Jun 2013

PNN April–June 2013

PNN Pharmacotherapy Line
Apr. 1, 2013 * Vol. 20, No. 62
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 30 issue of Lancet (2013; 381).
Clopidogrel, Aspirin & Oral Anticoagulation: In the WOEST study, patients undergoing percutaneous coronary interventions had fewer bleeding complications with clopidogrel plus oral anticoagulants when aspirin was dropped from the regimen (pp. 1107–15). The open-label trial, conducted in Belgium and the Netherlands, assessed a primary outcome of any bleeding episode within 1 year of PCI with double versus triple therapy: “573 patients were enrolled and 1-year data were available for 279 (98.2%) patients assigned double therapy and 284 (98.3%) assigned triple therapy. Mean ages were 70.3 (SD 7.0) years and 69.5 (8.0) years, respectively. Bleeding episodes were seen in 54 (19.4%) patients receiving double therapy and in 126 (44.4%) receiving triple therapy (hazard ratio [HR] 0.36, 95% CI 0.26–0.50, p < 0.0001). In the double-therapy group, six (2.2%) patients had multiple bleeding events, compared with 34 (12.0%) in the triple-therapy group. 11 (3.9%) patients receiving double therapy required at least one blood transfusion, compared with 27 (9.5%) patients in the triple-therapy group (odds ratio from Kaplan–Meier curve 0.39, 95% CI 0.17–0.84, p = 0.011).” (W. J. M. Dewilde, willemdewilde@yahoo.com)
Chlorhexidine Bathing in Critically Ill Children: Among 4,947 admissions of critically ill children at 10 U.S. units, the incidence of bacteremia was significantly reduced by daily chlorhexidine baths, compared with standard baths, researchers report (pp. 1099–106). The Pediatric SCRUB Trial Study Group reports that intention-to-treat results showed a nonsignificant 29% reduction in bacteremia incidence and a significant 36% reduction in per-protocol results with chlorhexidine. (A. M. Milstone, amilsto1@jhmi.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Vitamin D in Pregnancy & Neonatal Outcomes: A systematic review and meta-analysis finds that “vitamin D insufficiency is associated with an increased risk of gestational diabetes, pre-eclampsia, and small for gestational age infants” (f1169): “3,357 studies were identified and reviewed for eligibility. 31 eligible studies were included in the final analysis. Insufficient serum levels of 25-OHD were associated with gestational diabetes (pooled odds ratio 1.49, 95% confidence interval 1.18 to 1.89), pre-eclampsia (1.79, 1.25 to 2.58), and small for gestational age infants (1.85, 1.52 to 2.26). Pregnant women with low serum 25-OHD levels had an increased risk of bacterial vaginosis and low birthweight infants but not delivery by caesarean section.” (D. M. Rabi, oreen.Rabi@albertahealthservices.ca">Doreen.Rabi@albertahealthservices.ca)

>>>PNN NewsWatch
* FDA on Friday approved canagliflozin (Invokana, Janssen), a first-in-class agent for treatment of adults with type 2 diabetes. The sodium glucose co-transporter 2 (SGLT2) inhibitor is the only oral, once-daily medication available in the U.S. that offers improved glycemic control while also showing reduced body weight and systolic blood pressure in clinical trials, Janssen said in a news release. The drug works by blocking the reabsorption of glucose by the kidney, increasing glucose excretion, and lowering blood glucose levels in patients with diabetes who have elevated blood glucose levels. Its safety and effectiveness were evaluated in nine clinical trials involving over 10,285 patients with type 2 diabetes. The trials showed improvement in hemoglobin A1c levels and fasting plasma glucose levels, FDA said. The drug’s most common adverse effects are vulvovaginal candidiasis and urinary tract infection. Because canagliflozin is associated with a diuretic effect, it can cause a reduction in intravascular volume leading to orthostatic or postural hypotension. This may result in symptoms such as dizziness or fainting, particularly during the first 3 months of therapy.

>>>PNN JournalWatch
* Preexposure Prophylaxis for Adolescents and Young Adults at Risk for HIV Infection: Is an Ounce of Prevention Worth a Pound of Cure?, in
Clinical Infectious Diseases, 2013; 56: 1149–55. (B. G. Kapogiannis, kapogiannisb@mail.nih.gov)
* Pulmonary Hypertension in CKD, in
American Journal of Kidney Diseases, 2013; 61: 612–22. (C. Zoccali, carmine.zoccali@tin.it)
* Use and Spending on Antineoplastic Therapy for Medicare Beneficiaries With Cancer, in
Medical Care, 2013; 51: 351–60. (A. J. Davidoff)

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

PNN Pharmacotherapy Line
Apr. 2, 2013 * Vol. 20, No. 63
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 2 issue of the Annals of Internal Medicine (2013; 158).
Stopping Statins: Statins are often discontinued after an adverse event believed related to the drugs, a study shows, but many patients who are rechallenged are able to continue therapy with the same agent (pp. 526–34). In a retrospective cohort study, investigators combed electronic health records to determine reasons for discontinuation of statins in adult patients at two medical centers who received prescriptions for statins in 2000–08. Results showed: “Statins were discontinued at least temporarily for 57,292 of 107,835 patients. Statin-related events were documented for 18,778 (17.4%) patients. Of these, 11,124 had statins discontinued at least temporarily; 6,579 were rechallenged with a statin over the subsequent 12 months. Most patients who were rechallenged (92.2%) were still taking a statin 12 months after the statin-related event. Among the 2,721 patients who were rechallenged with the same statin to which they had a statin-related event, 1,295 were receiving the same statin 12 months later, and 996 of them were receiving the same or a higher dose.” (A. Turchin, aturchin@partners.org)
In assessing strengths and weaknesses of this study, the author of an accompanying editorial notes that adherence could be an issue because patients are not accustomed to taking a drug every day for the rest of their lives (
pp. 562–3). Regardless, he writes that better strategies are needed to promote statin adherence because statins can greatly reduce population prevalence of atherosclerotic cardiovascular disease. (S. M. Grundy)
Medical Management of Recurrent Nephrolithiasis: Increased fluid intake is generally sufficient for preventing recurrence in patients who have had one prior calcium kidney stone, according to authors of a systematic review (pp. 535–43). Patients with more past calcium stones should be treated with thiazides, citrate, or allopurinol, the group concludes: “In patients with 1 past calcium stone, low-strength evidence showed that increased fluid intake halved recurrent composite stone risk compared with no treatment (relative risk [RR], 0.45 [95% CI, 0.24 to 0.84]). Low-strength evidence showed that reducing soft-drink consumption decreased recurrent symptomatic stone risk (RR, 0.83 [CI, 0.71 to 0.98]). In patients with multiple past calcium stones, most of whom were receiving increased fluid intake, moderate-strength evidence showed that thiazides (RR, 0.52 [CI, 0.39 to 0.69]), citrates (RR, 0.25 [CI, 0.14 to 0.44]), and allopurinol (RR, 0.59 [CI, 0.42 to 0.84]) each further reduced composite stone recurrence risk compared with placebo or control, although the benefit from allopurinol seemed limited to patients with baseline hyperuricemia or hyperuricosuria. Other baseline biochemistry measures did not allow prediction of treatment efficacy. Low-strength evidence showed that neither citrate nor allopurinol combined with thiazide was superior to thiazide alone. There were few withdrawals among patients with increased fluid intake, many among those with other dietary interventions and more among those who received thiazide and citrate than among control patients. Reporting of adverse events was poor.” (H. A. Fink, howard.fink@va.gov)
Financial Incentives for Weight Loss: Among 105 employees of a children’s hospital with obesity, group financial incentives were more effective than individual payments for promoting weight loss over 24 weeks, a study shows (pp. 505–14). In the individual group, those who met or exceeded weight-loss goals received $100 per month; groups of 5 employees could split $500 per month for losing weight. Results showed: “Group-incentive participants lost more weight than control participants (mean between-group difference, 4.4 kg [95% CI, 2.0 to 6.7 kg]; P < 0.001) and individual-incentive participants (mean between-group difference, 3.2 kg [CI, 0.9 to 5.5 kg]; P = 0.008).” (J. T. Kullgren, jkullgre@med.umich.edu)

>>>PNN NewsWatch
* FDA has announced changes in the product labeling of OTC nicotine-replacement products used in smoking cessation. The new language advises consumers that it is safe in most cases to continue use for longer than the time periods indicated on the label. FDA also removed a warning that consumers should not use the products if they are still using tobacco products or other forms of nicotine replacement.

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

PNN Pharmacotherapy Line
Apr. 3, 2013 * Vol. 20, No. 64
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 3 issue of JAMA (2013; 309).
Duloxetine & Chemotherapy-Induced Peripheral Neuropathy: Five weeks of duloxetine significantly reduced symptoms in patients with painful chemotherapy-induced peripheral neuropathy, compared with placebo, according to a study of 231 patients (pp. 1359–67). Based on the Brief Pain Inventory-Short Form average-pain item, patients had these responses to duloxetine 30 mg daily for 1 week and 60 mg daily for 4 additional weeks: “Individuals receiving duloxetine as their initial 5-week treatment reported a mean decrease in average pain of 1.06 (95% CI, 0.72–1.40) vs 0.34 (95% CI, 0.01–0.66) among those who received placebo (P = .003; effect size, 0.513). The observed mean difference in the average pain score between duloxetine and placebo was 0.73 (95% CI, 0.26–1.20). Fifty-nine percent of those initially receiving duloxetine vs 38% of those initially receiving placebo reported decreased pain of any amount.” (E. M. Lavoie Smith, ellenls@umich.edu)
S. aureus Vaccine & Cardiothoracic Surgery: The investigational V710 vaccine against Staphylococcus aureus failed to prevent serious postoperative infections among patients undergoing median sternotomy and was associated with increased mortality when infections did occur, researchers report (pp. 1368–78). Patients received vaccine (n = 4,015) or placebo (n = 4,016) 14–60 days before cardiothoracic surgery, with these results: “The independent data monitoring committee recommended termination of the study after the second interim analysis because of safety concerns and low efficacy. At the end of the study, the V710 vaccine was not significantly more efficacious than placebo in preventing either [prevention of S. aureus bacteremia and/or deep sternal wound infection (including mediastinitis) through postoperative day 90] (22/3,528 V710 vaccine recipients [2.6 per 100 person–years] vs 27/3,517 placebo recipients [3.2 per 100 person–years]; relative risk, 0.81; 95% CI, 0.44-1.48; P = .58) or secondary end points despite eliciting robust antibody responses. Compared with placebo, the V710 vaccine was associated with more adverse experiences during the first 14 days after vaccination (1,219/3,958 vaccine recipients [30.8%; 95% CI, 29.4%–32.3%] and 866/3,967 placebo recipients [21.8%; 95% CI, 20.6%–23.1%], including 797 [20.1%; 95% CI, 18.9%–21.4%] and 378 [9.5%; 95% CI, 8.6%–10.5%] with injection site reactions and 66 [1.7%; 95% CI, 1.3%–2.1%] and 51 [1.3%; 95% CI, 1.0%–1.7%] with serious adverse events, respectively) and a significantly higher rate of multiorgan failure during the entire study (31 vs 17 events; 0.9 [95% CI, 0.6–1.2] vs 0.5 [95% CI, 0.3–0.8] events per 100 person–years; P = .04).” (V. G. Fowler Jr, fowle003@mc.duke.edu)
“The search continues” for an effective way of preventing postoperative
S. aureus infections, an editorialist writes (pp. 1408–9): “In 2008, the Centers for Medicare & Medicaid Services announced new nonpayment policies for preventable infections, including post-[coronary artery bypass graft] mediastinitis. While the ‘preventability’ of mediastinitis can be debated, these changes in reimbursement provide additional impetus to make significant investments in prevention. Infection prevention is fundamental for high-quality patient care. Even in this era of budgetary belt-tightening, adequate resources are essential to achieve meaningful change. Ultimately, the results of the study by Fowler et al say more about the need to rigorously study infection prevention in general than about S aureus per se.” (P. N. Malani, pmalani@umich.edu)
Melatonin & Type 2 Diabetes: “Further research is warranted to assess if melatonin secretion is a modifiable risk factor for diabetes within the general population,” authors conclude, based on findings of lower melatonin secretion among 370 women in the Nurses Health Study who had significantly increased risk of developing type 2 diabetes (pp. 1388–96). The case–control study produced these findings: “The median urinary ratios of 6-sulfatoxymelatonin to creatinine were 28.2 ng/mg (5%–95% range, 5.5–84.2 ng/mg) among cases and 36.3 ng/mg (5%–95% range, 6.9–110.8 ng/mg) among controls. Women with lower ratios of 6-sulfatoxymelatonin to creatinine had increased risk of diabetes (multivariable odds ratio, 1.48 [95% CI, 1.11–1.98] per unit decrease in the estimated log ratio of 6-sulfatoxymelatonin to creatinine).” (C. J. McMullan, cmcmullan1@partners.org)

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

PNN Pharmacotherapy Line
Apr. 4, 2013 * Vol. 20, No. 65
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 4 issue of the New England Journal of Medicine (2013; 368).
Antifungals for Cryptococcal Meningitis: Among 299 patients with cryptococcal meningitis, survival was improved with amphotericin B plus flucytosine, compared with amphotericin B alone, but amphotericin B plus fluconazole produced no survival benefit (pp. 1291–302). The open-label trial found these results with amphotericin B 1 mg/kg for 4 weeks (group 1) or 2 weeks (group 2, with flucytosine 100 mg/kg; group 3, with fluconazole 400 mg twice daily): “Fewer deaths occurred by days 14 and 70 among patients receiving amphotericin B and flucytosine than among those receiving amphotericin B alone (15 vs. 25 deaths by day 14; hazard ratio, 0.57; 95% confidence interval [CI], 0.30 to 1.08; unadjusted P = 0.08; and 30 vs. 44 deaths by day 70; hazard ratio, 0.61; 95% CI, 0.39 to 0.97; unadjusted P=0.04). Combination therapy with fluconazole had no significant effect on survival, as compared with monotherapy (hazard ratio for death by 14 days, 0.78; 95% CI, 0.44 to 1.41; P = 0.42; hazard ratio for death by 70 days, 0.71; 95% CI, 0.45 to 1.11; P = 0.13). Amphotericin B plus flucytosine was associated with significantly increased rates of yeast clearance from cerebrospinal fluid (−0.42 log10 colony-forming units [CFU] per milliliter per day vs. −0.31 and −0.32 log10 CFU per milliliter per day in groups 1 and 3, respectively; P < 0.001 for both comparisons). Rates of adverse events were similar in all groups, although neutropenia was more frequent in patients receiving a combination therapy.” (J. N. Day, jday@oucru.org)
“Cryptococcosis is the most common invasive fungal infection in the world and one of the most deadly,” an editorialist writes (
pp. 1354–6). “Robust studies like this trial provide important insights for how to manage cryptococcal meningitis better, and it is our job to implement its initial therapeutic principles, such as the use of rapid fungicidal regimens, worldwide.” (J. R. Perfect)
Cangrelor Platelet Inhibition During PCI: In 11,145 patients undergoing percutaneous coronary intervention (PCI), ischemic event frequencies were reduced with use of cangrelor, compared with clopidogrel, according to investigators with the CHAMPION PHOENIX trial (pp. 1303–13). Both urgent and elective PCIs were included in the study, which used a primary efficacy end point of a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization: “The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P = 0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P = 0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P = 0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.” (D. L. Bhatt, dlbhattmd@post.harvard.edu)
This study does not clearly define the place of cangrelor in dual antiplatelet therapy, editorialists write (
pp. 1356–7): “In the patients given cangrelor, a maximal antiplatelet effect was operative before and during PCI; this was not true in the case of the patients treated with clopidogrel. Approximately one fourth of the patients who were randomly assigned to clopidogrel received a 300-mg loading dose, which is inferior to a dose of 600 mg in achieving platelet inhibition and preventing periprocedural ischemic events. Furthermore, 37% of the patients in the clopidogrel group received the drug during or after PCI; as a result, the antiplatelet effects of clopidogrel were suboptimal at the time of PCI.” (R. A. Lange)

>>>PNN NewsWatch
* CVS Pharmacy will pay $11 million to the U.S. to settle civil penalty claims for recordkeeping violations under the Controlled Substances Act, the Department of Justice announced yesterday.

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

PNN Pharmacotherapy Line
Apr. 5, 2013 * Vol. 20, No. 66
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Apr. issue of Pharmacotherapy (2013; 33).
Asthma Drugs & Congenital Anomalies: Poor pregnancy outcomes observed among women with asthma are not the result of drug-induced congenital anomalies during the first trimester of pregnancy, according to a matched cohort analysis of the U.K. General Practice Research Database (pp. 363–8). Investigators found prevalences of any anomalies of 27.8 and 31.3 per 1,000 pregnancies, a relative risk of 1.1 (1.0–1.3). The group concludes: “We found no significant increased risk of congenital anomalies associated with exposure to asthma drugs in the first trimester of pregnancy. Also, the severity of asthma was not associated with an increased risk of congenital anomalies.” (S. S. Jick, sjick@bu.edu)
Trazodone & Field Sobriety Tests: Patients taking trazodone may be cognitively impaired while driving, according to results of a repeated-measures study of 45 healthy adults (pp. 369–74). Participants took the standardized field sobriety test (SFST), which includes the horizontal gaze nystagmus, walk-and-turn, and one-leg stand tests. Comparing single doses of trazodone 100 mg (n = 30) and acetaminophen 650 mg (n = 15), the researchers found these results: “At 2 hours post drug administration, there were no statistical differences in failure rates between the trazodone and acetaminophen groups (53.3% vs 20.0%, p = 0.054). However, the trazodone group exhibited more impairment clues within the individual tests of the SFST than the acetaminophen group.” (E. J. Ip, eric.ip@tu.edu)
Vancomycin in Pediatric Critical Care: In a retrospective cohort study of 113 patients receiving vancomycin in a pediatric intensive care unit, maintenance of the drug at levels exceeding 15 mcg/mL was not associated with increased rates of nephrotoxicity (pp. 392–400). Compared with a nephrotoxicity rate of 5.4% in a control group, 8.8% of patients with high trough vancomycin target levels had grade 1 nephrotoxicity, not a significant difference. Univariate and multiple variable analysis revealed significant relationships between nephrotoxicity and duration of vancomycin therapy, use of extracorporeal membrane oxygenation, and vasopressor use. (J. J. Cies, jeffrey.cies@gmail.com)
Professional Development for Clinical Pharmacists: ACCP’s desired professional development pathway for clinical pharmacists is described as “a lifelong, systematic process” in a document authored by the College’s 2012 Certification Affairs Committee (pp. e34–42): “After initial licensure within the state or jurisdiction in which the pharmacist intends to practice, completion of an accredited PGY1 pharmacy residency is recommended to further develop the knowledge and skills needed to optimize medication therapy outcomes. An accredited PGY2 pharmacy residency should be completed if a pharmacist wishes to seek employment in a specific therapeutic area or practice setting, if such a residency exists. Clinical pharmacists intending to conduct advanced research that is competitive for federal funding are encouraged to complete a fellowship or graduate education. Initial certification by the Board of Pharmacy Specialties or other appropriate sponsoring organizations should be completed in the desired primary therapeutic area or practice setting within 2 years after accepting a position within the desired specific therapeutic area or practice setting. Clinical pharmacists subsequently will need to meet the requirements to maintain pharmacist licensure and board certification. Traineeships, practice-based activities, and certificate programs can be used to obtain additional knowledge and skills that support professional growth.” (S. S. Shord, stacy.shord@fda.hhs.gov)

>>>PNN NewsWatch
* Citing a 313% increase in opioid-related deaths in the first decade of the this century, FDA Commissioner Margaret A. Hamburg blogs this week about the need for society to react “when pain relievers cause pain.” She describes a comprehensive approach the agency is taking. It includes encouraging basic research and development of abuse-deterrent formulations of opioids, modifying labeling, educating prescribers and patients, supporting mandatory training of prescribers before they register with DEA, finding innovative ways to package and store opioids, and improving the availability of products to treat abuse and overdose.

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

PNN Pharmacotherapy Line
Apr. 8, 2013 * Vol. 20, No. 67
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 6 issue of Lancet (2013; 381).
Bendamustine for Indolent, Mantle-Cell Lymphomas: Based on a study of 514 previously untreated patients with stage III or IV indolent or mantle-cell lymphoma, bendamustine plus rituximab may be a preferred first-line treatment for indolent lymphoma, yielding greater increases in progression-free survival than rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) (R-CHOP), researchers report (pp. 1203–10). The noninferiority study used a margin of 10% to make these findings: “At median follow-up of 45 months (IQR 25–57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2–65.7]; hazard ratio 0.58, 95% CI 0.44–0.74; p < 0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who received ≥3 cycles; p < 0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p < 0.0001), infections (96 [37%] vs 127 [50%]); p = 0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p < 0.0001), and stomatitis (16 [6%] vs 47 [19%]; p < 0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p = 0.024).” (M. J. Rummel, mathias.rummel@innere.med.uni-giessen.de)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Sodium, Potassium Intake: Three systematic reviews and meta-analyses examine diets high in potassium and low in sodium.
In hypertensive and normotensive individuals, reduced dietary sodium “causes significant and, from a population viewpoint, important falls in blood pressure,” authors conclude based on 34 trials of 3,230 people (
f1325): “Salt reduction is associated with a small physiological increase in plasma renin activity, aldosterone, and noradrenaline and no significant change in lipid concentrations. These results support a reduction in population salt intake, which will lower population blood pressure and thereby reduce cardiovascular disease. The observed significant association between the reduction in 24 hour urinary sodium and the fall in systolic blood pressure, indicates that larger reductions in salt intake will lead to larger falls in systolic blood pressure. The current recommendations to reduce salt intake from 9–12 to 5–6 g/day will have a major effect on blood pressure, but a further reduction to 3 g/day will have a greater effect and should become the long term target for population salt intake.” (F. J. He, f.he@qmul.ac.uk)
Data from 51 studies confirm this benefit of reduced sodium intake and further show that the intervention “has no adverse effect on blood lipids, catecholamine levels, or renal function” and exhibits a blood pressure benefit in children (
f1326). “Lower sodium intake is also associated with a reduced risk of stroke and fatal coronary heart disease in adults,” the authors add. “The totality of evidence suggests that most people will likely benefit from reducing sodium intake.” (N. J. Aburto, nancy.aburto@wfp.org)
Higher potassium intake mirrors these benefits of reduced sodium intake, the same research group reports (
f1378). In 33 studies showing reduced blood pressure with higher dietary potassium, findings also indicate: “Higher potassium intake was associated with a 24% lower risk of stroke (moderate quality evidence). These results suggest that increased potassium intake is potentially beneficial to most people without impaired renal handling of potassium for the prevention and control of elevated blood pressure and stroke.” (N. J. Aburto, nancy.aburto@wfp.org)

>>>PNN JournalWatch
* Preterm Birth and the Metabolic Syndrome in Adult Life: A Systematic Review and Meta-analysis, in
Pediatrics, 2013; 131: e1240–63. (J. R. C. Parkinson)
* Effects of Daily Iron Supplementation in 2- to 5-Year-Old Children: Systematic Review and Meta-analysis, in
Pediatrics, 2013; 131: 739–53. (J. Thompson)
* Clinical Update on the Management of Atrial Fibrillation, in
Pharmacotherapy, 2013; 33: 422–46. (I. Danelich, ilya.danelich@gmail.com)
* Compounding Pharmacy Conundrum: “We Cannot Live Without Them But We Cannot Live With Them” According to the Present Paradigm, in
Chest, 2013; 143: 896–900. (R. Guharoy, Roy.Guharoy1@umassmed.edu)

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

PNN Pharmacotherapy Line
Apr. 9, 2013 * Vol. 20, No. 68
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 8 issue of the JAMA Internal Medicine (2013; 173).
Mortality, Rehospitalization with High-Dose PPIs: In a study of 491 hospitalized patients with an average age of 80, mortality was increased over the following year among those treated with use of proton-pump inhibitors (PPIs) in regular and high doses (pp. 518–23). Using a time-dependent Cox proportional hazards regression analysis, investigators found these relationships between PPI use and mortality or a combined end point of death or rehospitalization: “The use of PPIs was independently associated with mortality (hazard ratio, 1.51 [95% CI, 1.03–2.77]) but not with the combined end point (1.49 [0.98–2.17]). An increased risk of mortality was observed among patients exposed to high-dose PPIs vs none (hazard ratio, 2.59 [95% CI, 1.22–7.16]).” (M. Maggio, marcellomaggio2001@yahoo.it)
Editorialists discuss the logic of PPIs for life in light of these and other research findings (
pp. 524–5): “Simply because a patient has tolerated a therapy for a long duration does not mean that it remains an appropriate treatment. Thoughtful review of a patient’s medication regimen in the context of any changes in medical status and potential future benefits should occur regularly, and those agents that may no longer be necessary should be considered for a trial of medication discontinuation. Further research to examine the perspectives of the key players involved in the decision—patients and providers—and the clinical, behavioral, cultural, and organizational factors that act as facilitators of and barriers to appropriate discontinuation of medication can enhance efforts to improve safe medication prescribing.” (A. Linsky, amy.linsky@va.gov)
GLP-1 Therapies & Pancreatitis: A population-based case–control study shows increased risk of hospitalization for pancreatitis among patients receiving glucagonlike peptide 1 (GLP-1)–based therapies such as exenatide and sitagliptin (pp. 534–9). Data from a large U.S. administrative database showed the following associations in patients hospitalized for pancreatitis (cases) and matched controls: “The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1–based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36–3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37–3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.” (S. Singh, sosingh@jhsph.edu)
Editorialists write that this study provides a timely reminder to clinicians (
pp. 539–41): “The GLP-1 class of drugs is heavily promoted (and prescribed) as having purported advantages that outweigh its risks. Singh and colleagues provide a timely reminder that, despite large numbers of underpowered studies claiming the contrary from marketing companies, little is yet known about long-term adverse effects of the GLP-1 class of drugs on the exocrine pancreas. Unfortunate recent history documents unacceptable delays by regulatory authorities to act on serious adverse effects detected in postmarketing surveillance of drugs for [type 2 diabetes], deemed 2 times a farce by [one writer in the case of rosiglitazone]. We hope history will not repeat itself with the GLP-1–based drugs, because in this case, 3 times would not be a charm.” (P. C. Butler, pbutler@mednet.ucla.edu)
Treatment of Restless Legs Syndrome: Dopamine agonists and calcium channel alpha-2-delta ligands are effective for reducing symptoms in patients with restless legs syndrome (RLS), conclude authors of a systematic review and meta-analysis (pp. 496–505). Patients with RLS had a 50% or greater reduction from baseline in mean [International Restless Legs Syndrome] symptom scale scores with dopamine agonist therapy compared with placebo (61% vs 41%) (risk ratio, 1.60 [95% CI, 1.38–1.86]; 7 trials) and calcium channel alpha-2-delta ligands compared with placebo (61% vs 37%) (risk ratio, 1.66 [95% CI, 1.33–2.09]; 3 trials). (T. J. Wilt, Tim.Wilt@va.gov)

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

PNN Pharmacotherapy Line
Apr. 10, 2013 * Vol. 20, No. 69
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 10 issue of JAMA, a genomics theme issue (2013; 309).
Genomics & Alzheimer Disease: In a meta-analysis of genetic data from 5,896 African Americans, variants in ABCA7 and other genes are linked to increased risk of Alzheimer disease (pp. 1483–92). The Alzheimer Disease Genetics Consortium compared 1,968 case participants with 3,928 control participants. All were 60 years or older when samples were obtained in 1989–2011. Genome-wide and gene-based tests showed the following: “Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47–2.12]; P = 2.2 × 10−9), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D prime <0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE epsilon-4–determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19–2.42]; P = 5.5 × 10−47). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005rpm2@columbia.edu)
“Health professionals as well as consumers attracted to personal genomics are interested in disease risk assessments using variants found through association studies,” writes an editorialist (
pp. 1527–8). Their clinical validity is likely substantial, given the doubling in risk of Alzheimer disease with variations in APOE and ABCA7. Clinical utility is another matter, the author concludes: “How useful is having this information? Here the answer is not so clear and depends on answering the question: useful to whom and useful in what way? An expert panel considered using the association between APOE epsilon-4 alleles and [late-onset Alzheimer disease] for risk prediction in an asymptomatic person and pronounced it unwarranted in the absence of effective preventive measures. Nonetheless, many individuals might have personal and financial planning reasons for determining their risk through genetic testing, and a randomized controlled trial of such testing failed to demonstrate serious emotional or psychological disturbances in individuals who chose to learn of their APOE epsilon-4 status. Clearly, when it comes to personal genomics, clinical utility remains in the eye of the beholder.” (R. L. Nussbaum, robert.nussbaum@ucsf.edu)
A Decade of Genome Data: It’s been 10 years since the completion of the Human Genome Project on Apr. 14, 2003, writes a JAMA contributing editor (pp. 1522–4). Reflecting on the articles in this theme issue—including ones on metagenomics in infectious disease (pp. 1502–10; M. J. Pallen, m.pallen@warwick.ac.uk) and advances in molecular genetic and genomic testing (pp. 1511–21; B. R. Korf, bkorf@uab.edu)—he writes: “This issue highlights that genomics remains a science of discovery rather than of clinical utility in most areas of medicine, despite enormous progress over the past decade. This will not continue to be the case. As genomics becomes incorporated into most aspects of medicine and has demonstrative effects on clinical outcomes, theme issues like this one will become unnecessary. The last decade has been dominated by enormous technological advances in the science of genomics, the next decade is likely to be dominated by its effect on diagnosis, prognosis, and clinical care. We invite readers to enjoy this issue and to contemplate the next developmental stage of genomics.” (W. G. Feero, w.gregory.feero@mainegeneral.org)

>>>PNN NewsWatch
* FDA has approved a combination product containing doxylamine succinate and pyridoxine hydrochloride (Diclegis, Duchesnay) for treatment of nausea and vomiting in pregnant women. The delayed-release tablet is intended for women who have not adequately responded to conservative management of nausea and vomiting during pregnancy, such as dietary and lifestyle modifications, FDA said. These modifications include eating several small meals instead of three large meals, eating bland foods that are low in fat and easy to digest, and avoiding smells that can trigger nausea.

