Jun 2010

PNN Quarterly File—Second Quarter 2010

PNN Pharmacotherapy Line
Apr. 1, 2010 * Vol. 17, No. 62
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 1 issue of the New England Journal of Medicine (2010; 362).
Whole-Genome Sequencing in Charcot–Marie–Tooth Neuropathy: The sequencing of individual patients’ entire genomes can be clinically useful, as exemplified by the identification of variants and diagnostic information among members of a family with a recessive form of Charcot–Marie–Tooth disease (pp. 1181–91). Investigators, after sequencing the whole genome of the first family member to present with neuropathy, identified and genotyped potentially related functional variants in family members, with these results: “We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot–Marie–Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome.” (R. A. Gibbs, agibbs@bcm.edu)
Noting that “individual genomes [are] on the horizon,” an editorialist provides this perspective on this study (
pp. 1235–6): “It is increasingly clear that the cost is fast approaching a threshold at which DNA sequencing will become a routine part of the diagnostic armamentarium. This raises many critical questions. Who will benefit from comprehensive sequencing? When in a person’s life should sequencing be done? How should we deal with the many variants of uncertain clinical significance? How should we interpret changes found outside of genes? How should we effectively communicate the results to patients in ways that will improve health without inducing neurosis? These questions have far-reaching implications for the education of health care professionals and patients as well as for health and social policy. [Authors of this study] provide a glimpse of the future for which we need to prepare.” (R. P. Lifton)
Risk of Prostate Cancer with Dutasteride: Over the 4 years of the REDUCE study, men taking dutasteride had a lower risk of incident prostate cancer and improved outcomes from benign prostatic hyperplasia (pp. 1192–202). Daily doses of 0.5 mg, compared with placebo, showed these results: “Among 6,729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3,305 men in the dutasteride group, as compared with 858 of the 3,424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P < 0.001).… Dutasteride therapy, as compared with placebo, resulted in a reduction in the rate of acute urinary retention (1.6% vs. 6.7%, a 77.3% relative reduction). The incidence of adverse events was similar to that in studies of dutasteride therapy for benign prostatic hyperplasia, except that in our study, as compared with previous studies, the relative incidence of the composite category of cardiac failure was higher in the dutasteride group than in the placebo group (0.7% [30 men] vs. 0.4% [16 men], P = 0.03).” (G. L. Andriole, andrioleg@wustl.edu)
An editorialist cautions against making clinical decisions based on this study (
pp. 1237–8): “Dutasteride and finasteride do not prevent prostate cancer but merely temporarily shrink tumors that have a low potential for being lethal, and they do not reduce the risk of a positive biopsy in patients who have an elevated PSA level (corrected for the effect of the drug) or an abnormal digital rectal examination.” (P. C. Walsh)

>>>PNN NewsWatch
* The antiparkinson product Stalevo may be associated with an increased risk of prostate cancer, FDA said yesterday. The Novartis product contains carbidopa/levodopa in combination with entacapone, which is also marketed by Novartis as the single-ingredient Comtan. Data from the Stalevo Reduction in Dyskinesia Evaluation–Parkinson’s Disease (STRIDE-PD) trial are being evaluated for further insights into increased development of prostate cancer by patients taking Stalevo, compared with carbidopa/levodopa alone.
*
Correction: In the article on biologic agents for rheumatoid arthritis in yesterday’s PNN, the first sentence should have stated that etanercept and adalimumab were more effective than infliximab, not adalimumab.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 2, 2010 * Vol. 17, No. 63
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
Apr. issue of Pediatrics (2010; 125).
Vitamin D Adherence, Status: Three articles assess aspects of vitamin D in pediatric patients and, in one study, their mothers.
Most U.S. infants are not consuming the currently recommended amounts of vitamin D, according to data from the Infant Feeding Practices Study II (
pp. 627–32). The 2005–07 data show these patterns based on the 2003 and 2008 recommendations of the American Academy of Pediatrics: “The use of oral vitamin D supplements was low, regardless of whether infants were consuming breast milk or formula, ranging from 1% to 13%, varying by age. Among infants who consumed breast milk but no formula, only 5% to 13% met either recommendation. Among mixed-fed infants, 28% to 35% met the 2003 recommendation, but only 9% to 14% would have met the 2008 recommendation. Among those who consumed formula but no breast milk, 81% to 98% met the 2003 recommendation, but only 20% to 37% would have met the 2008 recommendation.” (C. G. Perrine)
Suboptimal vitamin D status was common among 290 otherwise healthy low-income minority children in Atlanta, researchers report (
pp. 633–9). Data and serum samples collected during well-child visits showed low levels of 25-hydroxyvitamin D3 (< 30 ng/mL) in 96% of children. Older children were less likely to be deficient in the vitamin, as were children seen during spring and summer seasons. (C. R. Cole)
Similar findings come from a study of infants and mothers in Boston (
pp. 640–7). Among 459 mother/infant pairs in 2005–07, median 25-hydroxyvitamin D levels were 24.8 and 17.2 ng/mL among mothers and infants, respectively. Low levels of the vitamin were found in 30% of mothers who took prenatal vitamins, leading the authors to conclude that currently available products may not contain enough vitamin D. (A. Merewood)
Parental Concerns About Vaccine Safety: While acknowledging the effectiveness of vaccines in protecting children against disease, parents have concerns about vaccines—especially newer ones—that are not being adequately addressed, a national survey indicates (pp. 654–9). Conducted online in Jan. 2009, the survey of 2,521 parents with children currently younger than 18 years showed: “The response rate was 62%. Most parents agreed that vaccines protect their child(ren) from diseases; however, more than half of the respondents also expressed concerns regarding serious adverse effects. Overall, 11.5% of the parents had refused at least 1 recommended vaccine. Women were more likely to be concerned about serious adverse effects, to believe that some vaccines cause autism, and to have ever refused a vaccine for their child(ren). Hispanic parents were more likely than white or black parents to report that they generally follow their doctor’s recommendations about vaccines for their children and less likely to have ever refused a vaccine. Hispanic parents were also more likely to be concerned about serious adverse effects of vaccines and to believe that some vaccines cause autism.” (G. L. Freed)

>>>Psychiatry Report
Source:
Apr. issue of the American Journal of Psychiatry (2010; 167).
Neuroanatomy in ADHD: Responding to an article that describes morphologic abnormalities in the thalamic region of brains of youth with ADHD (pp. 397–408; I. Ivanov), an editorialist writes about “the shape of things to come” in research (pp. 363–5): “The study exemplifies the increasing sophistication of morphological studies as they incorporate novel measures of local shape, complexity, volume, and thickness and align structural MRI with other imaging modalities, such as the delineation of white matter tracts by diffusion tensor imaging and maps of brain activation generated by functional MRI (10). In structural neuroanatomic studies of ADHD, things are indeed shaping up well.” (P. Shaw)

>>>PNN NewsWatch
* State A/H1N1 influenza vaccination rates among people in the initial target groups ranged from 19.4% in Mississippi to 57.5% in Rhode Island, the CDC reports in today’s MMWR. The median vaccination rate in these groups between Oct. 2009 and Jan. 2010 was 33.2%. Vaccination rates were also low in Alabama, Georgia, and South Carolina, areas where infections have increased in recent weeks.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 5, 2010 * Vol. 17, No. 64
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 3 issue of Lancet (2010; 375).
Renal Outcomes with Benazepril, Amlodipine: Nephropathy is slowed in patients taking daily doses of benazepril 20 mg plus amlodipine 5 mg, compared with benazepril 20 mg plus hydrochlorothiazide 12.5 mg, according to the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial (pp. 1173–81). Clinicians should consider using the benazepril–amlodipine combination, the researchers conclude, based on these findings: “The trial was terminated early (mean follow-up 2.9 years [SD 0.4]) because of superior efficacy of benazepril plus amlodipine compared with benazepril plus hydrochlorothiazide. At trial completion, vital status was not known for 143 (1%) patients who were lost to follow-up (benazepril plus amlodipine, n = 70; benazepril plus hydrochlorothiazide, n = 73). All randomised patients were included in the [intention-to-treat] analysis. There were 113 (2.0%) events of chronic kidney disease progression in the benazepril plus amlodipine group compared with 215 (3.7%) in the benazepril plus hydrochlorothiazide group (HR 0.52, 0.41—0.65, p < 0.0001). The most frequent adverse event in patients with chronic kidney disease was peripheral oedema (benazepril plus amlodipine, 189 of 561, 33.7%; benazepril plus hydrochlorothiazide, 85 of 532, 16.0%). In patients with chronic kidney disease, angio-oedema was more frequent in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. In patients without chronic kidney disease, dizziness, hypokalaemia, and hypotension were more frequent in the benazepril plus hydrochlorothiazide group than in the benazepril plus amlodipine group.” (G. L. Bakris, gbakris@gmail.com)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 340).
Benefits of Treating Gestational Diabetes: Especially among women evaluated using a two-step screening process, gestational diabetes treatment prevents some perinatal complications, authors report (c1395): “Meta-analyses did not show significant differences for most single end points judged to be of direct clinical importance. In women specifically treated for gestational diabetes, shoulder dystocia was significantly less common (odds ratio 0.40, 95% confidence interval 0.21 to 0.75), and one randomised controlled trial reported a significant reduction of pre-eclampsia (2.5 v 5.5%, P = 0.02). For the surrogate end point of large for gestational age infants, the odds ratio was 0.48 (0.38 to 0.62). In the 13 randomised controlled trials of different intensities of specific treatments, meta-analysis showed a significant reduction of shoulder dystocia in women with more intensive treatment (0.31, 0.14 to 0.70).” (K. Horvath, Karl.Horvath@medunigraz.at)
Invasive Bacterial Disease in Malaria-Endemic Region: Current WHO guidelines failed to identify one-third of children with invasive bacterial disease and more than one-half of isolated organisms were not susceptible to currently recommended antimicrobials, according to a study conducted at a district hospital in a region of Tanzania where malaria is endemic (c1350): “Mortality among children with invasive bacterial disease was significantly higher (58/341, 17%) than in children without invasive bacterial disease (126/3298, 3.8%) (P < 0.001), and this was true regardless of the presence of Plasmodium falciparum parasitaemia. The sensitivity and specificity of WHO criteria in identifying invasive bacterial disease in slide positive children were 60.0% (95% confidence interval 58.0% to 62.1%) and 53.5% (51.4% to 55.6%), compared with 70.5% (68.2% to 72.9%) and 48.1% (45.6% to 50.7%) in slide negative children. In children with WHO criteria for invasive bacterial disease, only 99/211(47%) of isolated organisms were susceptible to the first recommended antimicrobial agent.” (H. Reyburn, Hugh.reyburn@lshtm.ac.uk)

