Mar 2013

PNN January-March 2013

PNN Pharmacotherapy Line
Jan. 2, 2013 * Vol. 20, No. 1
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2012; 345).
Epilepsy After Pandemic Influenza Vaccine: A register-based study finds no evidence of increased risk of hospital presentation for epilepsy after vaccination with the Swedish formulation of GlaxoSmithKline’s monovalent AS03 adjuvanted pandemic A/H1N1 influenza vaccine (Pandemrix), researchers report (e7594). The self-controlled case series included 373,398 infants, children, and adults and looked for hospital presentations 90 days before and 90 days after any dose of vaccine. Results showed: “859 people experienced epileptic seizures during the study period. There was no increased risk of seizures in people with previously diagnosed epilepsy (relative incidence 1.01, 95% confidence interval 0.74 to 1.39) and a non-significant decrease in risk for people without epilepsy (0.67, 0.27 to 1.65) during the day 1–7 risk period (where day 1 is the day of vaccination). In a second risk period (day 8–30), there was a non-significant increased risk of seizures in people without epilepsy (1.11, 0.73 to 1.70) but no increase in risk for those with epilepsy (1.00, 0.83 to 1.21).” (L. Arnheim-Dahlström, lisen.arnheim.dahlstrom@ki.se)

>>>Internal Medicine Report
Source:
Jan. 1 issue of the Annals of Internal Medicine (2013; 158).
Naloxone Provision to Heroin Users: Distributing naloxone to novice and experienced users of heroin for lay administration is likely to reduce overdoses and prove cost-effective, according to an integrated Markov and decision-analytic model based on published literature (pp. 1–9). Using a societal perspective and a lifetime horizon, investigatores found these results in a base-case analysis: “6% of overdose deaths were prevented with naloxone distribution; 1 death was prevented for every 227 naloxone kits distributed (95% CI, 71 to 716). Naloxone distribution increased costs by $53 (CI, $3 to $156) and quality-adjusted life–years by 0.119 (CI, 0.017 to 0.378) for an [incremental cost-effectiveness ratio (ICER)] of $438 (CI, $48 to $1,706).” The sensitivity analysis showed: “Naloxone distribution was cost-effective in all deterministic and probabilistic sensitivity and scenario analyses, and it was cost-saving if it resulted in fewer overdoses or emergency medical service activations. In a ‘worst-case scenario’ where overdose was rarely witnessed and naloxone was rarely used, minimally effective, and expensive, the ICER was $14,000. If national drug-related expenditures were applied to heroin users, the ICER was $2,429.” (P. O. Coffin, pcoffin@gmail.com)

>>>PNN NewsWatch
* FDA approved three new drugs before the year’s end, including the important factor Xa inhibitor apixaban (Eliquis; BMS, Pfizer). Apixaban was approved as an oral tablet for reducing risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Also approved was bedaquiline (Sirturo, Janssen) for use as part of combination therapy to treat adults with multidrug resistant pulmonary tuberculosis when other alternatives are not available. Sirturo received accelerated approval and was granted fast-track designation, priority review, and orphan-product status. Crofelemer (Fulyzaq, Salix) was approved for relief of symptoms of diarrhea in HIV/AIDS patients taking antiretroviral therapy. Before using the drug, health professionals should conduct proper testing to confirm patient’s diarrhea is not caused by an infection or gastrointestinal disease.

>>>PNN JournalWatch
* Effects of Fructose vs Glucose on Regional Cerebral Blood Flow in Brain Regions Involved With Appetite and Reward Pathways, in JAMA, 2013; 309: 63–70. (R. S. Sherwin, robert.sherwin@yale.edu)
* Fourth European Conference on Infections in Leukaemia (ECIL-4): Guidelines for Diagnosis and Treatment of Human Respiratory Syncytial Virus, Parainfluenza Virus, Metapneumovirus, Rhinovirus, and Coronavirus, in
Clinical Infectious Diseases, 2013; 56: 258–66. (H. H. Hirsch, hans.hirsch@unibas.ch)
* Inflammatory Markers and Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis, in
Diabetes Care, 2013; 36: 166–75. (L-G Liu, lgliu@mails.tjmu.edu.cn)
* Self-Monitoring of Blood Glucose in Noninsulin-Using Type 2 Diabetic Patients [point–counterpoint], in
Diabetes Care, 2013; 36: 176–8 and 179–82. (U. L. Malanda, uriell.malanda@rivm.nl; W. H. Polonsky, whp@behavioraldiabetes.org)
* Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: U.S. Preventive Services Task Force Recommendation Statement, in
Annals of Internal Medicine, 2013; 158: 47–54. (www.uspreventiveservicestaskforce.org)

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

PNN Pharmacotherapy Line
Jan. 3, 2013 * Vol. 20, No. 2
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 3 issue of the New England Journal of Medicine (2013; 368).
Sofosbuvir for Hepatitis C: Sofosbuvir, an oral nucleotide inhibitor of hepatitis C virus (HCV) polymerase, is useful in previously untreated patients with HCV genotype 1, 2, or 3 infection in combination with ribarvirin, a study shows (pp. 34–44). For 12 weeks, 40 patients received open-label treatment using one of eight interferon-sparing or interferon-free regimens, with results as follows: “Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia.” (E. J. Gane, edgane@adhb.govt.nz)
Oral Combination Antiviral Therapy for Hepatitis C: In patients with HCV genotype 1 infection, a preliminary 12-week study showed potential utility of a combination of a protease inhibitor, a nonnucleoside polymerase inhibitor, and ribavirin (pp. 45–53). The Phase 2a trial used open-label ABT-333 400 mg twice daily and ribavirin 1000–1200 mg/d and one of two daily doses of ABT-450/r. Groups 1 and 2 were treatment-naive patients, and they received daily doses of ABT-450 250 mg (group 1) or 150 mg (group 2) with ritonavir 100 mg. Group 3 included patients who had not responded adequately to prior therapy with peginterferon and ribavirin, and they received daily doses of ABT-450 150 mg and ritonavir 100 mg. Results showed: “A total of 17 of the 19 patients in group 1 (89%) and 11 of the 14 in group 2 (79%) had an extended rapid virologic response; a sustained virologic response 12 weeks after the end of treatment was achieved in 95% and 93% of the patients, respectively. In group 3, 10 of 17 patients (59%) had an extended rapid virologic response, and 8 (47%) had a sustained virologic response 12 weeks after therapy; 6 patients had virologic breakthrough, and 3 had a relapse. Adverse events included abnormalities in liver-function tests, fatigue, nausea, headache, dizziness, insomnia, pruritus, rash, and vomiting.” (F. Poordad, mailto:)

>>>JAMA Highlights
Source:
Jan. 2 issue of JAMA (2013; 309).
Maintenance Nifedipine Tocolysis in Threatened Preterm Labor: Adverse perinatal outcomes were not significantly affected by nifedipine-maintained tocolysis in a study of 406 women, researchers report (pp. 41–7). Participants had threateed preterm labor at 26–32 weeks. Following a completed course of corticosteroids and 48 hours of tocolysis, they were assigned to nifedipine 80 mg/d or placebo. A primary outcome of a composite of adverse perinatal outcomes (perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage >grade 2, periventricular leukomalacia >grade 1, or necrotizing enterocolitis) showed these effects of nifedipine: “Mean (SD) gestational age at randomization was 29.2 (1.7) weeks for both groups. Adverse perinatal outcome was not significantly different between groups: 11.9% (24/201; 95% CI, 7.5%–16.4%) for nifedipine vs 13.7% (28/205; 95% CI, 9.0%–18.4%) for placebo (relative risk, 0.87; 95% CI, 0.53–1.45).” (C. Roos, c.roos@obgyn.umcn.nl)
SSRIs in Pregnancy: In multivariate models, the risks of stillbirth, neonatal morbidity, and postneonatal morbidity were not elevated in a population-based cohort study of 1.634 million Nordic women who took SSRIs before delivering singleton births (pp. 48–54). A total of 29,228 mothers had an SSRI prescription filled during pregnancy. Drug exposure was linked to higher rates of stillbirth and postneonatal death, but risks fell into nonsignificant ranges after adjustment for maternal factors and prior psychiatric hospitalization. (O. Stephansson, lof.stephansson@ki.se">olof.stephansson@ki.se)

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

PNN Pharmacotherapy Line
Jan. 4, 2013 * Vol. 20, No. 3
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Jan. 8 issue of the Journal of the American College of Cardiology (2013; 61).
Aldosterone Antagonists at Discharge of Patients After MI: While rates of aldosterone antagonist use in patients following acute myocardial infarction (AMI) have increased in recent years, “the vast majority of AMI patients eligible for treatment fail to receive it at hospital discharge,” researchers report (pp. 35–40). Based on data from the American Heart Association’s Get with the Guidelines–Coronary Artery Disease national database, 81,570 post-AMI patients (11,255 of them eligible for aldosterone antagonist therapy) from 219 hospitals in 2006–09 had these prescriptions at discharge: “Among eligible patients, 1,023 (9.1%) were prescribed an aldosterone antagonist at discharge. Aldosterone antagonist use varied from 0% to 40% among hospitals. Patient and hospital characteristics independently associated with prescription of aldosterone antagonists were a history of diabetes, heart failure, coronary revascularization, and larger hospital size. Those with a history of kidney dysfunction, tobacco abuse, and higher ejection fraction were less likely to be prescribed an aldosterone antagonist. From 2006 to 2009, the use of aldosterone antagonists increased from 6.0% to 13.4% (p < 0.001).” (D. L. Bhatt)
“The divergence between clinical guidelines and practice” is explored in an accompanying editorial, which concludes (
pp. 41–3): “Clinical guidelines are valuable for applying data-based evidence derived from clinical studies to the direct care of patients. When there is a divergence between clinical practice and recommended guidelines, as exists in the use of aldosterone antagonists, the causes need to be identified. If poor adherence results from a lack of knowledge or means of implementation, corrective measures must be taken to improve outcomes. However, it must be accepted that failure to follow guidelines by the vast majority of physicians may indicate that the evidence base is not predictive of the results that will be obtained in contemporary clinical practice. Recommendations need to be re-evaluated based on how representative trial enrollees are of contemporary patients encountered by practicing physicians, newly emerging evidence, changes in context, and a broad view of why some guidelines are not embraced by physicians and/or patients. Resolving apparent discrepancies is fundamental to the processes by which advances in medicine and science are made.” (W. Y. W. Lew)
Clopidogrel, Platelets & Plasma Fibrinogen: Regardless of platelet activity as measured with the VerifyNow assay, “elevated fibrinogen is independently associated with the risk of ischemic myocardial injury following elective [percutaneous coronary intervention (PCI)] with clopidogrel pre-treatment, according to a study of 189 patients (pp. 23–34). Before elective PCI, participants received clopidogrel 75 mg daily for 7 or more days or a 600-mg bolus at least 12 hours in advance. Assessment of baseline fibrinogen and platelet reactivity showed these relationships with outcomes: “Incidence of troponin-defined periprocedural myocardial infarction (PPMI) (troponin I/T >3× upper limit of normal) was 13.9% and associated with elevated fibrinogen (363.1 ± 131.0 mg/dl vs. 309.1 ± 99.6 mg/dl; p = 0.017), higher age (68.2 ± 10.1 years vs. 63.0 ± 11.8 years; p = 0.040), and elevated platelet count. Fibrinogen level and age remained independently associated with PPMI following multiple variable and interaction testing. The incidence of creatine kinase-myocardial band (CK-MB)–defined PPMI (CK-MB >3× upper limit of normal) was 5.8% and associated with elevated fibrinogen (403.4 ± 128.0 mg/dl vs. 313.5 ± 104.6 mg/dl; p = 0.007). Platelet reactivity measurements were not associated with PPMI by either definition. Fibrinogen ≥345 mg/dl was significantly associated with both CK-MB–defined (p = 0.026) and troponin I/T–defined PPMI (p = 0.036). Fibrinogen effects were most prominent in the absence of systemic inflammation (C-reactive protein ≤0.5 mg/dl).” (E. Mahmud)

>>>PNN NewsWatch
* ASHP yesterday announced an initiative to seek provider status for pharmacists under the Social Security Act. “Achieving provider status will not be easy,” wrote CEO Paul Abramowitz. “It will take a massive grassroots effort by individual pharmacy practitioners and affiliated state societies leading state-based coalitions.” The action follows a similar November announcement by ACCP.

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

PNN Pharmacotherapy Line
Jan. 7, 2013 * Vol. 20, No. 4
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 5 issue of Lancet (2013; 381).
Serelaxin in Acute Heart Failure: In the RELAX-AHF trial, 1,161 patients hospitalized for acute heart failure had improved relief of dyspnea and other clinical outcomes when treated with serelaxin, compared with placebo, but the vasoactive form of recombinant human relaxin-2 had no effect on rehospitalizations (pp. 29–39). Study participants in this international trial received standard care plus intravenous infusions of placebo or serelaxin 30 mcg/d within 16 h of presentation.
Based on primary endpoints evaluating dyspnoea improvement of change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, intent-to-treat results showed: “Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120–775; p = 0.007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p = 0.70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan–Meier estimate, 13.0%]; serelaxin, 76 events [13.2%]; hazard ratio [HR] 1.02 [0.74–1.41], p = 0.89] or days alive out of the hospital up to day 60 (placebo, 47.7 [SD 12.1] days; serelaxin, 48.3 [11.6]; p = 0.37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0.63, 95% CI 0.42–0.93; p = 0.019).” (J. R. Teerlink,
john.teerlink@ucsf.edu)
Microsomal Triglyceride Transfer Protein Inhibitor in Hypercholesterolemia: Lomitapide, an investigational microsomal triglyceride transfer protein inhibitor, reduced LDL cholesterol by 50% at 26 weeks in a Phase III open-label trial of patients with homozygous familial hypercholesterolemia, researchers report (pp. 40–6). Current lipid-lowering therapy was maintained from 6 weeks before baseline through at least week 26 of the trial. With lomitapide doses of 5–60 mg/d, participants had these changes in LDL cholesterol levels during the study: “29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI –62 to –39) from baseline (mean 8.7 mmol/L [SD 2.9]) to week 26 (4.3 mmol/L [2.5]; p < 0.0001). Levels of LDL cholesterol were lower than 2.6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI –57 to –31; p < 0.0001) at week 56 and 38% (—52 to –24; p < 0.0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities.” (M. Cuchel, mcuchel@mail.med.upenn.edu)

>>>PNN JournalWatch
* The Influence of Cigarette Smoking on Viral Infections: Translating Bench Science to Impact COPD Pathogenesis and Acute Exacerbations of COPD Clinically, in Chest, 2013; 143: 196–206. (M. R. Stämpfli, stampfli@mcmaster.ca)
* Order Sets in Electronic Health Records: Principles of Good Practice, in
Chest, 2013; 143: 228–35. (J. D. McGreevey III, john.mcgreevey@uphs.upenn.edu)
* Current Status of Co-Occurring Mood and Substance Use Disorders: A New Therapeutic Target, in
American Journal of Psychiatry, 2013; 170: 23–30. (H. M. Pettinati, helenp@mail.med.upenn.edu)
* Bipolar Mixed States: An International Society for Bipolar Disorders Task Force Report of Symptom Structure, Course of Illness, and Diagnosis, in
American Journal of Psychiatry, 2013; 170: 31–42. (A. C. Swann, Alan.C.Swann@uth.tmc.edu)
* Antibiotic Prophylaxis for Urinary Tract Infections in Antenatal Hydronephrosis, in
Pediatrics, 2013; 131: e251–61. (L. H. Braga)
* Clinical Cancer Advances 2012: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology, in
Journal of Clinical Oncology, 2013; 31: 131–61. (L. Krilov, lada.krilov@asco.org)

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

PNN Pharmacotherapy Line
Jan. 8, 2013 * Vol. 20, No. 5
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Jan. issue of Pediatrics (2013; 131).
Trends in Pediatric ADRs to TMP–SMX: A shift in use of trimethoprim–sulfamethoxazole (TMP–SMX) to treatment of skin and soft tissue infections (SSTIs) has led to more adverse drug reactions (ADRs) to these drugs in recent years, a study shows (pp. e103–8). A retrospective chart review at a pediatric institution for 2000–09 provided data on trends on ADRs, and these were compared with TMP–SMX ADRs at 25 tertiary pediatric hospitals in the Pediatric Health Information System database. Combining prescribing rates from the National Ambulatory Medical Care Survey/National Hospital Ambulatory Medical Care Survey, the authors found these relationships: “At our institution, 109 children were diagnosed with a TMP–SMX ADR (5 cases from 2000 to 2004 as compared with 104 cases from 2005 to 2009). Fifty-eight percent had been treated for [an SSTI]. A similar trend was observed nationally, where the incidence of TMP–SMX ADRs more than doubled from 2004 to 2009 at comparable pediatric hospitals (P < .001). Although national outpatient data revealed no change in overall TMP–SMX prescribing, the percentage of children prescribed TMP–SMX for SSTI sharply increased during the study period (0%–2% [2000–2004]; 9%–17% [2005–2009]).” (J. L. Goldman)
NSAIDs in Late Pregnancy & Persisent Pulmonary Hypertension in Newborns: Persistent pulmonary hypertension of the newborn (PPHN) was not connected to use of NSAIDs in general or ibuprofen in particular during pregnancy in a large multicenter epidemiologic study, researchers report (pp. 79–87). Interviews of 377 women whose infants had PPHN and 836 matched control mothers of infants showed these patterns in PPHN occurrence and prescription and nonprescription drug use: “During the third trimester of gestation, 33 infants (8.8%) with PPHN were exposed to any NSAID compared with 80 (9.6%) controls (OR 0.8; 95% CI 0.5–1.3). We observed an elevated OR for PPHN risk among infants whose mothers consumed aspirin during the third-trimester; however, the lower 95% CI included the null. Neither nonaspirin NSAIDs at any time during pregnancy nor ibuprofen use during the third trimester was associated with an elevated risk of PPHN. Similarly, no association was observed between a mother’s third-trimester acetaminophen use and the occurrence of PPHN in her newborn.” (L. J. Van Marter)

>>>Psychiatry Report
Source:
Jan. issue of the American Journal of Psychiatry (2013; 170).
Moderate-Dose Lithium in Bipolar Disorder: A “pragmatic comparative effectiveness study” shows little added benefit of lithium in optimized personalized treatment (OPT) of 282 patients with bipolar disorder and sheds light on the “persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment” (pp. 102–10). Investigators looked at primary outcome measures of Clinical Global Impression Scale for Bipolar Disorder–Severity (CGI-BP-S) scores and “necessary clinical adjustments” (medication adjustments per month) in 283 outpatients with bipolar disorder who were assigned to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. Results showed: “The authors observed no statistically significant advantage of lithium plus OPT on CGI-BP-S scores, necessary clinical adjustments, or proportion with sustained remission. Both groups had similar outcomes across secondary clinical and functional measures. Fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).” (A. A. Nierenberg, anierenberg@partners.org)

>>>PNN NewsWatch
* In a statement, a blog, and a news story, APhA yesterday announced plans to “marshal [pharmacy’s] collective strength into one set of principles that all our organizations can support” on the hot issue of provider status. Recognizing the value of pharmacists’ clinical services is “the smart spend that pays,” APhA said it would tell Congress. “It is time for pharmacists to be recognized for the value they bring to improved patient outcomes,” added Steven T. Simenson, APhA President-elect and Chair of the organization’s Provider Status Task Force.

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

PNN Pharmacotherapy Line
Jan. 9, 2013 * Vol. 20, No. 6
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 9 issue of JAMA (2013; 309).
Vitamin D Supplementation in Symptomatic Osteoarthritis: In 146 participants with symptomatic knee osteoarthritis (OA), supplementation with vitamin D for 2 years failed to reduce knee pain and cartilage loss, researchers report (pp. 155–62). Vitamin D doses of 2000 IU/d, escalation as needed to produce 25-hydroxyvitamin D plasma levels of more than 36 ng/mL, produced these changes in primary outcomes of knee pain severity (Western Ontario and McMaster Universities [WOMAC] pain scale), and cartilage volume loss: “Eighty-five percent of the participants completed the study. Serum 25-hydroxyvitamin D levels increased by a mean 16.1 ng/mL (95% CI, 13.7 to 18.6) in the treatment group and by a mean 2.1 mg/mL (95% CI, 0.5 to 3.7) (P < .001) in the placebo group. Baseline knee pain was slightly worse in the treatment group (mean, 6.9; 95% CI, 6.0 to 7.7) than in the placebo group (mean, 5.8; 95% CI, 5.0 to 6.6) (P = .08). Baseline knee function was significantly worse in the treatment group (mean, 22.7; 95% CI, 19.8 to 25.6) than in the placebo group (mean, 18.5; 95% CI, 15.8 to 21.2) (P = .04). Knee pain decreased in both groups by a mean −2.31 (95% CI, −3.24 to −1.38) in the treatment group and −1.46 (95% CI, −2.33 to −0.60) in the placebo group, with no significant differences at any time. The percentage of cartilage volume decreased by the same extent in both groups (mean, −4.30; 95% CI, −5.48 to −3.12 vs mean, −4.25; 95% CI, −6.12 to −2.39) (P = .96).” (T. McAlindon, tmcalindon@tuftsmedicalcenter.org)
Gonorrheal Treatment Failure With Cefixime: At a Toronto clinic, a retrospective cohort study shows a high rate of treatment failure with cefixime in treatment of Neisseria gonorrhoeae infections (pp. 163–70): “There were 291 N gonorrhoeae culture-positive individuals identified. Of 133 who returned for test of cure, 13 were culture positive; 9 patients were determined to have experienced cefixime treatment failure, involving urethral (n = 4), pharyngeal (n = 2), and rectal (n = 3) sites. The overall rate of clinical treatment failure among those who had a test of cure was 6.77% (95% CI, 3.14%–12.45%; 9/133). The rate of clinical failure associated with a cefixime MIC of 0.12 µg/mL or greater was 25.0% (95% CI, 10.69%–44.87%; 7/28) compared with 1.90% (95% CI, 0.23%–6.71%; 2/105) of infections with cefixime MICs less than 0.12 µg/mL, with a relative risk of 13.13 (95% CI, 2.88–59.72; P < .001).” (V. G. Allen, vanessa.allen@oahpp.ca)
“Clinicians should treat patients diagnosed with gonorrhea with the highly effective, CDC-recommended regimen: ceftriaxone, 250 mg, as a single intramuscular dose plus either azithromycin, 1 g, or doxycycline, 100 mg, orally twice daily for a week,” editorialists write (
pp. 185–7; R.D. Kirkcaldy, rkirkcaldy@cdc.gov).
I.V. Acetaminophen & Pediatric Postoperative Morphine Requirements: In a Dutch study, postoperative administration of intermittent I.V. paracetamol (acetaminophen) with rescue morphine resulted in a lower cumulative morphine dose over 48 hours, compared with continuous morphine infusions (pp. 149–54). Study participants were 71 neonates or infants undergoing major thoracic (noncardiac) or abdominal surgery in 2008–10. All participants received loading doses of morphine 30 minutes before the end of surgery, followed by continuous morphine or intermittent intravenous paracetamol up to 48 hours postsurgery, with rescue morphine allowed in both groups. Results showed: “The cumulative median morphine dose in the first 48 hours postoperatively was 121 (interquartile range, 99–264) µg/kg in the paracetamol group (n = 33) and 357 (interquartile range, 220–605) µg/kg in the morphine group (n = 38), P < .001, with a between-group difference that was 66% (95% CI, 34%–109%) lower in the paracetamol group. Pain scores and adverse effects were not significantly different between groups.” (S. N. de Wildt, s.dewildt@erasmusmc.nl)
“Titrating morphine analgesia carefully (based on pain scores) is more labor intensive than the common practice of slightly oversedating infants who require opioid analgesia for painful conditions, such as following operations,” an editorialist writes (
pp. 183–4). “However, this [acetaminophen] approach may avoid the respiratory depression, hypotension, and opioid tolerance observed in many centers.” (K. J. S. Anand, kanand@uthsc.edu)

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

PNN Pharmacotherapy Line
Jan. 10, 2013 * Vol. 20, No. 7
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 10 issue of the New England Journal of Medicine (2013; 368).
Levonorgestrel Intrauterine System for Menorrhagia: Compared with usual medical therapy in the primary care setting, the levonorgestrel intrauterine system (IUS) was more effective than usual medical treatment in reducing the effect of heavy menstrual bleeding on quality of life, according to results of the ECLIPSE trial (pp. 128–37). A total of 571 women with menorrhagia received treatment with levonorgestrel-IUS or usual medical treatment (tranexamic acid, mefenamic acid, combined estrogen–progestogen, or progesterone alone) and assessed using a primary outcome of patient-reported scores on the Menorrhagia Multi-Attribute Scale (MMAS) over a 2-year period. Results showed: “MMAS scores improved from baseline to 6 months in both the levonorgestrel-IUS group and the usual-treatment group (mean increase, 32.7 and 21.4 points, respectively; P < 0.001 for both comparisons). The improvements were maintained over a 2-year period but were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group (mean between-group difference, 13.4 points; 95% confidence interval, 9.9 to 16.9; P < 0.001). Improvements in all MMAS domains (practical difficulties, social life, family life, work and daily routine, psychological well-being, and physical health) were significantly greater in the levonorgestrel-IUS group than in the usual-treatment group, and this was also true for seven of the eight quality-of-life domains. At 2 years, more of the women were still using the levonorgestrel-IUS than were undergoing the usual medical treatment (64% vs. 38%, P < 0.001). There were no significant between-group differences in the rates of surgical intervention or sexual-activity scores. There were no significant differences in serious adverse events between groups.” (ECLIPSE Trial Office, j.p.daniels@bham.ac.uk)
“In the United States, the levonorgestrel-IUS is currently approved for the indication of heavy bleeding only for women who choose it as a contraceptive method,” notes an editorialist (
pp. 184–5). “The data from [this] study … support broadening its approval to include menorrhagia more generally, whether or not contraception is needed.” (E. Espey)
Abiraterone in Metastatic Prostate Cancer: In 1,088 men with metastatic castration-resistant prostate cancer, abiraterone acetate 1000 mg plus prednisone 5 mg twice daily was significantly better than placebo plus prednisone on several clinical measures (pp. 138–48). “Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy,” the authors wrote of their study, which was unblinded early. Other superior results were noted for opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. (C. J. Ryan, ryanc@medicine.ucsf.edu)

>>>PNN NewsWatch
* Drug-related deaths and drug-treatable diseases are among core reasons why Americans are less likely to live to age 50 than are citizens of other high-income countries of the world, according to an Institute of Medicine study released yesterday. The report found that Americans’ health disadvantage exists at all ages from birth to age 75 and that even Americans with health insurance, college educations, higher incomes, and healthy behaviors appear to be sicker than their peers in other rich nations. Compared with Australia, Canada, Japan, and many western European countries, the U.S. is at or near the bottom in nine key areas of health: infant mortality and low birth weight; injuries and homicides; teenage pregnancies and sexually transmitted infections; prevalence of HIV and AIDS; drug-related deaths; obesity and diabetes; heart disease; chronic lung disease; and disability. These findings build on a 2011 Research Council report that documented a growing mortality gap among Americans over age 50. “It’s a tragedy. Our report found that an equally large, if not larger, disadvantage exists among younger Americans,” said Steven H. Woolf of Virginia Commonwealth University, chair of the panel that wrote the report. “I don’t think most parents know that, on average, infants, children, and adolescents in the U.S. die younger and have greater rates of illness and injury than youth in other countries.”

