Sep 2013

PNN July–September 2013

PNN Pharmacotherapy Line
July 1, 2013 * Vol. 20, No. 126
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Lithium for Suicide Prevention: “Lithium is an effective treatment for reducing the risk of suicide in people with mood disorders,” concludes a systematic review and meta-analysis (f3646): “48 randomised controlled trials (6,674 participants, 15 comparisons) were included. Lithium was more effective than placebo in reducing the number of suicides (odds ratio 0.13, 95% confidence interval 0.03 to 0.66) and deaths from any cause (0.38, 0.15 to 0.95). No clear benefits were observed for lithium compared with placebo in preventing deliberate self harm (0.60, 0.27 to 1.32). In unipolar depression, lithium was associated with a reduced risk of suicide (0.36, 0.13 to 0.98) and also the number of total deaths (0.13, 0.02 to 0.76) compared with placebo. When lithium was compared with each active individual treatment a statistically significant difference was found only with carbamazepine for deliberate self harm. Lithium tended to be generally better than the other active comparators, with small statistical variation between the results.” (A. Cipriani, andrea.cipriani@psych.ox.ac.uk)
Fatty Acids & Breast Cancer Risk: People who consume greater amounts of dietary n-3 polyunsaturated fatty acids (n-3 PUFA) from fish have lower risks of breast cancer, a study shows, and the authors conclude that prospective cohort studies should examine fish and alpha-linoleic acid intake (f3706): “Twenty six publications, including 20,905 cases of breast cancer and 883,585 participants from 21 independent prospective cohort studies were eligible. Eleven articles (13,323 breast cancer events and 687,770 participants) investigated fish intake, 17 articles investigated marine n-3 PUFA (16,178 breast cancer events and 527,392 participants), and 12 articles investigated alpha linolenic acid (14,284 breast cancer events and 405,592 participants). Marine n-3 PUFA was associated with 14% reduction of risk of breast cancer (relative risk for highest v lowest category 0.86 (95% confidence interval 0.78 to 0.94), I2 = 54), and the relative risk remained similar whether marine n-3 PUFA was measured as dietary intake (0.85, 0.76 to 0.96, I2 = 67%) or as tissue biomarkers (0.86, 0.71 to 1.03, I2 = 8%). Subgroup analyses also indicated that the inverse association between marine n-3 PUFA and risk was more evident in studies that did not adjust for body mass index (BMI) (0.74, 0.64 to 0.86, I2 = 0) than in studies that did adjust for BMI (0.90, 0.80 to 1.01, I2 = 63.2%). Dose-response analysis indicated that risk of breast cancer was reduced by 5% per 0.1g/day (0.95, 0.90 to 1.00, I2 = 52%) or 0.1% energy/day (0.95, 0.90 to 1.00, I2 = 79%) increment of dietary marine n-3 PUFA intake. No significant association was observed for fish intake or exposure to alpha linolenic acid.” (D. Li, duoli@zju.edu.cn)

>>>Lancet Highlights
Source:
June 29 issue of Lancet (2013; 381).
Multidisciplinary Management of Depression in Nursing Homes: In a Dutch study, researchers find a multidisciplinary approach to management of depression that includes assessment procedures can reduce depression prevalence in somatic units of nursing homes (pp. 2255–64). In 403 residents of 16 dementia units and 390 residents of 17 somatic units, the Act in Case of Depression (AiD) multidisciplinary program produced these results in comparison with usual care: “In somatic units, AiD reduced prevalence of depression (adjusted effect size −7.3%, 95% CI −13.7 to −0.9). The effect was not significant in dementia units (0.6, −5.6 to 6.8) and differed significantly from that in somatic units (p = 0.031). Adherence to depression assessment procedures was lower in dementia units (69% [SD 19%]) than in somatic units (82% [15%]; p = 0.045). Adherence to treatment pathways did not differ between dementia units (43% [SD 33%]) and somatic units (38% [40%]; p = 0.745).” (R. Leontjevas, roeslan.leontjevas@ou.nl)

>>>PNN JournalWatch
* Pathways to Quality Inpatient Management of Hyperglycemia and Diabetes: A Call to Action, in
Diabetes Care, 2013; 36: 1807–14. (B. Draznin, boris.draznin@ucdenver.edu)
* Depression in Parkinson’s Disease: Identification and Management, in
Pharmacotherapy, DOI: 10.1002/phar.1314. (J. J. Chen, jjchen@llu.edu)
* Adverse Effects Associated With Second-Generation Antipsychotic Long-Acting Injection Treatment: A Comprehensive Systematic Review, in
Pharmacotherapy, DOI: 10.1002/phar.1313. (S. Gentile, salvatore_gentile@alice.it)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 2, 2013 * Vol. 20, No. 127
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 2 issue of the Annals of Internal Medicine (2013; 159).
Salsalate in Type 2 Diabetes: In a 1-year trial, use of salsalate improved glycemia in patients with type 2 diabetes mellitus (T2DM), confirming results of short-term studies, but mixed cardiorenal signals were detected in the 283-participant trial (pp. 1–12). At 21 U.S. private practices and academic centers, participants taking 48 weeks of salsalate 3.5 g/d or placebo had these outcomes: “The mean HbA1c level over 48 weeks was 0.37% lower in the salsalate group than in the placebo group (95% CI, −0.53% to −0.21%; P < 0.001). Glycemia improved despite more reductions in concomitant diabetes medications in salsalate recipients than in placebo recipients. Lower circulating leukocyte, neutrophil, and lymphocyte counts show the anti-inflammatory effects of salsalate. Adiponectin and hematocrit levels increased more and fasting glucose, uric acid, and triglyceride levels decreased with salsalate, but weight and low-density lipoprotein cholesterol levels also increased. Urinary albumin levels increased but reversed on discontinuation; estimated glomerular filtration rates were unchanged.” (S. E. Shoelson, steven.shoelson@joslin.harvard.edu)
Pressure Ulcer Management Strategies: Two articles detail results of systematic comparative effectiveness reviews of studies on prevention and treatment of pressure ulcers.
In patients at higher risk for development of pressure ulcers, “more advanced static support surfaces are more effective than standard mattresses,” according to a review of risk-assessment instruments and preventive interventions (
pp. 28–38): “One good-quality trial found no evidence that use of a pressure ulcer risk assessment instrument, with or without a protocolized intervention strategy based on assessed risk, reduces risk for incident pressure ulcers compared with less standardized risk assessment based on nurses’ clinical judgment. In higher-risk populations, 1 good-quality and 4 fair-quality randomized trials found that more advanced static support surfaces were associated with lower risk for pressure ulcers compared with standard mattresses (relative risk range, 0.20 to 0.60). Evidence on the effectiveness of low–air-loss and alternating-air mattresses was limited, with some trials showing no clear differences from advanced static support surfaces. Evidence on the effectiveness of nutritional supplementation, repositioning, and skin care interventions versus usual care was limited and had methodological shortcomings, precluding strong conclusions.” (R. Chou, chour@ohsu.edu)
Moderate-strength evidence supports use of air-fluidized beds, protein supplementation, radiant heat dressings, and electrical stimulation for healing of pressure ulcers, the second review concludes (
pp. 39–50): “174 studies met inclusion criteria and 92 evaluated complete wound healing. In comparison with standard care, placebo, or sham interventions, moderate-strength evidence showed that air-fluidized beds (5 studies [n = 908]; high consistency), protein-containing nutritional supplements (12 studies [n = 562]; high consistency), radiant heat dressings (4 studies [n = 160]; moderate consistency), and electrical stimulation (9 studies [n = 397]; moderate consistency) improved healing of pressure ulcers. Low-strength evidence showed that alternating-pressure surfaces, hydrocolloid dressings, platelet-derived growth factor, and light therapy improved healing of pressure ulcers. The evidence about harms was limited.” (M. E. B. Smith, smithbet@ohsu.edu)
Treatment of Tick-Exposed Patients for Borrelia miyamotoi Infection: Bloodstream infections of a newly recognized spirochete, Borrelia miyamotoi, should be considered in tick-exposed patients who are presumptively diagnosed with human granulocytic anaplasmosis (HGA) but who have a delayed response to doxycycline treatment or have negative tests for Anaplasma phagocytophilum infection, according to authors who describe two case reports (pp. 21–7). The patients, at medical centers in Massachusetts and New Jersey, acutely presented with fever. “The presence of B. miyamotoi DNA in the peripheral blood and the patients’ eventual therapeutic response to doxycycline are consistent with the hypothesis that their illness was due to this newly recognized spirochete,” the authors conclude. (S. R. Telford III, sam.telford@tufts.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 3, 2013 * Vol. 20, No. 128
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 3 issue of JAMA (2013; 310).
Pharmacists & Home BP Telemonitoring: Compared with usual care over a 1-year period, pharmacist case management of patients using home blood pressure (BP) telemonitoring more frequently achieved target reductions in BP, researchers report, and the effect persisted during 6 months of nonintervention follow-up (pp. 46–56). Using a cluster randomized design, investigators recruited 450 adults with uncontrolled BP at 16 primary-care clinics in a Minneapolis-based integrated health system.
Pharmacists adjusted antihypertensive therapies based on BP data transmitted by telemonitors, with these results: “At baseline, enrollees were 45% women, 82% white, mean (SD) age was 61.1 (12.0) years, and mean systolic BP was 148 mm Hg and diastolic BP was 85 mm Hg. Blood pressure was controlled at both 6 and 12 months in 57.2% (95% CI, 44.8% to 68.7%) of patients in the telemonitoring intervention group vs 30.0% (95% CI, 23.2% to 37.8%) of patients in the usual care group (P = .001). At 18 months (6 months of postintervention follow-up), BP was controlled in 71.8% (95% CI, 65.0% to 77.8%) of patients in the telemonitoring intervention group vs 57.1% (95% CI, 51.5% to 62.6%) of patients in the usual care group (P = .003). Compared with the usual care group, systolic BP decreased more from baseline among patients in the telemonitoring intervention group at 6 months (−10.7 mm Hg [95% CI, −14.3 to −7.3 mm Hg]; P<.001), at 12 months (−9.7 mm Hg [95% CI, −13.4 to −6.0 mm Hg]; P < .001), and at 18 months (−6.6 mm Hg [95% CI, −10.7 to −2.5 mm Hg]; P = .004). Compared with the usual care group, diastolic BP decreased more from baseline among patients in the telemonitoring intervention group at 6 months (−6.0 mm Hg [95% CI, −8.6 to −3.4 mm Hg]; P < .001), at 12 months (−5.1 mm Hg [95% CI, −7.4 to −2.8 mm Hg]; P < .001), and at 18 months (−3.0 mm Hg [95% CI, −6.3 to 0.3 mm Hg]; P = .07).” (K. L. Margolis,
karen.l.margolis@healthpartners.com)
Comparing contemporary clinical care with technological expansion of financial transactions outside the walls of the bank, editorialists write (
pp. 40–1): “Absent a contraindication to home monitoring, patients should be provided with a validated BP monitor and BP measurements should be transmitted to each patient’s clinician, with follow-up patient-clinician communication by telephone or by electronic visits, if necessary. If home BP monitoring and team-based care were implemented broadly, hypertension management would be easier for patients, and the magnitude of BP reductions brought about by this change could lead to substantial reductions in cardiovascular events and mortality, which is something patients, clinicians, and policy makers can take to the bank.” (D. J. Magid, david.j.magid@kp.org)

>>>NEJM Highlights
Source:
New England Journal of Medicine (2013; 369).
Apixaban in Venous Thromboembolism: In the AMPLIFY trial of 5,395 patients with acute venous thromboembolism, a fixed-dose regimen of oral apixaban was noninferior to subcutaneous enoxaparin followed by oral warfarin and produced significantly less bleeding (DOI: 10.1056/NEJMoa1302507): “Apixaban was noninferior to conventional therapy (P < 0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (< 1.80) and difference in risk (< 3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P < 0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P < 0.001).” (G. Agnelli, agnellig@unipg.it)
“After 60 years of warfarin, it is an exciting time in thrombosis care,” an editorialist writes (
DOI: 10.1056/NEJMe1307413). “Shifting with care to new treatments is essential to safe and effective practice.” (M. Cushman)

>>>PNN NewsWatch
* PNN will not be published on Thurs and Fri., July 4–5, 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 8, 2013 * Vol. 20, No. 129
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 6 issue of Lancet (2013; 382).
Teriparatide Plus Denosumab in Osteoporosis: In women with postmenopausal osteoporosis at high risk of fracture, combination treatment with teriparatide and denosumab increases bone mineral density (BMD) more than either agent alone and more than previously reported with approved therapies, a study shows (pp. 50–6). Intention-to-treat results with teriparatide 20 mcg daily, denosumab 60 mg every 6 months, or both showed these results: “94 (94%) of 100 eligible women completed at least one study visit after baseline. At 12 months, posterior-anterior lumbar spine BMD increased more in the combination group (9.1%, [SD 3.9]) than in the teriparatide (6.2% [4.6], p = 0.0139) or denosumab (5.5% [3.3], p = 0.0005) groups. Femoral-neck BMD also increased more in the combination group (4.2% [3.0]) than in the teriparatide (0.8% [4.1], p = 0.0007) and denosumab (2.1% [3.8], p = 0.0238) groups, as did total-hip BMD (combination, 4.9% [2.9]; teriparatide, 0.7% [2.7], p < 0.0001; denosumab 2.5% [2.6], p = 0.0011).” (B. Z. Leder, bzleder@partners.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Fertility Treatment & Pediatric Mental Disorders: In a prospective, register-based cohort study from Denmark, the incidence of mental disorders was slightly increased among children born after ovulation induction/intrauterine insemination compared with children born after spontaneous conception, but not among those born after in vitro fertilization/intracytoplasmic sperm injection, researchers report (f3978). Data for 33,139 children born in 1995–2003 showed these patterns during follow-up when ages were 8–17 years: “The risk of mental disorders in children born after in vitro fertilisation or intracytoplasmic sperm injection was low, and was no higher than in spontaneously conceived children, except for a borderline significant increased risk of tic disorders (hazard ratio 1.40, 95% confidence interval 1.01 to 1.95; absolute risk 0.3%). In contrast, children born after ovulation induction with or without insemination had low but significantly increased risks of any mental disorder (1.20, 1.11 to 1.31; absolute risk 4.1%), autism spectrum disorders (1.20, 1.05 to 1.37; 1.5%), hyperkinetic disorders (1.23, 1.08 to 1.40; 1.7%), conduct, emotional, or social disorder (1.21, 1.02 to 1.45; 0.8%), and tic disorders (1.51, 1.16 to 1.96; 0.4%). There was no risk systematically related to any specific type of hormone drug treatment.” (B. Bay, bjornbay@me.com)

>>>PNN NewsWatch
* Olmesartan medoxomil (marketed as Benicar, Benicar HCT, Azor, Tribenzor, and generics) can cause sprue-like enteropathy, FDA said last week. Labeling changes warn that symptoms such as severe, chronic diarrhea with substantial weight loss can develop months to years after beginning olmesartan therapy, and hospitalization can be required for management.

>>>PNN JournalWatch
* A Systematic Review of Home-Based Childhood Obesity Prevention Studies, in
Pediatrics, 2013; 132: e193–200. (N. N. Showell, nshowel1@jhmi.edu)
* Systematic Review of Community-Based Childhood Obesity Prevention Studies, in
Pediatrics, 2013; 132: e201–10. (S. N. Bleich, sbleich@jhsph.edu)
* A Model of Placebo Response in Antidepressant Clinical Trials, in
American Journal of Psychiatry, 2013; 170: 723–33. (B. R. Rutherford, brr8@columbia.edu)
* Perioperative Risk and Management in Patients With Pulmonary Hypertension, in
Chest, 2013; 144: 329–40. (O. A. Minai, minaio@ccf.org)
* Biomarkers in Pulmonary Hypertension: What Do We Know?, in
Chest, 2013; 144: 274–83. (H. Olschewski, horst.olschewski@medunigraz.at)
* Management of Low Levels of High-Density Lipoprotein-Cholesterol, in
Circulation, 2013; 128: 72–8. (J. Plutzky, jplutzky@rics.bwh.harvard.edu)
* Effects of Nitric Oxide on Cell Proliferation: Novel Insights, in
Journal of the American College of Cardiology, 2013; 62: 89–95. (C. Napoli)
* Impairment of JCV-Specific T-cell Response by Corticotherapy: Effect on PML-IRIS Management?, in
Neurology, 2013; 81: 97–8. (H. Zahednasab)
* Motion for Debate: The Data Support Evidence-Based Management Recommendations for Cardiovascular Disease in Rheumatoid Arthritis, in
Arthritis & Rheumatism, 2013; 65: 1675–83. (M. J. L. Peters, mjl.peters@vumc.nl.will)
* Mental Health and the Global Agenda, in
New England Journal of Medicine, 2013; 369: 66–73. (A. Kleinman, kleinman@wjh.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 9, 2013 * Vol. 20, No. 130
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 8 issue of the JAMA Internal Medicine (2013; 174).
Cardiovascular Safety of Inhaled LABAs in COPD: Older patients with chronic obstructive pulmonary disease (COPD) had increased risks of cardiovascular events after beginning therapy with long-acting beta-agonists or anticholinergics, according to a study of health care databases from Ontario (pp. 1175–85). In 2003–09, patients older than 65 with new use of long-acting agents in the two drug classes had these outcomes: “Of 191,005 eligible patients, 53,532 (28.0%) had a hospitalization or an emergency department visit for a cardiovascular event. Newly prescribed long-acting inhaled beta-agonists and anticholinergics were associated with a higher risk of an event compared with nonuse of those medications (respective adjusted odds ratios, 1.31 [95% CI, 1.12–1.52; P < .001] and 1.14 [1.01–1.28; P = .03]). We found no significant difference in events between the 2 medications (adjusted odds ratio of long-acting inhaled beta-agonists compared with anticholinergics, 1.15 [95% CI, 0.95–1.38; P = .16]).” (A. Gershon, andrea.gershon@ices.on.ca)
The author of an invited commentary writes that this study adds to the body of knowledge about long-acting beta-agonists (LABAs) and muscarinic (anticholinergic) agents (LAMAs) but notes that no single study will satisfactorily resolve the ongoing controversy over COPD treatments (
pp. 1184–5): “At least 3 important questions cannot be addressed by this study. First, this study does not add to our understanding of the relative risks associated with LAMAs delivered by the HandiHaler or the Respimat Soft Mist Inhaler. These risks are likely to provide a major area of controversy going forward, and the results of the ongoing TIOSPIR safety study are necessary before firm recommendations can be made on the use of the Respimat Soft Mist Inhaler. Second, the analyses did not distinguish between the use of an LABA alone and an LABA–[inhaled corticosteroids] combination. Finally, although the authors recommend that ‘subjects should be monitored closely,’ a firm recommendation on what that monitoring should be cannot be made. Monitoring, of course, is the responsibility of an informed treating physician. The main contribution of this study is to highlight that responsibility.” (P. G. Woodruff, prescott.woodruff@ucsf.edu)
Adulterated Sexual Enhancement Supplements: Reflecting on the more than 330 dietary supplements identified by FDA over the past 5 years as adulterated with active pharmaceutical agents, authors of a Viewpoint article call on clinicians to advise patients to avoid all such products and for changes in the laws governing dietary supplements (pp. 1169–70): “Clinicians should advise patients that there are only 2 types of products available: (1) those that might be safe but do not work and (2) those that might work but are not safe. Therefore, patients should be counseled to avoid all of them. To further decrease the use of sexual enhancement supplements, we recommend having a low threshold for prescribing [phosphodiesterase-5 (PDE-5)] inhibitors when requested so that physicians can ensure that patients receive high-quality products and are counseled appropriately before their use. Patients who are keen on trying a sexual enhancer found in nature may wish to try the active ingredient in yohimbe, yohimbine, which is available only by prescription in the United States (appropriate counseling regarding adverse effects is still important).…
“Legislators should revise the law regulating dietary supplements such that manufacturers are not permitted to claim that a product will improve one’s sexual function (or any other function) until data are provided to the FDA to support such a claim. In addition, the US Drug Enforcement Agency’s analogue provision, which permits analogues of Schedule I and Schedule II substances to be considered Scheduled substances, should be applied to supplements with pharmaceutical analogues. Then all PDE-5 inhibitor analogues in supplements would, a priori, be legally considered unapproved new drugs. This designation would decrease administrative and legal barriers that currently delay the FDA’s response to each new analogue.” (P. A. Cohen,
pcohen@challiance.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 10, 2013 * Vol. 20, No. 131
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 10 issue of JAMA (2013; 310).
Concerns About Generic Clopidogrel Substitution: Given the “substantial variability in the pharmacokinetics of clopidogrel,” is it reasonable to proceed with routine substitution of Plavix with the 12 formulations of generic equivalents that have been approved by FDA? Authors of a Viewpoint article answer this question with a tentative “yes” (pp. 145–6): “We obtained bioequivalency data for 1 generic clopidogrel bisulfate product. In a study of 24 healthy adult men, plasma levels of clopidogrel bisulfate were measured after a single 150-mg dose periodically over 32 hours. The 90% CIs for the Cmax and AUC ratios were 82.0–124.2 and 86.4–122.6, respectively—just within the 80% to 125% standard. This result triggered a site visit to ‘make sure all raw data records, especially with regards to the analytical data, are acceptable. Plasma drug levels were very low and variable.’ No problems were identified, and the clinical and analytical data were deemed acceptable for FDA review. Metabolites of clopidogrel were measured, but no formal comparisons were required or made. Data from the other 11 approved generic clopidogrel bisulfate products are not yet available.…
“On balance, a transition to generic clopidogrel is reasonable and probably inevitable. Because no robust system currently exists for tracking and circulating outcomes with generic clopidogrel, clinicians should be vigilant for adverse events and aggressive in reporting. Moving forward, clinical realities may demand that drug manufacturers and the FDA consider different standards of bioequivalency for drugs such as clopidogrel and more transparency in data reporting.” (J. Doll,
jacob.doll@duke.edu)
Vitamin D Levels, Race & CHD Events: Data from the Multi-Ethnic Study of Atherosclerosis (MESA) show that white and Chinese participants had higher risks of coronary heart disease (CHD) with low 25-hydroxyvitamin D (25[OH]D) levels, but no such associations were noted in black or Hispanic patients (pp. 179–88). MESA included 6,436 participants who were free of known cardiovascular disease upon recruitment in 2000–02. Using a primary outcome of time to first adjudicated CHD event (myocardial infarction, angina, cardiac arrest, or CHD death), the investigators found: “During a median follow-up of 8.5 years, 361 participants had an incident CHD event (7.38 events per 1,000 person–years). Associations of 25(OH)D with CHD differed by race/ethnicity (P for interaction < .05). After adjustment, lower 25(OH)D concentration was associated with a greater risk of incident CHD among participants who were white (n = 167 events; hazard ratio [HR], 1.26 [95% CI, 1.06–1.49] for each 10-ng/mL decrement in 25(OH)D) or Chinese (HR, 1.67 [95% CI, 1.07–2.61]; n = 27). In contrast, 25(OH)D was not associated with risk of CHD in participants who were black (HR, 0.93 [95% CI, 0.73–1.20]; n = 94) or Hispanic (HR, 1.01 [95% CI, 0.77–1.33]; n = 73).” (I. H. de Boer, deboer@u.washington.edu)
Editorialists explore seasonal variability in vitamin D levels among people of various racial backgrounds and consider the influence of other body hormones, reaching this conclusion about the importance of MESA (
pp. 153–5): “This large, well-designed, multiethnic study adds important insights to the complex relationships among race/ethnicity, 25(OH)D concentrations, and CHD risk. The heterogeneity of the findings underscores the importance of exploring racial differences in clinical research and of not immediately generalizing results from ethnically homogeneous populations to other groups that may differ by race/ethnicity, sex, or age. Although the pooled data demonstrated a significant association between 25(OH)D and CHD, the subgroup analyses revealed marked differences underscoring the importance of examining such cohorts by race/ethnicity and thereby potentially discovering sociocultural or biological mediators that may affect cardiovascular health.” (K. C. Norris, knorris@ucla.edu)

>>>PNN NewsWatch
* Consumers who have applied sunscreen sprays must stay away from open flames, FDA cautions. In five separate incidents, people wearing now-recalled sunscreen spray near sources of flame suffered significant burns that required medical treatment. FDA said. But many marketed sunscreens and other products such as hairspray and insect repellent contain alcohol and other chemicals that could catch fire.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 11, 2013 * Vol. 20, No. 132
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 11 issue of the New England Journal of Medicine (2013; 369).
Hospitalizations for Pneumonia in Postvaccine Era: Among infants and children in the decade since introduction of the pneumococcal vaccine, hospitalizations for pneumonia declined at a faster-than-expected rate, researchers report (pp. 155–63). Using annual rates of hospitalization for pneumonia from the Nationwide Inpatient Sample, data from before (1997–99) and well after (2007–09) introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 show the following: “The annual rate of hospitalization for pneumonia among children younger than 2 years of age declined by 551.1 per 100,000 children (95% confidence interval [CI], 445.1 to 657.1), which translates to 47,000 fewer hospitalizations annually than expected on the basis of the rates before PCV7 was introduced. The rate for adults 85 years of age or older declined by 1,300.8 per 100,000 (95% CI, 984.0 to 1,617.6), which translates to 73,000 fewer hospitalizations annually. For the three age groups of 18 to 39 years, 65 to 74 years, and 75 to 84 years, the annual rate of hospitalization for pneumonia declined by 8.4 per 100,000 (95% CI, 0.6 to 16.2), 85.3 per 100,000 (95% CI, 7.0 to 163.6), and 359.8 per 100,000 (95% CI, 199.6 to 520.0), respectively. Overall, we estimated an age-adjusted annual reduction of 54.8 per 100,000 (95% CI, 41.0 to 68.5), or 168,000 fewer hospitalizations for pneumonia annually.” (M. R. Griffin, marie.griffin@vanderbilt.edu)
Arsenic for Acute Promyelocytic Leukemia: Combined with all-trans retinoic acid (ATRA) in a Phase III trial of patients with low-to-intermediate-risk acute promyelocytic leukemia (APL), arsenic trioxide was not inferior and was possibly superior to ATRA plus chemotherapy (pp. 111–21). Patients received ATRA plus arsenic trioxide for induction and consolidation therapy or standard ATRA–idarubicin induction therapy followed by three cycles of consolidation therapy with ATRA plus chemotherapy and maintenance therapy with low-dose chemotherapy and ATRA, with these results: “Complete remission was achieved in all 77 patients in the ATRA–arsenic trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA–chemotherapy group (95%) (P = 0.12). The median follow-up was 34.4 months. Two-year event-free survival rates were 97% in the ATRA–arsenic trioxide group and 86% in the ATRA–chemotherapy group (95% confidence interval for the difference, 2 to 22 percentage points; P < 0.001 for noninferiority and P = 0.02 for superiority of ATRA–arsenic trioxide). Overall survival was also better with ATRA–arsenic trioxide (P = 0.02). As compared with ATRA–chemotherapy, ATRA–arsenic trioxide was associated with less hematologic toxicity and fewer infections but with more hepatic toxicity.” (F. Lo-Coco, afrancesco.lo.coco@uniroma2.it)
“While the first eventual cure of APL by means of a synergistic targeted strategy without chemotherapy is heralded, there are [three] concerns to be addressed,” editorialists write (
pp. 186–7): The follow-up period (median, 34.4 months) is not long enough; the current risk-stratification system for APL has limited utility; and for high-risk patients who are incorrectly classified as low/intermediate by the current system, “new trials of more sophisticated therapy are warranted.” (S-J Chen)
Antibody Immunotherapy for Melanoma: Commenting on two studies of antibodies for immunotherapy in patients with melanoma (pp. 122–33, J. D. Wolchok, wolchokj@mskcc.org; pp. 134–44, A. Ribas, aribas@mednet.ucla.edu), editorialists write (pp. 187–9): “Both PD-1 and CTLA-4 serve as negative regulators of immune-cell activation; that is, when ligated, they trigger signaling pathways that interfere with immune-cell activation. Thus, therapies targeting CTLA-4 and PD-1 are often referred to as immune checkpoint blockers, because it is thought that they enable tumor-specific T cells to become activated and function in the immunosuppressive tumor microenvironment.…
“The clinical successes of CTLA-4 and PD-1 antibody immunotherapy in cancer are the outcomes of the correct recognition of the therapeutic potential of the molecules at the time of discovery, preclinical studies that showed high therapeutic potential, and well-designed and well-executed clinical trials. This partnership of basic science, translational science, and clinical medicine should be celebrated.” (J. L. Riley)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 12, 2013 * Vol. 20, No. 133
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
July 16 issue of the Journal of the American College of Cardiology (2013; 62).
Genetics & Channelopathies: Authors of a state-of-the-art article explore the genetic basis for three cardiac channelopathies: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, and Brugada syndrome (pp. 169–80): “For each disorder, we will discuss to what extent genetic knowledge and clinical genetic test results modify the way cardiologists should approach and manage affected patients. We will also address the optimal use of genetic testing, including its potential limitations and the potential medico-legal implications when such testing is not performed. We will highlight how important it is to understand the ways that genotype can affect clinical manifestations, risk stratification, and responses to the therapy. We will also illustrate the close bridge between molecular biology and clinical medicine, and will emphasize that consideration of the genetic basis for these heritable arrhythmia syndromes and the proper use and interpretation of clinical genetic testing should remain the standard of care.” (P. J. Schwartz)
Binge Drinking & Vascular Function: In 36 otherwise healthy young men and women, those who engaged in binge drinking had alterations in macrocirculation and microcirculation that “may represent early clinical manifestations of cardiovascular risk,” researchers report (pp. 201–7). Cardiovascular profiles, brachial artery endothelial-dependent flow-mediated dilation (FMD), and flow-independent nitroglycerin (NTG)–mediated dilation and vasoreactivity of resistance arteries (isolated from gluteal fat biopsies) showed these patterns in study participants who were binge drinkers (BD; five or more drinks within 2 hours for men; four or more drinks within 2 hours for women) and age-matched alcohol abstainers (A): “In the BD group, past-month mean number of binge episodes was 6 ± 1, and the mean duration of binge drinking behavior was 4 ± 0.6 years. FMD and NTG-mediated dilation were significantly lower in the BD group (FMD: 8.4 ± 0.7%, p = 0.022; NTG-mediated dilation: 19.6 ± 2%, p = 0.009) than in the A group (FMD: 11 ± 0.7%; NTG-mediated dilation: 28.6 ± 2%). Acetylcholine-induced and sodium nitroprusside–induced dilation in resistance arteries was not significantly different between the A and BD groups. However, endothelin-1–induced constriction was significantly enhanced in the BD group compared with the A group (p = 0.032). No differences between groups were found in blood pressure, lipoproteins, and C-reactive protein.” (M. Goslawski)

>>>Chest Highlights
Source:
July issue of Chest (2013; 144).
Acetylcysteine in COPD: In the 1-year HIACE trial, high-dose N-acetylcysteine therapy significantly improved small-airway function and reduced exacerbation frequency in 120 patients with chronic obstructive pulmonary disorder (pp. 106–18; H. N. Tse, drhoinam@gmail.com).