>>>PNN JournalWatch
* Prevention of Hip Fractures in Long-Term Care: Relevance of Community-Derived Data, in Journal of the American Geriatrics Society, 2010; 58: 738–45. (R. Crilly, rcrilly@uwo.ca)
* Growth Hormone: Health Considerations Beyond Height Gain, in
Pediatrics, 2010; 125: e906–18. (J. Ross)
* Roles of the Akt/GSK-3 and Wnt Signaling Pathways in Schizophrenia and Antipsychotic Drug Action, in
American Journal of Psychiatry, 2010; 167: 388–96. (Z. Freyberg)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 6, 2010 * Vol. 17, No. 65
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and Apr. 6 issue of the Annals of Internal Medicine (2010; 152).
New CONSORT Guidelines: Improved wording, consistency, and numbering style are among the 2010 changes to the CONSORT (Consolidated Standards of Reporting Trials) guidelines, last released in 2001 (early release). Panelists developed “CONSORT 2010 to assist authors in writing reports of randomized, controlled trials, editors and peer reviewers in reviewing manuscripts for publication, and readers in critically appraising published articles,” the authors note. “The CONSORT 2010 Explanation and Elaboration provides elucidation and context to the checklist items. We strongly recommend using the explanation and elaboration in conjunction with the checklist to foster complete, clear, and transparent reporting and aid appraisal of published trial reports.” Changes made in the CONSORT 2010 statement are summarized in a box in the article, and guidelines for other types of clinical trials can be accessed on the CONSORT website. (K. F. Schulz)
Antipsychotic-Associated Pneumonia in the Elderly: A dose-dependent increase in risk of community-acquired pneumonia was identified with antipsychotic agents in a study of elderly patients in the Netherlands (pp. 418–25). Using a population-based, nested, case–control analysis of the Dutch Integrated Primary Care Information database, investigators found: “258 case patients with incident pneumonia were matched to 1,686 control participants. Sixty-five (25%) of the case patients died in 30 days, and their disease was considered fatal. Current use of either atypical (odds ratio [OR], 2.61 [95% CI, 1.48 to 4.61]) or typical (OR, 1.76 [CI, 1.22 to 2.53]) antipsychotic drugs was associated with a dose-dependent increase in the risk for pneumonia compared with past use of antipsychotic drugs. Only atypical antipsychotic drugs were associated with an increase in the risk for fatal pneumonia (OR, 5.97 [CI, 1.49 to 23.98]).” (G. Trifirò, g.trifiro@erasmusmc.nl)
Alcohol Consumption in Social Networks: Group-level interventions are supported for problematic drinking by results of a study of social networks of participants in the Framingham Heart Study (pp. 426–33). Based on information supplied between 1971 and 2003 by 12,067 people, the investigators identified these patterns for alcohol consumption and social networks: “Clusters of drinkers and abstainers were present in the network at all time points, and the clusters extended to 3 degrees of separation. These clusters were not only due to selective formation of social ties among drinkers but also seem to reflect interpersonal influence. Changes in the alcohol consumption behavior of a person’s social network had a statistically significant effect on that person’s subsequent alcohol consumption behavior. The behaviors of immediate neighbors and coworkers were not significantly associated with a person’s drinking behavior, but the behavior of relatives and friends was.” (N. A. Christakis, christakis@hcp.med.harvard.edu)
Quality of Gadolinium-Enhanced MRIs: Technically adequate images are difficult to obtain with gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography, a study shows (pp. 434-43). Based on images obtained at 7 hospitals for 371 adults with diagnosed or excluded pulmonary embolism, investigators reached this conclusion: “Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures.” (P. D. Stein, steinp@trinity-health.org)

>>>PNN NewsWatch
* A new formulation of OxyContin was approved yesterday by FDA. Abuse-prevention changes were made to the oxycodone product to make tablets more difficult to cut, break, chew, crush, or dissolve.
* At FDA’s request, U.S. Marshals last week seized creams, capsules, tablets, gum, throat spray, and shampoos from
Beehive Botanicals in Haywood, WI. FDA alleges that the company made disease claims for the products, making them misbranded and unapproved new drugs.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 7, 2010 * Vol. 17, No. 66
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 7 issue of JAMA (2010; 303).
Tapering Methotrexate in Juvenile Arthritis: While prolonged therapy with methotrexate did not change the relapse rate among 364 children with juvenile idiopathic arthritis, researchers were able to associate higher levels of myeloid-related proteins 8 and 14 heterocomplex (MRP8/14), a phagocyte activation marker, with relapse risk (pp. 1266–73). The patients, seen at 61 centers in 29 countries in 2005–2006, continued methotrxate therapy for 6 or 12 months after induction of disease remission, with these results: “Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82–1.27; P = .86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82–1.41; P = .61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320–1,110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220–800] ng/mL; P = .003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62–0.90).” (D. Foell, dfoell@uni-muenster.de)
Quality of Care Among Overweight, Obese Patients: In the Medicare and Veterans Health Administration systems, overweight and obese patients receive care similar to that of normal-weight individuals, researchers report (pp. 1274–81). Investigators analyzed Medicare data from 1994–2006 and VHA data from 2003–04, identifying these results: “We found no evidence that obese or overweight patients were less likely to receive recommended care relative to normal-weight patients. Moreover, success rates were marginally higher for obese and/or overweight patients on several measures. The most notable differentials were observed for recommended diabetes care among Medicare beneficiaries: comparing obese vs normal-weight patients with diabetes, obese patients were more likely to receive recommended care on lipid screening (72% vs 65%; odds ratio, 1.37 [95% confidence interval, 1.09–1.73]) and HbA1c testing (74% vs 62%; odds ratio, 1.73 [95% confidence interval, 1.41–2.11]). All analyses were adjusted for sociodemographic factors, health status, clinical complexity, and visit frequency.” (V. W. Chang, vwchang@mail.med.upenn.edu)
Challenges of Multiple Comorbidities: Efforts to address chronic diseases have resulted in “individual disease ‘silos’” that are “reinforced by specialty organizations, advocacy groups, disease management organizations, and government at all levels,” authors of a commentary write (pp. 1303–4). These must be transformed into an approach that addresses several chronic diseases, the writers argue, an effort that is now under way on the research side: “The 2009 American Recovery and Reinvestment Act (ARRA) directed $400 million to the secretary of Health and Human Services to pursue elements of a national strategy for comparative effectiveness (now also referred to as patient-centered health research). The Federal Coordinating Council for Comparative Effectiveness Research identified patients with multiple chronic conditions as a priority population for whom the secretary of Health and Human Services should consider allocating research funds. As a result of this process, approximately $20 million in ARRA funds has been allocated to increasing knowledge of effective management of this population and accelerating the rate of findings. This includes a new infrastructure-development grant of $12 million to stimulate the development of data sets and methodological advances that can be used for the study of complex patient populations. This grant program requires that applicants plan for making the infrastructure they develop widely available, including creating deidentified data sets accessible to other researchers.” (A. K. Parekh, anand.parekh@hhs.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 8, 2010 * Vol. 17, No. 67
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 8 issue of the New England Journal of Medicine (2010; 362).
Cisplatin plus Gemcitabine in Biliary Tract Cancer: In 410 patients with advanced or metastatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer, cisplatin plus gemcitabine provided a significant survival advantage over gemcitabine alone without additional substantial toxicity, according to results of the Advanced Biliary Cancer (ABC)-01 trial (pp. 1273–81). The 24-week study yielded these results: “After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin–gemcitabine group and 8.1 months among the 206 patients in the gemcitabine group (hazard ratio, 0.64; 95% confidence interval, 0.52 to 0.80; P < 0.001). The median progression-free survival was 8.0 months in the cisplatin–gemcitabine group and 5.0 months in the gemcitabine-only group (P < 0.001). In addition, the rate of tumor control among patients in the cisplatin–gemcitabine group was significantly increased (81.4% vs. 71.8%, P = 0.049). Adverse events were similar in the two groups, with the exception of more neutropenia in the cisplatin–gemcitabine group; the number of neutropenia-associated infections was similar in the two groups.” (J. Bridgewater, j.bridgewater@ucl.ac.uk)
This study changes practice, editorialists write (
pp. 1335–7): “The results of the ABC-02 trial indicate that the cisplatin–gemcitabine combination should be considered a standard treatment option for patients with advanced biliary tract cancer. In addition, it shows that collaboration (in this case, among 37 centers in the United Kingdom) can permit progress in the treatment of a relatively uncommon group of cancers. Although this 3-month extension in survival among patients with biliary tract cancer is modest, it is a definite step forward. Further meaningful advances will depend on a better understanding of the molecular events that promote the development and sustain the growth of biliary tract cancer. With ABC-02, Valle and colleagues have provided an important foundation on which future clinical trials in biliary tract cancer can be built.” (B. M. Wolpin)
Vitamins C, E in Pregnancy-Associated Hypertension: Complications of pregnancy-associated hypertension were unaffected by vitamin C and E supplementation during weeks 9 through 16, researchers report (pp. 1282–91). Comparing daily doses of vitamin C 1,000 mg and vitamin E 400 IU with placebo, the investigators found: “A total of 10,154 women underwent randomization. The two groups were similar with respect to baseline characteristics and adherence to the study drug. Outcome data were available for 9,969 women. There was no significant difference between the vitamin and placebo groups in the rates of the primary outcome (6.1% and 5.7%, respectively; relative risk in the vitamin group, 1.07; 95% confidence interval [CI], 0.91 to 1.25) or in the rates of preeclampsia (7.2% and 6.7%, respectively; relative risk, 1.07; 95% CI, 0.93 to 1.24). Rates of adverse perinatal outcomes did not differ significantly between the groups.” (J. M. Roberts)