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

PNN Pharmacotherapy Line
Jan. 11, 2013 * Vol. 20, No. 8
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Jan. issue of Pharmacotherapy (2013; 33).
Antimicrobial Stewardship Pathway with Daptomycin: In patients with bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) with vancomycin minimum inhibitory concentrations (MICs) greater than 1 mg/L, an antimicrobial stewardship pathway for dactomycin improved clinical success without increasing treatment costs, researchers report (pp. 3–10). The analysis included 70 vancomycin-treated patients analyzed retrospectively from a phase I baseline period and 100 patients switched to dactomycin after initial vancomycin therapy per the institution’s MRSA bacteremia treatment pathway during phase II. Results showed: “Phase II patients were more likely to achieve clinical success than were phase I patients (75.0% vs 41.4%, p < 0.001). Phase II patients demonstrated a shorter total hospital length of stay and shorter durations of inpatient therapy, fever, and bacteremia. Treatment during phase I was independently associated with failure. Nine patients during phase I experienced nephrotoxicity, and two patients during phase II experienced increases in creatine kinase level. Costs were similar between phases I and II ($18,385 vs $19,755, p > 0.05), although the hospital readmission rate was higher in phase I (33% vs 21%, p = 0.08).” (M. J. Rybak, m.rybak@wayne.edu)
Physician Acceptance of Pharmacist Case Managers’ Recommendations: Opportunities to address chronic diseases during hospitalizations are possibly being lost in the current hospitalist model of care, according to authors who assessed physician responses to pharmacist case managers’ recommendations for 192 adult inpatients (pp. 11–21). All patients had one of nine cardiovascular or pulmonary diseases or diabetes mellitus or had received oral anticoagulation therapy, and all were discharged to community-based private physicians and community pharmacists. Pharmacy case managers evaluated patients and made recommendations to inpatient physicians, with these results: “Overall, 260 (48%) of the 546 recommendations were accepted. The acceptance rate was lower for patients who had an urgent care visit compared with the other patients (33.6% vs 52.2%, p = 0.033). High acceptance rates were noted for updating the record after medication reconciliation (36 patients [78%]) and when there was an actual allergy (2 [100%] of 2 patients) or medication error (2 [100%] of 2 patients). Physicians were less likely to accept recommendations related to drug indications (p < 0.001), drug efficacy (p = 0.041), and therapeutic drug and disease state monitoring (p = 0.011). Recommendations made for patients with a relatively greater number of drugs were also less likely to be accepted (p = 0.003).”
The authors add: “The fact that [pharmacy case manager] recommendations included medical conditions outside the scope of the primary reason for the hospital admission may have contributed to the low acceptance rate, which several inpatient physicians mentioned anecdotally. This observation is supported by a recent study that found hospitalists did not want to interfere with the prescribing of the patient’s primary physician.” (B. L. Carter,
barry.carter@uiowa.edu)

>>>PNN NewsWatch
* FDA yesterday announced it is requiring the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower their currently recommended doses of zolpidem. Recommended dosages of zolpidem for women should be lowered from 10 mg to 5 mg for immediate-release products (Ambien, Edluar, and Zolpimist) and from 12.5 mg to 6.25 mg for extended-release Ambien CR, FDA said. Product labeling should now recommend those lower doses for men, but FDA stopped short of taking the 10- and 12.5-mg products off the market. The labeling changes are based on findings in driving simulation and laboratory studies showing that, in some individuals, blood zolpidem levels the morning after use appear capable of impairing driving to a degree that increases the risk of a motor vehicle accident.
* In a new document,
FDA explains its current thinking about the studies that should be conducted to demonstrate that opioid formulations have abuse-deterrent properties, how those studies will be evaluated by the agency, and what labeling claims may be approved based on the results of those studies. FDA seeks public comment on “Guidance for Industry: Abuse-Deterrent Opioids–Evaluation and 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Jan. 14, 2013 * Vol. 20, No. 9
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 12 issue of Lancet (2013; 381).
Exenatide v. Liraglutide in Type 2 Diabetes: In an open-label randomized trial, once-daily liraglutide and once-weekly exenatide produced similar improvements in glycemic control, but greater reductions occurred in those on liraglutide, researchers report (pp. 117–24). Over 26 weeks at 105 sites in 19 countries, DURATION-6 trial participants showed these patterns based on a primary endpoint of change in glycated hemoglobin: “Of 912 randomised patients, 911 were included in the intention-to-treat analysis (450 liraglutide, 461 exenatide). The least-squares mean change in HbA1c was greater in patients in the liraglutide group (–1.48%, SE 0.05; n = 386) than in those in the exenatide group (–1.28%, 0.05; 390) with the treatment difference (0.21%, 95% CI 0.08–0.33) not meeting predefined non-inferiority criteria (upper limit of CI <0.25%). The most common adverse events were nausea (93 [21%] in the liraglutide group vs 43 [9%] in the exenatide group), diarrhoea (59 [13%] vs 28 [6%]), and vomiting 48 [11%] vs 17 [4%]), which occurred less frequently in the exenatide group and with decreasing incidence over time in both groups. 24 (5%) patients allocated to liraglutide and 12 (3%) allocated to exenatide discontinued participation because of adverse events.” (G. Schernthaner, guntram.schernthaner@meduniwien.ac.at)
Everolimus for Subependymal Giant Cell Astrocytomas: The mTOR inhibitor everolimus produced significant improvements in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex in the EXIST-1 trial, and investigators concluded that the therapy might be disease-modifying (pp. 125–32). The Phase III trial compared oral everolimus with placebo, with these results: “117 patients were randomly assigned to everolimus (n = 78) or placebo (n = 39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15–52; one-sided exact Cochran-Mantel-Haenszel test, p < 0.0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).” (D. N. Franz, tsclinic@cchmc.org)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Acute Renal Injury with Triple-Agent Hypotensive Therapy Plus NSAIDs: Patients on a regimen of ACE inhibitors, ARBs, and diuretics may need to avoid concomitant NSAID therapy, according to results of a retrospective case–control evaluation of acute kidney injury (e8525). Data on 487,772 users of antihypertensive drugs showed these patterns of kidney function: “During a mean follow-up of 5.9 (SD 3.4) years, 2,215 cases of acute kidney injury were identified (incidence rate 7/10,000 person years). Overall, current use of a double therapy combination containing either diuretics or angiotensin converting enzyme inhibitors or angiotensin receptor blockers with NSAIDs was not associated with an increased rate of acute kidney injury. In contrast, current use of a triple therapy combination was associated with an increased rate of acute kidney injury (rate ratio 1.31, 95% confidence interval 1.12 to 1.53). In secondary analyses, the highest risk was observed in the first 30 days of use (rate ratio 1.82, 1.35 to 2.46).” (S. Suiss, samy.suissa@mcgill.ca)

>>>PNN JournalWatch
* Oral Anticoagulation in Elderly Adults With Atrial Fibrillation: Integrating New Options with Old Concepts, in Journal of the American Geriatrics Society, 2013; 61: 143–50. (I. G. E. Zarraga, Ignatius.Zarraga@va.gov)
* Effectiveness of Long-term Acute Care Hospitalization in Elderly Patients With Chronic Critical Illness, in
Medical Care, 2013; 51: 4–10. (J. M. Kahn, kahnjm@upmc.edu)
* Uric Acid as a Target of Therapy in CKD, in
American Journal of Kidney Diseases, 2013; 61: 134–46. (D. I. Jilal, diana.jalal@ucdenver.edu)
* Advances in Adult Asthma Diagnosis and Treatment in 2012: Potential Therapeutics and Gene-Environment Interactions, in
Journal of Allergy and Clinical Immunology, 2013; 131: 47–54. (A. J. Apter, apter@mail.med.upenn.edu)
* The Ghost of Gehrig, in
Neurology, 2013; 80: 223–4. (J. L. Almodovar, Jorge.L.Almodovar-Suarez@hitchcock.org)

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

PNN Pharmacotherapy Line
Jan. 15, 2013 * Vol. 20, No. 10
Providing news and information about medications and their proper use

>>>Internal Medicine Report I
Source:
Jan. 14 issue of the JAMA Internal Medicine (2013; 173).
Using Automation to Increase Medication Use: Among adult members of Kaiser Permanente Southern California, automated telephone calls and mailed letters to those without statin refills during the past year improved fill rates, a study shows (pp. 38–43). Letters were mailed to members 1 week after phone calls were placed. Using a primary outcome measure of dispensing of a statin within 2 weeks of delivery of the letter, the investigators found these results among 5,216 patients: “Statins were dispensed to 42.3% of intervention participants and 26.0% of control participants (absolute difference, 16.3%; P < .001). The relative risk for the intervention vs control group was 1.63 (95% CI, 1.50–1.76). Intervention effectiveness varied slightly by age (P = .045) but was effective across all age strata. Differences in the frequency of statin dispensations persisted up to 1 year (P < .001).” (S. F. Derose, Stephen.F.Derose@kp.org)
A commentator examines where “the current state of the evidence leave[s] clinicians, patients, and policy makers as we approach the challenges of medication nonadherence” (
pp. 44–5): “The evidence to date reveals that medication nonadherence is a complex phenomenon and that no one solution will address it completely. Studies such as that of Derose and colleagues give us a set of tools with which we can chip away at the challenge of nonadherence. Improved integration of clinical systems may allow for more efficient and practical implementation of multimodal interventions to address multiple components of adherence.” (M. A. Fischer, mfischer@partners.org)
Health-System Factors & Antihypertensive Adherence: While racial and ethnic differences affect medication-taking behavior in the early phase of treating hypertension, health-system factors can be adjusted to attenuate these effects (pp. 54–61). A retrospective cohort study of 44,167 Kaiser Permanente Northern California members with hypertension who were new users of hypotensive medications in 2008 showed these relationships among race/ethnicity, health-system factors, early nonpersistence (failing to refill the first prescription within 90 days), and nonadherence (<80% of days covered during the 12 months following the start of treatment): “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)

>>>Internal Medicine Report II
Source:
Jan. 15 issue of the Annals of Internal Medicine (2013; 158).
CER of Hepatitis C Antiviral Treatment: Sustained virologic response (SVR) rates for chronic hepatitis C virus (HCV) infections genotype 1 are higher with triple therapy than with dual agents, according to a comparative effectiveness review (pp. 114–23). “Dual therapy with pegylated interferon alfa-2b plus ribavirin was associated with a lower likelihood of SVR than was pegylated interferon alfa-2a plus ribavirin (absolute difference, 8 percentage points [95% CI, 3 to 14 percentage points]) on the basis of 7 poor- to fair-quality trials. For genotype 2 or 3 infection, dual therapy for 12 to 16 weeks was associated with a lower likelihood of SVR than was therapy for 24 weeks, and lower doses of pegylated interferon alfa-2b were less effective than standard doses (2 to 4 fair-quality trials). For genotype 1 infection, fair-quality trials found that triple therapy with pegylated interferon, ribavirin, and either boceprevir (2 trials) or telaprevir (4 trials) was associated with a higher likelihood of SVR than was dual therapy (absolute difference, 22 to 31 percentage points).” (R. Chou, chour@ohsu.edu)

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

PNN Pharmacotherapy Line
Jan. 16, 2013 * Vol. 20, No. 11
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Online-first articles from and Jan. 16 issue of JAMA (2013; 309).
Energy Drinks & Caffeine-Related Adverse Effects: An editorialist discusses FDA investigations into the large amounts of caffeine in energy drinks and related concerns (pp. 243–4): “Product labels for most energy drinks do not list their caffeine content. Many energy drinks contain ‘natural’ ingredients, such as ginkgo or milk thistle, allowing these drinks to be regulated as ‘dietary supplements’ rather than as medications. The 1994 Dietary Supplement and Education Act classifies products containing herbs and other natural ingredients as supplements rather than drugs, allowing manufacturers to side-step disclosure of caffeine dose, even though some brands do provide the information. In contrast, caffeine-containing products such as No-Doz and Caffedrine, marketed as over-the-counter drugs, are required to provide dose.…
“The appropriate role of the FDA and other regulators in the oversight of energy drinks is yet to be defined. A logical first step might be to require placing the caffeine content of energy drinks on their label. In Sweden, restriction of caffeine tablet sales from 250 to 30 pills per customer appeared to decrease the rate of fatal caffeine overdoses, suggesting that deliberately restricting the sale of preparations with a high dose of caffeine might be an effective approach. Publicity about energy drink–related deaths should inform the public of the potential dangers of these products.” (K. A. Sepkowitz,
sepkowik@mskcc.org)
Risks of Energy Drinks Mixed With Alcohol: In a Viewpoint article, authors recommend actions for clinicians concerned about patients consuming alcohol and energy drinks concomitantly (pp. 245–6): “It is likely that young people will continue to mix alcohol with caffeine. Potential harms of [alcohol mixed with energy drinks (AMED)] warrant additional rigorous experimental and survey research to examine 3 critical questions. Is the relationship between AMED consumption and risky behavior confounded by personality traits? Does AMED consumption distort perceptions of intoxication? Does AMED consumption increase alcohol consumption, relative to drinking alcohol alone?
“For the present, however, consensus about these questions, and identification of gaps in knowledge, could be achieved by targeting research on this topic and by convening experts to assess existing evidence. Consensus panels might include participants from regulatory organizations, such as the FDA or the Consumer Product Safety Commission; research entities, such as the National Institutes of Health or the Institute of Medicine; and clinician organizations, such as the American Academy of Pediatrics. Such an effort could provide valuable guidance to emerging and future public health policy on AMED.” (J. Howland,
jhowl@bu.edu)
Bacterial Coinfection in Influenza: The case of a 58-year-old man who presented to a community hospital with fever, cough, myalgias, and shortness of breath that worsened over 5 days is used in a Clinician’s Corner article to review bacterial coinfection in influenza (pp. 275–82): “Bacterial coinfection complicated nearly all influenza deaths in the 1918 influenza pandemic and up to 34% of 2009 pandemic influenza A(H1N1) infections managed in intensive care units worldwide. More than 65,000 deaths attributable to influenza and pneumonia occur annually in the United States. Data from 683 critically ill patients with 2009 pandemic influenza A(H1N1) infection admitted to 35 intensive care units in the United States reveal that bacterial coinfection commonly occurs within the first 6 days of influenza infection, presents similarly to influenza infection occurring alone, and is associated with an increased risk of death. Pathogens that colonize the nasopharynx, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes, are most commonly isolated. Complex viral, bacterial, and host factors contribute to the pathogenesis of coinfection. Reductions in morbidity and mortality are dependent on prevention with available vaccines as well as early diagnosis and treatment.” (D. S. Chertow, chertowd@cc.nih.gov)

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

PNN Pharmacotherapy Line
Jan. 17, 2013 * Vol. 20, No. 12
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 17 New England Journal of Medicine (2013; 368).
Short-Course Antiretroviral Therapy: In 366 patients with primary HIV infection, 48-week courses of antiretroviral therapy (ART) initiated within 6 months of seroconversion delayed disease progression, but not for much longer than the period of drug treatment, according to results of the SPARTAC trial (pp. 207–17). Adults with primary HIV infection were assigned to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with these effects over a median follow-up period of 4.2 years on a primary end point of CD4+ count of less than 350 cells/mm3 or initiation of long-term ART: “The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P = 0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P = 0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P = 0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log10 copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events.” (J. Weber, j.weber@imperial.ac.uk)
Enhanced T-Cell Recovery With Early ART Initiation: Researchers report that, within 4 month of HIV-1 infection, patients have a “transient, spontaneous restoration of CD4+ T-cell counts,” and that this natural event can be enhanced through early initiation of antiretroviral therapy (ART) (pp. 218–30). CD4+ counts were studied over 48 months in 384 participants during the time window in which they were not receiving ART (study set 1) and 213 participants who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load (study set 2). Results showed: “Among the participants who were not receiving ART, CD4+ counts increased spontaneously, soon after HIV-1 infection, from the level at study entry (median, 495 cells per cubic millimeter; interquartile range, 383 to 622), reached a peak value (median, 763 cells per cubic millimeter; interquartile range, 573 to 987) within approximately 4 months after the estimated date of infection, and declined progressively thereafter. Recovery of CD4+ counts to 900 or more cells per cubic millimeter was seen in approximately 64% of the participants who initiated ART earlier (≤4 months after the estimated date of HIV infection) as compared with approximately 34% of participants who initiated ART later (>4 months) (P < 0.001). After adjustment for whether ART was initiated when the CD4+ count was 500 or more cells per cubic millimeter or less than 500 cells per cubic millimeter, the likelihood that the count would increase to 900 or more cells per cubic millimeter was lower by 65% (odds ratio, 0.35), and the rate of recovery was slower by 56% (rate ratio, 0.44), if ART was initiated later rather than earlier. There was no association between the plasma HIV RNA level at the time of initiation of ART and CD4+ T-cell recovery.” (S. K. Ahuja, ahujas@uthscsa.edu)
Editorialists write that these studies “provide strong supportive evidence suggesting a benefit for early [antiretroviral] therapy” in patients with HIV infection (
pp. 279–81; B. D. Walker).

>>>PNN NewsWatch
* FDA has licensed Flublok, the first trivalent influenza vaccine made using an insect virus expression system and recombinant DNA technology. Use of baculovirus rather than chicken eggs to produce large amounts of influenza hemagglutinin shortens the time needed for large-scale production of influenza vaccine. Flublok is approved for the prevention of seasonal influenza in people 18–49 years of age.

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

PNN Pharmacotherapy Line
Jan. 18, 2013 * Vol. 20, No. 13
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Jan. Journal of Allergy and Clinical Immunology (2013; 131).
Omalizumab in Nasal Polyps & Asthma: In 24 allergic and nonallergic patients with nasal polyps and comorbid asthma, omalizumab improved symptoms, “supporting the importance and functionality of local IgE formation in the airways,” researchers write (pp. 110–116.e1). Based on a primary end point of reduction in total nasal endoscopic polyp scores after 16 weeks, the investigators found these effects of 4–8 subcutaneous doses of omalizumab or placebo: “There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (−2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy.” (P. Gevaert, philippe.gevaert@UGent.be)
“These encouraging results suggest that more widespread application of omalizumab for [chronic rhinosinusitis with nasal polyposis (CRSwNP)] might be an option for the treatment of patients with recalcitrant CRSwNP, despite the expense and regardless of asthma status or systemic atopy,” an editorialist writes (
pp. 117–8). “Current treatment protocols for chronic rhinosinusitis (CRS) with or without nasal polyps are based on expert guidelines rather than randomized phase III clinical trials. The resultant, widespread nonspecific management of CRS with antibiotics, corticosteroids, and surgery, as currently used in the United States, leaves us with substantial residual morbidity. Moreover, the effect of frequent oral antibiotic use for CRS exacerbations on microbial resistance rates within a population has not been fully evaluated but is likely substantial. Hence there appears to be a compelling need for new strategies, including biologic agents, to treat this common disorder. The publication by Gevaert et al of this phase II proof-of-concept study with omalizumab further opens the door to more innovative strategies for the management of CRS in general and CRSwNP in particular.” (R. C. Kern, RKern@nmff.org)

Oncology Highlights
Source:
Jan. issue of the Journal of Clinical Oncology (2013; 31).
Foretinib in Papillary Renal Cell Carcinoma: A study of foretinib—an oral multikinase inhibitor targeting MET, VEGF, RON, AXL, and TIE-2 receptors—sheds light on the role of MET kinase in cancer therapy (pp. 181–6). In a Phase II trial, responses to foretinib dosed intermittently or daily were stratified by MET pathway activation status: “Overall, 74 patients were enrolled, with 37 in each dosing cohort. [Overall response rate] by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 was 13.5%, median progression-free survival was 9.3 months, and median overall survival was not reached. The presence of a germline MET mutation was highly predictive of a response (five of 10 v five of 57 patients with and without germline MET mutations, respectively). The most frequent adverse events of any grade associated with foretinib were fatigue, hypertension, gastrointestinal toxicities, and nonfatal pulmonary emboli.” (R. Srinivasan, ramasrin@mail.nih.gov)
“Choueiri et al have identified a highly active compound in a variant of kidney cancer by using a highly translational investigative approach that provides additional insight into the mechanism of benefit by identifying the subset of patients with a germline mutation in a putative target gene as a group that may experience high rates of benefit from therapy,” editorialists write (
pp. 169–70). “The findings and approach from this study may be generalizable to other non–[papillary renal cell carcinomas] models in which MET may play a critical role, in either the tumor or the tumor microenvironment. Given the introduction of a number of agents capable of inhibiting MET, translational approaches such as that presented by these investigators must be taken to understand the biologic underpinnings of the clinical impact of treatment.” (R. A. Figlin, robert.figlin@cshs.org)

>>>PNN NewsWatch
* FDA yesterday approved Octaplas (Octapharma), pooled plasma blood indicated for replacement of coagulation factors.
*
PNN will not be published on Mon., Jan. 21, King Day.

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

PNN Pharmacotherapy Line
Jan. 22, 2013 * Vol. 20, No. 14
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 19 issue of Lancet (2013; 381).
10-Valent Vaccine & Invasive Pneumococcal Disease: In the Finnish Invasive Pneumococcal disease (FinIP) vaccine trial, a pneumococcal vaccine containing 10 serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D (PHiD-CV10), tetanus toxoid, and diphtheria toxoid as the carrier proteins was highly effective in both 2 +1 and 3 + 1 dosing schedules, researchers report (pp. 214–22). Among 30,528 participants, just 13 culture-confirmed vaccine-type cases of invasive pneumococcal diseases occurred, including 0 in the PHiD-CV10 3 + 1 group, 1 in the PHiD-CV10 2 + 1 group, and 12 in the control groups. (A. A. Palmu, arto.palmu@thl.fi)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Beta-Blockers in Heart Failure/Reduced Ejection Fraction: “Benefits of beta-blockers in patients with heart failure with reduced ejection fraction seem to be mainly due to a class effect,” with no evidence of “superiority of any single agent over the others,” according to a systematic review and network meta-analysis (f55). Based on 21 trials of atenolol, bisoprolol, bucindolol, carvedilol, metoprolol, and nebivolol, the authors found: “As expected, in the overall analysis, beta blockers provided credible mortality benefits in comparison with placebo or standard treatment after a median of 12 months (odds ratio 0.69, 0.56 to 0.80). However, no obvious differences were found when comparing the different beta blockers head to head for the risk of death, sudden cardiac death, death due to pump failure, or drug discontinuation. Accordingly, improvements in left ventricular ejection fraction were also similar irrespective of the individual study drug.” (S. Chatterjee, sauravchatterjeemd@gmail.com)
Bisphosphonates & Risk of GI Cancers: The gastrointestinal irritation produced by bisphosphonates is not associated with increased risk of common GI cancers, conclude investigators who conducted a series of nested case–control studies (f114). Matching patients from the U.K. QResearch primary care database and the Clinical Practice Research Datalink (CPRD) who were aged 50 or older and had a diagnosis of a primary gastrointestinal cancer in 1997–2011 with up to five controls, the researchers found: “20,106 and 19,035 cases of colorectal cancer cases, 5,364 and 5,135 cases of oesophageal cancer cases, and 3,155 and 3,157 cases of gastric cancer were identified from QResearch and CPRD, respectively. Overall bisphosphonate use (at least one prescription) was not associated with risk of colorectal, oesophageal, or gastric cancers in either database. Adjusted odds ratios (95% confidence interval) for QResearch and CPRD were 0.97 (0.79 to 1.18) and 1.18 (0.97 to 1.43) for oesophageal cancer; 1.12 (0.87 to 1.44) and 0.79 (0.62 to 1.01) for gastric cancer; and 1.03 (0.94 to 1.14) and 1.10 (1.00 to 1.22) for colorectal cancer. Additional analyses showed no difference between types of bisphosphonate for risk of oesophageal and colorectal cancers. For gastric cancer, alendronate use was associated with an increased risk (1.47, 1.11 to 1.95; P = 0.008), but only in data from the QResearch database and without any association with duration and with no definitive confirmation from sensitivity analysis.” (Y. Vinogradova, yana.vinogradova@nottingham.ac.uk)

>>>PNN NewsWatch
* FDA on Friday approved use of onabotulinumtoxinA (Botox, Allergan) to treat adults with overactive bladder who cannot use or do not adequately respond to anticholinergic agents.

>>>PNN JournalWatch
* How To Value Technological Innovation: A Proposal for Determining Relative Clinical Value, in
Gastroenterology, 2013; 144: 5–8. (U. Ladabaum)
* Advances in Acute and Chronic Pancreatitis: From Development to Inflammation and Repair, in
Gastroenterology, 2013; 144: e1–4. (A. K. Rustgi, anil2@mail.med.upenn.edu)
* 2012 ACCF/AHA/HRS Focused Update Incorporated Into the ACCF/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities, in
Circulation, 2013; 127: e283–352. (American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society)
* Are Spondylarthritides Related But Distinct Conditions or a Single Disease With a Heterogeneous Phenotype?, in
Arthritis & Rheumatism, 2013; 65: 12–20. (D. Baeten, d.l.baeten@amc.uva.nl)

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

PNN Pharmacotherapy Line
Jan. 23, 2013 * Vol. 20, No. 15
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Jan. 23 issue of JAMA (2013; 309).
Improved Care Transitions & Medicare Rehospitalizations: In a comparison of 14 intervention and 50 nonintervention communities, quality improvements in care transitions were linked to lower all-cause 30-day rehospitalization and all-cause rehospitalization frequencies, but the rate of the 30-day rehospitalizations as a percentage of hospital discharges did not change significantly (pp. 381–91). Quality Improvement Organizations “facilitated community-wide quality improvement activities to implement evidence-based improvements in care transitions by community organizing, technical assistance, and monitoring of participation, implementation, effectiveness, and adverse effects,” the authors noted. One of the main interventions was the INTERACT tool kit, which includes medication management improvements.
Results showed: “The mean rate of 30-day all-cause rehospitalizations per 1,000 beneficiaries per quarter was 15.21 in 2006–2008 and 14.34 in 2009–2010 in the 14 intervention communities and was 15.03 in 2006–2008 and 14.72 in 2009–2010 in the 50 comparison communities, with the pre–post between-group difference showing larger reductions in rehospitalizations in intervention communities (by 0.56/1000 per quarter; 95% CI, 0.05–1.07; P = .03). The mean rate of hospitalizations per 1,000 beneficiaries per quarter was 82.27 in 2006–2008 and 77.54 in 2009–2010 in intervention communities and was 82.09 in 2006–2008 and 79.48 in 2009–2010 in comparison communities, with the pre–post between-group difference showing larger reductions in hospitalizations in intervention communities (by 2.12/1,000 per quarter; 95% CI, 0.47–3.77; P = .01). Mean community-wide rates of rehospitalizations as a percentage of hospital discharges in the intervention communities were 18.97% in 2006–2008 and 18.91% in 2009–2010 and were 18.76% in 2006–2008 and 18.91% in 2009–2010 in the comparison communities, with no significant difference in the pre–post between-group differences (0.22%; 95% CI, −0.08% to 0.51%; P = .14). Process control charts signaled onset of improvement coincident with initiating intervention.” (J. Lynn,
joanne.lynn@altarum.org)
The requirement under the health care reform law to reduce readmissions means that hospitals must “take care of the patient, not just the disease,” an editorialist writes (
pp. 394–6): “Efforts moving forward should involve implementation of broad patient-centered approaches that engage all members of a care team, especially front-line clinicians, and use proven quality improvement methods such as statistical process control to identify helpful interventions. This approach seems successful with implementation of Project BOOST (Better Outcomes by Optimizing Safe Transitions). As achieved by the quality improvement organization initiative, engaging the community in caring for a patient can facilitate enhanced connections with better care coordination, and may help deliver higher-quality care more cost efficiently—optimizing value.” (M. V. Williams, markwill@nmh.org)
Readmissions & Hospital’s Role in Communities: “Systems thinking argues for broadening the logic model to understand that patient outcomes are affected by a complex adaptive system that involves multiple individuals and entities including the patient, family caregivers, hospitals, postacute care facilities, home health agencies, physicians, other health care professionals, pharmacies, and public health and social service agencies,” authors of a Viewpoint article write (pp. 351–2). “To affect outcomes holistically, communities and care systems need to adopt a population-based measurement system that brings accountability to the triple aim of improving patient experience, enhancing population health, and reducing costs. Risk-based payment models may help support the attainment of these goals. For example, the Visiting Nurse Service of New York’s Choice Health Plan reported reductions in readmissions and hospital use for dually eligible Medicare and Medicaid beneficiaries enrolled in partially and fully capitated programs through continuous care management (including transitional care after a hospitalization) from an interdisciplinary team to help this vulnerable population live safely at home. The United States needs to learn not only what works from these and other promising examples but also how to disseminate effective approaches.” (D. McCarthy, dmccarthy@ihi.org)

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

PNN Pharmacotherapy Line
Jan. 24, 2013 * Vol. 20, No. 16
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 24 New England Journal of Medicine (2013; 368).
Peginesatide for Anemia in Chronic Kidney Disease: Two research articles and an editorial examine use of the erythropoietic agent peginesatide for anemia in patients with chronic kidney disease.
In two randomized, controlled, open-label, noninferiority studies (EMERALD 1 and EMERALD 2), patients with anemia and undergoing hemodialysis maintained hemoglobin levels similarly with monthly peginesatide or epoetin administered one to three times weekly, researchers report (
pp. 307–19). A composite safety end point of death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia was used to evaluate cardiovascular safety.
Results showed: “In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, −0.15 g per deciliter; 95% confidence interval [CI], −0.30 to −0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, −0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator [erythropoiesis-stimulating agent] in the pooled cohort.” (S. Fishbane,
sfishbane@nshs.edu)
According to two randomized, controlled, open-label studies (PEARL 1 and 2) of patients with chronic kidney disease who were not undergoing dialysis, monthly peginesatide was as effective as biweekly darbepoetin for increasing and maintaining hemoglobin levels, but cardiovascular events and mortality were increased (
pp. 320–32). Dose-adjusted peginesatide and darbepoetin produced these changes in a primary efficacy end point of mean change in hemoglobin and a composite cardiovascular safety end point: “In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], −0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, −0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide.” (I. C. Macdougall, iain.macdougall@nhs.net)
“Peginesatide can be used for anemia correction in patients undergoing hemodialysis, in which case its efficacy profile is similar to the profiles of established [erythropoiesis-stimulating agents (ESAs)], but concerns remain about its safety in patients not receiving hemodialysis,” writes an editorialist (
pp. 387–9). “Peginesatide has been recently approved in the United States for patients undergoing hemodialysis, but not for patients who are not receiving hemodialysis. Is there any advantage of using peginesatide rather than the existing ESAs? Less frequent dosing may be an advantage under certain circumstances. Peginesatide does not induce pure red-cell aplasia, but antibody development against this compound, although infrequent, may reduce its efficacy. As with any new class of drugs, prolonged experience and monitoring are necessary. Another important issue is cost. At a time when the prescription of much cheaper, biologically similar ESAs is steadily growing outside the United States, expensive new drugs will be competitive only if proven to result in better patient outcomes. Such outcomes remain to be demonstrated for peginesatide and other new types of ESAs that are in development.” (T. B. Drüeke)

>>>PNN NewsWatch
* FDA has approved deferasirox (Exjade, Novartis) for treating patients ages 10 years and older with chronic iron overload secondary to nontransfusion-dependent thalassemia.