>>>Pharmacotherapy Report
Source:
Early-release article from Pharmacotherapy (2013; 33).
Statin Persistence & LDL Reduction: Among nearly 100,000 real-world patients who began statin therapy in 1998–2008, persistence as measured by proportion of days covered (PDC) was strongly associated with LDL cholesterol reductions (DOI: 10.1002/phar.1326). In this retrospective, population-based cohort study, 87,219 primary-prevention and 15,139 secondary-prevention patients had these outcomes: “Significant (p < 0.001) reductions in LDL levels of 54, 33, and 13 mg/dl were noted among highly persistent (PDC ≥ 80%), moderately persistent (34% ≤ PDC < 79%), and poorly persistent statins users (PDC ≤ 33%), respectively. The reduction was observed as early as 2–3 weeks after therapy initiation. In a multivariable model controlling for baseline LDL level and traditional coronary heart disease risk factors (diabetes mellitus, hypertension), high persistence with statin therapy was associated with a 27% and 25% decrement in LDL level among the primary and secondary prevention cohorts, respectively. Similarly, a higher proportion of the persistent statins users reached their target LDL level within the study follow-up period: 80% and 58% among primary and secondary prevention cohorts, respectively, compared with only 28% and 17%, respectively, among poorly persistent patients.” (G. Chodick, hodik_g@mac.org.il)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 15, 2013 * Vol. 20, No. 134
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 13 issue of Lancet (2013; 382).
Clinical Severity of Avian Influenza A H7N9 Infection: Clinical courses of human infections of the avian influenza virus that emerged earlier this year in China are less severe than previously reported, according to an analysis of confirmed cases in a Chinese Center for Disease Control and Prevention database (pp. 138–45): “Of 123 patients with laboratory-confirmed avian influenza A H7N9 virus infection who were admitted to hospital, 37 (30%) had died and 69 (56%) had recovered by May 28, 2013. After we accounted for incomplete data for 17 patients who were still in hospital, we estimated the fatality risk for all ages to be 36% (95% CI 26–45) on admission to hospital. Risks of mechanical ventilation or fatality (69%, 95% CI 60–77) and of admission to an intensive care unit, mechanical ventilation, or fatality (83%, 76–90) were high. With assumptions about coverage of the sentinel surveillance network and health-care-seeking behaviour for patients with influenza-like illness associated with influenza A H7N9 virus infection, and pro-rata extrapolation, we estimated that the symptomatic case fatality risk could be between 160 (63–460) and 2,800 (1,000–9,400) per 100,000 symptomatic cases.” (J. T. Wu, joewu@hku.hk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
In-Hospital Tobacco Cessation Efforts: Systematic identification and smoking-cessation efforts can substantially improve cessation rates among inpatients who smoke, according to results of an open, cluster-randomized trial (f4004). At a large U. K. teaching hospital, 484 patients were randomized to intervention (behavioral and pharmacologic support) or usual care, with these results at 4 weeks: “All patients in the intervention group received at least brief advice to quit smoking, compared to 106 (46%) patients in the usual care group. Cessation at four weeks was achieved by 38% (n = 98) of intervention patients and 17% (n = 37) of usual care patients (adjusted odds ratio 2.10 (95% confidence interval 0.96 to 4.61), P = 0.06, number of patients needed to treat 8). Uptake of inpatient behavioural support, use of pharmacotherapy, and referral to and uptake of community support after discharge were all substantially and statistically significantly higher in the intervention group than in the usual care group. Cessation at six months was achieved by 19% (n = 47) of intervention and 9% (n = 19) of usual care patients, although this difference was not significant (adjusted odds ratio 1.53 (95% confidence interval 0.60 to 3.91); P = 0.37).” (R. L. Murray, rachael.murray@nottingham.ac.uk)

>>>PNN NewsWatch
* FDA on Friday approved afatinib (Gilotrif, Boehringer Ingelheim) for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express specific types of epidermal growth factor receptor (EGFR) gene mutations, as detected by a laboratory test approved concurrently (therascreen EGFR RGQ PCR Kit,). The tyrosine kinase’s safety and effectiveness were established in a clinical study of 345 participants with metastatic NSCLC whose tumors harbored EGFR mutations. Those receiving afatinib had progression-free survival that was 4.2 months later than those receiving chemotherapy. There was no statistically significant difference in overall survival. Common adverse effects of afatinib include diarrhea, skin breakouts that resemble acne, dry skin, pruritus, inflammation of the mouth, paronychia, decreased appetite, decreased weight, cystitis, nose bleed, runny nose, fever, eye inflammation, and hypokalemia. Serious adverse effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation and liver toxicity.

>>>PNN JournalWatch
* Are We Ready for an Outpatient Parenteral Antimicrobial Therapy Bundle? A Critical Appraisal of the Evidence, in
Clinical Infectious Diseases, 2013; 57: 419–24. (G. M. Allison, gallison@tuftsmedicalcenter.org)
* Critical Evaluation of Oncology Clinical Practice Guidelines, in
Journal of Clinical Oncology, 2013; 31: 2563–8. (S. L. Wong, wongsl@umich.edu)
* Development of a Community Pharmacy Disaster Preparedness Manual, in
Journal of the American Pharmacists Association, 2013; 53: 432–7. (A. Smith, april.smith@creighton.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 16, 2013 * Vol. 20, No. 135
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 16 issue of the Annals of Internal Medicine (2013; 159).
Every-Other-Day Low-Dose Aspirin & Cancer Risk: Among 33,682 healthy women in the Women’s Health Study, the risk of colorectal cancer was lower among those taking aspirin 100 mg every other day, compared with placebo (pp. 77–85). Participants were all women health professionals who were randomized to aspirin or placebo through 2004 and observed for 8 years. Results showed: “A total of 5,071 cancer cases (including 2,070 breast, 451 colorectal, and 431 lung cancer cases) and 1,391 cancer deaths were confirmed. Over the entire follow-up, aspirin had no association with total (hazard ratio [HR], 0.97 [95% CI, 0.92 to 1.03]; P = 0.31), breast (HR, 0.98 [CI, 0.90 to 1.07]; P = 0.65), or lung (HR, 1.04 [CI, 0.86 to 1.26]; P = 0.67) cancer. Colorectal cancer was reduced in the aspirin group (HR, 0.80 [CI, 0.67 to 0.97]; P = 0.021), primarily for proximal colon cancer (HR, 0.73 [CI, 0.55 to 0.95]; P = 0.022). The difference emerged after 10 years, with a posttrial reduction of 42% (HR, 0.58 [CI, 0.42 to 0.80]; P < 0.001). There was no extended effect on cancer deaths or colorectal polyps. More gastrointestinal bleeding (HR, 1.14 [CI, 1.06 to 1.22]; P < 0.001) and peptic ulcers (HR, 1.17 [CI, 1.09 to 1.27]; P < 0.001) occurred in the aspirin group.” (N. R. Cook, ncook@rics.bwh.harvard.edu)
Telaprevir for Chronic HCV Infections: Telaprevir (TVR), used with PEG-IFN-alpha-2a–ribavirin in patients with concomitant genotype 1 chronic hepatitis C virus (HCV) infection and HIV-1 infection, produced more adverse events than PEG-IFN-alpha-2a–ribavirin alone, researchers report (pp. 86–96). In an international study, 62 patients who were HCV treatment-naive and receiving none or one of two certain antiretroviral regimens for HIV-1 were assigned to TVR plus PEG-IFN-alpha-2a–ribavirin or PEG-IFN-alpha-2a–ribavirin alone, with these results: “Pruritus, headache, nausea, rash, and dizziness were higher with TVR plus PEG-IFN-alpha-2a–ribavirin during the first 12 weeks. During this period, serious adverse events occurred in 5% (2 in 38) of those receiving TVR plus PEG-IFN-alpha-2a–ribavirin and 0% (0 in 22) of those receiving placebo plus PEG-IFN-alpha-2a–ribavirin; the same number in both groups discontinued treatment due to adverse events. Sustained virologic response occurred in 74% (28 in 38) of patients receiving TVR plus PEG-IFN-alpha-2a–ribavirin and 45% (10 in 22) of patients receiving placebo plus PEG-IFN-alpha-2a–ribavirin. Rapid HCV suppression was seen with TVR plus PEG-IFN-alpha-2a–ribavirin (68% [26 in 38 patients] vs. 0% [0 in 22 patients] undetectable HCV RNA levels by week 4). Two patients had on-treatment HCV breakthrough with TVR-resistant variants. Patients treated with antiretroviral drugs had no HIV breakthroughs; antiretroviral exposure was not substantially modified by TVR.” (M. S. Sulkowski, msulkowski@jhmi.edu)
Branded Rx Drug Use in Medicare, VA Patients: Use of brand-name prescription drugs and medication costs are substantially higher among patients with diabetes who have Medicare Part D coverage than those in the VA system, according to a retrospective cohort study (pp. 105–14). Investigators looked at records of 1,061,095 Medicare Part D beneficiaries and 510,485 veterans, all 65 years or older and with diabetes. Percentages of patients taking oral hypoglycemics, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) who filled brand-name drug prescriptions and percentage of patients taking long-acting insulins who filled analogue prescriptions were analyzed along with sociodemographic- and health status–adjusted hospital referral region (HRR) brand-name drug use. with these results: “Brand-name drug use in Medicare was 2 to 3 times that in the VA: 35.3% versus 12.7% for oral hypoglycemics, 50.7% versus 18.2% for statins, 42.5% versus 20.8% for ACE inhibitors or ARBs, and 75.1% versus 27.0% for insulin analogues. Adjusted HRR-level brand-name statin use ranged (from the 5th to 95th percentiles) from 41.0% to 58.3% in Medicare and 6.2% to 38.2% in the VA. For each drug group, the 95th-percentile HRR in the VA had lower brand-name drug use than the 5th-percentile HRR in Medicare. Medicare spending in this population would have been $1.4 billion less if brand-name drug use matched that of the VA.” (W. F. Gellad, walid.gellad@va.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 17, 2013 * Vol. 20, No. 136
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 17 issue of JAMA (2013; 310).
Management of Cardiac Arrest Requiring Vasopressors: In 268 consecutive patients in cardiac arrest at three Greek tertiary centers who required epinephrine, vasopressin-epinephrine plus methylprednisolone during cardiopulmonary resuscitation (CPR) and stress-dose hydrocortisone in postresuscitation shock improved survival to hospital discharge with favorable neurological status, compared with epinephrine alone (pp. 270–9). Vasopressin-steroids-epinephrine (VSE) yielded these outcomes during use in up to five CPR cycles based on return of spontaneous circulation (ROSC) for 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2: “Follow-up was completed in all resuscitated patients. Patients in the VSE group vs patients in the control group had higher probability for ROSC of 20 minutes or longer (109/130 [83.9%] vs 91/138 [65.9%]; odds ratio [OR], 2.98; 95% CI, 1.39–6.40; P = .005) and survival to hospital discharge with CPC score of 1 or 2 (18/130 [13.9%] vs 7/138 [5.1%]; OR, 3.28; 95% CI, 1.17–9.20; P = .02). Patients in the VSE group with postresuscitation shock vs corresponding patients in the control group had higher probability for survival to hospital discharge with CPC scores of 1 or 2 (16/76 [21.1%] vs 6/73 [8.2%]; OR, 3.74; 95% CI, 1.20–11.62; P = .02), improved hemodynamics and central venous oxygen saturation, and less organ dysfunction. Adverse event rates were similar in the 2 groups.” (S. D. Mentzelopoulos, sdmentzelopoulos@yahoo.com)
Androgen Deprivation Therapy & Acute Kidney Injury: An increased risk of acute kidney injury (AKI) associated with androgen deprivation therapy (ADT) was observed in a nested case–control study of 10,250 men with newly diagnosed nonmetastatic prostate cancer, researchers report (pp. 289–96). Using the U.K. Clinical Practice Research Datalink, cases and controls from 1997 to 2008 showed these outcomes with use of ADT (categorized into six mutually exclusive groups) and renal injury: “During a mean follow-up of 4.1 (SD, 2.9) years, 232 incident cases of AKI were identified (rate, 5.5/1000 person–years). Overall, current use of any ADT was associated with an increased risk of AKI when compared with never use (OR, 2.48 [95% CI, 1.61–3.82]), generating a rate difference of 4.43/1,000 persons per year (95% CI, 1.54–7.33). This association was mainly driven by a combined androgen blockade consisting of gonadotropin-releasing hormone agonists with oral antiandrogens (OR, 4.50 [95% CI, 2.61–7.78]), estrogens (OR, 4.00 [95% CI, 1.06–15.03]), other combination therapies (OR, 4.04 [95% CI, 1.88–8.69]), and gonadotropin-releasing hormone agonists (OR, 1.93 [95% CI, 1.20–3.10]).” (S. Suissa, samy.suissa@mcgill.ca)
West Nile Virus: “West Nile virus has and will remain a formidable clinical and public health problem [in North America] for years to come,” conclude authors of a review article (pp. 308–15): “West Nile virus is now endemic throughout the contiguous United States, with 16,196 human neuroinvasive disease cases and 1,549 deaths reported since 1999. More than 780,000 illnesses have likely occurred. To date, incidence is highest in the Midwest from mid-July to early September. West Nile fever develops in approximately 25% of those infected, varies greatly in clinical severity, and symptoms may be prolonged. Neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis) develops in less than 1% but carries a fatality rate of approximately 10%. Encephalitis has a highly variable clinical course but often is associated with considerable long-term morbidity. Approximately two-thirds of those with paralysis remain with significant weakness in affected limbs. Diagnosis usually rests on detection of IgM antibody in serum or cerebrospinal fluid. Treatment is supportive; no licensed human vaccine exists. Prevention uses an integrated pest management approach, which focuses on surveillance, elimination of mosquito breeding sites, and larval and adult mosquito management using pesticides to keep mosquito populations low. During outbreaks or impending outbreaks, emphasis shifts to aggressive adult mosquito control to reduce the abundance of infected, biting mosquitoes. Pesticide exposure and adverse human health events following adult mosquito control operations for West Nile virus appear negligible.” (L. R. Petersen, lxp2@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 18, 2013 * Vol. 20, No. 137
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 18 issue of the New England Journal of Medicine (2013; 369).
Threshold-Based Insulin-Pump Interruption: Use of sensor-augmented insulin-pump therapy that interrupted dosing for 2 hours when blood glucose levels fell reduced episodes of nocturnal hypoglycemia in patients with type 1 diabetes over a 3-month period without affecting overall A1C levels, researchers report (pp. 224–32). Study participants were evaluated based on a primary outcome of area under the curve (AUC) for nocturnal hypoglycemic events, with these results: “A total of 247 patients were randomly assigned to receive sensor-augmented insulin-pump therapy with the threshold-suspend feature (threshold-suspend group, 121 patients) or standard sensor-augmented insulin-pump therapy (control group, 126 patients). The changes in glycated hemoglobin values were similar in the two groups. The mean AUC for nocturnal hypoglycemic events was 37.5% lower in the threshold-suspend group than in the control group (980 ± 1,200 mg per deciliter [54.4 ± 66.6 mmol per liter] × minutes vs. 1,568 ± 1,995 mg per deciliter [87.0 ± 110.7 mmol per liter] × minutes, P < 0.001). Nocturnal hypoglycemic events occurred 31.8% less frequently in the threshold-suspend group than in the control group (1.5 ± 1.0 vs. 2.2 ± 1.3 per patient-week, P < 0.001). The percentages of nocturnal sensor glucose values of less than 50 mg per deciliter (2.8 mmol per liter), 50 to less than 60 mg per deciliter (3.3 mmol per liter), and 60 to less than 70 mg per deciliter (3.9 mmol per liter) were significantly reduced in the threshold-suspend group (P < 0.001 for each range). After 1,438 instances at night in which the pump was stopped for 2 hours, the mean sensor glucose value was 92.6 ± 40.7 mg per deciliter (5.1 ± 2.3 mmol per liter). Four patients (all in the control group) had a severe hypoglycemic event; no patients had diabetic ketoacidosis.” (R. M. Bergenstal, richard.bergenstal@parknicollet.com)
Protected Speech & Comparative Effectiveness Research: Expansion of Section 114 of the Food and Drug Administration Modernization Act of 1997 could provide “a more flexible evidentiary framework for business-to-business communication of [comparative-effectiveness research (CER)] findings while retaining key protections,” the author of a Commentary article writes (pp. 209–11): “The entire debate over the promotion of CER findings has … been thrown for a loop by a series of recent court decisions, including the December 2012 ruling in United States v. Caronia, in which the Second Circuit court overturned a conviction of a drug company sales representative for off-label promotion on the grounds that FDA prohibitions of such promotion infringed the individual’s First Amendment right to free speech. Caronia continues a judiciary trend toward broadening the definition of protected speech and holds that the government cannot restrict truthful, non-misleading off-label promotion. Conceivably, the FDA will have to establish on a case-by-case basis whether any CER promotion, regardless of its intended audience, is ‘truthful.’ However, a great deal of uncertainty prevails, and it may be some time before there is clarity around the issue. In the meantime, expanding Section 114 to include CER could help Congress, the FDA, and perhaps even the Courts to consider and define more clearly the circumstances and audiences for which CER promotion can be truthful and non-misleading.” (P. J. Neumann)
Efficacy of Herpes Zoster Vaccine: Benefits of herpes zoster vaccine are clear in older patients, the author of a case study writes, including those older than 70 (pp. 255–63): “On the basis of the results of a recent clinical trial, the vaccine is now approved by the FDA to prevent herpes zoster in persons 50 years of age or older. The efficacy of the vaccine in preventing herpes zoster is 70% for persons 50 to 59 years of age, 64% for persons 60 to 69 years of age, and 38% for persons 70 years of age or older. However, vaccine efficacy in preventing postherpetic neuralgia is 66% for persons 60 to 69 years of age and is undiminished at 67% for persons 70 years of age or older. Although the effectiveness of the vaccine to prevent herpes zoster is reduced in persons 70 years of age or older, the increased risk of severe disease and the persisting efficacy of the vaccine in preventing postherpetic neuralgia in these older persons strongly favor vaccinating them.” (J. I. Cohen, jcohen@niaid.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 19, 2013 * Vol. 20, No. 138
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
Aug. 1 issue of Clinical Infectious Diseases (2013; 57).
Colistin Plus Rifampicin for Drug-Resistant Acinetobacter: In critical-care patients with serious infections of extensively drug-resistant (XDR) Acinetobacter baumannii, the addition of rifampicin to colistin failed to lower the 30-day mortality rate, a study shows (pp. 349–58). The authors did find an increased rate of pathogen eradication when rifampicin was used, but they conclude, “Rifampicin should not be routinely combined with colistin in clinical practice.”
Results for 210 patients with life-threatening XDR
A. baumannii infections had these outcomes for colistin with or without rifampicin: “Death within 30 days from randomization occurred in 90 (43%) subjects, without difference between treatment arms (P = .95). This was confirmed by multivariable analysis (odds ratio, 0.88 [95% confidence interval, .46–1.69], P = .71). A significant increase of microbiologic eradication rate was observed in the colistin plus rifampicin arm (P = .034). No difference was observed for infection-related death and length of hospitalization.” (R. Utili, riccardo.utili@unina2.it)
Vitamin D Levels & Pediatric Respiratory Tract Infections: In Canadian Hutterite communities during the respiratory virus season, lower serum levels of 25-hydroxyvitamin D (25(OH)D) was associated with increased risk of laboratory-confirmed viral respiratory tract infections (RTIs) in 743 children and adolescents (pp. 392–7). Prospectively gathered data on serum 25(OH)D levels, nasopharyngeal specimens, and laboratory-confirmed viral respiratory tract infections (RTIs) showed these results: “The median serum 25(OH)D level was 62.0 nmol/L (interquartile range, 51.0–74.0). A total of 229 participants (31%) developed at least 1 laboratory-confirmed viral RTI. Younger age and lower serum 25(OH)D levels were associated with increased risk of viral RTI. Serum 25(OH)D levels <75 nmol/L increased the risk of viral RTI by 50% (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.10–2.07, P = .011) and levels <50 nmol/L increased the risk by 70% (HR, 1.67; 95% CI, 1.16–2.40, P = .006).” (M. Loeb, loebm@mcmaster.ca)

>>>Oncology Highlights
Source:
July 20 issue of the Journal of Clinical Oncology (2013; 31).
Osteonecrosis of the Jaw After Adjuvant Zoledronic Acid: Oral health–related quality of life (Oral-QoL) was not adversely affected among 33 patients in the AZURE trial who developed osteonecrosis of the jaw (ONJ) after adjuvant zoledronate therapy, researchers report (pp. 2585–91): “Twenty-six cases were confirmed as being consistent with a diagnosis of ONJ, representing a cumulative incidence of 2.1% (95% CI, 0.9% to 3.3%) in the zoledronate arm. Three hundred sixty-two patients (74%) returned the [Oral Health Impact Profile-14] questionnaire. Neither the prevalence nor severity of impacts on Oral-QoL differed significantly between zoledronate patients and control patients.” (R. E. Coleman, r.e.coleman@sheffield.ac.uk)
Revisiting Survivorship Care Planning: Survivorship care plans (SCPs), instituted based on a 2006 Institute of Medicine (IOM) report, remain poorly studied, with few high-quality analyses of their impact on care delivery and cancer-survivor outcomes, authors argue (pp. 2651–3): “The question raised by the IOM report was broader than evaluation of SCPs; the question was how best to deliver high-quality transitional and follow-up care to cancer survivors. This is the question we should seek to answer with our science on survivorship care planning. This is the question that allows us to keep sight of the forest as well as the trees and improve outcomes for all cancer survivors.” (C. Parry, carla.parry@nih.gov)

>>>PNN NewsWatch
* A clinical trial of lenalidomide (Revlimid, Celgene) has been halted because of “significant safety concerns,” FDA said yesterday, including a 92% increased risk of mortality in patients being treated with the drug for chronic lymphocytic leukemia (CLL), compared with chlorambucil. The ORIGIN trial (NCT00910910) was evaluating lenalidomide, an approved drug, for a new use as an initial therapy for CLL in patients 65 years and older. Health professionals should be aware that lenalidomide is not approved to treat CLL, FDA said. Tumor flare reactions have occurred during investigational use of lenalidomide for CLL.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 22, 2013 * Vol. 20, No. 139
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 20 issue of Lancet (2013; 382).
Diarrheal Burden in Developing Countries: Rotavirus vaccine and zinc supplements are two existing interventions that could help reduce the burden of diarrheal diseases among children younger than 5 in developing countries, conclude investigators from the Global Enteric Multicenter Study (GEMS) (pp. 209–22). The 3-year, case–control study looked at the incidence of moderate-to-severe diarrhea among young children in sub-Saharan Africa and south Asia, with these results: “We enrolled 9,439 children with moderate-to-severe diarrhoea and 13,129 control children without diarrhoea. By analysing adjusted population attributable fractions, most attributable cases of moderate-to-severe diarrhoea were due to four pathogens: rotavirus, Cryptosporidium, enterotoxigenic Escherichia coli producing heat-stable toxin (ST-ETEC; with or without co-expression of heat-labile enterotoxin), and Shigella. Other pathogens were important in selected sites (eg, Aeromonas, Vibrio cholerae O1, Campylobacter jejuni). Odds of dying during follow-up were 8.5-fold higher in patients with moderate-to-severe diarrhoea than in controls (odd ratio 8.5, 95% CI 5.8–12.5, p < 0.0001); most deaths (167 [87.9%]) occurred during the first 2 years of life. Pathogens associated with increased risk of case death were ST-ETEC (hazard ratio [HR] 1.9; 0.99–3.5) and typical enteropathogenic E coli (HR 2.6; 1.6–4.1) in infants aged 0–11 months, and Cryptosporidium (HR 2.3; 1.3–4.3) in toddlers aged 12–23 months.” (K. L. Kotloff, kkotloff@medicine.umaryland.edu)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 347).
Acellular Pertussis Vaccine Effectiveness: Moderate effectiveness of acellular pertussis (Tdap) vaccines is demonstrated in a population of adolescents and adults in the Kaiser Permanente Northern California system (f4249). Case–control analysis of cases of pertussis in 2006–11 that were confirmed by polymerase chain reaction (PCR) showed these patterns in vaccinated and unvaccinated patients: “The study population included 668 PCR positive cases, 10,098 PCR negative controls, and 21,599 Kaiser Permanente Northern California matched controls. Tdap vaccination rates were 24.0% in PCR positive cases and 31.9% in PCR negative controls (P < 0.001). The adjusted estimate of effectiveness of Tdap vaccination against pertussis was 53.0% (95% confidence interval 41.9% to 62.0%) in the comparison with PCR controls, and 64.0% (55.5% to 70.9%) in the comparison with Kaiser Permanente Northern California controls.” (R. Baxter, roger.baxter@kp.org)
Overlapping Meta-analyses: Two-thirds of 73 meta-analyses published in 2010 were of topics that overlapped with other meta-analyses, a study shows (f4501). While some replication of meta-analyses “is possibly useful,” investigators conclude that overall “there is a waste of efforts”: “In 17 topics at least one author was involved in at least two of the overlapping meta-analyses. No characteristics of the index meta-analyses were associated with the potential for overlapping meta-analyses. Among pairs of overlapping meta-analyses in 20 randomly selected topics, 13 of the more recent meta-analyses did not include any additional outcomes. In three of the four topics with eight or more published meta-analyses, many meta-analyses examined only a subset of the eligible interventions or indications/settings covered by the index meta-analysis. Conversely, for statins in the prevention of atrial fibrillation after cardiac surgery, 11 meta-analyses were published with similar eligibility criteria for interventions and setting: there was still variability on which studies were included, but the results were always similar or even identical across meta-analyses.” (J. P. A. Ioannidis, jioannid@stanford.edu)

