Sep 2011

PNN Quarterly File—Third Quarter 2011

PNN Pharmacotherapy Line
July 1, 2011 * Vol. 18, No. 127
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
July issue of Pharmacotherapy (2011; 31).
Drug Prescribing in U.S. v. U.K.: Drug costs are likely higher in the U.S. than the U.K., concludes a study that shows higher prescribing levels for most indications and greater use of medications on patent (pp. 623–9). Investigators used 2004–06 data from the U.K. General Practice Research Database and the MarketScan Commercial Claims and Encounters Database for the U.S. to make these determinations: “Substantially higher proportions of people in the United States were prescribed antibiotics, statins, and postmenopausal hormones, but asthma drugs were prescribed more frequently in the United Kingdom. In those younger than 20 years, antidepressants and antipsychotics were prescribed more than twice as frequently in the United States, and males in the United States were far more likely to be prescribed drugs for attention-deficit–hyperactivity disorder than were their counterparts in the United Kingdom.” (H. Jick, hjick@bu.edu)
Paroxetine–Metoprolol Interaction: Extended-release (ER) formulations of metoprolol may be preferred in patients who are also taking paroxetine, researchers report, owing to inhibition of the metabolism of the beta-blocker by this antidepressant (pp. 630–41). In 15 healthy volunteers with at least one active cytochrome P450 2D6 allele, investigators found these effects of oral paroxetine 20 mg/day on the kinetics of immediate-release (IR) and ER metoprolol: “After receiving metoprolol on days 1 (before paroxetine) and 8 (after paroxetine), S- and R-metoprolol pharmacokinetic parameters and exercise heart rate and blood pressure responses were measured. The mean area under the plasma concentration–time curve values of both S- and R-metoprolol for each formulation were increased approximately 3- and 4-fold, respectively, by paroxetine. Paroxetine significantly increased the S- and R-metoprolol maximum concentration (Cmax) of each formulation and increased the elimination half-life of both isomers approximately 2-fold. When metoprolol IR was given with paroxetine, the S-metoprolol Cmax was significantly greater than that of either the 100-mg or 200-mg ER products. The maximum effect of metoprolol IR on heart rate was significantly greater than that of metoprolol ER 200 mg, independent of whether the agents were administered alone or with paroxetine. Both the heart rate and systolic blood pressure area under the effect-time curve values were significantly decreased by paroxetine.” (R. B. Parker, rparker@uthsc.edu)
C. difficile Infections with Antibiotics, Acid Suppression: At a community hospital in 2009, the risk of patients developing Clostridium difficile infections (CDI) was significantly lower than a 2008 national estimate, with use of antibiotics and acid-suppression therapies increasing those odds in hospitalized patients (pp. 642–48). Among 11,010 admissions during that year, 115 patients had stool samples positive for C. difficile A or B: “The incidence of CDI was 10.4 cases/1,000 patient admissions, which was significantly lower than the overall incidence reported in a 2008 national survey of 13.1 CDI cases/1,000 patient admissions (p = 0.021). Demographic and clinical data of the patients with CDI were collected by using electronic medical records. Patients were more likely to be elderly and female, and to have developed CDI during hospitalization. Of the 115 patients, 95 (82.6%) received acid-suppression therapy and 91 (79.1%) received antimicrobials. Of the patients receiving acid-suppression therapy, 72 (75.8%) received a proton pump inhibitor during their hospitalization, and 49 (51.6%) received both a proton pump inhibitor and an antibiotic. The most frequently used antibiotics in this population were fluoroquinolones, cephalosporins, and carbapenems, with a significantly larger proportion of patients who received carbapenems developing CDI compared with the other classes of antibiotics (p ≤ 0.05 for both comparisons). Patients receiving antimicrobial and acid-suppression therapy were more likely to develop CDI than those who did not receive these drugs.” (S. L. Lager)

>>>PNN NewsWatch
* Children exposed in utero to valproate products have lower cognitive test scores at ages 5 to 16, FDA warned yesterday. The agency suggested use of alternative agents in women of childbearing age when possible.
*
PNN will not be published on Mon., July 4, Independence Day.

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

PNN Pharmacotherapy Line
July 5, 2011 * Vol. 18, No. 128
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 2 issue of Lancet (2011; 378).
Outpatient Treatment of Acute Pulmonary Embolism: Outpatient care of patients with acute pulmonary embolism can be accomplished safely and effectively, according to results of an open-label, noninferiority trial conducted at 19 emergency departments in Europe and the U.S. (pp. 41–8). Patients with acute, symptomatic pulmonary embolism and a low risk of death (pulmonary embolism severity index risk classes I or II) were randomly assigned to outpatient (discharged within 24 hours) or inpatient care, with these results: “Between February, 2007, and June, 2010, we enrolled 344 eligible patients. In the primary analysis, one (0.6%) of 171 outpatients developed recurrent venous thromboembolism within 90 days compared with none of 168 inpatients (95% upper confidence limit [UCL] 2.7%; p = 0.011). Only one (0.6%) patient in each treatment group died within 90 days (95% UCL 2.1%; p = 0.005), and two (1.2%) of 171 outpatients and no inpatients had major bleeding within 14 days (95% UCL 3.6%; p = 0.031). By 90 days, three (1.8%) outpatients but no inpatients had developed major bleeding (95% UCL 4.5%; p = 0.086). Mean length of stay was 0.5 days (SD 1.0) for outpatients and 3.9 days (SD 3.1) for inpatients.” (D. Aujesky, drahomir.aujesky@insel.ch)
Texting for Smoking Cessation: A “txt2stop” intervention significantly improved smoking cessation rates at 6 months, researchers report (pp. 49–55). Among 5,800 smokers, texts with motivational messages and behavioral-change support had these effects in comparison with text messages with content unrelated to smoking: “Biochemically verified continuous abstinence at 6 months was significantly increased in the txt2stop group (10.7% txt2stop vs 4.9% control, relative risk [RR] 2.20, 95% CI 1.80–2.68; p < 0.0001). Similar results were obtained when participants that were lost to follow-up were treated as smokers (268 [9%] of 2,911 txt2stop vs 124 [4%] of 2,881 control [RR 2.14, 95% CI 1.74–2.63; p < 0.0001]), and when they were excluded (268 [10%] of 2,735 txt2stop vs 124 [4%] of 2,789 control [2.20, 1.79–2.71; p < 0.0001]).” (C. Free, caroline.free@lshtm.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
NSAIDs for Atrial Fibrillation/Flutter: Use of nonaspirin NSAIDs was associated with first diagnosis of atrial fibrillation or flutter in 32,602 patients, a case–control study shows (d3450): “2,925 cases (9%) and 21,871 controls (7%) were current users of either non-selective NSAIDs or COX 2 inhibitors. Compared with no use, the incidence rate ratio associating current drug use with atrial fibrillation or flutter was 1.33 (95% confidence interval 1.26 to 1.41) for non-selective NSAIDs and 1.50 (1.42 to 1.59) for COX 2 inhibitors. Adjustments for age, sex, and risk factors for atrial fibrillation or flutter reduced the incidence rate ratio to 1.17 (1.10 to 1.24) for non-selective NSAIDs and 1.27 (1.20 to 1.34) for COX 2 inhibitors. Among new users, the adjusted incidence rate ratio was 1.46 (1.33 to 1.62) for non-selective NSAIDs and 1.71 (1.56 to 1.88) for COX 2 inhibitors. Results for individual NSAIDs were similar.” (M. Schmidt, msc@dce.au.dk)

>>>PNN JournalWatch
* Update in Women’s Health: Evidence Published in 2010, in Annals of Internal Medicine, 2011; 155: 52–7. (J. P. Pregler)
* A Comparison of the Effects of 2 Types of Massage and Usual Care on Chronic Low Back Pain: A Randomized, Controlled Trial, in
Annals of Internal Medicine, 2011; 155: 1–9. (D. C. Cherkin)
* Chronic Kidney Disease Is Associated with the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study, in
Circulation, 2011; 123: 2946–53. (A. Alonso, alonso@umn.edu)
* Buprenorphine for Prescription Opioid Addiction in a Patient with Depression and Alcohol Dependence, in
American Journal of Psychiatry, 2011; 168: 675–9. (M. J. Fishman)
* A Systematic Review of Treatments for Refractory Depression in Older People, in
American Journal of Psychiatry, 2011; 168:681–8. (C. Cooper)
* New Insights About Infant and Toddler Skin: Implications for Sun Protection, in
Pediatrics, 2011; 128: 92–102. (A. S. Paller)
* Instruments to Detect Alcohol and Other Drug Misuse in the Emergency Department: A Systematic Review, in
Pediatrics, 2011; 128: e180–92. (A. S. Newton)
* Human Cytomegalovirus and Kidney Transplantation: A Clinician’s Update, in
American Journal of Kidney Diseases, 2011; 58: 118–26. (K. De Keyzer, kristel.dekeyzer@mail.be)

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

PNN Pharmacotherapy Line
July 6, 2011 * Vol. 18, No. 129
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article and July 6 issue of JAMA (2011; 306).
Regulation of Dietary Supplements: Reflecting on a 2009 report from the Government Accountability Office, the author of a Commentary details the checkered history of dietary supplement regulation since the tryptophan debacle of 1989 and passage of the Dietary Supplement Health and Education Act in 1994 (10.1001/jama.2011.982): “Since October 1994, when DSHEA became law, industry statements about life in a free society and the rights of consumers have frequently overridden practical arguments about the safety and efficacy of dietary supplements, resulting in a conversation that has privileged demagoguery over informed debate. The conversation needs a more sophisticated tone and the FDA took a positive step in 2007, issuing a rule on good manufacturing practices. Ideally, good manufacturing practices will help reduce availability of products containing contaminants such as pesticide residue or oxidation by-products; however, as the GAO investigations revealed, there is still room for improvement. Physicians should support future efforts to improve or reform DSHEA because individuals with serious medical conditions may be relying on products with no medicinal value. Like dietary supplements, the regulations should be efficacious and formulated for legitimate ends.” (B. E. Denham, bdenham@clemson.edu)
Quality of Care in Critical Access Rural Hospitals: Compared with other hospitals, critical access hospitals (CAHs) located in rural areas “had fewer clinical capabilities, worse measured processes of care, and higher mortality rates for patients with [acute myocardial infarction], [congestive heart failure], and pneumonia, researchers report (pp. 45–52). Retrospective analysis of Medicare fee-for-service beneficiaries seen at 4,738 U.S. hospitals shows that CAHs were 26.8% less likely to have intensive care units, cardiac-catheterization capabilities, or at least basic electronic health records. Thirty-day mortality rates were 23.5%, 13.4%, and 14.1% for AMI, CHF, and pneumonia, respectively, significantly higher than in non-CAHs (16.2%, 10.9%, and 12.1%). (K. E. Joynt, kjoynt@partners.org)
Lifestyle & Sudden Cardiac Death: Women who adhere to a low-risk lifestyle are at significantly lower risk of sudden cardiac death (SCD), according to 1984–2010 data from the Nurses Health Study (pp. 62–9). Low-risk lifestyle was defined as not smoking, having a BMI less than 25, exercising for 30 minutes or more each day, and adhering to a Mediterranean-type diet. Results showed: “The absolute risks of SCD were 22 cases/100,000 person–years among women with 0 low-risk factors, 17 cases/100,000 person–years with 1 low-risk factor, 18 cases/100,000 person–years with 2 low-risk factors, 13 cases/100,000 person–years with 3 low-risk factors, and 16 cases/100,000 person–years with 4 low-risk factors.” (S. E. Chiuve, schiuve@hsph.harvard.edu)

>>>PNN NewsWatch
* Rivaroxaban (Xarelto, Janssen) is the first oral factor Xa inhibitor to reach the U.S. market. Approved by FDA for prophylaxis of deep-vein thrombosis that may lead to a pulmonary embolism in people undergoing knee or hip replacement surgery, rivaroxaban was compared with enoxaparin in Phase III trials. Rivaroxaban and enoxaparin demonstrated similar safety profiles including low rates of major bleeding. Other potential adverse effects include fluid leakage from wounds, itching, pain in arms or legs, blisters, fainting, and muscle spasm. Rivaroxaban is taken once daily for 12 days following knee replacement and 35 days after hip replacement.
*
FDA has approved the first once-daily beta-2 agonist for treatment chronic obstructive pulmonary disease. Indacaterol inhalation powder (Arcapta Neohaler, Novartis) is indicated for long-term maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. In two Phase III trials of 641 patients with COPD, 12-week results showed significantly improved lung function at 24 hours, compared with placebo. The most common adverse reactions with the drug were cough, nasopharyngitis, headache, nausea, and oropharyngeal pain. A boxed warning cautions that long-acting beta-2 adrenergic agonists, including indacaterol, should not be used in patients with asthma, unless used with a long-term asthma control medication.

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

PNN Pharmacotherapy Line
July 7, 2011 * Vol. 18, No. 130
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 7 New England Journal of Medicine (2011; 365).
Preventing TB in Patients with HIV: Two studies and an editorial explore tuberculosis prevention in patients with HIV infections.
Three-month regimens for preventing tuberculosis in patients with HIV are effective but not superior to 6 months of daily isoniazid, researchers report (
pp. 11–20). In 1,148South African adults with HIV infection and positive tuberculin skin tests who were not on antiretroviral therapy, prophylactic regimens were studied: rifapentine 900 mg plus isoniazid 900 mg weekly for 12 weeks, rifampin 600 mg plus isoniazid 900 mg twice weekly for 12 weeks, isoniazid 300 mg daily for up to 6 years (continuous isoniazid), or isoniazid 300 mg daily for 6 months (control group). Results showed: “Incidence rates of active tuberculosis or death were 3.1 per 100 person–years in the rifapentine–isoniazid group, 2.9 per 100 person–years in the rifampin–isoniazid group, and 2.7 per 100 person–years in the continuous-isoniazid group, as compared with 3.6 per 100 person–years in the control group (P > 0.05 for all comparisons). Serious adverse reactions were more common in the continuous-isoniazid group (18.4 per 100 person–years) than in the other treatment groups (8.7 to 15.4 per 100 person–years). Two of 58 isolates of Mycobacterium tuberculosis (3.4%) were found to have multidrug resistance.” (R. E. Chaisson, rchaiss@jhmi.edu)
Results with prophylaxis were less positive among 548 HIV-infected and 804 HIV-uninfected infants who received isoniazid 10–20 mg/kg/d or placebo for 96 weeks (
pp. 21–31). The uninfected infants had been exposed to HIV, and all patients received the BCG vaccine within 30 days of birth. Results were as follows: “Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P = 0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P = 0.44). The rate of tuberculosis was 121 cases per 1,000 child–years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1,000 child–years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups.” (S. A. Madhi, madhis@rmpru.co.za)
Editorialists ask “what is thwarting tuberculosis prevention in high-burden settings” (
pp. 79–81): “In the near future, it should not be necessary, as it often is today, to wait for weeks or months to diagnose tuberculosis or identify drug resistance, during which time transmission continues. Unless the force of transmission can be reduced by intensified case finding and the use of new rapid diagnostics, resulting in more effective treatment, durable benefits from prevention strategies, either chemoprophylaxis or immunization, are likely to be elusive.” (E. Nardell)
Nesiritide in Heart Failure: A study shows little benefit from nesiritide in 7,141 patients with acute decompensated heart failure (pp. 32–43; C. M. O’Connor, conn002@mc.duke.edu">oconn002@mc.duke.edu), and an editorialist writes of a “lost decade” (pp. 81–2): “The FDA, without a prospective plan or capability to force the sponsor to perform a fitting trial after approval, unwittingly created a monster. Physicians, who prescribed nesiritide without definitive knowledge of efficacy or safety, particularly for off-label use such as for tune-up clinics, were treating patients without an adequate evidence base. The manufacturer in this case was the chief culprit because it widely promoted nesiritide in the early years after its approval but was unwilling to appropriate the resources to design and execute a compelling trial. The lack of resources is often cited as the reason why a pharmaceutical company cannot initiate a pivotal trial. But this problem can be addressed by focusing on a particular group of patients for whom the drug would be anticipated to have marked efficacy. This strategy has been remarkably successful in some recent trials, such as the study of a drug for cystic fibrosis in a select group of patients with a specific mutation; this study was a major advance that occurred more than two decades after the gene for cystic fibrosis was discovered.” (E. J. Topol)

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

PNN Pharmacotherapy Line
July 8, 2011 * Vol. 18, No. 131
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
July issue of the American Journal of Psychiatry (2011; 168).
Antidepressant Medication Combinations: Monotherapy using a selective serotonin reuptake inhibitor was just as effective as and possibly safer than combination treatment of depression, Combining Medications to Enhance Depression Outcomes (CO-MED) researchers report (pp. 689–701). The single-blind trial of 665 outpatients with at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder compared escitalopram with sustained-release bupropion plus escitalopram and venlafaxine plus mirtazapine, with these results: “Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram–placebo, 38.9% for bupropion–escitalopram, and 37.7% for venlafaxine–mirtazapine, and the response rates were 51.6%–52.4%. The mean number of worsening adverse events was higher for venlafaxine–mirtazapine (5.7) than for escitalopram–placebo (4.7). At 7 months, remission rates (41.8%–46.6%), response rates (57.4%–59.4%), and most secondary outcomes were not significantly different.” (M. H. Trivedi, madhukar.trivedi@utsouthwestern.edu)
An editorialist questions why patients responded to study drugs when they previously had relapses (
pp. 664–6): “A particularly striking feature of the CO-MED study group is the coexistence of the absence of treatment resistance, as specified by the entry criteria, and a high rate of chronicity. Although none of the participants had had an adequate monotherapy trial of an FDA-approved antidepressant within the current episode, over one-half of the group had a depressive episode that had been fully syndromal for at least the preceding 2 years. Why had they not undergone even one adequate antidepressant trial before the CO-MED effort came to pass? Whatever the answer, it seems likely that the average interval between episode onset and the receipt of first treatment was quite long. A number of prospective studies of major depressive disorder have shown the no-treatment interval to be as robust a predictor of poor outcome with treatment as neuroticism. Why this is so is a matter of speculation, but the measure’s association with poorer treatment response generally may well have narrowed differences between the regimens applied here.” (W. Coryell, william-coryell@uiowa.edu)
Antipsychotic Polypharmacy v. Monotherapy: Trials of monotherapy should be attempted in patients with schizophrenia who are controlled on two antipsychotic agents, a study concludes (pp. 702–8). A total of 127 adult outpatients were randomly assigned to remain on polypharmacy or be switched to monotherapy in the 6-month trial and a 6-month naturalistic follow-up: “Patients assigned to switch to monotherapy had shorter times to all-cause treatment discontinuation than those assigned to stay on polypharmacy. By month 6, 86% (N = 48) of those assigned to stay on polypharmacy were still taking both medications, whereas 69% (N = 40) of those assigned to switch to monotherapy were still taking the same medication. Most monotherapy discontinuations entailed returning to the original polypharmacy. The two groups did not differ with respect to psychiatric symptoms or hospitalizations. On average, the monotherapy group lost weight, whereas the polypharmacy group gained weight.” (S. M. Essock, se2176@columbia.edu)
“Clearly monotherapy, when tolerated and effective, is optimal,” editorialists write (
pp. 667–9). “When patients fail to respond to an adequate dose of an antipsychotic, clozapine is the only option with established efficacy. However, relatively few patients remain on a single antipsychotic for long, and adherence is often poor even when patients choose to remain on monotherapy. In other words, treating people with schizophrenia may require trials of several antipsychotics in order to find one that is well-tolerated at an effective dose. In some patients, combination treatment may be preferred after all other reasonable options have failed. In such patients, combination treatment using the lowest possible dose of each drug should be evaluated in a systematic, time-limited trial, and the evidence for benefit should be clear and well-documented if the combination is to be continued. As always, clinician judgment combined with patient preference must take over when treatment algorithms fall short.” (D. C. Goff, goff@psych.mgh.harvard.edu)

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

PNN Pharmacotherapy Line
July 11, 2011 * Vol. 18, No. 132
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 9 issue of Lancet, a theme issue on diabetes (2011; 378).
Diet v. Exercise in Type 2 Diabetes: An intensive diet intervention started soon after diagnosis of type 2 diabetes proved just as effective for improving glycemic control as diet plus exercise, researchers report (pp. 129–39). Participants, ages 30–80 years, had been diagnosed with diabetes for 5–8 months on study admission. Usual care (initial dietary consultation and follow-up every 6 months; control group), an intensive diet intervention (dietary consultation every 3 months with monthly nurse support), and diet intervention plus a pedometer-based activity program had these effects among 593 patients: “At 6 months, glycaemic control had worsened in the control group (mean baseline HbA1c percentage 6.72, SD 1.02, and at 6 months 6.86, 1.02) but improved in the diet group (baseline-adjusted difference in percentage of HbA1c –0.28%, 95% CI –0.46 to –0.10; p = 0.005) and diet plus activity group (–0.33%, –0.51 to –0.14; p < 0.001). These differences persisted to 12 months, despite less use of diabetes drugs. Improvements were also seen in bodyweight and insulin resistance between the intervention and control groups. Blood pressure was similar in all groups.” (R. C. Andrews, rob.andrews@bristol.ac.uk)
Use of A1C Levels in Diagnosing Prediabetes: Addition of a glycosylated hemoglobin criterion to diagnosis of diabetes improved detection beyond that with impaired fasting glucose alone, according to a longitudinal study conducted in Japan (pp. 147–55). Among 4,670 men and 1,571 women who were aged 24–82 years when they presented for a routine health check in 1997–2003, these results were noted when baseline diagnoses of diabetes were made using impaired fasting glucose (fasting plasma glucose 5.6–6.9 mmol/L) HbA1c of 5.7–6.4%, or both: “Mean follow-up was 4.7 (SD 0.7) years. 412 (7%) of 6,241 participants were diagnosed with prediabetes on the basis of the HbA1c 5.7–6.4% criterion. Screening by HbA1c alone missed 1,270 (61%) of the 2,092 prediabetic individuals diagnosed by a combination of impaired fasting glucose and HbA1c 5.7–6.4%. Overall cumulative probability of progression to diabetes did not differ significantly between participants with prediabetes discordantly diagnosed by either HbA1c or impaired fasting glucose alone (incidence was 7% for HbA1c alone [n = 412 individuals and 30 incident cases] and 9% for impaired fasting glucose alone [n = 1,270, 108 cases]; log-rank test, p = 0.3317). Multivariate-adjusted hazard ratios for incident diabetes were 6.16 (95% CI 4.33–8.77) for those diagnosed with prediabetes by impaired fasting glucose alone and 6.00 (3.76–9.56) for diagnosis by HbA1c alone, and were substantially increased to 31.9 (22.6–45.0) for diagnosis by both impaired fasting glucose and HbA1c compared with normoglycaemic individuals.” (H. Sone, hsone@md.tsukuba.ac.jp)

>>>PNN JournalWatch
* Glycaemic Control in Type 1 Diabetes During Real Time Continuous Glucose Monitoring Compared with Self Monitoring of Blood Glucose: Meta-Analysis of Randomised Controlled Trials Using Individual Patient Data, in BMJ, 2011; 343: d3805. (J. C. Pickup, john.pickup@kcl.ac.uk)
* Cardiovascular Risk Assessment of the Liver Transplant Candidate, in
Journal of the American College of Cardiology, 2011; 58: 223–31. (J. D. Flaherty, j-flaherty2@md.northwestern.edu)
* Glycemic Control in the ICU, in
Chest, 2011; 140: 212–20. (S. Finfer, sfinfer@george.org.au)
* Bone Marrow–Derived Stem Cells and Respiratory Disease, in
Chest, 2011; 140: 205–11. (S. M. Rankin, s.rankin@imperial.ac.uk)
* The Challenges of Antimicrobial Drug Resistance in Greece, in
Clinical Infectious Diseases, 2011; 53: 177–84. (S. Miyakis, miyakis@auth.gr)
* Palliative Care and the Quality of Life, in
Journal of Clinical Oncology, 2011; 29: 2750–2. (D. E. Meier)
* Targeting PI3K Signaling as a Therapeutic Approach for Colorectal Cancer, in
Gastroenterology, 2011; 141: 50–61. (T. M. Roberts, thomas_roberts@dfci.harvard.edu)
* Tenets for Developing Quality Measures for Ambulatory Clinical Pharmacy Services, in
Pharmacotherapy, 2011; 31: 723. (S. McBane)
* Nicotine Conjugate Vaccine as a Novel Approach to Smoking Cessation, in
Pharmacotherapy, 2011; 31: 703–13. (A. R. Ottney)

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

PNN Pharmacotherapy Line
July 12, 2011 * Vol. 18, No. 133
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 11 issue of the Archives of Internal Medicine (2011; 171).
Improving Blood Pressure Control: Behavioral and medication management can improve blood pressures in patients with hypertension, but effects are more pronounced on those with initially poor control, a study concludes (pp. 1173–80). This makes it important to identify “individuals most likely to benefit from potentially resource intensive programs,” the authors write. Patients seen at VA primary care clinics were randomized to either usual care or one of three telephone-based interventions: nurse-administered behavioral management, nurse- or physician-administered medication management, or both. Results showed: “The primary outcome was change in BP control measured at 6-month intervals over 18 months. Both the behavioral management and medication management alone showed significant improvements at 12 months—12.8% (95% confidence interval [CI], 1.6%–24.1%) and 12.5% (95% CI, 1.3%–23.6%), respectively—but not at 18 months. In subgroup analyses, among those with poor baseline BP control, systolic BP decreased in the combined intervention group by 14.8 mm Hg (95% CI, –21.8 to –7.8 mm Hg) at 12 months and 8.0 mm Hg (95% CI, –15.5 to –0.5 mm Hg) at 18 months, relative to usual care.” (H. B. Bosworth, hayden.bosworth@duke.edu)
These telemedicine results are disappointing, write editorialists (
pp. 1181–2): “Collectively, a large effort was made by the nurse clinicians to improve BP control rates, and while this type of intervention was effective in a previous 24-month study by the same investigative group, results were not sustained after 12 months in the present trial. In contrast, combining the behavioral management with antihypertensive therapeutic advice was associated with the maintenance of a moderate effect in the entire population for up to 18 months. Thus, it seems that to reduce the negative effects of clinical inertia and patient noncompliance that prevent the control of BP, a multipronged approach will be required. The cost of the combined intervention was estimated at $1,153 for 18 months, an amount that could be justified if a large enough proportion of patients achieved enough improvement in BP control to ultimately lead to a reduction in strokes, congestive heart failure, and other cardiovascular events in patients with uncontrolled hypertension.” (W. B. White, wwhite@nso1.uchc.edu)
Sodium/Potassium Intake & Mortality: Americans who consume a higher sodium-to-potassium ratio have significantly greater cardiovascular disease (CVD) and all-cause mortality, report researchers who analyzed data from the Third National Health and Nutrition Examination Survey Linked Mortality File (pp. 1183–91): “During a mean follow-up period of 14.8 years, we documented a total of 2,270 deaths, including 825 CVD deaths and 443 [ischemic heart disease (IHD)] deaths. After multivariable adjustment, higher sodium intake was associated with increased all-cause mortality (hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.03–1.41 per 1000 mg/d), whereas higher potassium intake was associated with lower mortality risk (HR, 0.80; 95% CI, 0.67–0.94 per 1000 mg/d). For sodium-potassium ratio, the adjusted HRs comparing the highest quartile with the lowest quartile were HR, 1.46 (95% CI, 1.27–1.67) for all-cause mortality; HR, 1.46 (95% CI, 1.11–1.92) for CVD mortality; and HR, 2.15 (95% CI, 1.48–3.12) for IHD mortality. These findings did not differ significantly by sex, race/ethnicity, body mass index, hypertension status, education levels, or physical activity.” (Q. Yang, qay0@cdc.gov)

>>>PNN NewsWatch
* The concentration of Genentech’s Tamiflu (oseltamivir phosphate) for oral suspension is being cut in half, FDA said yesterday, and the previously marketed product is being removed from the market. The new 6 mg/mL concentration is less likely to become frothy when shaken, the agency said. A revised dosing table based on volume is included with the product, along with compounding instructions for pharmacies in case of emergency situations only if the commercially available product is unavailable. A voluntary take-back program is in place for pharmacies, distributors, and wholesalers to use in returning 12 mg/mL product as Genentech begins shipping product with the new concentration.

