom onset in the index patient, transmission of RT-PCR–confirmed infection seemed to be reduced, an effect attributable to reductions in infection among participants using facemasks plus hand hygiene (adjusted odds ratio, 0.33 [95% CI, 0.13 to 0.87]). Adherence to interventions was variable.” (B. J. Cowling, bcowling@hku.hk)
Extended-Duration Antiviral Chemoprophylaxis Against Influenza: While associated with nausea and vomiting, extended-duration zanamivir and oseltamivir chemoprophylaxis prevented symptomatic influenza among immunocompetent white and Japanese adults, according to a meta-analysis of randomized, placebo-controlled, double-blinded human trials (early release). Neuraminidase inhibitors (NAIs) provided these benefits, the authors write: “Of 1,876 potentially relevant citations, 7 trials involving 7,021 unique participants met inclusion criteria. Data were pooled by using random-effects models. NAI chemoprophylaxis decreased the frequency of symptomatic influenza (relative risk [RR], 0.26 [95% CI, 0.18 to 0.37]; risk difference [RD], –3.9 percentage points [CI, –5.8 to –1.9 percentage points]) but not asymptomatic influenza (RR, 1.03 [CI, 0.81 to 1.30]; RD, –0.4 percentage point [CI, –1.6 to 0.9 percentage point). Adverse effects were not increased overall among NAI recipients (RR, 1.01 [CI, 0.94 to 1.08]; RD, 0.1 percentage point [CI, –0.2 to 0.4 percentage point), but nausea and vomiting were more common among those who took oseltamivir (RR, 1.48 [CI, 1.86 to 2.33]; RD, 1.7 percentage points [CI, 0.6 to 2.9 percentage points]). Prevention of influenza did not statistically significantly differ between zanamivir and oseltamivir.” (N. Khazeni)
Comparative Effectiveness Research: Comparative effectiveness research (CER), a controversial aspect cited by opponents of health care reform as a means of rationing and perhaps even euthanasia, is defined in a report from the Institute of Medicine (pp. 203–5). “CER is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition, or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels,” the report notes. The article makes recommendations for establishing a sustainable national CER program and provides recommendations for its infrastructure. (H. C. Sox)

>>>PNN NewsWatch
* FDA has announced approval a new statin, pitavastatin (Livalo, Kowa Pharmaceuticals America). Currently marketed in Japan, South Korea, Thailand, and China, pitavastatin will be marketed in the first quarter of 2010 in 1, 2, and 4 mg dosages. Its chemical structure includes a cyclopropyl group that the company claims contributes to a more effective inhibition of the HMG-CoA reductase enzyme and potentially affords greater LDL cholesterol clearance and reduction of plasma cholesterol. Also, Kowa notes, pitavastatin is only minimally metabolized by the liver through the cytochrome P450 pathway. Before the product is launched, Kowa plans to evaluate the U.S. market and seek a comarketing partner.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 5, 2009 * Vol. 16, No. 149
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Aug. 5 issue of JAMA, a theme issue on violence and human rights (2009; 302).
Asthma & Postraumatic Stress After World Trade Center Attacks: People exposed to the 9/11 terrorist attack on New York’s World Trade Center had high levels of asthma and posttraumatic stress (PS) symptoms 5–6 years after the 2001 event, researchers report (pp. 502–16). A longitudinal cohort study included wave 1 (W1) enrollment of 71,437 adults in 2003–04, including rescue/recovery workers, lower Manhattan residents, lower Manhattan office workers, and passersby and wave 2 (W2) completion of a 2006–07 survey by 46,322 members of the first group (68%). While asthmatic symptoms were highest in those cleaning up the disaster site, passersby who witnessed the event had the highest level of PTS symptoms: “Of W2 participants with no stated asthma history, 10.2% (95% confidence interval [CI], 9.9%–10.5%) reported new asthma diagnoses postevent. Intense dust cloud exposure on September 11 was a major contributor to new asthma diagnoses for all eligibility groups: for example, 19.1% vs 9.6% in those without exposure among rescue/recovery workers (adjusted odds ratio, 1.5 [95% CI, 1.4–1.7]). Asthma risk was highest among rescue/recovery workers on the WTC pile on September 11 (20.5% [95% CI, 19.0%–22.0%]). Persistent risks included working longer at the WTC site, not evacuating homes, and experiencing a heavy layer of dust in home or office. Of participants with no PTSD history, 23.8% (95% CI, 23.4%–24.2%) reported PTS symptoms at either W1 (14.3%) or W2 (19.1%). Nearly 10% (9.6% [95% CI, 9.3%–9.8%]) had PTS symptoms at both surveys, 4.7% (95% CI, 4.5%–4.9%) had PTS symptoms at W1 only, and 9.5% (95% CI, 9.3%–9.8%) had PTS symptoms at W2 only. At W2, passersby had the highest rate of PTS symptoms (23.2% [95% CI, 21.4%–25.0%]). Event-related loss of spouse or job was associated with PTS symptoms at W2.” (L. E. Thorpe, lthorpe@health.nyc.gov)
Elder Self-neglect and Abuse: Elder self-neglect and abuse is associated with an increased rate of mortality, according to the 1993–2005 longitudinal Chicago Health and Aging Project (CHAP; pp. 517–26). “Of 9,318 CHAP participants, 1,544 participants were reported for elder self-neglect and 113 participants were reported for elder abuse from 1993 to 2005. All CHAP participants were followed up for a median of 6.9 years (interquartile range, 7.4 years), during which 4,306 deaths occurred. In multivariable analyses, reported elder self-neglect was associated with a significantly increased risk of 1-year mortality (hazard ratio [HR], 5.82; 95% confidence interval [CI], 5.20–6.51). Mortality risk was lower but still elevated after 1 year (HR, 1.88; 95% CI, 1.67–2.14). Reported elder abuse also was associated with significantly increased risk of overall mortality (HR, 1.39; 95% CI, 1.07–1.84). Confirmed elder self-neglect or abuse also was associated with mortality. Increased mortality risks associated with either elder self-neglect or abuse were not restricted to those with the lowest levels of cognitive or physical function.” (X. Dong, xinqidong@gmail.com)
An editorialist calls for health professionals to focus on possible cases of elder self-neglect and abuse (pp. 570–1): “Assuming that the mortality related to elder self-neglect and abuse is causal, it could be interpreted as a failure of society and the health care system to adequately protect the most vulnerable older adults. To better address the complex needs of this burgeoning population, a stronger work force well prepared to care for older adults will be needed, as highlighted in a recent Institute of Medicine report. While awaiting evidence-based answers to the myriad unanswered questions regarding the epidemiology and management of elder self-neglect and abuse, health care professionals caring for older adults should act to renew the social contract with older individuals in the United States by supporting and expanding model programs for these potentially devastating disorders.” (T. M. Gill, thomas.gill@yale.edu)

>>>PNN NewsWatch
* Warnings about lymphomas and other cancers in patients taking tumor necrosis factor (TNF) blockers are being updated in product labeling, FDA announced yesterday. U.S. reports indicate that children and adolescents treated with TNF blockers have increased risk of cancers, with onset after an average of 30 months of therapy.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 6, 2009 * Vol. 16, No. 150
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Aug. 6 issue of the New England Journal of Medicine (2009; 361).
Treatment of Hepatitis C: Two peginterferon–ribavirin regimens were statistically similar when used in treatment of patients with chronic hepatitis C infection, a study shows (pp. 580–93). Doses (peginterferon alfa-2b at a standard dose of 1.5 mcg/kg/week or a low dose of 1.0 mcg/kg/week, plus ribavirin at a dose of 800–1,400 mg/day, or peginterferon alfa-2a at a dose of 180 mcg/week plus ribavirin at a dose of 1,000–1,200 mg/day) also made no difference over a 48-week period, as the results show: “Among 3,070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], –2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and –1.1% (95% CI, –5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively.” (J. G. McHutchison, mchut001@mc.duke.edu)
Thromboprophylaxis After Knee Replacement: The specific factor Xa inhibitor apixaban did not meet prespecified criteria for noninferiority, compared with enoxaparin, in a study of patients undergoing total knee replacement (pp. 594–604). But the agent was statistically similar to the older drug and had a lower propensity for bleeding when used before surgery and postoperatively for 10–14 days, the researchers report: “A total of 3,195 patients underwent randomization, with 1,599 assigned to the apixaban group and 1,596 to the enoxaparin group; 908 subjects were not eligible for the efficacy analysis. The overall rate of primary events was much lower than anticipated. The rate of the primary efficacy outcome was 9.0% with apixaban as compared with 8.8% with enoxaparin (relative risk, 1.02; 95% confidence interval, 0.78 to 1.32). The composite incidence of major bleeding and clinically relevant nonmajor bleeding was 2.9% with apixaban and 4.3% with enoxaparin (P = 0.03).” (M. R. Lassen, mirula@noh.regionh.dk)
Health Care Reform: Two of several articles on health care reform provide useful insights for pharmacists.
Quoting William Beveridge, the economist whose report led to establishment of the U.K. National Health Service, an author argues that it is a time for revolutions, not patches, in health care, and clinicians need to lead this effort (e8): “Clinicians must educate both policymakers and the wider public about appropriate levels of care. Health care systems all suffer from a disproportionately heavy focus on the treatment of acute illness and injury—the type of medical work glamorized on television—which consumes by far the most resources. But primary care accounts for most of the health care that is delivered: nearly a billion visits are made to physicians’ offices every year in the United States, but there are fewer than 40 million hospital stays. The current system of insurance and referrals can often lead to the unintended consequence of unnecessary referrals for the most expensive tests and treatments. Health problems related to lifestyle, such as obesity, smoking, and diabetes will be solved not by high-tech robotics and bigger hospitals but rather through access to family doctors, innovations in public health, and lessons from the emerging discipline of behavioral economics.” (A. Darzi)
To overcome fee constraints and externally imposed guidelines of managed care, physicians must “take on more financial responsibility for the choices they make on behalf of their patients,” an author writes. (pp. 623–8). He describes a system that can absorb risks and deliver information, thereby giving clinicians “the freedom to provide high-quality care at sustainable costs.” (H. S. Luft, lufth@pamfri.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 7, 2009 * Vol. 16, No. 151
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source: Aug. issue of the Journal of the American Geriatrics Society (2009; 57).
CPOE/Decision Support in the ED: Potentially inappropriate prescribing of medications for seniors was reduced through use of computerized physician order entry with decision support in an academic emergency department, researchers report (pp. 1388–94). Among 63 ED physicians, those in an intervention group that used CPOE systems advising against use of nine medications and suggesting safer alternatives showed these changes in medication prescribing: “The average age of the patients was 74, two-thirds were female, and just over half were African American. Decision support was provided 114 times to intervention physicians, who accepted 49 (43%) of the recommendations. Intervention physicians prescribed one or more inappropriate medications during 2.6% of ED visits by seniors, compared with 3.9% of visits managed by control physicians (P = .02; odds ratio = 0.55, 95% confidence interval = 0.34–0.89). The proportion of all prescribed medications that were inappropriate significantly decreased from 5.4% to 3.4%. The most common reason for rejecting decision support was that the patient had no prior problems with the medication.” (K. Terrell, kterrell@regenstrief.org)

