Dec 2012

PNN October–December 2012

PNN Pharmacotherapy Line
Oct. 1, 2012 * Vol. 19, No. 190
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 345).
Benzodiazepines & Dementia: In a prospective, population-based study from France, new use of benzodiazepines was linked to increased risk of dementia (e6231). “Considering the extent to which benzodiazepines are prescribed and the number of potential adverse effects of this drug class in the general population, indiscriminate widespread use should be cautioned against,” the authors conclude based on these data from 1,063 men and women with a mean age of 78.2 years: “During a 15 year follow-up, 253 incident cases of dementia were confirmed. New use of benzodiazepines was associated with an increased risk of dementia (multivariable adjusted hazard ratio 1.60, 95% confidence interval 1.08 to 2.38). Sensitivity analysis considering the existence of depressive symptoms showed a similar association (hazard ratio 1.62, 1.08 to 2.43). A secondary analysis pooled cohorts of participants who started benzodiazepines during follow-up and evaluated the association with incident dementia. The pooled hazard ratio across the five cohorts of new benzodiazepine users was 1.46 (1.10 to 1.94). Results of a complementary nested case–control study showed that ever use of benzodiazepines was associated with an approximately 50% increase in the risk of dementia (adjusted odds ratio 1.55, 1.24 to 1.95) compared with never users. The results were similar in past users (odds ratio 1.56, 1.23 to 1.98) and recent users (1.48, 0.83 to 2.63) but reached significance only for past users.” (S. Billioti de Gage, sophie.billiotidegage@u-bordeaux2.fr)
Postoperative NSAIDs & Anastomotic Leakage: At six Danish colorectal centers, diclofenac use increased the proportion of postsurgical patients with resection and primary anastomoses who developed anastomotic leakage (e6166). The authors concluded that COX-2–selective NSAIDs should be used with caution in these patients. Those with surgeries in 2006–09 had these rates of clinical anastomotic leakage at reoperation and 30-day mortality: “Of 2,756 patients with available data and included in the final analysis, 1,871 (68%) did not receive postoperative NSAID treatment (controls) and 885 (32%) did. In the NSAID group, 655 (74%) patients received ibuprofen and 226 (26%) received diclofenac. Anastomotic leakage verified at reoperation was significantly increased among patients receiving diclofenac and ibuprofen treatment, compared with controls (12.8% and 8.2% v 5.1%; P < 0.001). After unadjusted analyses and when compared with controls, more patients had anastomotic leakage after treatment with diclofenac (7.8% (95% confidence interval 3.9% to 12.8%)) and ibuprofen (3.2% (1.0% to 5.7%)). But after multivariate logistic regression analysis, only diclofenac treatment was a risk factor for leakage (odds ratio 7.2 (95% confidence interval 3.8 to 13.4), P < 0.001; ibuprofen 1.5 (0.8 to 2.9), P = 0.18). Other risk factors for anastomotic leakage were male sex, rectal (v colonic) anastomosis, and blood transfusion. 30 day mortality was comparable in the three groups (diclofenac 1.8% v ibuprofen 4.1% v controls 3.2%; P = 0.20).” (M. Klein, madsklein1@gmail.com)

>>>PNN NewsWatch
* FDA on Friday approved the first subcutaneous heart defibrillator and the use of adalimumab (Humira, Abbott) for treatment of moderate-to-severe ulcerative colitis in adults. The Subcutaneous Implantable Defibrillator (S-ICD) System uses a lead implanted just under the skin along the bottom of the rib cage and breast bone. Because the lead is placed subcutaneously rather than intravenously into the heart, physicians can implant the device without accessing a patient’s blood vessels or heart and without the need for fluoroscopy.

>>>PNN JournalWatch
* Using Electronic Health Care Records for Drug Safety Signal Detection: A Comparative Evaluation of Statistical Methods, in
Medical Care, 2012; 50: 890–7. (M. J. Schuemie)
* Peripheral Artery Disease and CKD: A Focus on Peripheral Artery Disease as a Critical Component of CKD Care, in
American Journal of Kidney Diseases, 2012; 60: 641–54. (P. S. Garimella, pranavgarimella@gmail.com)
* In Vitro Susceptibility Testing of Fluoroquinolone Activity Against
Salmonella: Recent Changes to CLSI Standards, in Clinical Infectious Diseases, 2012; 55: 1107–13. (R. M. Humphries, rhumphries@mednet.ucla.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 2, 2012 * Vol. 19, No. 191
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 2 issue of the Annals of Internal Medicine (2012; 157).
Assessing GFR in Older Patients: Two new equations to estimate glomerular filtration rate (GFR) have proven more accurate than existing equations for assessing kidney function in older adults with normal or mild to moderately reduced kidney function, researchers report, and one of the Berlin Initiative Study (BIS) equations can be used when cystatin C levels are not available (pp. 471–81). Among 610 participants aged 70 years or older, GFR as determined by iohexol plasma clearance had these relationships with the creatinine-based BIS1 and the creatinine- and cystatin C–based BIS2 equations: “The new BIS2 equation yielded the smallest bias followed by the creatinine-based BIS1 and Cockcroft–Gault equations. All other equations considerably overestimated GFR. The BIS equations confirmed a high prevalence of persons older than 70 years with a GFR less than 60 mL/min per 1.73 m2 (BIS1, 50.4%; BIS2, 47.4%; measured GFR, 47.9%). The total misclassification rate for this criterion was smallest for the BIS2 equation (11.6%), followed by the cystatin C equation 2 (15.1%) proposed by the Chronic Kidney Disease Epidemiology Collaboration. Among the creatinine-based equations, BIS1 had the smallest misclassification rate (17.2%), followed by the Chronic Kidney Disease Epidemiology Collaboration equation (20.4%).” (E. S. Schaeffner, elke.schaeffner@charite.de)
Using EHRs To Improve Clinical Outcomes in Diabetes: At Kaiser Permanente Northern California, use of a complete certified electronic health record (EHR) “was associated with improved drug treatment intensification, monitoring, and physiologic control among patients with diabetes, with greater improvements among patients with worse control and less testing in patients already meeting guideline-recommended glycemic and lipid targets” a study shows (pp. 482–9). Analyzing records of 169,711 patients with diabetes, investigators found these patterns: “Use of an EHR was associated with statistically significant improvements in treatment intensification after HbA1c values of 9% or greater (odds ratio, 1.10 [95% CI, 1.05 to 1.15]) or LDL-C values of 2.6 to 3.3 mmol/L (100 to 129 mg/dL) (odds ratio, 1.06 [CI, 1.00 to 1.12]); increases in 1-year retesting for HbA1c and LDL-C levels among all patients, with the most dramatic change among patients with the worst disease control (HbA1c levels ≥9% or LDL-C levels ≥3.4 mmol/L [≥130 mg/dL]); and decreased 90-day retesting among patients with HbA1c levels less than 7% or LDL-C levels less than 2.6 mmol/L (<100 mg/dL). The EHR was also associated with statistically significant reductions in HbA1c and LDL-C levels, with the largest reductions among patients with the worst control (0.06-mmol/L [2.19-mg/dL] reduction among patients with baseline LDL-C levels ≥3.4 mmol/L [≥130 mg/dL]; P < 0.001).” (M. Reed, mary.e.reed@kp.org)
Patients Reading Doctors’ Notes: In an “open notes” project in prominent health systems in Massachusetts, Pennsylvania, and Washington State, 13,564 patients frequently accessed the notes written about their conditions by 105 primary care providers (pp. 461–70). Many patients reported clinically relevant benefits from being able to return to the information, virtually all wanted the practice to continue, and notes were made available with minimal impact on physicians, the investigators concluded. (J. Walker, jwalker1@bidmc.harvard.edu)
An editorialist, writing of “pushing the envelope of electronic patient portals to engage patients in their care,” reached this conclusion in an accompanying piece (
pp. 525–6): “OpenNotes is a brave effort at pushing the frontier of patient engagement in their health. While an experiment like this raises concerns for many physicians, the strong message from patients is that it makes them better patients. OpenNotes or similar systems will, over time, become the norm, and physicians should embrace the concept while trying to identify the best ways to use it. It is critical that future work identify when these systems may pose risks; which patients benefit the most from them; and how best to incorporate them into an ever-increasing arsenal of electronic tools aimed at improving patient care, outcomes, and experience.” (C. L. Goldzweig, Caroline.Goldzweig@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 © 2012, 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
Oct. 3, 2012 * Vol. 19, No. 192
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 3 issue of JAMA (2012; 308).
Vitamin D & Respiratory Tract Infections: In 322 healthy adults in New Zealand over 18 months, vitamin D3 did not reduce the incidence or severity of upper respiratory tract infections (URTIs) (pp. 1333–9). VIDARIS trial participants received placebo or two doses of oral vitamin D3 200,000 IU 1 month apart and 100,000 IU monthly, with these results: “The mean baseline 25-OHD level of participants was 29 (SD, 9) ng/mL. Vitamin D supplementation resulted in an increase in serum 25-OHD levels that was maintained at greater than 48 ng/mL throughout the study. There were 593 URTI episodes in the vitamin D group and 611 in the placebo group, with no statistically significant differences in the number of URTIs per participant (mean, 3.7 per person in the vitamin D group and 3.8 per person in the placebo group; risk ratio, 0.97; 95% CI, 0.85–1.11), number of days of missed work as a result of URTIs (mean, 0.76 days in each group; risk ratio, 1.03; 95% CI, 0.81–1.30), duration of symptoms per episode (mean, 12 days in each group; risk ratio, 0.96; 95% CI, 0.73–1.25), or severity of URTI episodes. These findings remained unchanged when the analysis was repeated by season and by baseline 25-OHD levels.” (D. R. Murdoch, david.murdoch@otago.ac.nz)
“Clinicaltrials.gov lists at least 8 randomized, placebo-controlled trials of vitamin D to prevent respiratory infections,” writes an editorialist (
pp. 1375–6). “These trials vary in participant age, sample size, and vitamin D form, dosage, and frequency. The largest study that includes respiratory tract infections as a primary outcome is projected to enroll 720 senior housing residents and staff and follow them up for 1 year (clinicaltrials.gov identifier: NCT01069874). On a much larger scale, the ongoing VITAL study is a placebo-controlled, 2×2 factorial trial randomizing 20,000 men aged 50 years or older and women aged 55 years or older to determine whether 2000 IU/d of vitamin D or omega-3 fatty acid reduces cancer or cardiovascular outcomes over 5 years. Respiratory diseases and infections are ancillary outcomes, but the annual, mail-based follow-up is inferior to the methods used in VIDARIS for measuring the incidence of upper respiratory tract infections.” (J. A. Linder, jlinder@partners.org)
Beta Blockers & Outcomes in CAD: In a longitudinal observational study of 21,860 patients, beta-blocker use was not associated with a lower risk of a primary outcome composite of cardiovascular death, nonfatal MI, or nonfatal stroke in those with coronary artery disease (CAD) but no myocardial infarction (MI) (pp. 1340–9). Using the Reduction of Atherothrombosis for Continued Health (REACH) registry of patients with known prior MI, known CAD without MI, or those with CAD risk factors only, investigators determined: “With a median follow-up of 44 months (interquartile range, 35–45 months), event rates were not significantly different in patients with beta-blocker use compared with those without beta-blocker use for any of the outcomes tested, even in the prior MI cohort (489 [16.93%] vs 532 [18.60%], respectively; hazard ratio [HR], 0.90 [95% CI, 0.79–1.03]; P = .14). In the CAD without MI cohort, the associated event rates were not significantly different in those with beta-blocker use for the primary outcome (391 [12.94%]) vs without beta-blocker use (405 [13.55%]) (HR, 0.92 [95% CI, 0.79–1.08]; P = .31), with higher rates for the secondary outcome (1,101 [30.59%] vs 1,002 [27.84%]; odds ratio [OR], 1.14 [95% CI, 1.03-1.27]; P = .01) and for the tertiary outcome of hospitalization (870 [24.17%] vs 773 [21.48%]; OR, 1.17 [95% CI, 1.04–1.30]; P = .01). In the cohort with CAD risk factors only, the event rates were higher for the primary outcome with beta-blocker use (467 [14.22%]) vs without beta-blocker use (403 [12.11%]) (HR, 1.18 [95% CI, 1.02–1.36]; P = .02), for the secondary outcome [of the primary outcome plus hospitalization for atherothrombotic events or a revascularization procedure] (870 [22.01%] vs 797 [20.17%]; OR, 1.12 [95% CI, 1.00–1.24]; P = .04) but not for the tertiary outcomes of MI (89 [2.82%] vs 68 [2.00%]; HR, 1.36 [95% CI, 0.97–1.90]; P = .08) and stroke (210 [6.55%] vs 168 [5.12%]; HR, 1.22 [95% CI, 0.99-1.52]; P = .06). However, in those with recent MI (≤1 year), beta-blocker use was associated with a lower incidence of the secondary outcome (OR, 0.77 [95% CI, 0.64–0.92]).” (S. Bangalore, sripalbangalore@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 4, 2012 * Vol. 19, No. 193
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 4 issue of the New England Journal of Medicine (2012; 367).
Prasugrel in ACS Without Revascularization: Compared with clopidogrel 75 mg daily in 7,243 patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel 10 mg daily did not significantly affect a primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients under the age of 75 years, a study shows (pp. 1297–309). Patients were also taking aspirin during a median follow-up period of 17 months, and a secondary analysis looked at 2,083 patients ages 75 years or older who received prasugrel 5 mg or clopidogrel 75 mg daily: “The primary end point … occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group (hazard ratio in the prasugrel group, 0.91; 95% confidence interval [CI], 0.79 to 1.05; P = 0.21). Similar results were observed in the overall population. The prespecified analysis of multiple recurrent ischemic events (all components of the primary end point) suggested a lower risk for prasugrel among patients under the age of 75 years (hazard ratio, 0.85; 95% CI, 0.72 to 1.00; P = 0.04). Rates of severe and intracranial bleeding were similar in the two groups in all age groups. There was no significant between-group difference in the frequency of nonhemorrhagic serious adverse events, except for a higher frequency of heart failure in the clopidogrel group.” (M. T. Roe, matthew.roe@duke.edu)
Clinical Effects of Copy-Number Genetic Variants: Genomic disorders in which the number of copies of a gene varies can have widely divergent phenotypic presentations, researchers report (pp. 1321–31). Genomic disorders include conditions with “a characteristic set of clinically recognizable features, such as the Smith–Magenis syndrome, the Sotos syndrome, and the Williams–Beuren syndrome,” and copy-number variants have been implicated in schizophrenia, autism, cardiac disease, epilepsy, and intellectual disability. In this study, genomes of 2,312 children with a copy-number variant associated with intellectual disability and congenital abnormalities were analyzed using array comparative genomic hybridization, with these results: “Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10−38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P < 0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P < 0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02).” (E. E. Eichler, eee@gs.washington.edu)
“Why are diseases so variable?” an editorialist asks (
pp. 1350–2). The “three obvious candidates” affecting phenotypic expression are the environment, chance, and variability in inheritance, he writes before reaching this conclusion: “[This] robust study and careful analyses … show us one scenario that explains why persons with the same chromosomal abnormality may have very different clinical outcomes: some of them may simply have a second genetic event that makes matters worse for them. Such complexity is now being made more visible for genetic disease. We can look forward to further improvements in our understanding of the variation in genetic disease, which will in turn permit physicians to better inform their patients about the cause of their condition, its prognosis, and the therapy that is most likely to benefit them.” (H. G. Brunner)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 5, 2012 * Vol. 19, No. 194
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Oct. issue of Pharmacotherapy (2012; 32).
Pharmacist-Led Warfarin Self-Management Program: Compared with standard management at an anticoagulation clinic in a study of 114 patients, a pharmacist-led warfarin patient self-management program significant improved quality of life of patients receiving warfarin therapy, reduced the time required for anticoagulation monitoring, and produced a similar level of anticoagulation control (pp. 871–9). Study participants randomized to the pharmacist group received training in use of the CoaguChek XS device and a self-management dosing algorithm. Results showed: “After 4 months of follow-up, a significant improvement in the self-management group was observed compared with the control group in four of the five quality-of-life topics (p < 0.05). Improvements in knowledge were observed in both groups after the training session and persisted after 4 months (p < 0.05 for all). The time spent in the therapeutic range (80.0% in the self-management group vs 75% in the control group, p = 0.79) and in the extended therapeutic range ([target international normalized ratio ± 0.3] 93.2% in the self-management group vs 91.1% in the control group, p = 0.30) were similar between groups.” (L. Verret, lucie.verret@icm-mhi.org)
Cost of Invasive Fungal Infections: An economic analysis shows that costs of care of patients with invasive fungal infections is higher than for other patients and in an era new diagnostic and treatment options, more volatile than in past years (pp. 890–901). Using records of 2,000 hospitalized patients discharged in 2004–05 with diagnoses of aspergillosis, cryptococcosis, invasive candidiasis, or zygomycosis, investigators found these results in comparison with control patients who had similar underlying conditions without fungal infections: “After adjusting for race-ethnicity, sex, age, and comorbid illnesses, mean total hospital cost for cases was $32,196 more than for controls (p < 0.0001). Nonpharmacy costs accounted for the majority (63%) of this difference, and an additional $3,996 was attributed to systemic antifungal drugs. The mean length of hospital stay was longer for cases than controls (25.8 vs 18.4 days).” (E. D. Ashley, Elizabeth_doddsashley@urmc.rochester.edu)
Thrombosis in Hereditary Angioedema Treated with C1 Esterase Inhibitors: A retrospective analysis of the FDA adverse event reporting system (AERS) database shows “continuing reports of thrombotic events associated with the use of one C1 esterase inhibitor product among patients with hereditary angioedema” (pp. 902–9). “The AERS is incapable of establishing a causal link and detecting the true frequency of an adverse event associated with a drug,” the authors note, adding these findings: “Bayesian statistical methodology within the neural network architecture was implemented to identify potential signals of a drug-associated adverse event. A potential signal is generated when the lower limit of the 95% 2-sided confidence interval of the information component, denoted by IC025, is greater than zero. This suggests that the particular drug-associated adverse event was reported to the database more often than statistically expected from reports available in the database. Ten combination cases of thrombotic events associated with the use of one C1 esterase inhibitor product (Cinryze) were identified in patients with hereditary angioedema. A potential signal demonstrated by an IC025 value greater than zero (IC025 = 2.91) was generated for these combination cases.” (P. K. Gandhi, pgandhi@southcollegetn.edu)

>>>PNN NewsWatch
* Fungal infections associated with epidural injections of methylprednisolone from a compounding pharmacy appear to have sickened 35 people in 6 states, pharmacist.com reports. CDC and FDA said yesterday that at least 5 deaths have been associated with fungal infections that occurred after patients received injections of the product made by the New England Compounding Center in Framingham, MA. “All health care personnel [should] cease use and remove from their pharmacy inventories any product produced by the New England Compounding Center,” CDC’s Benjamin Park, MD, said during a news conference. Patients who received injections using product from any of the three recalled lots should be contacted to determine if they are having symptoms.
*
PNN will not be published on Mon., Oct. 8, Columbus Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 9, 2012 * Vol. 19, No. 195
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 8 issue of the Archives of Internal Medicine (2012; 172).
LABA Step-Off Therapy in Controlled Asthma: A systematic review and meta-analysis shows that discontinuance of long-acting beta-2-agonists (LABAs) in adults and older children with asthma controlled by inhaled corticosteroid (ICSs) and LABAs is associated with worsening of asthma impairment (pp. 1365–75). Based on a screening sample of 1,492 articles, authors found: “Only 5 trials involving patients aged 15 years or older fulfilled a priori–specified inclusion criteria. Results did not favor the LABA step-off approach compared with no change in treatment. The LABA step-off regimen increased asthma impairment, with worse Asthma Quality of Life Questionnaire score (mean difference [95% CI], 0.32 [0.14–0.51] points lower); worse Asthma Control Questionnaire score (0.24 [0.13–0.35] points higher); fewer symptom-free days (9.15% [1.62%–16.69%] less); and greater risk of withdrawal from study resulting from lack of efficacy or loss of asthma control (risk ratio, 3.27 [2.16–4.96]). Risk of exacerbations and deaths after LABA step-off were not evaluable because of the small number of events and short duration of follow-up.” (T. B. Casale, tbcasale@creighton.edu)
Focusing on FDA’s black-box warnings on LABA labels, editorialists call for an improved process for precautionary warnings (
pp. 1375–6): “The essential question remains: will regulatory authorities ever consider reevaluating their recommendations as the evidence evolves? Medicine is not a static field, as [these] results … illustrate. The current FDA-mandated megatrial to evaluate the safety of LABAs may not even be able to conclusively evaluate the hypothesis it was designed to address. In light of the fact that such a trial will take years to complete, coupled with the reality that clinicians must make decisions about if and how to use LABAs now, will the FDA seriously examine the results of [this] analysis … or will it merely criticize the analysis given several of the flaws noted in the study? We hope that this meta-analysis helps to lift some of the black clouds in the debate surrounding LABAs. Similarly, physicians must now reevaluate the contents of the black box for LABAs, particularly in individuals whose asthma is well controlled with combination LABA and ICS therapy.” (A. F. Shorr, andrew.shorr@gmail.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Opiate Substitution & HIV Transmission in Injection Drug Users: Opiate substitution therapies appear to reduce the risk of HIV transmission among people who inject drugs, according to results of a systematic review and meta-analysis (e5945). The findings could be attributable to greater motivation by those under treatment, the authors note, adding these details from a review of 15 studies of methadone maintenance treatment: “Data from nine of these studies could be pooled, including 819 incident HIV infections over 23,608 person years of follow-up. Opiate substitution treatment was associated with a 54% reduction in risk of HIV infection among people who inject drugs (rate ratio 0.46, 95% confidence interval 0.32 to 0.67; P < 0.001). There was evidence of heterogeneity between studies (I2 = 60%, chi square = 20.12, P = 0.010), which could not be explained by geographical region, site of recruitment, or the provision of incentives. There was weak evidence for greater benefit associated with longer duration of exposure to opiate substitution treatment.” (G. J. MacArthur, georgie.macarthur@bristol.ac.uk)

>>>PNN NewsWatch
* Eight people have died after being exposed to contaminated epidural steroids made at the New England Compounding Center, CNN reports. In all, 105 people have reported symptoms of meningitis, and as many as 13,000 patients may have been exposed to the product since May.

>>>PNN JournalWatch
* Global Trends in Antiretroviral Resistance in Treatment-Naive Individuals With HIV After Rollout of Antiretroviral Treatment in Resource-Limited Settings: A Global Collaborative Study and Meta-Regression Analysis, in
Lancet, 2012; 380: 1250–8. (S. Bertagnolio, bertagnolios@who.int)
* Effects of Tobacco Smoking and Nicotine on Cancer Treatment, in
Pharmacotherapy, 2012; 32: 920–31. (W. P. Petros, wpetros@hsc.wvu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 10, 2012 * Vol. 19, No. 196
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 10 issue of JAMA (2012; 308).
Research Needed on Med Use in Preterm Infants: Viewpoint authors call for a “radical new approach … to improve outcomes for the smallest, most vulnerable, and perhaps most complex patients” in society (pp. 1435–6): “The National Institutes of Health needs to enhance research efforts for maternal and child health, especially in view of the current emphasis on fetal and neonatal origins of adult diseases. All research proposals involving pregnant women or newborn infants should be evaluated at the National Institute of Child Health and Human Development regardless of where the grant proposal is submitted, with uniform review guidelines developed. Appropriate recommendations from the recent Institute of Medicine report should be followed, which has already begun with the recent Congressional reauthorization of the [Best Pharmaceuticals for Children Act (BPCA)] requiring a greater focus on neonatal drug development at the FDA. The BPCA prioritization program at the National Institute of Child Health and Human Development should be expanded to facilitate the immediate performance of many of these studies. Public and private insurance companies should reimburse treatment costs for infants participating in clinical trials because optimizing treatment guidelines and developing new therapeutics should improve outcome, reduce costs, and benefit all stakeholders (including insurance companies). The March of Dimes and other philanthropic organizations should support studies that generate best treatment practices to improve outcomes for this vulnerable population.” (J. M. Davis, jdavis@tuftsmedicalcenter.org)

>>>Cardiology Report
Source:
Oct. 16 issue of the Journal of the American College of Cardiology (2012; 60).
Long-Term Exercise Training in Chronic Heart Failure: Ten years of moderate supervised exercise training enabled patients with Class II and III chronic heart failure (CHF) to maintain functional capacity of more than 60% peak oxygen consumption (Vo2), according to data from Italy (pp. 1521–8). Twice-weekly sessions at a hospital gym produced these results for 123 training (T) and no-training (NT) patients: “In the T group, peak Vo2 was more than 60% of age- and gender-predicted maximum Vo2 each year during the 10-year study (p < 0.05 vs. the NT group). In NT patients, peak Vo2 decreased progressively with an average of 52 ± 8% of maximum Vo2 predicted. Ventilation relative to carbon dioxide output (VE/Vco2) slope was significantly lower (35 ± 9) in T patients versus NT patients (42 ± 11, p < 0.01). Quality-of-life score was significantly better in the T group versus the NT group (43 ± 12 vs. 58 ± 14, p < 0.05). During the 10-year study, T patients had a significant lower rate of hospital readmission (hazard ratio: 0.64, p < 0.001) and cardiac mortality (hazard ratio: 0.68, p < 0.001) than controls.” (R. Belardinelli, r.belardinelli@ospedaliriuniti.marche.it)