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

PNN Pharmacotherapy Line
Apr. 11, 2013 * Vol. 20, No. 70
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 11 New England Journal of Medicine (2013; 368).
Fibrinolysis v. Primary PCI in STEMI: In patients with acute ST-segment elevation myocardial infarction (STEMI) who could not undergo early primary percutaneous coronary intervention (PCI), tenecteplase, clopidogrel, and enoxaparin provided effective reperfusion, researchers report, but with increased risk of intracranial bleeding (pp. 1379–87). The 1,892 STREAM study participants presented within 3 hours of symptoms onset but where unable to undergo primary PCI within 1 hour. They were randomly assigned to primary PCI or fibrinolytic therapy before transport to the hospital. A primary end point of composite of death, shock, congestive heart failure, or reinfarction up to 30 days showed these results: “The primary end point occurred in 116 of 939 patients (12.4%) in the fibrinolysis group and in 135 of 943 patients (14.3%) in the primary PCI group (relative risk in the fibrinolysis group, 0.86; 95% confidence interval, 0.68 to 1.09; P = 0.21). Emergency angiography was required in 36.3% of patients in the fibrinolysis group, whereas the remainder of patients underwent angiography at a median of 17 hours after randomization. More intracranial hemorrhages occurred in the fibrinolysis group than in the primary PCI group (1.0% vs. 0.2%, P = 0.04; after protocol amendment, 0.5% vs. 0.3%, P = 0.45). The rates of nonintracranial bleeding were similar in the two groups.” (F. Van de Werf, frans.vandewerf@med.kuleuven.be)
“Rapid mechanical restoration of coronary flow with a stent” remains the treatment of choice for STEMI, an editorialist writes (
pp. 1446–7): “The findings of this trial could have a major effect on clinical practice and further highlight the prominence of timely PCI as the treatment of choice for STEMI. Health care systems can be reconfigured to provide such care, but there are a variety of practical barriers. When primary PCI cannot be performed, prompt fibrinolysis should be administered, with transfer to a PCI-capable center in the next several hours, especially in high-risk patients. A pharmacoinvasive approach, including initial half-dose fibrinolysis in the elderly, may be an option in selected circumstances, though it does not represent optimal care as compared with timely primary PCI.” (D. L. Bhatt)
EPOCH-Rituximab in Mediastinal B-Cell Lymphoma: Patients with primary mediastinal B-cell lymphoma did well without radiotherapy after therapy with dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine, prednisone, and rituximab (DA-EPOCH-R) (pp. 1408–16). The single-group, Phase II trial also provided filgrastim support to 51 previously untreated patients with the disease, who had these responses to infusional therapy alone: “The patients had a median age of 30 years (range, 19 to 52) and a median tumor diameter of 11 cm; 59% were women. During a median of 5 years of follow-up, the event-free survival rate was 93%, and the overall survival rate was 97%. Among the 16 patients who were involved in the retrospective analysis at another center, over a median of 3 years of follow-up, the event-free survival rate was 100%, and no patients received radiotherapy. No late morbidity or cardiac toxic effects were found in any patients. After follow-up ranging from 10 months to 14 years, all but 2 of the 51 patients (4%) who received DA-EPOCH-R alone were in complete remission. The 2 remaining patients received radiotherapy and were disease-free at follow-up.” (W. H. Wilson, wilsonw@mail.nih.gov)
Implementing Death With Dignity: A Death With Dignity program at a cancer center “has been well accepted by patients and clinicians,” authors write (pp. 1417–24): “Of the 40 participants who, after counseling and upon request, received a prescription for a lethal dose of secobarbital (35.1% of the 114 patients who inquired about the program), all died, 24 after medication ingestion (60% of those obtaining prescriptions). The participants at our center accounted for 15.7% of all participants in the Death with Dignity program in Washington (255 persons) and were typically white, male, and well educated. The most common reasons for participation were loss of autonomy (97.2%), inability to engage in enjoyable activities (88.9%), and loss of dignity (75.0%). Eleven participants lived for more than 6 months after prescription receipt. Qualitatively, patients and families were grateful to receive the lethal prescription, whether it was used or not.” (E. T. Loggers, eloggers@seattlecca.org)

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

PNN Pharmacotherapy Line
Apr. 12, 2013 * Vol. 20, No. 71
Providing news and information about medications and their proper use

>>>Circulation Highlights
Source:
Apr. 9 issue of Circulation (2013; 127).
Socioeconomics & Metabolic Risk Factors: An analysis of macroeconomic indicators and prevalence of four metabolic risk factors invalidates the common assumption that affluence and Westernization are responsible for an increased risk of diabetes and cardiovascular disease (pp. 1493–502). Instead, the authors conclude, “The changing associations of metabolic risk factors with macroeconomic variables indicate that there will be a global pandemic of hyperglycemia and diabetes mellitus, together with high blood pressure in low-income countries, unless effective lifestyle and pharmacological interventions are implemented.”
Investigators looked for associations between country-level risk factor estimates for 199 countries in 1980–2008 and per capita national income, a measure of Western diet, and body mass index (BMI) of those residing in urban areas, finding: “In 1980, there was a positive association between national income and population mean BMI, systolic blood pressure, and total cholesterol. By 2008, the slope of the association between national income and systolic blood pressure became negative for women and zero for men. Total cholesterol was associated with national income and Western diet in both 1980 and 2008. In 1980, BMI rose with national income and then flattened at ≈Int$7000; by 2008, the relationship resembled an inverted U for women, peaking at middle-income levels. BMI had a positive relationship with the percentage of urban population in both 1980 and 2008. Fasting plasma glucose had weaker associations with these country macro characteristics, but it was positively associated with BMI.” (M. Ezzati,
majid.ezzati@imperial.ac.uk)
“Regardless of limitations [of this study], these data and future analyses will help in describing the associations between global macroeconomic changes and contemporaneous population-level risk factor distribution for [cardiovascular disease], especially because health-related analyses by national income have often focused on life expectancy and mortality and not on risk factors,” writes an editorialist (
pp. 1451–2). “Despite a call for ‘a quantitative, scientific framework to guide healthcare scale-up in developing countries,’ the scale-up of noncommunicable disease prevention and treatment programs is hampered by lack of measurable targets and disagreement on the policies and interventions required, which in turn are often caused by lack of compelling data. The need for continuing research and continuing engagement with policy makers is highlighted by the fact that the United Nations High Level Meeting for Non-Communicable Diseases yielded disappointingly few ‘hard’ targets for noncommunicable diseases.” (A. Banerjee, a.banerjee.1@bham.ac.uk)

>>>PNN NewsWatch
* Green Valley Drugs is recalling all lots of all of sterile products compounded, repackaged, and distributed by the pharmacy due to lack of sterility assurance and concerns associated with its quality control processes, FDA said yesterday. The Henderson, NV, operation has a full list of recalled products on its website.
* In
a blog posted yesterday, FDA Commissioner Margaret A. Hamburg, MD, reiterated the agency’s commitment “to working with the states, industry, and Congress to put the necessary protections in place” with regard to pharmacy compounding. She said FDA inspectors made a variety of “observations” during inspections of 31 compounding pharmacies, including “unidentified black particles floating in vials of supposedly sterile medicine; rust and mold in ‘clean rooms’ where sterile injectable medications were produced; technicians handling supposedly sterile products with bare hands; and employees wearing nonsterile lab coats.” Hamburg noted that only 1 pharmacy did not have any variances from standards. “These inspectional observations reveal that there continues to be reason for concern about sterility deficiencies and other problems in some compounding pharmacies across the country – problems that could potentially affect the health of patients,” Hamburg wrote. “To carry out this proactive inspection effort, FDA had to shift resources from other areas, and this is not a sustainable approach for the longer term.”

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

PNN Pharmacotherapy Line
Apr. 15, 2013 * Vol. 20, No. 72
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Orlistat & Acute Liver Injury: Liver injury associated with the start of orlistat therapy may “reflect changes in health status associated with the decision to begin treatment rather than any causal effect of the drug,” researchers report based on a self-controlled case study of 94,695 patients (f1936). From the U.K. Clinical Practice Research Datalink and the Hospital Episode Statistics for 1999–2011, investigators determined: “Among 94,695 patients who received orlistat, 988 cases of acute liver injury were identified, with 335 confirmed as definite cases and 653 as probable cases. For all cases an increased incidence of liver injury was detected during the 90 day period before orlistat was first started, with an incidence rate ratio of 1.50 (95% confidence interval 1.10 to 2.06). The incidence remained raised during the first 30 days of treatment (2.21, 1.43 to 3.42), before returning to baseline levels with prolonged treatment. When the risk during the first 90 days of treatment was compared with the 90 days preceding first treatment, the incidence of liver injury was not increased (1.02, 0.67 to 1.56). An analysis restricted to definite cases showed no evidence of an increased risk of liver injury during treatment.” (I. Douglas, ian.douglas@lshtm.ac.uk)
RA, TNF Inhibitors & Malignant Melanoma: The small increase in absolute risk of malignant melanoma in patients with rheumatoid arthritis being treated with tumor necrosis factor inhibitors “may not markedly shift the overall risk–benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons,” based on a results of a population-based cohort study from Sweden (f1939). In 2001–10, investigators prospectively recorded data from national registers on 10,878 patients with rheumatoid arthritis treated with TNF inhibitors, 42,198 other patients with rheumatoid arthritis, and 162,743 matched controls: “113 first invasive melanomas occurred in rheumatoid arthritis patients not treated with biological drugs, and 393 occurred in the general population comparator cohort. Rheumatoid arthritis patients not treated with biological drugs were not at significantly increased risk of melanoma compared with the general population (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5). 38 first invasive melanomas occurred in rheumatoid arthritis patients treated with TNF inhibitors; these patients had an increased risk of melanoma compared with rheumatoid arthritis patients not treated with biological drugs (hazard ratio 1.5, 1.0 to 2.2; 20 additional cases per 100,000 person years). The risk of a second primary melanoma was non-significantly increased (hazard ratio 3.2, 0.8 to 13.1; n = 3 [versus] 10) in rheumatoid arthritis patients treated with TNF inhibitors compared with those not treated with biological drugs.” (P. Raaschou, pauline.raaschou@karolinska.se)

>>>PNN NewsWatch
* DEA on Friday announced rescheduling of methylone into Schedule I and moved to temporarily control three synthetic cannabinoids. Methylone is a synthetic stimulant sold “under the guise of ‘bath salts’ or ‘plant food,’” DEA says. “Users have reported impaired perception, reduced motor control, disorientation, extreme paranoia, and violent episodes. The long-term physical and psychological effects of these substances and their associated products are unknown but potentially severe.” The synthetic cannabinoids are “often seen in falsely marketed ‘herbal incense’ products,” DEA reports. “Over the past 3 years, smoke-able herbal blends are marketed under the guise of being ‘legal’ and have become increasingly popular.” The action controls these substances for up to 2 years, with the possibility of a 1-year extension, until a final action is taken.

>>>PNN JournalWatch
* Strategies for Improving Survival After In-Hospital Cardiac Arrest in the United States: 2013 Consensus Recommendations: A Consensus Statement From the American Heart Association, in
Circulation, 2013; 127: 1538–63. (my.americanheart.org/statements)
* Albuminuria in the Normal Range: The Lower Is Not the Better, in
Journal of the American College of Cardiology, 2013; 61: 1634–6. (C. Zoccali)
* What Is the Optimal Endocrine Therapy for Postmenopausal Women With Hormone Receptor–Positive Early Breast Cancer?, in
Journal of Clinical Oncology, 2013; 31: 1391–7. (N. Tung, ntung@bidmc.harvard.edu)

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

PNN Pharmacotherapy Line
Apr. 16, 2013 * Vol. 20, No. 73
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 16 issue of the Annals of Internal Medicine (2013; 158).
Medications for Reducing Risk of Primary Breast Cancer: In women at increased risk of developing breast tumors, tamoxifen provides better prophylaxis than does raloxifene but also increases the risk of endometrial cancer and cataracts, according to a systematic review conducted for the U.S. Preventive Services Task Force (pp. 604–14): “Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1,000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1,000 women. Neither reduced breast cancer–specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1,000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer.” (H. D. Nelson, nelsonh@ohsu.edu)
Patient-Centered Decision Making: When incorporating patient-centered decision making (PCDM) into health care processes, outcomes are better when attention is paid to “patient needs and circumstances” such as improved blood pressure control or loss of medication coverage, according to authors of an observational study conducted at two VA facilities (pp. 573–9). PCDM was defined as “the process of identifying clinically relevant, patient-specific circumstances and behaviors to formulate a contextually appropriate care plan.” In an analysis of 774 audio-recorded patient encounters with internal medicine resident physicians, these outcome measures were noted: “Among 548 contextual red flags, 208 contextual factors were confirmed, either when physicians probed or patients volunteered information. Physician attention to contextual factors (both probing for them and addressing them in care plans) varied according to the presenting contextual red flags. Outcome data were available for 157 contextual factors, of which PCDM was found to address 96. Of these, health care outcomes improved in 68 (71%), compared with 28 (46%) of the 61 that were not addressed by PCDM (P = 0.002).” (S. J. Weiner, sweiner@uic.edu)
The author of an accompanying editorial writes that interventions to increase physician attention to patient context should focus on helping physicians link to needed services and support systems that can help them solve their patients’ problems (
pp. 628–9): “There is ample evidence that patient-centered processes of communication can influence patient satisfaction, perceptions of care, shared decision making, and health behaviors. The communication process can also have major implications on whether adherence to treatment—a critical pathway to improving outcomes—is achieved.” (L. A. Cooper)
Online Professionalism: In a position paper, the American College of Physicians and the Federation of State Medical Boards examine and provide “recommendations about the influence of social media on the patient–physician relationship, the role of these media in public perception of physician behaviors, and strategies for physician–physician communication that preserve confidentiality while best using these technologies” (pp. 620–7): “User-created content and communications on Web-based applications, such as networking sites, media sharing sites, or blog platforms, have dramatically increased in popularity over the past several years, but there has been little policy or guidance on the best practices to inform standards for the professional conduct of physicians in the digital environment. Areas of specific concern include the use of such media for nonclinical purposes, implications for confidentiality, the use of social media in patient education, and how all of this affects the public’s trust in physicians as patient–physician interactions extend into the digital environment. Opportunities afforded by online applications represent a new frontier in medicine as physicians and patients become more connected.” (L. Snyder Sulmasy, lsnyder@acponline.org)

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

PNN Pharmacotherapy Line
Apr. 17, 2013 * Vol. 20, No. 74
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 17 issue of JAMA (2013; 309).
Surgical Complications & Hospital Finances: Hospitals have a higher margin on patients who have surgical complications than for other surgical patients when the payer is a private insurer or Medicare, a study shows (pp. 1599–606). “Depending on payer mix, many hospitals have the potential for adverse near-term financial consequences for decreasing postsurgical complications,” the investigators concluded. The retrospective study analyzed administrative data for 2010 from a nonprofit 12-hospital system in the southern U.S. It showed respective “contribution margins per patient” with complications were $39,017 and $1,749 higher for private insurers and Medicare. (A. A. Gawande, agawande@hsph.harvard.edu)
“Today, there are increasing calls for abandoning the time-honored fee-for-service compensation of clinicians and organizations that provide health care, which can tempt otherwise admirable people into dubious conduct,” writes an editorialist (
pp. 1634–5). “It is the impetus for ‘payment reform’ now attempted literally around the world.
“The current favorites in payment reform are fully bundled payments for all ambulatory, inpatient, and convalescent services for the treatment of episodic care or risk-adjusted annual capitation payments for helping patients manage chronic care. Under these payment methods, avoidable medical errors would not be rewarded financially.” (U. E. Reinhardt)
Income, Healthy Lifestyle & Cardiovascular Disease: Countries with varying income levels have low prevalences of coronary heart disease (CHD) patients with healthy lifestyle behaviors, with “even lower levels in poorer countries,” report investigators with the Prospective Urban Rural Epidemiology (PURE) study (pp. 1613–21). Based on prevalence of risk factors (smoking status, exercise level, and diet), the authors found these results in 17 countries (3 high-income countries [HIC], 7 upper-middle-income countries [UMIC], 3 lower-middle-income countries [LMIC], and 4 low-income countries [LIC]) in 2003–09: “Among 7,519 individuals with self-reported CHD (past event: median, 5.0 [interquartile range {IQR}, 2.0–10.0] years ago) or stroke (past event: median, 4.0 [IQR, 2.0–8.0] years ago), 18.5% (95% CI, 17.6%–19.4%) continued to smoke; only 35.1% (95% CI, 29.6%–41.0%) undertook high levels of work- or leisure-related physical activity, and 39.0% (95% CI, 30.0%–48.7%) had healthy diets; 14.3% (95% CI, 11.7%–17.3%) did not undertake any of the 3 healthy lifestyle behaviors and 4.3% (95% CI, 3.1%–5.8%) had all 3. Overall, 52.5% (95% CI, 50.7%-54.3%) quit smoking (by income country classification: 74.9% [95% CI, 71.1%–78.6%] in HIC; 56.5% [95% CI, 53.4%–58.6%] in UMIC; 42.6% [95% CI, 39.6%–45.6%] in LMIC; and 38.1% [95% CI, 33.1%–43.2%] in LIC).…” (K. Teo, koon.teo@phri.ca)

>>>PNN NewsWatch
* FDA yesterday approved updated labeling for Purdue Pharma L.P.’s reformulated OxyContin (oxycodone hydrochloride controlled-release) tablets. The new labeling indicates that the product has physical and chemical properties that are expected to make abuse via injection difficult and to reduce abuse via the intranasal route (snorting). FDA also has determined that the benefits of original OxyContin no longer outweigh its risks and that original OxyContin was withdrawn from sale for reasons of safety or effectiveness. Accordingly, FDA said, the agency will not accept or approve any abbreviated new drug applications that rely upon the approval of original OxyContin, which means that generic copies of the nondeterrent formulation cannot be marketed without clinical testing. The new OxyContin tablet is more difficult to crush, break, or dissolve, FDA added. It also forms a viscous hydrogel and cannot be easily prepared for injection. While the agency has determined that the physical and chemical properties of the reformulated product are expected to make the product difficult to inject and to reduce abuse via snorting, abuse of OxyContin by these routes, as well as the oral route, is still possible. The reformulated product also may reduce incidents of therapeutic misuse, such as crushing the product to sprinkle it onto food or to administer it through a gastric tube. When FDA finds that a new formulation has abuse-deterrent properties, the agency said it has the authority to require generics to have abuse-deterrent properties also.

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

PNN Pharmacotherapy Line
Apr. 18, 2013 * Vol. 20, No. 75
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 18 New England Journal of Medicine (2013; 368).
Cortisol Metabolism During Critical Illness: While “diagnostic and therapeutic implications … are unknown,” a study shows that reduced cortisol breakdown in critical illness results from suppressed expression and activity of cortisol-metabolizing enzymes (pp. 1477–88). This contributes to “hypercortisolemia and hence corticotropin suppression.” In 158 patients in intensive care and 64 matched controls, cortisol metabolism showed these patterns: “Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P < 0.001 for both comparisons). Cortisol production was 83% higher in the patients (P = 0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P ≤ 0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P < 0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P ≤ 0.004 for all comparisons).” (G. Van den Berghe, greet.vandenberghe@med.kuleuven.be)
This study “provides a convincing explanation for some of the elevation in plasma cortisol levels observed in critically ill patients,” an editorialist writes (
pp. 1547–9): “However, the authors do not address the mechanism of cortisol hypersecretion in the presence of suppressed corticotropin. Study patients with [systemic inflammatory response syndrome (SIRS)] had increased adrenal cortisol production; those without SIRS had normal production. Critically ill patients have a marked reduction in levels of cortisol-binding protein with proportional increases in free cortisol, which can diffuse into tissues. Levels of interstitial cortisol obtained by microdialysis in patients with sepsis correlated only moderately with total plasma cortisol levels, suggesting that plasma cortisol may not reflect tissue availability.” (C. E. Gomez-Sanchez)
Glutamine, Antioxidants in Critically Ill Patients: In 1,223 critically ill patients with multiorgan failure, “early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality,” researchers report (pp. 1489–97). Participants in the 2 X 2 factorial trial were on mechanical ventilation when they were randomly assigned to glutamine, antioxidants, both, or placebo. Administration of the supplements produced these outcomes: “There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P = 0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P = 0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P = 0.83).” (D. Heyland, dkh2@queensu.ca)
An editorialist speculates about reasons for increased mortality with glutamine supplements (
pp. 1549–50): “If low glutamine levels during acute critical illness reflect an adaptive and beneficial stress response rather than a conditional deficiency, interfering with such adaptation could be deleterious. Such an adaptive lowering of the glutamine level may involve its many functions or its simple fate as a nutritional substrate. Glutamine toxicity observed in the current study could be mediated by direct or indirect effects of the amino acid or its metabolites, by the higher total amount of amino acids provided to the glutamine group, or both. The higher dose would be in line with the results of the Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients trial, which revealed a poorer outcome associated with early parenteral nutrition during critical illness. This outcome was explained by the dose of amino acid rather than the amount of glucose infused.” (G. Van den Berghe)

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

PNN Pharmacotherapy Line
Apr. 19, 2013 * Vol. 20, No. 76
Providing news and information about medications and their proper use

>>>Infectious Diseases Report
Source:
May 1 issue of Clinical Infectious Diseases (2013; 56).
Resistance to Neuraminidase Inhibitors: In the 2008 Influenza Resistance Information Study (IRIS), investigators found that oseltamivir resistance among influenza viruses rarely emerged in the community, was generally found in toddlers, and clinical care was not compromised (pp. 1197–205). Neuraminidase inhibitor (NAI) resistance and clinical outcomes were studied by testing posterior nares swabs using reverse transcription polymerase chain reaction (RT-qPCR). Results of the global observational investigation showed: “Of 1,799 influenza-positive (RT-qPCR) patients, 1,281 had influenza A (47 seasonal H1N1; 335 H3N2; 899 H1N1pdm2009) and 518 had influenza B. Antivirals were administered to 1,041 (58%) patients (26, 245, 514, and 256, respectively). All seasonal H1N1 strains were genotypically (H275Y) and phenotypically resistant to oseltamivir. No genotypic resistance was detected in the day 1 samples of any other viral subtypes. Mutation-specific (MS) RT-PCR detected resistance to oseltamivir in 19 patients postbaseline (17 H1N1pdm2009 [H275Y]; 2 H3N2 [R292K]), 14 of whom were children aged ≤5 years. In 12 of 19 patients, viral loads were too low to permit cell culture and 14 of 19 were RT-qPCR negative by day 10. In 1 other H1N1pdm2009 patient, H275Y was detected by sequencing but not by MS RT-PCR. No emergent resistance was found in influenza B infections.” (R. J. Whitley, rwhitley@peds.uab.edu)
Neonatal Outcomes After Antenatal Influenza Immunization: Support for decisions to prioritize pregnant women for influenza vaccination during the 2009 pandemic comes from a retrospective cohort study of live births in the Georgia and mid-Atlantic Kaiser Permanente regions (pp. 1216–22). Looking at primary outcomes of third-trimester preterm birth (27–36 weeks), birth weight, low birth weight (LBW, <2500 g), and small for gestational age (SGA) babies, researchers found these results among 3,327 newborns during the pandemic period: “There were 327 (9.8%) preterm, 236 (7.4%) LBW, and 267 (8.4%) SGA births. Among H1N1-vaccinated mothers (n = 1,125), there were 86 (7.6%) preterm, 68 (6.4%) LBW, and 99 (9.3%) SGA births, and the mean birth weight was 3308.5 g (95% confidence interval [CI], 3276.6–3340.4). Among unvaccinated mothers (n = 1581), there were 191 (12.1%) preterm, 132 (8.8%) LBW, and 123 (8.2%) SGA births, and the mean birth weight was 3245.3 g (95% CI, 3216.5–3274.2). Infants of H1N1-vaccinated mothers had 37% lower odds of being born preterm than infants of unvaccinated mothers (adjusted odds ratio, 0.63 [95% CI, 0.47–0.84]). The mean birth weight difference between infants of H1N1-vaccinated mothers and infants of unvaccinated mothers was 45.1 g (95% CI, 1.8–88.3). There was no significant association between maternal H1N1 influenza immunization and LBW or SGA.” (S. B. Omer, somer@emory.edu)

>>>Allergy/Immunology Report
Source:
Apr. Journal of Allergy and Clinical Immunology (2013; 131).
IgG Replacement Therapy in Antibody Deficiency: With a goal of identifying laboratory and clinical guidelines for diagnosing antibody deficiency and institution of safe treatment, authors assess “the importance of accurate diagnosis of patients who have failed to produce specific antibodies to naturally encountered foreign proteins or polysaccharides or after vaccination and the appropriate institution of immunoglobulin replacement therapy” (pp. 1001–5): “With greater recognition and advanced cellular and molecular diagnostic technology, new entities and single-gene defects in patients with [primary immunodeficiency disease (PIDD)] are rapidly being defined. This, combined with treatment advances and newborn screening for severe combined immunodeficiency, has resulted in improved outcomes and survival and even permanent cures. Awareness of PIDD has also increased, but the guidelines for recognition remain to be validated. The zeal for registering and enrolling patients has potentially created a large body of ‘patients’ treated with immunoglobulin replacement unnecessarily. The complexity, diversity, and availability of laboratory testing have brought awareness of PIDD to the forefront, but because of an absence of standardization of certain assays, concerns about the correct diagnosis and appropriate treatment have increased.” (W. T. Shearer, wtsheare@TexasChildrensHospital.org)

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

PNN Pharmacotherapy Line
Apr. 22, 2013 * Vol. 20, No. 77
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 20 issue of Lancet (2013; 381).
Genetic Basis for Multiple Psychiatric Disorders: A genomewide analysis shows that single-nucleotide polymorphisms (SNPs)—especially those in genes for calcium-channel activity—are linked to five diverse psychiatric disorders (autism spectrum disorder, attention-deficit/hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia) (pp. 1371–9). “These results provide evidence relevant to the goal of moving beyond descriptive syndromes in psychiatry, and towards a nosology informed by disease cause,” the investigators write of these results from 33,332 cases and 27,888 controls of European ancestry: “SNPs at four loci surpassed the cutoff for genome-wide significance (p < 5 × 10−8) in the primary analysis: regions on chromosomes 3p21 and 10q24, and SNPs within two L-type voltage-gated calcium channel subunits, CACNA1C and CACNB2. Model selection analysis supported effects of these loci for several disorders. Loci previously associated with bipolar disorder or schizophrenia had variable diagnostic specificity. Polygenic risk scores showed cross-disorder associations, notably between adult-onset disorders. Pathway analysis supported a role for calcium channel signalling genes for all five disorders. Finally, SNPs with evidence of cross-disorder association were enriched for brain eQTL markers.” (Cross-Disorder Group of the Psychiatric Genomics Consortium)
Pediatric HIV Monitoring & First-Line Antiretroviral Therapy: In a study of 1,206 African children and adolescents with HIV, researchers found first-line antiretroviral therapy (ART) regimens could be used without routine laboratory toxicity monitoring (pp. 1391–403). The trial showed these findings for three-drug treatment (nonnucleoside reverse transcriptase inhibitor [NNRTI], lamivudine, abacavir; group A) versus four-drug induction (NNRTI, lamivudine, abacavir, zidovudine; groups B and C), decreasing after week 36 to three-drug NNRTI, lamivudine, plus abacavir (group B) or lamivudine, abacavir, plus zidovudine (group C): “47 (8%) children on clinically driven monitoring versus 39 (7%) on routine laboratory monitoring had a new WHO stage 4 event or died (hazard ratio [HR] 1.13, 95% CI 0.73–1.73, p = 0.59; non-inferiority criterion met). However, in years 2–5, rates were higher in children on clinically driven monitoring (1.3 vs 0.4 per 100 child–years, difference 0.99, 0.37–1.60, p = 0.002). One or more grade 3 or 4 adverse events occurred in 283 (47%) children on clinically driven versus 282 (47%) on routine laboratory monitoring (HR 0.98, 0.83–1.16, p = 0.83). Mean CD4 percentage change did not differ between ART groups at week 72 (16.5% [SD 8.6] vs 17.1% [8.5] vs 17.3% [8.0], p = 0.33) or week 144 (p = 0.69), but four-drug groups (B, C) were superior to three-drug group A at week 36 (12.4% [7.2] vs 14.1% [7.1] vs 14.6% [7.3], p < 0.0001). Excess grade 3 or 4 events in groups B (one or more events reported by 157 [40%] children in A, 190 [47%] in B; HR [B:A] 1.32, 1.07–1.63) and C (218 [54%] children in C; HR [C:A] 1.58, 1.29–1.94; global p = 0.0001) were driven by asymptomatic neutropenia in zidovudine-containing groups (B, C; 86 group A, 133 group B, 184 group C), but resulted in drug substitutions in only zero versus two versus four children, respectively.” (ARROW Trial Team)

>>>PNN JournalWatch
* Parental Depression, Maternal Antidepressant Use During Pregnancy, and Risk of Autism Spectrum Disorders: Population Based Case–Control Study, in
BMJ, 2013; 346: f2059. (D. Rai, dheeraj.rai@bristol.ac.uk)
* Effect of a Nicotine Vaccine on Nicotine Binding to Beta-2*-Nicotinic Acetylcholine Receptors In Vivo in Human Tobacco Smokers, in
American Journal of Psychiatry, 2013; 170: 399–407. (I. Esterlis, irina.esterlis@yale.edu)
* Infection Prevention in Long-Term Care: A Systematic Review of Randomized and Nonrandomized Trials, in
Journal of American Geriatrics Society, 2013; 61: 602–14. (M. Uchida, mu2188@columbia.edu)
* Oxytocin and Vasopressin: Social Neuropeptides With Complex Neuromodulatory Functions, in
Neurology, 2013; 80: 1521–8. (E. E. Benarroch, benarroch.eduardo@mayo.edu)
* Three-Dimensional Drug Printing: A Structured Review, in
Journal of the American Pharmacists Association, 2013; 53: 136–44. (I. D. Ursan, iursan2@uic.edu)
* Pharmacist Engagement in Medical Home Practices: Report of the APhA–APPM Medical Home Workgroup, in
Journal of the American Pharmacists Association, 2013; 53: e118–24. (M. D. Hogue, mdhogue@samford.edu)

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

PNN Pharmacotherapy Line
Apr. 23, 2013 * Vol. 20, No. 78
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 22 issue of the JAMA Internal Medicine (2013; 173).
Calcium & CVD Mortality: Men who take large amounts of supplemental calcium are at increased risk of dying from cardiovascular disease (CVD), but women are not similarly affected, according to a prospective study of 388,229 participants in the National Institutes of Health–AARP Diet and Health Study (pp. 639–46). The prospective study included patients aged 50–71 years from six states and two U.S. metropolitan areas. Calcium intake was determined at baseline in 1995–96, and analysis of subsequent deaths showed the following: “During a mean of 12 years of follow-up, 7,904 and 3,874 CVD deaths in men and women, respectively, were identified. Supplements containing calcium were used by 51% of men and 70% of women. In men, supplemental calcium intake was associated with an elevated risk of CVD death (RR > 1000 vs 0 mg/d, 1.20; 95% CI, 1.05–1.36), more specifically with heart disease death (RR, 1.19; 95% CI, 1.03–1.37) but not significantly with cerebrovascular disease death (RR, 1.14; 95% CI, 0.81–1.61). In women, supplemental calcium intake was not associated with CVD death (RR, 1.06; 95% CI, 0.96–1.18), heart disease death (1.05; 0.93–1.18), or cerebrovascular disease death (1.08; 0.87–1.33). Dietary calcium intake was unrelated to CVD death in either men or women.” (Q. Xiao, qian.xiao@nih.gov)
“The findings from the NIH-AARP Diet and Health Study add to the mounting evidence indicating that calcium supplements may be harmful to CVD,” an author writes in an accompanying commentary (
pp. 647–8). “The results are consistent with some but not all previous prospective studies on calcium supplement use in relation to CVD morbidity or mortality.…
“Available data are suggestive of adverse cardiovascular effects with an excessive intake of supplemental calcium. More large studies are needed to further assess the potential health risks or benefits of calcium supplement use on CVD morbidity and mortality. Meanwhile, a safe alternative to calcium supplements is to consume calcium-rich foods, such as low-fat dairy foods, beans, and green leafy vegetables, which contain not only calcium but also a cocktail of essential minerals and vitamins. These nondairy food sources of calcium have the added health benefits and have recently been reported to improve glycemic control in persons with diabetes. The paradigm ‘the more the better’ is invalid for calcium supplementation.” (S. C. Larsson,
susanna.larsson@ki.se)
Prolonged Antibiotic Treatment in Long-term Care: In a retrospective analysis of all long-term care residents in Ontario, researchers find that antibiotics are often prescribed for long durations in nursing homes and that prescriber preference rather than patient characteristics is linked to this practice (pp. 673–82). “Future trials should evaluate antibiotic stewardship interventions targeting prescriber preferences to systematically shorten average treatment durations to reduce the complications, costs, and resistance associated with antibiotic overuse,” the investigators conclude based on these findings: “Of 66,901 long-term care residents from 630 long-term care facilities, 50,061 (77.8%) received an incident antibiotic treatment course (with 51,540 antibiotic courses prescribed). The most commonly selected antibiotic treatment course was 7 days (in 21,136 courses [41.0%]), but 23,124 (44.9%) exceeded 7 days. Among the 699 physicians responsible for 20 or more antibiotic treatment courses, the median (interquartile range) proportion of treatment courses beyond 7 days was 43.5% (26.9%–62.9%) (range, 0%–97.1%). Twenty-one percent of prescribers had a higher-than-expected proportion of prescriptions beyond the 7-day threshold. Patient characteristics were similar across short-, average-, and long-duration prescribers. A mixed logistic model confirmed that prescribers were an important determinant of treatment duration (P < .001), with a relative odds of prolonged prescription of 3.84 for 75th vs 25th percentile prescribers.” (N. Daneman, nick.daneman@sunnybrook.ca)

>>>PNN NewsWatch
* Yet another compounding pharmacyBalanced Solutions of Lake Mary, FL—is voluntarily recalling all lots of its sterile nonexpired drug products due to a lack of sterility assurance and concerns with product quality controls.