>>>Psychiatry Highlights
Source: Aug. issue of the American Journal of Psychiatry (2009; 166).
Collaborative Suicide-Prevention Care in Seniors: Suicidality was reduced among 9,072 patients aged 60 years or older with major or minor depression when trained care managers used algorithms to offer recommendations to primary care physicians (pp. 882–90). In the Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT), interventions produced high utilization of depression treatment, reduced suicidal ideation, and improved the outcomes of major depression over 2 years among 9,072 patients, as follows: “Compared with patients receiving usual care, those receiving the intervention had a higher likelihood of receiving antidepressants and/or psychotherapy (84.9%–89% versus 49%–62%) and had a 2.2 times greater decline in suicidal ideation over 24 months. Treatment response occurred earlier on average in the intervention group and increased from months 18 to 24, while no appreciable increase in treatment response occurred in the usual care group during the same period. Among patients with major depression, a greater number achieved remission in the intervention group than in the usual-care group at 4 months (26.6% versus 15.2%), 8 months (36% versus 22.5%), and 24 months (45.4% versus 31.5%). Patients with minor depression had favorable outcomes regardless of treatment assignment.” (G. S. Alexopoulos, gsalexop@med.cornell.edu)

>>>PNN NewsWatch
* Alaris System electronic infusion pumps are the targets of a Class I recall, FDA announced yesterday. Cardinal Health recalled the pumps after identifying five problems, including failure of the occlusion warning message, syringe volume warning message, electrostatic discharge protection circuitry, and fluid ingress tubing.
* In a speech delivered yesterday in Washington, DC, Commissioner of Food and Drugs Margaret A. Hamburg, MD, said that her goal is an FDA that is “vigilant, strategic, quick, and visible.” She said she is committed “to prevent harm to the American people” through swift, aggressive, and effective enforcement of FDA laws and regulations. Hamburg added that some FDA enforcement actions over the past several years “have been hampered by unreasonable delays” and “in some cases, serious violations have gone unaddressed for far too long.” She added that the pathways for enforcement actions “can be too long and arduous when the public’s health is in jeopardy.” The Commissioner’s speech is available for viewing online.
* Generic drug names for Botox/Botox Cosmetic, Dysport, and Myobloc have been changed “to reinforce individual potencies and prevent medication errors,” FDA has announced. Seeking to differentiate among the various indications for the two types of botilinum toxin, FDA is requiring that a table of approved products and uses be added to the labeling of each product reflecting these new drug names: onabotulinumtoxinA (Botox or Botox Cosmetic), abobotulinumtoxinA (Dysport), and rimabotulinumtoxinB (Myobloc).

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 10, 2009 * Vol. 16, No. 152
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Aug. 8 issue of Lancet (2009; 374).
H1N1 2009 Influenza During Pregnancy: Morbidity and mortality figures from 34 pregnant women who were infected by the pandemic H1N1 2009 influenza virus support the need for early interventions in this population (pp. 451–8). During the initial weeks of the outbreak in the U.S., these outcomes in confirmed or probable cases were reported to the CDC: “From April 15 to May 18, 2009, 34 confirmed or probable cases of pandemic H1N1 in pregnant women were reported to CDC from 13 states. 11 (32%) women were admitted to hospital. The estimated rate of admission for pandemic H1N1 influenza virus infection in pregnant women during the first month of the outbreak was higher than it was in the general population (0.32 per 100,000 pregnant women, 95% CI 0.13–0.52 vs 0.076 per 100,000 population at risk, 95% CI 0.07–0.09). Between April 15 and June 16, 2009, six deaths in pregnant women were reported to the CDC; all were in women who had developed pneumonia and subsequent acute respiratory distress syndrome requiring mechanical ventilation.” (D. J. Jamieson, DJamieson@cdc.gov)
Treating Early Rheumatoid Arthritis: For patients whose early rheumatoid arthritis does not respond to methotrexate, addition of a tumor necrosis factor antagonist is clinically superior to conventional disease-modifying antirheumatic drugs, according to data from the Swedish Pharmacotherapy (Swefot) study (pp. 459–66). Patients (n = 487) with RA symptoms of less than a year’s duration were treated with methotrexate up to 20 mg/week. Those not responding within 3–4 months randomly received either sulfasalazine and hydroxychloroquine or infliximab, with these results based on a primary outcome of achievement of a good response according to European League Against Rheumatism criteria at 12 months: “Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10–2.30], p = 0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group.” (R.F. van Vollenhoven, ronald.van.vollenhoven@ki.se)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 339).
Corticosteroids for Pain Relief in Sore Throat: Corticosteroids are a useful addition to antibiotics in patients with sore throat, especially those with severe symptoms or exudate, according to authors of a systematic review and meta-analysis (b2976): “We included eight trials, consisting of 743 patients in total (369 children, 374 adults). 348 (47%) had exudative sore throat, and 330 (44%) were positive for group A beta-haemolytic streptococcus. In addition to antibiotics and analgesia, corticosteroids significantly increased the likelihood of complete resolution of pain at 24 hours (four trials) by more than three times (relative risk 3.2, 95% confidence interval 2.0 to 5.1), and at 48 hours (three trials) to a lesser extent (1.7, 1.3 to 2.1). Corticosteroids (six trials) reduced mean time to onset of pain relief by more than 6 hours (95% confidence interval 3.4 to 9.3, P < 0.001), although significant heterogeneity was present. The mean time to complete resolution was inconsistent across trials and a pooled analysis was not undertaken. Reporting of other outcomes was limited.” (M. Thompson, matthew.thompson@dphpc.ox.ac.uk)