>>>PNN JournalWatch
* Diagnostic, Functional, and Therapeutic Roles of microRNA in Allergic Diseases, in
Journal of Allergy and Clinical Immunology, 2013; 132: 3–13. (M. E. Rothenberg, Rothenberg@cchmc.org)
* Changes in Medical Student and Doctor Attitudes Toward Older Adults After an Intervention: A Systematic Review, in
Journal of the American Geriatrics Society, 2013; 61: 1188–96. (R. Samra, r.samra@mail.com)
* Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics, in
Gastroenterology, 2013; 145: 293–308. (N. T. Ventham, nventham@staffmail.ed.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 23, 2013 * Vol. 20, No. 140
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
July 22 of the JAMA Internal Medicine (2013; 173).
Statins & Adverse Musculoskeletal Events: A “full spectrum” of musculoskeletal conditions is more common among users of statins than nonusers, a cohort study shows, including arthropathies, injuries, and pain (pp. 1318–26). “Further studies are warranted,” the authors conclude, “especially in physically active individuals.” In the San Antonio Military Multi-Market, Tricare Prime/Plus beneficiaries had these outcomes based on statin use in 2003–10 for all musculoskeletal diseases (Msk1); arthropathies and related diseases (Msk1a); injury-related diseases such as dislocation, sprain, and strain (Msk1b); and drug-associated musculoskeletal pain (Msk2): “A total of 46,249 individuals met study criteria (13,626 statin users and 32,623 nonusers). Of these, we propensity score–matched 6,967 statin users with 6,967 nonusers. Among matched pairs, statin users had a higher OR for Msk1 (OR, 1.19; 95% CI, 1.08–1.30), Msk1b (1.13; 1.05–1.21), and Msk2 (1.09; 1.02–1.18); the OR for Msk1a was 1.07 (0.99–1.16; P = .07). Secondary and sensitivity analyses revealed higher adjusted ORs for statin users in all outcome groups.” (I. Mansi, ishak.mansi@va.gov)
Disparities in HIV Care & Treatment in the U.S.: “Significant age disparities … at each step of the continuum of care” are evident among Americans with HIV infection, researchers report (pp. 1337–44). Combining data from the CDC’s National HIV Surveillance System and the Medical Monitoring Project, the investigators found these disparities in care among people living with HIV who were aware or unaware of their infection: “Of the estimated 1,148,200 persons living with HIV in 2009 in the United States, 81.9% had been diagnosed, 65.8% were linked to care, 36.7% were retained in care, 32.7% were prescribed antiretroviral therapy, and 25.3% had a suppressed viral load (≤200 copies/mL). Overall, 857,276 persons with HIV had not achieved viral suppression, including 74.8% of male, 79.0% of black, 73.9% of Hispanic/Latino, and 70.3% of white persons. The percentage of blacks in each step of the continuum was lower than that for whites, but these differences were not statistically significant. Among persons with HIV who were 13 to 24 years of age, only 40.5% had received a diagnosis and 30.6% were linked to care. Persons aged 25 to 34, 35 to 44, and 45 to 54 years were all significantly less likely to achieve viral suppression than were persons aged 55 to 64 years.” (H. I. Hall, ixh1@cdc.gov)
Biofeedback for Hypertension in Diabetes: “No significant effect [was found for] device-guided lowering of breathing frequency on office-measured blood pressure in patients with type 2 diabetes,” according to a study of patients in the Netherlands (pp. 1346–50). In a double-blind, sham-controlled trial, 15-minute sessions with a device that guides breathing through musical tones produced these results: “Forty-eight patients were randomized; 21 patients (88%) in the intervention group and 24 patients (100%) in the control group completed the study. There were no significant changes in systolic and diastolic blood pressure, with a difference in systolic blood pressure of 2.35 mm Hg (95% CI, –6.50 to 11.20) in favor of the control group and a difference in diastolic blood pressure of 2.25 mm Hg (95% CI, –2.16 to 6.67) in favor of the intervention group. Three patients in the intervention group experienced adverse events.” (G. W. D. Landman, g.w.d.landman@isala.nl)
Community-Associated Clostridium difficile: In 2009–11, many patients with community-acquired Clostridium difficile infection (CDI) had been seen recently in outpatient settings, according to data from 8 U.S. states, and one-third of the cases would not have been prevented through antibiotic use (pp. 1359–67): “Of 984 patients with community-associated CDI, 353 (35.9%) did not receive antibiotics, 177 (18.0%) had no outpatient health care exposure, and 400 (40.7%) had low-level outpatient health care exposure. Thirty-one percent of patients without antibiotic exposure received proton pump inhibitors. Patients having CDI with no or low-level outpatient health care exposure were more likely to be exposed to infants younger than 1 year (P = .04) and to household members with active CDI (P = .05) compared with those having high-level outpatient health care exposure.” (F. C. Lessa, flessa@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 24, 2013 * Vol. 20, No. 141
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
July 24/31 issue of JAMA (2013; 310).
Physicians & Control of Health Care Costs: American physicians agree that they have “some responsibility to address health care costs,” generally agreed with ongoing quality initiatives, but had “less enthusiasm” about containing costs through changes in payment models, according to a national survey of 2,556 physicians in the AMA Masterfile (pp. 380–8). Using enthusiasm for 17 cost-containment strategies as an outcome measure, investigators report: “Most [respondents] believed that trial lawyers (60%), health insurance companies (59%), hospitals and health systems (56%), pharmaceutical and device manufacturers (56%), and patients (52%) have a ‘major responsibility’ for reducing health care costs, whereas only 36% reported that practicing physicians have ‘major responsibility.’ Most were ‘very enthusiastic’ for ‘promoting continuity of care’ (75%), ‘expanding access to quality and safety data’ (51%), and ‘limiting access to expensive treatments with little net benefit’ (51%) as a means of reducing health care costs. Few expressed enthusiasm for ‘eliminating fee-for-service payment models’ (7%). Most physicians reported being ‘aware of the costs of the tests/treatments [they] recommend’ (76%), agreed they should adhere to clinical guidelines that discourage the use of marginally beneficial care (79%), and agreed that they ‘should be solely devoted to individual patients’ best interests, even if that is expensive’ (78%) and that ‘doctors need to take a more prominent role in limiting use of unnecessary tests’ (89%). Most (85%) disagreed that they ‘should sometimes deny beneficial but costly services to certain patients because resources should go to other patients that need them more.’ In multivariable logistic regression models testing associations with enthusiasm for key cost-containment strategies, having a salary plus bonus or salary-only compensation type was independently associated with enthusiasm for ‘eliminating fee for service’ (salary plus bonus: odds ratio [OR], 3.3, 99% CI, 1.8–6.1; salary only: OR, 4.3, 99% CI, 2.2–8.5). In multivariable linear regression models, group or government practice setting (beta = 0.87, 95% CI, 0.29 to 1.45, P = .004; and beta = 0.99, 95% CI, 0.20 to 1.79, P = .01, respectively) and having a salary plus bonus compensation type (beta = 0.82; 95% CI, 0.32 to 1.33; P = .002) were positively associated with cost-consciousness. Finding the ‘uncertainty involved in patient care disconcerting’ was negatively associated with cost-consciousness (beta = −1.95; 95% CI, −2.71 to −1.18; P < .001).” (J. C. Tilburt, tilburt.jon@mayo.edu)
“The next decade requires ‘all hands on deck’ to create meaningful, lasting change in health care,” editorialists write (
pp. 374–5). “[This] study indicates that the medical profession is not there yet—that many physicians would prefer to sit on the sidelines while other actors in the health care system do the real work of reform. This could marginalize and demote physicians. Physicians must commit themselves to act like the captain of the health care ship and take responsibility for leading the United States to a better health care system that provides higher-quality care at lower costs.” (E. J. Emanuel, zemanuel@upenn.edu)
Rabies Transmission via Transplantation: Based on a recent case of rabies virus transmission through solid-organ transplantation, researchers conclude that “rabies should be considered in patients with acute progressive encephalitis of unexplained etiology, especially for potential organ donors” (pp. 398–407): “In retrospect, the donor’s clinical presentation (which began with vomiting and upper extremity paresthesias and progressed to fever, seizures, dysphagia, autonomic dysfunction, and brain death) was consistent with rabies. Rabies virus antigen was detected in archived autopsy brain tissue collected from the donor. The rabies viruses infecting the donor and the deceased kidney recipient were consistent with the raccoon rabies virus variant and were more than 99.9% identical across the entire N gene (1,349/1,350 nucleotides), thus confirming organ transplantation as the route of transmission. [Three] other organ recipients remained asymptomatic, with rabies virus neutralizing antibodies detected in their serum after completion of postexposure prophylaxis.” (M. J. Kuehnert, mgk8@cdc.gov)

>>>PNN NewsWatch
* FDA is warning 15 companies about marketing of dietary supplements and other products for prevention of diabetes.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 25, 2013 * Vol. 20, No. 142
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
July 25 issue of the New England Journal of Medicine (2013; 369).
RA Treatment After Methotrexate Failure: Older disease-modifying antirheumatic drugs are noninferior to methotrexate when used in patients whose rheumatoid arthritis has not responded to methotrexate alone, researchers report (pp. 307–18). In a 48-week trial, 353 patients with active rheumatoid arthritis despite methotrexate therapy were randomized to a triple regimen of methotrexate, sulfasalazine, and hydroxychloroquine or etanercept plus methotrexate. Nonrespondents were switched to the alternate treatment at 24 weeks. Results based on Disease Activity Score for 28-joint counts (DAS28) showed: “Both groups had significant improvement over the course of the first 24 weeks (P = 0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P < 0.001), and the response after switching did not differ significantly between the two groups (P = 0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (−2.1 with triple therapy and −2.3 with etanercept and methotrexate, P = 0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P = 0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.” (J. R. O’Dell, james.o’dell@va.gov)
Given the acceptance of biologic modifiers as second-line therapy in patients with rheumatoid arthritis, editorialists question if “these findings have arrived too late to influence modern practice” (
pp. 384–5): “Whether third-party payers who currently require failure of methotrexate monotherapy before prescription of expensive biologic therapy will change this policy to require failure of the cheaper nonbiologic combination is an interesting question. The development of more affordable biosimilar agents may change the treatment choices yet again, potentially rendering the studies with nonbiologic agents cited above irrelevant. We hope that with the ever-increasing number of effective treatments for rheumatoid arthritis, future recommendations for treatment will be guided by additional comparative-effectiveness studies such as the study by O’Dell et al. In addition, future identification of biomarkers to identify the patients who are most likely to have a response to, or are least likely to have side effects with, specific therapies will be the next great leap in the treatment of rheumatoid arthritis.” (J. M. Bathon)
Riociguat for Pulmonary Hypertension: Two studies and an editorial examine use of riociguat, an orally active soluble guanylate cyclase stimulator that also increases the sensitivity of soluble guanylate cyclase to nitric oxide, in patients with pulmonary hypertension.
In a Phase III trial of 261 patients with inoperable chronic thromboembolic pulmonary hypertension, riociguat significantly improved exercise capacity and pulmonary vascular resistance (
pp. 319–29). Six-minute walk times improved by 39 m with drug therapy, compared with a decrease of 6 m among those receiving placebo. Common adverse events, which occurred in both groups, were right ventricular failure and syncope.
The same research group reported a second Phase III trial of riociguat that showed similar improvements among 443 patients with symptomatic pulmonary arterial hypertension (
pp. 330–40). Pulmonary vascular resistance, NT-proBNP levels, WHO functional class, time to clinical worsening, and Borg dyspnea scores were also improved significantly with the drug. (H–A Ghofrani, ardeschir.ghofrani@innere.med.uni-giessen.de)
“The glass may be seen to be half empty because of the modest improvement in 6-minute walk distance with riociguat,” an editorialist writes (
pp. 386–8). “However, I view the glass as half full, because riociguat appears to be safe and is a promising addition to the pharmacopeia for Group 1 pulmonary hypertension and potentially the first effective oral therapy for inoperable Group 4 pulmonary hypertension.” (S. L. Archer)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 26, 2013 * Vol. 20, No. 143
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Aug. issue of Diabetes Care (2013; 36).
U.S. Prediabetes Prevalence: With prediabetes defined as hemoglobin A1c of 5.7 to <6.5% (A1C5.7), investigators find that prevalence of the condition increased greatly in 1999–2010 (pp. 2286–93). Data for 19,182 nonpregnant individuals aged 12 years or older from those years showed these patterns for A1C5.7: “Age-adjusted prediabetes prevalence increased from 27.4% (95% CI 25.1–29.7) in 1999–2002 to 34.1% (32.5–35.8) in 2007–2010. Among adults aged ≥18 years, the prevalence increased from 29.2% (26.8–31.8) to 36.2% (34.5–38.0). As single measures among individuals aged ≥12 years, A1C5.7 prevalence increased from 9.5% (8.4–10.8) to 17.8% (16.6–19.0), a relative increase of 87%, whereas [impaired fasting glucose] remained stable. These prevalence changes were similar among the total population, across subgroups, and after controlling for covariates.” (K. McKeever Bullard, hjo1@cdc.gov)
The rising prevalence of prediabetes has many implications, editorialists write (
pp. 2139–41). They recommend these actions upon diagnosis: “Once prediabetes is identified, the question of how best to reduce progression to diabetes and [cardiovascular disease (CVD)] remains. Both lifestyle changes and metformin can delay progression from [impaired glucose tolerance] to diabetes. Lifestyle modification can also reduce CVD risk factors up to 10 years later. To prevent progression of prediabetes, the American Diabetes Association recommends weight loss, moderate exercise, consideration of metformin (for those with BMI >35 kg/m2, age <60 years, or women with a history of gestational diabetes mellitus), and treatment of modifiable CVD risk factors.” (C. S. Fox, foxca@nhlbi.nih.gov)
SGLT1 Effects of Canagliflozin: Inhibition of sodium glucose cotransporter (SGLT) 1 receptors in the intestine contributes to canagliflozin’s actions on postprandial plasma glucose and insulin levels, researchers report (pp. 2154–61). The agent, primarily an SGLT 2 inhibitor, is also a low-potency SGLT 1 inhibitor. In a crossover study of 20 health study participants, these effects on the rates of appearance of radiolabelled oral glucose (RaO) were identified with placebo or canagliflozin 300 mg: “Compared with placebo, canagliflozin treatment reduced postprandial plasma glucose and insulin excursions (incremental 0- to 2-h area under the curve [AUC0–2h] reductions of 35% and 43%, respectively; P < 0.001 for both), increased 0- to 6-h urinary glucose excretion (UGE0–6h, 18.2 ± 5.6 vs. <0.2 g; P < 0.001), and delayed RaO. Canagliflozin reduced AUC RaO by 31% over 0 to 1 h (geometric means, 264 vs. 381 mg/kg; P < 0.001) and by 20% over 0 to 2 h (576 vs. 723 mg/kg; P = 0.002). Over 2 to 6 h, canagliflozin increased RaO such that total AUC RaO over 0 to 6 h was <6% lower versus placebo (960 vs. 1,018 mg/kg; P = 0.003).… Total glucose disposal over 0 to 6 h was similar across groups.” (D. Polidori, dpolido1@its.jnj.com)

>>>Medical Care Report
Source:
Aug. issue of Medical Care (2013; 51).
Opioid Prescribing in Emergency Departments: Potentially inappropriate prescribing and misuse of opioids was found in 10% of patients seen in emergency departments (EDs), a study shows (pp. 646–53). Using the 2009 Truven Health MarketScan Research Databases, researchers examined ED visits of enrollees aged 18–64 years to detect opioid prescriptions overlapping by 1 week or more; overlapping opioid and benzodiazepine prescriptions; high daily doses (≥100 morphine milligram equivalents); long-acting/extended-release (LA/ER) opioids for acute pain; and overlapping LA/ER opioids. Results showed: “We identified 400,288 enrollees who received at least one ED opioid prescription. At least one indicator applied to 10.3% of enrollees: 7.7% had high daily doses; 2.0% had opioid overlap; 1.0% had opioid-benzodiazepine overlap. Among LA/ER opioid prescriptions, 21.7% were for acute pain, and 14.6% were overlapping. Females were more likely to have at least one indicator.” (J. Logan)

>>>PNN NewsWatch
* FDA yesterday approved a simpler and faster test for Mycobacterium tuberculosis complex, one that also detects resistance to rifampin. The Xpert MTB/RIF Assay (Cepheid) tests for mycobacterial DNA and rifampin-resistance mutations. Results are available in 2 hours rather than the weeks currently 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 29, 2013 * Vol. 20, No. 144
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
July 27 issue of Lancet (2013; 382).
Iodine Status During Pregnancy & Cognitive Outcomes: Adequate iodine status early in pregnancy is associated with better cognitive development of children, a study shows, and assuring adequate iodine can be important even in countries such as the U.K. that are largely iodine replete (pp. 331–7). Based on “increasing evidence suggest[ing] that [the U.K.] might now be mildly iodine deficient,” investigators conducted the Avon Longitudinal Study of Parents and Children (ALSPAC). It tested for maternal iodine status in pregnancy and childhood intelligence quotient (IQ) scores at 8 years and reading ability at 9 years. Results showed: “The group was classified as having mild-to-moderate iodine deficiency on the basis of a median urinary iodine concentration of 91.1 µg/L (IQR 53.8–143; iodine-to-creatinine ratio 110 µg/g, IQR 74–170). After adjustment for confounders, children of women with an iodine-to-creatinine ratio of less than 150 µg/g were more likely to have scores in the lowest quartile for verbal IQ (odds ratio 1.58, 95% CI 1.09–2.30; p = 0.02), reading accuracy (1.69, 1.15–2.49; p = 0.007), and reading comprehension (1.54, 1.06–2.23; p = 0.02) than were those of mothers with ratios of 150 µg/g or more. When the less than 150 µg/g group was subdivided, scores worsened ongoing from 150 µg/g or more, to 50–150 µg/g, to less than 50 µg/g.” (M. P. Rayman, m.rayman@surrey.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Peer Academic Detailing & Antibiotic Prescribing: Antibiotic prescribing for acute respiratory tract infections was improved among general practitioners in Norway through visits from peer academic detailers and 1-day seminars, a study shows (f4403). Intervention groups were presented with national antibiotic prescribing guidelines during an initial visit and feedback on prescribing at a second visit. One-day seminars reinforced content presented during visits, with these results: “In an adjusted, multilevel model, the effect of the intervention on the 39 intervention groups (183 general practitioners) was a reduction (odds ratio 0.72, 95% confidence interval 0.61 to 0.84) in prescribing of antibiotics for acute respiratory tract infections compared with the controls (40 continuing medical education groups with 199 general practitioners). A corresponding reduction was seen in the odds (0.64, 0.49 to 0.82) for prescribing a non-penicillin V antibiotic when an antibiotic was issued. Prescriptions per 1,000 listed patients increased from 80.3 to 84.6 in the intervention arm and from 80.9 to 89.0 in the control arm, but this reflects a greater incidence of infections (particularly pneumonia) that needed treating in the intervention arm.” (S. Gjelstad, svein.gjelstad@medisin.uio.no)

>>>PNN NewsWatch
* FDA on Friday added new limits on the use of ketoconazole oral tablets and warnings about liver and adrenal gland problems associated with use of the drug. According to revised labeling and a new Medication Guide, ketoconazole oral tablets should not be a first-line treatment for any fungal infection and should be used for endemic mycoses only when alternative antifungal therapies are not available or tolerated. Topical formulations of ketoconazole have not been associated with liver damage, adrenal problems, or drug interactions, FDA added.
* Consumers should not use or purchase
Healthy Life Chemistry By Purity First B-50, FDA warned on Friday. The product is marketed as a vitamin B dietary supplement, but FDA analysis indicated presence of the anabolic steroids methasterone and dimethazine.

>>>PNN JournalWatch
* Pancreas Transplant Alone: A Procedure Coming of Age, in
Diabetes Care, 2013; 36: 2440–7. (R. W.G. Gruessner, rgruessner@surgery.arizona.edu)
* Trends and Predictors of Quality of Care in VA Nursing Homes Related to Serious Mental Illness, in
Medical Care, 2013; 51: 659–65. (H. Kim)
* Epigenetics Primer: Why the Clinician Should Care About Epigenetics, in
Pharmacotherapy, 2013; DOI: 10.1002/phar.1325. (J. D. Duarte, juliod@uic.edu)
* Penicillin Skin Testing: Potential Implications for Antimicrobial Stewardship, in
Pharmacotherapy, 2013; 33: 856–67. (N. R. Unger, nunger@nova.edu)
* Understanding Why Patients Of Low Socioeconomic Status Prefer Hospitals Over Ambulatory Care, in
Health Affairs, 2013; 32: 1196–203. (S. Kangovi, kangovi@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 30, 2013 * Vol. 20, No. 145
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2013; 33).
Palivizumab Prophylaxis for Respiratory Syncytial Virus in NICU: In 176 extremely low-birth-weight male infants with hemodynamically significant congenital heart disease, palivizumab was an effective prophylactic agent during outbreaks of respiratory syncytial virus (RSV) infection, according to a retrospective analysis that used an artificial intelligence model (DOI: 10.1002/phar.1333). Investigators looked at medical records of patients in a neonatal intensive care unit (NICU) and used artificial neural networks to assess patterns of prophylaxis and infections after identification of index cases in 2005–07: “Of the 176 infants, 31 (17.6%) received palivizumab during the outbreaks. All neural network configurations converged within 4 seconds in less than 400 training cycles. Infants who received palivizumab required supplemental oxygen for a shorter duration compared with controls (105.2 ± 7.2 days vs 113.2 ± 10.4 days, p = 0.003). This benefit was statistically significant in male infants whose birth weight was less than 0.7 kg and who had hemodynamically significant congenital heart disease. Length of NICU stay after identification of the index case and mortality were independent of palivizumab use.” (L. M. Saadah, loai_m_s@hotmail.com)
Adherence to Vancomycin Dosing, Monitoring Guidelines: “Many opportunities for future research and quality improvement strategies” with regard to vancomycin dosing and monitoring are revealed in a survey of 163 members of the Making a Difference in Infectious Diseases Pharmacotherapy (MAD-ID) Research Network (DOI: 10.1002/phar.1327): “The survey population represented a wide range of patient populations (96% adult, 49% pediatric, and 23% long-term care) and settings (52% not-for-profit nonuniversity, 31% university based, and 11% for profit). Automatic consultation of pharmacy services for all vancomycin dosing was reported in 51% of the institutions. Among the dosing and monitoring practices endorsed by the consensus guidelines, participant institutions commonly followed these recommendations: use of trough concentrations without peak concentrations, maintenance of trough concentration higher than 10 mg/L, and target trough concentrations of 15–20 mg/L for complicated infections. In contrast, there was less consistent application of appropriate timing of trough concentrations, use of loading doses, and use of actual body weight.” (M. J. Rybak, m.rybak@wayne.edu)

>>>Psychiatry Highlights
Source:
July issue of the American Journal of Psychiatry (2013; 170).
Antidepressants in Anxiety: Escitalopram, added to cognitive-behavioral therapy (CBT), produces short-term reductions in worry symptoms, researchers report (pp. 782–9). The 73 study participants were 60 years or older and had generalized anxiety disorder. Open-label escitalopram with or without CBT showed these effects: “Escitalopram augmented with CBT increased response rates on the Penn State Worry Questionnaire but not on the Hamilton Anxiety Rating Scale compared with escitalopram alone. Both escitalopram and CBT prevented relapse compared with placebo.” (J. L. Wetherell, jwetherell@ucsd.edu)

>>>PNN NewsWatch
* Serious and sometimes permanent neurologic and psychiatric adverse effects can occur with the antimalarial drug mefloquine, FDA warned yesterday. A boxed warning about these problems is being added to product labeling. Neurologic adverse effects can include dizziness, loss of balance, or ringing in the ears. Psychiatric adverse effects can include feeling anxious, mistrustful, depressed, or having hallucinations.
* Class-specific changes in
antibiotic use, rather than overall reductions, need to be considered in order to achieve the greatest benefit from antibiotic-reduction campaigns, according to an early-release article scheduled for publication in the Sept. issue of Antimicrobial Agents and Chemotherapy. “This underlines the importance of generating surveillance data on both antibiotic class-specific changes in antibiotic use and antibiotic resistance in the years following an antibiotic reduction campaign,” said author Laura Temime of the Conservatoire National des Arts et Metiers, Paris. “We believe that this research may help health policy makers and physicians in the design of more efficient antibiotic-reduction campaigns.”

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
July 31, 2013 * Vol. 20, No. 146
Providing news and information about medications and their proper use

>>>Nephrology Highlights
Source:
Aug. American Journal of Kidney Diseases (2013; 62).
Vaptans in Hyponatremia: Vasopressin receptor antagonists in the vaptan class are reviewed with respect to use in patients with hyponatremia (pp. 364–76): “Hyponatremia, the most commonly encountered electrolyte abnormality, affects as many as 30% of hospitalized patients. It is a powerful predictor of poor outcomes, especially in patients with congestive heart failure or cirrhosis. The failure to excrete electrolyte-free water that results from persistent secretion of antidiuretic hormone despite low serum osmolality usually underlies the development of hyponatremia. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. This review focuses on the role of the vasopressin receptor antagonists, or vaptans, in the treatment of hyponatremia. These recently introduced agents have the unique ability to induce an aquaresis, the excretion of electrolyte-free water without accompanying solutes. After a brief historical perspective and discussion of pharmacologic characteristics of vaptans, we review the accumulated experience with vaptans for the treatment of hyponatremia. Vaptans have been shown to increase serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia in a reproducible manner, but their safe use requires full understanding of their indications and contraindications.” (A. Greenberg, arthur.greenberg@duke.edu)
Critique of Global Guideline for BP Management in CKD: In a commentary, U.S. experts convened by the National Kidney Foundation criticize the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for blood pressure management in patients with chronic kidney disease (CKD) not on dialysis (pp. 201–13). Citing a “dearth of clinical trial evidence to provide strong evidence-based recommendations.” the experts write: “For patients with CKD with normal to mildly increased albuminuria, goal blood pressure has been relaxed to ≤140/90 mm Hg for both diabetic and nondiabetic patients. In contrast, KDIGO continues to recommend goal blood pressure ≤130/80 mm Hg for patients with chronic kidney disease with moderately or severely increased albuminuria and for all renal transplant recipients regardless of the presence of proteinuria, without supporting data. The expert panel thought the KDIGO recommendations were generally reasonable but lacking in sufficient evidence support and that additional studies are greatly needed.” (R. R. Townsend, townsend@exchange.upenn.edu)
BP Misclassification Based on Office Measurements: Comparing office-based blood pressure (BP) measurements with values from 24-hour ambulatory monitoring, investigators find that clinicians relying on office values misclassify one in three patients with hypertension and chronic kidney disease (CKD) (pp. 285–94). Among 5,693 patients in a Spanish registry, these patterns were evident: “The proportion with white-coat hypertension was 28.8% (36.8% of patients with office BP ≥140/90 mm Hg) and that of masked hypertension was 7.0% (but 32.1% of patients with office BP <140/90 mm Hg). Female sex, aging, obesity, and target-organ damage were associated with white-coat hypertension; aging and obesity were associated with masked hypertension. Only 21.7% and 8.1% of the CKD population had office BP <140/90 and <130/80 mm Hg, respectively. In contrast, 43.5% of individuals had average 24-hour BP <130/80 mm Hg.” (M. Gorostidi, manuel.gorostidi@sespa.princast.es)

>>>Health Affairs Report
Source:
July issue of Health Affairs (2013; 32).
Fluoxetine Savings Not Captured by Medicaid Programs: As generic fluoxetine came onto the U.S. market, state Medicaid programs missed $220 million in potential savings, researchers report (pp. 1204–11). Analysis of state Medicaid drug-utilization data maintained by CMS showed “large differences in states’ responses to generic availability.” The authors add: “States took between two and ten calendar quarters to reach 90 percent use of generic rather than brand-name fluoxetine and four to eight quarters to achieve a 50 percent decrease in reimbursement per pill.” (C. M. L. Kelton, chris.kelton@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 1, 2013 * Vol. 20, No. 147
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 1 issue of the New England Journal of Medicine (2013; 369).
Rituximab in ANCA-Associated Vasculitis: Patients who received a single dose of rituximab for severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis had noninferior 18-month outcomes compared with continuous conventional immunosuppressive therapy, researchers report (pp. 417–27). Participants in the RAVE trial received rituximab followed by placebo or cyclophosphamide administered for 3–6 months followed by azathioprine for 12–15 months, with these results: “A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide–azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P < 0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P = 0.01) and at 12 months (P = 0.009) but not at 18 months (P = 0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events.” (J. H. Stone, jhstone@partners.org)
Reacting to RAVE investigators making participant-level data available without requestors having a specific research plan or approved qualifications, an editorialist ponders questions created by such openness (
pp. 468–9): “As we consider the path ahead, key questions to ask of each new data-disclosure policy include the following. First, for which trials will participant-level data be available? In particular, will the policy perpetuate a dissemination bias by increasing the amount of information available for some trials while keeping other trial results inaccessible? Second, exactly what data and supporting documents will be available? Third, what will the process be, and how transparent will it be? For example, who will get access, who will decide, and what criteria will be used? What types of analyses of the participant-level data will be allowed, and what ongoing role would the trial sponsor have?” (D. A. Zarin)
Lenalidomide in High-Risk Smoldering Multiple Myeloma: In an open-label, Phase III trial, early treatment of high-risk smoldering myeloma with lenalidomide plus dexamethasone delayed progression to active disease and increased overall survival (pp. 438–47). Induction with the two drugs in 119 patients was followed by maintenance therapy with lenalidomide alone. Results showed: “After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P < 0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P = 0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower.” (J-F San Miguel, sanmiguel@usal.es)
Patient-Centered Oncologic Drug Development: Greater emphasis on patients is needed as drugs are developed for cancer, the author of a Perspective article writes (pp. 397–400): “The principal barrier remains a failure to prioritize the identification and confrontation of [patient] challenges up front. Moreover, when [patient-reported outcome] measurement is left until the postmarketing phase, it is often too late to adequately measure outcomes in a comparative trial, which leaves the true effect of a product on the patient experience uncertain. Ideally, moving forward, whenever representatives of a pharmaceutical company and a regulatory agency sit down to discuss a product-development program, they will ask the same question my patients ask of me: ‘How does this product make people feel?’” (E. Basch)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 2, 2013 * Vol. 20, No. 148
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Aug. issue of Pediatrics (2013; 132).
Dosing of 13-Valent Pneumococcal Conjugate Vaccine: The third dose in the 13-valent pneumococcal conjugate vaccine (PCV13) series costs $500 million and averts a moderate amount of disease and 2.5 deaths, a cost-effectiveness study concludes (pp. e324–32). Using a societal perspective, investigators applied a probabilistic model to a single birth cohort of 4.3 million and determined costs and disease burden with and without the 6-month dose of PCV13. Results showed: “Removing the third dose of PCV13 would annually save $500 million (in 2011$) but would also result in an estimated 2.5 additional deaths among inpatients with pneumonia or invasive pneumococcal disease. Such dose removal would also result in 261,000 estimated otitis media and 12,000 estimated pneumonia cases annually. These additional illnesses could be prevented through modest increases in coverage. Overall, societal savings per additional life-year lost would be ~$6 million. When nonfatal outcomes are also considered, savings would range from $143,000 to $4 million per additional quality adjusted life–year lost, depending on the assumptions used for otitis media.” (C. Stoecker)
Prenatal Alcohol Exposure & Educational Achievement: Depending on the dose, pattern, and timing of prenatal alcohol exposure, educational achievement at 8–9 years of age varies, researchers report (pp. e468–75). From the Randomly Ascertained Sample of Children born in Australia’s Largest State Study cohort, records for 4,056 infants born in 1995–97 showed these patterns based on children’s achievement of national benchmarks in school numeracy, reading, spelling, and writing tests and nonattendance for the tests: “Children were twice as likely not to achieve the benchmark for reading after heavy prenatal alcohol exposure during the first trimester (aOR 2.26; 95% CI 1.10–4.65) and for writing when exposed to occasional binge drinking in late pregnancy (aOR 2.35; 95% CI 1.04–5.43). Low-moderate prenatal alcohol exposure was not associated with academic underachievement.” (C. M. O’Leary)