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

PNN Pharmacotherapy Line
Apr. 24, 2013 * Vol. 20, No. 79
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 24 issue of JAMA (2013; 309).
Autism & Valproate: Maternal use of valproate during pregnancy significantly increased the risk of autism spectrum disorders and childhood autism among offspring in a population-based study conducted in Denmark (pp. 1696–703). Among all children born alive between 1996 and 2006, valproate use was associated with these outcomes: “Of 655,615 children born from 1996 through 2006, 5,437 were identified with autism spectrum disorder, including 2,067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4–14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%–1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%–0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%–7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7–4.9]) and an absolute risk of 2.50% (95% CI, 1.30%–4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7–10.0]). When restricting the cohort to the 6,584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%–7.81%) (adjusted HR, 1.7 [95% CI, 0.9–3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%–6.11%) (adjusted HR, 2.9 [95% CI, 1.4–6.0]) vs 2.44% (95% CI, 1.88%–3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%–1.49%) for childhood autism among 6,152 children not exposed to valproate.” (J. Christensen, jakob@farm.au.dk)
“Despite the established risks of fetal valproate exposure, valproate continues to be a common treatment in women of childbearing age,” editorialists write (
pp. 1730–1). “Valproate is an effective drug, but it appears that it is being prescribed for women of childbearing potential at a rate that does not fully consider the ratio of benefits to risks. This raises concern as to whether these women are receiving adequate information for informed consent based on a full understanding of the treatment risks and alternative therapies. Given the accumulating evidence linking fetal valproate exposure to congenital malformations, cognitive impairments, and autism, the use of valproate in women of childbearing potential should be minimized. Alternative medications should be sought. If no alternative effective medications can be found, the lowest effective dose of valproate should be used. Because approximately half of the pregnancies in the United States are unplanned, delaying discussions of treatment risks until a pregnancy is considered will leave a substantial number of children at unnecessary risk. Women of childbearing potential should be informed of the potential risks of fetal valproate exposure before valproate is prescribed.” (K. J. Meador, kimford.meador@emory.edu)
Beta-Blockers & Postoperative Mortality: In selected patients, beta-blockade during noncardiac, nonvascular surgery is associated with lower 30-day all-cause mortality, notes a retrospective cohort analysis of a population-based sample of 136,745 patients (pp. 1704–13). Lower mortality rates occurred in patients with 2 or more Revised Cardiac Risk Index factors, leading the investigators to conclude, “Our findings support use of a cumulative number of Revised Cardiac Risk Index predictors in decision making regarding institution and continuation of perioperative beta-blockade. A multicenter randomized trial involving patients at a low to intermediate risk by these factors would be of interest to validate these observational findings.” (M. J. London, londonm@anesthesia.ucsf.edu)
Release of DSM-5: “The first revision of … psychiatric nomenclature in almost 2 decades” will be released in May, authors report (pp. 1691–2). The new Diagnostic and Statistical Manual of Mental Disorders (DSM-5) combines several diagnoses under the autism spectrum disorder, elevates binge eating disorder to the main body of diagnoses, adds a disruptive mood dysregulation disorder “to reduce confusion about whether severe, chronic irritability should be considered characteristic of mania in children,” separates posttraumatic stress disorder from the anxiety disorders, removes the bereavement exclusion from diagnosis of major depressive disorder, and adds a substance use disorder that combines substance abuse and dependence. (D. J. Kupfer, kupferdj@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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Apr. 25, 2013 * Vol. 20, No. 80
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 25 issue of the New England Journal of Medicine (2013; 368).
Goal Achievement in Diabetes: From a national perspective, much progress has been made in diabetes care in the U.S., but much remains to be done with regard to goals established for the 1999–2010 period (pp. 1613–24). Authors used data for adults with self-reported diabetes from the National Health and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance System to examine risk-factor control, preventive practices, and risk scores for coronary heart disease, with these results: “From 1999 through 2010, the weighted proportion of survey participants who met recommended goals for diabetes care increased, by 7.9 percentage points (95% confidence interval [CI], 0.8 to 15.0) for glycemic control (glycated hemoglobin level <7.0%), 9.4 percentage points (95% CI, 3.0 to 15.8) for individualized glycemic targets, 11.7 percentage points (95% CI, 5.7 to 17.7) for blood pressure (target, <130/80 mm Hg), and 20.8 percentage points (95% CI, 11.6 to 30.0) for lipid levels (target level of low-density lipoprotein [LDL] cholesterol, <100 mg per deciliter [2.6 mmol per liter]). Tobacco use did not change significantly, but the 10-year probability of coronary heart disease decreased by 2.8 to 3.7 percentage points. However, 33.4 to 48.7% of persons with diabetes still did not meet the targets for glycemic control, blood pressure, or LDL cholesterol level. Only 14.3% met the targets for all three of these measures and for tobacco use. Adherence to the recommendations for annual eye and dental examinations was unchanged, but annual lipid-level measurement and foot examination increased by 5.5 percentage points (95% CI, 1.6 to 9.4) and 6.8 percentage points (95% CI, 4.8 to 8.8), respectively. Annual vaccination for influenza and receipt of pneumococcal vaccination for participants 65 years of age or older rose by 4.5 percentage points (95% CI, 0.8 to 8.2) and 6.9 percentage points (95% CI, 3.4 to 10.4), respectively, and daily glucose monitoring increased by 12.7 percentage points (95% CI, 10.3 to 15.1).” (M. K. Ali, ise1@cdc.gov)
A new model of clinical care is needed for diabetes care, editorialists write, and this will require a new “report card” (
pp. 1650–1): “Just as science evolves, so should clinical care. The next wave of improvement in the delivery of diabetes care will probably come through intensive quality improvement and a movement away from episodic care toward the chronic care model and panel management. A new report card should capture change and improvement, not only whether thresholds were reached. If incentive systems reward such improvements, perhaps then we’ll be on a winning streak.” (G. T. McMahon)
Intestinal Microbial Metabolism of Phosphatidylcholine: Microbes in the human gastrointestinal tract generate proatherosclerotic trimethylamine-N-oxide (TMAO) from dietary components, researchers report, and increased levels of the metabolite are linked to higher rates of cardiovascular events (pp. 1575–84). Healthy participants ingested a phosphatidylcholine challenge (two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) before and after oral broad-spectrum antibiotics that suppressed intestinal microbes, and levels of TMAO were followed in 4,007 patients undergoing elective coronary angiography: “Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P < 0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P < 0.001), as well as in lower-risk subgroups.” (S. L. Hazen, hazens@ccf.org)

>>>PNN NewsWatch
* Nora Apothecary & Alternative Therapies is voluntary recalling all unexpired sterile drug products compounded before Apr. 20, FDA reports. FDA inspectors recently identified concerns with the pharmacy’s quality control processes with regard to sterility assurance.

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

PNN Pharmacotherapy Line
Apr. 26, 2013 * Vol. 20, No. 81
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
May issue of Diabetes Care (2013; 36).
Hyperglycemia & Mortality Among Inpatients Receiving TPN: Noncritically ill inpatients who have hyperglycemia after receiving total parenteral nutrition (TPN) have rates of mortality that are 5.6 times higher than similar patients without such glucose excursions, researchers report (pp. 1061–6). At 19 Spanish hospitals, a prospective study assessed demographic, clinical, and laboratory factors and in-hospital mortality, with these results: “The study included 605 patients (mean age 63.2 ± 15.7 years). The daily mean TPN values were 1.630 ± 323 kcal, 3.2 ± 0.7 g carbohydrates/kg, 1.26 ± 0.3 g amino acids/kg, and 0.9 ± 0.2 g lipids/kg. Multiple logistic regression analysis showed that the patients who had mean blood glucose levels >180 mg/dL during the TPN infusion had a risk of mortality that was 5.6 times greater than those with mean blood glucose levels <140 mg/dL (95% CI 1.47–21.4 mg/dL) after adjusting for age, sex, nutritional state, presence of diabetes or hyperglycemia before starting TPN, diagnosis, prior comorbidity, carbohydrates infused, use of steroid therapy, SD of blood glucose level, insulin units supplied, infectious complications, albumin, C-reactive protein, and HbA1c levels.” (G. Olveira, gabrielm.olveira.sspa@juntadeandalucia.es)
Hypoglycemia, Insulin & Mortality Among Inpatients: Hospitalized patients with insulin-associated and spontaneous episodes of hypoglycemia had higher rates of mortality in a retrospective cohort study (pp. 1107–10). Data were obtained from electronic databases of patients hospitalized in 2008–10, and hypoglycemia was defined as one or more blood glucose levels of 50 mg/dL or less. Controls had glucose levels of 70 mg/dL or more. The investigators found: “There were four groups: 1) noninsulin-treated hypoglycemia (NTH) (n = 135), 2) insulin-treated hypoglycemia (ITH) (n = 961), 3) noninsulin-treated control (NTC) (n = 1,058), and 4) insulin-treated control (ITC) (n = 736). Mortality was higher in the ITH group compared with the ITC group (20.3 vs. 4.5%, P < 0.0001), with a relatively higher CCI (1.8 vs. 1.5%, P < 0.0001), but much higher in the NTH group compared with the NTC group (34.5 vs. 1.1%, P < 0.0001), with much higher CCI (2.4 vs. 1.1%, P < 0.0001). Mortality was higher in the NTH group compared with the ITH group (P < 0.0001) but lower in the NTC group compared with the ITC group (P < 0.0001). After controlling for age, sex, CCI, and admission to the intensive care unit, insulin treatment was associated with a lower mortality among the hypoglycemic patients; hazard ratio of death in the ITH group relative to the NTH group was 0.34 (95% CI 0.25–0.47, P < 0.0001).” (R. Garg, rgarg@partners.org)
Sitagliptin v. Glipizide in Chronic Renal Insufficiency: Among 426 patients with type 2 diabetes mellitus (T2DM) and chronic renal insufficiency, sitagliptin performed similarly to glipizide for lowering A1C levels and did so with lower risks of hyperglycemia and less weight gain (pp. 1067–73). With randomization stratified by renal status, cardiovascular disease, and heart failure, study participants received either sitagliptin 50 mg every day for moderate renal insufficiency and 25 mg every day for severe renal insufficiency or glipizide 2.5 mg every day, adjusted based on glycemic control to a 10-mg twice a day maximum dose. Results showed: “At week 54, treatment with sitagliptin was noninferior to treatment with glipizide in A1C change from baseline (−0.8 vs. −0.6%; between-group difference −0.11%; 95% CI −0.29 to 0.06) because the upper bound of the 95% CI was less than the prespecified noninferiority margin of 0.4%. There was a lower incidence of symptomatic hypoglycemia adverse events (AEs) with sitagliptin versus glipizide (6.2 and 17.0%, respectively; P = 0.001) and a decrease in body weight with sitagliptin (−0.6 kg) versus an increase (1.2 kg) with glipizide (difference, −1.8 kg; P < 0.001). The incidence of gastrointestinal AEs was low with both treatments.” (J. C. Arjona Ferreira, juan_arjona@merck.com)
Primary Care Physicians & Diabetes Care: Medication intensification and lifestyle counseling are key ways that primary care physicians (PCPs) provide better care to patients with diabetes, a study of 584,587 encounters shows (pp. 1147–52). Compared with covering physicians and midlevel providers, PCPs provided those interventions significantly more often. (A. Turchin, aturchin@partners.org)

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

PNN Pharmacotherapy Line
Apr. 29, 2013 * Vol. 20, No. 82
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 27 issue of Lancet (2013; 381).
Guillain-Barré Syndrome & Pandemic Influenza Vaccines: In the U.S., the number of excess cases of Guillain-Barré syndrome associated with influenza vaccine administration during the 2009 pandemic was less than 2 per million people vaccinated, a study shows (pp. 1461–8). Investigators searched six adverse event monitoring systems for cases among the 23 million Americans who received influenza A (H1N1) 2009 monovalent vaccination. A meta-analysis of data showed the following: “Influenza A (H1N1) 2009 monovalent inactivated vaccines were associated with a small increased risk of Guillain-Barré syndrome (incidence rate ratio 2.35, 95% CI 1.42–4.01, p = 0.0003). This finding translated to about 1.6 excess cases of Guillain-Barré syndrome per million people vaccinated.” Based on these findings, the authors conclude: “In view of the morbidity and mortality caused by 2009 H1N1 influenza and the effectiveness of the vaccine, clinicians, policy makers, and those eligible for vaccination should be assured that the benefits of inactivated pandemic vaccines greatly outweigh the risks.” (D. A. Salmon, dsalmon@jhsph.edu)
Retinol Supplementation in North India: In the cluster-randomized DEVTA trial in north India, twice-yearly supplements of retinol failed to reduce childhood mortality by the 20–30% seen in other studies, researchers report (pp. 1469–77). Preschool children received vitamin A in the form of retinyl acetate in oil 200,000 IU every 6 months orally, albendazole 400 mg tablets every 6 months orally, both, or neither, with these results: “Estimated compliance with 6-monthly retinol supplements was 86%. Among 2,581 versus 2,584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0.72 [SE 0.01] vs 0.62 [0.01] µmol/L, increase 0.10 [SE 0.01] µmol/L) and the prevalence of severe deficiency was halved (retinol <0.35 µmol/L 6% vs 13%, decrease 7% [SE 1%]), as was that of Bitot’s spots (1.4% vs 3.5%, decrease 2.1% [SE 0.7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1.0–6.0 years during the 5-year study were 3.01 retinol versus 3.15 control (absolute reduction 0.14 [SE 0.11], mortality ratio 0.96, 95% CI 0.89–1.03, p = 0.22), suggesting absolute risks of death between ages 1.0 and 6.0 years of approximately 2.5% retinol versus 2.6% control. No specific cause of death was significantly affected.” (R. Peto, rpeto@ctsu.ox.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Sitagliptin in Type 2 Diabetes: Patients with type 2 diabetes who were taking sitagliptin had no greater risk of all-cause mortality or hospitalization than did other those on other oral hypoglycemic drugs in a retrospective population-based cohort study (f2267). In new users of oral antidiabetic drugs who began therapy in 2004–09, a composite endpoint of all-cause hospital admission or mortality showed these patterns: “The cohort included 72,738 new users of oral antidiabetic drugs (8,032 (11%) used sitagliptin; 7,293 (91%) were taking it in combination with other agents) followed for a total of 182,409 patient years. The mean age was 52 (SD 9) years, 54% (39,573) were men, 11% (8,111) had ischemic heart disease, and 9% (6,378) had diabetes related complications at the time their first antidiabetic drug was prescribed. 14,215 (20%) patients met the combined endpoint. Sitagliptin users showed similar rates of all cause hospital admission or mortality to patients not using sitagliptin (adjusted hazard ratio 0.98, 95% confidence interval 0.91 to 1.06), including patients with a history of ischemic heart disease (adjusted hazard ratio 1.10, 0.94 to 1.28) and those with estimated glomerular filtration rate below 60 mL/min (1.11, 0.88 to 1.41).” (D. T. Eurich, deurich@ualberta.ca)

>>>PNN JournalWatch
* How Health Systems Could Avert ‘Triple Fail’ Events That Are Harmful, Are Costly, and Result in Poor Patient Satisfaction, in
Health Affairs, 2013; 32: 669–76. (G. Lewis, geraint.lewis@nhs.net)
* Is It Time to Write a Prescription for Coffee? Coffee and Liver Disease [commentary], in
Gastroenterology, 2013; 144: 670–2. (D. M. Torres)
* A Controlled Trial of Gluten-Free Diet in Patients With Irritable Bowel Syndrome-Diarrhea: Effects on Bowel Frequency and Intestinal Function, in
Gastroenterology, 2013; 144: 903–911.e3. (M. Camilleri, camilleri.michael@mayo.edu)

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

PNN Pharmacotherapy Line
Apr. 30, 2013 * Vol. 20, No. 83
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Apr. issue of the Journal of the American Geriatrics Society (2013; 61).
“Choosing Wisely”: Participation in the Choosing Wisely campaign led the American Geriatrics Society to identify criteria patients and professionals should consider about the safety and appropriateness of medical tests, medications, and procedures: whether the tests and procedures are evidence-based, whether any risks they pose might overshadow their potential benefits, whether they are redundant, and whether they are truly necessary (pp. 622–31). The campaign is sponsored by the American Board of Internal Medicine Foundation. With regard to medications, AGS provided this list of practices for professionals and patients to question (M. J. Samuel, mjsamuel@americangeriatrics.org):
* Don’t use antipsychotics as first choice to treat behavioral and psychological symptoms of dementia.
* Avoid using medications to achieve A1C levels below 7.5% in most adults age 65 or older; moderate control is generally better.
* Don’t use benzodiazepines or other sedative–hypnotics in older adults as first choices for insomnia, agitation, or delirium.
* Don’t use antimicrobials to treat bacteriuria in older adults unless specific urinary tract symptoms are present.
Gender & Medication Adherence Barriers: In the Cohort Study of Medication Adherence in Older Adults, researchers find differences between the sexes in factors associated with low antihypertensive medication adherence scores, with weight and sexual functioning affecting men and depression and poor provider communication influencing women (pp. 558–64). With low adherence defined as a score of 6 on the 8-item Morisky Medication Adherence Scale, investigators identified these patterns among 2,194 patients: “The prevalence of low medication adherence scores did not differ according to sex (women, 15.0%; men 13.1%; P = .21). In sex-specific multivariable models, having problems with medication cost and practicing fewer lifestyle modifications for blood pressure control were associated with low adherence scores in men and women. Factors associated with low adherence scores in men but not women were poor sexual functioning (odds ratio (OR) = 2.03, 95% confidence interval (CI) = 1.31–3.16 for men and OR = 1.28, 95% CI = 0.90–1.82 for women), and body mass index of 25.0 kg/m2 or more (OR = 3.23, 95% CI = 1.59–6.59 for men; OR = 1.23, 95% CI = 0.82–1.85 for women). Factors associated with low adherence scores in women but not men included dissatisfaction with communication with their healthcare provider (OR = 1.75, 95% CI = 1.16–2.65 for women; OR = 1.16, 95% CI = 0.57–2.34 for men) and depressive symptoms (OR = 2.29, 95% CI = 1.55–3.38 for women; OR = 0.93, 95% CI = 0.48–1.80 for men).” (M. Krousel-Wood, mawood@ochsner.org)

>>>Internal Medicine Report
Source:
Early-release article from the Annals of Internal Medicine (2013; 158).
Marathon Day at Mass General: A short article describes the factors that allowed Massachusetts General and other Boston-area hospitals to treat the large number of patients affected by the Patriot Day bombings, including the number of first responders stationed near the finish line of the Marathon, use of tourniquets, availability of ambulances on the scene, and presence of eight Level 1 trauma centers within 3 miles (doi: 10.7326/0003-4819-159-2-201307160-00648): “The timing of the explosions was also opportune; the incident occurred at the change of shift. The morning shift was completing the 7 am to 3 pm shift; the 3 pm to 11 pm shift was already in house. On every unit in the hospital the medical, nursing, and support staff stayed to assist however they could – it was as though there was immediate double coverage. It was a Monday; the hospital was relatively open and had not yet filled with the elective cases that tend to occur early in the week.” (A. Conn)

>>>PNN NewsWatch
* Prothrombin Complex Concentrate, Human (Kcentra, CSL Behring) has been approved by FDA for urgent reversal of vitamin K antagonist anticoagulation in adults with acute major bleeding. Previously, plasma was the only approved product for this indication.

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

PNN Pharmacotherapy Line
May 1, 2013 * Vol. 20, No. 84
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 1 issue of JAMA (2013; 309).
Vitamin D Supplements in Breastfed Infants: In 132 healthy, term, breastfed infants 1 month of age in Montreal, vitamin D supplements of 1600 IU/d increased plasma 25-hydroxyvitamin D (25[OH]D) concentrations to 75 nmol/L, researchers report (pp. 1785–92). Lower doses (400, 800, and 1200 IU/d) did not achieve this higher level advocated by some experts, but the study demonstrated a possible association between elevated 25(OH)D concentrations and hypercalcemia: “By 3 months, 55% (95% CI, 38%–72%) of infants in the 400-IU/d group achieved a 25(OH)D concentration of 75 nmol/L or greater vs 81%(95% CI, 65%–91%) in the 800-IU/d group, 92% (95% CI, 77%–98%) in the 1200-IU/d group, and 100% in the 1600-IU/d group. This concentration was not sustained in 97.5% of infants at 12 months in any of the groups. The 1600-IU/d dosage was discontinued prematurely because of elevated plasma 25(OH)D concentrations. All dosages established 25(OH)D concentrations of 50 nmol/L or greater in 97% (95% CI, 94%–100%) of infants at 3 months and sustained this in 98% (95% CI, 94%–100%) to 12 months. Growth and bone mineral content did not differ by dosage.” (H. Weiler, hope.weiler@mcgill.ca)
An editorialist discusses the controversy over the appropriate target plasma range for 25(OH)D (
pp. 1830–1): “If the target is 75 nmol/L or higher, then vitamin D intake of 400 IU/d is not enough for a substantial proportion of infants, especially those in northern parts of the United States or in Canada or who have darker skin pigmentation. However, based on the evidence that a vitamin D intake of 400 IU/d reliably prevents rickets and other identifiable bone health outcomes, it is unlikely that new data will be reported demonstrating inadequate bone health in infants who have a plasma 25(OH)D concentration greater than 50 nmol/L but less than 75 nmol/L. That the study by Gallo et al did not reach its predetermined target of plasma 25(OH)D concentration greater than 75 nmol/L with intakes of 400 IU/d does not indicate that a plasma 25(OH)D concentration of greater than 75 nmol/L has physiological benefits in infants.
“However, another question that needs to be answered is whether there are non–bone health reasons to target a plasma 25(OH)D concentration greater than 75 nmol/L. Answering such questions about non–bone health aspects of vitamin D nutrition can be accomplished only by rigorous clinical trials that include enough participants and establish clear outcomes before the study begins.” (S. A. Abrams,
sabrams@bcm.edu)
HPV Vaccine Regimens: Two doses of human papillomavirus (HPV) vaccine may be sufficient for many patients, a study shows, but “loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses” means that “more data on the duration of protection are needed before reduced-dose schedules can be recommended” (pp. 1793–802). In Canada, administration of two or three doses to girls ages 9–13 and three doses to young women ages 16–26 produced these results: “The [geometric mean titer (GMT)] ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62–2.65) for HPV-16 and 1.76 (95% CI, 1.41–2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651–8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512–1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73–1.23) for HPV-16 and 0.68 (95% CI, 0.54–0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36.” (S. R. M. Dobson, sdobson@cw.bc.ca)

>>>PNN NewsWatch
* FDA yesterday approved Teva’s Plan B One-Step for OTC sales to girls and women ages 15 years or older. Other emergency-contraceptive products on the market have varying age requirements (Plan B requires a prescription for girls under 17; ella is prescription only). The approval is unrelated to a recent federal court ruling that the Plan B products be OTC for all ages; the Obama administration has until May 5 to appeal that ruling.

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

PNN Pharmacotherapy Line
May 2, 2013 * Vol. 20, No. 85
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 2 issue of the New England Journal of Medicine (2013; 368).
Azithromycin & Cardiovascular Death: Among young and middle-aged adults in Denmark, use of azithromycin was not linked to increased risk of cardiovascular death, compared with use of penicillin V, researchers report (pp. 1704–12). A nationwide historical cohort study of adults 18–64 years of age showed these patterns for 1.1 million episodes of azithromycin use and 7.4 million episodes of use of penicillin V in 1997–2010: “The risk of death from cardiovascular causes was significantly increased with current use of azithromycin (defined as a 5-day treatment episode), as compared with no use of antibiotics (rate ratio, 2.85; 95% confidence interval [CI], 1.13 to 7.24). The analysis relative to an antibiotic comparator included 17 deaths from cardiovascular causes during current azithromycin use (crude rate, 1.1 per 1,000 person–years) and 146 during current penicillin V use (crude rate, 1.5 per 1,000 person–years). With adjustment for propensity scores, current azithromycin use was not associated with an increased risk of cardiovascular death, as compared with penicillin V (rate ratio, 0.93; 95% CI, 0.56 to 1.55). The adjusted absolute risk difference for current use of azithromycin, as compared with penicillin V, was −1 cardiovascular death (95% CI, −9 to 11) per 1 million treatment episodes.” (H. Svanström, htr@ssi.dk)
“The risks and benefits of antibacterial therapy should be considered in prescribing decisions,” write authors of a Commentary from FDA (
pp. 1665–8). “Pharmacologic and epidemiologic data point to lethal arrhythmias as a potential consequence of QT-interval prolongation with use of azithromycin, other macrolides, and fluoroquinolones. This possibility should give clinicians pause when they’re considering prescribing antibacterial drugs, especially for patients with preexisting cardiovascular risk factors or clinical conditions in which antibacterial drug therapy has limited benefits.” (A. D. Mosholder)
Penicillin for Leg Cellulitis Prophylaxis: Among 274 patients with recurrent leg cellulitis, penicillin was effective during periods of administration, but protection wained after drug therapy was stopped, a study shows (pp. 1695–703). In a double-blind study at 28 U.K. and Irish hospitals, penicillin 250 mg twice daily or placebo for 12 months had these effects: “The median time to a first recurrence of cellulitis was 626 days in the penicillin group and 532 days in the placebo group. During the prophylaxis phase, 30 of 136 participants in the penicillin group (22%) had a recurrence, as compared with 51 of 138 participants in the placebo group (37%) (hazard ratio, 0.55; 95% confidence interval [CI], 0.35 to 0.86; P = 0.01), yielding a number needed to treat to prevent one recurrent cellulitis episode of 5 (95% CI, 4 to 9). During the no-intervention follow-up period, there was no difference between groups in the rate of a first recurrence (27% in both groups). Overall, participants in the penicillin group had fewer repeat episodes than those in the placebo group (119 vs. 164, P = 0.02 for trend). There was no significant between-group difference in the number of participants with adverse events (37 in the penicillin group and 48 in the placebo group, P = 0.50).” (H. C. Williams, hywel.williams@nottingham.ac.uk)
Miravirsen for HCV: In a Phase IIa study of patients with chronic hepatitis C virus (HCV) genotype 1 infection, the antisense agent miravirsen “showed prolonged dose-dependent reductions in HCV RNA levels without evidence of viral resistance” (pp. 1685–94). The dose-ranging study showed significant and dose-related mean maximum reductions in HCV RNA levels with 3, 5, and 7 mg/kg doses over a 29-day period. (H. L. A. Janssen, harry.janssen@uhn.ca)

>>>PNN NewsWatch
* Use of tolvaptan (Samsca, Otsuka) should be limited to 30 days, and the drug should not be used in patients with underlying liver disease, FDA has concluded. Citing the risk of liver injury with the drug, including cases potentially requiring liver transplant or leading to death, FDA updated the product labeling by limiting use to 30 days, removing the indication for use in patients with cirrhosis, describing liver injuries seen in clinical trials, and recommending discontinuation of the drug in patients with symptoms of liver injury.
*
PNN turns 19 today, with 4,734 issues published since 1994.