>>>PNN NewsWatch
* Clinicians need to be aware of the approximately 10% difference in potency between “old” and “new” heparin products, FDA warned yesterday. Products labeled under the new USP monograph have less anticoagulant activity than those produced under the older standard (see PNN, Oct. 2, 2009).
* FDA has issued several warnings this week.
Stud Capsule for Men (Kanec USA), lot 060607-01/060108-01, expiring 6/2013, is being recalled nationally because it contains sildenafil, the Agency said. FDA also reported that US Oftalmi is voluntarily recalling all of its OTC eye and nasal drops—including four Camolyn products and Fisiolin Nasal Drops—because of manufacturing problems that could affect sterility. Warning letters have been sent to six medical spas in the U.S. and a company in Brazil about “false or misleading statements on their Web sites about drugs they claim will eliminate fat in a procedure called ‘lipodissolve’ or for otherwise misbranding lipodissolve products.”

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 9, 2010 * Vol. 17, No. 68
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
Apr. 13 issue of the Journal of the American College of Cardiology (2010; 55).
Dronedarone for Atrial Fibrillation: Two articles examine clinical utility of the new antiarrhythmic agent dronedarone.
Available data support use of dronedarone in “select patient populations as a second- or third-line agent,” authors of a viewpoint article conclude (
pp. 1569–76): “Dronedarone is a new antiarrhythmic agent that was recently approved for the prevention of cardiovascular hospitalization driven by atrial fibrillation/flutter. Its approval was based largely on the results of the ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter) trial, which demonstrated a significant 24% reduction in the combined end point of all-cause mortality and cardiovascular hospitalization, primarily driven by the latter. However, several other clinical trials have evaluated the impact of dronedarone on various cardiovascular end points and yielded mixed results. In this article, we summarize the available evidence concerning dronedarone, and offer practical recommendations to health care providers regarding its use in the treatment of atrial fibrillation.” (S. Kaul, kaul@cshs.org)
Recalling the “safety first” mantra of an old flecainide advertisement, commentary authors provide this assessment of mortality associated with dronedarone (
pp. 1577–9): “Four placebo-controlled studies of atrial fibrillation used a dronedarone dose of 800 mg daily. In total, these document 125 dead among 3,214 patients randomly allocated to dronedarone and 142 deaths among 2,825 randomly allocated to placebo. The ANDROMEDA study conducted with heart failure patients was terminated early because of increased mortality. Dronedarone reduced cardiovascular hospitalizations among patients by 24% in the ATHENA study, and such a direct clinical benefit has not been demonstrated for any other antiarrhythmic drug.
“Singh et al. [in the above viewpoint] provide many calculations of 95% significance interval for mortality in various subgroups treated with dronedarone. It should be noted that any attempt to make such calculations for other available antiarrhythmic drugs would result in confidence limits that include very high risks. If ‘safety first’ is the issue, the data for dronedarone are superior to those of other antiarrhythmic drugs for low/moderate-risk patients.” (C. Torp–Pedersen,
ctp@heart.dk)
Mipomersen for Hypercholesterolemia: An injectable antisense inhibitor of apolipoprotein B, mipomersen showed promise for reducing LDL cholesterol levels in patients with hypercholesterolemia who were already on stable statin therapy (pp. 1611–8). In a dose-escalation Phase II trial, investigators enrolled 74 participants. Various doses of the new drug produced these changes in serum apolipoprotein B and LDL cholesterol concentrations: “The apo B and LDL cholesterol were reduced by 19% to 54% and 21% to 52%, respectively, at doses of 100 mg/week mipomersen and higher in the 5-week treatment cohorts. Efficacy seemed to increase upon treatment for 13 weeks at a dose of 200 mg/week. Injection site reactions (mild to moderate erythema [90%]) and hepatic transaminase increases (17%) were the most common adverse events, leading to discontinuation in 2 subjects and 1 subject, respectively. In the 13-week treatment cohort, 5 of 10 subjects (50%) had elevations 3x the upper limit of normal, 4 of which persisted on 2 consecutive occasions.” (J. J. P. Kastelein, J.J.Kastelein@amc.uva.nl)

>>>PNN NewsWatch
* In a letter responding to a inquiry about the antibacterial agent triclosan by Rep. Edward J. Markey, a Massachusetts Democrat who chairs the House Energy and Commerce Subcommittee on Energy and the Environment, FDA said that it is conducting an ongoing scientific review into the safety of this compound. Triclosan is used in antibacterial soaps and body washes, toothpastes, and some cosmetics, and may also be found in a wide variety of other consumer products, such as clothing, kitchenware, furniture, and toys, according to FDA.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 12, 2010 * Vol. 17, No. 69
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 10 issue of Lancet (2010; 375).
Blood Pressure & Inhibition of Angiotensin II Receptor, Neprilysin: LCZ696, a first in class inhibitor of the angiotensin II receptor and the enzyme neprilysin, “holds promise for treatment of hypertension and cardiovascular disease,” investigators conclude based on a study of 1,328 patients in an active-comparator study (pp. 1255–66). Participants had mild or moderate hypertension. For 8 weeks, they received either placebo or one of several doses of LCZ696 or valsartan, with these results: “1,215 patients completed the 8-week treatment period. The average reduction in mean sitting diastolic blood pressure across the doses of LCZ696 versus the appropriate comparator dose of valsartan showed significantly greater reductions with LCZ696 (mean reduction: –2.17 mm Hg, 95% CI –3.28 to –1.06; p < 0.0001). The reduction in mean sitting diastolic blood pressure was significantly different for 200 mg LCZ696 versus 160 mg valsartan (–2.97 mm Hg, 95% CI –4.88 to –1.07, p = 0.0023) and for 400 mg LCZ696 versus 320 mg valsartan (–2.70 mm Hg, –4.61 to –0.80, p = 0.0055). LCZ696 was well tolerated and no cases of angio-oedema were reported; only three serious adverse events occurred during the 8-week treatment period, of which none was judged to be related to the study drug, and no patients died.” (L. M. Ruilope, ruilope@ad-hocbox.com)
Adjuvant Chemotherapy in Operable Non-Small-Cell Lung Cancer: Survival is improved through addition of adjuvant chemotherapy to treatment of patients with non-small-cell lung cancer, regardless of whether radiotherapy is used, according to two meta-analyses of published trials (pp. 1267–77): “The first meta-analysis of surgery plus chemotherapy versus surgery alone was based on 34 trial comparisons and 8,447 patients (3,323 deaths). We recorded a benefit of adding chemotherapy after surgery (hazard ratio [HR] 0.86, 95% CI 0.81—0.92, p < 0.0001), with an absolute increase in survival of 4% (95% CI 3–6) at 5 years (from 60% to 64%). The second meta-analysis of surgery plus radiotherapy and chemotherapy versus surgery plus radiotherapy was based on 13 trial comparisons and 2,660 patients (1,909 deaths). We recorded a benefit of adding chemotherapy to surgery plus radiotherapy (HR 0.88, 95% CI 0.81–0.97, p = 0.009), representing an absolute improvement in survival of 4% (95% CI 1–8) at 5 years (from 29% to 33%). In both meta-analyses we noted little variation in effect according to the type of chemotherapy, other trial characteristics, or patient subgroup.” (NSCLC Meta-analyses Collaborative Group)
TMP-SMX in HIV Infection: A study supports WHO recommendations for provision of trimethoprim–sulfamethoxazole for 72 weeks to African patients with HIV infections who are starting antiretroviral therapy (pp. 1278–86). In 3,179 patients, 14,214 years of follow-up produced these findings: “Present prophylaxis significantly reduced mortality (odds ratio 0.65, 95% CI 0.50–0.85; p = 0.001). Mortality risk reduction on ART was substantial to 12 weeks (0.41, 0.27–0.65), sustained from 12–72 weeks (0.56, 0.37–0.86), but not evident subsequently (0.96, 0.63–1.45; heterogeneity p = 0.02). Variation in mortality reduction was not accounted for by time on co-trimoxazole or current CD4 cell count. Prophylaxis reduced frequency of malaria (0.74, 0.63–0.88; p = 0.0005), an effect that was maintained with time, but we observed no effect on new WHO stage 4 events (0.86, 0.69–1.07; p = 0.17), CD4 cell count (difference vs non-users, –3 cells per µL [–12 to 6]; p = 0.50), or BMI (difference vs non-users, –0.04 kg/m2 [–0.20 to 0.13); p = 0.68].” (A. S. Walker, asw@ctu.mrc.ac.uk)