>>>Circulation Highlights
Source:
Oct. 9 issue of Circulation (2012; 126).
Activity–Genetic Interaction for BMIs in Adults: People can overcome or even reverse genetic predispositions to adiposity through greater physical activity, researchers report (pp. 1821–7). Data from the Nurses’ Health Study and the Health Professionals Follow-up Study showed these associations among genetic predispositions to obesity, body mass index (BMI), and a weighted genetic risk score calculated using 32 established BMI-associated variants : “In both women and men, the genetic associations with BMI strengthened with increased hours of TV watching. An increment of 10 points in the weighted genetic risk score was associated with 0.8 (SE, 0.4), 0.8 (SE, 0.2), 1.4 (SE, 0.2), 1.5 (SE, 0.2), and 3.4 (SE, 1.0) kg/m2 higher BMI across the 5 categories of TV watching (0–1, 2–5, 6–20, 21–40, and >40 h/wk; P for interaction = 0.001). In contrast, the genetic association with BMI weakened with increased levels of physical activity. An increment of 10 points in the weighted genetic risk score was associated with 1.5 (SE, 0.2), 1.3 (SE, 0.2), 1.2 (SE, 0.2), 1.2 (SE, 0.2), and 0.8 (SE, 0.2) kg/m2 higher BMI across the quintiles of physical activity. The interactions of TV watching and physical activity with genetic predisposition in relation to BMI were independent of each other.” (L. Qi, nhlqi@channing.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 11, 2012 * Vol. 19, No. 197
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 11 issue and website of the New England Journal of Medicine (2012; 367).
Calories From Soft Drinks: Reacting to three studies on consumption of sugar-sweetened and sugar-free beverages (pp. 1387–96, L. Qi, nhlqi@channing.harvard.edu; pp. 1397–406, J. C. de Ruyter, j.c.de.ruyter@vu.nl; pp. 1407–16, D. S. Ludwig, david.ludwig@childrens.harvard.edu), an editorialist explores the obesity epidemic and the contribution of soft drinks—the largest single caloric source in the U.S.—to growing waistlines (pp. 1462–3): “These randomized, controlled studies— in particular, the study by de Ruyter et al.— provide a strong impetus to develop recommendations and policy decisions to limit consumption of sugar-sweetened beverages, especially those served at low cost and in excessive portions, to attempt to reverse the increase in childhood obesity. Such interventions, if successful, may also help prevent the development of type 2 diabetes and its complications in youth.
“Taken together, these three studies suggest that calories from sugar-sweetened beverages do matter. Furthermore, policy decisions about sugar-sweetened beverages should not be considered in isolation. Other strategies to achieve and maintain normal weight, including increasing physical activity, will be important to stem the obesity epidemic and its effects. The time has come to take action and strongly support and implement the recommendations from the Institute of Medicine, the American Heart Association, the Obesity Society, and many other organizations to reduce consumption of sugar-sweetened beverages in both children and adults.” (S. Caprio)
Nonpayment for Preventable Infections: Infection rates at U.S. hospitals were unaffected by a 2008 CMS policy that reduced payment for central catheter–associated bloodstream infections and catheter-associated urinary tract infections. a study shows (pp. 1428–37). Compared with rates of ventilator-associated pneumonia—which was not targeted by the policy—rates of the regulated infections showed these patterns in 2006–11 data from the National Healthcare Safety Network: “A total of 398 hospitals or health systems contributed 14,817 to 28,339 hospital unit–months, depending on the type of infection. We observed decreasing secular trends for both targeted and nontargeted infections long before the policy was implemented. There were no significant changes in quarterly rates of central catheter–associated bloodstream infections (incidence-rate ratio in the postimplementation vs. preimplementation period, 1.00; P = 0.97), catheter-associated urinary tract infections (incidence-rate ratio, 1.03; P = 0.08), or ventilator-associated pneumonia (incidence-rate ratio, 0.99; P = 0.52) after the policy implementation. Our findings did not differ for hospitals in states without mandatory reporting, nor did it differ according to the quartile of percentage of Medicare admissions or hospital size, type of ownership, or teaching status.” (G. M. Lee, grace.lee@childrens.harvard.edu)
Fungal Meningitis Outbreak: Information for clinicians regarding the compounded product–associated outbreak of fungal meningitis is being updated regularly on the Journal’s website. Potentially exposed patients in the 23 states where the New England Compounding Center’s methylprednisolone products were distributed should be monitored for signs and symptoms of meningitis: headache, fever, stiff neck, or photophobia and a CSF profile consistent with meningitis (pleocytosis with or without low glucose, elevated protein). CDC does not currently recommend prophylactic antifungal treatment or lumbar punctures in asymptomatic patients. Organisms isolated clinically or on postmortem have included Aspergillus spp. the rare Exserohilum spp., and at least one patient with Propionibacterium acnes of unclear clinical relevance. Symptomatic patients can be treated empirically with high doses of voriconazole (6 mg/kg every 12 hours IV initially with regular serum monitoring) and higher-than-normal doses of liposomal amphotericin B (7.5 mg/kg IV daily). Intrathecal amphotericin B in either the deoxycholate or lipid formulations should be avoided due to limited data on its use and associated toxicities, and adjuvant steroids lack clear evidence for use, the site states. Cases should be reported to public health authorities and the FDA’s MedWatch program.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 12, 2012 * Vol. 19, No. 198
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Oct. issue of Pediatrics (2012; 130).
Medication Adherence in Pediatric Primary Care: Electronic prescribing is one intervention that can increase the rate of prescription filling for patients of pediatric primary care practices, a study suggests (pp. 620–6). In a retrospective observational analysis, prescription data from an electronic medical record were compared with those in Illinois Medicaid claims databases to determine prescription-filling rates for 4,833 patients who received 16,953 prescriptions: “Patients were 51% male; most (84%) spoke English and were African American (38.7%) or Hispanic (39.1%). Seventy-eight percent of all prescriptions were filled. Among filled prescriptions, 69% were filled within 1 day. African American, Hispanic, and male patients were significantly more likely to have filled prescriptions. Younger age was associated with filling within 1 day but not with filling within 60 days. Prescriptions for antibiotics, from one of the clinic sites, from sick/follow-up visits, and electronic prescriptions were significantly more likely to be filled.” (R. T. Zweigoron, rach_zweig@yahoo.com)
Medical Errors in Pediatric Inpatients: In pediatric inpatients, errors involving medications were rare, researchers report, with the number of chronic conditions significantly associated with iatrogenic medical errors (pp. e786–93). Using data from the 2006 Kids’ Inpatient Database (KID), the investigators found: “22.3% of pediatric inpatients had 1 chronic condition, 9.8% had 2 chronic conditions, and 12.0% had ≥3 chronic conditions. The overall medical error rate per 100 discharges was 3.0 (95% confidence interval [CI]: 2.8–3.3); it was 5.3 (95% CI: 4.9–5.7) in children with chronic conditions and 1.3 (95% CI: 1.2–1.3) in children without chronic conditions. The medical error rate per 1,000 inpatient days was also higher in children with chronic conditions. The association between chronic conditions and medical errors remained statistically significant in logistic regression models adjusting for patient characteristics, hospital characteristics, disease severity, and length of stay. In the adjusted model, the odds ratio of medical errors for children with 1 chronic condition was 1.40 (95% CI: 1.32–1.48); for children with 2 conditions, the OR was 1.55 (95% CI: 1.45–1.66); and for children with 3 conditions, the OR was 1.66 (95% CI: 1.53–1.81).” (H. Xiang, huiyun.xiang@nationwidechildrens.org)

>>>Psychiatry Highlights
Source:
Oct. issue of the American Journal of Psychiatry (2012; 169).
Antidepressant & NSAIDs: Patients with major depressive disorder appear to have poorer responses to antidepressants when they are also receiving NSAIDs, according to data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (pp. 1065–72). The interaction can be partially explained by confounding factors, but modest effects of NSAID therapy on antidepressant response remain after adjustment: “NSAID exposure was associated with a greater likelihood of depression classified as treatment resistant compared with depression classified as responsive to selective serotonin reuptake inhibitors (odds ratio = 1.55, 95% CI = 1.21–2.00). This association was apparent in the NSAIDs-only group but not in those using other agents with NSAID-like mechanisms (cyclooxygenase-2 inhibitors and salicylates). Inclusion of age, sex, ethnicity, and measures of comorbidity and health care utilization in regression models indicated confounding; association with outcome was no longer significant in fully adjusted models. Reanalysis of STAR*D results likewise identified an association in NSAIDs but not NSAID-like drugs, with more modest effects persisting after adjustment for potential confounding variables.” (R. H. Perlis, rperlis@partners.org)

>>>PNN NewsWatch
* Joint infections are another problem to watch for in patients exposed to the three recalled lots of methylprednisolone acetate produced by New England Compounding Center, CDC said yesterday. Upping the number of potentially exposed patients to 14,000, the agency said the product was injected into joints such as the knee, shoulder, and ankle in addition to the spine. CDC said it has contacted about 90% patients exposed to the products. While onset of symptoms has typically been 1–4 weeks, slow fungal growth means patients need to be alert for symptoms of meningitis or joint infections for several weeks.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 15, 2012 * Vol. 19, No. 199
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 13 issue of Lancet (2012; 380).
Vorapaxar for Secondary Prevention of Thrombosis: In the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial, vorapaxar therapy reduced the risk of cardiovascular death or ischemic events when added to standard antiplatelet treatment but increased the risk of moderate or severe bleeding in patients with histories of myocardial infarction (pp. 1317–24). In 26,449 patients, 2.5-mg doses of the protease-activated receptor 1 inhibitor had these effects on a primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke: “Median follow-up was 2.5 years (IQR 2.0–2.9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8,898 patients in the vorapaxar group and 750 of 8,881 in the placebo group (3-year Kaplan–Meier estimates 8.1% vs 9.7%, HR 0.80, 95% CI 0.72–0.89; p < 0.0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8,880 [3.4%, 3-year Kaplan–Meier estimate] vs 151/8,849 [2.1%, 3-year Kaplan–Meier estimate], HR 1.61, 95% CI 1.31–1.97; p < 0.0001). Intracranial haemorrhage occurred in 43 of 8,880 patients (0.6%, 3-year Kaplan–Meier estimate) with vorapaxar versus 28 of 8,849 (0.4%, 3-year Kaplan–Meier estimate) with placebo (p = 0.076). Other serious adverse events were equally distributed between groups.” (B. M. Scirica, bscirica@partners.org)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 345).
Tocolytic Therapy for Preterm Delivery: Among tocolytic agents for prevention of preterm delivery, prostaglandin inhibitors and calcium channel blockers produce the best odds of delaying delivery and improving neonatal and maternal outcomes, according to a systematic review and network meta-analysis of 95 articles (e6226): “Compared with placebo, the probability of delivery being delayed by 48 hours was highest with prostaglandin inhibitors (odds ratio 5.39, 95% credible interval 2.14 to 12.34) followed by magnesium sulfate (2.76, 1.58 to 4.94), calcium channel blockers (2.71, 1.17 to 5.91), beta mimetics (2.41, 1.27 to 4.55), and the oxytocin receptor blocker atosiban (2.02, 1.10 to 3.80). No class of tocolytic was significantly superior to placebo in reducing neonatal respiratory distress syndrome. Compared with placebo, side effects requiring a change of medication were significantly higher for beta mimetics (22.68, 7.51 to 73.67), magnesium sulfate (8.15, 2.47 to 27.70), and calcium channel blockers (3.80, 1.02 to 16.92). Prostaglandin inhibitors and calcium channel blockers were the tocolytics with the best probability of being ranked in the top three medication classes for the outcomes of 48 hour delay in delivery, respiratory distress syndrome, neonatal mortality, and maternal side effects (all cause).” (D. M. Haas, dahaas@iupui.edu)
HRT & Cardiovascular Events After Menopause: Compared with no treatment in a open-label trial, hormone-replacement therapy begun soon after menopause onset produced a positive risk–benefit scenario, researchers report (e6409). In 1,006 healthy women who began therapy in 1990–92, these outcomes were recorded based on a primary composite endpoint of death, admission to hospital for heart failure, or myocardial infarction: “After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P = 0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P = 0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P = 0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P = 0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70).” (L. L. Schierbeck, louise.schierbeck@gmail.com)

>>>PNN JournalWatch
* Toward Systems Neuroscience of ADHD: A Meta-Analysis of 55 fMRI Studies, in
American Journal of Psychiatry, 2012; 169: 1038–55. (F. X. Castellanos, francisco.castellanos@nyumc.org)
* IL-13 in Asthma and Allergic Disease: Asthma Phenotypes and Targeted Therapies, in
Journal of Allergy and Clinical Immunology, 2012; 130: 829–42. (J. L. Ingram, Jennifer.ingram@duke.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Oct. 16, 2012 * Vol. 19, No. 200
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 16 issue of the Annals of Internal Medicine (2012; 157).
Rilonacept for Familial Mediterranean Fever: An interleukin-1 decoy receptor, rilonacept, reduces the number of attacks in patients with familial Mediterranean fever (FMF) and “seems to be a treatment option for patients with colchicine-resistant or -intolerant FMF,” researchers report (pp. 533–41). Compared in 3-month courses with placebo, rilonacept 2.2 mg/kg (maximum dose, 160 mg) was tested in patients aged 4 years or older who were having at least 1 FMF attack per month: “8 males and 6 females with a mean age of 24.4 years (SD, 11.8) were randomly assigned. Among 12 participants who completed 2 or more treatment courses, the rilonacept–placebo attack risk ratio was 0.59 (SD, 0.12) (equal-tail 95% credible interval, 0.39 to 0.85). The median number of attacks per month was 0.77 (0.18 and 1.20 attacks in the first and third quartiles, respectively) with rilonacept versus 2.00 (0.90 and 2.40, respectively) with placebo (median difference, −1.74 [95% CI, −3.4 to −0.1]; P = 0.027). There were more treatment courses of rilonacept without attacks (29% vs. 0%; P = 0.004) and with a decrease in attacks of greater than 50% compared with the baseline rate during screening (75% vs. 35%; P = 0.006) than with placebo. However, the duration of attacks did not differ between placebo and rilonacept (median difference, 1.2 days [−0.5 and 2.4 days in the first and third quartiles, respectively]; P = 0.32). Injection site reactions were more frequent with rilonacept (median difference, 0 events per patient treatment month [medians of −4 and 0 in the first and third quartiles, respectively]; P = 0.047), but no differences were seen in other adverse events.” (P. J. Hashkes, hashkesp@szmc.org.il)
Insulin Signaling & Sleep Impairment: Concluding that “sleep may be an important regulator of energy metabolism in peripheral tissues,” investigators report that seven healthy adults developed insulin-resistant conditions in adipocytes when their sleep was restricted to 4.5 hours per night (pp. 549–57). In a crossover study that used 4-day testing periods, patients spent either 4.5 or 8.5 hours in bed while caloric intake and physical activity were controlled. Tests of adipocyte function, including the crucial phosphorylated Akt (pAkt) and total Akt (tAkt) levels, showed: “The insulin concentration for the half-maximal pAkt–tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt–tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity.” (M. J. Brady, mbrady@medicine.bsd.uchicago.edu)
This is the first clinical study to examine the causal pathways by which reduced sleep duration may directly contribute to diabetes and obesity, according to authors of an accompanying editorial (
pp. 593–4). They write that the study results point to a much wider influence of sleep on bodily functions, including metabolism, adipose tissue, cardiovascular function, and possibly more. The editorial authors caution that the study did not specify whether researchers standardized participants’ exposure to light, so it is difficult to determine if changes in the functionality of adipocytes were due to sleep deprivation or duration of exposure to light (or darkness). (F. P. Cappuccio)

>>>PNN NewsWatch
* In addition to the methylprednisolone preparations implicated previously, patients who have received epidural triamcinolone or perioperative cardioplegic solutions from New England Compounding Center (NECC) may be at risk of infection, FDA said yesterday. A patient with possible meningitis potentially associated with epidural triamcinolone acetonide was identified through active surveillance and reported to FDA, the agency said. Two transplant patients with Aspergillus fumigatus infection who were administered NECC cardioplegic solution during surgery have also been reported. “The sterility of any injectable drugs, including ophthalmic drugs that are injectable or used in conjunction with eye surgery, and cardioplegic solutions produced by NECC are of significant concern,” FDA said. “Out of an abundance of caution, patients who received these products should be alerted to the potential risk of infection.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Oct. 17, 2012 * Vol. 19, No. 201
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 17 issue of JAMA (2012; 308).
High-Dose Multivitamins at HAART Initiation: Compared with standard-dose vitamin supplements, high doses of multivitamin preparations had no effect on HIV disease progression or death in adults starting highly active antiretroviral therapy (HAART), but they may have raised liver enzymes (pp. 1535–44). In a randomized trial in Tanzania, 3,418 patients with HIV had these responses when started in 2006–08 on vitamin B complex, vitamin C, and vitamin E at high or standard levels: “The study was stopped early in March 2009 because of evidence of increased levels of alanine transaminase (ALT) in patients receiving the high-dose multivitamin supplement. At the time of stopping, 3,418 patients were enrolled (median follow-up, 15 months), and there were 2,374 HIV disease progression events and 453 observed deaths (2,460 total combined events). Compared with standard-dose multivitamin supplementation, high-dose supplementation did not reduce the risk of HIV disease progression or death. The absolute risk of HIV progression or death was 72% in the high-dose group vs 72% in the standard-dose group (risk ratio [RR], 1.00; 95% CI, 0.96–1.04). High-dose supplementation had no effect on CD4 count, plasma viral load, body mass index, or hemoglobin level concentration, but increased the risk of ALT elevations (1,239 events per 1,215 person–years vs 879 events per 1,236 person–years; RR, 1.44; 95% CI, 1.11–1.87) vs standard-dose supplementation.” (S. Isanaka, sisanaka@hsph.harvard.edu)
Chloride Restriction & Kidney Injury: Implemented in a tertiary intensive-care unit, a chloride-restrictive strategy for intravenous fluids was associated with significant decreases in the incidence of acute kidney injury (AKI) and the need for renal replacement therapy (RRT), researchers report (pp. 1566–72). A prospective open-label pilot study included 760 consecutively admitted ICU patients during a 6-month control period and 773 patients during 6 months of chloride restriction. In a 6-month phase-out period between the two study timeframes, attending specialist approval was required for use of chloride-rich IV fluids (0.9% saline, 4% succinylated gelatin solution, or 4% albumin solution). Results showed: “Chloride administration decreased by 144,504 mmol (from 694 to 496 mmol/patient) from the control period to the intervention period. Comparing the control period with the intervention period, the mean serum creatinine level increase while in the ICU was 22.6 µmol/L (95% CI, 17.5–27.7 µmol/L) vs 14.8 µmol/L (95% CI, 9.8-19.9 µmol/L) (P = .03), the incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%–16%; n = 105) vs 8.4% (95% CI, 6.4%–10%; n = 65) (P < .001), and the use of RRT was 10% (95% CI, 8.1%–12%; n = 78) vs 6.3% (95% CI, 4.6%–8.1%; n = 49) (P = .005). After adjustment for covariates, this association remained for incidence of injury and failure class of RIFLE-defined AKI (odds ratio, 0.52 [95% CI, 0.37–0.75]; P <.001) and use of RRT (odds ratio, 0.52 [95% CI, 0.33–0.81]; P = .004). There were no differences in hospital mortality, hospital or ICU length of stay, or need for RRT after hospital discharge.” (R. Bellomo, rinaldo.bellomo@austin.org.au)
“[These] findings … are important and should serve to focus more attention on the formulation of intravenous fluids,” editorialists write (
pp. 1583–5). “In light of the central role for intravenous fluids in perioperative, intensive, and nonintensive hospital care and the effects of fluid administration on physiology, biochemistry, clinical outcomes, and adverse events, intravenous fluid preparations are like drugs and deserve similar scientific and regulatory scrutiny. When physicians order an infusion of normal saline, Hartmann solution, or 20% albumin, these fluids bypass the gut, sometimes overrule the kidney, and reach into the deepest intracellular and interstitial crevices of the body. Clinicians owe it to patients to get intravenous fluid administration right.” (S. S. Waikar, swaikar@partners.org)

>>>PNN NewsWatch
* The number of patients with fungal infections associated with receipt of products from the New England Compounding Center stands at 233 patients in 15 states, CDC reports. Fifteen patients have died. Symptoms have generally occurred within 1–4 weeks of administration, but longer incubation periods have been noted in some patients.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 18, 2012 * Vol. 19, No. 202
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Oct. 18 issue of the New England Journal of Medicine (2012; 367).
Linezolid for Drug-Resistant Tuberculosis: In 41 patients with sputum-culture–positive extensively drug-resistant (XDR) tuberculosis, linezolid produced culture conversion but also adverse effects, a study shows (pp. 1508–18). In addition to their previous antitubercular regimen, participants received linezolid 600 mg/d on admission or after 2 months. Patients who had a sputum-smear conversion were randomized a second time to either continue on linezolid 600 mg daily doses or switch to linezolid 300 mg/d for 18 months or more. Results showed: “By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed.” (C. E. Barry, cbarry@niaid.nih.gov)
Ustekinumab in Refractory Crohn’s Disease: Compared with placebo, ustekinumab induction produced higher rates of response in patients with moderate-to-severe Crohn’s disease that was resistant to TNF antagonists, and responders had higher rates of remission during maintenance therapy, researchers report (pp. 1519–28). At week 0, 526 patients received intravenous ustekinumab 1, 3, or 6 mg/kg or placebo. In 145 patients with a response to the anti–interleukin-12 and -23 monoclonal antibody at 6 weeks, a second randomization assigned doses of ustekinumab 90 mg or placebo at weeks 8 and 16, with results: “The proportions of patients who [responded clinically at week 6] were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P = 0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P = 0.03) and response (69.4% vs. 42.5%, P < 0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab.” (W. J. Sandborn, wsandborn@ucsd.edu)
Kefauver–Harris Amendments at 50: Adding efficacy to the safety requirement for medications, the Kefauver–Harris amendments were signed into law 50 years ago this month by Pres. John F. Kennedy, according to a Perspective article (pp. 1481–3). Many parts of the original bill were left on “Congress’s cutting-room floor,” the authors note. The problems they addressed “have not disappeared but continue to confront those who would ensure access to innovative, safe, efficacious, and affordable therapeutics.” The pharmaceutical industry responded to the law by moving toward randomized, placebo-controlled trials, meaning that clinicians would rarely have direct comparisons of active agents. Since provisions forbidding me-too drugs were also eliminated, comparative efficacy remained unaddressed until legislation passed during the Obama administration funded federally sponsored comparisons. (J. A. Green)
Chocolate & Brains: Average per-capita chocolate consumption of countries tracks linearly with their number of Nobel laureates, according to a research note (pp. 1562–4). Switzerland boasts the greatest number of Nobel laureates, and its mean consumption of the cognitive stimulant is world’s highest at about 12 kg/yr/capita. Countries with 0 or 1 laureate—including China, Japan, Portugal, Greece, and Brazil—hover at “the minimally effective chocolate dose [of] around 2 kg per year,” the authors report, adding that “the slope of the regression line allows us to estimate that it would take about 0.4 kg of chocolate per capita per year to increase the number of Nobel laureates in a given country by 1.” (F. H. Messerli)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 19, 2012 * Vol. 19, No. 203
Providing news and information about medications and their proper use

>>>NECC Products: Clinical Course of Fungal Meningitis
The clinical course of one of the index cases of Exserohilum meningitis associated with epidural administration of preservative-free methylprednisolone acetate from the New England Compounding Center shows onset of symptoms on day 7 and rapid decline of CNS functions, with death on day 18. Postmortem autopsy showed “a grossly necrotic brainstem, and microscopic examination showed angioinvasive, septate fungal hyphae associated with diffuse vasculitis and hemorrhagic infarction in the brain and spinal cord,” according to a letter published early online yesterday by the Annals of Internal Medicine.
The 51-year-old woman initially sought emergency medical care for occipital headaches radiating to the face one week after having an epidural steroid injection in her neck. The otherwise healthy patient was hospitalized after returning to the emergency department the next day with troublesome neurologic symptoms. Over the next several days, her health continued to deteriorate rapidly, until she died 10 days later. The researchers conclude that the patient was infected with
Exserohilum species, a species of fungi with a short, unknown incubation time.
Clinicians and the public should be aware of the signs and symptoms of fungal meningitis following joint or bone injections, the authors conclude, because in this outbreak, rapid diagnosis and treatment may be necessary to prevent serious complications and death (J. L. Lyons).
In a
related editorial, also published early online, an author points to a 2002 outbreak of five cases of Exophiala (Wangiella) dermatitidis meningitis or arthritis related to contaminated, injectable, preservative-free methylprednisolone acetate prepared by a compounding pharmacy. The editorialist writes: “We learned, or thought we learned, several important lessons from the outbreak: that compounding of preservative-free corticosteroids requires meticulous sterility to ensure lack of fungal contamination; in the absence of that level of sterility and in an environment of highly concentrated steroids, fungi grow aggressively (this has also been occasionally observed in ophthalmology with the accidental treatment of fungal keratitis with topical steroids); and injection of fungus-contaminated corticosteroid solution into the parameninges allows fungus to travel through tissue planes into the subarachnoid space, leading to invasive mycosis.”
Writing that “it is clear that issues surrounding pharmacy compounding and its regulation will need to be revisited at the state and federal levels,” the editorialist notes, “Productive discourse between pharmacy societies, the FDA, the pharmaceutical industry, and the legislatures can hopefully balance the demand for individualized, designer products for patient care against the risks for outbreaks that cause suffering and death and that erode trust in public health systems. Otherwise, this will surely happen again.” (J. R. Perfect,
john.perfect@duke.edu)

>>>PNN NewsWatch
* Approval of ocriplasmin (Jetrea, ThromboGenics) for treatment of symptomatic vitreomacular adhesion (VMA) was announced yesterday by FDA. Administered by intravitreal injection, the enzyme breaks down proteins in the eye responsible for the movement of the vitreous away from the macula, thereby preventing the damage to the macula and resulting symptoms. Efficacy studies included 652 patients with symptomatic VMA; 26.5% of patients responded to ocriplasmin, compared with 10.1% with placebo. The most common adverse effects with ocriplasmin were eye floaters, conjunctival bleeding, eye pain, photopsia, blurred vision, unclear vision, vision loss, retinal edema, and macular edema.
*
CDC and FDA have confirmed the presence of Exserohilum rostratumin in unopened medication vials of preservative-free methylprednisolone acetate (80 mg/mL) from one of the three implicated lots from the New England Compounding Center (lot 08102012@51, BUD 2/6/2013). The laboratory confirmation further links steroid injections from these lots from NECC to the multistate outbreak of fungal meningitis and joint infections. Testing on the other two implicated lots of methylprednisolone acetate and other NECC injectables continues, the agencies said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 22, 2012 * Vol. 19, No. 204
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Oct. 20 issue of Lancet (2012; 380).
LCZ696 in Heart Failure: Compared with valsartan, a first-in-class angiotensin receptor neprilysin inhibitor reduced a marker of left ventricular wall stress in a Phase II trial of 266 patients with class II or III heart failure (pp. 1387–95). During 36 weeks of treatment with valsartan 160 mg or LCZ696 200 mg twice daily, these effects were observed: “NT-proBNP was significantly reduced at 12 weeks in the LCZ696 group compared with the valsartan group (LCZ696: baseline, 783 pg/mL [95% CI 670–914], 12 weeks, 605 pg/mL [512–714]; valsartan: baseline, 862 pg/mL [733–1012], 12 weeks, 835 [710–981]; ratio LCZ696/valsartan, 0.77, 95% CI 0.64–0.92, p = 0.005). LCZ696 was well tolerated with adverse effects similar to those of valsartan; 22 patients (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event.” (S. D. Solomon, ssolomon@rics.bwh.harvard.edu)
Resistance to Second-Line Antitubercular Drugs: CDC researchers quantify resistance patterns among adults with locally confirmed pulmonary multidrug-resistant (MDR) tuberculosis in 2005–08 in Estonia, Latvia, Peru, Philippines, Russia, South Africa, South Korea, and Thailand (pp. 1406–17). Looking for risk factors for resistance to second-line drugs and extensively drug-resistant (XDR) tuberculosis, the investigators found: “Among 1,278 patients, 43.7% showed resistance to at least one second-line drug, 20.0% to at least one second-line injectable drug, and 12.9% to at least one fluoroquinolone. 6.7% of patients had XDR tuberculosis (range across study sites 0.8–15.2%). Previous treatment with second-line drugs was consistently the strongest risk factor for resistance to these drugs, which increased the risk of XDR tuberculosis by more than four times. Fluoroquinolone resistance and XDR tuberculosis were more frequent in women than in men. Unemployment, alcohol abuse, and smoking were associated with resistance to second-line injectable drugs across countries. Other risk factors differed between drugs and countries.” (T. Dalton, tldalton@cdc.gov)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 345).
Acetazolamide for Prophylaxis of Altitude Sickness: Acetazolamide’s lowest effective dose for prevention of acute mountain sickness is 250 mg, according to a systematic review and meta-analysis of 11 studies (e6779): “Acetazolamide at doses of 250 mg, 500 mg, and 750 mg were all effective in preventing acute mountain sickness above 3000 m, with a combined odds ratio of 0.36 (95% confidence interval 0.28 to 0.46). At a dose of 250 mg daily the number needed to treat for acetazolamide to prevent acute mountain sickness was 6 (95% confidence interval 5 to 11). Heterogeneity ranged from I2=0% (500 mg subgroup) to I2=44% (750 mg subgroup).” (A. J. Avery, anthony.avery@nottingham.ac.uk)
Postoperative Respiratory Complications With Neuromuscular Blocking Agents: “Strategies … to prevent residual postoperative neuromuscular blockade should be revisited,” according to authors who studied 18,579 surgical patients who received intermediate-acting neuromuscular blocking agents and matching controls (e6329). The prospective, propensity-score, matched-cohort study found these results: “The use of intermediate acting neuromuscular blocking agents was associated with an increased risk of postoperative desaturation less than 90% after extubation (odds ratio 1.36, 95% confidence interval 1.23 to 1.51) and reintubation requiring unplanned admission to an intensive care unit (1.40, 1.09 to 1.80). Qualitative monitoring of neuromuscular transmission did not decrease this risk and neostigmine reversal increased the risk of postoperative desaturation less than 90% (1.32, 1.20 to 1.46) and reintubation (1.76, 1.38 to 2.26).” (M. Eikermann, meikermann@partners.org)