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

PNN Pharmacotherapy Line
May 3, 2013 * Vol. 20, No. 86
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2013; 33).
Statins & Risk of Psychologic Disorders: A retrospective observational cohort study finds no links between statin use and development of psychologic disorders such as schizophrenia, psychosis, major depression, and bipolar disorder (DOI: 10.1002/phar.1272). In the San Antonio Military Multi-Market Area, Tricare Prime or Plus records for 46,249 patients aged 30–85 years showed these patterns: “The occurrence of psychologic disorders between October 1, 2005, and March 1, 2010, was determined using prespecified groups of ICD-9-CM, Psych1: schizophrenia, schizoaffective disorders, and other psychosis; Psych2: major depression and bipolar disorder; Psych3: all psychologic disorders as identified by the Agency for Health Research and Quality-Clinical Classifications (except for categories of childhood or developmental psychiatric disorders). Between matched pairs of statin users and nonusers, the odds ratios and 95% confidence intervals were as follows: Psych1 (0.9, 0.75–1.05), Psych2 (1.02, 0.94–1.11), and Psych3 (1.02, 0.96–1.1), respectively.” (I. Mansi, ishak.mansi@va.gov)
Excessive Anticoagulation With Pharmacist-Managed Dosing of Warfarin: A retrospective nested case–control study shows that hospitalized patients with higher disease severity or poor nutritional status remain at greater risk of excessive anticoagulation despite use of a pharmacist-managed dosing protocol (DOI: 10.1002/phar.1280). For 87 case patients and 174 controls, these results were identified at a large academic tertiary medical center: “Two variables, severity of illness score (odds ratio [OR] 4.89, p < 0.001) and poor nutritional status (OR 4.27, p < 0.001), demonstrated strong independent associations with risk of excessive anticoagulation. Administration of interacting drugs that highly potentiate warfarin’s effect (OR 2.26, p = 0.011) and concurrent diarrheal illness (OR 4.75, p < 0.001) also displayed a statistically significant risk for excessive anticoagulation.” (T. Berg, berg.tamara1@mayo.edu)
Pharmacy Care of Dyslipidemia: At two VA primary care clinics, “veterans referred to a clinical pharmacist for treatment of dyslipidemia achieved significant reductions in [total cholesterol (TC)] and LDL,” a retrospective cohort study shows (DOI: 10.1002/phar.1273). Outcomes for 213 patients in the intervention (IT) cohort and 219 control patients receiving usual care (UC) were as follows: “Compared with the UC cohort, the adjusted difference in the mean final measured LDL for the IT cohort was −10.4 mg/dl (95% confidence interval [CI] −16.1 to −4.6, p < 0.001) and TC was −12.7 (95% CI −21.3 to −4.1, p = 0.004). There were no significant differences in the adjusted mean final measured HDL or [triglycerides] between the two groups. The NCEP/ATP III goal LDL was met in 80.3% of patients in the IT cohort and 65.3% of patients in the UC cohort (odds ratio [OR], 2.6; 95% CI 1.6–4.3, p < 0.001). Time to achieve goal LDL was significantly shorter for the IT cohort compared with the UC cohort (risk ratio, 1.8; 95% CI 1.2–2.8, log-rank p = 0.002).” (A. J. Zillich, azillich@purdue.edu)
Qualifications of Pharmacists Providing Direct Patient Care: ACCP’s Board of Regents reinforces the College’s 2006 position that direct patient care should be provided by residency-trained, board-certified pharmacists (DOI: 10.1002/phar.1285). “Since [2006], some members of the pharmacy profession have interpreted ACCP’s position as maintaining that all pharmacists—regardless of the focus of their professional practice activities—should complete formal postgraduate residency training and be board-certified specialists. That interpretation is not accurate. In this commentary, ACCP further defines ‘direct patient care’ and states that it believes that clinical pharmacists engaged in direct patient care should be board certified (i.e., and residency-trained or otherwise board eligible) and have established a valid collaborative drug therapy management (CDTM) agreement or have been formally granted clinical privileges. The rationale for this viewpoint is presented in detail. The pharmacy profession has appropriately invested substantial resources to ensure the quality of its accredited residency training programs and board certification processes. ACCP believes that these training and certification programs are essential steps in preparing clinical pharmacists to provide direct patient care.” (M. S. Maddux, mmaddux@accp.com)

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

PNN Pharmacotherapy Line
May 6, 2013 * Vol. 20, No. 87
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 4 issue of Lancet (2013; 381).
Tocilizumab v. Adalimumab in Rheumatoid Arthritis: Among 326 patients in whom methotrexate could not be used to treat rheumatoid arthritis, tocilizumab monotherapy was significantly more effective than adalimumab monotherapy, according to results of the ADACTA Phase IV trial (pp. 1541–50). Adult patients with severe rheumatoid arthritis for 6 months or more had these responses based on disease activity score at 28 joints (DAS28) from baseline to week 24: “The intention-to-treat population contained 325 patients (163 assigned to tocilizumab [8 mg/kg intravenously every 4 weeks], 162 assigned to adalimumab [40 mg subcutaneously every 2 weeks]). Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group –3.3) than in the adalimumab group (–1.8) patients (difference –1.5, 95% CI –1.8 to –1.1; p < 0.0001). 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts.” (A. Kavanaugh, akavanaugh@ucsd.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
C-Reactive Protein, Procalcitonin in Predicting Pneumonia: Among 2,280 patients with acute cough seen in European primary care centers, addition of C-reactive protein (CRP) data improved prediction of pneumonia, but procalcitonin information failed to add to the predictive power of symptom-and-sign clinical rules (f2450): “Six published ‘symptoms and signs models’ varied in their discrimination (area under receiver operating characteristics curve (ROC) ranged from 0.55 (95% confidence interval 0.50 to 0.61) to 0.71 (0.66 to 0.76)). The optimal combination of clinical prediction items derived from our patients included absence of runny nose and presence of breathlessness, crackles and diminished breath sounds on auscultation, tachycardia, and fever, with an ROC area of 0.70 (0.65 to 0.75). Addition of CRP at the optimal cut off of >30 mg/L increased the ROC area to 0.77 (0.73 to 0.81) and improved the diagnostic classification (net reclassification improvement 28%). In the 1,556 patients classified according to symptoms, signs, and CRP >30 mg/L as ‘low risk’ (<2.5%) for pneumonia, the prevalence of pneumonia was 2%. In the 132 patients classified as ‘high risk’ (>20%), the prevalence of pneumonia was 31%. The positive likelihood ratio of low, intermediate, and high risk for pneumonia was 0.4, 1.2, and 8.6 respectively. Measurement of procalcitonin added no relevant additional diagnostic information. A simplified diagnostic score based on symptoms, signs, and CRP >30 mg/L resulted in proportions of pneumonia of 0.7%, 3.8%, and 18.2% in the low, intermediate, and high risk groups, respectively.” (B. D. L. Broekhuizen, b.d.l.broekhuizen@umcutrecht.nl)

>>>PNN NewsWatch
* FDA has approved ezetimibe and atorvastatin tablets (Liptruzet, Merck) for treatment of elevated LDL cholesterol in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet when diet alone is not enough. While the combination product hits both sources of cholesterol—absorption and production—the company notes in a news release that “no incremental benefit of Liptruzet on cardiovascular morbidity and mortality over and above that demonstrated for atorvastatin has been established.”

>>>PNN JournalWatch
* Interventions for Preschool Children at High Risk for ADHD: A Comparative Effectiveness Review, in
Pediatrics, 2013; 131: e1584–604. (A. Charach)
* Beyond the NLRP3 Inflammasome: Autoinflammatory Diseases Reach Adolescence, in
Arthritis & Rheumatism, 2013; 65: 1137–47. (M. Gattorno, marcogattorno@ospedale-gaslini.ge.it)
* To RAS or Not to RAS? The Evidence for and Cautions with Renin-Angiotensin System Inhibition in Patients with Diabetic Kidney Disease, in
Pharmacotherapy, 2013; 33: 496–514. (W. L. St. Peter, WStPeter@cdrg.org)
* Over-the-Counter Access to Emergency Contraception Without Age Restriction: An Opinion of the Women’s Health Practice and Research Network of the American College of Clinical Pharmacy, in
Pharmacotherapy, 2013; 33: 549–57. (S. Rafie, srafie@ucsd.edu)

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

PNN Pharmacotherapy Line
May 7, 2013 * Vol. 20, No. 88
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 7 issue of the Annals of Internal Medicine (2013; 158).
Ambrisentan in Idiopathic Pulmonary Fibrosis: A study of patients with idiopathic pulmonary fibrosis (IPF) was terminated early when ambrisentan 10 mg/d failed to demonstrate efficacy and was associated with increased risk of disease progression and respiratory-related hospitalizations, researchers report (pp. 641–9). Patients were 40–80 years of age when they were started on placebo or ambrisentan, an endothelin A receptor–selective antagonist. Based on an end point of time to disease progression—defined as death, respiratory hospitalization, or a categorical decrease in lung function—results showed: “The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point.” (G. Raghu)
Smoking Cessation in Suspected TB: Among 1,955 adult smokers with suspected tuberculosis, provision of behavioral support alone or in combination with bupropion was effective for promoting cessation, according to a study conducted in Pakistan (pp. 667–75). Using a cluster randomized design, health centers were assigned to provide two brief behavioral support sessions (BSS), BSS plus 7 weeks of bupropion therapy (BSS+), or usual care, with these results: “Both treatments led to statistically significant relative risks (RRs) for abstinence compared with usual care (RR for BSS+, 8.2 [95% CI, 3.7 to 18.2]; RR for BSS, 7.4 [CI, 3.4 to 16.4]). Equivalence between the treatments could not be established. In the BSS+ group, 275 of 606 patients (45.4% [CI, 41.4% to 49.4%]) achieved continuous abstinence compared with 254 of 620 (41.0% [CI, 37.1% to 45.0%]) in the BSS group and 52 of 615 (8.5% [CI, 6.4% to 10.9%]) in the usual care group. There was substantial heterogeneity of program effects across clusters.” (K. Siddiqi, kamran.siddiqi@york.ac.uk)
USPSTF Recommendations for Vitamin D/Calcium Supplementation: The U.S. Preventive Services Task Force (USPSTF) makes these recommendations for vitamin D and calcium supplementation for prevention of fractures in adults (pp. 691–6; www.uspreventiveservicestaskforce.org):
* The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men. (I statement)
* The USPSTF concludes that the current evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D
3 and greater than 1,000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (I statement)
* The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D
3 and 1,000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. (D recommendation)

>>>PNN NewsWatch
* Pregnant women should not use valproate sodium for migraine prevention, FDA warned yesterday. Citing lower IQ scores among children whose mothers used products such as Depakote and Depacon during pregnancy, FDA concluded that the benefits of the drug for preventing migraine do not outweigh the risks of fetal harm. For other uses, including bipolar disorder and seizures, FDA said the drug may be needed when other agents are ineffective.

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

PNN Pharmacotherapy Line
May 8, 2013 * Vol. 20, No. 89
Providing news and information about medications and their proper use

>>>Chest Highlights
Source:
May issue of Chest (2013; 143).
Single-Dose Antibiotic for Early-Onset Pneumonia in Ventilation: In a prospective cohort study, early-onset ventilator-associated pneumonia (EO-VAP) occurred less frequently among comatose patients given a single antibiotic dose at intubation (pp. 1219–25). Setting the stage for a randomized controlled trial of the concept, investigators looked at the incidence of EO-VAP, late-onset VAP, and ventilator-associated tracheobronchitis among patients in 2007–08, all of whom did not receive antibiotic prophylaxis, or 2009–10, when single-dose antibiotics were used: “We included 129 patients (71 in the prophylaxis group and 58 in the control group). The global incidence of VAP and incidence of EO-VAP were lower in the prophylaxis group: 10.8 vs 28.4 episodes/1,000 days on mechanical ventilation (P = .015) and 4.4 vs 23.1 episodes/1,000 days on mechanical ventilation (P = .02), respectively. The incidence of late-onset VAP did not differ. The prophylaxis group tended toward lower incidence of ventilator-associated tracheobronchitis (15.5% vs 25.9%, P = .14). No differences in mortality were found between groups. The propensity-score regression analysis confirmed that a single dose of antibiotic prophylaxis was independently associated with lower incidence of EO-VAP (OR, 0.11; 95% CI, 0.02–0.58; P = .009).” (J. Vallés, jvalles@tauli.cat)
Glucose Control & Mortality: In a retrospective cohort analysis of critically ill patients treated with eProtocol-insulin in 2006–11, researchers find that moderate glucose control (90–140 mg/dL) was associated with greater mortality among those without diabetes but reduced mortality in those with diabetes compared with tight glucose control (80–110 mg/dL), leading the group to conclude that “a single glucose target does not appear optimal for all critically ill patients” (pp. 1226–34). Multivariate logistic regression for 30-day mortality found these associations: “We studied 3,529 patients in 12 different ICUs in eight different hospitals. Patients with diabetes had higher mean glucose (132 mg/dL vs 124 mg/dL) and greater glycemic variability (SD = 41 mg/dL vs 29 mg/dL) than did patients without diabetes (P < .01 for both comparisons). Tight glucose control was associated with increased frequency of moderate and severe hypoglycemia (30.3% and 3.6%) compared with moderate glucose control (14.3% and 2.0%, P < .01 for both). Multivariate analysis demonstrated that the moderate glucose target was independently associated with increased risk of mortality in patients without diabetes (OR, 1.36; 95% CI, 1.01–1.84; P = .05) but decreased risk of mortality in patients with diabetes (OR, 0.65; 95% CI, 0.45–0.93; P = .01).” (M. Lanspa, michael.lanspa@imail.org)

>>>Cardiology Report
Source:
May 14 issue of the Journal of the American College of Cardiology (2013; 61).
Lipid Lowering in Postmenopausal Women: In a substudy of the BELLES Trial (Beyond Endorsed Lipid Lowering with EBT Scanning), postmenopausal women with hyperlipidemia had greater regression of epicardial adipose tissue (EAT) when on statins, with intensive therapy more effective than moderate approaches to lipid lowering (pp. 1956–61). “This effect does not seem linked to low-density lipoprotein lowering and may be secondary to other actions of statins such as anti-inflammatory effects,” the authors noted. Patients on atorvastatin 80 mg/d were compared with those taking pravastatin 40 mg/d with respect to progression of coronary artery calcium (CAC) over a 1-year period: “Of 420 patients, 194 received atorvastatin and 226 pravastatin; the median low-density lipoprotein change was −53.3% and −28.3% with atorvastatin and pravastatin, respectively (p < 0.001). Baseline EAT correlated with age, body mass index, hypertension, diabetes mellitus, high-density lipoprotein, triglyceride levels, and CAC (p < 0.001). At the end of follow-up, EAT regressed more in the atorvastatin than in the pravastatin group (median, −3.38% vs. −0.83%, p = 0.025). The EAT percent change from baseline was significant in the atorvastatin, but not the pravastatin group (p < 0.001 and p = 0.2, respectively). There was no correlation between lipid lowering and EAT regression. CAC progressed significantly in both groups from baseline.” (P. Raggi)

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

PNN Pharmacotherapy Line
May 9, 2013 * Vol. 20, No. 90
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 9 issue of the New England Journal of Medicine (2013; 368).
N–3 Fatty Acids & Cardiovascular Mortality, Morbidity: Among patients with multiple cardiovascular risk factors or atherosclerotic vascular disease with no history of myocardial infarction, daily use of n–3 fatty acids failed to reduce cardiovascular morbidity and mortality compared with placebo, researchers report (pp. 1800–8). The double-blind, placebo-controlled trial enrolled patients being followed by 860 general practitioners in Italy. Random allocation to n–3 fatty acids 1 g daily or an olive oil placebo produced these findings: “Of the 12,513 patients enrolled, 6,244 were randomly assigned to n−3 fatty acids and 6,269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1,478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6,239 (11.7%) had received n−3 fatty acids and 745 of 6,266 (11.9%) had received placebo (adjusted hazard ratio with n−3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P = 0.58). The same null results were observed for all the secondary end points.” (Risk and Prevention Study Office, rep@marionegri.it)
Clinical Use of Oncogenic Mutations in Atypical CML: Researchers find that mutations in the colony-stimulating factor 3 gene “are common in patients with [chronic neutrophilic leukemia (CNL)] or atypical [chronic myeloid leukemia (CML)] and represent a potentially useful criterion for diagnosing these neoplasms” (pp. 1781–90). The authors used a combination of integrated deep sequencing plus screening of primary leukemia cells from patients with CNL or atypical (BCR-ABL1–negative) CML against panels of tyrosine kinase–specific small interfering RNAs or small-molecule kinase inhibitors, with these results: “We identified activating mutations in the gene encoding the receptor for colony-stimulating factor 3 (CSF3R) in 16 of 27 patients (59%) with CNL or atypical CML. These mutations segregate within two distinct regions of CSF3R and lead to preferential downstream kinase signaling through SRC family–TNK2 or JAK kinases and differential sensitivity to kinase inhibitors. A patient with CNL carrying a JAK-activating CSF3R mutation had marked clinical improvement after the administration of the JAK1/2 inhibitor ruxolitinib.” (J. W. Tyner, tynerj@ohsu.edu)
This approach can lead to “genetically informed therapy in leukemia,” writes an editorialist (
pp. 1838–9). “The study warrants attention for the elegance of the scientific approach and the implications for treatment of these rare diseases. Perhaps most important, the study provides an example of the future of target discovery in cancer.…
“[This study] shows the power of genetic screening to uncover new potential drug targets and provide a rationale for using drugs that are already available for other indications. Notably, the association between the
CSF3R mutation and CNL and atypical CML was found in a large sequencing of the ‘usual suspects’ of cancer signaling. Skeptics often deride large-scale screening studies as fishing expeditions, although these are actually an excellent idea if the object is to catch fish. Furthermore, the work went from identification of the CSF3R mutation, through in vitro studies, to a successful clinical application without a murine model. Thus, this study bucks the common notion that one cannot learn anything of significance without engineering a mouse that nature itself could not create.” (J. Radich)
Local Improvements in Obesity Prevention: Menu-labeling provisions in the Affordable Care Act offer communities an opportunity to address obesity prevention at the local level, according to authors of a Perspective article (pp. 1761–3): “State and local governments may … impose menu-labeling requirements identical to the ACA’s, which would allow them to enforce the ACA provisions.… FDA emphasizes that state and local governments can enact their own menu-labeling requirements for restaurants that do not fall within the ACA’s purview (i.e., restaurants with fewer than 20 locations that have not opted in to the ACA requirements).” (S. N. Bleich)

>>>PNN NewsWatch
* FDA yesterday warned of a “lack of sterility assurance” of drug products made by The Compounding Shop in St. Petersburg, FL. The company’s sterile products should be quarantined pending further instructions, 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
May 10, 2013 * Vol. 20, No. 91
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
May issue of Pediatrics (2013; 131).
Parental Factors in GERD Overtreatment: A survey of parents in a pediatric clinic shows increased interest in medication therapy when otherwise healthy infants are described as having gastroesophageal reflux disease (GERD) (pp. 839–45). The survey presented “a hypothetical clinical scenario describing an infant who cries and spits up excessively but is otherwise healthy.” When the scenario described the doctor giving a diagnosis of GERD, parents were more interested in using a medication for treatment, even when the scenario indicated that the drugs were probably ineffective, than when no label was given. “These findings suggest that use of disease labels may promote overtreatment by causing people to believe that ineffective medications are both useful and necessary,” the authors conclude. (L. D. Scherer)
Contraceptive Use in Young Adolescents: Most sexually active adolescent girls under age 15 do not use contraceptives, an analysis shows, illustrating the dilemma facing regulators and judges now deciding on the nonprescription availability of emergency contraceptives in this age group (pp. 886–91). An analysis of nationally representative data from the National Survey of Family Growth shows these patterns of sexual initiation, contraceptive use, and pregnancy among young adolescents: “Sexual activity is and has long been rare among those 12 and younger; most is nonconsensual. By contrast, most older teens (aged 17–19) are sexually active. Approximately 30% of those aged 15 to 16 have had sex. Pregnancy rates among the youngest teens are exceedingly low, for example, ~1 per 10,000 girls aged 12. Contraceptive uptake among girls as young as 15 is similar to that of their older counterparts, whereas girls who start having sex at 14 or younger are less likely to have used a method at first sex and take longer to begin using contraception.” (L. B. Finer)
Combatting the “Cinnamon Challenge”: Adolescents attempting the YouTube-driven “Cinnamon Challenge” craze have prompted poison center calls, emergency department visits, and hospitalizations for collapsed lungs, authors write (pp. 833–5). The challenge involves ingestion of one tablespoonful of ground cinnamon in 60 seconds without drinking fluids. The writers note: “Videos of people attempting the Cinnamon Challenge have become an Internet sensation. Typically, a video reveals a group of adolescents watching as someone taking the challenge begins coughing and choking when the spice triggers a severe gag reflex in response to a caustic sensation in the mouth and throat. As of August 10, 2012, there were 51,100 YouTube clips depicting the Cinnamon Challenge. One video was viewed >19 million times, predominantly by 13- to 24-year-olds, ages similar to people taking the Cinnamon Challenge and associated with the greatest need for conformity.” (S. E. Lipshultz, slipshultz@med.miami.edu)

>>>Allergy/Immunology Report
Source:
May issue of the Journal of Allergy and Clinical Immunology (2013; 131).
Immunotherapy Tablet for Ragweed Allergy: An allergy immunotherapy tablet (AIT) was effective for short ragweed-induced allergic rhinitis with or without conjunctivitis compared with placebo in a group of 784 adults (pp. 1342–9.e6; P. S. Creticos, psocrates@comcast.net)
Subcutaneous v. Sublingual Immunotherapy for Seasonal Allergic Rhinitis: Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are both effective for management of seasonal allergic rhinitis, but “superiority of one mode of administration over the other could not be consistently demonstrated through indirect comparison, and further research is needed to establish the comparative effectiveness of SCIT versus SLIT,” researchers report (pp. 1361–6). A systematic review, meta-analysis, and indirect comparison meta-analysis provided these insights: “Updated meta-analyses confirmed statistically significant benefits for SCIT and SLIT compared with placebo in adults and, to a lesser extent, in children. Only 1 head-to-head trial met the inclusion criteria; both this and the indirect comparisons did not provide conclusive results in favor of either SCIT or SLIT based on symptom-medication or quality-of-life scores. There was a trend toward favoring SCIT for symptom and medication scores.” (J. Dretzke, j.dretzke@bham.ac.uk)

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

PNN Pharmacotherapy Line
May 13, 2013 * Vol. 20, No. 92
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 11 issue of Lancet (2013; 381).
Community Treatment of Psychosis: Compulsory supervision of patients with psychosis under community treatment orders (CTOs) produces hospital readmission rates similar to those when patients are discharged under the U.K. Section 17 leave of absence, according to results of the OCTET trial (pp. 1627–33). The authors concluded, “We found no support in terms of any reduction in overall hospital admission to justify the significant curtailment of patients’ personal liberty.” In this nonblinded, parallel-arm randomized controlled trial, 336 patients were discharged through either CTO or Section 17, with these results: “At 12 months, despite the fact that the length of initial compulsory outpatient treatment differed significantly between the two groups (median 183 days CTO group vs 8 days Section 17 group, p < 0.001) the number of patients readmitted did not differ between groups (59 [36%] of 166 patients in the CTO group vs 60 [36%] of 167 patients in the Section 17 group; adjusted relative risk 1.0 [95% CI 0.75–1.33]).” (T. Burns, tom.burns@psych.ox.ac.uk)
Joint Crisis Plans in Psychosis: Use of Joint Crisis Plans (JCPs) is no more effective than usual care in management of patients with psychosis, according to results of the CRIMSON (CRisis plan IMpact: Subjective and Objective coercion and eNgagement) study (pp. 1634–41). A JCP is a “negotiated statement by a patient of treatment preferences for any future psychiatric emergency, when he or she might be unable to express clear views,” the investigators note, and two previous studies found their use beneficial. Conducted at four U.K. mental health clinics involving 64 care teams, the trial raises questions about incorporation of the approach into routine clinical practice: “569 participants were randomly assigned (285 to the intervention group and 284 to the control group). No significant treatment effect was seen for the primary outcome [of fewer compulsory admissions] (56 [20%] sectioned in the control group and 49 [18%] in the JCP group; odds ratio 0.90 [95% CI 0.58–1.39, p = 0.63]) or any secondary outcomes, with the exception of an improved secondary outcome of therapeutic relationships (17.3 [7.6] vs 16.0 [7.1]; adjusted difference –1.28 [95% CI –2.56 to –0.01, p = 0.049]). Qualitative data supported this finding.” (G. Thornicroft, graham.thornicroft@kcl.ac.uk)

>>>PNN NewsWatch
* FDA’s approval of GlaxoSmithKline’s Breo Ellipta provides a once-daily option to U.S. patients with chronic obstructive pulmonary disease (COPD). Breo Ellipta is a combination of fluticasone furoate and the long-acting beta-2-adrenergic agonist (LABA) vilanterol. In 7,700 patients with COPD, treatment with this combination improved lung function and reduced exacerbations compared with placebo. The product carries a boxed warning that LABAs increase the risk of asthma-related death. The safety and efficacy of Breo Ellipta in patients with asthma have not been established, and it is not approved for the treatment of asthma. FDA approved Breo Ellipta with a patient medication guide that warns against use as a rescue therapy to treat acute bronchospasm or in those younger than 18.

>>>PNN JournalWatch
* US Food and Drug Administration-Mandated Trials of Long-Acting Beta-Agonists Safety in Asthma: Will We Know the Answer?, in
Chest, 2013; 143: 1208–13. (S. Suissa, samy.suissa@mcgill.ca)
* Acne Vulgaris, in
BMJ, 2013; 346: f2634. (R. P. Dellavalle, robert.dellavalle@ucdenver.edu)
* A Pill for HIV Prevention: Déjà Vu All Over Again?, in
Clinical Infectious Diseases, 2013; 56: 1604–12. (J. E. Myers, jmyers@health.nyc.gov)
* Has the Time Come for Routine Trimethoprim–Sulfamethoxazole Prophylaxis in Patients Taking Biologic Therapies?, in
Clinical Infectious Diseases, 2013; 56: 1621–8. (D. L. Paterson, david.antibiotics@gmail.com)
* Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade and Hormonal Therapy for the Treatment of Primary HER2-Positive Breast Cancer: One More Step Toward Chemotherapy-Free Therapy [editorial], in
Journal of Clinical Oncology, 2013; 31: 1703–6. (J. Baselga, baselgaj@mskcc.org)
* Kidney Transplantation in the Older Adult, in
American Journal of Kidney Diseases, 2013; 61: 790–7. (G. A. Knoll, gknoll@ottawahospital.on.ca)
* T Cells in Asthma: Influences of Genetics, Environment, and T-Cell Plasticity, in
Journal of Allergy and Clinical Immunology, 2013; 131: 1267–74. (C. M. Lloyd, c.lloyd@imperial.ac.uk)

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

PNN Pharmacotherapy Line
May 14, 2013 * Vol. 20, No. 93
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 13 issue of the JAMA Internal Medicine (2013; 173).
VTE With Glucocorticoids: Patients receiving glucocorticoids had higher risks of venous thromboembolism (VTE) in a nationwide case–control study conducted in Denmark (pp. 743–52). Investigators identified 38,765 patients with VTE in 2005–11 and grouped them by time before VTE when they had glucocorticoid prescriptions filled (90 days or less, 91–365 days, more than 365 days) and type of present use (new or continuing). Results showed: “Systemic glucocorticoids increased VTE risk among present (adjusted IRR, 2.31; 95% CI, 2.18–2.45), new (3.06; 2.77–3.38), continuing (2.02; 1.88–2.17), and recent (1.18; 1.10–1.26) users but not among former users (0.94; 0.90–0.99). The adjusted IRR increased from 1.00 (95% CI, 0.93–1.07) for a prednisolone-equivalent cumulative dose of 10 mg or less to 1.98 (1.78–2.20) for more than 1000 to 2000 mg, and to 1.60 (1.49–1.71) for doses higher than 2000 mg. New use of inhaled (adjusted IRR, 2.21; 95% CI, 1.72–2.86) and intestinal-acting (2.17; 1.27–3.71) glucocorticoids also increased VTE risk.” The authors conclude, “Although residual confounding may partly explain this finding, we consider a biological mechanism likely because the association followed a clear temporal gradient, persisted after adjustment for indicators of severity of underlying disease, and existed also for noninflammatory conditions.” (S. A. Johannesdottir, saj@dce.au.dk)
“Given the already known serious adverse effects of glucocorticoids, establishing an elevated risk for venous thromboembolism with this study does not change the indications for glucocorticoids, but it should remind us to always make sure that the potential benefits of treatment outweigh the risks (eg, does this patient’s asthma require an inhaled corticosteroid?) and to be prepared to diagnose and treat thromboembolism,” a commentator writes of this study (
p. 752; M. H. Katz)
Nursing Home Hip Fractures & Nonbenzodiazepine Use: Among 15,528 long-stay residents of U.S. nursing homes, the risk of hip fracture was significantly higher with use of nonbenzodiazepine hypnotic drugs in a case–crossover study (pp. 754–61). Study participants were 50 years or older and had Medicare Parts A and D claims for hip fracture in 2007–08: “Among the study participants, 1,715 (11.0%) were dispensed a nonbenzodiazepine hypnotic drug before the hip fracture, with 927 exposure-discordant pairs included in the analyses. The mean (SD) age of participants was 81.0 (9.7) years, and 77.6% were female. The risk for hip fracture was elevated among users of a nonbenzodiazepine hypnotic drug (OR, 1.66; 95% CI, 1.45–1.90). The association between nonbenzodiazepine hypnotic drug use and hip fracture was somes [sic] greater in new users (OR, 2.20; 95% CI, 1.76–2.74) and in residents with mild vs moderate to severe impairment in cognition (OR, 1.86 vs 1.43; P = .06), with moderate vs total or severe functional impairment (OR, 1.71 vs 1.16; P = .11), with limited vs full assistance required with transfers (OR, 2.02 vs 1.43; P = .02), or in a facility with fewer Medicaid beds (OR, 1.90 vs 1.46; P = .05).” (S. D. Berry, sarahberry@hsl.harvard.edu)
The problem is lack of attention to sleeping difficulties, writes a commentator (
pp. 761–2): “It is striking that there has not been more research focused on addressing sleep as a way to minimize falls in older and institutionalized adults. Indeed, almost all single-intervention or multicomponent fall prevention studies fail to address sleep disorders as a risk factor for falls, with the exception of minimizing hypnotic use. Far greater attention should be paid to the palliation of sleeping difficulties through multifaceted nonpharmacologic interventions not only to improve quality of life in these individuals but also to reduce rates of falls and fractures.” (E. Widera, eric.widera@ucsf.edu)
Methemoglobinemia & Topical Anesthetic Use: Patients exposed to topical anesthetics during bronchoscopy, esophagogastroduodenoscopy, transesophageal echocardiogram, and endoscopic retrograde cholangiopancreatography are at risk for development of methemoglobinemia, according a retrospective study of 33 cases (pp. 771–6). Respective rates were 13.7 and 0.14 cases per 10,000 inpatient procedures for hospitalized and nonhospitalized patients, the researchers report. (D. A. Leffler, dleffler@caregroup.harvard.edu)