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

PNN Pharmacotherapy Line
Jan. 25, 2013 * Vol. 20, No. 17
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Jan. issue of Health Affairs (2013; 32).
Part D Spending, Adherence & Health Care Costs: In an analysis of regional Medicare spending on diabetes and heart failure treatments in 2006–07, investigators find that higher Part D spending is associated with higher adherence, as measured by drugs on hand (pp. 120–6). This did not translate into lower Medicare Part A and B costs for these diseases, however, as the authors explained: “We found that beneficiaries residing in areas characterized by higher adjusted drug spending had significantly more ‘therapy days’—days with recommended medications on hand—than did beneficiaries in lower-spending areas. However, we did not find that this factor translated into short-term savings in Medicare treatment costs for these two diseases. This result might not be surprising, since returns from medication adherence can take years to manifest. At the same time, discovering which regional factors are responsible for differences in drug spending and medication practices should be a high priority. If the observed differences are related to poor physician communication or lack of good care coordination, then appropriately designed policy tools—including accountable care organizations, medical homes, and provider quality reporting initiatives—might help address them.” (M. Dai, mingdail@umbc.edu)
Americans’ CAM Spending: During 2002–08, the amount spent on complementary and alternative medicines plateaued, a study finds (pp. 45–52). Inclusion of proven CAM therapies in new care and delivery models could help stem the rise in health care costs, the researchers conclude: “Examining trends in demand for complementary and alternative medicine services in the United States reported in the Medical Expenditure Panel Survey during 2002–08, we found that use of and spending on these services, previously on the rise, have largely plateaued. The higher proportion of out-of-pocket responsibility for payment for services may explain the lack of growth. Our findings suggest that any attempt to reduce national health care spending by eliminating coverage for complementary and alternative medicine would have little impact at best. Should some forms of complementary and alternative medicine—for example, chiropractic care for back pain—be proven more efficient than allopathic and specialty medicine, the inclusion of complementary and alternative medicine providers in new delivery systems such as accountable care organizations could help slow growth in national health care spending.” (M. A. Davis, matthew.a.davis@dartmouth.edu)

>>>Medical Care Report
Source:
Jan. issue of Medical Care (2013; 51).
VHA Readmission Costs: Diagnosis-related group payments for acute myocardial infarction (AMI), community-acquired pneumonia (CAP), and congestive heart failure (CHF) would need to be raised by 10%, 11.5%, and 16.6%, respectively, if these payments became 30-day bundled amounts for hospitals, researchers report (pp. 13–9). Based on data for these diseases from 129 Veterans Health Administration hospitals in 2005–09, the investigators find that “previous hospital readmission rates are poor predictors of readmission for future individual patients,” meaning that “policies using these measures to guide subsequent reimbursement are problematic for hospitals that are financially constrained”: “Hospital readmission rates in the previous quarter are not predictive of individual patient risk-adjusted readmission or of patients’ inpatient hospitalization episode cost in the subsequent quarter. Relative to those who were not readmitted within 30 days of index visit discharge, readmitted patients had 30-day episode costs that were 53.3% (P < 0.001), 82.8% (P < 0.001), and 79.8% (P < 0.001) higher for AMI, CAP, and CHF hospitalization episodes, respectively.” (J. M. Hockenberry)

>>>PNN NewsWatch
* “Don’t double up on acetaminophen,” FDA is cautioning consumers in a just-released update article. “Even if you still have fever or pain, it’s important not to take more than directed on the prescription or package label, notes FDA supervisory medical officer Sharon Hertz, M.D. But be careful, the word ‘acetaminophen’ is not always spelled out in full on the container’s prescription label. Abbreviations such as APAP, Acetaminoph, Acetaminop, Acetamin, or Acetam may be used instead.”

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

PNN Pharmacotherapy Line
Jan. 28, 2013 * Vol. 20, No. 18
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Jan. 26 issue of Lancet (2013; 381).
Regorafenib for Advanced Gastrointestinal Stromal Tumors: The efficacy and safety of regorafenib, an orally administered multikinase inhibitor, is studied in trials of patients with gastrointestinal stromal tumours (GIST) refractory to treatment with imatinib and sunitinib and with previously treated metastatic colorectal cancer.
In patients with metastatic GIST whose disease had progressed while on standard treatments, regorafenib produced significant increases in progression-free survival (PFS), compared with placebo (
pp. 295–302). In a Phase III GRID study—described by the authors as “the first clinical trial to show benefit from a kinase inhibitor in this highly refractory population of patients”—participants received either oral regorafenib 160 mg daily or placebo, plus best supportive care in both groups, for the first 3 weeks of 4-week cycles. Results showed: “From Jan 4 to Aug 18, 2011, 240 patients were screened and 199 were randomised to receive regorafenib (n = 133) or matching placebo (n = 66). Data cutoff was Jan 26, 2012. Median PFS per independent blinded central review was 4.8 months (IQR 1.4–9.2) for regorafenib and 0.9 months (0.9–1.8) for placebo (hazard ratio [HR] 0.27, 95% CI 0.19–0.39; p < 0.0001). After progression, 56 patients (85%) assigned placebo crossed over to regorafenib. Drug-related adverse events were reported in 130 (98%) patients assigned regorafenib and 45 (68%) patients assigned placebo. The most common regorafenib-related adverse events of grade 3 or higher were hypertension (31 of 132, 23%), hand-foot skin reaction (26 of 132, 20%), and diarrhoea (seven of 132, 5%).” (G. D. Demetri, gdemetri@partners.org)
“Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies,” CORRECT study group investigators conclude based on their Phase III international trial of the drug (
pp. 303–12). Patients received best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of 4-week cycles. With a primary endpoint of overall survival, the study showed: “Between April 30, 2010, and March 22, 2011, 1,052 patients were screened, 760 patients were randomised to receive regorafenib (n = 505) or placebo (n = 255), and 753 patients initiated treatment (regorafenib n = 500; placebo n = 253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6.4 months in the regorafenib group versus 5.0 months in the placebo group (hazard ratio 0.77; 95% CI 0.64–0.94; one-sided p = 0.0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%).” (E. Van Cutsem, eric.vancutsem@uzleuven.be)

>>>PNN NewsWatch
* FDA has approved Takeda’s alogliptin (Nesina) and two combination products— alogliptin plus metformin (Kazano) and alogliptin plus pioglitazone (Oseni)—for use with diet and exercise to improve blood glucose control in adults with type 2 diabetes. The DPP-4 inhibitor was studied in 14 clinical trials involving 8,500 patients with type 2 diabetes. As monotherapy, alogliptin reduced A1c levels by 0.4 to 0.6 percentage points, compared with placebo, during 26 weeks of therapy. Combination therapy with the drug produced further A1c decreases, averaging 0.4 to 1.1 percentage points.
*
Imatinib (Gleevec, Novartis) has been approved by FDA for use in children with newly diagnosed with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia.

>>>PNN JournalWatch
* Twenty-First Century Behavioral Medicine: A Context for Empowering Clinicians and Patients With Diabetes: A Consensus Report, in
Diabetes Care, 2013; 36: 463–70. (D. G. Marrero, dgmarrer@iupui.edu)
* A Systematic Review and Meta-analysis of the Association Between Depression and Insulin Resistance, in
Diabetes Care, 2013; 36: 480–9. (C. Kan, carol.kan@kcl.ac.uk)
* Ambulatory Blood Pressure Monitoring: Recent Evidence and Clinical Pharmacy Applications, in
Pharmacotherapy, 2013; 33: 69–83. (M. Ernst, michael-ernst@uiowa.edu)

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

PNN Pharmacotherapy Line
Jan. 29, 2013 * Vol. 20, No. 19
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Jan. 28 issue of the JAMA Internal Medicine (2013; 173).
Technology’s Impact on Weight Loss: Short-term weight loss was enhanced through patients’ use of personal digital assistants to record diet and physical activity, researchers report (pp. 105–11). Concluding that mobile technology may represent a scalable means of “augmenting the effect of physician-directed weight loss treatment,” study authors report these results from a 12-month trial at a VA outpatient clinic where participants attended biweekly weight-loss meeting, used PDAs, and received biweekly coaching calls for 6 months: “Sixty-nine adults received intervention (mean age, 57.7 years; 85.5% were men). A longitudinal intent-to-treat analysis indicated that the +mobile group lost a mean of 3.9 kg more (representing 3.1% more weight loss relative to the control group; 95% CI, 2.2–5.5 kg) than the standard group at each postbaseline time point. Compared with the standard group, the +mobile group had significantly greater odds of having lost 5% or more of their baseline weight at each postbaseline time point (odds ratio, 6.5; 95% CI, 2.5–18.6).” (B. Spring, bspring@northwestern.edu)
Commenting on this and a study of lifestyle interventions during the Diabetes Prevention Program (
pp. 113–21; J. Ma, maj@pamfri.org), editorialists write that the research provides a “foundation for future work” but leaves “many unanswered questions” (pp. 111–2): “Technology changes so quickly that many tools are obsolete by the time they have been thoroughly studied. Smartphones, for example, have largely replaced PDAs. We need to know what specific features of technology make it successful for weight loss. Is it, for example, convenience, personalization, or interactivity? These features could be incorporated into future tools no matter what form they take. We also need to know whether interventions such as those studied by Ma et al and Spring et al would be effective if used among unselected primary care patients rather than typical patients recruited for research. Along the same lines, we need to know how primary care physicians can efficiently and effectively incorporate technological tools into their practices to help their patients lose weight. These and related questions are now becoming the focus of intense research. Stay tuned! Thanks to simple technologies, the future of obesity research and treatments is starting to look brighter.” (G. Rao, grao@northshore.org)
Trends in Use of U.S. Ambulatory Health Care: Drug therapy improved in ambulatory care settings between 1999 and 2009, a study shows, and delivery of underused care also trended positively (pp. 142–8). But “limited changes” were found in “reduction of inappropriate care” in the National Ambulatory Medical Care Survey and the outpatient department component of the National Hospital Ambulatory Medical Care Survey from those years: “We observed a statistically significant improvement in 6 of 9 underuse quality indicators. There was an improvement in the use of antithrombotic therapy for atrial fibrillation; the use of aspirin, beta-blockers, and statins in coronary artery disease; the use of beta-blockers in congestive heart failure; and the use of statins in diabetes mellitus. We observed an improvement in only 2 of 11 overuse quality indicators, 1 indicator became worse, and 8 did not change. … Of the 2 misuse indicators, there was a decrease in the proportion of patients with a urinary tract infection who were prescribed an inappropriate antibiotic.” (M. S. Kale, minal.kale@mountsinai.org)
DMAA Availability After FDA Action: An April 27, 2012, warning letter sent by FDA to 10 manufacturers of DMAA supplements had little effect on Internet availability of products such as “Jack3d” and “OxyELITE Pro,” an investigator reports (pp. 164–5). A systematic search on May 17, 2012, using Google Search and Google Shopping found that all 16 products identified by FDA were still available online, including 6 that could be purchased from the manufacturers’ websites: “In many cases, the illegal DMAA-containing products were readily available through major online retailers. For example, 12 of the 16 products were available for sale through General Nutrition Centers (www.gnc.com). Eight of the 16 products were available through Drugstore.com. None of the websites reviewed provided any information about the products being illegal, adulterated, or otherwise not permitted for sale.” (P. J. Gregory, pgregory@creighton.edu)

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

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

>>>Chest Highlights
Source:
Jan. issue of Chest (2013; 143).
Cigarette Smoking & Viral Infections: “Understanding the impact of cigarette smoke on the immune system may unravel novel targets for therapies that could affect acute exacerbations and [chronic obstructive pulmonary disease (COPD)] pathogenesis,” authors write (pp. 196–206). “COPD is a complex syndrome that poses a serious health threat to >1.1 billion smokers worldwide. The stable disease is punctuated by episodes of acute exacerbation, which are predominantly the result of viral and bacterial infections. Despite their devastating health impact, mechanisms underlying disease exacerbations remain poorly understood. Mounting evidence suggests that cigarette smoke profoundly affects the immune system, compromising the host’s ability to mount appropriate immune and inflammatory responses against microbial agents. This review highlights recent advances in our understanding of the impact of cigarette smoke on type 1 interferon and IL-1 signaling cascades. The immune defects caused by cigarette smoke on these two key pathways contribute to the seemingly contradictory nature of cigarette smoke as both a damaging and a proinflammatory factor as well as an immunosuppressive factor.” (M. R. Stämpfli, stampfli@mcmaster.ca)
Treatment of Cystic Fibrosis Post-Ivacaftor: Approval of ivacaftor (Kalydeco, Vertex), the first drug approved for treatment of the underlying defect in cystic fibrosis (CF), “produced a great deal of excitement and hope,” authors report, but the drug benefits only “a small minority of the CF population” (pp. 207–13). Research into other CF transmembrane conductance regulator (CFTR) modulators is under way, as are other approaches: “In this review, we use the catalog of treatments currently under evaluation with the support of the Cystic Fibrosis Foundation, known as the Cystic Fibrosis Foundation Therapeutics Pipeline, as a platform to discuss the variety of candidate treatments for CF lung disease that promise to improve CF care. Many of these approaches target the individual components of the relentless cycle of airway obstruction, inflammation, and infection characteristic of lung disease in CF, whereas others are aimed directly at the gene defect, or the resulting dysfunctional protein, that instigates this cycle. We discuss how new findings from the laboratory have informed not only the development of novel therapeutics, but also the rationales for their use and the outcomes used to measure their effects.” (L. Hoffman, lhoffm@u.washington.edu)
Order Sets in Electronic Health Records: The experiences of an academic medical center in developing an electronic health record (EHR) are described (pp. 228–35): “Order sets represent one clinical decision support (CDS) tool within computerized provider order entry systems that may promote safe, efficient, and evidence-based patient care. A small number of order sets account for the vast majority of use, suggesting that some order sets have a higher value to clinicians than others. While EHR order sets can save time and improve processes of care, it remains less clear that EHR order sets have shown definite patient outcome benefits. There are general guidelines on CDS and usability that can be applied to the development of EHR order sets. Order set success requires leadership, planning, and resources as well as ongoing maintenance and evaluation.” (J. D. McGreevey III, john.mcgreevey@uphs.upenn.edu)

>>>PNN NewsWatch
* FDA yesterday approved mipomersen sodium (Kynamro, Genzyme) injection as an addition to lipid-lowering medications and diet to treat patients with homozygous familial hypercholesterolemia (HoFH). Treatment with mipomersen reduces LDL cholesterol, apolipoprotein B, total cholesterol, and non-HDL cholesterol. In a clinical trial of 51 patients with HoFH, LDL cholesterol levels fell by about 25% during the first 26 weeks in those receiving mipomersen. FDA approved Kynamro with a boxed warning about liver toxicity and a REMS with elements to assure safe use, including prescriber and pharmacy certification, and documentation of safe-use conditions, which requires a prescription authorization form for each new prescription. Common adverse reactions include injection site reactions, flu-like symptoms, nausea, headache, and elevations in serum transaminases.

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

PNN Pharmacotherapy Line
Jan. 31, 2013 * Vol. 20, No. 21
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Jan. 31 New England Journal of Medicine (2013; 368).
Donor Feces Infusions for Recurrent Clostridium difficile: Compared with vancomycin, nasogastric infusions of donor feces significantly improved resolution of Clostridium difficile infections in a study stopped at a interim analysis (pp. 407–15). A primary end point of resolution of diarrhea associated with C. difficile infection without relapse after 10 weeks showed: “Of 16 patients in the infusion group, 13 (81%) had resolution of C. difficile–associated diarrhea after the first infusion. The 3 remaining patients received a second infusion with feces from a different donor, with resolution in 2 patients. Resolution of C. difficile infection occurred in 4 of 13 patients (31%) receiving vancomycin alone and in 3 of 13 patients (23%) receiving vancomycin with bowel lavage (P < 0.001 for both comparisons with the infusion group). No significant differences in adverse events among the three study groups were observed except for mild diarrhea and abdominal cramping in the infusion group on the infusion day. After donor-feces infusion, patients showed increased fecal bacterial diversity, similar to that in healthy donors, with an increase in Bacteroidetes species and clostridium clusters IV and XIVa and a decrease in Proteobacteria species.” (J. J. Keller, keller@hagaziekenhuis.nl)
Fecal microbiota transplantation is “an old therapy [that has come] of age,” writes an editorialist (
pp. 474–5). “The significance of [this] study … goes far beyond the treatment of recurrent or severe C. difficile infection. The burgeoning field of microbiome research, initially made possible by technologies to identify bacterial 16S ribosomal RNA in complex biologic samples, has alerted us to the abundant, diverse, and influential nature of the gut microbiota.” (C. P. Kelly)
Fractional Doses of Inactivated Poliovirus Vaccine: Fractional doses of inactivated poliovirus vaccine (IPV) induce priming and seroconversion of more than 90% of infants, shows a study of 310 infants in Cuba at ages 4 and 8 months (pp. 416–24). The results mean that costs of polio vaccination campaigns can be reduced in low-income areas through use of split doses: “In the group receiving the first fractional dose of IPV, seroconversion to poliovirus types 1, 2, and 3 occurred in 16.6%, 47.1%, and 14.7% of participants, respectively, as compared with 46.6%, 62.8%, and 32.0% in the group receiving the first full dose of IPV (P < 0.008 for all comparisons). A priming immune response to poliovirus types 1, 2, and 3 occurred in 90.8%, 94.0%, and 89.6% of participants, respectively, in the group receiving the fractional dose as compared with 97.6%, 98.3%, and 98.1% in the group receiving the full dose (P = 0.01 for the comparison with type 3). After the administration of the second dose of IPV in the group receiving fractional doses, cumulative two-dose seroconversion to poliovirus types 1, 2, and 3 occurred in 93.6%, 98.1%, and 93.0% of participants, respectively, as compared with 100.0%, 100.0%, and 99.4% in the group receiving the full dose (P < 0.006 for the comparisons of types 1 and 3). The group receiving intradermal injections had the greatest number of adverse events, most of which were minor in intensity and none of which had serious consequences.” (R. W. Sutter, sutterr@who.int)
Antibiotics in Severe Acute Malnutrition: In 2,767 Malawian children ages 6–59 months with severe acute malnutrition, addition of antibiotics to treatment regimens significantly improved recovery and mortality rates, researchers report (pp. 425–35). Amoxicillin, cefdinir, or placebo for 7 days had these effects in combination with ready-to-use therapeutic food: “In the amoxicillin, cefdinir, and placebo groups, 88.7%, 90.9%, and 85.1% of the children recovered, respectively (relative risk of treatment failure with placebo vs. amoxicillin, 1.32; 95% confidence interval [CI], 1.04 to 1.68; relative risk with placebo vs. cefdinir, 1.64; 95% CI, 1.27 to 2.11). The mortality rates for the three groups were 4.8%, 4.1%, and 7.4%, respectively (relative risk of death with placebo vs. amoxicillin, 1.55; 95% CI, 1.07 to 2.24; relative risk with placebo vs. cefdinir, 1.80; 95% CI, 1.22 to 2.64). Among children who recovered, the rate of weight gain was increased among those who received antibiotics. No interaction between type of severe acute malnutrition and intervention group was observed for either the rate of nutritional recovery or the mortality rate.” (M. J. Manary, manary@kids.wustl.edu)

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

PNN Pharmacotherapy Line
Feb. 1, 2013 * Vol. 20, No. 22
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Feb. issue of Diabetes Care (2013; 36).
GPR40 Agonist in Type 2 Diabetes: In a Phase II trial of TAK-875, the GPR40 agonist “produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise,” researchers report (pp. 245–50). The 12-week study, conducted in Japanese patients, used doses of TAK-875 ranging from 6.25 to 200 mg daily. Results showed: “A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; −0.54, −0.67, −0.88, −1.27, −1.29, and −1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and −1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving ≥50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group.” (K. Kaku, kka@med.kawasaki-m.ac.jp)
Vitamin D in Prediabetes: Correction of hypovitaminosis D in patients with prediabetes had no effects on insulin markers or disease progression over a 1-year period in a study of 1,551 patients ages 40 years or older (pp. 260–6). Glucose tolerance tests identified patients with prediabetes, and those with 25-OH vitamin D (25-OHD) levels less than 30 ng/mL received weekly placebo or vitamin D, with these results: “25-OHD levels rapidly rose from 22 to nearly 70 ng/mL after vitamin D supplementation with a mean weekly dose of 88,865 IU. There were no differences between the placebo and vitamin D groups regarding fasting plasma glucose, 2-h glucose, or insulin secretion and sensitivity or in the percent developing diabetes or returning to normal glucose tolerance. No subjects experienced increased serum or urinary calcium levels. At 12 months, A1C levels were significantly slightly less (0.2%) in the vitamin D group.” (M. B. Davidson, mayerdavidson@cdrewu.edu)
Rapidly Acting Insulin Analogs Administered with Hyaluronidase: Coinjection of insulins aspart, glulisine, and lispro with recombinant human hyaluronidase (rHuPH20) produced ultra-rapid onsets of action and shorter durations of action, a study shows (pp. 273–5). In 14 healthy volunteers, subcutaneous administration of each of the rapidly acting analogs at doses of 0.15 units/kg produced these results with and without rHuPH20: “The commercial formulations had comparable insulin time-exposure and time-action profiles as follows: 50% exposure at 123–131 min and 50% total glucose infused at 183–186 min. With rHuPH20, the analogs had faster yet still comparable profiles: 50% exposure at 71–79 min and 50% glucose infused at 127–140 min. The accelerated absorption with rHuPH20 led to twice the exposure in the first hour and half the exposure beyond 2 h, which resulted in 13- to 25-min faster onset and 40- to 49-min shorter mean duration of insulin action.” (D. E. Vaughn, dvaughn@halozyme.com)
Thiazolidinediones & Risk of Colorectal Cancer: Patients with diabetes who are taking thiazolidinediones (TZDs) have a decreased risk of colorectal cancer, according to a case–control study of the Taiwan National Health Insurance Research Database (pp. 369–75). Cases were patients with a diagnosis of diabetes in 2000–08 that preceded a new diagnosis of colorectal cancer by at least 365 days. They were compared with control patients matched for sex, age, and the duration of diabetes, with these results: “A decreased risk of colorectal cancer was observed in patients who had used TZDs compared with those who had never used TZDs (adjusted odds ratio 0.86 [95% CI 0.79–0.94]). Furthermore, the benefit of a decreased colorectal cancer risk was also found with concomitant use of TZDs and low-dose aspirin or NSAIDs.” (P-C Chen, pchen@ntu.edu.tw)

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

PNN Pharmacotherapy Line
Feb. 4, 2013 * Vol. 20, No. 23
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Feb. 2 issue of Lancet (2013; 381).
CBT + Pharmacotherapy in Depression: In patients with pharmacotherapy-resistant depression, addition of cognitive–behavioral therapy (CBT) proved effective for reducing depressive symptoms, researchers report (pp. 375–84). In 469 patients ages 18–75 whose depression had failed to resolve during 6 weeks or more of antidepressant therapy, unmasked provision of CBT or continued usual care produced these outcomes over the following 12 months: “Between Nov 4, 2008, and Sept 30, 2010, we assigned 235 patients to usual care, and 234 to CBT plus usual care. 422 participants (90%) were followed up at 6 months and 396 (84%) at 12 months, finishing on Oct 31, 2011. 95 participants (46%) in the intervention group met criteria for response at 6 months compared with 46 (22%) in the usual care group (odds ratio 3.26, 95% CI 2.10–5.06, p < 0.001).” (N. Wiles, nicola.wiles@bristol.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Opioid Overdose Education & Nasal Naloxone Distribution: In 19 Massachusetts communities with state-supported overdose education and nasal naloxone distribution (OEND) programs, opioid overdose rates were reduced between 2002 and 2009, a study shows (f174). The interrupted time series looked at opioid-related deaths and assessed the effects of OEND services provided to at-risk users, social services staff, and family and friends of users. Results showed: “Among these communities, OEND programs trained 2,912 potential bystanders who reported 327 rescues. Both community-year strata with 1–100 enrollments per 100,000 population (adjusted rate ratio 0.73, 95% confidence interval 0.57 to 0.91) and community-year strata with greater than 100 enrollments per 100,000 population (0.54, 0.39 to 0.76) had significantly reduced adjusted rate ratios compared with communities with no implementation. Differences in rates of acute care hospital utilization were not significant.” (A. Y. Walley, awalley@bu.edu)
Dual RAS Blockade: While “dual blockade of the renin-angiotensin system may have seemingly beneficial effects on certain surrogate endpoints, it failed to reduce mortality and was associated with an excessive risk of adverse events such as hyperkalaemia, hypotension, and renal failure compared with monotherapy,” according to authors of a systematic review and meta-analysis (f360): “33 randomised controlled trials with 68,405 patients (mean age 61 years, 71% men) and mean duration of 52 weeks were included. Dual blockade of the renin-angiotensin system was not associated with any significant benefit for all cause mortality (relative risk 0.97, 95% confidence interval 0.89 to 1.06) and cardiovascular mortality (0.96, 0.88 to 1.05) compared with monotherapy. Compared with monotherapy, dual therapy was associated with an 18% reduction in admissions to hospital for heart failure (0.82, 0.74 to 0.92). However, compared with monotherapy, dual therapy was associated with a 55% increase in the risk of hyperkalaemia (P < 0.001), a 66% increase in the risk of hypotension (P < 0.001), a 41% increase in the risk of renal failure (P = 0.01), and a 27% increase in the risk of withdrawal owing to adverse events (P < 0.001). Efficacy and safety results were consistent in cohorts with and without heart failure when dual therapy was compared with monotherapy except for all cause mortality, which was higher in the cohort without heart failure (P = 0.04 v P = 0.15), and renal failure was significantly higher in the cohort with heart failure (P < 0.001 v P = 0.79).” (F. H. Messerli, messerli.f@gmail.com)

>>>PNN NewsWatch
* FDA on Friday approved glycerol phenylbutyrate (Ravicti, Hyperion Therapeutics) for chronic management of some urea cycle disorders (UCDs) in patients ages 2 years and older. The liquid product is taken 3 times daily and is intended for use in patients whose UCD cannot be managed by a protein-restricted diet or amino acid supplements alone. Ravicti must be used with a protein-restricted diet and, in some cases, dietary supplements.

>>>PNN JournalWatch
* Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association, in
Stroke, 2013; 44: STR.0b013e318284056a.