>>>PNN JournalWatch
* Contraception for Women: An Evidence Based Overview, in BMJ, 2009; 339: b2895. (J-J Amy, jeanjacques.amy@skynet.be)
* Pharmacological Management of Persistent Pain in Older Persons, in Journal of the American Geriatrics Society, 2009; 57: 1331–46. (E. Ickowicz, eickowicz@americangeriatrics.org)
* Primary Care Guidelines for the Management of Persons Infected with Human Immunodeficiency Virus: 2009 Update by the HIV Medicine Association of the Infectious Diseases Society of America, in Clinical Infectious Diseases, 2009; 49: 651–81. (J. A. Aberg, judith.aberg@nyumc.org)
* Safety of Long-Acting Beta-Agonists: Are New Data Really Required?, in Chest, 2009; 136: 604–7. (M. R. Sears, searsm@mcmaster.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 11, 2009 * Vol. 16, No. 153
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Aug. 10/24 issue of the Archives of Internal Medicine (2009; 170).
Thiazolidinediones & Fracture Risk: Both men and women are at greater risk of fractures when taking thiazolidinediones, especially pioglitazone, report authors of a prospective cohort study of 84,339 patients in British Columbia (pp. 1395–402). Comparing peripheral fracture rates in those who began treatment with a thiazolidinedione or a sulfonylurea, the investigators found: “The mean age of the patients in the study was 59 years, and 43% were women. In this cohort, treatment with a thiazolidinedione was associated with a 28% increased risk of peripheral fractures compared with treatment with a sulfonylurea (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.10–1.48). The use of pioglitazone hydrochloride was associated with an increased risk of peripheral fracture of 77% in women (HR, 1.76; 95% CI 1.32–2.38). Compared with exposure to sulfonylureas, exposure to pioglitazone was associated with more peripheral fractures in men (HR, 1.61; 95% CI 1.18–2.20), but we did not observe a similar association with exposure to rosiglitazone (HR, 1.00; 95% CI, 0.75–1.34).” (C. R. Dormuth, colin.dormuth@ti.ubc.ca)
Outcomes with Tiotropium in COPD: Mixed results were found when tiotropium was combined with other medications in treatment of chronic obstructive pulmonary disease, researchers report (pp. 1403–10). In a study of two separate cohorts in the VA system, tiotropium reduced mortality risks when combined with inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA). But adverse outcomes occurred when the drug was combined with other agents for COPD, the authors report, as follows: “For 42,090 patients in the base case, the regimen of tiotropium +ICS + LABA was associated with 40% reduced risk of death (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.45–0.79) compared with ICS + LABA. This combination was associated with reduced rates of COPD exacerbations (HR, 0.84; 95% CI, 0.73–0.97) and COPD hospitalizations (HR, 0.78; 95% CI, 0.62–0.98). Tiotropium in combination with 2 other medications was associated with increased risk of mortality, exacerbations, and hospitalizations.” (T. A. Lee, toddlee@uic.edu)
Bayesian Classification of Clinical Practice Guidelines: Ranking evidence according to the methodological quality of study data fails to consider the clinical relevance of findings, authors argue, concluding that a Bayesian approach to clinical practice guidelines is needed (pp. 1431–5): “We herein propose a more formal quantitative algorithm for the construction of guidelines using Bayes’s theorem to integrate the clinical trial evidence with a range of prior belief representing the skeptical point of view embodied in the null hypothesis (to the effect that treatment can be expected to produce no reduction in risk), and the enthusiastic point of view embodied in the alternative hypothesis (to the effect that treatment can be expected to produce a specified clinically important reduction in risk). The operative practical utility of this algorithm is illustrated by application to a representative meta-analysis of [randomized controlled trials]. We conclude that this quantitative schema has the potential to improve the quality and cost of evidence-based clinical management.” (G. A. Diamond, gadiamond@pol.net)
Hospitalists & Quality of Care: Commenting on a study showing that hospitals with hospitalists have a higher quality of care than do institutions without them (pp. 1389–94; L. López, llopez1@partners.org), editorialists make suggestions for future analyses of care in the inpatient setting (pp. 1351–2): “As a young field, hospital medicine has strengths and weaknesses. Future investigations should focus on defining the strengths and minimizing the weaknesses. We believe that hospitalists can help decrease hospital errors and improve safety if they are totally integrated with hospital processes and supported as champions for these important efforts. Lumping hospitalists without a consideration of organizational differences could hide the promise of excellent hospitalist groups. The major contribution of hospital medicine should involve system improvement along with excellent bedside care. We must understand the contributors as well as the detractors to excellence for the hospitalist movement to achieve its full potential.” (R. M. Centor, rcentor@uab.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 12, 2009 * Vol. 16, No. 154
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Aug. 12 issue of JAMA (2009; 302).
Aspirin & Colorectal Cancer Survival: In a prospective cohort study of 1,279 men and women with colorectal cancer, regular aspirin use, even at low doses, was associated with lower risk of both cancer-specific and overall mortality, with the benefits particularly pronounced among those whose tumors overexpressed cyclooxygenase 2 (pp. 649–58). Data from participants in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) were available from the 1980s through 2008, and participants had self-reported aspirin use based on milligrams ingested per week. Results showed these trends for post-diagnosis use of aspirin: “After a median follow-up of 11.8 years, there were 193 total deaths (35%) and 81 colorectal cancer–specific deaths (15%) among 549 participants who regularly used aspirin after colorectal cancer diagnosis, compared with 287 total deaths (39%) and 141 colorectal cancer–specific deaths (19%) among 730 participants who did not use aspirin. Compared with nonusers, participants who regularly used aspirin after diagnosis experienced a multivariate hazard ratio (HR) for colorectal cancer–specific mortality of 0.71 (95% confidence interval [CI], 0.53–0.95) and for overall mortality of 0.79 (95% CI, 0.65–0.97). Among 719 participants who did not use aspirin before diagnosis, aspirin use initiated after diagnosis was associated with a multivariate HR for colorectal cancer–specific mortality of 0.53 (95% CI, 0.33–0.86). Among 459 participants with colorectal cancers that were accessible for immunohistochemical assessment, the effect of aspirin differed significantly according to cyclooxygenase 2 (COX-2) expression (P for interaction = .04). Regular aspirin use after diagnosis was associated with a lower risk of colorectal cancer–specific mortality among participants in whom primary tumors overexpressed COX-2 (multivariate HR, 0.39; 95% CI, 0.20–0.76), whereas aspirin use was not associated with lower risk among those with primary tumors with weak or absent expression (multivariate HR, 1.22; 95% CI, 0.36-4.18).” Counting four daily 81-mg tablets as a 325-mg dose of aspirin, the study showed that patients taking the equivalent of 0.5 to 5 standard 325-mg tablets per week had adjusted reductions in colorectal cancer–specific and overall mortality of 43% and 31%, respectively. Those numbers for six or more 325-mg doses per week were 51% and 39%, respectively. (A. T. Chan, achan@partners.org)
Writing of a “promising new twist for an old drug” in an era of personalized medicine, an editorialist makes these points (pp. 688–9): “A major recent priority in clinical oncology has been to develop biomarkers for prognosis and to predict response to specific interventions. This quest for so-called personalized medicine reflects the serious toxicity of most cancer drugs with the concomitant low response; better definition of who is likely to respond would identify a smaller subgroup that is much more likely to benefit and spare other patients the toxicity. Such biomarkers reflect the longstanding success of hormone receptors and ERBB2 status in breast cancer to determine use of hormonal therapy and trastuzumab. In colorectal cancer, KRAS mutations have recently attained similar status as predictors of response to cetuximab and panitumumab, and BRAF mutations are likely to achieve similar status soon. The specificity of the response of colorectal cancers to aspirin for patients in whom tumors overexpressed COX-2 suggests that this potential future treatment comes with its own ready-made predictive biomarker.” (A. I. Neugut, ain1@columbia.edu)
Assessing Influenza History: Commentary authors write of the need to understand “influenza backward” (pp. 679–80): “If summer weather in the Northern Hemisphere slows viral spread, transmission may well resurge again in the fall or winter to create a seasonal wave, but pandemic history suggests that changes neither in transmissibility nor in pathogenicity are inevitable. It will be critical to assess the effect of large-scale pandemic outbreaks in the Southern Hemisphere in the current and coming (winter) months. Once again, influenza is showing its latest tricks and must be watched closely to understand what is happening. It is well to remember that, as Kierkegaard said about life, influenza epidemics are lived forward and understood backward.” (J. K. Taubenberger, taubenbergerj@niaid.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 13, 2009 * Vol. 16, No. 155
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Aug. 13 issue of the New England Journal of Medicine (2009; 361).
Severe Respiratory Disease with H1N1 Influenza: Two articles provide information and analysis of early cases of novel swine-origin influenza A (H1N1) virus (S-OIV) in Mexico.
The danger of severe respiratory disease with the S-OIV, especially in those born after the 1957 pandemic, is evident in the first study (pp. 674–9). Reported to the Mexican Ministry of Health between Mar. 24 and Apr. 29 of this year were 2,155 cases of severe pneumonia that led to 821 hospitalizations and 100 deaths. Nearly 30% of nasopharyngeal specimens during this period were positive for S-OIV. Researchers report these additional data: “During the study period, 87% of deaths and 71% of cases of severe pneumonia involved patients between the ages of 5 and 59 years, as compared with average rates of 17% and 32%, respectively, in that age group during the referent periods. Features of this epidemic were similar to those of past influenza pandemics in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population.” The group concludes: “During the early phase of this influenza pandemic, there was a sudden increase in the rate of severe pneumonia and a shift in the age distribution of patients with such illness, which was reminiscent of past pandemics and suggested relative protection for persons who were exposed to H1N1 strains during childhood before the 1957 pandemic. If resources or vaccine supplies are limited, these findings suggest a rationale for focusing prevention efforts on younger populations.” (S. M. Bertozzi, sbertozzi@correo.insp.mx)
The second article reports the following clinical and epidemiologic characteristics of persons hospitalized for pneumonia at the national tertiary hospital for respiratory illnesses in Mexico City who had laboratory-confirmed S-OIV infection (pp. 680–9): “From March 24 through April 24, 2009, a total of 18 cases of pneumonia and confirmed S-OIV infection were identified among 98 patients hospitalized for acute respiratory illness at the National Institute of Respiratory Diseases in Mexico City. More than half of the 18 case patients were between 13 and 47 years of age, and only 8 had preexisting medical conditions. For 16 of the 18 patients, this was the first hospitalization for their illness; the other 2 patients were referred from other hospitals. All patients had fever, cough, dyspnea or respiratory distress, increased serum lactate dehydrogenase levels, and bilateral patchy pneumonia. Other common findings were an increased creatine kinase level (in 62% of patients) and lymphopenia (in 61%). Twelve patients required mechanical ventilation, and seven died. Within 7 days after contact with the initial case patients, a mild or moderate influenza-like illness developed in 22 health care workers; they were treated with oseltamivir, and none were hospitalized.” (R. Perez-Padilla, perezpad@gmail.com)
Interpreting Drug-Risk Information: The benefits of a Congressionally mandated “Sentinel” system containing data on drug exposure and clinical events are discussed in a Perspective article (pp. 647–9): “The Sentinel system will have the potential to identify and quantify adverse-event signals with unprecedented power and speed. In doing so, it could help to optimize medications’ safety and benefit–risk relationships. Getting the system to function will be daunting but achievable, but making sure the numbers it generates are epidemiologically rigorous and clinically helpful will be of paramount importance. Ultimately, knowing what those numbers mean for practice and communicating that meaning effectively will present the biggest challenges of all.” (J. Avorn)

>>>PNN NewsWatch
* FDA yesterday issued a final rule, “Expanded Access to Investigational Drugs for Treatment Use,” that clarifies existing regulations and adds new types of expanded access to investigational drugs for treatment use. In 60 days, expanded access to investigational drugs for treatment use will be available to individual patients, including in emergencies; intermediate-size patient populations; and larger populations under a treatment protocol or treatment investigational new drug application.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 14, 2009 * Vol. 16, No. 156
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source: Aug.18 issue of the Journal of the American College of Cardiology (2009; 54).
High-Dose Atorvastatin Before PCI: A high-dose burst of atorvastatin improves the outcomes of patients on chronic statin therapy when they are undergoing percutaneous coronary intervention, according to results of the ARMYDA (Atorvastatin for Reduction of Myocardial Damage During Angioplasty) RECAPTURE study (pp. 558–65). The 383 study participants had stable angina (53%) or non–ST-segment elevation acute coronary syndromes (47%) and were on chronic statin therapy. Atorvastatin reload (80 mg 12 h before intervention, with a further 40-mg preprocedural dose) produced these results based on a primary end point of 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, or unplanned revascularization): “The primary end point occurred in 3.7% of patients treated with atorvastatin reload and in 9.4% in the placebo arm (p = 0.037); this difference was mostly driven by reduction in periprocedural myocardial infarction. There was lower incidence of post-procedural creatine kinase-myocardial band and troponin-I elevation greater than the upper limit of normal in the atorvastatin arm (13% vs. 24%, p = 0.017, and 37% vs. 49%, p = 0.021, respectively). Multivariable analysis identified atorvastatin reload as a predictor of decreased risk of 30-day incidence of major adverse cardiac events (odds ratio: 0.50, 95% confidence interval: 0.20 to 0.80; p = 0.039), mainly in patients with acute coronary syndromes (82% relative risk reduction; p = 0.027).” (G. Di Sciascio, g.disciascio@unicampus.it)
Prasugrel with GP IIb/IIIa Inhibitor in ACS/PCI: Prasugrel proved superior to clopidogrel in patients with acute coronary syndromes, some of whom were also receiving glycoprotein IIb/IIIa inhibitors, following percutaneous coronary intervention (pp. 678–85). In the TRITON–TIMI 38, 30-day end points in 13,608 randomized participants showed the following: “A total of 7,414 subjects (54.5%) received a GP IIb/IIIa inhibitor during their index hospitalization. There was a consistent benefit of prasugrel over clopidogrel for reducing cardiovascular death, myocardial infarction, or stroke in patients who did (hazard ratio: 0.76; 95% confidence interval: 0.64 to 0.90) or did not receive a GP IIb/IIIa inhibitor (hazard ratio: 0.78; 95% confidence interval: 0.63 to 0.97, pinteraction = 0.83). Prasugrel significantly reduced myocardial infarction, urgent revascularization, and stent thrombosis irrespective of GP IIb/IIIa inhibitor use. Although subjects treated with a GP IIb/IIIa inhibitor had greater rates of bleeding, the risk of Thrombolysis in Myocardial Infarction major or minor bleeding with prasugrel versus clopidogrel was not significantly different in patients who were or were not treated with GP IIb/IIIa inhibitor (pinteraction = 0.19).” (M. O’Donoghue, modonoghue@partners.org)
Bariatric, Dietary Weight Loss Reverse Heart Changes: Cardiovascular responses to excess weight are reversible through weight loss induced either by bariatric surgery or diet, researchers report (pp. 718–26). Cardiac magnetic resonance imaging showed these patterns in 30 obese participants who lost weight (17 by diet and 13 by surgery) and 7 obese patients with continued obesity: “Left and right ventricular masses were significantly increased, left ventricular diastolic function impaired, and aortic distensibility reduced in the obese. Both diet and bariatric surgery led to comparable, significant decreases in left and right ventricular masses, end-diastolic volume, and diastolic dysfunction, and an increase in aortic distensibility at all levels of the aorta, most pronounced distally (e.g., distal descending aorta 5.1 ± 1.8 mm Hg–1 x 10–3 before weight loss and 6.8 ± 2.5 mm Hg–1 x 10–3 after weight loss; p < 0.001). No improvements were observed in continued obesity.” (S. Neubauer, stefan.neubauer@cardiov.ox.ac.uk)