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

PNN Pharmacotherapy Line
July 13, 2011 * Vol. 18, No. 134
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 13 issue of JAMA (2011; 306).
Diagnostic Contribution of Bronchoalveolar Lavage: Therapy directed by bronchoalveolar lavage (BAL) results was no more effective among patients with cystic fibrosis than usual care, according to the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) trial (pp. 163–71). BAL-directed therapy was started in 84 randomly selected infants, while 86 others received standard therapy: “At age 5 years, 8 of 79 children (10%) in the BAL-directed therapy group and 9 of 76 (12%) in the standard therapy group had [Pseudomonas] aeruginosa in final BAL cultures (risk difference, −1.7% [95% confidence interval, −11.6% to 8.1%]; P = .73). Mean total [cystic fibrosis computed tomography] scores for the BAL-directed therapy and standard therapy groups were 3.0% and 2.8%, respectively (mean difference, 0.19% [95% confidence interval, −0.94% to 1.33%]; P = .74).” (C. E. Wainwright, claire_wainwright@health.qld.gov.au)
Novel Therapies for Septic Shock: Grand Rounds authors on septic shock “summarize the results of the clinical trials conducted during the last 4 decades, discuss some lessons learned, and suggest possible directions for future investigation” (pp. 194–9): “Many clinicians have … begun to question the dogma that severe sepsis and septic shock are caused by systemic inflammation.… Indeed, the [systemic inflammatory response syndrome] concept has been undermined by numerous observations that early systemic responses to infection actually prevent inflammation in the bloodstream and that patients with severe sepsis are usually profoundly immunosuppressed. An evolution-based explanation for organ hypofunction and shock is gaining ground, stating that beneficial (adaptive) early systemic reactions to infection may become maladaptive when they are driven by uncontrolled local infection or inflammation.” (A. F. Suffredini, asuffredini@cc.nih.gov)
WHO Pandemic Influenza Preparedness Framework: Describing the Apr. 2011 agreement on the World Health Organization’s pandemic influenza preparedness (PIP) framework for sharing of influenza viruses and access to vaccines as a “milestone in global governance of health,” Commentary authors also note limitations as exemplified by the 2006 refusal by Indonesia to provide avian influenza samples (pp. 200–1): “The framework seeks to strengthen pandemic influenza surveillance and response while enhancing global equity. Although the framework emphasizes the norm of sharing viruses, it does not create legally binding obligations on virus sharing. During the H5N1 and H1N1 crises, all states shared viruses, except for Indonesia’s H5N1 refusals. The framework reinforces a global norm but does not alter the status quo. Genetic sequence data sharing also does not represent a major shift, evidenced by the WHO director-general’s obligation to address obstacles to sharing these data. The framework’s most progressive reform for surveillance and response is increased transparency of virus transfers through the influenza virus tracking mechanism and standard material transfer agreements, which bolsters [Global Influenza Surveillance and Response System] legitimacy.” (L. O. Gostin, gostin@law.georgetown.edu)
IV Neuraminidase Inhibitors During 2009 Pandemic: Characteristics of patients who received the investigational intravenous neuraminidase inhibitors (NAIs) on an emergency-use basis during the 2009 A/H1N1 influenza pandemic are described (pp. 160–2): “Patients receiving IV NAIs were less likely to have renal disease and more likely to have serious illness, be obese, and begin treatment with any NAI later compared with patients receiving licensed NAIs. Among 1,417 patients with pH1N1 infection requiring intensive care unit admission, 1,336 (94%) received only oseltamivir and began NAIs a median of 3 days (range, 0–33 days) after onset of illness; 3% received an IV NAI.
“Most patients (88%) received oseltamivir prior to receiving an IV NAI, 1 started oseltamivir and peramivir simultaneously, 1 received peramivir as the first NAI, and 3 did not have dates recorded for antiviral use. Intravenous NAIs were initiated a median of 3 days (range, 0–12 days) after antiviral treatment was initiated; 16 of 38 patients (42%) with dates for antiviral use started IV NAIs within 2 days of treatment initiation. Ten patients received oseltamivir and IV NAI simultaneously for 2 or more days.” (A. M. Fry,
afry@cdc.gov)

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

PNN Pharmacotherapy Line
July 14, 2011 * Vol. 18, No. 135
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 14 New England Journal of Medicine (2011; 365).
Treatment of Localized Prostate Cancer: Short-term androgen-deprivation therapy (ADT), administered for 4 months before and during radiotherapy of localized prostate cancer, significantly improved disease-specific mortality and overall survival, researchers report (pp. 107–18). Among 1,979 eligible patients with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and a prostate-specific antigen (PSA) level of 20 ng/mL or less who were seen in 1994–2001, these results were noted with radiotherapy alone or radiotherapy with 4 months of ADT starting 2 months before radiotherapy: “The median follow-up period was 9.1 years. The 10-year rate of overall survival was 62% among patients receiving radiotherapy plus short-term ADT (the combined-therapy group), as compared with 57% among patients receiving radiotherapy alone (hazard ratio for death with radiotherapy alone, 1.17; P = 0.03). The addition of short-term ADT was associated with a decrease in the 10-year disease-specific mortality from 8% to 4% (hazard ratio for radiotherapy alone, 1.87; P = 0.001). Biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years were significantly improved with radiotherapy plus short-term ADT. Acute and late radiation-induced toxic effects were similar in the two groups. The incidence of grade 3 or higher hormone-related toxic effects was less than 5%. Reanalysis according to risk showed reductions in overall and disease-specific mortality primarily among intermediate-risk patients, with no significant reductions among low-risk patients.” (C. U. Jones, jonesc@radiological.com)
The difficulty of identifying men who would benefit most from ADT is reflected in an accompanying editorial (
pp. 169–71): “On October 20, 2010, the Food and Drug Administration asked manufacturers to add new warnings to the labeling of gonadotropin-releasing hormone (GnRH) agonists, a commonly used hormonal therapy that was used in the current study. The warning stated that men receiving GnRH agonists were at a small but increased risk for diabetes, heart attack, stroke, and sudden death. These risks appear to be important among men with known coronary artery disease-induced congestive heart failure, myocardial infarction, or both, in whom an increased risk of death has been observed after a median of 4 months of treatment with GnRH agonists. Given this warning and the results of the current study, it is reasonable to conclude that hormonal therapy is not indicated in men with low-risk disease. However, further study is needed to determine whether there was actually a benefit associated with combined therapy in men with low-risk disease and an adverse factor (including >50% positive findings on prostate biopsy, perineural invasion, a PSA velocity of >2 ng per milliliter per year [suggesting a Gleason score of 7], or all these features).” (A. V. D’Amico)
Placebo Effect in Asthma: Patient-reported outcomes were similar in patients who received albuterol inhalers, placebo inhalers, or sham acupuncture, compared with those receiving no intervention, a study shows (pp. 119–26). Albuterol produced improvements in objective outcomes, but the block-design study reports these overall data: “Among the 39 patients who completed the study, albuterol resulted in a 20% increase in FEV1, as compared with approximately 7% with each of the other three interventions (P < 0.001). However, patients’ reports of improvement after the intervention did not differ significantly for the albuterol inhaler (50% improvement), placebo inhaler (45%), or sham acupuncture (46%), but the subjective improvement with all three of these interventions was significantly greater than that with the no-intervention control (21%) (P < 0.001).” (M. E. Wechsler, mwechsler@partners.org)
“All medical procedures (active or inert) are meaningful—that is, they represent something—and meaning has effects,” an editorialist responds (
pp. 171–2). “Clinicians often dress up in special uniforms that convey power and authority. They have very expensive machines that can look inside your heart or brain. All this, plus the magnificence of the hospital building (ours has two helipads!), the decor of the office, the lights of the operating room, the computers on every lap, the magical prescription pad, and the caring nurse, piles up meaning with increasing power regardless of what may be in the capsule or syringe.” (D. E. Moerman)

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

PNN Pharmacotherapy Line
July 15, 2011 * Vol. 18, No. 136
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
July issue of the Journal of Allergy and Clinical Immunology (2011; 128).
Eosinophilic Esophagitis Recommendations: Consensus recommendations are updated for eosinophilic esophagitis (EoE), a condition that is increasing in “recognition and prevalence” (pp. 3–20.e6): “Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.” (C. A. Liacouras, liacouras@email.chop.edu)

>>>JAPhA Highlights
Source:
Jul/Aug issue of the Journal of the American Pharmacists Association (2011; 51).
MTM Programs for Medicare Part D: A nonexperimental study of medication therapy management programs available for Medicare Part D beneficiaries in 2007–08 provides “limited evidence” on which patients would benefit most from MTM, on features that achieve desired outcomes, and how MTM program performance should be measured (pp. 520–6). Based on information from 60 informants and case studies from 28 representatives of MTM programs, the authors found: “MTM programs used a variety of practice models. Medicare MTM programs used different eligibility criteria than MTM programs sponsored by Medicaid or other payers. MTM programs that required patients to opt-in had less success in enrolling participants than those using opt-out. Most MTM programs conducted annual medication reviews. Most non-Medicare MTM programs provided face-to-face interventions, whereas Medicare MTM programs relied more on telephone or mail; no research tested the effectiveness of different modes. Almost all MTM programs used pharmacists to provide services. Little research on Medicare MTM programs was available. Costs were commonly measured in the MTM literature, although results were inconsistent. A few studies demonstrated significant improvements in intermediate outcomes (e.g., low-density lipoprotein cholesterol), while less studies demonstrated an impact on serious sequelae (e.g., emergency department visits).” (S. J. Shoemaker, sarah_shoemaker@abtassoc.com)
Envisioning the ‘Pharmacist Benefit’: The 2011 Remington Medalist, California’s Paul W. Lofholm, PharmD, uses his career, which began with the Ninth Floor Project at UCSF in 1967, envisions a contemporary pharmacist benefit (pp. 474–6): “The provision of a pharmacist benefit would include a review of current therapy, including pharmacogenomics, patient consultation, an update of the drug profile (i.e., smart card), and at least an annual drug regimen review. This type of review is similar to what occurs in the skilled nursing home today by pharmacist consultants. The pharmacist’s emphasis is on therapeutics, costs, risks, and benefits in a particular patient. Clinical notes are written with a copy to the physician(s) summarizing the patient’s current drug history, analyzing drug usage (i.e., adherence), and listing recommendations of the pharmacist regarding therapeutics. The pharmacist would be expected to monitor the therapeutic plan as agreed upon by the medical home team, contributing drug and patient information to the team when applicable.”

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

PNN Pharmacotherapy Line
July 18, 2011 * Vol. 18, No. 137
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 16 issue of Lancet, a theme issue on HIV/AIDS timed to coincide with the 6th International AIDS Society meeting in Rome (2011; 378).
Rilpivirine v. Efavirenz in Treatment-Naive Patients with HIV: Two research studies assess efficacy of the non-nucleoside reverse transcriptase inhibitor rilpivirine (TMC278; Tibotec Pharmaceuticals) against efavirenz.
In a noninferiority trial, rilpivirine had a favorable safety profile and noninferior efficacy, compared with efavirenz, among treatment-naive patients with HIV-1 (
pp. 229–37). Over 96 weeks, Phase III trial investigators tested oral rilpivirine 25 mg and efavirenz 600 mg daily, with these results: “From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3.5% [95% CI −1.7 to 8.8]; pnon-inferiority < 0.0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2–4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p < 0.0001), as were rash and dizziness (p < 0.0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p < 0.0001).” (C. J. Cohen, ccohen@crine.org)
A second Phase III trial had similar results, finding that rilpivirine had noninferior efficacy compared with efavirenz, despite a higher virological failure rate, and a more favorable safety and tolerability profile (
pp. 238–46). In treatment-naive adults with HIV-1 infections, once-daily oral doses of the two drugs were given in the same doses as above along with tenofovir–disoproxil–fumarate and emtricitabine. Results showed: “346 patients were randomly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug, with 287 (83%) and 285 (83%) in the respective groups having a confirmed response at week 48. The point estimate from a logistic regression model for the percentage difference in response was –0.4 (95% CI –5.9 to 5.2), confirming non-inferiority with a 12% margin (primary endpoint). The incidence of virological failures was 13% (rilpivirine) versus 6% (efavirenz; 11% vs 4% by [intention-to-treat time-to-loss-of-virological-response]). Grade 2–4 adverse events (55 [16%] on rilpivirine vs 108 [31%] on efavirenz, p < 0.0001), discontinuations due to adverse events (eight [2%] on rilpivirine vs 27 [8%] on efavirenz), rash, dizziness, and abnormal dreams or nightmares were more common with efavirenz. Increases in plasma lipids were significantly lower with rilpivirine.” (J-M Molina, jean-michel.molina@sls.aphp.fr)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
Pain Treatment & Behavior in Nursing Home Residents: Among 352 nursing home residents with moderate to severe dementia, use of a systematic approach to pain treatment significantly reduced agitation, researchers report (d4065). Application of a stepwise pain-treatment protocol had these effects when tested over 8 weeks using a cluster research design: “Agitation was significantly reduced in the intervention group compared with control group after eight weeks (repeated measures analysis of covariance adjusting for baseline score, P < 0.001): the average reduction in scores for agitation was 17% (treatment effect estimate −7.0, 95% confidence interval −3.7 to −10.3). Treatment of pain was also significantly beneficial for the overall severity of neuropsychiatric symptoms (−9.0, −5.5 to −12.6) and pain (−1.3, −0.8 to −1.7), but the groups did not differ significantly for activities of daily living or cognition.” (C. Ballard, clive.ballard@kcl.ac.uk)

>>>PNN JournalWatch
* Preferential D2 or Preferential D3 Dopamine Agonists in Restless Legs Syndrome, in Neurology, 2011; 77: 110–7. (M. Manconi, mauro.manconi@eoc.ch)
* Is Vitamin D in Rheumatoid Arthritis a Magic Bullet or a Mirage? The Need to Improve the Evidence Base Prior to Calls for Supplementation, in
Arthritis & Rheumatism, 2011; 63: 1763–9. (P. Welsh, Paul.Welsh@glasgow.ac.uk)

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

PNN Pharmacotherapy Line
July 19, 2011 * Vol. 18, No. 138
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and July 19 issue of the Annals of Internal Medicine (2011; 155).
Life Expectancy with Combo Antiretroviral Therapy: Life expectancy is nearly normal among Ugandans with HIV infections who receive combination antiretroviral therapy (cART), researchers report (early release). Among 22,315 patients being treated in public-sector HIV/AIDS programs, 1,943 died during the study period. Analysis of all-cause mortality rates and abridged life tables showed the following: “After adjustment for loss to follow-up, crude mortality rates (deaths per 1,000 person–years) ranged from 26.9 (95% CI, 25.4 to 28.5) in women to 43.9 (CI, 40.7 to 47.0) in men. For patients with a baseline CD4 cell count less than 0.050 × 109 cells/L, the mortality rate was 67.3 (CI, 62.1 to 72.9) deaths per 1,000 person–years, whereas among persons with a baseline CD4 cell count of 0.250 × 109 cells/L or more, the mortality rate was 19.1 (CI, 16.0 to 22.7) deaths per 1,000 person–years. Life expectancy at age 20 years for the overall cohort was 26.7 (CI, 25.0 to 28.4) additional years and at age 35 years was 27.9 (CI, 26.7 to 29.1) additional years. Life expectancy increased substantially with increasing baseline CD4 cell count. Similar trends are observed for older age groups.” (E. J. Mills, emills@cfenet.ubc.ca)
Life expectancy in sub-Saharan Africa had been climbing during the latter half of the 20th century, until the HIV pandemic took hold in the 1990s (
early release). With cART, an editorialist writes, it’s “back to the future”: “In the past few months, 2 pivotal clinical trials convincingly demonstrated that some of the same antiretroviral drugs used for HIV treatment were highly effective in preventing infection when taken by HIV-negative men who have sex with men and dramatically decrease viral load and risk for transmission to others when taken by the HIV-positive partner in serodiscordant couples. Most recently, on 13 July 2011, it was announced that in a large clinical trial in Kenya and Uganda, as well as Botswana, the HIV-negative partner in serodiscordant couples, whether male or female, was also dramatically protected against infection with HIV by these antiretroviral therapies. With stunning swiftness, the era of HIV ‘treatment as prevention’—long imagined—has arrived.…
“Given this reality of AIDS epidemiology, coupled with its high prevalence in Africa, enabling HIV-infected young adults—its workers and parents—to live a normal lifespan is fundamental to returning Africa to its positive health trajectory of a few decades ago. Stunningly, a mere 30 years after one of the worst pandemics in history suddenly appeared, and although still without a vaccine or cure, we now possess the tools not only to treat but to comprehensively control AIDS in Africa. Despite the challenges, and amid stark, painful choices, somehow the work must be finished.” (D. Cotton,
dcotton@acponline.org)
Communicating Drug Risk/Benefit Data: Patients better comprehend benefits and risks of drugs when data are presented as percentages and absolute risks, according to a study of 2,944 adults (pp. 87–96). Using an online survey, researchers presented data as natural frequencies, variable frequencies, percentages, percentages plus natural frequencies, or percentages plus variable frequencies, with these results: “The average number of comprehension questions answered correctly was lowest in the variable frequency group and highest in the percent group (13.1 vs. 13.8; difference, 0.7 [95% CI, 0.3 to 1.1]). The proportion of participants who ‘passed’ the comprehension test (≥13 correct answers) was lowest in the natural and variable frequency groups and highest in the percent group (68% vs. 73%; difference, 5 percentage points [CI, 0 to 10 percentage points]). The largest format effect was seen for the 2 questions about absolute differences: the proportion correct in the natural frequency versus percent groups was 43% versus 72% (P < 0.001) and 73% versus 87% (P < 0.001).” (L. M. Schwartz)

>>>PNN NewsWatch
* FDA is warning of inadvertently increased radiation exposure in patients undergoing cardiac positron emission tomography (PET) scans with rubidium (Rb)-82 chloride injection from CardioGen-82 (Bracco Diagnostics). Two patients received more radiation than expected from CardioGen-82 because of strontium isotopes that may have been inadvertently injected due to a “strontium breakthrough” problem with CardioGen-82.

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

PNN Pharmacotherapy Line
July 20, 2011 * Vol. 18, No. 139
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 20 issue of JAMA (2011; 306).
Triptorelin & Chemotherapy-Induced Menopause: Temporary ovarian suppression by triptorelin reduced the occurrence of chemotherapy-induced early menopause among 281 patients in the PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6) study (pp. 269–76). In 2003–08, premenopausal women with breast cancer at 16 Italin clinics received triptorelin 3.75 mg intramuscularly at least 1 week before the start of and every 4 weeks during chemotherapy, with these results: “Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of −17% (95% confidence interval, −26% to −7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).” (L. Del Mastro, lucia.delmastro@istge.it)
These data “are intriguing and represent an important and encouraging addition” to the literature, editorialists write (
pp. 312–4). They conclude: “The most effective option for fertility preservation is assisted reproductive technology with embryo or oocyte cryopreservation, and this option should be discussed with young women facing chemotherapy for breast cancer and other curable malignancies. International guidelines recommend discussion of fertility options before starting chemotherapy, and when possible before surgery, to allow optimal timing for consultation and oocyte harvesting. When feasible, and for patients with hormone-insensitive disease, [gonadotropin-releasing hormone] agonist therapy to suppress ovarian function during chemotherapy is an additional treatment that can potentially expand fertility possibilities. Although recovering menses is not the same as fertility preservation, it is one step in the right direction.” (H. S. Rugo, hrugo@medicine.ucsf.edu)
HCV/HIV Coinfection: Authors of an NIH Grand Rounds article reach this conclusion based on the case of a 61-year-old man with coinfection of HIV and hepatitis C virus (pp. 294–301). “To date, our patient is clinically stable and contemplating future therapy with direct-acting agents as they become available. Development of therapeutic strategies to improve [sustained viral response (SVR)] rates in this group is essential from both a patient management and a public health point of view. Existing data suggest that these patients would benefit from an HCV regimen that does not rely on the host immune system. Eradication of HCV or chronic suppression of HCV replication may be achievable with long-term interferon-sparing direct-acting agents, but concerns regarding viral breakthrough and emergence of viral resistance remain. Hepatitis C virus lacks the 2 major impediments to eradication seen in most chronic viral infections, namely a clinically relevant viral reservoir and integration into the host genome. Therefore, it is plausible that effective suppression of HCV replication with potent anti-HCV agents could result in a marked improvement in SVR rates achieved in this population.” (C. Hadigan, hadiganc@niaid.nih.gov)
Using Pharmacogenetics Clinically: After reviewing early application of pharmacogenetic tests in clinical care, authors of a Commentary describe future use of gene studies (pp. 306–7): “For drugs with a narrow therapeutic index, pharmacogenetic studies may hold the potential to resurrect treatments previously withdrawn from the market, particularly for agents designed to fill underserved clinical niches (eg, [cannabinoid-1] receptor blockers for the treatment of obesity). For drugs with a wider therapeutic index (eg, beta-antagonists for hypertension), predictive models may need to include combinations of variants with relatively small main effects. For others (eg, beta-agonists for asthma), predictive models of response improve with the inclusion of genetic loci contributing to disease progression. Many examples are emerging (eg, metformin for type 2 diabetes mellitus) for which additional pharmacokinetic candidate genes (organic cation transporters and multidrug and toxin extrusion proteins) provide insights into absorption, distribution, and elimination beyond information already known about the drug’s metabolism.” (R. A. Wilke, russell.a.wilke@vanderbilt.edu)

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

PNN Pharmacotherapy Line
July 21, 2011 * Vol. 18, No. 140
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 21 issue of the New England Journal of Medicine (2011; 365).
Treatment of Hodgkin’s Lymphoma: Despite initially better results, long-term outcomes were not significantly different with an intensified regimen for treating Hodgkin’s lymphoma, compared with the standard ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) treatment (pp. 203–12). BEACOPP is an intensified regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. In 331 patients with previously untreated and unfavorable Hodgkin’s lymphoma, BEACOPP and ABVD produced these outcomes: “The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P = 0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P = 0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P = 0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P = 0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group.” (A. M. Gianni, alessandro.gianni@unimi.it)
An editorialist advocates use of the older ABVD regimen until advantages of the intensified strategy are proven (
pp. 264–5): “If the goal is cure with the least overall toxic effects, the strategy of ABVD therapy—reserving rescue therapy with high-dose chemotherapy and autologous hematopoietic stem-cell transplantation for patients in whom the primary treatment fails—must be favored. [These authors] speculate that the more intense treatment with escalated BEACOPP therapy may still be justified in patients who have many adverse prognostic factors at diagnosis, but they do not provide data identifying such a subgroup, probably because its small size precluded statistically valid conclusions.
“Hodgkin’s lymphoma has again provided a valuable lesson to the oncology community: once cure is regularly being attained in the majority of patients and curative secondary treatment is available, the clinically valid comparison is between strategies of overall, not just primary, treatment. An apparently more effective initial treatment may be unattractive because of increased toxic effects.” (J. M. Connors)

>>>PNN NewsWatch
* Ticagrelor (Brilinta, AstraZeneca) has been approved by FDA for reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndrome, including unstable angina, non–ST-elevation myocardial infarction, and ST-elevation myocardial infarction. The long-awaited oral agent inhibits platelets in a unique way: direct, reversible inhibition of P2Y12. Evidence of the drug’s effectiveness and safety was developed in the PLATO (A Study of Platelet Inhibition and Patient Outcomes) trial, a superiority study that compared ticagrelor with clopidogrel. In 18,624 patients in 43 countries with ACS, ticagrelor produced a greater reduction in the primary end point–a composite of cardiovascular death, myocardial infarction, or stroke–compared with clopidogrel (9.8% vs. 11.7% at 12 months; 1.9% absolute risk reduction; 16% relative risk reduction; 95% CI, 0.77 to 0.92; P < 0.001). A post-hoc analysis showed that concomitant aspirin in doses greater than 100 mg reduced the effectiveness of ticagrelor; when used with the new drug, aspirin should be used in doses no greater than 75–100 mg. The most commonly observed adverse reactions associated with the use of ticagrelor and clopidogrel were bleeding (11.6% vs.11.2%) and dyspnea (14% vs. 8%). Ticagrelor is administered twice daily in 90-mg doses; these follow an initial loading dose of 180 mg. Brilinta was approved with a Risk Evaluation and Mitigation Strategy. It includes educational outreach to physicians to alert them about the risk of using higher doses of aspirin. In addition, prescriptions for the drug, including refills, should be dispensed with a Medication Guide.

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

PNN Pharmacotherapy Line
July 22, 2011 * Vol. 18, No. 141
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
July issue of Health Affairs (2011; 30).
Generic Drugs for Prevention of Chronic Disease: The impact of generic drugs on the cost-effectiveness of preventive care is far greater than previously assumed, according to authors of a study that focused on cardiovascular disease (pp. 1351–7). After recalculating the cost inputs from a previous study, the investigators found: “Focusing on coronary artery disease, we demonstrate that prevention, with the appropriate use of generic medications, appears far more cost-effective than previously documented, and it may even save on costs. For example, an earlier study estimated that reducing blood pressure to widely established clinical guidelines in nondiabetic patients cost an estimated $52,983 per quality-adjusted life–year if a brand-name drug was used. However, we estimate that the cost is just $7,753 per quality-adjusted life–year at generic medication prices. As the nation attempts to find strategies to improve population health without adding to the unsustainably high cost of care, policy makers should focus on ensuring that patients have access to essential generic medications.” (W. H. Shrank, wshrank@partners.org)
Speed of Approval of Cancer Drugs: Data from 2003–10 show that oncology drugs reach the market faster in the U.S. than in Europe, researchers report (pp. 1375–81). Of 35 agents approved by either FDA or its counterpart, the European Medicines Agency, investigators found that 3 were approved first in Europe, while the rest came on the U.S. market first: “For [agents marketed first in the U.S.], the median time between the submission date and the approval date was 182 days, and twenty products were approved within 184 days. Only three of the thirty-two took more than a year to receive approval.
“The EMA did not approve nine of the thirty-two products that the FDA approved in this period. Although several of these products were in development in Europe at the time of our study, marketing authorization applications for two—Zolinza, a new drug to treat a type of lymphoma (cutaneous T-cell lymphoma), and Ixempra, for advanced breast cancer—were withdrawn during the EMA review process because of potential safety concerns.” (S. A. Roberts,
sroberts@focr.org)

>>>Medical Care Report
Source:
Aug. issue of Medical Care (2011; 30).
Physician View of AHRQ’s Prevention Quality Indicators: Clinicians support expanded uses of some prevention quality indicators (PQIs) of the Agency for Healthcare Research and Quality, but panelists in a face-validity study had reservations about the metrics (pp. 679–85). Three panels of 64 physicians considered 12 PQIs at three denominator levels (geographic area, payer, and large physician groups) and for three uses (quality improvement, comparative reporting, and pay for performance): “Panelists showed stronger support of the usefulness of chronic disease indicators at the payer and large physician group levels than for acute disease indicators. Panelists fully supported the usefulness of 2 indicators for comparative reporting (asthma, congestive heart failure) and no indicators for pay-for-performance applications. Panelists expressed serious concerns about the usefulness of all new applications of 3 indicators (angina, perforated appendix, dehydration). Panelists rated age, current comorbidities, earlier hospitalization, and socioeconomic status as the most important risk-adjustment factors.” (S. Davies)

>>>PNN NewsWatch
* A 2-fold increase in mortality with dronedarone (Multaq, Sanofi Aventis) in a recent clinical trial led to an FDA safety announcement yesterday. The Permanent Atrial fibriLLAtion Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study was stopped early based on 2-fold increases in deaths, strokes, and hospitalizations among patients with permanent atrial fibrillation, FDA said. The agency said that dronedarone should not be used in patients with permanent AF and suggested that patients talk with health professionals about whether to continue use for nonpermanent cases.
* The benefits of
oral bisphosphonates continue to outweigh risks, FDA said yesterday. The agency reviewed two epidemiologic studies, one showing a 2-fold increased risk of esophageal cancer with the drugs and the other showing no such relationship. FDA said it would continue reviewing drugs in this class and issue further updates as needed.

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

PNN Pharmacotherapy Line
July 25, 2011 * Vol. 18, No. 142
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 23 issue of Lancet (2011; 378).
GAD-Based Vaccine in Type 1 Diabetes: Antigen-based immunotherapy using glutamic acid decarboxylase (GAD) vaccine has shown promise in animal models of autoimmunity, but a clinical trial in 145 patients with recent-onset type 1 diabetes failed to demonstrate a benefit in people (pp. 319–27). Testing whether GAD formulated with aluminum hydroxide would be an effective vaccine in recently diagnosed patients, investigators administered two or three injections of GAD–alum and looked for changes in baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 hours of a 4-hour mixed meal tolerance test: “At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0.412 nmol/L (95% CI 0.349–0.478) in the GAD-alum group, 0.382 nmol/L (0.322–0.446) in the GAD-alum plus alum group, and 0.413 nmol/L (0.351–0.477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0.998 (95% CI 0.779–1.22; p = 0.98) for GAD-alum versus alum, and 0.926 (0.720–1.13; p = 0.50) for GAD-alum plus alum versus alum. HbA1c, insulin use, and the occurrence and severity of adverse events did not differ between groups.” (J. S. Skyler, jskyler@miami.edu)
Tamoxifen in Idiopathic Retroperitoneal Fibrosis: In an open-label trial of 40 patients, tamoxifen was less effective for prevention of relapses of idiopathic retroperitoneal fibrosis than usual treatment with glucocorticoids, researchers report (pp. 338–46). After induction therapy with prednisone for 1 month, patients received tapering prednisone or tamoxifen for 8 months, with these results: “After induction therapy, 36 of the 40 enrolled patients achieved remission and were randomly assigned to treatment (18 per group). One patient (6%) in the prednisone group and seven patients (39%) in the tamoxifen group relapsed by the end of treatment (difference −33% [95% CI −58 to −8, p = 0.0408]. The difference in relapse rate between the groups was sustained after the additional 18-month follow-up: the 26-month estimated cumulative relapse probability was 17% with prednisone and 50% with tamoxifen (difference −33% [−62 to −3, p = 0.0372]). Cushingoid changes and grade 2 hypercholesterolaemia were more common in the prednisone group than in the tamoxifen group (p = 0.0116 and p = 0.0408, respectively).” (A. Vaglio, augusto.vaglio@virgilio.it)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
MI Risk with Aspirin Discontinuation in Primary Care: Risks for nonfatal myocardial infarction are increased in primary-care patients who stop taking low-dose aspirin for secondary prevention, a study shows (d4094). A nested case–control study analyzed 38,513 patients who were 50–84 years of age when aspirin therapy began in 2000–07. Comparing those who stopped aspirin with those who continued, the authors found: “There were 876 non-fatal myocardial infarctions and 346 deaths from coronary heart disease. Compared with current users, people who had recently stopped taking aspirin had a significantly increased risk of non-fatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% confidence interval 1.12 to 1.84) and non-fatal myocardial infarction alone (1.63, 1.23 to 2.14). There was no significant association between recently stopping low dose aspirin and the risk of death from coronary heart disease (1.07, 0.67 to 1.69). For every 1,000 patients, over a period of one year there were about four more cases of non-fatal myocardial infarction among patients who discontinued treatment with low dose aspirin (recent discontinuers) compared with patients who continued treatment.” (L. A. García Rodríguez, lagarcia@ceife.es)

>>>PNN NewsWatch
* Updated labeling for varenicline (Chantix, Pfizer) includes information on how the product should be used in patients with stable cardiovascular disease and COPD.