>>>PNN JournalWatch
* Drug-Associated Acute Lung Injury: A Population-Based Cohort Study, in
Chest, 2012; 142: 845–50. (R.a Dhokarh, rdhokarh@gmail.com)
* Lack of Efficacy of Probiotics in Preventing Ventilator-Associated Pneumonia: A Systematic Review and Meta-analysis of Randomized Controlled Trials, in
Chest, 2012; 142: 859–68. (R-X Yin, yinruixing@yahoo.com.cn)
* Burden of Gastrointestinal Disease in the United States: 2012 Update, in
Gastroenterology, 2012; 142: 1179–87.e3. (N. J. Shaheen, nshaheen@med.unc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 23, 2012 * Vol. 19, No. 205
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Oct. 22 issue of the Archives of Internal Medicine (2012; 172).
Drug Shortages: A policy for ethical allocation of scarce drug products is presented in a special feature (pp. 1494–9): “The number of critical medication shortages in the United States has reached an unprecedented level, requiring decisions about allocating limited drug supplies. Ad hoc decisions are susceptible to arbitrary judgments, revealing preformed biases for or against groups of people. Health care institutions lack standardized protocols for rationing scarce drugs. We describe the principles on which an ethically justifiable policy of medication allocation during critical shortages was created at our hospital. Based on supportable scientific evidence and with all clinically similar patients treated as similarly deserving of consideration, drugs were distributed according to a hierarchy of clinical need and predicted efficacy. We explain the ethical rationale for the procedures we adopted, how the policy was implemented at a large academic medical center, and more than 1 year of experience with a number of different medications. Our experience has demonstrated the feasibility and utility of formulating a rational and ethically sound policy for scarce resource allocation in an academic teaching hospital that could be used in a variety of health care settings. The method has proven to be reliable, workable, and acceptable to clinicians, staff, and patients.” (P. M. Rosoff, philip.rosoff@duke.edu)
In an invited commentary, authors agree that “clinicians should work together with pharmacists to identify and procure an acceptable substitute for their patients” and generally support use of the above approach (
pp. 1499–500): “The framework described by Rosoff and colleagues provides a useful blueprint for a rational and ethically sound policy for allocating scarce medications. We urge clinicians to participate in the development and implementation of similar policies in their own health care institutions.” (P. A. Rochon, paula.rochon@wchospital.ca)
Geographic Variation in Antibiotic Prescribing: Among ambulatory older Americans, antibiotic use varies substantially by region and season, researchers report (pp. 1465–71). Quality improvement programs could reduce unnecessary antibiotics in high-use areas, the authors conclude based on these data from the Medicare Part D program in 2007–09: “Substantial geographic and quarterly variation in outpatient antibiotic prescribing existed across regions after adjusting for population characteristics. This variation could not be explained by differences in the prevalences of the underlying conditions. For example, the ratios of the 75th percentile to the 25th percentile of adjusted annual antibiotic spending were 1.31 across states and 1.32 across regions. The highest antibiotic use was in the South, where 21.4% of patients per quarter used an antibiotic, whereas the lowest antibiotic use was in the West, where 17.4% of patients per quarter used an antibiotic (P < .01). Regardless of region, the rate of antibiotic use was highest in the first quarter (20.9% in January through March) and was lowest in the third quarter (16.9% in July through September) (P < .01).” (Y. Zhang, ytzhang@pitt.edu)

>>>PNN NewsWatch
* Perampanel (Fycompa, Eisai) was approved yesterday by FDA for treatment of partial onset seizures in patients with epilepsy ages 12 years and older. The drug is a first-in-class noncompetitive AMPA-type glutamate receptor antagonist. It acts by reducing neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors. Results from three clinical trials of 1,480 patients showed that perampanel, as an adjunctive therapy, significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. The most commonly reported adverse events in the trials were dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain. Serious or life-threatening psychiatric problems, including violent and homicidal behavior, were seen more frequently in patients treated with perampanel. These reactions are described in a boxed warning in product labeling and a Med Guide that is to accompany each prescription. Marketing of the product is deferred while DEA considers placing the drug in a controlled substance schedule.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 24, 2012 * Vol. 19, No. 206
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Oct. 24/31 issue of JAMA (2012; 308).
Neurocognitive Development & Tight Glycemic Control: Among 700 patients younger than 17 admitted to a pediatric ICU in a Belgian hospital, those treated with tight glycemic control (TGC) had similar measures of intelligence at a 3-year follow-up as those who received usual care (UC) (pp. 1641–50). Researchers used the age-adjusted Wechsler IQ scales and other cognitive measures to determine: “Sixteen percent of patients declined participation or could not be reached (n = 113), resulting in 569 patients being alive and testable at follow-up. At a median (interquartile range [IQR]) of 3.9 (3.8–4.1) years after randomization, TGC in the ICU did not affect full-scale IQ score (median [IQR], 88.0 [74.0–100.0] vs 88.5 [74.3–99.0] for UC; P = .73) and had not increased incidence of poor outcomes (death or severe disability precluding neurocognitive testing: 19% [68/349] vs 18% [63/351] with UC; risk-adjusted odds ratio, 0.93; 95% CI, 0.60–1.46; P = .72). Other scores for intelligence, visual-motor integration, and memory also did not differ between groups. Tight glucose control improved motor coordination (9% [95% CI, 0%–18%] to 20% [95% CI, 5%–35%] better, all P ≤ .03) and cognitive flexibility (19% [95% CI, 5%-33%] better, P = .02). Brief hypoglycemia evoked by TGC was not associated with worse neurocognitive outcome.” (G. Van den Berghe, greet.vandenberghe@med.kuleuven.be)
“What is the real target” in pediatric glycemic control in critical care, an editorialist asks (
pp. 1687–8): “[This study] should draw the focus of attention away from the proverbial ‘trees’ and directly to the ‘forest’—hypoglycemia is not necessarily the problem, but rather just being admitted for cardiac critical care appears to be the real issue. Future studies should build on these findings to address additional questions, such as is the global neurocognitive deficit a reflection of premorbid state and genetic disease? If this is the case, perhaps there is little that can be achieved except for improving the practice of intensive care. Alternatively, is the neurocognitive morbidity a consequence of cumulative and many different noxious agents and insults during anesthesia and postoperative intensive care? If this is the case, physicians and other caregivers now have a new target and an imperative to follow up all critically ill children who receive [pediatric] ICU care.” (R. C. Tasker, robert.tasker@childrens.harvard.edu)
Risk Factors & PAD in Men: Most risk of peripheral artery disease (PAD) in men can be accounted for by smoking, hypertension, hypercholesterolemia, and type 2 diabetes, researchers report (pp. 1660–7). In 44,985 men followed since 1986, these associations were observed: “During a median follow-up of 24.2 years (interquartile range, 20.8–24.7 years), there were 537 cases of incident PAD. Each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other 3 risk factors and confounders. The age-adjusted incidence rates were 9 (95% CI, 6–14) cases/100,000 person–years (n = 19 incident cases) for 0 risk factors, 23 (95% CI, 18–28) cases/100,000 person–years (n = 99 incident cases) for 1 risk factor, 47 (95% CI, 39–56) cases/100,000 person–years (n = 176 incident cases) for 2 risk factors, 92 (95% CI, 76–111) cases/100,000 person–years (n = 180 incident cases) for 3 risk factors, and 186 (95% CI, 141–246) cases/100,000 person–years (n = 63 incident cases) for 4 risk factors. The multivariable-adjusted hazard ratio for each additional risk factor was 2.06 (95% CI, 1.88–2.26). Men without any of the 4 risk factors had a hazard ratio of PAD of 0.23 (95% CI, 0.14–0.36) compared with all other men in the cohort. In 96% of PAD cases (95% CI, 94%–98%), at least 1 of the 4 risk factors was present at the time of PAD diagnosis. The population-attributable risk associated with these 4 risk factors was 75% (95% CI, 64%–87%). The absolute incidence of PAD among men with all 4 risk factors was 3.5/1000 person–years.” (M. M. Joosten, hpmmj@channing.harvard.edu)

>>>PNN NewsWatch
* Lists of New England Compounding Center customers and products shipped since May 21, 2012, were released Monday by FDA. A 73-page list is organized by state and lists the customer and mailing address; the other list, 345 pages long, is alphabetical by customer name and lists products shipped and addresses.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 25, 2012 * Vol. 19, No. 207
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release articles from and Oct. 25 issue of the New England Journal of Medicine (2012; 367).
Index Case of Fungal Meningitis: The case of the first patient who developed fungal meningitis associated with epidural injections of apparently contaminated methylprednisolone is presented (10.1056/NEJMoa1212292). The causative agent in this patient was Aspergillus fumigatus, rather than the Exserohilum rostratum identified more commonly in later cases, and the patient was immunocompromised. After initial antibiotic treatment for presumed community-acquired meningitis and following 2 weeks of hospitalization with treatment for A. fumigatus, the patient had “no meaningful neurologic recovery. On hospital day 15, a repeat brain MRI showed that additional cerebral and cerebellar infarcts had developed. Given the severity of the neurologic injury, the family elected not to pursue aggressive medical intervention, and life support was discontinued. The patient died on hospital day 22.” (A. C. Pettit, april.pettit@vanderbilt.edu)
In a Current Concepts article on fungal infections associated with contaminated methylprednisolone injections, authors emphasize the importance of therapeutic drug monitoring in cases of meningitis caused by a fungal species that has rarely caused human disease and for which “there is little experience in treating” (
10.1056/NEJMra1212617): “The severity of the infection, the possibility of relatively decreased antifungal susceptibility, and the concentration-dependent toxicity of voriconazole make the measurement of serum antifungal drug levels extremely important. A voriconazole trough level of 2 to 5 µg per milliliter is recommended. Unpublished data from the Fungus Testing Laboratory at the University of Texas Health Science Center at San Antonio show that in 47% of more than 15,000 samples, voriconazole levels were 1 to 5 µg per milliliter, but 14% of samples had undetectable levels, and 15% had levels of more than 5 µg per milliliter. Of 167 measurements of cerebrospinal fluid, the median voriconazole level was 2.77 µg per milliliter, but there was substantial variability.” (C. A. Kauffman, ckauff@umich.edu)
Aspirin Use, Tumor Mutation & Colorectal Cancer: Postdiagnostic use of aspirin increases survival in patients with mutated-PIK3CA colorectal cancer, researchers report, but not among patients with wild-type PIK3CA tumors (pp. 1596–606). A study of 964 patients with rectal or colon cancer from the Nurses’ Health Study and the Health Professionals Follow-up Study showed these patterns of regular aspirin use after diagnosis and mutation status: “Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer–specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P < 0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P = 0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer–specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P = 0.76 by the log-rank test; P = 0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P = 0.96 by the log-rank test; P = 0.07 for interaction).” (A. T. Chan, achan@partners.org)
Opioid Prescribing for Known Abusers: Cultural changes and profits are two of the reasons physicians prescribe opioids for known abusers, writes an author of a Perspective article (pp. 1580–1): “Countless patients come to emergency departments and doctors’ offices throughout the country every day reporting pain and receiving opioids despite known or suspected addiction. Health care providers have become de facto hostages of these patients, yet the ultimate victims are the patients themselves, who are not getting the treatment for addiction they need and deserve.” (A. Lembke)

>>>PNN NewsWatch
* Another death and nine more cases of fungal meningitis associated with use of contaminated steroid injections were reported yesterday by CDC. The count is now at 317 cases and 24 deaths in 17 states. Michigan has seen the most cases (73), while Tennessee has the second highest case count (70) and the most deaths (9).

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 26, 2012 * Vol. 19, No. 208
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Nov. issue of Diabetes Care (2012; 35).
Curcumin in Prediabetes: In 240 patients with prediabetes, 9 months of treatment with curcumin extract significantly reduced progression to type 2 diabetes mellitus (T2DM), compared with placebo (pp. 2121–7). Efficacy of curcumin, the principal curcuminoid in turmeric, was tested using markers of changes in beta-cell function (homeostasis model assessment [HOMA]-beta, C-peptide, and proinsulin/insulin), insulin resistance (HOMA-IR), and anti-inflammatory cytokine (adiponectin), with these results: “After 9 months of treatment, 16.4% of subjects in the placebo group were diagnosed with T2DM, whereas none were diagnosed with T2DM in the curcumin-treated group. In addition, the curcumin-treated group showed a better overall function of beta-cells, with higher HOMA-beta (61.58 vs. 48.72; P < 0.01) and lower C-peptide (1.7 vs. 2.17; P < 0.05). The curcumin-treated group showed a lower level of HOMA-IR (3.22 vs. 4.04; P < 0.001) and higher adiponectin (22.46 vs. 18.45; P < 0.05) when compared with the placebo group.” (S. Chuengsamarn, somlukc@hotmail.com)
Basal LY2605541 v. Insulin Glargine: Glucose control and total hypoglycemia rates were similar in a Phase II study comparing the long-acting basal insulin LY2605541 against insulin glargine (GL) (pp. 2140–7). The 12-week trial included patients with type 2 diabetes on open-label GL or LY2605541 once daily in the morning: “At 12 weeks, [fasting blood glucose (FBG)] (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (−0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: −0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001).” (S. J. Jacober, jacober_scott_j@lilly.com)
Pharmacodynamic Effects of Cilostazol, Clopidogrel in PCI: In patients with type 2 diabetes who have undergone percutaneous coronary intervention, addition of cilostazol to clopidogrel 150 mg/d provides greater platelet inhibition and avoids effects of genetic polymorphisms, a study shows (pp. 2194–7). Researchers tested cilostazol 100 mg twice daily added to standard-dose clopidogrel (75 mg/d) (TRIPLE) against double-dose clopidogrel (150 mg/d) (DOUBLE) and checked for the influence of several polymorphisms that influence cytochrome P450 and ATP-binding cassette subfamily status: “TRIPLE versus DOUBLE showed greater [absolute change in 20-µM ADP-induced maximal platelet aggregation (∆MPA20)] (22.9 ± 11.6 vs.12.7 ± 15.5%; difference, 10.2% [95% CI 4.2–16.3]; P < 0.001). Carriage of one (beta coefficient, −5.4%; P = 0.162) and two CYP2C19 loss-of-function allele(s) (−8.3%; P = 0.007) were associated with lower ∆MPA20 in DOUBLE–treated patients, but not in TRIPLE-treated patients.” (Y-H Jeong, goodoctor@naver.com)
Measuring Adherence in Diabetes: The Adherence in Diabetes Questionnaire (ADQ) provides psychometrically valid results, a study shows, particularly when used in families with children and adolescents with type 1 diabetes (pp. 2161–6). Recruited through the Danish Registry of Childhood Diabetes, 1,028 caregivers and 766 children ages 2–17 years had these results on the ADQ: “There was good internal consistency for both the youth and caregiver reports and strong agreement between the caregiver and youth reports. Higher ADQ scores, indicating better adherence, were associated with better self-efficacy, more parental support, less diabetes-related conflict, and less experience with treatment barriers. Factor analysis supported maintaining the one-factor structure of the ADQ. Higher ADQ scores were associated with lower HbA1c levels.” (L. J. Kristensen, lenej@psy.au.dk)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Oct. 29, 2012 * Vol. 19, No. 209
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Economics of Pneumococcal Vaccination in Pediatrics: Pneumococcal vaccine programs in patients aged 2 years or older are unlikely to be cost-effective unless effectiveness of the 13-valent conjugate vaccine against nonbacteremic pneumococcal pneumonia is established, an analysis shows (e6879). Conducted from the perspective of English health care providers, the report assesses patterns in quality-adjusted life–years (QALYs) and costs: “Increasing indirect protection resulting from the vaccination programme of infants using the 13 valent pneumococcal conjugate vaccine means that the burden of disease preventable by targeting high risk groups will diminish in time. Under base case assumptions—that is, no overall impact on non bacteraemic pneumonia in high risk groups and assuming the high risk vaccination programme would be launched two to three years after the infant programme—the incremental cost effectiveness ratio was estimated to be more than £30,000 (37,216 euros; $48,210) per QALY gained for most risk groups. If, however, the vaccine does not offer protection against non-bacteraemic pneumococcal pneumonia or the vaccine was introduced concomitantly with the infant 13 valent pneumococcal conjugate vaccination programme then vaccinating high risk people would (more) likely be cost effective. Sensitivity analyses showed that the cost effectiveness was particularly sensitive to assumed herd benefits and vaccine efficacy estimates.” (M. Rozenbaum, m.h.rozenbaum@rug.nl)

>>>Lancet Highlights
Source:
Oct. 27 issue of Lancet (2012; 380).
Job Strain as Risk Factor for CHD: Reducing job stress among workers could decrease the incidence of coronary heart disease, but impact would be less than “tackling of standard risk factors, such as smoking,” researchers report (pp. 1491–7). Patient records from 13 European cohort studies conducted in 1995–2006 show these effects among men and women employed at baseline: “30,214 (15%) of 197,473 participants reported job strain. In 1.49 million person–years at risk (mean follow-up 7.5 years [SD 1.7]), we recorded 2,358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1.23 (95% CI 1.10–1.37). This effect estimate was higher in published (1.43, 1.15–1.77) than unpublished (1.16, 1.02–1.32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1.31, 1.15–1.48) and 5 years (1.30, 1.13–1.50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3.4%.” (M. Kivimäki, m.kivimaki@ucl.ac.uk)

>>>PNN NewsWatch
* FDA has approved omacetaxine mepesuccinate (Synribo; Teva, Pfizer) for treating adults with chronic or accelerated phase chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Accelerated approval was based on reduction in the percentage of cells expressing the Philadelphia chromosome in 14 of 76 patients (18.4%) with a mean time to major cytogenetic response of 3.5 months. Median reduction time was 12.5 months. Adverse effects were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, weakness/fatigue, injection site reaction, and lymphopenia.

>>>PNN JournalWatch
* Genes and Coronary Artery Disease: Where Are We?, in
Journal of the American College of Cardiology, 2012; 60: 1715–21. (R. Roberts, rroberts@ottawaheart.ca)
* Second Malignant Neoplasms: Assessment and Strategies for Risk Reduction, in
Journal of Clinical Oncology, 2012; 30: 3734–45. (M. E. Wood, marie.wood@uvm.edu)
* Medications for Adolescents and Young Adults With Autism Spectrum Disorders: A Systematic Review, in
Pediatrics, 2012; 130: 717–26. (D. Dove)
* Meta-analysis of Genetic Polymorphisms in Granulomatosis With Polyangiitis (Wegener’s) Reveals Shared Susceptibility Loci With Rheumatoid Arthritis, in
Arthritis & Rheumatism, 2012; 64: 3463–71. (P. A. Monach, pmonach@bu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Oct. 30, 2012 * Vol. 19, No. 210
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Oct. Journal of Allergy and Clinical Immunology (2012; 130).
High-Dose Sublingual Immunotherapy: In 207 children with grass pollen–allergic rhinoconjunctivitis, high-dose sublingual immunotherapy (SLIT) significantly reduced symptoms and medication use (pp. 886–93.e5). Patients received high-dose grass pollen SLIT or placebo daily for 1 pre-/co-seasonal period, and results showed: “Mean changes in the area under the curve of the [symptom-medication score (SMS)] from the baseline to the first grass pollen season after the start of treatment were −212.5 for the active group and −97.8 for the placebo group (P = .0040). Rhinoconjunctivitis SMS (P = .0020) and separated symptom and medication scores were also statistically different between the 2 groups (P = .0121 and P = .0226, respectively). The number of well days and the percentage of responders were greater in the active group. Changes in allergen-specific IgE and IgG levels indicated a significant immunologic effect. The treatment was well tolerated, and no serious treatment-related events were reported.” (U. Wahn, ulrich.wahn@charite.de)
SNPs in Asthma: “Single nucleotide polymorphisms associated with both asthma and autoimmune diseases might have opposite effects on immunopathogenesis,” researchers conclude based on data from 813 patients and 1,564 controls (pp. 861–68.e7). Various minor (and in one case major) alleles in the TNFAIP3 interacting protein 1 (TNIP1) gene contributed to or protected against asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, Crohn disease, ulcerative colitis, systemic lupus erythematosus, and systemic sclerosis. (X. Li, xinli@wfubmc.edu)

>>>Health Affairs Report
Source:
Oct. issue of Health Affairs (2012; 31).
Lack of Change with CER: Authors examine reasons why comparative effectiveness research fails to improve prescribing and look for remedies (pp. 2168–75): “Despite widespread enthusiasm about the potential impact of new investments in comparative effectiveness research, recent history suggests that scientific evidence may be slow to change clinical practice. Reflecting on studies conducted over the past decade, we identify five causes that underlie the failure of many comparative effectiveness studies to alter patient care. These are financial incentives, such as fee-for-service payment, that may militate against the adoption of new clinical practices; ambiguity of study results that hamper decision making; cognitive biases in the interpretation of new information; failure of the research to address the needs of end users; and limited use of decision support by patients and clinicians. Policies that encourage the development of consensus objectives, methods, and evidentiary standards before studies get under way and that provide strong incentives for patients and providers to use resources efficiently may help overcome at least some of these barriers and enable comparative effectiveness results to alter medical practice more quickly.” (J. W. Timbie, jtimbie@rand.org)
Use of Secondary Drug Patents: Tighter controls on manufacturers’ use of secondary patents are needed, according to authors of a case study (pp. 2286–94): “Pharmaceutical manufacturers rely on patents to protect their intellectual property and often seek to extend market exclusivity for their products to maximize their return on investment. One method is by obtaining patents on features other than the original active drug ingredient, including secondary patents on alternate formulations of the drug or on methods of administration. [These] secondary patents can extend market exclusivity and thus delay generic competition, [as in the case of] two key antiretroviral drugs for the management of HIV: ritonavir (Norvir) and lopinavir/ritonavir (Kaletra). We identified 108 patents, which together could delay generic competition until at least 2028—twelve years after the expiration of the patents on the drugs’ base compounds and thirty-nine years after the first patents on ritonavir were filed. Some of the secondary patents that were reviewed were found to be of questionable inventiveness. We argue that increased transparency for existing patents, stricter patentability standards, and increased opportunities to challenge patent applications and patents could reduce inappropriate market exclusivity extensions on brand-name drugs and open the door to lower-cost generics.” (T. Amin, tahir@i-mak.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Oct. 31, 2012 * Vol. 19, No. 211
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Oct. issue of the Journal of the American Geriatrics Society (2012; 60).
Self-Help for Insomnia in Older Patients with Chronic Disease: Six consecutively provided booklets with structured advice on important components of cognitive behavioral therapy for insomnia (CBT-I) were significantly better than treatment as usual (TAU) in a group of 193 self-referred patients aged 55–87 years with long-term conditions and chronic insomnia symptoms, a study shows (pp. 1803–10). In this patient group, “symptoms of daytime fatigue may be more closely associated with disease processes than with sleep quality,” the authors conclude. The CBT-I booklets covered self-monitoring, sleep restriction, stimulus control procedures, and cognitive strategies, and results based on sleep quality, as measured by the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI), showed the following: “In the self-help group, sleep outcomes showed significant improvements after treatment (PSQI, P < .001; ISI, P < .001; sleep efficiency, P < .001) and at 3-month (PSQI, P = .002; ISI, P = .006; sleep efficiency, P = .001) and 6-month (PSQI, P = .003; ISI, P = .003; sleep efficiency, P = .001) follow-up. Effect sizes were moderate (range of adjusted Cohen d = 0.51–0.75). Treatment had no effect on levels of daytime fatigue. Most treated participants (73%) said they would recommend the self-help program to others.” (K. Morgan, k.morgan@lboro.ac.uk)

>>>Infectious Disease Report
Source:
Nov. 15 issue of Clinical Infectious Diseases (2012; 55).
Zoster Vaccine Persistence: Researchers comparing the results of two zoster vaccine studies find “evidence of the persistence of vaccine efficacy through year 5 after vaccination” but conclude that “vaccine efficacy is uncertain beyond that point” (pp. 1320–8). The Shingles Prevention Study (SPS) showed that zoster vaccine was efficacious through 4 years after vaccination, the authors note. Reported in this article are results of the follow-up Short-Term Persistence Substudy (STPS) of 7,320 vaccine and 6,950 placebo recipients from SPS. Measures of vaccine efficacy included herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ through year 7 after vaccination. Findings included the following: “In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5.” (K. Schmader, kenneth.schmader@dm.duke.edu)

>>>PNN NewsWatch
* In states affected by this week’s Superstorm Sandy, pharmacists are struggling to get back in operation so they can help patients who lost medications in the flooding and fires and those who rely on first-of-the-month refills coming up tomorrow. At least one state board of pharmacy—in New York—has obtained an emergency order allowing dispensing of up to a 5-day supply of non–controlled-substance prescription drugs without a prescription. In other storm-related news, NPR describes the dramatic nighttime evacuation of New York University Langone Med. Ctr., located just off the East River in Manhattan, during the height of the tidal surge, wind, and rain on Monday evening. Other hospitals in the New York City area also had to evacuate patients, including Mount Sinai Med. Ctr. and Memorial Sloan-Kettering Cancer Ctr.
* The case count in the
fungal meningitis outbreak associated with contaminated injectable products has reached 363 patients in 19 states, CDC said yesterday, with 28 deaths. Media reports based on state and FDA inspections of the New England Compounding Center paint a picture of years of state neglect of adequate enforcement of compounding regulations by state boards of pharmacy and unsanitary conditions in clean rooms at the facility. A second Massachusetts compounding pharmacy has also surrendered its license; news reports say patients had been receiving intravenous infusions at the pharmacy.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 1, 2012 * Vol. 19, No. 212
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 1 issue of the New England Journal of Medicine (2012; 367).
Ivermectin Lotion for Head Lice: Topical application of an ivermectin lotion significantly reduced head-louse infestations in 765 patients at days 1, 7, and 14, compared with placebo, a study shows (pp. 1687–93). A single, 10-minute, at-home, dry-hair application of 0.5% ivermectin lotion or vehicle control produced these results: “In the intention-to-treat population, significantly more patients receiving ivermectin than patients receiving vehicle control were louse-free on day 2 (94.9% vs. 31.3%), day 8 (85.2% vs. 20.8%), and day 15 (73.8% vs. 17.6%) (P < 0.001 for each comparison). The frequency and severity of adverse events were similar in the two groups.” (W. G. Ryan, wgryan@yahoo.com)
Editorialists, noting that FDA approved this ivermectin formulation in Feb. of this year, make these recommendations (
pp. 1750–2): “With good comparative-effectiveness research still lacking, indirect comparisons support the 2010 American Academy of Pediatrics recommendations to use 1% permethrin or pyrethrin insecticide as first-line therapy. If resistance in the community has been proven or live lice are present 1 day after the completion of treatment, a switch to malathion may be necessary. Other options include wet combing or treatment with dimethicone or other topical agents, depending on the availability of the agents in the country. Nit removal is useful. Ivermectin should be the last choice, whether topical (for still-infested persons) or oral (especially for mass treatment). Management should also include more frequent checking for head-louse infestation in families and schools.” (O. Chosidow)
BRAF/MEK Inhibition in BRAF V600 Melanoma: In an open-label study of 247 patients with metastatic melanoma and BRAF V600 mutations, combined dabrafenib and trametinib significantly improved progression-free survival, compared with dabrafenib monotherapy, but with increased rates of pyrexia, researchers report (pp. 1694–703). Pharmacokinetic activity and safety were first evaluated with oral dabrafenib 75 or 150 mg twice daily and trametinib 1, 1.5, or 2 mg daily in 85 patients. A total of 162 patients were then assigned to dabrafenib 150 mg twice daily plus trametinib 1 or 2 mg once daily or dabrafenib monotherapy, with these results: “Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P < 0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03).” (J. Weber, jeffrey.weber@moffitt.org)
Mumps Outbreak in Orthodox Jewish Communities: Intense, face-to-face interactions in Jewish schools for boys in New York and New Jersey contributed to an outbreak of mumps in Orthodox Jewish communities in 2009–10, according to a public health investigation (pp. 1704–13). Among 3,502 cases of mumps, 97% occurred in Orthodox Jewish people. Adolescents (27%) and males (78% of adolescents) were “disproportionately affected,” the authors note. Orchitis occurred in 120 males, including 7% of males aged 12 years or older, and rates were significantly higher among unvaccinated individuals. (A. E. Barskey, abarskey@cdc.gov)
Fracture Risk with Zoledronate in Men: In a multicenter study of 1,199 men with primary or hypogonadism-associated osteoporosis, zoledronic acid therapy significantly reduced risks of vertebral fracture, compared with placebo (pp. 1714–23). Combined with calcium and vitamin D supplements, zoledronic acid produced a 1.6% rate of new vertebral fractures, significantly below the 4.9% seen in the placebo group over a 24-month period. Fewer moderate-to-severe vertebral fractures and less height loss were also noted among patients on active therapy. (S. Boonen, steven.boonen@uz.kuleuven.ac.be)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Nov. 2, 2012 * Vol. 19, No. 213
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Nov. issue of Pharmacotherapy (2012; 32).
Methylphenidate Costs in U.S., U.K.: For boys ages 5–14 years, the amount paid by private insurance companies in the U.S. was four times higher than costs in the national health system of the U.K., according to the third in an ongoing series of articles (pp. 970–3). Information for 6,405 U.S patients and 1,405 U.K. patients in the U.K. General Practice Research Database (GPRD) and MarketScan Commercial Claims and Encounters Database show the following: “Estimated annual costs/patient in the U.S. ranged from $402 for doses of 5–10 mg to $821 for doses greater than 20 mg. In the U.K., costs ranged from $146 for doses of 5–10 mg to $661 for doses greater than 20 mg. The total annual cost of the continuous receipt of methylphenidate in the U.S. was $170,199 compared with $39,393 in the U.K.” (H. Jick, HJick@bu.edu)
The study authors, commenting on these results and their previously reported studies, comment in an editorial (
pp. 967–9): “The costs of prescription drugs incur a large burden to the U.S. economy, whether paid by private insurance companies or the government that provides this service for the military, other government employees, the elderly, and others. An important factor that is likely to contribute to the extraordinary difference in drug costs between the U.S. and the U.K. is the drug industry’s ubiquitous use of coupons and discount cards that encourage the use of brand-name drugs. The results we present here are based on reliable, inexpensive, and transparent resources that can be used to form a basis for considering public and private policy related to the cost of prescription drugs. Information on a substantial majority of drugs, including those prescribed primarily to children, can be derived from these reliable electronic data resources. They yield critical insight that can lead to improvement of policy that provides greater efficiency and large cost savings.” (H. Jick, HJick@bu.edu)
Adverse Events with Colchicine: A case–control study of patients with elevated creatine kinase (CK) levels and/or non–cancer-related blood dyscrasias supports FDA-mandated cautions placed on the first branded colchicine product in 2009 (pp. 974–80). In 2006–09, these patterns were observed among patients exposed to colchicine (cases) within 100 days of a finding of elevated CK levels and/or blood dyscrasias and matched controls: “Cases experienced a higher rate of previous colchicine exposure compared with controls (0.6% vs 0.2%, odds ratio 3.9, 95% confidence interval 1.4–10.7). In addition, cases had higher hospitalization rates (14.9% vs 5.0%, p < 0.001), higher mean chronic disease scores (2.5 vs 0.0, p < 0.001), and were more likely to have been exposed to drugs that may increase the risk of adverse events due to an interaction with a CYP3A4 inhibitor drug (6.9% vs 2.3%, p < 0.001).” (B. A. Todd, brittany.x.todd@kp.org)