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

PNN Pharmacotherapy Line
May 15, 2013 * Vol. 20, No. 94
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 15 issue of JAMA (2013; 309).
Carotenoids, Fatty Acids in Age-Related Macular Degeneration: Among patients aged 50–85 years at risk for progression to advanced age-related macular degeneration (AMD), lutein + zeaxanthin may be appropriate carotenoids for a preventive formulation, especially in former smokers at increased risk of lung cancer, according to the Age-Related Eye Disease Study 2 (AREDS2) (pp. 2005–10). In the Phase III trial, 4,203 patients who opted out of the AREDS formulation containing beta-carotene received one of four randomly assigned substitutes: lutein 10 mg + zeaxanthin 2 mg, omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] 350 mg + eicosapentaenoic acid [EPA] 650 mg), lutein + zeaxanthin and DHA + EPA, or placebo, with these results: “Median follow-up was 5 years, with 1,940 study eyes (1,608 participants) progressing to advanced AMD. Kaplan–Meier probabilities of progression to advanced AMD by 5 years were 31% (493 eyes [406 participants]) for placebo, 29% (468 eyes [399 participants]) for lutein + zeaxanthin, 31% (507 eyes [416 participants]) for DHA + EPA, and 30% (472 eyes [387 participants]) for lutein + zeaxanthin and DHA + EPA. Comparison with placebo in the primary analyses demonstrated no statistically significant reduction in progression to advanced AMD (hazard ratio [HR], 0.90 [98.7% CI, 0.76–1.07]; P = .12 for lutein + zeaxanthin; 0.97 [98.7% CI, 0.82–1.16]; P = .70 for DHA + EPA; 0.89 [98.7% CI, 0.75–1.06]; P = .10 for lutein + zeaxanthin and DHA + EPA). There was no apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. More lung cancers were noted in the beta carotene vs no beta carotene group (23 [2.0%] vs 11 [0.9%], nominal P = .04), mostly in former smokers.” (E. Y. Chew, echew@nei.nih.gov)
Costs & 340B Drug Discounts: After reviewing problems with the 340B drug-discount program and its paradoxical effects ton costs of patient care, especially for cancer, authors of a Viewpoint ponder potential changes (pp. 1995–6): “Could the program be reconfigured to provide support to hospitals serving the most vulnerable patients while eliminating its cost-increasing effects? There are a number of available options. One option would be for hospitals and their affiliated contract pharmacies to be limited to providing the drugs they obtain at 340B discount rates only to those patients who are poor and uninsured. Administratively, this approach would be analogous to the process for Medicaid drug rebates in hospitals and probably most consistent with the original intent of the program. Manufacturers would benefit because the number of drugs sold at a discount would be reduced, and therefore the incentive to inflate prices for new drugs would be reduced. Eligible hospitals and their affiliated physicians would lose a source of profits. Patients and insurers would directly benefit through the elimination of 340B-created incentives to overprescribe expensive drugs and indirectly benefit through a slowdown in consolidation of hospitals with community-based clinical centers and physicians.
“Alternatively, hospitals and treating physicians could be required to pass on their savings from drug purchases to patients and their insurance providers, including Medicare. This approach would reduce the incentive for overutilization of high-priced drugs and lessen (but not eliminate) competition between outpatient cancer centers for well-insured patients. An intermediate version of this approach is to allow insurers to recoup some 340B profits from hospitals and physicians and pass those profits back to their beneficiaries. Congress would need to empower the Centers for Medicare & Medicaid Services to do the same for the Medicare program.” (R. M. Conti,
rconti@uchicago.edu)

>>>PNN NewsWatch
* FDA yesterday approved a new nimodipine oral solution (Nymalize, Arbor Pharmaceuticals) for treatment of patients with subarachnoid hemorrhage. Availability of the formulation should avoid adverse effects and deaths from intravenous injection of liquid contents of oral nimodipine capsules, FDA said.
*
FDA also approved the cobas EGFR Mutation Test (Roche), a companion diagnostic for erlotinib (Tarceva), along with an expanded use for erlotinib as a first-line treatment for patients with metastatic nonsmall cell lung cancers and certain EGFR mutations.

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

PNN Pharmacotherapy Line
May 16, 2013 * Vol. 20, No. 95
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 16 issue of the New England Journal of Medicine (2013; 368).
Sofosbuvir for Hepatitis C: Two research articles and an editorial explore use of the oral nucleotide polymerase inhibitor sofosbuvir for hepatitis C virus (HCV).
In two randomized Phase III trials of patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option, sofosbuvir plus ribavirin was effective when given for 12 or 16 weeks (
pp. 1867–77): “The rate of a sustained virologic response was 78% (95% confidence interval [CI], 72 to 83) with sofosbuvir and ribavirin, as compared with 0% with placebo (P < 0.001). Among previously treated patients, the rate of response was 50% with 12 weeks of treatment, as compared with 73% with 16 weeks of treatment (difference, −23 percentage points; 95% CI, −35 to −11; P < 0.001). In both studies, response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and, among patients with genotype 3 infection, lower among those with cirrhosis than among those without cirrhosis. The most common adverse events were headache, fatigue, nausea, and insomnia; the overall rate of discontinuation of sofosbuvir was low (1 to 2%).” (I. M. Jacobson, imj2001@med.cornell.edu)
In a pair of Phase II trials, sofosbuvir performed well in both open-label use and when compared with peginterferon for noninferiority (
pp. 1878–87): “In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir–ribavirin group and the peginterferon–ribavirin group. Response rates in the sofosbuvir–ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon.” (E. Lawitz, lawitz@txliver.com)
The way clinicians use interferon for HCV treatment will soon be changing, an editorialist predicts (
pp. 1931–2): “What are we to conclude from these studies? The low incidence of side effects, the relatively short duration of treatment, and the pangenotypic properties of the drugs are strong selling points of a sofosbuvir–ribavirin regimen and will probably lower the threshold for HCV treatment for both patients and physicians. The likely next step is to combine sofosbuvir with other direct-acting antivirals to enhance its potency. Is the interferonologist down and out? I do not think so, but it is surely time for reeducation.” (J. P. H. Drenth)
Physicians, Nurse Practitioners Differ on Primary Care: Two thirds of physicians believe they provide a higher-quality examination and consultation than do nurse practitioners, while three fourths of the latter group disagree, according to a U.S. survey that bodes poorly for resolving the nation’s primary-care shortage without strife (pp. 1898–906). The 467 responding nurse practitioners were more likely to believe that they should lead medical homes, compared with 505 physicians. and nurse practitioners differed in their belief that they should be allowed hospital admitting privileges and be paid equally for the same clinical services. (K. Donelan, kdonelan@partners.org)

>>>PNN NewsWatch
* Golimumab (Simponi, Janssen Ortho Biotech) was approved yesterday by FDA for treating adults with moderate to severe ulcerative colitis. The drug was already approved for rheumatoid arthritis. In a placebo-controlled trial of 513 patients, those using golimumab had greater clinical response and clinical remission and better appearance of the colon after 6 weeks. Maintenance of response for 54 weeks was demonstrated in a 310-patient study. Common adverse effects of the tumor necrosis factor–blocker are upper respiratory infection and injection-site redness.
*
FDA also yesterday approved radium Ra 223 dichloride (Xofigo, Bayer) for treatment of men with symptomatic late-stage (metastatic) castration-resistant prostate cancer. The agent, approved 3 months ahead of schedule under FDA’s priority review program, binds with bone minerals and delivers radiation directly to bone tumors.

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

PNN Pharmacotherapy Line
May 17, 2013 * Vol. 20, No. 96
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Association (2013; 53).
MTM in Minnesota: Maturation of medication therapy management (MTM) programs in Minnesota is detailed in two articles.
An audit of MTM billings submitted to the Minnesota Health Care Programs (MHCP) in 2008–10 found about 10% of claims were “upcoded,” with the auditor expressing “concerns that a number of claims billed at the highest complexity level were only 15 minutes long,” researchers report (
pp. 248–53): “190 claims were reviewed for 57 distinct pharmacies that billed for MTM services from 2008 to 2010, representing 4.5% of all claims submitted. The auditor reported that generally, the documentation within the electronic medical record had the least ‘up-coding’ of all documentation systems. A total of 18 claims were coded at a higher level than appropriate, but only 10 notices were sent out to recover money because the others did not meet the minimum $50 threshold.” These findings led to these observations by the authors: “Providers will need to be cautious of the conditions that they bill as complex and of how they define drug therapy problems. Everything for which is being billed must be clearly assessed or rationalized in the documentation note. The auditor expressed that overall, documentation was well done; however, many MTM providers are now asking how to internally prepare for future audits.” (S. Smith, smit2210@umn.edu)
Adoption of the Minnesota Department of Human Services (DHS) MTM program by patients and pharmacists increased from 2006 to 2011, and the “small percentage of patients reached should increase with subsequent years” with “better strategies to recruit patients and pharmacist providers,” authors conclude (
pp. 254–60). Analysis of claims, providers, and dollars compensated during this time period showed the following: “During 2011, 76 pharmacists were compensated a total of $210,716 for 2,427 claims. Of these claims, 1,009 were initial visits and 1,418 were follow-up visits. In each of the first 6 years of the program, an increase was seen in number of claims, number of pharmacists submitting claims, and dollars compensated. These increases followed exponential curves for total number of claims and dollars compensated with a declining logarithmic curve for pharmacists. From 2010 to 2011, the number of claims and dollars compensated did not increase as much from 2009 to 2010. However, claims data may still increase for 2011 as a result of late submissions. During 2011, the percentage of eligible patients provided services was estimated to be 5.7% to 7.6%.” (S. Larson, lars1904@umn.edu)
Drug/Dietary Supplement Inquiries by College Athletes: Tabulation and classification of nearly 25,000 drug and dietary supplement inquiries submitted to the National Center for Drug Free Sport through the Resource Exchange Center (REC) by college athletes and athletic personnel can inform pharmacists when they “advise, counsel and refer NCAA athletes regarding the use of banned and permitted substances,” investigators conclude (pp. 297–303): “Inquiries for prescription medications for albuterol inhalers, methylphenidate, amphetamines, and prednisone were the most common using a drug lookup function. The most common inquiries for over-the-counter medications included pseudoephedrine, loratadine, cetirizine, and caffeine. Among dietary supplements, inquiries for amino acids/metabolites, vitamins and minerals, and herbal products occurred most frequently. One dietary supplement, N.O.-Xplode (Bio-Engineered Supplements and Nutrition, Inc.), accounted for the majority of individual dietary supplement inquiries. Banned substances accounted for 30% of all inquiries submitted to the REC and 18% of medications searched in a drug lookup database.” (P. J. Ambrose, ambrosep@pharmacy.ucsf.edu)
Occupational Satisfaction, Stress Among Community Pharmacists: In an online survey of 303 independent and chain community pharmacists, “more than 50% stated that they were considering quitting their jobs” and 20% reported adverse mental health and relationship effects of their employment (pp. 282–96). “Substantive levels of occupational dissatisfaction and stress … are associated with a damaging promotion of community practice—a marker of a negative trajectory in sustaining this practice environment,” the authors conclude. (M. A. Munger, mmunger@hsc.utah.edu)

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

PNN Pharmacotherapy Line
May 20, 2013 * Vol. 20, No. 97
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 18 issue of Lancet, a theme issue on “Women Deliver” (2013; 381).
Contraceptive Need & Use in Developing Countries: “A substantial and unfinished agenda towards meeting couples’ reproductive needs” is uncovered in an analysis of national surveys conducted in developing countries in 2003, 2008, and 2012, and meeting this unmet need will require increased resources, improved access to contraceptives and supplies, and high-quality services and large-scale public education interventions aimed at reducing social barriers, authors conclude (pp. 1756–62). Based on responses of married and unmarried women aged 15–49 years, the investigators found: “The number of women wanting to avoid pregnancy and therefore needing effective contraception increased substantially, from 716 million (54%) of 1,321 million in 2003, to 827 million (57%) of 1,448 million in 2008, to 867 million (57%) of 1,520 million in 2012. Most of this increase (108 million) was attributable to population growth. Use of modern contraceptive methods also increased, and the overall proportion of women with unmet need for modern methods among those wanting to avoid pregnancy decreased from 29% (210 million) in 2003, to 26% (222 million) in 2012. However, unmet need for modern contraceptives was still very high in 2012, especially in sub-Saharan Africa (53 million [60%] of 89 million), south Asia (83 million [34%] of 246 million), and western Asia (14 million [50%] of 27 million). Moreover, a shift in the past decade away from sterilisation, the most effective method, towards injectable drugs and barrier methods, might have led to increases in unintended pregnancies in women using modern methods.” (J. E. Darroch, jedarroch@guttmacher.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Self-management in Long-term Conditions: An intervention designed to “enhance self management support in routine primary care did not add noticeable value to existing care for long term conditions,” researchers report (f2882). “The active components required for effective self management support need to be better understood, both within primary care and in patients’ everyday lives,” the authors conclude. The study included patients with diabetes, COPD, or irritable bowel syndrome. Results were as follows for the use of tools for assessing patients’ support needs, guidebooks on self-management, and a Web-based directory of self-management resources in the areas of northwest England where the study was conducted: “We randomised 44 practices and recruited 5,599 patients, representing 43% of the eligible population on the practice lists. 4,533 patients (81.0%) completed the six month follow-up and 4,076 (72.8%) the 12 month follow-up. No statistically significant differences were found between patients attending trained practices and those attending control practices on any of the primary or secondary outcomes. All effect size estimates were well below the prespecified threshold of clinically important difference.” (A Kennedy, a.kennedy@soton.ac.uk)

>>>PNN NewsWatch
* On Saturday, FDA expanded an April alert to include all sterile drug products made by NuVision Pharmacy in Dallas. FDA recommends that these products not be administered to patients.

>>>PNN JournalWatch
* Does Fetal Exposure to SSRIs or Maternal Depression Impact Infant Growth?, in
American Journal of Psychiatry, 2013; 170: 485–93. (K. L. Wisner, katherine.wisner@northwestern.edu)
* Sodium Valproate Use Is Associated With Reduced Parietal Lobe Thickness and Brain Volume, in
Neurology, 2013; 80: 1895–900. (G. D. Jackson, BRI@brain.org.au)
* Caring for Visually Impaired Patients, in
Journal of American Pharmacists Association, 2013; 53: e142–50. (K. B. Orrico, rricok@pamf.org">orricok@pamf.org)
* Spirometry: Tool for Pharmacy Practitioners To Expand Direct Patient Care Services, in
Journal of American Pharmacists Association, 2013; 53: 307–15. (M. J. Cawley, m.cawley@usciences.edu)
* The Slowdown in Health Care Spending in 2009–11 Reflected Factors Other Than the Weak Economy and Thus May Persist, in
Health Affairs, 2013; 32: 835–40. (M. E. Chernew, Chernew@hcp.med.harvard.edu)
* If Slow Rate of Health Care Spending Growth Persists, Projections May Be Off by $770 Billion, in
Health Affairs, 2013; 32: 841–50. (D. M. Cutler, dcutler@harvard.edu)

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

PNN Pharmacotherapy Line
May 21, 2013 * Vol. 20, No. 98
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Online-first articles and May 21 issue of the Annals of Internal Medicine (2013; 158).
Oxandrolone in Chronic Pressure Ulcers: Compared with placebo, the anabolic steroid oxandrolone did not significantly improve the healing or percentage of target pressure ulcers (TPUs) that remained closed after an 8-week trial, researchers report (pp. 718–26). At 16 inpatient units for spinal cord injury at VA medical centers, 212 patients received oxandrolone 20 mg/d or placebo, with these results: “24.1% (95% CI, 16.0% to 32.1%) of TPUs in oxandrolone recipients and 29.8% (CI, 21.0% to 38.6%) in placebo recipients healed (difference, −5.7 percentage points [CI, −17.5 to 6.8 percentage points]; P = 0.40). At 8-week follow-up, 16.7% (CI, 9.6% to 23.7%) of oxandrolone recipients and 15.4% (CI, 8.5% to 22.3%) of placebo recipients retained a healed TPU (difference, 1.3 percentage points [CI, −8.8 to 11.2 percentage points]; P = 0.70). No serious adverse events were related to oxandrolone. Liver enzyme levels were elevated in 32.4% (CI, 23.6% to 41.2%) of oxandrolone recipients and 2.9% (CI, 0.0% to 6.1%) of placebo recipients (P < 0.001).” (W. A. Bauman, william.bauman@va.gov)
Methadone-Associated Cardiac Arrhythmia: Reports to FDA’s Adverse Event Reporting System (FAERS) in 1997–2011 show that “methadone-associated arrhythmia [has] increased substantially and are disproportionately represented relative to other events with the drug,” authors conclude (pp. 735–40). Coadministration with antiretrovirals was especially problematic, according to the analysis of reports of adults with QTc prolongation or torsades de pointes and ventricular arrhythmia or cardiac arrest: “1,646 cases of ventricular arrhythmia or cardiac arrest and 379 cases of QTc prolongation or torsade de pointes were associated with methadone. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1 to 0.5) before the 2002 publication to a mean of 3.5 (CI, 2.5 to 4.8) after it. After 2000, methadone was the second-most common primary suspect in cases of QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associated with disproportionate reporting similar to that of antiarrhythmic agents known to promote torsade de pointes. Antiretroviral drugs for HIV were the most common coadministered drugs.” (M. J. Krantz, mori.krantz@dhha.org)
Suicide Risk Screening, Treatment Tools in Primary Care: Suicide risk screening tools that can be used in primary care “might help to identify some adults at increased risk for suicide but have limited ability to detect suicide risk in adolescents,” according to a systematic review prepared for the U.S. Preventive Services Task Force (pp. 741–54): “Evidence was insufficient to determine the benefits of screening in primary care populations; very limited evidence identified no serious harms. Minimal evidence suggested that screening tools can identify some adults at increased risk for suicide in primary care, but accuracy was lower in studies of older adults. Minimal evidence limited to high-risk populations suggested poor performance of screening instruments in adolescents. Trial evidence showed that psychotherapy reduced suicide attempts in high-risk adults but not adolescents. Most trials were insufficiently powered to detect effects on deaths.” (E. O’Connor, elizabeth.oconnor@kpchr.org)
Disagreement Over DSM-V: The Chair of the DSM-IV Task Force charges that the new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lacks sufficient scientific support, defies clinical common sense, and was prepared without adequate consideration of risk–benefit ratios and the economic cost of expanding the reach of psychiatry (online first). He recommends that physicians use DSM-5 cautiously, if at all. DSM-5 ignores the risk of overdiagnosis and introduces high-prevalence diagnoses that may actually be everyday problems, the author argues, noting that drug companies will take marketing advantage of the loose DSM definitions by promoting medications to address the chemical imbalances that cause those “disorders.” The author writes the DSM-5 review process was secretive, closed, and disorganized, with deadlines being consistently missed, and the American Psychiatric Association refused a petition for an independent scientific review of the DSM-5 that was endorsed by more than 50 mental health associations. (A. Frances)

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

PNN Pharmacotherapy Line
May 22, 2013 * Vol. 20, No. 99
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 22 issue of JAMA (2013; 309).
Escitalopram & Mental Stress–Induced Myocardial Ischemia: Lower rates of mental stress–induced myocardial ischemia (MSIMI) were recorded among patients taking escitalopram, compared with placebo, in the REMIT trial (pp. 2139–49). At a tertiary medical center in 2007–11, patients with clinically stable coronary heart disease and laboratory-diagnosed MSIMI were randomized to 6 weeks of escitalopram 5–20 mg/d or placebo, with these results: “Of 127 participants randomized to receive escitalopram (n = 64) or placebo (n = 63), 112 (88.2%) completed end point assessments (n = 56 in each group). At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4%–43.0%]) had absence of MSIMI during the 3 mental stressor tasks compared with patients taking placebo (17.5% [95% CI, 10.4%–24.5%]), based on the unadjusted multiple imputation model for intention-to-treat analysis. A significant difference favoring escitalopram was observed (odds ratio, 2.62 [95% CI, 1.06–6.44]). Rates of exercise-induced ischemia were slightly lower at 6 weeks in the escitalopram group (45.8% [95% CI, 36.6%–55.0%]) than in patients receiving placebo (52.5% [95% CI, 43.3%–61.8%]), but this difference was not statistically significant (adjusted odds ratio; 1.24 [95% CI, 0.60–2.58]; P = .56).” (W. Jiang, jiang001@mc.duke.edu)
Early Parenteral Nutrition in Critically Ill Patients Who Cannot Receive Enteral Nutrition: Among 1,372 critically ill adults with relative contraindications to early enteral nutrition (EN), early provision of parenteral nutrition (PN) produced no significant reductions in mortality or ICU or hospital stay, but did enable fewer days of invasive ventilation, a study shows (pp. 2130–8). In 2006–11 at ICUs in 31 hospitals in Australia and New Zealand, critically ill adults with relative contraindications to early EN and who were expected to receive critical care for more than 2 days were randomized to “pragmatic standard care” or early PN. Results showed: “Of 682 patients receiving standard care, 199 patients (29.2%) initially commenced EN, 186 patients (27.3%) initially commenced PN, and 278 patients (40.8%) remained unfed. Time to EN or PN in patients receiving standard care was 2.8 days (95% CI, 2.3 to 3.4). Patients receiving early PN commenced PN a mean of 44 minutes after enrollment (95% CI, 36 to 55). Day-60 mortality did not differ significantly (22.8% for standard care vs 21.5% for early PN; risk difference, −1.26%; 95% CI, −6.6 to 4.1; P = .60). Early PN patients rated day-60 quality of life (RAND-36 General Health Status) statistically, but not clinically meaningfully, higher (45.5 for standard care vs 49.8 for early PN; mean difference, 4.3; 95% CI, 0.95 to 7.58; P = .01). Early PN patients required fewer days of invasive ventilation (7.73 vs 7.26 days per 10 patient × ICU days, risk difference, −0.47; 95% CI, −0.82 to −0.11; P = .01) and, based on Subjective Global Assessment, experienced less muscle wasting (0.43 vs 0.27 score increase per week; mean difference, −0.16; 95% CI, −0.28 to −0.038; P = .01) and fat loss (0.44 vs 0.31 score increase per week; mean difference, −0.13; 95% CI, −0.25 to −0.01; P = .04).” (G. S. Doig, gdoig@med.usyd.edu.au)
These findings “add important knowledge to the ongoing debate about when, how much, and through what route critically ill patients should be fed,” an editorialist writes (
pp. 2165–6). He concludes, “For now clinicians should attempt to optimize oral/enteral nutrition, avoid forced starvation if at all possible, and judiciously use supplemental parenteral nutrition. Researchers should be encouraged to focus on understanding the biology of the starvation response and to explore mechanistic hypothesis of how nutrition intervention affects cellular and organ physiology. This recommendation is an essential step in the process of improving nutrition intervention for critically ill patients.” (J. B. Ochoa Gautier, choajb@upmc.edu">ochoajb@upmc.edu)
Treating Nonadherence: Medication nonadherence is a “medical condition” that can be diagnosed and treated, Viewpoint authors write (pp. 2105–6). “Based on identified barriers derived from systematic screening, patient-tailored interventions can be delivered in a safe, effective, and efficient manner, with systematic monitoring over time due to the dynamic process of medication adherence.… Synergism among multiple disciplines is necessary to successfully improve medication adherence for adults.” (Z. A. Marcum, zam12@pitt.edu)

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

PNN Pharmacotherapy Line
May 23, 2013 * Vol. 20, No. 100
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 23 New England Journal of Medicine (2013; 368).
Physician Payment Recommendations: It’s time to phase out fee-for-service payment, recommends the National Commission on Physician Payment Reform (pp. 2029–32). “Aggressive pursuit of new physician-payment models [should be done] with no delusions that the fee-for-service model will be swiftly or entirely eliminated,” authors write. Among the 12 recommendations, which “provide a blueprint for containing costs, improving patient care, and reducing expenditures on unnecessary care,” are these (S. A. Schroeder):
* The transition to an approach based on quality and value should start with testing new models of care over a 5-year period and incorporating them into increasing numbers of practices, with the goal of broad adoption by the end of the decade.
* Because the fee-for-service model will remain important into the future, even as the nation shifts to fixed-payment models, it will be necessary to continue recalibrating fee-for-service payments.
* For both Medicare and private insurers, fees should be increased for evaluation-and-management codes, which are currently undervalued. Fees for procedural diagnosis codes, which are generally overvalued and thus create incentives for overuse, should be frozen for 3 years. During this period, efforts should continue to improve the accuracy of relative values, which may result in some increases as well as some decreases in payments for specific services.
* Fee-for-service contracts should always include a component of quality or outcome-based performance reimbursement at a level sufficient to motivate a substantial change in behavior.
* For practices with fewer than five providers, changes in fee-for-service reimbursement should encourage methods for the practices to form virtual relationships and thereby share resources to increase the quality of care.
* As the nation moves from a fee-for-service system toward one that pays physicians through fixed payments, initial payment reforms should focus on areas in which there is substantial potential for cost savings and better quality of care.
* Measures should be put in place to safeguard access to high-quality care, assess the adequacy of risk-adjustment indicators, and promote strong physician commitment to patients.
* Medicare’s sustainable growth rate (SGR) adjustment should be eliminated.
* Cost-saving measures to offset the elimination of the SGR should come not only from reduced physician payment but also from the Medicare program as a whole. Medicare should also look for savings from reductions in inappropriate utilization of Medicare services.
* The Relative Value Scale Update Committee (RUC) should continue to make changes to become more representative of the medical profession as a whole and to make its decision making more transparent.… [CMS] should develop additional open, evidence-based, and expert processes beyond the recommendations of the RUC to validate the data and methods it uses to establish and update relative values.

>>>Gastroenterology Report
Source:
May issue of Gastroenterology (2013; 144).
Genetics of Fat-Soluble Vitamin Deficiency: Researchers identify a quartet of homozygous mutations among 10 pediatric patients that lead to disruption of amidation by bile acid and thereby produce deficiencies of fat-soluble vitamins (pp. 945–55.e6). Study participants had growth failure or transient neonatal cholestatic hepatitis. Analysis of urine, bile, and serum samples and sequence analysis of genes for bile acid-CoA:amino acid N-acyltransferase (BAAT) and bile acid-CoA ligase (SLC27A5) showed the following: “Levels of urinary bile acids were increased (432 ± 248 µmol/L) and predominantly excreted in unconjugated forms (79.4% ± 3.9%) and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile, and serum. Unconjugated bile acids accounted for 95.7% ± 5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4% ± 5.5% of the total. Duodenal bile acid concentrations were 12.1 ± 5.9 mmol/L, which is too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested.” (K. D. R. Setchell, kenneth.setchell@cchmc.org)

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

PNN Pharmacotherapy Line
May 24, 2013 * Vol. 20, No. 101
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
May issue of the Journal of the American Geriatrics Society (2013; 61).
Cost-Effectiveness of Vitamin D Screening v. Universal Supplementation: In community-dwelling older adults, population screening for vitamin D insufficiency and universal vitamin D supplementation are both cost-effective strategies, researchers report (pp. 707–14). Their findings, from a Markov model over a hypothetical 36-month period and based on a societal perspective, shows that screening would be more cost-effective in the oldest old population: “In women aged 65 to 80, population screening was slightly more cost-effective than universal supplementation, with an incremental [net monetary benefit (NMB)] of $224 compared with $189 (P < .001). Population screening in men was also more cost-effective than universal supplementation (incremental NMB $298 vs $260, P < .001). Results differed according to age group. In those aged 65, population screening had cost-effectiveness similar to that of universal supplementation in women ($59 vs $71) and men ($114 vs $120), whereas in those aged 80, population screening was substantially more cost-effective than universal supplementation in women ($563 vs $428) and men ($703 vs $571).” (R. H. Lee, r.lee@duke.edu)
Fracture Risk With Antipsychotic Medications: Among nursing home residents, initiation of antipsychotic medications is associated with fractures, with no differences among the commonly used agents, according to a study conducted in facilities in five states (pp. 715–22). A retrospective cohort was constructed using various data sets, and a time-to-event analysis showed these results for those aged 65 years or older: “Of 8,262 subjects (in 4,131 pairs), 4.3% suffered any fracture during observation, with 1% having a hip fracture during an average follow-up period of 93 ± 71 days (range 1–293 days). Antipsychotic initiation was associated with any fracture (hazard ratio (HR) = 1.39, P = .004) and hip fracture (HR = 1.76, P = .02). The highest risk was found for hip fracture when antipsychotic use was adjusted for dose (HR = 2.96, P = .008), but no differences in time to fracture were found between first- and second-generation agents or between individual drugs.” (S. Rigler, srigler@kumc.edu)
Management of Dementia: A population-based study of Medicare beneficiaries quantifies the use of medications for treating dementia in older adults and finds substantial use of psychoactive drugs in older adults with dementia (pp. 723–33). Beneficiaries had continuous A, B, and D coverage during 2008 and were alive this entire calendar year. With care setting categorized as no nursing home (NH) (0 months), partial NH (1–11 months), and full NH (12 months), the investigators report: “Community-dwellers represented 41.3% of the cohort, whereas 42.4% and 16.3% resided partially and fully in a NH, respectively. Annual prevalence of use was 57.1% for cognitive enhancers, 56.4% for antidepressants, 34.0% for antipsychotics, and 8.8% for mood stabilizers. Cognitive enhancer use was significantly lower in those with any NH stay (partial NH vs no NH, adjusted prevalence ratio (APR) = 0.84, 99% confidence interval (CI) = 0.83–0.86; full NH vs no NH, APR = 0.83, 99% CI = 0.81–0.85). In contrast, those with any NH residence had significantly higher use of all psychopharmacological medication classes than community-dwellers. More than half the cohort had consistent medication regimens during 2008 (64.8%). The number of psychopharmacological medication classes used increased with increasing NH stay duration.” (G. B. Rattinger, gratting@rx.umaryland.edu)
Antidepressants & COPD Mortality: More than one fifth of patients in a random sample of Medicare beneficiaries with chronic obstructive pulmonary disease also had a diagnosis of depression, a study shows (pp. 754–61). Analysis of Medicare beneficiaries in 2006–08 showed that 82.1% of those with COPD and depression were being treated for the latter condition, and those with baseline depression had higher risks of mortality (HR, 1.13, 95% CI, 1.09–1.18). (J. Qian, jzq0004@auburn.edu)

>>>PNN NewsWatch
* FDA yesterday approved the first A1C test labeled for diagnosing diabetes. The COBAS INTEGRA 800 Tina-quant HbA1cDx assay is manufactured by Roche.
*
PNN will not be published on Mon., May 27, Memorial Day.