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

PNN Pharmacotherapy Line
Feb. 5, 2013 * Vol. 20, No. 24
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 5 issue of the Annals of Internal Medicine (2013; 158).
Empiric Voriconazole in Fungal Meningitis: Fungal meningitis in patients exposed to contaminated methylprednisolone via epidural steroid injections (ESIs) often responded to empiric voriconazole therapy, according to a report of early clinical observations during the recent outbreak (pp. 154–61). At a large Virginia hospital, 172 patients who presented with exposure to contaminated ESI had these clinical findings: “131 [patients] had lumbar puncture because of symptoms or signs consistent with central nervous system disease. Twenty-five (19%) had neutrophilic meningitis. All were started on voriconazole therapy alone. Three patients developed stroke during treatment. Ten patients had arachnoiditis, another had an epidural abscess, and 9 had urine retention. Fifteen continued to receive voriconazole, and 10 were switched to amphotericin B. Cerebrospinal fluid leukocyte counts began to decrease by day 13 of treatment. Findings on MRI included ventriculitis, leptomeningeal enhancement, infarction, hemorrhage, and arachnoiditis. Serum voriconazole levels varied, and CSF concentrations of voriconazole were approximately 50% those of serum. Exserohilum rostratum and Cladosporium species have been cultured.” (T. M. Kerkering)
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 who conducted a systematic review of literature (pp. 169–78): “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 [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)
2013 Adult Immunization Schedule: The new adult recommendations of the CDC’s Advisory Committee on Immunization Practices are published (pp. 191–9). “Because a mix of quadrivalent and trivalent influenza vaccines may be available in 2013–14, the abbreviation for inactivated influenza vaccine has been changed from TIV (trivalent inactivated influenza vaccine) to IIV (inactivated influenza vaccine),” the Committee notes. ‘The abbreviation for live-attenuated influenza vaccine (LAIV) remains unchanged.” Substantive changes include information on use of 13-valent pneumococcal conjugate vaccine and the timing of its use relative to 23-valent pneumococcal polysaccharide vaccine in adults and expansion of use of tetanus, diphtheria, and acellular pertussis vaccine to include routine vaccination of adults aged 65 years or older and pregnant women during each pregnancy. (C. B. Bridges, cbridges@cdc.gov)
CER of PSA Screenings: A comparative effectiveness study of prostate-specific antigen screening in men finds that “PSA screening strategies that use higher thresholds for biopsy referral for older men and that screen men with low PSA levels less frequently can reduce harms while preserving lives” (pp. 145–53). Using a lifetime horizon and societal perspective, the investigators considered 35 screening strategies with various start and stop ages, screening intervals, and referral thresholds: “Without screening, the risk for prostate cancer death is 2.86%. A reference strategy that screens men aged 50 to 74 years annually with a PSA threshold for biopsy referral of 4 µg/L reduces the risk for prostate cancer death to 2.15%, with risk for overdiagnosis of 3.3%. A strategy that uses higher PSA thresholds for biopsy referral in older men achieves a similar risk for prostate cancer death (2.23%) but reduces the risk for overdiagnosis to 2.3%. A strategy that screens biennially with longer screening intervals for men with low PSA levels achieves similar risks for prostate cancer death (2.27%) and overdiagnosis (2.4%), but reduces total tests by 59% and false-positive results by 50%.” (R. Etzioni, retzioni@fhcrc.org)

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

PNN Pharmacotherapy Line
Feb. 6, 2013 * Vol. 20, No. 25
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 6 issue of JAMA (2013; 309).
Ramipril in PAD & Intermittent Claudication: In 212 patients with peripheral artery disease and intermittent claudication, ramipril 10 mg/d for 24 weeks significantly improved pain-free and maximum treadmill walking times and the physical functioning component of the SF-36 score (pp. 453–60). The study, conducted at three Australian hospitals, used a standard treadmill test, the SF-36, and the Walking Impairment Questionnaire (WIQ) to compared the effects of ramipril with placebo: “At 6 months, relative to placebo, ramipril was associated with a 75-second (95% CI, 60–89 seconds) increase in mean pain-free walking time (P < .001) and a 255-second (95% CI, 215–295 seconds) increase in maximum walking time (P < .001). Relative to placebo, ramipril improved the WIQ median distance score by 13.8 (Hodges–Lehmann 95% CI, 12.2–15.5), speed score by 13.3 (95% CI, 11.9–15.2), and stair climbing score by 25.2 (95% CI, 25.1–29.4) (P < .001 for all). The overall SF-36 median Physical Component Summary score improved by 8.2 (Hodges–Lehmann 95% CI, 3.6–11.4; P = .02) in the ramipril group relative to placebo. Ramipril did not affect the overall SF-36 median Mental Component Summary score.” (A. A. Ahimastos, a.ahimastos@alfred.org.au)
Medical research “still [has] miles to go” in the use of medications to improve walking performance in patients with PAD, writes an editorialist (
pp. 487–8): “Given the paucity of effective therapies for treating functional limitation in PAD and recent randomized controlled clinical trials that have failed to demonstrate improved walking performance in response to novel medical therapies in PAD, the magnitude of improvement associated with ramipril in the study by Ahimastos et al is particularly notable. Several aspects of the trial by Ahimastos et al should be considered. First, the trial was conducted in Australia and included Australian citizens. It is conceivable that the genetic makeup of Australian citizens may be more amenable to the favorable benefits of ACE inhibitors with regard to functional performance. Among participants without PAD, variation in the ACE genotype influences ACE enzyme activity and may determine responsiveness to exercise interventions and muscle quality.” (M. M. McDermott, mdm608@northwestern.edu)
Corticosteroid Injection in Lateral Epicondylalgia: In 165 patients with chronic unilateral lateral epicondylalgia, corticosteroid injections produced worse clinical outcomes after 1 year, compared with placebo, and physical therapy helped little (pp. 461–9). Participants in the Australian study had pain produced by actions such as gripping, palpation, resisted wrist or middle finger extension, or stretching of the forearm extensor muscles with reduced pain-free grip. Corticosteroids and/or physiotherapy produced these results: “Corticosteroid injection resulted in lower complete recovery or much improvement at 1 year vs placebo injection (83% vs 96%, respectively; relative risk [RR], 0.86 [99% CI, 0.75–0.99]; P = .01) and greater 1-year recurrence (54% vs 12%; RR, 0.23 [99% CI, 0.10–0.51]; P < .001). The physiotherapy and no physiotherapy groups did not differ on 1-year ratings of complete recovery or much improvement (91% vs 88%, respectively; RR, 1.04 [99% CI, 0.90–1.19]; P = .56) or recurrence (29% vs 38%; RR, 1.31 [99% CI, 0.73–2.35]; P = .25). Similar patterns were found at 26 weeks, with lower complete recovery or much improvement after corticosteroid injection vs placebo injection (55% vs 85%, respectively; RR, 0.79 [99% CI, 0.62–0.99]; P < .001) and no difference between the physiotherapy and no physiotherapy groups (71% vs 69%, respectively; RR, 1.22 [99% CI, 0.97–1.53]; P = .84). At 4 weeks, there was a significant interaction between corticosteroid injection and physiotherapy (P = .01), whereby patients receiving the placebo injection plus physiotherapy had greater complete recovery or much improvement vs no physiotherapy (39% vs 10%, respectively; RR, 4.00 [99% CI, 1.07–15.00]; P = .004). However, there was no difference between patients receiving the corticosteroid injection plus physiotherapy vs corticosteroid alone (68% vs 71%, respectively; RR, 0.95 [99% CI, 0.65-1.38]; P = .57).” (B. Vicenzino, b.vicenzino@uq.edu.au)

>>>PNN NewsWatch
* The Nutrition Facts label is 20 years old, FDA noted yesterday in an American Heart Month news release promoting heart-healthy lifestyles.

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

PNN Pharmacotherapy Line
Feb. 7, 2013 * Vol. 20, No. 26
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 7 issue of the New England Journal of Medicine (2013; 368).
Extended Rivaroxaban in Acute Illness: In a study that explored the appropriate duration of thromboprophylaxis in patients with acute medical illnesses, rivaroxaban administered for more than 1 month significantly reduced the risk of venous thromboembolism, compared with enoxaparin for 10 days (pp. 518–23). Participants were ages 40 years or older when they were hospitalized for medical illnesses such as heart failure, active cancer, or acute infectious disease, ischemic stroke, or respiratory insufficiency. All had reduced mobility.
One study group received subcutaneous enoxaparin 40 mg once daily for 10 days and oral placebo for 35 days. The other group received subcutaneous placebo for 10 days and oral rivaroxaban 10 mg once daily for 35 days. The following changes in a primary efficacy composite outcome of asymptomatic proximal or symptomatic venous thromboembolism up to day 10 (noninferiority test) and up to day 35 (superiority test) were observed: “A total of 8,101 patients underwent randomization. A primary efficacy outcome event occurred in 78 of 2,938 patients (2.7%) receiving rivaroxaban and 82 of 2,993 patients (2.7%) receiving enoxaparin at day 10 (relative risk with rivaroxaban, 0.97; 95% confidence interval [CI], 0.71 to 1.31; P = 0.003 for noninferiority) and in 131 of 2,967 patients (4.4%) who received rivaroxaban and 175 of 3,057 patients (5.7%) who received enoxaparin followed by placebo at day 35 (relative risk, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). A principal safety outcome event [composite of major or clinically relevant nonmajor bleeding] occurred in 111 of 3,997 patients (2.8%) in the rivaroxaban group and 49 of 4,001 patients (1.2%) in the enoxaparin group at day 10 (P < 0.001) and in 164 patients (4.1%) and 67 patients (1.7%) in the respective groups at day 35 (P < 0.001).” (A. T. Cohen,
alexander.cohen@kcl.ac.uk)
Topical Paromomycin/Gentamicin for Cutaneous Leishmaniasis: Paramomycin, with or without concomitant gentamicin, is effective for treating cutaneous leishmaniasis caused by Leishmania major, according to a study from Tunisia (pp. 524–32). A total of 375 patients with 1–5 ulcerative lesions had these responses to 15% paromomycin–0.5% gentamicin cream (WR 279,396), 15% paromomycin alone, or vehicle control when applied once daily for 20 days: “The rate of cure of the index lesion was 81% (95% confidence interval [CI], 73 to 87) for paromomycin–gentamicin, 82% (95% CI, 74 to 87) for paromomycin alone, and 58% (95% CI, 50 to 67) for vehicle control (P < 0.001 for each treatment group vs. the vehicle-control group). Cure of the index lesion was accompanied by cure of all other lesions except in five patients, one in each of the paromomycin groups and three in the vehicle-control group. Mild-to-moderate application-site reactions were more frequent in the paromomycin groups than in the vehicle-control group.” (M. Grogl, max.grogl@amedd.army.mil)
Daily Chlorhexidine Bathing & Hospital-Acquired Infections: Daily bathing of hospitalized patients with chlorhexidine significantly reduced acquisition of multidrug-resistant organisms (MDROs) and development of hospital-acquired septicemias in a multicenter, cluster-randomized, nonblinded crossover trial (pp. 533–42). In 9 ICUs and bone-marrow transplantation units in 6 hospitals, patients were bathed with either no-rinse 2% chlorhexidine–impregnated washcloths or with nonantimicrobial washcloths for a 6-month period. The hospitals then crossed over to the alternate treatment for the next 6 months, with these results: “A total of 7,727 patients were enrolled during the study. The overall rate of MDRO acquisition was 5.10 cases per 1,000 patient–days with chlorhexidine bathing versus 6.60 cases per 1,000 patient–days with nonantimicrobial washcloths (P = 0.03), the equivalent of a 23% lower rate with chlorhexidine bathing. The overall rate of hospital-acquired bloodstream infections was 4.78 cases per 1,000 patient–days with chlorhexidine bathing versus 6.60 cases per 1,000 patient–days with nonantimicrobial washcloths (P = 0.007), a 28% lower rate with chlorhexidine-impregnated washcloths. No serious skin reactions were noted during either study period.” (M. W. Climo, michael.climo@va.gov)

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

PNN Pharmacotherapy Line
Feb. 8, 2013 * Vol. 20, No. 27
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Feb. issue of Pharmacotherapy (2013; 33).
Antimicrobial Stewardship Through a Candidemia Care Bundle: The antimicrobial stewardship team (AST) at a large academic hospital improved patient care by implementing a comprehensive candidemia care bundle, researchers report (pp. 137–43). Bundle elements—utilization of appropriate antifungal agents with appropriate duration of use, removal of intravenous catheters, repeat blood cultures, monitoring of time until clearance of candidemia, and performance of ophthalmologic examinations—provided to 78 patients during an evaluation period produced these outcomes: “Compliance with all candidemia care bundle elements was significantly higher in the AST group versus the control group (78.0% vs 40.5%, p = 0.0016). Implementation of the care bundle significantly improved rates of ophthalmologic examination (97.6% vs 75.7%, p = 0.0108), selection of appropriate antifungal therapy (100% vs 86.5%, p = 0.0488), and compliance with an appropriate duration of therapy (97.6% vs 67.7%, p = 0.0012). In addition, the AST group had fewer excess total days of therapy beyond the recommended duration than the control group (5 vs 83 total antifungal days). Length of hospitalization (20 vs 21 days, p = 0.9184), time until clearance of candidemia (3 vs 3 days p = 0.610), rate of persistent candidemia (22% vs 40.5%, p = 0.126), and rate of recurrent candidemia (4.9% vs 5.4%, p = 0.916) were similar in the AST group versus the control group.” (J. Nagel, nageljl@umich.edu)
This study demonstrates that antimicrobial stewardship “goes well beyond antimicrobial drug choice and dosing,” editorialists write (
pp. 118–21): “Although some of the components of the candidemia care bundle are inherently drug focused, other quality indicators relate more to diagnostic evaluations or management of removable foci. The scope of stewardship has reached beyond drug therapy in other infection-related care bundles. One study evaluated outcomes associated with a Staphylococcus aureus bacteremia management bundle implemented by an infectious diseases consultation service.… Other published bundles for antimicrobial stewardship and ventilator associated pneumonia also extend beyond the scope of drug therapy and include process measures regarding documentation of rationale, obtaining indicated cultures, oral care, and elevating the head of the bed. These comprehensive care bundles highlight the need for interdisciplinary involvement in antimicrobial stewardship interventions. It is encouraging that the program described [in the above study] adds to the growing evidence that suggests that these initiatives can be successfully lead by infectious disease–trained pharmacists, with critical collaborations with infectious diseases staff, microbiologists, and infection control professionals.” (S. L. Davis, sldavis@wayne.edu)
Pharmacy-Based Comorbidity Measure: Using a longitudinal analysis of the Taiwanese national health insurance system database, investigators developed the Pharmacy-Based Disease Indicator (PBDI) and used it to predict accurately the risk of subsequent-year rehospitalization (pp. 126–36). The PBDI was based on the Chronic Disease Score framework and the Anatomical Therapeutic Chemical classification system. The comorbidity measure is “a function of 37 drug categories that correspond to major diseases in Taiwan,” the authors write. “The relationship between individuals’ PBDI score and subsequent-year hospitalization was evaluated by use of logistic regression models. Covariates in the models included age group, sex, PBDI score, and Deyo score. Using … two overlapping adult populations, we calculated both the PBDI score and the Deyo score for each individual in each year. Using subsequent-year hospitalization as the outcome and each comorbidity measure as the predictor, we demonstrated that the c statistic of the PBDI versus the Deyo version of the Charlson Index was 0.72 versus 0.69 for both the 2005 and 2006 populations. The Akaike information criterion, Bayesian information criterion, model calibration, and reclassification measures also confirmed the utility of the PBDI.” (M-S Lai, mslai@ntu.edu)

>>>PNN NewsWatch
* Problems in large-scale pharmacy compounding operations such as CAPS, PharMEDium, and ApotheCure have been “linked to deaths, illnesses, and safety failures for years,” the Washington Post reports this morning.

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

PNN Pharmacotherapy Line
Feb. 11, 2013 * Vol. 20, No. 28
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Effects on Poisonings, Liver Transplants of Reduced-Count Acetaminophen Packages: In the U.K., 1998 restrictions on the number of tablets allowed in packages of acetaminophen (paracetamol) have produced significant reductions in deaths from acetaminophen overdoses and some reductions in registrations for liver transplants, a study shows (f403). Among residents of England and Wales, these trends were noted in mortality and liver-unit activity before and after the national government restricted to 16 and 32 the number of tablets allowed in packages sold in nonpharmacies and pharmacies, respectively: “Compared with the pre-legislation level, following the legislation there was an estimated average reduction of 17 (95% confidence interval −25 to −9) deaths per quarter in England and Wales involving paracetamol alone (with or without alcohol) that received suicide or undetermined verdicts. This decrease represented a 43% reduction or an estimated 765 fewer deaths over the 11.25 years after the legislation. A similar effect was found when accidental poisoning deaths were included, and when a conservative method of analysis was used. This decrease was largely unaltered after controlling for a non-significant reduction in deaths involving other methods of poisoning and also suicides by all methods. There was a 61% reduction in registrations for liver transplantation for paracetamol induced hepatotoxicity [−11 (−20 to −1) registrations per quarter). But no reduction was seen in actual transplantations (−3 (−12 to 6)], nor in registrations after a conservative method of analysis was used.” (K. Hawton, keith.hawton@psych.ox.ac.uk)

>>>Lancet Highlights
Source:
Feb. 9 issue of Lancet (2013; 381).
Tofacitinib in Refractory Rheumatoid Arthritis: In a Phase III trial of 399 adult patients with active rheumatoid arthritis inadequately responsive to TNF inhibitors, the combination of the oral Janus kinase inhibitor tofacitinib and methotrexate produced “rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety,” researchers report (pp. 451–60). Participants received methotrexate plus tofacitinib 5 or 10 mg or placebo for 3 months. Participants on placebo were then advanced to one of the two active-drug groups for the second 3-month period. Results showed: “At month 3, ACR20 response rates were 41.7% (55 of 132 [95% CI vs placebo 6.06–28.41]; p = 0 .0024) for tofacitinib 5 mg twice a day and 48.1% (64 of 133; [12.45–34.92]; p < 0.0001) for tofacitinib 10 mg twice a day versus 24.4% (32 of 131) for placebo. Improvements from baseline in [Health Assessment Questionnaire–Disability Index] were −0.43 ([−0.36 to −0.15]; p < 0.0001) for 5 mg twice a day and −0.46 ([−0.38 to −0.17]; p < 0.0001) for 10 mg twice a day tofacitinib versus −0.18 for placebo; [disease activity score] < 2.6 rates were 6.7% (eight of 119; [0–10.10]; p = 0.0496) for 5 mg twice a day tofacitinib and 8.8% (11 of 125 [1.66–12.60]; p = 0.0105) for 10 mg twice a day tofacitinib versus 1.7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0–3 were diarrhoea (13 of 267; 4.9%), nasopharyngitis (11 of 267; 4.1%), headache (11 of 267; 4.1%), and urinary tract infection (eight of 267; 3.0%) across tofacitinib groups, and nausea (nine of 132; 6.8%) in the placebo group.” (G. R Burmester, gerd.burmester@charite.de)

>>>PNN NewsWatch
* Pomalidomide (Pomalyst, Celgene, Onyx) has been approved by FDA for treatment of patients with multiple myeloma that has progressed after other therapies.

>>PNN JournalWatch
* IOM Review of FDA-Approved Biologics Labeled or Studied for Pediatric Use, in
Pediatrics, 2013; 131: 328–35. (M. J. Field)
* Atopic Dermatitis: A Practice Parameter Update 2012, in
Journal of Allergy and Clinical Immunology, 2013; 131: 295–299.e27. (Joint Task Force on Practice Parameters, info@jcaai.org)
* Evidence for a Genetic Component for Substance Dependence in Native Americans, in
American Journal of Psychiatry, 2013; 170: 154–64. (C. L. Ehlers, cindye@scripps.edu)
* What Evidence Is Required for Drug Exposure To Be Causally Associated With Adverse Events? The Case for Case Reports Published in
Pharmacotherapy, in Pharmacotherapy, 2013; 33: 115–7. (C. L. De-Vane, Lindsay@pharmacotherapy.org)

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

PNN Pharmacotherapy Line
Feb. 12, 2013 * Vol. 20, No. 29
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Feb. 11 issue of the JAMA Internal Medicine (2013; 173).
Opioid Dose & Road Trauma: In Canada, drivers prescribed opioids were significantly more likely to have emergency department visits as a result of road trauma, researchers report (pp. 196–201). Groups included in the population-based nested case-control study were drivers, passengers, pedestrians, and bicyclists. Relationships among drug doses (very low to very high, based on <20 to ≥200 morphine equivalents daily) were as follows: “Among 549,878 eligible adults, we identified 5,300 cases with road trauma and matched an equal number of controls. Multivariate adjustment yielded no significant association between escalating opioid dose and odds of road trauma (adjusted odds ratio ranged between 1.00 and 1.09). However, a significant association between opioid dose and road trauma was observed among drivers. Compared with very low opioid doses, drivers prescribed low doses had a 21% increased odds of road trauma (adjusted odds ratio, 1.21 [95% CI, 1.02–1.42]); those prescribed moderate doses, 29% increased odds (1.29 [1.06–1.57]); those prescribed high doses, 42% increased odds (1.42 [1.15–1.76]); and those prescribed very high doses, 23% increased odds (1.23 [1.02–1.49]).” (T. Gomes, gomest@smh.ca)
After explaining that the FDA’s REMS for extended-release and long-acting opioids “is unlikely on its own to reverse the epidemic of deaths due to prescription opioids,” an editorialist reaches this conclusion about use of opioids for chronic nonmalignant pain (
p. 178): “As physicians, the relief of pain and suffering is core to our mission. It is so tempting to prescribe and steadily increase the doses of opioids for our patients with chronic pain because we believe that we have no alternative treatments. However, we must accept the limitations of our current chronic pain armamentarium and resist prescribing more opioids just because we believe that we have nothing better to offer. In the case of opioids for chronic pain, for the sake of our patients, less is often more.” (M. H. Katz, mkatz@dhs.lacounty.gov)
Pill Appearance & Antiepileptic Drug Nonadherence: In a study of generic and brand-name antiepileptic drugs (AEDs), patients were more frequently nonpersistent with therapy following changes in appearance of tablets and capsules (pp. 202–8). The nested case-control study of commercially insured patients in the U.S. examined nonpersistent patients who did not refill AED prescriptions within 5 days of the elapsed days supplied (cases) and matched controls with no delays in refills. Based on the two refills preceding nonpersistence, the researchers found these relationships with changes in the appearance of tablets and capsules: “The AEDs dispensed had 37 colors and 4 shapes. A total of 11,472 patients with nonpersistence were linked to 50,050 controls. Color discordance preceded 136 cases (1.20%) but only 480 controls (0.97%) (adjusted odds ratio [OR], 1.27 [95% CI, 1.04–1.55]). Shape discordance preceded 18 cases (0.16%) and 54 controls (0.11%) (OR, 1.47 [95% CI, 0.85–2.54]). Within the seizure disorder diagnosis subgroup, the risk of nonpersistence after changes in pill color was also significantly elevated (OR, 1.53 [95%, CI 1.07–2.18]).” (A. S. Kesselheim, akesselheim@partners.org)
Communication & Antidiabetic Drug Adherence: In the Diabetes Study of Northern California (DISTANCE), Kaiser Permanente patients on cardiometabolic medications had poorer refill adherence when there was poor communication with their health care providers (pp. 210–8). Communication scores on the 4-item Consumer Assessment of Healthcare Providers and Systems Survey (CAHPS) showed these patterns with respect to refills: “In this cohort, 30% had poor cardiometabolic medication refill adherence. For each 10-point decrease in CAHPS score, the adjusted prevalence of poor adherence increased by 0.9% (P = .01). Compared with patients offering higher ratings, patients who gave health care providers lower ratings for involving patients in decisions, understanding patients’ problems with treatment, and eliciting confidence and trust were more likely to have poor adherence, with absolute differences of 4% (P = .04), 5% (P = .02), and 6% (P = .03), respectively. Associations between communication and adherence were somewhat larger for hypoglycemic medications than for other medications.” (N. Ratanawongsa, ratanawongsan@medsfgh.ucsf.edu)

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

PNN Pharmacotherapy Line
Feb. 13, 2013 * Vol. 20, No. 30
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 13 issue of JAMA (2013; 309).
Tedizolid for Bacterial Skin, Skin-Structure Infections: Compared with linezolid, the new oxazolidinone tedizolid phosphate proved to be a statistically noninferior treatment for acute bacterial skin and skin-structure infections (ABSSSIs), researchers report (pp. 559–69). In the Phase III Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs 10-day Oral Linezolid Therapy (ESTABLISH-1) trial, 667 adults with ABSSSIs received oral tediolid phosphate 200 mg once daily or oral linezolid every 12 hours for 10 days, with these results: “In the intent-to-treat analysis set, the early clinical treatment response rates were 79.5% (95% CI, 74.8% to 83.7%) of 332 patients in the tedizolid phosphate group and 79.4% (95% CI, 74.7% to 83.6%) of 335 patients in the linezolid group (a treatment difference of 0.1% [95% CI, −6.1% to 6.2%]). The sustained clinical treatment response rates at the end of treatment (day 11) were 69.3% (95% CI, 64.0% to 74.2%) in the tedizolid phosphate group and 71.9% (95% CI, 66.8% to 76.7%) in the linezolid group (a treatment difference of −2.6% [95% CI, −9.6% to 4.2%]). Results of investigator-assessed clinical treatment success rates at a posttherapy evaluation visit (1–2 weeks after the end-of-treatment visit) were 85.5% (95% CI, 81.3% to 89.1%) in the tedizolid phosphate group and 86.0% (95% CI, 81.8% to 89.5%) in the linezolid group (a treatment difference of −0.5% [95% CI, −5.8% to 4.9%), and were similar for 178 patients with methicillin-resistant Staphylococcus aureus isolated from the primary lesion.” (P. Prokocimer, pprokocimer@triusrx.com)
“Tedizolid is a new oral antibiotic that appears efficacious using a short course and may have a better safety profile than linezolid,” editorialists write (
pp. 609–11). “The current study brings the Infectious Diseases Society of America’s 10 × 20 initiative 1 step closer to its goal of regulatory approval of 10 new antibacterial drugs with activity against drug-resistant bacteria by 2020. If approved, tedizolid will be the first oral drug in this initiative. ESTABLISH-1 also takes an important step toward validating the feasibility of implementing the new FDA end points for ABSSSI. Future studies should add to the understanding of which patients may be treated safely with shorter-course therapy and further explore the correlation between early and sustained response in ABSSSI.” (H. W. Boucher, hboucher@tuftsmedicalcenter.org)
Recurrence of H. pylori After Initial Eradication: Nonadherence and patient demographics were significant predictors of recurrence of Helicobacter pylori 1 year after successful eradication, according to a study of 1,463 adult patients from seven Latin American communities (pp. 578–86). Following 14-day triple therapy, 10-day sequential therapy, or 5-day concomitant therapy, the investigators found these results with 13C-urea breath tests (UBTs) administered 6–8 weeks and 1 year after treatment: “Among participants with UBT-negative results who had a 1-year follow-up UBT (n=1,091), 125 tested UBT positive, a recurrence risk of 11.5% (95% CI, 9.6%–13.5%). Recurrence was significantly associated with study site (P = .03), nonadherence to initial therapy (adjusted odds ratio [AOR], 2.94; 95% CI, 1.31–6.13; P = .01), and children in the household (AOR, 1.17; 95% CI, 1.01–1.35 per child; P = .03). Of the 281 with positive posttreatment UBT results, 138 completed re-treatment, of whom 93 tested UBT negative at 1 year. Among the 1,340 who had a 1-year UBT, 80.4% (95% CI, 76.4%–83.9%), 79.8% (95% CI, 75.8%–83.5%), and 77.8% (95% CI, 73.6%–81.6%) had UBT-negative results in the triple, sequential, and concomitant groups, respectively (P = .61), with 79.3% overall effectiveness (95% CI, 77.1%–81.5%). In a single-treatment course analysis that ignored the effects of re-treatment, the percentage of UBT-negative results at 1 year was 72.4% (95% CI, 69.9%–74.8%) and was significantly associated with study site (P < .001), adherence to initial therapy (AOR, 0.26; 95% CI, 0.15–0.42; P < .001), male sex (AOR, 1.63; 95% CI, 1.25–2.13; P < .001), and age (AOR, 1.14; 95% CI, 1.02–1.27 per decade; P = .02). One-year effectiveness among all 1,463 enrolled participants, considering all missing UBT results as positive, was 72.7% (95% CI, 70.3%–74.9%).” (D. R. Morgan, douglas.morgan@vanderbilt.edu)

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

PNN Pharmacotherapy Line
Feb. 14, 2013 * Vol. 20, No. 31
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 14 New England Journal of Medicine (2013; 368).
Neurostimulation in Parkinson’s Disease: In 251 patients with Parkinson’s disease and early motor complications, subthalamic stimulation improved quality of life significantly more than medical therapy, researchers report (pp. 610–22). Neurostimulation was accomplished by surgically implanting electrodes bilaterally in the subthalamic nucleus. Based on a primary end point of quality of life assessed with the Parkinson’s Disease Questionnaire summary index, the 2-year trial showed these results: “For the primary outcome of quality of life, the mean score for the neurostimulation group improved by 7.8 points, and that for the medical-therapy group worsened by 0.2 points (between-group difference in mean change from baseline to 2 years, 8.0 points; P = 0.002). Neurostimulation was superior to medical therapy with respect to motor disability (P < 0.001), activities of daily living (P < 0.001), levodopa-induced motor complications (P < 0.001), and time with good mobility and no dyskinesia (P = 0.01). Serious adverse events occurred in 54.8% of the patients in the neurostimulation group and in 44.1% of those in the medical-therapy group. Serious adverse events related to surgical implantation or the neurostimulation device occurred in 17.7% of patients. An expert panel confirmed that medical therapy was consistent with practice guidelines for 96.8% of the patients in the neurostimulation group and for 94.5% of those in the medical-therapy group.” (G. Deuschl, g.deuschl@neurologie.uni-kiel.de)
Subthalamic stimulation may provide “many additional years of good functioning” in “carefully chosen, highly functioning patients” with Parkinson’s disease, writes an editorialist who lists other emerging treatments (
pp. 675–6): “Alternative treatments include neurostimulation of other targets, such as the globus pallidus, and improved methods for delivery of levodopa. In advanced Parkinson’s disease, the benefit of pallidal stimulation may be similar to or less than the benefit of stimulation of the subthalamic nucleus. Sustained delivery of dopaminergic therapies has psychiatric and motor side effects that diminish efficacy. These approaches have not been compared with neurostimulation of the subthalamic nucleus in a population with early motor complications.” (C. M. Tanner)
Selumetinib-Enhanced Radioiodine Uptake: In 20 patients with thyroid cancer refractory to radioiodine, the selective mitogen-activated protein kinase (MAPK) pathway antagonist selumetinib increased uptake and retention of radioiodine, especially in patients with RAS-mutant disease (pp. 623–32). Selumetinib 75 mg twice daily for 4 weeks produced these outcomes with regard to uptake of therapeutic radioiodine: “[Patients’] median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.” (J. A. Fagin)
Influenza Unpredictability: Influenza is expected each winter, but “the timing and severity of these epidemics and the distribution of circulating viruses are highly variable and difficult to predict,” writes a Perspective author (pp. 589–92). “This season, circulating influenza strains are antigenically similar to the vaccine strains, except for one influenza B lineage not in the vaccine: approximately 90% of strains characterized by the CDC have been similar to the chosen vaccine viruses. Early data from a case–control study indicated that the estimated effectiveness of this season’s vaccine was 62% (95% confidence interval, 51 to 71%) overall. Since the current season may extend some months, increasing immunization coverage now with a vaccine providing moderate protection should mitigate the effects of the epidemic.” (J. Bresee)

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

PNN Pharmacotherapy Line
Feb. 15, 2013 * Vol. 20, No. 32
Providing news and information about medications and their proper use

>>>Circulation Report
Source:
Feb. 12 issue of Circulation (2013; 127).
Ticagrelor v. Clopidogrel After ACS: In the PLATelet inhibition and patient Outcomes (PLATO) study, ticagrelor demonstrated “an even greater absolute benefit … over clopidogrel than previously reported” for patients with acute coronary syndromes, investigators conclude (pp. 673–80). In 18,624 patients randomized to one of the two drugs, these results were noted: “Patients randomized to ticagrelor had 1,057 total primary end point events versus 1,225 for patients on clopidogrel (rate ratio, 0.86; 95% confidence interval, 0.79–0.93; P = 0.003). The number of additional events was numerically lower for ticagrelor (189 versus 205; P = 0.40), resulting in a hazard for time to second event/death of 0.80 (95% confidence interval, 0.70–0.90; P < 0.001) and a number needed to treat of 54. For cardiovascular death/myocardial infarction/stroke/(severe) recurrent ischemia/transient ischemic attack/arterial thrombotic events, total events were fewer with ticagrelor (2,030 versus 2,290; rate ratio, 0.88; 95% confidence interval, 0.82–0.95; P < 0.001), with fewer recurrent events with ticagrelor (740 versus 834; P = 0.01) and a highly significant concurrent reduction in hazard for time to second event or death of 0.83 (95% confidence interval, 0.75–0.91; P < 0.001). Recurrent PLATO major or Thrombolysis in Myocardial Infarction (TIMI) major non–coronary artery bypass graft bleeding events were infrequent and not different between the two therapies (P = 0.96 and 0.38, respectively).” (C. P. Cannon, cpcannon@partners.org)

>>>Chest Highlights
Source:
Feb. issue of Chest (2013; 143).
Omalizumab in Real-life Asthma Exacerbations: In adult patients with uncontrolled severe asthma, add-on therapy with omalizumab significantly lowered the risks of hospitalization and emergency department (ED) visits, a study shows (pp. 398–405). Asthma was uncontrolled despite inhaled and oral corticosteroids and a long-acting beta-2-agonist; omalizumab had not been previously used. Results showed: “Overall, 163 physicians recruited 767 patients, of whom 374 took omalizumab at least once (mean observation period, 20.4 months). Omalizumab use was associated with an adjusted relative risk of 0.57 (95% CI, 0.43–0.78) for hospitalization or ED visits for asthma. In users of omalizumab, the adjusted relative risk of hospitalization or ED visits for asthma during omalizumab treatment vs nontreatment periods was 0.40 (95% CI, 0.28–0.58).” (L. Grimaldi–Bensouda, Lamiae.Grimaldi@la-ser.com)
Immunobiology of Influenza Vaccines: A review article details how influenza vaccines induce immunity through interactions with the head and the stalk of viral surface hemagglutinin (HA) (pp. 502–10): “The head of the HA protein is the primary target of antibodies that confer protective immunity to influenza viruses. The underlying health status, age, and gene polymorphisms of vaccine recipients and, just as importantly, the extent of the antigenic match between the viruses in the vaccine and those that are circulating modulate influenza vaccine protection. Vaccine adjuvants and live attenuated influenza vaccine improve the breadth of immunity to seasonal and pandemic virus strains. Eliciting antibodies against the conserved HA stem region that cross-react with HAs within influenza virus types or subtypes would allow for the development of a universal influenza vaccine. The highly complex network of interactions generated after influenza infection and vaccination can be studied with the use of systems biology tools, such as DNA microarray chips. The use of systems vaccinology has allowed for the generation of gene expression signatures that represent key transcriptional differences between asymptomatic and symptomatic host responses to influenza infection. Additionally, the use of systems vaccinology tools has resulted in the identification of novel surrogate gene markers that are predictors of the magnitude of host responses to vaccines, which is critical to both vaccine development and public health. Identifying associations between variations in vaccine immune responses and gene polymorphisms is critical in the development of universal influenza vaccines.” (M. M. Gomez Lorenzo, gomezmm@niaid.nih.gov)

>>>PNN NewsWatch
* PNN will not be published on Mon., Feb. 18, Presidents Day.