>>>PNN JournalWatch
* Advance Provision of Emergency Contraception for Pregnancy Prevention, in Cochrane Library, 2010(2): CD005497. DOI: 10.1002/14651858.CD005497.pub2. (C. B. Polis, cpolis@jhsph.edu)
* New Anticoagulants, in
Circulation, 2010; 121: 1523–32. (J. Weitz, jweitz@thrombosis.hhscr.org)
* Novel Asthma-Associated Genes from Genome-Wide Association Studies: What Is Their Significance?, in
Chest, 2010; 137: 909–15. (Mi. Kabesch, Kabesch.Michael@mh-hannover.de)
* Clinical Management of Pandemic 2009 Influenza A(H1N1) Infection, in
Chest, 2010; 137: 916–25. (D. S. Hui, dschui@cuhk.edu.hk)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 13, 2010 * Vol. 17, No. 70
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 12 issue of the Archives of Internal Medicine (2010; 170).
Influenza Vaccination & Warfarin Therapy: Among 104 patients on stable vitamin K antagonist (VKA) therapy, influenza vaccination had no effect on INR values or weekly doses of warfarin sodium, researchers report (pp. 609–16). Patients received influenza vaccination and subsequent placebo administration, or vice versa, with these results: “Similar mean prothrombin times, expressed as the INR and VKA weekly dose, were found in patients after receiving vaccine or placebo. The absence of any vaccination effect on VKA treatment was confirmed using a linear mixed-effects model. The percentages of time that patients were in therapeutic range were 70.7% after receiving vaccine and 72.4% after receiving placebo (P = .57). There were no fatal or major bleeding events and 11 minor mucocutaneous hemorrhagic events. After vaccination, the percentage of seroprotected patients ranged from 92.0% to 100.0% depending on the vaccine antigen examined.” (A. Iorio, iorioa@unipg.it)
GI Bleeding from Warfarin, Urinary Antibiotic Therapy: Hemorrhage risk is increased during urinary antibiotic therapy in patients on warfarin, according to a population-based, nested case–control analysis of health care databases in Ontario in 1997–2007 (pp. 617–21). All patients included as cases were 66 years or older and had been hospitalized for upper gastrointestinal (UGI) tract hemorrhage. Comparing 10 age- and sex-matched control patients with each case, the researchers found: “We identified 134,637 patients receiving warfarin, of whom 2,151 cases were hospitalized for UGI tract hemorrhage. Cases were almost 4 times more likely than controls to have recently received cotrimoxazole (aOR, 3.84; 95% confidence interval [CI], 2.33–6.33). Treatment with ciprofloxacin was also associated with increased risk (aOR, 1.94; 95% CI, 1.28–2.95), but no significant association was observed with amoxicillin or ampicillin (1.37; 0.92–2.05), nitrofurantoin (1.40; 0.71–2.75), or norfloxacin (0.38; 0.12–1.26). Compared with amoxicillin or ampicillin, cotrimoxazole prescription was associated with an almost 3-fold risk (ratio of ORs, 2.80; 95% CI, 1.48–5.32).” (H. D. Fischer, Hadas.fischer@ices.on.ca)
Teleintensivist Impact on Ventilator Use: A health information technology bundle (HITB) with remote intensivist coverage (RIC) significantly improved mortality and reduced ventilator use among critically ill patients in a community hospital, a study shows (pp. 648–53). Teleintensivists were used at night to supplement daytime coverage by onsite critical care specialists, with these results: “A total of 954 control patients who received care for 16 months before the implementation of HITB-RIC and 959 study patients who received care for 10 months after the implementation were included in the analysis. Mortality for the control and intervention groups were 21.4% and 14.7%, respectively. In addition, the observed mortality for the intervention group was 75.8% (P < .001) of that predicted by the Acute Physiology and Chronic Health Evaluation IV hospital mortality equations, which was 29.5% lower relative to the control group. Regression results confirm that the hospital mortality of the intensive care unit patients was significantly lower after implementation of the intervention, controlling for predicted risk of mortality and do-not-resuscitate status. Overall, intervention patients also had significantly less (P = .001) use of mechanical ventilation, controlling for body-system diagnosis category and severity of illness.” (H. D. Paxton, Hannah_D.Paxton@lvhn.org)
CER, HCR, & the Future of Innovation: A Merck physician and pharmacist write about the impact of comparative effectiveness research and health care reform on biomedical innovation (pp. 596–9): “The challenges facing health care in the United States are significant. The ability to provide quality care to as many Americans as possible requires a value-based approach, incorporating evidence-based recommendations, effective health care provider implementation of these recommendations, and engaging patients with dignity and respect for individual preferences. We believe that well-done CER is a critical piece underlying this value-based approach, both for pharmaceuticals as well as for many other components of health care. We look forward to working in such an environment, one that we hope will balance quality, cost, and continued innovation, to the benefit of all people.” (R. K. Murray, richard_murray@merck.com)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 14, 2010 * Vol. 17, No. 71
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 14 issue of JAMA (2010; 303).
Suicide Risk with Anticonvulsants: Patients taking any of several anticonvulsant agents are at increased risk of suicidal acts or violent deaths, according to a cohort study of patients aged 15 years or older in the HealthCore Integrated Research Database (pp. 1401–9). Therapy begun with an anticonvulsant in 2001–06 showed these trends, relative to topiramate: “The study identified 26 completed suicides, 801 attempted suicides, and 41 violent deaths in 297,620 new episodes of treatment with an anticonvulsant (overall median follow-up, 60 days). The incidence of the composite outcomes of completed suicides, attempted suicides, and violent deaths for anticonvulsants used in at least 100 treatment episodes ranged from 6.2 per 1,000 person–years for primidone to 34.3 per 1,000 person–years for oxcarbazepine. The risk of suicidal acts was increased for gabapentin (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.11–1.80), lamotrigine (HR, 1.84; 95% CI, 1.43–2.37), oxcarbazepine (HR, 2.07; 95% CI, 1.52–2.80), tiagabine (HR, 2.41; 95% CI, 1.65–3.52), and valproate (HR, 1.65; 95% CI, 1.25–2.19), compared with topiramate. The analyses including violent death produced similar results. Gabapentin users had increased risk in subgroups of younger and older patients, patients with mood disorders, and patients with epilepsy or seizure when compared with carbamazepine.” (E. Patorno, epatorno@partners.org)
Seroconversion During A/H1N1 Influenza Epidemic: In Singapore, just 13% of the population seroconverted during last summer’s wave of influenza A/H1N1 before the epidemic subsided, researchers report (pp. 1383–91). The finding supports the possibility that targeted vaccinations could be enough to interrupt the transmission cycle in a population, the authors suggest, adding these details about their June through Oct. 2009 data: “Baseline titers of 40 or more were observed in 22 members (2.6%; 95% confidence interval [CI], 1.7%–3.9%) of the community, 114 military personnel (9.4%; 95% CI, 7.9%–11.2%), 37 hospital staff (6.6%; 95% CI, 4.8%–9.0%), and 20 participants from long-term care facilities (6.7%; 95% CI, 4.4%–10.1%). In participants with 1 or more follow-up serum samples, 312 military personnel (29.4%; 95% CI, 26.8%–32.2%) seroconverted compared with 98 community members (13.5%; 95% CI, 11.2%–16.2%), 35 hospital staff (6.5%; 95% CI, 4.7%–8.9%), and only 3 long-term care participants (1.2%; 95% CI, 0.4%–3.5%). Increased frequency of seroconversion was observed for community participants from households in which 1 other member seroconverted (adjusted odds ratio [OR], 3.32; 95% CI, 1.50–7.33), whereas older age was associated with reduced odds of seroconversion (adjusted OR, 0.77 per 10 years; 95% CI, 0.64–0.93). Higher baseline titers were associated with decreased frequency of seroconversion in community (adjusted OR for every doubling of baseline titer, 0.48; 95% CI, 0.27–0.85), military (adjusted OR, 0.71; 95% CI, 0.61–0.81), and hospital staff cohorts (adjusted OR, 0.50; 95% CI, 0.26–0.93).” (M. I. C. Chen, mark_chen@ttsh.com.sg)
Adverse Effects of Antidiabetic Drugs: Added to maximal metformin therapy, noninsulin antidiabetic drugs reduce glycemic levels similarly but differ in their effects on weight gain and risk of hypoglycemia, according to a Clinician’s Corner review article (pp. 1410–8). Thiazolidinediones, sulfonylureas, and glinides produced weight gain of 1.77 to 2.08 kg, according to data from 27 studies, and the latter two agents had increased rates of hypoglycemia. (C. I. Coleman, ccolema@harthosp.org)

