Mar 2012

PNN January–March 2012

PNN Pharmacotherapy Line
Jan. 3, 2012 * Vol. 19, No. 1
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 3 issue of the Annals of Internal Medicine (2012; 156).
Guidelines for Oral Antidiabetic Meds: Quality of published guidelines on oral antidiabetic medications varies considerably and is generally poor, researchers report (pp. 27–36). In a systematic review, 11 guidelines on oral medications for type 2 diabetes were assessed their consistency with a 2007 systematic review: “Ten guidelines agreed that thiazolidinediones are associated with higher rates of edema and congestive heart failure compared with other oral medications to treat type 2 diabetes. One guideline addressed no evidence-based conclusions, and 5 guidelines agreed with all 7 conclusions. The summary scores of the rigor of development (median, 28.6% [range, 16.7% to 100.0%]) and editorial independence (median, 75.0% [range, 8.3% to 100.0%]) domains varied greatly across guidelines. Guidelines that received higher quality scores contained more recommendations that were consistent with the evidence-based conclusions.” (W. L. Bennett)
Chiropractic for Neck Pain: Spinal manipulation therapy (SMT) and home exercise are similarly effective to each other, a study shows, and both are more effective than medication for neck pain (pp. 1–10). In a randomized trial, 272 patients aged 18–65 with nonspecific neck pain for 2–12 weeks were randomly assigned to receive SMT, medication, or home exercise with advice for 12 weeks. Up to 1 year after treatment, patients having 12 weeks of SMT reported greater pain relief than patients in the medication group. Patients in the home exercise with advice group reported just as much pain relief as those in the SMT group over the same period. However, patients having SMT reported that they were more satisfied with care than those in either of the other groups. (G. Bronfort)
Ethics Manual Published: The American College of Physicians has released the 6th edition of its Ethics Manual as a supplement to this issue (pp. 73–104). New topics in the updated manual address the patient–physician relationship during health catastrophes, providing culturally sensitive care, use of human biologic materials in research, social media and online professionalism, industry-sponsored research, and the challenges of taking care of so-called very important persons, such as those with a degree of fame or prestige.

>>>Diabetes Highlights
Source:
Jan. issue of Diabetes Care (2012; 35).
Weight Loss with Exenatide: In 41 obese nondiabetic women, a short course of exenatide reduced weight and waist circumference, according to a 35-week study (pp. 4–11). Participants had an average age of 48 (± 11) years and BMI of 33.1 (± 4.1) kg/sq m. Two 16-week treatment periods were separated by a 3-week washout period in the crossover trial, which showed these results: “Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (−7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (−2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss.” (J. Dushay, jdushay@bidmc.harvard.edu)
Cancer Risk with Metformin, Sulfonylureas: Patients taking metformin have a 10% lower risk of developing cancers than do those taking sulfonylureas, a Dutch analysis of prescription records shows (pp. 119–24). “Whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated,” the authors conclude. (B. H. Ch. Stricker, b.stricker@erasmusmc.nl)

>>>PNN JournalWatch
* New-Onset Diabetes After Renal Transplantation: Risk Assessment and Management, in
Diabetes Care, 2012; 35: 181–8. (L. Ghisdal, lidia.ghisdal@erasme.ulb.ac.be)
* Parental Smoking Cessation to Protect Young Children: A Systematic Review and Meta-analysis, in
Pediatrics, 2012; 129:141–52. (L. J. Rosen)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 4, 2012 * Vol. 19, No. 2
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 4 issue of JAMA (2012; 307).
Protein & Weight Gain: In 25 overfed patients living in a controlled setting, protein intake affected energy expenditure and storage of lean body mass, but caloric intake alone determined how much fat they accumulated, a study shows (pp. 47–55). The healthy, weight-stable participants were 18–35 years of age and had initial BMIs of 19–30 kg/sq m. During 10- to 12-week stays in a metabolic unit, they were randomized to low (5%), normal (15%), and high (25%) protein diets, and they were overfed by about 40% during the last 8 weeks. Results showed: “Overeating produced significantly less weight gain in the low protein diet group (3.16 kg; 95% CI, 1.88–4.44 kg) compared with the normal protein diet group (6.05 kg; 95% CI, 4.84–7.26 kg) or the high protein diet group (6.51 kg; 95% CI, 5.23–7.79 kg) (P = .002). Body fat increased similarly in all 3 protein diet groups and represented 50% to more than 90% of the excess stored calories. Resting energy expenditure, total energy expenditure, and body protein did not increase during overfeeding with the low protein diet. In contrast, resting energy expenditure (normal protein diet: 160 kcal/d [95% CI, 102–218 kcal/d]; high protein diet: 227 kcal/d [95% CI, 165–289 kcal/d]) and body protein (lean body mass) (normal protein diet: 2.87 kg [95% CI, 2.11–3.62 kg]; high protein diet: 3.18 kg [95% CI, 2.37–3.98 kg]) increased significantly with the normal and high protein diets.” (G. A. Bray, George.bray@pbrc.edu)
“[These] study results also suggest that body weight may underestimate the true hazards of overnutrition,” editorialists write (
pp. 86–7). “Overeating low protein diets may increase fat deposition leading to loss of lean body mass despite lesser increases in body weight,” the writers conclude. “Policy makers and primary care physicians need to understand the role of the Western diet in promoting overweight and obesity. Because this diet increases the risks of overnutrition through fat deposition beyond that detected by body mass index, the method used to assess the current obesity epidemic and the magnitude of the obesity epidemic may have been underestimated. Clinicians should consider assessing a patient’s overall fatness rather than simply measuring body weight or body mass index and concentrate on the potential complications of excess fat accumulation. The goals for obesity treatment should involve fat reduction rather than simply weight loss, along with a better understanding of nutrition science.” (Z. Li)
Bariatric Surgery & Long-term Cardiovascular Events: Cardiovascular events and deaths are reduced by bariatric surgery, compared with usual care, in obese patients, researchers report (pp. 56–65). In the Swedish Obese Subjects (SOS) study, 2,010 obese participants who underwent bariatric surgery were compared with 2,037 contemporaneously matched controls during 1987–2001. Analysis of outcomes through 2009 showed these results: “Bariatric surgery was associated with a reduced number of cardiovascular deaths (28 events among 2,010 patients in the surgery group vs 49 events among 2,037 patients in the control group; adjusted hazard ratio [HR], 0.47; 95% CI, 0.29–0.76; P = .002). The number of total first time (fatal or nonfatal) cardiovascular events (myocardial infarction or stroke, whichever came first) was lower in the surgery group (199 events among 2,010 patients) than in the control group (234 events among 2,037 patients; adjusted HR, 0.67; 95% CI, 0.54–0.83; P < .001).” (L. Sjöström, lars.v.sjostrom@medfak.gu.se)
“Interpreting the clinical importance of these results is complicated by the authors’ findings that reduced cardiovascular events among the surgical patients were not related to either baseline weight or weight loss,” editorialists write (
pp. 88–9). “In an earlier trial of mortality outcomes from the SOS study, improvements in mortality associated with bariatric surgery were unrelated to surgically induced weight loss. Some unidentified factor is associated with bariatric surgery operations resulting in fewer cardiovascular events and reductions in mortality that are not related to weight loss. Perhaps patients motivated enough to undergo bariatric procedures are more adherent with medical treatments or pursue a healthier diet, and these factors are not reflected in their BMI.” (E. H. Livingston, edward.livingston@utsouthwestern.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 5, 2012 * Vol. 19, No. 3
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 5 issue of the New England Journal of Medicine (2012; 366).
Herpes Simplex Vaccine: An investigational vaccine against genitally transmitted herpes simplex virus type 2 (HSV-2) was ineffective but showed some efficacy against HSV-1, researchers report (pp. 34–43). In a randomized controlled field trial of 8,323 women aged 18–30 years and seronegative for HSV-1 and HSV-2, the investigational vaccine (20 µg of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant) showed these effects when compared with a control hepatitis A vaccine given at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units: “The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], −29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (−8%; 95% CI, −59 to 26).” (R. B. Belshe, belsherb@slu.edu)
Genetic Basis of Chemoresistance in Colorectal Cancer: The gene for dickkopf homolog 4 protein (DKK4) is a potential target in research into agents that can improve responses to chemotherapy for colorectal cancer, a study shows (pp. 44–53). That gene is “a potential downstream target” of the gene encoding transcription factor AP-2 epsilon (TFAP2E). Researchers analyzed the relationship between these genes and patient response to chemotherapy by looking at the expression, methylation, and function of TFAP2E in colorectal-cancer cell lines and 5 cohorts with a total of 220 patients with colorectal cancer: “TFAP2E was hypermethylated in 38 of 74 patients (51%) in the initial cohort. Hypermethylation was associated with decreased expression of TFAP2E in primary and metastatic colorectal-cancer specimens and cell lines. Colorectal-cancer cell lines overexpressing DKK4 showed increased chemoresistance to fluorouracil but not irinotecan or oxaliplatin. In the four other patient cohorts, TFAP2E hypermethylation was significantly associated with nonresponse to chemotherapy (P < 0.001). Conversely, the probability of response among patients with hypomethylation was approximately six times that in the entire population (overall estimated risk ratio, 5.74; 95% confidence interval, 3.36 to 9.79). Epigenetic alterations of TFAP2E were independent of mutations in key regulatory cancer genes, microsatellite instability, and other genes that affect fluorouracil metabolism.” (M. P. A. Ebert, matthias.ebert@umm.de)
Genomics & Perinatal Care: The “complicated choices” faced by patients, practitioners, and policymakers regarding the application of genomic techniques in the perinatal period are described and analyzed in a review article (pp. 64–73): “All new genomic technologies are potentially applicable to preconception, prenatal, and newborn care, but whether and how they will be used are subject to debate. Although we are now able to interrogate the human genome with exquisite precision, genotype may not predict phenotype. The development and implementation of guidelines involve questions of input from consumers and advocates, conflict of interest, and cost-effectiveness analysis. Yet the development of outcome measures to evaluate clinical genetic services is in a nascent state. Clinicians are encouraged to keep up with advances and national recommendations. Each clinician is an important educator of patients and a key member of the referral network for specialized services to bridge the gap between the worlds of personalized medicine and evidence-based medicine.” (J. F. Strauss, jfstrauss@vcu.edu)

>>>PNN NewsWatch
* Effective Apr. 5, a number of extralabel uses of cephalosporins in cattle, swine, chickens, and turkeys will be banned, FDA said yesterday. FDA said it took the action to protect this antibiotic class for human uses.
*
Prevnar 13 (pneumococcal 13-valent conjugate vaccine, Wyeth) has been approved by FDA for use in people aged 50 years or older to prevent pneumonia and invasive disease caused by Streptococcus pneumoniae.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 6, 2012 * Vol. 19, No. 4
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Jan. 3 issue of the Journal of the American College of Cardiology (2012; 59).
Short-Term Preoperative Statin Treatment: Statins administered before cardiac surgery exert their beneficial effects by decreasing the amounts of detrimental oxidative radicals, researchers report (pp. 60–70). The mechanism of action for this effect appears to be a Rac1-mediated suppression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, which results in lower levels of myocardial superoxide anion (O2) and peroxynitrite (ONOO) production. Study participants were 42 patients who received 3-day courses of atorvastatin 40 mg/day or placebo before surgery. Investigators quantified oxidative radical concentrations in samples of right atrial appendages (RAAs) from 303 patients undergoing cardiac surgery who were followed until discharge. They also measured myocardial redox state in 26 RAA samples exposed to atorvastatin ex vivo.
Results showed: “Atrial O
2 (derived mainly from … NADPH oxidases) and ONOO were independently associated with increased risk of atrial fibrillation, the need for post-operative inotropic support, and the length of hospital stay. Pre-operative atorvastatin treatment suppressed atrial NADPH oxidase activity and myocardial O2 and ONOO production. Ex vivo incubation of RAA samples with atorvastatin induced a mevalonate-reversible and Rac1-mediated inhibition of NADPH oxidase.” (C. Antoniades, antoniad@well.ox.ac.uk)
This and a 2011
Circulation study (124: 335–45) by the same research group “provide important insights into the cholesterol-independent effects of statins on vascular and myocardial tissue,” an editorialist writes (pp. 71–3): “These studies are good examples of translational research confirming ex-vivo observations in human tissue and in hypothesis-generating clinical studies. As much as additional cellular studies are necessary to fully understand the signal transduction underlying the acute effects of statins, the main challenge for the future is to test the clinical relevance of statins by performing prospective trials with clinical endpoints.” (U. Laufs, ulrich@laufs.com)
Cardiac Uses of Phosphodiesterase-5 Inhibitors: Pathophysiology and trial data of phosphodiesterase-5 inhibitors (PDE5Is) for cardiac uses of the drugs are presented, including some evidence of benefits in hypertension, preeclampsia, and peripheral arterial disease (pp. 9–15): “PDE5Is might benefit cardiovascular diseases because phosphodiesterase-5 is also located elsewhere in the body, including the pulmonary and systemic vasculature and in hypertrophied myocardium. PDE5Is are approved for pulmonary arterial hypertension, given that they improved several hemodynamic and clinical parameters in large randomized trials. Initial evidence suggests that PDE5Is benefit patients with congestive heart failure and secondary pulmonary hypertension. PDE5Is seem to improve hemodynamic and clinical parameters in patients with high-altitude pulmonary edema (HAPE) and high-altitude pulmonary hypertension. In climbers with prior episodes of HAPE, PDE5Is prevented HAPE in 2 small randomized trials. In small randomized trials of PDE5Is, patients with Raynaud’s phenomenon demonstrated improved blood flow, fewer symptoms and frequency of attacks, and resolution of digital ulcers. In addition to enhancing vasodilation, PDE5Is seem to protect the myocardium through complex pathways that involve nitric oxide, cyclic guanosine monophosphate, protein kinase G, extracellular-signal-regulated kinase, B-cell lymphoma protein-2, and Rho kinase inhibition. In animal models of acute myocardial infarction, PDE5Is consistently reduced infarct size indicating cardioprotection and PDE5Is also promote reverse remodeling and reduce myocardial apoptosis, fibrosis, and hypertrophy. PDE5Is might also benefit patients with treatment-resistant hypertension, preeclampsia, or peripheral arterial disease.” (R. A. Kloner, rkloner@goodsam.org)

>>>PNN NewsWatch
* FDA has approved a single Risk Evaluation and Mitigation Strategy (REMS) for transmucosal immediate-release fentanyl products. This new shared system will replace the individual REMS for Abstral, Actiq, Fentora, Lazanda, and Onsolis and allow prescribers and pharmacies to enroll into just one system.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 9, 2012 * Vol. 19, No. 5
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 7 issue of Lancet (2012; 379).
Catheter-Directed Thrombolysis with Alteplase: In patients with high proximal deep-vein thrombosis (DVT) and low risk of bleeding, catheter-directed thrombolysis (CDT) using alteplase should be added to conventional anticoagulant treatment to lower the rate of sequelae from postthrombotic syndrome (PTS), according to authors of a Norwegian study (pp. 31–8). Participants in an open-label trial were 18–75 years of age and had a first-time iliofemoral DVT with symptom onset within 21 days. Frequency of PTS as assessed by Villalta score at 24 months and iliofemoral patency after 6 months showed these patterns with and without additional CDT: “209 patients were randomly assigned to treatment groups (108 control, 101 CDT). At completion of 24 months’ follow-up, data for clinical status were available for 189 patients (90%; 99 control, 90 CDT). At 24 months, 37 (41.1%, 95% CI 31.5–51.4) patients allocated additional CDT presented with PTS compared with 55 (55.6%, 95% CI 45.7–65.0) in the control group (p = 0.047). The difference in PTS corresponds to an absolute risk reduction of 14.4% (95% CI 0.2–27.9), and the number needed to treat was 7 (95% CI 4–502). Iliofemoral patency after 6 months was reported in 58 patients (65.9%, 95% CI 55.5–75.0) on CDT versus 45 (47.4%, 37.6–57.3) on control (p = 0.012). 20 bleeding complications related to CDT included three major and five clinically relevant bleeds.” (P. M. Sandset, p.m.sandset@medisin.uio.no)
Denosumab in Castration-Resistant Prostate Cancer: Improvement of the bone microenvironment with denosumab delays bone metastases in men with nonmetastatic castration-resistant prostate cancer, researchers report (pp. 39–46). In the Phase III trial, participants with prostate-specific antigen levels of 8.0 mcg/L or more or PSA doubling times of 10 months or less were included. Randomization to masked subcutaneous denosumab 120 mg or placebo every 4 weeks had these effects on a primary composite endpoint of time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause: “1,432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4.2 months compared with placebo (median 29.5 [95% CI 25.4–33.3] vs 25.2 [22.2–29.5] months; hazard ratio [HR] 0.85, 95% CI 0.73–0.98, p = 0.028). Denosumab also significantly delayed time to first bone metastasis (33.2 [95% CI 29.5–38.0] vs 29.5 [22.4–33.1] months; HR 0.84, 95% CI 0.71–0.98, p = 0.032). Overall survival did not differ between groups (denosumab, 43.9 [95% CI 40.1–not estimable] months vs placebo, 44.8 [40.1–not estimable] months; HR 1.01, 95% CI 0.85–1.20, p = 0.91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo.” (M. R. Smith, smith.matthew@mgh.harvard.edu)

>>>PNN NewsWatch
* Doripenem (Doribax, Janssen) is not approved for treatment of any type of pneumonia or for use in doses greater than 500 mg every 8 hours, FDA is warning clinicians in the wake of the early termination of a study of patients with ventilator-associated pneumonia. In the trial, all-cause 28-day mortality was higher among patients on the drug than with imipenem (21.5% versus 14.8%), and two measures of clinical cure rates were substantially lower with doripenem.
* All lots with certain expiry dates of
Excedrin, NoDoz, Bufferin, and Gas-X Prevention products and lots are being recalled in the U.S. because some may contain stray solid oral dosage forms from other Novartis products, the company said yesterday. Further information is available at www.novartisOTC.com.

>>>PNN JournalWatch
* Home Monitoring for Heart Failure Management, in
Journal of the American College of Cardiology, 2012; 59: 97–104. (G. C. Fonarow, gfonarow@mednet.ucla.edu)
* Risk of Mortality Among Individual Antipsychotics in Patients With Dementia, in
American Journal of Psychiatry, 2012; 169: 71–9. (H. C. Kales)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 10, 2012 * Vol. 19, No. 6
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Jan. 9 issue of the Archives of Internal Medicine (2012; 172).
Dabigatran & Acute Coronary Events: A broad swath of patients are at higher risk of myocardial infarction (MI) and acute coronary syndrome (ACS) while taking dabigatran, conclude authors of a meta-analysis (doi: 10.1001/archinternmed.2011.1666). Compared with warfarin, enoxaparin, or placebo and assessed using the fixed-effects Mantel-Haenszel (M-H) test, dabigatran showed these patterns in 30,514 patients with atrial fibrillation (2 trials), acute venous thromboembolism (1 trial), or ACS (1 trial), or requiring short-term prophylaxis of deep venous thrombosis (3 trials): “Dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group (dabigatran, 237 of 20 000 [1.19%] vs control, 83 of 10 514 [0.79%]; ORM-H, 1.33; 95% CI, 1.03–1.71; P = .03). The risk of MI or ACS was similar when using revised RE-LY trial results (ORM-H, 1.27; 95% CI, 1.00-–1.61; P = .05) or after exclusion of short-term trials (ORM-H, 1.33; 95% CI, 1.03–1.72; P = .03). Risks were not heterogeneous for all analyses (I2 = 0%; P .30) and were consistent using different methods and measures of association.” (K. Uchino, uchinok@ccf.org)
“Enthusiasm” bordering on near “euphoria to embrace the new” must be “restrained by the old aphorism of
primum non nocere,” an editorialist writes (doi: 10.1001/archinternmed.2011.1721): “New drugs have dangers that may become apparent long after the relatively pristine data of clinical trials have given way to the gritty reality of daily clinical drug use. In the face of alarming postmarketing reports, majority opinion was unanimous in the withdrawal of the cyclooxygenase 2 selective inhibitor rofecoxib. However, clinical pragmatism should not be underestimated: who among us as clinicians feel ready to withdraw the use of all nonsteroidal anti-inflammatory drugs from our clinical repertoire despite growing evidence from meta-analyses of a class effect on cardiovascular safety?” (J. M. Jacobs, jacobsj@hadassah.org.il)
Herbal Medications & Thyroid Hormone Economy: Herbal products for prostate problems had adverse effects on thyroid status in a 73-year-old man with hypothyroidism seconding to thyroid ablation, an author reports (pp. 58–60). Following diagnosis of prostate cancer in 1995, the patient was successfully treated with radiation. He later refused hormone treatment, became a vegetarian, and began using a series of herbal products with saw palmetto and Panax pseudoginseng. The author describes a variety of effects of the products on PSA levels and thyroid and other hormonal levels before concluding: “This patient’s case highlights how important it is for physicians to include questions about [complementary and alternative medicine (CAM)] use as a routine part of each visit and to be aware of the potential for important hormonally related adverse effects of PC-SPES and related herbal compounds. In addition to the change in thyroid hormone economy, patient use of CAM supplements could lead to physician misinterpretation of test results of the pituitary–adrenal or pituitary–testicular axes owing to herbally induced elevations in levels of [cortisol-binding globulin] and [sex hormone–binding globulin], respectively.” (L. Vigersky, Robert.vigersky@us.army.mil)

>>>PNN NewsWatch
**8 Efforts to get pharmacists recognized as providers received a strong push yesterday in the form of a report from the U.S. Public Health Service and a letter from the Surgeon General. Pharmacist.com reports that “Improving Patient and Health-System Outcomes Through Advanced Pharmacy Practice” focuses on existing practice models that are models for future systems and identifies needs suitable for pharmacists such as care of chronic diseases and increasing access to care.
* The quality problems at a Novartis plant that caused the OTC recall noted in yesterday’s PNN have spilled over to include some
opiate products from Endo Pharmaceuticals. The possibility of stray solid oral dosage forms being incorrectly placed in bottles affects these Endo products: Opana ER, Opana, Oxymorphone hydrochloride tablets, Percocet, Percodan, Endocet, Endodan, Morphine Sulfate Extended-Release Tablets, and Zydone.
*
Correction: The dosing frequency for doripenem reported in yesterday’s PNN should have been every 8 hours, not every 4 hours.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 11, 2012 * Vol. 19, No. 7
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 11 issue of JAMA (2012; 307).
Ideal Potassium Levels & AMI Mortality: While serum potassium levels of 4.0 to 5.0 mEq/L for patients in acute myocardial infarction (AMI) are generally recommended, concentrations between 3.5 and 4.5 mEq/L were associated with lower mortality rates among 38,689 patients with biomarker-confirmed AMI, researchers report (pp. 157–64). The currently used range is based on small studies conducted before beta-blockers and reperfusion procedures were available, the authors note. Analyzing data from 67 U.S. hospitals retrospectively, investigators found these patterns of AMI risk and potassium concentrations: “There was a U-shaped relationship between mean postadmission serum potassium level and in-hospital mortality that persisted after multivariable adjustment. Compared with the reference group of 3.5 to less than 4.0 mEq/L (mortality rate, 4.8%; 95% CI, 4.4%–5.2%), mortality was comparable for mean postadmission potassium of 4.0 to less than 4.5 mEq/L (5.0%; 95% CI, 4.7%–5.3%), multivariable-adjusted odds ratio (OR), 1.19 (95% CI, 1.04–1.36). Mortality was twice as great for potassium of 4.5 to less than 5.0 mEq/L (10.0%; 95% CI, 9.1%–10.9%; multivariable-adjusted OR, 1.99; 95% CI, 1.68–2.36), and even greater for higher potassium strata. Similarly, mortality rates were higher for potassium levels of less than 3.5 mEq/L. In contrast, rates of ventricular fibrillation or cardiac arrest were higher only among patients with potassium levels of less than 3.0 mEq/L and at levels of 5.0 mEq/L or greater.” (A. Goyal, agoyal4@emory.edu)
The results reinforce the need for potassium repletion in patients with AMI who have hypokalemia, editorialists write, but aggressively targeting levels above 4.5 mEq/L is not appropriate (
pp. 195–6): “Given that it is an inexpensive and relatively low-risk intervention, repletion of potassium for levels of less than 3.5 mEq/L remains reasonable. However, based on the report by Goyal et al, viewed together with previous smaller studies, potassium repletion for concentrations of 3.5 mEq/L to 4.0 mEq/L and routinely targeting levels greater than 4.5 mEq/L, do not appear justified.” (B. M. Scirica, bscirica@partners.org)
Marijuana Use & Pulmonary Function: Despite having many of the same constituents as tobacco, marijuana produces little to no change in pulmonary function during occasional or low cumulative use, according to data from the Coronary Artery Risk Development in Young Adults (CARDIA) longitudinal study (pp. 173–81). Repeated measurements of pulmonary function and smoking showed these patterns between 1986 and 2006 for a cohort of 5,115 Americans: “Marijuana exposure was nearly as common as tobacco exposure but was mostly light (median, 2–3 episodes per month). Tobacco exposure, both current and lifetime, was linearly associated with lower FEV1 and FVC. In contrast, the association between marijuana exposure and pulmonary function was nonlinear (P < .001): at low levels of exposure, FEV1 increased by 13 mL/joint–year (95% CI, 6.4 to 20; P < .001) and FVC by 20 mL/joint–year (95% CI, 12 to 27; P < .001), but at higher levels of exposure, these associations leveled or even reversed. The slope for FEV1 was −2.2 mL/joint-year (95% CI, −4.6 to 0.3; P = .08) at more than 10 joint–years and −3.2 mL per marijuana smoking episode/mo (95% CI, −5.8 to −0.6; P = .02) at more than 20 episodes/mo. With very heavy marijuana use, the net association with FEV1 was not significantly different from baseline, and the net association with FVC remained significantly greater than baseline (eg, at 20 joint–years, 76 mL [95% CI, 34 to 117]; P < .001).” (M. J. Pletcher, mpletcher@epi.ucsf.edu)
Prescription Drug Shortages: Basic economics is at work in the current shortage of prescription drugs, especially sterile injectables, according to a Viewpoint analysis, and that may mean an end to the low prices seen thus far with this class of generic drug products (pp. 153–4): “For consumers, any nudge in the direction of less regulation and more market influence means prices will increase. The rule of thumb for health care is that it is possible to optimize any 2 of 3 desirable parameters—quality, cost, and time. In the current situation, high quality and low cost have led to scarcity. The brief years of cheap generic intravenous drugs may be coming to an end. Perhaps, the old adage is correct, ‘be careful what you wish for.’” (B. K. Gehrett, thebkg17@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 12, 2012 * Vol. 19, No. 8
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 12 issue of the New England Journal of Medicine (2012; 366).
Anti-HER2 Agents for First-Line Breast Cancer Therapy: In patients with HER2-positive breast cancer, the combination of pertuzumab, trastuzumab, and docetaxel significantly prolonged progression-free survival, with no increase in cardiac toxic effects, according to the Phase III Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study (pp. 109–19). Both trastuzumab and pertuzumab are anti-HER2 humanized monoclonal antibodies; pertuzumab has the complementary mechanism of action of inhibiting receptor dimerization. Added to trastuzumab plus docetaxel, pertuzumab had these effects in 808 patients with HER2-positive metastatic breast cancer: “The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P < 0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group.” (J. Baselga, jbaselga@partners.org)
The “abundance of options” for HER2-positive breast cancer is lauded by an editorialist (
pp. 176–8): “Although HER2-positive breast cancer accounts for only 25 to 30% of breast cancers, the increasing therapeutic options provide hope to patients and considerable challenges for clinicians. For patients with metastatic breast cancer who have progressive disease, there may be numerous anti-HER2 agents available that could be used in combination or in sequence. In patients with early-stage breast cancer, more effective anti-HER2 agents as adjuvant therapies may translate into metastatic disease developing in fewer patients. Given the success of the pivotal trials of adjuvant trastuzumab therapy, clinical trials of adjuvant therapies, which are already large and expensive, will by necessity require even more subjects to detect small differences with a new agent. These are challenges that reflect the rewards of successful translational research, challenges we hope to face with other subsets of breast cancer.” (W. J. Gradishar)
Subclinical Atrial Fibrillation: Ischemic stroke and systemic emboli occur frequently in patients with pacemakers who have subclinical atrial fibrillation, researchers report (pp. 120–9). Participants in the 2,580-patient study were 65 years of age or older, had hypertension but no history of atrial fibrillation, and had had a pacemaker or defibrillator implanted recently: “By 3 months, subclinical atrial tachyarrhythmias detected by implanted devices had occurred in 261 patients (10.1%). Subclinical atrial tachyarrhythmias were associated with an increased risk of clinical atrial fibrillation (hazard ratio, 5.56; 95% confidence interval [CI], 3.78 to 8.17; P < 0.001) and of ischemic stroke or systemic embolism (hazard ratio, 2.49; 95% CI, 1.28 to 4.85; P = 0.007). Of 51 patients who had a primary outcome event, 11 had had subclinical atrial tachyarrhythmias detected by 3 months, and none had had clinical atrial fibrillation by 3 months. The population attributable risk of stroke or systemic embolism associated with subclinical atrial tachyarrhythmias was 13%. Subclinical atrial tachyarrhythmias remained predictive of the primary outcome after adjustment for predictors of stroke (hazard ratio, 2.50; 95% CI, 1.28 to 4.89; P = 0.008). Continuous atrial overdrive pacing did not prevent atrial fibrillation.” (S. J. Connolly, connostu@phri.ca)
“Until clinical trials targeting the population with short, asymptomatic episodes of high atrial rate are carried out, the current evidence simply does not address the question of whether treatment with warfarin or other anticoagulants is justifiable for the asymptomatic patient who has had a 6-minute episode of atrial fibrillation,” an editorialist writes (
pp. 178–80). “For now, therefore, I will continue to turn to the now-venerable CHADS2 score, consider applying it to patients with asymptomatic episodes of atrial fibrillation lasting for hours, and make a clinical judgment about the need for anticoagulation. I will also wait for definitive studies to be performed in this interesting, at-risk population.” (G. Lamas)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 13, 2012 * Vol. 19, No. 9
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Jan. issue of the American Journal of Psychiatry (2012; 169).
Accidental Overdose & Psychiatric/Abuse Disorders: VA patients who died from accidental drug overdoses were more likely to have psychiatric or substance-abuse disorders than patients dying of other causes, researchers report (pp. 64–70). In a patient cohort followed from 2000 to 2006, these associations were found: “Adjusting for demographic and clinical characteristics, hazard ratios of death by accidental overdose associated with prior psychiatric and substance use disorder diagnoses ranged from 1.8 to 8.8. Significant associations of non-substance-related psychiatric disorders with risk of death by accidental overdose persisted after additional adjustment for substance use disorders (hazard ratios from 1.2 to 1.8). Depressive disorders and anxiety disorders other than posttraumatic stress disorder had stronger associations with risk of medication-related overdose death (hazard ratios, 3.02 and 3.07, respectively) than with risk of overdose death related to alcohol or illegal drugs (hazard ratios, 1.89 and 1.23, respectively).” (A. S. B. Bohnert)
Mortality with Antipsychotics in Dementia: Individual antipsychotic agents have varying mortality risks when used in older patients with dementia, a retrospective cohort study shows (pp. 71–9). Based on analysis of VA data from 1999 to 2008, investigators also found that use of alternative agents such as valproic acid carries similar mortality risks: “In covariate-adjusted intent-to-treat analyses, haloperidol was associated with the highest mortality rates (relative risk = 1.54, 95% confidence interval [CI] = 1.38–1.73) followed by risperidone (reference), olanzapine (relative risk=0.99, 95% CI = 0.89–1.10), valproic acid and its derivatives (relative risk=0.91, 95% CI = 0.78–1.06), and quetiapine (relative risk = 0.73, 95% CI = 0.67–0.80). Propensity-stratified and propensity-weighted models as well as analyses controlling for site of care and medication dosage revealed similar patterns. The mortality risk with haloperidol was highest in the first 30 days but decreased significantly and sharply thereafter. Among the other agents, mortality risk differences were most significant in the first 120 days and declined in the subsequent 60 days during follow-up.” (H. C. Kales)