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

PNN Pharmacotherapy Line
Feb. 19, 2013 * Vol. 20, No. 33
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2013; 346).
Calcium Intake & Cardiovascular Mortality: Among 61,443 women followed for a median of 19 years, high long-term intake of dietary and supplemental calcium was associated with higher mortality rates from all causes and cardiovascular causes, but not from stroke, researchers report (f228). The prospective longitudinal cohort study, conducted among a Swedish mammography cohort, showed these relationships between calcium intake and mortality: “The risk patterns with dietary calcium intake were non-linear, with higher rates concentrated around the highest intakes (≥1,400 mg/day). Compared with intakes between 600 and 1,000 mg/day, intakes above 1,400 mg/day were associated with higher death rates from all causes (hazard ratio 1.40, 95% confidence interval 1.17 to 1.67), cardiovascular disease (1 49, 1.09 to 2.02), and ischaemic heart disease (2.14, 1.48 to 3.09) but not from stroke (0.73, 0.33 to 1.65). After sensitivity analysis including marginal structural models, the higher death rate with low dietary calcium intake (<600 mg/day) or with low and high total calcium intake was no longer apparent. Use of calcium tablets (6% users; 500 mg calcium per tablet) was not on average associated with all cause or cause specific mortality but among calcium tablet users with a dietary calcium intake above 1,400 mg/day the hazard ratio for all cause mortality was 2.57 (95% confidence interval 1.19 to 5.55).” (K. Michaëlsson, karl.michaelsson@surgsci.uu.se)
Hydroxyethyl Starch Formulation in Sepsis: Compared with crystalloid or albumin tested among patients in intensive-care units, hydroxyethyl starch 130/0.38-0.45 “increased the use of renal replacement therapy and transfusion with red blood cells, and resulted in more serious adverse events in patients with sepsis,” according to a meta-analysis of 9 trials of 3,456 patients (f839): “Overall, hydroxyethyl starch 130/0.38-0.45 versus crystalloid or albumin did not affect the relative risk of death (1.04, 95% confidence interval 0.89 to 1.22, 3414 patients, eight trials), but in the predefined analysis of trials with low risk of bias the relative risk of death was 1.11 (1.00 to 1.23, trial sequential analysis (TSA) adjusted 95% confidence interval 0.95 to 1.29, 3,016 patients, four trials). In the hydroxyethyl starch group, renal replacement therapy was used more (1.36, 1.08 to 1.72, TSA adjusted 1.03 to 1.80, 1,311 patients, five trials), and the relative risk of acute kidney injury was 1.18 (0.99 to 1.40, TSA adjusted 0.90 to 1.54, 994 patients, four trials). More patients in the hydroxyethyl starch group were transfused with red blood cells (1.29, 1.13 to 1.48, TSA adjusted 1.10 to 1.51, 973 patients, three trials), and more patients had serious adverse events (1.30, 1.02 to 1.67, TSA adjusted 0.93 to 1.83, 1,069 patients, four trials). The transfused volume of red blood cells did not differ between the groups (mean difference 65 mL, 95% confidence interval −20 to 149 mL, three trials).” (N. Haase, nicolai.haase@rh.regionh.dk)

>>>PNN JournalWatch
* Acupuncture in Patients With Seasonal Allergic Rhinitis: A Randomized Trial, in
Annals of Internal Medicine, 2013; 158: 225–34. (B. Brinkhaus)
* Comparative Effectiveness of Treatments for Open-Angle Glaucoma: A Systematic Review for the U.S. Preventive Services Task Force, in
Annals of Internal Medicine, 2013; 158: 271–9. (K. A. Robinson)
* Antimicrobial Prophylaxis and Outpatient Management of Fever and Neutropenia in Adults Treated for Malignancy: American Society of Clinical Oncology Clinical Practice Guideline, in
Journal of Clinical Oncology, 2013; 31: 794–810. (J. Seidenfeld, jerry.seidenfeld@asco.org)
* Antiangiogenic Agents, Chemotherapy, and the Treatment of Metastatic Transitional Cell Carcinoma, in
Journal of Clinical Oncology, 2013; 31: 670–5. (N. J. Vogelzang, nicholas.vogelzang@usoncology.com)
* Neutropenic Enterocolitis, a Growing Concern in the Era of Widespread Use of Aggressive Chemotherapy, in
Clinical Infectious Diseases, 2013; 56: 711–7. (L. Nesher, nesherl@yahoo.com)
* The Management of Dyslipidemia in CKD: New Analyses of an Expanding Dataset, in
American Journal of Kidney Diseases, 2013; 61: 371–4. (B. L. Kasiske, kasis001@umn.edu)
* Medication Dosing in Critically Ill Patients With Acute Kidney Injury Treated With Renal Replacement Therapy, in
American Journal of Kidney Diseases, 2013; 61: 490–500. (B. A. Mueller, muellerb@umich.edu)
* Cation-Chloride Cotransporters in the Nervous System: General Features and Clinical Correlations, in
Neurology, 2013; 80: 756–63. (E. E. Benarroch, benarroch.eduardo@mayo.edu)

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

PNN Pharmacotherapy Line
Feb. 20, 2013 * Vol. 20, No. 34
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 20 issue of JAMA (2013; 309).
Hydroxyethyl Starch & Acute Kidney Injury: In critically ill patients, “clinical use of hydroxyethyl starch for acute volume resuscitation is not warranted due to serious safety concerns,” according to a systematic review and meta-analysis (pp. 678–88). The intervention failed to reduce mortality overall, and a significantly increased risk of mortality and renal failure was evident when results of retracted studies were removed: “We included 38 eligible trials comparing hydroxyethyl starch to crystalloids, albumin, or gelatin. The majority of trials were categorized as having an unclear risk or high risk of bias. For the 10,880 patients in studies contributing mortality data, the risk ratio (RR) for death among patients randomized to receive hydroxyethyl starch was 1.07 (95% CI, 1.00 to 1.14; I2, 0%; absolute risk [AR], 1.20%; 95% CI, −0.26% to 2.66%). This summary effect measure included results from 7 trials performed by an investigator whose subsequent research had been retracted because of scientific misconduct. When we excluded these 7 trials that involved 590 patients, hydroxyethyl starch was found to be associated with increased mortality among 10,290 patients (RR, 1.09; 95% CI, 1.02 to 1.17; I2, 0%; AR, 1.51%; 95% CI, 0.02% to 3.00%), increased renal failure among 8,725 patients (RR, 1.27; 95% CI, 1.09 to 1.47; I2, 26%; AR, 5.45%; 95% CI, 0.44% to 10.47%), and increased use of renal replacement therapy among 9,258 patients (RR, 1.32; 95% CI, 1.15 to 1.50; I2, 0%; AR, 3.12%; 95% CI, 0.47% to 5.78%).” (R. Zarychanski, ryan.zarychanski@cancercare.mb.ca)
“More harm than good” comes from hydroxyethyl starch therapy, editorialists write (
pp. 723–4): “In addition to confirming the potential nephrotoxic effect associated with hydroxyethyl starch, this meta-analysis is the first to demonstrate that use of hydroxyethyl starch for acute volume replacement is also associated with a significant risk of mortality. However, this meta-analysis does not add direct evidence to inform the long-standing controversy about colloids vs crystalloids, due to the heterogeneity of hydroxyethyl starch comparators, which included 0.9% sodium chloride, Ringer’s lactate, Ringer’s acetate, gelatin, albumin, and plasma. This observation is not a limitation of the study, but rather of the current literature. Thoughtfully planned, adequately powered, and rigorously conducted randomized controlled trials will be needed to assess the issues of safety and efficacy of hydroxyethyl starch 130/0.4 starch vs crystalloids. Until then, the results of the study by Zarychanski et al indicate that the harms of hydroxyethyl starch most likely outweigh the benefits and suggest that these products should not be used for acute volume resuscitation of critically ill patients.” (M. Antonelli, m.antonelli@rm.unicatt.it)
Leukocyte Telomere Length & Respiratory Viral Infection: Shorter T-cell telomere lengths were linked increased risk of experimentally induced upper respiratory viral infections in 152 healthy adult volunteers, researchers report (pp. 699–705). Telomeres are known to shorten with repeated cell divisions, and this can lead to cell inactivity and death. Telomere length was measured in peripheral blood mononuclear cells (PBMCs) and T-cell subsets (CD4, CD8CD28+, CD8CD28&minusWinking before and for 5 days after exposure to rhinovirus 39: “Rates of infections and clinical illness were 69% (n = 105) and 22% (n = 33), respectively. Shorter telomeres were associated with greater odds of infection, independent of prechallenge virus-specific antibody, demographics, contraceptive use, season, and body mass index (PBMC: odds ratio [OR] per 1-SD decrease in telomere length, 1.71 [95% CI, 1.08–2.72]; n = 128 [shortest tertile 77% infected; middle, 66%; longest, 57%]; CD4: OR, 1.76 [95% CI, 1.15-2.70]; n = 146 [shortest tertile 80% infected; middle, 71%; longest, 54%]; CD8CD28+: OR, 1.93 [95% CI, 1.21–3.09], n = 132 [shortest tertile 84% infected; middle, 64%; longest, 58%]; CD8CD28−: OR, 2.02 [95% CI, 1.29–3.16]; n = 144 [shortest tertile 77% infected; middle, 75%; longest, 50%]). CD8CD28− was the only cell population in which shorter telomeres were associated with greater risk of clinical illness (OR, 1.69 [95% CI, 1.01–2.84]; n = 144 [shortest tertile, 26%; middle, 22%; longest, 13%]). The association between CD8CD28− telomere length and infection increased with age (CD8CD28− telomere length × age interaction, b = 0.09 [95% CI, 0.02-0.16], P = .01, n = 144).” (S. Cohen, scohen@cmu.edu)

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

PNN Pharmacotherapy Line
Feb. 21, 2013 * Vol. 20, No. 35
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Feb. 21 New England Journal of Medicine (2013; 368).
Extended Treatment of Venous Thromboembolism: In two articles, results of three studies are presented. An editorialist analyzes the findings.
In patients with symptomatic deep-vein thrombosis or pulmonary embolism, “extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding,” according to findings from the AMPLIFY-EXT trial (
pp. 699–708). At entry to this part of the study, patients had been treated for venous thromboembolism for 6–12 months with anticoagulation therapy.
After randomization to one of the two doses of apixaban or placebo, these results were recorded: “A total of 2,486 patients underwent randomization, of whom 2,482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P < 0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.” (G. Agnelli,
agnellig@unipg.it)
In the RE-MEDY and RE-SONATE trials, extended-duration dabigatran 150 mg twice daily was effective and safer than warfarin in patients with venous thromboembolism, but bleeding risks were higher than with placebo (
pp. 709–18). The two trials produced these results: “In the active-control study, recurrent venous thromboembolism occurred in 26 of 1,430 patients in the dabigatran group (1.8%) and 18 of 1,426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P = 0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P = 0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P < 0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups.” (S. Schulman, schulms@mcmaster.ca)
“Although it is hazardous to make comparisons across trials, the recurrence rates for the placebo groups in the dabigatran and apixaban trials are consistent with rates in previous trials involving patients with unprovoked venous thromboembolism. Improved risk-stratification strategies are needed to identify patients who have the greatest risk of recurrence,” an editorialist writes (
pp. 767–9). “These are the patients who stand to benefit most from extended anticoagulant treatment of a first unprovoked episode of venous thromboembolism.” (J. M. Connors)

>>>PNN NewsWatch
* In boxed warnings and other labeling changes of products containing codeine, FDA is calling on health professionals to prescribe an alternate analgesic for postoperative pain control in children who are undergoing tonsillectomy and/or adenoidectomy. Fatalities have occurred with codeine in children who have obstructive sleep apnea or are ultrarapid codeine metabolizers.

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

PNN Pharmacotherapy Line
Feb. 22, 2013 * Vol. 20, No. 36
Providing news and information about medications and their proper use

>>>Geriatrics Highlights
Source:
Feb. Journal of the American Geriatrics Society (2013; 61).
Flexible-Dose Fesoterodine in Overactive Bladder: In 794 patients aged 65 or older, flexible doses of fesoterodine improved symptoms of overactive bladder (OAB), compared with placebo, and was well tolerated (pp. 185–93). At 61 outpatient clinics in Europe, Israel, and Turkey, patients with OAB assigned to the fesoterodine group were started on 4-mg doses. This could increase to 8 mg at week 4 or 8, and raised doses could be lowered to 4 mg at week 8. Over 12 weeks, results showed: “By week 8, 64% of fesoterodine-treated and 71% of placebo-treated participants opted for dose escalation. At week 12, the fesoterodine group had statistically significantly greater improvement than the placebo group in urgency episodes, micturitions, nocturnal micturitions, incontinence pad use, and OAB Questionnaire scores but not urgency urinary incontinence episodes. Responder rates on [Treatment Benefit Scale], [Patient Perception of Bladder Condition], [Urgency Perception Scale], and [OAB Satisfaction Questionnaire] were statistically significantly higher with fesoterodine. Improvements in most diary variables and participant-reported outcomes were greater with fesoterodine than placebo in participants in both age groups and when administered in the morning and evening. Rates of dry mouth and constipation were 34% and 9% with fesoterodine and 5% and 3% with placebo, respectively. Rates of adverse events and discontinuations were generally similar in participants in both age groups. There was no change in [Mini-Mental State Examination] score.” (A. Wagg, adrian.wagg@ualberta.ca)
Antihypertensive Therapy & Cerebral Hemodynamics: In older adults with hypertension and executive dysfunction, ARBs “may preferentially preserve cerebral hemodynamics and executive function,” researchers report (pp. 194–201). A 1-year, community-based study tested lisinopril, candesartan, and hydrochlorothiazide effects on cerebral blood flow velocity (BFV) as measured by Doppler ultrasonography: “Of the 53 participants, 47 had successful insonation (mean age 72; 70% white; 57% women). There was a tendency toward an increase in BFV in the candesartan group and a decrease in the lisinopril and hydrochlorothiazide groups (between-group P = .57) that was significant in those with low BFV at baseline (ihajjar@usc.edu)
Psychotropic Meds & Care Transitions: Use of psychotropic medications rises dramatically upon admissions to care homes, according to an analysis of the national prescribing database in Northern Ireland (pp. 215–21). Among 250,617 adults 65 or older, “20.3% of those in care homes were dispensed an antipsychotic in January 2009, compared with 1.1% of those in the community,” the authors write. “Antipsychotic drug dispensing increased from 8.2% before entry to 18.6% after entering care (risk ratio (RR) = 2.26, 95% confidence interval (CI)=1.96–2.59) and hypnotic drug dispensing from 14.8% to 26.3% (RR=1.78, 95% CI=1.61–1.96).” (A. Maguire, amaguire22@qub.ac.uk)

>>>PNN NewsWatch
* The International Academy of Compounding Pharmacists now says it “will support legislation requiring pharmacies that operate like drug manufacturers to register with the Food and Drug Administration and be subject to stricter standards enforced by the agency,” according to this morning’s Washington Post. David G. Miller, Executive Vice President, told the Post that “the size of the operation shouldn’t matter,” a position challenged by others quoted in the article.
* Health professionals should make full use of
antiviral medications in view of the influenza vaccine’s poor protection against the type A virus in circulation this season, CDC said yesterday. Those 65 or older are at especially high 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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Feb. 25, 2013 * Vol. 20, No. 37
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
Feb. and Mar. issues of Gastroenterology (2013; 144).
Statins & Liver Cancer: Use of statins is associated with lower risks of hepatocellular carcinoma (HCC), especially in Asian but also in Western populations, according to a systematic review and meta-analysis of 10 studies (pp. 323–32). “Randomized clinical trials in populations at high risk for HCC (especially in Asian populations with hepatitis B) are warranted,” the authors conclude, adding these findings from 4,298 cases of HCC in nearly 1.5 million people: “Statin users were less likely to develop HCC than statin nonusers (adjusted OR, 0.63; 95% CI, 0.52–0.76), although the results were heterogeneous (P = .01, I2 = 59%). This heterogeneity could be accounted for by study location (Asian population [n = 4]: adjusted OR, 0.52; 95% CI, 0.42–0.64; Western population [n = 6]: adjusted OR, 0.67; 95% CI, 0.53–0.85) and design (observational studies [n = 7]: adjusted OR, 0.60; 95% CI, 0.49–0.73; clinical trials [n = 3]: adjusted OR, 0.95; 95% CI, 0.62–1.45).” (W. Sanchez, sanchez.william@mayo.edu)
H. pylori & Aspirin Use: In patients who develop gastrointestinal bleeds while on low-dose aspirin (ASA), eradication of Helicobacter pylori can reduce risks of recurrent bleeding, and high-risk ASA users should be tested for the bacterium in an effort to provide appropriate gastroprotective strategies, researchers report (pp. 528–35). Among three cohorts of patients using less than 160 mg/d of aspirin, three groups were studied prospectively: 249 patients who were H. pylori–positive and who received eradication therapy after a bleed; 118 H. pylori–negative patients who resumed enteric-coated ASA after a bleed; and 537 average-risk new users of ASA without a history of ulcers. Results during 5,048 patient–years of follow-up showed: “The incidence of ulcer bleeding (per 100 patient–years) in the H pylori–eradicated cohort (0.97; 95% confidence interval [CI], 0.53–1.80) did not differ significantly from that of the average-risk cohort (0.66; 95% CI, 0.38−0.99). The H pylori–negative cohort had a high incidence of recurrent bleeding (5.22; 95% CI, 3.04−8.96) (incidence rate ratio, 8.52; 95% CI, 4.29−16.95 vs the average-risk cohort).” (F. K. L. Chan, fklchan@cuhk.edu.hk)
PPIs & Osteoporosis: Reacting to an population-based study from Canada (Am J Gastroenterol. 2012; 107: 1361–9), an author assesses proper management of potentially reduced calcium absorption in patients taking proton-pump inhibitors (pp. 650–2): “Should every GERD patient in our gastroenterology practices be started on vitamin D and calcium therapy with their PPI prescriptions and referred for BMD testing? Based on the recent study from Targownik et al and the prior literature, I would make the argument that the typical GERD patient without significant comorbidities or risk for fractures not be referred to the bone density clinic for testing and treatment. However, gastroenterologists should discuss this issue with GERD patients who do have other risk factors for hip fracture so that testing can be performed if indicated. Certainly in GERD patients with established osteoporosis, PPI therapy should be continued if indicated because there is no evidence that it worsens this preexisting condition. In patients with milder heartburn symptoms, step-down therapy to H2-receptor antagonists can be considered if patients have adequately controlled symptoms and are able to demonstrate healing of erosive esophagitis.” (Lauren B. Gerson)

>>>PNN NewsWatch
* FDA on Friday approved ado-trastuzumab emtansine (Kadcyla, Genentech) for treatment of patients with HER2-positive, late-stage (metastatic) breast cancer. In a clinical trial of 991 patients, ado-trastuzumab emtansine produced a median survival of 9.6 months, compared with 6.4 months with lapatinib plus capecitabine. Thrombocytopenia and liver-enzyme elevations are among the adverse effects of the new drug.

>>>PNN JournalWatch
* Role of the Microenvironment in the Pathogenesis and Treatment of Hepatocellular Carcinoma, in
Gastroenterology, 2013; 144: 512–27. (J. M. Llovet, josep.llovet@mssm.edu)
* Profits and Pandemics: Prevention of Harmful Effects of Tobacco, Alcohol, and Ultra-Processed Food and Drink Industries, in
Lancet, 2013; 381: 670–9. (R. Moodie, r.moodie@unimelb.edu.au)
* Seven Million Americans Live In Areas Where Demand For Primary Care May Exceed Supply By More Than 10 Percent, in
Health Affairs, 2013: 10.1377/hlthaff.2012.0913. (E. S. Huang, ehuang@medicine.bsd.uchicago.edu)

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

PNN Pharmacotherapy Line
Feb. 26, 2013 * Vol. 20, No. 38
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Feb. 25 issue of the JAMA Internal Medicine (2013; 173).
Conflicts of Interest in Medicaid Drug Selection: State-level committees that choose drug products for Medicaid programs have inadequate policies for managing conflicts of interest (COI), report researchers who concluded, “With expected growth of Medicaid due to health care reform, the selection of drugs for Medicaid patients should be protected from the influence of COI” (doi: 10.1001/jamainternmed.2013.2522). For 47 states and the District of Columbia, a content analysis of COI policies showed wide variability: “Policy documents were obtained for 27 of the programs (56%)—14 from websites and 13 by contacting Medicaid officials. We found high variability in COI policies, lack of public availability, and inconsistent enforcement and management of COI among states. The most common management strategy was disclosure of COI in 67% of policies (18 of 27), followed by self-recusal in 52% of policies (14 of 27). Only 15% of policies (4 of 27) ban certain relationships with industry.” (L. Bero, berol@pharmacy.ucsf.edu)
Aspirin Use & Age-Related Macular Degeneration: In an Australian population-based cohort, regular use of aspirin was associated with new-onset neovascular age-related macular degeneration (AMD) (pp. 258–64). Four examinations of participants over a 15-year period revealed these associations: “Of 2,389 baseline participants with follow-up data available, 257 individuals (10.8%) were regular aspirin users and 63 of the 2,389 developed neovascular AMD. Persons who were regular aspirin users were more likely to have incident neovascular AMD: the 15-year cumulative incidence was 9.3% in users and 3.7% in nonusers. After adjustment for age, sex, smoking, history of cardiovascular disease, systolic blood pressure, and body mass index, persons who were regular aspirin users had a higher risk of developing neovascular AMD (odds ratio [OR], 2.46; 95% CI, 1.25–4.83). The association showed a dose-response effect (multivariate-adjusted P = .01 for trend). Aspirin use was not associated with the incidence of geographic atrophy (multivariate-adjusted OR, 0.99; 95% CI, 0.59–1.65).” (J. J. Wang, jiejin.wang@sydney.edu.au)
Decision Support in Antibiotic Stewardship: Antibiotic overuse in primary-care patients with acute bronchitis can be reduced through decision-support strategies, a study shows (pp. 267–73). At 33 practices in an integrated health system, decision support for acute cough illness produced these outcomes: “Compared with the baseline period, the percentage of adolescents and adults prescribed antibiotics during the intervention period decreased at the printed decision support intervention sites (from 80.0% to 68.3%) and at the computer-assisted decision support intervention sites (from 74.0% to 60.7%) but increased slightly at the control sites (from 72.5% to 74.3%). After controlling for patient and clinician characteristics, as well as clustering of observations by clinician and practice site, the differences for the intervention sites were statistically significant from the control sites (P = .003 for control sites vs printed decision support intervention sites and P = .01 for control sites vs computer-assisted decision support intervention sites) but not between themselves (P = .67 for printed decision support intervention sites vs computer-assisted decision support intervention sites). Changes in total visits, 30-day return visit rates, and proportion diagnosed as having uncomplicated acute bronchitis were similar among the study sites.” (R. Gonzales, ralphg@medicine.ucsf.edu)

>>>PNN NewsWatch
* FDA on Monday approved regorafenib (Stivarga, Bayer) for treatment of patients with advanced gastrointestinal stromal tumors that cannot be surgically removed and no longer respond to other FDA-approved treatments. The multikinase inhibitor was originally approved for treatment of colorectal cancer in Sept. 2012.
* A nationwide recall of all lots of
Omontys Injection (Affymax; Takeda) is under way, FDA said on Sunday. The agency said it has received 19 reports of anaphylaxis in patients, including serious and sometimes fatal hypersensitivity reactions, following their first dose of the agent, which is used in adult patients on dialysis. Until further notice, health care providers should stop using Omontys and return the product to Takeda, FDA said.