>>>PNN JournalWatch
* Systematic Review and Meta-Analysis: Do Clinical Trials Testing Antimuscarinic Agents for Overactive Bladder Adequately Measure Central Nervous System Adverse Events?, in Journal of the American Geriatrics Society, 2011; 59: 1332–9. (C. Tannenbaum, cara.tannenbaum@umontreal.ca)

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

PNN Pharmacotherapy Line
July 26, 2011 * Vol. 18, No. 143
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 25 issue of the Archives of Internal Medicine (2011; 171).
Cranberries for UTIs: Trimethoprim-sulfamethoxazole 480 mg once daily was more effective for preventing recurrent urinary tract infections than cranberry capsules 500 mg twice daily, a study of 221 premenopausal women shows (pp. 1270–8). Resistance to TMP-SMX was a primary impetus for exploring use of alternative medicines in this situation, and TMP-SMX use clearly selected for resistant strains of Escherichia coli. But the researchers still found superiority for TMP-SMX in a 12-month trial: “The mean number of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (4.0 vs 1.8; P = .02), and the proportion of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Median time to the first symptomatic UTI was 4 months for the cranberry and 8 months for the TMP-SMX group. After 1 month, in the cranberry group, 23.7% of fecal and 28.1% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant, whereas in the TMP-SMX group, 86.3% of fecal and 90.5% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant. Similarly, we found increased resistance rates for trimethoprim, amoxicillin, and ciprofloxacin in these E coli isolates after 1 month in the TMP-SMX group. After discontinuation of TMP-SMX, resistance reached baseline levels after 3 months. Antibiotic resistance did not increase in the cranberry group. Cranberries and TMP-SMX were equally well tolerated.” (S. E. Geerlings, s.e.geerlings@amc.uva.nl)
An editorialist writes that “few botanical dietary supplements have lived up to their claims as effective ‘alternative’ medicines, and until more is known about phytochemical disposition in humans, efficacy concerns will continue to plague these products” (
pp. 1279–80). Noting that “cranberry has the potential to dispel some of this uncertainty,” he explains: “Evidence from other studies points to the utility of cranberry products in reducing UTI recurrence and that type-A proanthocyanidins, through a reduction in the adhesiveness of uropathogenic bacteria, may underlie this effect. An examination of the relevant ex vivo data implies that proanthocyanidin urinary metabolites may also play a role in cranberry’s utility in lessening UTI recurrence. This inference stems from the extensive presystemic metabolism (oxidative and conjugative) of most plant polyphenols, that urinary concentrations of proanthocyanidin metabolites far exceed that of parent compounds, and that metabolites of other plant polyphenols either retain or exhibit enhanced pharmacologic activity. Cranberry extracts, therefore, may act as pro-drugs for the production of active urinary polyphenolic metabolites.” (B. J. Gurley, gurleybillyj@uams.edu)
Dabigatran Use in Older Patients: An increased area under the serum dabigatran concentration–time curve of 40–60% in older patients increases their risk of overdose and bleeding, writes an author who also reports two cases (pp. 1285–6). Because of reduced kidney function, the predominantly renally cleared drug likely produced rectal bleeding and death in an 84-year-old woman and epistaxis in an 89-year-old woman, the author writes, adding: “Patients included in the RE-LY trial in the dabigatran 110- and 150-mg groups had a mean (SD) age of 71.4 (8.6) years and 71.5 (8.8) years, respectively, weighing 82.9 (19.9) kg and 82.5 (19.4) kg, respectively, with a CrCL higher than 30 mL/min/1.73 m2. The trial was therefore neither designed nor powered to assess the safety profile of the drug in elderly patients with low body weight. Finally, dabigatran AUC is increased by approximately 60% when coadministrated orally with 1 dose of 600-mg amiodarone, which is a strong inhibitor of P-glycoprotein, of which dabigatran is a substrate.” (M. Legrand, matthieu.m.legrand@gmail.com)

>>>PNN NewsWatch
* Enhancing individualization of drug therapy, determining better ways to conduct pivotal clinical trials, following medications once they come onto the market, and improving the safe use of drugs are among the “science and research needs” of FDA’s Center for Drug Evaluation and Research, according to a report published yesterday in the Federal Register. When final, the report will guide CDER in its strategic planning of internal research initiatives. Public comments on the report can be made for the next 60 days.

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

PNN Pharmacotherapy Line
July 27, 2011 * Vol. 18, No. 144
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 27 issue of JAMA (2011; 306).
Medicare Part D & Nondrug Medical Spending: Costs of nondrug medical spending, particularly for acute and postacute care, fell significantly following implementation of Medicare Part D for beneficiaries who previously had limited drug coverage, researchers report (pp. 402–9). Patients self-reported the extent of their prior drug coverage. Longitudinal survey data and linked Medicare claims for 2004–07 were analyzed for 6,001 Medicare beneficiaries from the Health and Retirement Study, with these results: “Total nondrug medical spending was differentially reduced after January 1, 2006, for beneficiaries with limited prior drug coverage (−$306/quarter [95% confidence interval {CI}, −$586 to −$51]; P = .02), relative to beneficiaries with generous prior drug coverage. This differential reduction was explained mostly by differential changes in spending on inpatient and skilled nursing facility care (−$204/quarter [95% CI, −$447 to $2]; P = .05). Differential reductions in spending on physician services (−$67/quarter [95% CI, −$134 to −$5]; P = .03) were not associated with differential changes in outpatient visits (−0.06 visits/quarter [95% CI, −0.21 to 0.08]; P = .37), suggesting reduced spending on inpatient physician services for beneficiaries with limited prior drug coverage. In contrast, nondrug medical spending in the control cohort did not differentially change after January 1, 2004, for beneficiaries with limited prior drug coverage in 2002 ($14/quarter [95% CI, −$338 to $324]; P = .93), relative to beneficiaries with generous prior coverage.” (J. M. McWilliams, mcwilliams@hcp.med.harvard.edu)
Mutations in Barrett Esophagus & Esophageal Adenocarcinoma: Looking for explanations for the 350% increase in incidence of esophageal adenocarcinoma (EAC) over the past 3 decades, investigators find that presence of a specific gene, MSR1, is associated with presence of the precursor condition, Barrett’s esophagus (BE), and EAC (pp. 410–9). Genotyping of 21 concordant-affected and 11 discordant sibling pairs showed the following: “Three major genes, MSR1, ASCC1, and CTHRC1 were associated with BE/EAC (all P < .001). In addition, 13 patients (11.2%) with BE/EAC carried germline mutations in MSR1, ASCC1, or CTHRC1. MSR1 was the most frequently mutated, with 8 of 116 (proportion, 0.069; 95% confidence interval [CI], 0.030–0.130; P < .001) cases with c.877C>T (p.R293X). An independent validation series confirmed germline MSR1 mutations in 2 of 58 cases (proportion, 0.035; 95% CI, 0.004-0.120; P = .09). MSR1 mutation resulted in CCND1 up-regulation in peripheral-protein lysate. Immunohistochemistry of BE tissues in MSR1 -mutation carriers showed increased nuclear expression of CCND1.” (C. Eng, engc@ccf.org)

>>>PNN NewsWatch
* Linezolid (Zyvox, Pfizer), when administered to patients taking serotonergic agents for psychiatric diagnoses, can produce serotonin syndrome, FDA warned yesterday. The agency said the exact mechanism of the drug interaction is unknown but that linezolid is known to inhibit monoamine oxidase A. When linezolid is given to patients taking serotonergic psychiatric medications, high levels of serotonin may build up in the brain, causing toxicity. Signs and symptoms of serotonin syndrome include mental changes (confusion, hyperactivity, memory problems), muscle twitching, excessive sweating, shivering or shaking, diarrhea, trouble with coordination, and/or fever. FDA advised clinicians to avoid such combinations of drugs, with consideration given to stopping psychiatric medications when life-threatening infections require linezolid therapy. These would include infections of vancomycin-resistant Enterococcus faecium and nosocomial pneumonia and complicated skin and skin structure infections, including cases caused by methicillin-resistant Staphylococcus aureus.
* Similar problems have been found with
methylene blue, FDA also warned. Serotonin syndrome has occurred in patients taking combinations of serotonergic psychiatric medications and receiving methylene blue as a dye in diagnostic or therapeutic procedures or for treatment of methemoglobinemia, vasoplegic syndrome, ifosfamide-induced encephalopathy, or cyanide poisoning. FDA gave similar advice as with linezolid: Avoid the combination, but when life-threatening situations require methylene blue administration, attempt to interrupt treatment with the psychiatric medications temporarily.

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

PNN Pharmacotherapy Line
July 28, 2011 * Vol. 18, No. 145
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 28 New England Journal of Medicine (2011; 365).
Bardoxolone Methyl in CKD, Type 2 Diabetes: The oral antioxidant inflammation modulator bardoxolone methyl improved renal function in patients with chronic kidney disease and type 2 diabetes when used for 24 weeks, a study shows (pp. 327–36). Improvements persisted up to 52 weeks, with these effects on glomerular filtration rates in 227 adults who received placebo or bardoxolone in various doses: “Patients receiving bardoxolone methyl had significant increases in the mean (± SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m2 of 8.2 ± 1.5 ml in the 25-mg group, 11.4 ± 1.5 ml in the 75-mg group, and 10.4 ± 1.5 ml in the 150-mg group; P < 0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m2 of 5.8 ± 1.8 ml, 10.5 ± 1.8 ml, and 9.3 ± 1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl.” (P. E. Pergola, ppergola@raparesearch.com)
Protection from Rotavirus Infection: Looking for an explanation for lower-than-expected efficacy of rotavirus vaccines in India, investigators find that natural infections of the virus also fail to produce protection against reinfections (pp. 337–46). Researchers attribute this to high viral diversity in urban slums of Vellore, where they conducted twice-weekly home visits beginning at birth: “Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections.” (G. Kang, gkang@cmcvellore.ac.in)
Microbial Genomics & Infectious Diseases: The author of a review article makes these observations about future study of microbial genomics in an effort to treat infectious diseases (pp. 347–57): “Without question, the techniques for microbial and viral genome sequencing are becoming increasingly rapid and less expensive. Genome sequencing of a microbe or virus will soon be easier than characterization of its growth-based behavior in the laboratory. In the next 3 to 5 years, direct shotgun sequencing of the DNA and RNA in a clinical sample may become a routine matter. What is less clear is how clinically relevant information will be most effectively extracted from the ensuing massive amounts of data. In the near term, genomic and metagenomic analyses of microbes are most likely to be useful in areas such as the cataloguing and understanding of microbial and viral diversity in the human body, the identification of molecular determinants of virulence and symbiosis, and real-time tracking of particular strains of pathogens. Such analyses will also provide a deeper understanding of how pathogens spread and cause disease and will identify new targets for therapies and antigens for vaccines. Thoughtfully designed clinical and epidemiologic studies will be required to see the full realization of these benefits.” (D. A. Relman, relman@stanford.edu)
In a Perspective article, FDA officials discuss the risk–benefit of high-dose simvastatin therapy (
pp. 285–7): “During the next year, the FDA will closely monitor prescription-use data to determine whether the safety-labeling changes and the communication outreach are having their intended effects of limiting new initiation of high-dose simvastatin therapy and guiding appropriate use of concomitant medications with simvastatin. If evidence indicates that these measures are not effective, the agency will consider additional regulatory action, including withdrawal of high-dose simvastatin from the market.” (A. Egan)

>>>PNN NewsWatch
* CardioGen-82 is being voluntarily recalled by its manufacturer, Bracco Diagnostics. The generator is used to produce rubidium (Rb)-82 chloride injection, which is used in PET scans of the heart. This action upgrades the recent FDA warning (see PNN, July 19) that patients were receiving more radiation than expected during scans that used CardioGen-82.

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

PNN Pharmacotherapy Line
July 29, 2011 * Vol. 18, No. 146
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (2011; 34).
Early Glycemic Control in Pregnancy: Women with type 1 diabetes who have high A1C levels before and during pregnancy are more likely to develop pre-eclampsia, a study shows, producing the conclusion that “optimal glycemic control both early and throughout pregnancy may reduce the risk of pre-eclampsia in women with type 1 diabetes” (pp. 1683–8). In the randomized controlled Diabetes and Pre-eclampsia Intervention Trial (DAPIT), 749 women had A1C values available for up to 6 months before pregnancy, at the first antenatal visit, and/or at 26 weeks’ and 34 weeks’ gestation.
These patterns were evident for study outcomes of pre-eclampsia and gestational hypertension: “Pre-eclampsia and gestational hypertension developed in 17 and 11% of pregnancies, respectively. Women who developed pre-eclampsia had significantly higher A1C values before and during pregnancy compared with women who did not develop pre-eclampsia (P < 0.05, respectively). In early pregnancy, A1C ≥8.0% was associated with a significantly increased risk of pre-eclampsia (odds ratio 3.68 [95% CI 1.17–11.6]) compared with optimal control. At 26 weeks’ gestation, A1C values ≥6.1% (good: 2.09 [1.03–4.21]; moderate: 3.20 [1.47–7.00]; and poor: 3.81 [1.30–11.1]) and at 34 weeks’ gestation A1C values ≥7.0% (moderate: 3.27 [1.31–8.20] and poor: 8.01 [2.04–31.5]) significantly increased the risk of pre-eclampsia compared with optimal control. The adjusted odds ratios for pre-eclampsia for each 1% decrement in A1C before pregnancy, at the first antenatal visit, at 26 weeks’ gestation, and at 34 weeks’ gestation were 0.88 (0.75–1.03), 0.75 (0.64–0.88), 0.57 (0.42–0.78), and 0.47 (0.31–0.70), respectively. Glycemic control was not significantly associated with gestational hypertension.” (D. R. McCance,
david.mccance@belfasttrust.hscni.net)
Nurse Case Management in Diabetes: In 556 veterans, control of hypertension, hyperglycemia, and hyperlipidemia was improved with nurse case management, compared with usual care (pp. 1689–94). Nurses used a therapeutic algorithm in caring for patients assigned to the case management group, and these differences emerged in a primary outcome (blood pressure <130/80 mmHg, A1C <8.0%, and LDL cholesterol <100 mg/dL) in the 1-year study: “A greater number of individuals assigned to case management achieved the primary study outcome of having all three outcome measures under control (61 [21.9%] compared with 28 [10.1%] in the usual care group [P < 0.01]). In addition, a greater number of individuals assigned to the intervention group achieved the individual treatment goals of [A1C] <8.0% (73.7 vs. 65.8%, P = 0.04) and BP <130/80 mmHg (45.0 vs. 25.4%, P < 0.01), but not for LDL [cholesterol] <100 mg/dL (57.6 vs. 55.4%, P = 0.61), compared with those in the usual care group.” (A. Ishani, isha0012@umn.edu)
Needle-Free Jet Insulin Injection: Improved pharmacokinetic and pharmacodynamic profiles —ones more similar to those of endogenous insulin secretion — were evident among 18 healthy volunteers following injection of insulin aspart with a needle-free jet device, researchers report (pp. 1804–8). In a crossover study, insulin was administered subcutaneously either by conventional pen or jet injector, with these results determined based on the glucose infusion rate (GIR) needed to maintain euglycemia: “The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ~40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices.” (B. E. de Galan, b.degalan@aig.umcn.nl)

>>>PNN NewsWatch
* The maximum daily dose for single-ingredient Extra Strength Tylenol products has been lowered to 3 g/d, McNeil announced yesterday. Product with the new labeling will ship in fall 2011. Other acetaminophen products from the company will be similarly relabeled in 2012.

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

PNN Pharmacotherapy Line
Aug. 1, 2011 * Vol. 18, No. 147
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 30 issue of Lancet (2011; 378).
Treatment of Depression in Dementia: The standard practice of treating depression in patients with dementia with drugs such as sertraline and mirtazapine should be reconsidered, authors conclude based on a study showing no benefit with these agents over placebo (pp. 403–11). In the Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial, participants with possible or probable Alzheimer’s disease and depressions received sertraline 150 mg/d, mirtazapine 45 mg/d, or placebo, with these results: “Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1.17, 95% CI −0.23 to 2.58; p = 0.10) or mirtazapine (0.01, −1.37 to 1.38; p = 0.99), or between participants in the mirtazapine and sertraline groups (1.16, −0.25 to 2.57; p = 0.11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 [26%]) than did participants in the sertraline group (46 of 107, 43%; p = 0.010) or mirtazapine group (44 of 108, 41%; p = 0.031), and fewer serious adverse events rated as severe (p = 0.003). Five patients in every group died by week 39.” (S. Banerjee, sube.banerjee@kcl.ac.uk)
“The HTA-SADD trial does not advocate abandonment of antidepressants in people with Alzheimer’s disease and depression,” writes the author of a commentary (pp. 375–6). “Anecdotally, clinicians report successful treatment of patients with antidepressants. Therapeutic trials for individual patients are warranted, although not as first-line treatment unless depression is severe. Antidepressants might have benefits to other psychiatric symptoms secondary to dementia, as indicated by reports that hallucinations, delusions, and agitation benefit from citalopram. Finally, there are anecdotal accounts of use of electroconvulsive therapy in severe depression.”(H. Brodaty,
h.brodaty@unsw.edu.au)
Co-stimulation Modulation with Abatacept in Type 1 Diabetes: Abatacept therapy in patients recently diagnosed with type 1 diabetes was beneficial for 6 months, researchers report, indicating a window during which T-cell activation can be modulated (pp. 412–9). Focusing on the immunopathogenesis of the disease and its relationship with T-cell autoimmunity, the investigators administered abatacept 10 mg/kg, up to 1000 mg/dose, or placebo to 112 patients aged 6–45 years. Results showed: “Adjusted C-peptide [geometric mean 2-h area-under-the-curve] was 59% (95% CI 6.1–112) higher at 2 years with abatacept (n = 73, 0.378 nmol/L) than with placebo (n = 30, 0.238 nmol/L; p = 0.0029). The difference between groups was present throughout the trial, with an estimated 9.6 months’ delay (95% CI 3.47–15.6) in C-peptide reduction with abatacept. There were few infusion-related adverse events (36 reactions occurred in 17 [22%] patients on abatacept and 11 reactions in six [17%] on placebo). There was no increase in infections (32 [42%] patients on abatacept vs 15 [43%] on placebo) or neutropenia (seven [9%] vs five [14%]).” (J. S. Skyler, jskyler@miami.edu)

>>>PNN NewsWatch
* The process through which most medical devices are approved at FDA is open for debate, the agency said on Friday. Similar to FDA’s generic-approval pathway, medical devices can be marketed if manufacturers successfully show that their device is substantially equivalent to another legally marketed “predicate” device. This 510(k) clearance process was reviewed by the Institute of Medicine at FDA’s request, and its recommendations are now open for public comment.

>>>PNN JournalWatch
* Oxytocin Bolus Versus Oxytocin Bolus and Infusion for Control of Blood Loss at Elective Caesarean Section: Double Blind, Placebo Controlled, Randomised Trial, in BMJ, 2011; 343: d4661. (S. R. Sheehan, sharonrsheehan@gmail.com)
* Cancer Immunotherapy: Sipuleucel-T and Beyond, in
Pharmacotherapy, 2011; 31: 813–28. (D. H. Cauley, dcauley@mdanderson.org)
* An Opinion Paper Outlining Recommendations for Training, Credentialing, and Documenting and Justifying Critical Care Pharmacy Services, in
Pharmacotherapy, 2011; 31: 829. (W. Dager)
* N-of-1 Trials in the Medical Literature: A Systematic Review, in
Medical Care, 2011; 49: 761–8. (N. B. Gabler)

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

PNN Pharmacotherapy Line
Aug. 2, 2011 * Vol. 18, No. 148
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 2 issue of the Annals of Internal Medicine (2011; 155).
Syphilis Rates Among Men Who Have Sex with Men: Rates of primary and secondary syphilis increased substantially in 2005–08 among men who have sex with men, a CDC report shows (pp. 145–51). The increase was greatest among Hispanic and black MSM, compared with whites, and in younger age groups. Federal data from 27 states showed these patterns: “For each year during 2005 to 2008, 27 states from all U.S. census regions reported data on the sex of sex partners for 70% or more of male cases of primary and secondary syphilis. Regression analysis revealed significantly different trends in rates of primary and secondary syphilis: Absolute increases in rates among black MSM and Hispanic MSM were, respectively, 8.0 times and 2.4 times the absolute increase in rate among white MSM. By region, rates among MSM increased 30% in the Midwest, 48% in the South, 73% in the Northeast, and 77% in the West. By age group, the largest absolute increase in rates occurred among MSM aged 20 to 29 years.” (J. R. Su, ezu2@cdc.gov)
Editorialists, noting that “incident syphilis in young MSM is a highly accurate predictor of subsequent HIV infection,” paint a case for action (
pp. 192–3): “This new syphilis epidemic needs to be met by novel and responsive public health approaches. Are funds expended in ways that address current MSM behaviors? For example, many MSM with newly diagnosed syphilis or HIV met their sexual partners recently on the Internet. In addition to working with the electronic venues where MSM meet sexual partners, community-based screening needs to be scaled up to increase testing opportunities where MSM may congregate: for example, bathhouses, bars, and nightclubs.” (K. H. Mayer, kmayer@fenwayhealth.org)
Cost Shifts with Hospitalist Care: While hospitalist care was associated with decreased length of stay and hospital costs among a national cohort of Medicare patients, postdischarge expenses were higher among those cared for by hospitalists, compared with primary care physicians (pp. 152–9). Using data from 2001–06, investigators found that the cost shift more than consumed the dollars saved through hospitalist care: “Hospital length of stay was 0.64 day less among patients receiving hospitalist care. Hospital charges were $282 lower, whereas Medicare costs in the 30 days after discharge were $332 higher (P < 0.001 for both). Patients cared for by hospitalists were less likely to be discharged to home (odds ratio, 0.82 [95% CI, 0.78 to 0.86]) and were more likely to have emergency department visits (odds ratio, 1.18 [CI, 1.12 to 1.24]) and readmissions (odds ratio, 1.08 [CI, 1.02 to 1.14]) after discharge. They also had fewer visits with their primary care physician and more nursing facility visits after discharge.” (Y-F Kuo, yokuo@utmb.edu)
Omega-3 Fatty Acids & CHF: Older adults with higher levels of circulating individual and total omega-3 fatty acid concentrations have a lower incidence of congestive heart failure, researchers report (pp. 160–70). Included in the analysis were 2,735 U.S. adults without prevalent heart disease who were enrolled in the Cardiovascular Health Study from 1992 to 2006. Comparison of a cohort of 555 cases of CHF with control patients showed the following: “After multivariate adjustment, plasma phospholipid [eicosapentaenoic acid (EPA)] concentration was inversely associated with incident CHF; risk was approximately 50% lower in the highest versus the lowest quartile (hazard ratio [HR], 0.52 [95% CI, 0.38 to 0.72]; P for trend = 0.001). In similar analyses, trends toward lower risk were seen for [docosapentaenoic acid (DPA)] (HR, 0.76 [CI, 0.56 to 1.04]; P for trend = 0.057) and total long-chain omega-3 fatty acids (HR, 0.70 [CI, 0.49 to 0.99]; P for trend = 0.062) but not for [docosahexaenoic acid (DHA)] (HR, 0.84 [CI, 0.58 to 1.21]; P for trend = 0.38). In analyses censored to the middle of follow-up (7 years) to minimize exposure misclassification over time, multivariate-adjusted HRs were 0.48 for EPA (CI, 0.32 to 0.71; P for trend = 0.005), 0.61 for DPA (CI, 0.39 to 0.95; P for trend = 0.033), 0.64 for DHA (CI, 0.40 to 1.04; P for trend = 0.057), and 0.51 for total omega-3 fatty acids (CI, 0.32 to 0.80; P for trend = 0.003).” (D. Mozaffarian, dmozaffa@hsph.harvard.edu)

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

PNN Pharmacotherapy Line
Aug. 3, 2011 * Vol. 18, No. 149
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 3 issue of JAMA, a theme issue on violence and human rights (2011; 306).
Risperidone for Antidepressant-Resistant PTSD: In 296 patients with military-related posttraumatic stress disorder (PTSD) who had not responded to treatment with the only FDA-approved agents for this condition (SSRIs), risperidone was also ineffective for relieving symptoms in a 6-month trial, researchers report (pp. 493–502). Several instruments were used to detect progress: the Clinician-Administered PTSD Scale (CAPS) (range, 0–136), Montgomery–Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V). Results showed: “Change in CAPS scores from baseline to 24 weeks in the risperidone group was −16.3 (95% CI, −19.7 to −12.9) and in the placebo group, −12.5 (95% CI, −15.7 to −9.4); the mean difference was 3.74 (95% CI, −0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, −0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, −0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, −0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, −0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, −1.13, 95% CI, −2.58 to 0.32; P = .13; SF-36V mental component mean difference, −0.26; 95% CI, −2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively.” (J. H. Krystal, john.krystal@yale.edu)
Interventions for military-related PSTD must meet “veterans where they are,” an editorialist writes (
pp. 549–51). He makes these comments about drug therapy for the condition: “Studies of other medication categories used to augment SSRI treatment have generally been disappointing, with the exception of prazosin, an alpha-1-adrenergic receptor antagonist, that has shown benefit in improving sleep through reduction of physiological reactivity associated with nightmares. Although benzodiazepines are widely prescribed, they are relatively contraindicated and should be discouraged. Any short-term alleviation of anxiety symptoms (which reinforces the perception of benefit) is offset by evidence that they can interfere with extinction of fear conditioning and worsen recovery. Benzodiazepines are associated with tolerance and dependence and can become almost impossible to discontinue in combat veterans due to rebound exacerbation of symptoms (particularly sleep disturbance and anger).” (C. W. Hoge, charles.hoge@us.army.mil)
Elder Abuse & Self-neglect: Patients’ own self-neglect should be considered a type of elder abuse, argue authors of a Clinicians’ Corner article (pp. 532–40). Using the case of a 70-year-old women “who neglects herself and dies despite multiple contacts with the medical community,” the authors examine the need for public health and interdisciplinary team approaches to a problem they say will become more common as the number of older adults increases around the world: “The complexities of elder self-neglect require the coordination of medical, social, and legal professionals as well as the broader community to balance the duty to protect and the duty to respect civil liberties. How self-neglect relates to other types of elder abuse is just beginning to be understood. As the number of older adults, and particularly the oldest old, those older than age 85 years, continues to increase at an exponential rate, the issue of elder mistreatment will also increase. Data and outcomes from longitudinal studies will be critical to inform future practice and policy to protect this vulnerable population. The more that is understood about root causes and outcomes, the more effectively prevention and intervention strategies can be targeted.” (L. Mosqueda, mosqueda@uci.edu)

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

PNN Pharmacotherapy Line
Aug. 4, 2011 * Vol. 18, No. 150
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online articles from and Aug. 4 issue of the New England Journal of Medicine (2011; 365).
Lebrikizumab Treatment in Adults with Asthma: Lung function improved in adults with asthma treated with lebrikizumab, a monoclonal antibody to interleukin-13, according to an early-release article (10.1056/NEJMoa1106469). All participants were inadequately controlled with inhaled corticosteroids when they were randomized to lebrikizumab or placebo. Using a primary efficacy outcome of the relative change in prebronchodilator forced expiratory volume in 1 second (FEV1) from baseline to week 12, researchers found the following: “At baseline, patients had a mean FEV1 that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 µg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV1 was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV1 was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV1 was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045).” (J. G. Matthews, matthews.john@gene.com)
Use of Prescribing Data for Drug Promotion: Two articles explore commercial speech in light of the June Supreme Court decision striking down a Vermont law that banned selling of pharmacy records for data-mining use in drug promotions.
The Vermont law “had a fatal self-inflicted wound,” notes the author of a Perspective article (10.1056/
NEJMp1107614): “By prominently announcing that the state intended to tip the balance in the ‘marketplace for ideas’ against drug companies, the law dug itself into a constitutional hole: state interference with that marketplace was likely to provoke the ire of a majority of the Supreme Court. Writing for the Court, Justice Anthony Kennedy stated, ‘[t]he more benign and, many would say, beneficial speech of pharmaceutical marketing is also entitled to the protection of the First Amendment.’” (K. Outterson)
Despite
Sorrell v. IMS Health, Inc., states may be able to write laws that would pass legal muster, writers argue in an online article (10.1056/NEJMhle1107678): “There are two avenues along which data-mining laws could be recrafted so that they might survive judicial scrutiny. First, the Court suggested that a broader ban on the use of prescribing data might be acceptable—provided that the state showed no animus toward drug marketers. The majority wrote that if Vermont’s law had “provided that prescriber-identifying information could not be sold or disclosed except in narrow circumstances then the State might have a stronger position.’ For example, disclosure might be limited to purposes related to law enforcement and public health activities. Such a policy would be better tailored to protect physician privacy.…
“A second potential approach to future data-mining laws would be to give physicians a menu of privacy options. Allowing physicians to select which uses of their prescribing data to permit would avoid a blanket ban on all disclosures, maximize the law’s responsiveness to physicians’ privacy concerns, and give equal treatment to various viewpoints on detailing. The majority noted that simply converting the statute to a Maine-style opt-out model ‘would not necessarily save’ it, but hinted that a broader range of privacy options might.” (M. M. Mello,
mmello@hsph.harvard.edu)

>>>PNN NewsWatch
* FDA yesterday approved the first specific treatment for scorpion stings. Centruroides (Scorpion) Immune F(ab&rsquoWinking2 (Equine) Injection (Anascorp, Rare Disease Therapeutics) was approved based on a trial in 15 children with neurological signs of scorpion stings. These signs resolved within 4 hours of treatment in the eight subjects who received Anascorp, but in only one of the seven participants who received the placebo. The most common adverse effects were vomiting, fever, rash, nausea, itchiness, headache, runny nose, and muscle pain.