>>>Infectious Diseases Report
Source:
Jan. 15 issue of Clinical Infectious Diseases (2012; 54).
Multidrug-Resistant Tuberculosis in Children: Individualized care can lead to successful outcomes in children infected by multidrug-resistant (MDR) tuberculosis, even with advanced disease on presentation and coinfection with HIV, authors conclude (pp. 157–66). At a pediatric hospital in South Africa, all children younger than 15 with diagnoses of MDR tuberculosis in 2003–08 were identified. Outcomes were categorized based on 2-month sputum-culture conversion, treatment episode outcomes, and survival: “A total of 111 children (median age, 50 months) were included. The diagnosis was delayed in children who had no identified MDR-tuberculosis index case (median delay, 123 vs 58 days; P < .001). Sixty-two percent of patients (53 of 85) were sputum-smear positive, and 43% of patients (43 of 100) were human immunodeficiency virus (HIV) infected. Overall, 82% had favorable treatment outcomes; total mortality was 12%. Malnutrition was associated with failure to culture-convert at 2 months (odds ratio [OR], 4.49 [95% confidence interval {CI}, 1.32–15.2]; P = .02) and death (OR, 15.0 [95% CI, 1.17–192.5]; P = .04) in multivariate analysis. HIV coinfection (OR, 24.7 [95% CI, 1.79–341.1]; P = .02) and the presence of extrapulmonary tuberculosis (OR, 37.8 [95% CI, 2.78–513.4]; P = .006) predicted death.” (J. Seddon, jseddon@sun.ac.za)

>>>PNN NewsWatch
* Bedford Laboratories yesterday issued a new guidance regarding a prior recall of its polymyxin B and vecuronium bromide for injection products. Hospitals, emergency departments, clinics, physician offices, and other health care facilities and providers should not use the recalled lots for patient care and should immediately quarantine any product for return, the company said. The recall, originally issued on Aug. 2, was initiated after discovery of visible glass particles in a limited number of vials.
*
PNN will not be published on Mon., Jan. 16, King Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 17, 2012 * Vol. 19, No. 10
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 17 issue of the Annals of Internal Medicine (2012; 156).
Vitamin D in COPD: High doses of vitamin D reduced incidence of exacerbations of chronic obstructive pulmonary disease only in patients with severe deficiencies of the nutrient, a study shows (pp. 105–14). Others in the 182-patient study did not benefit from supplementation with vitamin D 100,000 IU every 4 weeks for 1 year, the authors report: “Mean serum 25-(OH)D levels increased significantly in the vitamin D group compared with the placebo group (mean between-group difference, 30 ng/mL [95% CI, 27 to 33 ng/mL]; P < 0.001). The median time to first exacerbation did not significantly differ between the groups (hazard ratio, 1.1 [CI, 0.82 to 1.56]; P = 0.41), nor did exacerbation rates, FEV1, hospitalization, quality of life, and death. However, a post hoc analysis in 30 participants with severe vitamin D deficiency (serum 25-[OH]D levels <10 ng/mL) at baseline showed a significant reduction in exacerbations in the vitamin D group (rate ratio, 0.57 [CI, 0.33 to 0.98]; P = 0.042).” (A. Lehouck)

>>>Lancet Highlights
Source:
Jan. 14 issue of Lancet (2012; 379).
Enoxaparin Followed by Idrabiotaparinux in Pulmonary Embolism: Compared with warfarin in patients with acute symptomatic pulmonary embolism, the activated factor X indirect inhibitor idrabiotaparinux provides an alternative to post-enoxaparin therapy and is associated with less bleeding, researchers report (pp. 123–9). In a noninferiority trial at 291 centers in 37 countries, participants received enoxaparin 1 mg/kg twice daily followed by either subcutaneous idrabiotaparinux at a starting dose of 3 mg or adjusted-dose warfarin with an INR target of 2–3 for 3–6 months. Results showed: “Between Aug 1, 2006, and Jan 31, 2010, we enrolled 3,202 patients aged 18–96 years. 34 (2%) of 1,599 patients randomly allocated to receive enoxaparin–idrabiotaparinux and 43 (3%) of 1,603 patients randomly allocated to receive enoxaparin–warfarin had recurrent venous thromboembolism (odds ratio 0.79, 95% CI 0.50–1.25; pnon-inferiority = 0.0001). 72 (5%) of 1,599 patients in the enoxaparin–idrabiotaparinux group and 106 (7%) of 1,603 patients in the enoxaparin–warfarin group had clinically relevant bleeding (0.67, 0.49–0.91; psuperiority = 0.0098). We noted similar differences in outcomes in those patients treated to 6 months.” (H. R. Büller, h.r.buller@amc.uva.nl)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Antihypertensive Drugs & Risk of Gout: Drug classes used for treatment of hypertension differ in their propensity to cause gout, according to a nested case–control study of patients in the U.K. general practice database from 2000 to 2007 (d8190). Analysis of 24,768 incident cases of gout in adults aged 20–79 and 50,000 matched controls showed the following results: “After adjusting for age, sex, body mass index, visits to the general practitioner, alcohol intake, and pertinent drugs and comorbidities, the multivariate relative risks of incident gout associated with current use of antihypertensive drugs among those with hypertension (n = 29,138) were 0.87 (95% confidence interval 0.82 to 0.93) for calcium channel blockers, 0.81 (0.70 to 0.94) for losartan, 2.36 (2.21 to 2.52) for diuretics, 1.48 (1.40 to 1.57) for beta-blockers, 1.24 (1.17 to 1.32) for angiotensin converting enzyme inhibitors, and 1.29 (1.16 to 1.43) for non-losartan angiotensin II receptor blockers. Similar results were obtained among those without hypertension. The multivariate relative risks for the duration of use of calcium channel blockers among those with hypertension were 1.02 for less than one year, 0.88 for 1–1.9 years, and 0.75 for two or more years and for use of losartan they were 0.98, 0.87, and 0.71, respectively (both P < 0.05 for trend).” (H. K. Choi, hchoius@bu.edu)

>>>PNN JournalWatch
* Severe Asthma: Advances in Current Management and Future Therapy, in
Journal of Allergy and Clinical Immunology, 2012; 129: 48–59. (P. J. Barnes, p.j.barnes@imperial.ac.uk)
* The Challenge and Promise of the Genomic Era, in
Journal of Clinical Oncology, 2012; 30: 203–9. (G. W. Sledge Jr.)
* Appropriate Use of Screening and Diagnostic Tests to Foster High-Value, Cost-Conscious Care, in
Annals of Internal Medicine, 2012; 156: 147–9. (A. Qaseem)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 18, 2012 * Vol. 19, No. 11
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and Jan. 18 issue of JAMA (2012; 307).
Cangrelor Bridging Therapy in Cardiac Surgery: Cangrelor can be used to maintain platelet inhibition in patients whose thienopyridines are stopped before cardiac surgery, researchers report (pp. 265–74). In 210 patients with acute coronary syndrome (ACS) or treated with a coronary stent and receiving a thienopyridine while awaiting coronary artery bypass grafting (CABG) surgery, thienopyridines were stopped and patients received cangrelor or placebo for at least 48 hours, until 1–6 hours before CABG surgery. Based on a primary efficacy end point of platelet reactivity (measured in P2Y12 reaction units [PRUs]), results showed: “The dose of cangrelor determined in 10 patients in the open-label stage was 0.75 µg/kg per minute. In the randomized phase, a greater proportion of patients treated with cangrelor had low levels of platelet reactivity throughout the entire treatment period compared with placebo (primary end point, PRU <240; 98.8% (83 of 84) vs 19.0% (16 of 84); relative risk [RR], 5.2 [95% CI, 3.3–8.1] P < .001). Excessive CABG surgery–related bleeding occurred in 11.8% (12 of 102) vs 10.4% (10 of 96) in the cangrelor and placebo groups, respectively (RR, 1.1 [95% CI, 0.5–2.5] P = .763). There were no significant differences in major bleeding prior to CABG surgery, although minor bleeding episodes were numerically higher with cangrelor.” (E. J. Topol, etopol@scripps.edu)
Obesity Among Americans: Two studies examine rates of obesity among American adults and children.
Just over one third of adult men and women have body mass indexes that place them in the obese category (≥30 kg/sq m), the first study shows (
10.1001/jama.2012.39). As shown in the 2009–10 National Health and Nutrition Examination Survey, age-adjusted mean BMI was 28.7 (95% CI, 28.3–29.1) for men and 28.7 (95% CI, 28.4–29.0) for women. Prevalence of obesity was 35.5% among men and 35.8% among women. (K. M. Flegal, kmf2@cdc.gov)
In 2009–10, 16.9% of American children and adolescents were obese, a second report indicates (
10.1001/jama.2012.40). “In 2009–2010, 9.7% (95% CI, 7.6%–12.3%) of infants and toddlers had a high weight-for-recumbent length and 16.9% (95% CI, 15.4%–18.4%) of children and adolescents from 2 through 19 years of age were obese,” the authors write. “There was no difference in obesity prevalence among males (P = .62) or females (P = .65) between 2007–2008 and 2009–2010. However, trend analyses over a 12-year period indicated a significant increase in obesity prevalence between 1999–2000 and 2009–2010 in males aged 2 through 19 years (odds ratio, 1.05; 95% CI, 1.01–1.10) but not in females (odds ratio, 1.02; 95% CI, 0.98–1.07) per 2-year survey cycle. There was a significant increase in BMI among adolescent males aged 12 through 19 years (P = .04) but not among any other age group or among females.” (C. L. Ogden, cogden@cdc.gov)

>>>PNN NewsWatch
* Glucarpidase (Voraxaze, BTG International) has been approved by FDA for treatment of toxic plasma concentrations of methotrexate (> 1 µmol/L) in patients with delayed methotrexate clearance due to impaired renal function. Glucarpidase, administered intravenously, rapidly reduces methotrexate levels by breaking the chemotherapy drug down to a form that can be eliminated from the body through nonrenal (primarily hepatic) paths. Approved under priority review, glucarpidase was studied in 290 patients in two open-label trials. In a subset of 22 treatment-evaluable patients, 10 achieved rapid and sustained clinically important reduction in plasma methotrexate concentration, defined as an attainment of plasma methotrexate concentration ≤1 µmol/L within 15 minutes following glucarpidase administration and sustained for up to 8 days. The most common adverse reactions (incidence >1%) with the drug were paresthesias, flushing, nausea and/or vomiting, hypotension, and headache.
* Two additional cases of progressive multifocal leukoencephalopathy (PML) have been reported with
brentuximab vedotin (Adcetris, Seattle Genetics). Due to the serious nature of PML, FDA added a boxed warning highlighting this risk to the drug label. When brentuximab was approved in Aug. 2011, one case of PML had been reported.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 19, 2012 * Vol. 19, No. 12
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 19 issue of the New England Journal of Medicine (2012; 366).
RAS Mutations with BRAF Inhibitors: Patients treated with BRAF inhibitors such as vemurafenib are at greater risk of cutaneous squamous-cell carcinomas and keratoacanthomas because of mutations in the RAS gene that lead to a paradoxical activation of mitogen-activated protein kinase (MAPK)–pathway signaling and accelerated growth of these lesions, researchers report (pp. 207–15). Tumor samples from patients treated with vemurafenib were analyzed to identify oncogenic mutations, with these results: “Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with [MAPK] pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.” (A. Ribas, aribas@mednet.ucla.edu)
Appropriate actions for clinicians based on these findings are outlined by an editorialist (
pp. 271–3): “First, I think that patients being given BRAF inhibitors should be tested to determine their RAS status, since the potential for secondary tumor development is of concern. Although cutaneous squamous-cell carcinomas are not deadly, these lesions can be life-threatening when they occur in other organs. As we apply treatment with BRAF inhibitors to other tumor types, we would be well advised to analyze a patient’s RAS status before therapy is begun. Second, these data underscore how critical it is to understand the mechanism of action of targeted therapies, which not only will alert us to potential clinical toxic effects (e.g., squamous-cell carcinomas), but can help us rationally design alternative or complementary therapies (e.g., MEK inhibition). BRAF inhibition is an excellent platform for personalized medicine, since resistance and secondary tumor development can largely be predicted from the changing molecular profile of the patient. The lessons we are learning from BRAF inhibitors will pave the way for future targeted therapies in other types of cancers.” (A. T. Weeraratna)
Agents for Hepatitis C Genotype 1: Two direct-acting antiviral agents, used alone or in combination with peginterferon and ribavirin, provided sustained virologic responses in patients with chronic hepatitis C virus (HCV) genotype 1 who had not responded to prior therapy, an open-label, Phase IIa study shows (pp. 216–24). Study participants received the NS5A replication complex inhibitor daclatasvir 60 mg once daily and the NS3 protease inhibitor asunaprevir 600 mg twice daily alone (group A, 11 patients) or in combination with peginterferon alfa-2a and ribavirin (group B, 10 patients) for 24 weeks, with these results: “A total of 4 patients in group A (36%; 2 of 9 with HCV genotype 1a and 2 of 2 with genotype 1b) had a sustained virologic response at 12 weeks after treatment and also at 24 weeks after treatment. Six patients (all with HCV genotype 1a) had viral breakthrough while receiving therapy, and resistance mutations to both antiviral agents were found in all cases; 1 patient had a viral response at the end of treatment but had a relapse after the treatment period. All 10 patients in group B had a sustained virologic response at 12 weeks after treatment, and 9 had a sustained virologic response at 24 weeks after treatment. Diarrhea was the most common adverse event in both groups. Six patients had transient elevations of alanine aminotransferase levels to more than 3 times the upper limit of the normal range.” (A. S. Lok, aslok@med.umich.edu)
Continued success with these agents could provide “a watershed moment in the treatment of hepatitis C,” an editorialist writes (
pp. 273–5): “We are on the threshold of a treatment revolution that will greatly improve the effectiveness of HCV therapy by dramatically increasing the number of persons treated. There has never been a more exciting time for patients and providers who grapple with this silent killer.” (R. T. Chung)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 20, 2012 * Vol. 19, No. 13
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Jan. issue of Pharmacotherapy (2012; 32).
U.K. v. U.S. Statin Costs: Private companies in the U.S. spent 4 times as much for statins in 2005 for people younger than 65 than did the National Health Service in the U.K., researchers report (pp. 1–6). Data on statin use and costs were obtained from the U.K. General Practice Research Database (GPRD) and MarketScan Commercial Claims and Encounters Database for the U.S. For 1.6 million people in the GPRD and 1.6 million matched Americans, these costs were determined for the 91,474 Americans and 68,217 Brits who were taking statins: “Estimated drug costs were determined by random sampling. Estimated annual costs/patient in the U.S. ranged from $313 for generic lovastatin to $1,428 for nongeneric simvastatin. In the U.K., annual costs/patient ranged from $164 for generic simvastatin to $509 for nongeneric atorvastatin. The total annual cost of the continuous receipt of statins in the U.S. was $64.9 million compared with $15.7 million in the U.K. In June 2006, after our study results were analyzed, the U.S. Food and Drug Administration approved generic simvastatin. We thus derived cost estimates for simvastatin use during 2006 and found that more than 60% of simvastatin users switched to the generic product, which reduced the cost/pill by more than 50%.” (H. Jick, hjick@bu.edu)
Primary Prophylactic CSFs & Febrile Neutropenia: In an analysis of the use and impact of primary prophylactic colony-stimulating factors (CSFs) in patients undergoing myelosuppressive chemotherapy for three different types of cancer, investigators were not able to make a complete assessment because of low rates of febrile neutropenic events in two cancers and generally low use of CSFs in all (pp. 7–19). Patients with colorectal cancer or non–small cell lung cancer (NSCLC) had few events and low use of the agents, while patients with breast cancer were treated more often with positive results: “Initial chemotherapy regimen, CSF use (filgrastim or pegfilgrastim), and febrile neutropenia events were evaluated after the first chemotherapy administration. Subsequently, febrile neutropenia rates in patients receiving primary prophylactic CSF were compared with febrile neutropenia rates in patients receiving CSF in settings other than primary prophylaxis or not at all. The impact of primary prophylactic CSF could not be assessed for patients with colorectal cancer or NSCLC because only 1 and 18 febrile neutropenia events, respectively, occurred in those receiving primary prophylactic CSF. Of the 998 patients with breast cancer, 72 (7.2%) experienced febrile neutropenia, 28 of whom received primary prophylactic CSF. In the patients with breast cancer, we observed that primary prophylactic CSF use was associated with reduced febrile neutropenia rates; however, the analysis may have been confounded by unmeasured factors associated with febrile neutropenia.” (S. D. Ramsey, sramsey@fhcrc.org)
Bivalirudin Dosing Strategies in Obesity: Dosing based on total body weight is most accurate for bivalirudin in obese patients with heparin-induced thrombocytopenia, a study shows (pp. 20–6). In 135 patients treated in 2004–09, investigators found: “The mean ± SD doses that achieved aPTT goal with total (actual), adjusted, and ideal body weights in this group were 0.1 ± 0.07, 0.11 ± 0.08, and 0.14 ± 0.09 mg/kg/hour, respectively. Of the three weight-based dosing approaches, total body weight followed by adjusted body weight provided the closest correlation to rates observed at the target aPTT goal. The secondary analysis compared initial doses of bivalirudin, doses required to reach goal aPTT, time to achieve goal aPTT, and clinical outcomes (number of patients not achieving goal, new thrombosis, major bleeding, and 30-day all-cause mortality) between the obese and nonobese groups. A significant difference in initial dose was noted between groups; however, no significant differences in dose required to achieve goal aPTT, time to achieve goal aPTT, and clinical outcomes were noted between the obese and nonobese groups.” (W. E. Dager, william.dager@ucdmc.ucdavis.edu)

>>>PNN NewsWatch
* William E. Evans, PharmD, Director/CEO of St. Jude Children’s Res. Hosp. in Memphis, will receive the 2012 Remington Honor Medal, APhA said. Evans, professor at the U. Tenn. Colleges of Pharmacy and Medicine and ACCP past president, was recognized for pharmacogenomic and cancer research.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 23, 2012 * Vol. 19, No. 14
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 21 issue of Lancet (2012; 379).
Nevirapine in Breastfed Infants: In infants up to 6 months of age, nevirapine prophylaxis can protect against mother-to-child transmission of HIV-1 during breastfeeding, a study shows (pp. 221–8). The drug was given to the infants once daily for 6, 14, or 28 weeks in the Phase III HPTN 046 trial, with these effects on a primary efficacy endpoint of HIV-1 infection at 6 months: “Between June 19, 2008, and March 12, 2010, we randomly allocated 1,527 infants (762 nevirapine and 765 placebo); five of whom had HIV-1 infection at randomisation and were excluded from the primary analyses. In Kaplan–Meier analysis, 1.1% (95% CI 0.3–1.8) of infants who received extended nevirapine developed HIV-1 between 6 weeks and 6 months compared with 2.4% (1.3–3.6) of controls (difference 1.3%, 95% CI 0–2.6), equating to a 54% reduction in transmission (p = 0.049). However, mortality (1.2% for nevirapine vs 1.1% for placebo; p = 0.81) and combined HIV infection and mortality rates (2.3% vs 3.2%; p = 0.27) did not differ between groups at 6 months. 125 (16%) of 758 infants given extended nevirapine and 116 (15%) of 761 controls had serious adverse events, but frequency of adverse events, serious adverse events, and deaths did not differ significantly between treatment groups.” (H. M. Coovadia, hcoovadia@match.org.za)
Beta-2 Agonists in ARDS: Intravenous salbutamol increased mortality among patients early in episodes of acute respiratory distress syndrome (ARDS), according to investigators with the BALTI-2 study (pp. 229–35). At 46 U.K. intensive-care units in 2006–10, intubated and mechanically ventilated patients ages 16 years or older who were within 72 hours of ARDS onset randomly received either salbutamol 15 mcg/kg ideal bodyweight per hour or placebo for up to 7 days, with these results: “We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1.47, 95% CI 1.03–2.08).” (F. G. Smith, f.gaosmith@bham.ac.uk)

>>>PNN NewsWatch
* The risks and benefits of continuing treatment with natalizumab (Tysabri, Biogen Idec) should be carefully considered in patients who test positive for anti-JC virus (JCV) antibodies and have one or more of the other known risk factors for progressive multifocal leukoencephalopathy (PML), FDA said on Friday. Testing positive for anti-JCV antibodies has now been identified as a risk factor, the agency added. Patients with that and two other known risk factors (longer duration of drug treatment, especially beyond 2 years, and prior treatment with an immunosuppressant) have an estimated risk of PML of 11/1,000 users.

>>>PNN JournalWatch

* The Natural History of Self-harm from Adolescence to Young Adulthood: A Population-Based Cohort Study, in
Lancet, 2012; 379: 236–41. (P. Moran, paul.moran@kcl.ac.uk)
* Observational Studies on the Risk of Cancer Associated with Tumor Necrosis Factor Inhibitors in Rheumatoid Arthritis: A Review of Their Methodologies and Results, in
Arthritis & Rheumatism, 2012; 64: 21–32. (D. H. Solomon, dsolomon@partners.org)
* What Do MicroRNAs Mean for Rheumatoid Arthritis?, in
Arthritis & Rheumatism, 2012; 64: 11–20. (F. Apparailly, florence.apparailly@inserm.fr)
* Antiplatelet Therapy and Proton Pump Inhibition: Clinician Update, in
Circulation, 2012; 125: 375–80. (D. L. Bhatt, LBHATTMD@post.harvard.edu">DLBHATTMD@post.harvard.edu)
* Increasing Incidence and Prevalence of the Inflammatory Bowel Diseases with Time, Based on Systematic Review, in
Gastroenterology, 2012; 142: 56–54.e42. (G. G. Kaplan, ggkaplan@ucalgary.ca)
* Inflammation in Pulmonary Arterial Hypertension, in
Chest, 2012; 141: 210–21. (M. Humbert, marc.humbert@abc.aphp.fr)
* Combined Pulmonary Fibrosis and Emphysema Syndrome: A Review, in
Chest, 2012; 141: 222–31. (M. D. Jankowich, Matthew_jankowich@brown.edu)
* Prevalence of Unplanned Hospitalizations Caused by Adverse Drug Reactions in Older Veterans, in
Journal of the American Geriatrics Society, 2012; 60: 34–41. (Z. A. Marcum, zam12@pitt.edu)
* Preventing and Resolving Drug Therapy Problems by Understanding Patients’ Medication Experiences, in
Journal of the American Pharmacists Association, 2012; 52: 71–80. (D. Ramalho-de Oliveira, djenane.oliveira@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 24, 2012 * Vol. 19, No. 15
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Jan. 23 issue of the Archives of Internal Medicine (2012; 172).
Positive-Affect Intervention & Medication Adherence in Hypertension: Compared with patient education (PE) alone in 256 blacks with hypertension, PE plus positive-affect induction and self-affirmation (PA) produced higher medication adherence but similar blood pressures, a study shows (doi:10.1001/archinternmed.2011.1307). Patients in both groups received a culturally tailored hypertension self-management workbook, a behavioral contract, and bimonthly telephone calls. Those in the PA group also were given small gifts and received bimonthly telephone calls “to help them incorporate positive thoughts into their daily routine and foster self-affirmation,” the investigators note, adding these details about study results: “The baseline characteristics were similar in both groups: the mean BP was 137/82 mm Hg; 36% of the patients had diabetes; 11% had stroke; and 3% had chronic kidney disease. Based on the intention-to-treat principle, medication adherence at 12 months was higher in the PA group than in the PE group (42% vs 36%, respectively; P = .049). The within-group reduction in systolic BP (2.14 mm Hg vs 2.18 mm Hg; P = .98) and diastolic BP (–1.59 mm Hg vs –0.78 mm Hg; P = .45) for the PA group and PE group, respectively, was not significant.” (G. Ogedegbe, Olugbenga.Ogedegbe@nyumc.org)
Commenting on this and similar articles that were also released early (carotid plaque screening and smoking cessation,
doi:10.1001/archinternmed.2011.1326, N. Rodondi, Nicolas.Rodondi@insel.ch; increasing physical activity in patients with asthma through PA, doi:10.1001/archinternmed.2011.1316, C. A. Mancuso, mancusoc@hss.edu; and PA in promoting activity after percutaneous coronary interventions, doi:10.1001/archinternmed.2011.1311, J. C. Peterson, jcpeters@med.cornell.edu), an editorialist writes (doi:10.1001/archinternmed.2011.1948): “With current reforms in the delivery of primary care in the form of medical homes and collaborative care programs, we are beginning to establish the infrastructure to support improving the communication- and relationship-centered dimensions of care. Such infrastructure will be necessary to do the intensive interrelational work required to motivate and sustain change in patients. To borrow a notion from Peabody, the secret in motivating patients may be in the caring. We should seek to study and improve the efficacious constructs of such caring first before we resort to expensive testing technologies as a short cut. There are no simple solutions to motivating patients. A picture may be worth a thousand words, but relationships move mountains when it comes to transformative personal change. For motivating patients toward optimal health behaviors, we should direct our focus of clinical care processes and research onto the complex human relationship dimensions and away from the allure of simple ‘pictures’ to circumvent what is really hard work to be done by both patients and physicians.” (P. G. O’Malley, pomalley@usuhs.mil)
Nocturnal Leg Cramps & Prescription Drug Use: Use of specific drug classes increases the risk of requiring cramp treatment in the following year, researchers report (pp. 120–6). Inhaled long-acting beta-2-agonists (LABAs), potassium-sparing diuretics, and thiazidelike diuretics increase the occurrence of leg cramps, while use of statins and loop diuretics—previously viewed as possible contributors to leg cramps—were not implicated in an analysis of linked health care databases for 4.2 million residents of British Columbia with attention on new prescriptions for quinine: “Adjusted sequence ratios (95% CIs) for the 3 drug classes were 1.47 (1.33–1.63 [P < .001]) for diuretics, 1.16 (1.04–1.29 [P = .004]) for statins, and 2.42 (2.02–2.89 [P < .001]) for LABAs. For diuretic subclasses, adjusted sequence ratios (95% CIs) were 2.12 (1.61–2.78 [P < .001]) for potassium sparing, 1.48 (1.29–1.68 [P < .001]) for thiazidelike, and 1.20 (1.00–1.44 [P = .07]) for loop. For LABA subclasses, adjusted sequence ratios (95% CIs) were 2.17 (1.56–3.02) for LABAs alone and 2.55 (2.06–3.12) for LABAs–corticosteroids (P < .001 for both).” (S. R. Garrison, scott.garrison@ti.ubc.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 25, 2012 * Vol. 19, No. 16
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 25 issue of JAMA (2012; 307).
Lansoprazole in Poorly Controlled Pediatric Asthma: Children with poorly controlled asthma despite inhaled corticosteroid therapy and no symptoms of gastroesophageal reflux (GER) did not benefit from addition of the PPI lansoprazole, researchers report (pp. 373–80). Asymptomatic GER is thought to be prevalent among children with asthma, but lansoprazole increased adverse drug reactions with no appreciable positive effects despite nearly half of children having abnormal stomach pHs. At 19 U.S. academic clinical centers, 306 children with poor asthma control who were receiving inhaled corticosteroid treatment received either lansoprazole 15 or 30 mg/d or placebo, with these effects on change in Asthma Control Questionnaire (ACQ) score (range, 0–6; a 0.5-unit change is considered clinically meaningful): “The mean age was 11 years (SD, 3 years). The mean difference in change (lansoprazole minus placebo) in the ACQ score was 0.2 units (95% CI, 0.0–0.3 units). There were no statistically significant differences in the mean difference in change for the secondary outcomes of forced expiratory volume in the first second (0.0 L; 95% CI, −0.1 to 0.1 L), asthma-related quality of life (−0.1; 95% CI, −0.3 to 0.1), or rate of episodes of poor asthma control (relative risk, 1.2; 95% CI, 0.9–1.5). Among the 115 children with esophageal pH studies, the prevalence of GER was 43%. In the subgroup with a positive pH study, no treatment effect for lansoprazole vs placebo was observed for any asthma outcome. Children treated with lansoprazole reported more respiratory infections (relative risk, 1.3 [95% CI, 1.1–1.6]).” (J. T. Holbrook, jholbroo@jhsph.edu)
Citing the dangers of “therapeutic creep,” an editorialist writes (
pp. 406–7): “Clinicians extend the use of a treatment with real or suggestive therapeutic effects observed in a certain age group or in patients with a certain disease phenotype to other patients in whom the efficacy has never been demonstrated. Therapeutic creep in the treatment of asthma is not limited to PPIs. Combination therapy with inhaled corticosteroids and long-acting beta-agonists has been shown to improve asthma symptoms and lung function in children whose symptoms are poorly controlled with inhaled corticosteroids, but such a regimen is not superior to the use of monotherapy with inhaled corticosteroids in patients not previously treated with the latter. This evidence notwithstanding, use of combination therapy has markedly drifted from children with severe disease, for whom it is justified, to children with milder disease, for whom it is not, and is currently prescribed as often as monotherapy for patients with mild asthma naive to inhaled corticosteroids.” (F. D. Martinez, fernando@arc.arizona.edu)
Vaccine Responses After PFC Exposure: In 587 children studied since their births in 1999–2001, elevated exposure to perfluorinated compounds (PFCs) was linked to reduced humoral responses to routine immunizations (pp. 391–7). PFCs in children’s serum at age 5 “showed uniformly negative associations with antibody levels, especially at age 7 years,” the investigators note. (P. Grandjean, pgrand@hsph.harvard.edu)
Constitutionality of ACA: With the 2012 presidential in full swing on the Republican side and Pres. Obama defending elements of health care reform in last night’s State of the Union address, Viewpoint authors provide a legal analysis of the upcoming Supreme Court review of the Affordable Care Act (pp. 369–70): “Since 1971, when President Nixon and Senator Edward Kennedy proposed competing plans, health care reform has played a central role in politics and public policy. Yet, it took almost 30 years before a multifaceted health reform bill became law. The legal, political, and policy stakes of the Supreme Court’s decision are vast. The ACA will achieve near universal coverage, something that seemed unimaginable just a short time ago. Health reform envisages a social contract in which everyone shares the cost, recognizing that virtually everyone will become ill one day. The ACA and its individual mandate are not unjustified limits on freedom, but rather are vital to a decent society. If the social contract must be accomplished through the private market, then the simple logic of insurance must prevail, which is to spread the risk among the rich and poor, healthy and sick, young and old alike.” (L. O. Gostin, gostin@law.georgetown.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 26, 2012 * Vol. 19, No. 17
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 26 New England Journal of Medicine (2012; 366).
Bevacizumab & Neoadjuvant Chemotherapy in Breast Cancer: Two articles and an editorial explore use of bevacizumab in women with breast cancer.
In 1,948 patients with early-stage breast cancer, addition of bevacizumab to neoadjuvant chemotherapy “significantly increased the rate of pathological complete response among patients with HER2-negative early-stage breast cancer,” researchers report (
pp. 299–309). Study participants received epirubicin and cyclophosphamide followed by docetaxel, with or without concomitant bevacizumab, with these results: “Overall, the rates of pathological complete response were 14.9% with epirubicin and cyclophosphamide followed by docetaxel and 18.4% with epirubicin and cyclophosphamide followed by docetaxel plus bevacizumab (odds ratio with addition of bevacizumab, 1.29; 95% confidence interval, 1.02 to 1.65; P = 0.04); the corresponding rates of pathological complete response were 27.9% and 39.3% among 663 patients with triple-negative tumors (P = 0.003) and 7.8% and 7.7% among 1,262 patients with hormone-receptor–positive tumors (P = 1.00). Breast-conserving surgery was possible in 66.6% of the patients in both groups. The addition of bevacizumab, as compared with neoadjuvant therapy alone, was associated with a higher incidence of grade 3 or 4 toxic effects (febrile neutropenia, mucositis, the hand–foot syndrome, infection, and hypertension) but with a similar incidence of surgical complications.” (G. von Minckwitz, gunter.vonminckwitz@germanbreastgroup.de)
A second study came to similar conclusions in women with more advanced disease based on a primary end point of pathological complete response (
pp. 310–20). A total of 1,206 patients with metastatic breast cancer had these responses to docetaxel plus capecitabine or docetaxel plus gemcitabine, with or without bevacizumab: “The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P = 0.69). Both capecitabine and gemcitabine were associated with increased toxic effects—specifically, the hand–foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P = 0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor–positive and hormone-receptor–negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand–foot syndrome, and mucositis.” (H. D. Bear, hdbear@vcu.edu)
Editorialists write that the rekindled “bevacizumab debate” centers on “fighting fire with fire” (
pp. 374–5): “These two well-performed trials do not resolve existing controversies surrounding bevacizumab therapy. If surrogate end points like progression-free survival in patients with metastatic breast cancer and pathological complete response in the neoadjuvant setting are ultimately predictive of survival benefits in earlier-stage disease, then the use of these surrogates in clinical research will be vindicated, and the FDA’s decision to withdraw the indication of bevacizumab for metastatic breast cancer will be further called into question. However, in the context of unsustainable expenditures for cancer care in the United States, any survival benefit of bevacizumab, or other molecularly targeted drugs, will be balanced against the considerable development costs of modern molecularly targeted oncology drugs.” (A. J. Montero)