>>>PNN NewsWatch
* An abuse-resistant opioid product was approved by FDA yesterday. Embeda (King Pharmaceuticals) contains morphine sulfate and naltrexone hydrochloride in extended-release capsules that provide around-the-clock analgesia with a single oral dose. Taken as directed, an inner core containing naltrexone is not released, but if the product is tampered with by crushing or chewing, the opioid antagonist counteracts the morphine effects.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 17, 2009 * Vol. 16, No. 157
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Aug. 15 issue of Lancet (2009; 374).
Lowering Target Systolic BP Targets: The goal for systolic blood pressures in nondiabetic patients with hypertension should be reduced, based on results from the Cardio-Sis (Studio Italiano Sugli Effetti CARDIOvascolari del Controllo della Pressione Arteriosa SIStolica) trial (pp. 525–33). At 44 Italian centers, 1,111 patients with systolic blood pressures of 150 mm Hg or greater were randomly assigned to treatment with a target systolic blood pressure of less than 140 mm Hg (usual control) or less than 130 mm Hg (tight control). Using a primary endpoint of the rate of electrocardiographic left ventricular hypertrophy identified within 2 years after randomization, the authors found: “Over a median follow-up of 2.0 years (IQR 1.93–2.03), systolic and diastolic blood pressure were reduced by a mean of 23.5/8.9 mm Hg (SD 10.6/7.0) in the usual-control group and by 27.3/10.4 mm Hg (11.0/7.5) in the tight-control group (between-group difference 3.8 mm Hg systolic [95% CI 2.4–5.2], p < 0.0001; and 1.5 mm Hg diastolic [0.6—2.4]; p = 0.041). The primary endpoint occurred in 82 of 483 patients (17.0%) in the usual-control group and in 55 of 484 patients (11.4%) of the tight-control group (odds ratio 0.63; 95% CI 0.43–0.91; p = 0.013). A composite cardiovascular endpoint occurred in 52 (9.4%) patients in the usual-control group and in 27 (4.8%) in the tight-control group (hazard ratio 0.50, 95% CI 0.31–0.79; p = 0.003). Side-effects were rare and did not differ significantly between the two groups.” (P. Verdecchia, verdec@tin.it)
Surgical v. Warfarin Management of Nonvalvular Atrial Fibrillation: Percutaneous closure of the left atrial appendage (LAA) provides a noninferior alternative to warfarin therapy in patients with nonvalvular atrial fibrillation, researchers conclude (pp. 435–42). In the PROTECT AF (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) study, 707 patients participated based on their having at least one of the following: previous stroke or transient ischemic attack, congestive heart failure, diabetes, hypertension, or age of 75 years or older. Comparing surgical closure with warfarin therapy titrated to INRs of 2.0 to 3.0 and assessing results based on a primary composite endpoint of stroke, cardiovascular death, and systemic embolism, the investigators noted: “At 1,065 patient–years of follow-up, the primary efficacy event rate was 3.0 per 100 patient–years (95% credible interval [CrI] 1.9–4.5) in the intervention group and 4.9 per 100 patient–years (2.8–7.1) in the control group (rate ratio [RR] 0.62, 95% CrI 0.35–1.25). The probability of non-inferiority of the intervention was more than 99.9%. Primary safety events were more frequent in the intervention group than in the control group (7.4 per 100 patient–years, 95% CrI 5.5–9.7, vs 4.4 per 100 patient–years, 95% CrI 2.5–6.7; RR 1.69, 1.01–3.19).” (D. R. Holmes, holmes.david@mayo.edu)
>>>PNN NewsWatch
* FDA on Friday announced approval of the second-generation (atypical) antipsychotic agent asenapine (Saphris, Schering-Plough) for treatment of adults with schizophrenia or bipolar I disorder. The product carries the class boxed warning of increased risk of death associated with off-label use of second-generation antipsychotic agents for treatment of behavioral problems in older people with dementia-related psychosis. The most common adverse reactions reported by patients in clinical trials being treated for schizophrenia with asenapine were akathisia, oral hypoesthesia, and somnolence. In bipolar trials, somnolence, dizziness, movement disorders other than akathisia, and weight increase.
* Glucose test strips that use the reagent glucose dehydrogenase pyrroloquinoline quinone should not be used in patients also receiving therapeutic products containing nonglucose sugars (maltose, galactose, and xylose), as test results may be falsely elevated, FDA announced. Peritoneal dialysis solutions and certain immunoglobulins contain the sugars.

>>>PNN JournalWatch
* Neuraminidase Inhibitors for Treatment and Prophylaxis of Influenza in Children: Systematic Review and Meta-analysis of Randomised Controlled Trials, in BMJ, 2009; 339: b3172. (M. Thompson, matthew.thompson@dphpc.ox.ac.uk)
* The CD40/CD40 Ligand System: Linking Inflammation with Atherothrombosis, in the Journal of the American College of Cardiology, 2009; 54: 669–77. (C. Antoniades, antoniades@vodafone.net.gr)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 18, 2009 * Vol. 16, No. 158
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Aug. 18 issue of the Annals of Internal Medicine (2009; 151).
Chinese Herbal Supplement for Rheumatoid Arthritis: A significantly greater response in patients with active rheumatoid arthritis was observed with a Chinese herbal supplement than with sulfasalazine, researchers report (pp. 229–40). Extracts of the medicinal plant Tripterygium wilfordii Hook F (TwHF), administered as 60 mg three times daily and sulfasalazine 1 g twice daily showed these effects in 121 patients with active disease and 6 or more painful, swollen joints based on 20% improvement in the American College of Rheumatology criteria (ACR 20): “Outcome data were available for only 62 patients at 24 weeks. In a mixed-model analysis that imputed data for patients who dropped out, 65.0% (95% CI, 51.6% to 76.9%) of the TwHF group and 32.8% (CI, 21.3% to 46.0%) of the sulfasalazine group met the ACR 20 response criteria (P = 0.001). Patients receiving TwHF also had significantly higher response rates for ACR 50 and ACR 70 in mixed-model analyses. Analyses of only completers showed similar significant differences between the treatment groups. Significant improvement was demonstrated in all individual components of the ACR response, including the Health Assessment Questionnaire disability score. Interleukin-6 levels rapidly and significantly decreased in the TwHF group. Although not statistically significant, radiographic progression was lower in the TwHF group. The frequency of adverse events was similar in both groups.” (R. Goldbach-Mansky, goldbacr@mail.nih.gov)
Effects of Free Antiretroviral Treatment Program: In China, a free national antiretroviral program lowered mortality among adults with HIV infection, but the cumulative immunologic treatment failure rate was 50% at 5 years because of lack of availability of second-line medications (pp. 241–51). The National Free Antiretroviral Treatment Program admitted more than 52,000 patients in 2002–08, with these results: “Of 52,191 patients, 48,785 were included. Median age was 38 years, 58% were men, 53% were infected through plasma or blood, and the median baseline CD4 cell count was 0.118 x 109 cells/L. Mortality was greatest during the first 3 months of treatment (22.6 deaths per 100 person–years) but decreased to a steady rate of 4 to 5 deaths per 100 person–years after 6 months and maintained this rate over the subsequent 4.5 years. The strongest mortality risk factors were a baseline CD4 cell count less than 0.050 x 109 cells/L (adjusted hazard ratio [HR] compared with a count 0.200 x 109 cells/L, 3.3 [95% CI, 2.9 to 3.8]) and having 4 to 5 baseline symptom categories (adjusted HR compared with no baseline symptom categories, 3.4 [CI, 2.9 to 4.0]). Treatment failure was determined among 31,070 patients with 1 or more follow-up CD4 cell counts. Overall, treatment failed for 25% of patients (12.0 treatment failures per 100 person–years), with the cumulative treatment failure rate increasing to 50% at 5 years.” (F. Zhang, treatment@chinaaids.cn)
Pharmacogenetics in Warfarin Dosing: The time for incorporating pharmacogenetics into warfarin dosing has not yet come, authors of a Perspective article argue (pp. 270–3): “Warfarin pharmacogenetic analysis is now commercially available, and results can help predict starting and maintenance doses. However, genetics account for only about one third of all dosing variation, and whether knowledge of polymorphisms reduces bleeding and thrombotic complications remains unclear. Testing has not been shown to be cost-effective. In our estimation, testing does not seem to be as important as full consideration of clinical factors coupled with conscientious prothrombin time monitoring and sage dosage adjustment. Warfarin has always been problematic, and genetic testing is unlikely to make our job as practitioners easier. Even if genetic analysis is ultimately found to play some role, clinical management of warfarin will continue to be difficult and demanding for those who undertake it. Further study is required before warfarin pharmacogenetic testing can be recommended.” (M. H. Rosove, mrosove@mednet.ucla.edu)