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

PNN Pharmacotherapy Line
Aug. 5, 2011 * Vol. 18, No. 151
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Aug. issue of Pharmacotherapy (2011; 31).
Pharmacogenomics at FDA: Officials provide “a window into some ways in which the FDA is enabling individualized therapeutics through its mission-critical activities” (pp. 729–35): “Pharmacogenomics is the study of how genetic variations influence responses to drugs, diagnostics, or biologic agents. The field of pharmacogenomics has significant potential to enhance drug development and aid in making regulatory decisions. The United States Food and Drug Administration (FDA) has supported pharmacogenomics for nearly a decade by providing regulatory advice and reviewing applications, with the intent of discovering and applying genetic determinants of treatment effects. The FDA will continue to develop policies and processes centered on genomics and individualized therapeutics to guide rational drug development. It will also continue to inform the public of clinically relevant pharmacogenomic issues through various mechanisms of communication, such as drug labeling. In this review, we provide a perspective on several pharmacogenomic activities at the FDA. In addition, we attempt to clarify what we believe are several misperceptions regarding the FDA’s pharmacogenomic initiatives.” (I. Zineh, Issam.Zineh@fda.hhs.gov)
Validating Antibiotic Allergies in Pediatrics: An allergy assessment questionnaire was useful in determining that 58 of 100 reported antibiotic allergies among pediatric patients fulfilled criteria for an immunologically mediated reaction, researchers report (pp. 736–41). At a tertiary-care children’s hospital, parents/caregivers of 100 inpatients were interviewed using a standardized allergy-assessment questionnaire, with these results: “Reported allergies were categorized as immunologically mediated reactions in 58%, non–immunologically mediated adverse drug reactions in 27%, no reaction in 3%, and unknown in 12%. Reactions to penicillins, cephalosporins, or sulfonamides were reported most frequently and were attributed to immunologically mediated reactions in 68% (26/38), 74% (17/23), and 67% (10/15) of instances, respectively.” (C. Knoderer, cknodere@butler.edu)
Effects of Reported Antimicrobial Allergies in Hospitalized Patients: Inpatients with antimicrobial allergy labels in their medical records had longer lengths of hospital stay and worse clinical outcomes than other patients, according to a retrospective cohort study (pp. 742–7). Investigators looked at medical records of 11,872 adults who received at least one antimicrobial agent during hospital stays in 2007–08, finding these patterns: “Presence of an allergy label in the medical record was associated with increased length of stay, a higher ICU admission rate, receipt of more than one antimicrobial, and a higher mortality rate during the hospitalization. Logistic regression models were used to assess the association of allergy label with these outcomes while adjusting for covariates (age group, sex, surgery during hospitalization, and season of admission); multiple regression was used to model the association of allergy label with length of stay. On average, length of stay was 1.21 days (unadjusted) and 1.16 days (adjusted for covariates) longer in patients with allergy labels. The likelihood of an ICU admission was 1.4 times (adjusted odds ratio [OR] 1.42, 95% confidence interval [CI] 1.21–1.67) higher in patients with allergy labels. Presence of an allergy label was also associated with receipt of more than one antibiotic during the hospitalization (crude OR 1.61, 95% CI 1.43–1.81) and a 1.6-fold higher risk of dying during the hospitalization (crude OR 1.56, 95% CI 1.20–2.04). Presence of an allergy label was not associated with an increased risk of readmission within 4 weeks of discharge (adjusted OR 0.71, 95% CI 0.63–0.80).” (L. Charneski, lcharnes@rx.umaryland.edu)

>>>PNN NewsWatch
* American Regent is recalling multiple lots of Vasopressin Injection, USP, FDA said yesterday. The concern is that some vials may not maintain their potency to the stated expiration dates.
* Consistency of prescription and nonprescription labels for products containing
acetaminophen is the focus of a new white paper from the National Council for Prescription Drug Programs. Recommendations include always spelling out the name of the drug and using standardized concomitant use/liver damage warning language.

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

PNN Pharmacotherapy Line
Aug. 8, 2011 * Vol. 18, No. 152
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 6 issue of Lancet (2011; 378).
Teplizumab for Type 1 Diabetes: Complementing the T-cell effects of abatacept reported in the Aug. 1 PNN, a study shows that teplizumab, an anti-CD3 monoclonal antibody, might prevent decline in B-cell function only in patients with recent-onset of type 1 diabetes and in children (pp. 487–97). In a 2-year trial, 516 patients aged 8–35 years were randomized to 14-day full-dose teplizumab, 14-day low-dose teplizumab, 6-day full-dose teplizumab, or placebo at baseline and week 26, with these effects on a primary outcome of percentage of patients with insulin use of less than 0.5 U/kg per day and glycated hemoglobin A1c (HbA1C) of less than 6.5% at 1 year: “The primary outcome did not differ between groups at 1 year: 19.8% (41/207) in the 14-day full-dose group; 13.7% (14/102) in the 14-day low-dose group; 20.8% (22/106) in the 6-day full-dose group; and 20.4% (20/98) in the placebo group. 5% (19/415) of patients in the teplizumab groups were not taking insulin at 1 year, compared with no patients in the placebo group at 1 year (p = 0.03). Across the four study groups, similar proportions of patients had adverse events (414/417 [99%] in the teplizumab groups vs 98/99 [99%] in the placebo group) and serious adverse events (42/417 [10%] vs 9/99 [9%]). The most common clinical adverse event in the teplizumab groups was rash (220/417 [53%] vs 20/99 [20%] in the placebo group).” (N. Sherry, nsherry@partners.org)
H. pylori Eradication: In a diverse Latin American population, the standard 14-day regimen for eradication of Helicobacter pylori performed better than shorter therapies, researchers report (pp. 507–14). In a 2009–10 study of 1,463 patients, standard therapy (14 days of lansoprazole, amoxicillin, and clarithromycin) was compared with 5 days of lansoprazole, amoxicillin, clarithromycin, and metronidazole (concomitant therapy) and 5 days of lansoprazole and amoxicillin followed by 5 days of lansoprazole, clarithromycin, and metronidazole (sequential therapy). Results showed: “The probability of eradication with standard therapy was 82.2% (401 of 488), which was 8.6% higher (95% adjusted CI 2.6–14.5) than with concomitant therapy (73.6% [360 of 489]) and 5.6% higher –0.04% to 11.6) than with sequential therapy (76.5% [372 of 486]). Neither four-drug regimen was significantly better than standard triple therapy in any of the seven [geographic] sites.” (E. R. Greenberg, e.r.greenberg@dartmouth.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
CYP2C19 Testing & Clopidogrel Dosing: Individualization of clopidogrel therapy based on polymorphisms in the CYP2C19 gene is not supported by results of systematic review and meta-analysis (d4588): “5 studies met the inclusion criteria. The random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 loss of function allele versus non-carriers combining nine studies was 1.77 (95% confidence interval 1.31 to 2.40; P < 0.001). This nominally significant odds ratio was subject to considerable bias across the studies (small study effect bias and replication diversity). The adjustment for these quality modifiers tended to abolish the association. The corresponding random effects summary odds ratio of major adverse cardiovascular events for 12 studies combined was 1.11 (0.89 to 1.39; P = 0.36). The random effects summary odds ratio of stent thrombosis in carriers versus non-carriers of at least one CYP2C19*17 gain of function allele for three studies combined was 0.99 (0.60 to 1.62; P = 0.96), and the corresponding odds ratio of major adverse cardiovascular events in five studies was 0.93 (0.75 to 1.14; P = 0.48). The overall quality of epidemiological evidence was graded as low, which excludes reliable clinical assessments.” (D. Taubert, dirk.taubert@medizin.uni-koeln.de)

>>>PNN JournalWatch
* Antidepressant Use and Risk of Adverse Outcomes in Older People: Population Based Cohort Study, in BMJ, 2011; 343: d4551. (C. Coupland, carol.coupland@nottingham.ac.uk)
* The NIMH-CATIE Schizophrenia Study: What Did We Learn?, in
American Journal of Psychiatry, 2011; 168: 770–5. (T. S. Stroup, stroups@nyspi.columbia.edu)
* Perinatal and Neonatal Risk Factors for Autism: A Comprehensive Meta-analysis, in
Pediatrics, 2011; 128: 344–55. (H. Gardener, hgardener@med.miami.edu)

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

PNN Pharmacotherapy Line
Aug. 9, 2011 * Vol. 18, No. 153
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 8/22 issue of the Archives of Internal Medicine (2011; 171).
Antibiotic Prescribing Based on Procalcitonin Algorithms: Authors of a systematic review offer recommendations for use of procalcitonin algorithms in making antibiotic therapy decisions in patients with low, moderate, and high acuity (pp. 1322–31): “We found no significant difference in mortality between procalcitonin-treated and control patients overall (odds ratio, 0.91; 95% confidence interval, 0.73–1.14) or in primary care (0.13; 0–6.64), [emergency department (ED)] (0.95; 0.67–1.36), and intensive care unit (0.89; 0.66–1.20) settings individually. A consistent reduction was observed in antibiotic prescription and/or duration of therapy, mainly owing to lower prescribing rates in low-acuity primary care and ED patients, and shorter duration of therapy in moderate- and high-acuity ED and intensive care unit patients. Measurement of procalcitonin levels for antibiotic decisions in patients with respiratory tract infections and sepsis appears to reduce antibiotic exposure without worsening the mortality rate.” (P. Schuetz, philipp.schuetz@post.harvard.edu)
Preventing Diabetes with Lifestyle Modification: A group of 641 overweight Japanese patients with impaired glucose levels were able to reduce their risk of type 2 diabetes through lifestyle modification, a study shows (pp. 1352–60). Compared with patients assigned to frequent interventions over 36 months, those receiving individual instructions and follow-up support for lifestyle modification had these outcomes: “Estimated cumulative incidences of type 2 diabetes were 12.2% in the frequent intervention group and 16.6% in the control group. Overall, the adjusted hazard ratio in the frequent intervention group was 0.56 (95% confidence interval, 0.36–0.87). In the post hoc subgroup analyses, the hazard ratio reduced to 0.41 (95% confidence interval, 0.24–0.69) among participants with impaired glucose tolerance at baseline, and to 0.24 (0.12–0.48) among those with baseline hemoglobin A1c levels of 5.6% or more (the Japan Diabetes Society method). Such risk reduction was not observed among those with isolated impaired fasting glucose findings or baseline hemoglobin A1c levels of less than 5.6%.” (T. Saito, zpls@nifty.com)
Previous studies have had limited interventions and have shown mixed effects in reducing risk of type 2 diabetes in at-risk populations, an invited commentator writes, making these results “highly relevant” (
pp. 1361–2): “The greatest risk reductions (approximately 75%) were achieved with the thiazolidinedione drugs troglitazone or pioglitazone hydrochloride. Troglitazone is no longer available because of its hepatotoxicity. All thiazolidinediones have worrisome side effects, including edema and sustained weight gain. By contrast, metformin hydrochloride, although less effective in reducing diabetes incidence, causes modest weight loss that is sustained for at least 10 years. In 2 trials, lifestyle weight-loss interventions resulted in large (58%) diabetes risk reductions. Comparing the effects of different drugs with each other or with weight loss is difficult, however, because most trials tested only one intervention, and the trials differed in eligibility criteria, outcome assessment, drug dosage, lifestyle intervention intensity, and treatment of the comparison group. The Diabetes Prevention Program compared a lifestyle intervention and metformin use directly and found that the lifestyle intervention was more effective; however, in the Indian Diabetes Prevention Programme, metformin use, a weight loss intervention, and a combination of both had similar effects.” (W. C. Knowler, knowler@nih.gov)
Soy Isoflavones in Menopause: Soy isoflavones, administered daily in 200-mg doses for 2 years, did not reduce bone loss or relieve menopausal symptoms among 248 perimenopausal women, researchers report (pp. 1363–9): “No significant differences were found between the participants receiving soy tablets (n = 122) and those receiving placebo (n = 126) regarding changes in bone mineral density in the spine (–2.0% and –2.3%, respectively), the total hip (–1.2% and –1.4%, respectively), or the femoral neck (–2.2% and –2.1%, respectively). A significantly larger proportion of participants in the soy group experienced hot flashes and constipation compared with the control group.” (S. Levis, slevis@med.miami.edu)

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

PNN Pharmacotherapy Line
Aug. 10, 2011 * Vol. 18, No. 154
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 10 issue of JAMA (2011; 306).
Genomics in Drug Trials: The next generation of DNA sequencing will involve genome-wide association studies (GWAS), and these will be useful in planning clinical drug trials, Commentary authors write (pp. 652–3): “Applied to pharmacological traits, GWAS have … led to important discoveries with potential clinical application. For example, a GWAS of patients with chronic hepatitis C infection identified common [single-nucleotide polymorphisms (SNPs)] in the inosine triphosphatase (ITPA) gene that protect against ribavirin-induced hemolytic anemia. A GWAS for glycemic response to metformin identified a SNP associated with treatment success at a locus containing ATM, the ataxia telangiectasia mutated gene. Both GWAS revealed unexpected biological pathways, highlighting the importance of an unbiased approach over a candidate gene approach because existing knowledge of a drug’s mechanisms of action may be limited, even for widely used medications. Pharmacogenomic studies of warfarin response, on the other hand, provide good examples of how GWAS complement and extend candidate gene studies. For instance, a GWAS reported by Takeuchi et al confirmed previously described variants of CYP2C9 and VKORC1 but also discovered contribution of other metabolizing enzymes (CYP4F2).” (J. J. Yang, jun.yang@stjude.org)
Sleep-Disordered Breathing & Cognitive Impairment: The risk of cognitive impairment was greater among a group of older women with disordered breathing during sleep, researchers report, compared with those with normal sleep-breathing patterns (pp. 613–9). Study participants were 298 women without dementia (mean age of 82.3 ± 3.2 years) who underwent overnight polysomnography in 2002–04 as part of the Study of Osteoporotic Fractures. With 15 or more events per hour of sleep defining sleep-disordered breathing, researchers determined: “Compared with the 193 women without sleep-disordered breathing, the 105 women (35.2%) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (31.1% [n = 60] vs 44.8% [n = 47]; adjusted odds ratio [AOR], 1.85; 95% confidence interval [CI], 1.11–3.08). Elevated oxygen desaturation index (≥15 events/hour) and high percentage of sleep time (>7%) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR, 1.71 [95% CI, 1.04–2.83] and AOR, 2.04 [95% CI, 1.10–3.78], respectively). Measures of sleep fragmentation … or sleep duration … were not associated with risk of cognitive impairment.” (K. Yaffe, kristine.yaffe@ucsf.edu)
HIV Screening: In a Clinician’s Corner article on early HIV testing, the advantages of early treatment are discussed (pp. 637–44): “Randomized controlled trial data support the benefit of antiretroviral therapy in patients with a CD4 cell count of 350/µL or less, and observational cohort data support it in those with a CD4 cell count greater than 350/µL. There may even be clinical benefit in treating patients with a CD4 cell count greater than 500/µL, although no consensus exists among experts on whether to recommend antiretroviral therapy in this group.
“In addition to antiretroviral therapy, potential individual health benefits of HIV screening include initiation of opportunistic infection prophylaxis, which may also result in fewer complications and hospitalizations and decreased mortality. Patients receiving effective antiretroviral therapy appear less likely to transmit HIV infection to seronegative sexual partners. This association has been shown in observational studies of both men who have sex with men and heterosexual persons and in a recent randomized controlled trial of heterosexual serodiscordant couples. Other potential public health benefits include reduction of perinatal, sexual, and parenteral transmission and improved epidemiologic monitoring.” (H. Libman,
hlibman@bidmc.harvard.edu)

>>>PNN NewsWatch
* Mortality data from the Santé Adulte GH Enfant (SAGhE) study regarding somatropin (recombinant human growth hormone) are “inconclusive,” FDA said. The agency will continue the safety issue.
*
APhA yesterday launched a new drug-news website, www.aphadruginfoline.com. The site digitizes the group’s print newsletter by the same name and offers assessments of studies and alerts on FDA actions.

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

PNN Pharmacotherapy Line
Aug. 11, 2011 * Vol. 18, No. 155
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online-only content and the Aug. 11 issue of the New England Journal of Medicine (2011; 365).
Preventing HIV Transmission with Early Antiretroviral Therapy: In 1,763 discordant couples, early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, researchers report (pp. 493–505). About half of the participants were men and from Africa; all had CD4 counts of 350–550 cells/cu mm. Infected partners received antiretroviral therapy immediately or on a delayed basis (when CD4 counts declined or HIV-1–related symptoms occurred. Results showed: “As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person–years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person–years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P < 0.001). Subjects receiving early therapy had fewer treatment end points [occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death] (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P = 0.01).” (M. S. Cohen, mscohen@med.unc.edu)
“Antiretroviral therapy is by no means perfect and is not the ultimate answer to controlling and ending the HIV epidemic,” an editorialist writes (
pp. 561–2). “Adverse events, emergence of drug-resistant viral strains, maintenance of adherence, sustainability, and cost are just some of the concerns. However, this is precisely the wrong time to limit access to antiretroviral therapy in resource-limited settings, since we have the tools in hand to maintain or restore health in infected persons and reduce transmission to their sexual partners.” (S. M. Hammer)
Early v. Late Parenteral Nutrition: In critically ill patients, late initiation of parenteral nutrition was associated with faster recovery and fewer complications, a study shows, compared with early initiation (pp. 506–17). Enteral nutrition was insufficient for all 2,312 study participants, who were adults in intensive-care units. Early initiation was defined as within 48 hours of ICU admission. Results showed: “Patients in the late-initiation group had a relative increase of 6.3% in the likelihood of being discharged alive earlier from the ICU (hazard ratio, 1.06; 95% confidence interval [CI], 1.00 to 1.13; P = 0.04) and from the hospital (hazard ratio, 1.06; 95% CI, 1.00 to 1.13; P = 0.04), without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P = 0.008) and a lower incidence of cholestasis (P < 0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P = 0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of 1,110 euros (about $1,600) (P = 0.04).” (G. Van den Berghe, greet.vandenberghe@med.kuleuven.be)
Finding the Will to Act on Generic Drug Labels: “Congress or the FDA can change the Supreme Court’s conclusion” in the Pliva v. Mensing case, authors write in a Perspective article, and “finding the political will to make these changes should not be impossible” (10.1056/NEJMp1107832). The 5–4 decision, handed down June 23, held that, since generic drug labels are required under federal law to be identical to those of the brand-name product, “state courts [are] preempted from making any finding of liability based on a generic-drug manufacturer’s failure to change its label.” The ruling leaves no recourse for patients who are injured as a result of inadequate labeling of generic drug products, “a result that doesn’t seem to trouble the majority,” the authors write. “The justices in the majority blame this unfair and arbitrary result on what they see as incompetent federal regulation and make no attempt to reconcile the federal law with state law as the lower courts did. The dissenters argue that this nonsensical outcome could not have been intended. Both Congress and the FDA meant to strengthen drug safety (a point the majority entirely ignores), not to empower generic-drug makers to inadequately label their products.” (L. H. Glantz)

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

PNN Pharmacotherapy Line
Aug. 12, 2011 * Vol. 18, No. 156
Providing news and information about medications and their proper use

>>>Psychiatry Report
Source:
Aug. issue of the American Journal of Psychiatry (2011; 168).
Cognitive Effects of Second-Generation Antipsychotics in AD: Use of second-generation antipsychotics in patients with Alzheimer disease hastens the decline in cognition, according to data from the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer’s Disease (CATIE-AD) study (pp. 831–9). Among 421 outpatients with AD and psychosis or agitated/aggressive behavior, olanzapine, quetiapine, or risperidone produced “worsening cognitive function at a magnitude consistent with 1 year’s deterioration compared with placebo,” the authors concluded based on these results: “Overall, patients showed steady, significant declines over time in most cognitive areas, including in scores on the Mini-Mental State Examination (MMSE; –2.4 points over 36 weeks) and the cognitive subscale of the Alzheimer’s Disease Assessment Scale (–4.4 points). Cognitive function declined more in patients receiving antipsychotics than in those given placebo on multiple cognitive measures, including the MMSE, the cognitive subscale of the Brief Psychiatric Rating Scale, and a cognitive summary score summarizing change on 18 cognitive tests.” (C. L. P. Vigen)
Genetic Linkage for Depression in Heavy Smoking Families: Researchers found a strong linkage between major depressive disorder and a locus on chromosome 3 in a study of 91 Australian heavy-smoking families (pp. 848–52). The Nicotine Addiction Genetics linkage project conducted genomewide studies of the 91 families and 25 Finnish families with sibling pairs (n = 33) who had MDD. Using a measure of linkage between genetic loci, the LOD score, the researchers “found a genome-wide significant multipoint LOD score of 4.14 for major depressive disorder on chromosome 3 at 24.9 cM (3p26-3p25)” in the Australian patients. “These converging findings suggest that the genomic region spanning across 3p26-3p25 is an important area for further investigation in genetic research on major depressive disorder,” write the authors. “Given the small number of Finnish affected sibling pairs, the lack of confirmation in this particular sample is not unexpected. The genetic variants accounting for this linkage signal have not yet been convincingly identified.” (M. L. Pergadia)
Computer-Assisted Psychiatric Treatment: Computer-assisted determination of treatments for patients with psychiatric disorders have shown promise in clinical trials, but overall the evidence remains weak because of methodological flaws in studies conducted to date, researchers report (pp. 790–9). Analyzing the methods of 75 studies conducted in 1990–2010, the investigators found: “Results indicated marked heterogeneity in study quality. No study met all 14 basic quality standards, and three met 13 criteria. Consistent weaknesses were noted in evaluation of treatment exposure and adherence, rates of follow-up assessment, and conformity to intention-to-treat principles. Studies utilizing weaker comparison conditions (e.g., wait-list controls) had poorer methodological quality scores and were more likely to report effects favoring the computer-assisted condition.” (B. D. Kiluk)

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (2011; 128).
Vaccine Nearly Eliminates Varicella Deaths: In the U.S. during 12 years of 1-dose varicella vaccination, deaths from chickenpox were reduced by 97%, a CDC analysis shows (pp. 214–20). Mortality Multiple Cause-of-Death records show these outcomes in 2002–07 and during the prevaccine era, and researchers conclude that the current 2-dose program has the potential to eliminate deaths completely: “During the 12 years of the mostly 1-dose US varicella vaccination program, the annual average mortality rate for varicella listed as the underlying cause declined 88%, from 0.41 per million population in 1990–1994 to 0.05 per million population in 2005–2007. The decline occurred in all age groups, and there was an extremely high reduction among children and adolescents younger than 20 years (97%) and among subjects younger than 50 years overall (96%). In the last 6 years analyzed (2002–2007), a total of 3 deaths per age range were reported among children aged 1 to 4 and 5 to 9 years, compared with an annual average of 13 and 16 deaths, respectively, during the prevaccine years.” (M. Marin)

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

PNN Pharmacotherapy Line
Aug. 15, 2011 * Vol. 18, No. 157
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 13 issue of Lancet (2011; 378).
Hepatitis B/C in Injection Drug Users: Hepatitis C virus (HCV) is especially common among injection drug users (IDUs) around the world and poses “a key challenge to public health,” according to authors who conducted a systematic review of 1,125 studies and other information sources (pp. 571–83). These patterns were reported for HCV antibodies (anti-HCV), hepatitis B virus (HBV) antibodies (anti-HBc), or HBV surface antigen (HBsAg) in studies of IDUs with more than 40 participants in which not all were HIV-positive: “We located eligible reports with data for prevalence of anti-HCV in IDUs for 77 countries; midpoint prevalence estimates suggested 60–80% of IDUs had anti-HCV in 25 countries and more than 80% of IDUs did so in 12 countries. About 10.0 million (range 6.0–15.2) IDUs worldwide might be anti-HCV positive. China (1.6 million), USA (1.5 million), and Russia (1.3 million) had the largest such populations. We identified eligible HBsAg reports for 59 countries, with midpoint prevalence estimates of 5–10% in 21 countries and more than 10% in ten countries. Worldwide, we estimate 6.4 million IDUs are anti-HBc positive (2.3–9.7 million), and 1.2 million (0.3–2.7 million) are HBsAg positive.” (L. Degenhardt, louisa@burnet.edu.au)
AVI-4658 in Duchenne Muscular Dystrophy: In a Phase II dose-ranging study, weekly infusions of AVI-4658 were safe and produced potentially beneficial biochemical changes in 19 children and adolescents with Duchenne muscular dystrophy, researchers report (pp. 595–605). The drug is one of a class of phosphorodiamidate morpholino oligomers (PMOs), which act as antisense oligonucleotides that disrupt transcription of mutated genes on the X chromosome. In this study, the first in which a PMO has been administered systemically, 12 weekly infusions showed these results: “AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p = 0.0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8.9% (95% CI 7.1–10.6) to 16.4% (10.8–22.0) of normal control after treatment (p = 0.0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0.9% to 17%, and from 0% to 7.7% of normal muscle, respectively. The dystrophin-associated proteins alpha-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts.” (F. Muntoni, f.muntoni@ich.ucl.ac.uk)

>>>PNN JournalWatch
* Risk Prediction in Cardiovascular Medicine: Integrating Information from Novel Risk Factors with Calculated Risks—The Critical Impact of Risk Factor Prevalence, in Circulation, 2011; 124: 741–5. (A. J. Kooter, jkooter@vumc.nl)
* Unapproved Prescription Cough, Cold, and Allergy Drug Products: Recent US Food and Drug Administration Regulatory Action on Unapproved Cough, Cold, and Allergy Medications, in
Chest, 2011; 140: 295–300. (C. E. Lee, charles.lee@fda.hhs.gov)
* Accountability for Medical Error: Moving Beyond Blame to Advocacy, in
Chest, 2011; 140: 519–26. (S. K. Bell, Sbell1@bidmc.harvard.edu)
* The Primary Care Cardiologist [editorial], in
Journal of the American College of Cardiology, 2011; 58: 881–2. (A. N. DeMaria, ademaria@acc.org)
* Progression of CKD in Hispanics: Potential Roles of Health Literacy, Acculturation, and Social Support, in
American Journal of Kidney Diseases, 2011; 58: 282–90. (C. M. Lora, clora1@uic.edu)
* Therapeutic Strategies to Reduce Asthma Exacerbations, in
Journal of the Allergy and Clinical Immunology, 2011; 128: 257–63. (P. M. O’Byrne, byrnep@mcmaster.ca">obyrnep@mcmaster.ca)
* The Importance of the Gastrointestinal Tract in the Control of Bone Mass Accrual, in
Gastroenterology, 2011; 141: 439–42. (G. Karsenty, gk2172@columbia.edu)
* A Randomized, Double-Blind, Placebo-Controlled Trial of Simvastatin to Treat Alzheimer Disease, in
Neurology, 2011; 77: 556–63. (M. Sano, mary.sano@mssm.edu)

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

PNN Pharmacotherapy Line
Aug. 16, 2011 * Vol. 18, No. 158
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 16 issue of the Annals of Internal Medicine (2011; 155).
Oseltamivir v. Chinese Therapy for H1N1 Influenza: The Chinese traditional therapy maxingshigan–yinqiaosan may provide an effective alternative to oseltamivir for treating patients with H1N1 influenza virus infection, a study shows (pp. 217–25). At 11 hospitals in 4 provinces of China, 410 young adults, ages 15–59 years, received either oseltamivir 75 mg twice daily; maxingshigan–yinqiaosan decoction (with 12 Chinese herbal medicines, including honey-fried Herba Ephedrae) 200 mL 4 times daily; oseltamivir plus maxingshigan–yinqiaosan; or no intervention (control), with these effects on time to fever resolution: “Significant reductions in the estimated median time to fever resolution compared with the control group (26.0 hours [95% CI, 24.0 to 33.0 hours]) were seen with oseltamivir (34% [95% CI, 20% to 46%]; P < 0.001), maxingshigan–yinqiaosan (37% [CI, 23% to 49%]; P < 0.001), and oseltamivir plus maxingshigan–yinqiaosan (47% [CI, 35% to 56%]; P < 0.001). Time to fever resolution was reduced by 19% (CI, 0.3% to 34%; P = 0.05) with oseltamivir plus maxingshigan–yinqiaosan compared with oseltamivir. The interventions and control did not differ in terms of decrease in symptom scores (P = 0.38). Two patients who received maxingshigan–yinqiaosan reported nausea and vomiting.” (C. Wang)
Pain Management After Hip Fracture: For acute management of pain following hip fracture, nerve blockade has the best level of evidence for effectiveness, according to a comparative effectiveness systematic review (pp. 234–45). Investigators found a paucity of data on treatment of chronic pain and management of pain in nursing home residents with dementia, as noted in these results: “83 unique studies (64 RCTs, 5 non-RCTs, and 14 cohort studies) were included that addressed nerve blockade (n = 32), spinal anesthesia (n = 30), systemic analgesia (n = 3), traction (n = 11), multimodal pain management (n = 2), neurostimulation (n = 2), rehabilitation (n = 1), and complementary and alternative medicine (n = 2). Overall, moderate evidence suggests that nerve blockades are effective for relieving acute pain and reducing delirium. Low-level evidence suggests that preoperative traction does not reduce acute pain. Evidence was insufficient on the benefits and harms of most interventions, including spinal anesthesia, systemic analgesia, multimodal pain management, acupressure, relaxation therapy, transcutaneous electrical neurostimulation, and physical therapy regimens, in managing acute pain.” (A. M. Abou-Setta)
NICE Recommendations for Management of Chronic Heart Failure in Adults: The U.K. National Institute for Health and Clinical Excellence (NICE) updates its 2003 clinical guideline on heart failure in adults (pp. 252–9). Included are information on the role of serum natriuretic peptide measurement, echocardiography, and specialist assessment in the diagnosis of heart failure; a pathway for pharmacologic treatment, rehabilitation, and pacing therapy; and a recommendation to monitor patients with heart failure by using serial measurement of serum natriuretic peptide. “First-line therapy with beta-blockers and ACE inhibitors is indicated for all patients with heart failure with left ventricular systolic dysfunction, regardless of the severity of their symptoms,” the authors write, adding : “High-quality evidence shows that ACE inhibitors and beta-blockers reduce morbidity and increase survival in patients with left ventricular systolic dysfunction. New low-quality evidence shows that beta-blockers reduce mortality in older adults (age 65 years) but do not lead to statistically significant differences in quality of life or number of hospitalizations in this age group. High-quality evidence shows that no difference exists between selective beta-blockers (for example, metoprolol) and nonselective beta-blockers (for example, carvedilol) on the combined end point of mortality and hospitalization, and moderate-quality evidence from 1 trial shows lower mortality when the nonselective beta-blocker carvedilol is used. High-quality evidence shows that the same outcomes are achieved whether ACE inhibitor or beta-blocker therapy is started first.” (J. Mant)

>>>PNN NewsWatch
* FDA is seeking comment on proposed guidelines for researchers and manufacturers conducting high-quality clinical studies of medical devices.