>>>PNN NewsWatch
* Inhalers with ozone-depleting chlorofluorocarbons will be removed from the U.S. market over a 3-year period beginning this June, FDA said yesterday. June 14 is the last date for manufacturing, selling, or dispensing Tilade Inhaler (nedocromil) and Alupent Inhalation Aerosol (metaproterenol). Azmacort Inhalation Aerosol (triamcinolone) and Intal Inhaler (cromolyn) will be removed on Dec. 31 of this year, and sales of Aerobid Inhaler System (flunisolide) will stop on June 30, 2011. On the last day of 2013, Combivent Inhalation Aerosol (albuterol/ipratropium) and Maxair Autohaler (pirbuterol) will be phased out, completing the U.S. pharmaceutical commitments to the Montreal Protocol on Substances that Deplete the Ozone Layer.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 15, 2010 * Vol. 17, No. 72
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 15 New England Journal of Medicine (2010; 362).
Lenient v. Strict Rate Control in AF: Among 614 patients with permanent atrial fibrillation, clinical outcomes were similar with strict versus lenient rate control, but the latter was easier to achieve, researchers report (pp. 1363–73). The lenient rate control targeted a resting heart rate of less than110 bpm, while strict rate control sought to achieve a resting heart rate of less than 80 bpm and heart rate during moderate exercise of 110 bpm. Using a primary composite outcome of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events, the investigators found these results over 2–3 years: “The estimated cumulative incidence of the primary outcome at 3 years was 12.9% in the lenient-control group and 14.9% in the strict-control group, with an absolute difference with respect to the lenient-control group of –2.0 percentage points (90% confidence interval, –7.6 to 3.5; P < 0.001 for the prespecified noninferiority margin). The frequencies of the components of the primary outcome were similar in the two groups. More patients in the lenient-control group met the heart-rate target or targets (304 [97.7%], vs. 203 [67.0%] in the strict-control group; P < 0.001) with fewer total visits (75 [median, 0], vs. 684 [median, 2]; P < 0.001). The frequencies of symptoms and adverse events were similar in the two groups.” (I. C. Van Gelder, i.c.van.gelder@thorax.umcg.nl)
Several clinical inferences can be drawn from this trial, an editorialist writes (
pp. 1439–41): “First, a heart-rate target of less than 110 beats per minute at rest, although it may make physicians feel uncomfortable, is probably as useful as the current guideline-recommended target heart rates at rest and during exercise, at least in the medium term. Many patients will continue to be symptomatic under the rate-control approach, whether a strict or more lenient target heart rate is used. The RACE II study does not suggest that ventricular rate control is not needed, only that the conventional therapeutic target needs to be reassessed. At a minimum, the study indicates that reflexive, ‘recipe-based’ adherence to a rate-control target does not seem sensible and that an approach emphasizing the adjustment of therapy on the basis of symptoms and general well-being can be safely recommended.” (P. Dorian)
Treatment of Crohn’s Disease: Patients with moderate or severe Crohn’s disease have a greater chance of achieving corticosteroid-free remission when azathioprine and infliximab are used together, a study shows (pp. 1383–95). Comparing combination therapy with monotherapy using each of the two agents, researchers found: “Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P = 0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P < 0.001 for the comparison with combination therapy and P = 0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P = 0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P < 0.001 for the comparison with combination therapy and P = 0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group.” (W. J. Sandborn, sandborn.william@mayo.edu)
Alglucosidase Alfa in Late-Onset Pompe’s Disease: Alglucosidase alfa improved walking distance and stabilized pulmonary function over an 18-month period in 90 pediatric and adult patients with late-onset Pompe’s disease (pp. 1396–406). After 78 weeks of treatment, 6-minute walk times improved by a mean of 28.1 meters in the alglucosidase alfa group, compared with placebo. Forced vital capacity increased by an average of 3.4 percentage points. Adverse events, serious adverse events, and infusion-associated reactions were similar in the two groups. Urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure occurred only in patients taking active drug. (A. T. van der Ploeg, a.vanderploeg@erasmusmc.nl)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 16, 2010 * Vol. 17, No. 73
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
Apr. issue of the Journal of Allergy and Clinical Immunology (2010; 125).
Use of Influenza Vaccine in Patients with Egg Allergy: Responding to an article in the Mar. issue of JACI on ovalbumin content in 2009–10 seasonal and H1N1 monovalent influenza vaccines (pp. 749–751.e1), an editorialist supports cautious use of influenza vaccine in those with egg allergy (pp. 800–2): “Patients with egg allergy for whom influenza vaccine is indicated can and should be vaccinated to decrease the morbidity and mortality associated with the disease. Based on available data, consideration can be given to administering a vaccine with a stated ovalbumin content of less than 1 µg per 0.5-mL dose [a table is provided in the article with this information] as a single dose without prior vaccine skin testing. Such immunization should take place in a setting in which personnel and equipment are available to recognize and treat anaphylaxis. Future studies are needed to validate this approach. When a low-ovalbumin vaccine is not available or in the case of more severe egg allergy, a more conservative approach might be warranted.” (J. M. Kelso, kelso.john@scrippshealth.org)
Mepolizumab in Hypereosinophilic Syndromes & Asthma: Mepolizumab, an anti-interleukin-5 monoclonal antibody, may be effective for long-term treatment of patients with selected eosinophilic disorders, conclude authors of a review article (pp. 803–13): “The hypereosinophilic syndromes (HESs) are a heterogeneous group of diseases characterized by peripheral blood eosinophilia with end-organ damage and varying in severity from nonspecific symptoms to life-threatening. Treatment objectives are a safe reduction of blood and tissue eosinophil levels and prevention of eosinophil-mediated tissue damage. Current treatment of patients with HESs, who lack the FIP-1–like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) fusion gene, is mainly systemic corticosteroid therapy. Eosinophil development from hematopoietic progenitor cells is regulated by IL-5, which influences maturation, differentiation, mobilization, activation, and survival. Consequently, inhibiting IL-5 is a logical therapeutic objective for patients with HESs or selected patients with asthma. Mepolizumab is a fully humanized anti–IL-5 monoclonal IgG1 antibody that binds to free IL-5 with high affinity and specificity to prevent IL-5 from associating with the IL-5 receptor complex alpha-chain on the surface of eosinophils. In clinical trials with patients with HESs, mepolizumab reduced blood eosinophil counts and the maintenance corticosteroid dose and had no major safety concerns. Mepolizumab reduced airway and blood eosinophils and prevented asthma exacerbations.” (W. W. Busse, wwb@medicine.wisc.edu)

>>>Infectious Disease Report
Source:
May 1 issue of Clinical Infectious Diseases (2010; 50).
Treatment Options in Schistosomiasis: In patients coinfected by organisms causing malaria and schistosomiasis, use of a combination of mefloquine and artesunate appears to enable patients to clear the malaria parasitemia and have less morbidity with schistosomiasis, researchers report (pp. 1205–13). In an open-label trial, these results were reported: “A total of 83 [Schistosoma] haematobium–infected schoolchildren were included in the study. Cure rates of mefloquine, artesunate, mefloquine–artesunate, and praziquantel against S. haematobium at day 26 after treatment were 21%, 25%, 61%, and 88%, respectively. Both mefloquine–artesunate and praziquantel resulted in egg reduction rates >95%. Significantly lower egg reduction rates were seen in the artesunate (85%) and mefloquine groups (74%). In children coinfected with S. mansoni, praziquantel and mefloquine–artesunate, but not mefloquine and artesunate alone, resulted in high cure rates and egg reduction rates. Mefloquine, artesunate, and mefloquine–artesunate completely cured infections due to Plasmodium falciparum. No effects were found against soil-transmitted helminths and intestinal protozoa. Abdominal pain was the most frequent adverse event, with a higher incidence among children treated with mefloquine (89%), mefloquine–artesunate (83%), and artesunate (60%) than among children treated with praziquantel (46%).” (J. Keiser, jennifer.keiser@unibas.ch)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 19, 2010 * Vol. 17, No. 74
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 17 issue of Lancet (2010; 375).
Alcohol Pricing & Health: Especially for people with drinking problems, alcohol-pricing policies can have significant effects on health and health economic outcomes, researchers report (pp. 1355–64). Using an epidemiologic model to assess 18 pricing policies, investigators relied on English data from the Expenditure and Food Survey and the General Household Survey for average and peak alcohol consumption to make these calculations: “General price increases were effective for reduction of consumption, health-care costs, and health-related quality of life losses in all population subgroups. Minimum pricing policies can maintain this level of effectiveness for harmful drinkers while reducing effects on consumer spending for moderate drinkers. Total bans of supermarket and off-license discounting are effective but banning only large discounts has little effect. Young adult drinkers aged 18–24 years are especially affected by policies that raise prices in pubs and bars.” (R. C. Purshouse, r.purshouse@sheffield.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 340).
Preventive Care Outreach & Quality of Life: In a target population of high-risk adults, a provider-initiated primary care outreach effort failed to significantly affect quality-adjusted life years (QALYs), use and costs of health and social services, functional status, self-rated health, or mortality (c1480). Among 719 patients aged 75 years or older and not receiving home-care services, a 12-month intervention consisted of visits by home-care nurses, assessment and collaborative care planning, health promotion, and referrals as needed. Results showed: “The mean difference in QALYs between intervention and control patients during the study period was not statistically significant (0.017, 95% confidence interval –0.022 to 0.056; P = 0.388). The mean difference in overall cost of prescription drugs and services between the intervention and control groups was not statistically significant, (–$C165 (£107; 118 euros; $162), 95% confidence interval –$C16,545 to $C16,214; P = 0.984). Changes over 12 months in functional status and self rated health were not significantly different between the intervention and control groups. Ten patients died in each group.” (J. Ploeg, ploegj@mcmaster.ca)
Challenges in Blood Pressure Measurement: Using 24-hour ambulatory blood pressure monitoring, researchers identify a new framework for diagnosis and management of hypertension (c1104). At 11 Australian centers, data show differences in blood pressure measurements obtained through ambulatory measurement, physician office staff, and physicians: “Mean age of [8,575] participants was 56 years (SD 15) with mean body mass index 28.9 (5.5) and mean clinic systolic/diastolic blood pressure 142/82 mm Hg (19/12); 4,626 (54%) were women. Average clinic measurements by trained staff were 6/3 mm Hg higher than daytime ambulatory blood pressure and 10/5 mm Hg higher than 24 hour blood pressure, but 9/7 mm Hg lower than clinic values measured by doctors. Daytime ambulatory equivalents derived from trained staff clinic measurements were 4/3 mm Hg less than the 140/90 mm Hg clinic threshold (lower limit of grade 1 hypertension), 2/2 mm Hg less than the 130/80 mm Hg threshold (target upper limit for patients with associated conditions), and 1/1 mm Hg less than the 125/75 mm Hg threshold. Equivalents were 1/2 mm Hg lower for women and 3/1 mm Hg lower in older people compared with the combined group.” (G. A. Head, geoff.head@baker.edu.au)