>>>PNN NewsWatch
* Microbial contaminants in additional products from the New England Compounding Center were reported yesterday by CDC and FDA. Bacteria rarely associated with clinical infections were found in three lots of betamethasone and one lot of cardioplegia solution: betamethasone lot 08202012@141 (Paenibacillus pabuli/amolyticus, Bacillus idriensis, Bacillus flexus, Bacillus simplex, Lysinibacillus sp.); betamethasone lot 07032012@22 (Bacillus niabensis, Bacillus circulans); betamethasone lot 07302012@52 (Bacillus lentus, Bacillus circulans); and cardioplegia solution lot 09242012@55 (Bacillus halmapalus, Brevibacillus choshinensis).
*
Ameridose, an FDA-registered manufacturer and state-licensed pharmacy compounding company that shares management with the New England Compounding Center, has recalled all of its unexpired products to the health professional level. The list of recalled products runs 53 pages on the company’s website, and several of the injectable products contain drugs in short supply, including sodium bicarbonate, succinylcholine, atropine, bupivacaine, lidocaine, and furosemide. Instructions on returning recalled products are on the company’s website. No clinical infections associated with these products have been reported; FDA said it recommended the recall “out of an abundance of caution.” The agency requests that health professionals use the MedWatch system for reporting adverse reactions associated with Ameridose products.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 5, 2012 * Vol. 19, No. 214
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 3 issue of Lancet (2012; 380).
Gabapentin for Refractory Chronic Cough: Based on a study showing efficacy of gabapentin for treating refractory chronic cough, investigators conclude that central reflex sensitization is “a relevant mechanism” in this condition (pp. 1583–9). Participants in the trial were adults with refractory chronic cough of more than 8 weeks’ duration and no active respiratory disease or infection. Gabapentin in doses up to 1,800 mg daily or placebo for 10 weeks showed these results: “62 patients were randomly assigned to gabapentin (n=32) or placebo (n=30) and ten patients withdrew before the study end. Gabapentin significantly improved cough-specific quality of life compared with placebo (between-group difference in [Leicester cough questionnaire] score during treatment period 1.80, 95% CI 0.56–3.04; p = 0.004; number needed to treat of 3.58). Side-effects occurred in ten patients (31%) given gabapentin (the most common being nausea and fatigue) and three (10%) given placebo.” (N. M. Ryan, nicole.ryan@newcastle.edu.au)
Dengue Vaccine in Schoolchildren: In a Phase IIb, proof-of-concept trial, Thai schoolchildren responded to a recombinant, live-attenuated, tetravalent dengue vaccine without undue safety concerns, providing the first evidence that a safe vaccine against the disease is possible (pp. 1559–67). Children aged 4–11 years randomly received three injections of dengue vaccine or control injections (rabies vaccine or placebo), with these results: “4,002 participants were assigned to vaccine (n = 2,669) or control (n = 1,333). 3,673 were included in the primary analysis (2,452 vaccine, 1,221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30.2% (95% CI –13.4 to 56.6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose.” (D. Wallace, derek.wallace@sanofipasteur.com)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Dietary Fish, Omega-3s, & Cerebrovascular Disease: Long- chain omega-3 fatty acids are just one of several nutrients abundant in fish that likely play a role in primary and secondary prevention of cerebrovascular disease, researchers report (e6698). Results of a systematic review and meta-analysis of 26 prospective cohort studies and 12 randomized controlled trials of 794,000 patients and 34,817 cerebrovascular outcomes showed that circulating levels of omega-3 fatty acids were not associated with cerebrovascular disease: “In cohort studies comparing categories of fish intake the pooled relative risk for cerebrovascular disease for 2–4 servings a week versus ≤1 servings a week was 0.94 (95% confidence intervals 0.90 to 0.98) and for ≥5 servings a week versus 1 serving a week was 0.88 (0.81 to 0.96). The relative risk for cerebrovascular disease comparing the top thirds of baseline long chain omega 3 fatty acids with the bottom thirds for circulating biomarkers was 1.04 (0.90 to 1.20) and for dietary exposures was 0.90 (0.80 to 1.01). In the randomised controlled trials the relative risk for cerebrovascular disease in the long chain omega 3 supplement compared with the control group in primary prevention trials was 0.98 (0.89 to 1.08) and in secondary prevention trials was 1.17 (0.99 to 1.38). For fish or omega 3 fatty acids the estimates for ischaemic and haemorrhagic cerebrovascular events were broadly similar.” (O. H. Franco, .franco@erasmusmc.nl">o.franco@erasmusmc.nl)

>>>PNN JournalWatch
* Sucrose for Procedural Pain Management in Infants, in
Pediatrics, 2012; 130: 918–25. (D. Harrison)
* Synaptic Mechanisms Underlying Rapid Antidepressant Action of Ketamine, in
American Journal of Psychiatry, 2012; 169: 1150–6. (E. T. Kavalali, ege.kavalali@utsouthwestern.edu)
* Calcific Aortic Stenosis: A Disease of the Valve and the Myocardium, in
Journal of the American College of Cardiology, 2012; 60: 1854–63. (M. R. Dweck)
* Clinical Practice Guideline for the Diagnosis and Management of Group A Streptococcal Pharyngitis: 2012 Update by the Infectious Diseases Society of America, in
Clinical Infectious Diseases, 2012; 55: e86–102. (S. T. Shulman, sshulman@northwestern.edu)
* Local Antimicrobial Administration for Prophylaxis of Surgical Site Infections, in
Pharmacotherapy, 2012; 32: 1006–19. (P. Huiras, paul.huiras@bmc.org)
* Aspirin for Primary Prevention of Cardiovascular Disease Events, in
Pharmacotherapy, 2012; 32: 1020–35. (C. W. Nemerovski, CNEMERO1@hfhs.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 6, 2012 * Vol. 19, No. 215
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 6 issue of the Annals of Internal Medicine (2012; 157).
Sulfonylureas v. Metformin Monotherapy in Type 2 Diabetes: In a comparative effectiveness analysis of newly initiated treatment of type 2 diabetes, patients receiving sulfonylureas had a significantly greater chance of having adverse cardiovascular disease (CVD) outcomes than did those who began on metformin (pp. 601–10). Data from the National Veterans Health Administration databases and Medicare files showed these patterns for CVD outcomes (acute myocardial infarction and stroke) and death: “Among 253,690 patients initiating treatment (98,665 with sulfonylurea therapy and 155,025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1,000 person–years in sulfonylurea users and 10.4 per 1,000 person–years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1,000 person–years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score–matched cohort analysis; and in sensitivity analyses.” (C. L. Roumie, christianne.roumie@vanderbilt.edu)
Medicine is just beginning to emerge “from the Dark Ages” when it comes to cardiovascular effects of antidiabetic drugs, writes an editorialist (
pp. 671–2). After describing three successive shocks required to get cardiovascular (CV) outcomes considered by FDA when approving new agents for diabetes (the near-approval of muraglitazar in 2005 despite CV concerns, meta-analysis of rosiglitazone safety data that became available after court settlements in 2007, and the 2008 NIH termination of an intensification trial after increased CV mortality was observed in aggressively treated patients), the author closes with an analysis of sulfonylureas: “How might sulfonylureas increase adverse CV outcomes? One theory focuses on their adverse effects on ischemic preconditioning, an adaptive mechanism that allows the myocardium to resist necrosis after intermittent periods of ischemia. Another hypothesis relates to sulfonylurea-induced hypoglycemia, which theoretically may result in myocardial ischemia. Regardless of mechanism, this scientific question demands a definitive answer. In the absence of an industry-sponsored study, public health authorities should conduct such a clinical trial. With more than two thirds of diabetic patients dying of CV causes and millions of patients currently receiving sulfonylureas, this question must be resolved with high-quality evidence. Continued darkness is not an acceptable option.” (S. E. Nissen, nissens@ccf.org)
Obama v. Romney: As Americans go to the polls, three authors explore the prospects for health care over the next 4 years under a Romney or second Obama administration (pp. 665–6, D. Blumenthal, dblumenthal@partners.org; pp. 667–8, R. A. Berenson, rberenson@urban.org; pp. 669–70, G. R. Wilensky, gwilensky@projecthope.org). Berenson, the least partisan of the trio, notes an important aspect in health care economics ignored thus far by both Democrats and Republicans: “Although some laud the promise of Big Medicine built on mega-hospital systems that absorb physician practices to provide missing consistency and reliability in the provision of health care services, others are less sanguine about this prospect—in part because monopoly behavior raises prices but also because of uncertainty about how professionalism would fare in an overtly commercially oriented health system. Yet, given the current trends of hospital consolidations and acquisitions of physician practices, it is likely that Big Medicine will come to dominate U.S. health care, like it or not. So far, the developing, divergent views on Big Medicine have not divided into polarized, red and blue positions. That provides some hope that policymakers will actually explore the merits of Big Medicine in a bipartisan manner to help shape its evolution to serve the public interest, as its advocates wish.”

>>>PNN NewsWatch
* With U.S. Senate committee hearings on pharmacy compounding set for Nov. 15, APhA has responded to a series of questions from the Senators. The fungal meningitis outbreak “was not the result of poor compounding,” APhA wrote, but “apparent large-scale, unauthorized and unlicensed manufacturing.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 7, 2012 * Vol. 19, No. 216
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Online article from and Nov. 7 issue of JAMA (2012; 308).
Multivitamins & Male Cardiovascular Disease: In a study of 14,461 male U.S. physicians over more than a decade, daily multivitamins had no significant effect on major cardiovascular disease (CVD) events, myocardial infarction (MI), stroke, or CVD mortality, researchers report (pp. 1751–60). The Physicians’ Health Study II showed these results from 1997 through June 2011: “During a median follow-up of 11.2 (interquartile range, 10.7–13.3) years, there were 1,732 confirmed major cardiovascular events. Compared with placebo, there was no significant effect of a daily multivitamin on major cardiovascular events (11.0 and 10.8 events per 1,000 person–years for multivitamin vs placebo, respectively; hazard ratio [HR], 1.01; 95% CI, 0.91–1.10; P = .91). Further, a daily multivitamin had no effect on total MI (3.9 and 4.2 events per 1,000 person–years; HR, 0.93; 95% CI, 0.80–1.09; P = .39), total stroke (4.1 and 3.9 events per 1,000 person–years; HR, 1.06; 95% CI, 0.91–1.23; P = .48), or CVD mortality (5.0 and 5.1 events per 1,000 person–years; HR, 0.95; 95% CI, 0.83–1.09; P = .47). A daily multivitamin was also not significantly associated with total mortality (HR, 0.94; 95% CI, 0.88–1.02; P = .13). The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD (P = .62 for interaction).” (H. D. Sesso, hsesso@hsph.harvard.edu)
“Robust data from multiple trials clearly confirm that CVD cannot be prevented or treated with vitamins,” writes an editorialist (
pp. 1802–3). “Nonetheless, many people with heart disease risk factors or previous CVD events lead sedentary lifestyles, eat processed or fast foods, continue to smoke, and stop taking lifesaving prescribed medications, but purchase and regularly use vitamins and other dietary supplements, in the hope that this approach will prevent a future myocardial infarction or stroke. This distraction from effective CVD prevention is the main hazard of using vitamins and other unproven supplements. The message needs to remain simple and focused: CVD is largely preventable, and this can be achieved by eating healthy foods, exercising regularly, avoiding tobacco products, and, for those with high risk factor levels or previous CVD events, taking proven, safe, and effective medications.” (E. M. Lonn, eva.lonn@phri.ca)
High-Dose Dexamethasone During Cardiac Surgery: Compared with placebo, dexamethasone 1 mg/kg as a single intraoperative dose during cardiac surgery had no significant effect on the 30-day incidence of a composite of death, myocardial infarction, stroke, renal failure, or respiratory failure (pp. 1761–7). The study included 4,494 adults at 8 cardiac surgical centers in the Netherlands, Results showed: “A total of 157 patients (7.0%) in the dexamethasone group and 191 patients (8.5%) in the placebo group reached the primary study end point (relative risk, 0.83; 95% CI, 0.67–1.01; absolute risk reduction, −1.5%; 95% CI, −3.0% to 0.1%; P = .07). Dexamethasone was associated with reductions in postoperative infection, duration of postoperative mechanical ventilation, and lengths of intensive care unit and hospital stays. In contrast, dexamethasone was associated with higher postoperative glucose levels.” (J. M. Dieleman, s.dieleman@umcutrecht.nl)
Platelet Function With Medically Managed ACS: Prasugrel produced significantly lower platelet reactivity than clopidogrel in a subgroup of 2,564 patients from the TRILOGY ACS trial (doi: 10.1001/jama.2012.17312). Based on measurements of the P2Y12 reaction units in patients with medically managed unstable angina or non–ST-segment elevation myocardial infarction, researchers found the drugs comparable clinically: “No significant differences existed between prasugrel vs clopidogrel in the occurrence of [a composite of cardiovascular death, myocardial infarction, or stroke] through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.” (M. Roe, matthew.roe@duke.edu)

>>>PNN NewsWatch
* Republican governors in 30 states will have a large impact on implementation of the Affordable Care Act during Pres. Barack Obama’s second term, reports Kaiser Health News. Southern states that delayed now have only a few days to commit to setting up health exchanges with or without the federal government.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 8, 2012 * Vol. 19, No. 217
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Online article and Nov. 8 issue of the New England Journal of Medicine (2012; 367).
Regulating Pharmacy Compounding: After recounting the history of Section 503A(c) of the FDA statutes—passed by Congress in 1997 but partially invalidated in the 2002 Supreme Court decision Thompson v. Western States Medical Center—the author of a Perspective article reaches this conclusion about federal oversight of compounding pharmacies (DOI: 10.1056/NEJMp1212667): “Contamination is only one of five categories of risk associated with compounding pharmacies; the others are subpotency, superpotency, overmedication, and medication replacement. Other policy levers that may be needed include enhanced transparency for state-level regulation, mandatory disclosures to physicians and patients, mandatory reporting of adverse events, user fees to support oversight, clear FDA authority to register and inspect nontraditional compounding pharmacies, enhanced incentives for internal whistleblowers, and modification of reimbursement rules to blunt the economic incentives driving industrial-scale compounding.
“Fungal contamination at [New England Compounding Center] has sickened more than 400 patients and killed at least 29. But it’s important to note that many patients received these sterile injections for back and joint pain, a procedure that lacks high-quality evidence of efficacy. These problems cannot be laid entirely at the feet of compounders when clinicians persist in clinical practices despite weak evidence of efficacy.” (K. Outterson)
Trastuzumab Emtansine for Advanced Breast Cancer: In 991 patients with previously treated HER2-positive advanced breast cancer, trastuzumab emtansine (T-DM1) significantly improved progression-free and overall survival with a good safety profile, researchers report (pp. 1783–91). T-DM1 incorporates trastuzumab and the microtubule-inhibitory agent DM1, which has cytotoxic activity. Patients had failed courses of trastuzumab and a taxane when they were randomized to T-DM1 or lapitinib plus capecitabine. Results showed: “Median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P < 0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P < 0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P < 0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar–plantar erythrodysesthesia were higher with lapatinib plus capecitabine.” (S. Verma, sunil.verma@sunnybrook.ca)
T-DM1 is under FDA review for women with advanced breast cancer that has progressed after treatment with trastuzumab, an editorialist notes, adding (
pp. 1847–8): “In view of the efficacy and excellent safety profile of this agent, the ongoing randomized trial evaluating use in the first-line setting (ClinicalTrials.gov number, NCT01120184), and the many other studies examining trastuzumab emtansine across a broad range of disease contexts, it seems likely that a major shift in our basic approach to the treatment of HER2-positive cancers is imminent. This new approach will almost certainly incorporate trastuzumab emtansine, as well as a more general appreciation and acceptance of the use of [antibody–drug conjugates (ADCs)] in the routine care of patients with solid-tumor cancers. The development of preclinical and clinical data on ADCs will provide guidance for the next generation of these agents, with better targeting and improved linkers that may carry many more drug molecules. The largest remaining challenge may be in identifying the most specific and appropriate tumor-cell surface proteins to target. With the understanding that ADCs are chemotherapeutics that will be used in combination treatment regimens, the time may have arrived for this technology to become a major contributor to improved cancer therapy.” (B. A. Teicher)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 9, 2012 * Vol. 19, No. 218
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
Nov. issue of the American Journal of Psychiatry (2012; 169).
Prenatal Antidepressants v. Maternal Depression: Compared with children born to healthy, nondepressed mothers, those exposed to venlafaxine and SSRIs during pregnancy had significantly lower intelligence scores at 3 years to 6 years, 11 months of age, researchers report, and children exposed to untreated or treated maternal depression in utero had more behavioral problems (pp. 1165–74). In a cohort study, prospectively collected data on children born to 240 mothers who took venlafaxine or SSRIs during pregnancy, were depressed but not treated during pregnancy, or were nondepressed and healthy during pregnancy showed these trends: “The children exposed to venlafaxine, SSRIs, and maternal depression during pregnancy had similar full-scale IQs (105, 105, and 108, respectively). The IQs of the venlafaxine and SSRI groups were significantly lower than that of the children of nondepressed mothers (112). The three groups exposed to maternal depression had consistently, but nonsignificantly, higher rates of most problematic behaviors than the children of nondepressed mothers. Severity of maternal depression in pregnancy and at testing predicted child behavior. Maternal IQ and child sex predicted child IQ. Antidepressant dose and duration during pregnancy did not predict any cognitive or behavioral outcome.” (I. Nulman, irena.nulman@sickkids.ca)
“Health care providers should keep in mind that in order to prescribe antidepressants during pregnancy, the indication must be compelling,” an editorialist writes (
pp. 1130–2). “Not only is it crucial to establish an axis I diagnosis, it is also important to assess the degree of distress and the burden of illness that the pregnant woman is experiencing. It is also paramount to have a frank discussion with the patient (and whenever possible, with her partner in attendance) on the pros and cons of using antidepressants during pregnancy based on the most recent available evidence and to obtain her or their consent.” (M. Steiner, mst@mcmaster.ca)

>>>Pediatrics Highlights
Source:
Nov. issue of Pediatrics (2012; 130).
Cord Blood Vitamin D & Infant Allergies: Reduced vitamin D status during pregnancy increases infants’ chances of developing eczema during their first year of life, according to a study of cord blood (CB) 25-hydroxyvitamin D3 (25[OH]D3) concentrations (pp. e1128–35). For 231 high-risk infants, CB vitamin D levels, maternal vitamin D intake, and allergic diseases during infancy showed these relationships: “Maternal intake of supplemental vitamin D was significantly correlated with CB 25(OH)D3 concentration (rho = 0.244, P = .003), whereas dietary vitamin D did not influence CB levels. There was significant seasonal variation in CB 25(OH)D3 concentration suggesting that sunlight exposure was an important determinant. Lower CB vitamin D status was observed in infants that developed eczema (P = .018), and eczema was significantly more likely in those with concentrations <50 nmol/L in comparison with those with concentrations ≥75 nmol/L (odds ratio 2.66; 95% confidence interval 1.24–5.72; P = .012). This association remained significant after adjustment for multiple confounding factors. The associations between CB 25(OH)D3 concentration and allergen sensitization, immunoglobulin E-mediated food allergy, and eczema severity (SCORing Atopic Dermatitis) were not significant.” (A. P. Jones)
Physician Attitudes Toward Vaccinations at School: In a Colorado survey, family physicians and pediatricians supported school-located vaccination programs for their publicly insured patients but not for privately insured ones (pp. 887–96). “Lesser support for vaccination of their privately insured patients and concerns regarding attendance at well-child visits suggests the perceived financial impact from school-located vaccination is a barrier and merits additional examination,” study authors conclude. (E. V. McCormick)

>>>PNN NewsWatch
* Tofacitinib (Xeljanz, Pfizer), a Janus kinase inhibitor, has been approved by FDA for treatment of adults with moderately to severely active rheumatoid arthritis. The orally active agent is approved for monotherapy and in combination with methotrexate or other nonbiologic DMARDs.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 12, 2012 * Vol. 19, No. 219
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2012; 345).
Bipolar Disorder During Pregnancy: Treated or not, bipolar disorder during pregnancy is associated with increased risks of adverse pregnancy outcomes, according to a Swedish population-based cohort study (e7085). Of 332,137 women delivering in 2006–09, those with a history of at least two bipolar diagnoses showed these patterns when treated (n = 320) or untreated (n = 554): “Of the untreated women, 30.9% (n = 171) were induced or had a planned caesarean delivery compared with 20.7% (n = 68,533) without bipolar disorder (odds ratio 1.57, 95% confidence interval 1.30 to 1.90). The corresponding values for the treated women were 37.5% (n = 120) (2.12, 1.68 to 2.67). The risks of preterm birth in both treated and untreated women were increased by 50%. Of the untreated women, 3.9% (n = 542) had a microcephalic infant compared with 2.3% (324,844) of the women without bipolar disorder (1.68, 1.07 to 2.62). The corresponding values for the treated women were 3.3% (n = 311) (1.26, 0.67 to 2.37). Similar trends were observed for risks of infants being small for gestational age infants for weight and length. Among infants of untreated women, 4.3% (n = 24) had neonatal hypoglycaemia compared with 2.5% (n = 8,302) among infants of women without bipolar disorder (1.51, 1.04 to 2.43), and 3.4% (n = 11) of the treated women (1.18, 0.64 to 2.16). The analyses of variation in outcomes did not support any significant differences between treated and untreated women.” (R. Bodén, robert.boden@neuro.uu.se)
Cardiovascular Events With Varenicline: Compared with bupropion, varenicline produced no increased risk of major cardiovascular events during use for smoking cessation, researchers report (e7176). In a nationwide cohort study from Denmark in 2007–10, registry data showed: “There were 57 major cardiovascular events among varenicline users (6.9 cases per 1,000 person years) compared with 60 events among bupropion users (7.1 cases per 1,000 person years); the hazard ratio for any major event was 0.96 (95% confidence interval 0.67 to 1.39). Varenicline use was not associated with an increased risk of acute coronary syndrome (1.20, 0.75 to 1.91), ischaemic stroke (0.77, 0.40 to 1.48), and cardiovascular death (0.51, 0.13 to 2.02). In subgroup analyses, the risk of any major cardiovascular event was not significantly different between patients with and without a history of cardiovascular disease (1.24 (0.72 to 2.12) and 0.83 (0.51 to 1.36), respectively; P = 0.29).” (H. Svanström, htr@ssi.dk)
Melatonin in Childhood Neurodevelopmental Disorder: In 146 children with neurologic an developmental disorders, melatonin 0.5–12 mg before bedtime produced faster onset of sleep but earlier waking times, according to results of a randomized controlled trial (e6664): “Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n = 110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P = 0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.” (P. Gringras, Paul.Gringras@gstt.nhs.uk)