>>>PNN NewsWatch
* Some 45 million doses of novel H1N1 influenza vaccine will be available by mid-October, HHS announced yesterday. Availability is delayed by manufacturing problems, but some 20 million doses should be added weekly after that date.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 19, 2009 * Vol. 16, No. 159
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Aug. 19 issue of JAMA (2009; 302).
HPV Vaccine: A research study, Special Communication, and editorial focus on quadrivalent human papillomavirus recombinant vaccine (qHPV).
Girls and women immunized with qHPV had rates of adverse events after immunization (AEFIs) similar to those of other vaccines, but higher frequencies of syncope and venous thromboembolism have been reported to the Vaccine Adverse Event Reporting System (VAERS) (pp. 750–7). Data from 2006–08 show the following: “VAERS received 12,424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.” (B. A. Slade, bfs9@cdc.gov)
Implications for “adolescent health and medical professionalism” and criticisms of Merck educational and promotional activities are detailed in the second article (pp. 781–6): “The messages and the methods by which the [HPV] vaccine was marketed present important challenges to physician practice and medical professionalism. By making the vaccine’s target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to adolescents was maximized, and the subpopulations most at risk practically ignored. The vaccine manufacturer also provided educational grants to professional medical associations (PMAs) concerned with adolescent and women’s health and oncology. The funding encouraged many PMAs to create educational programs and product-specific speakers’ bureaus to promote vaccine use. However, much of the material did not address the full complexity of the issues surrounding the vaccine and did not provide balanced recommendations on risks and benefits. As important and appropriate as it is for PMAs to advocate for vaccination as a public good, their recommendations must be consistent with appropriate and cost-effective use.” (S. M. Rothman, smr4@columbia.edu)
The editorialist adds this perspective on HPV vaccine (pp. 795–6): “When weighing evidence about risks and benefits, it is also appropriate to ask who takes the risk, and who gets the benefit. Patients and the public logically expect that only medical and scientific evidence is put on the balance. If other matters weigh in, such as profit for a company or financial or professional gains for physicians or groups of physicians, the balance is easily skewed. The balance will also tilt if the adverse events are not calculated correctly.” (C. Haug, charlotte.haug@legeforeningen.no)
Antibiotic Prescribing for Respiratory Tract Infections: In an analysis of prescribing patterns for acute respiratory tract infections in 1995 and 2006, researchers found that prescribing of antibiotics declined overall but increased for the broad-spectrum quinolones and azithromycin (pp. 758–66). The latter pattern has implications for the “emergence of antibiotic-resistant microorganisms, in particular [Streptococcus] pneumoniae,” the group concludes. (C. G. Grijalva, carlos.grijalva@vanderbilt.edu)
Lower Estradiol Doses in Receptor-Positive Breast Cancer: Estradiol doses of 6 mg daily provided equivalent clinical benefits as 30-mg doses, and with fewer serious adverse events, in a study of women with advanced aromatase inhibitor–resistant hormone receptor–positive breast cancer (pp. 774–80). Three of seven patients with estradiol-sensitive disease responded to retreatment with aromatase inhibitors, which suggests resensitization to estrogen deprivation, the authors note. They conclude: “6 mg of estradiol daily, which produces estradiol levels similar to those in ovulating premenopausal women, is an active low-cost treatment for postmenopausal women with advanced breast cancer and acquired resistance to aromatase inhibitor treatment and should be further investigated.” (M. J. Ellis, mellis@dom.wustl.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 20, 2009 * Vol. 16, No. 160
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Aug. 20 issue of the New England Journal of Medicine (2009; 361).
Denosumab & Bone Mineral Density: Two research studies and an editorial present data on use of the monoclonal antibody denosumab for preventing and treating bone loss in men and women.
In 1,468 men receiving androgen-deprivation therapy for nonmetastatic prostate cancer, denosumab increased bone mineral density in the lumbar spine, femoral neck, and total hip significantly better than placebo (pp. 745–55). Results showed these effects of 60-mg doses of the receptor activator of nuclear factor-kappa-B ligand subcutaneously every 6 months: “At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P < 0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P = 0.006). Rates of adverse events were similar between the two groups.” (M. R. Smith, smith.matthew@mgh.harvard.edu)
In women with osteoporosis, denosumab 60 mg subcutaneously every 6 months produced significantly fewer vertebral, nonvertebral, and hip fractures than did placebo, researchers report (pp. 756–65). Using a primary end point of new vertebral fracture and secondary end points of nonvertebral and hip fractures, this 36-month trial showed: “As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P < 0.001)—a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P = 0.04) — a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) — a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.” (S. R. Cummings, hglicklandes@sfcc-cpmc.net)
An editorialist places these findings in a broader context (pp. 818–20). “The real need in osteoporosis treatment is for additional anabolic agents. The use of teriparatide leads to new bone formation, but not all patients have a response to treatment, and the skeletal response wanes over time, limiting its anabolic effect. Fortunately, a number of anabolic drugs are in development, and an increasing number of treatment options will be available. Beyond the science driving new drug development, however, will remain the art of being a physician. Specifically, our success or failure in combating osteoporosis increasingly depends not so much on the drugs available to us but rather on our ability to engage our patients and ensure that they take the medications we prescribe.” (S. Khosla)
Heroin for Opioid Addiction: Injectable diacetylmorphine was significantly more effective for treating opioid addiction than oral methadone, Canadian researchers conclude based on study of 226 patients, but overdoses and seizures occurred more commonly with the injectable agent (pp. 777–86; M. T. Schechter, martin.schechter@ubc.ca) An editorialist notes the history of this controversial agent (pp. 820–1): “Switzerland and the Netherlands have integrated the prescription of heroin into their medical systems, while Germany and Spain have hesitated. In the mid-1990s, the Australian government discontinued a heroin trial. Will the ‘homegrown’ results from the [this] trial have more impact in North America than the results from Europe? We will now wait to see what political or professional factors will support or oppose the conclusions of this study in its home territory, and whether the historical legacy of heroin will matter.” (V. Berridge)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 21, 2009 * Vol. 16, No. 161
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source: Aug. issue of the Journal of Allergy and Clinical Immunology (2009; 124).
Predicting Asthma Activity: Among patients highly adherent to antiasthmatic therapies being treated using guidelines, various predictors of asthma activity “have little predictive power,” authors of a 546-patient study conclude (pp. 213–21.e1). Participants in the Asthma Control Evaluation Study were adolescents and young adults, and evaluation of a number of predictive clinical indicators showed these results over a 46-week period: “The baseline characteristics we examined accounted for only a small portion of the variance for future maximum symptom days and exacerbations—11.4% and 12.6%, respectively. Future exacerbations were somewhat predicted by asthma symptoms, albuterol use, previous exacerbations, and lung function, whereas maximum symptom days were predicted, also to a modest extent, by symptoms, albuterol use, and previous exacerbations, but not lung function.” (R. S. Gruchalla, Rebecca.Gruchalla@utsouthwestern.edu)
Ambiguity in Food-Allergy Labels: Consumers with food allergies are challenged by vague and ambiguous food labels, a study shows (pp. 337–41). Calling for additional regulation of such labels, the investigators note these findings from a supermarket survey of unique manufactured food products: “Overall, 17% of 20,241 products surveyed contain advisory labels. Chocolate candy, cookies, and baking mixes were the 3 categories of 24 with the greatest frequency (≥40%). Categorically, advisory warnings included ‘may contain’ (38%), ‘shared equipment’ (33%), and ‘within plant’ (29%). The subsurvey disclosed 25 different types of advisory terminology. Nonspecific terms, such as ‘natural flavors’ and ‘spices’ were found on 65% of products and were not linked to a specific ingredient for 83% of them. Additional ambiguities included unclear sources of soy (lecithin vs protein), nondisclosure of sources of gelatin and lecithin, and simultaneous disclosure of ‘contains’ and ‘may contain’ for the same allergen, among others.” (M. M. Pieretti, mariah.pieretti@mssm.edu)

>>>Rheumatology Highlights
Source: Aug. issue of Arthritis & Rheumatism (2009; 60).
MTX Catabolism & Efficacy: Phenotypic variations can alter patient responses to methotrexate, according to a study of patients with rheumatoid arthritis, and folic/folinic acid supplementation can alter the response (pp. 2257–61). The MTX catabolite, 7-OH MTX, was determined using two 24-hour urine collections, and patient symptoms at weeks 6 and 7 were determined. In addition, folic acid and folinic acid were administered in doses of 1 mg/day between weeks 6 and 7, with these results: “Folic acid inhibited aldehyde oxidase (AO), the enzyme that produces 7-OH-MTX, but folinic acid did not. Excretion of 7-OH-MTX (determined as a percentage of the dose of MTX or as mg 7-OH-MTX/gm creatinine) was not normally distributed (n = 39). Patients with marked improvement in swelling and pain/tenderness indices had a lower mean 7-OH-MTX excretion level (P < 0.05). Patients who received folic acid supplements had decreased 7-OH-MTX excretion (P = 0.03). Relatively high 7-OH-MTX excretion was correlated with relatively high MTX excretion and with relatively low MTX retention in vivo (P < 0.05) (n = 35).” (S. L. Morgan, slmorgan@uab.edu)