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

PNN Pharmacotherapy Line
May 28, 2013 * Vol. 20, No. 102
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 27 issue of the JAMA Internal Medicine (2013; 173).
Preventing Catheter-Associated Urinary Tract Infections: Hospitals in Michigan—where a statewide Keystone Bladder Bundle Initiative has focused on “practices aimed at timely removal of urinary catheters”—more frequently use “key prevention practices” and have lower rates of catheter-associated urinary tract infections (CAUTIs) than do other states, a study shows (pp. 874–9). A 2009 survey of 470 infection preventionist shows these patterns of CAUTI prevention practices and CAUTI-specific standardized infection ratios: “Michigan hospitals, compared with hospitals in the rest of the United States, more frequently participated in collaboratives to reduce health care–associated infection (94% vs 67%, P < .001) and used bladder scanners (53% vs 39%, P = .04), as well as catheter reminders or stop orders and/or nurse-initiated discontinuation (44% vs 23%, P < .001). More frequent use of preventive practices coincided with a 25% reduction in CAUTI rates in the state of Michigan, a significantly greater reduction than the 6% overall decrease observed in the rest of the United States.” (S. Saint, saint@med.umich.edu)

>>>Lancet Highlights
Source:
May 25 issue of Lancet (2013; 381).
Estrogen Receptor Modulators in Breast Cancer Prevention: Selective estrogen receptor modulators (SERMs) reduce the incidence of invasive estrogen-positive breast cancer during treatment and for at least 5 years afterwards, report authors who conducted a meta-analysis of four agents (pp. 1827–34). Using a primary endpoint of incidence of all breast cancer during a 10-year follow-up period, the investigators report: “We analysed data for 83,399 women with 306,617 women–years of follow-up. Median follow-up was 65 months (IQR 54–93). Overall, we noted a 38% reduction (hazard ratio [HR] 0.62, 95% CI 0.56–0.69) in breast cancer incidence, and 42 women would need to be treated to prevent one breast cancer event in the first 10 years of follow-up. The reduction was larger in the first 5 years of follow-up than in years 5–10 (42%, HR 0.58, 0.51–0.66; p < 0.0001 vs 25%, 0.75, 0.61–0.93; p = 0.007), but we noted no heterogeneity between time periods. Thromboembolic events were significantly increased with all SERMs (odds ratio 1.73, 95% CI 1.47–2.05; p < 0.0001). We recorded a significant reduction of 34% in vertebral fractures (0.66, 0.59–0.73), but only a small effect for non-vertebral fractures (0.93, 0.87–0.99).” (J. Cuzick, j.cuzick@qmul.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Telemonitoring in Uncontrolled Hypertension: In 20 primary care practices in Scotland, self-monitoring of uncontrolled hypertension using telemonitoring was effective for lowering blood pressure, but the intervention also increased use of health care resources, researchers report (f3030). A total of 401 adult patients with mean daytime ambulatory blood pressures of 135/85 mm Hg or greater (but less than 211/136 mm Hg) were randomized to usual care or self-measurement and transmission of blood pressures via website, with these results: “Primary outcome data were available for 90% of participants (182 and 177, respectively). The mean difference in daytime systolic ambulatory blood pressure adjusted for baseline and minimisation factors between intervention and usual care was 4.3 mm Hg (95% confidence interval 2.0 to 6.5; P = 0.0002) and for daytime diastolic ambulatory blood pressure was 2.3 mm Hg (0.9 to 3.6; P = 0.001), with higher values in the usual care group. The intervention was associated with a mean increase of one general practitioner (95% confidence interval 0.5 to 1.6; P = 0.0002) and 0.6 (0.1 to 1.0; P = 0.01) practice nurse consultations during the course of the study.” (B. McKinstry, brian.mckinstry@ed.ac.uk)

>>>PNN JournalWatch
* Transforming Cardiovascular Health Through Genes and Environment: Presidential Address at the American Heart Association 2012 Scientific Sessions, in
Circulation, 2013; 127: 2066–70. (D. K. Arnett, arnett@uab.edu)
* Ethnic Differences in the Relationship Between Insulin Sensitivity and Insulin Response: A Systematic Review and Meta-analysis, in
Diabetes Care, 2013; 36: 1789–96. (K. Kodama, kkodama@stanford.edu)

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

PNN Pharmacotherapy Line
May 29, 2013 * Vol. 20, No. 103
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (2013; 36).
Grape Polyphenols, Oxidative Stress & Insulin Resistance: In a study of 38 overweight or obese first-degree relatives of patients with type 2 diabetes, a natural mixture of nutritional doses of grape polyphenols (PPs) prevented fructose-induced oxidative stress and insulin resistance (IR), researchers report (pp. 1454–61). Study participants, all of them otherwise healthy, were randomized to grape PP 2 g/d or placebo (PCB) for 8–9 weeks. During the last 6 days of supplementation, participants received fructose 3 g/kg/d, with these results: “In the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid–reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs.” (A. Avignon, a-avignon@chu-montpellier.fr)
Omega-3 Fatty Acids & Kidney Injury in Diabetes: Long-term trials of long-chain n-3 polyunsaturated fatty acid (n-3 PUFA) supplements are justified on the basis of a randomized crossover trial of 31 patients with diabetes, authors conclude (pp. 1462–9). Daily doses of n-3 PUFA 4 g were provided to study participants, all of whom had adult-onset diabetes and little or no protein in their urine. The study used a main outcome measure of urine albumin excretion and secondary markers of kidney injury, kidney function, and estimated glomerular filtration rate (eGFR) to find these results: “At baseline, mean BMI was 31.6 kg/m2, median eGFR was 76.9 mL/min/1.73 m2, and median 24-h urine albumin excretion was 161 mg/day. Compared with placebo, n-3 PUFA had nonsignificant effects on urine albumin excretion (−7.2%; 95% CI −20.6 to 8.5; P = 0.35) and significant effects on urine [neutrophil gelatinase-associated lipocalin (NGAL)] excretion (−16% [−29.1 to −0.5%]; P = 0.04). There was no effect on serum markers of kidney function or eGFR. In subgroup analyses, there were significant decreases in 24-h urinary excretion of albumin, NGAL, [liver fatty acid–binding protein], and [N-acetyl beta-d-glucosaminidase (NAG)] among participants taking medications that block the renin–angiotensin–aldosterone system.” (E. R. Miller III, ermiller@jhmi.edu)

>>>Medical Care Report
Source:
June issue of Medical Care (2013; 51).
Patient-Centered Medical Home Demonstration Project: In a patient-centered medical home (PCMH) in New Jersey, researchers found “little evidence of reductions in health care utilization or cost and minimal evidence of improvements in quality of care” based on outcomes in 10,000 plan members (pp. 487–93). The PCMH, encompassing eight primary care practices, was compared with 24 other practices before and after implementation of the PCMH in 2011, with these results: “The study cohort included 35,059 members during the study period 2010–2011—10,004 in the 8 PCMH practices and 25,055 in the 24 comparison practices. Health care utilization and costs did not significantly change with adoption of the PCMH model. In testing for changes in Healthcare Effectiveness and Data Information Set (HEDIS) quality measures, rates of mammography increased in PCMH practices after PCMH implementation compared to non-PCMH practices, by 2.2 percentage points on a base of 69.5% (P < 0.001). Rates of nephropathy screening also increased (by 6.6 percentage points on a base of 51.8%; P = 0.05). Changes in 7 other HEDIS quality measures following PCMH implementation were not statistically significant.” (R. M. Werner)

>>>PNN NewsWatch
* Sterile products made by Main Street Family Pharmacy of Newtown, TN, should not be administered to patients, FDA said on Friday, citing seven reports of adverse reactions to steroid injections compounded there. All reports involved preservative free methylprednisolone acetate (80 mg/mL).

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

PNN Pharmacotherapy Line
May 30, 2013 * Vol. 20, No. 104
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 30 New England Journal of Medicine (2013; 368).
Genomic and Epigenomic Analysis of AML: Research conducted by the Cancer Genome Atlas Research Network identifies mutation drivers in 200 adult patients with de novo acute myeloid leukemia (AML), finding that “a complex interplay of genetic events contributes to AML pathogenesis” (pp. 2059–74). Whole-genome (n =50) and whole-exome sequencing (n = 150) revealed these patterns: “AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories.” (T. J. Ley, timley@wustl.edu)
An editorialist writes of “the beginning of the end of the beginning in cancer genomics” (
pp. 2138–40): “In 1803, a few years before the inaugural issue of the Journal, Thomas Jefferson commissioned Meriwether Lewis and William Clark to survey the vast unknown American frontier. Lewis and Clark departed from St. Louis, where Ley et al. initiated the [above] AML genome survey. Less than a century later, the western frontier was declared ‘closed,’ but land surveyors did not disappear; today, they focus on construction projects and property boundaries. Likewise, although the initial epic AML genomic survey that began in St. Louis is now largely complete and surveys of other neoplasms will soon conclude, the use of genomics in quotidian practice is just beginning.” (D. P. Steensma)
Insurance for Young American Adults: An evaluation of 480,000 emergency department visits in the U.S. in 2009–11 quantifies the increase in insurance coverage among young American adults as a result of passage of the Affordable Care Act (pp. 2105–12): “After the ACA provision took effect, private coverage of nondiscretionary visits to emergency departments by young adults increased by 3.1 percentage points (95% confidence interval [CI], 2.3 to 3.9; relative increase, 5.2%; P < 0.001), as compared with similar visits in the control group. The percentage of visits by uninsured young adults also fell significantly (−1.7 percentage points; 95% CI, −2.8 to −0.7; relative decrease, 9.1%; P < 0.001). The rates of nondiscretionary visits that were covered by Medicaid or other nonprivate insurers remained relatively steady throughout the study period. The coverage expansion led to an estimated 22,072 visits to emergency departments by newly insured young adults and $147 million in associated costs that were covered by private insurance plans during a 1-year period.” (A. Mulcahy, amulcahy@rand.org)

>>>PNN NewsWatch
* FDA has approved dabrafenib (Tafinlar) and trametinib (Mekinist), products of GlaxoSmithKline, for treatment of metastatic or unresectable melanoma. The agency also approved the THxID BRAF genetic test (Genentech), a companion diagnostic that will help determine if a patient’s melanoma cells have V600E or V600K mutations in the BRAF gene. Dabrafenib, a BRAF inhibitor, is approved to treat patients with melanoma whose tumors express the BRAF V600E gene mutation. Trametinib, an MEK inhibitor, is approved to treat patients whose tumors express the BRAF V600E or V600K gene mutations. The drugs are approved as single agents. Women of child-bearing age should be advised of the potential for fetal harm. Men and women should also be advised of the potential for infertility with these drugs.
*
Critical shortages of injectable trace elements and phosphate products needed for total parenteral nutrition solutions could be alleviated by FDA’s decision to allow import of agents by Fresenius Kabi USA from its Norwegian plant, the agency said yesterday.

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

PNN Pharmacotherapy Line
May 31, 2013 * Vol. 20, No. 105
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Early-release articles from Pharmacotherapy (2013; 33).
Individualized Medication Assessment/Planning in Primary Care: “The burden of managing and continuously monitoring multiple medications in medically complex older adults” potentially can be addressed through an individualized medication assessment and planning (iMAP) program, conclude authors of a 64-patient study (DOI: 10.1002/phar.1274). For 6 months, a convenience sample of patients in a primary-care practice was enrolled in an iMAP program that included comprehensive medication therapy management at baseline and 3 and 6 months. Results showed: “There was a significant reduction in mean number of [medication-related problems (MRPs)]/patient (4.2 at baseline vs 1.0 at 6 mo, p < 0.0001) when adjusted for number of medications, race, and pharmacist. The prevalence of MRPs at 6 months compared with baseline was also significant (p < 0.0008). Acute health services utilization was assessed by medical record abstraction. The 64 patients experienced a rate of 8.3 events/100 person–months (64 total events) during the 12-month prestudy period. During the 6-month study period, the same patients experienced 5.4 events/100 person–months (20 total events). Thus, we noted a reduction in acute health services utilization of 35%. Physicians were enthusiastically supportive of iMAP.” (M. T. Roth, mroth@unc.edu)
ADEs Associated With Hospital Admissions: Age greater than 65, use of five or more drugs, and initiation of therapy with high-risk drugs are associated with hospitalizations for adverse drug events (ADEs), researchers report (DOI: 10.1002/phar.1287). At two U.K. hospitals, clinical pharmacists identified and interviewed patients whose admissions were associated with drug-related problems. A multidisciplinary team evaluated the contribution of ADEs to the hospital admission, along with the ADEs’ causality, severity, and preventability. Regression analysis showed the following relationships: “Of the 3,904 patients included in the analysis, 439 (11.2%) were judged by the review panel to have experienced ADEs. Of these, 209 patients (47.6%) experienced preventable ADEs. Four independent variables were found to have significant relationships with ADE admissions and preventability of ADEs: patient age, length of time since starting new drug, total number of prescription drugs, and hospital site. Drug classes most commonly associated with preventable ADEs were antiplatelet drugs, anticoagulants, diuretics (loop and thiazide diuretics), angiotensin-converting enzyme inhibitors, and antiepileptic drugs.” (D. Ashcroft, darren.ashcroft@manchester.ac.uk)
Daptomycin in Inpatients With Obesity: High-risk patients with obesity frequently have elevations in creatine phosphokinase (CPK) while receiving daptomycin, according to a retrospective cohort study at 13 southeastern U.S. hospitals (DOI: 10.1002/phar.1298). But drug-discontinuation rates are low, the authors find, based on these experiences with 126 inpatients in 2005–10: “CPK elevations more than 1,000 units/L occurred in 8.4% of evaluable patients and specifically in 1 (3.6%), 3 (10.3%), and 4 (10.5%) patients in BMI class I, II, and III, respectively (p = 0.554). CPK elevations more than 500 units/L occurred in 13.7% of patients with no statistically significant difference noted across BMI classes. Discontinuation due to ADEs occurred in 8 patients (6.3%). One patient developed rhabdomyolysis on day 9 of therapy. Clinical effectiveness was documented in 71% of patients and was consistent across BMI classes.” (P. B. Bookstaver, bookstaver@sccp.sc.edu)

>>>PNN NewsWatch
* FDA is advising health professionals against using magnesium sulfate injection for more than 5–7 days to stop preterm labor in pregnant women. This off-label use of the drug may lead to low calcium levels and bone problems in the developing baby or fetus, including osteopenia and bone fractures. The shortest duration of treatment that can result in harm to the baby is not known. FDA added. New information based on this warning is being added product labeling for Magnesium Sulfate Injection, USP 50%.
* All sterile drug products compounded by
Lowlite Investments d/b/a Olympia Pharmacy that have not reached beyond-use dates are being recalled because of lack of assurance of sterility, FDA said yesterday.

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

PNN Pharmacotherapy Line
June 3, 2013 * Vol. 20, No. 106
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 1 issue of Lancet (2013; 381).
Interleukin-1 Antagonism in Type 1 Diabetes: Testing the possibility of immunoactive agents in patients with type 1 diabetes of recent onset, investigators find that canakinumab and anakinra are safe but not effective as single immunomodulatory drugs (pp. 1905–15). “Interleukin-1 blockade might be more effective in combination with treatments that target adaptive immunity in organ-specific autoimmune disorders,” the group concludes, based on these results with 12 months of the anti-interleukin-1 antibody canakinumab and 9 months with anakinra, an interleukin-1 antagonist: “69 patients were randomly assigned to canakinumab (n = 47) or placebo (n = 22) monthly for 12 months and 69 were randomly assigned to anakinra (n = 35) or placebo (n = 34) daily for 9 months. No interim analyses were done. 45 canakinumab-treated and 21 placebo-treated patients in the canakinumab trial and 25 anakinra-treated and 26 placebo-treated patients in the anakinra trial were included in the primary analyses. The difference in C peptide area under curve between the canakinumab and placebo groups at 12 months was 0.01 nmol/L (95% CI –0.11 to 0.14; p = 0.86), and between the anakinra and the placebo groups at 9 months was 0.02 nmol/L (–0.09 to 0.15; p = 0.71). The number and severity of adverse events did not differ between groups in the canakinumab trial. In the anakinra trial, patients in the anakinra group had significantly higher grades of adverse events than the placebo group (p = 0.018), which was mainly because of a higher number of injection site reactions in the anakinra group.” (T. Mandrup–Poulsen, tmpo@sund.ku.dk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Double-Dose Oseltamivir in Severe Influenza: At 13 hospitals in southeast Asia, double doses of oseltamivir provided no clinical or virological advantages over standard doses in children and adults with confirmed severe influenza, researchers report (f3039). Results with 75 versus 150 mg twice daily or the pediatric equivalents of the antiviral agent produced these results: “Of 326 patients (including 246 (75.5%) children aged <15), 165 and 161 were randomised to double or standard dose oseltamivir, respectively. Of these, 260 (79.8%) were infected with influenza virus A (133 (40.8%) with A/H3N2, 72 (22.1%) with A/H1N1-pdm09, 38 (11.7%) with seasonal A/H1N1, 17 (5.2%) with A/H5N1) and 53 (16.2%) with influenza virus B. A further 3.9% (13) were false positive by rapid antigen test (negative by RT-PCR and no rise in convalescent haemagglutination inhibition titers). Similar proportions of patients were negative for RT-PCR on day five of treatment: 115/159 (72.3%, 95% confidence interval 64.9% to 78.7%) double dose recipients versus 105/154 (68.2%, 60.5% to 75.0%) standard dose recipients; difference 4.2% (−5.9 to 14.2); P=0.42. No differences were found in clearance of virus in subgroup analyses by virus type/subtype, age, and duration of illness before randomisation. Mortality was similar: 12/165 (7.3%, 4.2% to 12.3%) in double dose recipients versus 9/161 (5.6%, 3.0% to 10.3%) in standard dose recipients. No differences were found between double and standard dose arms in median days on supplemental oxygen (3 (interquartile range 2-5) v 3.5 (2-7)), in intensive care (4.5 (3-6) v 5 (2-11), and on mechanical ventilation (2.5 (1-16) v 8 (1-16)), respectively. No important differences in tolerability were found.” (J. Farrar, jfarrar@oucru.org)

>>>PNN JournalWatch
* Pneumonia and Pneumonia Related Mortality in Patients With COPD Treated With Fixed Combinations of Inhaled Corticosteroid and Long Acting Beta-2 Agonist: Observational Matched Cohort Study (PATHOS), in
BMJ, 2013; 346: f3306. (C. Janson, christer.janson@medsci.uu.se)
* Effectiveness of Hormonal and Surgical Therapies for Cryptorchidism: A Systematic Review, in
Pediatrics, 2013; 131: e1897–907. (D. Penson)
* Epidemiology, Prognosis, and Treatment of Resistant Hypertension, in
Pharmacotherapy, 2013; 33: 10.1002/phar.1297. (S. M. Smith, steven.smith@ucdenver.edu)
* Reducing the Risk of Obesity: Defining the Role of Weight Loss Drugs, in
Pharmacotherapy, 2013; 33 10.1002/phar.1277. (H. Ling, linghua_cn@hotmail.com)
* Understanding Iron: Promoting Its Safe Use in Patients With Chronic Kidney Failure Treated by Hemodialysis, in
American Journal of Kidney Diseases, 2013; 61: 992–1000. (N. D. Vaziri, ndvaziri@uci.edu)

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

PNN Pharmacotherapy Line
June 4, 2013 * Vol. 20, No. 107
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 4 issue of the Annals of Internal Medicine (2013; 158).
Aspirin v. LMWHs After Total Hip Arthroplasty: In 778 patients with total hip arthroplasty (THA) in 2007–10, aspirin was noninferior to dalteparin for extended prophylaxis against venous thromboembolism (VTE), a study shows (pp. 800–6). At 12 tertiary care orthopedic referral centers in Canada, patients who had unilateral procedures received 10 days of dalteparin prophylaxis followed by randomization to dalteparin or aspirin for 28 days, with these results: “Five of 398 patients (1.3%) randomly assigned to dalteparin and 1 of 380 (0.3%) randomly assigned to aspirin had VTE (absolute difference, 1.0 percentage point [95% CI, −0.5 to 2.5 percentage points]). Aspirin was noninferior (P < 0.001) but not superior (P = 0.22) to dalteparin. Clinically significant bleeding occurred in 5 patients (1.3%) receiving dalteparin and 2 (0.5%) receiving aspirin. The absolute between-group difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (CI, −0.3 to 3.8 percentage points; P = 0.091) in favor of aspirin.” (D. Anderson, david.anderson@cdha.nshealth.ca)
OTC Oral Contraceptives: While the American College of Obstetricians and Gynecologists (ACOG) came out in support of nonprescription access to oral contraceptives in December and the products are available over the counter (OTC) in more than 100 countries around the world, Americans “will not be seeing an OTC oral contraceptive product on the shelf of a local pharmacy any time soon,” writes the author of an opinion piece (pp. 839–40). After reviewing the legal and political hurdles that would have to be cleared for OTC access to birth control pills, the author concludes: “The decision by ACOG to support OTC access to contraceptive pills was certainly bold, and it is likely that not all practicing obstetrician–gynecologists agree with it. But the evidence to date clearly indicates that oral contraception could be safely provided OTC and that women would use it effectively. Given the potential for opposition from various social and professional groups, the ACOG statement may help to motivate a pharmaceutical company or other sponsor to perform the required research for an oral contraceptive product to become available OTC. At the same time, advocacy will be needed to ensure insurance coverage of OTC contraceptives, ideally without a prescription, so that this effort has the greatest possible impact on unintended pregnancy. Making at least some formulations of the pill available without a prescription will increase the options available to women to help them better meet their contraceptive needs.” (D. Grossman, Grossman@ibisreproductivehealth.org">DGrossman@ibisreproductivehealth.org)
Sunscreen & Skin Aging: In 930 healthy adults younger than 55 years of age, regular use of sunscreen stopped skin aging over a 4.5-year period, researchers report (pp. 781–90). The study, conducted in Australia at a latitude of 26 degrees south, compared daily versus discretionary use of broad-spectrum sunscreen and/or beta-carotene 30 mg, with these results: “The daily sunscreen group showed no detectable increase in skin aging after 4.5 years. Skin aging from baseline to the end of the trial was 24% less in the daily sunscreen group than in the discretionary sunscreen group (relative odds, 0.76 [95% CI, 0.59 to 0.98]). Beta-carotene supplementation had no overall effect on skin aging, although contrasting associations were seen in subgroups with different severity of aging at baseline.” (A. C. Green)
Meaningful Use & EHRs: Few physicians with electronic health records (EHRs) in late 2011 and early 2012 were successfully using the technology to meet required meaningful-use criteria, according to a national survey (pp. 791–9): “A total of 43.5% of physicians reported having a basic EHR, and 9.8% met meaningful use criteria. Computerized systems for managing patient populations were not widespread; fewer than one half of respondents reported the presence of computerized systems for any of the patient population management tasks included in the survey. Physicians with such functionalities reported that these systems varied in ease of use. Physicians with an EHR that met meaningful use criteria were significantly more likely than those not meeting the standard to rate panel management tasks as easy.” (C. M. DesRoches, cdesroches@mathematica-mpr.com)

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

PNN Pharmacotherapy Line
June 5, 2013 * Vol. 20, No. 108
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 5 issue of JAMA (2013; 309).
Glucocorticoids in COPD Exacerbations: Five-day courses of glucocorticoids are noninferior to 14-day regimens in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD), researchers report (pp. 2223–31). The REDUCE trial tested whether current guidelines of 7–14 days of systemic glucocorticoid therapy can be modified. In 314 patients presenting to five Swiss emergency departments with acute COPD exacerbations, prednisone 40 mg daily for 5 or 14 days produced these results: “Hazard ratios for the short-term vs conventional treatment group were 0.95 (90% CI, 0.70 to 1.29; P = .006 for noninferiority) in the intention-to-treat analysis and 0.93 (90% CI, 0.68 to 1.26; P = .005 for noninferiority) in the per-protocol analysis, meeting our noninferiority criterion. In the short-term group, 56 patients (35.9%) reached the primary end point; 57 (36.8%) in the conventional group. Estimates of reexacerbation rates within 180 days were 37.2% (95% CI, 29.5% to 44.9%) in the short-term; 38.4% (95% CI, 30.6% to 46.3%) in the conventional, with a difference of −1.2% (95% CI, −12.2% to 9.8%) between the short-term and the conventional. Among patients with a reexacerbation, the median time to event was 43.5 days (interquartile range [IQR], 13 to 118) in the short-term and 29 days (IQR, 16 to 85) in the conventional. There was no difference between groups in time to death, the combined end point of exacerbation, death, or both and recovery of lung function. In the conventional group, mean cumulative prednisone dose was significantly higher (793 mg [95% CI, 710 to 876 mg] vs 379 mg [95% CI, 311 to 446 mg], P < .001), but treatment-associated adverse reactions, including hyperglycemia and hypertension, did not occur more frequently.” (J. Rutishauser, j.rutishauser@unibas.ch)
“Less is clearly more” in use of steroids for COPD exacerbations, editorialists write (
pp. 2272–3): “The clinical implications of this study are clear. Most patients with acute COPD exacerbations can be treated with a 5-day course of prednisone or equivalent (40 mg daily). Furthermore, this regimen can be applied across all GOLD (Global Initiative for Chronic Obstructive Lung Disease) categories of disease severity. This is welcome news for patients with COPD who experience multiple exacerbations annually and are exposed to repeated courses of systemic corticosteroids. These findings will enable clinicians to minimize steroid exposure and reduce the risk of steroid-related toxicity in these patients.” (D. D. Sin, don.sin@hli.ubc.ca)
Management of Metabolic Syndrome: In a 12-month trial of 120 patients with type 2 diabetes, mild to moderate obesity, and elevated C peptide levels, addition of gastric bypass surgery to lifestyle-intensive medical management improved odds of reaching a composite goal of A1C < 7%, LDL cholesterol < 100 mg/dL, and systolic blood pressure < 130 mm Hg (pp. 2240–9). At four teaching hospitals in the U.S. and Taiwan, all study participants received the intensive protocol, and 60 were randomly assigned to Roux-en-Y gastric bypass, with these results: “After 12 months, 28 participants (49%; 95% CI, 36%–63%) in the gastric bypass group and 11 (19%; 95% CI, 10%–32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9–11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3–3.6) and lost 26.1% vs 7.9% of their initial body weight compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%–20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group.” (S. Ikramuddin, ikram001@umn.edu)
While an “optimal approach for treatment of obesity and diabetes remains unknown,” editorialists write, “Bariatric surgery does result in substantial weight loss with excellent diabetes control but is offset by initial high cost and risks of surgical complications” (
pp. 2274–5; B. M. Wolfe, wolfeb@ohsu.edu).

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

PNN Pharmacotherapy Line
June 6, 2013 * Vol. 20, No. 109
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 6 issue of the New England Journal of Medicine (2013; 368).
Eculizumab in Atypical Hemolytic–Uremic Syndrome: In 37 patients with atypical hemolytic–uremic syndrome, the terminal complement inhibitor “eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function,” researchers report (pp. 2169–81). Patients were 12 years or older when they participated in two Phase II trials, with these results: “A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×109 per liter (P < 0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event–free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.” (C. M. Legendre, christophe.legendre@nck.aphp.fr)
Codeine Risks After Adenotonsillectomy: “A combination of case reporting and our evolving understanding of genetic influences on drug response has clarified the need to avoid [codeine] after adenotonsillectomy,” report authors of a Perspective article (pp. 2155–7). While “the only well-documented cases of death or respiratory arrest after codeine treatment in ultrarapid-metabolizing children have involved patients who have just undergone adenotonsillectomy,” the writers note, “Performing routine genotyping before prescribing codeine was not recommended [by FDA] for several reasons. Some of the patients who died or in whom respiratory depression developed were genetically extensive metabolizers, so patients with ‘normal’ genotyping results may still be at risk. Also, since the number that would need to be screened to prevent such a rare toxic effect would be very high, and since preoperative laboratory assessments are not routine before adenotonsillectomy, the practicality of genotyping is questionable.” (J. A. Racoosin)
Global Health Model From the AIDS Pandemic: “[The] unprecedented global response to the AIDS pandemic can serve as a model for the response to other global health threats,” authors of a review write (pp. 2210–8). “The response to the pandemic required a coordinated global effort, which has been led by the Joint United Nations Program on HIV/AIDS since 1996. This transformational response helped redefine what is meant by health diplomacy and led to a new culture of accountability in international development. Tiered pricing of medicines became commonplace, and renewed optimism provided a boost for research on other neglected global health issues. This response to the AIDS pandemic highlighted the shortage of health care workers, inadequate availability of essential medications, and weaknesses in primary health care and public health systems. The stigma of HIV infection and inequities in the care of those infected focused attention on social and medical equity and human rights.” (P. Piot, director@lshtm.ac.uk)

>>>PNN NewsWatch
* Federal officials are reviewing yesterday’s Second Circuit Court of Appeals ruling that two-dose emergency contraceptive products be made available immediately to consumers of all ages without a prescription, the New York Times reports. The ruling adds “another layer of confusion to a complex and intensely political fight over the drug’s availability,” the newspaper reports. A reporter from the Washington Post adds, “Don’t expect emergency contraceptives to show up next to toothpaste and Advil tomorrow” and notes that Plan B manufacturer Teva Pharmaceutical “has told me previously that it would take ‘a few months’ to deal with the logistics of new labeling and other steps necessary to move its product out onto drugstore shelves.”