>>>PNN JournalWatch
* Associations of Kidney Disease Measures With Mortality and End-Stage Renal Disease in Individuals With and Without Hypertension: A Meta-Analysis, in
Lancet, 2012; 380: 1649–61. (J. Coresh, ckdpc@jhmi.edu)
* Associations of Kidney Disease Measures With Mortality and End-Stage Renal Disease in Individuals With and Without Diabetes: A Meta-Analysis, in
Lancet, 2012; 380: 1662–73. (J. Coresh, ckdpc@jhmi.edu)
* Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, in
Chest, 2012; 142: e1S–e111S. (R. P. Baughman, bob.Baughman@uc.edu)
* Novel Antiinflammatory Therapies for COPD, in
Chest, 2012; 142: 1300–7. (N. J. Gross, grossnicholas1@gmail.com)
* Role of Policy and Government in the Obesity Epidemic, in
Circulation, 2012; 126: 2345–52. (N. L. Novak, nicole.l.novak@gmail.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 13, 2012 * Vol. 19, No. 220
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 12 issue of Archives of Internal Medicine (2012; 172).
Combination New-Generation Oral Anticoagulation With Antiplatelet Therapy: The increased rate of major bleeding events when anti-Xa or direct thrombin inhibitors are combined with antiplatelet therapy in patients after acute coronary syndrome (ACS) “might offset all ischemic benefits,” according to a systematic review and meta-analysis (pp. 1537–45). The authors write: “For the period January 1, 2000, through December 31, 2011, we identified 7 prospective randomized placebo-controlled clinical trials that met the study criteria, involving 31,286 patients. Based on the pooled results, the use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an ACS was associated with a dramatic increase in major bleeding events (odds ratio, 3.03; 95% CI, 2.20–4.16; P < .001). Significant but moderate reductions in the risk for stent thrombosis or composite ischemic events were observed, without a significant effect on overall mortality. For the net clinical benefit, treatment with new-generation oral anticoagulant agents provided no advantage over placebo (odds ratio, 0.98; 95% CI, 0.90–1.06; P = .57).” (A. Komócsi, andras.komocsi@aok.pte.hu)
The role of novel oral anticoagulants (NOACs) in treatment of ACS is explored in an accompanying commentary (
pp. 1546–7): “Would NOACs be useful for specific populations of patients with ACS? The meta-analysis by Komócsi et al explored subgroups by percentage of use of dual antiplatelet therapy and showed no significant differences across subpopulations. Trials included in the meta-analysis were not performed among patients with specific types of ACS; therefore, it is unknown whether the effects of NOACs differ among patients with unstable angina, ST-elevation MI, and non–ST-elevation MI. Also, no data are available to date on the use of NOACs in patients with ACS taking prasugrel or ticagrelor, undergoing percutaneous coronary interventions, or having indications for anticoagulation (eg, cancer, mitral stenosis, mechanical prosthetic valves, or prior stroke without atrial fibrillation). Trials are needed to evaluate the use of NOACs in these specific populations with ACS.” (A. V. Hernandez, adrianhernandezdiaz@gmail.com)
Zonisamide for Weight Reduction: In adults with obesity, zonisamide 400 mg daily “moderately enhanced weight loss achieved with diet and lifestyle counseling but had a high incidence of adverse events,” researchers report (pp. 1557–64). In the 1-year trial of patients with mean body mass index of 37.6, zonisamide or placebo plus dietary and lifestyle counseling produced these results: “Of the 225 randomized patients, 218 (96.9%) provided 1-year follow-up assessments. Change in body weight was −4.0 kg (95% CI, −5.8 to −2.3 kg; least squares mean, −3.7%) for placebo, −4.4 kg (−6.1 to −2.6 kg; −3.9%; P = .79 vs placebo) for 200 mg of zonisamide, and −7.3 kg (−9.0 to −5.6 kg; −6.8%; P = .009 vs placebo) for 400 mg of zonisamide. In the categorical analysis, 23 (31.1%) assigned to placebo, 26 (34.2%; P = .72) assigned to 200 mg of zonisamide, and 41 (54.7%; P = .007) assigned to 400 mg of zonisamide achieved 5% or greater weight loss; for 10% or greater weight loss, the corresponding numbers were 6 (8.1%), 17 (22.4%; P = .02), and 24 (32.0%; P < .001). Gastrointestinal, nervous system, and psychiatric adverse events occurred at a higher incidence with zonisamide than with placebo.” (K. M. Gadde, kishore.gadde@duke.edu)
Angioedema With RAS Agents: Among agents that target the renin–angiotensin–aldosterone system, ACE inhibitors and aliskiren are associated with 3-fold increases in risk of angioedema, compared with beta-blockers, a retrospective cohort study shows (pp. 1582–9). “Cumulative incidences per 1,000 persons were 1.79 (95% CI, 1.73–1.85) cases for ACEIs, 0.62 (95% CI, 0.55–0.69) cases for ARBs, 1.44 (95% CI, 0.58–2.96) cases for aliskiren, and 0.58 (95% CI, 0.54–0.61) cases for beta-blockers,” the authors report. “The incidence rates per 1,000 person–years were 4.38 (95% CI, 4.24–4.54) cases for ACEIs, 1.66 (95% CI, 1.47–1.86) cases for ARBs, 4.67 (95% CI, 1.88–9.63) cases for aliskiren, and 1.67 (95% CI, 1.56–1.78) cases for beta-blockers. Compared with the use of beta-blockers, the adjusted hazard ratios were 3.04 (95% CI, 2.81–3.27) for ACEIs, 1.16 (95% CI, 1.00–1.34) for ARBs, and 2.85 (95% CI, 1.34–6.04) for aliskiren.” (S. Toh, darrentoh@post.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 14, 2012 * Vol. 19, No. 221
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 14 issue of JAMA (2012; 308).
Multivitamins for Prevention of Male Cancer: In the 14,461-patient Physicians’ Health Study II, daily multivitamin supplements “modestly but significantly reduced the risk of total cancer,” researchers report (pp. 1871–80). Participants, all men aged 50 years or older, began taking daily multivitamins in 1997 and continued through June 2011. Results showed: “During a median (interquartile range) follow-up of 11.2 (10.7–13.3) years, there were 2,669 men with confirmed cancer, including 1,373 cases of prostate cancer and 210 cases of colorectal cancer. Compared with placebo, men taking a daily multivitamin had a statistically significant reduction in the incidence of total cancer (multivitamin and placebo groups, 17.0 and 18.3 events, respectively, per 1,000 person–years; hazard ratio [HR], 0.92; 95% CI, 0.86–0.998; P = .04). There was no significant effect of a daily multivitamin on prostate cancer (multivitamin and placebo groups, 9.1 and 9.2 events, respectively, per 1,000 person–years; HR, 0.98; 95% CI, 0.88–1.09; P = .76), colorectal cancer (multivitamin and placebo groups, 1.2 and 1.4 events, respectively, per 1,000 person–years; HR, 0.89; 95% CI, 0.68–1.17; P = .39), or other site-specific cancers. There was no significant difference in the risk of cancer mortality (multivitamin and placebo groups, 4.9 and 5.6 events, respectively, per 1,000 person–years; HR, 0.88; 95% CI, 0.77–1.01; P = .07). Daily multivitamin use was associated with a reduction in total cancer among 1,312 men with a baseline history of cancer (HR, 0.73; 95% CI, 0.56–0.96; P = .02), but this did not differ significantly from that among 13,329 men initially without cancer (HR, 0.94; 95% CI, 0.87–1.02; P = .15; P for interaction = .07).” (J. M. Gaziano, jmgaziano@partners.org)
It may be “too soon to tell men that vitamins prevent cancer,” editorialists write (
pp. 1916–7): “Before drawing a definitive conclusion from this study that daily multivitamins reduce the risk of cancer in men, physicians and other readers must be convinced that the observed treatment effect is real and thus is likely to be reproduced in future experience, rather than a random event that is unlikely to recur. Making this determination requires considering the details of the study design, the biological foundation for the observed effect, prior results from similar efforts, the apparent strength of the evidence, the consistency of the results with known aspects of the diseases in question, and overt and hidden multiplicities. That assessment seems to point to remaining uncertainty regarding the effect of multivitamin supplementation on the risk of cancer in men.” (R. J. Lewis, roger@emedharbor.edu)
Nucleoside Analogues & Liver Cancer Recurrence: Recurrence of hepatocellular carcinoma (HCC) was less common among patients treated with nucleoside analogues, according a cohort study of 4,569 patients in Taiwan (pp. 1906–13): “The treated cohort had a higher prevalence of liver cirrhosis when compared with the untreated cohort (48.6% vs 38.7%; P < .001), but lower risk of HCC recurrence (n = 106 [20.5%] vs n = 1,765 [43.6%]; P < .001), and lower overall death (n = 55 [10.6%] vs n = 1,145 [28.3%]; P < .001). After adjusting for competing mortality, the treated cohort had a significantly lower 6-year HCC recurrence rate (45.6%; 95% CI, 36.5%–54.6% vs untreated, 54.6%; 95% CI, 52.5%-56.6%; P < .001). Six-year overall mortalities for treated cohorts were 29.0% (95% CI, 20.0%–38.0%) and for untreated 42.4% (95% CI, 40.0%–44.7%; P < .001).” (C-Y Wu, chun@vghtc.gov.tw)
Preventing Fatal Opioid Overdoses: Authors suggest a comprehensive approach to reducing America’s opioid overdose deaths (pp. 1863–4). “Federal government response has focused primarily on monitoring and securing the drug supply,” the group notes before adding other roles for the government, communities, and health professionals. “Federal agencies are uniquely situated to address national public health crises through increasing awareness, funding, and coordinated action. Community-based organizations, state and local health departments, and professional societies have taken the lead in developing, implementing, and publicizing overdose education and naloxone distribution as a component in a comprehensive response to this veritable epidemic. The federal government should actively support research and programmatic action on overdose education and naloxone access.” (L. Beletsky, l.beletsky@neu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 15, 2012 * Vol. 19, No. 222
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 15 issue of the New England Journal of Medicine (2012; 367).
Reinfection & Relapse in Recurrent Lyme Disease: Patients who relapse after being treated as recommended for Lyme disease more likely have new infections rather relapses, a study shows (pp. 1883–90). Patients who developed subsequent episodes of erythema migrans were included in the analysis, which looked for these genotypes of the gene-encoding outer-surface protein C (ospC) of Borrelia burgdorferi strains in cultures of skin or blood specimens: “B. burgdorferi isolates obtained from 17 patients who received a diagnosis of erythema migrans between 1991 and 2011 and who had 22 paired episodes of this lesion (initial and second episodes) were available for testing. The ospC genotype was found to be different at each initial and second episode. Apparently identical genotypes were identified on more than one occasion in only one patient, at the first and third episodes, 5 years apart, but different genotypes were identified at the second and fourth episodes.” (R. B. Nadelman, robert_nadelman@nymc.edu)
Patient-advocacy groups “promote months or years of antibiotic therapy for ‘chronic Lyme disease,’” an editorialist notes, rather than the shorter courses recommended by the Infectious Diseases Society of America (
pp. 1950–1): “Chronic Lyme disease has become a common diagnosis for medically unexplained pain or neurocognitive or fatigue symptoms, even when there is little or no evidence of previous B. burgdorferi infection.… As concluded by the Infectious Diseases Society of America, there is no evidence of persistent B. burgdorferi infection in human patients after recommended courses of antibiotic therapy. Although B. burgdorferi infection may persist for years in untreated patients, the weight of evidence is strongly against persistent infection as the explanation for persistent symptoms in antibiotic-treated patients with Lyme disease.” (A. C. Steere)
Atorvastatin & PCSK9 Antibody in Hypercholesterolemia: Added to low doses of atorvastatin, a monoclonal antibody that increases recycling of LDL receptors and reduces LDL cholesterol levels achieves more lowering of LDL cholesterol levels than does increasing the atorvastatin dose to 80 mg, researchers report (pp. 1891–900). In a Phase II trial, 92 patients with LDL cholesterol levels of 100 mg/dL or more during treatment with atorvastatin 10 mg daily had these changes when SAR236553 was added to their regimens or their atorvastatin doses were increased to 80 mg daily for 2 weeks: “The least-squares mean (± SE) percent reduction from baseline in LDL cholesterol was 73.2 ± 3.5 with 80 mg of atorvastatin plus SAR236553, as compared with 17.3 ± 3.5 with 80 mg of atorvastatin plus placebo (P < 0.001) and 66.2 ± 3.5 with 10 mg of atorvastatin plus SAR236553. All the patients who received SAR236553, as compared with 52% of those who received 80 mg of atorvastatin plus placebo, attained an LDL cholesterol level of less than 100 mg per deciliter, and at least 90% of the patients who received SAR236553, as compared with 17% who received 80 mg of atorvastatin plus placebo, attained LDL cholesterol levels of less than 70 mg per deciliter (1.8 mmol per liter).” (E A. Stein, esteinmrl@aol.com)
Hydroxyethyl Starch for Fluid Resuscitation: In the intensive-care unit, patients resuscitated with 6% hydroxyethyl starch (with a molecular weight of 130 kD and a molar substitution ratio of 0.4) had similar 90-day mortality rates as those given saline, according to a study of 3,315 patients (pp. 1901–11; J. A. Myburgh, jmyburgh@georgeinstitute.org.au).

>>>PNN NewsWatch
* A bill in Congress that would increase federal regulation of large-scale compounding pharmacies gained support during a day of emotional testimony on Wednesday before a House oversight committee, pharmacist.com reports. The bill, introduced by Rep. Ed Markey, a Massachusetts Democrat, provides for federal regulation of operations that are engaging in manufacturing. It exempts compounding pharmacies dispensing specific products to specific patients and following USP standards. Pharmacy organizations are expected to testify today before a Senate panel looking into the fungal outbreak associated with products from the New England Compounding Center.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 16, 2012 * Vol. 19, No. 223
Providing news and information about medications and their proper use

>>>Nephrology Highlights
Source:
Dec. American Journal of Kidney Diseases (2012; 60).
Mortality & Influenza, Pneumococcal Vaccination in Dialysis Patients: At 1,033 dialysis facilities, investigators found significant and independent benefits of influenza and pneumococcal vaccination on survival of 36,966 patients on dialysis treatment (pp. 959–65). Study participants had at least 1 year of dialysis treatment at the end of 2005. Adjusted odds ratio for all-cause mortality was 0.79 (CI, 0.72–0.86) for influenza vaccine alone and 0.70 (0.62–0.78) for coadministration of influenza and pneumococcal vaccines, suggesting synergism. (T. C. Bond, tcbphd2@gmail.com)
While lauding these authors for conducting this observational study, editorialists write that controlled trials are badly needed (
pp. 890–2): “The available evidence tests our faith in the use of observational studies to make decisions about vaccinations in dialysis patients. A reasonable conclusion is that current strategies for influenza or pneumococcal vaccination in the dialysis population are minimally effective—merely a well-intentioned ‘shot in the arm.’ The time to consider alternative approaches has arrived. For example, newer vaccine formulations exist that may be better suited for the dialysis population. Adjuvants such as AS03A and MF59 can act as a delivery system for the virus and potentiate the immunogenic response. A recent study showed a significantly higher antibody response in hemodialysis patients who use the AS03A adjuvant vaccine compared with the standard vaccine. A high-dose influenza vaccine that contains 3 times the amount of virus compared with standard vaccine currently is approved for the general elderly population and also could offer a more robust choice for the dialysis population. Additionally, in December 2011, the US Food and Drug Administration expanded approval of the 13-valent pneumococcal conjugate vaccine for adults 50 years and older. This new vaccine is believed to have greater antigenicity in immune-compromised populations and should be tested in the dialysis patient population. With these alternative options now available, the nephrology community should strongly consider comparing their efficacy formally with a randomized controlled clinical trial.” (A V. Kshirsagar, sagar@med.unc.edu)

>>>Allergy/Immunology Report
Source:
Nov. issue of the Journal of Allergy and Clinical Immunology (2012; 130).
HPV in Immunodeficiency: Human papillomavirus (HPV) infections are “almost universal and eventually asymptomatic, but pathologic infection with HPV is severe, recurrent, and recalcitrant to therapy,” write authors of a review article (pp. 1030–48). “It is also an underappreciated manifestation of primary immunodeficiency,” they note, adding these details: “Treatment and cure of HPV in the immunocompromised is both imperative and challenging. Multiple modalities are often required, including destructive treatments, topical therapies, systemic antiviral agents, and immunomodulators. Two HPV vaccines, bivalent and quadrivalent, are commercially available, and routine vaccination with the quadrivalent vaccine for prevention of HPV is recommended by the Advisory Committee on Immunization Practices for female and male patients aged 11 to 26 years.195, 196 Successful primary treatment of HPV-associated intraepithelial neoplasia with the quadrivalent vaccine has been recently reported.197, 198, 199, 200 A role for HPV vaccination in the setting of immunodeficiency is undefined but likely warranted.
“When warts are numerous, recurrent, and recalcitrant, clinicians should suspect underlying immune defects, especially if occurring with other infections, atopy, autoimmunity, or malignancy. The types and locations of other infections (viral vs fungal vs opportunistic) can greatly help in formulating a guided differential diagnosis…. A thorough history and physical examination and focused laboratory testing should help guide an informed and prudent search for the specific immune defect” (J. W. Leiding,
jleiding@health.usf.edu)

>>>PNN NewsWatch
* In comments before a Senate committee, ASHP and the International Academy of Compounding Pharmacy supported new legislation that clearly distinguishes between manufacturing-type operations and traditional compounding by pharmacists, pharmacist.com reports.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 19, 2012 * Vol. 19, No. 224
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 17 issue of Lancet (2012; 380).
Utility of Clinical Scores in AF Treated with Apixaban, Warfarin: Several scores commonly used in practice for assessing drug effects in patients with atrial fibrillation may be less useful for tailoring treatment with apixaban than with warfarin, a study shows (pp. 1749–58). Apixaban “has benefits over warfarin that are consistent across patient risk of stroke and bleeding as assessed by the CHADS2, CHA2DS2VASc, and HAS-BLED scores,” investigators in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial report. Among the trial’s 18,201 patients, these outcomes were found with apixaban 5 mg twice daily or warfarin dosed to an INR of 2–3: “Apixaban significantly reduced stroke or systemic embolism with no evidence of a differential effect by risk of stroke (CHADS2 1, 2, or ≥3, p for interaction = 0.4457; or CHA2DS2VASc 1, 2, or ≥3, p for interaction = 0.1210) or bleeding (HAS-BLED 0—1, 2, or ≥3, p for interaction = 0.9422). Patients who received apixaban had lower rates of major bleeding than did those who received warfarin, with no difference across all score categories (CHADS2, p for interaction = 0.4018; CHA2DS2VASc, p for interaction = 0.2059; HAS-BLED, p for interaction = 0.7127). The relative risk reduction in intracranial bleeding tended to be greater in patients with HAS-BLED scores of 3 or higher (hazard ratio [HR] 0.22, 95% CI 0.10—0.48) than in those with HAS-BLED scores of 0—1 (HR 0.66, 0.39—1.12; p for interaction = 0.0604).” (R. D. Lopes, renato.lopes@duke.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
VT Safety of Novel Oral Anticoagulants: Compared with vitamin K antagonists, the newer agents rivaroxaban, dabigatran, ximelagatran, and apixaban have similar risks of recurrence of venous thromboembolism and all-cause mortality, according to a systematic review and random-effects meta-analysis (e7498). Only rivaroxaban was associated with a decreased risk of bleeding, the authors report based on these results: “Nine studies met our inclusion criteria, involving 16,701 patients evaluated for efficacy and 16,611 for safety. Data were stratified according to different novel oral anticoagulants. For recurrent acute venous thromboembolism, there were no significant differences in events rates between any of the anticoagulants and conventional treatment (rivaroxaban (four studies): relative risk 0.85, 95% confidence interval 0.55 to 1.31; dabigatran (two studies): 1.09, 0.76 to 1.57; ximelagatran (two studies): 1.06, 0.62 to 1.80; and apixaban (one study): 0.98, 0.20 to 4.79). Rivaroxaban reduced the risk of major bleeding compared with conventional treatment (0.57, 0.39 to 0.84), whereas other novel oral anticoagulants did not (0.76 (0.49 to 1.18) for dabigatran; 0.54 (0.28 to 1.03) for ximelagatran; 2.95 (0.12 to 71.82) for apixaban). For all cause mortality there were no significant differences between the novel oral anticoagulants and conventional treatment (0.96 (0.72 to 1.27) for rivaroxaban; 1.00 (0.67 to 1.50) for dabigatran; 0.67 (0.42 to 1.08) for ximelagatran; 6.89 (0.36 to 132.06) for apixaban). The adjusted indirect comparison between rivaroxaban and dabigatran did not show superiority of either drug over the others for major bleeding (0.75, 0.41 to 1.34) or the other endpoints.” (B. D. Fox, benjamin.fox@mcgill.ca)

>>>PNN JournalWatch
* The Risk of Adverse Cardiac and Bleeding Events Following Noncardiac Surgery Relative to Antiplatelet Therapy in Patients With Prior Percutaneous Coronary Intervention, in
Journal of the American College of Cardiology, 2012; 60: 2005–16. (S. Singla)
* Mortality Rates in Patients With Rheumatoid Arthritis Treated With Tumor Necrosis Factor Inhibitors: Drug-Specific Comparisons in the Swedish Biologics Register, in
Arthritis & Rheumatism, 2012; 64: 3502–10. (J. F. Simard, julia.simard@ki.se)
* Boulevard of Broken Dreams: Drug Approval for Older Adults With Acute Myeloid Leukemia, in
Journal of Clinical Oncology, 2012; 30: 4061–3. (M. A. Sekeres, sekerem@ccf.org)
* Emerging Treatment Options for Advanced-Stage Mycosis Fungoides, in
Journal of Clinical Oncology, 2012; 30: 4064–70. (Reed E. Drews, rdrews@bidmc.harvard.edu)
* Burden of Gastrointestinal Disease in the United States: 2012 Update, in
Gastroenterology, 2012; 143: 1179–87.e3. (N. J. Shaheen, nshaheen@med.unc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 20, 2012 * Vol. 19, No. 225
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Nov. 20 issue of the Annals of Internal Medicine (2012; 157).
Testosterone Effects on Sildenafil Response: Addition of testosterone to a sildenafil regimen failed to improve erectile function in a group of 140 men with erectile dysfunction and low testosterone levels, researchers report (pp. 681–91). At baseline, participants aged 40–70 years had scores less than 26 on the erectile function domain (EFD) of the International Index of Erectile Function and total testosterone levels less than 11.45 nmol/L (<330 ng/dL) or free testosterone levels less than 173.35 pmol/L (<50 pg/mL). Optimization of prior sildenafil doses followed by placebo or daily transdermal gel delivering testosterone 10 g produced these outcomes: “Administration of sildenafil alone was associated with a substantial increase in EFD score (mean, 7.7 [95% CI, 6.5 to 8.8]), but change in EFD score after randomization did not differ between the groups (difference, 2.2 [CI, −0.8 to 5.1]; P = 0.150). The findings were similar for other domains of sexual function in younger men, more obese men, and men with lower baseline testosterone levels or an inadequate response to sildenafil alone. Frequency of adverse events was similar for testosterone and placebo groups.” (M. Spitzer, matthew.spitzer@bmc.org)
Pharmacy Dispensing of Electronically Discontinued Medications: Electronic discontinuation of medication orders in the ambulatory setting is an underused feature of electronic health records, according to authors who retrospectively studied 30,406 adult patients seen in a Massachusetts group practice (pp. 700–5). All patients had had an order for antihypertensive, antiplatelet, anticoagulant, oral hypoglycemic, or statin medication discontinued in 2008–09. During the following 12 months, these dispensing patterns were identified for discontinued orders: “Among 83,902 targeted medications that were electronically discontinued, 1,218 (1.5% [95% CI, 1.4% to 1.5%]) were subsequently dispensed by the pharmacy a mean of 1.0 (SD, 0.3) time during the 12-month follow-up. Among the top 10 most frequently electronically discontinued medications, the rate of subsequent dispensing by a pharmacy ranged from 0.9% for metformin to 2.5% for metoprolol. Manual chart review of 416 medication-dispensing events that were predefined as high risk according to an automated algorithm identified potential harm in 50 (12%) cases, including clinical reactions (n = 18), laboratory abnormalities (n = 17), duplicated medication classes dispensed (n = 8), and potential allergic reactions (n = 7).” (A. S. Allen, aallen0@partners.org)
Diagnosing, Managing Stable Ischemic Heart Disease: Two clinical practice guidelines provide recommendations on the diagnosis (pp. 729–34) and treatment (pp. 735–43; A. Qaseem, aqaseem@acponline.org) of stable ischemic heart disease (IHD).
The diagnosis document offers 28 recommendations that address initial diagnosis of the patient who might have stable IHD, cardiac stress testing to assess the risk for death or myocardial infarction in patients diagnosed with stable IHD, and coronary angiography for risk assessment.
The treatment guideline provides 48 specific recommendations that address patient education, management of proven risk factors (dyslipidemia, hypertension, diabetes, physical activity body weight, and smoking), risk factor reduction strategies of unproven benefit, medical therapy to prevent myocardial infarction and death and to relieve symptoms, alternative therapy, revascularization to improve survival and symptoms, and patient follow-up. “The initial approach to all patients should be focused on eliminating unhealthy behaviors, such as smoking, and effectively promoting lifestyle changes that reduce cardiovascular risk, such as increasing weight loss, physical activity, and adopting a healthy diet,” the authors write. “In addition, for most patients, an evidence-based set of pharmacologic interventions is indicated to reduce the risk for future events. The presumed mechanism by which these interventions are effective is by stabilizing the coronary plaque to prevent rupture and thrombosis. These include antiplatelet agents; lipid-lowering agents, in particular hydroxymethylglutaryl coenzyme A reductase inhibitors (statins); and beta-blockers. Angiotensin-converting enzyme (ACE) inhibitors are indicated in many patients with stable IHD, especially those with diabetes or left ventricular dysfunction.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 21, 2012 * Vol. 19, No. 226
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 21 issue of JAMA (2012; 308).
Citicoline in Traumatic Brain Injury: The nutraceutical citicoline, used for 90 days, was no more effective than placebo for improving functional and cognitive status among 1,213 patients with mild, moderate, or severe traumatic brain injury (TBI), researchers report (pp. 1993–2000). In the Citicoline Brain Injury Treatment Trial (COBRIT), enteral or oral citicoline 2000 mg or placebo produced these changes in the TBI-Clinical Trials Network Core Battery and other scales: “Rates of favorable improvement for the Glasgow Outcome Scale–Extended were 35.4% in the citicoline group and 35.6% in the placebo group. For all other scales the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. The citicoline and placebo groups did not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95% CI, 0.83–1.15]); in addition, there was no significant treatment effect in the 2 severity subgroups (global OR, 1.14 [95% CI, 0.88–1.49] and 0.89 [95% CI, 0.72–1.49] for moderate/severe and complicated mild TBI, respectively). At the 180-day evaluation, the citicoline and placebo groups did not differ significantly with respect to the primary outcome (global OR, 0.87 [95% CI, 0.72–1.04]).” (R. D. Zafonte, rzafonte@partners.org)
Citicoline is “an intermediate in the generation of phosphatidylcholine from choline,” which is used for making acetylcholine in the brain and membrane components phosphatidylcholine and sphingomyelin, according to an accompanying editorial (
pp. 2032–3). The writers conclude: “The primary importance of the COBRIT study reported by Zafonte et al is that it conclusively demonstrated the lack of efficacy of citicoline monotherapy for TBI. It is unlikely that this finding can be accounted for by limitations in the study design or conduct. The broader implication of the COBRIT study may be that no single therapeutic agent is likely to be sufficient to improve functional outcomes for patients with TBI. The diverse and complex nature of the pathological mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery. Future studies of TBI treatment should be designed to incorporate multiple treatment interventions and comprehensive TBI rehabilitation strategies, either as components of the intervention or standardized across study treatment groups.”(R. L. Ruff, robert.ruff1@va.gov)
Fish Oil & Postoperative AF: In the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) trial, fish oil supplements failed to provide a significant advantage in reducing the risk of postoperative atrial fibrillation (AF), compared with placebo, in 1,516 patients who had undergone cardiac surgery (pp. 2001–11). Study participants received placebo or loading doses of fish oil preoperatively and postoperatively until hospital discharge or postoperative day 10, with these results: “At enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, 0.96 [95% CI, 0.77–1.20]; P = .74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P = .70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; ≥3 episodes: 18 [2.4%] vs 21 [2.8%]) (P = .73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events.” (D. Mozaffarian, dmozaffa@hsph.harvard.edu)

>>>PNN NewsWatch
* Important details about implementation of the Affordable Care Act were published yesterday by CMS, Kaiser Health News reports. The proposed regulations, which appear to balance among competing priorities of stakeholders while retaining state latitude for choosing benchmark plans and benefits, are open for comments for 30 days. Substantial changes are not expected, as insurers need clarity quickly.
*
PNN will not be published on Thurs. and Fri., Nov. 22–23, Thanksgiving holidays.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 26, 2012 * Vol. 19, No. 227
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Nov. 24 issue of Lancet (2012; 380).
Alemtuzumab for Multiple Sclerosis: Two articles present results of the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, Studies One and Two (CARE-MS I and II).
Alemtuzumab, an anti-CD52 monoclonal antibody, reduced relapses with an acceptable safety profile in the Phase II, 2-year CARE-MS I study of patients with previously treated relapsing–remitting multiple sclerosis (
pp. 1819–28). Adults aged 18–50 years had these responses to intravenous alemtuzumab 12 mg/d for 5 days at baseline (n = 376) and once daily for 3 days at 12 months or subcutaneous interferon beta 1a 44 mcg once daily for 5 days at baseline (n = 187): “75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0.45 [95% CI 0.32–0.63]; p < 0.0001), corresponding to a 54.9% improvement with alemtuzumab. Based on Kaplan–Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p < 0.0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0.70 [95% CI 0.40–1.23]; p = 0.22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma.” (J. A. Cohen, cohenj@ccf.org)
In the Phase III, 2-year CARE-MS II study, first-line use of alemtuzumab reduced relapse rates with less sustained accumulation of disability in 667 patients with relapsing–remitting multiple sclerosis (
pp. 1829–39). In addition to the regimens tested in the Phase II trial, a higher dose of alemtuzumab (24 mg/d) was included but later discontinued to aid recruitment: “104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0.51 [95% CI 0.39–0.65]; p < 0.0001), corresponding to a 49.4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p < 0.0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0.58 [95% CI 0.38–0.87]; p = 0.008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.” (A. J. Coles, ajc1020@medschl.cam.ac.uk)