>>>PNN NewsWatch
* FDA has approved Hiberix (GlaxoSmithKline), a Haemophilus influenzae Type b (Hib) vaccine, as a booster dose for children 15 months through 4 years old. The approval addresses a nationwide shortage of Hib vaccine that began in December 2007 due to a voluntary recall by the manufacturer and subsequent production suspension of Merck’s PedvaxHIB and COMVAX, two of four vaccines licensed in the United States for primary and booster immunization against invasive disease due to Hib.
* Eight companies must seek FDA approval of unlawful topical ibuprofen products they are currently marketing, the agency said yesterday. Warning letters have been issued for the products Emuprofen, BioEntropic 15% Ibuprofen Crème, Ibunex Topical Ibuprofen, LoPain AF 15% Ibuprofen Crème, IB-RELIEF, Profen HP, IbuPRO-10 Plus, and IBU-RELIEF 12.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 24, 2009 * Vol. 16, No. 162
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source: Early-release articles from BMJ (2009; 339).
Risks of Glitazones: Continued use of rosiglitazone “may not be justified,” according to authors of a study showing a significantly lower risk of heart failure and death with pioglitazone (b2942). Noting that the two drugs produced similar clinical results in patients with diabetes, the investigators provide these findings from a retrospective cohort study of patients in Ontario aged 66 years or older that used a composite outcome measure of death or hospital admission for either acute myocardial infarction or heart failure: “39,736 patients who started on either pioglitazone or rosiglitazone were identified. During the six year study period, the composite outcome was reached in 895 (5.3%) of patients taking pioglitazone and 1,563 (6.9%) of patients taking rosiglitazone. After extensive adjustment for demographic and clinical factors and drug doses, pioglitazone treated patients had a lower risk of developing the primary outcome than did patients treated with rosiglitazone (adjusted hazard ratio 0.83, 95% confidence interval 0.76 to 0.90). Secondary analyses revealed a lower risk of death (adjusted hazard ratio 0.86, 0.75 to 0.98) and heart failure (0.77, 0.69 to 0.87) with pioglitazone but no significant difference in the risk of acute myocardial infarction (0.95, 0.81 to 1.11). One additional composite outcome would be predicted to occur annually for every 93 patients treated with rosiglitazone rather than pioglitazone.” (D. Juurlink, dnj@ices.on.ca)
Smokeless Tobacco Use & Cardiovascular Events: People using smokeless tobacco products have higher risks of fatal myocardial infarction and stroke, conclude authors of a systematic review and meta-analysis (b3060). “11 studies, mainly in men, were included,” the authors write. “Eight risk estimates were available for fatal myocardial infarction: the relative risk for ever use of smokeless tobacco products was 1.13 (95% confidence 1.06 to 1.21) and the excess risk was restricted to current users. The relative risk of fatal stroke, on the basis of five risk estimates, was 1.40 (1.28 to 1.54). The studies from both the United States and Sweden showed an increased risk of death from myocardial infarction and stroke. The inclusion of non-fatal myocardial infarction and non-fatal stroke lowered the summary risk estimates. Data on dose-response were limited but did not suggest a strong relation between risk of dying from either disease and frequency or duration of use of smokeless tobacco products.” (P. Boffetta, boffetta@iarc.fr)

>>>Lancet Highlights
Source: Aug. 22 issue of Lancet (2009; 374).
Mortality in Patients with Schizophrenia: A population-based cohort study from Finland, the FIN11 study, indicates that restrictions on use of clozapine should be reassessed (pp. 620–7). Antipsychotic drug use produced lower long-term mortality among nearly 67,000 patients with schizophrenia than no use. Clozapine produced the lowest mortality risk (HR, 0.74), while quetiapine produced significantly higher risks (1.41), compared with perphenazine. (J. Tiihonen, jari.tiihonen@niuva.fi)

>>>PNN NewsWatch
* Vigabatrin (Sabril, Lundbeck) Oral Solution has been approved to treat infantile spasms in children ages 1 month to 2 years, FDA announced on Friday. The first drug approved in the U.S. for this use, vigabatrin was previously approved for adult use in combination with other medications to treat complex partial seizures that have not responded adequately to previous drug therapies.

>>>PNN JournalWatch
* Clinical Diagnosis of Depression in Primary Care: A Meta-analysis, in Lancet, 2009; 374: 609–19. (A. J. Mitchell, Alex.Mitchell@leicspart.nhs.uk)
* Idiopathic Retroperitoneal Fibrosis: A Review of the Pathogenesis and Approaches to Treatment, in American Journal of Kidney Diseases, 2009; 54: 546–53. (R. D. Swartz, rswartz@umich.edu)
* The Challenge of Follow-on Biologics for Treatment of Multiple Sclerosis, in Neurology, 2009; 73: 552–9. (S. C. Reingold, scra.llc@earthlink.net)
* The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies that Evaluate Health Care Interventions: Explanation and Elaboration, in Annals of Internal Medicine, 2009; 151: W-65–W-94. (A. Liberati, alesslib@mailbase.it)
* The Public’s Acceptance of Novel Vaccines During a Pandemic: A Focus Group Study and its Application to Influenza H1N1, in Emerging Health Threats Journal, 2009; 2: e8. (N. Henrich, natalie.henrich@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 25, 2009 * Vol. 16, No. 163
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source: Sept. 1/15 issues of Clinical Infectious Diseases (2009; 49).
Rosiglitazone in Malaria: Peroxisome proliferator–activated receptor gamma agonists such as rosiglitazone provide a useful adjunct to antimalarial therapy aimed at nonsevere cases of Plasmodium falciparum infection, researchers report (pp. 841–9). In a Phase I/II trial conducted in Thailand, 140 patients received rosiglitazone 4 mg or placebo twice daily for 4 days, with these results: “For the 70 patients who received rosiglitazone, parasite clearance from peripheral blood was significantly enhanced, compared with the 70 patients who received a placebo (mean 50% [parasite clearance time (PCT)], 19.0 h vs. 24.6 h [P = .029]; mean 90% PCT, 30.9 h vs. 40.4 h [P = .004]). Also, the patients who received rosiglitazone had reduced inflammatory responses to infection, compared with the patients who received a placebo (ie, interleukin-6 levels at 24 h [P < .005] and at 48 h [P = .013] and monocyte chemoattractant protein-1 level at 48 h [P = .05]). There were no significant differences between the 2 groups with regard to safety and tolerability of treatment, and there were no admissions the intensive care unit or deaths.” (K. C. Kain, kevin.kain@uhn.on.ca)
Impact of Quinolone Restrictions on Resistance: The number of urinary Escherichia coli isolates resistant to quinolones declined immediately in a community after restriction of ciprofloxacin prescribing was restricted across Israel (pp. 869–75). In a retrospective, quasi-experimental ecological study before, during, and after the restriction, the proportion of quinolone-susceptible E. coli urine isolates showed these patterns: “We found a significant decline in quinolone consumption, measured as defined daily doses (DDDs) per month, between the preintervention and intervention periods (point estimate, −1,827.3 DDDs per month; 95% confidence interval [CI], −2,248.8 to −1,405.9 DDDs per month; P < .001). This decline resulted in a significant decrease in E. coli nonsusceptibility to quinolones, from a mean of 12% in the preintervention period to a mean of 9% in the intervention period (odds ratio, 1.35; P = .014). The improved susceptibility pattern reversed immediately when quinolone consumption rose. Moreover, a highly significant inverse relationship was found between the level of quinolone use (regardless of intervention period) and the susceptibility of E. coli urine isolates to quinolone (odds ratio, 1.70; 95% CI, 1.26–2.28). During the months of highest quinolone use (8,321 DDDs per month), the proportion of nonsusceptibility was 14%, whereas during the months of lowest quinolone use (4,027 DDDs per month), the proportion of nonsusceptibility was 9%. An average decrease in resistance of 1.16% was observed for each decrease of 1,000 DDDs.” (M. Chowers, chowersm@post.tau.ac.il)
Inevitable Hospital-Acquired Infections: Despite inclusion of hospital-acquired infections on a Medicare list of nonreimbursable “never events,” prevention of “significant proportions” of cases of iatrogenic infection is not possible, authors of a Viewpoint article argue (pp. 743–6). “Attempts to eliminate [nosocomial infections] may have unwanted clinical and economic outcomes, and compliance with coding and billing requirements will have a significant effect on research conducted using administrative databases. Although this reimbursement change is a step toward reducing the rate of preventable adverse events, its current form does not provide guidance with regard to how hospitals may hope to reduce the rate of these infections, and it uses individual case-based rather than process-based or population-based outcome measures, which makes benchmarking and goalsetting difficult.” (F. Doloresco, frediii@buffalo.edu)

>>>PNN NewsWatch
* The safety of orlistat is the focus of an ongoing review, FDA said yesterday. The agency received 32 reports of serious liver injury in patients taking orlistat in 1999–2008, with 30 of the cases from outside the U.S. The cases included 27 patients who were hospitalized and 6 with liver failure. The most commonly reported adverse events with the weight-loss drug, marketed as Xenical and Alli, included jaundice, weakness, and stomach pain.
* In a blog posted yesterday, APhA CEO Tom Menighan provides an assessment of prospects for health care reform and inclusion of pharmacy-favorable provisions in the bills.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 26, 2009 * Vol. 16, No. 164
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Aug. 26 issue of JAMA (2009; 302).
Genetics of Platelet Response to Clopidogrel: Patients with a specific cytochrome P450 genotype, CYP2C19*2, have diminished platelet response to clopidogrel and poorer cardiovascular outcomes, according to the Pharmacogenomics of Antiplatelet Intervention (PAPI) study conducted in 2006–08 (pp. 849–57). Researchers used ex vivo platelet aggregometry, genotyping, and examination of platelet function and cardiovascular outcomes in an independent sample of 227 patients undergoing percutaneous coronary intervention to gather the following results: “Platelet response to clopidogrel was highly heritable (h2 = 0.73; P < .001). Thirteen single-nucleotide polymorphisms on chromosome 10q24 within the CYP2C18–CYP2C19–CYP2C9–CYP2C8 cluster were associated with diminished clopidogrel response, with a high degree of statistical significance (P = 1.5 x 10–13 for rs12777823, additive model). The rs12777823 polymorphism was in strong linkage disequilibrium with the CYP2C19*2 variant, and was associated with diminished clopidogrel response, accounting for 12% of the variation in platelet aggregation to ADP (P = 4.3 x 10–11). The relation between CYP2C19*2 genotype and platelet aggregation was replicated in clopidogrel-treated patients undergoing coronary intervention (P = .02). Furthermore, patients with the CYP2C19*2 variant were more likely (20.9% vs 10.0%) to have a cardiovascular ischemic event or death during 1 year of follow-up (hazard ratio, 2.42; 95% confidence interval, 1.18–4.99; P = .02).” (A. R. Shuldiner, ashuldin@medicine.umaryland.edu)
Antiplatelet therapy is close to requiring a patient-tailored pharmacogenomic approach, an editorialist writes (pp. 896–7): “The study by Shuldiner et al moves closer to fulfilling the promise of pharmacogenomic testing in tailoring antiplatelet therapy to the individual patient. Strides toward individualized therapy have already been made in cancer care and human immunodeficiency virus treatment. Antiplatelet therapy seems well suited to a tailored approach, and future investigations should pursue this promising area.” (D. L. Bhatt, dlbhattmd@alum.mit.edu)
Drug-Resistant Typhoid Fever: Based on analysis of 1,902 U.S. cases of typhoid fever, CDC researchers report an increasing proportion of Salmonella ser Typhi strains with decreased susceptibility to fluoroquinolones (pp. 859–65). Travel to the Indian subcontinent was common among those with typhoid fever, and 13% of clinical isolates had multidrug resistance (ampicillin, chloramphenicol, and trimethoprim–sulfamethoxazole). In addition, 38% were resistant to nalidixic acid, and 97% of those strains also had decreased ciprofloxacin susceptibility. (M. F. Lynch, mlynch1@cdc.gov)
Hormonal Therapy in Prostate Cancer: All-cause mortality is significantly increased among men with coronary artery disease–associated congestive heart failure or myocardial infarction who receive neoadjuvant hormonal therapy following radiation treatment of prostate cancer (pp. 866–73). During a median follow-up period of 5.1 years, 26.3% of those with prior CAD-induced CHF or MI died, compared with 11.2% of such men who did not receive neoadjuvant HT. Among men without CAD events or with only one CAD risk factor, no such association was found between all-cause mortality and neoadjuvant HT use. (A. Nanda, ananda@partners.org)