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

PNN Pharmacotherapy Line
Feb. 27, 2013 * Vol. 20, No. 39
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Feb. 27 issue of JAMA (2013; 309).
Spironolactone in Heart Failure With Preserved Ejection Fraction: In the Aldo-DHF Randomized Controlled Trial, “long-term aldosterone receptor blockade improved left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms, or quality of life in patients with heart failure with preserved ejection fraction,” researchers report (pp. 781–91). Conducted at 10 German and Austrian sites in 2007–12, the trial tested spironolactone 25 mg once daily versus placebo over a 12-month follow-up period.
Results showed: “Diastolic function (E/e´Winking decreased from 12.7 (SD, 3.6) to 12.1 (SD, 3.7) with spironolactone and increased from 12.8 (SD, 4.4) to 13.6 (SD, 4.3) with placebo (adjusted mean difference, −1.5; 95% CI, −2.0 to −0.9; P < .001). Peak VO
2 did not significantly change with spironolactone vs placebo (from 16.3 [SD, 3.6] mL/min/kg to 16.8 [SD, 4.6] mL/min/kg and from 16.4 [SD, 3.5] mL/min/kg to 16.9 [SD, 4.4] mL/min/kg, respectively; adjusted mean difference, +0.1 mL/min/kg; 95% CI, −0.6 to +0.8 mL/min/kg; P = .81). Spironolactone induced reverse remodeling (left ventricular mass index declined; difference, −6 g/m2; 95% CI, −10 to−1 g/m2; P = .009) and improved neuroendocrine activation (N-terminal pro–brain-type natriuretic peptide geometric mean ratio, 0.86; 95% CI, 0.75–0.99; P = .03) but did not improve heart failure symptoms or quality of life and slightly reduced 6-minute walking distance (–15 m; 95% CI, –27 to –2 m; P = .03). Spironolactone also modestly increased serum potassium levels (+0.2 mmol/L; 95% CI, +0.1 to +0.3; P < .001) and decreased estimated glomerular filtration rate (−5 mL/min/1.73 m2; 95% CI, −8 to −3 mL/min/1.73 m2; P < .001) without affecting hospitalizations.” (B. Pieske, burkert.pieske@medunigraz.at)
“Ultimately, the Aldo-DHF trial provides valuable new information but is not particularly reassuring in terms of either the efficacy or safety of [mineralocorticoid antagonists (MRAs)] for patients with [heart failure with preserved ejection fraction (HFpEF)],” editorialists write (
pp. 825–6). “A large trial, TOPCAT, is expected to report the effects of spironolactone on morbidity and mortality in a similar population but with more advanced disease. In the meantime, MRAs appear useful for managing congestion and preventing diuretic-induced hypokalemia with the attendant risk of sudden arrhythmic death. It is likely that these benefits are independent of cardiac phenotype but might be more prominent in those with impaired aldosterone degradation due to hepatic congestion. Whether MRAs exert important benefits for patients with HFpEF through other mechanisms such as reducing fibrosis, inflammation, and adrenergic activity may take longer to unravel.” (J. G. F. Cleland, j.g.cleland@hull.ac.uk)
Breast Cancer in American Women: The incidence of advanced breast cancer in young American women increased alarmingly between 1976 and 2009, according to an analysis of the U.S. National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (pp. 800–5): “The incidence of breast cancer with distant involvement at diagnosis increased in 25- to 39-year-old women from 1.53 (95% CI, 1.01 to 2.21) per 100,000 in 1976 to 2.90 (95% CI, 2.31 to 3.59) per 100,000 in 2009. This is an absolute difference of 1.37 per 100,000, representing an average compounded increase of 2.07% per year (95% CI, 1.57% to 2.58%; P < .001) over the 34-year interval. No other age group or extent-of-disease subgroup of the same age range had a similar increase. For 25- to 39-year-olds, there was an increased incidence in distant disease among all races and ethnicities evaluated, especially non-Hispanic white and African American, and this occurred in both metropolitan and nonmetropolitan areas. Incidence for women with estrogen receptor–positive subtypes increased more than for women with estrogen receptor–negative subtypes.” (R. H. Johnson, rebecca.johnson@seattlechildrens.org)

>>>PNN NewsWatch
* Ospemifene (Osphena, Shionogi) has been approved by FDA to treat women experiencing moderate to severe dyspareunia. This form of pain during sexual intercourse results from vulvar and vaginal atrophy. The estrogen agonist/antagonist acts on vaginal tissues to reverse these detrimental changes.

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

PNN Pharmacotherapy Line
Feb. 28, 2013 * Vol. 20, No. 40
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Early-release article and Feb. 28 issue of the New England Journal of Medicine (2013; 368).
Ondansetron in Pregnancy: Adverse fetal outcomes were not increased with use of ondansetron during pregnancy, according to an analysis of 608,385 pregnancies in Denmark (pp. 814–23). Using a 1:4 ratio of women exposed to ondansetron and those not exposed to the drug, investigators assessed pregnancies that ended in spontaneous abortion (1,849 exposed women vs. 7,396 unexposed women), stillbirth (1,915 vs. 7,660), any major birth defect (1,233 vs. 4,932), preterm delivery (1,792 vs. 7,168), and birth of infants at low birth weight and small for gestational age (1,784 vs. 7,136) to find the following: “Receipt of ondansetron was not associated with a significantly increased risk of spontaneous abortion, which occurred in 1.1% of exposed women and 3.7% of unexposed women during gestational weeks 7 to 12 (hazard ratio, 0.49; 95% confidence interval [CI], 0.27 to 0.91) and in 1.0% and 2.1%, respectively, during weeks 13 to 22 (hazard ratio, 0.60; 95% CI, 0.29 to 1.21). Ondansetron also conferred no significantly increased risk of stillbirth (0.3% for exposed women and 0.4% for unexposed women; hazard ratio, 0.42; 95% CI, 0.10 to 1.73), any major birth defect (2.9% and 2.9%, respectively; prevalence odds ratio, 1.12; 95% CI, 0.69 to 1.82), preterm delivery (6.2% and 5.2%; prevalence odds ratio, 0.90; 95% CI, 0.66 to 1.25), delivery of a low-birth-weight infant (4.1% and 3.7%; prevalence odds ratio, 0.76; 95% CI, 0.51 to 1.13), or delivery of a small-for-gestational-age infant (10.4% and 9.2%; prevalence odds ratio, 1.13; 95% CI, 0.89 to 1.44).” (B. Pasternak, bjp@ssi.dk)
Medicinal Use of Marijuana: Authors and online readers debate the medicinal use of marijuana in a Clinical Decisions exchange (pp. 866–8). Reacting to the case of “Marilyn,” a 68-year-old with metastatic breast cancer, a proponent of medicinal marijuana writes, “In Colorado, a handful of physicians write half the state’s prescriptions for medicinal marijuana, for questionable indications. Just because a few rogue doctors flout lax legislation to abet pot-mill commerce, that doesn’t justify depriving all physicians of the right to prescribe medicinal marijuana. No trials under the auspices of [FDA] have compared medicinal marijuana with traditional analgesics. Because of marijuana’s Schedule I status, industry is thwarted in its attempts to develop compounds with endocannabinoid agonist or antagonist qualities that might have analgesic, appetite-modulatory, immunosuppressant, antiemetic, neuroleptic, or antineoplastic effects, among other possibilities.” (J. M. Bostwick)
Writing against medicinal use of smoked cannabis, two authors note the availability of options legal under federal law: “Two prescription cannabinoids are available, dronabinol (Marinol) (a synthetic ∆
9-THC) and nabilone (Cesamet) (a ∆9-THC congener), which are FDA-approved for the treatment of chemotherapy-induced nausea and vomiting. These medications have shown efficacy in the management of pain and distress. In contrast to smoked marijuana, they feature oral administration, chemical purity, precise dosages, and a slower onset but sustained duration of action. They may be less likely than smoked marijuana to induce anxiety, panic, and negative mood states, but they have otherwise similar side-effect profiles.” (G. M. Reisfield)
Dietary Prevention of CVD: In a study stopped early because of positive results, the risk of major cardiovascular events was reduced by about 30% in 7,447 patients at high risk by following a Mediterranean diet supplemented with extra-virgin olive oil or nuts (doi: 10.1056/NEJMoa1200303). The PREDIMED Study, conducted in Spain, found these outcomes based on a primary end point of myocardial infarction, stroke, or death from cardiovascular causes: “The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported.” (R. Estruch, restruch@clinic.ub.es)

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

PNN Pharmacotherapy Line
Mar. 1, 2013 * Vol. 20, No. 41
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Mar. issue of Diabetes Care (2013; 36).
Weekly Taspoglutide v. Twice-Daily Exenatide: Efficacy was good with weekly doses of the long-acting glucagon-like peptide 1 receptor agonist taspoglutide in a comparison with twice-daily exenatide in 1,189 patients with type 2 diabetes, but adverse effects were much worse, including “unacceptable levels of nausea/vomiting, injection-site reactions, and systemic allergic reactions,” researchers report (pp. 498–504). Study participants, all overweight and with inadequately controlled diabetes, were switched from metformin plus a thiazolidinedione to either subcutaneous taspoglutide 10 or 20 mg weekly or exenatide 10 mcg twice daily, with these results: “Mean baseline HbA1c was 8.1%. Both doses of taspoglutide reduced HbA1c significantly more than exenatide (taspoglutide 10 mg: –1.24% [SE 0.09], difference –0.26, 95% CI –0.37 to –0.15, P < 0.0001; taspoglutide 20 mg: –1.31% [0.08], difference –0.33, –0.44 to –0.22, P < 0.0001; exenatide: –0.98% [0.08]). Both taspoglutide doses reduced fasting plasma glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide 10 mg, –1.6 kg; taspoglutide 20 mg, –2.3 kg) as did exenatide (–2.3 kg), which was greater than with taspoglutide 10 mg (P < 0.05). HbA1c and weight effects were maintained after 52 weeks. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide antibodies were detected in 49% of patients.” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
Insulin LY2605541 v. Insulin Glargine in Type 1 Diabetes: Insulin LY605541 produced “greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses,” compared with insulin glargine, in a study of 137 patients with type 1 diabetes (pp. 522–8). The Phase II, open-label, crossover trial compared the once-daily basal insulins over 8 weeks. Using a noninferiority margin of 10.8 mg/dL, the investigators found: “LY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02).” (S. J. Jacober, jacober_scott_j@lilly.com)
Impact of Generic Drugs on Hypertension in Diabetes: In the Results from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study, access to generic antihypertensive medications did not resolve racial disparities in blood pressure (BP) outcomes, indicating multifactorial reasons for poor BP control (pp. 591–7). These outcomes were noted among 5,375 participants: “The percentage of subjects accessing generically available antihypertensive medications increased significantly from 66% in 2003 to 81% in 2007 (P < 0.0001), and the odds of achieving a BP <130/80 mmHg in 2007 was 66% higher (odds ratio 1.66 [95% CI 1.30–2.10]) than in 2003. Nevertheless, <50% of participants achieved this goal. African American race, male sex, limited income, and medication nonadherence were significant predictors of inadequate BP control. There was no significant relationship between access to generic antihypertensives and BP control when other demographic factors were included in the model (0.98 [0.96–1.00]).” (D. M. Cummings, cummingsd@ecu.edu)

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

PNN Pharmacotherapy Line
Mar. 4, 2013 * Vol. 20, No. 42
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 2 issue of Lancet (2013; 381).
Dolutegravir in HIV-1 Infection: The once-daily HIV integrase inhibitor dolutegravir (S/GSK1349572) was noninferior to raltegravir in a Phase III trial of 822 antiretroviral-naive adults with HIV-1 infection, researchers report (pp. 735–43). In the SPRING-2 study, participants received dolutegravir 50 mg once daily or raltegravir 400 mg twice daily, with these results: “At 48 weeks, 361 (88%) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 (85%) in the raltegravir group (adjusted difference 2.5%; 95% CI –2.2 to 7.1). Adverse events were similar between treatment groups. The most common events were nausea (59 [14%] patients in the dolutegravir group vs 53 [13%] in the raltegravir group), headache (51 [12%] vs 48 [12%]), nasopharyngitis (46 [11%] vs 48 [12%]), and diarrhoea (47 [11%] in each group). Few patients had drug-related serious adverse events (three [<1%] vs five [1%]), and few had adverse events leading to discontinuation (ten [2%] vs seven [2%] in each group). CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per µL. Rates of graded laboratory toxic effects were similar. We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir, whereas of the patients with virologic failure who received raltegravir, one (6%) had integrase treatment-emergent resistance and four (21%) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance.” (F. Raffi, francois.raffi@wanadoo.fr)
Immunosuppression for Progressive Membranous Nephropathy: In patients with “idiopathic membranous nephropathy and deteriorating excretory renal function, 6 months’ therapy with prednisolone and chlorambucil is the treatment approach best supported by our evidence,” investigators in a randomized controlled trial conclude (pp. 744–51). Cyclosporine should be avoided in these patients, the group adds, citing these results from a comparison of supportive and immunosuppressive therapies in 108 patients: “Risk of further 20% decline in renal function was significantly lower in the prednisolone and chlorambucil group than in the supportive care group (19 [58%] of 33 patients reached endpoint vs 31 [84%] of 37, hazard ratio [HR] 0.44 [95% CI 0.24–0.78]; p = 0.0042); risk did not differ between the ciclosporin (29 [81%] of 36) and supportive treatment only groups (HR 1.17 [0.70–1.95]; p = 0.54), but did differ significantly across all three groups (p = 0.003). Serious adverse events were frequent in all three groups but were higher in the prednisolone and chlorambucil group than in the supportive care only group (56 events vs 24 events; p = 0.048).” (P. W. Mathieson, p.mathieson@bristol.ac.uk)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
Narcolepsy With Pandemic Influenza Vaccine: Data from England support findings from Finland of an increased risk of narcolepsy developing after vaccination of children and adolescents with ASO3-adjuvanted pandemic A/H1N1 2009 vaccine (f794). Among 245 children and young people with onset of narcolepsy after Jan. 2008, the authors found: “75 had narcolepsy (56 with cataplexy).… Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57,500 and 1 in 52,000 doses.” (E. Miller, liz.miller@hpa.org.uk)

>>>PNN JournalWatch
* Health Care Interventions to Improve the Quality of Diabetes Care in African Americans: A Systematic Review and Meta-analysis, in
Diabetes Care, 2013; 36: 760–8. (I. Ruiz-Pérez, isabel.ruiz.easp@juntadeandalucia.es)
* Low-Dose Heparin Use and the Patency of Peripheral IV Catheters in Children: A Systematic Review, in
Pediatrics, 2013; 131: e864–72. (M. Kumar)
* Metabolic Syndrome and Metabolic Abnormalities in Bipolar Disorder: A Meta-Analysis of Prevalence Rates and Moderators, in
American Journal of Psychiatry, 2013; 170: 265–74. (D. Vancampfort, davy.vancampfort@uc-kortenberg.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Mar. 5, 2013 * Vol. 20, No. 43
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 5 issue of and Patient Safety supplement to the Annals of Internal Medicine (2013; 158).
Resistant Gonococcal Isolates & Sexual Practices: Compared with men who have sex exclusively with women (MSW), men who have sex with men (MSM) are at significantly higher risk of infection with strains of Neisseria gonorrhoeae that are resistant to ceftriaxone, azithromycin, and other antibiotics, according to an analysis of 6 years of data from the Gonococcal Isolate Surveillance Project (pp. 321–8). In 30 U.S. cities, men with 34,600 episodes of symptomatic urethral gonorrhea showed these patterns of resistance to or elevated minimum inhibitory concentrations (MICs) of antimicrobials used to treat gonorrhea: “In all U.S. regions except the West, isolates from MSM were significantly more likely to exhibit elevated MICs of ceftriaxone and azithromycin than isolates from MSW (P < 0.050). Isolates from MSM had a high prevalence of resistance to ciprofloxacin, penicillin, and tetracycline and were significantly more likely to exhibit antimicrobial resistance than isolates from MSW (P < 0.001).” (R. Kirkcaldy, rkirkcaldy@cdc.gov)
Hepatitis C Virus Eradication & Hepatocellular Carcinoma: Moderate evidence supports aggressive treatment of hepatitis C virus (HCV) as a means of reducing risk of hepatocellular carcinoma (HCC), according to results of a meta-analysis of 18 observational studies (pp. 329–37). Comparing therapy-derived sustained virologic response (SVR) with no response to therapy among HCV-infected persons, the authors found that “SVR was associated with reduced risk for HCC (relative risk for all persons, 0.24 [95% CI, 0.18 to 0.31], moderate-quality evidence; advanced liver disease hazard ratio, 0.23 [CI, 0.16 to 0.35], moderate-quality evidence).” The group concludes, “With the availability of newer and more effective therapies, SVR rates can be increased and HCC incidence rates can be reduced in HCV-infected persons. The association between SVR and HCC should be considered when weighing the benefits and harms of identifying and treating HCV-infected persons.” (R. L. Morgan, evf5@cdc.gov)
Medication Reconciliation During Transitions of Care: An important concern “with medication reconciliation pertains to the reliance on pharmacists,” write authors of a review of this practice during transitions of care (pp. 397–403). “Pharmacists have proven roles in the prevention of [adverse drug events]; however, they are in short supply in most hospitals. Thus, involving pharmacists in medication reconciliation, as most published studies have done, risks taking these personnel away from other important activities related to patient safety.” In 20 interventions assessed in 18 studies, the investigators found: “Pharmacists performed medication reconciliation in 17 of the 20 interventions. Most unintentional discrepancies identified had no clinical significance. Medication reconciliation alone probably does not reduce postdischarge hospital utilization but may do so when bundled with interventions aimed at improving care transitions.” (K. G. Shojania, kaveh.shojania@sunnybrook.ca)
Transitional Care Interventions & Patient Safety: “The strategies hospitals should implement to improve patient safety at hospital discharge remain unclear,” conclude authors of a systematic review of transitional care interventions (pp. 433–40). Focusing on reduction of specific adverse events (AEs), the group writes: “Despite the rapid proliferation of transitional care strategies in the race to reduce hospital readmissions, there has been a notable lack of attention to the potential additional benefit of strategies to reduce specific postdischarge AEs. Postdischarge AEs should also be targeted in quality improvement efforts because they still represent significant failures to ensure patient safety, even if they do not ultimately lead to [emergency department] visits or readmissions. Medication safety interventions led by clinical pharmacists seem to be a promising approach, indicating a need for larger trials with an explicit plan to measure clinically significant AEs. Further research in this field should also follow recently published recommendations to standardize intervention nomenclature and reproducibility, identify target populations most likely to benefit from specific interventions, measure patient-centered outcomes, and rigorously report and evaluate cost and implementation factors.” (S. Rennke, srennke@medicine.ucsf.edu)

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

PNN Pharmacotherapy Line
Mar. 6, 2013 * Vol. 20, No. 44
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 6 issue of JAMA (2013; 309).
TNF Inhibitors & Herpes Zoster: Among new users of anti–tumor necrosis factor (anti-TNF) agents, herpes zoster cases were no more common than among nonusing cohorts, researchers report (pp. 887–95). Users had rheumatoid arthritis (RA), inflammatory bowel disease, and psoriasis, psoriatic arthritis, or ankylosing spondylitis in 1998 through 2007. Compared with 25,742 patients initiating nonbiologic disease-modifying antirheumatic drugs (DMARDs), 33,324 new anti-TNF users had these incidence rates of herpes zoster: “Crude incidence rates among anti-TNF users were 12.1 per 1,000 patient–years (95% CI, 10.7–13.6) for RA, 11.3 per 1,000 patient–years (95% CI, 7.7–16.7) for inflammatory bowel disease, and 4.4 per 1,000 patient–years (95% CI, 2.8–7.0) for psoriasis, psoriatic arthritis, or ankylosing spondylitis. Baseline use of corticosteroids of 10 mg/d or greater among all disease indications was associated with elevated risk (adjusted hazard ratio [HR], 2.13 [95% CI, 1.64–2.75]) compared with no baseline use. For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR, 1.00 [95% CI, 0.77–1.29]) and comparable between all 3 anti-TNF therapies studied. Across all disease indications, the adjusted HR was 1.09 (95% CI, 0.88–1.36).” (K. L. Winthrop, Winthrop@ohsu.edu)
Antiplatelet Therapy in Intermittent Claudication: Thienopyridines have the strongest evidence of lowering all-cause and cardiovascular diseases (CVD) mortality among patients with intermittent claudication, according to a Clinician’s Corner article (pp. 926–7): “This review demonstrates that antiplatelet agents are associated with lower rates of all-cause and CVD mortality compared with placebo in patients with stable intermittent claudication. Compared with aspirin, clopidogrel and picotamide were associated with lower all-cause mortality and fewer cardiovascular events.
“Compared with placebo, antiplatelet agents have a significant risk of adverse events including dyspepsia and adverse events leading to cessation of therapy. Although there was no statistically significant difference in the risk of major bleeding between antiplatelet treatment and placebo, this result must be interpreted with caution because only 2 trials with a relatively small number of participants reported this outcome, and the 95% CIs were wide.” (P. F. Wong,
pwong23@hotmail.com)
Chronic Back Pain & Prescription Opioid Misuse: Management of patients with possible prescription opioid misuse is explored in a Clinician’s Corner write-up (pp. 919–25). “Informed consent and patient–prescriber agreements are important strategies to ensure that patients understand treatment goals and potential opioid risks,” the author writes. “Monitoring for benefit and opioid misuse is accomplished by having frequent face-to-face assessments, performing urine drug tests, monitoring pill counts, and reviewing prescription drug monitoring program data, when available.” (D. P. Alford, dan.alford@bmc.org)
New York City guidelines for prescribing of opioids in the city’s emergency departments “are important first steps toward addressing” the opioid epidemic, Viewpoint authors write (
pp. 879–80): “Many physicians and patients have had unreasonable expectations of opioids and have seriously underestimated their risks. It is time to collectively lower expectations and prescribe these drugs less readily, to fewer patients, at lower doses, and for shorter periods. The New York City guidelines align with this view and are simple, sensible, and easy to follow. The next steps should be to monitor for intended and unintended consequences and to develop similar guidelines for other specialties, understanding that such measures may encounter resistance. As with impaired driving, meaningful change in the prescribing of opioids may require legislative action. Any such measures must ensure that patients with chronic pain or opioid addiction are not abandoned.” (D. N. Juurlink, david.juurlink@ices.on.ca)

>>>PNN NewsWatch
* Policies passed by the APhA House of Delegates during the just-completed Annual Meeting include revisions to the medication-classification system and access to pharmacists’ services. A new business item calls for support of pharmacists’ roles in primary care.

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

PNN Pharmacotherapy Line
Mar. 7, 2013 * Vol. 20, No. 45
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 7 issue of the New England Journal of Medicine (2013; 368).
Endovascular Treatment for Acute Ischemic Stroke: Two studies fail to support use of endovascular treatment in patients with acute ischemic stroke, and an editorialist supports first-line intravenous thrombolysis and a moratorium on surgical approaches until studies demonstrate positive results.
Patients with moderate-to-severe acute ischemic stroke treated with intravenous tissue plasminogen activator (t-PA) had similar functional outcomes as with t-PA followed by endovascular therapy, the Interventional Management of Stroke (IMS) III study shows (
pp. 893–903). All study participants received t-PA within 3 hours of symptom onset, and they received additional endovascular therapy or t-PA in a 2:1 ratio, with these results: “The study was stopped early because of futility after 656 participants had undergone randomization (434 patients to endovascular therapy and 222 to intravenous t-PA alone). The proportion of participants with a modified Rankin score of 2 or less at 90 days did not differ significantly according to treatment (40.8% with endovascular therapy and 38.7% with intravenous t-PA; absolute adjusted difference, 1.5 percentage points; 95% confidence interval [CI], −6.1 to 9.1, with adjustment for the National Institutes of Health Stroke Scale [NIHSS] score [8–19, indicating moderately severe stroke, or ≥20, indicating severe stroke]), nor were there significant differences for the predefined subgroups of patients with an NIHSS score of 20 or higher (6.8 percentage points; 95% CI, −4.4 to 18.1) and those with a score of 19 or lower (−1.0 percentage point; 95% CI, −10.8 to 8.8). Findings in the endovascular-therapy and intravenous t-PA groups were similar for mortality at 90 days (19.1% and 21.6%, respectively; P = 0.52) and the proportion of patients with symptomatic intracerebral hemorrhage within 30 hours after initiation of t-PA (6.2% and 5.9%, respectively; P = 0.83).” (J. P. Broderick, joseph.broderick@uc.edu)
Results of the SYNTHESIS Expansion trial show that “endovascular therapy is not superior to standard treatment with intravenous t-PA,” investigators conclude (
pp. 904–13). A total of 362 patients with acute ischemic stroke who presented within 4.5 hours of symptom onset had these outcomes with endovascular therapy (intraarterial thrombolysis with recombinant [t-PA], mechanical clot disruption or retrieval, or a combination of these approaches) or intravenous t-PA: “The median time from stroke onset to the start of treatment was 3.75 hours for endovascular therapy and 2.75 hours for intravenous t-PA (P < 0.001). At 3 months, 55 patients in the endovascular-therapy group (30.4%) and 63 in the intravenous t-PA group (34.8%) were alive without disability (odds ratio adjusted for age, sex, stroke severity, and atrial fibrillation status at baseline, 0.71; 95% confidence interval, 0.44 to 1.14; P = 0.16). Fatal or nonfatal symptomatic intracranial hemorrhage within 7 days occurred in 6% of the patients in each group, and there were no significant differences between groups in the rates of other serious adverse events or the case fatality rate.” (A. Ciccone, alfonso.ciccone@aopoma.it)
“A decision by Medicare to place a moratorium on reimbursement for endovascular treatment of acute ischemic stroke outside of randomized trials would facilitate recruitment in … urgently needed trials,” an editorialist writes (
pp. 952–5). “Once the new trials are completed, endovascular treatment will have been given ample opportunity to prove itself.” (M. I. Chimowitz)
Omalizumab in Urticaria: In 323 patients with chronic idiopathic urticaria who had not responded to high doses of antihistamines, omalizumab reduced clinical symptoms and signs, according to a Phase III trial (pp. 924–35): “At week 12, the mean (± SD) change from baseline in the weekly itch-severity score was −5.1 ± 5.6 in the placebo group, −5.9 ± 6.5 in the 75-mg group (P = 0.46), −8.1 ± 6.4 in the 150-mg group (P = 0.001), and −9.8 ± 6.0 in the 300-mg group (P < 0.001). Most prespecified secondary outcomes at week 12 showed similar dose-dependent effects. The frequency of adverse events was similar across groups. The frequency of serious adverse events was low, although the rate was higher in the 300-mg group (6%) than in the placebo group (3%) or in either the 75-mg or 150-mg group (1% for each).” (K. Rosén, rosen.karin@gene.com)

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

PNN Pharmacotherapy Line
Mar. 8, 2013 * Vol. 20, No. 46
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
Mar. issue of Pharmacotherapy (2013; 33).
ACCP PBRN Reports of Medication Errors: Data on medication errors reported by members of the ACCP practice-based research network demonstrate the “role clinical pharmacists play with regard to drug error interventions,” researchers report (pp. 253–65). Based on 779 complete reports from 53 clinical pharmacists, the authors found: “Drug errors occurred in both the inpatient (61%) and outpatient (39%) settings. Therapeutic categories most frequently associated with drug errors were systemic antiinfective (25%), hematologic (21%), and cardiovascular (19%) drugs. Approximately 95% of drug errors did not result in patient harm; however, 33 drug errors resulted in treatment or medical intervention, 6 resulted in hospitalization, 2 required treatment to sustain life, and 1 resulted in death. The types of drug errors were categorized as prescribing (53%), administering (13%), monitoring (13%), dispensing (10%), documenting (7%), and miscellaneous (4%). Clinical pharmacist interventions included communication (54%), drug changes (35%), and monitoring (9%). Approximately 89% of clinical pharmacist recommendations were accepted by the prescribers: 5% with drug therapy modifications, 28% due to clinical pharmacist prescriptive authority, and 56% without drug therapy modifications.” (G. M. Kuo, gmkuo@ucsd.edu)
Thromboprophylaxis in Orthopedic Surgery: In a comparative effectiveness analysis of venous thromboembolism (VTE) prophylaxis in major orthopedic surgery, the combination of pharmacologic and mechanical interventions was more effective than either strategy alone (pp. 275–83). “However, due to primarily insufficient evidence for most outcomes evaluated, the balance of benefits to harms of combined pharmacologic and mechanical prophylaxis versus either strategy alone cannot be determined in patients undergoing major orthopedic surgery,” the authors conclude, adding: “No significant difference was found in the rate of pulmonary embolism or nonfatal pulmonary embolism when the combination of pharmacologic and mechanical prophylaxis was compared to pharmacologic prophylaxis alone, with low strength of evidence. The risk of deep vein thrombosis (DVT) was significantly decreased in the combination group (relative risk [RR] 0.48 [95% confidence interval (CI) 0.32–0.72]), with moderate strength of evidence, with benefits of combination therapy persisting in the total knee replacement subgroup (RR 0.41 [95% CI 0.25–0.68]). There was insufficient evidence to evaluate other final or intermediate outcomes or harms. In the comparison of combined pharmacologic and mechanical prophylaxis to mechanical prophylaxis alone, there was insufficient evidence to evaluate any final health outcomes or harms. There was no significant difference in the risk of proximal DVT when comparing combination prophylaxis to mechanical prophylaxis alone (RR 0.78 [95% CI 0.35–1.74]) based on low strength of evidence.” (C. M. White, cmwhite@harthosp.org)
Botulinum Toxin Primer: A review details key aspects of the four botulinum neurotoxin (BoNT) formulations licensed for use in the U.S.: abobotulinumtoxinA, incobotulinumtoxinA, onabotulinumtoxinA, and rimabotulinumtoxinB (pp. 304–18): “These revised name designations were established to reinforce the understanding that each BoNT product has an individual potency and is not interchangeable with any other BoNT product. The therapeutic use of BoNTs is expanding and new formulations are on the horizon.” (J. J. Chen, jjchen@llu.edu)

Neurogenetic Disorders & Treatment of Seizures: Neurogenetic syndromes with sufficient information to evaluate treatments—autism spectrum disorders, Angelman syndrome, Rett syndrome, Dravet syndrome, and tuberous sclerosis complex—are reviewed (pp. 330–43): “Due to a paucity of information regarding the mechanisms by which seizures are generated in the various disorders, approach to seizure control is primarily based on clinical experience and a limited amount of study data exploring patient outcomes. Although exposure of the developing brain to antiepileptic medications is of some concern, the control of epileptic activity is an important undertaking in these individuals, as the severity of eventual developmental delay often appears to correlate with the severity of seizures. As such, early aggressive therapy is warranted.” (M. A. Faulkner, faulkner@creighton.edu)