>>>PNN JournalWatch
* The Dawn of a New Era: Transforming Our Domestic Response to Hepatitis B & C, in Gastroenterology, 2010; 138: 1225–30.e3. (H. El-Serag, hasheme@bcm.tmc.edu)
* Genetic Approaches to Functional Gastrointestinal Disorders, in
Gastroenterology, 2010; 138: 1276–85. (E. A. Mayer, emayer@ucla.edu)
* Epidemiology of Gout in Women: Fifty-Two-Year Followup of a Prospective Cohort, in
Arthritis & Rheumatism, 2010; 62: 1069–76. (H. Choi, hchoius@bu.edu)
* Molecular Mechanisms of Hepcidin Regulation: Implications for the Anemia of CKD, in
American Journal of Kidney Diseases, 2010; 55: 726–41. (J. L. Babitt, babitt.jodie@mgh.harvard.edu)
* A Patient with Severe Hyponatremia and Hypokalemia: Osmotic Demyelination Following Potassium Repletion, in
American Journal of Kidney Diseases, 2010; 55: 742–8. (T. Berl)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 20, 2010 * Vol. 17, No. 75
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and Apr. 20 issue of the Annals of Internal Medicine (2010; 152).
Lactose Intolerance & Nutrient Intake: Patients with lactose intolerance often do not consume enough calcium and vitamin D, according to findings of an NIH consensus development conference (early release). Reacting to findings in a review article on this topic that was also released early (T. J. Wilt, tim.wilt@med.va.gov), the panelists conclude: “Many individuals with real or perceived lactose intolerance avoid dairy and ingest inadequate amounts of calcium and vitamin D, which may predispose them to decreased bone accrual, osteoporosis, and other adverse health outcomes. Most persons do not need to eliminate dairy consumption completely. Evidence-based dietary approaches with and without dairy foods and supplementation strategies are needed to ensure appropriate consumption of calcium and other nutrients in lactose-intolerant individuals. Educational programs and behavioral approaches for individuals and their healthcare providers should be developed and validated to improve the nutrition and symptoms of individuals with lactose intolerance and dairy avoidance.” (www.consensus.nih.gov or 888/644-2667)
Rosuvastatin for Primary Prevention: Healthy older patients have fewer major cardiovascular events when placed on rosuvastatin therapy, according to a study that included those without hyperlipidemia but with elevated C-reactive protein levels (pp. 488–96). In the JUPITER trial (Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin), 17,802 patients, including 5,695 participants aged 70 years or more, showed these results while taking rosuvastatin 20 mg daily or placebo: “The 32% of trial participants 70 years or older accrued 49% (n = 194) of the 393 confirmed primary end points. The rates of [a first cardiovascular event] in this age group were 1.22 and 1.99 per 100 person–years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio, 0.61 [95% CI, 0.46 to 0.82]; P < 0.001). Corresponding rates of all-cause mortality in this age group were 1.63 and 2.04 (hazard ratio, 0.80 [CI, 0.62 to 1.04]; P = 0.090). Although no significant heterogeneity was found in treatment effects by age, absolute reductions in event rates associated with rosuvastatin were greater in older persons. The relative rate of any serious adverse event among older persons in the rosuvastatin versus placebo group was 1.05 (CI, 0.93 to 1.17).” (R. J. Glynn, rglynn@rics.bwh.harvard.edu)
HCR & Primary Care: Passage of the health care reform law offers both “promise and peril” for primary care, a Perspectives author writes (early release): “The Patient Protection and Affordable Care Act (PPACA) of 2010 … has the potential to reestablish primary care as the foundation of US health care delivery. The legislation authorizes specific programs to stabilize and expand the primary care physician workforce, provides an immediate 10% increase in primary care physician payment, creates an opportunity to correct the skewed resource-based relative value scale, and supports innovation in primary care practice. Nevertheless, the peril is that the PPACA initiatives may not alter the current trend toward an increasingly specialized physician workforce. To realize the potential for the PPACA to achieve a more equitable balance between generalist and specialist physicians, all primary care advocates must actively engage in the long rebuilding process.” (J. D. Goodson)

>>>PNN NewsWatch
* Twelve years after trastuzumab was approved for use in women with breast cancer, medical science still doesn’t know how to accurately detect which tumors are HER2 positive, a New York Times article reports this morning. “HER2 tests, for instance, can give false-positives up to 20 percent of the time, wrongly telling women they need the drug when they do not,” Gina Kolata writes. “Five percent to 10 percent of the time the tests can falsely tell a woman that she should not take the drug, when she should.” Furthermore, Kolata continues, “Herceptin testing for breast cancer is easy compared with what is coming next”—use of the drug in those with stomach tumors, “which almost always have sections that are positive for HER2 and sections that are negative.”
* FDA is readying a plan to curtail Americans’ dietary
salt intake, the Washington Post reports today.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 21, 2010 * Vol. 17, No. 76
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 21 issue of JAMA (2010; 303).
Added Sugars & Dyslipidemias: Adverse changes in lipid levels are associated with higher intake of dietary added sugars, researchers report (pp. 1490–7). Lower HDL cholesterol levels and higher concentrations of LDL cholesterol in women and triglycerides were evident with increased intake of caloric sweeteners in processed and prepared foods in the analysis of data from the National Health and Nutrition Examination Survey (NHANES) 1999–2006: “A mean of 15.8% of consumed calories was from added sugars. Among participants consuming less than 5%, 5% to less than 17.5%, 17.5% to less than 25%, and 25% or greater of total energy as added sugars, adjusted mean HDL-C levels were, respectively, 58.7, 57.5, 53.7, 51.0, and 47.7 mg/dL (P < .001 for linear trend), geometric mean triglyceride levels were 105, 102, 111, 113, and 114 mg/dL (P < .001 for linear trend), and LDL-C levels modified by sex were 116, 115, 118, 121, and 123 mg/dL among women (P = .047 for linear trend). There were no significant trends in LDL-C levels among men. Among higher consumers (10% added sugars) the odds of low HDL-C levels were 50% to more than 300% greater compared with the reference group (<5% added sugars).” (M. B. Vos, mvos@emory.edu)
Mortality in Pregnant Women with A/H1N1 Influenza: An analysis of CDC data from April through December 2009 confirms that a disproportionate number of pregnant women died from the A/H1N1 pandemic influenza virus (pp. 1517–25). These clinical characteristics and treatment patterns were identified in the study: “We received reports on 788 pregnant women in the United States with 2009 influenza A(H1N1) with symptom onset from April through August 2009. Among those, 30 died (5% of all reported 2009 influenza A[H1N1] influenza deaths in this period). Among 509 hospitalized women, 115 (22.6%) were admitted to an ICU. Pregnant women with treatment more than 4 days after symptom onset were more likely to be admitted to an ICU (56.9% vs 9.4%; relative risk [RR], 6.0; 95% confidence interval [CI], 3.5–10.6) than those treated within 2 days after symptom onset. Only 1 death occurred in a patient who received treatment within 2 days of symptom onset. Updating these data with the CDC’s continued surveillance of ICU admissions and deaths among pregnant women with symptom onset through December 31, 2009, identified an additional 165 women for a total of 280 women who were admitted to ICUs, 56 of whom died. Among the deaths, 4 occurred in the first trimester (7.1%), 15 in the second (26.8%), and 36 in the third (64.3%).” (M. A. Honein, mhonein@cdc.gov)
Primary Care Physicians & Health Care Reform: A contracting scope of practice and the income differential between primary care and specialist physicians present major obstacles to replenishing the ranks of frontline physicians, Commentary authors write (pp. 1535–6). After setting a goal of convincing 50% of new medical students to choose pediatrics, family medicine, or general internal medicine as their career path, the writers note: “To achieve these goals, primary care physicians need a different set of clinical responsibilities and skills. They must become leaders in efforts to avoid preventable hospitalizations for patients with chronic diseases, eliminate inappropriate or equivocal surgery and radiologic procedures, and help individuals die with the least pain and without expenditures of vast amounts of money. The workflow of the medical system must be redesigned so that primary care clinicians can perform procedures and carry out tasks for which they have been trained. In addition, for patients with single or multiple chronic illnesses, primary care physicians must provide a greater proportion of the continuing care.” (R. H. Brook, robert_brook@rand.org)