>>>PNN NewsWatch
* Last night’s passing of Sen. Edward M. Kennedy of Massachusetts will likely leave a vacancy in the Senate for at least 5 months, placing Democrats 1 vote short of cloture as the important health care reform debate moves forward. A 2004 change in Massachusetts law requires a special election in the event of a Senate vacancy, and the vote comes 145–160 days later, the New York Times reports. Also, Kennedy was chair of the important Senate Committee on Health, Education, Labor, & Pensions, one of two Senate panels considering HCR legislation. While the death of this champion of causes such as universal health care may reunite Democrats around one of the centerpieces of his long legislative legacy, whether it will also bring some GOP colleagues into a spirit of bipartisanship on HCR is much less certain.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 27, 2009 * Vol. 16, No. 165
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source: Aug. 27 issue of the New England Journal of Medicine (2009; 361).
Uncontrolled Hypertension: Despite successes in hypertension over the past 50 years—especially its diagnosis and research into hypotensive medications—adequate treatment of the disease has not kept pace, the author of a Special Article writes (pp. 878–87): “The increase in body weight in the population is a critical factor in the increase in the prevalence of hypertension.… To combat obesity, support from families, schools, community and religious organizations, government, insurers, food and beverage industries, health care providers, and the general public will be essential. Population-wide strategies—such as redesigning of roads and walkways to promote cycling and walking and the expansion of school health education and physical education programs—should be combined with individually targeted interventions to alter dietary intake and increase physical activity. Recent progress provides some cause for optimism: public awareness of the major contributors to childhood obesity and the health risks involved has increased, and support has grown for making a number of essential changes, some of which are beginning to be mandated in several states.” (A. V. Chobanian, achob@bu.edu)
Public Health Preparedness & Health Care Reform: Elements of health care reform are critical to the nation’s preparedness for public health emergencies such as the H1N1 (novel) influenza pandemic now occurring, according to a Perspective author who now serves in the Obama administration (pp. 843–5). The article, written before the author was appointed as Assistant Secretary for Preparedness and Response in HHS, makes these observations in advance of the department’s upcoming presentation of a national health security strategy, scheduled to go to Congress in Dec.: “A key challenge facing public health officials who are planning responses to a potentially more severe H1N1 influenza epidemic this fall is finding a way to quickly link information regarding who is vaccinated to information about the subsequent use of health care services by these people. Such linking will be essential for detecting and interpreting reports of adverse events after vaccination and determining the effectiveness of vaccines in preventing illness. Whereas some countries with universal health care systems can readily gather and use such information, the fact that not all Americans are accounted for in our system and the lack of [health information technology] make it impossible to do so in most of the United States.” (N. Lurie)

>>>Gastroenterology Report
Source: Aug. issue of Gastroenterology (2009; 137).
Antidiabetic Therapies & Pancreatic Cancer: In patients with diabetes, those who had used metformin have lower risks of developing pancreatic cancer, while patients on insulin or insulin secretagogues have an increased risk, researchers report (pp. 412–5). Among 973 patients with pancreatic adenocarcinoma (including 259 patients with diabetes) and 863 controls (including 109 patients with diabetes), these findings were identified for 2004–08: “Diabetic patients who had taken metformin had a significantly lower risk of pancreatic cancer compared with those who had not taken metformin (odds ratio, 0.38; 95% confidence interval, 0.22–0.69; P = .001), with adjustments for potential confounders. This difference remained statistically significant when the analysis was restricted to patients with a duration of diabetes >2 years or those who never used insulin. In contrast, diabetic patients who had taken insulin or insulin secretagogues had a significantly higher risk of pancreatic cancer compared with diabetic patients who had not taken these drugs.” (D. Li, dli@mdanderson.org)

>>>PNN NewsWatch
* Stolen vials of Levemir (Novo Nordisk) still may be on the market, FDA warned yesterday. In a news release, the agency said that evidence gathered to date suggests that the stolen insulin was not stored and handled properly and may be dangerous for people to use. Three lots of Levemir were reported stolen in June, totaling 129,000 vials. Only about 2% of the total amount stolen has been recovered, FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 28, 2009 * Vol. 16, No. 166
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source: Aug. and Sept. issues of Medical Care (2009; 47).
Physician Communication & Treatment Adherence: Communication is an important factor in patient adherence to treatment, and it is one which physicians can control and can be trained to do better, authors write (pp. 826–34). In a meta-analysis of 106 correlational studies and 21 experimental interventions, the researchers found: “Physician communication is significantly positively correlated with patient adherence; there is a 19% higher risk of non-adherence among patients whose physician communicates poorly than among patients whose physician communicates well. Training physicians in communication skills results in substantial and significant improvements in patient adherence such that with physician communication training, the odds of patient adherence are 1.62 times higher than when a physician receives no training.” (K. B. Haskard Zolnierek, kh36@txstate.edu)
For research into adherence, it’s time to move from “prediction to understanding,” editorialists write (pp. 823–5): “We believe that theorizing in regard to moderator effects is a primary challenge to advancing research in our field, although it is rarely done. This kind of analysis is theoretical and speculative because there are often alternative explanations for a given moderator result and because moderators tend to be so highly correlated with each other that teasing apart their independent effects demands more studies than commonly found for any given meta-analytic review. Nevertheless, without it, investigators lack the conceptual grounding necessary to make the theoretical leaps that energize the field and move our work forward. At the risk of putting too fine a point on the argument, we can liken progress in our field to progress in decoding the human genome. We have in some measure decoded the DNA of patient-provider communication; however, we have only just begun to explore the gene–environment interaction.” (D. L. Roter, droter@jhsph.edu)
Referrals for Short Stature: Pediatricians are influenced just as much by family concerns or their own attitudes as by physiologic factors when making the decision to refer children with short stature for growth hormone therapy, according to a study of 1,268 U.S. practitioners (pp. 858–65). Since just 1 additional referral per U.S. pediatrician would increase GH costs by more than $100 million/y, the authors maintain that the following findings are important: “While patient indicators (height, growth pattern) influenced referrals (P < 0.001), consumer drivers (family concern) and physician attitudes had almost as great an impact—especially for children with less severe growth impairment (P < 0.001). Physician belief that short stature impairs emotional well-being and physician characteristics (female, older, shorter, beliefs about drug company information) increased referrals (P < 0.03–0.001)—independent of growth parameters.” (L. Cuttler, leona.cuttler@case.edu)
Chronic Care: The quality of care of chronic illnesses continues to need improvement, a study of large medical groups shows, and financial incentives are likely needed to drive change (pp. 932–9).Looking at the change in use of commonly recommended chronic illness care management processes (CMPs) in 369 large medical groups (with 20 or more physicians), the investigators found: “Use of CMP increased from 6.25 to 7.67 (of a total of 17; P <= 0.001), that is, by 23%, between 2000 and 2006. Increases were greatest for those practices receiving financial rewards for quality; those participating in quality improvement activities; and those practices that were profitable. Most of the increase was in use of registries and in patient self-management support services.” (S. M. Shortell, shortell@berkeley.edu)
After a decade with the chronic care model (CCM), some progress has been made, editorialists note, but with much opportunity for more (pp. 929–31): “Although [these] authors find a greater uptake for patients with diabetes, how do we develop strategies that improve practice in other chronic illness, especially those like depression that may complicate care to patients with any chronic illness. Adopting components of the CCM can transform [the] healthcare system. This article suggests that although we are moving in the right direction, broader implementation of the CCM remains a challenge.” (G. L. Jackson, george.l.jackson@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Aug. 31, 2009 * Vol. 16, No. 167
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source: Aug. 29 issue of Lancet, a theme issue on COPD (2009; 374).
Roflumilast for COPD: Therapies targeted at subgroups of patients with chronic obstructive pulmonary disease should be explored in future studies, conclude authors reporting the results of two clinical trials (pp. 685–94). Patients, all of them older than 40 years of age, received either oral roflumilast 500 mcg or placebo once daily for 52 weeks, with these results: “In both studies, the prespecified primary endpoints were achieved and were similar in magnitude. In a pooled analysis, prebronchodilator FEV1 increased by 48 mL with roflumilast compared with placebo (p < 0.0001). The rate of exacerbations that were moderate or severe per patient per year was 1.14 with roflumilast and 1.37 with placebo (reduction 17% [95% CI 8—25], p < 0.0003). Adverse events were more common with roflumilast (1,040 [67%]) than with placebo (963 [62%]); 219 (14%) patients in the roflumilast group and 177 (12%) in the placebo group discontinued because of adverse events. In the pooled analysis, the difference in weight change during the study between the roflumilast and placebo groups was −2.17 kg.” (P. M. A. Calverley, pmacal@liverpool.ac.uk)
Roflumilast Plus Bronchodilators for COPD: Added to long-acting bronchodilators, roflumilast improved lung function in two trials of patients older than 40 years with COPD (pp. 695–703). The authors report these results with roflumilast 500 mcg daily over 24 weeks: “In the salmeterol plus roflumilast trial, 466 patients were assigned to and treated with roflumilast and 467 with placebo; in the tiotropium plus roflumilast trial, 371 patients were assigned to and treated with roflumilast and 372 with placebo. Compared with placebo, roflumilast consistently improved mean prebronchodilator FEV1 by 49 mL (p < 0.0001) in patients treated with salmeterol, and 80 mL (p < 0.0001) in those treated with tiotropium. Similar improvement in postbronchodilator FEV1 was noted in both groups. Furthermore, roflumilast had beneficial effects on other lung function measurements and on selected patient-reported outcomes in both groups. Nausea, diarrhoea, weight loss, and, to a lesser extent, headache were more frequent in patients in the roflumilast groups. These adverse events were associated with increased patient withdrawal.” (K. F. Rabe, k.f.rabe@lumc.nl)