>>>PNN NewsWatch
* FDA has approved ingenol mebutate gel (Picato, Leo Pharma) in concentrations of 0.015% (for face and scalp treatment over 3 days) and 0.05% (for the trunk and extremities for 2 days) for topical treatment of actinic keratosis (AK). In four Phase III clinical studies of more than 1,000 patients with actinic keratosis, a significantly higher proportion of those treated with ingenol gel saw complete clearance of AKs in the field of treatment as compared with placebo. The most common adverse events were local skin reactions, including erythema, flaking/scaling, crusting and swelling.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 27, 2012 * Vol. 19, No. 18
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (2012; 35).
Metformin’s Effects on Glycemic Control: Higher doses of metformin could be used to maximize lowering of glycosylated hemoglobin levels without increasing gastrointestinal adverse effects, according to results of a meta-analysis (pp. 446–54). Investigators grouped data from studies published since 1950 that lasted 12 weeks or more and included either metformin monotherapy or combination therapy. Results showed: “A total of 35 trials were identified for the main analysis and 7 for the dose-comparison analysis. Metformin monotherapy lowered HbA1c by 1.12% (95% CI 0.92–1.32; I2 = 80%) versus placebo, metformin added to oral therapy lowered HbA1c by 0.95% (0.77–1.13; I2 = 77%) versus placebo added to oral therapy, and metformin added to insulin therapy lowered HbA1c by 0.60% (0.30–0.91; I2 = 79.8%) versus insulin only. There was a significantly greater reduction in HbA1c using higher doses of metformin compared with lower doses of metformin with no significant increase in side effects.” (J. A. Hirst, jennifer.hirst@phc.ox.ac.uk)
Long-Term Fenofibrate Therapy: Based on results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate therapy should not be contraindicated in patients with moderate renal impairment, investigators conclude, adding that “current guidelines may be too restrictive” (pp. 218–25). In 9,795 patients with type 2 diabetes, baseline renal function was assessed. Patients were grouped by estimated glomerular filtration rate (eGFR) as follows: 30–59, 60–89, and ≥90 mL/min/1.73 m2). Patients taking fenofibrate 200 mg/d or placebo had these outcomes over 5 years: “Overall, fenofibrate reduced total cardiovascular events, compared with placebo (hazard ratio 0.89 [95% CI 0.80–0.99]; P = 0.035). This benefit was not statistically different across eGFR groupings (P = 0.2 for interaction) (eGFR 30–59 mL/min/1.73 m2: 0.68 [0.47–0.97], P = 0.035; eGFR ≥90 mL/min/1.73 m2: 0.85 [0.70–1.02], P = 0.08). ESRD rates were similar between treatment arms, without adverse safety signals of fenofibrate use in renal impairment.” (R-D Ting, rudee.ting@ctc.usyd.edu.au)
CVD Risk with Flavan-3-ols & Isoflavones: In 93 postmenopausal women with type 2 diabetes, 1 year of supplementation with flavan-3-ols and isoflavones improved biomarkers of risk for cardiovascular disease (CVD), researchers report (pp. 226–32). Participants received placebo or 27 g/day (split dose) flavonoid-enriched chocolate (containing 850 mg flavan-3-ols [90 mg epicatechin] and 100 mg isoflavones [aglycone equivalents)]/day), with these results: “Compared with the placebo group, the combined flavonoid intervention resulted in a significant reduction in estimated peripheral insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR] −0.3 ± 0.2; P = 0.004) and improvement in insulin sensitivity (quantitative insulin sensitivity index [QUICKI] 0.003 ± 0.00; P = 0.04) as a result of a significant decrease in insulin levels (−0.8 ± 0.5 mU/L; P = 0.02). Significant reductions in total cholesterol:HDL-cholesterol (HDL-C) ratio (−0.2 ± 0.1; P = 0.01) and LDL-cholesterol (LDL-C) (−0.1 ± 0.1 mmol/L; P = 0.04) were also observed. Estimated 10-year total coronary heart disease risk (derived from UK Prospective Diabetes Study algorithm) was attenuated after flavonoid intervention (flavonoid +0.1 ± 0.3 vs. placebo 1.1 ± 0.3; P = 0.02). No effect on blood pressure, HbA1c, or glucose was observed.” (A. Cassidy, a.cassidy@uea.ac.uk)

>>>PNN NewsWatch
* Acting on behalf of FDA, the U.S. Dept. of Justice has filed a consent decree of permanent injunction against the parent Indian company and the U.S. subsidiary of Ranbaxy. Ranbaxy’s facilities in the Indian cities of Paonta Sahib, Batamandi, and Dewas have been on FDA import alert since 2008, FDA said in a news release, and Ranbaxy has closed a Gloversville, NY, facility. The agency emphasized that the public should not be concerned that any drugs from those facilities are currently in the U.S. market. The consent decree requires that Ranbaxy comply with detailed data-integrity provisions before FDA will resume reviewing drug applications containing data or other information from the Paonta Sahib, Batamandi, and Dewas facilities.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 30, 2012 * Vol. 19, No. 19
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 28 issue of Lancet (2012; 379).
Capecitabine & Oxaliplatin for Gastric Cancer: In patients with operable gastric cancer, adjuvant capecitabine plus oxaliplatin therapy should be considered after curative D2 gastrectomy, conclude investigators in the CLASSIC trial (pp. 315–21). At 37 centers in South Korea, China, and Taiwan, resected patients with stage II–IIIB gastric cancer received adjuvant chemotherapy of eight 3-week cycles of oral capecitabine 1000 mg/sq m twice daily on days 1 to 14 of each cycle plus intravenous oxaliplatin 130 mg/sq m on day 1 of each cycle) for 6 months or surgery only, with these results: “1,035 patients were randomised (520 to receive chemotherapy and surgery, 515 surgery only). Median follow-up was 34.2 months (25.4–41.7) in the chemotherapy and surgery group and 34.3 months (25.6–41.9) in the surgery only group. 3 year disease-free survival was 74% (95% CI 69–79) in the chemotherapy and surgery group and 59% (53–64) in the surgery only group (hazard ratio 0.56, 95% CI 0.44–0.72; p < 0.0001). Grade 3 or 4 adverse events were reported in 279 of 496 patients (56%) in the chemotherapy and surgery group and in 30 of 478 patients (6%) in the surgery only group. The most common adverse events in the intervention group were nausea (n = 326), neutropenia (n = 300), and decreased appetite (n = 294).” (Y-J Bang, bangyj@snu.ac.kr)
Azithromycin Versus Penicillin for Yaws: In an open-label, noninferiority, randomized trial conducted in Papua New Guinea, a single oral dose of azithromycin was noninferior to benzathine benzylpenicillin for treatment of confirmed cases of yaws in children ages 6 months to 15 years, researchers report (pp. 342–7). Using a primary endpoint of treatment efficacy (cure rate defined serologically as a decrease in rapid plasma reagin titer of at least two dilutions by 6 months after treatment, and, in participants with primary ulcers, also by epithelialization of lesions within 2 weeks), the study showed: “We allocated 124 patients to the azithromycin group and 126 to the benzathine benzylpenicillin group. In the per-protocol analysis, after 6 months of follow-up, 106 (96%) of 110 patients in the azithromycin group were cured, compared with 105 (93%) of 113 in the benzathine benzylpenicillin group (treatment difference –3.4%; 95% CI –9.3 to 2.4), thus meeting prespecified criteria for non-inferiority. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (ten [8%] in the azithromycin group vs eight [7%] in the benzathine benzylpenicillin group).” (O. Mitjà, riolmitja@hotmail.com">oriolmitja@hotmail.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Pandemic Influenza Vaccine Effectiveness: Among residents of Denmark with chronic illnesses, administration of the pandemic influenza A/H1N1 vaccine significantly reduced infections but not influenza-related hospital admissions, a historical cohort study indicates (d7901). National health reports for Nov. 2009 to Jan. 2010 showed these trends among 388,069 people under 65 years of age with diagnoses of chronic illnesses at least 5 years previously: “The effectiveness of pandemic vaccine against confirmed H1N1 infection 14 days after one dose of vaccine was 49% (95% confidence interval 10% to 71%). The effectiveness of vaccine against admission to hospital for confirmed H1N1 infection was 44% (−19% to 73%).” (H-D Emborg, hde@ssi.dk)

>>>PNN NewsWatch
* Axitinib (Inlyta, Pfizer) has been approved by FDA for treatment of patients with advanced renal cell carcinoma. In a trial of 723 patients, the orally active kinase inhibitor produced a median progression-free survival of 6.7 months, significantly longer than the 4.7 months observed with standard treatment (sorafenib). Adverse effects of axitinib include diarrhea, hypertension, fatigue, decreased appetite, nausea, dysphonia (loss of voice), palmar–plantar erythrodysesthesia (hand–foot syndrome), weight loss, vomiting, asthenia, and constipation.

>>>PNN JournalWatch
* Macronutrients, Food Groups, and Eating Patterns in the Management of Diabetes: A Systematic Review of the Literature, 2010, in
Diabetes Care, 2012; 35: 434–45. (S. A. Dunbar, sdunbar@diabetes.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Jan. 31, 2012 * Vol. 19, No. 20
Providing news and information about medications and their proper use

>>>Nephrology Highlights
Source:
Feb. American Journal of Kidney Diseases (2012; 59).
Interaction Between Sevelamer & Fat-Soluble Vitamins: Referring to studies in this issue that report data suggesting interactions between vitamins D (pp. 177–85; M. I. Yilmaz, mahmutiyilmaz@yahoo.com) and K (pp. 186–95; T. Krueger, tkrueger@ukaachen.de) and the polymer sevelamer, editorialists conclude that this hypothesis “remains untested” (pp. 165–7). Sevelamer, which binds dietary phosphate in the gastrointestinal tract, is used for treating hyperphosphatemia in patients with chronic kidney disease who are on dialysis. “Since the concurrent use of sevelamer with thyroxine, ciprofloxacin, cyclosporine, or mycophenolate mofetil has been shown to reduce the bioavailability of these drugs, the American Society of Health-System Pharmacists recommends that these drugs be ingested at least 1 hour before or 3 hours after taking sevelamer, to prevent these potential drug interactions,” the editorialists write. “Consequently, we propose that clinicians should be cognizant that sevelamer might also decrease the absorption of vitamin D originating from dietary sources thereby reducing 25-hydroxyvitamin D levels, and might reduce the bioavailability of oral calcitriol. Consequently, it would be prudent to administer sevelamer and oral vitamin D supplements or vitamin D analogues several hours apart. Studies are necessary to test this hypothesis.” (B. L. Jaber, bertrand.jaber@steward.org)
Clinical Outcomes of Hyponatremia in Cancer Patients: In hospitalized patients with cancer and low serum sodium levels, longer lengths of stay and higher mortality were found in a retrospective analysis of prospectively collected data (pp. 222–8). Over a 3-month period in 2006, patients were categorized as eunatremia (serum sodium, 135–147 mEq/L) and mild (134–130 mEq/L), moderate (129–120 mEq/L), and severe (<120 mEq/L) hyponatremia, and these clinical outcomes were observed: “In 4,702 admissions in 3,357 patients with cancer, hyponatremia (serum sodium <135 mEq/L) was noted in 47% of admissions. It was mild in 36%, moderate in 10%, and severe in 1%. Hyponatremia was acquired during the hospital stay in 24%. Using the first admission data, mean length of stay was 5.6 ± 5.0 days for patients with eunatremia and 9.9 ± 9.2, 13.0 ± 14.1, and 11.5 ± 12.6 days for those with mild, moderate, and severe hyponatremia, respectively. The respective HRs in the multivariate Cox model for longer hospital stay, using patients with eunatremia as reference, were 1.92 (95% CI, 1.75–2.13; P < 0.01), 2.94 (95% CI, 2.56–3.45; P < 0.01), and 2.32 (95% CI, 1.32–4.00; P = 0.01). 283 (8.4%) deaths occurred during 90 days, and in the multivariate model, the respective HRs for 90-day mortality for mild, moderate, and severe hyponatremia were 2.04 (95% CI, 1.42–2.91; P < 0.01); 4.74 (95% CI, 3.21–7.01; P < 0.01), and 3.46 (95% CI, 1.05–11.44; P = 0.04). These findings were consistent when analyses were repeated with sodium levels in tertiles.” (A. K. Salahudeen, aksalahudeen@mdanderson.org)

>>>PNN NewsWatch
* Vismodegib (Erivedge, Genentech) was approved yesterday by FDA for treatment of adult patients with metastatic basal cell carcinoma (BCC) or locally advanced BCC who are not candidates for surgery or radiation. The approval is the first for patients with these forms of BCC, the most common skin cancer. The orally active drug is taken once daily and works by inhibiting the Hedgehog pathway, a pathway that is active in most basal cell cancers and only a few normal tissues, such as hair follicles. FDA approval of vismodegib (pronounced vis-mo-DEJ-ib) was based on results of ERIVANCE BCC (SHH4476g), a pivotal international, single-arm, multicenter, two-cohort, open-label, Phase II study that enrolled 104 patients with advanced BCC, including locally advanced BCC (71) and metastatic BCC (33). The study showed vismodegib shrank lesions in 43% (27/63) of patients with locally advanced BCC and 30% of patients (10/33) with metastatic BCC. The median duration of response was 7.6 months. The most common adverse effects of vismodegib are muscle spasms, hair loss, changes in or loss of taste, weight loss, tiredness, nausea, diarrhea, decreased appetite, constipation, vomiting, and joint aches. Women should avoid becoming pregnant while on the drug, and sexually active heterosexual men should use condoms with spermicide during therapy and for 2 months afterward.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 1, 2012 * Vol. 19, No. 21
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Feb. issue of Pharmacotherapy (2012; 32).
Pharmacogenomics & PBMs: The view of pharmacy benefits managers toward pharmacogenomics is presented in a Medco-authored special article (pp. 103–11): “Recently, the separate trajectories of pharmacy benefit management and pharmacogenomics converged. Pharmacogenomic tests have become more widely available for clinical use and at costs within the range of typical health care services. Pharmacy benefit payers continue to seek the precision they can apply to their coverage policies and clinical programs that pharmacogenomics offers. We describe how pharmacogenomics can now make sense as part of a pharmacy benefit and also how pharmacogenomics can be applied in a benefit coverage policy and clinical programs. Detail is provided on clinical program development and implementation processes featuring pharmacogenomics. We also discuss the research needed to support ongoing program development involving pharmacogenomics and describe the current roles of benefit payers and administrators in these research efforts. The legal and ethical dimensions of applying pharmacogenomics in pharmacy benefits are covered and in particular how benefit payers and administrators need to navigate between genetic exceptionalism and applicable laws and regulations. Finally, some thoughts are provided on future opportunities and challenges for pharmacogenomics in pharmacy benefit management and pharmacy in general.” (J. R. Teagarden, russell_teagarden@medco.com)
Primary Care Management of Anticoagulation: Among 62 adult patients who were stabilized on anticoagulants by staff in an Anticoagulation Management Service (AMS), outcomes did not differ if their care was transferred to primary care physicians (PCPs), researchers report (pp. 112–9). The prospective randomized trial, conducted at a tertiary medical facility and PCP practices in Canada, showed these outcomes: “Of 295 patients screened, most were excluded from the study for denying consent or for having previous bleeding or clotting complications while taking warfarin. Patients in the AMS and PCP groups who completed the study were similar in age (median 70 and 76 yrs, respectively), and most had atrial fibrillation as an indication for warfarin (75% and 83%, respectively). The primary outcome measure—mean percentage of time within the desired international normalized ratio (INR) range after 6 months—was compared between the two groups, using both the actual range (INR 2.5 ± 0.5) and an expanded range (INR 2.5 ± 0.7). No significant difference was noted in this outcome between the groups (73.5 ± 19.1% vs 76.9 ± 24.5% for the AMS vs PCP groups, p = 0.54). Other outcome measures were rates of thrombotic and hemorrhagic events resulting in emergency department visits or hospitalizations, patients’ overall satisfaction with warfarin therapy, and patients’ preferred anticoagulation management strategy. Two hemorrhagic events and one thrombotic event occurred in each group. Patients were more satisfied with their anticoagulant management by the AMS relative to PCP care (p = 0.01), and given the choice, patients preferred AMS care (p = 0.001).” (T. J. Bungard, tammy.bungard@ualberta.ca)

>>>PNN NewsWatch
* FDA has approved ivacaftor (Kalydeco, Vertex) for treatment of a rare form of cystic fibrosis (CF) in patients ages 6 years and older who have the G551D mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. About 4% of the 30,000 people with CF in the U.S. carry this mutation, the agency said. Two 48-week, placebo-controlled clinical studies involving 213 patients with the G551D mutation, one in patients ages 12 years and older and another in patients ages 6 years to 11 years, demonstrated significant and sustained improvement in lung function with the drug, which potentiates the effects of the CFTR protein. An FDA-cleared CF mutation test should be used to determine whether the G551D mutation is present, FDA said, if patients’ status is unknown. The most common adverse effects of ivacaftor include upper respiratory tract infection, headache, stomachache, rash, diarrhea, and dizziness.
* Pfizer has recalled 14 lots of
Lo/Ovral-28 (norgestrel and ethinyl estradiol)Tablets and 14 lots of Norgestrel and Ethinyl Estradiol Tablets (generic) because of possible inexact numbers of inert or active ingredient tablets and out-of-sequence tablets, FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 2, 2012 * Vol. 19, No. 22
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 2 issue of the New England Journal of Medicine (2012; 366).
ABVD Alone Limited-Stage Hodgkin’s Lymphoma: By reducing late treatment-related deaths, chemotherapy alone proved superior to chemotherapy plus radiation in 405 patients with limited-stage Hodgkin’s lymphoma, a study shows (pp. 399–408). Patients received doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy alone or subtotal nodal radiation therapy, with or without ABVD therapy, with these results: “The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P = 0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P = 0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P = 0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkin’s lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkin’s lymphoma or early toxic effects from the treatment and 20 were related to another cause.” (R. M. Meyer, rmeyer@ctg.queensu.ca)
Ulipristal for Uterine Fibroids: Two research studies and an editorial examine use of ulipristal in women with uterine fibroids.
In 242 women, 13 weeks of oral ulipristal acetate 5 or 10 mg daily controlled uterine bleeding in more than 90% of patients, compared with 19% for placebo (
pp. 409–20). Rates of amenorrhea were 73% with ulipristal 5 mg, 82% for ulipristal 10 mg, and 6% for placebo, and the respective median changes in total fibroid volume were –21%, –12%, and +3%, the researchers report. Two serious adverse events occurred, uterine hemorrhage in one patient on ulipristal 10 mg and fibroid protruding through the cervix in a patient in the placebo group. (J. Donnez, jacques.donnez@uclouvain.be)
Those same daily oral doses of ulipristal acetate were noninferior to monthly intramuscuar injections of leuprolide acetate 3.75 mg in a study of 307 patients with symptomatic fibroids and excessive uterine bleeding (
pp. 421–32): “Uterine bleeding was controlled in 90% of patients receiving 5 mg of ulipristal acetate, in 98% of those receiving 10 mg of ulipristal acetate, and in 89% of those receiving leuprolide acetate, for differences (as compared with leuprolide acetate) of 1.2 percentage points (95% confidence interval [CI], −9.3 to 11.8) for 5 mg of ulipristal acetate and 8.8 percentage points (95% CI, 0.4 to 18.3) for 10 mg of ulipristal acetate. Median times to amenorrhea were 7 days for patients receiving 5 mg of ulipristal acetate, 5 days for those receiving 10 mg of ulipristal acetate, and 21 days for those receiving leuprolide acetate. Moderate-to-severe hot flashes were reported for 11% of patients receiving 5 mg of ulipristal acetate, for 10% of those receiving 10 mg of ulipristal acetate, and for 40% of those receiving leuprolide acetate (P < 0.001 for each dose of ulipristal acetate vs. leuprolide acetate).” (J. Donnez, jacques.donnez@uclouvain.be)
Using evidence-based medicine in treatment of uterine fibroids need not be an oxymoron, an editorialist writes while calling more research (
pp. 471–3): “Studies of progesterone-receptor modulators as treatment for fibroids date back almost two decades. Since that time, innovations in interventional therapies have provided effective, minimally invasive alternatives to hysterectomy. Unfortunately, the rate of hysterectomy continues to be high, and there remains substantial need for effective medical therapy. The present studies represent an important step in that direction.” (E. A. Stewart)

>>>PNN NewsWatch
* Imatinib (Gleevec, Novartis) has been granted regular approval for treatment of adult patients following surgical removal of CD117-positive gastrointestinal stromal tumors (GIST). FDA had granted accelerated approvals for imatinib in various subsets of patients with GIST in 2002 and 2008. The drug should be taken for 36 months rather than the standard 12 months, FDA said. The 5-year survival rate was 92% with 36 months of treatment, significantly longer than the 82% observed with 12 months of treatment.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 3, 2012 * Vol. 19, No. 23
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Feb. issue of Pediatrics (2012; 129).
Hepatitis A Vaccination Among American Teenagers: Despite incremental changes in CDC recommendations regarding hepatitis A vaccination, coverage against the disease remains low in the United States, a study shows (pp. 213–21). In the 2009 National Immunization Survey–Teen, more than half of 20,066 adolescents ages 13–17 years were unprotected against hepatitis A as they matured into adulthood. Study participants were divided into three groups: those in states where hepatitis A vaccination has been recommended universally since 1999 (group 1), those where consideration has been recommended since 1999 (2), and those where universal child vaccination at 1 year has been recommended since 2006 (3). Results showed: “In 2009, national 1-dose HepA coverage among adolescents was 42.0%. Seventy percent of vaccinees completed the 2-dose series. One-dose coverage was 74.3% among group 1 states, 54.0% for group 2 states, and 27.8% for group 3 states. The adjusted prevalence ratios of vaccination initiation were highest for states with a vaccination requirement and for adolescents whose providers recommended HepA.” (C. G. Dorell)
Immune Thrombocytopenic Purpura After Vaccination: While low, an elevated risk of vaccine-related immune thrombocytopenic purpura (ITP) in children and adolescents was uncovered in an analysis of data from five managed-care organizations for 2000–09. (pp. 248–55). Among a cohort of 1.8 million children ages 6 weeks to 17 years, these associations between pediatric vaccinations and ITP were identified: “There were 197 chart-confirmed ITP cases out of 1.8 million children in the cohort. There was no elevated risk of ITP after any vaccine in early childhood other than MMR in the 12- to 19-month age group. There was a significantly elevated risk of ITP after hepatitis A vaccine at 7 to 17 years of age, and for varicella vaccine and tetanus–diphtheria–acellular pertussis vaccine at 11 to 17 years of age. For hepatitis A, varicella, and tetanus-diphtheria-acellular pertussis vaccines, elevated risks were based on one to two vaccine-exposed cases. Most cases were acute and mild with no long-term sequelae.” (S. T. O’Leary, sean.o’leary@childrenscolorado.org)
Antibiotic Administration Choices for Acute Pyelonephritis: While failing to demonstrate noninferiority in comparison with sequential intravenous/oral antibiotics, a clinical trial supports use of oral antibiotics in children with acute pyelonephritis (e269–75). Children ages 1–36 months with their first case of pyelonephritis (n = 171) were prospectively assigned to oral cefixime for 10 days or intravenous ceftriaxone for 4 days followed by oral cefexime for 6 days, with these effects on acute renal lesions at baseline and 6–8 months later: “There were no significant differences between the 2 groups in any clinical characteristic. Initial scintigraphy results were abnormal for 119 children. Ninety-six children were measured for renal scarring at the follow-up scintigraphy (per protocol analysis population). The incidence of renal scarring was 30.8% in the oral treatment group and 27.3% for children who received the sequential treatment.” (N. Bocquet)
Iatrogenic Dosing Errors with Intravenous Acetaminophen Tenfold overdoses of acetaminophen are being reported with the intravenous formulation of this hepatotoxic agent, clinicians at the Rocky Mountain Poison and Drug Center report (pp. 349–53): “An intravenous formulation of acetaminophen was introduced to the United States in 2011. Experience from Europe indicates that serious dosing errors are likely to occur. Most events have involved a 10-fold dosing error in small children caused by calculating the dosage in milligrams, but then administering the solution in milliliters. The solution is 10 mg/mL; therefore, a 10-fold overdose occurs. Evaluation of overdose with the intravenous formulation is similar to oral overdose. A serum acetaminophen concentration should be drawn 4 hours after the infusion was started or as soon thereafter as possible. If the serum acetaminophen concentration plots above the treatment line on the Rumack–Matthew nomogram, treatment with acetylcysteine should be initiated. Health care providers are encouraged to contact their regional poison center (1-800-222-1222) so that dosing errors will be reported, and the experience with this new product can be accumulated.” (R. C. Dart)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 6, 2012 * Vol. 19, No. 24
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 4 issue of Lancet (2012; 379).
Polychemotherapy Regimens for Early Breast Cancer: Some taxane-plus-anthracycline–based or higher-cumulative-dosage anthracycline-based regimens that do not require stem cells provided the greatest reductions in breast cancer mortality in a meta-analysis of long-term outcomes with various polychemotherapy regimens, researchers report (pp. 432–44). Overall, 10-year gains from a one-third reduction in breast cancer mortality were related to the absolute risks of the chemotherapy regimens, but more information on tumor gene expression and quantitative immunohistochemistry would be useful for individualizing care. Results showed: “In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities.” (Early Breast Cancer Trialists’ Collaborative Group, bc.overview@CTSU.ox.ac.uk)
Global Malaria Mortality: While donor-supported malaria-control activities have lowered disease mortality in Africa, an analysis of international data shows that the number of deaths is higher than previously estimated, especially among adults (pp. 413–31). Data from 1980 to 2010 reflected some progress: “Global malaria deaths increased from 995,000 (95% uncertainty interval 711,000–1,412,000) in 1980 to a peak of 1,817,000 (1,430,000–2,366,000) in 2004, decreasing to 1,238,000 (929,000–1,685,000) in 2010. In Africa, malaria deaths increased from 493,000 (290,000–747,000) in 1980 to 1,613,000(1,243,000–2,145,000) in 2004, decreasing by about 30% to 1,133,000 (848,000–1,591,000) in 2010. Outside of Africa, malaria deaths have steadily decreased from 502,000 (322,000–833,000) in 1980 to 104,000 (45,000–191,000) in 2010. We estimated more deaths in individuals aged 5 years or older than has been estimated in previous studies: 435,000 (307,000–658,000) deaths in Africa and 89,000 (33,000–177,000) deaths outside of Africa in 2010.” (C. J. L. Murray, cjlm@u.washington.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Enoxaparin v. Heparin in PCI: Particularly in patients with ST-elevation myocardial infarction, enoxaparin is superior to unfractionated heparin for reducing mortality and bleeding outcomes during percutaneous coronary interventions, according to a systematic review and meta-analysis (e553): “23 trials representing 30,966 patients were identified, including 10,243 patients (33.1%) undergoing primary percutaneous coronary intervention for ST elevation myocardial infarction, 8,750 (28.2%) undergoing secondary percutaneous coronary intervention after fibrinolysis, and 11,973 (38.7%) with non-ST elevation acute coronary syndrome or stable patients scheduled for percutaneous coronary intervention. A total of 13,943 patients (45.0%) received enoxaparin and 17,023 (55.0%) unfractionated heparin. Enoxaparin was associated with significant reductions in death (relative risk 0.66, 95% confidence interval 0.57 to 0.76; P < 0.001), the composite of death or myocardial infarction (0.68, 0.57 to 0.81; P < 0.001), and complications of myocardial infarction (0.75, 0.6 to 0.85; P < 0.001), and a reduction in incidence of major bleeding (0.80, 0.68 to 0.95; P = 0.009). In patients who underwent primary percutaneous coronary intervention, the reduction in death (0.52, 0.42 to 0.64; P < 0.001) was particularly significant and associated with a reduction in major bleeding (0.72, 0.56 to 0.93; P = 0.01).” (G. Montalescot, gilles.montalescot@psl.aphp.fr)