>>>Psychiatry Report
Source:
Aug. issue of the American Journal of Psychiatry (2013; 170).
Precessation Nicotine Patches & Treatment Adaptations: Reductions in ad-lib use of tobacco while on precessation nicotine patches can indicate whether a patient is likely to succeed in stopping smoking on patches alone, a study shows (pp. 860–7). In a double-blind, parallel-arm adaptive treatment trial, 606 cigarette smokers received open-label nicotine patch therapy for 2 weeks before their quit dates. Those whose ad-lib smoking did not decrease by more than 50% were randomly assigned to nicotine patch alone, “rescue” treatment with bupropion augmentation, or rescue treatment with varenicline alone. Those whose smoking decreased by 50% or more but who lapsed after the quit date were randomly assigned to one of the rescue treatments. Results showed: “Smokers who did not respond adequately to precessation nicotine patch benefited from bupropion augmentation; abstinence rates at end of treatment were 16% with nicotine patch alone and 28% with bupropion augmentation (odds ratio = 2.04, 95% CI = 1.03–4.01). Switching to varenicline produced less robust effects, but point abstinence at 6 months was 6.6% with the patch alone and 16.5% with a switch to varenicline (odds ratio = 2.80, 95% CI = 1.11–7.06). Postquit adaptive changes in treatment had no significant effects on any abstinence outcome.” (J. E. Rose, jed.rose@duke.edu)

>>>PNN NewsWatch
* FDA yesterday warned consumers of rare but serious skin reactions with acetaminophen. The reactions—Stevens–Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis—can be fatal. Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen, FDA said. Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away, FDA added, and anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 5, 2013 * Vol. 20, No. 149
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 3 issue of Lancet (2013; 382).
Individualized Treatment Targets in Diabetes: For patients with type 2 diabetes, clinicians can use individualized A1C target levels during treatment with vildagliptin without tolerability issues, according to a study conducted in an older population (pp. 409–16). In a European study, drug-naive or inadequately controlled patients aged 70 years or older were assigned individualized treatment targets based on age, baseline A1C, comorbidities, and frailty status. Randomized treatment with vildagliptin 50 mg once or twice daily or placebo yielded these outcomes: “Between Dec 22, 2010, and March 14, 2012, we randomly assigned 139 patients each to the vildagliptin and placebo groups. 37 (27%) of 137 patients in the placebo group achieved their individualised targets by education and interactions with the study team alone and 72 (52.6%) of 137 patients achieved their target in the vildagliptin group (adjusted odds ratio 3.16, 96.2% CI 1.81–5.52; p < 0.0001). This finding was accompanied by a clinically relevant 0.9% reduction in HbA1c from a baseline of 7.9% with vildagliptin and a between-group difference of –0.6% (98.8% CI –0.81 to –0.33; p < 0.0001). The overall safety and tolerability was similar in the vildagliptin and placebo groups, with low incidence of hypoglycaemia and no emergence of new safety signals.” (W. D. Strain, d.strain@exeter.ac.uk)
Initial Treatment of Intracerebral Hematomas: In patients with spontaneous supratentorial lobar intracerebral hematomas, the STICH II study confirms that “early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage” for those without intraventricular hemorrhage (pp. 397–408). Among 297 patients assigned to early surgical hemotoma evacuation (within 12 hours of randomization), 59% had an unfavorable outcome, slightly less than the 62% of 286 patients on early conservative medical therapy (odds ratio 0.86 [0.62 to 1.20]; p = 0.367). (B. A Gregson, barbara.gregson@ncl.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Severe Hypoglycemia & Cardiovascular Disease: In patients with type 2 diabetes, severe hypoglycemia is associated with increased risk of cardiovascular disease, a meta-analysis shows (f4533). In addition to assessing the strength of available data for this relationship, investigators used a bias analysis “to examine the sensitivity of the association to possible uncontrolled confounding by unmeasured comorbid severe illness”: “Of 3,443 citations screened, six eligible studies with 903,510 participants were identified. In the conventional random effects meta-analysis, severe hypoglycaemia was strongly associated with a higher risk of cardiovascular disease (relative risk 2.05, 95% confidence interval 1.74 to 2.42; P < 0.001). The excess fraction of cardiovascular disease incidence that was attributable to severe hypoglycaemia (the population attributable fraction) was 1.56% (95% confidence interval 1.32% to 1.81%; P < 0.001). Although moderate heterogeneity across the studies was suggested (I2 = 73.1%; P = 0.002 for heterogeneity), most subgroups showed similar results in stratified analyses. The bias analysis indicated that comorbid severe illness alone may not explain the association between hypoglycaemia and cardiovascular disease; to explain this association, comorbid severe illness would have had to be extremely strongly associated with both severe hypoglycaemia and cardiovascular disease.” (M. Noda, mnoda@hosp.ncgm.go.jp)

>>>PNN JournalWatch
* DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale, in
American Journal of Psychiatry, 2013; 170: 834–51. (D. S. Hasin, dsh2@columbia.edu)
* Efficacy of Functional Remediation in Bipolar Disorder: A Multicenter Randomized Controlled Study, in
American Journal of Psychiatry, 2013; 170: 852–9. (E. Vieta, evieta@clinic.ub.es)
* Strategies for More Rapid Translation of Cellular Therapies for Children: A US Perspective, in
Pediatrics, 2013; 132: 351–8. (R. Sanchez)
* Clinical Reasoning for the Infectious Disease Specialist: A Primer to Recognize Cognitive Biases, in
Clinical Infectious Diseases, 2013; 57: 573–8. (J. M. Rodriguez, mrodri2@uab.edu)
* Epigenetics Primer: Why the Clinician Should Care About Epigenetics, in
Pharmacotherapy, 2013; 33: DOI 10.1002/phar.1325. (J. D. Duarte, juliod@uic.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 6, 2013 * Vol. 20, No. 150
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 6 issue of the Annals of Internal Medicine (2013; 159).
Personalized Estimates of Benefit From Preventive Care : Magnitude and rank order of personalized estimates of benefits can help patients understand the value of such preventive interventions, researchers report (pp. 161–8). Using a mathematical model with a lifetime horizon and individual perspective, the investigators estimated personalized gain in life expectancy associated with various U.S. Preventive Services Task Force (USPSTF) recommendations for nonpregnant adults: “Increases in life expectancy varied more than 100-fold across USPSTF recommendations, and the rank order of benefits varied considerably among patients. For an obese man aged 62 years who smoked and had hypercholesterolemia, hypertension, and a family history of colorectal cancer, the model’s top 3 recommendations (from most to least gain in life expectancy) were tobacco cessation (adding 2.8 life–years), weight loss (adding 1.6 life–years), and blood pressure control (adding 0.8 life–year). Lower-ranked recommendations were a healthier diet, aspirin use, cholesterol reduction, colonoscopy, screening for abdominal aortic aneurysm, and HIV testing (each adding 0.1 to 0.3 life–years). For a person with the same characteristics plus uncontrolled type 2 diabetes mellitus, the model’s top 3 recommendations were diabetes control, tobacco cessation, and weight loss (each adding 1.4 to 1.8 life–years).” (G. B. Taksler, glentaksler@gmail.com)
Primary-Care Interventions To Reduce Alcohol Misuse: In an update of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening and behavioral counseling interventions in primary care to reduce alcohol misuse, the task force makes two recommendations (pp. 210–8):
* The USPSTF recommends that clinicians screen adults aged 18 years or older for alcohol misuse and provide persons engaged in risky or hazardous drinking with brief behavioral counseling interventions to reduce alcohol misuse. (Grade B recommendation)
* The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening and behavioral counseling interventions in primary care settings to reduce alcohol misuse in adolescents. (I statement)
The recommendations apply to adolescents aged 12–17 years and adults but not to those seeking evaluation or treatment for alcohol misuse, the Task Force wrote. (
www.uspreventiveservicestaskforce.org)
Self-Measured Blood Pressure Monitoring: Self-monitoring of blood pressure (BP) in adults with hypertension, recommended in clinical guidelines, lowers BP, a review article concludes (pp. 185–94). However, the authors add, “The BP effect beyond 12 months and long-term benefits remain uncertain”: “For [self-measured blood pressure (SMBP)] monitoring alone versus usual care (26 comparisons), moderate-strength evidence supports a lower BP with SMBP monitoring at 6 months (summary net difference, −3.9 mm Hg and −2.4 mm Hg for systolic BP and diastolic BP) but not at 12 months. For SMBP monitoring plus additional support versus usual care (25 comparisons), high-strength evidence supports a lower BP with use of SMBP monitoring, ranging from −3.4 to −8.9 mm Hg for systolic BP and from −1.9 to −4.4 mm Hg for diastolic BP, at 12 months in good-quality studies. For SMBP monitoring plus additional support versus SMBP monitoring alone or with less intense additional support (13 comparisons), low-strength evidence fails to support a difference. Across all comparisons, evidence for clinical outcomes is insufficient. For other surrogate or intermediate outcomes, low-strength evidence fails to show differences.” (K. Uhlig)
Adding Laypersons to Primary-Care Teams: Lay “care guides” on primary-care teams “can improve care for some patients with chronic disease at low cost,” a study shows (pp. 176–84). In six Minnesota clinics, these outcomes were noted for 2,135 patients over a 1-year period: “Patients with care guides achieved more goals than usual care patients (82.6% vs. 79.1%; odds ratio, 1.31 [95% CI, 1.16 to 1.47]; P < 0.001); reduced unmet goals by 30.1% compared with 12.6% for usual care patients; and improved more than usual care patients in meeting several individual goals, including not using tobacco. Estimated cost was $286 per patient per year.” (K. Radel, kimberly.radel@allina.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 7, 2013 * Vol. 20, No. 151
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article and Aug. 7 issue of JAMA (2013; 310).
Naltrexone in Alcohol Dependence & PTSD: Among patients with comorbid alcohol dependence and posttraumatic stress disorder (PTSD), the percentage of days drinking was significantly reduced by naltrexone therapy, a study shows (pp. 488–95). Prolonged exposure therapy—consisting of 12 weekly 90-minute sessions followed by 6 biweekly sessions during which imaginal therapy was used to revisit and process traumatic events—did not exacerbate participants’ alcohol-use disorders. The single-blind trial included 165 participants and used the Timeline Follow-Back Interview and the PTSD Symptom Severity Interview to assess the percentage of days drinking alcohol and PTSD severity, respectively, with these results: “Participants in all 4 treatment groups had large reductions in the percentage of days drinking (mean change, −63.9% [95% CI, −73.6% to −54.2%] for prolonged exposure therapy plus naltrexone; −63.9% [95% CI, −73.9% to −53.8%] for prolonged exposure therapy plus placebo; −69.9% [95% CI, −78.7% to −61.2%] for supportive counseling plus naltrexone; and −61.0% [95% CI, −68.9% to −53.0%] for supportive counseling plus placebo). However, those who received naltrexone had lower percentages of days drinking than those who received placebo (mean difference, 7.93%; P = .008). There was also a reduction in PTSD symptoms in all 4 groups, but the main effect of prolonged exposure therapy was not statistically significant. Six months after the end of treatment, participants in all 4 groups had increases in percentage of days drinking. However, those in the prolonged exposure therapy plus naltrexone group had the smallest increases.” (E. B. Foa, foa@mail.med.upenn.edu)
This “study provides evidence regarding the treatment of this commonly occurring comorbidity and provides hope that the gap in treatment provision for this population may begin to narrow,” an editorialist writes while noting these study limitations (
pp. 482–3): “Research undertaken with this population is particularly challenging. This is not surprising given the nature of the research, in which participants are asked to confront some of the most terrifying events that have ever happened to them, and simultaneously try to abstain from using alcohol and other drugs, which are often the only means by which they have felt that they could cope with the consequences of those events. Nonetheless, the small group sizes and low rate of retention in the study by Foa and colleagues limited the analyses that could be conducted. Only 56% of the original cohort completed the posttreatment and follow-up interviews. It is unclear whether retention in the study was related to any baseline characteristics (eg, severity of alcohol use or PTSD), which may have introduced bias in the results.” (K. Mills)
Pharmacovigilance, Liability for Generic Drugs: Three U.S. Supreme Court decisions handed down over the past 4 years have both eliminated any liability of generic-drug manufacturers for adverse effects and made it unlikely that new adverse drug events with these products will be identified unless FDA acts or the Sentinel System to improve pharmacovigilance continues, according to authors of a Viewpoint article (doi: 10.1001/jama.2013.228349): “As generic drugs come to make up an ever-larger share of medication use, the likelihood will increase that knowledge about a drug’s risks will remain incomplete or poorly characterized at the time a generic version is introduced. This trio of Supreme Court decisions, followed by the FDA’s recent stated rulemaking intentions, sets the stage for creation of an independent organization with pharmacoepidemiologic expertise to assess the adverse effects of generic drugs in concert with the agency. Whatever the future of Sentinel, this research effort could leverage the rapid proliferation of public and private data sets that make enormous populations available for such systematic adverse-effect surveillance. The results of these analyses could be provided to the FDA, which would determine whether the common generic drug label needed to be adjusted or whether accumulating data about the relative risks of potentially fatal adverse events for drugs like sulindac meant that it remained as safe as others in its class, required additional labeling, or should be taken off the market.” (A. S. Kesselheim, akesselheim@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 8, 2013 * Vol. 20, No. 152
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 8 issue of the New England Journal of Medicine (2013; 369).
Ibrutinib in Mantle-Cell Lymphoma: In a Phase II study of 111 patients with relapsed or refractory mantle-cell lymphoma, oral ibrutinib 560 mg/d showed “durable single-agent efficacy,” researchers report (pp. 507–16). Ibrutinib (PCI-32765) is an orally active irreversible inhibitor of the cytoplasmic protein Bruton’s tyrosine kinase; BTK is implicated in the pathogenesis of B-cell cancers. Patients were categorized as having received at least 2 cycles of bortezomib therapy or 2 or fewer such cycles. Results showed: “The median age was 68 years, and 86% of patients had intermediate-risk or high-risk mantle-cell lymphoma according to clinical prognostic factors. Patients had received a median of three prior therapies. The most common treatment-related adverse events were mild or moderate diarrhea, fatigue, and nausea. Grade 3 or higher hematologic events were infrequent and included neutropenia (in 16% of patients), thrombocytopenia (in 11%), and anemia (in 10%). A response rate of 68% (75 patients) was observed, with a complete response rate of 21% and a partial response rate of 47%; prior treatment with bortezomib had no effect on the response rate. With an estimated median follow-up of 15.3 months, the estimated median response duration was 17.5 months (95% confidence interval [CI], 15.8 to not reached), the estimated median progression-free survival was 13.9 months (95% CI, 7.0 to not reached), and the median overall survival was not reached. The estimated rate of overall survival was 58% at 18 months.” (M. L. Wang, miwang@mdanderson.org)
“A phase 3 study of ibrutinib in combination with bendamustine and rituximab as front-line therapy in mantle-cell lymphoma (NCT01776840) is ongoing, as is a phase 1b trial (NCT01569750) assessing the feasibility of incorporating ibrutinib into the combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP),” editorialists write (
pp. 571–2). “These and other studies currently planned (e.g., to test the usefulness of ibrutinib in the context of maintenance treatment strategies) will clarify the proper place of this compound in the management of mantle-cell lymphoma, a disease whose refractoriness to treatment may be yielding to new agents.” (E. Zucca)
Glucose Levels & Dementia: Patients with elevated glucose levels—including those without diabetes—may be at higher risk of developing dementia, according to a regression analysis of data from the Adult Changes in Thought study (pp. 540–8). Among 232 participants with diabetes and 1,835 participants without the condition (mean age, 76), these patterns were noted: “During a median follow-up of 6.8 years, dementia developed in 524 participants (74 with diabetes and 450 without). Among participants without diabetes, higher average glucose levels within the preceding 5 years were related to an increased risk of dementia (P = 0.01); with a glucose level of 115 mg per deciliter (6.4 mmol per liter) as compared with 100 mg per deciliter (5.5 mmol per liter), the adjusted hazard ratio for dementia was 1.18 (95% confidence interval [CI], 1.04 to 1.33). Among participants with diabetes, higher average glucose levels were also related to an increased risk of dementia (P = 0.002); with a glucose level of 190 mg per deciliter (10.5 mmol per liter) as compared with 160 mg per deciliter (8.9 mmol per liter), the adjusted hazard ratio was 1.40 (95% CI, 1.12 to 1.76).” (P. K. Crane, pcrane@uw.edu)
Achieving Single-Payer Efficiencies in the U.S.: A “payer-agnostic” strategy of care provided by Children’s Hospital of Los Angeles and AltaMed Health Services—patient-centric care is provided regardless of insurance status—shows how the advantages of a single-payer system can be achieved in the complicated U.S. health care financing system, authors write (pp. 502–3): “A shift toward a single standard of care is important not only from an ethical standpoint but also, we believe, for improving operational efficiency. It also aligns with new care-delivery models, such as the patient-centered medical home and accountable care organizations aimed at improving the quality and efficiency of care. If insurers and provider groups can make the leap together, it may be possible to reap some of the benefits of single-payer health care within the existing multipayer system.” (M. E. Hochman)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 9, 2013 * Vol. 20, No. 153
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Aug. 13 issue of the Journal of the American College of Cardiology (2013; 62).
Prasugrel 5 mg in Very Elderly Patients: In patients 75 years of age or older with stable coronary artery disease (CAD) and receiving aspirin, prasugrel 5 mg was noninferior to prasugrel 10 mg in nonelderly (NE) patients, the GENERATIONS study shows (pp. 577–83). Investigators looked at pharmacodynamic (PD) response and active metabolite pharmacokinetics (PKs) in 73 very elderly (VE) patients, and 82 NE (45–64 years) patients who were receiving prasugrel 5 and 10 mg and clopidogrel 75 mg in three periods of 12 days each in blinded, crossover fashion. Results showed: “Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, [maximum platelet aggregation] was significantly lower (57 ± 14%) than clopidogrel (63 ± 14%; p < 0.001) in VE but higher than prasugrel 10 mg in NE (46 ± 12%; p < 0.001). PD response by [light transmission aggregometry, VerifyNow P2Y12, and vasodilator-associated stimulated phosphoprotein] during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg.” (D. Erlinge)
Obstructive Sleep Apnea: Two articles explore risks of obstructive sleep apnea (OSA).
Among 10,701 consecutive adults undergoing their first diagnostic polysomnogram in 1987–2003 who were followed longitudinally for up to 15 years, presence of OSA was associated with incident sudden cardiac death (SCD), researchers report (
pp. 610–6). Physiological data on the apnea-hypopnea index (AHI), nocturnal oxygen saturation (O2sat), and relevant comorbidities showed these relationships with OSA: “During an average follow-up of 5.3 years, 142 patients had resuscitated or fatal SCD (annual rate 0.27%). In multivariate analysis, independent risk factors for SCD were age, hypertension, coronary artery disease, cardiomyopathy or heart failure, ventricular ectopy or nonsustained ventricular tachycardia, and lowest nocturnal O2sat (per 10% decrease, hazard ratio [HR]: 1.14; p = 0.029). SCD was best predicted by age >60 years (HR: 5.53), apnea-hypopnea index >20 (HR: 1.60), mean nocturnal O2sat <93% (HR: 2.93), and lowest nocturnal O2sat <78% (HR: 2.60; all p < 0.0001).” (A. S. Gami)
“OSA exacerbates the cardiometabolic risk attributed to obesity and the metabolic syndrome,” conclude authors of a review article (
pp. 569–76): “Obesity predisposes to OSA, and the prevalence of OSA is increasing worldwide because of the ongoing epidemic of obesity. Recent evidence has shown that surrogate markers of cardiovascular risk, including sympathetic activation, systemic inflammation, and endothelial dysfunction, are significantly increased in obese patients with OSA versus those without OSA, suggesting that OSA is not simply an epiphenomenon of obesity. Moreover, findings from animal models and patients with OSA show that intermittent hypoxia exacerbates the metabolic dysfunction of obesity, augmenting insulin resistance and nonalcoholic fatty liver disease. In patients with the metabolic syndrome, the prevalence of moderate to severe OSA is very high (~60%). In this population, OSA is independently associated with increased glucose and triglyceride levels as well as markers of inflammation, arterial stiffness, and atherosclerosis. A recent randomized, controlled, crossover study showed that effective treatment of OSA with continuous positive airway pressure for 3 months significantly reduced several components of the metabolic syndrome, including blood pressure, triglyceride levels, and visceral fat. Finally, several cohort studies have consistently shown that OSA is associated with increased cardiovascular mortality, independent of obesity.” (L. F. Drager)

>>>PNN NewsWatch
* FDA yesterday approved the first rapid HIV test for simultaneous detection of HIV-1 p24 antigen as well as antibodies to both HIV-1 and HIV-2. Approved as an aid in the diagnosis of HIV-1 and HIV-2 infection, the Alere Determine HIV-1/2 Ag/Ab Combo test (Orgenics) is for use by trained professionals, does not distinguish between antibodies to HIV-1 and HIV-2, and is not intended to be used for screening of blood donors.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 12, 2013 * Vol. 20, No. 154
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 10 issue of Lancet (2013; 382).
Blood-Pressure Targets in Lacunar Stroke: Reduction of systolic blood pressures to less than 130 mm Hg is likely beneficial in patients with recent lacunar stroke, according to results of the SPS3 study (pp. 507–15). Comparing targets of 130–149 and less than 130 mm Hg, investigators found nonsignificant but trending results based on a primary outcome of reduction in all stroke (including ischemic strokes and intracranial hemorrhages): “3,020 enrolled patients, 1,519 in the higher-target group and 1,501 in the lower-target group, were followed up for a mean of 3.7 (SD 2.0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137–139) in the higher-target group and 127 mm Hg (95% CI 126–128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0.81, 95% CI 0.64–1.03, p = 0.08), disabling or fatal stroke (0.81, 0.53–1.23, p = 0.32), and the composite outcome of myocardial infarction or vascular death (0.84, 0.68–1.04, p = 0.32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0.37, 0.15–0.95, p = 0.03). Treatment-related serious adverse events were infrequent.” (SPS3 Study Group)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Global Eradication Rates for H. pylori Infection: Viewed worldwide, eradication rates for Helicobacter pylori using pre-existing or new therapies are suboptimal, according to a systematic review and meta-analysis of 46 randomized controlled trials (f4587): “5,666 patients were randomised to sequential therapy and 7,866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative risk 1.21, 95% confidence interval 1.17 to 1.25; I2 = 29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 10 day triple therapy (1.11, 1.04 to 1.19; I2 = 67.2%; NNT 10, 7 to 15), but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I2 = 54.3%), bismuth based therapy (1.01, 0.95 to 1.06; I2 = 21.1%), and non-bismuth based therapy (0.99, 0.94 to 1.05; I2 = 52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin.” (L. Gatta, gattalg@gmail.com)
HPV in Cervical Cancer Prevention: A review article provides useful information on the role of vaccinations against human papillomavirus (HPV) in prevention of cervical cancer, including these summary points (f4781; H. Kitchener, Henry.kitchener@manchester.ac.uk):
* Prophylactic vaccination against HPV types 16 and 18 is predicted to further reduce deaths from cervical cancer, among a screened population.
* Vaccination against HPV types 6 and 11 will result in a decline in genital warts.
* HPV testing in the screening program is now routinely used in England to triage women with low grade cytological abnormalities for colposcopy referral, and similarly for test of cure after treatment.
* HPV-negative women are at very low risk and can avoid the need for repeated annual recall, and screening intervals could be extended.
* Secondary prevention based on HPV testing with a simple treatment algorithm, if feasible in developing countries, might prevent many deaths.
* If primary prevention through vaccination were implemented in developing countries, millions of deaths from cervical cancer could be prevented over the next 50 years.

>>>PNN JournalWatch
* Bridging Immunity and Lipid Metabolism by Gut Microbiota, in
Journal of Allergy and Clinical Immunology, 2013; 132: 253–62. (N. Shulzhenko, natalia.shulzhenko@oregonstate.edu)
* Principal Component Analysis of PiB Distribution in Parkinson and Alzheimer Diseases, in
Neurology, 2013; 81: 520–7. (M. C. Campbell, meghanc@npg.wustl.edu)
* Evidence That Systemic Sclerosis Is a Vascular Disease, in
Arthritis & Rheumatism, 2013; 65: 1953–62. (F. M. Wigley, fwig@jhmi.edu)
* “Pills” and the Air Passages, in
Chest, 2013; 144: 651–60. (A. C. Mehta, Mehtaa1@ccf.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 13, 2013 * Vol. 20, No. 155
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Aug. 12/26 issue of the JAMA Internal Medicine (2013; 173).
Bacterial Whole-Genome Sequencing: Benchtop DNA sequencing platforms that can rapidly provide an accurate whole-genome sequence (WGS) “represents an important advance” in diagnostic and public health microbiology, authors conclude (pp. 1397–404). They provide two examples of WGS investigations of nosocomial outbreaks of vancomycin-resistant Enterococcus faecium and carbapenem-resistant Enterobacter cloacae: “WGS accurately discriminated between outbreak and nonoutbreak isolates and was superior to conventional typing methods. We compared WGS with standard methods for the identification of the mechanism of carbapenem resistance in a range of gram-negative bacteria (Acinetobacter baumannii, E cloacae, Escherichia coli, and Klebsiella pneumoniae). This demonstrated concordance between phenotypic and genotypic results, and the ability to determine whether resistance was attributable to the presence of carbapenemases or other resistance mechanisms. Whole-genome sequencing was used to recapitulate reference laboratory typing of clinical isolates of Neisseria meningitidis and to provide extended phylogenetic analyses of these.” (S. J. Peacock, sjp97@medschl.cam.ac.uk)
“Bacterial WGS will take diagnostics to the next level by providing unprecedented fidelity in bacterial identification and characterization,” editorialists write (
pp. 1405–6). “It will facilitate identification of single base changes or single gene acquisitions associated with novel symptoms and help elucidate the basis of acute and chronic infection. Whole-genome sequencing will facilitate tracking nosocomial infections and monitoring the spread of successful clones, as well as tracing epidemics, foodborne outbreaks, bioterrorism attacks, and zoonotic events. It will grant hitherto unimaginable insights into molecular pathogenesis (pathogenomics), providing the information needed to facilitate the designs of new vaccines and novel strain-specific therapeutics, especially for multidrug-resistant organisms, that will disable the microbe without obliterating an entire species or disrupting the normal microbiome.” (G. D. Ehrlich, gehrlich@wpahs.org)
Treatment & Work Loss in Early Rheumatoid Arthritis: Despite a “radiological superiority” of biological therapies over conventional agents in rheumatoid arthritis, patients with methotrexate-resistant early disease had similar rates of work loss over a 2-year period while on the drugs (pp. 1407–14). Participants were those who did not achieve low disease activity during 3–4 months of methotrexate therapy. They were assigned to infliximab or sulfasalazine plus hydroxychloroquine, with these results: “Of 204 eligible patients, 105 were randomized to biological and 99 to conventional treatment. Seven patients in the biological and 4 in the conventional treatment group never received the study drug, and 72 and 52 patients, respectively, followed the study per protocol for 21 months. The baseline mean (SD) work loss was 17 (13) d/mo (median, 16 d/mo) in both groups (mean difference, 0.6 d/mo; 95% CI, −3.0 to 3.9). The mean changes in work loss at 21 months were −4.9 d/mo in the biological and −6.2 d/mo in the conventional treatment group (adjusted mean difference, 1.6 d/mo; 95% CI, −1.2 to 4.4). Including only patients receiving at least 1 dose of assigned treatment, the adjusted mean difference was 1.5 d/mo (95% CI, −1.5 to 4.4), and in per-protocol analysis the adjusted mean difference was 0.3 d/mo (95% CI, −2.8 to 3.8).” (J. K. Eriksson, Jonas.Eriksson@ki.se)