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

PNN Pharmacotherapy Line
June 7, 2013 * Vol. 20, No. 110
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
June issue of the American Journal of Psychiatry (2013; 170).
Need for FDA Warning Regarding Higher Citalopram Doses: In a large study of nearly 1 million patients taking citalopram or sertraline, investigators found no increased risk of cardiac problems or mortality associated with doses of citalopram higher than 40 mg/d (pp. 642–50). “These results raise questions regarding the continued merit of the FDA warning” about higher doses, the authors conclude, based on these findings for 618,450 citalopram users and 365,898 sertraline users in the VA system: “Citalopram daily doses >40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.68, 95% CI = 0.61–0.76), all-cause mortality (adjusted hazard ratio = 0.94, 95% CI = 0.90–0.99), and noncardiac mortality (adjusted hazard ratio = 0.90, 95% CI = 0.86–0.96) compared with daily doses of 1–20 mg. No increased risks of cardiac mortality were found. Citalopram daily doses of 21–40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.80, 95% CI = 0.74–0.86) compared with dosages of 1–20 mg/day but did not have significantly different risks of any cause of mortality. The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and either all-cause or noncardiac mortality.” (K. Zivin, kzivin@umich.edu)
Transitions in Illicit Drug Use Status: Because alcohol and tobacco use is associated with transitions to problematic illicit use of drugs, clinicians should address “all co-occurring disorders and substance use in patient assessments and treatment planning, both to prevent adverse transitions and to promote positive transitions,” a study shows (pp. 660–70). Two interviews of 34,653 adults conducted 3 years apart showed these patterns for 32,675 past-year nonusers, 861 past-year asymptomatic drug users, and 1,117 past-year symptomatic drug users: “Among baseline nonusers, 95.4% continued to be nonusers at follow-up, 2.1% became asymptomatic users, and 2.5% developed problem use. Among baseline asymptomatic users, 66.6% had stopped using drugs at follow-up, 14.3% continued to be asymptomatic users, and 19.1% had developed problem use. Nearly half (49.0%) of those with problem use at baseline had stopped using drugs at follow-up, 10.9% had transitioned to asymptomatic use, and 40.1% continued to have problem use. Younger age, male sex, white race, and not being married were associated with progression from nonuse to use or problem use, as were alcohol and tobacco use and disorders, major depression, and schizotypal, borderline, and narcissistic personality disorders. Panic disorder and avoidant personality disorder were associated with less progression.” (W. M. Compton, wcompton@nida.nih.gov)

>>>Pediatrics Report
Source:
June issue of Pediatrics (2013; 131).
Acellular v. Whole-Cell Pertussis Vaccines in Teenagers: Among American teenagers, whole-cell pertussis vaccine provided better protection during outbreaks than the acellular formulation, researchers report (pp. e1716–22). A case–control study of Kaiser Permanente Northern California (KPNC) patients born in 1994–99 who received four doses of pertussis-containing vaccines during their first 2 years of life showed these patterns for combined diphtheria, tetanus toxoids, whole-cell pertussis (DTwP) and combined acellular pertussis (DTaP) vaccines: “We compared 138 [polymerase chain reaction (PCR)]-positive cases with 899 PCR-negative and 54,339 KPNC-matched controls. Teenagers who had received 4 DTwPs were much less likely to be pertussis PCR-positive than those who had received 4 DTaPs (odds ratio 5.63, 95% confidence interval 2.55–12.46) or mixed DTwP/DTaP vaccines (odds ratio 3.77, 95% confidence interval 1.57–9.07). Decreasing number of DTwP doses was significantly associated with increased pertussis risk (P < .0001).” (N. P. Klein)

>>>PNN NewsWatch
* Bacterial and fungal growth has been identified in two unopened 10-mL vials of preservative-free methylprednisolone acetate 80 mg/mL prepared by Main Street Family Pharmacy of Newbern, TN, FDA reported yesterday.

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

PNN Pharmacotherapy Line
June 10, 2013 * Vol. 20, No. 111
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 8 issue of Lancet, a China-themed issue (2013; 381).
Enterovirus 71 Vaccine in Chinese Children: In a Phase III trial of children 6–35 months of age at four Chinese centers, enterovirus 71 (EV71) vaccine was effective, safe, and immunogenic, researchers report (pp. 2024–32). The randomized trial assigned children to receive an inactivated alum-adjuvant EV71 vaccine or alum-adjuvant placebo on days 0 and 28, with these effects on EV71-associated hand, foot, and mouth disease (HFMD) and EV71-associated disease from day 56 to month 14: “10,245 participants were enrolled and assigned: 5,120 to vaccine versus 5,125 to placebo. 4,907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4,939 (with 30 cases of EV71-associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90.0% (95% CI 67.1–96.9) against EV71-associated HFMD (p = 0.0001) and 80.4% (95% CI 58.2–90.8) against EV71-associated disease (p < 0.0001). Serious adverse events were reported by 62 of 5,117 (1.2%) participants in the vaccine group versus 75 of 5,123 (1.5%) in the placebo group (p = 0.27). Adverse events occurred in 3,644 (71.2%) versus 3,603 (70.3%; p = 0.33).” (F-C Zhu, jszfc@vip.sina.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Depression Care Management & Mortality in Older Adults: Intensive management of depression in older adults lowers mortality rates to levels similar to those in patients without depression and significantly lower than in patients with depression receiving usual care, a study shows (f2570). At 20 primary-care practices in New York City, Philadelphia, and Pittsburgh, 1,226 patients were stratified into age groups of 60–74 and 75 or older. Over a 2-year period, “a depression care manager worked with primary care physicians in intervention practices to provide algorithm based care for depression, offering psychotherapy, increasing antidepressant dose if indicated, and monitoring symptoms, adverse effects of drugs, and adherence to treatment,” the investigators report, noting these effects on mortality risk over a median of 98 months: “In baseline clinical interviews, 396 people were classified as having major depression, 203 had clinically significant minor depression, and 627 did not meet criteria for depression. At follow-up, 405 patients had died. Patients with major depression in usual care were more likely to die than were those without depression (hazard ratio 1.90, 95% confidence interval 1.57 to 2.31). In contrast, patients with major depression in intervention practices were at no greater risk than were people without depression (hazard ratio 1.09, 0.83 to 1.44). Patients with major depression in intervention practices, relative to usual care, were 24% less likely to have died (hazard ratio 0.76, 0.57 to 1.00; P = 0.05). Preliminary data on cause of death are provided. No significant effect on mortality was found for minor depression.” (C. F. Reynolds III, Reynoldscf@upmc.edu)

>>>PNN JournalWatch
* Evaluation and Management of Pill Aspiration: Case Discussion and Review of the Literature, in
Chest, 2013; 143: 1791–5. (C. L. Channick, cchannick@partners.org)
* Psychiatric Clearance for Patients Started on Interferon-Alpha-Based Therapies, in
American Journal of Psychiatry, 2013; 170: 592–7. (F. E. Lotrich, lotrichfe@upmc.edu)
* Current Perspectives on Systems Immunology Approaches to Rheumatic Diseases, in
Arthritis & Rheumatism, 2013; 65: 1407–17. (D. Chaussabel, dchaussabel@benaroyaresearch.org)
* Automated Surveillance for Healthcare-Associated Infections: Opportunities for Improvement, in
Clinical Infectious Diseases, 2013; 57: 85–93. (M. S. M. van Mourik, m.s.m.vanmourik-2@umcutrecht.nl)
* Evolution and Emergence of Therapeutic Monoclonal Antibodies: What Cardiologists Need to Know, in
Circulation, 2013; 127: 2222–30. (I. Foltz, ifoltz@amgen.com)
* Burden of Uncontrolled Epilepsy in Patients Requiring an Emergency Room Visit or Hospitalization, in
Neurology, 2013; 80: no. 23 2170. (S. Balestrini)
* Cardiac Complications of Thoracic Irradiation, in
Journal of the American College of Cardiology, 2013; 61: 2319–28. (D. M. Kaye)
* 2012 ACCF/AHA Focused Update Incorporated Into the ACCF/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction, in
Journal of the American College of Cardiology, 2013; 61: e179–347. (J. L. Anderson)

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

PNN Pharmacotherapy Line
June 11, 2013 * Vol. 20, No. 112
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 10 issue of the JAMA Internal Medicine (2013; 173).
New Ideas About Influenza Vaccines: An author argues that influenza “is less fearful than advertised, the vaccines are less beneficial than believed, and the harms of vaccines are not easily dismissed” (pp. 1014–6). He concludes: “Lost amidst the hum of annual influenza vaccine campaigns is the basic fact that influenza vaccines target a disease that is, for most people, self-limiting. While unpleasant, today, tragedies are rare. And for those who wish to be proactive, systematic reviews of nonpharmaceutical interventions—largely based on studies of severe acute respiratory syndrome—have shown impressive evidence that measures like handwashing and wearing masks and gowns reduce the incidence of respiratory diseases. Large head-to-head trials comparing vaccines against measures such as handwashing are needed.
“To summarize, the evidence that influenza represents a threat of public health proportions is questionable, the evidence that influenza vaccines reduce important patient-centered outcomes such as mortality is unreliable, the assumption that past influenza vaccine safety is predictive of future experience is unsound, and nonpharmaceutical interventions to manage influenza-like illness exist.” (P. Doshi,
pnd@jhu.edu)
Treatment of Mild Hypertension: Maintaining that treatment of hypertension at diastolic blood pressures of 90–100 mm Hg is often unnecessary, the author of a Viewpoint article supports conclusions reached in a 2012 Cochrane review that advocates treatment of otherwise healthy adults at 160/100 mm Hg (pp. 956–7): “In view of the mounting evidence of both waste and harm, it is well time that we returned to the higher threshold of 160/100 mm Hg for the pharmaceutical treatment of hypertension in otherwise healthy people. The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure provides a timely opportunity for achieving this, but, with the probable degree of industry entanglement, it seems a remote possibility. However, sooner or later the pharmaceutical treatment of mild hypertension seems likely to be consigned to what the novelist Amitav Ghosh has described as ‘medicine’s vast graveyard of discredited speculations.’” (I. Heath, iona.heath22@yahoo.co.uk)
Oncology Trial Characteristics: Analysis of trials of patients with cancer demonstrates that they are significantly less rigorous than studies of patients with other conditions (pp. 972–9). Investigators looked at all interventional clinical studies registered on ClinicalTrials.gov in 2007–10 to validate classifications and assess subgroups based on cancer types and design characteristics. Results showed: “Of 40,970 interventional studies registered between October 2007 and September 2010, a total of 8,942 (21.8%) focused on oncology. Compared with other specialties, oncology trials were more likely to be single arm (62.3% vs 23.8%; P < .001), open label (87.8% vs 47.3%; P < .001), and nonrandomized (63.9% vs 22.7%; P < .001). There was moderate but significant correlation between number of trials conducted by cancer type and associated incidence and mortality (Spearman rank correlation coefficient, 0.56 [P = .04] and 0.77 [P = .001], respectively). More than one-third of all oncology trials were conducted solely outside North America.” (A. P. Abernethy, amy.abernethy@duke.edu)
Acute Care for Elders Unit: Lower costs and reduced 30-day readmissions resulted when hospitalists cared for 818 patients aged 70 years or older in an Acute Care for Elders (ACE) unit in a tertiary academic medical center, researchers report (pp. 981–7). A retrospective cohort study showed these relationships between type of care and direct costs for ACE and usual care (UC) patients: “The mean (SD) variable direct cost per patient was $2,109 ($1,870) for ACE and $2,480 ($2,113) for UC (P = .009). Adjusted cost ratios revealed significant cost savings for patients with low (0.82; 95% CI, 0.72–0.94) or moderate (0.74; 95% CI, 0.62–0.89) [case mix index (CMI)] scores; care was cost neutral for patients with high CMI scores (1.13; 95% CI, 0.93–1.37). Significantly fewer ACE patients than UC patients were readmitted within 30 days of discharge (7.9% vs 12.8%; P = .02).” (K. L. Flood, kflood@uabmc.edu)

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

PNN Pharmacotherapy Line
June 12, 2013 * Vol. 20, No. 113
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 12 issue of JAMA (2013; 309).
Outpatient Antimicrobial Stewardship for Pediatricians: Adherence to prescribing guidelines for treatment of outpatients with acute respiratory tract infections (ARTIs) was improved by education, audits, and feedback in a network of 25 pediatric primary care practices in Pennsylvania and New Jersey, a study shows (pp. 2345–52). A total of 162 clinicians participated in the cluster-randomized trial. Intervention clusters received 1 hour of onsite clinician education and 1 year of personalized quarterly audits and feedback about ARTI prescribing, with these results in comparison with usual-care clusters: “Broad-spectrum antibiotic prescribing decreased from 26.8% to 14.3% (absolute difference, 12.5%) among intervention practices vs from 28.4% to 22.6% (absolute difference, 5.8%) in controls (difference of differences [DOD], 6.7%; P = .01 for differences in trajectories). Off-guideline prescribing for children with pneumonia decreased from 15.7% to 4.2% among intervention practices compared with 17.1% to 16.3% in controls (DOD, 10.7%; P < .001) and for acute sinusitis from 38.9% to 18.8% in intervention practices and from 40.0% to 33.9% in controls (DOD, 14.0%; P = .12). Off-guideline prescribing was uncommon at baseline and changed little for streptococcal pharyngitis (intervention, from 4.4% to 3.4%; control, from 5.6% to 3.5%; DOD, −1.1%; P = .82) and for viral infections (intervention, from 7.9% to 7.7%; control, from 6.4% to 4.5%; DOD, −1.7%; P = .93).” (J. S. Gerber, gerberj@email.chop.edu)
After noting that “prescribing antibiotics judiciously is becoming universally embraced as a virtue by clinicians,” an editorialist notes these challenges in implementing “guideline-recommended care across the entire health care system” (
pp. 2388–9): “Gerber et al and the participating practices and clinicians have accomplished meaningful improvement in antibiotic prescribing for ARTIs in their pediatric patients. However, broad-spectrum antibiotic overuse continues in humans across age groups and conditions, as well as in agricultural use and other factors that drive emerging resistance. The good news is that a range of effective techniques for promoting judicious prescribing in ambulatory care have been developed and tested; it is also apparent that the influence and benefit of any of these interventions will vary greatly across settings. Tailoring strategies to contextual factors and adapting them further during implementation may well be more effective than merely rolling out the approach with the greatest average effect in the average practice.” (J. A. Finkelstein, jonathan.finkelstein@childrens.harvard.edu)
Enhancing Communications with EHRs: Electronic health records (EHRs) can enhance communications with patients, Viewpoint authors write, if properly implemented in primary care (pp. 2327–8): “Using the EHR as a relational tool is a strategy for improving individual and population-based health outcomes, for various studies have shown that interventions aimed at increasing patient activation have led to significant improvements in the management of chronic disease, mental illness, and other health-related behaviors or conditions. The health care community may find the EHR to be an untapped means of encouraging patient–physician collaboration and for enhancing patient activation during the clinic visit. Future empirical studies are needed to explore the potential benefits of this expanded use of the EHR on quantitative measures of patient activation.” (A. White, amina.white@nih.gov)

>>>PNN NewsWatch
* Plan B One-Step will soon be available without a prescription to consumers of all ages, if a federal district court agrees to a counterproposal offered by the Obama administration in the legal battle over OTC availability of emergency contraceptives, pharmacist.com reports. Courts had varied in rulings with regard to OTC availability of one-dose versus two-dose products, but they left the door open for FDA to rule on whether significant differences in consumer ability to use the two products meant that only the one-dose product should be available to all age groups. FDA did make that claim, and it is now awaiting new labeling for Plan B One-Step from Teva. The government promised the courts that FDA will approve that labeling “without delay.”

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

PNN Pharmacotherapy Line
June 13, 2013 * Vol. 20, No. 114
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles and June 13 issue of the New England Journal of Medicine (2013; 368).
Triple Therapy for Rheumatoid Arthritis: In 353 patients with active rheumatoid arthritis despite methotrexate therapy, sulfasalazine and hydroxychloroquine added to methotrexate was noninferior to etanercept plus methotrexate, researchers report (10.1056/NEJMoa1303006). Triple therapy was tested for 48 weeks, with a 24-week crossover for patients with no improvement. Results showed: “Both groups had significant improvement over the course of the first 24 weeks (P = 0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P < 0.001), and the response after switching did not differ significantly between the two groups (P = 0.08). The change between baseline and 48 weeks in the [Disease Activity Score for 28-joint counts (DAS28)] was similar in the two groups (−2.1 with triple therapy and −2.3 with etanercept and methotrexate, P = 0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P = 0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.” (J. R. O’Dell, james.o’dell@va.gov)
These results may “have arrived too late to influence modern practice, in which arguably a TNF inhibitor is the preferred next step when methotrexate alone is inadequate,” editorialists write (
10.1056/NEJMe1306381): “Whether third-party payers who currently require failure of methotrexate monotherapy before prescription of expensive biologic therapy will change this policy to require failure of the cheaper nonbiologic combination is an interesting question. The development of more affordable biosimilar agents may change the treatment choices yet again, potentially rendering the studies with nonbiologic agents cited above irrelevant. We hope that with the ever-increasing number of effective treatments for rheumatoid arthritis, future recommendations for treatment will be guided by additional comparative-effectiveness studies such as the study by O’Dell et al. In addition, future identification of biomarkers to identify the patients who are most likely to have a response to, or are least likely to have side effects with, specific therapies will be the next great leap in the treatment of rheumatoid arthritis.” (J. M. Bathon)
Decolonization to Prevent MRSA Infections in ICUs: In routine practice at 43 hospitals, clinical isolation and bloodstream infection rates with methicillin-resistant Staphylococcus aureus (MRSA) were reduced more through universal decolonization than by targeted efforts or screening and isolation, a study shows (pp. 2255–65). A total of 74 ICUs and 74,256 patients had these outcomes with the three approaches to MRSA containment based on proportional-hazards modeling: “In the intervention period versus the baseline period, modeled hazard ratios for MRSA clinical isolates were 0.92 for screening and isolation (crude rate, 3.2 vs. 3.4 isolates per 1,000 days), 0.75 for targeted decolonization (3.2 vs. 4.3 isolates per 1,000 days), and 0.63 for universal decolonization (2.1 vs. 3.4 isolates per 1,000 days) (P = 0.01 for test of all groups being equal). In the intervention versus baseline periods, hazard ratios for bloodstream infection with any pathogen in the three groups were 0.99 (crude rate, 4.1 vs. 4.2 infections per 1,000 days), 0.78 (3.7 vs. 4.8 infections per 1,000 days), and 0.56 (3.6 vs. 6.1 infections per 1,000 days), respectively (P < 0.001 for test of all groups being equal). Universal decolonization resulted in a significantly greater reduction in the rate of all bloodstream infections than either targeted decolonization or screening and isolation. One bloodstream infection was prevented per 54 patients who underwent decolonization. The reductions in rates of MRSA bloodstream infection were similar to those of all bloodstream infections, but the difference was not significant. Adverse events, which occurred in 7 patients, were mild and related to chlorhexidine.” (S. S. Huang, sshuang@uci.edu)

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

PNN Pharmacotherapy Line
June 14, 2013 * Vol. 20, No. 115
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
June 18 issue of the Journal of the American College of Cardiology (2013; 61).
Stent Efficacy After Dual-Antiplatelet Discontinuation: Two second-generation cobalt-chromium stents that elute limus analogues showed similar efficacy at a 2-year follow-up to strict discontinuation of dual antiplatelet therapy (DAPT) after 12 months, researchers report (pp. 2406–16). Included in the randomized TWENTE trial were the Resolute zotarolimus-eluting stent (ZES) (Medtronic) and Xience V everolimus-eluting stent (EES) (Abbott Vascular). Results at 2 years for 1,391 patients showed the following: “The rate of continuation of DAPT beyond 12 months was very low (5.4%). The primary endpoint of target vessel failure, a composite of cardiac death, target vessel–related myocardial infarction, and target vessel revascularization, did not differ between ZES and EES (10.8% vs. 11.6, p = 0.65), despite fewer target lesion revascularizations in patients with EES (2.6% vs. 4.9%, p = 0.03). The patient-oriented composite endpoint was similar (16.4% vs. 17.1%, p = 0.75). Two-year rates of definite or probable stent thrombosis were 1.2% and 1.4%, respectively (p = 0.63). Very late definite or probable stent thrombosis occurred only in 2 patients in each study arm (0.3% vs. 0.3%, p = 1.00).” (C. von Birgelen)
Paclitaxel-Eluting Stents for Femoropopliteal Lesions: A paclitaxel-coated drug-eluting stent (DES) showed positive 2-year outcomes in patients with femoropopliteal artery disease, a study shows (pp. 2417–27). A total of 474 patients randomly received primary DES implantation or percutaneous transluminal angioplasty (PTA). Among 120 patients with acute PTA failure, a second randomization assigned them to receive either provisional DES or a bare-metal stent (BMS), with these results in comparison with a control group from a single-arm primary DES study of 787 patients: “Compared with the control group, the primary DES group demonstrated significantly superior 2-year event-free survival (86.6% vs. 77.9%, p = 0.02) and primary patency (74.8% vs. 26.5%, p < 0.01). In addition, the provisional DES group exhibited superior 2-year primary patency compared with the provisional BMS group (83.4% vs. 64.1%, p < 0.01) and achieved higher sustained clinical benefit (83.9% vs. 68.4%, p = 0.05). Two-year freedom from target lesion revascularization with primary DES placement was 80.5% in the single-arm study and 86.6% in the RCT.” (M. D. Dake)

>>>Circulation Report
Source:
June 11 issue of Circulation (2013; 127).
Statins, Bisphosphonates for Atherosclerotic Plaques: A combination of a statin plus a bisphosphonate may be required for reducing atherosclerotic plaque in different regions of the aorta, according to a study of atorvastatin 20 mg and etidronate 400 mg (pp. 2327–35). In a randomized, open-label trial of 108 participants with hypercholesterolemia, the drugs produced these changes in a primary end point of percent change in maximal vessel wall thickness of atherosclerotic plaques in the thoracic and abdominal aortas as measured by magnetic resonance imaging after 12 months of treatment: “In both the combination therapy and atorvastatin groups, maximal vessel wall thickness of the thoracic aorta was reduced by 13.8% (95% confidence interval, −16.4 to −11.3) and 12.3% (95% confidence interval, −14.9 to −9.7), respectively. These reduction rates were comparable between groups (P = 0.61). Meanwhile, in the etidronate group, maximal vessel wall thickness of the thoracic aorta remained unchanged (2.2%; 95% confidence interval, −0.3 to 4.8). Conversely, maximal vessel wall thickness of the abdominal aorta was reduced more effectively in the combination therapy group (−11.4%) than in the atorvastatin group (−0.9%; P < 0.001) and the etidronate group (5.5%; P = 0.006).” (T. Kawahara, k-tetsuy@niirou.jp)

>>>PNN NewsWatch
* FDA has expanded the approved indications for denosumab (Xgeva, Amgen) to include treatment of adults and some adolescents with giant cell tumor of the bone.
* Long-time community pharmacist, educator, author, and editor
Angele D’Angelo died this week at age 80. After retiring as professor and dean of pharmacy at St. John’s U. in 1990, she served as Editor-in-Chief of US Pharmacist until 2003. D’Angelo was profiled by the New York Times on Nov. 3, 1985, when she was a leader in the women-in-pharmacy movement.

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

PNN Pharmacotherapy Line
June 17, 2013 * Vol. 20, No. 116
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 15 issue of Lancet (2013; 381).
Eradicating HIV-1 Reservoirs: A review article considers “new approaches to unravelling the complex virus–host interactions that lead to persistent [HIV] infection and latency, and discuss the rationale for combination of novel treatment strategies with available antiretroviral treatment options to cure HIV” (pp. 2109–17): “Antiretroviral therapy for HIV infection needs lifelong access and strict adherence to regimens that are both expensive and associated with toxic effects. A curative intervention will be needed to fully stop the epidemic. The failure to eradicate HIV infection during long-term antiretroviral therapy shows the intrinsic stability of the viral genome in latently infected CD4T cells and other cells, and possibly a sustained low-level viral replication. Heterogeneity in latently infected cell populations and homoeostatic proliferation of infected cells might affect the dynamics of virus production and persistence. Despite potent antiretroviral therapy, chronic immune activation, inflammation, and immune dysfunction persist, and are likely to have important effects on the size and distribution of the viral reservoir. The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to finding a cure.” (R. P. Sekaly, rpsekaly@vgtifl.org)
Antiretroviral Prophylaxis in Injecting Drug Users: At 17 Thai drug-treatment clinics, the risk of HIV infection was reduced in injecting drug users through daily use of oral tenofovir, a study shows (pp. 2083–90). In blocks of 4, participants were randomly assigned to tenofovir or placebo using either daily directly observed therapy or monthly visits. Combined with monthly HIV testing, individualized risk-reduction and adherence counseling, blood safety assessments at 3 months, and the option of condoms and methadone treatment, the intervention showed: “Between June 9, 2005, and July 22, 2010, we enrolled 2,413 participants, assigning 1,204 to tenofovir and 1,209 to placebo. Two participants had HIV at enrolment and 50 became infected during follow-up: 17 in the tenofovir group (an incidence of 0.35 per 100 person–years) and 33 in the placebo group (0.68 per 100 person–years), indicating a 48.9% reduction in HIV incidence (95% CI 9.6–72.2; p = 0.01). The occurrence of serious adverse events was much the same between the two groups (p = 0.35). Nausea was more common in participants in the tenofovir group than in the placebo group (p = 0.002).” (M. Martin, Znd9@cdc.gov)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Antibiotic Prophylaxis After Urinary Catheter Removal: Following short-term urinary catheterization, provision of antimicrobial prophylaxis to properly identified patients can reduce the rate of urinary-tract infections, according to results of a systematic review and meta-analysis (f3147): “Seven controlled studies had symptomatic urinary tract infection after catheter removal as an endpoint; six were randomized controlled trials (five published; one in abstract form) and one was a non-randomized controlled intervention study. Five of these seven studies were in surgical patients. Studies were heterogeneous in the type and duration of antimicrobial prophylaxis and the period of observation. Overall, antibiotic prophylaxis was associated with benefit to the patient, with an absolute reduction in risk of urinary tract infection of 5.8% between intervention and control groups. The risk ratio was 0.45 (95% confidence interval 0.28 to 0.72). The number needed to treat to prevent one urinary tract infection was 17 (12 to 30).” (J. Marschall, jmarscha@dom.wustl.edu)

>>>PNN JournalWatch
* Microbial Influence on Tolerance and Opportunities for Intervention With Prebiotics/Probiotics and Bacterial Lysates, in
Journal of Allergy and Clinical Immunology, 2013; 131: 1453–63. (P. I. Pfefferle, pfefferl@med.uni-marburg.de)
* The Timing Hypothesis and Hormone Replacement Therapy: A Paradigm Shift in the Primary Prevention of Coronary Heart Disease in Women.
Part 1: Comparison of Therapeutic Efficacy and Part 2: Comparative Risks, in Journal of the American Geriatrics Society, 2013; 61: 1005–10 and 1011–8. (H. N. Hodis, athero@usc.edu)
* International Myeloma Working Group Recommendations for the Treatment of Multiple Myeloma–Related Bone Disease, in
Journal of Clinical Oncology, 2013; 31: 2347–57. (E. Terpos, eterpos@med.uoa.gr)

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

PNN Pharmacotherapy Line
June 18, 2013 * Vol. 20, No. 117
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 18 issue of the Annals of Internal Medicine (2013; 158).
Rivaroxaban After Vitamin K Antagonists: Bleeding episodes with rivaroxaban differ in frequency based on prior treatment with vitamin K antagonists (VKA), according to results of the ROCKET AF trial (pp. 861–8). Efficacy and safety of rivaroxaban were compared with warfarin among 14,264 VKA–naive and VKA–experienced patients, with these results: “Overall, 7,897 (55.4%) patients were VKA-experienced and 6,367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient–years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003).” (K. W. Mahaffey, kenneth.mahaffey@dm.duke.edu)
Statin Toxicity With Macrolides: In Ontario, continuous users of statins who were older than 65 had greater risks for toxicity when interacting macrolide antibiotics were prescribed, researchers report (pp. 869–76). Using a primary outcome of hospitalization with rhabdomyolysis within 30 days of a prescription with clarithromycin, erythromycin, or azithromycin, the investigators found these results in a population-based cohort study: “Atorvastatin was the most commonly prescribed statin (73%) followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis (absolute risk increase, 0.02% [95% CI, 0.01% to 0.03%]; relative risk [RR], 2.17 [CI, 1.04 to 4.53]) or with acute kidney injury (absolute risk increase, 1.26% [CI, 0.58% to 1.95%]; RR, 1.78 [CI, 1.49 to 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [CI, 0.17% to 0.33%]; RR, 1.56 [CI, 1.36 to 1.80]).” (A. Garg, amit.garg@lhsc.on.ca)
Recombinant Human Bone Morphogenetic Protein-2 in Spinal Fusion: Recombinant human bone morphogenetic protein-2 (rhBMP-2), a product widely used as an alternative to iliac crest bone graft (ICBG) to promote fusion in spinal surgery, “reduces pain by a clinically insignificant amount, and increases early postsurgical pain compared with ICBG,” according to 24-month results of a meta-analysis of individual data from 11 trials sponsored by Medtronic (pp. 877–89): “Primary outcomes were pain (assessed with the Oswestry Disability Index [ODI] or Short Form-36), fusion, and adverse events. At 24 months, ODI scores were 3.5% lower (better) with rhBMP-2 than with ICBG (95% CI, 0.5% to 6.5%) and radiographic fusion was 12% higher (CI, 2% to 23%). At or shortly after surgery, pain was more common with rhBMP-2 (odds ratio, 1.78 [CI, 1.06 to 2.95]). Cancer was more common after rhBMP-2 (relative risk, 1.98 [CI, 0.86 to 4.54]), but the small number of events precluded definite conclusions.” (L. A. Stewart)
Based on this and a second meta-analysis of rhBMP-2 (
pp. 890–902; R. Fu), editorialists advise clinicians to “carefully weigh the demonstrated and potential benefits and harms as well as the costs when considering the adoption and use of new health care technologies, such as rhBMP-2” (pp. 912–3): “Early adopters of new technologies are often critical of hospital administrators and payers who scrutinize use of such technologies because of a lack of clinical evidence to justify the incremental cost associated with their use. These early adopters often cite the difficulties of demonstrating a new technology’s comparative clinical effectiveness that are due to the time lag required for clinical follow-up. However, as Alan Garber, former health economist at Stanford University and the current Provost of Harvard University, has aptly noted, ‘Since no intervention is assumed to be effective until it has been proved effective, the burden of proof for a new medical intervention is placed on its advocates. Examining the evidence requirement from their point of view is an important step toward understanding its consequences.’” (K. J. Bozic)