>>>PNN JournalWatch
* Fidaxomicin: A Novel Macrocyclic Antibiotic Approved for Treatment of
Clostridium difficile Infection, in Clinical Infectious Diseases, 2012; 54: 568–74. (A. A. Venugopal, anilrudh.venugopal@stjohn.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 7, 2012 * Vol. 19, No. 25
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Feb. 7 issue of the Annals of Internal Medicine (2012; 156).
Guideline for Oral Treatment of Type 2 Diabetes: Metformin is confirmed as the preferred first-line oral agent for use in pharmacologic treatment of type 2 diabetes in a clinical guideline from the American College of Physicians, but the group says that evidence is insufficient to provide advice for second-line oral agents (pp. 218–31). Based on a systematic literature review of the 1996 through Apr. 2010 period, the ACP Clinical Guidelines Committee makes these recommendations about oral medications (A. Quseem):
* ACP recommends that clinicians add oral pharmacologic therapy in patients diagnosed with type 2 diabetes when lifestyle modifications, including diet, exercise, and weight loss, have failed to adequately improve hyperglycemia (Grade: strong recommendation; high-quality evidence).
* ACP recommends that clinicians prescribe monotherapy with metformin for initial pharmacologic therapy to treat most patients with type 2 diabetes (Grade: strong recommendation; high-quality evidence).
* ACP recommends that clinicians add a second agent to metformin to treat patients with persistent hyperglycemia when lifestyle modifications and monotherapy with metformin fail to control hyperglycemia (Grade: strong recommendation; high-quality evidence).
Recommended Adult Immunizations: In two figures, the CDC’s Advisory Committee on Immunization Practices provides recommendations to clinicians for adult immunizations (pp. 211–7). A table in the article lists contraindications and precautions for commonly used adult vaccines. (CDC Advisory Committee on Immunization Practices)
In a related editorial, several controversial vaccine topics are discussed, including the economics and politics of vaccination policy, vaccination of males against human papillomavirus, hepatitis B vaccination for patients with diabetes, and use of tetanus, diphtheria, and acellular pertussis boosters in pregnancy (
pp. 243–5). Egg allergy concerns with influenza vaccination are also covered: “Egg allergy is no longer a contraindication to influenza vaccination. Data from at least 17 studies of more than 2,600 egg-allergic patients have debunked concerns that traces of ovalbumin egg protein could trigger a serious allergic reaction. Egg-allergic patients must get the inactivated flu shot because that is what has been studied. No skin tests are needed before vaccinating, and the entire vaccine dose can be given at one time. Patients should be observed for 30 minutes after receiving the vaccine.” (S. A. Fryhofer)
GFR Equations in Creatinine Standardization Era: Comparison of two equations for estimating glomerular filtration rate (GFR) led to the conclusion that neither is “optimal for all populations and GFR ranges” (early release). Since “clinical laboratories are increasingly reporting estimated … GFR by using serum creatinine assays traceable to a standard reference material,” the researchers wanted “to review the performance of GFR estimating equations to inform the selection of a single equation by laboratories and the interpretation of estimated GFR by clinicians.” Examination of available cross-sectional studies in adults of at least 2 creatinine-based GFR estimating equations with a reference GFR measurement showed the following: “Eligible studies compared the MDRD (Modification of Diet in Renal Disease) Study and CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations or modifications thereof. In 12 studies in North America, Europe, and Australia, the CKD-EPI equation performed better at higher GFRs (approximately >60 mL/min per 1.73 m2) and the MDRD Study equation performed better at lower GFRs. In 5 of 8 studies in Asia and Africa, the equations were modified to improve their performance by adding a coefficient derived in the local population or removing a coefficient.” (A. Earley)
End-of-Life Care Discussions in Advanced Cancer: Despite national guidelines calling for end-of-life discussions with patients with life expectancy of less than 1 year, a study finds that 2,155 patients with stage IV lung or colorectal cancer had such conversations late in the course of their illnesses, if at all, usually during acute hospital care, and often with providers other than oncologists (pp. 204–10; J. W. Mack)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 8, 2012 * Vol. 19, No. 26
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 8 issue of JAMA (2012; 307).
Serogroup B Meningococcal Vaccine: A multicomponent serogroup B Neisseria meningitidis (4CMenB) vaccine was immunogenic against reference strains when administered to 1,885 infants, and the effects were produced without interference with other vaccines given concomitantly, researchers report (pp. 573–82). The vaccine was administered on four schedules between 2 and 7 months; routine vaccines given to the participants during this period were 7-valent pneumococcal and combined diphtheria, tetanus, acellular pertussis, inactivated polio, hepatitis B, and Haemophilus influenzae type b vaccines.
Based on percentages of participants with human complement serum bactericidal activity (hSBA) titers of 1:5 or greater against 3 MenB strains specific for vaccine antigens, results showed: “After three 4CMenB vaccinations, 99% or more of infants developed hSBA titers of 1:5 or greater against strains 44/76-SL and 5/99. For NZ98/254, this proportion was 79% (95% CI, 75.2%–82.4%) for vaccination at 2, 4, and 6 months with routine vaccines, 86.1% (95% CI, 82.9%–89.0%) for vaccination at 2, 4, and 6 months without routine vaccines, and 81.7% (95% CI, 76.6%–86.2%) for vaccination at 2, 3, and 4 months with routine vaccines. Responses to routine vaccines given with 4CMenB were noninferior to routine vaccines alone for all antigens, except for the responses to pertactin and serotype 6B pneumococcal polysaccharide. Fever was seen following 26% (158/602) to 41% (247/607) of 4CMenB doses when administered alone, compared with 23% (69/304) to 36% (109/306) after routine vaccines given alone and 51% (306/605) to 61% (380/624) after 4CMenB and routine vaccines administered together.” (M. Snape,
matthew.snape@paediatrics.ox.ac.uk)
These results are promising, editorialists write, but caution is merited as clinicians “inch toward” a serogroup B meningococcal vaccine for infants (
pp. 614–5): “The potential of 4CMenB vaccine to reduce serogroup B meningococcal disease is substantial, but it cannot be compared with the success of conjugate vaccine programs. 4CMenB vaccine may not reduce nasopharyngeal carriage or produce herd immunity, as the serogroup C conjugate vaccine did in the United Kingdom. Booster doses may be required to sustain protection but may not confer the same degree of immunologic memory as conjugate vaccines. Countries will have to weigh the benefits of serogroup B vaccination against the costs of adding vaccines to the infant schedule. However, the anticipated licensure of this vaccine in Europe and other countries means that for the first time vaccines to prevent all 5 of the serogroups that cause most meningococcal disease worldwide will be available.” (A. C. Cohn, acohn@cdc.gov)
Cefpodoxime for Acute Uncomplicated Cystitis: A short course of cefpodoxime did not meet noninferiority criteria among 300 women with acute uncomplicated cystitis, compared with ciprofloxacin, a study shows (pp. 583–9). Women received oral ciprofloxacin 250 mg twice daily or cefpodoxime 100 mg proxetil twice daily for 3 days, with these results: “The overall clinical cure rate at the 30-day visit with the intent-to-treat approach in which [32] patients lost to follow-up were considered as having clinical cure was 93% (139/150) for ciprofloxacin compared with 82% (123/150) for cefpodoxime (difference of 11%; 95% CI, 3%–18%); and for the intent-to-treat approach in which patients lost to follow-up were considered as having not responded to treatment, the clinical cure rate was 83% (124/150) for ciprofloxacin compared with 71% (106/150) for cefpodoxime (difference of 12%; 95% CI, 3%–21%). The microbiological cure rate was 96% (123/128) for ciprofloxacin compared with 81% (104/129) for cefpodoxime (difference of 15%; 95% CI, 8%–23%). At first follow-up, 16% of women in the ciprofloxacin group compared with 40% of women in the cefpodoxime group had vaginal E coli colonization.” (T. M. Hooton, thooton@med.miami.edu)
Intussusception with Pentavalent Rotavirus Vaccine: No increased intussusception risk was seen among U.S. infants receiving 786,725 doses of pentavalent rotavirus vaccine (RV5), according to data from the Vaccine Safety Datalink (pp. 598–604). After doses, 21 cases of intussception were seen during the first month; 20.9 cases had been expected. (I. M. Shui, ishui@hsph.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 9, 2012 * Vol. 19, No. 27
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 9 issue of the New England Journal of Medicine (2012; 366).
Everolimus in Advanced Breast Cancer: Everolimus increased progression-free survival in 724 patients with hormone-receptor–positive advanced breast cancer who had recurrence or progression while receiving a nonsteroidal aromatase inhibitor for adjuvant therapy and/or for treatment of advanced disease, a study shows (pp. 520–9). Administered with the exemestane, the mammalian target of rapamycin (mTOR) inhibitor everolimus produced these results: “Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P < 0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P < 0.001).” (J. Baselga, jbaselga@partners.org)
Regional Variation in Medicare Part D Drug Spending: Greater use of branded drugs in certain parts of the U.S. is a key contributor to regional variations Medicare Part D drug spending, while per-capita prescription volume had little impact, researchers report (pp. 530–8). Among 4.7 million beneficiaries in 2008, prescription-drug use and expenditures were analyzed overall and for three drug categories: ACE inhibitors, statins, and SSRIs/SNRIs, with these differences identified per capita across hospital-referral regions (HRRs): “Mean adjusted per capita pharmaceutical spending ranged from $2,413 in the lowest to $3,008 in the highest quintile of HRRs. Most (75.9%) of that difference was attributable to the cost per prescription ($53 vs. $63). Regional differences in cost per prescription explained 87.5% of expenditure variation for ACE inhibitors and ARBs and 56.3% for statins but only 36.1% for SSRIs and SNRIs. The ratio of branded-drug to total prescriptions, which correlated highly with cost per prescription, ranged across HRRs from 0.24 to 0.45 overall and from 0.24 to 0.55 for ACE inhibitors and ARBs, 0.29 to 0.60 for statins, and 0.15 to 0.51 for SSRIs and SNRIs.”
Discussing these results, the authors noted: “Although it is unclear what rate of branded-drug use among Medicare beneficiaries would be preferable, our finding that branded-drug use differed by a factor of almost two across regions provides a signal of potentially wasteful prescribing in some regions. We estimate that the Medicare program and beneficiaries would have saved $4.5 billion if branded-drug use in all HRRs had been similar to that in the lowest quintile. This finding is consistent with studies showing the potential for greater generic use and resultant savings on the part of commercial insurance plans, Medicaid, Veterans Affairs medical centers, and the elderly.” (J. M. Donohue,
jdonohue@pitt.edu)
Tai Chi for Parkinson’s Disease: In patients with mild-to-moderate Parkinson’s disease, Tai Chi training reduced balance impairments and improved functional capacity and reduced falls, according to a 195-participant study (pp. 511–9). Compared with resistance training and stretching, tai chi showed these outcomes in two weekly sessions of 60 minutes over 24 weeks: “The tai chi group performed consistently better than the resistance-training and stretching groups in maximum excursion (between-group difference in the change from baseline, 5.55 percentage points; 95% confidence interval [CI], 1.12 to 9.97; and 11.98 percentage points; 95% CI, 7.21 to 16.74, respectively) and in directional control (10.45 percentage points; 95% CI, 3.89 to 17.00; and 11.38 percentage points; 95% CI, 5.50 to 17.27, respectively).” (F. Li, fuzhongl@ori.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 10, 2012 * Vol. 19, No. 28
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Feb. 14 issue of the Journal of the American College of Cardiology (2012; 59).
Pre-Diabetes, Metabolic Syndrome, & Cardiovascular Risk: In a state-of-the-art paper, an author reviews current knowledge of the relationships among pre-diabetes, metabolic syndrome, and cardiovascular risk (pp. 635–43): “Pre-diabetes represents an elevation of plasma glucose above the normal range but below that of clinical diabetes. Pre-diabetes can be identified as either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The latter is detected by oral glucose tolerance testing. Both IFG and IGT are risk factors for type 2 diabetes, and risk is even greater when IFG and IGT occur together. Pre-diabetes commonly associates with the metabolic syndrome. Both in turn are closely associated with obesity. The mechanisms whereby obesity predisposes to pre-diabetes and metabolic syndrome are incompletely understood but likely have a common metabolic soil. Insulin resistance is a common factor; systemic inflammation engendered by obesity may be another. Pre-diabetes has only a minor impact on microvascular disease; glucose-lowering drugs can delay conversion to diabetes, but whether in the long run the drug approach will delay development of microvascular disease is in dispute. To date, the drug approach to prevention of microvascular disease starting with pre-diabetes has not been evaluated. Pre-diabetes carries some predictive power for macrovascular disease, but most of this association appears to be mediated through the metabolic syndrome. The preferred clinical approach to cardiovascular prevention is to treat all the metabolic risk factors. For both pre-diabetes and metabolic syndrome, the desirable approach is lifestyle intervention, especially weight reduction and physical activity. When drug therapy is contemplated and when the metabolic syndrome is present, the primary consideration is prevention of cardiovascular disease. The major targets are elevations of cholesterol and blood pressure.” (S. M. Grundy, scott.grundy@utsouthwestern.edu)

>>>Circulation Report
Source:
Feb. 7 issue of Circulation (2012; 125).
Ischemic Events with Dabigatran v. Warfarin: Data from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study show a nonsignificant increase in myocardial infarction (MI) events in patients on dabigatran, compared with those on warfarin, in patients with atrial fibrillation (pp. 669–76). Other ischemic events occurred at similar rates with the two drugs and in patients with higher and lower risk of myocardial ischemia, the authors report, adding these details: “MI occurred at annual rates of 0.82% and 0.81% with dabigatran 110 or 150 mg BID compared with 0.64% with warfarin (hazard ratio [HR] 1.29, 95% confidence interval [CI] 0.96–1.75, P = 0.09 for dabigatran 110 mg; HR 1.27, 95% CI 0.94–1.71, P = 0.12 for dabigatran 150 mg). Annual rates of a composite of MI, unstable angina, cardiac arrest, and cardiac death were 3.16% per year with dabigatran 110 mg, 3.33% per year with dabigatran 150 mg, and 3.41% per year with warfarin (HR versus warfarin 0.93, 95% CI 0.80–1.06, P = 0.28 for dabigatran 110 mg and HR 0.98, 95% CI 0.85–1.12, P = 0.77 for dabigatran 150 mg). Events prespecified as ‘net clinical benefit’ (all strokes, systemic embolism, MI, pulmonary embolism, major bleeding, and all-cause death) occurred at a rate of 7.34% per year with dabigatran 110 mg, 7.11% per year with dabigatran 150 mg, and 7.91% per year with warfarin (HR 0.92, 95% CI 0.84–1.01, P = 0.09 for dabigatran 110 mg and HR 0.90, 95% CI 0.82–0.99, P = 0.02 for dabigatran 150 mg). The relative effects of dabigatran versus warfarin on myocardial ischemic events were consistent in patients with or without a baseline history of MI or coronary artery disease.” (S. H. Hohnloser, Hohnloser@em.uni-frankfurt.de)

>>>PNN NewsWatch
* FDA yesterday issued three draft guidance documents outlining its ideas on the approval process for biosimilars. The health care reform law created an abbreviated approval pathway for biological products, intended to be similar to that for generic drugs. These documents, soon open for public comment, outline scientific and quality considerations for demonstrating biosimilarity to a reference product and provide answers to common questions.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 13, 2012 * Vol. 19, No. 29
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 11 issue of Lancet (2012; 379).
Memantine for Dementia in Middle-Aged Adults with Down’s Syndrome: Agents for Alzheimer’s disease may not work in adults older than 40 with dementia and Down’s syndrome, according to investigators who studied memantine in a group of such patients (pp. 528–36). Prevalence of Alzheimer’s disease is high in this group, and many individuals have pathological changes similar to those found in patients with the disease. At four learning disability centers in the U.K. and Norway, 173 adults older than 40 with karyotypic or clinically diagnosed Down’s syndrome and with or without dementia had these changes in DAMES (dementia, age group, total Down’s syndrome attention, memory, executive function, sex) score and adaptive behavior scale (ABS) I and II when receiving memantine or placebo for 52 weeks: “Both groups declined in cognition and function but rates did not differ between groups for any outcomes. After adjustment for baseline score, there were non-significant differences between groups of –4.1 (95% CI –13.1 to 4.8) in DAMES scores, –8.5 (–20.1 to 3.1) in ABS I scores, and 2.0 (–7.2 to 11.3) in ABS II scores, all in favour of controls. 10 (11%) of 88 participants in the memantine group and six (7%) of 85 controls had serious adverse events (p = 0.33). Five participants in the memantine group and four controls died from serious adverse events (p = 0.77).” (C. Ballard, clive.ballard@kcl.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 344).
Driving After Cannabis Consumption: Driving after using marijuana is associated with increased risk of motor vehicle crashes, particularly fatal ones, a meta-analysis of 9 studies shows (e536): “Driving under the influence of cannabis was associated with a significantly increased risk of motor vehicle collisions compared with unimpaired driving (odds ratio 1.92 (95% confidence interval 1.35 to 2.73); P = 0.0003); we noted heterogeneity among the individual study effects (I2 = 81). Collision risk estimates were higher in case–control studies (2.79 (1.23 to 6.33); P = 0.01) and studies of fatal collisions (2.10 (1.31 to 3.36); P = 0.002) than in culpability studies (1.65 (1.11 to 2.46); P = 0.07) and studies of non-fatal collisions (1.74 (0.88 to 3.46); P = 0.11).” (M. Asbridge, mark.asbridge@dal.ca)
Symptoms During Menopause: Symptom profiles among women in menopause are identified in a U.K.-representative cohort study (e402). Longitudinal assessment of 695 women followed since birth in 1946 and annually from age 47 to 54 showed these patterns for 20 common health symptoms that fell into psychological, somatic, vasomotor, and sexual discomfort symptom groups: “For vasomotor symptoms, 14% of women (n = 83) had the early severe profile that also peaked around early postmenopause and then declined noticeably; 11% (n = 67) had the late severe profile of bothersome symptoms that increased rapidly in perimenopause and remained high for four years or more after menopause. Women were less likely to have a profile for severe vasomotor symptoms if they were from a non-manual social class (odds ratio 0.79, 95% confidence interval 0.57 to 1.01) or had degree level qualifications (0.37, 0.18 to 0.77). The 14% of women (n = 85) who had the late severe profile for sexual discomfort showed a similar increase in symptoms until menopause, with symptoms persisting after menopause. Married women were more likely to have the late severe or late moderate profile than women of other marital status (2.40, 1.30 to 4.41).” (G. D. Mishra, g.mishra@sph.uq.edu.au)

>>>PNN JournalWatch
* The Impact of Anti-infective Drug Shortages on Hospitals in the United States: Trends and Causes, in
Clinical Infectious Diseases, 2012; 54: 684–91. (M. Scheetz, mscheetz@nmh.org)
* Ethanol Locks to Prevent Catheter-Related Bloodstream Infections in Parenteral Nutrition: A Meta-Analysis, in
Pediatrics, 2012; 129: 318–29. (C. Oliveira)
* The Diet Factor in Attention-Deficit/Hyperactivity Disorder, in
Pediatrics, 2012; 129: 330–7. (J. G. Millichap)
* Persistent Pulmonary Hypertension of the Newborn and Selective Serotonin Reuptake Inhibitors: Lessons From Clinical and Translational Studies, in
American Journal of Psychiatry, 2012; 169: 134–40. (M. Occhiogrosso, mbc2003@med.cornell.edu)
* New Approaches to Personalized Medicine for Asthma: Where Are We?, in
Journal of Allergy and Clinical Immunology, 2012; 129: 327–34. (S. T. Weiss, scott.weiss@channing.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 14, 2012 * Vol. 19, No. 30
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Feb. 13 issue of the Archives of Internal Medicine (2012; 172).
Supplements & Cancer: In patients with cardiovascular disease, relatively low doses of B vitamins and/or omega-3 fatty acids provided no beneficial effects on cancer outcomes, researchers report (doi: 10.1001/archinternmed.2011.1450). In an ancillary study of the Supplementation With Folate, Vitamins B6 and B12 and/or Omega-3 Fatty Acids (SU.FOL.OM3) secondary prevention trial conducted in 2003–09, 2,501 individuals aged 45–80 years were randomized in a 2X2 factorial design to 5-methyltetrahydrofolate 0.56 mg, pyridoxine hydrochloride 3 mg, and cyanocobalamin 0.02 mg; eicosapentaenoic and docosahexaenoic acid 600 mg in a 2:1 ratio; B vitamins and omega-3 fatty acids; or placebo. Results showed: “After 5 years of supplementation, incident cancer was validated in 7.0% of the sample (145 events in men and 29 in women), and death from cancer occurred in 2.3% of the sample. There was no association between cancer outcomes and supplementation with B vitamins (HR, 1.15 [95% CI, 0.85–1.55]) and/or omega-3 fatty acids (HR, 1.17 [95% CI, 0.87–1.58]). There was a statistically significant interaction of treatment by sex, with no effect of treatment on cancer risk among men and increased cancer risk among women for omega-3 fatty acid supplementation (HR, 3.02 [95% CI, 1.33–6.89]).” (V. A. Andreeva, v.andreeva@uren.smbh.univ-paris13.fr)
Aspirin & Vascular, Nonvascular Outcomes: Aspirin prophylaxis in patients with prior cardiovascular disease (CVD) did not reduce cardiovascular death or cancer mortality, according to a meta-analysis of 9 randomized controlled trials of at least 1,000 participants each (pp. 209–16). Nonfatal myocardial infarction (MI) was lowered in those receiving aspirin, the investigators found: “During a mean (SD) follow-up of 6.0 (2.1) years involving over 100,000 participants, aspirin treatment reduced total CVD events by 10% (OR, 0.90; 95% CI, 0.85–0.96; number needed to treat, 120), driven primarily by reduction in nonfatal MI (OR, 0.80; 95% CI, 0.67–0.96; number needed to treat, 162). There was no significant reduction in CVD death (OR, 0.99; 95% CI, 0.85–1.15) or cancer mortality (OR, 0.93; 95% CI, 0.84–1.03), and there was increased risk of nontrivial bleeding events (OR, 1.31; 95% CI, 1.14–1.50; number needed to harm, 73). Significant heterogeneity was observed for coronary heart disease and bleeding outcomes, which could not be accounted for by major demographic or participant characteristics.” (S. R. K. Seshasai, rkondapa@sgul.ac.uk)
Need for Better Trials of Drugs for RA: Practical and ethical concerns about studies of biologic disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis lead authors to conclude that “exposing patients in control arms who had a previous partial response or nonresponse to an inadequate treatment could lead to irreversible deterioration in condition” (pp. 237–44). Analysis of protocols in ClinicalTrials.gov through Oct. 1, 2009, show few head-to-head comparisons of these drugs: “Among the 91 trials identified (15 DMARD-naive trials, 63 biologic-naive trials, and 13 biologic–second-line trials) involving 18,554 patients in control arms (3,059, 13,095, and 2,400 patients, respectively), only 5 compared biologic DMARDs head-to-head (2 of 7 noncommercially funded trials and 3 of 84 commercially funded trials). Two-thirds (66%) of these trials are ongoing. Networks of treatment comparisons reflect a predominant use of placebo as a comparator (81 of 102 comparisons among the 91 trials). In all 15 DMARD-naive trials, all control patients received a new treatment. In 54 of the 63 biologic-naive trials, 9,224 of the 13,095 control patients received their previously ineffective treatment, 3,848 for more than 6 months, despite high levels of disease activity and contrary to guidelines. In biologic–second-line trials, 851 of the 2,400 control patients received treatment comparable to their previously ineffective one.” (C. Estellat, candice.estellat@bch.aphp.fr)