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

PNN Pharmacotherapy Line
Aug. 17, 2011 * Vol. 18, No. 159
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 17 issue of JAMA (2011; 306).
Pegloticase for Gout: Pegloticase, a mammalian recombinant uricase approved last year by FDA, was more effective than placebo for lowering uric acid levels when administered as 12 biweekly I.V. infusions in 225 patients with severe gout, allopurinol intolerance or refractoriness, and serum uric acid concentration of 8.0 mg/dL or greater (pp. 711–20). The study used a primary end point of uric acid levels less than 6 mg/dL at months 3 and 6 to assess the efficacy of three dosing patterns: pegloticase 8 mg at each infusion, pegloticase alternating with placebo at successive infusions (resulting in monthly doses of active drug), and placebo only.
Results showed: “In trial C0405 the primary end point was reached in 20 of 43 patients in the biweekly group (47%; 95% CI, 31%–62%), 8 of 41 patients in the monthly group (20%; 95% CI, 9%–35%), and in 0 patients treated with placebo (0/20; 95% CI, 0%–17%; P < .001 and <.04 for comparisons between biweekly and monthly groups vs placebo, respectively). Among patients treated with pegloticase in trial C0406, 16 of 42 in the biweekly group (38%; 95% CI, 24%–54%) and 21 of 43 in the monthly group (49%; 95% CI, 33%–65%) achieved the primary end point; no placebo-treated patients reached the primary end point (0/23; 95% CI, 0%–15%; P = .001 and < .001, respectively). When data in the 2 trials were pooled, the primary end point was achieved in 36 of 85 patients in the biweekly group (42%; 95% CI, 32%–54%), 29 of 84 patients in the monthly group (35%; 95% CI, 24%–46%), and 0 of 43 patients in the placebo group (0%; 95% CI, 0%–8%; P < .001 for each comparison). Seven deaths (4 in patients receiving pegloticase and 3 in the placebo group) occurred between randomization and closure of the study database (February 15, 2008).” (M. A. Becker,
mbecker@medicine.bsd.uchicago.edu)
Radioactive Iodine for Thyroid Cancer: Unexplained hospital characteristics influence the likelihood of patients with thyroid cancer being treated with radioactive iodine, a study shows (pp. 721–8). Researchers looked at 189,219 patients treated at 981 hospitals in the U.S. National Cancer Database between 1990 and 2008. Multilevel analysis showed an increase in use of radioactive iodine over the period and that nearly one-third of variance was explained by hospital characteristics rather than clinical or patient-specific ones: “Between 1990 and 2008, across all tumor sizes, there was a significant increase in the proportion of patients with well-differentiated thyroid cancer receiving radioactive iodine (1,373/3,397 [40.4%] vs 11,539/20,620 [56.0%]; P < .001). Multivariable analysis of patients treated from 2004 to 2008 found that there was a statistical difference in radioactive iodine use between American Joint Committee on Cancer stages I and IV (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.31–0.37) but not between stages II/III and IV (for stage II vs stage IV, OR, 0.97; 95% CI, 0.88–1.07 and for stage III vs stage IV, OR, 1.06; 95% CI, 0.95–1.17). In addition to patient and tumor characteristics, hospital volume was associated with radioactive iodine use. Wide variation in radioactive iodine use existed, and only 21.1% of this variation was accounted for by patient and tumor characteristics. Hospital type and case volume accounted for 17.1% of the variation. After adjusting for available patient, tumor, and hospital characteristics, 29.1% of the variance was attributable to unexplained hospital characteristics.” (M. R. Haymart, meganhay@umich.edu)
This “substantial between-hospital variation in [radioactive iodine (RAI)] use suggests clinical uncertainty and perhaps inappropriate use of RAI in thyroid cancer management,” an editorialist notes, adding (
pp. 762–3): “Ultimately, treatment decisions are made by patients, not practitioners and not policy makers. Patients rely on physicians and other health care professionals to deliver the most amount of information possible about treatment risks and benefits. Patients then can consider these issues in the context of their own individual preferences. Policy makers should not interfere with this process unless the evidence they use to mandate care is substantial. Because of uncertainty in the integrity of most administrative databases and registries and the inherent limitation in the amount of information they contain about patient care, policy should only rarely be made based on findings from these sources.” (E. H. Livingston, edward.livingston@utsouthwestern.edu)

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

PNN Pharmacotherapy Line
Aug. 18, 2011 * Vol. 18, No. 160
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 18 New England Journal of Medicine (2011; 365).
Antiretroviral Drug Resistance: A variety of mechanisms account for resistance to antiretroviral drugs, according to a review article that addresses both types of reverse-transcriptase inhibitors (NRTIs and NNRTIs) and protease, integrase, and entry inhibitors (pp. 637–46): “Compelling biochemical and virologic data illustrate the differential effect of genetic background on both the type and degree of HIV-1 resistance to antiretroviral drugs, as has been documented for resistance to NRTIs, NNRTIs, and protease inhibitors. For protease inhibitors, genetic background, including polymorphisms in each subtype, can affect the extent to which primary mutations alter protein binding or protease function. Hence, some polymorphisms can act as the equivalent of secondary resistance mutations.
“It is important to continue to do research on the role of polymorphisms in the development of drug resistance. In some cases, drug exposure may lead to amplification of such polymorphisms as A98G/S in reverse transcriptase and M36I, K20I, and L89M in protease, leading to a potential for resistance. In parts of Africa, treatment failure has been reported in as many as 40% of patients after 2 years. Resistance rates of more than 80% to two drug classes have been reported in India after failure of first-line regimens using combinations of NRTIs and NNRTIs. Studies are needed to assess genotypes both before and after therapy in the context of possible associations between polymorphisms and drug resistance. This area of research could include polymorphism variability in variants of the same subtype in different geographic regions. This information might improve the efficacy of certain drug combinations over others in the context of second- or third-line therapeutic strategies.” (M. A. Wainberg,
mark.wainberg@mcgill.ca)
Interleukin-36 & Pustular Psoriasis: A study of nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis reveals a relationship between that condition and aberrant interleukin-36Ra structure and function that leads to unregulated secretion of inflammatory cytokines (pp. 620–8). The investigators used homozygosity mapping and direct sequencing to identify these genetic and biochemical patterns: “We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin-36–receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor–like 2 (interleukin-1 receptor–related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine-induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients.” (A. Smahi, asma.smahi@inserm.fr)

>>>PNN NewsWatch
* FDA yesterday approved an important new agent for melanoma and a diagnostic test for identifying patients who should receive the drug. Vemurafenib (Zelboraf, Genentech/Roche), an orally active, small molecule kinase inhibitor, is indicated for treatment of BRAF V600E mutation-positive, inoperable, or metastatic melanoma. Also approved was the cobas 4800 BRAF V600 Mutation Test (Roche). “Zelboraf is the first and only FDA-approved personalized medicine shown to improve survival in people with BRAF V600E mutation-positive metastatic melanoma, demonstrating the benefits of Roche’s personalized health care approach,” the company said in a news release. In clinical trials that used dacarbazine as a comparator, patients on vemurafenib had significantly less mortality risk (56%) and risk of disease progression or death (74%). About 26% of patients developed cutaneous squamous cell carcinoma with the new drug, requiring surgery. Patients treated with vemurafenib should avoid sun exposure. Vemurafenib will be available in 2 weeks only through specialty mail-service pharmacies.

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

PNN Pharmacotherapy Line
Aug. 19, 2011 * Vol. 18, No. 161
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (2011; 59).
Antidepressant Misuse in VA Living Centers: Potential problems with antidepressant underuse, overuse, and inappropriate use were uncovered in study of in 3,692 older Veterans Affairs Community Living Center (CLC) residents in 2004–05 (pp. 1412–20). A longitudinal study showed these patterns: “Selective serotonin reuptake inhibitors were the most commonly prescribed antidepressant. Of the 877 residents with depression, 25.4% did not receive an antidepressant, suggesting potential underuse. Of residents with depression who received antidepressants, 57.5% had potential inappropriate use due primarily to problems seen with drug–drug and drug–disease interactions. Of the 2,815 residents who did not have depression, 1,190 (42.3%) were prescribed one or more antidepressants; only 48 (4.0%) of these had a Food and Drug Administration–approved labeled indication, suggesting potential overuse. Overall, only 17.6% of antidepressant use was appropriate (324/1,844). The only consistent resident factor associated with potential underuse and overuse use was taking an antipsychotic without evidence of schizophrenia (underuse: adjusted relative risk ratio (ARRR) = 0.56, 95% confidence interval (CI) = 0.33–0.94; overuse: adjusted odds ratio = 1.52, 95% CI = 1.21–1.91). Having moderate to severe pain (ARRR = 1.54, 95% CI = 1.08–2.20) and the prescribing of an anxiolytic or hypnotic (ARRR = 1.33, 95% CI = 1.02–1.74) increased the risk of potential inappropriate antidepressant use.” (J. T. Hanlon, jth14@pitt.edu)
Improving Medication Use: Two articles discuss ways of improving medication monitoring and prescribing.
Strategies for monitoring medication use that will reduce occurrence of adverse drug events (ADEs) can improve quality and outcomes of care, authors write (
pp. 1513–20): “These strategies include using health information technology to link pharmacy and laboratory data, prospective delineation of risk, and patient outreach and activation, all within a framework of team-based approaches to patient management. Although many of these strategies are theoretically possible now, they are poorly used and will be difficult to implement without a significant restructuring of medical practice. An enhanced focus on medication monitoring will also require a new conceptual framework to re-engineer the prescribing process. With this approach, prescribing quality does not hinge on static attributes of the initial prescribing decision but entails a dynamic process in which the benefits and harms of drugs are actively monitored, managed, and reassessed over time.” (M. Steinman, mike.steinman@ucsf.edu)
A systematic review makes these observations about reports of criteria for assessing inappropriate prescribing in patients aged 65 years or older (
pp. 1521–30): “Most criteria were explicit, consensus validated, based totally or partly on Beers criteria, and focused on pharmacological appropriateness of prescribing and some were old. Drug- and disease-oriented explicit criteria require regular updating and are country specific. Implicit, person-specific criteria are universal and do not need updating, although their use requires up-to-date professional skills. Unlike explicit criteria, implicit criteria have been validated in people. Some of the 14 criteria were noncomprehensive, mainly because of the intended purpose. To conclude, different criteria exist for optimizing prescribing for individuals aged 65 and older. Possible deficiencies must be recognized and trade-offs made when selecting criteria for use. In the future, more-comprehensive and -timely criteria are needed.” (M. Dimitrow, maarit.dimitrow@helsinki.fi)

>>>Chest Highlights
Source:
Aug. issue of Chest (2011; 140).
Timing of Follow-up INR Testing: Patients with in-range INR results may be able to be seen less frequently than monthly, researchers report (pp. 359–65). Among 104,451 patients at VA anticoagulation clinics, the mean follow-up interval varied from 25 to 38 days. While shorter intervals were associated with better risk-adjusted time in therapeutic range, the statistical significance of the relationship disappeared for those with in-range first and second values, leading the authors to conclude that longer intervals can be considered for stable patients. (A. J. Rose, adamrose@bu.edu)

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

PNN Pharmacotherapy Line
Aug. 22, 2011 * Vol. 18, No. 162
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 20 issue of Lancet (2011; 378).
Augmenting Systolic Function with Omecamtiv: Two studies and an editorial report initial clinical experiences with an investigational agent for heart failure.
Left ventricular systolic function was augmented in 34 healthy men by omecamtiv mecarbil, according to a first-in-man, dose-escalating, crossover study of the selective cardiac myosin activator (
pp. 667–75). Concluding that the trial supports “potential clinical use of the drug in patients with heart failure,” the investigators provide these results of 6-hour intravenous infusions of omecamtiv mecarbil or placebo once a week for 4 weeks: “The maximum tolerated dose of omecamtiv mecarbil was 0.5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r2 = 0.99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p < 0.0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0.625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time.” (J. R .Teerlink, john.teerlink@ucsf.edu)
A second trial, this one of 45 patients with systolic heart failure caused by left ventricular dysfunction, showed that omecamtiv mecarbil improved cardiac function (
pp. 676–83). The Phase II trial used crossover, dose-ranging infusions of the drug for 2, 24, or 72 hours, with these results: “45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9.7 mL) were recorded, associated with a small reduction in heart rate (up to 2.7 beats per min; p < 0.0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p = 0.0026) and end-diastolic volumes (16 mL, p = 0.0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged.” (J. G. F. Cleland, j.g.cleland@hull.ac.uk)
Lancet editors discuss reviews published in this issue of nonpharmacologic strategies for managing heart failure (p. 637): “Implantable cardioverter defibrillators are standard therapy for patients at risk of sudden cardiac death. Cardiac resynchronisation therapy with a pacemaker or defibrillator is another well established treatment, with beneficial effects on the underlying mechanisms of disease in appropriate groups of patients with heart failure. Telemedicine in management of heart failure is also addressed [in this issue]. The aspiration in telemedical approaches to heart failure is to monitor adherence to care plans to the benefit of medical outcomes and quality of life for patients, to optimise the use of scarce specialist expertise in cardiology, and to reduce admissions. Substantial practical limitations remain in development of safe and effective cardiotelecommunication systems, however.”

>>>PNN JournalWatch
* Intravenous Enoxaparin or Unfractionated Heparin in Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction: The International Randomised Open-Label ATOLL Trial, in Lancet, 2011; 378: 693–703. (G. Montalescot, gilles.montalescot@psl.aphp.fr)
* Inconsistency Between Direct and Indirect Comparisons of Competing Interventions: Meta-epidemiological Study, in
BMJ, 2011; 343: d4909. (F. Song, fujian.song@uea.ac.uk)
* The Looming Expansion and Transformation of Public Substance Abuse Treatment Under the Affordable Care Act, in
Health Affairs, 2011; 30: 1402–10. (J. A. Buck, jeffrey.buck@cms.hhs.gov)
* Group Health’s Initiative To Avert Opioid Misuse and Overdose Among Patients with Chronic Noncancer Pain, in
Health Affairs, 2011; 30: 1420–4. (M. R. Von Korff, vonkorff.m@ghc.org)

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

PNN Pharmacotherapy Line
Aug. 23, 2011 * Vol. 18, No. 163
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Sept. 1 issue of Clinical Infectious Diseases (2011; 53).
Education for Reducing Antibiotic Use: Use and costs of antibiotics were reduced by a multipronged educational strategy in Quebec, researchers report (pp. 433–9). The effort was prompted by a rise in Clostridium difficile infections in the Canadian province, and it targeted physicians and pharmacists. Following development and distribution of 11 user-friendly guidelines and launching of a dedicated website for the program, promotion by professional organizations, universities, and experts and cooperation of the pharmaceutical industry produced these results: “In 2004, antibiotic consumption per capita was 23.3% higher in Canada generally than in Quebec. After the guidelines dissemination, the gap between Quebec and the other Canadian provinces increased by 4.1 prescriptions/1,000 inhabitants (P = .0002), and the trend persisted 36 months later. Antibiotic costs fell $134.5/1,000 inhabitants in Quebec compared with the rest of Canada (P = .054).” (K. Weiss, weisscan@aol.com)
Fidaxomicin Versus Vancomycin for Clostridium difficile: Among patients with Clostridium difficile infections in two Phase III trials, the narrow-spectrum macrocyclic fidaxomicin was significantly more effective than vancomycin for achieving clinical cure in the presence of concomitant antibiotic (CA) therapy and for preventing recurrence regardless of CA use (pp. 440–7). Study participants received 10 days of fidaxomicin 200 mg every 12 hours or vancomycin 125 mg every 6 hours, with these results: “CAs were prescribed for 27.5% of subjects during study participation. The use of CAs concurrent with CDI treatment was associated with a lower cure rate (84.4% vs 92.6%; P < .001) and an extended time to resolution of diarrhea (97 vs 54 hours; P < .001). CA use during the follow-up was associated with more recurrences (24.8% vs 17.7%; not significant), and CA administration at any time was associated with a lower global cure rate (65.8% vs 74.7%; P = .005). When subjects received CAs concurrent with CDI treatment, the cure rate was 90.0% for fidaxomicin and 79.4% for vancomycin (P = .04). In subjects receiving CAs during treatment and/or follow-up, treatment with fidaxomicin compared with vancomycin was associated with 12.3% fewer recurrences (16.9% vs 29.2%; P = .048).” (K. Mullane, kmullane@medicine.bsd.uchicago.edu)

>>>Oncology Highlights
Source:
Aug. 20 issue of the Journal of Clinical Oncology (2011; 29).
High-Dose Chemotherapy for Breast Cancer: Reflecting on two analyses of adjuvant high-dose chemotherapy (HDC) for breast cancer that found no significant effects on overall survival (pp. 3214–23, pp. 3224–31, D. A. Berry, dberry@mdanderson.org), editorialists revisit the “troubled quest” that characterized efforts to more aggressively treat this disease (pp. 3205–6). “There is encouraging evidence that current breast cancer research is avoiding the pitfalls that beset HDC. Often, phase III data from two or more large, well-conducted clinical trials are awaited before novel therapies are adopted. Even when early results are promising, researchers are required to present follow-up data for long-term key outcomes before final adjudication occurs. Contemporary examples, such as research into bisphosphonate therapy in the adjuvant setting, bevacizumab, and the poly(adenosine diphosphate)-ribose polymerase inhibitors in metastatic disease, illustrate this point. It is now generally accepted that phase III trials are often required to establish tomorrow’s standard of care. Insurers should routinely cover clinical costs for patients who are enrolled onto legitimate peer-reviewed clinical trials, as does Medicare. In return, clinical investigators have an obligation to report good quality data, to run trials according to the accepted ethical and statistical guidelines, and to report all results, including negative findings. Moreover, the overall tenor of research is increasingly shifting toward one of required translation, with correlative studies and aggressive upfront investigation into biomarkers that are predictive of benefit or the lack thereof. The extensive progress in stratifying breast cancer by biologic pathways and therefore by druggable targets invokes hope of more elegant, less toxic, and highly effective therapies across all of the subtypes.” (A. D. Elias, anthony.elias@ucdenver.edu)

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

PNN Pharmacotherapy Line
Aug. 24, 2011 * Vol. 18, No. 164
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 24 issue of JAMA (2011; 306).
Medication Discontinuation During ICU/Hospital Admission: Unintentional discontinuation of medications in patients with chronic diseases admitted to hospitals or intensive-care units is common, affecting up to 20% of patients on antiplatelet/anticoagulant drugs, and those whose drugs are stopped are at higher risk of death, emergency department visits, or emergent hospitalization within the following year, a study shows (pp. 840–7). A population-based cohort study of hospitalizations and outpatient prescriptions in Ontario showed these patterns during 1997–2009 for patients who did not refill statins, antiplatelet/anticoagulant drugs, levothyroxine, respiratory inhalers, and gastric acid–suppressing drugs within 90 days after discharge: “Patients admitted to the hospital (n = 187,912) were more likely to experience potentially unintentional discontinuation of medications than controls (n = 208,468) across all medication groups examined. The adjusted ORs (AORs) ranged from 1.18 (95% CI, 1.14–1.23) for discontinuing levothyroxine in 12.3% of hospitalized patients (n = 6,831) vs 11.0% of controls (n = 7,114) to an AOR of 1.86 (95% CI, 1.77–1.97) for discontinuing antiplatelet/anticoagulant agents in 19.4% of hospitalized patients (n = 5,564) vs 11.8% of controls (n = 2,535). With ICU exposure, the AORs ranged from 1.48 (95% CI, 1.39–1.57) for discontinuing statins in 14.6% of ICU patients (n = 1,484) to an AOR of 2.31 (95% CI, 2.07–2.57) for discontinuing antiplatelet/anticoagulant agents in 22.8% of ICU patients (n = 522) vs the control group. Admission to an ICU was associated with an additional risk of medication discontinuation in 4 of 5 medication groups vs hospitalizations without an ICU admission. One-year follow-up of patients who discontinued medications showed an elevated AOR for the secondary composite outcome of death, emergency department visit, or emergent hospitalization of 1.07 (95% CI, 1.03–1.11) in the statins group and of 1.10 (95% CI, 1.03–1.16) in the antiplatelet/anticoagulant agents group.” (C. M. Bell, bellc@smh.toronto.on.ca)
Biologic Therapies for Psoriasis & Cardiovascular Events: A meta-analysis, while possibly underpowered, finds no significant association between use of interleukin(IL)-12 and -23 inhibitors and major adverse cardiovascular events (MACEs) in patients with chronic plaque psoriasis (CPP) (pp. 864–71). The drugs, ustekinumab and briakinumab, were compared with anti–tumor necrosis factor–alpha (TNF-alpha) agents (adalimumab, etanercept, and infliximab) in randomized controlled trials (RCTs). Meta-analysis of study results showed the following: “A total of 22 RCTs comprising 10,183 patients met the predefined inclusion criteria. The primary outcome measure was MACE, a composite end point of myocardial infarction, cerebrovascular accident, or cardiovascular death during the placebo-controlled phase of treatment in patients receiving at least 1 dose of study agent or placebo. Absolute risk differences were used as an effect measure. There was no evidence of statistical heterogeneity across the studies using the I2 statistic (I2 = 0), allowing for combination of trial results using the Mantel–Haenszel fixed-effects method. During the placebo-controlled phases of the anti–IL-12/23 studies, 10 of 3,179 patients receiving anti–IL-12/23 therapies experienced MACEs compared with zero events in 1474 patients receiving placebo (Mantel-Haenszel risk difference, 0.012 events/person–year; 95% confidence interval [CI], −0.001 to 0.026; P =.12). In the anti–TNF-alpha trials, only 1 of 3,858 patients receiving anti–TNF-alpha agents experienced a MACE compared with 1 of 1,812 patients receiving placebo (Mantel–Haenszel risk difference, −0.0005 events/person-year; 95% CI, −0.010 to 0.009; P = .94).” (C. Ryan, caitriona.ryan@baylorhealth.edu)
Cholesterol-Lowering Foods in Hyperlipidemia: Combining foods with recognized cholesterol-lowering properties into a “dietary portfolio” proved more effective than recommendations for a low-saturated fat therapeutic diet in patients with hyperlipidemia, researchers report (pp. 831–9). The dietary portfolio emphasized incorporation of plant sterols, soy protein, viscous fibers, and nuts. LDL-C reductions from an overall initial mean of 171 mg/dL were 13.8% for an intensive dietary portfolio, 13.1% for a routine dietary portfolio, and 3.0% for a control diet. (D. J. A. Jenkins, cyril.kendall@utoronto.ca)

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

PNN Pharmacotherapy Line
Aug. 25, 2011 * Vol. 18, No. 165
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 25 New England Journal of Medicine (2011; 365).
Azithromycin for Preventing COPD Exacerbations: Administered prophylactically for 1 year, azithromycin reduced exacerbations of chronic obstructive pulmonary disease, improving quality of life but decreasing hearing in about a quarter of those on the drug, a study shows (pp. 689–98). Participants (n = 1,142) were at increased risk of exacerbations on study entry; they had no hearing impairment, resting tachycardia, or risk of QT interval prolongation. Results showed: “The median time to the first exacerbation was 266 days (95% confidence interval [CI], 227 to 313) among participants receiving azithromycin, as compared with 174 days (95% CI, 143 to 215) among participants receiving placebo (P < 0.001). The frequency of exacerbations was 1.48 exacerbations per patient–year in the azithromycin group, as compared with 1.83 per patient–year in the placebo group (P = 0.01), and the hazard ratio for having an acute exacerbation of COPD per patient–year in the azithromycin group was 0.73 (95% CI, 0.63 to 0.84; P < 0.001). The scores on the St. George’s Respiratory Questionnaire (on a scale of 0 to 100, with lower scores indicating better functioning) improved more in the azithromycin group than in the placebo group (a mean [±SD] decrease of 2.8 ± 12.8 vs. 0.6 ± 11.4, P = 0.004); the percentage of participants with more than the minimal clinically important difference of −4 units was 43% in the azithromycin group, as compared with 36% in the placebo group (P = 0.03). Hearing decrements were more common in the azithromycin group than in the placebo group (25% vs. 20%, P = 0.04).” (R. K. Albert, ralbert@dhha.org)
Looking at study results in light of “advice from Hippocrates,” an editorialist supports azithromycin use (
pp. 753–4): “In my opinion, the findings of Albert and coworkers—that the interval between the study onset and the first acute exacerbation of COPD was almost twice as long in the patients receiving long-term azithromycin treatment as in the patients receiving placebo and that patients in the azithromycin group had a significant improvement in the quality of life—tip the scales toward the benefits of azithromycin treatment. However, if azithromycin is going to be used in patients who are known to have frequent exacerbations of COPD, then the local antibiotic resistance patterns should be closely monitored. It also makes sense to ask whether, in such patients, subsequent exacerbations should be treated empirically with a different class of antibiotics. On balance, however, the long-term use of azithromycin to prevent acute exacerbations of COPD would not seem to be at odds with the classical advice of Hippocrates…, ‘Do good, not harm.’” (N. M. Siafakas)
Apixaban & Antiplatelet Therapy After Acute Coronary Syndrome: In the APPRAISE-2 trial, addition of apixaban to antiplatelet therapy after acute coronary syndrome increased major bleeding episodes without significantly lowering recurrent ischemic events, researchers report (pp. 699–708). Patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events received apixaban 5 mg twice daily or placebo in addition to standard antiplatelet therapy, with these results: “The trial was terminated prematurely after recruitment of 7,392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3,705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient–years) and in 293 of the 3,687 patients (7.9%) assigned to placebo (14.0 events per 100 patient–years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P = 0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3,673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient–years) and in 18 of the 3,642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient–years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P = 0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.” (J. H. Alexander, john.h.alexander@duke.edu)

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

PNN Pharmacotherapy Line
Aug. 26, 2011 * Vol. 18, No. 166
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
Sept. issue of Medical Care (2011; 49).
Effects of Medicare Part D: Medicare beneficiaries, particularly those who were sick and poor, “experienced significant improvements in prescription drug use in 2007,” researchers report, the result of implementation of Part D benefit in 2006 (pp. 834–41). In 2000 to 2007, annual prescription drug fills and out-of-pocket drug costs were analyzed for community-dwelling patients in the Medicare Current Beneficiary Survey. Actual post-Part D outcomes were compared with projected 2000–05 values, with these results: “We observed significant average per person increases of 1.8 prescription fills [95% confidence interval (CI), 1.1–2.5] in 2006 and 3.4 prescription fills (95% CI, 2.7–4.1) in 2007 above pre-Part D increases of 0.9 prescription fills per year. Average out-of-pocket [OOP] drug costs decreased significantly by $143 (95% CI, –182.5 to –103.1) in 2006 and $148 (95% CI, –181.2 to –114.1) in 2007 above average pre-Part D increases of $12 per year. Prescription fills did not change for beneficiaries with fair to poor health until 2007 when large increases occurred (increases of 3.7 to 11.0 fills above pre-Part D trends). Significant reductions in OOP drug costs occurred in 2006 and persisted into 2007 across all groups except for sick and poor beneficiaries without Medicaid.” (B. A. Briesacher, Becky.Briesacher@umassmed.edu)
Factors in Nursing Home to Community Transitions: By addressing factors that reduce transition of patients from nursing homes into the community, state Medicaid programs could improve discharge rates, authors conclude (pp. 790–6). In Minnesota, 24,648 first-time admissions to 378 nursing facilities were studied in 2005–06, with these results: “Rates of community discharge … were highest in facilities with more residents preferring community discharge, more Medicare days, higher nurse staffing levels, and higher occupancy. In addition, facilities had higher community discharge rates if they were located in markets with a greater ratio of home and community-based services recipients to nursing home residents and with larger populations.” (G. Arling, GArling@IUPUI.edu)

>>>Health Affairs Report
Source:
Aug. issue of Health Affairs (2011; 30).
Drug Pricing in Rich vs. Poor Countries: Cost-effectiveness thresholds could be used to achieve appropriate drug prices in rich versus poor countries, authors write (pp. 1529–378): “We found that in rich countries, insurance coverage can make consumers insensitive to price, which means that manufacturers’ prices are largely unrestrained unless payers intervene. In middle- and low-income countries, where most consumers pay for drugs out of pocket, we found that the poorest countries face the highest prices, relative to their mean per capita income. We recommend that countries and payers set their own cost-effectiveness thresholds to reflect how much they are willing to pay for ‘health gain’—in other words, for a measured improvement in the health of a person or a population. Adopting this approach broadly should lead to appropriate price differences across and within countries, benefiting consumers and manufacturers alike.” (P. M. Danzon, danzon@wharton.upenn.edu)

>>>PNN NewsWatch
* FDA yesterday approved the orphan drug icatibant (Firazyr, Shire Human Genetic Therapies), a bradykinin B2 receptor antagonist, for treatment of acute attacks of hereditary angioedema (HAE) in adults. HAE is a debilitating rare genetic disease characterized by recurrent, sometimes disfiguring, and often painful episodes of acute swelling of the face, GI tract, extremities, or genitals. Laryngeal attacks can be life threatening in some cases. The drug was studied in three clinical trials, FAST 1, 2, and 3. In FAST-3 (n =98), median time to 50% reduction in HAE symptoms was significantly reduced when patients self-injected icatibant, compared with placebo (2.0 versus 19.8 hours). Injection site reactions occurred in almost all patients (97%) in clinical trials. These most frequently included redness and swelling. Other common adverse reactions reported in at least 1% of patients included fever, transaminase increase, dizziness, and rash. Firazyr will be marketed in prefilled syringes that can be stored at ambient room temperatures up to 77 degrees Fahrenheit.