>>>PNN NewsWatch
* FDA yesterday approved dolutegravir (Tivicay, GlaxoSmithKline), an orally active, once-daily integrase strand transfer inhibitor approved for use in treatment-naive and -experienced adults with HIV, including those who have been treated with other integrase strand transfer inhibitors. Dolutegravir is also approved for children ages 12 years and older weighing at least 40 kg who are treatment-naive or -experienced but have not previously taken other integrase strand transfer inhibitors. Safety and efficacy in adults was established in 2,539 participants receiving dolutegravir or raltegravir, each in combination therapy, or a fixed-dose combination of efavirenz, emtricitabine, and tenofovir. Adverse effects include insomnia, headache, hypersensitivity reactions, and abnormal liver function in participants co-infected with hepatitis B and/or C.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 14, 2013 * Vol. 20, No. 156
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 14 issue of JAMA (2013; 310).
U.S. Health Status: Life expectancy at birth and healthy life expectancy (HALE) increased in the U.S. between 1990 and 2010, a study shows, but the country’s rates of morbidity and chronic disability put it in a lower position within rankings of similar countries (pp. 591–608). Compared with 34 countries in the Organisation for Economic Co-operation and Development (OECD), U.S. health status showed these changes in a wide variety of measures: “US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of [years of life lost due to premature mortality (YLLs)] in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of [years lived with disability (YLDs)] in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of [disability-adjusted life-years (DALYs)] than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th.” (C. J. L. Murray, cjlm@uw.edu)
“Despite a level of health expenditures that would have seemed unthinkable a generation ago, the health of the US population has improved only gradually and has fallen behind the pace of progress in many other wealthy nations,” writes an editorialist (
pp. 585–6). “Setting the United States on a healthier course will surely require leadership at all levels of government and across the public and private sectors and actively engaging the health professions and the public. Analyses such as the US Burden of Disease can help identify priorities for research and action and monitor the state of progress over time. If all constituents do their parts, the apt subtitle for the next generation’s analysis of US health will be not ‘doing better and feeling worse (still)’ but ‘getting better faster than ever.’” (H. V. Fineberg, fineberg@nas.edu)
Barrett Esophagus & Esophageal Cancer: Medical therapy and endoscopic interventions can be indicated for patients with Barrett esophagus, depending on the types of dysplasia present, according to authors of a review article (pp. 627–36). Articles published between 1984 and April of this year show the following: “Risk factors for cancer in Barrett esophagus include chronic GERD, hiatal hernia, advanced age, male sex, white race, cigarette smoking, and obesity with an intra-abdominal body fat distribution. The annual risk of esophageal cancer is approximately 0.25% for patients without dysplasia and 6% for patients with high-grade dysplasia. High-quality studies have found no significant differences in cancer incidence for patients with Barrett esophagus whose GERD is treated medically or surgically. Endoscopic eradication therapy with radiofrequency ablation significantly reduces the frequency of progression to cancer for patients with high-grade dysplasia.” (S. J. Spechler, sjspechler@aol.com)
NIH Bails on National Guidelines: A June 19 announcement by the National Heart, Lung, and Blood Institute (NHLBI) means that updated guidelines for hypertension, lipids, and obesity will not be issued by the federal government, according to a news article (pp. 568–9). JNC8/JNC 2013, ATP4, and Obesity 2—which had been reported as “imminent” or “expected within 6 months” for years—will instead come from professional associations. “NHLBI reported it was getting out of the guideline writing business to concentrate on publishing systematic evidentiary reviews, which could then be used by appropriate scientific associations … to create their own guidelines,” the report notes. Michael Lauer, MD, Director of Cardiovascular Sciences at the NHLBI, said he expects all the guidelines to be issued within a year. (M. Mitka)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 15, 2013 * Vol. 20, No. 157
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 15 issue of the New England Journal of Medicine (2013; 369).
Finasteride & Prostate Cancer Prevention: In the Prostate Cancer Prevention Trial (PCPT), finasteride reduced the risk of prostate cancer during 18 years of follow-up but with increased rates of high-grade prostate cancer and no significant differences in overall survival or survival after diagnosis of prostate cancer (pp. 603–10). Data collected for an additional year after the 2003 publication of this study showed the following outcomes based on a search of the Social Security Death Index through Oct. 2011: “Among 18,880 eligible men who underwent randomization, prostate cancer was diagnosed in 989 of 9,423 (10.5%) in the finasteride group and 1,412 of 9,457 (14.9%) in the placebo group (relative risk in the finasteride group, 0.70; 95% confidence interval [CI], 0.65 to 0.76; P < 0.001). Of the men who were evaluated, 333 (3.5%) in the finasteride group and 286 (3.0%) in the placebo group had high-grade cancer (Gleason score, 7 to 10) (relative risk, 1.17; 95% CI, 1.00 to 1.37; P = 0.05). Of the men who died, 2,538 were in the finasteride group and 2,496 were in the placebo group, for 15-year survival rates of 78.0% and 78.2%, respectively. The unadjusted hazard ratio for death in the finasteride group was 1.02 (95% CI, 0.97 to 1.08; P = 0.46). Ten-year survival rates were 83.0% in the finasteride group and 80.9% in the placebo group for men with low-grade prostate cancer and 73.0% and 73.6%, respectively, for those with high-grade prostate cancer.” (I. M. Thompson Jr., thompsoni@uthscsa.edu)
Because of the equivocal results regarding prophylactic finasteride, an editorialist writes, “The safest conclusion is that [finasteride] has no short- or long-term effect on all-cause mortality, so we cannot recommend its use to prolong life” (
pp. 670–1). Prevention of future suffering might be a consideration, but only with routine PSA screening. The writer concludes, “For men who choose regular prostate-cancer screening, the use of finasteride meaningfully reduces the risk of prostate cancer and thus the morbidity associated with treatment of the disease. Whether the use of the drug has either a positive or a negative effect on prostate-cancer–specific mortality remains unknown, but either way the effect is probably very small and does not result in any difference in life expectancy. Men who are aware of and understand the benefits, risks, and uncertainties associated with the use of finasteride for prevention may make a rational decision to take the drug to reduce the harm of screening. Of course, another way to reduce the harm of screening is to choose not to be screened.” (M. LeFevre)
Interferon-Free Regimens in Chronic Hepatitis C Virus Infections: Interferon-free treatment with faldaprevir in combination with deleobuvir plus ribavirin provided sustained virologic responses in one-half to two-thirds of 362 previously untreated patients with chronic hepatitis C virus (HCV) genotype 1 infection, researchers report (pp. 630–9). Five groups were studied in the Phase IIb, open-label trial: faldaprevir 120 mg once daily and deleobuvir 600 mg three times daily, plus ribavirin, for 16, 28, or 40 weeks (TID16W, TID28W, or TID40W, respectively); faldaprevir 120 mg once daily and deleobuvir 600 mg twice daily, plus ribavirin, for 28 weeks (BID28W); and faldaprevir 120 mg once daily and deleobuvir 600 mg three times daily, without ribavirin, for 28 weeks (TID28W-NR). Results showed: “The primary end point [of sustained virologic response 12 weeks after the completion of therapy] was met in 59% of patients in the TID16W group, 59% of patients in the TID28W group, 52% of patients in the TID40W group, 69% of patients in the BID28W group, and 39% of patients in the TID28W-NR group. The sustained virologic response 12 weeks after the completion of therapy did not differ significantly according to treatment duration or dosage among ribavirin-containing regimens. This response was significantly higher with TID28W than with TID28W-NR (P = 0.03). Rates of a sustained virologic response 12 weeks after the completion of therapy were 56 to 85% among patients with genotype 1b infection versus 11 to 47% among patients with genotype 1a infection and 58 to 84% among patients with IL28B CC versus 33 to 64% with non-CC genotypes. Rash, photosensitivity, nausea, vomiting, and diarrhea were the most common adverse events.” (S. Zeuzem, zeuzem@em.uni-frankfurt.de)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 16, 2013 * Vol. 20, No. 158
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Aug. issue of Clinical Infectious Diseases (2013; 57).
Antibiotic Resistance & the Environment: An important element in dealing with antibiotic resistance includes management of waste containing antibiotic residues and antibiotic-resistant microorganisms, write authors of a review article (pp. 704–10): “Antibiotic resistance and associated genes are ubiquitous and ancient, with most genes that encode resistance in human pathogens having originated in bacteria from the natural environment (eg, beta-lactamases and fluoroquinolones resistance genes, such as qnr). The rapid evolution and spread of ‘new’ antibiotic resistance genes has been enhanced by modern human activity and its influence on the environmental resistome. This highlights the importance of including the role of the environmental vectors, such as bacterial genetic diversity within soil and water, in resistance risk management. We need to take more steps to decrease the spread of resistance genes in environmental bacteria into human pathogens, to decrease the spread of resistant bacteria to people and animals via foodstuffs, wastes and water, and to minimize the levels of antibiotics and antibiotic-resistant bacteria introduced into the environment. Reducing this risk must include improved management of waste containing antibiotic residues and antibiotic-resistant microorganisms.” (R. Finley, rita.finley@phac-aspc.gc.ca)
Medical Students & Antimicrobial Stewardship Knowledge: Gaps in medical students’ knowledge about antimicrobial stewardship result from curricular differences and variability in formative education, according to findings of a survey of students at three medical schools (pp. 631–8). Conducted in early 2012, the 24-item survey conducted at U. Miami, Johns Hopkins U., and U. Washington showed these patterns: “Three hundred seventeen of 519 (61%) students completed the survey; 92% of respondents agreed that strong knowledge of antimicrobials is important in their careers, and 90% said that they would like more education on appropriate use of antimicrobials. Mean correct knowledge score (11 items) was 51%, with statistically significant differences between study sites and sources of information used to learn about antimicrobials. Only 15% had completed a clinical infectious diseases rotation during medical school; those who had done so rated the quality of their antimicrobial education significantly higher compared to those who had not (mean, 3.93 vs 3.44, on a 5-point scale; P = .0003). There were no statistically significant associations between knowledge scores and having had an infectious diseases clinical elective. Only one-third of respondents perceived their preparedness to be adequate in some fundamental principles of antimicrobial use.” (L. Abbo, labbo@med.miami.edu)

>>>Allergy/Immunology Report
Source:
Aug. issue of the Journal of Allergy and Clinical Immunology (2013; 132).
Vitamin D & IL-17A Production in Severe Asthma: Increased levels of cytokines produced by Th17 cells were reduced by vitamin D, 1-alpha, 25-dihydroxyvitamin D3 (1,25[OH]2D3) but not by steroids in cultures from patients with moderate-to-severe asthma (pp. 297–304.e3): “Asthmatic patients synthesized much higher levels of IL-17A and IL-22 than nonasthmatic control subjects, with patients with [steroid-resistant] asthma expressing the highest levels of IL-17A. Glucocorticoids did not inhibit IL-17A cytokine expression in patients and enhanced production in cultures from control subjects. Treatment with 1,25(OH)2D3 with or without dexamethasone significantly reduced both IL-17A and IL-22 levels. An antagonist of the ectonucleotidase CD39 reversed 1,25(OH)2D3-mediated inhibition of the IL-17A response.” (C. M. Hawrylowicz, catherine.hawrylowicz@kcl.ac.uk)

>>>PNN NewsWatch
* Updated descriptions of peripheral neuropathy as an adverse effect of fluoroquinolones are being added to product labeling, FDA said yesterday. The risk of peripheral neuropathy occurs with fluoroquinolones that are taken by mouth or injection. If a patient develops symptoms of peripheral neuropathy, the fluoroquinolone should be stopped, and the patient should be switched to another, nonfluoroquinolone antibacterial drug, unless the benefit of continued treatment outweighs the risk.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 19, 2013 * Vol. 20, No. 159
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 17 issue of Lancet (2013; 382).
Prasugrel v. Clopidogrel in Acute Coronary Syndromes: In the TRILOGY ACS trial, prasugrel demonstrated benefits over clopidogrel in patients who had undergone angiography for non–ST-segment elevation acute coronary syndrome, researchers report (pp. 605–13). “When angiography is done for acute coronary syndrome and anatomic coronary disease confirmed, the benefits and risks of intensive antiplatelet treatment exist whether the patient is treated with drugs or percutaneous coronary intervention,” the investigators concluded. Results were based on a primary endpoint of cardiovascular death, myocardial infarction, or stroke at 30 months: “7,243 patients younger than 75 years were included in the TRILOGY ACS primary analysis. 3,085 (43%) had angiography at baseline, 4,158 (57%) had not. Fewer patients who had angiography reached the primary endpoint at 30 months compared with those who did not have angiography, according to Kaplan–Meier analysis (281/3,085 [12.8%] vs 480/4,158 [16.5%], adjusted hazard ratio [HR] 0.63, 95% CI 0.53–0.75; p < 0.0001). The proportion of patients who reached the primary endpoint was lower in the prasugrel group than in the clopidogrel group for those who had angiography (122/1,524 [10.7%] vs 159/1,561 [14.9%], HR 0.77, 95% CI 0.61–0.98; p = 0.032) but did not differ between groups in patients who did not have angiography (242/2,096 [16.3%] vs 238/2,062 [16.7%], HR 1.01, 0.84–1.20; p = 0.94; pinteraction = 0.08). Overall, TIMI major bleeding and GUSTO severe bleeding were rare. Bleeding outcomes tended to be higher with prasugrel but did not differ significantly between treatment groups in either angiography cohort.” (S. D. Wiviott, swiviott@partners.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
IV Iron Therapy & Allogeneic Blood Transfusion: Intravenous iron therapy increases hemoglobin concentrations and thereby reduces the need for allogeneic red blood cell transfusion, authors of a systematic review and meta-analysis conclude, but “this potential benefit is counterbalanced by a potential increased risk of infection” (f4822): “Of the 75 trials meeting the inclusion criteria, 72 studies including 10,605 patients provided quantitative outcome data for meta-analysis. Intravenous iron was associated with an increase in haemoglobin concentration (standardised mean difference 6.5 g/L, 95% confidence interval 5.1 g/L to 7.9 g/L) and a reduced risk of requirement for red blood cell transfusion (risk ratio 0.74, 95% confidence interval 0.62 to 0.88), especially when intravenous iron was used with erythroid stimulating agents (ESAs) or in patients with a lower baseline plasma ferritin concentration. There were no significant interactions between the efficacy of intravenous iron and type or dose administered. Intravenous iron was, however, associated with a significant increase in risk of infection (relative risk 1.33, 95% confidence interval 1.10 to 1.64) compared with oral or no iron supplementation. The results remained similar when only high quality trials were analysed.” (E. Litton, ed.litton@health.wa.gov.au)

>>>PNN NewsWatch
* FDA reminds health professionals about safety concerns with all sterile drug products made and distributed by NuVision Pharmacy, a compounding pharmacy in Dallas, TX. Health professionals should not administer any NuVision sterile products to patients because the products’ sterility is not assured, the agency said in a follow-up to a May 18 notice. FDA said NuVision has repeatedly declined to recall its sterile products and that the agency cannot require NuVision to undertake such recalls. NuVision recalled methylcobalamin injection and lyophilized injection products due to a lack of sterility assurance and quality control concerns, FDA said, adding that adverse effects have not been reported with other products.

>>>PNN JournalWatch
* The Promise of Pharmacoepidemiology in Helping Clinicians Assess Drug Risk, in
Circulation, 2013; 128: 745–8. (J. Avorn, javorn@medsoc.harvard.edu)
* Update of Studies on Drug-Related Problems in Older Adults, in
Journal of the American Geriatrics Society, 2013; 61: 1365–8. (J. T. Hanlon, jth14@pitt.edu)
* Maintenance Therapy for Advanced Lung Cancer: Who, What, and When?, in
Journal of Clinical Oncology, 2013; 31: 2983–90. (D. E. Gerber, david.gerber@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 21, 2013 * Vol. 20, No. 161
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 21 issue of JAMA (2013; 310).
Blood Pressure Control in a Large Hypertension Program: Hypertension control rates improved significantly following implementation of a large-scale program in the Kaiser Permanente Northern California (KPNC) system, researchers report (pp. 699–705). KPNC patients diagnosed with hypertension in 2001–09 were included in the analysis. An evidence-based, four-step hypertension control algorithm was developed for clinicians, single-pill lisinopril–hydrochlorothiazide therapy was promoted, and a medical assistant in each KPNC center conducted follow-up visits 2–4 weeks after medication adjustments. Based on Healthcare Effectiveness Data and Information Set (HEDIS) and National Committee for Quality Assurance (NCQA) quality measures, the multifaceted approach yielded these outcomes: “The KPNC hypertension registry included 349,937 patients when established in 2001 and increased to 652,763 by 2009. The NCQA HEDIS commercial measurement for hypertension control within KPNC increased from 43.6% (95% CI, 39.4%–48.6%) to 80.4% (95% CI, 75.6%–84.4%) during the study period (P < .001 for trend). In contrast, the national mean NCQA HEDIS commercial measurement increased from 55.4% to 64.1%. California mean NCQA HEDIS commercial rates of hypertension were similar to those reported nationally from 2006–2009 (63.4% to 69.4%).” (M. G. Jaffe, marc.jaffe@kp.org)
“Fully integrated health systems (such as KPNC) that assume full responsibility by both insuring and delivering health care are particularly invested in managing risk factors to reduce downstream costs,” editorialists write (
pp. 695–6). “Accordingly, these health care organizations implement non–physician-centered solutions, such as follow-up visits with medical assistants and telemonitoring to track blood pressure readings with pharmacists authorized to adjust medications. These approaches are less likely to be implemented in fee-for-service environments in which such elements of care would increase costs and potentially reduce reimbursements. The transition to value-based models in all sectors of US health care and the looming growth of accountable care organizations and shared savings models provides a framework wherein health care organizations have the flexibility to implement care models optimized to deliver the best outcomes at the lowest cost, without being constrained to face-to-face physician encounters to drive reimbursement. In this context, studies such as [this] one on the science of health system–level quality improvement are particularly powerful and hopefully will prompt hypertension guidelines and perhaps other guidelines to include recommendations about system-level approaches to managing risk factors.” (A. Goyal, agoyal4@emory.edu)
Race, Urinary Albumin Excretion & CHD: Commenting on a study that confirms blacks’ increased susceptibility to vascular injury with higher urinary albumin excretion (pp. 706–14; O. M. Gutiérrez, gutierr@uab.edu">ogutierr@uab.edu), editorialists seek explanations and identify next steps (pp. 697–8): “The key questions … are why black individuals have higher levels of albuminuria than white individuals and what can be done to reduce [cardiovascular disease (CVD)] risk in this higher-risk population before the first CVD event. These questions can only be answered if all study participants had equal access to and comparable use of medical care and healthy living strategies beginning early in life, such that genetic factors that may influence kidney disease can be distinguished from factors related to indolent chronic disease (metabolic syndrome, hypertension, type 2 diabetes, and prediabetes), all of which are at least somewhat preventable with healthy living, are more common overall in black individuals and people of lower socioeconomic status, and are associated with CVD and higher albuminuria levels.
“Until these complex relationships are better disentangled, the study by Gutiérrez and colleagues reinforces that even mild elevations in urine ACR (10–29.9 mg/g) are associated with increased CVD risk, even though this level of albuminuria will have no meaningful systemic effects. Differentiating between low normal (<10 mg/g) and high normal (10–30 mg/g) urinary ACR may further aid in cardiovascular risk stratification, particularly in black individuals, and motivate prevention and heightened monitoring of these individuals.” (W. C. Winkelmayer,
wcw1@stanford.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 22, 2013 * Vol. 20, No. 162
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and Aug. 22 issue of the New England Journal of Medicine (2013; 369).
Vedolizumab for Ulcerative Colitis, Crohn’s Disease: Two studies and an editorial examine the use of gut lymphocyte trafficking blockade in inflammatory bowel conditions.
In two Phase III trials of patients with ulcerative colitis, the monoclonal antibody vedolizumab was more effective than placebo for induction and maintenance therapy, researchers report (
pp. 699–710). Cohort 1 (n = 374) received vedolizumab 300 mg or placebo intravenously at weeks 0 and 2 for induction; cohort 2 (n = 521) received open-label vedolizumab at weeks 0 and 2 for maintenance. With response defined as a reduction in Mayo Clinic score of 3 points or more and a decrease of 30% or more from baseline, with accompanying decrease in rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1, results showed: “Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P < 0.001). At week 52, 41.8% of patients who continued to receive vedolizumab every 8 weeks and 44.8% of patients who continued to receive vedolizumab every 4 weeks were in clinical remission (Mayo Clinic score ≤2 and no subscore >1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P < 0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P < 0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups.” (B. G. Feagan, bfeagan@robarts.ca)
Used similarly in patients with Crohn’s disease, vedolizumab produced mixed results with regard to remission and scores on a disease-activity scale (
pp. 711–21). A total of 368 patients received induction therapy with vedolizumab 300 mg or placebo at weeks 0 and 2; in an open-label maintenance trial, 747 patients received open-label doses at weeks 0 and 2, with these results: “At week 6, a total of 14.5% of the patients in cohort 1 who received vedolizumab and 6.8% who received placebo were in clinical remission (i.e., had a score on the Crohn’s Disease Activity Index [CDAI] of ≤150, with scores ranging from 0 to approximately 600 and higher scores indicating greater disease activity) (P = 0.02); a total of 31.4% and 25.7% of the patients, respectively, had a CDAI-100 response (≥100-point decrease in the CDAI score) (P = 0.23). Among patients in cohorts 1 and 2 who had a response to induction therapy, 39.0% and 36.4% of those assigned to vedolizumab every 8 weeks and every 4 weeks, respectively, were in clinical remission at week 52, as compared with 21.6% assigned to placebo (P < 0.001 and P = 0.004 for the two vedolizumab groups, respectively, vs. placebo). Antibodies against vedolizumab developed in 4.0% of the patients. Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, in patients receiving vedolizumab than in patients receiving placebo. Vedolizumab, as compared with placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).” (W. J. Sandborn, wsandborn@ucsd.edu)
“Given the results of these two phase 3 studies, it is likely that vedolizumab will become part of the growing armamentarium of new drugs available to the practicing gastroenterologist for the treatment of [inflammatory bowel disease], particularly in patients who did not have a response to a TNF inhibitor,” an editorialist writes (
pp. 775–6; F. Cominelli)
Pharmacy Approach on Abusive Controlled Substance Prescribing: CVS Caremark has used data mining in addressing abusive prescribing of controlled substances, according to a Perspective article (DOI: 10.1056/NEJMp1308222). High-risk prescribers were identified as those above the 98th percentile for volume and 95th percentile for proportion of controlled substance prescribing. Among 1 million prescribers, 42 prescribers were high risk. About half of those responded with legitimate reasons for their prescribing patterns; the others were put on a do-not-dispense list for CVS nationally with little resistance. (M. Betses)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 23, 2013 * Vol. 20, No. 163
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Aug. issue of the Journal of the American Geriatrics Society (2013; 61).
Med Rec After Hospitalizations: Unintentional medication discrepancies were cut by 71% among 1,543 older adults when pharmacists and technicians provided medication reconciliation services during hospitalizations at 12 Dutch acute-care facilities, a study shows (pp. 1262–8). Using the Best Possible Medication History (BPMH) intervention—which combines information from community pharmacies, medication containers, and structured interviews of patients—investigators found these changes in a primary outcome measure of proportion of participants with one or more unintentional medication discrepancies: “The [primary outcome] was reduced from 62% to 32% [odds ratio (OR) = 0.29, 95% confidence interval (CI) = 0.23–0.37]. These results remained statistically significant after adjustment for type of department and hospital (OR = 0.20, 95% CI = 0.15–0.26), and this effect remained stable for 6 months. Stratified analysis showed that no effect from the intervention was evident in the three hospitals with a mixed-model intervention, in contrast to the hospitals with a pharmacy-based intervention. The medication discrepancy types ‘omission’ and ‘dosage or strength’ occurred most frequently and were the main types that the intervention influenced.” (P. M. L. A. van den Bemt, p.vandenbemt@erasmusmc.nl)
Antidiabetic Drugs, Renal Function & Cardiovascular Disease: Antihyperglycemic agents not recommended for use in older adults with type 2 diabetes mellitus (T2DM) and renal insufficiency, especially sulfonylureas, are used frequently, according to a cross-sectional analysis of 19 hospital-based diabetes mellitus clinics in 2007 and 2008 (pp. 1253–61). In such patients, metformin use was associated with lower rates of cardiovascular events in the analysis of 15,733 participants in the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study: “Across age quartiles, [estimated glomerular filtration rate (eGFR)] declined progressively at a time-linear rate, with an acceleration in older adults, whereas albuminuria increased; age and eGFR were associated with cardiovascular events independently of other confounders. With increasing age, percentage of participants using lifestyle treatments for their T2DM and taking metformin or glitazones fell; percentage taking sulfonylureas and repaglinide rose, and percentage taking insulin remained stable. In eGFR categories 3 and 4, use of metformin was 41.4% and 14.5%, respectively, and that of sulfonylureas was 34.2% and 18.1%, respectively. Inappropriate prescription of these agents, especially sulfonylureas, increased with age. Metformin was independently associated with lower prevalence of cardiovascular disease for any age quartile and eGFR category than all other treatments.” (A. Solini, anna.solini@med.unipi.it)

>>>Health Affairs Highlights
Source:
Aug. issue of Health Affairs (2013; 32).
Drug Innovation & First-In-Class Pharmaceuticals: When measured by approval of first-in-class products, drug innovation has been steady in recent decades, authors write (pp. 1433–9): “We examined [new molecular entity (NME)] approvals during 1987–2011 and propose the three distinct subcategories of NMEs—first-in-class, advance-in-class, and addition-to-class—to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or ‘me too,’ drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole.” (M. Lanthier, michael.lanthier@fda.hhs.gov)

>>>PNN NewsWatch
* FDA yesterday advised pharmacies of concerns about the adequacy of testing performed by Front Range Laboratories, a testing laboratory the agency said is used by more than 100 pharmacies in 32 states to verify quality, sterility, and expiration dating for compounded products.
* A product labeled primarily in Spanish and sold chiefly on the Internet contains unlabeled diclofenac,
FDA said yesterday. Ortiga should not be used, the agency said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 26, 2013 * Vol. 20, No. 164
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Aug. 24 issue of Lancet (2013; 382).
Once-Daily Dolutegravir in HIV: The once-daily HIV integrase inhibitor dolutegravir was well tolerated and had greater virologic activity than twice-daily raltegravir in SAILING, a Phase III trial of patients with HIV-1 (pp. 700–8). Study participants were antiretroviral-experienced but integrase-inhibitor-naive when they were randomized to once-daily dolutegravir 50 mg or twice-daily raltegravir 400 mg, with investigator-selected background therapy. Results showed: “Analysis included 715 patients (354 dolutegravir; 361 raltegravir). At week 48, 251 (71%) patients on dolutegravir had HIV-1 RNA less than 50 copies per mL versus 230 (64%) patients on raltegravir (adjusted difference 7.4%, 95% CI 0.7 to 14.2); superiority of dolutegravir versus raltegravir was then concluded (p = 0.03). Significantly fewer patients had virological failure with treatment-emergent integrase-inhibitor resistance on dolutegravir (four vs 17 patients; adjusted difference –3.7%, 95% CI –6.1 to –1.2; p = 0.003). Adverse event frequencies were similar across groups; the most commonly reported events for dolutegravir versus raltegravir were diarrhoea (71 [20%] vs 64 [18%] patients), upper respiratory tract infection (38 [11%] vs 29 [8%]), and headache (33 [9%] vs 31 [9%]). Safety events leading to discontinuation were infrequent in both groups (nine [3%] dolutegravir, 14 [4%] raltegravir).” (P. Cahn, pcahn@huesped.org.ar)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 347).
Risk for Severe or Complicated Influenza Illness: A systematic review and meta-analysis finds poor evidence as to which patients are at increased risk of developing severe or complicated influenza illness and that “some well accepted risk factors, including pregnancy and ethnicity, could not be confirmed as risks” (f5061). The analysis shows that the immediate postpartum period carries a high risk of pandemic influenza–associated mortality: “63,537 articles were identified of which 234 with a total of 610,782 participants met the inclusion criteria. The evidence supporting risk factors for severe outcomes of influenza ranged from being limited to absent. This was particularly relevant for the relative lack of data for non-2009 H1N1 pandemics and for seasonal influenza studies. Limitations in the published literature included lack of power and lack of adjustment for confounders was widespread: adjusted risk estimates were provided for only 5% of risk factor-outcome comparisons in 39 of 260 (15%) studies. The level of evidence was low for ‘any risk factor’ (odds ratio for mortality 2.77, 95% confidence interval 1.90 to 4.05 for pandemic influenza and 2.04, 1.74 to 2.39 for seasonal influenza), obesity (2.74, 1.56 to 4.80 and 30.1, 1.74 to 2.39), cardiovascular diseases (2.92, 1.76 to 4.86 and 1.97, 1.06 to 3.67), and neuromuscular disease (2.68, 1.91 to 3.75 and 3.21, 1.84 to 5.58). The level of evidence was very low for all other risk factors. Some well accepted risk factors such as pregnancy and belonging to an ethnic minority group could not be identified as risk factors. In contrast, women who were less than four weeks post partum had a significantly increased risk of death from pandemic influenza (4.43, 1.24 to 15.81).” (M. Loeb, loebm@mcmaster.ca)
Antidepressants & Postpartum Hemorrhage: “Exposure to serotonin and non-serotonin reuptake inhibitors, including selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, and tricyclics, close to the time of delivery was associated with a 1.4 to 1.9-fold increased risk for postpartum hemorrhage,” report authors of a cohort study of low-income American women (f4877). “While potential confounding by unmeasured factors cannot be ruled out, these findings suggest that patients treated with antidepressants during late pregnancy are more likely to experience postpartum hemorrhage.” (K. Palmsten, kkp762@mail.harvard.edu)