>>>PNN NewsWatch
* Tafluprost ophthalmic solution (Zioptan) has been approved by FDA for reducing elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension, Merck reports. The product is the first preservative-free prostaglandin analogue.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 15, 2012 * Vol. 19, No. 31
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 15 issue of JAMA (2012; 307).
Cardiac Effects of Vitamin D in Chronic Kidney Disease: Supplements of an active vitamin D compound had no effects on cardiac structure or function in a 48-week trial in participants with chronic kidney disease (CKD) in the PRIMO (Paricalcitol Capsule Benefits in Renal Failure–Induced Cardiac Morbidity) trial, researchers report (pp. 674–84). In 227 patients in 11 countries in 2008–10, paricalcitol 2 mcg daily was compared with placebo in terms of changes in left ventricular mass index and left ventricular ejection fraction: “Treatment with paricalcitol reduced parathyroid hormone levels within 4 weeks and maintained levels within the normal range throughout the study duration. At 48 weeks, the change in left ventricular mass index did not differ between treatment groups (paricalcitol group, 0.34 g/m2.7 [95% CI, −0.14 to 0.83 g/m2.7] vs placebo group, −0.07 g/m2.7 [95% CI, −0.55 to 0.42 g/m2.7]). Doppler measures of diastolic function including peak early diastolic lateral mitral annular tissue velocity (paricalcitol group, −0.01 cm/s [95% CI, −0.63 to 0.60 cm/s] vs placebo group, −0.30 cm/s [95% CI, −0.93 to 0.34 cm/s]) also did not differ. Episodes of hypercalcemia were more frequent in the paricalcitol group compared with the placebo group.” (R. Thadhani, thadhani.r@mgh.harvard.edu)
This study provides “more questions than answers,” editorialists write (
pp. 722–3): “The deciding factor for whether to prescribe paricalcitol (vitamin D) for patients with CKD should be based on improvement in important clinical outcomes rather than other end points. At this time, paracalcitol cannot be recommended for patients with CKD. The PRIMO trial needs to be followed by a larger trial adequately powered to assess clinical end points such as cardiac-related hospitalizations, dialysis events, and mortality. Considering the competition for public funding of clinical trials in CKD, the pro–vitamin D research groups may face an uphill battle to keep this treatment option viable for patients with CKD.” (S. D. Anker, s.anker@cachexia.de)
Amoxicillin for Acute Rhinosinusitis: Compared with placebo, amoxicillin 1500 mg/d for 10 days did not reduce symptoms of acute rhinosinusitis at day 3 of treatment, a study shows (pp. 685–92). Participants were recruited at 10 community practices in Missouri in 2006–09. A primary outcome of improvement in disease-specific quality of life after 3–4 days of treatment assessed with the Sinonasal Outcome Test-16 showed these results: “A total of 166 adults (36% male; 78% with white race) were randomized to amoxicillin (n = 85) or placebo (n = 81); 92% concurrently used 1 or more symptomatic treatments (94% for amoxicillin group vs 90% for control group; P = .34). The mean change in Sinonasal Outcome Test-16 scores was not significantly different between groups on day 3 (decrease of 0.59 in the amoxicillin group and 0.54 in the control group; mean difference between groups of 0.03 [95% CI, −0.12 to 0.19]) and on day 10 (mean difference between groups of 0.01 [95% CI, −0.13 to 0.15]), but differed at day 7 favoring amoxicillin (mean difference between groups of 0.19 [95% CI, 0.024 to 0.35]). There was no statistically significant difference in reported symptom improvement at day 3 (37% for amoxicillin group vs 34% for control group; P = .67) or at day 10 (78% vs 80%, respectively; P = .71), whereas at day 7 more participants treated with amoxicillin reported symptom improvement (74% vs 56%, respectively; P = .02). No between-group differences were found for any other secondary outcomes. No serious adverse events occurred.” (J. M. Garbutt, jgarbutt@dom.wustl.edu)
Oral HPV Infection Prevalence: Among Americans ages 14–69 years, the prevalence of oral human papillomavirus (HPV) infection is 6.9%, with cases more common among men than women, according to a study conducted with the 2009–10 National Health and Nutrition Examination Survey (NHANES) (pp. 693–703). “Vaccine efficacy against oral HPV infection is unknown, and therefore vaccination cannot currently be recommended for the primary prevention of oropharyngeal cancer,” the authors conclude. “Given an analysis of US cancer registry data recently projected that the number of HPV-positive oropharyngeal cancers diagnosed each year will surpass that of invasive cervical cancers by the year 2020, perhaps such vaccine trials are warranted.” (M. Gillison, maura.gillison@osumc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 16, 2012 * Vol. 19, No. 32
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 16 issue of the New England Journal of Medicine (2012; 366).
Prehospital Management of Status Epilepticus: In children and adults in status epilepticus, intramuscular midazolam proved just as safe and effective as intravenous lorazepam for prehospital seizure control, researchers report (pp. 591–600). In a double-blind, randomized, noninferiority trial, patients in status epilepticus for at least 5 minutes and still in convulsions when paramedics arrived received intramuscular and intravenous agents or matching placebo, with these results: “At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P < 0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups.” (R. Silbergleit, robert.silbergleit@umich.edu)
An editorialist writes that new options may enable family and friends to administer anticonvulsants for status epilepticus (
pp. 659–60): “Home treatment with nasal or buccal benzodiazepines will soon be widely available and may help prevent status epilepticus and visits to the emergency department for patients who are at risk for prolonged or repetitive seizures (‘clusters&rsquoWinking. A comparison between the intramuscular and nasal or buccal routes for administering midazolam is needed, as is more research to determine the next step when first-line treatment fails, including the possible usefulness of combinations of medications and neuroprotective agents. Finally, seizure anticipation or warning systems are under development that may allow abortive treatment—perhaps in an automated manner—even before clinical seizure activity occurs. Thus, the future of care for seizure emergencies is quite bright. The study reported by Silbergleit and colleagues is an important step in this direction. As soon as a practical intramuscular autoinjector for midazolam becomes widely available, the findings in this study should lead to a systematic change in the way patients in status epilepticus are treated en route to the hospital.” (L. J. Hirsch)
Semuloparin Thromboprophylaxis in Chemotherapy: Compared with placebo, the ultra-low-molecular-weight heparin semuloparin reduced the incidence of thromboembolic events in patients receiving chemotherapy for cancer (pp. 601–9). Patients had metastatic or locally advanced solid tumors and were beginning chemotherapy when they were randomized to subcutaneous semuloparin 20 mg once daily or placebo until there was a change of chemotherapy regimen. Results showed: “The median treatment duration was 3.5 months. Venous thromboembolism occurred in 20 of 1,608 patients (1.2%) receiving semuloparin, as compared with 55 of 1,604 (3.4%) receiving placebo (hazard ratio, 0.36; 95% confidence interval [CI], 0.21 to 0.60; P < 0.001), with consistent efficacy among subgroups defined according to the origin and stage of cancer and the baseline risk of venous thromboembolism. The incidence of clinically relevant bleeding was 2.8% and 2.0% in the semuloparin and placebo groups, respectively (hazard ratio, 1.40; 95% CI, 0.89 to 2.21). Major bleeding occurred in 19 of 1589 patients (1.2%) receiving semuloparin and 18 of 1583 (1.1%) receiving placebo (hazard ratio, 1.05; 95% CI, 0.55 to 1.99). Incidences of all other adverse events were similar in the two study groups.” (G. Agnelli, agnellig@unipg.it)

>>>PNN NewsWatch
* A counterfeit version of Avastin 400 mg/16 mL containing no active ingredient (bevacizumab) is in distribution in the U.S., FDA warned yesterday. Some medical practices may have purchased the fake product, which displays batch numbers B6010, B6011 or B86017.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 17, 2012 * Vol. 19, No. 33
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Feb. Journal of the American Geriatrics Society (2012; 60).
Vitamin D Supplementation in Kidney Dysfunction: In 403 frail older women in Japanese nursing homes with poor renal function, low levels of 25-hydroxy-vitamin D3 [25(OH)D3] and high intact parathyroid hormone (intact PTH) indicated poor vitamin D–activating capacity and possible need for cholecalciferol supplementation, a study concludes (pp. 251–5). The nursing homes residents, with a mean age of 86.5 years, had these clinical values while participating in a clinical trial of hip protectors: “25(OH)D3, which is thought to reflect vitamin D status in the body, was surveyed and found to have a mean value of 16.7 ng/mL. 25(OH)D3 was less than 16 ng/mL in 49.1% of all participants. Creatinine clearance (CCr) was less than 30 mL/min in 20.1% of participants. Participants with serum 25(OH)D3 less than 16 ng/mL and CCr less than 30 mL/min had significantly higher levels of intact PTH and serum [cross-linked N-telopeptide of type I collagen]. Participants with a CCr less than 30 mL/min had significantly lower levels of 1,25(OH)2D3.” (Y. Terabe, yst-trb@ncgg.go.jp)
Need for Vitamin D Treatment of Prefrailty: In the Invecchiare in Chianti (InCHIANTI) study, adults aged 65 and older recovered from prefraility when treated with supplements of vitamin D, researchers report, but those who had advanced into frailty before supplements were given did not (pp. 256–64). In Tuscany, 1,155 patients were studied prospectively. Serum 25-hydroxyvitamin D [25(OH)D] concentrations, frailty state, and vital status were as follows at 3 and 6 years after enrollment: “The median (interquartile range) 25(OH)D concentration was 16.0 ng/mL (10.4–25.6 ng/mL; multiply by 2.496 to convert to nmol/L). Prefrail participants with 25(OH)D levels less than 20 ng/mL were 8.9% (95% confidence interval (CI) = 2.5–15.2%) more likely to die, 3.0% (95% CI = −5.6–14.6%) more likely to become frail, and 7.7% (95% CI = −3.5–18.7%) less likely to become robust than prefrail participants with 25(OH)D levels of 20 ng/mL or more. In prefrail participants, each 5-ng/mL decrement of continuous 25(OH)D was associated with 1.46 times higher odds of dying (95% CI = 1.18–2.07) and 1.13 higher odds of incident frailty (95% CI = 0.90–1.39) than with recovery of robustness. Transitions from robustness or frailty were not associated with 25(OH)D levels.” (M. Shardell, mshardel@epi.umaryland.edu)

>>>Allergy/Immunology Report
Source:
Feb. issue of the Journal of Allergy and Clinical Immunology (2012; 129).
Fungi & Allergic Lower Respiratory Tract Diseases: In a review article, authors examine the relationship between fungal exposure and allergies of the lower respiratory tract (pp. 280–91): “Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation.… The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain TH2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.” (A. P. Knutsen, knutsenm@slu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 21, 2012 * Vol. 19, No. 34
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Early-release article from Lancet (2012; 379).
Pharmacist-Led Information Technology Intervention for Medication Errors: In the primary care setting in the U.K., a pharmacist-led information technology intervention (PINCER) that used feedback, educational outreach, and dedicated support was superior to computer-generated simple feedback for reducing a range of medication errors, researchers report (doi: 10.1016/S0140-6736(11)61817-5). The system relied on computerized systems in general practices to permit pharmacists to review patients’ medical records. Interventions included discussions with family doctors to decide on actions to be taken; invitation of patients to be reviewed or to have blood tests; and working with members of the practice team to improve local safety systems. Results showed: “72 general practices with a combined list size of 480,942 patients were randomised. At 6 months’ follow-up, patients in the PINCER group were significantly less likely to have been prescribed a non-selective NSAID if they had a history of peptic ulcer without gastroprotection (OR 0.58, 95% CI 0.38–0.89); a beta blocker if they had asthma (0.73, 0.58—0.91); or an ACE inhibitor or loop diuretic without appropriate monitoring (0.51, 0.34–0.78). PINCER has a 95% probability of being cost effective if the decision-maker’s ceiling willingness to pay reaches £75 per error avoided at 6 months.” (A. J. Avery, tony.avery@nottingham.ac.uk)

>>>Internal Medicine Report
Source:
Feb. 21 issue of the Annals of Internal Medicine (2012; 156).
New Protease Inhibitors for Chronic Hepatitis C: For treating patients with advanced fibrosis associated with chronic hepatitis C virus infection, universal triple therapy and interleukin-28B–guided triple therapy are cost effective when the least expensive protease inhibitor is used, a study shows (pp. 279–90). Using a lifetime horizon and societal perspective, cost-effectiveness analysis shows these results when patients with CC genotypes received standard therapy and those with non-CC types were given triple therapy: “For patients with mild and advanced fibrosis, universal triple therapy reduced the lifetime risk for hepatocellular carcinoma by 38% and 28%, respectively, and increased quality-adjusted life expectancy by 3% and 8%, respectively, compared with standard therapy. Gains from IL-28B–guided triple therapy were smaller. If the protease inhibitor costs $1,100 per week, universal triple therapy costs $102,600 per [quality-adjusted life–year (QALY)] (mild fibrosis) or $51,500 per QALY (advanced fibrosis) compared with IL-28B–guided triple therapy and $70,100 per QALY (mild fibrosis) and $36,300 per QALY (advanced fibrosis) compared with standard therapy.” In sensitivity analysis, the authors found that the results were influenced by costs of protease inhibitors and rates of treatment adherence. (S. Liu)

>>>PNN NewsWatch
* FDA has approved mifepristone under the brand name Korlym (Corcept Therapeutics) for controlling blood glucose levels in adults with endogenous Cushing’s syndrome who have type 2 diabetes or glucose intolerance and are not candidates for surgery or who have not responded to prior surgery. The agent works by blocking the binding of cortisol to its receptor. Because of the drug’s abortifacient effects, its use for this indication is contraindicated in pregnant women. Korlym will be distributed only through a restricted system involving a central pharmacy.

>>>PNN JournalWatch
* New Anemia Therapies: Translating Novel Strategies from Bench to Bedside, in
American Journal of Kidney Diseases, 2012; 59: 444–51. (I. Macdougall, iain.macdougall@nhs.net)
* Managing Older Adults with CKD: Individualized Versus Disease-Based Approaches, in
American Journal of Kidney Diseases, 2012; 59: 293–302. (A. M. O’Hare, ann.ohare@va.gov)
* Discussions About Treatment Restrictions in Chronic Neurologic Diseases: A Structured Review, in
Neurology, 2012; 78: 590–7. (A. A. Seeber, a.a.seeber@amc.uva.nl)
* Pharmacologic and Compression Therapies for Postthrombotic Syndrome: A Systematic Review of Randomized Controlled Trials, in
Chest, 2012; 141: 308–20. (S. R. Kahn, susan.kahn@mcgill.ca)
* Are Either or Both Hyperuricemia and Xanthine Oxidase Directly Toxic to the Vasculature? A Critical Appraisal, in
Arthritis & Rheumatism, 2012; 64: 327–38. (R. A. Terkeltaub, rterkeltaub@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 © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 22, 2012 * Vol. 19, No. 35
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 22 issue of JAMA (2012; 307).
Pneumococcal Vaccination Strategies: In a pharmacoeconomic modeling study, 13-valent pneumococcal conjugate vaccine (PCV13) was more cost-effective than 23-valent pneumococcal polysaccharide vaccine (PPSV23), researchers report (pp. 804–12). The analysis, which assumed baseline cohorts of U.S. adults aged 50 years, “was sensitive to assumptions about PCV13 effectiveness against nonbacteremic pneumococcal pneumonia and the magnitude of potential indirect effects from childhood PCV13 on pneumococcal serotype distribution,” the authors add. A Markov state-transition model, lifetime horizon, and societal perspective were used in the study, and the primary outcome measures were pneumococcal disease cases prevented and incremental costs per quality-adjusted life–year (QALY) gained: “In the base case scenario, administration of PCV13 as a substitute for PPSV23 in current recommendations (ie, vaccination at age 65 years and at younger ages if comorbidities are present) cost $28,900 per QALY gained compared with no vaccination and was more cost-effective than the currently recommended PPSV23 strategy. Routine PCV13 at ages 50 and 65 years cost $45,100 per QALY compared with PCV13 substituted in current recommendations. Adding PPSV23 at age 75 years to PCV13 at ages 50 and 65 years gained 0.00002 QALYs, costing $496,000 per QALY gained. Results were robust in sensitivity analyses and alternative scenarios, except when low PCV13 effectiveness against nonbacteremic pneumococcal pneumonia was assumed or when greater childhood vaccination indirect effects were modeled. In these cases, PPSV23 as currently recommended was favored.” (K. J. Smith, smithkj2@upmc.edu)
“Policy makers likely will need to decide whether to recommend a change in the strategy for immunization of adults in the absence of definitive data on all values that contribute to analysis of the potential cost-effectiveness of a change in policy,” an editorialist writes (
pp. 847–9). “The analyses by Smith et al provide a reasonable framework with which to approach this issue. However, if recommendations are made to switch to PCV13 for adults, the degree to which subsequent decreases in rates of both invasive pneumococcal infections and NPP among adults are due to a switch to PCV13 for adults or to the already implemented administration of PCV13 to children might never be known. What does seem clear is that improvements in vaccines against pneumococci and increased rates of immunization likely will result in continued reductions in the incidence of infections due to this common pathogen.” (E. D. Shapiro, eugene.shapiro@yale.edu)
The Constitution & Prescriber-Identified Pharmacy Data: The heightened judicial scrutiny used by the U.S. Supreme Court in the Sorrell v IMS Health case could be problematic as cases involving FDA move forward, the a Viewpoint author writes (pp. 787–8): “A federal court recently found, for example, that the US Food and Drug Administration may have violated the First Amendment by requiring graphic images on tobacco packaging. The Supreme Court, moreover, has already used heightened scrutiny to invalidate California’s ban on violent video games to deter youth violence.” (L. O. Gostin, gostin@law.georgetown.edu)

>>>PNN NewsWatch
* Responding to a critical shortage of Doxil (doxorubicin hydrochloride liposome injection) and rapidly declining supplies of methotrexate, FDA yesterday allowed temporary importation of a replacement drug, Lipodox, and expedited approval of a new manufacturer for preservative-free methotrexate. FDA said its exercise of enforcement discretion for Lipodox is a temporary, limited arrangement specific to Sun Pharma Global FZE and its authorized distributor, Caraco Pharmaceutical Laboratories Ltd. Like Doxil, Lipodox can be used for treatment of ovarian cancer after failure of platinum-based chemotherapy and in AIDS-related Kaposi’s sarcoma and multiple myeloma. The preservative-free methotrexate product is manufactured by APP Pharmaceuticals and should be available in March. FDA also said that Hospira has expedited release of additional methotrexate, with 31,000 vials shipping yesterday. FDA is also working to increase supplies through other manufacturers of methotrexate, including Mylan and Sandoz Pharmaceuticals.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 23, 2012 * Vol. 19, No. 36
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 23 issue of the New England Journal of Medicine (2012; 366).
Vemurafenib in Advanced Melanoma: More than half of patients with previously treated BRAF V600–mutant metastatic melanoma had clinical responses to vemurafenib, and overall median survival time was 16 months, a Phase II trial shows (pp. 707–14). Vemurafenib 960 mg orally twice daily was administered until the development of unacceptable toxic effects or disease progression. Results showed: “A total of 132 patients had a median follow-up of 12.9 months (range, 0.6 to 20.1). The confirmed overall response rate was 53% (95% confidence interval [CI], 44 to 62; 6% with a complete response and 47% with a partial response), the median duration of response was 6.7 months (95% CI, 5.6 to 8.6), and the median progression-free survival was 6.8 months (95% CI, 5.6 to 8.1). Primary progression was observed in only 14% of patients. Some patients had a response after receiving vemurafenib for more than 6 months. The median overall survival was 15.9 months (95% CI, 11.6 to 18.3). The most common adverse events were grade 1 or 2 arthralgia, rash, photosensitivity, fatigue, and alopecia. Cutaneous squamous-cell carcinomas (the majority, keratoacanthoma type) were diagnosed in 26% of patients.” (J. A. Sosman, jeff.sosman@vanderbilt.edu)
Genomics & Intellectual Disability: Rapid advances in genetic research have quickly led to greater understanding of autism and other intellectual disabilities, authors of a review article report (pp. 733–43): “Chromosome microarrays and next-generation sequencing have revolutionized gene discovery in intellectual disability, autism, and other disorders. Chromosome microarray analysis, which is recommended as a first-line test in the genetic workup of children with intellectual disability, developmental delays, autism, or congenital anomalies, provides a molecular diagnosis in 15 to 20% of cases. Exome sequencing has proved to be successful in the research laboratory and is moving rapidly into the diagnostic laboratory. As the data continue to accumulate, our understanding of genes, pathways, and molecular mechanisms will continue to evolve and translate into better diagnosis, prognosis, and therapies for these severe disorders.” (H. C. Mefford, hmefford@u.washington.edu)

>>>PNN NewsWatch
* RxAlly, an alliance of more than 20,000 pharmacies nationwide, was launched yesterday at a press event in Washington, DC. Headed by former NCPA CEO Bruce Roberts, RxAlly will contract with payers and reimburse member pharmacies for delivery of patient-centric services that have been shown to optimize health outcomes. RxAlly members include Walgreens, which brings 7,800 locations into the alliance, several regional chains that are members of the Chain Drug Consortium (Bartell Drugs, Discount Drug Mart, Kerr Drug, Kinney Drugs, Lewis, Navarro Discount Pharmacy, Thrifty White Pharmacy, and USA Drug), and several groups of independent pharmacies (Academy of Independent Pharmacy of Georgia, American Associated Pharmacies, American Pharmacies, American Pharmacy Cooperative, Carolina Allied Pharmaceutical Services, EPIC Pharmacies, Independent Pharmacy Cooperative, and PBA Health).
* For a
Supreme Court that will be taking on cases involving many of the most controversial political and social issues of our time in the coming weeks and months, yesterday’s 5–4 split over the relatively simple legal questions involved in a California Medicaid case could be a harbinger of split decisions to come. In Douglas v. California Pharmacists Association (and related cases), the Court’s progressive wing joined with swing-vote Anthony M. Kennedy to remand the case back to the Ninth Circuit for further deliberation. The central constitutional question—whether the Supremacy Clause allows private citizens to sue states over reductions in Medicaid reimbursement inconsistent with federal Medicaid law—is left to the lower court to consider, reports the website SCOTUSblog. The majority left the door open to legal challenges brought under the Administrative Procedure Act. Chief Justice John G. Roberts, Jr., and the rest of the Court’s conservative wing dissented strongly, arguing that federal law provides no right to sue over such reductions in Medicaid payments.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 24, 2012 * Vol. 19, No. 37
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (2012; 35).
Attitudes & Drug-Free Remission in Newly Diagnosed Type 2 Diabetes: Success in achieving long-term remission of newly diagnosed type 2 diabetes through use of continuous insulin is affected by patient attitudes, a study shows (pp. 474–81). Continuous subcutaneous insulin infusion (CSII) for 2–3 weeks has been shown to improve beta-cell function and insulin sensitivity, and this can produce long-term remission without need for further antidiabetic medications. In this trial, newly diagnosed patients with type 2 diabetes received such an infusion and were invited to complete a Diabetes Care Profile (DCP) tool at baseline and at months 3, 6, and 12. Results showed: “Near normoglycemia was achieved by 118 patients after short-term CSII, with 65 remaining in drug-free remission for >1 year. They had significantly better glycemic control and greater restoration of acute insulin response after CSII as well as higher educational attainment compared with patients experiencing relapse. They also achieved higher scores in positive attitude, (belief in) importance of care, care ability, self-care adherence, and less negative attitude. Differences between the two groups became greater over time. Cox proportional hazards model analysis indicated that greater self-care adherence (hazard ratio 0.184, P < 0.001) and homeostasis model assessment of insulin resistance before treatment (0.854, P = 0.053) were independent predictors for long-term remission, whereas elevated 2-h postprandial plasma glucose after CSII (1.156, P = 0.015) was a risk factor for relapse.” (Y. Li, easd04lyb@126.com)
Taspoglutide Monotherapy in Drug-Naive Type 2 Diabetes: In a Phase III trial, once-weekly taspoglutide improved glycemic control, reduced body weight, and was generally well tolerated, compared with placebo (pp. 485–7). The 24-week study included 373 participants with previously untreated type 2 diabetes. Weekly subcutaneous taspoglutide 10 or 20 mg or placebo produced these results: “HbA1c reductions from baseline were greater with taspoglutide 10 and 20 mg than placebo (least squares mean [SE] changes: –1.01% [0.07], –1.18% [0.06], and –0.09% [0.07], respectively; both P < 0.0001 vs. placebo). Decreases in bodyweight were greater with taspoglutide 10 mg (–1.45 kg [0.32]) and with 20 mg (–2.25 kg [0.30]) than placebo (–1.23 kg [0.31]; P = 0.61 and P = 0.02 for taspoglutide 10 and 20 mg vs. placebo, respectively). Gastrointestinal adverse events and injection site reactions were more common with taspoglutide than placebo.” (I. Raz, ntv502@netvision.net.il)
Newly Initiated Insulin Therapy in Type 2 Diabetes: In an analysis of 1,139 patients with type 2 diabetes who started insulin therapy during an 18-month period in 2009–10, intervening at lower levels of A1C was associated with improved goal attainment and independent increases in glycemic response (pp. 495–7): “Mean A1C at insulin initiation was 8.2 vs. 9.2% among those who did and did not attain A1C <7% (P < 0.001). Within a mean of 5 months, 464 (40.7%) patients attained A1C <7%. In multivariable analyses controlling for insulin regimen, dose, and oral agent use, preinsulin A1C was responsible for nearly all the explained variance in A1C change. Each one percentage point of preinsulin A1C reduced the probability of attaining <7% by 26% (odds ratio 0.74 [95% CI 0.68–0.80]).” (G. A. Nichols, greg.nichols@kpchr.org)
Coronary Artery Calcium Testing for Guiding Aspirin Use: Coronary artery calcium (CAC) testing may be useful in determining which patients with diabetes should take low-dose aspirin for primary prevention, researchers report (pp. 624–6). In 2,384 individuals with diabetes who were referred for CAC testing, these patterns were observed over a mean of 5.6 years of follow-up and assessed using an end point of all-cause mortality: “There were 162 deaths (6.8%) in the population. CAC was a strong predictor of mortality across age-groups (age <50, 50–59, ≥60), sex, and risk factor burden (0 vs. ≥1 additional risk factor). In individuals without a clear indication for aspirin per current guidelines, CAC stratified risk, identifying patients above and below the 10% risk threshold of presumed aspirin benefit.” (K. Nasir, knasir1@jhmi.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 27, 2012 * Vol. 19, No. 38
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 25 issue of Lancet (2012; 379).
Stem Cells for Macular Degeneration: In the first report of transplantation of human embryonic stem cells (hESCs) into people, subretinal placement of hESC-derived retinal pigment epithelium (RPE) into patients with Stargardt’s macular dystrophy and dry age-related macular degeneration was safe and tolerable, researchers report (pp. 713–20). Preoperative and postoperative ophthalmic examinations showed these oucomes in two prospective clinical trials: “Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt’s macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).” (S. D. Schwartz, schwartz@jsei.ucla.edu)
Lithium Toxicity Profile: Based on 385 studies identified through a systematic review and assessed in a meta-analysis, the toxicity profile of lithium is further elucidated (pp. 721–8): “On average, glomerular filtration rate was reduced by −6.22 mL/min (95% CI −14.65 to 2.20, p = 0.148) and urinary concentrating ability by 15% of normal maximum (weighted mean difference −158.43 mOsm/kg, 95% CI −229.78 to −87.07, p < 0.0001). Lithium might increase risk of renal failure, but the absolute risk was small (18 of 3,369 [0.5%] patients received renal replacement therapy). The prevalence of clinical hypothyroidism was increased in patients taking lithium compared with those given placebo (odds ratio [OR] 5.78, 95% CI 2.00–16.67; p = 0.001), and thyroid stimulating hormone was increased on average by 4.00 iU/mL (95% CI 3.90–4.10, p < 0.0001). Lithium treatment was associated with increased blood calcium (+0.09 mmol/L, 95% CI 0.02–0.17, p=0.009), and parathyroid hormone (+7.32 pg/mL, 3.42–11.23, p < 0.0001). Patients receiving lithium gained more weight than did those receiving placebo (OR 1.89, 1.27–2.82, p = 0.002), but not those receiving olanzapine (0.32, 0.21–0.49, p < 0.0001). We recorded no significant increased risk of congenital malformations, alopecia, or skin disorders.” (J. R. Geddes, john.geddes@psych.ox.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Nursing Home Resident Mortality & Antipsychotic Drugs: Additional evidence of an increased risk of mortality in older patients who are taking antipsychotic agents comes from a study of U.S. nursing homes (e977). Among 75,445 new users of the drugs, these patterns were evident in 2001–05: “Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.” (K. F. Huybrechts, khuybrechts@partners.org)

>>>PNN JournalWatch
* Deepening Drug Shortages, in
Health Affairs, 2012; 31: 263–6. (D. Wilson, duffwilson@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 28, 2012 * Vol. 19, No. 39
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Feb. 27 issue of the Archives of Internal Medicine (2012; 172).
Telephonic Motivational Interviewing for Osteoporosis Medication Adherence: In a 1-year trial of 1,046 patients receiving newly prescribed medications for osteoporosis, motivational interviewing delivered by telephone did not improve adherence rates over those observed in control patients who received mailed educational materials, researchers report (doi: 10.1001/archinternmed.2011.1977). All study participants received 7 mailings on topics such as exercise, fall prevention, and recommendations for calcium intake. Those in the motivational interviewing group also received telephone conferences 1–2 times per month with a behavioral scientist and clinical expert. Results showed: “The groups were balanced at baseline, with a mean age of 78 years; 93.8% were female. In an intention-to-treat analysis, median adherence was 49% (interquartile range, 7%–88%) in the intervention arm and 41% (2%–86%) in the control arm (P = .07, Kruskal–Wallis test). There were no differences in self-reported fractures.” (D. H. Solomon, dsolomon@partners.org)
“Motivating behavioral change has become a core competency for clinicians,” editorialists write (
doi: 10.1001/archinternmed.2012.155). They conclude: “Strategies to induce behavior change, including motivational interviewing, peer health counselors, and automated technology-based systems such as text messages, all show promise. Future interventions must be informed by evidence and experience. Findings from well-performed, pragmatic trials, such as the one undertaken by Solomon et al, will help us to identify where motivational interviewing is applicable, the features that are efficacious, and those that are not. This study and others provide data that can help us—and our patients—do better.” (S. A. Berkowitz, Seth.Berkowitz@ucsf.edu)
Positive-Affect Intervention & Hypertension Medication Adherence: Compared with patient education (PE) alone, a positive-affect induction and self-affirmation (PA) approach was more effective for improving adherence to antihypertensive medications but not for reducing blood pressure (BP) among 256 blacks with hypertension, a study shows (pp. 322–6). In 2 primary care practices, patients received a culturally tailored hypertension self-management workbook, a behavioral contract, and bimonthly telephone calls designed to help them overcome barriers to medication adherence. Those in the intervention group also received small gifts and bimonthly telephone calls to help them incorporate positive thoughts into their daily routine and foster self-affirmation. Investigators report these outcomes: “The baseline characteristics were similar in both groups: the mean BP was 137/82 mm Hg; 36% of the patients had diabetes; 11% had stroke; and 3% had chronic kidney disease. Based on the intention-to-treat principle, medication adherence at 12 months was higher in the PA group than in the PE group (42% vs 36%, respectively; P = .049). The within-group reduction in systolic BP (2.14 mm Hg vs 2.18 mm Hg; P = .98) and diastolic BP (–1.59 mm Hg vs –0.78 mm Hg; P = .45) for the PA group and PE group, respectively, was not significant.” (G. O. Ogedegbe, Olugbenga.Ogedegbe@nyumc.org)
Reflecting on this and a second study that used ultrasonographic images of plaque to motivate patients to stop smoking (
pp. 329–36; J. C. Peterson, jcpeters@med.cornell.edu), editorialists write that a “picture” is not always enough to get patients to change unhealthy behaviors (doi: 10.1001/archinternmed.2011.1948): “The secret in motivating patients may be in the caring. We should seek to study and improve the efficacious constructs of such caring first before we resort to expensive testing technologies as a short cut. There are no simple solutions to motivating patients. A picture may be worth a thousand words, but relationships move mountains when it comes to transformative personal change. For motivating patients toward optimal health behaviors, we should direct our focus of clinical care processes and research onto the complex human relationship dimensions and away from the allure of simple ‘pictures’ to circumvent what is really hard work to be done by both patients and physicians.” (P. G. O’Malley, pomalley@usuhs.mil)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Feb. 29, 2012 * Vol. 19, No. 40
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Mar. issue of Pharmacotherapy (2012; 32).
Treatment Effect of Hormonal Emergency Contraceptives: Published data on the effectiveness of hormonal emergency contraception can be misleading because placebo controls have never been used and baseline pregnancy risk is often ignored, researchers report (pp. 210–21). Based on analysis of pooled data from 34 studies of pregnancy outcomes with the Yuzpe or levonorgestrel emergency contraceptive regimens, the investigators found: “The pooled observed pregnancy rates for studies of the Yuzpe and levonorgestrel regimens were 2.0% (95% confidence interval [CI] 1.5–2.5%) and 1.7% (95% CI 1.2–2.2%), respectively. Against expected pregnancy rates of 4–8%, relative emergency contraceptive effectiveness ranges were 50.0–75.0% and 57.5–78.8% for the Yuzpe and levonorgestrel regimens, respectively. Absolute risk reductions were 2.0–6.0% and 2.3–6.3%, respectively. This means that 17–50 women would need to have received the Yuzpe regimen and 16–43 women the levonorgestrel regimen to prevent one pregnancy.” (M. Levine, levine@mail.ubc.ca)
Pharmacist Care in Dyslipidemia: In 21 studies, care of patients with dyslipidemia by pharmacists yielded these outcomes (pp. 222–33): “The mean LDL level was 10.7 mg/dl lower in the enhanced pharmacy care groups compared with the standard care groups (95% confidence interval [CI] –16.9 to –4.6 mg/dl), with moderate heterogeneity. The mean total cholesterol level was significantly lower in the enhanced pharmacy care groups compared with the standard care groups; however, these results were highly heterogeneous. Patients who received enhanced pharmacist care were also more likely than those receiving standard care to achieve target lipid parameters (odds ratio [OR] 2.46, 95% CI 1.43–4.25) and to have a lipid panel ordered or recommended by a pharmacist during the study (OR 2.05, 95% CI 1.30–3.24). Patients in the pharmacist intervention groups were almost twice as likely as patients in the standard care groups to have a change in lipid-lowering therapy (OR 1.82, 95% CI 1.09–3.06). Adherence data could not be analyzed.” (R. T. Tsuyuki, ross.tsuyuki@ualberta.ca)