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

PNN Pharmacotherapy Line
Aug. 29, 2011 * Vol. 18, No. 167
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 27 issue of Lancet (2011; 378).
Breast Cancer Risk Reductions with Tamoxifen: Adjuvant tamoxifen, given for 5 years to women with estrogen-receptor (ER)–positive breast cancer, reduces 15-year risks of recurrence and death, according to a meta-analysis of individual patient data from 20 trials of 21,457 women (pp. 771–84). ER status was the only significant predictor of proportional risk reductions, the authors note, adding that “the absolute risk reductions produced by tamoxifen depend on the absolute breast cancer risks (after any chemotherapy) without tamoxifen”: “In [ER]-positive disease (n = 10,645), allocation to about 5 years of tamoxifen substantially reduced recurrence rates throughout the first 10 years (RR 0.53 [SE 0.03] during years 0–4 and RR 0.68 [0.06] during years 5–9 [both 2p < 0.00001]; but RR 0.97 [0.10] during years 10–14, suggesting no further gain or loss after year 10). Even in marginally ER-positive disease (10–19 fmol/mg cytosol protein) the recurrence reduction was substantial (RR 0.67 [0.08]). In ER-positive disease, the RR was approximately independent of progesterone receptor status (or level), age, nodal status, or use of chemotherapy. Breast cancer mortality was reduced by about a third throughout the first 15 years (RR 0.71 [0.05] during years 0–4, 0.66 [0.05] during years 5–9, and 0.68 [0.08] during years 10–14; p < 0.0001 for extra mortality reduction during each separate time period). Overall non-breast-cancer mortality was little affected, despite small absolute increases in thromboembolic and uterine cancer mortality (both only in women older than 55 years), so all-cause mortality was substantially reduced. In ER-negative disease, tamoxifen had little or no effect on breast cancer recurrence or mortality.” (Early Breast Cancer Trialists’ Collaborative Group, bc.overview@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2011; 343).
Vitamin A Supplements in Children Younger than 5: Vitamin A supplements administered to children aged 6 months to 5 years reduced mortality, morbidity, and vision problems in 43 trials of 215,633 children, a systematic review and meta-analysis shows (d5094): “Seventeen trials including 194,483 participants reported a 24% reduction in all cause mortality (rate ratio = 0.76, 95% confidence interval 0.69 to 0.83). Seven trials reported a 28% reduction in mortality associated with diarrhoea (0.72, 0.57 to 0.91). Vitamin A supplementation was associated with a reduced incidence of diarrhoea (0.85, 0.82 to 0.87) and measles (0.50, 0.37 to 0.67) and a reduced prevalence of vision problems, including night blindness (0.32, 0.21 to 0.50) and xerophthalmia (0.31, 0.22 to 0.45). Three trials reported an increased risk of vomiting within the first 48 hours of supplementation (2.75, 1.81 to 4.19).” (Z. A. Bhutta, zulfiqar.bhutta@aku.edu)
Chocolate & the Heart: Patients consuming greater amounts of chocolate have lower risks of cardiometabolic disorders, researchers report (d4488). In a systematic review and meta-analysis of 7 studies of 114,009 participants, 5 studies showed a beneficial association between higher chocolate consumption and cardiometabolic risks, with a 37% reduction in cardiovascular disease and a 29% reduction in stroke at the highest intake levels. (O. H. Franco, hf22@medschl.cam.ac.uk">ohf22@medschl.cam.ac.uk)

>>>PNN NewsWatch
* On Friday, FDA approved crizotinib (Xalkori, Pfizer) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)–positive, as detected by an FDA-approved test. The agent is the first-ever approved therapy that targets the ALK enzyme, which is present in about 3–5% of NSCLC tumors. Crizotinib, available immediately through a number of specialty pharmacies, causes several adverse reactions in more than 25% of patients: vision disorders (visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects), nausea, diarrhea, vomiting, edema, and constipation.

>>>PNN JournalWatch
* Apixaban versus Warfarin in Patients with Atrial Fibrillation, in New England Journal of Medicine, doi 10.1056/NEJMoa1107039 (study and related editorial released early). (C. B. Granger, christopher.granger@duke.edu)

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

PNN Pharmacotherapy Line
Aug. 30, 2011 * Vol. 18, No. 168
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (2011; 34).
Insulin Delivery by Pumps During Flights: Reduction in atmospheric pressure, as occurs during airplane flights, “causes predictable, unintended insulin delivery in pumps by bubble formation and expansion of existing bubbles,” and this can lead to hypoglycemia, researchers report (pp. 1932–3). Acting on reports of flight-related low blood glucose in children and adults with type 1 diabetes who are on pump-delivered insulin therapy, the investigators tested 10 insulin pumps by measuring or changing ambient pressures and looking for effects on insulin delivery, bubble formation, bubble size, and cartridge plunger movement: “During a flight (200 mm Hg pressure decrease), excess insulin delivery of 0.623% of the cartridge volume occurred (P < 0.001, Student t test). In hypobaric chamber studies, bubbles developed in the insulin when the pressure decreased and displaced the insulin out of the cartridge. Pre-existing bubbles changed in size consistent with Boyle law. Cartridge plunger movement did not occur in normal flight conditions but did occur when catastrophic plane depressurization was mimicked.” (B. R. King, bruce.king@hnehealth.nsw.gov.au)
Glycemic Effects of Telmisartan in High-Risk Patients: In the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) study, telmisartan had did not reduce incident diabetes or produce regression of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT) to normoglycemia in 3,488 adults who were at high risk for cardiovascular disease but free from diabetes (pp. 1902–7). The participants, who were 61% men and averaged 67 years in age, received telmisartan 80 mg or placebo in addition to usual care, with these results: “During a median 56 months, 21.8% of participants treated with telmisartan and 22.4% of those on placebo developed diabetes (relative ratio 0.95 [95% CI 0.83–1.10]; P = 0.51). Participants originally diagnosed with IFG and/or IGT were equally likely to regress to normoglycemia (26.9 vs. 24.5%) or to progress to incident diabetes (20.1 vs. 21.1%; P = 0.59) on telmisartan or placebo.” (J. I. Barzilay, joshua.barzilay@kp.org)
Emergency Department A1C Screening for Diabetes: Visits to the emergency department provide an opportunity for screening adults for diabetes using hemoglobin A1c levels, a study shows (pp. 1908–12). Comfirming cutpoints identified in outpatient studies, the investigators found these results in a prospective observational study in which adults presenting for emergent care of acute illness were tested and later seen for fasting blood glucose measurement and a 2-h oral glucose tolerance test (OGTT): “A total of 618 patients were included, with a mean age of 49.7 (±14.9) years and mean HbA1c of 5.68% (± 0.86). On the basis of an OGTT, the prevalence of previously undiagnosed prediabetes and diabetes was 31.9 and 10.5%, respectively. The optimal HbA1c-screening cutoff for prediabetes was 5.7% (area under the curve [AUC] = 0.659, sensitivity = 55%, and specificity = 71%), for dysglycemia 5.8% (AUC = 0.717, sensitivity = 57%, and specificity = 79%), and for diabetes 6.0% (AUC = 0.868, sensitivity = 77%, and specificity = 87%).” (R. Silverman, rsilverman@nshs.edu)
Lifestyle Counseling for Type 2 Diabetes Risk Reduction: In Dutch primary care settings, lifestyle counseling reduced risk factors for type 2 diabetes, according to a study of 925 patients at high risk of the disease (pp. 1919–25). Compared with usual care over a 1.5-year period, participants had these changes in weight and other parameters when they received counseling by general and nurse practitioners: “Both groups showed modest changes in glucose values, weight measures, physical activity, energy intake, and fiber intake. Differences between groups were significant only for total physical activity, saturated fat intake, and fiber intake. Differences between general practices were significant for BMI and 2-h glucose but not for energy intake and physical activity. In the intervention group, the nurse practitioners’ mean years of work experience was significantly longer in individuals who were successful at losing weight or maintaining a stable weight compared with unsuccessful individuals. Furthermore, successful individuals more often had a partner.” (P. W. A. Vermunt, p.w.a.vermunt@uvt.nl)

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

PNN Pharmacotherapy Line
Sept. 1, 2011 * Vol. 18, No. 170
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and Sept. 1 issue of the New England Journal of Medicine (2011; 365).
Apixaban in Atrial Fibrillation: Compared with warfarin, apixaban was more effective and safer for treating atrial fibrillation in 18,201 patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial (10.1056/NEJMoa1107039). The trial compared apixaban 5 mg twice daily with warfarin therapy dosed to an INR of 2.0 to 3.0. The drugs had these effects on a primary outcome of ischemic or hemorrhagic stroke or systemic embolism: “The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P < 0.001 for noninferiority; P = 0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P < 0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P = 0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < 0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P = 0.42).” (C. B. Granger, christopher.granger@duke.edu)
While cost will continue to drive use of inexpensive warfarin, alternatives to that agent herald a new era in anticoagulation in patients with atrial fibrillation, writes an editorialist (
10.1056/NEJMe1109748): “The original mission to replace warfarin began with a search for drugs that were simply noninferior to warfarin. The ARISTOTLE trial, in conjunction with the RE-LY and ROCKET AF trials, suggests that apixaban, dabigatran, and rivaroxaban have gone even further. Across three large studies with different populations of patients with atrial fibrillation, the direct thrombin and factor Xa inhibitors have been shown to have a more favorable bleeding profile than warfarin and are at least as efficacious. Information about another direct factor Xa inhibitor, edoxaban, in patients with atrial fibrillation, will be available at the conclusion of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48, NCT00781391). After all this time, a new era of anticoagulation appears to be emerging for patients with atrial fibrillation.” (J. L. Mega)
EHRs & Diabetes Care: Federal policies encouraging meaningful use of electronic health records may improve the care of patients with diabetes across a range of insurance types, a study shows (pp. 825–33). Researchers calculated differences in achievement of composite standards for diabetes care and outcomes with paper- versus EHR-based records, with these results: “From July 2009 through June 2010, data were reported for 27,207 adults with diabetes seen at 46 practices; safety-net practices accounted for 38% of patients. After adjustment for covariates, achievement of composite standards for diabetes care was 35.1 percentage points higher at EHR sites than at paper-based sites (P < 0.001), and achievement of composite standards for outcomes was 15.2 percentage points higher (P = 0.005). EHR sites were associated with higher achievement on eight of nine component standards. Such sites were also associated with greater improvement in care (a difference of 10.2 percentage points in annual improvement, P < 0.001) and outcomes (a difference of 4.1 percentage points in annual improvement, P = 0.02). Across all insurance types, EHR sites were associated with significantly higher achievement of care and outcome standards and greater improvement in diabetes care. Results confined to safety-net practices were similar.” (R. D. Cebul, rdc@case.edu)

>>>PNN NewsWatch
* Contamination of pharmacy-repackaged bevacizumab (Avastin, Genentech) for off-label intravitreal injections has caused a cluster of Streptococcus endophthalmitis infections in three Florida clinics, FDA said. At least 12 patients have been affected, with some losing all remaining vision in the infected eye.

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

PNN Pharmacotherapy Line
Sept. 2, 2011 * Vol. 18, No. 171
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Sept. issue of Pediatrics (2011; 128).
Suicidality with Antidepressants in Adolescence: Important differences in antidepressant-related suicidality behaviors are identified among patients in early versus late adolescence (pp. 447–54). A review of Tennessee Medicaid records for 1995–2006 showed these patterns among patients aged 10–14 and 15–18 years: “Of the 250 cases reviewed, 65.6% were female and 26.4% were aged 10 to 14 years. Medication ingestion was the most frequent method of suicidal behavior for both early and late adolescents; however, early adolescents were significantly more likely to use hanging as a method of suicide. Nearly one-half of the adolescents had previously attempted suicide. Early adolescents were significantly more likely to have a history of sexual abuse and significantly less likely to have a history of substance abuse. Early adolescents were also significantly more likely than older adolescents to have a history of a psychotic disorder and to report hallucinations before the suicide attempt.” (W. O. Cooper, william.cooper@vanderbilt.edu)
Comparative Effectiveness of Antibiotics in Skin Infections: A second cohort analysis of the Tennessee Medicaid database shows that clindamycin was superior to trimethoprim–sulfamethoxazole or beta-lactams for treatment of pediatric skin and soft-tissue infections (SSTIs), based on treatment failures and recurrences (pp. e479–87). Associations were stronger among children aged 0–17 years who had drainage procedures of incident SSTIs in 2004–07: “Among the 6,407 children who underwent drainage, there were 568 treatment failures (8.9%) and 994 recurrences (22.8%). The adjusted odds ratios for treatment failure were 1.92 (95% confidence interval [CI]: 1.49–2.47) for trimethoprim–sulfamethoxazole and 2.23 (95% CI: 1.71–2.90) for beta-lactams. The adjusted hazard ratios for recurrence were 1.26 (95% CI: 1.06–1.49) for trimethoprim–sulfamethoxazole and 1.42 (95% CI: 1.19–1.69) for beta-lactams. Among the 41,094 children without a drainage procedure, there were 2,435 treatment failures (5.9%) and 5,436 recurrences (18.2%). The adjusted odds ratios for treatment failure were 1.67 (95% CI: 1.44–1.95) for trimethoprim–sulfamethoxazole and 1.22 (95% CI: 1.06–1.41) for beta-lactams; the adjusted hazard ratios for recurrence were 1.30 (95% CI: 1.18–1.44) for trimethoprim–sulfamethoxazole and 1.08 (95% CI: 0.99–1.18) for beta-lactams.” (D. J. Williams, derek.williams@vanderbilt.edu)
Prenatal DHA Supplementation & Colds: Infants born to women who took supplements of docosahexaenoic acid (DHA) during pregnancy had fewer colds at 1 month and shorter duration of illness symptoms at 1, 3, and 6 months, researchers report (pp. e505–12). Pregnant women took 400 mg of the long-chain polyunsaturated fatty acids or placebo from 18 to 22 weeks’ gestation, with these results for about 850 infants: “The occurrence of a combined measure of cold symptoms was lower in the DHA group at 1 month (OR: 0.76; 95% CI: 0.58–1.00). At 1 month, the DHA group experienced 26%, 15%, and 30% shorter duration of cough, phlegm, and wheezing, respectively, but 22% longer duration of rash (all P ≤ .01). At 3 months, infants in the DHA group spent 14% less time ill (P < .0001). At 6 months, infants in the DHA group experienced 20%, 13%, 54%, 23%, and 25% shorter duration of fever, nasal secretion, difficulty breathing, rash, and ‘other illness,’ respectively, but 74% longer duration of vomiting (all P < .05).” (U. Ramakrishnan, uramakr@emory.edu)

>>>PNN NewsWatch
* The Reclast brand of zoledronic acid should not be used in patients with creatinine clearances of less than 35 mL/min or in those with acute renal impairment, FDA said yesterday. Labeling changes are being made to reflect this guidance; dose reductions for the Zometa brand of the drug, indicated for use in patients with cancer, are already provided in that drug product’s FDA-approved labeling.
*
Asenapine (Saphris, Merck) can cause serious allergic reactions, including Type I hypersensitivity reactions, FDA said on Thursday. Based on 52 case reports, the label for the antipsychotic agent is being updated to warn of reactions that may include anaphylaxis, angioedema, low blood pressure, rapid heart rate, swollen tongue, difficulty breathing, wheezing, or rash.
*
PNN will not be published on Mon., Sept. 5, Labor Day.

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

PNN Pharmacotherapy Line
Sept. 6, 2011 * Vol. 18, No. 172
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 6 issue of the Annals of Internal Medicine (2011; 155).
Reconsidering Long-Term Opioid Therapy: Pointing to the large increase in opioid prescribing over the past 20 years, authors of an ideas/opinion article maintain that “the rise in opioid prescribing has outpaced the evidence regarding this practice” (pp. 325–8): “The rate of opioid addiction among patients receiving long-term opioid therapy remains unclear, but research suggests that opioid misuse is not rare. Recent studies report increased risks for serious adverse events, including fractures, cardiovascular events, and bowel obstruction, although further research on medical risks is needed. New data indicate that opioid-related risks may increase with dose. From a societal perspective, higher-dose regimens account for the majority of opioids dispensed, so cautious dosing may reduce both diversion potential and patient risks for adverse effects. Limiting long-term opioid therapy to patients for whom it provides decisive benefits could also reduce risks. Given the warning signs and knowledge gaps, greater caution and selectivity are needed in prescribing long-term opioid therapy. Until stronger evidence becomes available, clinicians should err on the side of caution when considering this treatment.” (M. Von Korff)

>>>Lancet Highlights
Source:
Sept. 3 issue of Lancet, a 9/11 theme issue (2011; 378).
Mortality Among 9/11 Survivors: Overall mortality is lower than expected among people “exposed” to the Sept. 11, 2001 World Trade Center (WTC) disaster, investigators report, although risks of death from cardiovascular disease are doubled in nonrescue personnel with high levels of exposure (pp. 879–87). Groups included in the analysis included rescue and recovery workers and volunteers; lower Manhattan area residents, workers, school staff, and students; and commuters and passers-by on 9/11. Standardized mortality ratios (SMRs) in these groups showed: “We identified 156 deaths in 13,337 rescue and recovery workers and 634 deaths in 28,593 non-rescue and non-recovery participants. All-cause SMRs were significantly lower than that expected for rescue and recovery participants (SMR 0.45, 95% CI 0.38–0.53) and non-rescue and non-recovery participants (0.61, 0.56–0.66). No significantly increased SMRs for diseases of the respiratory system or heart, or for haematological malignancies were found. In non-rescue and non-recovery participants, both intermediate and high levels of WTC-related exposure were significantly associated with mortality when compared with low exposure (adjusted hazard ratio 1.22, 95% CI 1.01–1.48, for intermediate exposure and 1.56, 1.15–2.12, for high exposure). High levels of exposure in non-rescue and non-recovery individuals, when compared with low exposed non-rescue and non-recovery individuals, were associated with heart-disease-related mortality (adjusted hazard ratio 2.06, 1.10–3.86). In rescue and recovery participants, level of WTC-related exposure was not significantly associated with all-cause mortality (adjusted hazard ratio 1.25, 95% CI 0.56–2.78, for high exposure and 1.03, 0.52–2.06, for intermediate exposure when compared with low exposure).” (J. E. Cone, jcone@health.nyc.gov)

>>>PNN NewsWatch
* Swine-origin influenza A/H3N2 with a reassortant gene from the 2009 pandemic strain has produced disease in two patients in the U.S., CDC reports. In an advance-release MMWR article, public health officials wrote that two children younger than 5, one in Indiana and the other in Pennsylvania, had infections in July and August. Both recovered. PCR analysis of the influenza virus showed that it contained the matrix gene from the pandemic avian influenza A/H1N1 strain.

>>>PNN JournalWatch
* Magnesium Intake and Risk of Type 2 Diabetes: Meta-analysis of Prospective Cohort Studies, in Diabetes Care, 2011; 34: 2116–22. (L-Q Qin, dongjy@mail3.sysu.edu.cn)
* Prevention of Varicella: Update of Recommendations for Use of Quadrivalent and Monovalent Varicella Vaccines in Children, in
Pediatrics, 2011; 128: 630–2. (American Academy of Pediatrics Committee on Infectious Diseases)
* Aldosterone-Induced Fibrosis in the Kidney: Questions and Controversies, in
American Journal of Kidney Diseases, 2011; 58: 471–9. (R. Gong, rujun_gong@brown.edu)
* Revisiting “Older” Antimicrobials in the Era of Multidrug Resistance, in
Pharmacotherapy, 2011; 31: 912–21. (J. M. Pogue, jpogue@dmc.org)

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

PNN Pharmacotherapy Line
Sept. 7, 2011 * Vol. 18, No. 173
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 7 issue of JAMA (2011; 306).
21st Century Genomics Education: “The rate at which new genomic applications enter the clinician’s armamentarium appears to have reached an inflection point and is likely to accelerate from here,” Commentary authors write, concluding that it is “time to get serious about genomics education for all health care professionals” (pp. 989–90): “The complexity of the emerging picture of genomics ensures that all clinicians will need informatics support to interpret and act on genomic information relevant to patient care. Ensuring that high-quality software tools are available to clinicians will be more important than forcing them to understand the intricacies of how those tools work. For example, in most environments, clinicians are expected to know that the US Food and Drug Administration labeling recommends pharmacogenomic testing to help guide prescribing for several diverse types of medications, such as clopidogrel, carbamazepine, and abacavir. Future clinical informatics systems could alleviate this burden by automatically interpreting the effects of a patient’s pharmacogenomic profile on a prescribing choice and offering specific dosage suggestions as well as educational options in real time. Some health care systems have made inroads toward developing health informatics systems with such genomic capabilities. The development and widespread adoption of interoperable, genomics-enabled clinical informatics systems will require effective national leadership in the decades to come.” (W. G. Feero, feerow@mail.nih.gov)

>>>Infectious Disease Report
Source:
Oct. 1 issue of Clinical Infectious Diseases (2011; 53).
Antibiotic Prescribing & Pneumococcal Resistance: Antibiotic resistance is more common among invasive pneumococcal disease (IPD) isolates in areas where antibiotic use is higher, researchers report (pp. 631–9). CDC data on Streptococcus pneumoniae infections were analyzed against IMS prescribing information, yielding these results: “Yearly prescribing rates during the period 1996–2003 for children <5 years of age decreased by 37%, from 4.23 to 2.68 prescriptions per capita per year (P < .001), and those for persons ≥5 years of age decreased by 42%, from 0.98 to 0.57 prescriptions per capita per year (P < .001); increases in azithromycin prescribing were noted for both groups. Sites with high rates of antibiotic prescribing had a higher proportion of IPD nonsusceptibility than did low-prescribing sites (P = .003 for penicillin, P < .001 for every other antibiotic class). Cephalosporin and macrolide prescribing were associated with penicillin and multidrug nonsusceptibility and serotype 19A IPD (P < .001).” (L. A. Hicks, lhicks@cdc.gov)
It’s “time to ‘get smarter’” with outpatient antibiotic prescribing, an editorialist writes (
pp. 640–3): “These data illustrate that there is both opportunity and need to improve outpatient antibiotic prescribing in the United States. Although there has been increasing interest in antibiotic stewardship in the hospital setting—indeed, no major infectious disease conference goes without several symposia on this topic—antibiotic stewardship in the outpatient setting has been somewhat neglected, despite the fact that the vast majority of all antibiotics for human use are prescribed in the primary care setting and despite evidence that outpatient antibiotic use can influence resistance rates within facilities. The CDC has promoted judicious antibiotic use since 1995 through the ‘Get Smart: Know When Antibiotics Work’ campaign, but good data linking the campaign to decreased antibiotic use are scarce for the reasons…. In addition, most statewide campaigns were relatively limited and poorly funded compared with mass-media campaigns in other countries. In 2010, for example, not one of the 5 highest prescribing states in 2009 seems to have received funding in the context of the ‘Get Smart’ campaign.” (B. Hunter, huttner.benedikt@gmail.com)
Behavioral Change in Antimicrobial Prescribing: Efforts to change antibiotic prescribing habits have not incorporated qualitative research into prescribing habits, according to a systematic review of 10 studies (pp. 651–62): “Quantitative studies reporting interventions to optimize antimicrobial prescribing behavior do not use theoretical science or primary research to inform the design and choice of the interventions deployed.” (E. Charani, e.charani@imperial.ac.uk)

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

PNN Pharmacotherapy Line
Sept. 8, 2011 * Vol. 18, No. 174
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 8 issue of the New England Journal of Medicine (2011; 365).
Rivaroxaban in Nonvalvular Atrial Fibrillation: In 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke, the oral factor Xa inhibitor rivaroxaban was noninferior to warfarin for stroke prevention, report investigators with the ROCKET AF trial (pp. 883–91). Rivaroxaban 20 mg daily or dose-adjusted warfarin produced these results in noninferiority analysis using a primary end point of stroke or systemic embolism: “In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P < 0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P < 0.001 for noninferiority; P = 0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1,475 patients in the rivaroxaban group (14.9% per year) and in 1,449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P = 0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P = 0.02) and fatal bleeding (0.2% vs. 0.5%, P = 0.003) in the rivaroxaban group.” (M. R. Patel, manesh.patel@duke.edu)
Adding to the endorsement of oral factor Xa inhibitors made in last week’s ARISTOTLE report (see PNN, Sept. 1), editorialists write (pp. 952–3): “For the management of atrial fibrillation, oral alternatives to warfarin have arrived. Their simplicity of use is attractive, and they appear to have an efficacy similar to that of warfarin, with the proviso that comparisons seem to depend on how easily the patient can be treated with warfarin. An important concern that these clinical trials do not address is the absence of antidotes to rapidly reverse the anticoagulant effects of either rivaroxaban or dabigatran in the case of life-threatening hemorrhage or surgery. All these issues need to be taken into account in clinical decision making. Further studies will be necessary to refine the treatment of a growing population of patients with atrial fibrillation in order to reduce the risk of stroke.” (G. J. del Zoppo)
Genetics of Daptomycin Resistance in Enterococci: Mutations in genes coding for two proteins are all that is needed for enterococci to development resistance to daptomycin, a study shows (pp. 892–900). Whole-genome sequencing showed that “mutations in genes encoding LiaF and a [glycerophosphoryl diester phosphodiesterase]–family protein were necessary and sufficient for the development of resistance to daptomycin during the treatment of vancomycin-resistant enterococci.” LiaF is lipid II cycle-interfering antibiotics protein whose function is unknown. (C. A. Arias, cesar.arias@uth.tmc.edu)
Drug-Resistant Epilepsy: Combination therapy is one option for managing drug-resistant epilepsy, write authors of a Current Concepts review (pp. 919–26): “Generating robust clinical evidence of suitable combinations of antiepileptic drugs has been challenging because of the large number of possible combinations of drugs and dose ranges. The strongest evidence in favor of synergism comes from nonrandomized, controlled studies involving adults who received a combination of sodium valproate and lamotrigine for partial-onset and generalized seizures (class III evidence); these observations are supported by animal models. Other combinations that are sometimes recommended, largely on the basis of anecdotal reports or studies with small samples, include valproate with ethosuximide for absence seizures (class IV evidence) and lamotrigine with topiramate for a range of seizure types (class IV evidence).” (P. Kwan, patrickkwan@cuhk.edu.hk)

>>>PNN NewsWatch
* Warnings of infection with Legionella and Listeria have been added to the product labeling for all tumor necrosis factor–alpha blockers, FDA said yesterday. The labeling suggests evaluating the relative risks and benefits of TNF-alpha blockers before initiating therapy in patients with chronic or recurrent infection and patients with underlying conditions that may predispose them to infection.