>>>PNN JournalWatch
* Learning About New Therapies: Phase 3 Clinical Studies—and Beyond, in
Diabetes Care, 2013; 36: 2453–5. (M. C. Riddle, riddle@ohsu.edu)
* A Call for Evidence-Based Medical Treatment of Opioid Dependence in the United States and Canada, in
Health Affairs, 2013; 32: 1462–9. (B. Nosyk, bnosyk@cfenet.ubc.ca)
* Identifying Patients at Increased Risk for Unplanned Readmission, in
Medical Care, 2013; 51: 761–6. (E. H. Bradley)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 27, 2013 * Vol. 20, No. 165
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Sept. issue of Diabetes Care (2013; 36).
Benefits of Low-Intensity Exercise in Obese Adults: In 11 sedentary obese adults, low-intensity exercise improved insulin sensitivity into the next day better than more intense sessions, a result that was partly the result of lower systemic fatty acid uptake with low-intensity sessions, researchers report (pp. 2516–22). Mean BMI for the three men and eight women was 37 kg/sq m. On two occasions during three experimental trials, the participants exercised to expend 350 kcal during afternoon exercise. Sessions were identical except that exercise intensity (50% or 65% of peak oxygen uptake [EX50 and EX65, respectively]) and duration of exercise (55 or 70 min) varied. Compared with the same individuals during a control (CON) phase, metabolic parameters showed the following: “Exercise increased insulin sensitivity the next day, but whereas the 35% improvement after EX50 compared with CON was statistically significant (P = 0.01), the 20% improvement after EX65 was not (P = 0.17). Despite nearly identical values between CON and EX65 (P = 0.88), systemic fatty acid uptake was lower after EX50 compared with EX65 (P = 0.02), but not quite significant compared with CON (P = 0.07). Importantly, the change in fatty acid uptake after exercise compared with CON was negatively correlated with the change in insulin sensitivity for all trials (r = −0.60, P = 0.003).” (J. F. Horowitz, jeffhoro@umich.edu)
Insulin Glargine, Fatty Acids in Cardiovascular Disease: In the Glucose Reduction and Atherosclerosis Continuing Evaluation (ORIGIN-GRACE) study, insulin glargine but not n-3 polyunsaturated fatty acid (n-3FA) supplements reduced carotid intima-media thickness (CIMT) (pp. 2466–74). In 1,184 people with cardiovascular (CV) disease and/or CV risk factors plus impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes, open-label insulin glargine plus n-3FA or placebo had these primary trial outcomes (annualized rate of change in maximum CIMT for the common carotid, bifurcation, and internal carotid artery segments) and secondary outcomes (annualized rates of change in maximum CIMT for the common carotid and the common carotid plus bifurcation): “Compared with standard care, insulin glargine reduced the primary CIMT outcome, but the difference was not statistically significant (difference = 0.0030 ± 0.0021 mm/year; P = 0.145) and significantly reduced the secondary CIMT outcomes (differences of 0.0033 ± 0.0017 mm/year [P = 0.049] and 0.0045 ± 0.0021 mm/year [P = 0.032], respectively). There were no differences in the primary and secondary outcomes between the n-3FA supplement and placebo groups.” (E. M. Lonn, eva.lonn@phri.ca)
Once-Daily Lixisenatide in Type 2 Diabetes: Two studies examine utility of a once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in patients with type 2 diabetes and poor glycemic control.
Lixisenatide may provide an alternative in patients whose type 2 diabetes is inadequately controlled by stable basal insulin, according to results of the GetGoal-L trial (
pp. 2489–96). Participants were 495 patients who were randomized to lixisenatide 20 mcg or placebo for 24 weeks with basal insulin. Results showed: “With lixisenatide, the placebo-corrected change of HbA1c from baseline was –0.4% (95% CI –0.6 to –0.2; P = 0.0002), and mean HbA1c at end point was 7.8%. HbA1c <7.0% (53 mmol/mol) was attained by more lixisenatide (28%) than placebo (12%; P < 0.0001) participants. Lixisenatide reduced plasma glucose levels after a standardized breakfast (placebo-corrected reduction, –3.8 mmol/L; P < 0.0001); seven-point glucose profiles showed a reduction persisting through the day. Reductions in body weight (placebo corrected, –1.3 kg; P < 0.0001) and insulin dosage (–3.7 units/day; P = 0.012) were greater with lixisenatide.” (M. C. Riddle, riddlem@ohsu.edu)
Similarly, in a study of 446 patients with elevated A1C levels after initiation of insulin glargine, “adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA
1c goals with recently initiated basal insulin,” the same research group concludes (pp. 2497–503; M. C. Riddle, riddlem@ohsu.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 28, 2013 * Vol. 20, No. 166
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Aug. 28 issue of JAMA (2013; 310).
Sofosbuvir & Ribavirin in Hepatitis C: In a 24-week trial of 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 and unfavorable treatment characteristics, sofosbuvir and weight-based or low-dose ribavirin produced improved sustained virologic responses (SVRs), researchers report (pp. 804–11). In the open-label trial, 10 participants with early to moderate liver fibrosis were first treated with sofosbuvir 400 mg/d and weight-based ribavirin for 24 weeks. The other 50 participants with all stages of liver fibrosis were then randomized to sofosbuvir with either weight-based or low-dose (600 mg/d) ribavirin for 24 weeks, with these results: “In the first part of the study, 9 participants (90%; 95% CI, 55%–100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%–85%) in the weight-based group and 48% (95% CI, 28%–69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.” (S. Kottilil, skottilil@niaid.nih.gov)
SNP Associated with CHD in Patients with Diabetes: Investigators identify a single-nucleotide polymorphism in a glutamic acid metabolic gene that is associated with coronary heart disease (CHD) among persons with but not without diabetes (pp. 821–8). Using five sets of longitudinal data from CHD cases and CHD-negative controls, the authors assessed 2.5 million common genetic variants: “A variant on chromosome 1q25 (rs10911021) was consistently associated with CHD risk among diabetic participants, with risk allele frequencies of 0.733 in cases vs 0.679 in controls (odds ratio, 1.36 [95% CI, 1.22–1.51]; P = 2 × 10−8). No association between this variant and CHD was detected among nondiabetic participants, with risk allele frequencies of 0.697 in cases vs 0.696 in controls (odds ratio, 0.99 [95% CI, 0.87–1.13]; P = .89), consistent with a significant gene × diabetes interaction on CHD risk (P = 2 × 10−4). Compared with protective allele homozygotes, rs10911021 risk allele homozygotes were characterized by a 32% decrease in the expression of the neighboring glutamate-ammonia ligase (GLUL) gene in human endothelial cells (P = .0048). A decreased ratio between plasma levels of gamma-glutamyl cycle intermediates pyroglutamic and glutamic acid was also shown in risk allele homozygotes (P = .029).” (L. Qi, nhlqi@channing.harvard.edu)
Cost, Quality Outcomes With Commercial ACO: Medicare beneficiaries in Massachusetts enrolled in a commercial accountable care organization had lower costs but not consistently improved quality, a study shows (pp. 829–36). In 2007–10, older Medicare beneficiaries had these outcomes while enrolled in the Blue Cross Blue Shield of Massachusetts Alternative Quality Contract (AQC): “Before entering the AQC, total quarterly spending per beneficiary for the intervention group was $150 (95% CI, $25–$274) higher than for the control group and increased at a similar rate. In year 2 of the intervention group’s exposure to the AQC, this difference was reduced to $51 (95% CI, −$109 to $210; P = .53), constituting a significant differential change of −$99 (95% CI, −$183 to −$16; P = .02) or a 3.4% savings relative to an expected quarterly mean of $2,895. Savings in year 1 were not significant (differential change, −$34; 95% CI, −$83 to $16; P = .18). Year 2 savings derived largely from lower spending on outpatient care (differential change, −$73; 95% CI, −$97 to −$50; P < .001), particularly for beneficiaries with 5 or more conditions, and included significant differential changes in spending on procedures, imaging, and tests.” (J. M. McWilliams, mcwilliams@hcp.med.harvard.edu)

>>>PNN NewsWatch
* JCB Laboratories, Wellness Pharmacy, and Park Pharmacy & Compounding Center have recalled multiple sterile products as a result of the problems identified recently at Front Range Laboratories (see PNN, Aug. 23).

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 29, 2013 * Vol. 20, No. 167
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Aug. 29 New England Journal of Medicine (2013; 369).
Apixaban in Acute Venous Thromboembolism: Fixed doses of oral apixaban are noninferior to subcutaneous enoxaparin and warfarin in 5,395 patients with acute venous thromboembolism and produce less bleeding, AMPLIFY trial investigators report (pp. 799–808). The double-blind study compared apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months against conventional therapy using a primary efficacy outcome of recurrent symptomatic venous thromboembolism or death related to venous thromboembolism and principal safety outcomes of major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding.
Results showed: “The primary efficacy outcome occurred in 59 of 2,609 patients (2.3%) in the apixaban group, as compared with 71 of 2,635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], −0.4 percentage points; 95% CI, −1.3 to 0.4). Apixaban was noninferior to conventional therapy (P < 0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P < 0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P < 0.001). Rates of other adverse events were similar in the two groups.” (G. Agnelli,
agnellig@unipg.it)
“Shifting with care to new treatments is essential to safe and effective practice,” an editorialist writes (
pp. 865–6). She provides a table listing six components of a protocol for using new anticoagulant agents; it is based patient preference, patient selection, drug interactions, adherence, follow-up, and monitoring. (M. Cushman)
Macitentan in Pulmonary Arterial Hypertension: Macitentan, a new dual endothelin-receptor antagonist, significantly reduced morbidity and mortality among 742 patients with symptomatic pulmonary arterial hypertension, researchers report (pp. 809–18). Based on a primary end point of time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension, participants receiving placebo or macitentan 3 mg or 10 mg once daily had these outcomes: “The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P = 0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P < 0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia.” (T. Pulido, tpulido@prodigy.net.mx)
Oral Fluconazole & Birth Defects: First-trimester exposure to fluconazole 150 or 300 mg was associated with increased risk of tetralogy of Fallot but not 14 other birth defects previously identified as possibly linked to maternal use of the drug, according to a registry-based cohort study from Denmark (pp. 830–9): “Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7,352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21).… A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71).” (D. Mølgaard-Nielsen, dnl@ssi.dk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Aug. 30, 2013 * Vol. 20, No. 168
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2013; 33).
Nonclinical Outcomes With New Warfarin Management Method: A new method for managing patients on warfarin therapy—the international normalized ratio self-testing with online remote monitoring and management (STORM2)—is “more convenient, less complicated, preferred by patients, and saves patients time and money compared with clinic management,” according to a pre/post study conducted in 43 patients (DOI: 10.1002/phar.1344). STORM2 provides a point-of-care assay device to patients and access to an online portal for entering results and symptoms. Clinicians are alerted when aberrant results are entered. Compared with usual care provided before the intervention, STORM2 produced these results: “Overall 90% of responders preferred STORM2 to traditional clinic management. The [Duke Anticoagulation Satisfaction Scale] questions indicated that patients were more satisfied with their anticoagulation treatment and more likely to recommend oral anticoagulation to a friend after experiencing STORM2. In addition, patients found STORM2 to be less complicated and more convenient than traditional clinic management. For each traditional monthly visit, patients drove 20 miles and expended a total of 1.8 hours; using 55¢/mile for mileage reimbursement and $15/hour for lost wages, the cost for each visit was $38. The total cost for four STORM2 visits per month was $10, for a net savings of $28 per patient per month. A total of 76% of patients were willing to pay additional money to eliminate a monthly clinic visit.” (H. I. Bussey, bussey@gcresearch.com)
Clinical Outcomes With New Warfarin Management Method: In a second study based on STORM2, results in 55 patients on long-term warfarin therapy showed a significant increase in time spent in therapeutic range, and pharmacogenetic testing demonstrated a need for higher-than-usual doses in those with certain gene patterns (DOI: 10.1002/phar.1343). Use of the STORM2 intervention and analysis of polymorphisms in the genes for vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 isoenzyme produced these results: “The percentage of time that the INR is within the time in therapeutic range (TTR) improved from 56% before the intervention to 81% after the intervention (p < 0.0001), and time spent at extreme INR values of lower than 1.5 or higher than 5 was reduced from 3.1% to 0.4% (p = 0.01). Clinician time was less than 10 minutes per four patient visits per month. Genetic polymorphisms did not correlate with INR stability or the increase in warfarin dose after vitamin K supplementation. The content of the vitamin K product, however, was only 34–76% of the labeled amount. Patients with the GG VKORC1 genotype required a higher warfarin dose than predicted by the genomic-based dosing chart in the warfarin package insert.” (H. I. Bussey, bussey@gcresearch.com)
Topical Atorvastatin for Pressure Ulcers: Compared with placebo, atorvastatin ointment 1% produced significantly faster healing among 104 patients with stage I or II pressure ulcers, researchers report (DOI: 10.1002/phar.1339). These results, based on the 2-digit Stirling Pressure Sore Severity Scale, were observed during assessment on days 7 and 14 of a 14-day trial of the ointments: “The baseline stage of the pressure ulcers did not differ significantly between the control and atorvastatin groups. However, the mean ± SD stage of pressure ulcers significantly decreased in the atorvastatin group compared with the control group on day 7 (0.97 ± 0.76 vs 1.74 ± 0.75, p < 0.01) and day 14 (0.42 ± 0.67 vs 1.71 ± 0.78, p < 0.01) of treatment. In addition, the mean ± SD surface areas of ulcers in the atorvastatin group were significantly declined compared with the control group after 7 days (5.55 ± 4.55 vs 9.41 ± 5.03 cm2, p < 0.01) and 14 days (3.72 ± 4.45 vs 10.41 ± 6.41 cm2, p < 0.01) of treatment.” (H. Khalili, khalilih@tums.ac.ir)

>>>PNN NewsWatch
* FDA said yesterday it is investigating the possibility of progressive multifocal leukoencephalopathy in patients with possible multiple sclerosis who receive fingolimod (Gilenya, Novartis). The concern is based on a patient in Europe who developed the rare brain infection while on the drug; the person had not been previously treated with natalizumab, an agent previously associated with PML.
*
PNN will not be published on Mon., Sept. 2, 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 3, 2013 * Vol. 20, No. 169
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 3 issue of the Annals of Internal Medicine (2013; 159).
Methylprednisolone Injections in Carpal Tunnel Syndrome: Injected for idiopathic carpal tunnel syndrome (CTS), methylprednisolone significantly reduced symptoms at 10 weeks and surgery at 1 year, a study shows, but 73% or more of patients still had surgery for the condition within 1 year (pp. 309–17). In Sweden, adults with CTS were randomized to methylprednisolone 40 or 80 mg or placebo in blinded fashion, with these results: “Improvement in CTS symptom severity scores at 10 weeks was greater in patients who received 80 mg of methylprednisolone and 40 mg of methylprednisolone than in those who received placebo (difference in change from baseline, −0.64 [95% CI, −1.06 to −0.21; P = 0.003] and −0.88 [CI, −1.30 to −0.46; P < 0.001], respectively), but there were no significant differences at 1 year. The 1-year rates of surgery were 73%, 81%, and 92% in the 80-mg methylprednisolone, 40-mg methylprednisolone, and placebo groups, respectively. Compared with patients who received placebo, those who received 80 mg of methylprednisolone were less likely to have surgery (odds ratio, 0.24 [CI, 0.06 to 0.95]; P = 0.042). With time to surgery incorporated, both the 80- and 40-mg methylprednisolone groups had lower likelihood of surgery (hazard ratio, 0.46 [CI, 0.27 to 0.77; P = 0.003] and 0.57 [CI, 0.35 to 0.94; P = 0.026], respectively).” (I. Atroshi, Isam.Atroshi@skane.se)

>>>Lancet Highlights
Source:
Aug. 31 issue of Lancet (2013; 382).
Vascular, Upper GI Effects of NSAIDs: A large meta-analysis shows that the vascular effects of high-dose diclofenac and possibly ibuprofen are similar to those of the selective COX-2 inhibitors, while high-dose naproxen carries less risk (pp. 769–79). Data from 280 trials of NSAIDs versus placebo (124,513 participants) and 474 trials comparing NSAIDs (229,296 participants) showed these patterns based on vascular and coronary events and upper gastrointestinal complications: “Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1.37, 95% CI 1.14–1.66; p = 0.0009) or diclofenac (1.41, 1.12–1.78; p = 0.0036), chiefly due to an increase in major coronary events (coxibs 1.76, 1.31–2.37; p = 0.0001; diclofenac 1.70, 1.19–2.41; p = 0.0032). Ibuprofen also significantly increased major coronary events (2.22, 1.10–4.48; p = 0.0253), but not major vascular events (1.44, 0.89–2.33). Compared with placebo, of 1,000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0.93, 0.69–1.27). Vascular death was increased significantly by coxibs (1.58, 99% CI 1.00–2.49; p = 0.0103) and diclofenac (1.65, 0.95–2.85, p = 0.0187), non-significantly by ibuprofen (1.90, 0.56–6.41; p = 0.17), but not by naproxen (1.08, 0.48–2.47, p = 0.80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1.81, 1.17–2.81, p = 0.0070; diclofenac 1.89, 1.16–3.09, p = 0.0106; ibuprofen 3.97, 2.22–7.10, p < 0.0001; and naproxen 4.22, 2.71–6.56, p < 0.0001).” (Coxib and traditional NSAID Trialists’ Collaboration)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Efficacy, Safety of Anticoagulants: Oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) reduce recurrence of venous thromboembolism, according to a systematic review and meta-analysis (f5133). Aspirin is the least efficacious for this indication, and vitamin K antagonists carry the highest risk of bleeding, researchers report (M. Carrier, mcarrier@ottawahospital.on.ca)

>>>PNN JournalWatch
* The Ankle–Brachial Index for Peripheral Artery Disease Screening and Cardiovascular Disease Prediction Among Asymptomatic Adults: A Systematic Evidence Review for the U.S. Preventive Services Task Force, in
Annals of Internal Medicine, 2013; 159: 333–41. (www.ahrq.gov)
* A Day in the Life of a Corporate Retail Pharmacist, in
Annals of Internal Medicine, 2013; 159: 366–7. (D. D. Dore, david_dore@brown.edu)
* The Transfer of Drugs and Therapeutics Into Human Breast Milk: An Update on Selected Topics, in
Pediatrics, 2013; 132: e796–809. (H. C. Sachs)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 4, 2013 * Vol. 20, No. 170
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 4 issue of JAMA (2013; 310).
Adherence With a CVD Polypill: Compared with usual care, use of a polypill for blood pressure, cholesterol, and platelet control significantly improved adherence, systolic blood pressure (SBP), and LDL cholesterol among 2,004 patients with or at high risk of cardiovascular disease (CVD), researchers report (pp. 918–29). Patients were assigned to either usual care or one of two fixed-dose combination (FDC) formulations. Both polypills contained aspirin 75 mg, simvastatin 40 mg, and lisinopril 10 mg; they differed in that one included atenolol 50 mg and the other hydrochlorothiazide 12.5 mg.
Results of the UMPIRE trial showed small but significant differences: “At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1,233 (61.5%) of 2,004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12–18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26–1.41; P < .001) with concurrent reductions in SBP (−2.6 mm Hg; 95% CI, −4.0 to −1.1 mm Hg; P < .001) and LDL-C (−4.2 mg/dL; 95% CI, −6.6 to −1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74–4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3–2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5–2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94–2.24; P = .09) between the groups.” (S. Thom,
s.thom@imperial.ac.uk)
These results are promising, an editorialist writes, but the polypill is not the solution if polypharmacy is the problem (
pp. 910–1): “Although the potential remains for use of various CVD polypills in certain settings, the precise advantage of this strategy remains largely unproven. Until additional rigorous data are available that demonstrate that the polypill improves clinical CVD outcomes, it may be more important to carefully assess the multiple medications many patients currently are prescribed, often by several physicians. Another way to reduce the number of pills patients are taking is to eliminate those medications for which the benefits are marginal.” (J. M. Gaziano, jmgaziano@partners.org)
Pediatric 13-Valent Pneumococcal Conjugate Vaccine Schedules: In infants, four different immunization schedules for 13-valent pneumococcal conjugate vaccine (PCV) produced statistically identical antibody levels after the booster dose for most serotypes, a study shows (pp. 930–7). A total of 400 infants received PCV13 either at ages 2, 4, and 6 months (2-4-6); at ages 3 and 5 months (3-5); at ages 2, 3, and 4 months (2-3-4); or at ages 2 and 4 months (2-4), with a booster dose at age 11.5 months. Results based on antibody geometric mean concentrations (GMCs) showed: “The primary outcome, GMCs at 1 month after the booster dose, was not significantly different between schedules for 70 of 78 comparisons. The 2-4-6 schedule was superior to the 2-3-4 schedule for serotypes 18C (10.2 µg/mL [95% CI, 8.2–12.7] vs 6.5 µg/mL [95% CI, 5.4–7.8]) and 23F (10.9 µg/mL [95% CI, 9.0–13.3] vs 7.3 µg/mL [95% CI, 5.8-9.2]) and superior to the 2-4 schedule for serotypes 6B (8.5 µg/mL [95% CI, 7.1–10.2] vs 5.1 µg/mL [95% CI 3.8–6.7]), 18C (6.6 µg/mL [95% CI, 5.7–7.7]), and 23F (7.2 µg/mL [95% CI, 5.9–8.8]). For serotype 1, the 3-5 schedule (11.7 µg/mL [95% CI, 9.6–14.3]) was superior to the other schedules. Geometric mean concentrations for all 13 serotypes ranged between 1.6 and 19.9 µg/mL. Secondary outcomes demonstrated differences 1 month after the primary series. The 2-4-6 schedule was superior compared with the 3-5, 2-3-4, and 2-4 schedules for 3, 9, and 11 serotypes, respectively. Differences between schedules persisted until the booster dose.” (J. Spijkerman, j.spijkerman@umcutrecht.nl)

>>>PNN NewsWatch
* A federal judge has approved a consent decree barring Dakota Laboratories LLC and its president from manufacturing and distributing drugs, FDA said 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 5, 2013 * Vol. 20, No. 171
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and Sept. 5 issue of the New England Journal of Medicine (2013; 369).
Dabigatran Use With Mechanical Heart Valves: Compared with warfarin, dabigatran produced increased rates of thromboembolic and bleeding complications in groups of patients who had undergone aortic- or mitral-valve replacement within the past 7 days and at least 3 months earlier (DOI: 10.1056/NEJMoa1300615). Dabigatran was dosed at 150, 220, or 300 mg twice daily based on renal function, while warfarin dose was titrated to INRs of 2–3 or 2.5–3.5 based on thromboembolic risk. Results showed: “The trial was terminated prematurely after the enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group. In the as-treated analysis, dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischemic or unspecified stroke occurred in 9 patients (5%) in the dabigatran group and in no patients in the warfarin group; major bleeding occurred in 7 patients (4%) and 2 patients (2%), respectively. All patients with major bleeding had pericardial bleeding.” (F. Van de Werf, frans.vandewerf@med.kuleuven.be)
Cardiovascular Risks With Saxagliptin: In 16,492 patients with type 2 diabetes and histories or increased risk of cardiovascular events, saxagliptin use was not associated with increases in ischemic events, but hospitalizations for heart failure occurred more frequently during a median of 2.1 years of therapy (DOI: 10.1056/NEJMoa1307684). With the primary end point defined as a composite of cardiovascular death, myocardial infarction, or ischemic stroke, these results were recorded with DPP-4 inhibition or placebo: “A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan–Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P = 0.99 for superiority; P < 0.001 for noninferiority); the results were similar in the ‘on-treatment’ analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1,059 patients in the saxagliptin group and in 1,034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan–Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P = 0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P = 0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
PhRMA Rankings for Social Responsibility: Major pharmaceutical companies “are becoming more organized in their approaches to global access” to essential medicines, writes the author of a Commentary article (pp. 896–9). Based on rankings in the Access to Medicine Index, the 2012 report shows these trends: “At the highest-ranked companies, active leadership on improving access is coming from the top, and more companies are setting meaningful targets. Many companies have increased their investment in relevant research, and some now devote as much as 20% of their research resources to addressing the needs of the poor, for which the direct economic return is, at best, doubtful. For instance, Sanofi is adapting its leishmaniasis drug, which currently requires health workers to administer repeated injections, to develop a product that patients can apply to their skin at home. Johnson & Johnson is working on a simple, portable, rapid screening test for tuberculosis that is meant to yield results within minutes. More companies are using tiered pricing schemes and applying them to a broader range of products and in more countries, although the overall effect on affordability is still unclear.” (H. V. Hogerzeil)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 6, 2013 * Vol. 20, No. 172
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Sept. issue of the American Journal of Psychiatry (2013; 170).
Metformin for Weight Loss in Antipsychotic Therapy: In 148 patients with antipsychotic-treated schizophrenia or schizoaffective disorder, metformin “was modestly effective in reducing weight and other risk factors for cardiovascular disease,” researchers report (pp. 1032–40). With mean BMI at baseline of 27 kg/sq m, patients had these outcomes during 16 weeks of metformin therapy with doses titrated up to 1000 mg twice daily: “Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was −3.0 kg (95% CI=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI=−2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6). Metformin also demonstrated a significant between-group advantage for BMI (−0.7; 95% CI=−1.1 to −0.2), triglyceride level (−20.2 mg/dL; 95% CI=−39.2 to −1.3), and hemoglobin A1c level (−0.07%; 95% CI=−0.14 to −0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation.” (L. F. Jarskog, jarskog@med.unc.edu)
“Metformin augmentation of antipsychotics is an evidence-based option to reduce antipsychotic-associated cardiometabolic effects,” an editorialist writes (
pp. 947–52). “However, the overall weight loss is modest compared with the weight generally gained on antipsychotics, and metformin should likely only be added after a clinical trial of a psychosocial intervention for weight loss has proven to be ineffective. Such interventions include psychoeducation focused on nutritional counseling, caloric expenditure, and portion control; behavioral self-management including motivational enhancement; goal setting; regular weigh-ins; self-monitoring of daily food and activity levels; and dietary and physical activity modifications. More placebo-controlled trials of metformin, at least in adults, are not likely to advance our knowledge regarding strategies to control antipsychotic-associated weight gain, unless they last at least 6 months, are sufficiently large to identify mediators and moderators, and/or have a discontinuation phase.” (C. U. Correll, ccorrell@lij.edu)

>>>Pediatrics Report
Source:
Sept. issue of Pediatrics (2013; 132).
Rotavirus Vaccination at NICU Discharge: An alternative strategy is needed for rotavirus immunization among infants with very low birth weight (VLBW; birth weight ≤1500 g) or extremely low birth weight (ELBW; birth weight <1000 g), a study indicates (pp. e662–5). At Parkland Hospital in Dallas, a prospective, observational cohort of infants with VLBW who were discharged in 2008–10 had these rotavirus vaccination patterns upon discharge from the neonatal intensive care unit: “A total of 63% (135 of 213) of VLBW infants did not receive rotavirus vaccine. The reasons for not providing vaccine included the following: <42 days of age at discharge (56 of 213; 26%), >84 or 104 days of age at discharge (48 of 213; 23%), or missed (35 of 213; 16%). The majority (75%) who were too old for vaccination at the time of discharge were ELBW.” (K. A. Stumpf)
Probiotics in Early Life, Atopy & Asthma: A lowering in risk of atopy and IgE levels results from probiotic administration during pregnancy or in early life, a meta-analysis of randomized controlled trials shows, but the risk of asthma or wheeze is not affected (pp. e666–76). The analysis also shows that one commonly used probiotic strain may be associated with worse outcomes: “Probiotics were effective in reducing total immunoglobulin E (IgE) (mean reduction: –7.59 U/mL [95% confidence interval (CI): –14.96 to –0.22]; P = .044). Meta-regression showed that the reduction in IgE was more pronounced with longer follow-up. Probiotics significantly reduced the risk of atopic sensitization when administered prenatally (relative risk: 0.88 [95% CI: 0.78 to 0.99]; P = .035 for positive result on the skin prick test and/or elevated specific IgE to common allergens) and postnatally (relative risk: 0.86 [95% CI: 0.75 to 0.98]; P = .027 for positive result on skin prick test). Administration of Lactobacillus acidophilus, compared with other strains, was associated with an increased risk of atopic sensitization (P = .002). Probiotics did not significantly reduce asthma/wheeze (relative risk: 0.96 [95% CI: 0.85 to 1.07]).” (N. Elazab)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 9, 2013 * Vol. 20, No. 173
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 7 issue of Lancet (2013; 382).
Human Papillomavirus Infection in Men: Published with a commentary on the natural history of oral human papillomavirus (HPV) infection in men (pp. 839–41; gdsouza@jhsph.edu) and a review of HPV and cervical cancer (pp. 889–99; henry.kitchener@manchester.ac.uk), a study shows that oral infections of oncogenic strains of HPV are rare in men and that healthy men generally clear them within 1 year (pp. 877–87). In the HPV Infection in Men (HIM) cohort study, oral rinse-and-gargle samples and semiannual questionnaires over 4 years showed the following for men residing in Brazil, Mexico, and the U.S.: “1,626 men aged 18–73 years and with a median follow-up of 12.7 months (IQR 12.1–14.7) were included in the analysis. During the first 12 months of follow-up, 4.4% (95% CI 3.5–5.6; n = 115 incident infections) of men acquired an incident oral HPV infection, 1.7% (1.2–2.5; n = 53 incident infections) an oral oncogenic HPV infection, and 0.6% (0.3–1.1; n = 18 incident infections) an oral HPV 16 infection. Acquisition of oral oncogenic HPV was significantly associated with smoking and not being married or cohabiting, but was similar across countries, age groups, and reported sexual behaviours. Median duration of infection was 6.9 months (95 % CI 6.2–9.3; n = 45 cleared infections) for any HPV, 6.3 months (6.0–9.9; n = 18 cleared infections) for oncogenic HPV, and 7.3 months (6.0–not estimable; n = 5 cleared infections) for HPV 16. Eight of the 18 incident oral HPV 16 infections persisted for two or more study visits.” (A. R. Kreimer, kreimera@mail.nih.gov)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Journal Policies & Editors’ Views on Trial Registration, Publication Bias: Released in conjunction with a quadrennial peer-review meeting of biomedical editors, a study shows that smaller journals have not implemented recommended policies on registration of clinical trials and their editors and publishers are concerned that such policies would put them at a disadvantage when competing for manuscripts (f5248). Following examination of the instructions for authors of 200 randomly selected medical journals, investigators surveyed 13 editors and 13 publishers about their differing trial-registration policies: “Only 55/200 journals (28%) required trial registration according to their instructions and a further three (2%) encouraged it. The editors and publishers interviewed explained their journals’ reluctance to require registration in terms of not wanting to lose out to rival journals, not wanting to reject otherwise sound articles or submissions from developing countries, and perceptions that such policies were not relevant to all journals. Some interviewees considered that registration was unnecessary for small or exploratory studies.” (E. Wager, liz@sideview.demon.co.uk)

>>>PNN NewsWatch
* Reviewed under FDA’s priority-review program, paclitaxel protein-bound particles for injectable suspension, albumin-bound (Abraxane, Celgene) was approved on Friday for use in treating patients with late-stage (metastatic) pancreatic cancer. Abraxane was previously approved for treatment of breast cancer (in 2005) and nonsmall-cell lung cancer (2012).
*
University Compounding Pharmacy of San Diego is voluntarily recalling products, including Testosterone Cypionate (Sesame Oil), Testosterone Cypionate/Testosterone Proprionate, and PGE-1 NS, for injection, to the consumer level, FDA said yesterday, because of lack of sterility assurance.