>>>JAPhA Highlights
Source:
Mar./Apr. issue of the Journal of the American Pharmacists Association, a theme issue on reimbursement for medication therapy management services (2012; 52).
Outpatient Pharmacy Services & Billing: Billing techniques and reimbursement for medication therapy management (MTM) services are inconsistent, according to a cross-sectional study conducted in Feb. 2011 among members of relevant APhA, ASHP, and ACCP sections and networks (pp. 154–60). Responding to an online survey, members provided this information about their practice settings, pharmacy services performed, billing technique, and payers, as well as reasons for not billing: “MTM services were provided by 287 pharmacists. The most common practice settings included physician office (23.6%), health-system outpatient facility (21.7%), and community pharmacy (20.2%). A total of 149 of 276 pharmacists (54.0%) reported billing for MTM services; 16 of 276 (5.8%) did not know if they were currently billing. Community pharmacists were more likely to bill than all other sites combined (80.5% vs. 53.1%, P < 0.001), and pharmacists with >75% of visits face-to-face were more likely to bill (66.2% vs. 46.6%, P < 0.002).” (S. J. Beatty, beatty.52@osu.edu)

>>>PNN NewsWatch
* Elimination of routine hepatic monitoring and addition of warnings about cognitive dysfunction and hyperglycemia were among the classwide changes announced yesterday for statins by FDA. Drug interactions involving lovastatin were also added to that product’s labeling, including ones with protease inhibitors and certain antibacterial and antifungal agents. The agency said that “serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing this rare side effect.” Statins may also cause cognitive effects such as memory loss and confusion; these are generally reversible on drug discontinuation. New warnings for statins also note a small increased risk of becoming hyperglycemic or being diagnosed with type 2 diabetes while on the drugs.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 1, 2012 * Vol. 19, No. 41
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 1 issue of the New England Journal of Medicine (2012; 366).
Nicotine Replacement in Pregnancy: Added to behavioral therapy in women who were smoking during pregnancy, nicotine-replacement therapy neither provided benefits nor worsened outcomes, a U.K. study shows (pp. 787–98). All 1,050 study participants received behavioral cessation support and were randomly assigned to placebo or nicotine (15 mg/16 h) patches, with these results: “There was no significant difference in the rate of abstinence from the quit date until delivery between the nicotine-replacement and placebo groups (9.4% and 7.6%, respectively; unadjusted odds ratio with nicotine-replacement therapy, 1.26; 95% confidence interval, 0.82 to 1.96), although the rate was higher at 1 month in the nicotine-replacement group than in the placebo group (21.3% vs. 11.7%). Compliance was low; only 7.2% of women assigned to nicotine-replacement therapy and 2.8% assigned to placebo used patches for more than 1 month. Rates of adverse pregnancy and birth outcomes were similar in the two groups.” (C. Harrison, claire.harrison@gstt.nhs.uk)
“Although placebo-controlled trials of nicotine-replacement therapy in pregnancy have been negative, two randomized but not placebo-controlled studies of the effectiveness of nicotine-replacement therapy in pregnant smokers showed that nicotine replacement increased quit rates,” writes an editorialist (
pp. 846–7). “In one of these studies, adherence to therapy was reported to be a predictor of treatment response. The behavioral counseling in these studies was relatively intensive, in terms of the length of the initial counseling visit and the number of subsequent visits, which may have influenced the response rates to medication.” (C. Oncken)
JAK Inhibitor Therapy for Myeloproliferative Neoplasm: Data from two pivotal Phase III trials and an editorial examine use of ruxolitinib, a recently approved drug (see PNN, Nov. 17), for intermediate-2 and high-risk myelofibrosis.
Among 219 patients, oral ruxolitinib was effective in 28% of patients, compared with none of those receiving best available alternatives (
pp. 787–98). The new drug produced marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. Overall survival was not changed. (C. Harrison, claire.harrison@gstt.nhs.uk)
In a second trial, 41.9% of patients on ruxolitinib and 0.7% of patients in the placebo group reached a primary end point of 35% reduction in spleen volume at 24 weeks (
pp. 799–807; S. Verstovsek, sverstov@mdanderson.org).
An editorialist writes (
pp. 844–6): “What happened with ruxolitinib therapy in patients with myelofibrosis was somewhat unexpected (i.e., a primarily anticytokine rather than selective anticlonal effect) but has arguably broadened our insight regarding the pathogenetic role of the paraneoplastic features of the disease, including the possible contribution of cytokines or JAK–STAT to splenic extramedullary hematopoiesis. However, transient palliation of symptoms should not be confused with the primary goal of molecularly targeted cancer therapy, which is to eradicate or suppress the neoplastic clone. Given its presumed mechanism of action, ruxolitinib is unlikely to secure disease modification, but it is an important addition to the current armamentarium of palliative drugs in myelofibrosis. Approximately 30% of patients with myelofibrosis present with ruxolitinib-sensitive symptoms, and the drug might be useful in a fraction of these patients who are not candidates for allogeneic stem-cell therapy or for clinical trials of potentially better drugs, including newer and more selective JAK inhibitors.” (A. Tefferi)

>>>PNN NewsWatch
* FDA yesterday licensed the first quadrivalent influenza vaccine, FluMist Quadrivalent (MedImmune). All other currently marketed influenza vaccines are trivalent, containing two type A strains and one type B strain. The quadrivalent product contains the two type A strains (A/H1N1 and A/H3N2) as well as B/Yamagata and B/Victoria strains. These have been circulating during recent influenza seasons, according to a company news release that cited CDC data. The vaccine is approved for use in children and adults ages 2 to 49 years of age.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 2, 2012 * Vol. 19, No. 42
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Mar. issue of Pediatrics (2012; 129).
Infantile Colic After in Utero Nicotine Exposure: In a cohort study, infants exposed to nicotine replacement therapy (NRT) or smoking during pregnancy were significantly more likely to have infantile colic at 6 months of age, and the risks were statistically similar with NRT as with smoking (e652–8). Data from maternal interviews during pregnancy and at 6 months postpartum, recorded in the Danish National Birth Cohort in 1996–2002, showed these associations for 63,128 live-born singleton infants: “A total of 46,660 infants (73.9%) were unexposed to nicotine during pregnancy; 207 (0.3%) were exposed to NRT, 15,016 (23.8%) were exposed to smoking, and 1,245 (2.0%) to both. A total of 4,974 (7.9%) infants fulfilled Wessel’s modified criteria for infantile colic. Prenatal nicotine exposure was associated with elevated risk for infantile colic in the offspring. Compared with the unexposed, NRT users had an adjusted odds ratio (OR) (95% confidence interval) of 1.6 (1.0–2.5; P = .03), smokers had OR = 1.3 (1.2–1.4), and women who both smoked and used NRT had OR = 1.6 (1.3–1.9). Partners’ smoking was not associated with infantile colic after adjustment for maternal smoking.” (I. Milidou)
Vitamin D & Cognitive Development: Babies born to mothers with low vitamin D levels during pregnancy are more likely to have language impairment at 5 and 10 years of age, researchers report (pp. 485–93). In 743 white women in Western Australia, serum 25(OH)-vitamin D concentrations were measured at 18 weeks’ gestation. The Child Behavior Checklist was used at 6 points between 2 and 17 years of age of offspring. Results showed: “Chi-square analyses revealed no significant associations between maternal 25(OH)-vitamin D serum quartiles and offspring behavioral/emotional problems at any age. In contrast, there were significant linear trends between quartiles of maternal vitamin D levels and language impairment at 5 and 10 years of age. Multivariate regression analyses, incorporating a range of confounding variables, found that the risk of women with vitamin D insufficiency (≤46 nmol/L) during pregnancy having a child with clinically significant language difficulties was increased close to twofold compared with women with vitamin D levels >70 nmol/L.” (A. J. O. Whitehouse)
Nursing Case Management in Asthma: Improved health outcomes resulted from nursing-based comprehensive care to low-income patients with asthma (pp. 465–72). In four urban ZIP Codes, nurse case management and home visits targeted patients with high rates of emergency department (ED) and hospital admissions, with these results: “The program provided services to 283 children. Participants were 55.1% male; 39.6% African American, 52.3% Latino; 72.7% had Medicaid; 70.8% had a household income <$25,000. Twelve-month data show a significant decrease in any (≥1) asthma ED visits (68.0%) and hospitalizations (84.8%), and any days of limitation of physical activity (42.6%), patient missed school (41.0%), and parent missed work (49.7%) (all P < .0001). Patients with greatest functional impairment from ED visits, limitation of activity, and missed school were more likely to have any nurse home visit and greater number of home visits. There was a significant reduction in hospital costs compared with the comparison community (P < .0001), and a return on investment of 1.46.” (E. R. Woods)
Impact of Orphan Drug Act: A total of 38 orphan drugs with pediatric indications were approved during 2000–09, according to an analysis of internal FDA data (pp. 516–21). “The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second,” the authors write. “More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20,000 than for any other prevalence subgroup.” (C. Thorat)

>>>PNN NewsWatch
* FDA has approved two new pancrelipase products, Ultresa and Viokace, both from Aptalis Pharma U.S. Ultresa is a delayed-release capsule used to treat children and adults with cystic fibrosis. Viokace, in combination with a PPI, is used to treat adults who cannot digest food normally, including adults with chronic pancreatitis and those who have undergone pancreatectomy. Viokace’s safety and efficacy in children have not been established.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 5, 2012 * Vol. 19, No. 43
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 344).
Self-monitoring in Noninsulin-Treated Type 2 Diabetes: Clinically meaningful effects of self-monitoring of type 2 diabetes were not evident in a meta-analysis of 2,552 patients being treated with antidiabetic agents other than insulin (e486). Based on six trials published since 2000 and meeting inclusion criteria, the authors found: “A mean reduction in HbA1c level of −2.7 mmol/mol (95% confidence interval −3.9 to −1.6; 0.25%) was observed for those using self monitoring of blood glucose levels compared with no self monitoring at six months. The mean reduction in HbA1c level between groups was 2.0 mmol/mol (3.2 to 0.8; 0.25%) at three months (five trials) and 2.5 mmol/mol (4.1 to 0.9; 0.35%) at 12 months (three trials). These estimates were unchanged after imputing missing data, and estimates of effect in trials with higher loss to follow-up or a possibility of co-intervention compared with those with lower loss to follow-up and no co-intervention did not differ significantly (P = 0.21). The difference in HbA1c levels between groups was consistent across age, baseline HbA1c level, sex, and duration of diabetes, although the numbers of older and younger people and those with HbA1c levels >86 mmol/mol (10%) were insufficient for interpretation. No changes occurred in systolic blood pressure (−0.2 mm Hg, 95% confidence interval −1.4 to 1.0), diastolic blood pressure (−0.1 mm Hg, −0.9 to 0.6), or total cholesterol level (−0.1 mol/L, 95% confidence interval −0.2 to 0.1).” (A. Farmer, andrew.farmer@phc.ox.ac.uk)
Cost-effective Intervention Strategies for Cardiovascular Risk Factors: In resource-limited countries, interventions for preventing cardiovascular disease, diabetes, and tobacco-related disease can still be cost-effective, researchers report (e607). One of several articles in this issue that look at cost-effectiveness of prevention interventions in countries in sub-Saharan Africa with very high adult and high child mortality (AfrE) and countries in southeast Asia with high adult and high child mortality (SearD), this analysis found these effects of interventions on cost per disability-adjusted life–year (DALY) averted, expressed in international dollars ($Int) for 2005: “Most of the interventions studied were considered highly cost effective, meaning they generate one healthy year of life at a cost of <$Int2000 (which is the gross domestic product per capita of the two regions considered here). Interventions that offer particularly good monetary value, and which could be considered for prioritised implementation or scale up, include demand reduction strategies of the Framework Convention for Tobacco Control (<$Int950 and <$Int200 per DALY averted in AfrE and SearD respectively); combination drug therapy for people with a >25% chance of experiencing a cardiovascular event over the next decade, either alone or together with specific multidrug regimens for the secondary prevention of post-acute ischaemic heart disease and stroke (<$Int150 and <$Int230 per DALY averted in AfrE and SearD respectively); and retinopathy screening and glycaemic control for patients with diabetes (<$Int2100 and <$Int950 per DALY averted in AfrE and SearD respectively).” (M. Ortegón, monica.ortegon@urosario.edu.co)

>>>PNN JournalWatch
* Ductal Carcinoma in situ of the Breast, in
BMJ, 2012; 344: e797. (N. L. P. Barnes, nicolabarnes@doctors.org.uk)
* Life-Threatening Respiratory Pasteurellosis Associated with Palliative Pet Care, in
Clinical Infectious Diseases, 2012; 54: e55–7. (J. P. Myers, myersj@summahealth.org)
* Eczema Vaccinatum, in
Clinical Infectious Diseases, 2012; 54: 832–40. (J. L. Reed, jennifer.reed@fda.hhs.gov)
* Antipsychotics for Children and Young Adults: A Comparative Effectiveness Review, in
Pediatrics, 2012; 129: e771–84. (J. C. Seida)
* Platelet Biology and Response to Antiplatelet Therapy in Women: Implications for the Development and Use of Antiplatelet Pharmacotherapies for Cardiovascular Disease, in
Journal of the American College of Cardiology, 2012; 59: 891–900. (T. Y. Wang, tracy.wang@duke.edu)
* Cardiovascular Care in an Increasingly Diverse Community, in
Circulation, 2012; 125: 1037–42. (G. N. Graham, garth.graham@medicine.ufl.edu)
* Emerging Antiplatelet Therapy for Coronary Artery Disease and Acute Coronary Syndrome, in
Pharmacotherapy, 2012; 32: 244–73. (E. M. Davis, edavis@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 © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 6, 2012 * Vol. 19, No. 44
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Mar. 6 issue of the Annals of Internal Medicine (2012; 156).
Influenza Diagnosis, Treatment: Review articles consider the accuracy of rapid influenza diagnostic tests (RIDTs) and the role of antivirals in treatment of infections.
Influenza infections can be detected but not ruled out through use of RIDTs, according to a meta-analysis of available evidence (
early release): “There were 159 studies that evaluated 26 RIDTs, and 35% were conducted during the H1N1 pandemic. Failure to report whether results were assessed in a blinded manner and the basis for patient recruitment were important quality concerns. The pooled sensitivity and specificity were 62.3% (95% CI, 57.9% to 66.6%) and 98.2% (CI, 97.5% to 98.7%), respectively. The positive and negative likelihood ratios were 34.5 (CI, 23.8 to 45.2) and 0.38 (CI, 0.34 to 0.43), respectively. Sensitivity estimates were highly heterogeneous, which was partially explained by lower sensitivity in adults (53.9% [CI, 47.9% to 59.8%]) than in children (66.6% [CI, 61.6% to 71.7%]) and a higher sensitivity for influenza A (64.6% [CI, 59.0% to 70.1%) than for influenza B (52.2% [CI, 45.0% to 59.3%).” (C. Chartrand)
While the evidence overall is less than optimal, oral oseltamivir and inhaled zanamivir may be better than no treatment in patients with influenza infections, researchers report (
early release). A systematic review and meta-analysis of 74 articles provides these insights into utility of the antiviral agents: “Meta-analyses of the few studies providing effects with adjustment for confounders suggest that in high-risk populations, oral oseltamivir may reduce mortality (odds ratio, 0.23 [95% CI, 0.13 to 0.43]; low-quality evidence), hospitalization (odds ratio, 0.75 [CI, 0.66 to 0.89]; low-quality evidence), and duration of symptoms (33 hours [CI, 21 to 45 hours]; very low–quality evidence) compared with no treatment. Earlier treatment with oseltamivir was generally associated with better outcomes. Inhaled zanamivir may lead to shorter symptom duration (23 hours [CI, 17 to 28 hours]; moderate-quality evidence) and fewer hospitalizations (odds ratio, 0.66 [CI, 0.37 to 1.18]) but more complications than no treatment. Direct comparison of oral oseltamivir and inhaled zanamivir suggests no important differences in key outcomes. Data from 1 study suggests that oral amantadine may reduce mortality and pneumonia associated with influenza A. No included study evaluated rimantadine.” (J. Hsu)
Low-Dose Prednisone & Methotrexate for Early RA: Administered with a methotrexate (MTX)–based, tight-control strategy in patients with early rheumatoid arthritis (RA), low-dose prednisone improved patient outcomes, a study shows (pp. 329–39). At seven Dutch hospitals, 236 patients wit RA of less than 1 year duration received MTX with either prednisone or placebo, with these effects on radiograms: “Erosive joint damage after 2 years was limited and less in the group receiving MTX and prednisone (n = 117) than in the group receiving MTX and placebo (n = 119). The MTX and prednisone strategy was also more effective in reducing disease activity and physical disability, achieving sustained remission, and avoiding the addition of cyclosporine or biologic treatment. Adverse events were similar in both groups, but some occurred less in the MTX and prednisone group.” (M. F. Bakker)
Risk of Crohn Disease & Ulcerative Colitis with Aspirin & NSAIDs: Women are at higher risk of developing Crohn disease (CD) or ulcerative colitis (UC) when they take NSAIDs but not aspirin, according to the prospective cohort Nurses’ Health Study I (pp. 350–9). The risks of incident CD and UC between 1990 and 2008 were as follows based on exposure to NSAIDs and aspirin: “123 incident cases of CD and 117 cases of UC occurred over 18 years and 1,295,317 person–years of follow-up. Compared with nonusers, women who used NSAIDs at least 15 days per month seemed to have increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100,000 person–years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to 2.56]) and UC (absolute difference, 7 cases per 100,000 person–years [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99]). Less frequent NSAID use was not clearly associated with risk for CD or UC, and there was no clear association between aspirin use and disease.” (A. N. Ananthakrishnan)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 7, 2012 * Vol. 19, No. 45
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 7 issue of JAMA (2012; 307).
Early Surgery in Drug-Resistant Temporal Lobe Epilepsy: In 38 participants in the Early Randomized Surgical Epilepsy Trial (ERSET), early surgical treatment of temporal lobe epilepsy provided better outcomes than continued antiepileptic drug (AED) therapy (pp. 922–30). During year 2 of follow-up, none of 23 patients treated medically and 11 of 15 surgical patients were seizure free, the investigators report, adding that trial was stopped early because of slow enrollment. (J. Engel Jr., engel@ucla.edu)
Early diagnosis is also “critical” in this patient population, an editorialist adds (
pp. 966–8): “The sooner patients with [mesial temporal lobe epilepsy] are diagnosed, the sooner they can receive needed medical, surgical, and counseling attention. This requires that physicians in primary care practices be aware of the constellation of clinical presentations that is ‘epilepsy.’ Primary care physicians need to partner with level III or level IV epilepsy centers in which patients who are difficult to diagnose can be properly evaluated, and patients who have refractory epilepsy can receive treatment, including medical management, neurosurgical evaluations, counseling, and work training.” (D. L. Schomer, dschomer@bidmc.harvard.edu)
Effects of 5-Alpha Reductase Inhibitors & Fat-Free Mass: Blockade of conversion of testosterone to 5-alpha testosterone by 5-alpha reductase inhibitors does not affect changes in fat-free mass in response to the male hormone, researchers in the 5-alpha Reductase Trial report (pp. 931–9). Among 139 men in eight treatment groups who received various testosterone doses plus either dutasteride or placebo, these results were noted: “The mean fat-free mass gained by the dutasteride groups was 0.6 kg (95% CI, −0.1 to 1.2 kg) when receiving 50 mg/wk of testosterone enanthate, 2.6 kg (95% CI, 0.9 to 4.3 kg) for 125 mg/wk, 5.8 kg (95% CI, 4.8 to 6.9 kg) for 300 mg/wk, and 7.1 kg (95% CI, 6.0 to 8.2 kg) for 600 mg/wk. The mean fat-free mass gained by the placebo groups was 0.8 kg (95% CI, −0.1 to 1.7 kg) when receiving 50 mg/wk of testosterone enanthate, 3.5 kg (95% CI, 2.1 to 4.8 kg) for 125 mg/wk, 5.7 kg (95% CI, 4.8 to 6.5 kg) for 300 mg/wk, and 8.1 kg (95% CI, 6.7 to 9.5 kg) for 600 mg/wk. The dose-adjusted differences between the dutasteride and placebo groups for fat-free mass were not significant (P = .18). Changes in fat mass, muscle strength, sexual function, prostate volume, sebum production, and hematocrit and lipid levels did not differ between groups.” (S. Bhasin, bhasin@bu.edu)
Mental Health Disorders & Opioid Use: U.S. veterans of the wars in Iraq and Afghanistan who have mental health disorders are at increased risk of receiving opioids for pain, high-risk opioid use, and adverse clinical outcomes, according to results of a retrospective cohort study (pp. 940–7). A diagnosis of posttraumatic stress disorder (PTSD) was particularly likely to result in potentially problematic opioid use, the investigators reported based on analysis of VA records for 2005–10: “A total of 15,676 veterans were prescribed opioids within 1 year of their initial pain diagnosis. Compared with 6.5% of veterans without mental health disorders, 17.8% (adjusted relative risk [RR], 2.58; 95% CI, 2.49–2.67) of veterans with PTSD and 11.7% (adjusted RR, 1.74; 95% CI, 1.67-–1.82) with other mental health diagnoses but without PTSD were significantly more likely to receive opioids for pain diagnoses. Of those who were prescribed pain medication, veterans with PTSD were more likely than those without mental health disorders to receive higher-dose opioids (22.7% vs 15.9%, adjusted RR, 1.42; 95% CI, 1.31–1.54), receive 2 or more opioids concurrently (19.8% vs 10.7%, adjusted RR, 1.87; 95% CI, 1.70–2.06), receive sedative hypnotics concurrently (40.7% vs 7.6%, adjusted RR, 5.46; 95% CI, 4.91–6.07), or obtain early opioid refills (33.8% vs 20.4%; adjusted RR, 1.64; 95% CI, 1.53–1.75). Receiving prescription opioids (vs not) was associated with an increased risk of adverse clinical outcomes for all veterans (9.5% vs 4.1%; RR, 2.33; 95% CI, 2.20–2.46), which was most pronounced in veterans with PTSD.” (K. H. Seal, karen.seal@ucsf.edu)

>>>PNN NewsWatch
* Lucinactant (Surfaxin, Discovery Laboratories) was approved yesterday by FDA for prevention of respiratory distress syndrome (RDS) in premature infants at high risk of RDS.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 8, 2012 * Vol. 19, No. 46
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 8 issue of the New England Journal of Medicine (2012; 366).
Continuing Donepezil in Moderate-to-Severe AD: In patients progressing from mild-to-moderate to moderate-to-severe Alzheimer’s disease, continuing donepezil is a reasonable strategy, one that produces benefits equivalent to adding memantine or switching to that drug alone, a study shows (pp. 893–903). A total of 295 community-dwelling patients were included in the trial. All had been on donepezil for at least 3 months and had moderate-to-severe Alzheimer’s disease on study entry. Scores on the Standardized Mini–Mental State Examination (SMMSE) and the Bristol Activities of Daily Living Scale (BADLS) showed these patterns: “Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P < 0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P < 0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.” (R. Howard, robert.j.howard@kcl.ac.uk)
This study, Donepezil and Memantine in Moderate to Severe Alzheimer’s Disease (DOMINO), provides some guidance on when cholinesterase inhibitors can be safely discontinued as Alzheimer’s disease progresses, writes an editorialist (
pp. 957–9): “Although memantine appears to be helpful for the treatment of moderate-to-severe Alzheimer’s disease when used alone or when replacing donepezil, the results of the DOMINO trial do not support the typical use in the United States, and an FDA-approved use, as add-on therapy to established donepezil treatment. In contrast to the benefits observed in a 6-month U.S. trial, in the longer DOMINO trial, adding memantine to donepezil, as compared with continuing donepezil alone, was not associated with better cognition or function. The conflicting results of these two trials suggest the need for further study of the benefits and risk of using memantine as add-on therapy to donepezil in patients with moderate-to-severe cognitive impairment.” (L. S. Schneider)
Enzyme Replacement in Hypophosphatasia: In infants and young children with life-threatening hypophosphatasia, replacement of the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP) improved skeletal radiographs and pulmonary and physical function, researchers report (pp. 904–13). Open-label ENB-0040—a bone-targeted, recombinant human TNSALP—was administered to young patients with life-threatening or debilitating perinatal or infantile hypophosphatasia. Results showed: “Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5-prime-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti–ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment.” (M. P. Whyte, mwhyte@shrinenet.org)
Pasireotide in Cushing’s Disease: In a Phase III trial, cortisol levels were reduced in patients with Cushing’s disease who received pasireotide, supporting use of the somatostatin receptor binder for treatment of corticotropin-secreting pituitary adenomas (pp. 914–24). Of those receiving a lower dose of the agent, 12 of 82 patients met a primary end point, as did 21 of 80 patients on a higher dose. (B. M. K. Biller, bbiller@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 9, 2012 * Vol. 19, No. 47
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Mar. 13 issue of the Journal of the American College of Cardiology (2012; 59).
Dietary Intervention for HAART Dyslipidemia: Patients with HIV-1 newly started on highly active antiretroviral therapy (HAART) can avoid drug-related dyslipidemia by reducing the amount of fat in their diet, researchers report (pp. 979–88). These results support current recommendations that were previously lacking evidence of efficacy. Among 83 patients, dietary interventions based on the National Cholesterol Education Program produced these differences in lipid profiles: “Diet resulted in reduction of percentage of fat intake (from 31 ± 7% to 21 ± 3% of calories), while controls presented no change in percentage of fat intake. Plasma cholesterol (from 151 ± 29 mg/dl to 190 ± 33 mg/dl) and low-density lipoprotein cholesterol (from 85 ± 24 mg/dl to 106 ± 31 mg/dl) increased in the control group and were unchanged in the diet group. Plasma triglycerides were reduced by diet (from 135 ± 67 mg/dl to 101 ± 42 mg/dl) and increased in the control group (from 134 ± 70 mg/dl to 160 ± 76 mg/dl). After 1-year follow-up, 21% of patients who received diet had lipid profile compatible with dyslipidemia compared with 68% (p < 0.001) of controls.” (J. P. Ribeiro, jpribeiro@cpovo.net)
Cardioprotection in AMI: A number of adjunctive therapies, including several drugs, are emerging as effective for limiting the infarct size in patients who have acute myocardial infarction (AMI), review authors write (pp. 969–78): “Rapid advances in the treatment of AMI, mainly through timely reperfusion, have substantially improved outcomes in patients presenting with acute coronary syndrome and particularly ST-segment elevation myocardial infarction. A vast amount of research, both translational and clinical, has been published on various pharmacological and interventional techniques to prevent myocardial cell death during the time of ischemia and subsequent reperfusion.… Examples of interventional techniques that have proven beneficial are ischemic post-conditioning and remote ischemic per-conditioning, both of which can reduce infarction size. Lowering core body temperature with cold saline infusion and cooling catheters have also been shown to be effective in certain circumstances. The most promising pharmaceutical cardioprotective agents at this time appear to be adenosine, atrial natriuretic peptide, and cyclosporine, with other potentially effective medications in the pipeline. Additional pre-clinical and clinical research is needed to further investigate newer cardioprotective strategies to continue the current trend of improving outcomes following AMI.” (R. A. Kloner, rkloner@goodsam.org)

>>>Circulation Report
Source:
Mar. 6 issue of Circulation (2012; 125).
Fatty Acids & Atrial Fibrillation: U.S. men and women older than 65 with higher circulating levels of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) and docosahexaenoic acid levels had lower risk of incident atrial fibrillation (AF), according to prospectively collected data from the Cardiovascular Health Study (pp. 1084–93). During 31,169 person–years of follow-up in 1992–2006, 3,326 participants who were free of AF or heart failure at baseline had these outcomes based on fatty acid levels: “In multivariable Cox models adjusted for other risk factors, the relative risk in the top versus lowest quartile of total n-3 PUFAs (eicosapentaenoic acid + docosapentaenoic acid + docosahexaenoic acid) levels was 0.71 (95% confidence interval, 0.57–0.89; P for trend = 0.004) and of DHA levels was 0.77 (95% confidence interval, 0.62–0.96; P for trend = 0.01). Eicosapentaenoic acid and docosapentaenoic acid levels were not significantly associated with incident AF. Evaluated nonparametrically, both total n-3 PUFAs and docosahexaenoic acid showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results.” (D. Mozaffarian, dmozaffa@hsph.harvard.edu)

>>>PNN NewsWatch
* The American Pharmacists Association opens its annual meeting today in New Orleans. Its House of Delegates will consider policies on the drug supply shortage, contemporary pharmacy practice, and controlled substances regulation.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 12, 2012 * Vol. 19, No. 48
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 10 issue of Lancet (2012; 379).
Systolic BP Differences Between Arms & Disease: Patients who have differences of 15 mm Hg or more in systolic blood pressures (SBPs) measured on each arm may be at greater risk of vascular disease and death, according to a systematic review and meta-analysis (pp. 905–14). The authors looked for studies that showed differences in SBP between arms along with data for subclavian stenosis, peripheral vascular disease, cerebrovascular disease, cardiovascular disease, or survival. Results showed: “We identified 28 eligible studies for review, 20 of which were included in our meta-analyses. In five invasive studies using angiography, mean difference in SBP between arms was 36.9 mm Hg (95% CI 35.4–38.4) for proven subclavian stenosis (>50% occlusion), and a difference of 10 mm Hg or more was strongly associated with subclavian stenosis (risk ratio [RR] 8.8, 95% CI 3.6–21.2). In non-invasive studies, pooled findings showed that a difference of 15 mm Hg or more was associated with peripheral vascular disease (nine cohorts; RR 2.5, 95% CI 1.6–3.8; sensitivity 15%, 9–23; specificity 96%, 94–98); pre-existing cerebrovascular disease (five cohorts; RR 1.6, 1.1–2.4; sensitivity 8%, 2–26; specificity 93%, 86–97); and increased cardiovascular mortality (four cohorts; hazard ratio [HR] 1.7, 95% CI 1.1–2.5) and all-cause mortality (HR 1.6, 1.1–2.3). A difference of 10 mm Hg or higher was associated with peripheral vascular disease (five studies; RR 2.4, 1.5–3.9; sensitivity 32%, 23–41; specificity 91%, 86–94).” (C. E. Clark, christopher.clark@pms.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Antidepressants in Patients with Dementia: When antidepressants were discontinued in people with dementia and neuropsychiatric symptoms in the DESEP study, depressive symptoms increased, researchers report (e1566). Included in the study were 128 patients with Alzheimer’s disease, dementia or vascular dementia, and neuropsychiatric symptoms but no depressive disorder. All had been prescribed escitalopram, citalopram, sertraline, or paroxetine for 3 months or more. Compared with continued antidepressant therapy, investigators found these results on the 10-item Cornell scale of depression in dementia and the neuropsychiatric inventory when antidepressants were stopped over a 1-week period in the intervention patients: “Using a linear multilevel model analysis, we found that the discontinued group had significantly higher scores on the Cornell scale after 25 weeks than the continuation group (difference −2.89 (95% confidence interval −4.76 to −1.02); P = 0.003). We saw a similar result in the mean total score for the neuropsychiatric inventory after 25 weeks, but this difference was non-significant (−5.96 (−12.35 to 0.44); P = 0.068). We confirmed these results by non-response analysis (>30% worsening on the Cornell scale)–significantly more patients worsened in the discontinuation group than in the continuation group (32 (54%) v 17 (29%); P = 0.006). We found no significant differences between the groups for secondary outcomes. Forty seven (37%) patients withdrew from the study early.” (S. Bergh, sverre.bergh@sykehuset-innlandet.no)

>>>PNN NewsWatch
* FDA has approved GINTUIT (Organogenesis), the first cell-based product made from allogeneic human cells and bovine collagen. It is indicated for topical application to a surgically created vascular wound bed in treatment of mucogingival conditions in adults.