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

PNN Pharmacotherapy Line
Sept. 9, 2011 * Vol. 18, No. 175
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Sept. 6 issue of Circulation (2011; 124).
Fatty Acids & Sinus Rhythm Maintenance After Cardioversion: Addition of n-3 polyunsaturated fatty acids (n-3 PUFAs) improved maintenance of sinus rhythm in 199 patients with persistent atrial fibrillation, researchers report (pp. 1100–6). Study participants had had at least one relapse following cardioversion and were being treated with amiodarone and a renin–angiotensin–aldosterone system inhibitor. They were randomized to placebo or n-3 PUFAs 2 g/d before undergoing cardioversion 4 weeks later, with these results: “At the 1-year follow up, the probability of maintenance of sinus rhythm was significantly higher in the n-3 PUFAs–treated patients compared with the placebo group (hazard ratio, 0.62 [95% confidence interval, 0.52 to 0.72] and 0.36 [95% confidence interval, 0.26 to 0.46], respectively; P = 0.0001).” (L. Dei Cas, deicas@med.unibs.it)
Editorialists note that these results are “consistent with basic science data but curiously at odds with similar clinical studies” and that PUFAs are not recommended in the 2010 European Society of Cardiology Guidelines “because of the absence of robust evidence” (
pp. 1093–6). They add these details about possible mechanisms of action for PUFA benefits: “The content of individual PUFAs, mainly EPA and DHA, may be more important than the total PUFA concentration because the electrophysiological effects produced by different PUFA components are not the same. DHA exerts a stronger sodium current block whereas EPA (and [alpha]-linolenic acid found in vegetable oils) have a greater potential to block potassium currents. In the population-based Kuopio Ischemic Heart Disease Risk Factor Study high serum DHA content was associated with a 38% reduction in relative risk of incident AF, but no such association was found for EPA. In the secondary prevention studies, DHA levels increased to a lesser extent than that of EPA. Kowey et al reported a greater increment in EPA content (about 250–300% from baseline) compared with DHA concentration (a 100% increase). Also in the study by Bianconi et al, EPA levels more than doubled, whereas DHA levels only increased by 25%.” (I. Savelieva, isavelie@sgul.ac.uk)

>>>Cardiology Highlights
Source:
Sept. 13 issue of the Journal of the American College of Cardiology (2011; 58).
Iron Homeostasis in Chronic Heart Failure: In patients with chronic heart failure, iron deficiency may be a more important marker and therapeutic target than anemia, a study shows (pp. 1241–51). The researchers, who conclude that “disordered iron homeostasis in patients with CHF relates to impaired exercise capacity and survival and appears prognostically more ominous than anemia,” quantified iron and clinical indices in 157 patients with CHF: “Several observations were made. First, iron homeostasis was deranged in anemic and nonanemic subjects and characterized by diminished circulating (transferrin saturation) and functional (mean cell hemoglobin concentration) iron status in the face of seemingly adequate stores (ferritin). Second, while iron overload and elevated iron stores were rare (1%), iron deficiency (transferrin saturation <20%) was evident in 43% of patients. Third, disordered iron homeostasis related closely to worsening inflammation and disease severity and strongly predicted lower hemoglobin levels independently of age, sex, erythrocyte sedimentation rate, New York Heart Association (NYHA) functional class, and creatinine. Fourth, the etiologies of anemia varied with disease severity, with an iron-deficient substrate (anemia of chronic disease and/or iron-deficiency anemia) evident in 16%, 72%, and 100% of anemic NYHA functional class I or II, III, and IV patients, respectively. Although anemia of chronic disease was more prevalent than iron-deficiency anemia, both conditions coexisted in 17% of subjects. Fifth, iron deficiency was associated with lower peak oxygen consumption and higher ratios of ventilation to carbon dioxide production and identified those at enhanced risk for death (hazard ratio: 3.38; 95% confidence interval: 1.48 to 7.72; p = 0.004) independently of hemoglobin. Nonanemic iron-deficient patients had a 2-fold greater risk for death than anemic iron-replete subjects.” (D. O. Okonko, biokonko@aol.com">obiokonko@aol.com)

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

PNN Pharmacotherapy Line
Sept. 12, 2011 * Vol. 18, No. 176
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 10 issue of Lancet (2011; 378).
Managing Asthma in Pregnancy Using Fraction of Exhaled Nitric Oxide: Use of a validated treatment algorithm based on fraction of exhaled nitric oxide (FENO) reduced exacerbations during pregnancy in 220 nonsmoking women, a study shows (pp. 983–90). At two antenatal clinics in Australia, participants were assigned before 22 weeks’ gestation to algorithm management based on either clinical symptoms or FENO concentrations, which were used to uptitrate (above 29 ppb) or downtitrate (below 16 ppb) the dose of inhaled corticosteroids. Results showed: “The exacerbation rate was lower in the FENO group than in the control group (0.288 vs 0.615 exacerbations per pregnancy; incidence rate ratio 0.496, 95% CI 0.325–0.755; p = 0.001). The number needed to treat was 6. In the FENO group, quality of life was improved (score on short form 12 mental summary was 56.9 [95% CI 50.2—59.3] in FENO group vs 54.2 [46.1—57.6] in control group; p = 0.037) and neonatal hospitalisations were reduced (eight [8%] vs 18 [17%]; p = 0.046).” (H. Powell, heather.powell@hnehealth.nsw.gov.au)
Note: The American Thoracic Society in May approved official clinical practice guidelines on interpretation of F
ENO for clinical treatment of airway disease (see Am J Respir Crit Care Med. 2011; 184: 602–15).
Genetic Risk Loci for Asthma: The concept of genotype-dependent treatment of asthma with tocilizumab, an antagonist of interleukin-6, is supported by data in a genome-wide study of 2,669 patients with physician-diagnosed asthma and 4,528 controls from Australia and data from previous studies (pp. 1006–14): “Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n = 57,800): rs4129267 (OR 1.09, combined p = 2.4×10−8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1.09, p = 1.8×10−8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1.33, p = 7×10−4, suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2.” (M. A. R. Ferreira, manuel.ferreira@qimr.edu.au)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
Severity of 2009 Pandemic A/H1N1 Influenza in England: The 2009 influenza pandemic was a relatively mild one in England, researchers report, but the A/H1N1 strain was capable of infecting one-quarter of people in various subgroups (d5408). Case and infection severity ratios increased between waves: “In the summer wave of A/H1N1 influenza, 0.54% (95% credible interval 0.33% to 0.82%) of the estimated 606,100 (419,300 to 886,300) symptomatic cases were hospitalised, 0.05% (0.03% to 0.08%) entered intensive care, and 0.015% (0.010% to 0.022%) died. These correspond to 3,200 (2300 to 4,700) hospital admissions, 310 (200 to 480) intensive care admissions, and 90 (80 to 110) deaths in the summer wave. In the second wave, 0.55% (0.28% to 0.89%) of the 1,352,000 (829,900 to 2,806,000) estimated symptomatic cases were hospitalised, 0.10% (0.05% to 0.16%) were admitted to intensive care, and 0.025% (0.013% to 0.040%) died. These correspond to 7,500 (5,900 to 9,700) hospitalisations, 1,340 (1,030 to 1,790) admissions to intensive care, and 240 (310 to 380) deaths. Just over a third (35% (26% to 45%)) of infections were estimated to be symptomatic.” (A. M. Presanis, anne.presanis@mrc-bsu.cam.ac.uk)

>>>PNN JournalWatch
* Gastrin in Gastrointestinal Diseases, in Gastroenterology, 2011; 141: 814–18.e3. (D. Fourmy, aniel.Fourmy@inserm.fr">Daniel.Fourmy@inserm.fr)
* Asthma in the Elderly: Current Understanding and Future Research Needs—A Report of a National Institute on Aging (NIA) Workshop, in
Journal of Allergy and Clinical Immunology, 2011; 128: S4–S24. (M. J. King, m.james.king@me.com)
* Advancing Asthma Care: The Glass Is Only Half Full!, in
Journal of Allergy and Clinical Immunology, 2011; 128: 485–94. (S. Szefler, szeflers@njhealth.org)

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

PNN Pharmacotherapy Line
Sept. 13, 2011 * Vol. 18, No. 177
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Sept. 12 issue of the Archives of Internal Medicine (2011; 171).
Pharmacist Care in Management in CVD Risk Factors: In outpatients, pharmacist-directed care improves management of major cardiovascular disease (CVD) risk factors, conclude Canadian and Swiss authors who conducted a systematic review and meta-analysis of 30 randomized controlled trials involving 11,765 patients (pp. 1441–53): “Pharmacist interventions exclusively conducted by a pharmacist or implemented in collaboration with physicians or nurses included patient educational interventions, patient-reminder systems, measurement of CVD risk factors, medication management and feedback to physician, or educational intervention to health care professionals. Pharmacist care was associated with significant reductions in systolic/diastolic blood pressure (19 studies [10,479 patients]; –8.1 mm Hg [95% confidence interval {CI}, –10.2 to –5.9]/–3.8 mm Hg [95% CI,–5.3 to –2.3]); total cholesterol (9 studies [1121 patients]; –17.4 mg/L [95% CI,–25.5 to –9.2]), low-density lipoprotein cholesterol (7 studies [924 patients]; –13.4 mg/L [95% CI,–23.0 to –3.8]), and a reduction in the risk of smoking (2 studies [196 patients]; relative risk, 0.77 [95% CI, 0.67 to 0.89]). While most studies tended to favor pharmacist care compared with usual care, a substantial heterogeneity was observed.” (V. Santschi, valerie.santschi@gmail.com)
Pharmacist Care of Cholesterol Management in Diabetes: Remote physician–pharmacist team-based care significantly improved LDL cholesterol levels and goal attainment among 6,963 patients with diabetes mellitus (DM), researchers report (pp. 1480–6). The 2-year Oregon study involved use of the health information technology tool CareManager, which “provided automated DM-related point-of-care prompts, a Web-based registry, and performance feedback with benchmarking,” the authors write, adding these results: “Patients in the intervention arm were more likely to achieve their target LDL-C levels compared with controls (78% vs 50%; P = .003). The mean LDL-C level was 12 mg/dL lower in the intervention arm compared with the control arm (P < .001). The rate of LDL-C testing was significantly higher in the intervention arm compared with the control arm. Patients in the intervention arm were also 15% more likely to receive a prescription for a lipid-lowering medication (P = .008). There was no significant difference in patient satisfaction between study arms (P = .15).” (G. A. Pape, ginger.pape@providence.org)
Describing collaborative care and the medical home as “a good match,” an editorialist (
pp. 1428–9) comments on this and another study in which pharmacists were part of care teams for patients with stable ischemic heart disease (pp. 1471–9; S. D. Fihn, stephan.fihn@va.gov): “It would be nice if collaborative care had generic components that could be performed by a variety of team members. For example, does the collaborative care of depression and anxiety require the expertise of a psychiatrist, or could other mental health assets suffice? This has resource implications that would influence the cost-effectiveness of collaborative care. One could envision broadly skilled case managers (as regular members of the medical home team) deployed to the collaborative care process once a diagnosis has been made and the patient deemed eligible.” (P. G. O’Malley, pomalley@usuhs.mil)
Lifestyle Modification, CV Risk Reduction & Erectile Dysfunction: Lifestyle modification and pharmacotherapy for cardiovascular (CV) risk factors improve sexual health and reduce erectile dysfunction in men, according to results of a systematic review and meta-analysis of 6 clinical trials of 740 participants (10.1001/archinternmed.2011.440). Randomized controlled trials that included at least 6 weeks of lifestyle modification intervention or pharmacotherapy for CV risk factor reduction showed the following: “Lifestyle modifications and pharmacotherapy for CV risk factors were associated with statistically significant improvement in sexual function (IIEF-5 score): weighted mean difference, 2.66 (95% CI, 1.86–3.47). If the trials with statin intervention (n = 143) are excluded, the remaining 4 trials of lifestyle modification interventions (n = 597) demonstrate statistically significant improvement in sexual function: weighted mean difference, 2.40 (95% CI, 1.19–3.61).” (B. P. Gupta, gupta.bhanu@mayo.edu)

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

PNN Pharmacotherapy Line
Sept. 14, 2011 * Vol. 18, No. 178
Providing news and information about medications and their proper use

>>>Asthma/Immunology Report
Source:
Sept. Journal of Allergy and Clinical Immunology (2011; 128).
Obesity & Asthma Phenotype: Obesity produces a unique phenotype of asthma, according to a study of 44 patients undergoing bariatric surgery (pp. 508–15.e2). Asthma in these patients may require a “distinct therapeutic approach,” the authors note. The prospective study looked at baseline asthma control, airway hyperresponsiveness (AHR), and markers of asthmatic inflammation in 23 patients with and 21 patients without asthma. Follow-up data were collected 12 months later in the patients with asthma. Results showed: “At baseline, asthmatic patients had lower FEV1 and forced vital capacity and lower numbers of lymphocytes in bronchoalveolar lavage fluid. After surgery, asthmatic participants experienced significant improvements in asthma control (asthma control score, 1.55 to 0.74; P < .0001) and asthma quality of life (4.87 to 5.87, P < .0001). Airways responsiveness to methacholine improved significantly (methacholine PC20, 3.9 to 7.28, P = .03). There was a statistically significant interaction between IgE status and change in airways responsiveness (P for interaction = .01). The proportion of lymphocytes in bronchoalveolar lavage fluid and the production of cytokines from activated peripheral blood CD4+ T cells increased significantly.” (A. E. Dixon, Anne.dixon@vtmednet.org)
Improving Adherence in Asthma: While individualized problem-solving (PS) and asthma education (AE) were equivalent in improving adherence and asthma outcomes in adults with moderate to severe asthma, researchers found that two elements of those approaches—monitoring inhaled corticosteroid (ICS) adherence with provision of medications and attention—were linked to better outcomes (pp. 516–23.e5). Results showed: “333 adults were randomized: 49 ± 14 years of age, 72% female, 68% African American, 7% Latino, mean FEV1 of 66% ± 19%, and 103 (31%) with hospitalizations and 172 (52%) with [emergency department (ED)] visits for asthma in the prior year. There was no difference between groups in overall change in any outcome (P > .20). Mean adherence (61% ± 27%) decreased significantly (P = .0004) over time by 14% and 10% in the AE and PS groups, respectively. Asthma control improved overall by 15% (P = .002). In both groups FEV1 and quality of life improved by 6% (P = .01) and 18% (P < .0001), respectively. However, the improvement in FEV1 only occurred during monitoring but not subsequently after randomization. Rates of ED visits and hospitalizations did not significantly decrease over the study period.” (A. J. Aptar, apter@mail.med.upenn.edu)

>>>Rheumatology Report
Source:
Sept. issue of Arthritis & Rheumatism (2011; 63).
Adipokines in Early RA: Serum adipokine levels are predictors of radiographic progression in early rheumatoid arthritis, researchers report (pp. 2567–74). “Distinct underlying biologic mechanisms” could be involved with the soluble immunologic mediators, the authors add, noting these relationships between radiographic progression and serum levels of leptin, visfatin, resistin, adiponectin, adipsin, tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6) in 253 patients with RA in the Early Arthritis Cohort: “Levels of IL-6, TNF-alpha, visfatin, and adiponectin were positively associated with radiographic progression over 4 years. This association was independent of BMI. However, only adiponectin levels remained significantly associated with radiographic progression when the model was corrected for the presence of [anti–cyclic citrullinated peptide (anti-CCP)] antibodies, whereas a trend was observed for IL-6. The association of both TNF-alpha and visfatin with radiographic damage disappeared after correction for the presence of anti-CCP antibodies, which is consistent with the fact that the levels of both cytokines correlated significantly with anti-CCP antibody levels in these patients.” (A. Ioan-Facsinay, A.Ioan@lumc.nl)

>>>PNN NewsWatch
* Million Hearts is a new public–private partnership that seeks to prevent 1 million heart attacks and strokes over the next 5 years. Announced yesterday, the campaign focuses on ABCS (aspirin, blood pressure and cholesterol control, and stopping smoking) and, within pharmacy, includes Walgreens, APhA, NCPA, the National Alliance of State Pharmacy Associations, and the Alliance for Patient Medication Safety.

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

PNN Pharmacotherapy Line
Sept. 15, 2011 * Vol. 18, No. 179
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 15 issue of the New England Journal of Medicine (2011; 365).
Aggressive Medical Therapy v. Stenting for Stroke Prevention: Aggressive medical therapy proved better than medicines plus percutaneous transluminal angioplasty and stenting (PTAS) in patients with atherosclerotic intracranial arterial stenosis, according to the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (pp. 993–1003). The risk of early stroke was high with stenting, and the risk of stroke with medicines was lower than expected, the investigators report, adding these details about their results: “Enrollment was stopped after 451 patients underwent randomization, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%) and 5.8% in the medical-management group (nonfatal stroke, 5.3%; non–stroke-related death, 0.4%) (P = 0.002). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Currently, the mean duration of follow-up, which is ongoing, is 11.9 months. The probability of the occurrence of a primary end-point event over time differed significantly between the two treatment groups (P = 0.009), with 1-year rates of the primary end point of 20.0% in the PTAS group and 12.2% in the medical-management group.” (M. I. Chimowitz, mchimow@musc.edu)
After noting that this is the third trial that “has failed to show a benefit of that strategy over medical therapy for the prevention of stroke,” an editorialist notes dichotomies in reimbursement and approval patterns for stents (
pp. 1054–5): “CMS played an important role in expediting the conduct of the SAMMPRIS trial. The FDA approved the Wingspan stent for clinical use under a humanitarian device exemption in 2005 and approved the use of the device for the SAMMPRIS trial under an investigational device exemption. However, CMS did not reimburse for the Wingspan device outside of its use in a randomized trial. Recruitment within the trial proceeded quite well. Similarly, CMS, despite lobbying by physicians and industry, reimbursed for carotid stenting in asymptomatic patients only if the stenting was performed within the context of a trial. This action facilitated recruitment into the [Carotid Revascularization Endarterectomy versus Stenting Trial (CREST)]. In contrast, endovascular devices for the treatment of acute stroke have been cleared by the FDA through the 510(k) pathway and reimbursed by CMS without demonstration of clinical benefit. Not surprisingly, the use of these devices in clinical practice is increasing, while recruitment into trials designed to show the clinical efficacy of the endovascular treatment in patients with acute stroke has lagged.” (J. P. Broderick)
Blood-Stage Malaria Vaccine: The malaria vaccine FMP2.1/AS02A, a recombinant protein based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, was not effective for preventing clinical malaria in 400 Malian children, researchers report, but it might have provided strain-specific efficacy (pp. 1004–13). Using a primary end point of clinical malaria (fever and at least 2,500 parasites/cu mm of blood) and a secondary end point of clinical malaria caused by parasites with the apical membrane antigen 1 (AMA1) DNA sequence found in the vaccine strain, the investigators found the following in the 6-month trial: “The cumulative incidence of the primary end point was 48.4% in the malaria-vaccine group and 54.4% in the control group; efficacy against the primary end point was 17.4% (hazard ratio for the primary end point, 0.83; 95% confidence interval [CI], 0.63 to 1.09; P = 0.18). Efficacy against the first and subsequent episodes of clinical malaria, as defined on the basis of various parasite-density thresholds, was approximately 20%. Efficacy against clinical malaria caused by parasites with AMA1 corresponding to that of the vaccine strain was 64.3% (hazard ratio, 0.36; 95% CI, 0.08 to 0.86; P = 0.03). Local reactions and fever after vaccination were more frequent with the malaria vaccine.” (C. V. Plowe, cplowe@medicine.umaryland.edu)
Telaprevir for Hepatitis C: A 24-week regimen of peginterferon–ribavirin with 12 weeks of telaprevir was noninferior to the same regimen for 48 weeks in patients who had undetectable viral levels at weeks 4 and 12, a 352-patient study shows (pp. 1014–24; K. E. Sherman, shermake@ucmail.uc.edu).

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

PNN Pharmacotherapy Line
Sept. 16, 2011 * Vol. 18, No. 180
Providing news and information about medications and their proper use

>>>Nephrology Highlights
Source:
Sept. issue of the American Journal of Kidney Diseases (2011; 58).
Vitamin D in CKD: Low serum levels of 25-hydroxyvitamin D (25[OH]D) are an independent risk factor for mortality in patients with chronic kidney disease, according to a systematic review and meta-analysis (pp. 374–82). Whether vitamin D supplementation can improve survival is unproven, the group adds: “10 studies with an overall sample of 6,853 patients with CKD were included. Relative risk of mortality per 10-ng/mL (25-nmol/L) increase in 25(OH)D level was 0.86 (95% CI, 0.82–0.91), with no indication of publication bias or significant heterogeneity (I2 = 15%; P = 0.3). Summary estimates for CKD cohorts with and without dialysis treatment showed homogeneous results (P = 0.9).” (S. Gandini, sara.gandini@ieo.it)
Obesity, Metabolic Syndrome, Lower Economic Status, & CKD: Data from the Whitehall II cohort in the U.K. show that two potentially modifiable factors—obesity and metabolic syndrome—account for up to a quarter of the association between lower socioeconomic status and decreased glomerular filtration rates (pp. 389–97). Among a group of 5,533 U.K-based Europeans (73% men), these relationships were identified in a cross-sectional analysis: “Participants in a lower compared with higher occupational grade were at increased odds of having decreased GFR (age- and sex-adjusted OR, 1.31; 95% CI, 1.12–1.53; P = 0.001). Socioeconomic disparity in [lean mass index (LMI)] was evident in women, but not men. After further adjustment for BMI and components of metabolic syndrome, the odds of decreased GFR in whites with a lower compared with higher occupational grade was attenuated by 23.3% (OR, 1.23; 95% CI, 1.06–1.45; P = 0.008). Adjustment for LMI explained 15% of the association between [socioeconomic status] and estimated GFR.” (T. M. Al-Qaoud, dr.talqaoud@gmail.com)

>>>Oncology Report
Source:
Sept. 10 issue of the Journal of Clinical Oncology (2011; 29).
Androgen Deprivation Therapy & Cardiovascular Risk: Among 7,248 men in the CaPSURE registry, no unique association could be identified between androgen deprivation therapy (ADT) and elevated risk of cardiovascular mortality (CVM) (pp. 3510–6). Men with prostate cancer were treated with local only therapy, primary ADT monotherapy, local treatment plus ADT, and watchful waiting/active surveillance (WW/AS), with these effects on prostate cancer–specific mortality (PCSM), CVM, and all-cause mortality: “Patients treated with ADT or WW/AS had a higher likelihood of PCSM than those treated with local therapy alone. Patients treated with primary ADT had an almost two-fold greater likelihood of CVM (HR, 1.94; 95% CI, 1.29 to 2.97) than those treated with local therapy alone; however, patients treated with WW/AS had a greater than two-fold increased risk of CVM (HR, 2.46; 95% CI, 1.53 to 3.95). A propensity-matching algorithm in a subset of 1,391 patients was unable to find a significant difference in CVM between those who did or did not receive ADT.” (M. R. Cooperberg, mcooperberg@urology.ucsf.edu)
These retrospectively analyzed data do not resolve the controversy over ADT and CVM, but an editorialist writes that the study does “[open] up an important new avenue of research inquiry” (
pp. 3500–2): “Additional analyses using large administrative data sets (eg, SEER-Medicare) may confirm the authors’ findings, although these data sets lack detailed clinical information. Of course, doing [a randomized controlled trial (RCT)] to answer the question would be considered unethical as well as unfeasible for various reasons. We are left with calling on the investigators of current phase III RCTs of ADT to shed light on this important subject. In the interim, the issue remains vexing, and a careful risk–benefit discussion must be held with each patient considering ADT. It is also prudent to carefully evaluate each patient’s cardiovascular risk factors and optimize those that are modifiable (eg, hypercholesterolemia, smoking, hypertension), because the greatest killer of older men with non–high-risk prostate cancer remains cardiovascular disease.” (S. M. H. Alibhai, shabbir.alibhai@uhn.on.ca)

>>>PNN NewsWatch
* Ondansetron may increase the risk of developing prolongation of the QT interval and torsades de pointes, FDA warned yesterday.

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

PNN Pharmacotherapy Line
Sept. 19, 2011 * Vol. 18, No. 181
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 17 issue of Lancet (2011; 378).
Drug-Eluting v. Bare-Metal Stents in PCI: Drug-eluting stents are preferred over bare-metal versions in patients undergoing percutaneous coronary intervention for de novo saphenous vein graft lesions, according to results of ISAR-CABG (Is Drug-Eluting-Stenting Associated with Improved Results in Coronary Artery Bypass Grafts?) (pp. 1071–8). In a randomized superiority trial, patients received bare-metal or drug-eluting stents of three types: permanent-polymer paclitaxel-eluting stents, permanent-polymer sirolimus-eluting stents, or biodegradable-polymer sirolimus-eluting stents, with these effects on a primary endpoint of the combined incidence of death, myocardial infarction, and target lesion revascularization at 1 year: “610 patients were allocated to treatment groups (303 drug-eluting stent, 307 bare-metal stent). Drug-eluting stents reduced the incidence of the primary endpoint compared with bare-metal stents (44 [15%] vs 66 [22%] patients; hazard ratio [HR] 0.64, 95% CI 0.44–0.94; p = 0.02). Target lesion revascularisation rate was reduced by drug-eluting stents (19 [7%] vs 37 [13%] patients; HR 0.49, 95% CI 0.28–0.86; p = 0.01). No significant differences were seen between drug-eluting stents and bare-metal stents regarding all-cause mortality (15 [5%] vs 14 [5%] patients; HR 1.08, 95% CI 0.52–2.24; p = 0.83), myocardial infarction (12 [4%] vs 18 [6%]; HR 0.66, 95% CI 0.32–1.37; p = 0.27), or definite or probable stent thrombosis (2 [1%] in both groups; HR 1.00, 95% CI 0.14–7.10; p = 0.99).” (J. Mehilli, mehilli@dhm.mhn.de)
Carboplatin/Paclitaxel Doublet Chemotherapy in Lung Cancer: In older patients with advanced non-small-cell lung cancer, carboplatin and weekly paclitaxel doublet chemotherapy produced greater survival benefits than did vinorelbine or gemcitabine monotherapy, Intergroupe Francophone de Cancérologie Thoracique (IFCT) investigators report about their study 0501 (pp. 1079–88). The open-label trial also found greater toxicity with doublet chemotherapy. Patients aged 70–89 years with locally advanced or metastatic NSCLC received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy, with these effects on overall survival: “451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30.3 months (range 8.6–45.2). Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (hazard ratio 0.64, 95% CI 0.52–0.78; p < 0.0001); 1-year survival was 44.5% (95% CI 37.9–50.9) and 25.4% (19.9–31.3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48.4%] vs 28 [12.4%]; asthenia 23 [10.3%] vs 13 [5.8%]).” (E. Quoix, elisabeth.quoix@chru-strasbourg.fr)

>>>PNN NewsWatch
* Several oral contraceptive products have been recalled by the generic manufacturer Qualitest Pharmaceuticals, a division of Endo, because of potential packaging errors. Specific lots of Cyclafem 7/7/7, Cyclafem 1/35, Emoquette, Gildess FE 1.5/30 and 1/20, Orsythia, Previfem, and Tri-Previfem may contain blister packs that are turned 180 degrees, thereby reversing the intended weekly orientation of tablets and hiding the expiration date of the product.

>>>PNN JournalWatch
* Toxicology in the ICU. Part 1: General Overview and Approach to Treatment, in Chest, 2011; 140: 795–806. (M. Levine, michael.levine@bannerhealth.com)
* Statins and Brain Dysfunction: A Hypothesis to Reduce the Burden of Cognitive Impairment in Patients Who Are Critically Ill, in
Chest, 2011; 140: 580–5. (A. Morandi, morandi.alessandro@gmail.com)
* Can We Improve Adherence to Preventive Therapies for Cardiovascular Health?, in
Circulation, 2011; 124: 1276–82. (J. K. Ockene, Judith.ockene@umassmed.edu)
* Infections in Patients with Hematologic Neoplasms and Hematopoietic Stem Cell Transplantation: Neutropenia, Humoral, and Splenic Defects, in
Clinical Infectious Diseases, 2011; 53: 798–806. (A. Safdar, amar.safdar@nyumc.org)
* Androgen Receptor Rediscovered: The New Biology and Targeting the Androgen Receptor Therapeutically, in
Journal of Clinical Oncology, 2011; 29: 3651–8. (C. J. Ryan, ryanc@medicine.ucsf.edu)

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

PNN Pharmacotherapy Line
Sept. 20, 2011 * Vol. 18, No. 182
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Sept. 20 issue of the Annals of Internal Medicine (2011; 155).
Management of Transient Loss of Consciousness: The guidelines of the U.K. National Institute for Health and Clinical Excellence (NICE) for management of transient loss of consciousness (TLoC) is presented (early release): “The panel made clear recommendations regarding the assessment of a person after TLoC, which emphasized the importance of clinical reasoning in diagnosis. Persons with uncomplicated faint, situational syncope, or orthostatic hypotension should receive electrocardiography but do not otherwise require immediate further investigation or specialist referral. Persons with features that suggest epilepsy should be referred for specialist neurologic assessment; brief seizure activity was recognized as a common occurrence during syncope that should not be regarded as indicating epilepsy. Persons with a suspected cardiac cause for TLoC or in whom TLoC is unexplained after initial assessment should receive specialist cardiovascular assessment. Guidance was provided on the appropriate choices of cardiovascular investigation, according to the presenting clinical circumstances.” (P. N. Cooper, paul.cooper@manchester.ac.uk)
Hepatitis C Virus Therapy Adherence & Outcomes: Higher levels of adherence to interferon and ribavirin therapy increase early and sustained hepatitis C virus (HCV) virologic responses, according to a study conducted among 5,706 patients with HCV genotypes 1, 2, 3, and 4 (pp. 353–60). A retrospective cohort analysis of data in the National Veterans Affairs Hepatitis C Clinical Case Registry showed these results for patients with HCV infection who received at least one prescription for both pegylated interferon and ribavirin between 2003 and 2006: “Early virologic response increased with higher levels of adherence to ribavirin therapy over the initial 12 weeks (patients with HCV genotype 1 or 4, 25 of 68 [37%] with ≤40% adherence vs. 1,367 of 2,187 [63%] with 91% to 100% adherence [P < 0.001]; patients with HCV genotype 2 or 3, 12 of 18 [67%] with ≤40% adherence vs. 651 of 713 [91%] with 91% to 100% adherence [P < 0.001]). Among patients with HCV genotype 1 or 4, sustained response increased with higher adherence to ribavirin therapy over the second, third, and fourth 12-week intervals. Results were similar for adherence to interferon therapy. Mean adherence to therapy with interferon and ribavirin decreased by 3.4 and 6.6 percentage points per 12-week interval, respectively (P for trend < 0.001 for each drug). Patients who received growth factors or thyroid medications during treatment had higher mean adherence to antiviral therapy.” (V. Lo Re III, vincentl@mail.med.upenn.edu)
Using Real-Time Biosurveillance To Improve Streptococcal Diagnoses: In 82,062 visits to Minute Clinics in the U.S., use of data on the recent local proportion positive (RLPP) improved diagnosis of group A streptococcal (GAS) pharyngitis in patients aged 15 years or older, researchers report (pp. 345–52). When incidence of GAS had been high in the past 14 days, clinicians were more aggressive in their interpretation of the 5-factor Centor scores, and they backed off when recent cases were few, as noted here: “Increased RLPP correlated with the likelihood of GAS pharyngitis (r2 = 0.79; P < 0.001). Local incidence data enhanced diagnostic models. For example, when the RLPP was greater than 0.30, managing patients with Centor scores of 1 as if the scores were 2 would identify 62,537 previously missed patients annually while misclassifying 18,446 patients without GAS pharyngitis. Decreasing the score of patients with Centor values of 3 by 1 point for an RLPP less than 0.20 would spare unnecessary antibiotics for 166,616 patients while missing 18,812 true-positive cases.” (A. M. Fine)
Cost-Conscious Care by Physicians: The need to practice medicine “in a cost-conscious fashion” has become so great that this should be added as a seventh core competency of physicians, writes an author with the American College of Physicians (pp. 386–8): “To assure that training programs, faculty, and residents pay sufficient attention to the need for cost control, I propose that the cost-awareness component of systems-based practice be … elevated to the level of a new, seventh general competency…, perhaps designated ‘cost-conscious care and stewardship of resources.’” (S. E. Weinberger, sweinberger@acponline.org)