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

PNN Pharmacotherapy Line
Mar. 11, 2013 * Vol. 20, No. 47
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 9 issue of Lancet (2013; 381).
10 Years of Tamoxifen in Breast Cancer: Continuing adjuvant tamoxifen in women with estrogen-receptor (ER)–positive breast cancer for an additional 5 years halves the rate of disease-related mortality in the second decade after diagnosis, the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial shows (pp. 805–16). The study included 12,894 women with early breast cancer who had completed 5 years of treatment with tamoxifen. They were randomly allocated to continue tamoxifen to 10 years or stop at 5 years (open control), with these results: “Among women with ER-positive disease, allocation to continue tamoxifen reduced the risk of breast cancer recurrence (617 recurrences in 3,428 women allocated to continue vs 711 in 3,418 controls, p = 0.002), reduced breast cancer mortality (331 deaths vs 397 deaths, p = 0.01), and reduced overall mortality (639 deaths vs 722 deaths, p = 0.01). The reductions in adverse breast cancer outcomes appeared to be less extreme before than after year 10 (recurrence rate ratio [RR] 0.90 [95% CI 0.79–1.02] during years 5–9 and 0.75 [0.62–0.90] in later years; breast cancer mortality RR 0.97 [0.79–1.18] during years 5–9 and 0.71 [0.58–0.88] in later years). The cumulative risk of recurrence during years 5–14 was 21.4% for women allocated to continue versus 25.1% for controls; breast cancer mortality during years 5–14 was 12.2% for women allocated to continue versus 15.0% for controls (absolute mortality reduction 2.8%). Treatment allocation seemed to have no effect on breast cancer outcome among 1,248 women with ER-negative disease, and an intermediate effect among 4,800 women with unknown ER status. Among all 12,894 women, mortality without recurrence from causes other than breast cancer was little affected (691 deaths without recurrence in 6,454 women allocated to continue versus 679 deaths in 6,440 controls; RR 0.99 [0.89–1.10]; p = 0.84). For the incidence (hospitalisation or death) rates of specific diseases, RRs were as follows: pulmonary embolus 1.87 (95% CI 1.13–3.07, p = 0.01 [including 0.2% mortality in both treatment groups]), stroke 1.06 (0.83–1.36), ischaemic heart disease 0.76 (0.60–0.95, p = 0.02), and endometrial cancer 1.74 (1.30–2.34, p = 0.0002). The cumulative risk of endometrial cancer during years 5–14 was 3.1% (mortality 0.4%) for women allocated to continue versus 1.6% (mortality 0.2%) for controls (absolute mortality increase 0.2%).” (C. Davies, atlas@ctsu.ox.ac.uk)
Everolimus for Angiomyolipoma: In angiomyolipomas associated with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis, everolimus reduces the volume of these slow-growing tumors with an acceptable safety profile, EXIST-2 researchers report (pp. 817–24). The Phase III trial tested oral everolimus 10 mg/d against placebo in 118 patients, with these results: “At the data cutoff, double-blind treatment was ongoing for 98 patients; two main reasons for discontinuation were disease progression (nine placebo patients) followed by adverse events (two everolimus patients; four placebo patients). The angiomyolipoma response rate was 42% (33 of 79 [95% CI 31–53%]) for everolimus and 0% (0 of 39 [0–9%]) for placebo (response rate difference 42% [24–58%]; one-sided Cochran-Mantel-Haenszel test p < 0.0001). The most common adverse events in the everolimus and placebo groups were stomatitis (48% [38 of 79], 8% [3 of 39], respectively), nasopharyngitis (24% [19 of 79] and 31% [12 of 39]), and acne-like skin lesions (22% [17 of 79] and 5% [2 of 39]).” (J. J. Bissler, john.bissler@cchmc.org)

>>>PNN JournalWatch
* Strategies of Clopidogrel Load and Atorvastatin Reload to Prevent Ischemic Cerebral Events in Patients Undergoing Protected Carotid Stenting: Results of the Randomized ARMYDA-9 CAROTID Study, in
Journal of the American College of Cardiology, 2013; doi: 10.1016/j.jacc.2013.01.015. (G. Patti)
* Glucose-Insulin-Potassium Revived: Current Status in Acute Coronary Syndromes and the Energy-Depleted Heart, in
Circulation, 2013; 127: 1040–8. (L. H. Opie, lionel.opie@uct.ac.za)
* Integrating Advanced Practice Providers Into Medical Critical Care Teams, in
Chest, 2013; 143: 847–50. (J. M. Madison, mark.madison@umassmed.edu)
* Cardiovascular Disease in COPD: Mechanisms, in
Chest, 2013; 143: 798–807. (W. MacNee, w.macnee@ed.ac.uk)
* Clinical Phenotypes of Chronic Obstructive Pulmonary Disease and Asthma: Recent Advances, in
Journal of Allergy and Clinical Immunology, 2013; 131: 627–34. (E. R. Sutherland, sutherlande@njhealth.org)

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

PNN Pharmacotherapy Line
Mar. 12, 2013 * Vol. 20, No. 48
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Mar. 11 issue of the JAMA Internal Medicine (2013; 173).
Treatment Choices of Primary-Care Physicians in Hyperlipidemia: In a national survey, primary-care physicians frequently chose primary prevention for patients with hyperlipidemia whose Framingham risk scores (≤5%) did not support outcome benefits, researchers report (doi: 10.1001/jamainternmed.2013.2797). Survey respondents evaluated six hypothetical patients with varying risk factors and demographic and clinical characteristics, all of whom did not have coronary heart disease. In two vignettes of low-risk patients with LDL cholesterol levels of 180 mg/dL, “significantly more health providers treated the 40-year-old man with well-controlled hypertension (88.9%) compared with the 50-year-old woman (73.5%) (P < .001)” with no risk factors, the author explain. “The number needed to treat (NNT) was identified as being lower in the man compared with the woman at both 5 and 20 years (P < .001). Health care providers reported a significantly lower perceived NNT for outcomes at 20 years compared with 5 years in both the male and female patient (P < .001).…
“In vignettes 5 and 6, a 75-year-old man (LDL-C level of 140 mg/dL) was compared with a 50-year-old woman (LDL-C level of 145 mg/dL). Both patients had hypertension and used tobacco. Respondents recommended similar treatment rates (86.6% vs 88.9%).” (M. E. Johansen,
mikejoha@med.umich.edu)
After noting that a common reason why physicians do not follow clinical guidelines at the point of care is that the documents are “complicated and hard to remember,” a journal editor makes this observation (
doi: 10.1001/jamainternmed.2013.286): “One solution may be readily available: robust decision aids to make it easy for physicians to calculate risk and appropriately prescribe statins. Until then, this survey reminds us to consider baseline risk when considering whether to initiate pharmacologic treatment.” (R. F. Redberg)
Long-Term Benefits of Diabetes Group Visits: Patients with diabetes have sustained clinical and economic benefits from participation in group medical clinics (GMCs) for 13–18 months after care ends, according to a research letter (doi: 10.1001/jamainternmed.2013.2803). At two VA facilities, 239 patients were seen in GMCs; expenditure and utilization outcomes and clinical measurements showed these patterns for patients managed in the GMCs and through usual care: “Estimated mean outpatient expenditures were similar between arms during and after the trial, while estimated mean total expenditures for the GMC patients were significantly lower (–$7,504; 95% CI, –$14,286 to –$721; P = .003) 13 to 18 months after the trial owing to lower obseverd inpatient admissions during the same period.…
“Trends in clinic SBP values diverged from baseline to become significantly lower (relative improvement of 3.1 mm Hg; 95% CI, −5.3 to −0.9 mm Hg; P = .007) for GMC compared with usual care patients by the end of the 12-month trial. This improvement was sustained for the first 6 months after trial completion (estimated SBP was 3.1 mm Hg lower [95% CI, −5.8 to −0.4 mm Hg; P = .03] for GMC compared with usual care patients). However, relative improvement in clinic SBP declined for GMC patients compared with usual care patients (18 months after the trial, 0.8 mm Hg lower [95% CI, −5.7 to 4.2 mm Hg; P = .76]).” (G. L. Jackson,
george.l.jackson@duke.edu)
Ascorbic Acid Supplements & Kidney Stones: High doses of ascorbic acid supplements are associated with a doubling in risk of kidney stones in men, a study concludes (pp. 386–8). In the Cohort of Swedish Men (COSM), 436 first cases of kidney stones were identified among 48,850 participants. Frequency of ascorbic acid supplement use data yielded these hazard ratios among the men: “Ascorbic acid use was associated with a statistically significant 2-fold increased risk. In contrast, multivitamin use was not associated with kidney stone risk (RR, 0.86 [95% CI, 0.62–1.19]).
“Users of only ascorbic acid taking fewer than 7 (median) and 7 or more tablets per week showed increased risks of RR, 1.66 (95% CI, 0.99–2.79) and RR, 2.23 (95% CI, 1.28–3.88), respectively, compared with supplement nonusers in the full multivariate-adjusted model (P value for trend = .001).” (A. Åkesson,
Agneta.Akesson@ki.se)

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

PNN Pharmacotherapy Line
Mar. 13, 2013 * Vol. 20, No. 49
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 13 issue of JAMA (2013; 309).
Smoking Cessation & Weight Gain: Despite increased body mass following smoking cessation, the net effects on the cardiovascular system support stopping tobacco use, according to a study of patients without diabetes (pp. 1014–21). In a prospective community-based cohort study that used data from the Framingham Offspring Study, investigators found these risks and benefits in patients categorized as current smokers, recent quitters (4 years or less), long-term quitters (more than 4 years), and nonsmokers: “After a mean follow-up of 25 (SD, 9.6) years, 631 CVD events occurred among 3,251 participants. Median 4-year weight gain was greater for recent quitters without diabetes (2.7 kg [interquartile range {IQR}, −0.5 to 6.4]) and with diabetes (3.6 kg [IQR, −1.4 to 8.2]) than for long-term quitters (0.9 kg [IQR, −1.4 to 3.2] and 0.0 kg [IQR, −3.2 to 3.2], respectively, P < .001). Among participants without diabetes, age- and sex-adjusted incidence rate of CVD was 5.9 per 100 person–examinations (95% CI, 4.9–7.1) in smokers, 3.2 per 100 person–examinations (95% CI, 2.1–4.5) in recent quitters, 3.1 per 100 person–examinations (95% CI, 2.6–3.7) in long-term quitters, and 2.4 per 100 person–examinations (95% CI, 2.0–3.0) in nonsmokers. After adjustment for CVD risk factors, compared with smokers, recent quitters had a hazard ratio (HR) for CVD of 0.47 (95% CI, 0.23–0.94) and long-term quitters had an HR of 0.46 (95% CI, 0.34–0.63); these associations had only a minimal change after further adjustment for weight change. Among participants with diabetes, there were similar point estimates that did not reach statistical significance.” (C. Clair, carole.willi@gmail.com)
Commenting on this study and an opinion piece that discusses counseling patients to stop smoking around the time of surgery (
pp. 993–4; J. Maa, john.maa@ucsfmedctr.org), editorialists write (pp. 1032–3): “Data from the study by Clair et al can be used to reassure patients concerned about the health effects of cessation-related weight gain. About 50% of female smokers and about 25% of male smokers are ‘weight concerned,’ which may discourage quit attempts and quitting success. Although such reassurance may not assuage concerns about the effects of weight gain on appearance, it may nevertheless be helpful. Furthermore, even though no treatments have been shown to reliably prevent cessation-related weight gain, exercise regimens may be beneficial, and use of nicotine replacement medications can suppress weight gain during their use.” (M. C. Fiore)
Bleeding Events & Inpatient Mortality After PCI: Bleeding with percutaneous coronary intervention (PCI) was linked to an increased risk of in-hospital mortality in an analysis of 3.4 million procedures (pp. 1022–9). In the CathPCI Registry for 2004–11, investigators found 57,246 bleeding events (1.7%) and 22,165 in-hospital deaths (0.65%): “The adjusted population attributable risk for mortality related to major bleeding was 12.1% (95% CI, 11.4%–12.7%) in the entire CathPCI cohort. The propensity-matched population consisted of 56,078 procedures with a major bleeding event and 224,312 controls. In this matched cohort, major bleeding was associated with increased in-hospital mortality (5.26% vs 1.87%; risk difference, 3.39% [95% CI, 3.20%–3.59%]; NNH = 29 [95% CI, 28–31]; P < .001). The association between major bleeding and in-hospital mortality was observed in all strata of preprocedural bleeding risk (low: 1.62% vs 0.17%; risk difference, 1.45% [95% CI, 1.13%–1.77%], NNH = 69 [95% CI, 57–88], P < .001; intermediate: 3.27% vs 0.71%; risk difference, 2.56% [95% CI, 2.33%–2.79%], NNH = 39 [95% CI, 36–43], P < .001; and high: 8.16% vs 3.45%; risk difference, 4.71% [95% CI, 4.35%–5.07%], NNH = 21 [95% CI, 20–23], P < .001). Although both access-site and non–access-site bleeding were associated with increased in-hospital mortality (2.73% vs 1.87%; risk difference, 0.86% [95% CI, 0.66%–1.05%], NNH = 117 [95% CI, 95–151], P < .001; and 8.25% vs 1.87%; risk difference, 6.39% [95% CI, 6.04%–6.73%], NNH = 16 [95% CI, 15–17], P < .001, respectively), the NNH was lower for nonaccess bleeding.” (A. K. Chhatriwalla, achhatriwalla@saint-lukes.org)

>>>PNN NewsWatch
* Azithromycin labeling has been updated to strengthen warnings about QT interval prolongation and potentially fatal torsades de pointes, FDA said yesterday.

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

PNN Pharmacotherapy Line
Mar. 14, 2013 * Vol. 20, No. 50
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Mar. 19 issue of the Journal of the American College of Cardiology (2013; 61).
CVD Risk Prediction, Lipoprotein(a) & Genotypes: Prediction of risk of myocardial infarction (MI) and coronary heart disease (CHD) is improved substantially by inclusion of extreme lipoprotein(a) levels and corresponding LPA risk genotypes, researchers report (pp. 1146–56). Among 8,720 Danish participants in a general population study from 1991–94 through 2011, these relationships were noted: “For individuals with lipoprotein(a) levels ≥80th percentile (≥47 mg/dl), 23% (p < 0.001) of MI events and 12% (p < 0.001) of CHD events were reclassified correctly, while no events were reclassified incorrectly for either endpoint. As some incorrect reclassification of individuals with no events occurred, addition of lipoprotein(a) levels ≥80th percentile overall yielded net reclassification indices of +16% (95% confidence interval: 8% to 24%) and +3% (−1% to 8%) for MI and CHD, respectively. Corresponding net reclassification indices for number of [kringle IV type 2] repeats ≤21st percentile were +12% (5% to 19%) and +4% (0% to 8%), for rs3798220 carrier status +15% (−14% to 44%) and +10% (−10% to 30%), and for rs10455872 carrier status +16% (6% to 26%) and +2% (−1% to 6%). Considering only individuals at 10% to 19.9% absolute 10-year MI and CHD risk, addition of extreme lipoprotein(a) levels or corresponding LPA risk genotypes improved risk prediction even further.” (B. G. Nordestgaard)
Yoga in Atrial Fibrillation: In the pre–post YOGA My Heart Study, patients with paroxysmal atrial fibrillation (AF) had improved symptoms, arrhythmia burden, heart rate, blood pressure, anxiety and depression scores, and quality of life scores following twice-weekly, 60-min yoga training for 3 months (pp. 1177–82). Symptomatic AF episodes fell significantly, from 3.8 ± 3 to 2.1 ± 2.6, as did symptomatic non-AF episodes (2.9 ± 3.4 vs. 1.4 ± 2.0) and asymptomatic AF episodes (0.12 ± 0.44 vs. 0.04 ± 0.20). (D. Lakkireddy)
Possibility for Biological Pacemakers: Responding to a study in dogs showing that transfer of the HCN2/SkM1 gene into the left bundle branch can provide a biological pacemaker (pp. 1192–201; M. R. Rosen), editorialists conclude that “a biological alternative to electrical pacemakers is extremely significant for the possible clinical applications and the improvement in patient management” (pp. 1202–3). The authors describe four obstacles to clinical utility of this approach: getting the construct to work in the atrium, durability and longevity, showing that the construct is not arrhythmogenic and responds to autonomic influences, and resolution of problems if a ventricular pacemaker results. (M. Vatta)

>>>Circulation Report
Source:
Mar. 12 issue of Circulation (2013; 127).
Imatinib Mesylate in Pulmonary Arterial Hypertension: In a study of 202 patients with advanced pulmonary arterial hypertension (PAH), imatinib “improved exercise capacity and hemodynamics,” but “serious adverse events and study drug discontinuations were common” (pp. 1128–38). A primary outcome of change in 6-minute walk distance showed these changes in participants who were on two (59%) or three (41%) PAH therapies: “After 24 weeks, the mean placebo-corrected treatment effect on 6-minute walk distance was 32 m (95% confidence interval, 12–52; P = 0.002), an effect maintained in the extension study in patients remaining on imatinib. Pulmonary vascular resistance decreased by 379 dyne·s·cm−5 (95% confidence interval, −502 to − 255; P < 0.001, between-group difference). Functional class, time to clinical worsening, and mortality did not differ between treatments. Serious adverse events and discontinuations were more frequent with imatinib than placebo (44% versus 30% and 33% versus 18%, respectively). Subdural hematoma occurred in 8 patients (2 in the core study, 6 in the extension) receiving imatinib and anticoagulation.” (M. M. Hoeper, hoeper.marius@mh-hannover.de)

>>>PNN NewsWatch
* FDA yesterday approved technetium Tc 99m tilmanocept (Lymphoseek Injection, Navidea), a first-in-class mannose receptor (CD206) binding radiopharmaceutical agent for use in lymphatic mapping procedures to assist in the localization of lymph nodes that drain a primary tumor in patients with breast cancer or melanoma.

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

PNN Pharmacotherapy Line
Mar. 15, 2013 * Vol. 20, No. 51
Providing news and information about medications and their proper use

>>>Pediatric Highlights
Source:
Mar. issue of Pediatrics (2013; 131).
Chronic Acetaminophen Exposure & Pediatric Acute Liver Failure: Among 895 children enrolled in the multinational Pediatric Acute Liver Failure (PALF) study in 2002–09, chronic exposure (CE) to acetaminophen was associated with lower bilirubin and higher alanine aminotransferase levels than among children with no exposure (NE) to the drug (pp. e740–6). The investigators report that “outcomes with CE were worse than with [single-dose exposure (SE)] but better than with NE” and conclude, “Potential reasons for this outcomes advantage over non–[acetaminophen]-exposed subjects should be explored.” With CE defined as multiple doses over 2 or more days, the results of the study showed the following: “Patients with CE compared with those with SE were younger (3.5 vs 15.2 years, P < .0001), less likely to be female (46% vs 82%, P < .0001), and more likely to be Hispanic (25% vs 7%, P = .001), but they did not differ significantly from the NE group. At enrollment, total bilirubin was lower with CE than with NE (3.2 vs 13.1 mg/dL, P < .001). Alanine aminotransferase levels were higher with CE than with NE (2,384 vs 855 IU/L, P < .0001), but lower than with SE (5140 IU/L, P < .0001). Survival without liver transplantation at 21 days was worse for CE than for SE (68% vs 92%, P = .0004) but better than for NE (49%, P = .008).” (M. A. Leonis)
Tobacco Smoke Exposure in Asthma: More than half of children and adolescents with asthma continue to be exposed to environmental tobacco smoke (ETS), a study shows, and one in six adolescents with asthma use tobacco smoke products (TSPs) (pp. 407–14). ETS declined between National Health and Nutrition Examination Surveys (NHANES) conducted in 1988–94 and 2005–10 but remains high, especially among low-income youth: “Among adolescents (aged 12–19 years) with asthma in 2005–2010, 17.3% reported TSP use. Among youth (aged 4–19 years) with asthma who did not use TSPs, 53.2% were exposed to ETS and 17.6% had in-home smoke exposure. Among low-income youth, 70.1% and 28.1% had exposure to ETS and in-home smoke, respectively. After controlling for sociodemographic factors, higher prevalence of exposure to ETS and in-home smoke persisted among low-income youth. Between 1988–1994 and 2005–2010, there was a decline in ETS and in-home smoke exposure (both P < .001).” (B. K. Kit)

>>>Allergy/Immunology Report
Source:
Mar. issue of the Journal of Allergy and Clinical Immunology (2013; 131).
Asthma Exacerbations After Stopping Low-Dose Inhaled Corticosteroids: Discontinuation of low doses of inhaled corticosteroids (ICSs) in patients with well-controlled asthma increases exacerbations, compared with continuation, researchers report (pp. 724–729.e2). In a systematic review and meta-analysis of seven randomized controlled trials, interruptions in ICS therapy showed these outcomes over follow-up periods of 3 months or more: “The relative risk for an asthma exacerbation in patients who stopped ICSs compared with those who continued use was 2.35 (95% CI, 1.88–2.92; P < .001; I2 = 0%), as determined by using data pooled from trials with a mean follow-up of 27 weeks. The pooled absolute risk difference for an asthma exacerbation was 0.23 (95% CI, 0.16–0.30; P < .001; I2 = 44%). Patients who discontinued ICSs also had a decreased FEV1 of 130 mL (95% CI, 40–210 mL; P = .003; I2 = 53%), a decreased mean morning peak expiratory flow of 18 L/min (95% CI, 6–29 L/min; P = .004; I2 = 82%), and an increased mean standardized asthma symptom score of 0.43 SDs (95% CI, 0.28–0.58 SDs; P < .001; I2 = 0%).” (M. A. Rank, rank.matthew@mayo.edu)

>>>PNN NewsWatch
* A reported increase in risk of pancreatitis and pancreatic duct metaplasia in patients with type 2 diabetes being treated with incretin mimetics is under investigation, FDA said yesterday. Exenatide and sitagliptin were implicated in a recent article released in advance of print by JAMA Internal Medicine (doi: 10.1001/jamainternmed.2013.2720; S. Singh, sosingh@jhsph.edu); other agents under investigation include liraglutide, saxagliptin, alogliptin, and linagliptin.

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

PNN Pharmacotherapy Line
Mar. 18, 2013 * Vol. 20, No. 52
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 16 issue of Lancet (2013; 381).
Etanercept Continuation in RA: In patients with moderately active rheumatoid arthritis, continuation of etanercept in conventional or reduced doses with methotrexate was more efficacious than methotrexate alone, according to results of the PRESERVE study (pp. 918–29). Conducted at 80 centers on four continents, the trial enrolled adult patients with moderate disease activity scores in 28 joints (DAS28) who had been receiving methotrexate 15–25 mg/wk for at least 8 weeks. During an open-label, 36-week period, participants received etanercept 50 mg/wk in addition to methotrexate; those who achieved low disease activity were eligible for a blinded, 52-week phase of etanercept 25 or 50 mg with methotrexate or methotrexate plus placebo.
Results showed: “604 (72.4%) of 834 enrolled patients were eligible for the double-blind period, of whom 202 were assigned to 50 mg etanercept plus methotrexate, 202 to 25 mg etanercept plus methotrexate, and 200 to placebo plus methotrexate. At week 88, 166 (82.6%) of 201 patients who had received at least one dose of 50 mg etanercept and one or more DAS28 evaluations had low disease activity, compared with 84 (42.6%) of 197 who had received placebo (mean difference 40.8%, 95% CI 32.5–49.1%; p < 0.0001). Additionally, 159 (79.1%) of 201 patients given 25 mg etanercept had low disease activity at week 88 (mean difference from placebo 35.9%, 27.0–44.8%; p < 0.0001).” (J. S Smolen,
josef.smolen@wienkav.at)

>>>Oncology Highlights
Source:
Mar. 20 issue of the Journal of Clinical Oncology (2013; 31).
Off-Label Oncolytic Use & Spending: Evaluation of a pharmacy database shows that chemotherapy use is more often within FDA-approved parameters than off label, but about half of off-label use is outside clinical settings approved by the National Comprehensive Care Network (NCCN) Compendium recommendations (pp. 1134–9). Prescribing data from IntrinsiQ Intellidose data systems for the most commonly prescribed anticancer drugs/chemotherapies that were patent protected and administered intravenously to patients in 2010 showed these use and cost patterns: “On-label use amounted to 70%, and off-label use amounted to 30%. Fourteen percent of use conformed to an NCCN-supported off-label indication, and 10% of off-label use was associated with an FDA-approved cancer site, but an NCCN-unsupported cancer stage and/or line of therapy. Total national spending on these chemotherapies amounted to $12 billion (B; $7.3B on-label, $2B off-label and NCCN supported; $2.5B off-label and NCCN unsupported).” (R. M. Conti, rconti@uchicago.edu)
This study “sets a benchmark for discourse on off-label prescribing in routine practice in oncology,” an editorialist writes (
pp. 1125–7). “Although their overall estimation is reassuring, their findings on individual agents, especially those for which more than 50% of use is off label, are of concern. There is a need for additional information, especially on the extent of off-label prescribing of oral cancer agents. In the meantime, investment is needed to facilitate the process of drug prescribing in oncology at the patient, provider, and system levels to warrant that the prescribing that does occur ensures the optimal risk-benefit ratio for individual patients and the system as a whole. Greater scrutiny at the reimbursement level is most likely to have the greatest impact in the short term.” (M. K. Krzyzanowska, monika.krzyzanowska@uhn.ca)

>>>PNN JournalWatch
* Markers of Response for the Antiangiogenic Agent Bevacizumab, in
Journal of Clinical Oncology, 2013; 31: 1219–30. (D. Lambrechts, diether.lambrechts@vib-kuleuven.be)
* The Diversity and Management of Chronic Hepatitis B Virus Infections in the United Kingdom: A Wake-up Call, in
Clinical Infectious Diseases, 2013; 56: 951–60. (A. Rodger, alison.rodger@ucl.ac.uk)
* Promising New Assays and Technologies for the Diagnosis and Management of Infectious Diseases, in
Clinical Infectious Diseases, 2013; 56: 996–1002. (P. Schuetz, schuetzph@gmail.com)
* The Unknown Profession: A Geriatrician, in
Journal of the American Geriatrics Society, 2013; 61: 447–9. (P. M. Abadir, Pabadir1@jhmi.edu)
* Ethical and Quality Pitfalls in Electronic Health Records, in
Neurology, 2013; 80: 1057–61. (J. L. Bernat, bernat@dartmouth.edu)

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

PNN Pharmacotherapy Line
Mar. 19, 2013 * Vol. 20, No. 53
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 19 issue of the Annals of Internal Medicine (2013; 173).
Chlorthalidone v. HCTZ for Hypertension: In an observational cohort study, chlorthalidone failed to demonstrate superiority over hydrochlorothiazide in a population of older adults with hypertension, but hypokalemia and other electrolyte abnormalities were common with chlorthalidone (pp. 447–55). In 29,873 individuals in Ontario aged 66 years or older with hypertension, newly started chlorthalidone or hydrochlorothiazide showed these outcomes based on a primary composite outcome of death or hospitalization for heart failure, stroke, or myocardial infarction over 5 years: “During follow-up, chlorthalidone recipients (n = 10,384) experienced the primary outcome at a rate of 3.2 events per 100 person–years of follow-up, and hydrochlorothiazide recipients experienced 3.4 events per 100 person–years of follow-up (adjusted hazard ratio, 0.93 [95% CI, 0.81 to 1.06]). Patients treated with chlorthalidone were more likely to be hospitalized with hypokalemia (adjusted hazard ratio, 3.06 [CI, 2.04 to 4.58]) or hyponatremia (adjusted hazard ratio, 1.68 [CI, 1.24 to 2.28]). In 9 post hoc analyses comparing patients initially prescribed 12.5, 25, or 50 mg of chlorthalidone per day with those prescribed 12.5, 25, or 50 mg of hydrochlorothiazide per day, the former were more likely to be hospitalized with hypokalemia for all 6 comparisons in which a statistically significant association was found. The results of other effectiveness and safety outcomes were also consistent with those of the main analysis.” (I. A. Dhalla, dhallai@smh.ca)
Aristolochic Acid Nephropathy: Authors of a narrative review recount the identification of renal disease associated with Chinese herbs and recent related developments (pp. 469–77): “It has been 20 years since the first description of a rapidly progressive renal disease that is associated with the consumption of Chinese herbs containing aristolochic acid (AA) and is now termed aristolochic acid nephropathy (AAN). Recent data have shown that AA is also the primary causative agent in Balkan endemic nephropathy and associated urothelial cancer. Aristolochic acid nephropathy is associated with a high long-term risk for renal failure and urothelial cancer, and the potential worldwide population exposure is enormous. This evidence-based review of the diagnostic approach to and management of AAN draws on the authors’ experience with the largest and longest-studied combined cohort of patients with this condition. It is hoped that a better understanding of the importance of this underrecognized and severe condition will improve epidemiologic, preventive, and therapeutic strategies to reduce the global burden of this disease.” (G. M. Lord, graham.lord@kcl.ac.uk)
Health Care Reform: An author describes for physicians the “road to health reform” over the next 4 years (pp. 487–8): “Despite the challenges, the journey to a health care system that covers nearly everyone while lowering per capita spending is one that is well worth taking. The Institute of Medicine recently found that although the United States spends more on health care than any other country, its outcomes are worse on most measures of health. This is the health care that we have and are trying to move away from.
“Physicians can help the United States chart a path to a better health care system by urging their states to expand coverage and urging Congress to enact responsible ways to reduce health care spending that preserve funding for programs essential to public health. Physicians can lead efforts to develop new ways to deliver patient-centered care. Most important, physicians can bring to the policy discussion their unique perspectives on what it is like to try to deliver compassionate, ethical, and high-quality care to patients in a system that too often stands in the way.” (R. B. Doherty)

>>>PNN NewsWatch
* All sterile products produced by New Jersey specialty pharmacy Med Prep Consulting are being recalled because of potential fungal contamination, FDA said. Health care providers at a Connecticut hospital observed floating particles, later identified as fungus, in five bags of magnesium sulfate intravenous solution. That product may have been distributed to additional facilities in Connecticut, New Jersey, Pennsylvania, and Delaware. Until further notice, health care providers should stop using and return all products made by Med Prep Consulting.