>>>PNN JournalWatch
* Intracoronary Versus Intravenous Bolus Abciximab During Primary Percutaneous Coronary Intervention in Patients with Acute ST-Elevation Myocardial Infarction: A Randomised Trial, in
Lancet, 2012; 379: 923–31. (H. Thiele, thielh@medizin.uni-leipzig.de)
* New Anemia Therapies: Translating Novel Strategies from Bench to Bedside, in
American Journal of Kidney Diseases, 2012; 59: 444–51. (I. C. Macdougall, iain.macdougall@nhs.net)
* Advances in Upper Airway Diseases and Allergen Immunotherapy in 2011, in
Journal of Allergy and Clinical Immunology, 2012; 129: 646–52. (P. C. Avila, pa@northwestern.edu)
* Meta-analysis of Randomized Controlled Trials for the Incidence and Risk of Treatment-Related Mortality in Patients with Cancer Treated with Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors, in
Journal of Clinical Oncology, 2012; 30: 871–7. (T. K. Choueiri, toni_choueiri@dfci.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 13, 2012 * Vol. 19, No. 49
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Mar. 12 issue of the Archives of Internal Medicine (2012; 172).
Dabigatran & Acute Coronary Events: Myocardial infarction (MI) and acute coronary syndrome (ACS) occur more often in patients taking dabigatran, compared with warfarin, enoxaparin, and placebo, a meta-analysis indicates (pp. 397–402). The original RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial had suggested a small increased risk of MI with dabigatran versus warfarin in patients with atrial fibrillation, the authors note, adding these details from their systematic review: “Seven trials were selected (N = 30,514), including 2 studies of stroke prophylaxis in atrial fibrillation, 1 in acute venous thromboembolism, 1 in ACS, and 3 of short-term prophylaxis of deep venous thrombosis.… Dabigatran was significantly associated with a higher risk of MI or ACS than that seen with agents used in the control group (dabigatran, 237 of 20 000 [1.19%] vs control, 83 of 10 514 [0.79%]; ORM-H, 1.33; 95% CI, 1.03–1.71; P = .03). The risk of MI or ACS was similar when using revised RE-LY trial results (ORM-H, 1.27; 95% CI, 1.00–1.61; P = .05) or after exclusion of short-term trials (ORM-H, 1.33; 95% CI, 1.03–1.72; P = .03). Risks were not heterogeneous for all analyses (I2 = 0%; P ≥ .30) and were consistent using different methods and measures of association.” (K. Uchino, uchinok@ccf.org)
Long-Term Opioid Use: Authors of two commentaries discuss long-term opioid use.
“Among persons seeking treatment for opioid abuse, women are more likely than men to report having received their opioids in the form of a legitimate prescription,” authors write (
pp. 431–2). “As such, physicians may have a greater opportunity to prevent the misuse of opioids by women. Sex-specific risks include endocrinopathy, infertility, polypharmacy, unintentional poisoning, and abuse; these factors should influence decision making regarding initiating or continuing opioid therapy. Sex-specific monitoring in women who are taking opioids includes ongoing assessment for pregnancy plans, endocrinopathy, physician shopping, and the use of opioids to medicate psychosocial factors. Before initiating opioid treatment for chronic pain, in women or men, prescribers should fully assess the individual risks and benefits of the therapy and have a thorough discussion of the goals, risks, and consequences of such therapy with each patient.” (B. D. Darnall, darnallb@ohsu.edu)
Long-term opioid therapy (LtOT) should be reframed more positively, authors maintain (
pp. 433–4): “The collective clinical experience from 20 years of liberal opioid prescribing for chronic pain, together with the findings of recent population-based studies, suggests that LtOT may benefit patients with severe suffering that has been refractory to other medical and psychological treatments but that it is not often effective in achieving the goals originally envisaged, such as complete pain relief and functional restoration. This reframing of LtOT is a more honest appraisal of how it is actually used in practice. It would allow better patient selection and help to avoid the disastrous effects of promising more of opioids than they can achieve.” (M. D. Sullivan, sullimar@uw.edu)
Red Meat & Mortality: Eating red meat is associated with greater total, cardiovascular disease (CVD), and cancer mortality, the Health Professionals Follow-up Study (1986–2008) and the Nurses’ Health Study (1980–2008) show (doi: 10.1001/archinternmed.2011.2287). Among 37,698 men and 83,644 women who were free of cardiovascular disease (CVD) and cancer at baseline, these risks were noted based on food-frequency questionnaires administered every 4 years: “The pooled hazard ratio (HR) (95% CI) of total mortality for a 1-serving-per-day increase was 1.13 (1.07–1.20) for unprocessed red meat and 1.20 (1.15–1.24) for processed red meat. The corresponding HRs (95% CIs) were 1.18 (1.13–1.23) and 1.21 (1.13–1.31) for CVD mortality and 1.10 (1.06–1.14) and 1.16 (1.09–1.23) for cancer mortality. We estimated that substitutions of 1 serving per day of other foods (including fish, poultry, nuts, legumes, low-fat dairy, and whole grains) for 1 serving per day of red meat were associated with a 7% to 19% lower mortality risk. We also estimated that 9.3% of deaths in men and 7.6% in women in these cohorts could be prevented at the end of follow-up if all the individuals consumed fewer than 0.5 servings per day (approximately 42 g/d) of red meat.” (F. B. Hu, frank.hu@channing.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 14, 2012 * Vol. 19, No. 50
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 14 issue of JAMA (2012; 307).
Azithromycin & Toxigenic E. coli: Long-term carriage of a toxin-producing strain of Escherichia coli is reduced by oral azithromycin therapy, researchers report (pp. 1046–52). In Germany in May 2011, an outbreak of Shiga toxin–producing enteroaggregative E. coli (STEC O104:H4) infection with a high incidence of hemolytic uremic syndrome (HUS) occurred. While antibiotic treatment of STEC is usually discouraged because of its potential to increase HUS, 65 affected patients at one German center were included in a study of prophylactic azithromycin as part of a therapeutic regimen of the C5 antibody eculizumab. During 39.3 days of follow-up, results showed: “Twenty-two patients received oral azithromycin and 43 patients did not receive antibiotic treatment. Among antibiotic-treated patients, long-term STEC carriage (>28 days) was observed in 1 of 22 patients (4.5%; 95% CI, 0%–13.3%) compared with 35 of 43 patients (81.4%; 95% CI, 69.8%–93.0%) who were not treated with antibiotics (P < .001). All 22 patients receiving azithromycin treatment had at least 3 STEC-negative stool specimens after the completion of treatment, and no recurrence of STEC was observed in these patients. As proof of principle, 15 patients who initially were not treated with antibiotics and were long-term STEC carriers were treated with oral azithromycin given for 3 days and subsequently had negative stool specimens.” (J. K.-M. Knobloch, Johannes.Knobloch@uksh.de)
Hospital Spending Intensity & Outcomes: Ontario hospitals with higher spending intensity have lower mortality, readmission, and cardiac event rates, according to an analysis of patients admitted in 1998–2008 for acute myocardial infarction (AMI) (n = 179,139), congestive heart failure (CHF) (n = 92,377), hip fracture (n = 90,046), or colon cancer (n = 26,195) (pp. 1037–45). Using primary outcomes of 30-day and 1-year mortality and readmissions and major cardiac events (readmissions for AMI, angina, CHF, or death) for AMI and CHF, the investigators found: “Patients’ baseline health status was similar across hospital expenditure groups. Patients admitted to hospitals in the highest- vs lowest-spending intensity terciles had lower rates of all adverse outcomes. In the highest- vs lowest-spending hospitals, respectively, the age- and sex-adjusted 30-day mortality rate was 12.7% vs 12.8% for AMI, 10.2% vs 12.4% for CHF, 7.7% vs 9.7% for hip fracture, and 3.3% vs 3.9% for CHF; fully adjusted relative 30-day mortality rates were 0.93 (95% CI, 0.89–0.98) for AMI, 0.81 (95% CI, 0.76–0.86) for CHF, 0.74 (95% CI, 0.68–0.80) for hip fracture, and 0.78 (95% CI, 0.66–0.91) for colon cancer. Results for 1-year mortality, readmissions, and major cardiac events were similar. Higher-spending hospitals had higher nursing staff ratios, and their patients received more inpatient medical specialist visits, interventional (AMI cohort) and medical (AMI and CHF cohorts) cardiac therapies, preoperative specialty care (colon cancer cohort), and postdischarge collaborative care with a cardiologist and primary care physician (AMI and CHF cohorts).” (T. A. Stukel, stukel@ices.on.ca)
Bending the Cost Curve with Genomics: “Genomics has the potential to improve health care value by ensuring that the most effective treatment is used in the most appropriate patients,” writes the author of a Viewpoint article that explores the impact on costs of care personalized through genetics (pp. 1031–2). “Although it is too soon to know the extent of this potential benefit, basing the rational use of health care on advances in science rather than on the need to save dollars is likely to be more acceptable to patients and physicians and, therefore, ultimately more successful.” (K. Armstrong, karmstro@mail.med.upenn.edu)

>>>PNN NewsWatch
* The APhA House of Delegates approved policy statements on drug supply shortages, contemporary pharmacy practice, and controlled substances during two meetings at APhA2012 in New Orleans, pharmacist.com reports. New business items in the House addressed counterfeit medications and provider status for pharmacists under the Social Security Act. William Riffee of Gainesville, FL, was elected Speaker-elect of the House; he will take office at APhA2013, slated for March 1–4 in Los Angeles.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 15, 2012 * Vol. 19, No. 51
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and Mar. 15 issue of the New England Journal of Medicine (2012; 366).
Oral Laquinimod for Multiple Sclerosis: In a 24-month, Phase III trial, oral laquinimod was significantly more effective than placebo in 1,106 patients with relapsing–remitting multiple sclerosis for slowing the progression of disability and reducing the rate of relapse (pp. 1000–9). Participants received oral laquinomod 0.6 mg or placebo once daily, with these effects on a primary end point of annualized relapse rate at 24 months: “Treatment with laquinimod as compared with placebo was associated with a modest reduction in the mean (± SE) annualized relapse rate (0.30 ± 0.02 vs. 0.39 ± 0.03, P = 0.002) and with a reduction in the risk of confirmed disability progression (11.1% vs. 15.7%; hazard ratio, 0.64; 95% confidence interval, 0.45 to 0.91; P = 0.01). The mean cumulative numbers of gadolinium-enhancing lesions and new or enlarging lesions on T2-weighted images were lower for patients receiving laquinimod than for those receiving placebo (1.33 ± 0.14 vs. 2.12 ± 0.22 and 5.03 ± 0.08 vs. 7.14 ± 0.07, respectively; P < 0.001 for both comparisons). Transient elevations in alanine aminotransferase levels to greater than three times the upper limit of the normal range were observed in 24 patients receiving laquinimod (5%) and 8 receiving placebo (2%).” (G. Comi, comi.giancarlo@hsr.it)
Ingenol Mebutate Gel & Actinic Keratosis: A new topical field therapy for actinic keratosis, ingenol mebutate gel (0.015% for face and scalp and 0.05% for trunk and extremities) was more effective than placebo for completely clearing symptoms at 57 days, researchers report (pp. 1010–9). At four centers, 547 patients were enrolled into two studies of the new agent. They applied the appropriate product onto lesions on the face or scalp for 3 consecutive days or the trunk or extremities for 2 consecutive days, with these results: “In a pooled analysis of the two trials involving the face and scalp, the rate of complete clearance was higher with ingenol mebutate than with placebo (42.2% vs. 3.7%, P < 0.001). Local reactions peaked at day 4, with a mean maximum composite score of 9.1 on the local-skin-response scale (which ranges from 0 to 4 for six types of reaction, yielding a composite score of 0 to 24, with higher numbers indicating more severe reactions), rapidly decreased by day 8, and continued to decrease, approaching baseline scores by day 29. In a pooled analysis of the two trials involving the trunk and extremities, the rate of complete clearance was also higher with ingenol mebutate than with placebo (34.1% vs. 4.7%, P < 0.001). Local skin reactions peaked between days 3 and 8 and declined rapidly, approaching baseline by day 29, with a mean maximum score of 6.8. Adverse events were generally mild to moderate in intensity and resolved without sequelae.” (N. Swanson, swansonn@ohsu.edu)
Contraceptives & Political Headaches: Reflecting on the recent political storm over contraceptives, the author of a Perspective article writes (10.1056/NEJMp1202701): “Since the average American woman spends 5 years pregnant (or trying to be) and 30 years trying not to get pregnant, nearly 99% of sexually active women have used birth control. And the most effective contraceptives—such as the birth-control pill and intrauterine devices (IUDs)—are unavailable except by prescription, which makes them part of the health care system rather than merely a lifestyle choice akin to eschewing cosmetics. That such contraceptives constitute health care is even clearer when one considers the reduction of maternal and neonatal morbidity and mortality from the spacing out of births or the use of oral contraceptives for conditions ranging from acne to uterine fibroid tumors.” (R. A. Charo)

>>>PNN NewsWatch
* Generic escitalopram is now on the U.S. market, following yesterday’s FDA approval of a bioequivalent alternative to Lexapro (Forest). The generic product will be marketed by Teva and its subsidiary company, IVAX, and will enjoy 180 days of market exclusivity.
* Accepting the 2012 Remington Honor Medal during APhA2012,
William E. Evans, PharmD, attributed his success to a “culture without strict boundaries, a culture of collaboration, compassion, innovation and quality” at St. Jude Children’s Research Hospital in Memphis. His remarks will be published in the Jul/Aug issue of JAPhA.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 16, 2012 * Vol. 19, No. 52
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
Mar. issue of Chest (2012; 141).
Bronchoscopy in Refractory Asthma: In difficult-to-treat cases of asthma, bronchoscopy can be used to identify phenotypes and provide information useful in determining direct therapy, a study shows (pp. 599–606). Among 58 patients with refractory asthma, fiber-optic bronchoscopy revealed the following: “Five mutually exclusive phenotypes were formulated based on bronchoscopic evaluation: gastroesophageal reflux, subacute bacterial infection, tissue eosinophilia, combination, and nonspecific. Specific directed therapy yielded a significant improvement in the Asthma Control Test and pulmonary function for the entire group as well as for each defined subgroup except for the nonspecific group. Of interest, visual scoring of the supraglottic abnormalities identified 34 of 35 patients with gastroesophageal reflux and may give a better insight into asthmatic problems associated with chronic proximal reflux than standard testing.” (R. J. Martin, martinr@njhealth.org)
Medication Chart Intervention in Thromboembolism Prophylaxis: In 2,371 medical and surgical inpatients, the multifaceted Australian National Inpatient Medication Chart (NIMC) intervention provided a sustained improvement in used of venous thromboembolism (VTE) over a 1-year period, researchers report (pp. 632–41). Retrospective analysis of consecutive admissions at a major referral hospital showed these patterns among study outcomes: “Following NIMC intervention, prophylaxis use increased from 52.7% to 66.5% in medical patients and from 77.5% to 89.1% in surgical patients (P < .001). This increase was still evident 12 months postintervention. After intervention, prophylaxis initiated on admission increased from 65.0% to 83.6% in medical patients and from 60.7% to 78.0% in surgical patients (P < .01); adherence rates to recommended guidelines increased from 55.6% to 71.0% in medical patients and from 53.6% to 75.6% in surgical patients (P < .01). More VTE risk factors independently triggered prophylaxis usage postintervention. The improved quality of prophylaxis did not significantly reduce VTE incidence (risk ratio, 0.88; 95% CI, 0.48–1.62). The rate of prophylaxis-related complications remained similar before and after intervention.” (D. S. H. Liu, dshliu@bigpond.com)

>>>Geriatrics Report
Source:
Mar. issue of the Journal of the American Geriatrics Society (2012; 60).
Safety of Antipsychotic Medications in Nursing Homes: In a comparative study of use of first- and second-generation antipsychotic medications (APMs) in long-term care facilities, investigators find differing safety patterns, reinforcing the need to “carefully select” and monitor these agents and the doses used, authors write (pp. 420–9). Cohort analysis of data on 83,959 Medicaid-eligible nursing home residents in 45 states who began APMs in 2001–05 showed: “Risks of bacterial infections (hazard ratio (HR) = 1.25, 95% confidence interval (CI) = 1.05–1.49) and possibly myocardial infarction (HR = 1.23, 95% CI = 0.81–1.86) and hip fracture (HR = 1.29, 95% CI = 0.95–1.76) were higher, and risks of cerebrovascular events (HR = 0.82, 95% CI = 0.65–1.02) were lower in participants initiating conventional APMs than in those initiating atypical APMs. Little variation existed between individual atypical APMs, except for a somewhat lower risk of cerebrovascular events with olanzapine (HR = 0.91, 95% CI = 0.81–1.02) and quetiapine (HR = 0.89, 95% CI = 0.79–1.02) and a lower risk of bacterial infections (HR = 0.83, 95% CI = 0.73–0.94) and possibly a higher risk of hip fracture (HR = 1.17, 95% CI = 0.96–1.43) with quetiapine than with risperidone. Dose-response relationships were observed for all events (HR = 1.12, 95% CI = 1.05–1.19 for high vs low dose for all events combined).” (K. F. Huybrechts, khuybrechts@partners.org)

>>>PNN NewsWatch
* FDA is warning consumers to avoid skin creams, beauty and antiseptic soaps, or lotions that might contain mercury. The products are marketed as skin lighteners and antiaging treatments, especially in Latino, Asian, African, and Middle Eastern neighborhoods as well as online. Adolescents also may use these products as acne treatments, FDA added. Products with this toxic metal have been found in at least seven states.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 19, 2012 * Vol. 19, No. 53
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 344).
Inpatient Safety in Developing Countries: In eight developing countries, a convenience sample of 26 hospitals showed substantial risk of adverse events among 15,548 patients (e832). “8.2% [of records] showed at least one adverse event, with a range of 2.5% to 18.4% per country. Of these events, 83% were judged to be preventable, while about 30% were associated with death of the patient. About 34% adverse events were from therapeutic errors in relatively non-complex clinical situations. Inadequate training and supervision of clinical staff or the failure to follow policies or protocols contributed to most events.”
Based on these findings, the authors conclude: “Unsafe patient care represents a serious and considerable danger to patients in the hospitals that were studied, and hence should be a high priority public health problem. Many other developing and transitional economies will probably share similar rates of harm and similar contributory factors.… The identified adverse event rates show an estimate that should stimulate and facilitate the urgent institution of appropriate remedial action and also to trigger more research. Prevention of these adverse events will be complex and involves improving basic clinical processes and does not simply depend on the provision of more resources.” (R. Wilson,
ross.wilson@nychhc.org)
DPP-4 Inhibitors in Type 2 Diabetes: Dipeptidyl peptidase-4 (DPP-4) inhibitors are reasonable agents for use in type 2 diabetes, authors of a systematic review and meta-analysis conclude based on 19 studies of 13,881 patients (e1369). Randomization to DPP-4 inhibitors or comparator drugs yielded these pooled effects on achieving glycosylated hemoglobin levels less than 7%: “Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA1c (weighted mean difference 0.20, 95% confidence interval 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11). As a second line treatment, DPP-4 inhibitors were inferior to [glucagon-like peptide-1 (GLP-1)] agonists (0.49, 0.31 to 0.67) and similar to pioglitazone (0.09, −0.07 to 0.24) in reducing HbA1c and had no advantage over sulfonylureas in the attainment of the HbA1c goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14). DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference −1.92, −2.34 to −1.49) or pioglitazone (−2.96, −4.13 to −1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18). Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment. In most trials comparing a DPP-4 inhibitor with sulfonylureas combined with metformin, the risk for hypoglycaemia was higher in the group treated with a sulfonylurea. Incidence of any serious adverse event was lower with DPP-4 inhibitors than with pioglitazone. Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators.” (A. Tsapas, atsapas@auth.gr)

>>>Lancet Highlights
Source:
Mar. 17 issue of Lancet (2012; 379).
Cord Cleansing with Chlorhexidine: Two studies show efficacy of cord cleansing with chlorhexidine in rural Bangladesh (pp. 1022–8; A. H. Baqui, abaqui@jhsph.edu) and rural Pakistan (pp. 1029–36; Z. A. Bhutta, zulfiqar.bhutta@aku.edu).