>>>PNN NewsWatch
* While agreeing with the bottom line of a new Institute of Medicine report on the need for reduced sodium intake by Americans, FDA yesterday denied reports in the Washington Post that it had begun the process of regulating sodium content in foods. Responding to a flurry of criticisms by industry trade associations, the agency said an interagency working group would be established to review IOM recommendations and work with public health, consumer, and industry groups in identifying an action plan.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 22, 2010 * Vol. 17, No. 77
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 22 issue of the New England Journal of Medicine (2010; 362).
Nateglinide, Valsartan in Prediabetes: Effects of nateglinide and valsartan on the incidence of diabetes and cardiovascular events in patients with impaired glucose tolerance are explored in two trials conducted by the NAVIGATOR Study Group.
Five years’ treatment with the short-acting insulin secretagogue nateglinide did not reduce incidence of diabetes or affect cardiovascular outcomes in 9,306 patients (
pp. 1463–76). All patients had impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors. They received either nateglinide 60 mg or placebo three times daily in a 2 X 2 factorial design with valsartan or placebo. Using three coprimary outcomes (development of diabetes, a core cardiovascular outcome, and an extended cardiovascular outcome), the investigators found: “After adjustment for multiple testing, nateglinide, as compared with placebo, did not significantly reduce the cumulative incidence of diabetes (36% and 34%, respectively; hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15; P = 0.05), the core composite cardiovascular outcome (7.9% and 8.3%, respectively; hazard ratio, 0.94, 95% CI, 0.82 to 1.09; P = 0.43), or the extended composite cardiovascular outcome (14.2% and 15.2%, respectively; hazard ratio, 0.93, 95% CI, 0.83 to 1.03; P = 0.16). Nateglinide did, however, increase the risk of hypoglycemia.” (R. R. Holman, rury.holman@dtu.ox.ac.uk)
Turning their attention to the renin–angiotensin system, the NAVIGATOR investigators found that valsartan in doses up to 160 mg daily reduced diabetes incidence but failed to affect the rate of cardiovascular events (
pp. 1477–90): “The cumulative incidence of diabetes was 33.1% in the valsartan group, as compared with 36.8% in the placebo group (hazard ratio in the valsartan group, 0.86; 95% confidence interval [CI], 0.80 to 0.92; P < 0.001). Valsartan, as compared with placebo, did not significantly reduce the incidence of either the extended cardiovascular outcome (14.5% vs. 14.8%; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P = 0.43) or the core cardiovascular outcome (8.1% vs. 8.1%; hazard ratio, 0.99; 95% CI, 0.86 to 1.14; P = 0.85).” (R. M. Califf, calif001@mc.duke.edu)
An editorialist adds this perspective on the trials (
pp. 1533–5): “The results from the NAVIGATOR study do not support the contention that reducing postprandial hyperglycemia has a specific role in preventing diabetes or reducing cardiovascular disease. Other than increasing the rate of hypoglycemia by a factor of two, nateglinide had little effect. Although the authors suggest that the prevention of diabetes with valsartan might make it a preferred drug as compared with antihypertensive drugs that potentially worsen glycemia, valsartan was relatively weak in preventing diabetes, and it did not lower the rates of cardiovascular disease. The prevention of diabetes remains a critical public health priority, but for now we should steer away from these two drugs and use effective lifestyle interventions and, in selected persons, metformin to combat the epidemic.” (D. M. Nathan)
Vaccines against Neisseria meningitidis: Authors of a review of vaccines against Neisseria meningitidis identify these challenges (pp. 1511–20). “First, we must improve the immunogenicity of meningococcal vaccines in infants, since this age group is still the most vulnerable to meningococcal infection. This is especially true in the United States, where MenC does not provide adequate coverage; although multivalent conjugate vaccines are licensed for use, they currently do not provide protection for infants. Second, we must ensure that variations of any newly identified antigens do not limit future vaccine efficacy. Finally, we must select vaccines that induce herd immunity to provide the dramatic disease reduction seen with MenC. Only then will it be possible to provide the broad-ranging vaccine against N. meningitidis group B that has so far remained elusive.” (R. Borrow, ray.borrow@hpa.org.uk)

>>>PNN NewsWatch
* A boxed warning for severe liver injury has been added to the product labeling of propylthiouracil, FDA announced yesterday. The agency suggested that patients being started on treatment for hyperthyroidism be initially managed with other agents or modalities, such as methimazole, radioactive iodine, or surgery, and that propylthiouracil be reserved for those who cannot tolerate first-line therapies.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 23, 2010 * Vol. 17, No. 78
Providing news and information about medications and their proper use

>>>Health Affairs Highlights
Source:
Web articles from Health Affairs (2010).
Berwick’s Triple Aim: Don Berwick was nominated earlier this week to head the Centers for Medicare & Medicaid Services. A blog reviews the writings of this pediatrician, Harvard professor, and head of the Institute for Healthcare Improvement, focusing especially on Berwick’s “Triple Aim” of care, health, and cost. The writer points to the following Berwick-authored passage as indicative of his tendencies when for moving the United States toward the Triple Aim: “If we could ever find the political nerve, we strongly suspect that financing and competitive dynamics such as the following, purveyed by governments and payers, would accelerate interest in the Triple Aim and progress toward it: (1) global budget caps on total health care spending for designated populations, (2) measurement of and fixed accountability for the health status and health needs of designated populations, (3) improved standardized measures of care and per capita costs across sites and through time that are transparent, (4) changes in payment such that the financial gains from reduction of per capita costs are shared among those who pay for care and those who can and should invest in further improvements, and (5) changes in professional education accreditation to ensure that clinicians are capable of changing and improving their processes of care.” (C. Fleming)
How Obama Achieved Health Care Reform: In a blog posted a few days after President Obama signed the health care reform legislation into law, eight rules for presidential management of health reform, as detailed in the book The Heart of Power, were revisited as they applied to the current situation. Obama got an A+ for passion, C+ for speed, B– for “bring a plan with you,” for better or worse, an A for “hush the economists,” B+ for going public, A– for managing Congress, A for “forget the professional standards review organizations, and for learning how to lose, an F that “will not count in his final grade.” The writer concludes, “Obama faces serious challenges in implementing this legislation. The reported selection of Don Berwick as the new CMS Administrator, (a position not filled on a permanent basis since Mark McClellan resigned in September 2006!) is a good start, but a prodigious amount of regulatory wordsmithery remains. The president will also have to protect the funding for coverage expansions from the inevitable deficit reduction challenges he and Congress will face when the economy actually recovers.
“Nevertheless, Obama put a structure in place to close an unconscionable gap in health coverage for Americans and has written a triumphal concluding chapter of the second edition of
The Heart of Power.” (J. Goldsmith)

>>>Medical Care Report
Source:
May issue of Medical Care (2010; 48).
Adherence in Medicare Part D: Patients had better adherence to medications for hypertension, diabetes, and hyperlipidemia after Part D prescription drug coverage was added to their Medicare Advantage plans, a study shows (pp. 409–17). Using a quasiexperimental, pre–post design, adults aged 65 years or older with one or more of the above three conditions who were continuously enrolled in a large Pennsylvania insurer’s Medicare Advantage products in 2004–07 showed these patterns of adherence based on medication possession ratios (MPRs): “Part D improved MPRs in the group without prior drug coverage by 13.4 percentage points (95% CI, 10.1–16.8), 17.9 (95% CI, 13.7–22.1), and 13.5 (95% CI, 11.5–15.5) for those with hyperlipidemia, diabetes, and hypertension, respectively. Adherence improved less in the other 2 groups with limited prior drug benefits. Although the proportion of beneficiaries in the intervention groups who attained good adherence levels increased after Part D, less than 50%, 68%, and 78% of beneficiaries with hyperlipidemia, diabetes, and hypertension, respectively, attained good adherence.” (Y. Zhang)

>>>PNN NewsWatch
* Speaking yesterday to a group of health journalists in Chicago, CDC Director Thomas R. Frieden, MD, MPH, announced a new effort to encourage states to implement coordinated, high-impact strategies that could “end the stall in the decline of U.S. smoking rate.” Smoke-free laws, hard-hitting ads, public funding for cessation support, and increased cigarette prices are key tools, he said.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 26, 2010 * Vol. 17, No. 79
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
Apr. 24 issue of Lancet (2010; 375).
MDV3100 in Castration-Resistant Prostate Cancer: An investigational androgen-receptor antagonist showed promise in a Phase I/II trial of 140 men with progressive, metastatic, castration-resistant prostate cancer (pp. 1437–46). Dose-escalation cohorts showed these responses to MDV3100 at five U.S. centers: “We noted antitumour effects at all doses, including decreases in serum prostate-specific antigen of 50% or more in 78 (56%) patients, responses in soft tissue in 13 (22%) of 59 patients, stabilised bone disease in 61 (56%) of 109 patients, and conversion from unfavourable to favourable circulating tumour cell counts in 25 (49%) of the 51 patients. PET imaging of 22 patients to assess androgen-receptor blockade showed decreased 18F-fluoro-5-alpha-dihydrotestosterone binding at doses from 60 mg to 480 mg per day (range 20–100%). The median time to progression was 47 weeks (95% CI 34—not reached) for radiological progression. The maximum tolerated dose for sustained treatment (>28 days) was 240 mg. The most common grade 3–4 adverse event was dose-dependent fatigue (16 [11%] patients), which generally resolved after dose reduction.” (H. I. Scher, scherh@mskcc.org)
Liraglutide v. Sitagliptin in Type 2 Diabetes: In a comparison of the glucagon-like peptide-1 agonist liraglutide and the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes, the GLP-1 agent proved superior and safe, researchers report (pp. 1447–56). In an open-label trial, adults with type 2 diabetes with inadequate glycemic control on metformin in doses of 1,500 mg or more daily for at least 3 months, subcutaneous liraglutide 1.2 or 1.8 mg daily or oral sitagliptin 100 mg daily showed these effects over 26 weeks: “Greater lowering of mean HbA1c (8.5% at baseline) was achieved with 1.8 mg liraglutide (–1.50%, 95% CI –1.63 to –1.37, n = 218) and 1.2 mg liraglutide (−1.24%, −1.37 to –1.11, n = 221) than with sitagliptin (–0.90%, –1.03 to –0.77, n = 219). Estimated mean treatment differences for liraglutide versus sitagliptin were –0.60% (95% CI –0.77 to –0.43, p < 0.0001) for 1.8 mg and –0.34% (–0.51 to –0.16, p < 0.0001) for 1.2 mg liraglutide. Nausea was more common with liraglutide (59 [27%] patients on 1.8 mg; 46 [21%] on 1.2 mg) than with sitagliptin (10 [5%]). Minor hypoglycaemia was recorded in about 5% of participants in each treatment group.” (R. E. Pratley, richard.pratley@uvm.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 340).
Nurse-Led Home Management of Chronic Fatigue Syndrome: “Pragmatic rehabilitation” and supportive listening by trained nurse therapists improved short-term chronic fatigue syndrome symptoms more than general practitioner management, according to a study of 296 adult patients with CFS or myalgic encephalomyelitis or encephalitis (c1777). Interventions were delivered in patient homes in 10 sessions over 18 weeks by three nurses, with these results: “Immediately after treatment (at 20 weeks), patients allocated to pragmatic rehabilitation (n = 95) had significantly improved fatigue (effect estimate –1.18, 95% confidence interval –2.18 to –0.18; P = 0.021) but not physical functioning (–0.18, 95% CI –5.88 to +5.52; P = 0.950) compared with patients allocated to treatment as usual (n = 100). At one year after finishing treatment (70 weeks), there were no statistically significant differences in fatigue or physical functioning between patients allocated to pragmatic rehabilitation and those on treatment as usual (–1.00, 95% CI –2.10 to +0.11; P = 0.076 and +2.57, 95% CI 3.90 to +9.03; P = 0.435). At 20 weeks, patients allocated to supportive listening (n = 101) had poorer physical functioning than those allocated to treatment as usual (–7.54, 95% CI –12.76 to –2.33; P = 0.005) and no difference in fatigue. At 70 weeks, patients allocated to supportive listening did not differ significantly from those allocated to treatment as usual on either primary outcome.” (A. J. Wearden, alison.wearden@manchester.ac.uk)