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

PNN Pharmacotherapy Line
Mar. 20, 2013 * Vol. 20, No. 54
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 20 issue of JAMA (2013; 309).
Aliskiren in Heart Failure: In the ASTRONAUT trial, random allocation of patients hospitalized for heart failure (HF) to aliskiren was no better than with standard therapy in terms of cardiovascular (CV) deaths or HF rehospitalizations at 6 or 12 months (pp. 1125–35). Study participants were adults with left ventricular ejection fractions (LVEFs) of 40% or less, elevated natriuretic peptides (brain natriuretic peptide [BNP] ≥400 pg/mL or N -terminal pro-BNP [NT-proBNP] ≥1600 pg/mL), and signs and symptoms of fluid overload. Aliskiren 150–300 mg or placebo daily over a median of 11.3 months yielded these results: “In total, 1,639 patients were randomized, with 1,615 patients included in the final efficacy analysis cohort (808 aliskiren, 807 placebo). Mean age was 65 years; mean LVEF, 28%; 41% of patients had diabetes mellitus, mean estimated glomerular filtration rate, 67 mL/min/1.73 m2. At admission and randomization, median NT-proBNP levels were 4,239 pg/mL and 2,718 pg/mL, respectively. At randomization, patients were receiving diuretics (95.9%), beta-blockers (82.5%), angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (84.2%), and mineralocorticoid receptor antagonists (57.0%). In total, 24.9% of patients receiving aliskiren (77 CV deaths, 153 HF rehospitalizations) and 26.5% of patients receiving placebo (85 CV deaths, 166 HF rehospitalizations) experienced the primary end point at 6 months (hazard ratio [HR], 0.92; 95% CI, 0.76–1.12; P = .41). At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations; HR, 0.93; 95% CI, 0.79–1.09; P = .36). The rates of hyperkalemia, hypotension, and renal impairment/renal failure were higher in the aliskiren group compared with placebo.” (M. Gheorghiade, m-gheorghiade@northwestern.edu)
Eritoran in Severe Sepsis: In a 1,961-patient ACCESS trial, 28-day mortality from severe sepsis was similar with placebo and eritoran, a synthetic lipid A antagonist that blocks gram-negative lipopolysaccharide from binding at the cell surface MD2-TLR4 receptor (pp. 1154–62). Initiation of the study drug or placebo within 12 hours of first-organ dysfunction in patients with severe sepsis produced these changes in 28-day all-cause mortality in this Phase III trial: “In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1,304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88–1.26; difference in mortality rate, −1.1; 95% CI, −5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1,304) in the placebo group, Kaplan–Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85–1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups.” (S. M. Opal, Steven_Opal@brown.edu)
ACOs & Population Health: Accountable care organizations (ACOs) have three well-known goals, authors write: to control health care costs, to drive quality in health care, and to improve population health (pp. 1119–20). In a Viewpoint article, the writers reach this conclusion about “difficult issues” embodied in the population-health goal: “George Orwell argued that by choosing one’s language with care, ‘one can think more clearly, and to think clearly is a necessary first step. . . .’ It is not merely a semantic issue, of little importance, if ACOs are described, or self-described, as working to improve population health when what they are really doing is improving medical care for their own patients. If the good name of population health continues to be used in this way, it will be difficult to understand what ACOs are doing, what tasks they are not doing but should be done, who can do these tasks, how performance on these tasks should be measured, and how and for whom incentives should be created.” (D. J. Noble, djn2004@med.cornell.edu)

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

PNN Pharmacotherapy Line
Mar. 21, 2013 * Vol. 20, No. 55
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 21 issue of the New England Journal of Medicine (2013; 368).
Medical Therapy v. Closure of Patent Foramen Ovale After Cryptogenic Stroke: Contrary to some previous studies, use of a medical device to close patent foramen ovale in adult patients following cryptogenic strokes was superior to treatment with antiplatelet agents, according to results of the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial (pp. 1092–100). Patients with ischemic strokes of indeterminate origin were assigned to either medical therapy with aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole or to treatment with the Amplatzer PFO Occluder device within 21 days of study entry.
Results showed: “We enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapy group received one or more antiplatelet medications (74.8%) or warfarin (25.2%). Treatment exposure between the two groups was unequal (1,375 patient–years in the closure group vs. 1,184 patient–years in the medical-therapy group, P = 0.009) owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 95% confidence interval [CI], 0.22 to 1.11; P = 0.08). The between-group difference in the rate of recurrent stroke was significant in the prespecified per-protocol cohort (6 events in the closure group vs. 14 events in the medical-therapy group; hazard ratio, 0.37; 95% CI, 0.14 to 0.96; P = 0.03) and in the as-treated cohort (5 events vs. 16 events; hazard ratio, 0.27; 95% CI, 0.10 to 0.75; P = 0.007). Serious adverse events occurred in 23.0% of the patients in the closure group and in 21.6% in the medical-therapy group (P = 0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group (4.2%), but the rate of atrial fibrillation or device thrombus was not increased.” (J. D. Carroll,
john.carroll@ucdenver.edu)
Responding to this and a study of percutaneous closure of patent foramen ovale in cryptogenic embolism (
pp. 1083–91; B. Meier, bernhard.meier@insel.ch), editorialists find there is “still no closure on the question of [patent foramen ovale] closure” (pp. 1152–3): “We are left for the moment to make decisions under conditions of uncertainty. In such circumstances, evidentiary standards vary among decision makers—patients, clinicians, authors of practice guidelines, and regulatory authorities—depending not only on the interpretation of the results, but also on the potential consequences of their decisions. Some of them may interpret the data as supporting closure of a patent foramen ovale as a viable therapeutic option, even while conceding the failure of trials to show the superiority of closure over medical therapy. Yet given the prevalence of patent foramen ovale in the general population, the enormous potential for overuse of percutaneous closure of a patent foramen ovale, and the relatively low risk of stroke in patients who are treated medically, the routine use of this therapy seems unwise without a clearer view of who, if anyone, is likely to benefit. To that end, it is excellent news that the RESPECT investigators are continuing to accrue data on the patients they enrolled and that other studies of closure of patent foramen ovale are ongoing. Randomized studies of closure may come to an end, however, if the Amplatzer device is approved. Thus, all eyes will be on the regulatory agencies to see how they will interpret these results in light of their own evidentiary standards.” (S. R. MesséWinking

>>>PNN NewsWatch
* FDA yesterday announced approval of gadoterate meglumine (Dotarem, Guerbet) for use in magnetic resonance imaging (MRI) of the brain, spine, and associated tissues of patients ages 2 years and older. In a clinical trial of 245 adult and 38 pediatric patients ages 2 years and older with suspected CNS abnormalities, the gadolinium-based contrast agent during MRIs helped radiologists better see CNS lesions. Dotarem also helped the radiologists identify lesion borders and other lesion features. The product carries a boxed warning about the risk of nephrogenic systemic fibrosis in those exposed to gadoterate meglumine.

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

PNN Pharmacotherapy Line
Mar. 22, 2013 * Vol. 20, No. 56
Providing news and information about medications and their proper use

>>>Infectious Disease Report
Source:
Apr. 15 issue of Clinical Infectious Diseases (2013; 56).
Community-Associated MRSA in Patients with HIV: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) burden was significantly higher among hospitalized patients with HIV compared with inpatients without the infection, and those with HIV more often carried the problematic USA300 strain, researchers report (pp. 1067–74). In 2011–12, cultures from nasal and extranasal sites showed these patterns in relation to risk factors: “Of 745 patients (374 HIV-infected, 371 HIV-negative), 15.7% were colonized with CA-MRSA at any site: 20% of HIV and 11% of HIV-negative patients (relative prevalence = 1.8, P = .002). HIV-infected patients had a higher prevalence of nasal, extranasal, and exclusive extranasal colonization as well as higher colonization burden. Perirectal and inguinal areas were the extranasal sites most frequently colonized, and 38.5% of colonized patients had exclusive extranasal colonization. Seventy-three percent of isolates were identified as USA300. Among HIV-infected patients, male sex, younger age, and recent incarceration were positively associated whereas Hispanic ethnicity was negatively associated with higher colonization burden. Among HIV-negative patients, temporary housing (homeless, shelter, or substance abuse center) was the only factor associated with higher colonization burden. Predictors of USA300 included HIV, younger age, illicit drug use, and male sex; all but 1 colonized individual with current or recent incarceration carried USA300.” (K. Popovich, kyle_popovich@rush.edu)
Varicella Immune Response, Depression & Antidepressants: Among community-dwelling older adults in the Depression Substudy of the Shingles Prevention Study (SPS), those with depression had lower responses to high-titer live attenuated varicella zoster virus (VZV) vaccine (zoster vaccine), and treatment with antidepressants normalized these responses (pp. 1085–93). SPS included 40 participants with major depressive disorder and 52 age- and sex-matched controls with no history of depression. Cell-mediated immunity (CMI) to VZV was measured before zoster vaccination or placebo and 6 weeks, 1 year, and 2 years later, with these results: “Depressed subjects who were not treated with antidepressant medications had lower levels of VZV-CMI following administration of zoster vaccine than nondepressed controls or depressed subjects receiving antidepressants even when antidepressant medications failed to alter depressive symptom severity (P < .005). Similar results were obtained taking into account the time-varying status of depression and use of antidepressant medications, as well as changes in depressive symptoms, during the postvaccination period.” (M. R. Irwin, mirwin1@ucla.edu)

>>>Health Affairs Highlights
Source:
Mar. issue of Health Affairs (2013; 32).
Medicaid Incentive Programs Targeting Healthy Behavior: Mixed results have emanated from three Medicaid incentive programs, according to an analysis of experiences to date (pp. 497–507). The programs were part of a 10-state project funded by CMS for $85 million. Results showed: “On the one hand, in Florida only about half of the $41.3 million in available credits was ‘claimed’ by enrollees between 2006 and 2011. On the other, Idaho’s incentive program was credited with improving the proportion of children who were up-to-date on well-child visits. Our findings suggest that Medicaid incentive programs should be designed so that enrollees can understand them and so that the incentives are attractive enough to motivate participation. Medicaid incentive programs also should be subject to rigorous evaluation to more clearly establish their effectiveness.” (K. J. Blumenthal, kjblumenthal@gmail.com)
Mortality Among American Women: Social and environmental determinants of health need to be addressed to counter rising mortality rates among women in 42.8% of U.S. counties, a study shows (pp. 451–8). Women had lower mortality rates if they had greater education, did not live in the South or West, and did not smoke. (D. A. Kindig, dakindig@wisc.edu)

>>>PNN NewsWatch
* Expanding an earlier action, Clinical Specialties Compounding Pharmacy of Augusta, GA, has now recalled all of its sterile products because of lack of sterility assurance, FDA said.

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

PNN Pharmacotherapy Line
Mar. 25, 2013 * Vol. 20, No. 57
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Mar. 23 issue of Lancet (2013; 381).
Folate Supplements & Cancer: A meta-analysis of studies of links between folic acid supplements and incidence of various cancers provides reassurance that inclusion of the nutrient in cereals and flour is safe (pp. 1029–36). The analysis included studies that used doses higher than those in fortified foods. Combined results from 13 trials of 49,621 participants showed: “During a weighted average scheduled treatment duration of 5.2 years, allocation to folic acid quadrupled plasma concentrations of folic acid (57.3 nmol/L for the folic acid groups vs 13.5 nmol/L for the placebo groups), but had no significant effect on overall cancer incidence (1,904 cancers in the folic acid groups vs 1,809 cancers in the placebo groups, RR 1.06, 95% CI 0.99–1.13, p = 0.10). There was no trend towards greater effect with longer treatment. There was no significant heterogeneity between the results of the 13 individual trials (p = 0.23), or between the two overall results in the cardiovascular prevention trials and the adenoma trials (p = 0.13). Moreover, there was no significant effect of folic acid supplementation on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site.” (R. Clarke, robert.clarke@ctsu.ox.ac.uk)
New TB Vaccine in Previously Vaccinated Infants: A new vaccine against tuberculosis was well tolerated but poorly effective in infants previously vaccinated with the BCG product, researchers report (pp. 1021–8). A modified Vaccinia Ankara virus expressing antigen 85A (MVA85A) was tested in a Phase IIb trial of infants ages 4–6 months, with these results: “Between July 15, 2009, and May 4, 2011, we enrolled 2,797 infants (1,399 allocated MVA85A and 1,398 allocated placebo). Median follow-up in the per-protocol population was 24.6 months (IQR 19.2–28.1), and did not differ between groups. More infants who received MVA85A than controls had at least one local adverse event (1,251 [89%] of 1,399 MVA85A recipients and 628 [45%] of 1,396 controls who received the allocated intervention) but the numbers of infants with systemic adverse events (1,120 [80%] and 1,059 [76%]) or serious adverse events (257 [18%] and 258 (18%) did not differ between groups. None of the 648 serious adverse events in these 515 infants was related to MVA85A. 32 (2%) of 1,399 MVA85A recipients met the primary efficacy endpoint [of incident tuberculosis] (tuberculosis incidence of 1.15 per 100 person–years [95% CI 0.79 to 1.62]; with conversion in 178 [13%] of 1,398 infants [95% CI 11.0 to 14.6]) as did 39 (3%) of 1,395 controls (1.39 per 100 person–years [1.00 to 1.91]; with conversion in 171 [12%] of 1,394 infants [10.6 to 14.1]). Efficacy against tuberculosis was 17.3% (95% CI –31.9 to 48.2) and against M tuberculosis infection was –3.8% (–28.1 to 15.9).” (M. D. Tameris, michele.tameris@uct.ac.za)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2013; 346).
High-Potency Statins & Acute Kidney Injury: Compared with low-potency statins, rosuvastatin, atorvastatin, and simvastatin in doses of 10, 20, and 40 mg or more, respectively, are associated with increased rates of diagnosis of acute kidney injury on hospital admission, according to a retrospective observational analysis of 2 million patients in Canadian, U.K., and U.S. administrative databases (f880): “In patients with non-chronic kidney disease, current users of high potency statins were 34% more likely to be hospitalized with acute kidney injury within 120 days after starting treatment (fixed effect rate ratio 1.34, 95% confidence interval 1.25 to 1.43).” (C. R. Dormuth, colin.dormuth@ti.ubc.ca)

>>>PNN NewsWatch
* FDA on Friday approved Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)-(Equine) (Cangene Corp.) to treat patients showing signs of botulism following documented or suspected exposure to botulinum neurotoxin. Also approved was a tobramycin inhaler, TOBI Podhaler (Novartis) for management of Pseudomonas aeruginosa in patients with cystic fibrosis.

>>>PNN JournalWatch
* Economic Costs of Diabetes in the U.S. in 2012, in
Diabetes Care, 2013; 36: 1033–46. (American Diabetes Association, mpetersen@diabetes.org)
* Wellness Incentives in the Workplace: Cost Savings Through Cost Shifting to Unhealthy Workers, in
Health Affairs, 2013; 32: 468–76. (J. R. Horwitz, Horwitz@law.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 © 2013, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, MA, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN. Quarterly files archived at www.PharmacotherapyNewsNetwork.com.

PNN Pharmacotherapy Line
Mar. 26, 2013 * Vol. 20, No. 58
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Mar. 25 issue of the JAMA Internal Medicine (2013; 173).
Oral Glucocorticoid Use & Acute Pancreatitis: In a population-based case–control study from Sweden, patients 40–84 years of age had higher risk of a first episode of acute pancreatitis when they were taking oral glucocorticoids, researchers report (pp. 444–9). Based on current, recent, and former use of glucocorticoids 30, 31–180, and after 180 days before an index date, respectively, investigators found these risk patterns among 6,161 cases of acute pancreatitis and 61,637 controls: “The risk of acute pancreatitis was increased among current users of oral glucocorticoids compared with nonusers (OR, 1.53; 95% CI, 1.27–1.84). This risk was highest 4 to 14 days after drug dispensation (OR, 1.73; 95% CI, 1.31–2.28) and attenuated thereafter. There was no association between oral glucocorticoid use and acute pancreatitis immediately after drug dispensation. There was no increased risk of acute pancreatitis among recent or former users of glucocorticoids compared with nonusers.” (O. Sadr-Azodi, mid.azodi@ki.se">omid.azodi@ki.se)
New Approach to Smoking Cessation: At 10 Houston-area family practice clinics, an Ask–Advise–Connect (AAC) approach significantly improved enrollment in smoking-cessation efforts over those achieved with an Ask–Advise–Refer (AAR) program, a study shows (pp. 458–64). For both approaches, “clinic staff were trained to assess and record the smoking status of all patients at all visits in the electronic health record, and smokers were given brief advice to quit,” the authors report. “In the AAC clinics, the names and telephone numbers of smokers who agreed to be connected were sent electronically to the quitline daily, and patients were called proactively by the quitline within 48 hours. In the AAR clinics, smokers were offered a quitline referral card and encouraged to call on their own.” Results showed: “In the AAC clinics, 7.8% of all identified smokers enrolled in treatment vs 0.6% in the AAR clinics (t4 = 9.19 [P < .001]; odds ratio, 11.60 [95% CI, 5.53–24.32]), a 13-fold increase in the proportion of smokers enrolling in treatment.” (J. I. Vidrine, jirvinvidrine@mdanderson.org)
Medication Adherence in Heart Failure: In a study of medication possession ratios (MPRs) in 306 Dartmouth hospital referral regions (HRRs), investigators found that higher rates of drug spending did not systematically produce better adherence to medications for heart failure (HF) (pp. 468–70). National Medicare Part D data from 2007–09 showed the following: “On average, 52% of patients had good adherence (MPR ≥0.8) for HF medications, but the proportion of having good adherence varied by area, from the lowest 36% to the highest 71%. There was similar variation in the intensity of medication treatment and adherence among HRRs. Drug spending varies more across HRRs than the number of prescriptions, partially owing to the mix of drugs used. For example, the area at the 90th percentile of drug spending had per-person drug spending that was 31% higher than the area at the 10th percentile of drug spending but had only 15% higher number of prescriptions. Drug spending was moderately positively [correlated] with intensity of treatment and the number of prescriptions (r = 0.19; P = .001) but had little correlation with adherence measures (r = 0.04; P = .44).” (Y. Zhang, ytzhang@pitt.edu)
Branding Through Professional Attire: Commenting on a study of patients and families regarding their preferences for attire of physicians (pp. 465–7; H. T. Stelfox, tstelfox@ucalgary.ca), commentary authors write (pp. 467–8): “As professionals, it is important to be aware that patients and families may be affected by our appearance and attire. In the absence of compelling reasons to wear nonprofessional attire, physicians should consider patient preferences in the interest of fostering comfort and trust. However, the impact of the white coat is attributable to its use over time and its recognizability as a brand label. Brand labels can be changed, and if the disadvantages of the white coat or any other professional symbol are demonstrated to outweigh their benefits, we should consider a different branding mechanism (eg, badges or other identifying attire). Finally, we should not oversell the importance of attire. While professional appearance might contribute to first impressions, professional behavior is likely to be far more important to patients and families.” (pp. 467–8). (M. C. Beach, mcbeach@jhmi.edu)

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

PNN Pharmacotherapy Line
Mar. 27, 2013 * Vol. 20, No. 59
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Mar. 27 issue of JAMA (2013; 309).
EDTA Chelation After Myocardial Infarction: A randomized trial fails to support routine use of disodium EDTA chelation therapy for reducing cardiovascular events after myocardial infarction (MI) (pp. 1241–50). Modestly improved outcomes support further research into the long-standing practice, investigators in the TACT Randomized Trial conclude, “but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.”
Patients randomly received 40 infusions of placebo or EDTA, ascorbate, B vitamins, electrolytes, procaine, and heparin over approximately 1 year. Based on a primary end point of a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina, results showed: “Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69–0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70–1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54–1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34–1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64–1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35–1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results.” (G. A. Lamas,
gervasio.lamas@msmc.com)
“Given the numerous concerns with this expensive, federally funded clinical trial, including missing data, potential investigator or patient unmasking, use of subjective end points, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and do not demonstrate a benefit of chelation therapy,” an editorialist writes in further arguing against routine use of EDTA (
pp. 1293–4). “The findings of TACT should not be used as a justification for increased use of this controversial therapy.” (S. E. Nissen, nissens@ccf.org)
Azithromycin, Erythromycin in Bronchiectasis: Two macrolide antibiotic regimens are assessed in adult patients with non–cystic fibrosis bronchiectasis.
Azithromycin 250 mg daily for 12 months was significantly better than placebo for reducing infectious exacerbations in the BAT (Bronchiectasis and Long-term Azithromycin Treatment) study (
pp. 1251–9): “Forty-three participants (52%) received azithromycin and 40 (48%) received placebo and were included in the modified intention-to-treat analysis. At end of study, the median number of exacerbations in the azithromycin group was 0 (interquartile range [IQR], 0–1), compared with 2 (IQR, 1–3) in the placebo group (P < .001). Thirty-two (80%) placebo-treated vs 20 (46%) azithromycin-treated individuals had at least 1 exacerbation (hazard ratio, 0.29 [95% CI, 0.16–0.51]).” (J. Altenburg, j.altenburg@mca.nl)
In the BLESS Randomized Controlled Trial, erythromycin ethylsuccinate 400 mg twice daily produced these changes in a primary outcome of annualized mean rate of protocol-defined pulmonary exacerbations (PDPEs) (
pp. 1260–7): “Six-hundred seventy-nine patients were screened, 117 were randomized (58 placebo, 59 erythromycin), and 107 (91.5%) completed the study. Erythromycin significantly reduced PDPEs both overall (mean, 1.29 [95% CI, 0.93–1.65] vs 1.97 [95% CI, 1.45–2.48] per patient per year; incidence rate ratio [IRR], 0.57 [95% CI, 0.42–0.77]; P = .003), and in the prespecified subgroup with baseline Pseudomonas aeruginosa airway infection (mean difference, 1.32 [95% CI, 0.19–2.46]; P = .02).” (D. J. Serisier, david.serisier@mater.org.au)
The “resistance price” may outweigh clinical benefits of daily antibiotic therapy, editorialists write (
pp. 1295–6). If antibiotics are used, the authors recommend appropriate baseline studies of cardiac, hearing, and liver function, and ongoing monitoring of antibiotic resistance in both patients and the community. (J. S. Elborn, s.elborn@qub.ac.uk)

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

PNN Pharmacotherapy Line
Mar. 28, 2013 * Vol. 20, No. 60
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Mar. 28 New England Journal of Medicine (2013; 368).
Darbepoetin Alfa in Systolic Heart Failure: In 2,278 patients with systolic heart failure and mild-to-moderate anemia, treatment with darbepoetin alfa failed to improve outcomes, according to investigators in the RED-HF trial (pp. 1210–9). Dosed to achieve a hemoglobin target of 13 g/dL, darbepoetin alfa produced these changes in a primary composite outcome of death from any cause or hospitalization for worsening heart failure: “The primary outcome occurred in 576 of 1,136 patients (50.7%) in the darbepoetin alfa group and 565 of 1,142 patients (49.5%) in the placebo group (hazard ratio in the darbepoetin alfa group, 1.01; 95% confidence interval, 0.90 to 1.13; P = 0.87). There was no significant between-group difference in any of the secondary outcomes. The neutral effect of darbepoetin alfa was consistent across all prespecified subgroups. Fatal or nonfatal stroke occurred in 42 patients (3.7%) in the darbepoetin alfa group and 31 patients (2.7%) in the placebo group (P = 0.23). Thromboembolic adverse events were reported in 153 patients (13.5%) in the darbepoetin alfa group and 114 patients (10.0%) in the placebo group (P = 0.01). Cancer-related adverse events were similar in the two study groups.” (K. Swedberg, karl.swedberg@gu.se)
Circulating Tumor DNA as Monitor of Metastatic Breast Cancer: In a proof-of-concept analysis, circulating tumor DNA proved to be “an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer” (pp. 1199–209). In 30 women with this condition, radiographic imaging of tumors combined with whole-genome sequencing, personalized assays of circulating tumor DNA, assays of cancer antigen (CA) 15-3, and counts of circulating tumor cells yielded these results: “Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%).” (C. Caldas, carlos.caldas@cruk.cam.ac.uk)
While expressing reservations and concluding that circulating tumor DNA requires further study and cost-effectiveness evaluation, editorialists are optimistic about the clinical and research utility of this approach (
pp. 1249–50): “Complete pathological remissions in patients treated with neoadjuvant therapies are not only reliably predictive of better outcomes but also were recently proposed by the Food and Drug Administration as a valid surrogate for drug approval. Nonetheless, some patients in whom a complete pathological remission is achieved eventually have a relapse, whereas others in whom such a remission is not achieved never have a recurrence. Perhaps assays of circulating tumor DNA, which has an impressive dynamic range, could more reliably predict patients who might not need further therapy or identify those with localized breast cancer who would be adequately treated by lumpectomy alone. The apparent high sensitivity of the assay suggests that it might be used to screen for recurrences in asymptomatic patients with previously diagnosed early-stage disease—although this potential use has not been proven to improve patient outcomes. Finally, identification of new mutations in circulating tumor DNA over time might inform the clinician about tumor evolution and provide evidence to support new treatment targets not identifiable in the primary tumor.” (M. Lippman)

>>>PNN NewsWatch
* FDA has approved dimethyl fumarate (Tecfidera, Biogen Idec) for oral treatment of adults with relapsing forms of multiple sclerosis (MS). Approved for first-line therapy, the agent is the first Nrf2 pathway activator on the U.S market. In clinical trials, dimethyl fumarate significantly reduced the proportion of patients with MS who relapsed by 49%, the annualized relapse rate by 53%, and 12-week confirmed disability progression by 38%, compared with placebo, over a 2-year period. White blood cell counts should be measured before and monitored for decreases during therapy. The most common adverse effects with dimethyl fumarate include flushing, nausea, vomiting, and diarrhea.

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

PNN Pharmacotherapy Line
Mar. 29, 2013 * Vol. 20, No. 61
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
Apr. issue of Diabetes Care (2013; 36).
myo-Inositol Supplements & Gestational Diabetes Mellitus: In 220 nonobese pregnant women with family histories of type 2 diabetes, use of the dietary supplement myo-inositol reduced the incidence of gestational diabetes mellitus (GDM) and fetal macrosomia, according to a 2-year, open-label study (pp. 854–7). Beginning at the end of their first trimester, participants received myo-inositol 2 g plus folic acid 200 mcg twice daily or folate alone, with these results: “Incidence of GDM was significantly reduced in the myo-inositol group compared with the placebo group: 6 vs. 15.3%, respectively (P = 0.04). In the myo-inositol group, a reduction of GDM risk occurrence was highlighted (odds ratio 0.35). A statistically significant reduction of fetal macrosomia in the myo-inositol group was also highlighted together with a significant reduction in mean fetal weight at delivery. In the other secondary outcome measures, there were no differences between groups.” (R. D’Anna, rosariodanna@tin.it)
After noting that
myo-inositol is present in many foods (fresh fruits and vegetables, beans, grains, nuts), an editorialist points out the potential impact of this finding if it is confirmed in larger, better controlled trials (pp. 777–9): “This study by D’Anna et al., along with earlier investigations of the effect of inositol supplementation on insulin resistance in GDM subjects and in preventing GDM in women with [polycystic ovary syndrome], lays the groundwork for more and larger studies to test the hypothesis that inositol supplementation can prevent GDM in the general pregnant population, including overweight and obese gravidas. myo-Inositol is inexpensive, particularly compared with most prescribed medications. If this intervention turns out to be safe and effective it could have a profound impact on improving pregnancy outcomes and lowering health care costs. If GDM diagnosed by the new ADA recommended criteria is preventable by an intervention such as this, the anticipated onslaught of new cases may be dampened considerably!” (D. R. Coustan, dcoustan@wihri.org)
Dispersed Insulin Injection Strategy: Effects of a fast-acting insulin analog were enhanced through use of nine dispersed injections of 2 units each, compared with a single injection of 18 units, researchers report (pp. 780–5). Before a clinical trial, insulin aspart was injected ex vivo into explanted abdominal skin flaps and the surface-to-volume ratio of the subcutaneous insulin depot was measured. In 12 patients with type 1 diabetes, a single injection of insulin aspart was then compared with a dispersed injection strategy in a euglycemic glucose clamp study, with these results: “The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08).” (T. R. Pieber, endo@medunigraz.at)
Medication Adherence Self-Reports: Easily administered self-reports of medication adherence proved valid in a study of adult patients taking oral medications for type 2 diabetes, but methods requiring reports of missing doses were “vulnerable to bias from depression severity” (pp. 831–7). Study participants completed a set of medication adherence self-reports with varied scales and time frames, and a subsample used Medication Event Monitoring System (MEMS) bottle caps. Results showed: “Participant (n = 170, 57% men, 81% white, mean HbA1c 8.3% [SD, 1.7]) adherence self-reports were significantly (r = −0.18 to −0.28; P < 0.03) associated with lower HbA1c. In the subsample (n = 88), all self-reports were significantly (r = 0.35 to 0.55; P ≤ 0.001) associated with MEMS-measured adherence. Depression significantly moderated the relationship between three of six self-reports and HbA1c.; at high levels of depression, associations with HbA1c. became nonsignificant.” (J. S. Gonzalez, jeffrey.gonzalez@einstein.yu.edu)

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