>>>PNN JournalWatch
* Diuretics or Ultrafiltration for Acute Decompensated Heart Failure and Cardiorenal Syndrome?, in
American Journal of Kidney Diseases, 2013; 62: 453–6. (B. J. Freda, benjamin.freda@bhs.org)
* Future of High-Density Lipoprotein Infusion Therapies: Potential for Clinical Management of Vascular Disease, in
Circulation, 2013; 128: 1112–21. (B. Kingwell, bronwyn.kingwell@bakeridi.edu.au)
* Natural Killer Cell Biology: An Update and Future Directions, in
Journal of Allergy and Clinical Immunology, 2013; 132: 536–44. (K. S. Campbell, kerry.campbell@fccc.edu)
* Efficacy and Safety of Proton Pump Inhibitors in the Management of Pediatric Gastroesophageal Reflux Disease, in
Pharmacotherapy, 2013; 33: 956–71. (J. Tjon, james.tjon@sickkids.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 10, 2013 * Vol. 20, No. 174
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 9 issue of the JAMA Internal Medicine (2013; 173).
Early Surgery for Prosthetic Valve Endocarditis: Compared with medical therapy alone, early surgery for prosthetic valve endocarditis (PVE) lowered in-hospital and 1-year mortality, researchers report, but the association did not hold after adjustment for survivor bias (pp. 1495–504). In the observational International Collaboration on Endocarditis–Prospective Cohort Study (ICE-PCS), patients with infective endocarditis had these outcomes with valve replacement during the index hospitalization versus medical therapy: “Of the 1,025 patients with PVE, 490 patients (47.8%) underwent early surgery and 535 individuals (52.2%) received medical therapy alone. Compared with medical therapy, early surgery was associated with lower in-hospital mortality in the unadjusted analysis and after controlling for treatment selection bias (in-hospital mortality: hazard ratio [HR], 0.44 [95% CI, 0.38–0.52] and lower 1-year mortality: HR, 0.57 [95% CI, 0.49–0.67]). The lower mortality associated with surgery did not persist after adjustment for survivor bias (in-hospital mortality: HR, 0.90 [95% CI, 0.76–1.07] and 1-year mortality: HR, 1.04 [95% CI, 0.89–1.23]). Subgroup analysis indicated a lower in-hospital mortality with early surgery in the highest surgical propensity quintile (21.2% vs 37.5%; P = .03). At 1-year follow-up, the reduced mortality with surgery was observed in the fourth (24.8% vs 42.9%; P = .007) and fifth (27.9% vs 50.0%; P = .007) quintiles of surgical propensity.” (T. Lalani, tlalani@idcrp.org)
Patients with prosthetic valve infection “fill us with dread,” writes an editorialist (
pp. 1504–5): “The poor outcomes and high mortality associated with PVE are sobering, and even more so if we reflect that early surgical debridement and re-replacement may not overcome the impact of powerful risk factors when survivor bias is included. Age, heart failure, stroke, chronic illness, Staphylococcus aureus infection, and health care–associated infection dominated the clinical course and may have diminished the positive effect of surgical intervention on outcomes in this series. This work by Lalani et al reinforces a profound respect for the serious morbidity of PVE and the heterogeneity of its anatomic and functional consequences. Surgery, as critical as it may be, cannot abrogate the influence of these other factors. A balanced consideration of host, bacteriologic, and hemodynamic factors that includes the individual patient’s ability to accommodate and tolerate, at least in the short term, regurgitation and fistulous shunts may allow us a more individualized approach to these challenging situations.” (A. F. Bolger, abolger@medsfgh.ucsf.edu)
Contraindicated Beta-Blockers Used in Heart Failure: Performance measures encouraging use of beta-blockers in patients hospitalized for heart failure need to be implemented carefully because of contraindications that are already being missed in practice, authors of a retrospective cohort study conclude (pp. 1547–9). Data from Premier’s Perspective database for 2009–10 show these patterns of beta-blocker usage in 237,812 patients with heart failure and markers of clinical instability (hospitalized in an intensive care unit, evidence of fluid overload or volume depletion, and recent treatment with an intravenous positive inotropic agent): “The hospitalizations in which beta-blocker therapy was started comprised 24.9% [primary cohort], 30.9% [age-restricted cohort], and 40.4% [acute myocardial infarction–restricted cohort] of all heart failure hospitalizations potentially eligible for beta-blocker therapy initiation. More than 40% of beta-blocker therapy starters had at least 1 potential contraindication to treatment. Approximately one-third received concomitant intravenous diuretics on the day of discharge, and up to one-fifth had received intravenous inotropes during hospitalization. Potential contraindications were higher among cohorts with higher specificity for systolic dysfunction.” (K. Dharmarajan, kumar.dharmarajan@yale.edu)
Reference Laboratory Values for Digoxin: Evidence that serum digoxin levels above 0.9 ng/mL are harmful has not been incorporated into practice, according to a survey of 60 laboratory directors (pp. 1552–4): “Most respondents defined a therapeutic reference range as 0.8 to 2.0 ng/mL; 56 of 60 report [serum digoxin concentrations] of 2.0 ng/mL or greater as being within the normal range.” (P. J. Hauptman, hauptmpj@slu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 11, 2013 * Vol. 20, No. 175
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 11 issue of JAMA (2013; 310).
Prednisolone, Pentoxifylline in Severe Alcoholic Hepatitis: Addition of pentoxifylline to a prednisolone-based treatment regimen for severe alcoholic hepatitis yielded no benefit in terms of 6-month survival, a study shows (pp. 1033–41). One potential advantage emerged—fewer cases of hepatorenal syndrome with pentoxifylline—but the authors note that the study may have been underpowered to detect a significant advantage. The study compared prednisolone 40 mg once daily and pentoxifylline 400 mg or placebo 3 times a day for 28 days, with these results in 270 patients: “In intention-to-treat analysis, 6-month survival was not different in the pentoxifylline–prednisolone and placebo–prednisolone groups (69.9% [95% CI, 62.1%–77.7%] vs 69.2% [95% CI; 61.4%–76.9%], P = .91), corresponding to 40 vs 42 deaths, respectively. In multivariable analysis, only the Lille model and the Model for End-Stage Liver Disease score were independently associated with 6-month survival. At 7 days, response to therapy assessed by the Lille model was not significantly different between the 2 groups (Lille model score, 0.41 [95% CI, 0.36–0.46] vs 0.40 [95% CI, 0.35–0.45], P = .80). The probability of being a responder was not different in both groups (62.6% [95% CI, 53.9%–71.3%] vs 61.9% [95% CI, 53.7%–70.3%], P = .91). The cumulative incidence of hepatorenal syndrome at 6 months was not significantly different in the pentoxifylline–prednisolone and the placebo–prednisolone groups (8.4% [95% CI, 4.8%–14.8%] vs 15.3% [95% CI, 10.3%–22.7%], P = .07).” (P. Mathurin, philippe.mathurin@chru-lille.fr)
“Corticosteroids and pentoxifylline are currently the only and most successful medical treatments available for severe alcoholic hepatitis despite providing only modest improvements in mortality,” editorialists write (
pp. 1029–30). “The results reported by Mathurin and colleagues demonstrate that the sum (corticosteroids and pentoxifylline) is no greater than the individual parts for preventing mortality in well-characterized patients with severe alcoholic hepatitis. Pentoxifylline may remain a useful option for patients who have contraindications to receiving corticosteroids; however, this group was not studied by Mathurin and colleagues. The study also emphasizes the importance of developing new treatments for severe alcoholic hepatitis. These future studies also should include well-conducted evaluations of liver transplantation for carefully selected patients with severe alcoholic hepatitis not responding to medical management.” (D. L. Halegoua-De Marzio)
SSRIs in Stroke Recovery: While supporting evidence is poor in quality, studies suggest that patients with stroke have improved recoveries with selective serotonin reuptake inhibitors (SSRIs), even if not depressed (pp. 1066–7). In a clinical evidence synopsis article, authors provide a meta-analysis of 52 trials and 4,060 participants: “Twenty-three trials provided dependency or disability data. One trial of 118 participants showed dependency at the end of treatment to be lower in those allocated fluoxetine for the proportion of participants with a modified Rankin Scale (mRS) of 3 to 5: 42 of 57 participants (74% [95% CI, 61% to 83%]) in SSRI group vs 50 of 55 participants (91% [95% CI, 80% to 96%]) in control group (P = .02); NNT, 6 [95% CI, 4 to 29]. For disability, SSRIs were superior to controls (22 trials, 1,310 participants: SMD, 0.92 [95% CI, 0.62 to 1.23]; NNT, 3 [95% CI, 2 to 3]). At the end of treatment, SSRIs were associated with better neurological recovery than controls (29 trials, 2,011 participants: SMD, −1.00 [95% CI, −1.26 to −0.75]; NNT, 2 [95% CI, 2 to 3]), better depression scores (39 trials, 2,728 participants; continuous variables: SMD, −1.91, [95% CI, −2.34 to −1.48]; NNT, 2 [95% CI, 2 to 2]; and 8 trials; dichotomous variable: 112 of 381 participants depressed in SSRI group vs 180 of 390 participants in control, RR, 0.43 [95% CI, 0.24 to 0.77]; NNT, 6 [95% CI, 5 to 10]) and less anxiety (8 trials, 413 participants: SMD, −0.77 [95% CI, −1.52 to −0.02]; NNT, 3 [95% CI, 2 to 89]).” (G. E. Mead, Gillian.e.mead@ed.ac.uk)

>>>PNN NewsWatch
* FDA yesterday announced class-wide safety labeling changes and new postmarketing study requirements for all extended-release and long-acting opioid analgesics intended to treat 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 12, 2013 * Vol. 20, No. 176
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 12 New England Journal of Medicine (2013; 369).
Prasugrel Pretreatment in Non–ST-Segment Elevation ACS: Among 4,033 patients with non–ST-segment elevation (NSTE) acute coronary syndromes, prasugrel administered before angiography did not reduce the rate of major ischemic events up to 30 days but did increase the rate of major bleeding complications, ACCOAST investigators report (pp. 999–1010). Study participants had positive troponin levels and were scheduled to have coronary angiography within 2–48 hours. Compared with placebo, pretreatment prasugrel produced these results: “The rate of the primary efficacy end point, a composite of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout) through day 7, did not differ significantly between the two groups (hazard ratio with pretreatment, 1.02; 95% confidence interval [CI], 0.84 to 1.25; P = 0.81). The rate of the key safety end point of all Thrombolysis in Myocardial Infarction (TIMI) major bleeding episodes, whether related or not related to coronary-artery bypass grafting (CABG), through day 7 was increased with pretreatment (hazard ratio, 1.90; 95% CI, 1.19 to 3.02; P = 0.006). The rates of TIMI major bleeding and life-threatening bleeding not related to CABG were increased by a factor of 3 and 6, respectively. Pretreatment did not reduce the rate of the primary outcome among patients undergoing PCI (69% of the patients) but increased the rate of TIMI major bleeding at 7 days. All the results were confirmed at 30 days and in prespecified subgroups.” (G. Montalescot, gilles.montalescot@psl.aphp.fr)
Platelet P2Y
12 inhibition may streamline care of those with non–ST-segment elevation myocardial infarction (NSTEMI), an editorialist writes (pp. 1056–7): “Because current guidelines recommend P2Y12 inhibition soon after hospital admission, many patients with NSTEMI who need CABG will have received P2Y12 antagonists before the catheterization. Administration of P2Y12 inhibitors within 5 days before CABG has been linked to excess bleeding and prolonged hospitalization, prompting recommendations that CABG be delayed until 5 to 7 days after discontinuation of P2Y12 antagonists. As a consequence, early P2Y12-inhibition therapy is an important cause of delay in performing CABG, adding inefficiency and cost to the care of patients with NSTEMI. However, the work of Montalescot and coworkers indicates that one can safely pursue a more parsimonious approach of reserving prasugrel administration until after angiography. With this strategy, P2Y12 treatment can be limited to patients who will be undergoing PCI, and patients with NSTEMI who require [coronary-artery bypass grafting] will be able to avoid unnecessary delays. Further studies will be needed to determine whether newer agents, administered only after angiography, can improve the efficiency of caring for patients with NSTEMI.” (J. F. Keaney)
Panitumumab & RAS Status in Colorectal Cancer: In metastatic colorectal cancers, non–KRAS mutations can affect response to therapy, a study shows, and tumors without such mutations respond well with panitumumab plus FOLFOX4 (oxaliplatin, fluorouracil, and leucovorin) regimen (pp. 1023–34). In a prospective–retrospective analysis, 639 patients with metastatic colorecal cancer had these outcomes: “Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab–FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P = 0.004). Overall survival was 26.0 months in the panitumumab–FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P = 0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab–FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor.” (J-Y Douillard, jean-yves.douillard@ico.unicancer.fr)

>>>PNN NewsWatch
* FDA has approved onabotulinumtoxinA (Botox Cosmetic, Allergan) for temporary improvement of moderate to severe lateral canthal lines (crow’s feet) in adults.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 13, 2013 * Vol. 20, No. 177
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Sept. 10 issue of Circulation (2013; 128).
HDL—Time To Tweak? Evidence continues to mount that cardioprotection from HDL cholesterol is complicated (pp. 1189–97). In the JUPITER trial, investigators found that HDL particle number (HDL-P) “may be a better marker of residual risk than chemically measured HDL-C or apoA-I.” Among 10,886 participants without cardiovascular disease (CVD) at baseline, rosuvastatin 20 mg/d or placebo produced these results: “Levels were examined with first CVD (n = 234). HDL-P correlated better with apoA-I (Spearman r = 0.69, P < 0.0001) than with HDL-C (r = 0.55, P < 0.0001). Rosuvastatin lowered low-density lipoprotein cholesterol (49%) and raised HDL-C (6.1%), apoA-I (2.1%), HDL-P (3.8%), and HDL size (1.2%); all P < 0.0001. Among placebo-allocated individuals, on-treatment HDL-C, apoA-I, and HDL-P had similar inverse associations with CVD (risk factor–adjusted hazard ratio and 95% confidence interval per 1 standard deviation: 0.79 [0.63–0.98], 0.75 [0.62–0.92], and 0.81 [0.67–0.97], respectively). Among rosuvastatin-allocated individuals, on-treatment HDL-P had a statistically significant and somewhat stronger association with CVD (0.73, 0.57–0.93, P = 0.01) than HDL-C (0.82, 0.63–1.08, P = 0.16) or apoA-I (0.86, 0.67–1.10, P = 0.22). Among rosuvastatin-allocated individuals, on-treatment HDL-P remained significant (0.72, 0.53–0.97, P = 0.03) after additionally adjusting for HDL-C. In risk factor–adjusted models, HDL size showed no significant association with CVD.” (S. Mora, smora@partners.org)
4-Factor Prothrombin Complex Concentrate in Major Bleeding: In a Phase IIIb open-label, noninferiority trial, 4-factor prothrombin complex concentrate (4F-PCC) was “an effective alternative to plasma for urgent reversal of vitamin K antagonist therapy in major bleeding events,” researchers report (pp. 1234–43). Among 202 patients, intention-to-treat results showed: “Median (range) baseline international normalized ratio was 3.90 (1.8–20.0) for the 4F-PCC group and 3.60 (1.9–38.9) for the plasma group. Effective hemostasis was achieved in 72.4% of patients receiving 4F-PCC versus 65.4% receiving plasma, demonstrating noninferiority (difference, 7.1% [95% confidence interval, –5.8 to 19.9]).” (R. Sarode, ravi.sarode@utsouthwestern.edu)

>>>Cardiology Report
Source:
Sept. 17 issue of the Journal of the American College of Cardiology (2013; 62).
Coffee Consumption & Health Outcomes: Potentially beneficial effects of habitual coffee consumption must be weighed against caffeine’s adverse effects, authors write in a review (pp. 1043–51): “From a cardiovascular (CV) standpoint, coffee consumption may reduce the risk of type 2 diabetes mellitus and hypertension, as well as other conditions associated with CV risk such as obesity and depression; but it may adversely affect lipid profiles depending on how the beverage is prepared. Regardless, a growing body of data suggests that habitual coffee consumption is neutral to beneficial regarding the risks of a variety of adverse CV outcomes including coronary heart disease, congestive heart failure, arrhythmias, and stroke. Moreover, large epidemiological studies suggest that regular coffee drinkers have reduced risks of mortality, both CV and all-cause. The potential benefits also include protection against neurodegenerative diseases, improved asthma control, and lower risk of select gastrointestinal diseases. A daily intake of ~2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects for most of the studied health outcomes. However, most of the data on coffee’s health effects are based on observational data, with very few randomized, controlled studies, and association does not prove causation. Additionally, the possible advantages of regular coffee consumption have to be weighed against potential risks (which are mostly related to its high caffeine content) including anxiety, insomnia, tremulousness, and palpitations, as well as bone loss and possibly increased risk of fractures.” (J. H. O’Keefe)

>>>PNN NewsWatch
* Compounding-pharmacy recalls continue as a result of problems at Front Range Laboratories, a testing laboratory. This week, Avella Specialty Pharmacy, Leiter’s Compounding Pharmacy, and Park Compounding Sterile Medication have recalled products because of lack of sterility assurance.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 16, 2013 * Vol. 20, No. 178
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 14 issue of Lancet (2013; 382).
Canagliflozin v. Glimepiride in Type 2 Diabetes: In a noninferiority, Phase III trial of patients with type 2 diabetes inadequately controlled with metformin, canaglifozin reduced A1C levels to a greater extent than did glimepiride, CANTATA-SU researchers report (pp. 941–50). Over 52 weeks, adult patients received the sodium–glucose cotransporter 2 inhibitor canaglifozin 100 or 300 mg/d or glimepiride uptitrated to 6 or 8 mg/d, with these results: “1,450 of 1,452 randomised patients received at least one dose of glimepiride (n = 482), canagliflozin 100 mg (n = 483), or canagliflozin 300 mg (n = 485). For lowering of HbA1c at 52 weeks, canagliflozin 100 mg was non-inferior to glimepiride (least-squares mean difference −0.01% [95% CI −0.11 to 0.09]), and canagliflozin 300 mg was superior to glimepiride (–0.12% [–0.22 to −0.02]). 39 (8%) patients had serious adverse events in the glimepiride group versus 24 (5%) in the canagliflozin 100 mg group and 26 (5%) in the 300 mg group. In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group, we recorded a greater number of genital mycotic infections (women: 26 [11%] and 34 [14%] vs five [2%]; men: 17 [7%] and 20 [8%] vs three [1%]), urinary tract infections (31 [6%] for both canagliflozin doses vs 22 [5%]), and osmotic diuresis-related events (pollakiuria: 12 [3%] for both doses vs one [<1%]; polyuria: four [<1%] for both doses vs two [<1%]).” (W. T. Cefalu, william.cefalu@pbrc.edu)
Antipsychotic Agents in Schizophrenia: Used in treatment of schizophrenia in clinical trials, antipsychotic agents differ “substantially” in adverse effects and have “small but robust differences … in efficacy,” according to results of a Bayesian-framework, multiple-treatments meta-analysis using both direct and indirect comparisons (pp. 951–62): “We identified 212 suitable trials, with data for 43,049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0.88, 0.73–1.03; amisulpride 0.66, 0.53–0.78; olanzapine 0.59, 0.53–0.65; risperidone 0.56, 0.50–0.63; paliperidone 0.50, 0.39–0.60; zotepine 0.49, 0.31–0.66; haloperidol 0.45, 0.39–0.51; quetiapine 0.44, 0.35–0.52; aripiprazole 0.43, 0.34–0.52; sertindole 0.39, 0.26–0.52; ziprasidone 0.39, 0.30–0.49; chlorpromazine 0.38, 0.23–0.54; asenapine 0.38, 0.25–0.51; lurasidone 0.33, 0.21–0.45; and iloperidone 0.33, 0.22–0.43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0.43 for the best drug (amisulpride) to 0.80 for the worst drug (haloperidol); for extrapyramidal side-effects 0.30 (clozapine) to 4.76 (haloperidol); and for sedation 1.42 (amisulpride) to 8.82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0.09 for the best drug (haloperidol) to −0.74 for the worst drug (olanzapine), for prolactin increase 0.22 (aripiprazole) to −1.30 (paliperidone), and for QTc prolongation 0.10 (lurasidone) to −0.90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.” (S. Leucht, stefan.leucht@lrz.tum.de)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 347).
Combined oral Contraceptives & Venous Thrombosis: All combined oral contraceptives increased patients’ risk of venous thrombosis, with differences realated to the type of progestogen used and the dose of ethinylestradiol, in a systematic review and meta-analysis of 26 observational studies (f5298; O. M. Dekkers, .m.dekkers@lumc.nl">o.m.dekkers@lumc.nl).

>>>PNN JournalWatch
* The “Epic” Challenge of Optimizing Antimicrobial Stewardship: The Role of Electronic Medical Records and Technology, in
Clinical Infectious Diseases, 2013; 57: 1005–13. (R. Kullar, ravina.kullar@gmail.com)
* Targeting Activated KIT Signaling for Melanoma Therapy, in
Journal of Clinical Oncology, 2013; 31: 3288–90. (B. C. Bastian)
* Navigating Complex Patients Using an Innovative Tool: The MTM Spider Web, in
Journal of the American Pharmacists Association, 2013; 53: 530–8. (C. M. Morello, candismorello@ucsd.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 17, 2013 * Vol. 20, No. 179
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Sept. 17 issue of the Annals of Internal Medicine (2013; 159).
Tolvaptan Costs in Polycystic Kidney Disease: In a cost-effectiveness study that used data from the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) trial, investigators conclude that tolvaptan likely slows the progression to end-stage renal disease (ESRD) and death, but its price would need to be reduced by 95% to compare favorably with common medical interventions (pp. 382–9). The study included findings from other published literature from 1993–2012 and used a lifetime horizon and societal perspective. Results of the base-case and sensitivity analyses showed: “Tolvaptan prolonged the median age at ESRD onset by 6.5 years and increased life expectancy by 2.6 years. At $5,760 per month, tolvaptan cost $744,100 per quality-adjusted life–year gained compared with standard care.
“For patients with autosomal dominant polycystic kidney disease that progressed more slowly, the cost per quality-adjusted life–year gained was even greater for tolvaptan.” (K. Erickson,
kevine1@stanford.edu)
Blood Pressure & Mortality in Chronic Kidney Disease: In a historical cohort study of 651,749 VA patients with chronic kidney disease (CKD), the optimal blood pressure (BP) range appeared to be a systolic BP (SBP) of 130–159 mm Hg and a diastolic BP (DBP) of 70–89 mm Hg, researchers report (pp. 233–42). In addition, “It may not be advantageous to achieve ideal SBP at the expense of lower-than-ideal DBP in adults with CKD,” authors write based on these results for 2005–12: “Patients with SBP of 130 to 159 mm Hg combined with DBP of 70 to 89 mm Hg had the lowest adjusted mortality rates, and those in whom both SBP and DBP were concomitantly very high or very low had the highest mortality rates. Patients with moderately elevated SBP combined with DBP no less than 70 mm Hg had consistently lower mortality rates than did patients with ideal SBP combined with DBP less than 70 mm Hg. Results were consistent in subgroups of patients with normal and elevated urinary microalbumin–creatinine ratios.” (C. P. Kovesdy, csaba.kovesdy@va.gov)
Varenicline for Smoking Cessation in Depression: In a Phase IV trial, 525 adults with current or past major depression had better smoking cessation rates with varenicline than placebo over a 12-week period, and the drug did not worsen symptoms of depression and anxiety (pp. 390–400). Based on results from the active treatment period and 40 weeks of nontreatment follow-up, investigators determined: “68.4% versus 66.5% of the varenicline and placebo groups, respectively, completed the study. Varenicline-treated participants had higher [continuous abstinence rates] versus placebo at weeks 9 to 12 (35.9% vs. 15.6%; odds ratio [OR], 3.35 [95% CI, 2.16 to 5.21]; P < 0.001), 9 to 24 (25.0% vs. 12.3%; OR, 2.53 [CI, 1.56 to 4.10]; P < 0.001), and 9 to 52 (20.3% vs. 10.4%; OR, 2.36 [CI, 1.40 to 3.98]; P = 0.001). There were no clinically relevant differences between groups in suicidal ideation or behavior and no overall worsening of depression or anxiety in either group. The most frequent adverse event was nausea (varenicline, 27.0%; placebo, 10.4%). Two varenicline-group participants died during the nontreatment phase.” (R. M. Anthenelli, robert.anthenelli@va.gov)
Clinical Care Teams: Clinical pharmacists should be members of dynamic clinical care teams, according to a policy paper issued by the American College of Physicians that covers professionalism, licensure, reimbursement, and research (doi: 10.7326/0003-4819-159-9-201311050-00710): “Although physicians have extensive education, skills, and training that make them uniquely qualified to exercise advanced clinical responsibilities within teams, well-functioning teams will assign responsibilities to advanced practice registered nurses, other registered nurses, physician assistants, clinical pharmacists, and other health care professionals for specific dimensions of care commensurate with their training and skills to most effectively serve the needs of the patient.” (American College of Physicians)

>>>PNN NewsWatch
* The first generic version of capecitabine (Teva) was approved yesterday for treatment of metastatic colorectal and breast cancers.
*
FDA has issued an import alert for drug products made at Ranbury’s facility in Mohali, India.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 18, 2013 * Vol. 20, No. 180
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 18 issue of JAMA (2013; 310).
Aliskiren & Coronary Disease in Prehypertension: Progression of coronary atherosclerosis was not slowed by aliskiren therapy in 613 patients with prehypertension and coronary artery disease, according to results of the AQUARIUS (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) trial (pp. 1135–44). After coronary intravascular ultrasound (IVUS) imaging, participants received aliskiren 300 mg or placebo orally daily for 104 weeks. Results, including a repeat IVUS after at least 72 weeks of treatment, showed these effects on a primary efficacy parameter of change in percent atheroma volume (PAV) from baseline to study completion: “Evaluable imaging data were available at baseline and follow-up for 458 participants (74.7%). The primary IVUS efficacy parameter, PAV, did not differ between participants treated with aliskiren (−0.33%; 95% CI, −0.68% to 0.02%) and placebo (0.11%; 95% CI, −0.24% to 0.45%) (between-group difference, −0.43% [95% CI, −0.92% to 0.05%]; P = .08). The secondary IVUS efficacy parameter, [normalized total atheroma volume (TAV)], did not differ between participants treated with aliskiren (−4.1 mm3; 95% CI, −6.27 to −1.94 mm3) and placebo (−2.1 mm3; 95% CI, −4.21 to 0.07 mm3) (between-group difference, −2.04 mm3 [95% CI, −5.03 to 0.95 mm33]; P = .18). There were no significant differences in the proportion of participants who demonstrated regression of PAV (56.9% vs 48.9%; P = .08) and TAV (64.4% vs 57.5%; P = .13) in the aliskiren and placebo groups, respectively.” (S. J. Nicholls, stephen.nicholls@sahmri.com)
AQUARIUS findings—and those from ASTRONAUT (Aliskiren Trial on Acute Heart Failure Outcomes), which also found no effect of aliskiren—are difficult to assess, editorialists write (
pp. 1130–1): “The interpretation of the difference in clinical outcomes between study groups in AQUARIUS … should consider the small number of events observed and the fact that the study was not powered for this objective. Furthermore, because the study did not meet its prespecified primary objective, other secondary and exploratory findings are therefore of uncertain significance. However, despite the methodological problems with AQUARIUS, and the importance of cautiously interpreting the clinical observations, these findings could be used to generate the hypothesis that aliskiren may have an effect on clinical outcomes in patients who have coronary artery disease but no diabetes or significant renal dysfunction—a different patient population from those in the [Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE)] and ASTRONAUT studies.” (J-C Tardif)
Managing Alcohol & Drug Dependence: In the Addiction Health Evaluation and Disease Management (AHEAD) study, chronic care management (CCM) failed to improve abstinence rate, compared with a primary care appointment, among patients with dependence on alcohol and other drugs, researchers report (pp. 1156–67). A total of 563 people were recruited in 2006–08. CCM included “longitudinal care coordinated with a primary care clinician; motivational enhancement therapy; relapse prevention counseling; and on-site medical, addiction, and psychiatric treatment, social work assistance, and referrals (including mutual help). Those in the control group received a primary care appointment and list of treatment resources. Results showed: “There was no significant difference in abstinence from opioids, stimulants, or heavy drinking between the CCM (44%) and control (42%) groups (adjusted odds ratio, 0.84; 95% CI, 0.65–1.10; P = .21). No significant differences were found for secondary outcomes of addiction severity, health-related quality of life, or drug problems. No subgroup effects were found except among those with alcohol dependence, in whom CCM was associated with fewer alcohol problems (mean score, 10 vs 13; incidence rate ratio, 0.85; 95% CI, 0.72–1.00; P = .048).” (R. Saitz, rsaitz@bu.edu)
These results “may suggest that the glass is half full rather than half empty” for CCM, an editorialist writes (
pp. 1132–4): “The CCM concept is sound, at least for some chronic illnesses, and highly relevant to today’s evolving health care system. More research on CCM of addiction is clearly warranted to identify specific CCM approaches that may be useful for specific substance-using populations.” (P. G. O’Connor, patrick.oconnor@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 19, 2013 * Vol. 20, No. 181
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 19 issue of the New England Journal of Medicine (2013; 369).
Sustaining Health Care Through Cost-effective Innovation: With the editors of the Harvard Business Review, NEJM editors have launched a series of daily blog-like articles that seek to “address foundational principles in the formulation of a high-value health care system, … address the management of innovation in the organization and delivery of health care, and … focus on the solutions developed by physician leaders and practitioners on the front lines,” according to an editorial (pp. 1163–4). “The collaborative publishing project between the Journal and the Harvard Business Review comes at a turning point in American health care. Never before have the interests of the health care community and the business community been better aligned. As Journal editors, we have already benefited from the collaboration through new colleagues, innovative ideas, and fresh perspectives. As the 2-month pilot project unfolds, we hope you will reap the same benefits. We look forward to receiving your comments about the project, and we hope to continue the collaboration in the future as key stakeholders in health care seek a high-performing health care system that can meet the country’s current and future needs.” (G. D. Curfman)
One of the first of these daily blogs being published over the next 2 months,
“Why Health Care Is Stuck—And How to Fix It,” is a summary of an article in the October issue of Harvard Business Review. In “The Strategy That Will Fix Health Care,” a pair of authors describe the role of pharmacists in “integrated practice units”: “[Multidisciplinary teams are] already starting to be applied to high-risk, high-cost patients through so-called Patient-Centered Medical Homes. But the opportunity to substantially enhance value in primary care is far broader. At Geisinger Health System, in Pennsylvania, for example, the care for patients with chronic conditions such as diabetes and heart disease involves not only physicians and other clinicians but also pharmacists, who have major responsibility for following and adjusting medications. The inclusion of pharmacists on teams has resulted in fewer strokes, amputations, emergency department visits, and hospitalizations, and in better performance on other outcomes that matter to patients.” (M. E. Porter)
Screening Tests for Colorectal Cancer: Reacting to two studies that quantify the impact of colonoscopies, sigmoidoscopies, and fecal blood detection in reducing mortality (pp. 1095–105, A. T. Chan, achan@partners.org; pp. 1106–14, A. Shaukat), editorialists conclude (pp. 1164–6): “Both colonoscopy and fecal occult-blood testing are effective for colorectal-cancer screening, and these new studies support current screening guidelines. Both tests have been improved since they were used among the participants in either study. However, the two studies are different, which makes direct comparisons of effectiveness difficult, especially with observational data. The uncertainties regarding the biologic characteristics of cancer, variations in the quality of colonoscopy, and the development of cancers during the interval between scheduled screening tests make it unclear which test is better over a 10-year period: an infrequent, high-sensitivity test (colonoscopy) or a frequent, moderate-sensitivity test (fecal occult-blood testing or [fecal immunochemical test]). The randomized trials currently under way will help shed light on this key question and others regarding the biologic features of cancer, screening participation, and the overall effectiveness of colorectal-cancer screening programs.” (T. R. Levin)
Drug Tracking Through Protein Denaturation: Cellular thermal shift assay (CETSA) provides a means of “measuring drug-target binding inside cells [and thereby] facilitating the studies of variables such as drug transport, activation, tissue distribution, target specificity, and resistance,” according to a Clinical Implications of Basic Research article (pp. 1168–9). The technique uses lysates of cultured mammalian cells to detect effects of drugs during heating. Based on levels of target protein remaining in soluble fractions at each temperature, Western blots can show changes in the “melting point” of the protein when drugs are added to the mixture, indicating pharmacologic interactions with the protein and the possibility of drug action. (J. Huang)