>>>PNN JournalWatch
* Insulin-like Growth Factors in the Brain and Their Potential Clinical Implications, in
Neurology, 2012; 79: 2148–53. (E. E. Benarroch, benarroch.eduardo@mayo.edu)
* Gait and Cognition: A Complementary Approach to Understanding Brain Function and the Risk of Falling, in
Journal of the American Geriatrics Society, 2012; 60: 2127–36. (M. Montero-Odasso, mmontero@uwo.ca)
* Clinical and Economic Burden of Community-Acquired Pneumonia in the Medicare Fee-for-Service Population, in
Journal of the American Geriatrics Society, 2012; 60: 2137–43. (R. Sato, reiko.sato@pfizer.com)
* Allergic Rhinitis and Its Impact on Asthma (ARIA): Achievements in 10 Years and Future Needs, in
Journal of Allergy and Clinical Immunology, 2012; 130: 1049–62. (J. Bousquet, jean.bousquet@inserm.fr)
* Ten Modifiable Health Risk Factors Are Linked to More Than One-Fifth Of Employer-Employee Health Care Spending, in
Health Affairs, 2012; 31: 2474–84. (R. Z. Goetzel, ron.goetzel@truvenhealth.com)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 27, 2012 * Vol. 19, No. 228
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from the Archives of Internal Medicine (2012; 172).
Preventing Excessive Acetaminophen Dosing in Hospitals: Interventions are needed to prevent supratherapeutic dosing of acetaminophen in hospitalized patients, investigators conclude after finding that multiple factors contribute to the problem (doi: 10.1001/2013.jamainternmed.438). Retrospective review of electronic health records of adult patients admitted to two tertiary-care hospitals in 2010–11 showed the following: “A total of 14,411 patients (60.7%) were exposed to acetaminophen, of whom 955 (6.6%) exceeded the 4 g per day maximum recommended dose. In addition, 22.3% of patients who were 65 years or older and 17.6% of patients with chronic liver diseases exceeded the recommended limit of 3 g per day. Patients receiving excessive doses of acetaminophen tended to have significant alkaline phosphatase elevations, although causal relationship cannot be concluded. A significantly higher risk of supratherapeutic dosing was observed in hospital A (HR, 1.6 [95% CI, 1.4–1.8]), white patients (HR, 1.5 [95% CI, 1.3–1.7]), patients diagnosed as having osteoarthritis (HR, 1.4 [95% CI, 1.3–1.6]), and those who received scheduled administrations (HR, 16.6 [95% CI, 13.5–20.6]), multiple product formulations (HR, 2.4 [95% CI 2.0–2.9]), or the 500-mg strength formulation (HR, 1.9 [95% CI, 1.5–2.3]). A lower risk was found for pro re nata (as needed) administrations (HR, 0.7 [95% CI, 0.6–0.9]) and in nonsurgical and non–intensive care units (HR, 0.6 [95% CI, 0.5–0.7]).” (L. Zhou, Lzhou2@partners.org)
Health information technology could help in preventing supratherapeutic acetaminophen dosing, writes the author of an invited commentary (
doi: 10.1001/2013.jamainternmed.607): “To drive change and innovation we need a large investment in performance improvement and process engineering, business intelligence systems, and analytical capabilities to take full advantage of HIT and to move us toward the goal of becoming a rapid-learning health system. Most health care organizations lack the expertise and personnel to take advantage of the data from EHR and other sources to improve care. Of equal concern is the fact that many organizations also are strapped for resources and cannot make such investments even if they want to. I suggest that health care organizations create partnerships with companies in the private sector to create learning systems. Technology companies, insurance companies, device companies, and consulting firms, among others, can bring needed expertise in analytics, computer science, and performance improvement that are lacking in health care. Moreover, these companies can be the source of capital investment that will be necessary for success.” (W. H. Ettinger, wettinger@accretivehealth.com)

>>>NEJM Highlights
Source:
Nov. 22 issue of the New England Journal of Medicine (2012; 367).
ADHD Meds & Criminality: Based on an analysis of Swedish national registers, use of medications for attention-deficit/hyperactivity disorder is associated with lower rates of criminality (pp. 2006–14). ADHD medication use and criminal convictions in 2006–09 showed these relationships based on Cox regression analyses: “As compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime).” (P. Lichtenstein, paul.lichtenstein@ki.se)

>>>PNN NewsWatch
* FDA last week licensed Flucelvax (Novartis), the first seasonal influenza vaccine produced using cultured animal cells instead of fertilized chicken eggs. Flucelvax is approved to prevent seasonal influenza in people ages 18 years and older. Advantages of cell culture technology include the ability to maintain an adequate supply of readily available, previously tested and characterized cells for use in vaccine production and the potential for a faster start-up of the vaccine manufacturing process in the event of a pandemic, FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 28, 2012 * Vol. 19, No. 229
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Nov. 28 issue of JAMA (2012; 308).
Outcomes of Drug Therapy in Heart Failure: Researchers and an editorialist examine associations between drug use and outcomes in patients with heart failure and reduced ejection fraction.
Aldosterone antagonist therapy started at hospital discharge was not independently associated with improved mortality or cardiovascular readmissions, authors write, but the drugs were linked to improved heart failure readmissions among some older patients with heart failure and reduced ejection fraction (
pp. 2097–107). Based on Medicare claims in 2005–10, investigators found: “Among 5,887 patients who met the inclusion criteria, the mean age was 77.6 years; of those 1,070 (18.2%) started aldosterone antagonist therapy at discharge. Cumulative incidence rates among treated and untreated patients were 49.9% vs 51.2% (P = .62) for mortality; 63.8% vs 63.9% (P = .65) for cardiovascular readmission; and 38.7% vs 44.9% (P < .001) for heart failure readmission at 3 years; and 2.9% vs 1.2% (P < .001) for hyperkalemia readmission within 30 days and 8.9% vs 6.3% (P = .002) within 1 year. After inverse weighting for the probability of treatment, there were no significant differences in mortality (hazard ratio [HR], 1.04; 95% CI, 0.96–1.14; P = .32) and cardiovascular readmission (HR, 1.00; 95% CI, 0.91–1.09; P = .94). Heart failure readmission was lower among treated patients at 3 years (HR, 0.87; 95% CI, 0.77–0.98; P = .02). Readmission associated with hyperkalemia was higher with aldosterone antagonist therapy at 30 days (HR, 2.54; 95% CI, 1.51–4.29; P < .001) and 1 year (HR, 1.50; 95% CI, 1.23–1.84; P < .001).” (A. F. Hernandez, adrian.hernandez@duke.edu)
An analysis of similar data from the Swedish Heart Failure Registry showed that renin-angiotensin system (RAS) antagonists were associated with lower all-cause mortality (
pp. 2108–17): “In the matched [heart failure with preserved ejection fraction (HFPEF)] cohort, 1-year survival was 77% (95% CI, 75%–78%) for treated patients vs 72% (95% CI, 70%–73%) for untreated patients, with a hazard ratio (HR) of 0.91 (95% CI, 0.85–0.98; P = .008). In the overall HFPEF cohort, crude 1-year survival was 86% (95% CI, 86%–87%) for treated patients vs 69% (95% CI, 68%–71%) for untreated patients, with a propensity score–adjusted HR of 0.90 (95% CI, 0.85–0.96; P = .001). In the HFPEF dose analysis, the HR was 0.85 (95% CI, 0.78–0.83) for 50% or greater of target dose vs no treatment (P < .001) and 0.94 (95% CI, 0.87–1.02) for less than 50% of target dose vs no treatment (P = .14). In the age and propensity score–matched [heart failure with reduced ejection fraction] analysis, the HR was 0.80 (95% CI, 0.74–0.86; P < .001).” (L. H. Lund, lars.lund@alumni.duke.edu)
Two conclusions can be reached based on these observational studies, an editorialist writes (
pp. 2144–6): “What then should physicians conclude from these 2 observational studies that would appear to contradict the clinical trial evidence? If all of the evidence is carefully considered in its totality, it would be sound to conclude that (1) renin-angiotensin system antagonists are reasonable agents to control hypertension in heart failure with preserved ejection fraction, and (2) aldosterone antagonists are effective drugs in heart failure with reduced ejection fraction but should be used carefully and selectively. Although clinical trials should remain the gold standard for testing hypotheses, observational studies bridge the gap from the scientific rigor of clinical trials to real-world experience. Clinical trials are a reminder of the rigor of medicine as a science; observational studies are a reminder that medicine is still an art.” (J. C. Fang, james.fang@uhhospitals.org)
Pertussis & Vaccine Status: During the 2010 pertussis outbreak in California, children with the disease in 15 counties were more likely to have not received the full 5-dose childhood series of diphtheria, tetanus, and acellular pertussis vaccine (DTaP), with an odds ratio of 0.11 (95% CI, 0.06–0.21) researchers report (pp. 2126–32). Odds of having pertussis were also higher with increased time since completion of the 5-dose series (OR, 0.29; 95% CI, 0.15–0.54), indicating “a progressive decrease in estimated vaccine effectiveness each year after the final dose of pertussis vaccine.” (L. K. Misegades, lmisegades@cdc.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Nov. 29, 2012 * Vol. 19, No. 230
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Nov. 29 issue of the New England Journal of Medicine (2012; 367).
Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias: The oral tyrosine kinase inhibitor ponatinib (AP24534) “was highly active in heavily pretreated patients with [Philadelphia (Ph)-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I [gatekeeper] mutation, other mutations, or no mutations,” researchers report (pp. 2075–88). Through blockade of native and mutated BCR-ABL, ponatinib acts in patients despite failure of other tyrosine kinase inhibitors. In a Phase I dose-escalation study, these effects were noted with ponatinib 2–60 mg once daily over a median follow-up period of 56 weeks: “Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.” (J. E. Cortes, jcortes@mdanderson.org)
Dalcetrapib in Recent Acute Coronary Syndrome: Among 15,871 patients with recent acute coronary syndrome, the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib increased HDL cholesterol levels but failed to significantly affect the risk of recurrent cardiovascular events, the dal-OUTCOMES study shows (pp. 2089–99). Patients received dalcetrapib 600 mg daily or placebo along with “the best available evidence-based care.” With a primary end point of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation, results showed: “At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1,135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P = 0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P < 0.001 for both comparisons).” (G. G. Schwartz, gregory.schwartz@va.gov)
Bedside Antiplatelet Monitoring in Coronary Stenting: Compared with standard antiplatelet therapy without monitoring, platelet-function monitoring and treatment adjustment for coronary stenting produced no significant improvements in clinical outcomes (pp. 2100–9). The VerifyNow P2Y12 and aspirin point-of-care assays were used in the catheterization laboratory before stent implantation and in the outpatient clinic 2–4 weeks later. A primary end point of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation occurred in 34.6% of patients in the monitoring group and 31.1% of those receiving standard care (hazard ratio, 1.13; 95% CI, 0.98 to 1.29; P = 0.10). (G. Montalescot, gilles.montalescot@psl.aphp.fr)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Nov. 30, 2012 * Vol. 19, No. 231
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Dec. issue of Diabetes Care (2012; 35).
Dual Reporting of A1C Units: Diabetes Care is now requiring reporting of glycosylated hemoglobin levels both as percentages derived from Diabetes Control and Complications Trial (DCCT) units and in Système International (SI) units of mmol/mol, editorialists write (pp. 2415–6): “The decision to require dual reporting was made with the understanding that the change would have significant implications for authors and readers, but our rationale for implementing this change was based on several factors. First, we recognize that there is now, and will continue to be for the foreseeable future, controversy on how to report the HbA1c. As elegantly outlined in the review [in this issue; pp. 2674–80; D. B. Sacks, sacksdb@mail.nih.gov], Sacks describes the history of the measurement of HbA1c, the process leading to standardization to DCCT/NGSP numbers, and the rationale for the global use of International Federation of Clinical Chemistry and Laboratory Medicine standardization. It is clear that there are strong opinions on which units to use, and as a result, the ways HbA1c results are reported to clinicians already differ among countries of the world (see Table 5 in [the article by Sacks]). Given these differences, there is an obvious concern of being able to compare past studies using one unit with future studies reporting with a different unit. More concerning is that young clinicians in some countries may, in only a few years, not recognize HbA1c in percent DCCT units.” (W. T. Cefalu, cefaluwt@pbrc.edu)
Estimating the Glycation Gap: The glycation gap—the difference between measured A1C and the value predicted by regression on fructosamine—can be reliably estimated using pairs of A1C and fructosamine levels obtained 1 month apart, researchers report (pp. 2447–50). In 311 patients with type 1 or type 2 diabetes for whom such measurements were available, the investigators found these patterns for instantaneous (gg) and mean (GG) glycation gaps: “Stable glycemia was shown by 144 patients. In 90% of unstable case subjects, a change in medication was identified as the cause of instability. Among 129 stable patients with an average of eight gg determinations prior to [time 0], GG correlated closely with the mean of these prior determinations (r2 = 0.902, slope 1.025, intercept −0.038).” (S. Rodríguez-Segade, ssegade@telefonica.net)
Analgesics in Peripheral Neuropathic Pain: Analgesic efficacy of amitriptyline, duloxetine, and pregabalin was similar in patients with chronic diabetic peripheral neuropathic pain (DPNP), a study of patients with type 1 or type 2 diabetes shows (pp. 2451–8). Patients received placebo during an 8-day run-in period followed by 14 days of lower-dose and 14 days of higher-dose medication, with these results: “All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group.” (M. E. V. Eriksson, m.eriksson@surrey.ac.uk)
Medication Nonadherence in Diabetes: Aggressive reduction of medication nonadherence (MNA) is needed in type 2 diabetes, shows a study of medication possession ratios (MPRs) of 740,195 veterans (pp. 2533–9): “Mean MPR for the full sample over 5 years was 0.78, with a mean of 0.93 for the adherent group and 0.58 for the MNA group. In fully adjusted models, all annual cost categories increased ~3% per year (P = 0.001) during the 5-year study time period. MNA was associated with a 37% lower pharmacy cost, 7% lower outpatient cost, and 41% higher inpatient cost. Based on sensitivity analyses, improving adherence in the MNA group would result in annual estimated cost savings ranging from ~$661 million (MPR <0.6 vs. ≥0.6) to ~$1.16 billion (MPR <1 vs. 1). Maximal incremental annual savings would occur by raising MPR from <0.8 to ≥0.8 ($204,530,778) among MNA subjects.” (L. E. Egede, egedel@musc.edu)

>>>PNN NewsWatch
* FDA has approved cabozantinib (Cometriq, Exelixis) for treatment of medullary thyroid cancer.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 3, 2012 * Vol. 19, No. 232
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 1 issue of Lancet (2012; 380).
Cyclosporine, Infliximab in Severe Refractory Ulcerative Colitis: In 115 patients with acute severe ulcerative colitis refractory to intravenous steroids, cyclosporine produced treatment failures similar in number to infliximab, researchers report (pp. 1909–15). Study participants were adults who had had an acute severe flare of ulcerative colitis that was treated unsuccessfully with high-dose intravenous steroids. In 2007–10 at 27 European centers, patients received either intravenous cyclosporine 2 mg/kg/d for 1 week followed by oral drug until day 98 or infliximab 5 mg/kg on days 0, 14, and 42. Treatment failure was defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, or a severe adverse event leading to treatment interruption, colectomy, or death. Investigators found that treatment failure occurred in 35 (60%) patients given cyclosporine and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI −7 to 19; P = 0.52) and that 9 (16%) patients in the cyclosporine group and 14 (25%) in the infliximab group had severe adverse events. (D. Laharie, david.laharie@chu-bordeaux.fr)
Antimicrobial Catheters for Decreasing UTIs: The incidence of catheter-associated urinary tract infections (CAUTIs) was not reduced through use of silver alloy–coated catheters in 6,394 adult patients (pp. 1927–35). Study participants needed short-term catheterization, defined as 14 days or fewer, during hospitalizations in the U.K. Allocated to a silver alloy-coated catheter, a nitrofural-impregnated catheter, or a standard polytetrafluoroethylene (PTFE)coated catheter (control group), patients had these results based on a primary outcome of incidence of symptomatic urinary tract infection for which an antibiotic was prescribed by 6 weeks: “Compared with 271 (12.6%) of 2,144 participants in the control group, 263 (12.5%) of 2,097 participants allocated a silver alloy catheter had the primary outcome (difference –0.1% [95% CI –2.4 to 2.2]), as did 228 (10.6%) of 2,153 participants allocated a nitrofural catheter (–2.1% [–4.2 to 0.1]). Rates of catheter-related discomfort were higher in the nitrofural group than they were in the other groups.” (R. Pickard, robert.pickard@newcastle.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Self-Management, Routine Monitoring in COPD: In patients with chronic obstructive pulmonary disease (COPD) receiving usual care, programs of comprehensive self-management and routine monitoring failed to provide long-term benefits, a study shows (e7642). Conducted at 15 general practices in the Netherlands, the investigation compared usual care alone with a self-management program of four tailored sessions with ongoing telephone support provided by nurses or addition of a routine monitoring program. Results showed: “165 patients were allocated to self management (n = 55), routine monitoring (n = 55), or usual care alone (n = 55). At 24 months, adjusted treatment differences between the three groups in mean chronic respiratory questionnaire total score were not significant. Secondary outcomes did not differ, except for exacerbation management. Compared with usual care, more exacerbations in the self management group were managed with bronchodilators (odds ratio 2.81, 95% confidence interval 1.16 to 6.82) and with prednisolone, antibiotics, or both (3.98, 1.10 to 15.58).” (E. Bischoff, E.Bischoff@elg.umcn.nl)

>>>PNN JournalWatch
* Effectiveness of Lifestyle Interventions in Child Obesity: Systematic Review With Meta-analysis, in
Pediatrics, 2012; 130: e1647–71. (M. Ho)
* Long-Term Complications of Therapeutic Exposures in Childhood: Lessons Learned From Childhood Cancer Survivors, in
Pediatrics, 2012; 130: 1141–3. (S. Bhatia)
* CKiD (CKD in Children) Prospective Cohort Study: A Review of Current Findings, in
American Journal of Kidney Diseases, 2012; 60: 1002–11. (C. J. Wong, wongcy8@stanford.edu)
* Initial Validation of a Self-Report Measure of the Extent of and Reasons for Medication Nonadherence, in
Medical Care, 2012; 50: 1013–9. (C. I. Voils)
* A Survey Of Primary Care Doctors In Ten Countries Shows Progress in Use of Health Information Technology, Less in Other Areas, in
Health Affairs, 2012: 10.1377/hlthaff.2012.0884. (C. Schoen, cs@cmwf.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 4, 2012 * Vol. 19, No. 233
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Dec. 4 issue of the Annals of Internal Medicine (2012; 157).
Improving Adherence to Self-administered Medications: In a systematic review, three interventions were found to improve adherence to more than one chronic disease treated with self-administered medications: reduced out-of-pocket expenses, case management, and patient education with behavioral support (pp. 785–95). Investigators analyzed data from “randomized controlled trials of patient, provider, or systems interventions to improve adherence to long-term medications and nonrandomized studies of policy interventions to improve medication adherence,” with these results: “The evidence was synthesized separately for each clinical condition; within each condition, the type of intervention was synthesized. Two reviewers graded the strength of evidence by using established criteria. From 4,124 eligible abstracts, 62 trials of patient-, provider-, or systems-level interventions evaluated 18 types of interventions; another 4 observational studies and 1 trial of policy interventions evaluated the effect of reduced medication copayments or improved prescription drug coverage. Clinical conditions amenable to multiple approaches to improving adherence include hypertension, heart failure, depression, and asthma. Interventions that improve adherence across multiple clinical conditions include policy interventions to reduce copayments or improve prescription drug coverage, systems interventions to offer case management, and patient-level educational interventions with behavioral support.” (M. Viswanathan, viswanathan@rti.org)
Warfarin v. New Oral Anticoagulants for AF, VT: “New oral anticoagulants [NOACs] are a viable option for patients receiving long-term anticoagulation,” a systematic review concludes, but “treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment” (pp. 796–807). Looking at randomized controlled trials (RCTs) of atrial fibrillation (AF) and venous thromboembolism (VTE), researchers found these results in comparisons of warfarin versus NOACs such as direct thrombin inhibitors (DTIs) and factor Xa (FXa) inhibitors: “Six good-quality RCTs compared NOACs (2 DTI studies, 4 FXa inhibitor studies) with warfarin. In AF, NOACs decreased all-cause mortality (risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]); in VTE, NOACs did not differ for mortality or VTE outcomes. Across indications, adverse effects of NOACs compared with warfarin were fatal bleeding (RR, 0.60 [CI, 0.46 to 0.77]), major bleeding (RR, 0.80 [CI, 0.63 to 1.01]), gastrointestinal bleeding (RR, 1.30 [CI, 0.97 to 1.73]), and discontinuation due to adverse events (RR, 1.23 [CI, 1.05 to 1.44]). Subgroup analyses suggest a higher risk for myocardial infarction with DTIs than with FXa inhibitors. Bleeding risk for NOACs may be increased in persons older than 75 years or those receiving warfarin who have good control.” (S. S. Adam)
Patient-Centered Medical Home: The patient-centered medical home (PCMH) “holds promise for improving the experiences of patients and staff and potentially for improving care processes, but current evidence is insufficient to determine effects on clinical and most economic outcomes,” conclude authors of a systematic review (online first): “In 19 comparative studies, PCMH interventions had a small positive effect on patient experiences and small to moderate positive effects on the delivery of preventive care services (moderate strength of evidence). Staff experiences were also improved by a small to moderate degree (low strength of evidence). Evidence suggested a reduction in emergency department visits (risk ratio [RR], 0.81 [95% CI, 0.67 to 0.98]) but not in hospital admissions (RR, 0.96 [95% CI, 0.84 to 1.10]) in older adults (low strength of evidence). There was no evidence for overall cost savings.” (G. L. Jackson, george.l.jackson@duke.edu)

>>>PNN NewsWatch
* Influenza is off to an early start in the U.S. this year, the CDC said yesterday, portending a worse-than-usual season. Clinical isolates are matching well with this year’s influenza vaccine, with A/H3N2 dominating in the community. “It’s time to get vaccinated if you haven’t been already gotten vaccinated,” CDC Director Thomas Frieden said. “The early nature of the cases as well as the specific strains we’re seeing suggest that this could be a bad flu year.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 5, 2012 * Vol. 19, No. 234
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Dec. issue of Pharmacotherapy (2012; 32).
Med Errors in Kidney Transplants: Medication-related problems (MRPs) were found commonly in a retrospective review of patient records at a transplant center (pp. 1053–60). The analysis included two types of MRPs: adverse drug events and severe or significant patient-induced medication errors such as taking the wrong dose or taking a medication at an incorrect frequency. Results showed: “Thirty-seven (8%) of the 476 patients developed a clinically significant MRP. Univariate and confirmatory multivariate analyses revealed that female sex, African American race, pretransplantation diabetes mellitus, delayed graft function, and retransplant recipients were independent risk factors for developing an MRP. Patients with MRPs had significantly higher rates of acute rejection (11% vs 30%, p = 0.004), cytomegalovirus infection (15% vs 30%, p = 0.033), and 30-day readmissions (5% vs 16%, p = 0.018). Graft survival was also significantly lower in patients who had MRPs (p < 0.001).” (D. J. Taber, taberd@musc.edu)
Oseltamivir Kinetics in Critically Ill Patients: Pharmacokinetics of oseltamivir and oseltamivir carboxylate may differ in critically ill patients, according to a small study of individuals on continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation (pp. 1061–9). The study included 12 patients aged 13 years or older in 2009–10. Pharmacokinetic analysis of 150-mg doses of oseltamivir administered nasogastrically or nasoenterically every 12 hours showed a higher-than-expected median oseltamivir carboxylate AUC from 0 to 12 hours, authors wrote. Median maximum plasma concentration and AUC0–12 values were 83.4 ng/ml and 216 ng•h/ml, respectively, for the prodrug oseltamivir and 2,000 ng/mL and 21,500 ng•h/mL, respectively, for oseltamivir carboxylate, its active metabolite. (R. F. Eyler, rachel.eyler@uconn.edu)
Patient Self-Management of Warfarin Using Online Messaging of Venipuncture Results: A pilot study of a novel approach to patient self-management (PSM) of warfarin therapy shows that support tools and online messaging of INR values determined from venipuncture samples merit further study in a randomized controlled trial (pp. 1078–84). During a prospective, open-label, 3-month trial, 44 patients with atrial fibrillation who had been on warfarin for more than 6 months received dosing decision support tools during a 2-hour live PSM training class, with these results based on time in therapeutic INR range (TTR): “No significant difference in TTR occurred between the 90 days before PSM program participation and the 90 days of PSM (82.9% vs 81.2%, p = 0.65). The mean number of INR tests performed for each patient increased from 2.97 before PSM program participation to 4.38 during PSM (p < 0.01). No bleeding or thrombotic events occurred during the PSM phase.” (B. Simmons, brandon.x.simmons@kp.org)
Bipolar Disorder & Drug Therapy in Pediatrics: Complex drug regimens are common in children and adolescents diagnosed with bipolar disorder, researchers report (pp. 1085–94). Regimens often include multiple classes of psychotropic drugs, according to this retrospective analysis of a private insurance claims database for 2005–07: “The annual treated prevalence of any bipolar spectrum disorder in this privately insured population was 0.24% in 2005 and 0.26% in 2006 and 2007. Approximately 25% of diagnoses were for children younger than 13 years. Approximately 30% of children had coexisting attention-deficit–hyperactivity disorder during the year. In each year, 35% of patients used no psychotropic drug therapy in the 30-day period after their most recent diagnosis. Twenty-five percent used one psychotropic drug, and 40% used two or more drugs. The most common drug regimens were antipsychotic or mood stabilizer (lithium or anticonvulsant) monotherapy and the combination of mood stabilizers and antipsychotics.” (S. B. Dusetzina, dusetzina@hcp.med.harvard.edu)

>>>PNN NewsWatch
* Extending a June 29 warning of torsades de pointes with the highest dosage of ondansetron, FDA yesterday said that the 32-mg single intravenous premixed solutions of the product will no longer be available. That dose has also been removed from the approved product labeling.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 6, 2012 * Vol. 19, No. 235
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 6 issue of the New England Journal of Medicine (2012; 367).
Fungal Meningitis Outbreak in Tennessee: Health officials describe demographics and clinical characteristics and outcomes of Tennessee patients who had “fungal infections of the central nervous system following epidural or paraspinal glucocorticoid injections of preservative-free methylprednisolone acetate prepared by a single compounding pharmacy” (pp. 2194–203): “The median age of the 66 case patients was 69 years (range, 23 to 91). The median time from the last epidural glucocorticoid injection to symptom onset was 18 days (range, 0 to 56). Patients presented with meningitis alone (73%), the cauda equina syndrome or focal infection (15%), or posterior circulation stroke with or without meningitis (12%). Symptoms and signs included headache (in 73% of the patients), new or worsening back pain (in 50%), neurologic symptoms (in 48%), nausea (in 39%), and stiff neck (in 29%). The median cerebrospinal fluid white-cell count on the first lumbar puncture among patients who presented with meningitis, with or without stroke or focal infection, was 648 per cubic millimeter (range, 6 to 10,140), with 78% granulocytes (range, 0 to 97); the protein level was 114 mg per deciliter (range, 29 to 440); and the glucose concentration was 44 mg per deciliter (range, 12 to 121) (2.5 mmol per liter [range, 0.7 to 6.7]). A total of 22 patients had laboratory confirmation of Exserohilum rostratum infection (21 patients) or Aspergillus fumigatus infection (1 patient). The risk of infection increased with exposure to lot 06292012@26, older vials, higher doses, multiple procedures, and translaminar approach to epidural glucocorticoid injection. Voriconazole was used to treat 61 patients (92%); 35 patients (53%) were also treated with liposomal amphotericin B. Eight patients (12%) died, seven of whom had stroke.” (M. A. Kainer, marion.kainer@tn.gov)
Aliskiren in Type 2 Diabetes: In patients with type 2 diabetes who are at high risk for cardiovascular and renal events, “addition of aliskiren to standard therapy with renin–angiotensin system blockade … is not supported … and may even be harmful,” researchers conclude (pp. 2204–13). In 8,561 patients, aliskiren 300 mg daily or placebo as an adjunct to ACE inhibitor or an angiotensin-receptor blocker produced these changes in a primary end point of composite of the time to cardiovascular death or a first occurrence of cardiac arrest with resuscitation; nonfatal myocardial infarction; nonfatal stroke; unplanned hospitalization for heart failure; end-stage renal disease, death attributable to kidney failure, or the need for renal-replacement therapy with no dialysis or transplantation available or initiated; or doubling of the baseline serum creatinine level: “The trial was stopped prematurely after the second interim efficacy analysis. After a median follow-up of 32.9 months, the primary end point had occurred in 783 patients (18.3%) assigned to aliskiren as compared with 732 (17.1%) assigned to placebo (hazard ratio, 1.08; 95% confidence interval [CI], 0.98 to 1.20; P = 0.12). Effects on secondary renal end points were similar. Systolic and diastolic blood pressures were lower with aliskiren (between-group differences, 1.3 and 0.6 mm Hg, respectively) and the mean reduction in the urinary albumin-to-creatinine ratio was greater (between-group difference, 14 percentage points; 95% CI, 11 to 17). The proportion of patients with hyperkalemia (serum potassium level, ≥6 mmol per liter) was significantly higher in the aliskiren group than in the placebo group (11.2% vs. 7.2%), as was the proportion with reported hypotension (12.1% vs. 8.3%) (P < 0.001 for both comparisons).” (H-H Parving, hhparving@dadlnet.dk)
Contamination of Topical Antiseptic Products: Infections of Burkholderia cepacia, Bacillus cereus, Pseudomonas aeruginosa, Serratia marcescens, and other bacteria have occurred with use of contaminated topical antiseptic products, Commentary authors write (pp. 2170–3). Because FDA does not require sterile preparation of products such as povidone–iodine and chlorhexidine gluconate, “microbial stowaways”—including organisms rarely encountered clinically—may be present or may be introduced by end users. Clinical symptoms and infections may result. FDA is holding hearings on the matter on Dec. 12–13. (C. Y. Chang)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 7, 2012 * Vol. 19, No. 236
Providing news and information about medications and their proper use