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

PNN Pharmacotherapy Line
Sept. 21, 2011 * Vol. 18, No. 183
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 21 issue of JAMA (2011; 306).
Erectile Function After Prostate Cancer Treatment: About one-half of men with pretreatment functional erections are affected by therapies for prostate cancer, according to data from the community-based Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) (pp. 1205–14). Medications and other devices for erectile dysfunction are commonly used in these patients, says the study, which provides these details about men at greatest risk of erectile problems and declines in the sexual function domain of health-related quality of life (HRQOL): “Two years after prostate cancer treatment, 368 (37% [95% CI, 34%–40%]) of all patients and 335 (48% [95% CI, 45%–52%]) of those with functional erections prior to treatment reported functional erections; 531 (53% [95% CI, 50%–56%]) of patients without penile prostheses reported use of medications or other devices for erectile dysfunction. Pretreatment sexual HRQOL score, age, serum prostate-specific antigen level, race/ethnicity, body mass index, and intended treatment details were associated with functional erections 2 years after treatment. Multivariable logistic regression models predicting erectile function estimated 2-year function probabilities from as low as 10% or less to as high as 70% or greater depending on the individual’s pretreatment patient characteristics and treatment details. The models performed well in predicting erections in external validation among CaPSURE cohort patients (areas under the receiver operating characteristic curve, 0.77 [95% CI, 0.74–0.80] for prostatectomy; 0.87 [95% CI, 0.80–0.94] for external radiotherapy; and 0.90 [95% CI, 0.85–0.95] for brachytherapy).” (M. G. Sanda, msanda@bidmc.harvard.edu)
An editorialist discusses this study in light of the new Patient-Centered Outcomes Research Institute, which has proposed a working definition of such studies (
pp. 1258–9): “The promise of patient-centered outcomes research will be realized not only when high-quality outcomes data are available for all common medical problems but also when patients are routinely informed and invited to participate in their health care decisions. To achieve this promise, patients must increasingly be encouraged to adopt the position of ‘no decision about me, without me.’” (M. J. Barry, mbarry@partners.org)
High Residual Platelet Reactivity After Clopidogrel Loading: After percutaneous coronary intervention with use of clopidogrel, patients who have high residual platelet reactivity (HRPR) are at significantly greater risk of ischemic events both in the short and long term, researchers report (pp. 1215–23). Among 1,789 consecutive patients with acute coronary syndromes (ACS) in 2005–09, treatment with aspirin 325 mg (both initially and for maintenance) and clopidogrel 600 mg (loading dose) followed by 75 mg/d for at least 6 months showed these effects on a primary end point of cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow-up: “The primary end point event rate was 14.6% (36/247) in patients with HRPR and 8.7% (132/1,525) in patients with low residual platelet reactivity (absolute risk increase, 5.9%; 95% CI, 1.6%–11.1%; P = .003). Stent thrombosis was higher in the HRPR group compared with the low residual platelet reactivity group (6.1% [15/247] vs 2.9% [44/1,525]; absolute risk increase, 3.2%; 95% CI, 0.4%–6.7%; P = .01). By multivariable analysis, HRPR was independently associated with the primary end point (hazard ratio, 1.49; 95% CI, 1.08–2.05; P = .02) and with cardiac mortality (hazard ratio, 1.81; 95% CI, 1.18–2.76; P = .006).” (D. Antoniucci, david.antoniucci@virgilio.it)
Cognitive Behavioral Therapy in Pediatric OCD: Added to medication management of 124 pediatric outpatients with obsessive-compulsive disorder (OCD), cognitive behavioral therapy (CBT) was significantly better than instructions in CBT, a study shows (pp. 1224–32): “The number needed-to-treat analysis with the plus CBT vs medication management only in order to see 1 additional patient at week 12, on average, was estimated as 3; for the plus CBT vs the plus instructions in CBT strategy, the number needed to treat was also estimated as 3; for the plus instructions in CBT vs medication management only the number needed to treat was estimated as 25.” (M. E. Franklin, marty@mail.med.upenn.edu)

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

PNN Pharmacotherapy Line
Sept. 22, 2011 * Vol. 18, No. 184
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 22 New England Journal of Medicine (2011; 365).
Tyrosine Kinase Inhibition in Idiopathic Pulmonary Fibrosis: In 432 patients with idiopathic pulmonary fibrosis, the highest tested dose of a tyrosine kinase inhibitor, BIBF 1120, “was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life,” compared with placebo, researchers report (pp. 1079–87). Participants in the Phase II trial received one of four oral doses of BIB 1120 or placebo, and investigators gauged responses using a primary end point of annual rate of decline in forced vital capacity (FVC): “In the group receiving 150 mg of BIBF 1120 twice a day, FVC declined by 0.06 liters per year, as compared with 0.19 liters per year in the placebo group, a 68.4% reduction in the rate of loss with BIBF 1120 (P = 0.06 with the closed testing procedure for multiplicity correction; P = 0.01 with the hierarchical testing procedure). This dose also resulted in a lower incidence of acute exacerbations, as compared with placebo (2.4 vs. 15.7 per 100 patient–years, P = 0.02) and a small decrease in the [St. George’s Respiratory Questionnaire] score (assessed on a scale of 0 to 100, with lower scores indicating better quality of life) as compared with an increase with placebo (−0.66 vs. 5.46, P = 0.007). Gastrointestinal symptoms (which led to more discontinuations in the group receiving 150 mg twice a day than in the placebo group) and increases in levels of liver aminotransferases were more frequent in the group receiving 150 mg of BIBF 1120 twice daily than in the placebo group.” (L. Richeldi, luca.richeldi@unimore.it)
Rotavirus Vaccine & Diarrhea in U.S. Children: Since U.S. clinicians began vaccinating infants using pentavalent rotavirus vaccine (RV5) in 2006, “diarrhea-associated health care utilization and medical expenditures for U.S. children have decreased substantially,” a CDC study shows (pp. 1108–17). MarketScan databases were used to assess RV5 coverage and diarrhea-associated health care use in 2007–09 versus 2001–06 in children under 5 years of age, with these results: “By December 31, 2008, at least one dose of RV5 had been administered in 73% of children under 1 year of age, 64% of children 1 year of age, and 8% of children 2 to 4 years of age. Among children under 5 years of age, rates of hospitalization for diarrhea in 2001–2006, 2007–2008, and 2008–2009 were 52, 35, and 39 cases per 10,000 person–years, respectively, for relative reductions from 2001–2006 by 33% (95% confidence interval [CI], 31 to 35) in 2007–2008 and by 25% (95% CI, 23 to 27) in 2008–2009; rates of hospitalization specifically coded for rotavirus infection were 14, 4, and 6 cases per 10,000 person–years, respectively, for relative reductions in the rate from 2001–2006 by 75% (95% CI, 72 to 77) in 2007–2008 and by 60% (95% CI, 58 to 63) in 2008–2009. In the January–June periods of 2008 and 2009, the respective relative rate reductions among vaccinated children as compared with unvaccinated children were as follows: hospitalization for diarrhea, 44% (95% CI, 33 to 53) and 58% (95% CI, 52 to 64); rotavirus-coded hospitalization, 89% (95% CI, 79 to 94) and 89% (95% CI, 84 to 93); emergency department visits for diarrhea, 37% (95% CI, 31 to 43) and 48% (95% CI, 44 to 51); and outpatient visits for diarrhea, 9% (95% CI, 6 to 11) and 12% (95% CI, 10 to 15). Indirect benefits (in unvaccinated children) were seen in 2007–2008 but not in 2008–2009. Nationally, for the 2007–2009 period, there was an estimated reduction of 64,855 hospitalizations, saving approximately $278 million in treatment costs.” (U. D. Parashar, uparashar@cdc.gov)
Using Asthma Phenotypes for Personalized Medicine: Reflecting on a previously released article on the interleukin-13 inhibitor lebrikizumab that is printed in this issue (see PNN, Aug. 4; pp. 1088–98; J. G. Matthews, matthews.john@gene.com), an editorialist imagines a time when personalized medicine is the standard of care for asthma (pp. 1141–4): “As we look toward the goal of treating patients with this heterogeneous disease in a more personalized fashion, it is refreshing to see a trial in which there is acknowledgement that not all patients will respond similarly to an intervention. Although larger studies are needed to verify this observation, future trials should strive to include stratification of patients according to the expected phenotype to help us personalize the response to asthma treatment.” (M. Kraft)

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

PNN Pharmacotherapy Line
Sept. 23, 2011 * Vol. 18, No. 185
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Sept. issue of the Journal of the American Geriatrics Society (2011; 59).
Psychoactive Drugs & Crashes in Older Drivers: Motor vehicle crashes requiring hospitalization occur more frequently among older drivers who are taking psychoactive medications, a study shows (pp. 1575–80). In a retrospective population-based case-crossover study that linked the Western Australian Hospital Morbidity Data System and the Pharmaceutical Benefits Scheme databases, these risks were found based on 616 individuals aged 60 years or older who were hospitalized after crashes in 2002–08: “Greater risk for a hospitalization crash was found for older drivers prescribed benzodiazepines (odds ratio (OR) = 5.3, 95% confidence interval (CI) = 3.6–7.8, P < .001), antidepressants (OR = 1.8, 95% CI = 1.0–3.3, P = .04), and opioid analgesics (OR = 1.5, 95% CI = 1.0–2.3, P = .05). Crash risk was significantly greater in men prescribed a benzodiazepine (OR = 6.2, 95% CI = 3.2–12.2, P < .001) or an antidepressant (OR = 2.7, 95% CI = 1.1–6.9, P = .03). Women prescribed benzodiazepines (OR = 4.9, 95% CI = 3.1–7.8, P < .001) or opioid analgesics (OR = 1.8, 95% CI = 1.1–3.0, P = .03) also had a significantly greater crash risk. Subgroup analyses further suggested that drivers with (OR = 4.0, 95% CI = 2.9–8.1, P < .001) and without (OR = 6.0, 95% CI = 3.8–9.5, P < .001) a chronic condition who were prescribed benzodiazepines were at greater crash risk. Drivers with a chronic condition taking antidepressants (OR = 3.4, 95% CI = 1.3–8.5, P = .01) also had a greater crash risk.” (L. Meuleners, L.Meuleners@curtin.edu.au)
Patient Age & Cost-Effectiveness of Oral Bisphosphonates: Across five decades of life, 5 years’ treatment with oral bisphosphonates for osteoporosis prevention is cost-effective in women, researchers report (pp. 1642–9). Concluding that “advanced age should not prevent consideration of osteoporosis treatment based on cost effectiveness,” the investigators conducted simulations of hypothetical cohorts with starting ages ranging from 50 to 90. Women were divided into life expectancy quartiles (sickest, lowest quartile; average health, two middle quartiles; and healthiest group, highest quartile) and followed until age 100 or death. Results showed: “In the healthiest group, all costs were less than $18,000 per [quality-adjusted life year (QALY)]. In the median quartiles of life expectancy, lifetime costs per QALY were less than $27,000 for patients at all ages; treatment became cost-saving at a starting age of 75 and remained so through a starting age of 85. Even in the sickest group, although osteoporosis treatment was not cost-saving, it remained cost-effective through a starting age of 90 with lifetime costs of less than $43,000 per QALY.” (C. S. Colón-Emeric, colon001@mc.duke.edu)

>>>JAPhA Highlights
Source:
Sept/Oct issue of the Journal of the American Pharmacists Assoc. (2011; 51).
Medication Error Rates in Telepharmacies: In the North Dakota Telepharmacy Project, 14 community pharmacies using real-time audiovisual equipment to dispense medications at distant sites, or telepharmacies, had slightly higher but equivalent medication error rates as 8 comparison community pharmacies (pp. 580–90). Quality-related event (QREs) were “near misses” caught in the pharmacy and “errors” discovered after dispensing to patients, Results showed: “During a 45-month period, the remote telepharmacy group reported 47,078 prescriptions and 631 QREs compared with 123,346 prescriptions and 1,002 QREs in the standard pharmacy group. Results for near misses (pharmacy discovery) and errors (patient discovery) for the remote and comparison sites were 553 and 887 and 78 and 125, respectively. Percentage of ‘where the mistake was caught’ (i.e., pharmacist check) for the remote and comparison sites were 58% and 69%, respectively.” (D Friesner, daniel.friesner@ndsu.edu)

>>>PNN NewsWatch
* Primatene Mist will be off the market after Dec. 31, and FDA is warning patients still using the OTC epinephrine inhalers that they need to seek medical care to obtain prescription alternatives now. The product is being removed because the manufacturer has not reformulated the propellant to remove ozone-depleting chlorofluorocarbons, FDA said, and all currently available therapeutic alternatives require a prescription.

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

PNN Pharmacotherapy Line
Sept. 26, 2011 * Vol. 18, No. 186
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 24 issue of Lancet (2011; 378).
IgG Immunoadsorption in E. coli Uremic Syndrome: Implemented in 12 patients as rescue therapy during the May 2011 outbreak of Shiga toxin-producing enterohemorrhagic Escherichia coli O104:H4 in northern Germany, immunoglobulin G immunoadsorption can “safely be used to rapidly ameliorate … severe neurological complications,” researchers report (pp. 1166–73). The authors note these results in a prospective noncontrolled trial of IgG immunoadsorption processing of 12 L plasma volumes on 2 consecutive days followed by replacement with intravenous IgG 0.5 g/kg: “We enrolled 12 patients who initially presented with enteritis and subsequent renal failure; 10 (83%) of 12 patients needed renal replacement therapy by a median of 8.0 days (range 5–12). Neurological complications (delirium, stimulus sensitive myoclonus, aphasia, and epileptic seizures in 50% of patients) occurred at a median of 8.0 days (range 5–15) and mandated mechanical ventilation in nine patients. Composite neurological symptom scores increased in the 3 days before immunoadsorption to 3.0 (SD 1.1, p = 0.038), and improved to 1.0 (1.2, p = 0.0006) 3 days after immunoadsorption. In non-intubated patients, improvement was apparent during immunoadsorption (eg, disappearance of aphasia). Five patients who were intubated were weaned within 48 h, two within 4 days, and two patients needed continued ventilation for respiratory problems. All 12 patients survived and ten had complete neurological and renal function recovery.” (A. Greinacher, greinach@uni-greifswald.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2011; 343).
Multimodal System for Preventing Medication Errors: Implemented for anesthetic drugs in the operating suite, a patented multimodal system, SAFERSleep, reduced medication errors, particularly those during the recording process (d5543). The system uses customized drug trays to promote a well-organized workspace and aseptic technique, the investigators report, along with prefilled syringes, large color-coded labels, a barcode reader, touch screen with auditory and visual verification, automatic compilation of an anesthetic record, on-screen and audible warnings if antibiotics are not administered, and procedural rules. Results showed: “The overall mean rate of drug errors per 100 administrations was 9.1 (95% confidence interval 6.9 to 11.4) with the new system (one in 11 administrations) and 11.6 (9.3 to 13.9) with conventional methods (one in nine administrations) (P = 0.045 for difference). Most were recording errors, and, though fewer drug administration errors occurred with the new system, the comparison with conventional methods did not reach significance. Rates of errors in drug administration were lower when anaesthetists consistently applied two key principles of the new system (scanning the drug barcode before administering each drug and keeping the voice prompt active) than when they did not: mean 6.0 (3.1 to 8.8) errors per 100 administrations v 9.7 (8.4 to 11.1) respectively (P = 0.004). Lapses in the vigilance latency task occurred in 12% (58/471) of cases with the new system and 9% (40/473) with conventional methods (P = 0.052). The records generated by the new system were more legible, and anaesthetists preferred the new system, particularly in relation to long, complex, and emergency cases. There were no differences between new and conventional systems in respect of outcomes in patients or anaesthetists’ workload.” (A. F. Merry, a.merry@auckland.ac.nz)

>>>PNN JournalWatch
* Reduced Risk of Colorectal Cancer with Metformin Therapy in Patients with Type 2 Diabetes: A Meta-analysis, in Diabetes Care, 2011; 34: 2323–8. (Z-J Zhang, zhang.zj@msn.com)
* Potential Safety Gaps in Order Entry and Automated Drug Alerts: A Nationwide Survey of VA Physician Self-Reported Practices with Computerized Order Entry, in
Medical Care, 2011; 49: 904–10. (J. R. Spina)
* Integrated Telehealth and Care Management Program for Medicare Beneficiaries with Chronic Disease Linked to Savings, in
Health Affairs, 2011; 30: 1689–97. (L. C. Baker, laurence.baker@stanford.edu)
* Early Lessons from Accountable Care Models in the Private Sector: Partnerships Between Health Plans and Providers, in
Health Affairs, 2011; 30: 1718–27. (A. Higgins, ahiggins@ahip.org)

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

PNN Pharmacotherapy Line
Sept. 27, 2011 * Vol. 18, No. 187
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 26 issue of the Archives of Internal Medicine (2011; 171).
HAART Initiation & Outcomes: Starting highly active antiretroviral therapy (HAART) at CD4 cell counts of less than 500/µL resulted in slower disease progression than when the drugs were initiated at cell counts of 500–799/µL, a study shows (pp. 1560–9). In an observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), investigators looked at a primary outcome of time to AIDS or death with HAART initiated in the baseline month compared with those who did not. Stratified analysis yielded these patterns: “Of 9,455 patients with 52,268 person–years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/µL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43–0.81), 0.75 (0.49–1.14), and 1.10 (0.67–1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44–1.15), 0.51 (0.33–0.80), and 1.02 (0.49–2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14–38) and 34 (20–115) in CD4 cell count strata of 200 to 349 and 350 to 499/µL, respectively.” (M. Jonsson Funk, mfunk@unc.edu)
“Because the incidence of AIDS and death among patients with CD4 cell counts of 350 to 499 /µL was low, it is not surprising that the absolute reduction in incidence during 3 years was correspondingly low (–2.9%)” in this study, writes the author of an invited commentary (
pp. 1569–70). “Jonsson Funk et al caution that given the modest benefit of HAART in this stratum, the risks and benefits of HAART during an extended period must be weighed for each patient. While this advice is certainly sound, it is important to note that although the authors examined the influence of HAART on all-cause mortality, they were unable to study directly the effects of HAART on non-AIDS-defining events, such as cardiovascular disease, neurological disease, and other end-organ complications of HIV-1 infection. These complications may cause significant morbidity without contributing to mortality over the relatively short time frame considered herein.” (D. R. Kuritzkes, dkuritzkes@partners.org)
Caffeine & Depression in Women: Depression risk dropped as women consumed more caffeinated coffee in longitudinal study of 50,739 women in the U.S. (pp. 1571–8). Questionnaires, which included self-reported physician-diagnosed depression, completed from 1980 to 2004 showed the following: “During 10 years of follow-up (1996–2006), 2,607 incident cases of depression were identified. Compared with women consuming 1 or less cup of caffeinated coffee per week, the multivariate relative risk of depression was 0.85 (95% confidence interval, 0.75–0.95) for those consuming 2 to 3 cups per day and 0.80 (0.64–0.99; P for trend <.001) for those consuming 4 cups per day or more. Multivariate relative risk of depression was 0.80 (95% confidence interval, 0.68–0.95; P for trend = .02) for women in the highest (550 mg/d) vs lowest (<100 mg/d) of the 5 caffeine consumption categories. Decaffeinated coffee was not associated with depression risk.” (A. Ascherio, aascheri@hsph.harvard.edu)
Despite these and other available data, it’s still too early to recommend that women drink coffee, a commentator writes (
p. 1578): “ This study makes an important contribution because it is, to my knowledge, the first large-scale study of coffee consumption to evaluate a mental health outcome in women. Previous work has focused mainly on the effects of caffeine on cardiovascular disease (generally finding no overall effect on cardiovascular disease incidence or mortality), inflammation (generally showing modest decreases in markers of systemic inflammation), and particular types of malignant neoplasms, including breast cancer and esophageal cancer (generally showing no or modest protective effects). Taken together, these results reassure coffee drinkers that there seem to exist no glaringly deleterious health consequences to coffee consumption. As health care professionals, however, it seems premature to recommend coffee consumption until studies with methodologies better able to determine causality are conducted.” (S. A. Berkowitz)

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

PNN Pharmacotherapy Line
Sept. 28, 2011 * Vol. 18, No. 188
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 28 issue of JAMA (2011; 306).
Saw Palmetto for BPH Symptoms: In a dose-ranging study of the widely used supplement saw palmetto, the herbal product was no more effective than placebo, even with daily servings increased by 3-fold (pp. 1344–51). At 11 North American sites, 369 men aged 45 years or older participated in the double-blind, randomized, controlled trial. All had peak urinary flow rates of at least 4 mL/s and American Urological Association Symptom Index (AUASI) scores of 8–24 at two screening visits. To simulate the use of dietary supplements without a formal diagnosis by health professionals, the researchers did not require that participants have confirmed benign prostatic hyperplasia, but they did exclude those who had used alpha-blockers in the past month or 5-alpha reductase inhibitors within the past 3 months. Results showed: “Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (−2.20 points; 95% CI, −3.04 to −0.36) with saw palmetto extract and from 14.69 to 11.70 points (−2.99 points; 95% CI, −3.81 to −2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified.”
The investigators concluded, “Do our findings apply to other saw palmetto extract preparations? We studied only 1 extract and because the potential active ingredients and mechanisms are unknown, our findings may not be generalizable. Nevertheless, a recent series of negative trials using different saw palmetto extract preparations makes it increasingly unlikely a dose of some preparation will be identified that is better than placebo.” (M. J. Barry,
mbarry@partners.org)
Off-Label Uses of Second-Generation Antipsychotics: Used for indications not approved by FDA, atypical antipsychotic drugs produce minimal benefits in patients with dementia, anxiety disorder, or obsessive-compulsive disorder, according to authors of a systematic review (pp. 1359–69). “For global behavioral symptom scores associated with dementia in elderly patients, small but statistically significant benefits were observed for aripiprazole, olanzapine, and risperidone,” the article notes. “Quetiapine was associated with benefits in the treatment of generalized anxiety disorder, and risperidone was associated with benefits in the treatment of obsessive-compulsive disorder; however, adverse events were common.”
The group adds these details of their literature review: “Of 12,228 citations identified, 162 contributed data to the efficacy review. Among 14 placebo-controlled trials of elderly patients with dementia reporting a total global outcome score that includes symptoms such as psychosis, mood alterations, and aggression, small but statistically significant effects sizes ranging from 0.12 and 0.20 were observed for aripiprazole, olanzapine, and risperidone. For generalized anxiety disorder, a pooled analysis of 3 trials showed that quetiapine was associated with a 26% greater likelihood of a favorable response (defined as at least 50% improvement on the Hamilton Anxiety Scale) compared with placebo. For obsessive-compulsive disorder, risperidone was associated with a 3.9-fold greater likelihood of a favorable response (defined as a 25% improvement on the Yale-Brown Obsessive Compulsive Scale) compared with placebo. In elderly patients, adverse events included an increased risk of death (number needed to harm [NNH] = 87), stroke (NNH = 53 for risperidone), extrapyramidal symptoms (NNH = 10 for olanzapine; NNH = 20 for risperidone), and urinary tract symptoms (NNH range = 16–36). In nonelderly adults, adverse events included weight gain (particularly with olanzapine), fatigue, sedation, akathisia (for aripiprazole), and extrapyramidal symptoms.” (A. Ruelaz Maher,
Alicia.Ruelaz@cshs.org)

>>>PNN NewsWatch
* FDA is continuing its review of the risks of blood clots in women taking drospirenone-containing oral contraceptives. Two advisory panels will take up the controversy at a Dec. 8 meeting.

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

PNN Pharmacotherapy Line
Sept. 29, 2011 * Vol. 18, No. 189
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and Sept. 29 issue of the New England Journal of Medicine (2011; 365).
Zoledronic Acid in Breast Cancer: In an open-label, Phase III trial of 3,360 patients with early-stage breast cancer, zoledronic acid had no effect on disease-free survival (10.1056/NEJMoa1105195). Past research showed that bisphosphonates reduce recurrence and death in such patients, but 5 years of zoledronic acid therapy provided minimal support for this use: “At a median follow-up of 59 months, there was no significant between-group difference in the primary end point, with a rate of disease-free survival of 77% in each group (adjusted hazard ratio in the zoledronic acid group, 0.98; 95% confidence interval [CI], 0.85 to 1.13; P = 0.79). Disease recurrence or death occurred in 377 patients in the zoledronic acid group and 375 of those in the control group. The numbers of deaths—243 in the zoledronic acid group and 276 in the control group—were also similar, resulting in rates of overall survival of 85.4% in the zoledronic acid group and 83.1% in the control group (adjusted hazard ratio, 0.85; 95% CI, 0.72 to 1.01; P = 0.07). In the zoledronic acid group, there were 17 confirmed cases of osteonecrosis of the jaw (cumulative incidence, 1.1%; 95% CI, 0.6 to 1.7; P < 0.001) and 9 suspected cases; there were no cases in the control group. Rates of other adverse effects were similar in the two study groups.” (R. E. Coleman, r.e.coleman@sheffield.ac.uk)
Genetic Basis of Steroid Response in Asthma: In patients with asthma, a functional variant of the glucocorticoid-induced transcript 1 gene (GLCCI1) significantly decreases response to inhaled glucocorticoids, researchers report (pp. 1173–83). Starting with 534,290 single-nucleotide polymorphisms (SNPs), the authors selected a few statistically powerful variants using a family-based screening algorithm and looked for changes in lung function in response to inhaled glucocorticoids: “We identified a significant pharmacogenetic association at SNP rs37972, replicated in four independent populations totaling 935 persons (P = 0.0007), which maps to … GLCCI1 and is in complete linkage disequilibrium (i.e., perfectly correlated) with rs37973. Both rs37972 and rs37973 are associated with decrements in GLCCI1 expression. In isolated cell systems, the rs37973 variant is associated with significantly decreased luciferase reporter activity. Pooled data from treatment trials indicate reduced lung function in response to inhaled glucocorticoids in subjects with the variant allele (P = 0.0007 for pooled data). Overall, the mean (± SE) increase in forced expiratory volume in 1 second in the treated subjects who were homozygous for the mutant rs37973 allele was only about one third of that seen in similarly treated subjects who were homozygous for the wild-type allele (3.2 ± 1.6% vs. 9.4 ± 1.1%), and their risk of a poor response was significantly higher (odds ratio, 2.36; 95% confidence interval, 1.27 to 4.41), with genotype accounting for about 6.6% of overall inhaled glucocorticoid response variability.” (K. G. Tantisira, rekgt@channing.harvard.edu)
Describing these and previous results as “a step toward personalized asthma treatment,” a
Journal editor provides this perspective (pp. 1245–6): “Although these research results are a step forward, they are not the end of the road. For example, an article in the September 22 issue of the Journal showed that patients with asthma who had a certain biochemical signature were more likely to respond to an anti–interleukin-13 monoclonal antibody than were those without such a signature. In each case, the next step must be to mount clinical trials in which patients are stratified according to their biologic signature to determine whether knowledge of this information leads to better clinical outcomes. If personalized medicine is going to become a reality, we need to design and execute these critical trials.” (J. M. Drazen)
Cytisine for Smoking Cessation: A high-affinity, partial alpha-4, beta-2 nicotinic acetylcholine agonist, cytisine sustained an 8.4% abstinence rate at 12 months in a clinical trial of 740 smokers, compared with 2.4% with placebo (pp. 1193–200). Gastrointestinal adverse effects were more common with the drug, which the investigators described as lower priced than other available agents for smoking cessation and therefore potentially more affordable for global cessation efforts. (R. West, robert.west@ucl.ac.uk)

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

PNN Pharmacotherapy Line
Sept. 30, 2011 * Vol. 18, No. 190
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (2011; 34).
Estimating Mealtime Insulin Doses in Type 1 Diabetes: An algorithm developed in healthy patients that relies on food insulin index (FII) may be useful for estimating mealtime insulin doses in patients with type 1 diabetes, researchers report (pp. 2146–51). In this study, 28 adults with type 1 diabetes being treated with insulin pump therapy consumed two different breakfast meals with differing carbohydrate content but otherwise the same energy, glycemic index, fiber, and calculated insulin demand (FII = 60). On three consecutive mornings, patients determined their insulin bolus dose using these methods: a carbohydrate-counting algorithm for the high-carbohydrate meal (A); carbohydrate counting for lower-carbohydrate meal B, which produced half the insulin dose; or the FII algorithm dose determined for meal A but applied to meal B. Results showed: “Compared with carbohydrate counting, the FII algorithm significantly decreased glucose incremental area under the curve over 3 h (–52%, P = 0.013) and peak glucose excursion (–41%, P = 0.01) and improved the percentage of time within the normal blood glucose range (4–10 mmol/L) (31%, P = 0.001). There was no significant difference in the occurrence of hypoglycemia.” (J.C. Brand-Miller, jennie.brandmiller@sydney.edu.au)
Lifestyle Interventions in Severe Obesity, Type 2 Diabetes: Behavioral weight loss programs are just as viable an option in those with BMIs of 40 or more as in less obese patients, according to research that showed similar patterns of adherence, percentage of weight loss, and improvement in cardiovascular disease risk (pp. 2152–7). In the Look AHEAD trial (Action for Health in Diabetes), participants were categorized by BMI (overweight, BMI of 25–30; class I, 30–35; class II, 35–40; severe obesity, 40 or more) and assigned to either intensive lifestyle intervention (ILI) or diabetes support and education, with these results: “At 1 year, severely obese participants in the ILI group lost −9.04 ± 7.6% of initial body weight, which was significantly greater (P < 0.05) than ILI participants who were overweight (−7.43 ± 5.6%) and comparable to class I (−8.72 ± 6.4%) and class II obese (−8.64 ± 7.4%) participants. All BMI groups had comparable improvements in fitness, [physical activity], LDL cholesterol, triglycerides, blood pressure, fasting glucose, and HbA1c at 1 year. ILI treatment session attendance was excellent and did not differ among weight categories (severe obese 80% vs. others 83%; P = 0.43).” (J. L. Unick, junick@lifespan.org)
Yoga for Oxidative Stress: In 123 patients with type 2 diabetes, addition to usual care of yoga for 3 months improved measures of oxidative stress, BMI, and glycemic control, a study shows (pp. 2208–10). Patients were stratified by presence of microvascular complications, macrovascular complications, and peripheral neuropathy, and results showed: “In comparison with standard care alone, yoga resulted in significant reduction in BMI, glycemic control, and malondialdehyde and increase in glutathione and vitamin C. There were no differences in waist circumference, waist-to-hip ratio, blood pressure, vitamin E, or superoxide dismutase in the yoga group at follow-up.” (S. V. Hegde, shreelaxmi.hegde@gmail.com)

>>>Pharmacotherapy Report
Source:
Oct. issue of Pharmacotherapy (2011; 31).
Adherence Maps After ACS Discharge: Using geographic information system (GIS) technology, maps were produced of areas of high and low adherence to prescribed statins, ACE inhibitors, H2 blockers, and aspirin in patients with acute coronary syndromes discharged from a university teaching hospital (pp. 927–33): “The analysis was performed at the census tract level by using the percentage of nonadherent patients within a census tract to represent adherence for the people living within that tract, standardized by the number of residents in a census tract aged 40 years or older. Hot Spot Analysis identified unique geographic areas of high, neutral, and low adherence in the southeast area. Highly adherent census tracts were primarily located in and around the city where the university hospital and clinics are located. Areas of low adherence were located to the west, southwest, and southeast of the city. All other census tracts were considered neutral in adherence rates.” (C. Hoang)

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