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 20, 2013 * Vol. 20, No. 182
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Sept. issue of Chest (2013; 144).
Cardiovascular Safety of Roflumilast in COPD: An oral phosphodiesterase 4 inhibitor developed for use in patients with COPD, roflumilast, should be evaluated on its cardiovascular benefits, according to authors who analyzed the frequency of major adverse cardiovascular events (MACEs) with the drug (pp. 758–65). In 14 trials of patients with moderate to very severe COPD, rates of MACE and a MACE composite of cardiovascular death, nonfatal myocardial infarction, and stroke showed these patterns over 12–52 weeks: “Of 6,563 patients receiving roflumilast, 52 experienced MACEs (14.3 per 1,000 patient–years), and of 5,491 patients receiving placebo, 76 experienced MACEs (22.3 per 1,000 patient–years). The MACE composite rate was significantly lower for roflumilast compared with placebo (hazard ratio, 0.65; 95% CI, 0.45-0.93; P = .019).” (W. B. White, wwhite@nso1.uchc.edu)
Editorialists discuss this trial along with registry-based results from in a second study (
pp. 750–7; G. Campo, cmpglc@unife.it) that stratified older patients with ST-segment elevation MI (STEMI) by presence or absence of COPD (pp. 723–6): “The link between the two studies published in this issue is that elderly patients with one dominant acute or chronic event almost invariably present with concomitant acute or chronic diseases that may influence the outcome of the patient. Thus, patients with STEMI or COPD must be properly investigated and possibly treated for concomitant diseases. It is likely that proper treatment of concomitant COPD could improve the outcome of cardiac patients, as suggested not only by the study of White et al but also by another study with other agents. Likewise, it is likely that treatment of concomitant chronic diseases, particularly cardiovascular diseases, in patients with COPD might improve their outcome. Because concomitant chronic diseases are often underdiagnosed, and studies on chronically ill elderly patients whose concomitant diseases are well characterized have never been performed, this lack presents a unique opportunity for promising clinical research. From this perspective, the ongoing Study to Understand Mortality and Morbidity in COPD (the SUMMIT study) is particularly timely. SUMMIT aims to assess the effect of COPD medications (ie, inhaled fluticasone furoate/vilanterol and individual components) on the survival of patients with moderate COPD and either a history of, or increased risk for, cardiovascular disease.” (L. M. Fabbri, leonardo.fabbri@unimore.it)

>>>JAPhA Report
Source:
Sept/Oct issue of the Journal of the American Pharmacists Association (2013; 53).
Patients’ MTM Decisions: Medicare beneficiaries prefer to receive comprehensive medication reviews (CMRs) provided under Part D from their usual pharmacy or at a convenient place, according to a survey of patients in Minnesota and Maryland (pp. 482–7). Respondents to a mailed survey reported the following: “The valid response rate was 33.4% (238 of 713). Among the proposed factors, ‘knowing the out-of-pocket cost’ (4.12 ± 1.28 [mean ± SD]) and ‘conducting in the usual pharmacy’ (4.01 ± 1.37) were most important in making a decision to get a CMR. Factors rated significantly more important by those who had versus had not received a CMR included ‘usual pharmacy,’ ‘receiving medication list,’ ‘physician’s support,’ and ‘pharmacists discuss changes with physicians.’ About one-third (30.6%) of respondents reported having pharmacist-provided CMRs within the previous year. Most respondents believed that having CMRs was important for their health (90.6%) and were satisfied with the results of CMRs (94.7%).” (W. R. Doucette, william-doucette@uiowa.edu)
Anticholinergic Burden in Older Adults: Among 341 patients referred to a visiting pharmacist program, nearly one-half had a clinically relevant score on an anticholinergic cognitive burden (ACB) scale (pp. 496–504). “The ACB score could be used as a component of MTM services in a variety of practice settings to identify older adults who are at higher risk for potential central and peripheral adverse effects related to cumulative anticholinergic activity of their medications,” the authors conclude. “Additional research to measure the clinical impact of ACB assessment and modification is needed.” (M. C. Pruchnicki, pruchnicki.1@osu.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 23, 2013 * Vol. 20, No. 183
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Sept. 21 issue of Lancet, a theme issue on Countdown to 2015 (2013; 382).
Adjuvant Trastuzumab in HER2-Positive Breast Cancer: In the HERceptin Adjuvant (HERA) trial, 2 years of adjuvant trastuzumab was not more effective than 1 year of treatment in 3,105 patients with HER2-positive early breast cancer, researchers report (pp. 1021–8). In the Phase III trial, 5,102 patients received either standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both for 1 or 2 years. Analysis of those who were disease-free 12 months after randomization to a traztuzumab group showed these outcomes based on disease-free survival during a median of 8 years of follow-up: “We recorded 367 events of disease-free survival in 1,552 patients in the 1 year group and 367 events in 1,553 patients in the 2 year group (hazard ratio [HR] 0.99, 95% CI 0.85–1.14, p = 0.86). Grade 3–4 adverse events and decreases in left ventricular ejection fraction during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20.4%] vs 275 [16.3%] grade 3–4 adverse events, and 120 [7.2%] vs 69 [4.1%] decreases in left ventricular ejection fraction, respectively). HRs for a comparison of 1 year of trastuzumab treatment versus observation were 0.76 (95% CI 0.67–0.86, p < 0.0001) for disease-free survival and 0.76 (0.65–0.88, p = 0.0005) for overall survival, despite crossover of 884 (52%) patients from the observation group to trastuzumab therapy.” (A. Goldhirsch, aaron.goldhirsch@ieo.it)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 347).
Stress Ulcer Prophylaxis & Nosocomial Pneumonia: In patients undergoing coronary artery bypass grafts, those receiving proton-pump inhibitors had a slightly increased risk of developing postoperative pneumonia, according to a retrospective cohort analysis of the Premier Research Database (f5416). Outcomes based on drug therapy in the immediate postoperative period showed these results: “Overall, 492 (5.0%) of the 9,830 patients receiving a proton pump inhibitor and 487 (4.3%) of the 11,384 patients receiving an H2 receptor antagonist developed postoperative pneumonia during the index hospital admission. After propensity score adjustment, an elevated risk of pneumonia associated with treatment with proton pump inhibitors compared with H2 receptor antagonists remained (relative risk 1.19, 95% confidence interval 1.03 to 1.38). In the instrumental variable analysis, use of a proton pump inhibitor (compared with an H2 receptor antagonist) was associated with an increased risk of pneumonia of 8.2 (95% confidence interval 0.5 to 15.9) cases per 1,000 patients.” (B. T. Bateman, bbateman@partners.org)
Smoking &Antiplatelet Efficacy: Used for prevention of cardiovascular events, the efficacy of antiplatelet drugs occurs primarily in smokers, with little benefit in nonsmokers, according to a systematic review and meta-analysis of nine randomized trials (f5307): “Trials include[d] 74,489 patients, of whom 21,717 (29%) were smokers. Among smokers, patients randomized to clopidogrel experienced a 25% reduction in the primary composite clinical outcome of cardiovascular death, myocardial infarction, and stroke compared with patients in the control groups (relative risk 0.75, 95% confidence interval 0.67 to 0.83). In nonsmokers, however, clopidogrel produced just an 8% reduction in the composite outcome (0.92, 0.87 to 0.98). Two studies investigated prasugrel plus aspirin compared with clopidogrel plus aspirin, and one study investigated ticagrelor plus aspirin compared with clopidogrel plus aspirin. In smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers.” (J. J. Gagne, jgagne1@partners.org)

>>>PNN JournalWatch
* Rhabdomyolysis, in
Chest, 2013; 144: 1058–65. (J. L. Zimmerman, janicez@tmhs.org)
* Early Administration of Azathioprine vs Conventional Management of Crohn’s Disease: A Randomized Controlled Trial, in
Gastroenterology, 2013; 145: 758–765.e2. (J. Cosnes, jacques.cosnes@sat.aphp.fr)
* Medicaid Expansion: Chronically Homeless Adults Will Need Targeted Enrollment and Access to a Broad Range of Services, in
Health Affairs, 2013; 32: 1552–9. (J. Tsai, Jack.Tsai@yale.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 24, 2013 * Vol. 20, No. 184
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Sept. 23 issue of the JAMA Internal Medicine (2013; 173).
Trends in Management of Spine-Related Pain: Publication of numerous clinical guidelines has failed to improve management and treatment of spine-related disease in the U.S., a study shows (pp. 1573–81). Instead, the authors conclude, “management of back pain has relied increasingly on guideline discordant care,” with fewer NSAIDs and more narcotic analgesics. Analysis of nationally representative data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey showed these patterns of care of patients with primary complaints of back or neck pain for 1999 through 2010: “We identified 23,918 visits for spine problems, representing an estimated 440 million visits. Approximately 58% of patients were female. Mean age increased from 49 to 53 years (P < .001) during the study period. Nonsteroidal anti-inflammatory drug or acetaminophen use per visit decreased from 36.9% in 1999–2000 to 24.5% in 2009–2010 (unadjusted P < .001). In contrast, narcotic use increased from 19.3% to 29.1% (P < .001). Although physical therapy referrals remained unchanged at approximately 20%, physician referrals increased from 6.8% to 14.0% (P < .001). The number of radiographs remained stable at approximately 17%, whereas the number of computed tomograms or magnetic resonance images increased from 7.2% to 11.3% during the study period (P < .001). These trends were similar after stratifying by short-term vs long-term presentations, visits to [primary care physician (PCPs)] vs non-PCPs, and adjustment for age, sex, race/ethnicity, PCP status, symptom duration, region, and metropolitan location.” (B. E. Landon, landon@hcp.med.harvard.edu)
“Guideline-based care for low back pain can be better standardized through the use of consistent checklist-based algorithms by well-trained, multidisciplinary clinical teams with the time, collective ability, and systems to support such care,” an editorialist writes (
pp. 1581–3). “Such systemization will also require sophisticated information systems and registries to track patient-reported outcomes, coordinate care, facilitate shared decision making, and promote successful self-management known to speed recovery. Large-scale collection of consistent and extensive patient-level (not administrative) data could then also be aggregated and prospectively analyzed by expert groups of researchers and program evaluation methodologists to look for key success factors and quick identification of outliers that require more intensive therapies. The pieces to this puzzle are available and just waiting to be put together.” (D. E. Casey Jr., donald.casey@nyumc.org)
Evidence-Based Clinical Decision Support in Primary Care: In a randomized controlled trial, inclusion of two well-validated integrated clinical prediction rules—the Walsh rule for streptococcal pharyngitis and the Heckerling rule for pneumonia—in electronic health records improved decisions made by 168 primary care providers during 40,003 patient visits, researchers report (pp. 1584–91). Compared with usual care, intervention group providers produced these results when tools were available for helping with complex decision making: “The intervention group completed the integrated clinical prediction rule tool in 57.5% of visits. Providers in the intervention group were significantly less likely to order antibiotics than the control group (age-adjusted relative risk, 0.74; 95% CI, 0.60–0.92). The absolute risk of the intervention was 9.2%, and the number needed to treat was 10.8. The intervention group was significantly less likely to order rapid streptococcal tests compared with the control group (relative risk, 0.75; 95% CI, 0.58–0.97; P = .03).” (T. G. McGinn, tmcginn@nshs.edu)
Calcium-Channel Blockers & Breast Cancer Risk: “Long-term current use of calcium-channel blockers in particular [is] associated with breast cancer risk,” conclude investigators who conducted a case–control study of antihypertensive medications used by patients in the Seattle area (pp. 1629–37). Increased risks of invasive ductal breast cancer (OR, 2.4; 95% CI, 1.2–4.9; P = .04 for trend) and invasive lobular breast cancer (OR, 2.6; 95% CI, 1.3–5.3; P = .01 for trend) were found for calcium-channel blockers of all types. Use of diuretics, beta-blockers, and ACE inhibitors showed no increased risk. (C. I. Li, cili@fhcrc.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 25, 2013 * Vol. 20, No. 185
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Sept. 25 issue of JAMA (2013; 310).
Sensor-Augmented Insulin Pump Therapy: In 95 patients with type 1 diabetes, the frequency of severe and moderate hypoglycemic episodes was lower with administration of insulin using a sensor-augmented pump that suspended drug administration at preset serum glucose thresholds, compared with standard insulin pump, researchers report (pp. 1240–7). Patients, recruited in 2009–12 in Australia, were randomized to insulin pump only or automated insulin suspension for 6 months, with these effects on a primary outcome of combined incidence of severe (hypoglycemic seizure or coma) and moderate hypoglycemia (an event requiring assistance for treatment): “Of the 95 patients randomized, 49 were assigned to the standard-pump (pump-only) therapy and 46 to the low-glucose suspension group. The mean (SD) age was 18.6 (11.8) years; duration of diabetes, 11.0 (8.9) years; and duration of pump therapy, 4.1 (3.4) years. The baseline rate of severe and moderate hypoglycemic events in the pump-only group was 20.7 vs 129.6 events per 100 patient–months in the low-glucose suspension group. After 6 months of treatment, the event rates decreased from 28 to 16 in the pump-only group vs 175 to 35 in the low-glucose suspension group. The adjusted incidence rate per 100 patient–months was 34.2 (95% CI, 22.0–53.3) for the pump-only group vs 9.5 (95% CI, 5.2–17.4) for the low-glucose suspension group. The incidence rate ratio was 3.6 (95% CI, 1.7–7.5; P <.001). There was no change in glycated hemoglobin in either group: mean, 7.4 (95% CI, 7.2–7.6) to 7.4 (95% CI, 7.2–7.7) in the pump-only group vs mean, 7.6 (95%, CI, 7.4–7.9) to 7.5 (95% CI, 7.3–7.7) in the low-glucose suspension group. Counterregulatory hormone responses to hypoglycemia were not changed. There were no episodes of diabetic ketoacidosis or hyperglycemia with ketosis.” (T. W. Jones, tim.jones@health.wa.gov.au)
Combined with results of other recently published trials, these findings “demonstrate the ability of sensor-augmented insulin pumps with threshold suspension function to provide a significant reduction in severe hypoglycemia,” an editorialist writes (
pp. 1235–6). “These data can now be used to evaluate the health economic benefits of this therapy and also can be used by clinicians, payers, and regulatory authorities to help make this therapy and technology more widely available to patients who struggle daily with hypoglycemia.” (P. Choudhary, pratik.choudhary@kcl.ac.uk)
Difficult-to-Control Hypertension in Older Patients: The case of a 91-year-old woman with refractory hypertension serves as the basis for a discussion of the treatment of high blood pressure in older patients (pp. 1274–80): “Hypertension in elderly people differs from that in younger people in that (1) hypertension is predominantly systolic because of vascular stiffness; (2) it is associated with reduced baroreflex sensitivity, which increases blood pressure variability and vulnerability to hypotension during common daily activities; (3) it is associated with cognitive and functional decline as well as adverse cardiovascular outcomes; and (4) hypertension may be beneficial in frail people older than 85 years. Treatment of healthy patients up to age 85 years with most antihypertensive medications reduces cardiovascular morbidity and mortality and possibly cognitive and functional decline.” The authors conclude, “Although patients in their 90s have not been studied, any ambulatory and independent patient older than 80 years should have multiple blood pressure measurements taken during their usual daily activities, and if these show persistent hypertension, these patients should be treated judiciously.” (L. A. Lipsitz, lipsitz@hsl.harvard.edu)

>>>PNN NewsWatch
* To prevent accidental exposure in children and pets, FDA is requiring color changes on fentanyl patches (Duragesic and generic) so that they can be seen more easily. The agency reiterated that used fentanyl patches require proper disposal after use: fold the patch, sticky sides together, and flush it down the toilet right away.
*
FDA on Monday issued final guidance for developers of mobile medical apps—those that perform the same functions as traditional medical devices. The guidance applies to devices that, for example, control pumps or glucose meters.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 26, 2013 * Vol. 20, No. 186
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Sept. 26 issue of the New England Journal of Medicine (2013; 369).
Genomic Clues to Sources of C. difficile Infection: Contrary to the current assumption that symptomatic patients are sources of most infections of Clostridium difficile, the bacterium can be acquired from a genetically diverse array of sources outside health care systems, a study shows (pp. 1195–205). In Oxfordshire, U. K., in 2007–11, investigators performed whole-genome sequencing on isolates from 145 symptomatic patients with C. difficile infection. Analysis of single-nucleotide variants (SNVs) and evolution rates produced these results: “Of 1,250 C. difficile cases that were evaluated, 1,223 (98%) were successfully sequenced. In a comparison of 957 samples obtained from April 2008 through March 2011 with those obtained from September 2007 onward, a total of 333 isolates (35%) had no more than 2 SNVs from at least 1 earlier case, and 428 isolates (45%) had more than 10 SNVs from all previous cases. Reductions in incidence over time were similar in the two groups, a finding that suggests an effect of interventions targeting the transition from exposure to disease. Of the 333 patients with no more than 2 SNVs (consistent with transmission), 126 patients (38%) had close hospital contact with another patient, and 120 patients (36%) had no hospital or community contact with another patient. Distinct subtypes of infection continued to be identified throughout the study, which suggests a considerable reservoir of C. difficile.” (D. W. Eyre, david.eyre@ndm.ox.ac.uk)
While this study challenges “the traditional concept that symptomatic patients in hospitals account for most
C. difficile transmission and infection,” its practical implications are less far-reaching, an editorialist writes (pp. 1263–4): “The findings will not alter recommendations that basic control measures are essential. Infrequent transmission from symptomatic patients in the study hospitals may in fact attest to the effectiveness of well-implemented control programs. The major implication of the study is that control of C. difficile will require that we move beyond the usual suspects (symptomatic patients in hospitals). Although additional work is needed to identify sources of acquisition, Eyre et al. have shown the potential for highly discriminatory typing methods to transform our understanding of the transmission of C. difficile and other health care–associated pathogens.” (C. J. Donskey)
CMX001 for Prevention of Cytomegalovirus Disease: In patients who had undergone hematopoietic-cell transplants, oral CMX001 for 3 months lowered risk of acquiring cytomegalovirus (CMV) disease, researchers report (pp. 1227–36). CMX100 is active in vitro against CMV and other double-stranded DNA viruses. In 230 patients during 2009–11, randomization to CMX001 or placebo (3:1) produced these outcomes based on a primary outcome of a CMV event (CMV disease or a plasma CMV DNA level greater than 200 copies/mL when the study drug was discontinued): “The incidence of CMV events was significantly lower among patients who received CMX001 at a dose of 100 mg twice weekly than among patients who received placebo (10% vs. 37%; risk difference, −27 percentage points; 95% confidence interval, −42 to −12; P = 0.002). Diarrhea was the most common adverse event in patients receiving CMX001 at doses of 200 mg weekly or higher and was dose-limiting at 200 mg twice weekly. Myelosuppression and nephrotoxicity were not observed.” (F. M. Marty, fmarty@partners.org)
Prescription-Drug Coupons: An analysis of cost implications at the population level confirms that prescription-drug coupons are not an exception to the “no free lunch” rule (pp. 1188–9): “Physicians need to talk to their commercially insured patients about the implications of drug-coupon use and make sure that their inclination to reduce short-term out-of-pocket spending doesn’t come at the cost of higher long-term expenses for themselves and society.” (J. S. Ross)

>>>PNN NewsWatch
* Boxed warnings about risk of reactivation of hepatitis B virus (HBV) infection have been added to product labeling of ofatumumab (Arzerra, GlaxoSmithKline) and rituximab (Rituxan, Genentech), FDA said yesterday. Revised labels also include additional recommendations for screening, monitoring, and managing patients on these drugs to decrease this risk.

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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 27, 2013 * Vol. 20, No. 187
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Oct. issue of Diabetes Care (2013; 36).
Intensive SMBG & Glycemic Control: “Structured [intensive self-monitoring of blood glucose (SMBG)] improves glycemic control and provides guidance in prescribing diabetes medications in patients with relatively well-controlled noninsulin-treated type 2 diabetes,” according to a 12-month study of 1,024 patients (pp. 2887–94). At 39 clinics in Italy, standardized education was provided to study participants, who were then randomized to intensive structured monitoring (ISM) with 4-point glycemic profiles (fasting, preprandial, 2-h postprandial, and postabsorptive measurements) performed 3 d/wk or active control (AC) therapy with 4-point glycemic profiles performed at baseline and at 6 and 12 months. Results showed: “Intent-to-treat analysis showed greater HbA1c reductions over 12 months in ISM (−0.39%) than in AC patients (−0.27%), with a between-group difference of −0.12% (95% CI, −0.210 to −0.024; P = 0.013). In the per-protocol analysis, the between-group difference was −0.21% (−0.331 to −0.089; P = 0.0007). More ISM than AC patients achieved clinically meaningful reductions in HbA1c (>0.3, >0.4, or >0.5%) at study end (P < 0.025). The proportion of patients reaching/maintaining the risk target at month 12 was similar in ISM (74.6%) and AC (70.1%) patients (P = 0.131). At visits 2, 3, and 4, diabetes medications were changed more often in ISM than in AC patients (P < 0.001).” (E. Bosi, bosi.emanuele@hsr.it)
Afternoon Exercise & Closed-Loop Insulin Delivery: In 12 patients with type 1 diabetes, automated feedback-controlled closed-loop (CL) insulin delivery has the potential to reduce nocturnal hypoglycemia (NH) regardless of afternoon activities, researchers report (pp. 2909–14). During two 48-h inpatient study periods, participants received usual open-loop (OL) control or CL control insulin in crossover fashion. Each admission had a sedentary day and an exercise day. Results showed these patterns: “Among 12 subjects (age 12–26 years, A1C 7.4 ± 0.6%), antecedent exercise increased the frequency of NH (reference blood glucose <60 mg/dL) during OL control from six to eight events. In contrast, there was only one NH event each on nights with and without antecedent exercise during CL control (P = 0.04 vs. OL nights). Overnight, the percentage of glucose values in target range was increased with CL control (P < 0.0001). Insulin delivery was lower between 10:00 P.M. and 2:00 A.M. on nights after exercise on CL versus OL, P = 0.008.” (J. L. Sherr, jennifer.sherr@yale.edu)
Lixisenatide v. Exenatide in Type 2 Diabetes: In a comparison of once-daily lixisenatide 20 mcg and twice-daily exenatide 10 mcg, patients poorly controlled on metformin showed noninferior efficacy results and slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability with lixisenatide, a study shows (pp. 2945–51): “Responder rate (HbA1c <7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P < 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P < 0.05).” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
Metformin & Mortality After Breast Cancer: In patients older than 65 with breast cancer and recent-onset diabetes, a population-based study from Ontario fails to find an association between improved survival and increased cumulative metformin duration (pp. 3018–26). Data from 1997 to 2008 showed the following: “Of 2,361 breast cancer patients identified, mean (± SD) age at cancer diagnosis was 77.4 ± 6.3 years, and mean follow-up was 4.5 ± 3.0 years. There were 1,101 deaths(46.6%), among which 386 (16.3%) were breast cancer–specific deaths. No significant association was found between cumulative duration of past metformin use and all-cause mortality (adjusted hazard ratio 0.97 [95% CI 0.92–1.02]) or breast cancer–specific mortality (0.91 [0.81–1.03]) per additional year of cumulative use.” (I. C. Lega, iliana.lega@wchospital.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Sept. 30, 2013 * Vol. 20, No. 188
Providing news and information about medications and their proper use

>>>Geriatrics Report
Source:
Sept. issue of the Journal of the American Geriatrics Society (2013; 61).
Medication Reviews by Physicians in Older Adults With Hip Fracture: A randomized trial from Sweden shows that physician-conducted medication reviews increased use of fracture-preventing drugs among 199 older adults with hip fracture, but the intervention did not lower use of medications that increase risk of falls (pp. 1464–72). Medication reviews were communicated orally and in writing to hospital physicians during hospital stays and to general practitioners after discharge. Medication use 12 months after discharge showed these patterns for intervention and control patients: “At admission, 26% of intervention and 29% of control participants were taking fracture-preventing drugs, and 12% and 11%, respectively, were taking bone-active drugs, predominantly bisphosphonates. After 12 months, 77% of intervention and 58% of control participants were taking fracture-preventing drugs (P = .01), and 29% and 15%, respectively, were taking bone-active drugs (P = .04). Mean number of fall-risk-increasing drugs per participants was 3.1 (intervention) and 3.1 (control) at admission and 2.9 (intervention) and 3.1 (control) at 12 months (P = .62). No significant differences in hard endpoints were found. The responding physicians (n = 65) appreciated the intervention; on a scale from 1 (very bad) to 6 (very good), the median rating was 5 (interquartile range (IQR) 4–6) for the oral part and 5 (IQR 4–5.5) for the text part.” (C. Sjöberg, christina.a.sjoberg@vgregion.se)
ACE Inhibitors & AD Progression in Older Adults: Community-dwelling older adults with mild to moderate Alzheimer’s disease had slower rates of cognitive decline when they were taking ACE inhibitors, report investigators who conducted a 4-year prospective cohort study at 16 French memory clinics (pp. 1482–8; M. E. Soto, soto-martin.me@chu-toulouse.fr).

>>>Neurology Highlights
Source:
Sept. 24 issue of Neurology (2013; 61).
Factors Affecting tPA Use in Acute Stroke: Uncertainty, beliefs, and biases affect the decision to use tissue plasminogen activator (tPA) in patients with acute stroke, a preliminary investigation shows (pp. 1130–3). An online survey of neurologists in Ontario achieved a 69% response rate and showed the following: “Seventy-nine percent (79%) of respondents were less likely to administer IV tPA to patients with dementia, and many were less likely to treat patients from nursing homes, with more severe strokes, or over age 80. All respondents recognized the presence of diagnostic uncertainty, and 87% believed that uncertainty in interpreting advanced imaging affected their use of tPA. The majority of respondents (70%) believed that a large left middle cerebral artery territory stroke was a fate worse than death. Four percent did not believe that IV tPA is an effective treatment for stroke.” (M. C. F. Shamy, michel.shamy@utoronto.ca)

>>>PNN NewsWatch
* FDA has added a boxed warning to labeling of intravenous tigecycline (Tygacil, Wyeth) about increased risk of death when the agent is used for unapproved indications. Data analyzed since a 2010 warning showed deaths were often from worsening infections, complications of infections, and other underlying medical conditions.

>>>PNN JournalWatch
* Antidepressant Medication as a Risk Factor for Type 2 Diabetes and Impaired Glucose Regulation: Systematic Review, in
Diabetes Care, 2013; 36: 3337–45. (K. Barnard, k.barnard@southampton.ac.uk)
* The Preclinical Phase of Rheumatoid Arthritis: What Is Acknowledged and What Needs To Be Assessed?, in
Arthritis & Rheumatism, 2013; 65: 2219–32. (H. W. van Steenbergen, H.W.van_Steenbergen@lumc.nl)
* 2013 Update of the 2011 American College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for the Medical Therapy of Children With Systemic Juvenile Idiopathic Arthritis and Tuberculosis Screening Among Children Receiving Biologic Medications, in
Arthritis & Rheumatism, 2013; 65: 2499–512. (P. F. Weiss, weisspa@email.chop.edu)
* Priorities in Pediatric Epilepsy Research: Improving Children’s Futures Today, in
Neurology, 2013; 81: 1166–75. (A. T. Berg, atberg@luriechildrens.org)
* How to Teach Medication Management: A Review of Novel Educational Materials in Geriatrics, in
Journal of the American Geriatrics Society, 2013; 61: 1598–601. (R. Ramaswamy, ravishankar.ramaswamy@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.