>>>Psychiatry Report
Source:
Dec. issue of the American Journal of Psychiatry (2012; 12).
Folate in Resistant Depression: In two sequential comparative trials, l-methylfolate improved depressive symptoms among patients with SSRI-resistant major depressive disorder, researchers report (pp. 1267–74). In two successive 30-day periods during which SSRI dosages were maintained constant, 148 study participants received l-methylfolate for 60 days (7.5 mg/day for 30 days followed by 15 mg/day for 30 days), placebo for 30 days followed by l-methylfolate (7.5 mg/day) for 30 days, or placebo for 60 days. In a second trial of 75 patients with an identical design, l-methylfolate dosages were 15 mg/day during both 30-day periods. Results showed: “In the first trial, no significant difference was observed in outcomes between the treatment groups. In the second trial, adjunctive l-methylfolate at 15 mg/day showed significantly greater efficacy compared with continued SSRI therapy plus placebo on both primary outcome measures (response rate and degree of change in depression symptom score) and two secondary outcome measures of symptom severity. The number needed to treat for response was approximately six in favor of adjunctive l-methylfolate at 15 mg/day. l-Methylfolate was well tolerated, with rates of adverse events no different from those reported with placebo.” (G. I. Papakostas, gpapakostas@partners.org)
Genetic variation may be one reason methylfolate works for patients with refractory depression, writes an editorialist (
pp. 1223–5): “[This] study suggests that l-methylfolate is a useful treatment for depression that has proved to be resistant to a course of SSRI treatment. Previous studies of folic acid, folinic acid, and l-methylfolate support this contention. l-Methylfolate was well tolerated and may be preferred by patients for that reason. It may be particularly helpful in patients with the TT genetic variant. The efficacy of l-methylfolate in resistant depression has not been compared with that of other adjunctive agents, nor has long-term use of the agent been reported in major depression. The potential value of long-term administration of l-methylfolate in individuals with recurrent depression and the genetic enzyme deficiency is particularly intriguing.” (J. C. Nelson, craign@lppi.ucsf.edu)

>>>Pediatrics Highlights
Source:
Dec. issue of Pediatrics (2012; 130).
Buprenorphine Safety in Pediatrics: A small child died after ingesting a caretaker’s buprenorphine, report authors who question the drug’s presumed safety in pediatric patients (e1700–3): “Postmortem toxicology analysis showed free serum concentrations of 52 ng/mL and 39 ng/mL for buprenorphine and norbuprenorphine, respectively. No other drugs were detected. Autopsy did not find signs of injury or trauma. The theoretical safety provided by the ceiling effect in respiratory depression from buprenorphine may not apply to children, and buprenorphine may cause dose-dependent respiratory depression.” (H. K. Kim)
Booster Mumps Vaccine During Outbreak: In middle- and high-school students, a third dose of measles–mumps–rubella (MMR) vaccine was associated with a decline in incidence of mumps during a 2009–10 outbreak (e1567–74). Offered to members of a religious community in the northeastern U.S., the booster dose showed these effects: “The overall attack rates (AR) for all sixth- to 12th-grade students declined from 4.93% in the prevaccination period to 0.13% after vaccination (P < .001). Villagewide, overall AR declined by 75.6% after the intervention. A decline occurred in all age groups but was significantly greater (96.0%) among 11- to 17-year-olds, the age group targeted for vaccination, than among all other age groups.” (I. U. Ogbuanu)

>>>PNN NewsWatch
* Heparin labeling is being standardized to show the total amount of drug in the entire container followed by the number of USP units per milliliter, FDA said yesterday. The agency said it supports the USP proposal to revise the labeling section of USP monographs for Heparin Lock Flush Solution, USP, and Heparin Sodium Injection, USP, to clearly state the total drug strength on the label. The FDA action ensures that labels for heparin products comply with USP’s general requirements for all small-volume injectable products, which currently display the total drug content.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 10, 2012 * Vol. 19, No. 237
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 8 issue of Lancet (2012; 380).
PCSK9 Monoclonal Antibody for Hypercholesterolemia: Efficacy and safety of AMG 145, a human monoclonal antibody against the LDL-cholesterol–raising proprotein convertase subtilisin/kexin type 9 (PCSK9), is examined as monotherapy and in combination with statins.
A Phase II dose-ranging study supports further assessment of AMG 145 in larger studies, researchers conclude (
pp. 1995–2006). Participants received subcutaneous AMG 145 70 mg, 105 mg, or 140 mg, or placebo every 2 weeks; subcutaneous AMG 145 280 mg, 350 mg, or 420 mg or placebo every 4 weeks; or oral ezetimibe 10 mg/day, with these results: “406 patients were assigned to AMG 145 70 mg (n = 45), 105 mg (n = 46), or 140 mg (n = 45) every 2 weeks; AMG 145 280 mg (n = 45), 350 mg (n = 45), or 420 mg (n = 45) every 4 weeks; placebo every 2 weeks (n = 45) or every 4 weeks (n = 45); or ezetimibe (n = 45). AMG 145 significantly reduced LDL-C concentrations in all dose groups (mean baseline LDL-C concentration 3.7 mmol/L [SD 0.6]; changes from baseline with every 2 weeks AMG 145 70 mg −41.0% [95% CI −46.2 to −35.8]; 105 mg −43.9% [–49.0 to −38.7]; 140 mg −50.9% [–56.2 to −45.7]; every 4 weeks AMG 145 280 mg −39.0% [–44.1 to –34.0]; 350 mg −43.2% [–48.3 to −38.1]; 420 mg −48.0% [–53.1 to −42.9]; placebo every 2 weeks −3.7% [–9.0 to 1.6]; placebo every 4 weeks 4.5% [–0.7 to 9.8]; and ezetimibe −14.7% [–18.6 to −10.8]; p < 0.0001 for all doses vs placebo or ezetimibe). Treatment-emergent adverse events occurred in 136 (50%) of 271 patients in the AMG 145 groups, 41 (46%) of 90 patients in the placebo groups, and 26 (58%) of 45 patients in the ezetimibe group; no deaths or serious treatment-related adverse events were reported.” (M. J. Koren, mkoren@encoredocs.com)
“PCSK9 inhibition could be a new model in lipid management,” investigators conclude based on data from a second Phase II trial that included patients on a stable dose of a statin with or without ezetimibe (
pp. 2007–17): “631 patients with hypercholesterolaemia were randomly assigned to AMG 145 70 mg (n = 79), 105 mg (n = 79), or 140 mg (n = 78), or matching placebo (n = 78) every 2 weeks; or AMG 145 280 mg (n = 79), 350 mg (n = 79), and 420 mg (n = 80), and matching placebo (n = 79) every 4 weeks. At the end of the dosing interval at week 12, the mean LDL-C concentrations were reduced generally dose dependently by AMG 145 every 2 weeks (ranging from 41.8% to 66.1%; p < 0.0001 for each dose vs placebo) and AMG 145 every 4 weeks (ranging from 41.8% to 50.3%; p < 0.0001). No treatment-related serious adverse events occurred. The frequencies of treatment-related adverse events were similar in the AMG 145 and placebo groups (39 [8%] of 474 vs 11 [7%] of 155); none of these events were severe or life-threatening.” (R. P. Giugliano, rgiugliano@partners.org)

>>>PNN JournalWatch
* American Academy of Pediatrics Policy Statement: Emergency Contraception, in
Pediatrics, 2012; 130: 1174–82. (AAP Committee on Adolescence)
* What Have We Learned About Patients With Heart Failure and Preserved Ejection Fraction From DIG-PEF, CHARM-Preserved, and I-PRESERVE?, in
Journal of the American College of Cardiology, 2012; 60: 2349–56. (R. T. Campbell)
* Cancer Therapy–Induced Cardiac Toxicity in Early Breast Cancer: Addressing the Unresolved Issues, in
Circulation, 2012; 126: 2749–63. (L. W. Jones, lee.w.jones@duke.edu)
* State-of-the-Art Monitoring of Cytomegalovirus-Specific Cell-Mediated Immunity After Organ Transplant: A Primer for the Clinician, in
Clinical Infectious Diseases, 2012; 55: 1678–89. (D. Kumar, deepali.kumar@ualberta.ca)
* The Nature of the Association Between Childhood ADHD and the Development of Bipolar Disorder: A Review of Prospective High-Risk Studies, in
American Journal of Psychiatry, 2012; 169: 1247–55. (A. Duffy, acduffy@ucalgary.ca)
* ECT in Treatment-Resistant Depression, in
American Journal of Psychiatry, 2012; 169: 1238–44. (C. H. Kellner, charles.kellner@mssm.edu)
* Inpatient Statin Use Predicts Improved Ischemic Stroke Discharge Disposition, in
Neurology, 2012; 79: 2294. (O. Kano)
* Antiangiogenic Therapy for Cancer: An Update, in
Pharmacotherapy, 2012; 32: 1095–111. (P. R. Somanath, sshenoy@georgiahealth.edu)
* Antifungal Susceptibility Testing: A Primer for Clinicians, in
Pharmacotherapy, 2012; 32: 1112–22. (K. Kuper, kristine.kuper@cardinalhealth.com)
* Drug-Induced Gynecomastia, in
Pharmacotherapy, 2012; 32: 1123–40. (J. D. Bowman, bowman@pharmacy.tamhsc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 11, 2012 * Vol. 19, No. 238
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Dec. 10/24 issue of the Archives of Internal Medicine (2012; 172).
Enoxaparin in Moderate Renal Impairment: Patients with moderate renal impairment who receive enoxaparin are at increased risk of major bleeding, according to a report that calls for further study of an appropriate dose in this population (pp. 1713–8). In patients who received enoxaparin sodium 1 mg/kg every 12 hours or 1.5 mg/kg once daily during a 6-month period in 2009, these outcomes were noted in 105 patients with normal (CrCl > 80 mL/min) and 59 patients with moderate (CrCl 30–50 mL/min) renal function: “The primary outcome occurred in 6 of 105 patients (5.7%) with normal renal function vs 13 of 59 patients (22.0%) with moderate renal impairment, representing an unadjusted odds ratio of 4.7 (95% CI, 1.7–13.0; P = .002). The odds ratio using multivariable logistic regression adjusting for differences in risk was 3.9 (95% CI, 0.97–15.6; P = .055). There was no recurrent thromboembolism in either group.” (D. D. DeCarolis, douglas.decarolis@va.gov)
“As with unfractionated heparin, enoxaparin dosing is weight based; however, enoxaparin relies more on the kidneys for metabolism,” writes an editorialist (
pp. 1718–20). “Although studies demonstrate accumulation of this low-molecular-weight heparin in patients with compromised renal clearance, the current recommended dose for patients with moderate renal impairment is the same as for those with normal renal function. Currently, there are no recommendations for dose reduction until CrCl is less than 30 mL/min.…
“The work by DeCarolis and colleagues adds to an important body of work that should lead clinicians to take caution with the use of enoxaparin in patients with moderate renal impairment, particularly in the perioperative period, and to insist on an evidence-based update of current dosing recommendations for patients receiving any anticoagulant that is renally cleared. Arming the providers with safer dosing guidelines will help to achieve the national effort to reduce harm related to these agents.” (T. Minichiello,
minichie@medicine.ucsf.edu)
Hip Fracture After Starting Antihypertensives in Older Patients: Among a population of hypertensive community-dwelling older patients, initiation of antihypertensive drugs was associated with an immediate increase in risk of hip fracture, researchers report (pp. 1739–44). Analysis of administrative health care databases in Ontario showed these patterns in a population-based, self-controlled case series: “Among the 301,591 newly treated hypertensive community-dwelling elderly patients, 1,463 hip fractures were identified during the observation period. Hypertensive elderly persons who began receiving an antihypertensive drug had a 43% increased risk of having a hip fracture during the first 45 days following treatment initiation relative to the control periods (incidence rate ratio, 1.43; 95% CI, 1.19–1.72).” (D. Butt, debra.butt@utoronto.ca)
Health Systems & Antihypertensive Adherence: Changes in health-system policies can overcome racial and ethnic differences in adherence during the early phase of antihypertensive treatment, a Kaiser retrospective cohort study of 44,167 patients shows (doi: 10.1001/2013.jamainternmed.955): “More than 30% of patients were early nonpersistent and 1 in 5 were nonadherent to therapy. Nonwhites were more likely to exhibit both types of suboptimal medication-taking behavior compared with whites. In logistic regression models adjusted for sociodemographic, clinical, and health system factors, nonwhite race was associated with early nonpersistence (black: odds ratio, 1.56 [95% CI, 1.43–1.70]; Asian: 1.40 [1.29–1.51]; Hispanic: 1.46 [1.35–1.57]) and nonadherence (black: 1.55 [1.37–1.77]; Asian: 1.13 [1.00–1.28]; Hispanic: 1.46 [1.31–1.63]). The likelihood of early nonpersistence varied between Asians and Hispanics by choice of first-line therapy. In addition, racial and ethnic differences in nonadherence were appreciably attenuated when medication co-payment and mail-order pharmacy use were accounted for in the models.” (A. S. Adams, Alyce.S.Adams@kp.org)

>>>PNN NewsWatch
* FDA has expanded the approved use of abiraterone acetate (Zytiga, Janssen) to include treatment of men with metastatic castration-resistant prostate cancer before receiving chemotherapy. The agent was originally approved for use after treatment with docetaxel.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 12, 2012 * Vol. 19, No. 239
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 12 issue of JAMA (2012; 308).
Acetazolamide for Sleep Apnea at High Altitudes: The combination of acetazolamide and autoadjusted continuous positive airway pressure (autoCPAP) controlled obstructive sleep apnea (OSA) among 51 patients who traveled from their homes below 800-m altitudes to moderately high elevations of 1,630 and 2,590 m, a study shows (pp. 2390–8). Participants underwent baseline tests at a university hospital at 490 m and then travelled to Swiss mountain resorts (2 days at the lower elevation and 1 at the higher). While at elevated altitudes, participants received acetazolamide 750 mg/d or placebo in addition to autoCPAP in crossover fashion, with these results: “Acetazolamide and autoCPAP treatment was associated with higher nocturnal oxygen saturation at 1,630 m and 2,590 m than placebo and autoCPAP: medians, 94% (interquartile range [IQR], 93%–95%) and 91% (IQR, 90%–92%) vs 93% (IQR, 92%–94%) and 89% (IQR, 87%–91%), respectively. Median increases were 1.0% (95% CI, 0.3%–1.0%) and 2.0% (95% CI, 2.0%–2.0). Median night-time spent with oxygen saturation less than 90% at 2,590 m was 13% (IQR, 2%–38%) vs 57% (IQR, 28%–82%; P < .001). Acetazolamide and autoCPAP resulted in better control of sleep apnea at 1,630 m and 2,590 m than placebo and autoCPAP: median apnea/hypopnea index was 5.8 events per hour (5.8/h) (IQR, 3.0/h–10.1/h) and 6.8/h (IQR, 3.5/h–10.1/h) vs 10.7/h (IQR, 5.1/h–17.7/h) and 19.3/h (IQR, 9.3/h–29.0/h), respectively; median reduction was 3.2/h (95% CI, 1.3/h–7.5/h) and 9.2 (95% CI, 5.1/h–14.6/h).” (K. E. Bloch, konrad.bloch@usz.ch)

>>>Infectious Diseases Report
Source:
Dec. 15 issue of Clinical Infectious Diseases (2012; 55).
Resistance to Second-Line TB Drugs: Risk factors for developing acquired resistance (AR) to injectable SLDs (INJ SLDs) include “age, positive HIV status, [multidrug-resistant (MDR)] tuberculosis and initial treatment with any SLD, while the only predictor for AR to fluoroquinolones was MDR tuberculosis at treatment initiation,” researchers report (pp. 1600–7). Analysis of 1993–2008 data from the U.S. National Tuberculosis Surveillance System showed the following: “The baseline prevalence of MDR and extensively drug-resistant (XDR) tuberculosis was 12.6% (1,864/14,770) and 0.38% (56/14,770), respectively. Of 2,274 individuals without initial resistance to INJ SLDs, 49 (2.2%) acquired resistance. Of 1,141 initially susceptible to fluoroquinolones, 32 (2.8%) acquired resistance. The AR to INJ SLDs was associated with age group 25–44 years (adjusted odds ratio [aOR], 2.7; 95% confidence interval [CI], 1.2–6.3), positive HIV status (aOR, 2.5; 95% CI, 1.3–4.7), MDR at treatment initiation (aOR, 5.5; 95% CI, 2.9–10.5), and treatment with any SLD (aOR, 2.4; 95% CI,1.2–4.7). The AR to fluoroquinolones was associated with MDR tuberculosis at treatment initiation (aOR, 6.5; 95% CI, 2.9–14.6).” (J. V. Ershova, jershova@cdc.gov)
Hormonal Contraceptive Use & S. aureus Nasal Carriage: A cohort study of healthy volunteers identifies a link between use of hormonal contraceptives and persistent nasal carriage of Staphylococcus aureus, and this “may substantially increase the human S. aureus reservoir with potential impact on S. aureus infection and transmission,” authors conclude (pp. 1625–32): “At baseline, 266 of 1,180 volunteers (22.5%) were classified as persistent nasal carriers. Compared with women not using hormonal contraceptives, women taking reproductive hormones (odds ratio [OR]. 1.88; 95% confidence interval [CI], 1.29–2.75; P = .001) and men (OR., 1.57; 95% CI, 1.08–2.28; P = .02) were more likely to be persistent carriers. These associations remained stable after adjusting for known risk factors of nasal carriage. Women taking hormonal contraceptives and being persistent carriers at baseline were more likely to remain carriers after a median follow-up time of 70 days than women not using such medication (OR, 3.25; 95% CI, 1.44–7.34; P = .005). No patterns of association could be observed between persistent carriage among women and type of progestin or dose of estrogen used. Assuming causality and using estimates from multivariable logistic regression, we approximated that 20% (95% CI, 2.4%–34.9%) of persistent nasal carriage among women represented by our sample is attributable to hormonal contraception.” (P. Zanger, philipp.zanger@uni-tuebingen.de)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Dec. 13, 2012 * Vol. 19, No. 240
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 13 issue of the New England Journal of Medicine (2012; 367).
Malaria Vaccine: Three monthly doses of the candidate malaria vaccine RTS,S/AS01 provided modest protection in 6,537infants ages 6–12 weeks, researchers report (pp. 2284–95). Begun with the first vaccination of the Expanded Program on Immunization, malaria vaccine or a comparator vaccine produced these results in seven African countries: “The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person–year in the RTS,S/AS01 group and 0.40 per person–year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, −7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222).” (S. Mian-McCarthy, smian-mccarthy@path.org)
Despite equivocal results, this trial advances research in some respects, writes an editorialist (
pp. 2349–51): “The results of this trial suggest that this candidate malaria vaccine is not ready to become part of the routine panel of infant immunizations. However, this trial did show protection in a subset of children and thus should be used as an opportunity to enlighten researchers regarding the host responses that correlate with vaccine protection. There are many vaccine candidates in the pipeline that use alternative parasite targets and vaccination strategies. Whether leaders in malaria-vaccine development will be able to support the costs needed to integrate sophisticated host-response studies or other value-added studies into these future vaccine trials remains to be seen. The results of this immunization trial suggest that a malaria vaccine is possible, but a more detailed understanding of effective host responses will be necessary to achieve this goal and avert the illnesses and deaths associated with this devastating infection for millions of children.” (J. P. Daily)
RAS-Mutant Leukemia Progression With RAF Inhibitors: In a brief report, authors describe “accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib,” a selective RAF inhibitor (pp. 2316–21). “Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal,” the writers note, adding this explanation for their finding, “Vemurafenib … extends survival among patients with BRAF V600E–mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E–mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors.” (P. B. Chapman, chapmanp@mskcc.org)
Medications Essential During Megadisasters: The need for medications is the “most obvious and critical concern” with regard to maintenance of supply chains in megadisasters such as Superstorm Sandy, an author writes (pp. 2269–71): “Visits to shelters in the region revealed that many people lacked backup medication supplies or prescriptions. Patients— and shelter managers —often had little information about how or where to obtain these necessities.” (I. Redlener)

>>>PNN NewsWatch
* An FDA-mandated meta-analysis confirms a nonsignificant but increased risk of major adverse cardiovascular events in patients using varenicline (Chantix, Pfizer) for smoking cessation. Cardiovascular-related death, nonfatal myocardial infarction, or nonfatal stroke occurred in 13 of 4,190 patients on varenicline and 6 of 2,812 patients on placebo. These incidence rates, 0.31% and 0.21%, respectively, produced a hazard ratio of 1.95 for major adverse cardiovascular events with active therapy, but the 95% confidence interval includes the 1.0 value (0.79–4.82), indicating nonsignificance.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 14, 2012 * Vol. 19, No. 241
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Dec. issue of the Journal of Allergy and Clinical Immunology (2012; 130).
LABAs in Asthma: In an invited commentary, authors provide guidance on the difficult decisions surrounding use of long-acting beta-agonists (LABAs) in treatment of asthma (pp. 1256–9): “The benefit/risk balance of LABA therapy is an ongoing controversy that has engendered vigorous debate among well-intentioned authorities. This debate has raised doubts and confusion in the minds of both clinicians and patients. The [National Asthma Education and Prevention Program (NAEPP)’s Expert panel report 3 (EPR-3)] carefully positioned LABAs in the treatment of asthma. First, there is no place for using LABAs as long-term control monotherapy. Second, advancing from step 2, where an [inhaled corticosteroid (ICS)] is the preferred step, to step 3, the clinician has the option of either a low-dose ICS plus LABA or a medium-dose ICS. Beyond step 4, ICS/LABA combinations are the preferred treatment. While we await information from current trials and a future expert panel review of studies available since the EPR-3’s publication for an update of the NAEPP’s asthma guidelines, our own review of current information leads us to conclude that there are no data to modify the EPR-3 approach. However, selecting which agent for step down remains an unresolved issue. Although arguments can be made for either approach, discontinuing a LABA versus decreasing the ICS dose, no comparative study has addressed this directly; however, current observations do not fully support withdrawing the LABA as the first step-down medication. The ongoing required FDA studies will provide information on LABA safety but not necessarily step-down approaches. If these ongoing FDA-required studies indicate LABAs are safe, the question on the effectiveness and safety of a LABA step down will remain largely unanswered. If there are safety concerns that arise in the FDA-required safety trials, the question on step down will require further thought.” (S. J. Szefler, szeflers@njhealth.org)
Maternal Probiotics & Eczema in Infants: Prenatal and postnatal probiotics given to mothers with positive skin-prick tests can reduce the risk eczema in their babies, a study shows (pp. 1355–60). Among 205 mother–infant pairs, mothers with allergic disease and atopic sensitization received either Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999 (LPR+BL999), L. paracasei ST11 and B. longum BL999 (ST11+BL999), or placebo for 2 months before delivery and for the first 2 months of breastfeeding, with these results: “The risk of developing eczema during the first 24 months of life was significantly reduced in infants of mothers receiving LPR+BL999 (odds ratio [OR], 0.17; 95% CI, 0.08–0.35; P < .001) and ST11+BL999 (OR, 0.16; 95% CI, 0.08–0.35; P < .001). The respective ORs for chronically persistent eczema were 0.30 (95% CI, 0.12–0.80; P = .016) and 0.17 (95% CI, 0.05–0.56; P = .003). Probiotics had no effect on the risk of atopic sensitization in the infants. No adverse effects were related to the use of probiotics.” (S. Rautava, samrau@utu.fi)

>>>Chest Highlights
Source:
Dec. Chest (2012; 142).
Interdisciplinary Collaboration in Critical Care: Noting the benefits of interdisciplinary collaboration as “an essential building block for successful health-care teams,” authors of an “Ahead of the Curve” article advocate increased adoption of this model in critical care (pp. 1611–9): “The very short time frames over which the care needs of critically ill or injured adults change and the team approach taken by nearly all ICUs strongly suggest that interdisciplinary collaboration is also beneficial in this setting. In this commentary, we define interdisciplinary collaboration and share the story of how we successfully redesigned and transformed our system-wide, interdisciplinary collaborative model for delivering critical care in order to share the lessons we learned as the process evolved with those who are about to embark on a similar challenge. We anticipate that those health-care systems that successfully implement interdisciplinary collaboration will be ahead of the curve in providing high-quality care at as low a cost as possible. Such institutions will also potentially be better positioned for improving teaching and providing a better foundation for critical care research in their institutions.” (R. S. Irwin, Richard.Irwin@umassmemorial.org)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 17, 2012 * Vol. 19, No. 242
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Dec. 15 issue of Lancet (2012; 380).
Worldwide Mortality by Age, Geography: Global life expectancy continues to climb but “with substantial heterogeneity … across age groups, among countries, and over different decades,” researchers report (pp. 2071–94). One of several articles in this issue on global health, this report contains estimates of mortality rates in children ages 0–4 years and adults ages 15–59 years. Results show: “From 1970 to 2010, global male life expectancy at birth increased from 56.4 years (95% UI 55.5–57.2) to 67.5 years (66.9–68.1) and global female life expectancy at birth increased from 61.2 years (60.2–62.0) to 73.3 years (72.8–73.8). Life expectancy at birth rose by 3–4 years every decade from 1970, apart from during the 1990s (increase in male life expectancy of 1.4 years and in female life expectancy of 1.6 years). Substantial reductions in mortality occurred in eastern and southern sub-Saharan Africa since 2004, coinciding with increased coverage of antiretroviral therapy and preventive measures against malaria. Sex-specific changes in life expectancy from 1970 to 2010 ranged from gains of 23–29 years in the Maldives and Bhutan to declines of 1–7 years in Belarus, Lesotho, Ukraine, and Zimbabwe. Globally, 52.8 million (95% UI 51.6–54.1 million) deaths occurred in 2010, which is about 13.5% more than occurred in 1990 (46.5 million [45.7–47.4 million]), and 21.9% more than occurred in 1970 (43.3 million [42.2–44.6 million]). Proportionally more deaths in 2010 occurred at age 70 years and older (42.8% in 2010 vs 33.1% in 1990), and 22.9% occurred at 80 years or older. Deaths in children younger than 5 years declined by almost 60% since 1970 (16.4 million [16.1–16.7 million] in 1970 vs 6.8 million [6.6–7.1 million] in 2010), especially at ages 1–59 months (10.8 million [10.4–11.1 million] in 1970 vs 4.0 million [3.8–4.2 million] in 2010). In all regions, including those most affected by HIV/AIDS, we noted increases in mean ages at death.” (H. Wang, haidong@uw.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Dog Detection of C. difficile: In a proof-of-concept study, a trained dog detected Clostridium difficile in patients by walking through wards with more than 90% accuracy, a study shows (e7396). An entertaining 10-min film explains how Cliff, a beagle, “sees” the world through his nose and shows him working a ward at a Dutch hospital. In tests of the dog’s ability to detect the bacterium in stool samples and during 30 detection rounds each with 10 patients, one of whom had C. difficile, these results were obtained: “The dog’s sensitivity and specificity for identifying C difficile in stool samples were both 100% (95% confidence interval 91% to 100%). During the detection rounds, the dog correctly identified 25 of the 30 cases (sensitivity 83%, 65% to 94%) and 265 of the 270 controls (specificity 98%, 95% to 99%).” (M. K. Bomers, m.bomers@vumc.nl)

>>>PNN NewsWatch
* FDA approved three new drugs on Friday. Ponatinib (Iclusig, ARIAD), an oral tyrosine kinase inhibitor covered recently in PNN (see Nov. 29), is indicated for treatment of adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). The orphan drug pasireotide diaspartate injection (Signifor, Novartis Pharma Stein) was approved for the treatment of Cushing’s disease patients who cannot be treated surgically. Approved for treating inhalational anthrax was raxibacumab injection (Human Genome Sciences). Raxibacumab also was approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate.