>>>BMJ Highlights
Source: Early-release article from BMJ (2009; 339).
Emergence of H1N1 Influenza: Clinical cases of influenza A/H1N1 infection, as identified through self-samples of people who called a National Health Service health line in the U.K., mirror those of laboratory-diagnosed cases at Health Protection Agency (HPA) units, researchers report. (b3403). In six English regions in late May and June of this year, these results showed that reports to regional laboratories can be used to estimate levels of infection in local communities: “Influenza A/H1N1 2009 infections were detected in 91 (7%) of the 1,385 self sampled specimens tested. In addition, eight instances of influenza A/H3 infection and two cases of influenza B infection were detected. The weekly rate of change in the proportions of infected individuals according to self obtained samples closely matched the rate of increase in the proportions of infected people reported by HPA regional laboratories. Comparing the data from both systems showed that local community transmission was occurring in London and the West Midlands once HPA regional laboratories began detecting 100 or more influenza A/H1N1 2009 infections, or a proportion positive of over 20% of those tested, each week.” (A. .J Elliot, alex.elliot@hpa.org.uk)

>>>PNN JournalWatch
* Safety and Immunological Efficacy of a DNA Vaccine Encoding Prostatic Acid Phosphatase in Patients with Stage D0 Prostate Cancer, in Journal of Clinical Oncology, 2009; 27: 4047–54. (D. G. McNeel, dm3@medicine.wisc.edu)
* Thrombotic Events in Cancer Patients Receiving Antiangiogenesis Agents, in Journal of Clinical Oncology, 2009; 27: 10.1200/JCO.2009.22.3875. (Maurizio Zangari, maurizio.zangari@hsc.utah.edu)
* Dietary Sugars Intake and Cardiovascular Health. A Scientific Statement from the American Heart Association, in Circulation, 2009; 10.1161/CIRCULATIONAHA.109.192627.
* Metformin for Obesity in Children and Adolescents: A Systematic Review, in Diabetes Care, 2009; 32: 1743–5. (R. M. Viner, r.viner@ich.ucl.ac.uk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Sept. 1, 2009 * Vol. 16, No. 168
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source: Early-release article from and Sept. 1 issue of the Annals of Internal Medicine (2009; 151).
High-Dose Statins v. Combination Lipid-Lowering Therapy: Mortality and clinical outcomes are similar with high-dose statin therapy and combinations of lipid-lowering drugs such as statins with ezetimibe, according to a systematic review of 102 studies (early release). Limited and very-low-quality evidence precludes firm conclusions, however, as noted in this synthesis of available data: “The main analysis compared combination therapy with high-dose statin monotherapy in high-risk patients. Very-low-strength evidence showed that statin–ezetimibe (2 trials; n = 439) and statin–fibrate (1 trial; n = 166) combinations did not reduce mortality more than high-dose statin monotherapy. No trials compared the effect of combination therapy versus high-dose statin monotherapy on the incidence of myocardial infarction, stroke, or revascularization procedures. Two statin–ezetimibe trials (n = 295) demonstrated higher low-density lipoprotein cholesterol goal attainment with combination therapy (odds ratio, 7.21 [95% CI, 4.30 to 12.08]). Trials in lower-risk patients did not show a difference in mortality.” (M. Sharma)
Warfarin Anticoagulation in AF: The net clinical benefits of warfarin anticoagulation in patients with atrial fibrillation—that is, consideration of both the risk of ischemic stroke and the risk of intracranial hemorrhage—should be assessed in clinical decision-making, a research study concludes (pp. 297–305). In an integrated health care system, the records of 13,559 adults with nonvalvular AF were reviewed for net clinical benefit (defined as the annual rate of ischemic strokes and systemic emboli prevented by warfarin minus intracranial hemorrhages attributable to warfarin, multiplied by an impact weight), with these results: “Patients accumulated more than 66,000 person–years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS2 [1 point for each of congestive heart failure, hypertension, age, and diabetes and 2 points for stroke] stroke risk categories 0 and 1 to 2.22% per year (CI, 0.58% to 3.75%) in CHADS2 categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used.” (D. E. Singer, dsinger@partners.org)
Low Carbs v. Low Fat in Diabetes: In overweight patients just diagnosed with type 2 diabetes, a low-carbohydrate, Mediterranean-style diet produced more favorable changes in glycemic control and coronary risk factors and delayed the need for hypoglycemic medications, compared with a low-fat diet, researchers report (pp. 306–14). At a teaching hospital in Naples, Italy, 215 patients with A1C levels less than 11% were randomized to a Mediterranean-style diet (less than 50% of daily calories from carbohydrates) or a low-fat diet (less than 30% of daily calories from fat). Results showed: “After 4 years, 44% of patients in the Mediterranean-style diet group and 70% in the low-fat diet group required treatment (absolute difference, –26.0 percentage points [95% CI, –31.1 to –20.1 percentage points]; hazard ratio, 0.63 [CI, 0.51 to 0.86]; hazard ratio adjusted for weight change, 0.70 [CI, 0.59 to 0.90]; P < 0.001). Participants assigned to the Mediterranean-style diet lost more weight and experienced greater improvements in some glycemic control and coronary risk measures than did those assigned to the low-fat diet.” (D. Giugliano, dario.giugliano@unina2.it)
Quality of Care at Retail Clinics: Among enrollees of a Minnesota health plan with otitis media, pharyngitis, or urinary tract infection, care received at retail clinics was less costly than in physician offices, urgent care centers, or emergency departments, with no apparent decline in quality or receipt of preventive care (pp. 321–8). An evaluation of 2,100 care episodes showed similar prescription drug costs in retail clinics, physician offices, and urgent care centers; these were higher in emergency departments. Aggregate quality scores were lower among those cared for in EDs. (A. Mehrotra, mehrotra@rand.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2009, 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.

PNN Pharmacotherapy Line
Sept. 2, 2009 * Vol. 16, No. 169
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source: Sept. 2 issue of JAMA (2009; 302).
Timing of Interventions for Acute Coronary Syndromes: Immediate versus delayed invasive intervention for acute coronary syndromes made no difference in frequencies of myocardial infarction, as measured by peak troponin levels, in the Angioplasty to Blunt the Rise of Troponin in Acute Coronary Syndromes Randomized for an Immediate or Delayed Intervention (ABOARD) study (pp. 947–54). Among 352 patients, these results were recorded for interventions on admission or the next working day: “Time from randomization to sheath insertion was 70 minutes with immediate intervention vs 21 hours with delayed intervention. The primary end point did not differ between the 2 strategies (median [interquartile range] troponin I value, 2.1 [0.3–7.1] ng/mL vs 1.7 [0.3–7.2] ng/mL in the immediate and delayed intervention groups, respectively; P = .70). The key secondary end point was observed in 13.7% (95% confidence interval, 8.6%–18.8%) of the group assigned to receive immediate intervention and 10.2% (95% confidence interval, 5.7%–14.6%) of the group assigned to receive delayed intervention (P = .31). The other end points, as well as major bleeding, did not differ between the 2 strategies.” (G. Montalescot, gilles.montalescot@psl.aphp.fr)
Mass Azithromycin Distribution for Trachoma Control: In trachoma-endemic Ethiopia, mass distribution of oral azithromycin reduced mortality in children, researchers report (pp. 962–8). Using a cluster-randomized trial design, the investigators tested three azithromycin treatment schedules—annual treatment of all residents, biannual treatment of all residents, or quarterly treatment of just children—and compared results with a fourth group for which treatment was delayed by 1 year. Results showed: “The odds ratio for childhood mortality in the intervention communities was 0.51 (95% confidence interval, 0.29–0.90; P = .02; clustered logistic regression) compared with the control group. In the treated communities, the estimated overall mortality rate during this period for children aged 1 to 9 years in the untreated group was 8.3 per 1,000 person–years (95% confidence interval, 5.3–13.1), while among the treated communities, the estimated overall mortality rate was 4.1 per 1,000 person–years (95% confidence interval, 3.0–5.7) for children aged 1 to 9 years.” (T. M. Lietman, tom.lietman@ucsf.edu)
Corticosteroid and Antiviral Treatment for Bell Palsy: Corticosteroids have fewer unsatisfactory outcomes, compared with other therapies, when used for treating patients with Bell palsy, and addition of antiviral agents supplements provides benefits, according to a systematic review and meta-analysis (pp. 985–93): “Eighteen trials involving 2,786 patients were eligible. Regression analysis identified a synergistic effect when corticosteroids and antiviral agents were administered in combination compared with alone (odds ratio for interaction term, 0.54 [95% confidence interval {CI}, 0.35–0.83]; P = .004). Meta-analysis using a random-effects model showed corticosteroids alone were associated with a reduced risk of unsatisfactory recovery (relative risk [RR], 0.69 [95% CI, 0.55–0.87]; P = .001) (number needed to treat to benefit 1 person, 11 [95% CI, 8–25]), a reduced risk of synkinesis and autonomic dysfunction (RR, 0.48 [95% CI, 0.36–0.65]; P < .001) (number needed to treat to benefit 1 person, 7 [95% CI, 6–10]), and no increase in adverse effects. Antiviral agents alone were not associated with a reduced risk of unsatisfactory recovery (RR, 1.14 [95% CI, 0.80–1.62]; P = .48). When combined with antiviral agents, corticosteroids were associated with greater benefit (RR, 0.48 [95% CI, 0.29–0.79]; P = .004) than antiviral agents alone. When combined with corticosteroids, antiviral agents were associated with greater risk reduction of borderline significance compared with corticosteroids alone (RR, 0.75 [95% CI, 0.56–1.00]; P = .05).” (G. H. Guyatt, guyatt@mcmaster.ca)
Reductioni