>>>PNN JournalWatch
* The Effect of Gastric Bypass on the Pharmacokinetics of Serotonin Reuptake Inhibitors, in
American Journal of Psychiatry, 2012; 169: 256–63. (G. G. Hamad, hamadg@upmc.edu)
* Striatal Dopamine Transporter Alterations in ADHD: Pathophysiology or Adaptation to Psychostimulants? A Meta-Analysis, in
American Journal of Psychiatry, 2012; 169: 264–72. (P. Fusar-Poli, p.fusar@libero.it)
* The Evidence for a Role of B Cells in Multiple Sclerosis, in
Neurology, 2012; 78: 823–32. (S. V. Ramagopalan, s.ramagopalan@qmul.ac.uk)
* Nonsteroidal Anti-inflammatory Drug Use Reduces Risk of Adenocarcinomas of the Esophagus and Esophagogastric Junction in a Pooled Analysis, in
Gastroenterology, 2012; 142: 442–452.e5. (L. M. Liao, liaolm@mail.nih.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 20, 2012 * Vol. 19, No. 54
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Mar. 20 issue of the Annals of Internal Medicine (2012; 156).
Preventing VTE After Hip/Knee Replacement: Based on a systematic review and meta-analysis, investigators showed that lower doses of oral direct factor Xa inhibitors “achieve a small absolute risk reduction in symptomatic deep venous thrombosis without increasing bleeding,” compared with low-molecular-weight heparins (LMWHs) in patients undergoing total hip or knee replacement (early release): “In 22 trials, high-quality evidence indicated that the absolute effect of factor Xa inhibitors and LMWH does not differ in terms of all-cause mortality (risk difference, 0 fewer deaths per 1,000 patients [95% CI, 2 fewer to 1 more death]) or nonfatal pulmonary embolism (risk difference, 0 fewer events per 1,000 patients [CI, 1 fewer to 2 more events]). Factor Xa inhibitors can prevent 4 instances of symptomatic deep venous thrombosis per 1,000 treated patients (CI, 3 to 6 fewer events; high-quality evidence) but may increase major bleeding by 2 more events per 1,000 patients (CI, 0 to 4 more events; moderate-quality evidence). High, but not lower, doses of oral factor Xa inhibitors increased bleeding compared with LMWH.” (I. Neumann)
Dapagliflozin & High Insulin Doses in Type 2 Diabetes: In patients with type 2 diabetes that is uncontrolled despite high doses of insulin, the sodium–glucose cotransporter 2 inhibitor dapagliflozin “improves glycemic control, stabilizes insulin dosing, and reduces weight without increasing major hypoglycemic episodes,” researchers report (pp. 405–15). In a randomized controlled trial conducted in Europe and North America, 808 study participants on admission were receiving at least 30 units daily of insulin and up to two oral antidiabetic agents. After placebo or one of three doses of dapagliflozin was added, these results were noted over a 48-week period: “800 patients were analyzed. After 24 weeks, mean hemoglobin A1c decreased by 0.79% to 0.96% with dapagliflozin compared with 0.39% with placebo (mean difference, −0.40% [95% CI, −0.54% to −0.25%] in the 2.5-mg group, −0.49% [CI, −0.65% to −0.34%] in the 5-mg group, and −0.57% [CI, −0.72% to −0.42%] in the 10-mg group). Daily insulin dose decreased by 0.63 to 1.95 U with dapagliflozin and increased by 5.65 U with placebo (mean difference, −7.60 U [CI, −10.32 to −4.87 U] in the 2.5-mg group, −6.28 U [CI, −8.99 to −3.58 U] in the 5-mg group, and −6.82 U [CI, −9.56 to −4.09 U] in the 10-mg group). Body weight decreased by 0.92 to 1.61 kg with dapagliflozin and increased by 0.43 kg with placebo (mean differences, −1.35 kg [CI, −1.90 to −0.80 kg] in the 2.5-mg group, −1.42 kg [CI, −1.97 to −0.88 kg] in the 5-mg group, and −2.04 kg [CI, −2.59 to −1.48 kg] in the 10-mg group). These effects were maintained at 48 weeks. Compared with the placebo group, patients in the pooled dapagliflozin groups had a higher rate of hypoglycemic episodes (56.6% vs. 51.8%), events suggesting genital infection (9.0% vs. 2.5%), and events suggesting urinary tract infection (9.7% vs. 5.1%).” (J. P. H. Wilding, j.p.h.wilding@liverpool.ac.uk)
Vitamin D Dose–Response in Postmenopausal Women: Daily doses of vitamin D3 of 800 IU were effective for raising serum levels to above 50 nmol/L in a study of 163 healthy postmenopausal women (pp. 425–37). Over a 1-year period beginning in winter or spring of 2007 or 2008, placebo or doses of vitamin D3 ranging from 400 IU to 4800 IU per day produced these serum concentrations: “The mean baseline 25-(OH)D level was 39 nmol/L. The dose response was curvilinear and tended to plateau at approximately 112 nmol/L in patients receiving more than 3200 IU/d of vitamin D3. The RDA of vitamin D3 to achieve a 25-(OH)D level greater than 50 nmol/L was 800 IU/d. A mixed-effects model predicted that 600 IU of vitamin D3 daily could also meet this goal. Compared with participants with a normal body mass index (<25 kg/m2), obese women (≥30 kg/m2) had a 25-(OH)D level that was 17.8 nmol/L lower. Parathyroid hormone levels at 12 months decreased with an increasing dose of vitamin D3 (P = 0.012). Depending on the criteria used, hypercalcemia occurred in 2.8% to 9.0% and hypercalciuria in 12.0% to 33.0% of participants; events were unrelated to dose.” (J. C. Gallagher, jcg@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 © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 21, 2012 * Vol. 19, No. 55
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 21 issue of JAMA (2012; 307).
Sedation During Prolonged Mechanical Ventilation: In two Phase III trials conducted in 1,000 patients in ICUs and on mechanical ventilation, the alpha-2 agonist dexmedetomidine was not inferior to midazolam and propofol (pp. 1151–60). Dexmedetomidine, marketed in the U.S. in 1999 and closely related to clonidine, showed some advantages (better ability to communicate pain and compared with midazolam, shorter duration of ventilation) but also produced more adverse effects, including hypotension and bradycardia: “Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% CI, 0.97–1.18) and dexmedetomidine/propofol, 1.00 (95% CI, 0.92–1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours [IQR, 67–337]) vs midazolam (164 hours [IQR, 92–380]; P = .03) but not with dexmedetomidine (97 hours [IQR, 45–257]) vs propofol (118 hours [IQR, 48–327]; P = .24). Patients’ interaction (measured using [visual analogue scale]) was improved with dexmedetomidine (estimated score difference vs midazolam, 19.7 [95% CI, 15.2–24.2]; P < .001; and vs propofol, 11.2 [95% CI, 6.4–15.9]; P < .001). Length of ICU and hospital stay and mortality were similar.” (J. Takala, jukka.takala@insel.ch)
“With the focus on cost containment at many hospitals, consideration of expense may preclude broad use without more tangible long-term outcome data and without confirmation that the benefits are due to the choice of sedative and not solely the lighter sedation levels achieved,” an editorialist writes (
pp. 1195–7). “Dexmedetomidine comes off patent in the United States in 2013. When there is no longer a need to weigh the drug acquisition costs, even uncertain improvements in the patient experience should be justification enough for broader use of dexmedetomidine in the ICU.” (H. Wunsch, hw2125@columbia.edu)
Prehospital Epinephrine in Out-of-Hospital Cardiac Arrest: In a Japanese study of out-of-hospital cardiac arrest (OHCA), prehospital use of epinephrine was associated with short-term benefits but reduced mortality and functional outcomes at 1 month (pp. 1161–8). In 2005–08, OHCAs in 417,188 adult patients showed these outcomes: “Return of spontaneous circulation before hospital arrival was observed in 2,786 of 15,030 patients (18.5%) in the epinephrine group and 23,042 of 402,158 patients (5.7%) in the no-epinephrine group (P < .001); it was observed in 2,446 (18.3%) and 1,400 (10.5%) of 13,401 propensity-matched patients, respectively (P < .001). In the total sample, the numbers of patients with 1-month survival and survival with [Cerebral Performance Category (CPC) 1 or 2] and [Overall Performance Category (OPC) 1 or 2], respectively, were 805 (5.4%), 205 (1.4%), and 211 (1.4%) with epinephrine and 18,906 (4.7%), 8,903 (2.2%), and 8,831 (2.2%) without epinephrine (all P <.001). Corresponding numbers in propensity-matched patients were 687 (5.1%), 173 (1.3%), and 178 (1.3%) with epinephrine and 944 (7.0%), 413 (3.1%), and 410 (3.1%) without epinephrine (all P <.001).…Among all patients, negative associations were observed between prehospital epinephrine and long-term outcome measures (adjusted ORs: 1-month survival, 0.46 [95% CI, 0.42–0.51]; CPC 1–2, 0.31 [95% CI, 0.26–0.36]; and OPC 1–2, 0.32 [95% CI, 0.27–0.38]; all P < .001). Similar negative associations were observed among propensity-matched patients (adjusted ORs: 1-month survival, 0.54 [95% CI, 0.43–0.68]; CPC 1–2, 0.21 [95% CI, 0.10–0.44]; and OPC 1–2, 0.23 [95% CI, 0.11–0.45]; all P < .001).” (A. Hagihara, hagihara@hsmp.med.kyushu-u.ac.jp)
Despite the challenges of conducting a trial of epinephrine in critically ill patients, an editorialist writes that such a study is now needed (
pp. 1198–200): “Properly evaluating this traditional therapy now seems necessary and timely and should consist of a rigorously conducted and adequately powered clinical trial comparing epinephrine with placebo during cardiac arrest. Such a trial has previously seemed unethical, and investigators who have attempted to perform this comparison have received unwarranted criticism in their communities. While awaiting results of such a definitive trial, physicians and other practitioners involved in cardiac resuscitation must consider carefully whether continued use of epinephrine is justified.” (C. W. Callaway, callawaycw@upmc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 22, 2012 * Vol. 19, No. 56
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 22 issue of the New England Journal of Medicine (2012; 366).
Integrated Genetic Profiling in Acute Myeloid Leukemia: Targeting of patients with acute myeloid leukemia (AML) who will respond best to high-dose induction chemotherapy is possible through integrated genetic profiling, researchers report (pp. 1079–89). A mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin showed these patterns: “We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P = 0.001 for FLT3-ITD, P = 0.009 for MLL-PTD, P = 0.05 for ASXL1, and P = 0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P = 0.05 for CEBPA and P = 0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P = 0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P = 0.67).” (R. L. Levine, leviner@mskcc.org)
Tenecteplase or Alteplase in Acute Ischemic Stroke: A Phase IIb trial of 75 patients with acute ischemic stroke indicates that tenecteplase produced significantly better reperfusion and clinical outcomes, compared with alteplase (pp. 1099–107). All study participants had a perfusion lesion at least 20% larger than the infarct core on CT imaging and an associated vessel occlusion on CT angiography. Based on a coprimary end points of the proportion of the perfusion lesion that was reperfused at 24 hours and extent of clinical improvement at 24 hours using the 42-point National Institutes of Health Stroke Scale (NIHSS), the investigators found these patterns for alteplase 0.9 mg/kg and tenecteplase 0.1 or 0.25 mg/kg given less than 6 hours after stroke onset: “The three treatment groups each comprised 25 patients. The mean (± SD) NIHSS score at baseline for all patients was 14.4 ± 2.6, and the time to treatment was 2.9 ± 0.8 hours. Together, the two tenecteplase groups had greater reperfusion (P = 0.004) and clinical improvement (P < 0.001) at 24 hours than the alteplase group. There were no significant between-group differences in intracranial bleeding or other serious adverse events. The higher dose of tenecteplase (0.25 mg per kilogram) was superior to the lower dose and to alteplase for all efficacy outcomes, including absence of serious disability at 90 days (in 72% of patients, vs. 40% with alteplase; P = 0.02).” (M. Parsons, mark.parsons@hnehealth.nsw.gov.au)
Monoclonal Antibody for Lowering LDL Cholesterol: Three Phase I trials of a monoclonal antibody to an LDL-raising serine protease indicate that the agent can lower LDL cholesterol levels in healthy volunteers and patients with familial or nonfamilial hypercholesterolemia (pp. 1108–18). REGN727/SAR236553 (REGN727) targets proprotein convertase subtilisin/kexin 9. Administered intravenously or subcutaneously, REGN727 showed these effects: “Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of −39.2, −53.7, and −61.0 percentage points, respectively, as compared with placebo (P < 0.001 for all comparisons).” (E. A. Stein, aesteinmrl@aol.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 23, 2012 * Vol. 19, No. 57
Providing news and information about medications and their proper use

>>>Medical Care Highlights
Source:
Apr. issue of Medical Care (2012; 50).
Health Literacy & Instruction Recall: Adults aged 55–74 years had difficulty recalling spoken instructions delivered by health professionals at an academic internal medicine clinic and three federally qualified health centers, especially when they had low health literacy, a study shows (pp. 277–82). Medical instructions were provided to 755 patients for hypothetical wound care and GERD diagnosis. Recall was as follows: “The majority (71.6%) of participants had adequate health literacy skills, and these individuals performed significantly better in correctly recalling spoken information than those with marginal and low literacy in both scenarios: [wound care—mean (SD): low 2.5 (1.3) vs. marginal 3.5 (1.3) vs. adequate 4.6 (1.1); P < 0.001), GERD: low 4.2(1.7) vs. marginal 5.2 (1.7) vs. adequate 6.5 (1.7); P < 0.001]. Regardless of literacy level, overall recall of information was poor. Few recognized pain (28.5%) or fever (28.2%) as signs of infection. Only 40.5% of participants correctly recalled when to take their GERD pills.” (D. M. McCarthy)
Language Barriers & Hospital Discharge Instructions: In a study of 308 patients being discharged from two urban hospitals in 2005–08, understanding of a follow-up appointment and medication information was poor, particularly for those of limited English-proficiency (LEP) (pp. 283–9): “Of the 308 patients, 203 were LEP. Rates of understanding were low overall for follow-up appointment type (56%) and the 3 medication outcomes (category 48%, purpose 55%, both 41%). In unadjusted analysis, LEP patients were less likely than English-proficient patients to know appointment type (50% vs. 66%; P = 0.01), medication category (45% vs. 54%; P = 0.05), and medication category and purpose combined (38% vs. 47%; P = 0.04), but equally likely to know medication purpose alone. These results persisted in the adjusted models for medication outcomes: LEP patients had lower odds of understanding medication category (odds ratio 0.63; 95% confidence interval, 0.42–0.95); and category/purpose (odds ratio 0.59; 95% confidence interval, 0.39–0.89).” (L. S. Karliner)

>>>Health Affairs Report
Source:
Early-release article from and Mar. issue of Health Affairs (2012; 31).
Delaying ICD-10: CMS has “signaled” the agency may delay implementation of the new International Classification of Diseases (ICD-10-CM), and authors argue for that, noting that too much change in health information technology is already under way (10.1377/hlthaff.2011.1258): “We are concerned that adopting this new classification system for reimbursement will be disruptive and costly and will offer no material improvement over the current system. Because the health care community is also working to integrate health information technology and federal meaningful-use specifications that require the adoption of other complex coding standardization systems (such as the system called SNOMED CT), we recommend that the Centers for Medicare and Medicaid Services consider delaying the adoption of ICD-10-CM. Policy makers should also begin planning now for ways to make the coming transition to ICD-11 as tolerable as possible for the health care and payment community.” (C. G. Chute, chute@mayo.edu)
ACA Before Supreme Court: In advance of the Monday start of the Supreme Court’s oral arguments about the health care reform law, an author assesses three “sleeper” issues before the justices that go beyond the individual mandate to obtain health insurance (pp. 471–4): “One [issue] is whether the Court can actually decide the constitutionality of the individual mandate now—or must wait until the first penalty is assessed in 2015 for an individual not complying with the health insurance requirement. A second will determine whether—if the Court invalidates the mandate—the rest of the Affordable Care Act, a portion of the Act, or none of the Act has to be tossed out along with it.
“Perhaps the biggest sleeper of them all is the question of whether the states are being unconstitutionally coerced by the law’s requirement that they expand Medicaid to cover millions of the uninsured—even though the federal government will pay all the costs for the first two years, and 90 percent of the costs from 2020 on.” (T.R. Goldman,
trgoldman@earthlink.net)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 26, 2012 * Vol. 19, No. 58
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from the New England Journal of Medicine (2012; 366).
Vorapaxar for Secondary Atherothrombotic Prevention: In a study presented this weekend at the American College of Cardiology meeting in Chicago and released by NEJM in advance of print, vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis but also increased the risk of moderate or severe bleeding, including intracranial hemorrhage (10.1056/NEJMoa1200933). Based on a composite primary efficacy end point of death from cardiovascular causes, myocardial infarction, or stroke, the study showed these effects of vorapaxar 2.5 mg daily for a median of 30 months: “At 3 years, the primary end point had occurred in 1,028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P < 0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1,259 patients (11.2%) in the vorapaxar group and 1,417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P = 0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P < 0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P < 0.001).” (D. A. Morrow, dmorrow@partners.org)

>>>Lancet Highlights
Source:
Mar. 24 issue of Lancet (2012; 379).
Dutasteride in Prostate Cancer: “Dutasteride could provide a beneficial adjunct to active surveillance for men with low-risk prostate cancer,” conclude authors of a 3-year study of the 5-alpha reductase inhibitor (pp. 1103–11). Patients included in the trial were aged 48–82 years and had low-volume, Gleason score 5–6 prostate cancer and had elected active surveillance of their conditions. Once-daily dutasteride 0.5 mg or placebo showed these outcomes as determined by 12-core biopsies at 18 and 36 months: “Between Aug 10, 2006, and March 26, 2007, we randomly allocated 302 participants, of whom 289 (96%) had at least one biopsy procedure after baseline and were included in the primary analysis. By 3 years, 54 (38%) of 144 men in the dutasteride group and 70 (48%) of 145 controls had prostate cancer progression (pathological or therapeutic; hazard ratio 0.62, 95% CI 0.43–0.89; p = 0.009). Incidence of adverse events was much the same between treatment groups. 35 (24%) men in the dutasteride group and 23 (15%) controls had sexual adverse events or breast enlargement or tenderness. Eight (5%) men in the dutasteride group and seven (5%) controls had cardiovascular adverse events, but there were no prostate cancer-related deaths or instances of metastatic disease.” (N. E. Fleshner, neil.fleshner@utoronto.ca)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 344).
Nicotine Replacement Therapy & Telephone Quitline Support: Smoking cessation rates were not improved by free nicotine replacement therapy or proactive contact by personnel at a national telephone quitline in England, researchers report (e1696). A total of 2,591 nonpregnant smokers who called the quitline and agreed to set a quit date were randomized to standard support, proactive support, proactive support with nicotine replacement therapy, or standard support with nicotine replacement therapy. Results showed: “At six months, 17.7% (n = 229) of those offered nicotine replacement therapy reported smoking cessation compared with 20.1% (n = 261) not offered such therapy (odds ratio 0.85, 95% confidence interval 0.70 to 1.04), and 18.2% (n = 236) offered proactive counselling reported smoking cessation compared with 19.6% (n = 254) offered standard support (0.91, 0.75 to 1.11). Data validated by carbon monoxide readings changed the findings for nicotine replacement therapy only, with smoking cessation validated in 6.6% (85/1,295) of those offered nicotine replacement therapy compared with 9.4% (122/1,296) not offered such therapy (0.67, 0.50 to 0.90).” (T. Coleman, tim.coleman@nottingham.ac.uk)

>>>PNN JournalWatch
* Fish Consumption, Dietary Long-Chain n-3 Fatty Acids, and Risk of Type 2 Diabetes, in
Diabetes Care, 2012; 35: 918–29. (A. Wolk, alicja.wolk@ki.se)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 27, 2012 * Vol. 19, No. 59
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Mar. 26 issue of the Archives of Internal Medicine (2012; 172).
Improved Outcomes in Warfarin therapy: Patients with nonvalvular atrial fibrillation (AF) have low rates of residual stroke and systemic embolism when taking warfarin, according to a meta-analysis of eight randomized controlled trials that reported on 55,789 patient–years of therapy (10.1001/archinternmed.2012.121). Compared with a previously conducted meta-analysis, the proportion of time spent in therapeutic anticoagulation and stroke rates were significantly better, the authors note: “Overall time spent in the therapeutic range was 55% to 68%. The annual incidence of stroke or systemic embolism in patients with AF taking warfarin was estimated to be 1.66% (95% CI, 1.41%–1.91%). Major bleeding rates varied from 1.40% to 3.40% per year across the studies. The risk of stroke per year was significantly higher in elderly patients (2.27%), female patients (2.12%), patients with a history of stroke (2.64%), and patients reporting no previous exposure to vitamin K antagonists (1.96%). There was a significant increase in the annual incidence of stroke with progressively increasing CHADS2 (congestive heart failure, hypertension, age, diabetes, and prior stroke) scores.” (V. Menon, menonv@ccf.org)
Antipsychotic Use & MI in Treated Dementia: In Quebec in 2000–09, older community-dwelling patients being treated for dementia with cholinesterase inhibitors had greater risk of myocardial infarction, researchers report (10.1001/archinternmed.2012.28). The retrospective cohort analysis used the province’s prescription drug database to identify 37,138 new users of cholinesterase inhibitors, 10,969 of whom also started antipsychotic (AP) agents: “Within 1 year of initiating AP treatment, 1.3% of [those on both types of drugs] had an incident MI. Hazard ratios for the risk of MI after initiation of AP treatment were 2.19 (95% CI, 1.11–4.32) for the first 30 days, 1.62 (95% CI, 0.99–2.65) for the first 60 days, 1.36 (95% CI, 0.89–2.08) for the first 90 days, and 1.15 (95% CI, 0.89–1.47) for the first 365 days. [A] self-controlled case series study conducted among 804 incident cases of MI among new AP users yielded incidence rate ratios of 1.78 (95% CI, 1.26–2.52) for the 1- to 30-day period, 1.67 (95% CI, 1.09–2.56) for the 31- to 60-day period, and 1.37 (95% CI, 0.82–2.28) for the 61- to 90-day period.” (Y. Moride, yola.moride@umontreal.ca)
Motivational Interviewing & Osteoporosis Adherence: Telephonic motivational interviewing of patients starting drugs for osteoporosis failed to improve adherence over levels achieved with direct mail, a study shows (pp. 477–83). From a large pharmacy benefits program for Medicare beneficiaries, 2,087 participants were recruited. They received either telephone-based counseling using motivational interviewing or mailed educational materials, with these results: “The groups were balanced at baseline, with a mean age of 78 years; 93.8% were female. In an intention-to-treat analysis, median adherence was 49% (interquartile range, 7%–88%) in the intervention arm and 41% (2%–86%) in the control arm (P = .07, Kruskal-Wallis test). There were no differences in self-reported fractures.” (D. H. Solomon, dsolomon@partners.org)
Influenza Vaccine Effectiveness: Using the instrumental variable (IV) analysis method, investigators show that the impact of influenza vaccine in older patients is not as great as observational studies have indicated (pp. 484–91). Based on nearly 13 million person–influenza seasons of experience from Ontario, immunization significantly reduced the composite of hospitalizations for pneumonia and influenza and all-cause mortality but not for mortality alone, as noted here: “Logistic regression produced adjusted odds ratios of 0.67 (95% CI, 0.62-0.72) for all-cause mortality during influenza seasons and 0.85 (0.83-0.86) during post–influenza seasons when influenza is not circulating, suggesting the presence of bias. In contrast, IV analysis yielded adjusted odds ratios of 0.94 (95% CI, 0.84–1.03) during influenza seasons and 1.13 (1.07–1.19) during post–influenza seasons. For the composite of hospitalization for pneumonia and influenza and death, logistic regression produced adjusted odds ratios of 0.74 (95% CI, 0.70–0.78) during influenza seasons and 0.88 (0.87–0.90) during post–influenza seasons, whereas IV analysis produced adjusted odds ratios of 0.86 (95% CI, 0.79–0.92) and 1.02 (0.97–1.06), respectively.” (J. C. Kwong, jeff.kwong@utoronto.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 28, 2012 * Vol. 19, No. 60
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 28 issue of JAMA (2012; 307).
Adjuvant Imatinib in Operable GIST: Compared with 1 year of therapy with imatinib, 3 years’ adjuvant treatment produces superior outcomes in patients with operable gastrointestinal stromal tumor (GIST), a study shows (pp. 1265–72). Started within 12 weeks of GIST surgery, oral imatinib 400 mg/d for 12 or 36 months produced these effects on recurrence-free survival (RFS) in a Phase III, open-label trial in Europe: “Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32–0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22–0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence.” (H. Joensuu, heikki.joensuu@hus.fi)
Imatinib was approved earlier this year by FDA for adjuvant use after resection in adults with
KIT-positive GISTs (see PNN, Feb. 2), an editorialist notes (pp. 1312–4). FDA recommended 36 months of treatment but noted that the “optimal duration of treatment is unknown.”
“Some clinicians will use imatinib for a longer period, perhaps choosing to treat patients indefinitely,” the editorialist writes. “Investigators and clinicians alike will increasingly face the question of best postoperative duration of treatment with cytostatic, biologic targeted agents. However, correlative science provides little guidance. Laboratory biomarker studies may eventually provide information about which patients are unlikely to have recurrence, and thus are not capable of benefitting from any adjuvant therapy, but questions about curability or duration will not be answered by preclinical trials. As pathway-driven adjuvant therapy becomes more prolonged, increasing patients’ tolerance of even low-grade toxicities will be critical to improve their adherence to expensive treatments that could last for decades.” (C. D. Blanke,
cblanke@bccancer.bc.ca)
Medication Copayments & Health Services Use in Childhood Asthma: Higher copayments for asthma medications leads to slightly reduced use of the drugs in children aged 5 years or older with asthma and significantly higher rates of hospitalization for the disease, researchers report (pp. 1284–91). In 8,834 children who began asthma treatment in 1997–2007, insurance claims showed the following: “The mean annual out-of-pocket asthma medication cost was $154 (95% CI, $152–$156) among children aged 5 to 18 years and $151 (95% CI, $148–$153) among those younger than 5 years. Among 5,913 children aged 5 to 18 years, filled asthma prescriptions covered a mean of 40.9% of days (95% CI, 40.2%–41.5%). During 1-year follow-up, 121 children (2.1%) had an asthma-related hospitalization and 220 (3.7%) had an [emergency department (ED)] visit. Among 2,921 children younger than 5 years, mean medication use was 46.2% of days (95% CI, 45.2%–47.1%); 136 children (4.7%) had an asthma-related hospitalization and 231 (7.9%) had an ED visit. An increase in out-of-pocket medication costs from the 25th to the 75th percentile was associated with a reduction in adjusted medication use among children aged 5 to 18 years (41.7% [95% CI, 40.7%–42.7%] vs 40.3% [95% CI, 39.4%–41.3%] of days; P = .02) but no change among younger children. Adjusted rates of asthma-related hospitalization were higher for children aged 5 to 18 years in the top quartile of out-of-pocket costs (2.4 [95% CI, 1.9–2.8] hospitalizations per 100 children vs 1.7 [95% CI, 1.3–2.1] per 100 in bottom quartile; P = .004) but not for younger children. Annual adjusted rates of ED use did not vary across out-of-pocket quartiles for either age group.” (A. B. Jena, jena.anupam@mgh.harvard.edu)

>>>PNN NewsWatch
* Peginesatide (Omontys, Affymax) was approved by FDA yesterday for treatment of anemia in adult dialysis patients with chronic kidney disease. The erythropoietic agent is given once a month.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 29, 2012 * Vol. 19, No. 61
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 29 issue of the New England Journal of Medicine (2012; 366).
Interleukin-2 Agents for Plaque Psoriasis: Two studies and an editorial discuss use of interleukin-17 modifiers in plaque psoriasis.
In a Phase II trial of 198 patients with plaque psoriasis, the human anti–interleukin-17–receptor monoclonal antibody brodalumab (AMG 827) significantly improved psoriasis area-and-severity index (PASI) scores over a 12-week period (
pp. 1181–9). Participants had moderate-to-severe plaque psoriasis on admission to the dose-ranging study, which produced these results: “At week 12, the mean percentage improvements in the PASI score were 45.0% among patients receiving 70 mg of brodalumab, 85.9% among those receiving 140 mg, 86.3% among those receiving 210 mg, 76.0% among those receiving 280 mg, and 16.0% among those receiving placebo (P < 0.001 for all comparisons with placebo). An improvement of at least 75% and at least 90% in the PASI score at week 12 was seen in 77% and 72%, respectively, of the patients in the 140-mg brodalumab group and in 82% and 75%, respectively, of the patients in the 210-mg group, as compared with 0% in the placebo group (P < 0.001 for all comparisons). The percentage of patients with a static physician’s global assessment of clear or minimal disease was 26%, 85%, 80%, and 69% with the 70-mg, 140-mg, 210-mg, and 280-mg doses, respectively, of brodalumab, as compared with 3% with placebo (P < 0.01 for all comparisons with placebo). Two cases of grade 3 neutropenia were reported in the 210-mg brodalumab group. The most commonly reported adverse events in the combined brodalumab groups were nasopharyngitis (8%), upper respiratory tract infection (8%), and injection-site erythema (6%).” (K. A. Papp, kapapp@probitymedical.com)
A second Phase II study examined ixekizumab (LY2439821), a humanized anti–interleukin-17 monoclonal antibody, for psoriasis treatment (
pp. 1190–9). Various doses of the drug produced these changes in PASI scores at 12 weeks in 142 patients with chronic moderate-to-severe plaque psoriasis: “The percentage of patients with a reduction in the PASI score by at least 75% was significantly greater with ixekizumab (except with the lowest, 10-mg dose)—150 mg (82.1%), 75 mg (82.8%), and 25 mg (76.7%)—than with placebo (7.7%, P < 0.001 for each comparison), as was the percentage of patients with a reduction in the PASI score by at least 90%: 150 mg (71.4%), 75 mg (58.6%), and 25 mg (50.0%) versus placebo (0%, P < 0.001 for each comparison). Similarly, a 100% reduction in the PASI score was achieved in significantly more patients in the 150-mg group (39.3%) and the 75-mg group (37.9%) than in the placebo group (0%) (P < 0.001 for both comparisons). Significant differences occurred at as early as 1 week and were sustained through 20 weeks. Adverse events occurred in 63% of patients in both the combined ixekizumab groups and in the placebo group. No serious adverse events or major cardiovascular events were observed.” (C. Leonardi, aleonardi@centralderm.com)
Interleukin-17 is “an important cytokine in host defense,” writes an editorialist, but “much more evidence exists for the role of tumor necrosis factor (TNF) in these responses” (
pp. 1251–2). Still, the prospects of drugs targeting interleukin-17 are positive, he adds, largely because of “side effects [of anti-TNF agents] such as severe infections and the formation of antidrug antibodies.” (A. Waisman)
Severability of the Individual Mandate: Whether the Supreme Court can find the individual mandate provision of the Affordable Care Act unconstitutional but uphold the rest of the law is discussed in a Perspective article (e19). The analysis is particularly cogent in view of this week’s oral arguments before the Court, where the individual mandate appeared likely to be viewed as Congressional overreaching based on the Commerce Clause of the U.S. Constitution by a majority of the justices. (S. Y. Sessions)

>>>PNN NewsWatch
* Citalopram should not be used in daily doses higher than 40 mg, FDA said yesterday, because of the possibility of arrhythmias. Use of the antidepressant at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation, FDA added. A revised drug label describes precautions useful in lower-risk patients and says that reduced doses should be used in patients older than 60 years.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.

PNN Pharmacotherapy Line
Mar. 30, 2012 * Vol. 19, No. 62
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Apr. issue of Diabetes Care (2012; 35).
Metformin & Diabetes Prevention: Prevention of type 2 diabetes with metformin is explored in two studies and an editorial.
The studies were conducted by the Diabetes Prevention Program Research Group (
dppmail@bsc.gwu.edu). From the payer perspective, lifestyle changes were cost-effective and metformin was marginally cost-saving, compared with placebo, for prevention of type 2 diabetes over a 10-year period (pp. 723–30). The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) showed these results with intensive lifestyle intervention or metformin in high-risk adults: “Over 10 years, the cumulative, undiscounted per capita direct medical costs of the interventions, as implemented during the DPP, were greater for lifestyle ($4,601) than metformin ($2,300) or placebo ($769). The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ($24,563 lifestyle vs. $25,616 metformin vs. $27,468 placebo). The cumulative, combined total direct medical costs were greatest for lifestyle and least for metformin ($29,164 lifestyle vs. $27,915 metformin vs. $28,236 placebo). The cumulative quality-adjusted life–years (QALYs) accrued over 10 years were greater for lifestyle (6.81) than metformin (6.69) or placebo (6.67). When costs and outcomes were discounted at 3%, lifestyle cost $10,037 per QALY, and metformin had slightly lower costs and nearly the same QALYs as placebo.”
Adding the experiences of an open-label extension to those of the double-blind portion of DPP, investigators showed that metformin “for diabetes prevention is safe and well tolerated” and that “weight loss is related to adherence to metformin and is durable for at least 10 years of treatment” (
pp. 731–7): “No significant safety issues were identified. Gastrointestinal symptoms were more common in metformin than placebo participants and declined over time. During the DPP, average hemoglobin and hematocrit levels were slightly lower in the metformin group than in the placebo group. Decreases in hemoglobin and hematocrit in the metformin group occurred during the first year following randomization, with no further changes observed over time. During the DPP, metformin participants had reduced body weight and waist circumference compared with placebo (weight by 2.06 ± 5.65% vs. 0.02 ± 5.52%, P < 0.001, and waist circumference by 2.13 ± 7.06 cm vs. 0.79 ± 6.54 cm, P < 0.001 in metformin vs. placebo, respectively). The magnitude of weight loss during the 2-year double-blind period was directly related to adherence (P < 0.001). Throughout the unblinded follow-up, weight loss remained significantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P < 0.001), and this was related to the degree of continuing metformin adherence (P < 0.001).”
“With the current economic realities facing our nation and with the ever-changing health care delivery landscape, the financial costs of [preventive metformin] will indeed drive the discussion,” an editorialist comments (
pp. 663–5). “On the one hand, one can argue that we cannot afford to implement prevention on a national level. On the other hand, we could also argue that we cannot afford not to! Perhaps one day the clinical research findings regarding delaying progression to type 2 diabetes in high-risk populations will become an integral and routine aspect of our health care system.” (W. T. Cefalu)
Long-Term, Once-Weekly Exenatide: In an 84-week extension of a 26-week trial, exenatide once weekly (EQW) showed sustained superior glycemic control, greater weight loss, and less hyperglycemia than did daily insulin glargine (IG) in 415 patients with type 2 diabetes (pp. 683–9). A1C levels fell more with EQW (1.2 v. 1.0 percentage points), and larger proportions of patients achieved A1C targets of 7 (44.6% v. 36.8%). The authors add, “Patients taking EQW lost 2.1 kg of body weight, whereas those taking IG gained 2.4 kg (P < 0.001). Among patients taking metformin plus sulfonylurea, the incidence of minor hypoglycemia was 24% for EQW patients vs. 54% for IG patients (P < 0.001); among patients taking metformin alone, it was 8% for EQW patients vs. 32% for IG patients (P < 0.001). Among adverse events occurring in ≥5% of patients, diarrhea and nausea occurred more frequently (P < 0.05) in the EQW group than in the IG group (12 vs. 6% and 15 vs. 1%, respectively).” (M. Diamant, m.diamant@vumc.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at http://homepage.mac.com/lmposey/PNN.