>>>PNN JournalWatch
* Guideline for the Management of Fever and Neutropenia in Children With Cancer and/or Undergoing Hematopoietic Stem-Cell Transplantation, in
Journal of Clinical Oncology, 2012; 30: 4427–38. (L. Sung, lillian.sung@sickkids.ca)
* Palliative and Therapeutic Harmonization: A Model for Appropriate Decision-Making in Frail Older Adults, in
Journal of the American Geriatrics Society, 2012; 60: 2326–32. (P. Moorhouse, paige.moorhouse@cdha.nshealth.ca)
* Diabetes in Older Adults: A Consensus Report, in
Journal of the American Geriatrics Society, 2012; 60: 2342–56. (J. B. Halter, jhalter@med.umich.edu)
* Histamine-1 Receptor Antagonism for Treatment of Insomnia, in
Journal of the American Pharmacists Association, 2012; 52: e210–9. (J. P. Vande Griend, joseph.vandegriend@ucdenver.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Dec. 18, 2012 * Vol. 19, No. 243
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Dec. 18 issue of the Annals of Internal Medicine (2012; 157).
Epidural Corticosteroids in Sciatica: The procedure involved in the recent fungal meningitis outbreak—epidural corticosteroid injection— is questioned in a systematic review and meta-analysis of available evidence of studies of sciatica (pp. 865–77). “The available evidence suggests that epidural corticosteroid injections offer only short-term relief of leg pain and disability for patients with sciatica,” the authors conclude. “The small size of the treatment effects, however, raises questions about the clinical utility of this procedure in the target population.” Analysis of 25 published reports of 23 studies showed these findings: “The pooled results showed a significant, although small, effect of epidural corticosteroid injections compared with placebo for leg pain in the short term (mean difference, −6.2 [95% CI, −9.4 to −3.0]) and also for disability in the short term (mean difference, −3.1 [CI, −5.0 to −1.2]). The long-term pooled effects were smaller and not statistically significant. The overall quality of evidence according to the GRADE classification was rated as high.” (R. Z. Pinto, rafaelzambelli@gmail.com)
Adalimumab for Hidradenitis Suppurativa: Administered once weekly, adalimumab reduces symptoms in patients with moderate to severe hidradenitis suppurativa (HS), researchers report (pp. 846–55). Use of the anti-TNF-alpha antibody was assessed in 154 adults patients with HS, described by the authors as “a chronic, painful skin disease characterized by abscesses, nodules, and draining fistulas in the axilla and groin of young adults.” In the Phase II trial, patients received either adalimumab 40 mg/wk, adalimumab 40 mg every other week (EOW), or placebo during a blinded 16-week period 1 and adalimumab 40 mg EOW (or every week if symptoms continued) during an open-label, 36-week period 2, with these results: “At week 16, 3.9% of placebo patients (2 of 51), 9.6% of EOW patients (5 of 52), and 17.6% of weekly patients (9 of 51) achieved clinical response (EOW vs. placebo strata-adjusted difference, 5.6% [95% CI, −4.0% to 15.3%]; P = 0.25; weekly vs. placebo strata-adjusted difference, 13.7% [CI, 1.7% to 25.7%]; P = 0.025). Serious adverse event rates were 3.9%, 5.8%, and 7.8% for placebo, EOW, and weekly patients, respectively (EOW vs. placebo difference, 1.8% [CI, −6.4% to 10.1%]; weekly vs. placebo difference, 3.9% [CI, −5.2% to 13.0%]). Significantly greater improvements in patient-reported outcomes and pain were seen in the weekly dosing group than in the placebo group. A decrease in response was seen after the switch from weekly to EOW dosing in period 2.” (A. B. Kimball, harvardskinstudies@partners.org)
Probiotics for Prevention of Clostridium difficile Diarrhea: In adult and pediatric patients, probiotic prophylaxis reduces the incidence of Clostridium difficile–associated diarrhea (CDAD) in patients taking antibiotics, according to a systematic review and meta-analysis (pp. 878–88): “Twenty trials including 3,818 participants met the eligibility criteria. Probiotics reduced the incidence of CDAD by 66% (pooled relative risk, 0.34 [95% CI, 0.24 to 0.49]; I2 = 0%). In a population with a 5% incidence of antibiotic-associated CDAD (median control group risk), probiotic prophylaxis would prevent 33 episodes (CI, 25 to 38 episodes) per 1,000 persons. Of probiotic-treated patients, 9.3% experienced adverse events, compared with 12.6% of control patients (relative risk, 0.82 [CI, 0.65 to 1.05]; I2 = 17%).” (B. C. Johnston, bradley.johnston@sickkids.ca)

>>>PNN NewsWatch
* In the 2013–14 influenza season, a quadrivalent vaccine will be available, thanks to yesterday’s FDA approval of Fluarix Quadrivalent (GlaxoSmithKline). The intramuscular vaccine is the first influenza product to cover four strains—adding a second B strain to the two A strains and one B strain in trivalent products. The product is indicated for use in children ages 3 years or older and adults. Since 2000, two B virus strains, Victoria and Yamagata, have co-circulated to varying degrees each season, GSK said: “Various degrees of mismatch have occurred between the B strain included in trivalent vaccines and the B strain that actually circulated, causing an increased risk of influenza-related morbidity across all age groups – children, adults and the elderly. Fluarix Quadrivalent helps protect against the two A strains and adds coverage against a second B strain.”

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 19, 2012 * Vol. 19, No. 244
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and Dec. 19 issue of JAMA (2012; 308).
Compounding ‘Still in the Dark Ages’: Countering pharmacy’s “we’ve always compounded” defense, editorialists review compounding-related problems from the early 2000s and compare them with similar factors in the recent fungal meningitis outbreak (pp. 2461–2): “The debacle at the New England Compounding Center … indicates that compounding has yet to fully emerge from the Dark Ages. Congressional hearings will call attention to the need to stop certain high-risk compounding practices and more closely oversee those that remain. Legislation clarifying FDA’s authority and empowering the agency to establish national standards for compounding, including adverse event reporting, should follow. State agencies should serve as partners in oversight and enforcement. Physicians and patients should routinely discuss the potential risks of using compounded products, particularly in the rapidly expanding world of pain management. All compounding pharmacies must take responsibility for the quality of what they produce.
“The meningitis outbreak of 2012 exposes how far the health care system still needs to go to protect patients from unsafe products. Fortunately, there is reason for hope. The urgent and coordinated response to the crisis, involving clinicians and public health officials across the country, has helped to inform and protect the public. If only a fraction of this energy can be applied to the task of prevention, the compounding problem could be fixed. Ten years from now, this outbreak should be more than just another chapter in the book of drug compounding tragedies. Instead, it should be remembered as the moment public health and the health care system came together to write a different ending.” (J. M. Sharfstein,
joshua.sharfstein@maryland.gov)
Aspirin & Age-Related Macular Degeneration: A 20-year longitudinal study of 4,926 people finds “a small but statistically significant association between regular aspirin use and incidence of neovascular [age-related macular degeneration (AMD)]” (pp. 2469–78). In the Beaver Dam Eye Study, Wisconsin residents ages 43–86 years at baseline showed these AMD incidence patterns during eye examinations every 5 years over a median of 14.8 years: “There were 512 incident cases of early AMD (of 6,243 person–visits at risk) and 117 incident cases of late AMD (of 8,621 person–visits at risk) over the course of the study. Regular aspirin use 10 years prior to retinal examination was associated with late AMD (hazard ratio [HR], 1.63 [95% CI, 1.01–2.63]; P = .05), with estimated incidence of 1.76% (95% CI, 1.17%–2.64%) in regular users and 1.03% (95% CI, 0.70%–1.51%) in nonusers. For subtypes of late AMD, regular aspirin use 10 years prior to retinal examination was significantly associated with neovascular AMD (HR, 2.20 [95% CI, 1.20–4.15]; P = .01) but not pure geographic atrophy (HR, 0.66 [95% CI, 0.25–1.95]; P = .45). Aspirin use 5 years (HR, 0.86 [95% CI, 0.71–1.05]; P = .13) or 10 years (HR, 0.86 [95% CI, 0.65–1.13]; P = .28) prior to retinal examination was not associated with incident early AMD.” (B. E. K. Klein, kleinb@epi.ophth.wisc.edu)
PCSK9 Antibody in Statin-Intolerant Patients: In a Phase II trial of 160 statin-intolerant patients, “subcutaneous administration of a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels and was associated with short-term tolerability,” researchers report (pp. 2497–506). AMG145 (also studied in reports covered in the July 9, Nov. 15, and Dec. 10 PNNs) or placebo administered every 4 weeks lowered mean LDL cholesterol levels at week 12 by 67–110 mg/dL at varying weekly doses, compared with 14 mg/dL in a placebo/ezetimibe group. Coronary artery disease, acute pancreatitis, hip fracture, or syncope occurred in 4 patients, and myalgia was the most common treatment-emergent adverse event. (E. A. Stein, esteinmrl@aol.com)

>>>PNN NewsWatch
* Combined use of sodium oxybate (Xyrem, Jazz Pharmaceuticals) with alcohol or CNS depressants can markedly impair consciousness and may lead to respiratory depression, FDA said yesterday. Alcohol use is a new contraindication added to the Xyrem label, the agency added, and hypnotic drugs were previously contraindicated. The use of Xyrem with other CNS depressant drugs should also generally be avoided.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 20, 2012 * Vol. 19, No. 245
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article from and Dec. 20 issue of New England Journal of Medicine (2012; 367).
Fungal Infections & Contaminated Methylprednisolone Injections: A preliminary report illustrates the “substantial morbidity and mortality” associated with epidural administration of contaminated methylprednisolone from the New England Compounding Center (doi: 10.1056/NEJMoa1213978): “As of October 19, 2012, more than 99% of 13,534 potentially exposed persons had been contacted. As of December 10, there were 590 reported cases of infection in 19 states, with 37 deaths (6%). As of November 26, laboratory evidence of Exserohilum rostratum was present in specimens from 100 case patients (17%). Additional data were available for 386 case patients (65%); 300 of these patients (78%) had meningitis. Case patients had received a median of 1 injection (range, 1 to 6) of implicated methylprednisolone acetate. The median age of the patients was 64 years (range, 16 to 92), and the median incubation period was 20 days (range, 0 to 120); 33 patients (9%) had a stroke.” (B. J. Park, bpark1@cdc.gov)
Noting that “designer” pharmacies “are essential if our health care system is to serve populations with particular needs,”
Journal editors call for FDA to have “broader powers to monitor and control the agents produced by such pharmacies and any adverse events that are associated with them” (pp. 2436–7): “[The fungal meningitis outbreak and other events] make it clear that we need new legislation that gives the FDA stronger and better control of compounding pharmacies. Representative Ed Markey (D-MA) has introduced such legislation: the Verifying Authority and Legality in Drug (VALID) Compounding Act. The bill, if passed, would give the FDA broader powers to regulate compounding pharmacies while at the same time giving the agency the latitude to ensure that such pharmacies can continue to produce needed medical products. It would preserve state regulatory authority over traditional compounding pharmacies that make customized drugs for individual patients but would place pharmacies that operate as drug manufacturers under FDA regulation. This bill is a generally appropriate step forward, and we believe it should receive strong bipartisan support.” (J. M. Drazen)
Treatment of Systemic Juvenile Idiopathic Arthritis: Research studies examine monoclonal antibody treatment of systemic juvenile idiopathic arthritis (JIA).
Compared with placebo, the humanized, antihuman interleukin-6–receptor monoclonal antibody tocilizumab was effective for severe persistent systemic JIA in a Phase III trial (
pp. 2385–95). Doses of 8 or 12 mg/kg (for weights above or below 30 kg) produced these results: “At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P < 0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids.” (F. De Benedetti, fabrizio.debenedetti@opbg.net)
Two Phase III trials demonstrated efficacy of canakinumab in systemic JIA with active systemic features (
pp. 2396–406). The selective, fully human, anti–interleukin-1-beta monoclonal antibody produced an adapted JIA ACR 30 response in 36 of 43 (84%), compared with 4 of 41 (10%) taking placebo (P < 0.001) in the double-blind trial. In an open-label study, authors reported that “the average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%).” (N. Ruperto, nicolaruperto@ospedale-gaslini.ge.it)

>>>PNN NewsWatch
* Teleprevir (Incivek, Vertex) can produce serious and potentially fatal skin reactions, including toxic epidermal necrolysis and Stevens–Johnson syndrome, when used with peginterferon alfa and ribavirin to treat hepatitis C, FDA warned yesterday. Some patients died when they continued to receive Incivek combination treatment after developing a progressive rash and systemic symptoms.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 21, 2012 * Vol. 19, No. 246
Providing news and information about medications and their proper use

>>>Diabetes Report
Source:
Jan. issue of and supplement to Diabetes Care (2013; 36).
2013 Clinical Practice Recommendations: In its annual update to recommended medical care for diabetes, the American Diabetes Association makes these key points in the pharmacotherapy and immunization sections (pp. S4–10) of the 56-page document (pp. S11–66):
* For type 1 diabetes, most patients should receive multiple-dose insulin or continuous subcutaneous insulin infusion, generally with insulin analogs; be educated on how to determine prandial insulin dose; and be screened for other autoimmune diseases as appropriate.
* Unless contraindicated and if tolerated, metformin is the preferred initial pharmacologic agent for type 2 diabetes. After 3–6 months of noninsulin monotherapy at maximal tolerated doses, a second agent can be added if A1C targets are not met. Choices are another oral agent, insulin, or a GLP-1 agonist.
* Choice of pharmacologic agents in type 2 diabetes should be made using a patient-centered approach.
* Insulin therapy is “eventually indicated for many patients with type 2 diabetes” because of “the progressive nature” of the disease.
* Vaccines recommended are annual influenza (all patients with diabetes 6 months or older); pneumococcal polysaccharide (2 years or older) with revaccination (for those 65 or older if the last vaccine was more than 5 years ago); and hepatitis B (19–59 years and sometimes 60 years or older).
Motivating Diabetes Prevention Through Genetic Risk Counseling: A program of personalized genetic risk counseling was not enough to prompt overweight individuals to lose weight or improve their self-reported motivation and adherence to a diabetes-prevention program, researchers report (pp. 13–9). Risk counseling was based on presence of 36 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes. Participants were allocated to genetic testing or no testing. Tested participants in the top and bottom quartiles of risk based on presence of SNPs received genetic risk counseling, with these results: “The 108 participants enrolled in the diabetes prevention program included 42 participants at higher diabetes genetic risk, 32 at lower diabetes genetic risk, and 34 untested control subjects. Mean age was 57.9 ± 10.6 years, 61% were men, and average BMI was 34.8 kg/m2, with no differences among randomization groups. Participants attended 6.8 ± 4.3 group sessions and lost 8.5 ± 10.1 pounds, with 33 of 108 (30.6%) losing ≥5% body weight. There were few statistically significant differences in self-reported motivation, program attendance, or mean weight loss when higher-risk recipients and lower-risk recipients were compared with control subjects (P > 0.05 for all but one comparison).” (R. W. Grant, richard.w.grant@kp.org)
Insulin Intensification & Socioeconomic Factors: Youth with type 1 diabetes were more often switched to more intensive (MI) insulin regimens if they were white and from upper socioeconomic groups, a study shows (pp. 27–33). “Of the 1,606 participants with a mean follow-up of 36 months, 51.7% changed to an MI regimen, 44.7% had [no change (NC)], and 3.6% changed to a [less intensive (LI)] regimen. Participants who were younger, non-Hispanic white, and from families of higher income and parental education and who had private health insurance were more likely to be in MI or NC groups. Those in MI and NC groups had lower baseline A1C (P = 0.028) and smaller increase in A1C over time than LI (P < 0.01). Younger age, continuous subcutaneous insulin pump therapy, and change to MI were associated with higher probability of achieving target A1C levels.” (C. Pihoker, catherine.pihoker@seattlechildrens.org)

>>>PNN NewsWatch
* Dabigatran etexilate mesylate (Pradaxa, Boehringer-Ingelheim) should not be used to prevent major thromboembolic events in patients with mechanical heart valves, FDA said yesterday. The European RE-ALIGN trial was recently stopped because dabigatran users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than were users of warfarin. There was also more bleeding after valve surgery in the dabigatran users than in the warfarin users.
*
PNN will not be published on Mon. and Tues., Dec. 24–25, Christmas Eve and Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 26, 2012 * Vol. 19, No. 247
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Dec. 26 issue of JAMA (2012; 308).
Management of Varicose Veins: The case of a 68-year-old woman with varicose veins is used to review chronic venous disease and its associated symptoms (pp. 2612–21): “Chronic venous disease … is manifested by a spectrum of signs and symptoms, including cosmetic spider veins, asymptomatic varicosities, large painful varicose veins, edema, hyperpigmentation and lipodermatosclerosis of skin, and ulceration. However, there is no definitive stepwise progression from spider veins to ulcers and, in fact, severe skin complications of varicose veins, even when extensive, are not guaranteed. Treatment options range from conservative (eg, medications, compression stockings, lifestyle changes) to minimally invasive (eg, sclerotherapy or endoluminal ablation), invasive (surgical techniques), and hybrid (combination of ≥1 therapies).” (A. Hamdan, ahamdan@bidmc.harvard.edu)

>>>Circulation Report
Source:
Dec. 18 issue of Circulation (2012; 126).
Arginase Inhibition in CAD & Type 2 DM: In patients with coronary artery disease and type 2 diabetes mellitus, inhibition of arginase “markedly improves endothelial function … suggesting that increased arginase activity is a key factor in the development of endothelial dysfunction,” researchers report (pp. 2943–50). Three groups of 16 patients each had CAD, CAD+Diabetes, or neither condition (control). Infusions of the arginase inhibitor N-omega-hydroxy-nor-l-arginine (nor-NOHA) at 0.1 mg/min with the nitric oxide synthase inhibitor NG-monomethyl l-arginine showed these results: “Nor-NOHA markedly increased endothelium-dependent vasodilatation (up to 2-fold) in patients with CAD+Diabetes and CAD (P < 0.001) but not in the control group. NG-monomethyl l-arginine completely inhibited the increase in endothelium-dependent vasodilatation induced by nor-NOHA. Endothelium-independent vasodilatation was slightly improved by nor-NOHA in the CAD+Diabetes group. Arginase I was expressed in vascular smooth muscle cells and endothelial cells, and arginase II was expressed in endothelial cells of patients with and without diabetes mellitus.” (A. Shemyakin, alexey.shemyakin@ki.se)
BMI & Incident HTN: After adjustment for other contributing factors, increasing weight over the lifespan was strongly associated with increasing risk of hypertension among 1,132 white men in The Johns Hopkins Precursors Study (pp. 2983–9). During a median follow-up period of 46 years, investigators found these associations between body mass index (BMI) and hypertension based on 508 men who developed hypertension: “Obesity (BMI ≥30 kg/m2) in young adulthood was strongly associated with incident hypertension (hazard ratio, 4.17; 95% confidence interval, 2.34–7.42). Overweight (BMI 25 to <30 kg/m2) also signaled increased risk (hazard ratio, 1.58; 95% confidence interval, 1.28–1.96). Men of normal weight at age 25 years who became overweight or obese at age 45 years were at increased risk compared with men of normal weight at both times (hazard ratio, 1.57; 95% confidence interval, 1.20–2.07), but not men who were overweight or obese at age 25 years who returned to normal weight at age 45 years (hazard ratio, 0.91; 95% confidence interval, 0.43–1.92). After adjustment for time-dependent number of cigarettes smoked, cups of coffee taken, alcohol intake, physical activity, parental premature hypertension, and baseline BMI, the rate of change in BMI over the life course increased the risk of incident hypertension in a dose-response fashion, with the highest risk among men with the greatest increase in BMI (hazard ratio, 2.52; 95% confidence interval, 1.82–3.49).” (H. M. Shihab, hshihab1@jhmi.edu)

>>>PNN NewsWatch
* FDA on Friday approved teduglutide (Gattex, NPS Pharmaceuticals) for subcutaneous treatment of adult patients with short bowel syndrome who are dependent on parenteral support.

>>>PNN JournalWatch
* How to Use a Noninferiority Trial: Users’ Guides to the Medical Literature, in
JAMA, 2012; 308: 2605–11. (G. H. Guyatt, guyatt@mcmaster.ca)
* Cherry Consumption and Decreased Risk of Recurrent Gout Attacks, in
Arthritis & Rheumatism, 2012; 64: 4004–11. (Y. Zhang, yuqing@bu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, 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
Dec. 27, 2012 * Vol. 19, No. 248
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Dec. 27 issue of the New England Journal of Medicine (2012; 367).
Drug Shortages & Poorer Responses in Hodgkin’s Lymphoma: Substitution of cyclophosphamide for mechlorethamine in treatment of children with Hodgkin’s lymphoma has produced significantly lower 2-year event-free survival rates, according to authors of a Commentary article (pp. 2461–3). The Stanford V regimen—12 weeks of vinblastine, mechlorethamine, doxorubicin, vincristine, bleomycin, etoposide, and prednisone—was adopted by the Pediatric Hodgkin Lymphoma Consortium in 2002 for patients with high-risk disease and in 2006 for those with intermediate-risk conditions. After a shortage of mechlorethamine developed in 2009, clinicians began substituting cyclophosphamide based on literature reports.
The authors report that a comparison of efficacy measures before (n =181) and during (n = 40) the shortage show the following: “Cyclophosphamide was significantly less effective (2-year event-free survival, 75% with cyclophosphamide [SE, 12.5%] vs. 88% with mechlorethamine [SE, 2.5%; P = 0.01 by the log-rank test]). We can think of no credible explanation for this dramatic difference in event-free survival other than the drug substitution, since careful analysis of our data demonstrated that patients in the cyclophosphamide cohort did not have more unfavorable clinical features than those in the mechlorethamine cohort. In fact, patients in the cyclophosphamide cohort were less likely to have B symptoms (fever, unintentional weight loss, and night sweats) and more likely to have intermediate-risk or high-risk Hodgkin’s lymphoma, with no difference in mediastinal bulk or stage distribution.” (M. L. Metzger)
Cinacalcet in Cardiovascular Disease: In 3,883 patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis, the calcimimetic agent cinacalcet had no significant effect on risk of death or major cardiovascular events during up to 64 months of follow-up in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial (pp. 2482–94). Patients continued conventional therapies during the trial, including phosphate binders and/or vitamin D sterols. Based on a primary composite end point of time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event, the intent-to-treat results showed: “The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1,948 patients (48.2%) in the cinacalcet group and 952 of 1,935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P = 0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.” (G. M. Chertow, gchertow@stanford.edu)
“EVOLVE results leave the clinician [without] clear evidence that cinacalcet provides protection against cardiovascular events and raises questions about the drug’s side-effect profile and safety, with a potential underestimation of both effects owing to high crossover rates,” editorialists write (
pp. 2541–2). “Physicians will no doubt continue to prescribe this drug, and patients will continue to take it. Yet neither group will have a clear, objective understanding of the balance between risks and benefits.
“The real insights from this study are for clinical trialists and regulators. We need to change the way we study the effects of new drugs and integrate these changes into regulatory processes, guideline development, and clinical practice. If such goals can be achieved, even a negative result from the EVOLVE trial will have had a very positive effect.” (V. Perkovic)

>>>PNN NewsWatch
* FDA has approved lomitapide (Juxtapid, Aegerion) for reduction of LDL cholesterol, total cholesterol, apolipoprotein B, and non-HDL cholesterol in patients with homozygous familial hypercholesterolemia (HoFH). Lomitapide is intended for use in combination with a low fat diet and other lipid-lowering treatments. In a clinical trial of 29 patients with HoFH, lomitapide lowered LDL cholesterol levels by approximately one-half during the first 26 weeks of therapy.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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
Dec. 28, 2012 * Vol. 19, No. 249
Providing news and information about medications and their proper use

>>>PNN’s Top 10 for 2012
A year as shocking as it was predictable in many ways, 2012 provided some clear lessons for pharmacy.
1 Pharmacy Compounding: The story of deaths from contaminated products from the New England Compounding Center broke quietly (Oct. 5) but quickly morphed into the biggest pharmacy story in a decade (Dec. 6, 20). Unlike the case of Kansas City pharmacist Robert Courtney—which made this topic the top news story of 2002—NECC will keep pharmacy compounding in the spotlight. Also likely is increased federal authority over compounding pharmacies that cross into manufacturing, something FDA has sought for years (Nov. 8, 15, 16). A Dec. 19 JAMA editorial about “still in the Dark Ages” compounding doesn’t bode well for “we’ve always done it this way.”
2 Drug Shortages: Driving the need for compounded sterile products is the “unprecedented” number of critical medication shortages (Oct. 23). The human cost of this economic reality (Jan. 11) is just now becoming clear (Dec. 27). No real solutions are in sight, and the scrutiny of pharmacy compounding is worsening an already-bad situation.
3 Health Care Reform & the Supreme Court: Pharmacy-friendly provisions of the Affordable Care Act survived an anxiously awaited U.S. Supreme Court decision (June 29). With Pres. Obama’s re-election (Nov. 8), full implementation of the health care reform law was assured. The pressure is now on for CMS, insurers, health systems/providers, and health professionals to be ready for 2014 (Apr. 3, June 22, Aug. 29, Sept. 12) and the law’s tweaks to Medicaid and Medicare Part D (Feb. 9, Apr. 3, June 5, Sept. 13).
4 Busy Times at FDA: The number of new drugs approved in 2012—some three dozen—matched FDA’s performance of last year. The agency was as active as it has been since 2002–04 when Mark McClellan was Commissioner, producing warnings in 2012 on an almost-daily basis. FDA’s Global Engagement Report (Apr. 25) detailed ideas for improving quality of medications imported into the U.S., but by the end of the year, domestic pharmacy compounding had added to the complexity of FDA’s responsibilities.
5 Pharmacists’ New Roles: Provider status for pharmacists was endorsed in a Surgeon General’s report early in 2012 (Jan. 10). The many reports this year of pharmacists’ impact when placed in collaborative clinical roles (Feb. 29, May 22, July 3, Aug. 6, Oct. 12, Dec. 14) showed why the ability to bill for services is increasingly important.
6 Genomics & Personalized Care: Genomics continues to transform clinical medicine. Numerous studies reported in PNN during 2012 illustrate this shift, even to the point of cancer care focusing on genes rather than tumor types (July 9). All that means more personalized care (Jan. 17, Feb. 1, Mar. 14, Apr. 27, July 9, Oct. 4, Oct. 30), an area where pharmacists excel (June 8, 15; Sept. 7, 24; Oct. 5).
7 Technology: Woven tightly with the complexities of genomics is the availability of technology for processing vast amounts of genetic information. From texting (Apr. 25) and other uses of mobile devices (July 9) to telehealth (May 8), bedside genomics (May 7), and implications of fully implemented electronic health and medical records (Oct. 2), 2012 pointed toward a fundamentally different future.
8 Antibiotic Stewardship: The war between microbes and man continues—and not always in man’s favor (Oct. 22). Through antibiotic stewardship programs (July 9, Aug. 3), health-system pharmacists seek to improve our odds.
9 Dietary Supplements: Vitamin D (Feb. 17, Mar. 5, Apr. 16, July 5, Oct. 3, and others) and probiotics (May 9, Oct. 22, Dec. 18) fared favorably throughout the year in many studies, even as data supporting fish oils waned (July 26, Sept. 12, Nov. 5).
10 Vaccines: Quadrivalent (Mar. 1, Dec. 18) and cell-culture influenza vaccines (Nov. 27) promised choices going into the 2013–14 season. Zoster vaccine boosters may be needed (Oct. 31), and researchers assessed the economics of another pharmacy-important product, pneumococcal vaccine (Oct. 29).

>>>PNN NewsWatch
* Personalized doses (3 mg/kg twice daily for 5 days) and proper dosing devices are needed for infants 2 weeks to 1 year receiving oseltamivir based on last week’s FDA approval of Tamiflu (Genentech) for treatment of influenza.
*
PNN will not be published on Mon. and Tues., Dec. 31–Jan. 1, New Year’s Eve and Day.

PNN Pharmacotherapy Line is published via e-mail each business day except U.S. holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2012, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, 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.