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

PNN Pharmacotherapy Line
June 19, 2013 * Vol. 20, No. 118
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 19 issue of JAMA (2013; 309).
MMR Boosters & Juvenile Idiopathic Arthritis: Booster doses of live attenuated measles–mumps–rubella (MMR) vaccination was effective in 137 patients with juvenile idiopathic arthritis (JIA), researchers report, and had no detrimental effects on disease activity (pp. 2449–56). Patients were randomized to MMR boosters or no vaccination; those on biologic therapies had those treatments discontinued at five times the half-lives before vaccination. Disease activity as measured by the Juvenile Arthritis Disease Activity Score (JADAS-27) and other outcome indicators showed these results: “Of 137 randomized patients, 131 were analyzed in the modified intention-to-treat analysis, including 60 using methotrexate and 15 using biologics. Disease activity during complete follow-up did not differ between 63 revaccinated patients (JADAS-27, 2.8; 95% CI, 2.1–3.5) and 68 controls (JADAS-27, 2.4; 95% CI, 1.7–3.1), with a difference of 0.4 (95% CI, −0.5 to 1.2), within the equivalence margin of 2.0. At 12 months, seroprotection rates were higher in revaccinated patients vs controls (measles, 100% vs 92% [95% CI, 84%–99%]; mumps, 97% [95% CI, 95%–100%] vs 81% [95% CI, 72%–93%]; and rubella, 100% vs 94% [95% CI, 86%–100%], respectively), as were antibody concentrations against measles (1.63 vs 0.78 IU/mL; P = .03), mumps (168 vs 104 RU/mL; P = .03), and rubella (69 vs 45 IU/mL; P = .01). Methotrexate and biologics did not affect humoral responses, but low patient numbers precluded definite conclusions.” (M. W. Heijstek, m.w.heijstek@umcutrecht.nl)
MRIs in Diagnosis of Compounding-Associated Infections: Magnetic resonance imaging (MRI) screening of asymptomatic or minimally symptomatic patients who had received spinal or paraspinal injections of contaminated lots of compounded methylprednisolone showed that about one-fifth had abnormal results, and all but one of these patients met the CDC definition for probable or confirmed fungal spinal or paraspinal infection, a study shows (pp. 2465–72). At a pain facility where 172 patients had received injections from a highly contaminated lot, screening MRIs were performed. Results showed: “Of the 172 patients screened, MRI was abnormal in 36 (21%), showing epidural or paraspinal abscess or phlegmon, arachnoiditis, spinal osteomyelitis or diskitis, or moderate to severe epidural, paraspinal, or intradural enhancement. Of the 115 patients asked about new or worsening back or neck pain, lower extremity weakness, or radiculopathy symptoms, 35 (30%) had at least 1 symptom. Thirty-five of the 36 patients with abnormal MRIs met the [CDC] case definition for probable (17 patients) or confirmed (18 patients) fungal spinal or paraspinal infection. All 35 patients were treated with antifungal agents (voriconazole, with or without liposomal amphotericin B), and 24 required surgical debridement. At the time of surgery, 17 of 24 patients (71%), including 5 patients who denied having symptoms, had laboratory evidence of fungal infection.” (A. N. Malani, malania@trinity-health.org)
“Continued vigilance for the search for late fungal infections in patients exposed to spinal injections with contaminated steroids is needed and collaborative efforts to follow up these patients long-term will be paramount for decreasing associated morbidity and mortality,” editorialists write (
pp. 2493–5). “Risk factors include site of injection and the specific lot number of the steroids. These findings suggest MRI of the injection site may be an effective screening procedure in some patients but should not be widely adopted, particularly for patients who received peripheral joint injections, given the much lower attack rate. For patients who received spinal injections with steroids from an unknown lot number, MRI-based screening may be appropriate. Whether patients with normal initial MRI findings receive reimaging at a later date remains a difficult question in this evolving outbreak.” (T. F. Patterson, patterson@uthscsa.edu)

>>>PNN NewsWatch
* FDA is investigating two unexplained deaths in patients who received intramuscular injections of olanzapine pamoate (Zyprexa Relprevv, Lilly). The patients died 3–4 days after receiving an appropriate dose of the drug, well after the recommended 3-hour observation period, and both had very high olanzapine blood levels after death.

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

PNN Pharmacotherapy Line
June 20, 2013 * Vol. 20, No. 119
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 20 issue of the New England Journal of Medicine (2013; 368).
Rapid Lowering of Blood Pressure in Acute Intracerebral Hemorrhage: Aggressive lowering of elevated systolic blood pressures in patients with acute intracerebral hemorrhage showed promising results in a trial conducted in 2,839 patients, but more study is needed to identify significant differences for key outcomes such as death and severe disability (pp. 2355–65). INTERACT2 participants—about two-thirds of them recruited in China—had spontaneous intracerebral hemorrhage within the prior 6 hours when they were randomized to intensive treatment with agents of the physicians’ choice with a target systolic blood pressure below 140 mm Hg or guideline-recommended treatment with a target of under 180 mm Hg. A primary outcome of death or major disability (defined as a score of 3–6 on the modified 0–6 Rankin scale) at 90 days: “Among the 2,794 participants for whom the primary outcome could be determined, 719 of 1,382 participants (52.0%) receiving intensive treatment, as compared with 785 of 1,412 (55.6%) receiving guideline-recommended treatment, had a primary outcome event (odds ratio with intensive treatment, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The ordinal analysis showed significantly lower modified Rankin scores with intensive treatment (odds ratio for greater disability, 0.87; 95% CI, 0.77 to 1.00; P = 0.04). Mortality was 11.9% in the group receiving intensive treatment and 12.0% in the group receiving guideline-recommended treatment. Nonfatal serious adverse events occurred in 23.3% and 23.6% of the patients in the two groups, respectively.” (C. S. Anderson, canderson@georgeinstitute.org.au)
A study that could confirm and extend these findings is under way, an editorialist writes (
pp. 2426–7): “The Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) II trial is the ongoing North American complement to INTERACT2. This study also randomly assigns patients to a target systolic blood pressure of less than 140 mm Hg or less than 180 mm Hg but requires the use of nicardipine as the sole blood-pressure–lowering agent. It is hoped that this trial, which has similar primary and secondary end points and results due in 2016, will corroborate the results of INTERACT2. Nonetheless, given that INTERACT2 showed a trend toward a reduction in the primary outcome of death or severe disability, significant improvement in secondary functional outcomes, and reassuring safety data, acute blood-pressure reduction to a target systolic blood pressure of 140 mm Hg or less appears to be a reasonable option for patients with spontaneous intracerebral hemorrhage.” (J. A. Frontera)
Clopidogrel in Systemic-to-Pulmonary-Artery Shunts: In a study of 906 infants in the first 3 months of life with cyanotic congenital heart disease palliated with a systemic-to-pulmonary-artery shunt, clopidogrel did not reduce mortality or shunt-related morbidity (pp. 2377–84). Most infants were also taking aspirin when they were randomized to clopidogrel 0.2 mg/kg/d or placebo. Results showed: “The rate of the composite primary end point [of death or heart transplantation, shunt thrombosis, or performance of a cardiac procedure due to an event considered to be thrombotic in nature before 120 days of age] did not differ significantly between the clopidogrel group (19.1%) and the placebo group (20.5%) (absolute risk difference, 1.4 percentage points; relative risk reduction with clopidogrel, 11.1%; 95% confidence interval, –19.2 to 33.6; P = 0.43), nor did the rates of the three components of the composite primary end point. There was no significant benefit of clopidogrel treatment in any subgroup, including subgroups defined by shunt type. Clopidogrel recipients and placebo recipients had similar rates of overall bleeding (18.8% and 20.2%, respectively) and severe bleeding (4.1% and 3.4%, respectively).” (D. L. Wessel, dwessel@childrensnational.org)
Crizotinib in Advanced ALK-Positive Lung Cancer: An oral tyrosine kinase inhibitor that targets the anaplastic lymphoma kinase gene (ALK) proved superior to chemotherapy in a Phase III trial of 347 patients with locally advanced or metastatic ALK-positive lung cancer, researchers report (pp. 2385–94). Median progression-free survival was 7.7 months with crizotinib versus 3.0 months with chemotherapy. (A. T. Shaw, ashaw1@partners.org)

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

PNN Pharmacotherapy Line
June 21, 2013 * Vol. 20, No. 120
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
June issue of Health Affairs (2013; 32).
Economic Impact of Not Expanding Medicaid Under ACA: In the 14 states that have opted out of Medicaid expansion under the Affordable Care Act, 3.6 million fewer people will be insured, federal transfer payments will drop by $8.4 billion, and state spending for uncompensated care will climb by $1 billion, according to a RAND Corp. analysis (pp. 1030–6): “States that opt out of the expansion will be subject to the reductions in Medicare payments and disproportionate-share hospital payments, as well as various other taxes and fees in the Affordable Care Act. Thus, there may be large net transfers of federal funds out of the states that do not expand Medicaid.
“If some states choose not to expand Medicaid eligibility in spite of the budgetary and economic impact of that decision, the federal government could consider expanding the eligibility for premium and cost-sharing subsidies on the individual exchanges to people with incomes below 100 percent of poverty. However, making people eligible for subsidies would not fully make up for the decline in the coverage rate that would result from failing to expand Medicaid eligibility.” (C. C. Price,
cprice@rand.org)
ACA-Related Uncertainty About Funding of AIDS Drug-Assistance Programs: Managers of AIDS drug-assistance programs are unclear about the impact of the Affordable Care Act on the federal support they currently receive, researchers report (pp. 1063–71). Semistructured interviews of program managers from 22 states identified these concerns: “Many of the managers predicted that their programs will change focus to provide ‘wrap-around services,’ such as helping newly insured clients finance out-of-pocket expenses, including copayments, deductibles, and premiums. Although program managers acknowledged that they must adapt to a changing environment, many said that they were overwhelmed by the complexity of the Affordable Care Act, and some expressed fear that state AIDS Drug Assistance Programs would be eliminated entirely. To remain viable, such programs must identify and justify the need for services in the context of the Affordable Care Act and receive sufficient political support and funding.” (E. G. Martin, emartin@albany.edu)

>>>Medical Care Report
Source:
July issue of Medical Care (2013; 51).
Responses to FDA Actions for Physician-Administered Drugs: In the case of bevacizumab, physicians administering the agent in their offices responded appropriately to emerging concerns about safety and effectiveness, according to data from a population-based audit of oncologists’ prescribing (pp. 622–7). Investigators analyzed the IntrinsiQ Intellidose database to determine the monthly number of patients with breast cancer treated with bevacizumab in Jan. 2008 through Apr. 2012. They found these changes in prescribing as FDA approved the drug (Feb. 2008), held meetings to discuss data suggesting risks exceeded benefits (July 2010 and June 2011), and withdrew market approval (Nov. 2011): “Bevacizumab use for breast cancer increased significantly after FDA approval. After all regulatory actions, there was a 65% decline (95% CI, 64%–65%) in use compared with the period before the first meeting. The largest decline was in the 6-month period after the first meeting (37%; 95% CI, 28%–47%). The rate of decline did not differ by patient or cancer characteristics and differed minimally by office affiliation.” (R. M. Conti)
Antipsychotic ADRs & Part D Cost-Sharing: In a study of 10,190 Medicare Advantage beneficiaries with schizophrenia, bipolar disorder, or no mental health diagnoses, interruptions in antipsychotic use is linked to cost-sharing problems (pp. 614–21). Increased cost sharing was associated with more hospitalizations and emergency department visits among those using the drugs for approved indications but not in users with no approved diagnoses. (V. Fung)

>>>PNN NewsWatch
* FDA yesterday approved Plan B One-Step as a nonprescription product for postcoital contraception in all women of child-bearing potential. Just how quickly Teva will supply OTC-labeled products to pharmacies is not clear. FDA did not similarly approve other types of emergency contraception—including less expensive generic alternatives—so the controversy over availability is not over.

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

PNN Pharmacotherapy Line
June 24, 2013 * Vol. 20, No. 121
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 22 issue of Lancet (2013; 381).
Daclizumab High-Yield Process in Relapsing-Remitting Multiple Sclerosis: During 1 year of treatment with daclizumab high-yield process (HYP), 621 patients with relapsing-remitting multiple sclerosis had clinically important improvements in annualized relapse rate, the SELECT study shows (pp. 2167–75). European participants 18–55 years randomly received subcutaneous injections of daclizumab HYP 150 or 300 mg or placebo every 4 weeks for 52 weeks, with these results: “The annualised relapse rate was lower for patients given daclizumab HYP 150 mg (0.21, 95% CI 0.16–0.29; 54% reduction, 95% CI 33–68%; p < 0.0001) or 300 mg (0.23, 0.17–0.31, 50% reduction, 28–65%; p = 0.00015) than for those given placebo (0.46, 0.37–0.57). More patients were relapse free in the daclizumab HYP 150 mg (81%) and 300 mg (80%) groups than in the placebo group (64%; p < 0.0001 in the 150 mg group and p = 0.0003 in the 300 mg group). 12 (6%) patients in the placebo group, 15 (7%) of those in the daclizumab 150 mg group, and 19 (9%) in the 300 mg group had serious adverse events excluding multiple sclerosis relapse. One patient given daclizumab HYP 150 mg who was recovering from a serious rash died because of local complication of a psoas abscess.” (R. Gold, ralf.gold@ruhr-uni-bochum.de)
Maternal Vitamin D Status & Offspring Outcomes: Bone mineral content (BMC) measures in children at 9–10 years of age showed no relationship with maternal vitamin D levels during pregnancy, a study shows (pp. 2176–83). In the Avon Longitudinal Study of Parents and Children, these relationships among maternal 25(OH)D concentration in pregnancy and offspring total body less head (TBLH) and spinal BMC by trimester: “3,960 mother-and-offspring pairs, mainly of white European origin, were assessed (TBLH BMC n = 3,960, spinal BMC n = 3,196). Mean offspring age was 9.9 years. 2,644 (67%) mothers had sufficient, 1,096 (28%) insufficient, and 220 (6%) deficient 25(OH)D concentrations in pregnancy, but TBLH and spinal BMC did not differ between offspring of mothers in the lower two groups versus sufficient 25(OH)D concentration. No associations with offspring BMC were found for any trimester, including the third trimester, which is thought to be most relevant (TBLH BMC confounder-adjusted mean difference −0.03 g per 10.0 nmol/L, 95% CI −1.71 to 1.65; spinal BMC 0.04 g per 10.0 nmol/L, 95% CI −0.12 to 0.21).” (D. A. Lawlor, d.a.lawlor@bristol.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Pregnancy Outcomes With Daily Prenatal Iron Use: “Daily prenatal use of iron substantially improved birth weight in a linear dose–response fashion, probably leading to a reduction in risk of low birth weight,” authors of a systematic review and meta-analysis conclude (f3443). “An improvement in prenatal mean haemoglobin concentration linearly increased birth weight,” they add, citing 48 randomized trials of 17,793 women and 44 cohort studies of 1.9 million women. (B. A. Haider, bah201@mail.harvard.edu)

>>>PNN NewsWatch
* FDA on Friday expanded the approved use of telavancin (Vibativ, Theravance) to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by Staphylococcus aureus. Vibativ should be used for the treatment of HABP/VABP only when alternative treatments are not suitable. In clinical trials of 1,532 patients, 28-day mortality rates were similar with telavancin and vancomycin among patients presumed to test positive for S. aureus taken at baseline, except for patients who had pre-existing kidney problems. More patients with pre-existing kidney problems treated with telavancin died compared with those treated with vancomycin. Telavancin can also cause new or worsening kidney problems in patients, FDA said, and this information has been added to Vibativ’s Boxed Warning.

>>>PNN JournalWatch
* Thiazide-Associated Hyponatremia: A Population-Based Study, in
American Journal of Kidney Diseases, 2013; 62: 67–72. (B. H. Stricker, b.stricker@erasmusmc.nl)
* An Analysis of the New York University Emergency Department Algorithm’s Suitability for Use in Gauging Changes in ED Usage Patterns, in
Medical Care, 2013; 51: 10.1097/MLR.0b013e318242315b. (K. Jones)

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

PNN Pharmacotherapy Line
June 25, 2013 * Vol. 20, No. 122
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 24 issue of the JAMA Internal Medicine (2013; 173).
SSRIs & Surgical Outcomes: A retrospective study of adult patients undergoing surgery confirms single-site studies of adverse outcomes when selective serotonin reuptake inhibitors (SSRIs) are used in the perioperative period (pp. 1075–81). A prospective study is needed to determine whether patient factors or the SSRIs themselves are producing the elevated risks, the investigators conclude, adding these details from 375 U.S. hospitals who cared for 530,416 patients in 2006–08: “Patients receiving SSRIs were more likely to have obesity, chronic pulmonary disease, or hypothyroidism (P < .001 for each) and more likely to have depression (41.0% vs 6.2%, P < .001). After adjustment, patients receiving SSRIs had higher odds of in-hospital mortality (adjusted odds ratio, 1.20 [95% CI, 1.07–1.36]), bleeding (1.09 [1.04–1.15]), and readmission at 30 days (1.22 [1.18–1.26]). Similar results were observed in propensity-matched analyses, although the risk of inpatient mortality was attenuated among patients with depression. Sensitivity analyses suggest that, to invalidate our results, an unmeasured covariate would have to have higher prevalence and be more strongly associated with mortality than any covariate included in our models.” (A. D. Auerbach, ada@medicine.ucsf.edu)
Commenting on the study, authors of an invited commentary “echo the authors’ call for a well-designed randomized trial on the management of SSRI medications before and after elective surgery” but do not advocate changes in clinical practice based on current evidence (
pp. 1082–3): “This article presents new information regarding the risks of perioperative SSRI use; should it change clinical practice? Even if a causal relationship exists, the number needed to harm is quite large, and thus the attendant increase in absolute risk for the average patient would be very small. Conversely, the cessation of SSRI therapy before surgery may precipitate a discontinuation syndrome, worsen depression, and increase sensitivity to postoperative pain. Physicians should continue to initiate SSRI therapy only when clinically indicated. Internists, anesthesiologists, and surgeons should be aware of potential bleeding risks in patients receiving SSRIs in the perioperative setting. Overall, however, we do not believe the evidence base has evolved sufficiently to confirm that patients should routinely have their SSRI therapy tapered or discontinued before surgery.” (D. G. Hackam, dhackam@uwo.ca)
Cognition & Subsidized Drug Benefits: Medicare beneficiaries with low cognition have trouble understanding how to use the Part D low-income subsidy (LIS), a study shows (pp. 1100–7). Analysis of survey data from the Health and Retirement Study showed these patterns among older Medicare beneficiaries who were likely eligible for LIS: “Compared with LIS-eligible beneficiaries in the top quartile of overall cognition, those in the bottom quartile were significantly less likely to report Part D enrollment (adjusted rate, 63.5% vs 52.0%; P = .002), LIS awareness (58.3% vs 33.3%; P = .001), and LIS application (25.5% vs 12.7%; P < .001). Lower numeracy was also associated with lower rates of Part D enrollment (P = .03) and LIS application (P = .002). Reported receipt of the LIS was associated with significantly lower annual out-of-pocket drug spending (adjusted mean difference, −$256; P = .02) and premium costs (−$273; P = .02).” (J. M. McWilliams, mcwilliams@hcp.med.harvard.edu)
Costs & Physician Specialty Society Guidelines: Health care costs are considered by just over one-half of U.S. physician specialty societies that produce clinical guidance documents, a study shows, and only about one-half of those make it clear how costs are factored into the recommendations (pp. 1091–7): “Methodological statements for clinical guidance documents indicated that 17 of 30 physician societies (57%) explicitly integrated costs, 4 (13%) implicitly considered costs, 3 (10%) intentionally excluded costs, and 6 (20%) made no mention. Of the 17 societies that explicitly integrated costs, 9 (53%) consistently used a formal system in which the strength of recommendation was influenced in part by costs, whereas 8 (47%) were inconsistent in their approach or failed to mention the exact mechanism for considering costs.” (S. D. Pearson, pearsonsd@cc.nih.gov)

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

PNN Pharmacotherapy Line
June 26, 2013 * Vol. 20, No. 123
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 26 issue of JAMA (2013; 309).
Aspirin Use & BRAF Colorectal Cancers: Longitudinal data show variations in effective of daily aspirin use for preventing colorectal cancer depending on whether the tumor had wild-type or mutated BRAF genes (pp. 2563–71). In the Nurses’ Health Study and the Health Professionals Follow-up Study, data were collected every 2 years beginning in 1980 and 1986, respectively. Colorectal carcinoma incidence according to BRAF mutation status showed the following: “Among 127,865 individuals, with 3,165,985 person–years of follow-up, we identified 1,226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF–wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], −9.7; 95% CI, −12.6 to −6.7 per 100,000 person–years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, −0.3 to 1.7 per 100,000 person–years: P for heterogeneity = .037, between BRAF–wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF–wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, −19.8; 95% CI, −26.3 to −13.3 per 100,000 person–years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005).” (A. T. Chan, achan@partners.org)
“Studies of the
BRAF and PIK3CA genes provide important information with respect to the effect of aspirin before and after diagnosis of colorectal cancer,” an editorialist writes (pp. 2598–9). “If validated in future studies, these findings suggest that the colorectal cancer preventive effect of aspirin in healthy individuals is predominantly mediated by its action on the RAS-RAF-MEK-ERK signaling pathway. Similarly, the improved outcome of patients with PIK3CA-mutated tumors suggests that, once colorectal cancer developed, aspirin may predominantly influence the PI3K-PTEN-AKT-mTOR signaling pathway. In summary, these results identify biomarkers of response to aspirin administered either preventively or therapeutically and are likely to help tailor the use of aspirin in the prevention and treatment of colorectal cancer.” (B. Pasche, bpasche@uabmc.edu)
Preventable Spending for High-Cost Medicare Patients: A small proportion of Medicare beneficiaries in the highest 10% based on spending have preventable costs, a study shows, but it may be difficult to control those (pp. 2572–8). In Medicare files for 2009–10, patients in the top decile for both years had these experiences: “The 10% of Medicare patients in the high-cost group were older, more often male, more often black, and had more comorbid illnesses than non–high-cost patients. In 2010, 32.9% (95% CI, 32.9%–32.9%) of total [emergency department (ED)] costs were incurred by high-cost patients. Based on validated algorithms, 41.0% (95% CI, 40.9%–41.0%) of these costs among high-cost patients were potentially preventable compared with 42.6% (95% CI, 42.6%–42.6%) among non–high-cost patients. High-cost patients accounted for 79.0% (95% CI, 79.0%–79.0%) of inpatient costs, 9.6% (95% CI, 9.6%–9.6%) of which were due to preventable hospitalizations; 16.8% (95% CI, 16.8%–16.8%) of costs within the non–high-cost group were due to preventable hospitalizations. Comparable proportions of ED spending (43.3%; 95% CI, 43.3%–43.3%) and inpatient spending (13.5%; 95% CI, 13.5%–13.5%) were preventable among persistently high-cost patients. Regions with high primary care physician supply had higher preventable spending for high-cost patients.” (K. E. Joynt, kjoynt@partners.org)

>>>PNN NewsWatch
* FDA yesterday announced its first regulatory decisions about tobacco products, authorizing marketing of two products and denying four applications. The Family Smoking Prevention and Tobacco Control Act of 2009 allows FDA to make decisions based on whether new products present different questions of public health than do products already on the U.S. market.

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

PNN Pharmacotherapy Line
June 27, 2013 * Vol. 20, No. 124
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 27 issue of the New England Journal of Medicine (2013; 368).
Treatment of Fungal Infections From Contaminated Injections: In a review article, authors provide clinical recommendations for management of fungal infections associated with contaminated methylprednisolone injections (pp. 2495–500). “This outbreak of fungal meningitis caused by injection of contaminated methylprednisolone is in late evolution; there are now known to be more than 700 patients who have been affected. The primary pathogen is [Exserohilum] rostratum. It is encouraging to note that clinically apparent disease has developed in only a small percentage of exposed patients. However, among patients who have been infected, some have died, others have major complications, and some remain in chronic care or rehabilitation centers. Even some patients who are doing well in respect to symptoms caused by the infection continue to have major issues with side effects from the antifungal agents. Management recommendations will probably continue to change as more information becomes available regarding the natural history and pathogenesis of these infections.” (C. A. Kauffman, ckauff@umich.edu)
Dupilumab in Persistent Asthma: An investigational monoclonal antibody provided positive results in a 12-week trial of patients with persistent, moderate-to-severe asthma and blood eosinophil levels of 300 cells/µL or more who discontinued long-acting beta-agonists at week 4 and tapered and stopped inhaled glucocorticoids during weeks 6–9, researchers report (pp. 2455–66). Dupilumab is “a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor,” the authors wrote, and the agent provided these results when administered subcutaneously once weekly: “A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P < 0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with [type 2 helper T-cell]-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo.” (S. Wenzel, wenzelse@upmc.edu)
Concluding that “more work needs to be done, “ an editorialist provides this analysis of the results of this study (
pp. 2511–3): “Although one of the biggest unmet needs is for add-on therapy to inhaled glucocorticoids and [long-acting beta-agonists (LABAs)], this study, using a withdrawal design, was not designed to show a beneficial adjuvant effect of dupilumab. Rather, it shows that dupilumab is able to substitute inhaled glucocorticoids and LABAs in a specific subgroup of patients with asthma, but whether or not this drug has added value over treatment with inhaled glucocorticoids and LABAs in patients with moderate-to-severe asthma remains to be established. This is both clinically and biologically important, because inhaled glucocorticoids and LABAs target type 2 helper T cell pathways, so we may need to look elsewhere to find the needed treatments for difficult-to-treat asthma.” (M. E. Wechsler)
Integrating Care Through e-Referrals: Use of an online system for connecting primary-care providers with specialists in more than 40 services is helping streamline care at San Francisco General Hosp., Perspective authors write (pp. 2450–3). The e-Referral system has the potential for expediting care while reducing costs. (A. H. Chen)

>>>PNN NewsWatch
* “Breakthrough therapy” is a designation FDA is beginning to apply to new drugs, Commissioner Janet Woodcock, MD, reports in a blog: “This new designation is now helping FDA assist drug developers expedite the development of new drugs with preliminary clinical evidence that indicates the drug may offer a substantial improvement over available therapies for patients with serious or life-threatening diseases. Although the designation is not yet even a year old, FDA has received 62 requests to grant this new designation to products under development.”

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

PNN Pharmacotherapy Line
June 28, 2013 * Vol. 20, No. 125
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
July issue of Diabetes Care (2013; 36).
Assessing Safety of Incretin-Based Therapies, Other Drugs: Several articles in this issue of Diabetes Care focus on drug-safety analyses as they apply to the current debate about incretin-based therapies and other antidiabetic drugs.
A review of “some recent signals associated with diabetes therapies [that illustrate] the difficulties in ascribing causality and evaluating absolute risk, predictability, prevention, and containment” provides the factual basis for the discussions presented in other articles (
pp. 2098–106): “Individual clinical trials are necessarily restricted for patient selection, number, and duration; they can introduce allocation and ascertainment bias and they often rely on biomarkers to estimate long-term clinical outcomes. In diabetes, the risk perspective is inevitably confounded by emergent comorbid conditions and potential interactions that limit therapeutic choice, hence the need for new therapies and better use of existing therapies to address the consequences of protracted glucotoxicity. However, for some therapies, the adverse effects may take several years to emerge, and it is evident that faint initial signals under trial conditions cannot be expected to foretell all eventualities. Thus, as information and experience accumulate with time, it should be accepted that benefit–risk deliberations will be refined, and adjustments to prescribing indications may become appropriate.” (C. J. Bailey, c.j.bailey@aston.ac.uk)
Of 20 recommendations made by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) in 2009–12, the agency’s Division of Metabolism and Endocrinology Products (DMEP) agreed with just 60%, an author finds (
pp. 1823–6). “Lack of concordance between the EMDAC members and subsequent actions should not be interpreted as either EMDAC or FDA action being correct or incorrect. In fact, the action taken may be in full agreement with key points elicited during the committee’s discussions but not in the polling of the individual members. Alternatively, the FDA’s decision may have reflected considerations or data not available to the committee at the time of the vote. For example, if committee members indicated that certain additional information would change their votes, and this information is available to the FDA, the FDA’s action may be concordant with the committee’s recommendations but not their dichotomous vote. Rather, the relatively low degree of concordance should be viewed as reinforcing the challenges faced by the EMDAC. The discordance also raises the question as to whether EMDAC members are prepared to make a ‘yes’ or ‘no’ vote on issues as complex as benefit–risk assessment based on only a few hours of readings and deliberations. Discordance also suggests that the weighting of benefits and risks by committee members may differ from those of the DMEP and/or that they are being incompletely communicated during the meeting.” (E. P. Brass, ebrass@ucla.edu)
Commenting on such “signals and noise in drug-safety analyses,” editorialists make these points about incretin-based therapies (
pp. 1804–6; W. T. Cefalu, cefaluwt@pbrc.edu):
* Cancer events in nine ongoing cardiovascular outcome trials of GLP-1 receptor agonists and DPP-4 inhibitors should be pooled and assessed using meta-analysis by experts independent of drug manufacturers.
* A blue-ribbon panel of experts should address patient-level data from these trials, including the incidence of pancreatitis, pancreatic cancer, thyroid cancer, and other relevant adverse outcomes.
* Manufacturers should work collaboratively in studying the occurrence of pancreatitis and pancreatic cancer.
* The “current pharmacovigilance system based on the spontaneous reporting (MedWatch) [should] be re-evaluated.”

>>>PNN NewsWatch
* FDA yesterday approved recombinant coagulation factor IX (Rixubis, Baxter) for prophylactic use. The product is indicated in patients with hemophilia B who are 16 years of age and older and require control and prevention of bleeding episodes, perioperative management, and routine use to prevent or reduce the frequency of bleeding episodes.

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