>>>PNN JournalWatch
* Practice Parameter Update: Evaluation and Management of Driving Risk in Dementia, in Neurology, 2010; 74: 1316–24. (American Academy of Neurology, guidelines@aan.com)
* Multidisciplinary Meeting on Male Breast Cancer: Summary and Research Recommendations, in
Journal of Clinical Oncology, 2010; 28: 2114–22. (L. A. Korde, lkorde@u.washington.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 27, 2010 * Vol. 17, No. 80
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Apr. 26 issue of the Archives of Internal Medicine (2010; 170).
Interruptions & Med Errors: Nurses made significantly more medication-administration errors after being interrupted, according to a study conducted at two Australian teaching hospitals (pp. 683–90). Failure rates were high at the hospitals, with only one in five drug administrations not having some clinical error (such as wrong drug or dose) or procedural failure (such as failure to read medication label or check patient identification). During 4,271 medication administrations to 720 patients by 98 nurses, these relationships were observed: “Each interruption was associated with a 12.1% increase in procedural failures and a 12.7% increase in clinical errors. The association between interruptions and clinical errors was independent of hospital and nurse characteristics. Interruptions occurred in 53.1% of administrations (95% confidence interval [CI], 51.6%–54.6%). Of total drug administrations, 74.4% (n = 3,177) had at least 1 procedural failure (95% CI, 73.1%–75.7%). Administrations with no interruptions (n = 2005) had a procedural failure rate of 69.6% (n = 1,395; 95% CI, 67.6%–71.6%), which increased to 84.6% (n = 148; 95% CI, 79.2%–89.9%) with 3 interruptions. Overall, 25.0% (n = 1067; 95% CI, 23.7%-26.3%) of administrations had at least 1 clinical error. Those with no interruptions had a rate of 25.3% (n = 507; 95% CI, 23.4%–27.2%), whereas those with 3 interruptions had a rate of 38.9% (n = 68; 95% CI, 31.6%–46.1%). Nurse experience provided no protection against making a clinical error and was associated with higher procedural failure rates. Error severity increased with interruption frequency. Without interruption, the estimated risk of a major error was 2.3%; with 4 interruptions this risk doubled to 4.7% (95% CI, 2.9%–7.4%; P < .001).” (J. I. Westbrook, J.Westbrook@usyd.edu.au)
A nurse is direct in an accompanying editorial about “giving medication administration the respect it is due” (
pp. 690–2): “Who, exactly, is to be held accountable for high error rates in medication administration? The answer seems clear, as confirmed by Westbrook et al: the entire professional medical, nursing, and administrative team. The time has come for nurses, physicians, pharmacists, and all hospital staff to align behind the goal of a safer medication administration process.” (J. Kliger, jkliger@thecenter.ucsf.edu)
Benzodiazepines, Drug Coverage, & Hip Fracture: While exclusion of benzodiazepines from coverage under Medicare Part D quickly reduced use of these drugs in nursing home residents without supplemental coverage, the rate of hip fracture among the patients was not significantly altered, researchers report (pp. 693–8). In fact, the risk of fractures was higher, but not significantly so, among those not on benzodiazepines, a finding the authors surmise might have resulted from “use of a wide array of agents with a mixture of positive and negative associations with fracture risk.” Using data from a single pharmacy and covering more than 1 million residents, including 51,000 with fracture data, the researchers found these patterns in 2005–07: “The no-supplemental-coverage policy resulted in an immediate and significant reduction of 10 absolute points in benzodiazepine use (27.0% to 17.0%) after Medicare Part D was implemented (95% confidence interval, –0.11 to –0.09; P < .001). Benzodiazepine use remained stable in the partial-supplemental- and complete-supplemental-coverage states. Hazard ratios for incident hip fracture were 1.60 (95% confidence interval, 1.05 to 2.45; P = .03) in the no-supplemental-coverage state after Medicare Part D implementation and 1.17 (95% confidence interval, 0.93 to 1.46; P = .18) in the partial-supplemental-coverage states, relative to complete-supplemental-coverage states.” (B. A. Briesacher, Becky.Briesacher@umassmed.edu)

>>>PNN NewsWatch
* Additional premarketing requirements for infusion pumps are part of an FDA initiative seeking to reduce risks of persistent safety problems with the devices. The agency has also scheduled a May 25–26 workshop to discuss observed problems. In the past 5 years, more than 56,000 reports of adverse events associated with pumps have been reported to FDA; these involved the deaths of 500 patients.
* A new site for patients to report
medical harm is available at www.EmpoweredPatientCoalition.org. Consumers Union Safe Patient Project is collaborating with the Empowered Patient Coalition in this effort.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 28, 2010 * Vol. 17, No. 81
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Apr. 28 issue of JAMA (2010; 303).
High-Dose B Vitamins in Diabetic Nephropathy: Adverse outcomes occurred more often in patients given high doses of B vitamins as a means of lowering elevated homocysteine levels and slowing nephropathy in patients with diabetes (pp. 1603–9). Glomerular filtration rates declined more rapidly in those given folic acid 2.5 mg, vitamin B6 25 mg, and vitamin B12 1 mg daily, and cardiovascular events were more common, the results show: “The mean (SD) follow-up during the trial was 31.9 (14.4) months. At 36 months, radionuclide GFR decreased by a mean (SE) of 16.5 (1.7) mL/min/1.73 m2 in the B-vitamin group compared with 10.7 (1.7) mL/min/1.73 m2 in the placebo group (mean difference, –5.8; 95% confidence interval [CI], –10.6 to –1.1; P = .02). There was no difference in requirement of dialysis (hazard ratio [HR], 1.1; 95% CI, 0.4–2.6; P = .88). [Myocardial infarction, stroke, revascularization, and all-cause mortality] occurred more often in the B-vitamin group (HR, 2.0; 95% CI, 1.0–4.0; P = .04). Plasma total homocysteine decreased by a mean (SE) of 2.2 (0.4) µmol/L at 36 months in the B-vitamin group compared with a mean (SE) increase of 2.6 (0.4) µmol/L in the placebo group (mean difference, –4.8; 95% CI, –6.1 to –3.7; P < .001, in favor of B vitamins).”
The authors conclude that routine use of high-dose B vitamin therapy should be discouraged, adding: “If the homocysteine theory of atherosclerosis is to be proved or disproved with certainty, it may be necessary to find alternative, nonvitamin strategies to lower homocysteine, such as enhancing the conversion of homocysteine to cysteine in the liver or enhancing urinary excretion. To this end, investigators have begun to examine the use of agents capable of thiol exchange, liberating homocysteine bound by disulfide bonds to proteins; therefore, facilitating its urinary excretion and lowering plasma levels significantly without the use of vitamins.” (J. D. Spence,
dspence@robarts.ca)
Coronary Artery Calcium Scores in CHD Risk Prediction: Addition of coronary artery calcium score (CACS) to traditional risk factors for coronary heart disease provides significantly improved classifications, researchers report (pp. 1610–6). Data for 6,814 participants in the Multi-Ethnic Study of Atherosclerosis show these patterns for a model based on age, sex, tobacco use, systolic blood pressure, antihypertensive medication use, total and HDL cholesterol, and race/ethnicity (model 1) and those factors plus CACS (model 2): “During a median of 5.8 years of follow-up among a final cohort of 5,878, 209 CHD events occurred, of which 122 were myocardial infarction, death from CHD, or resuscitated cardiac arrest. Model 2 resulted in significant improvements in risk prediction compared with model 1 (net reclassification improvement = 0.25; 95% confidence interval, 0.16–0.34; P < .001). In model 1, 69% of the cohort was classified in the highest or lowest risk categories compared with 77% in model 2. An additional 23% of those who experienced events were reclassified as high risk, and an additional 13% without events were reclassified as low risk using model 2.” (P. Greenland)

>>>PNN NewsWatch
* FDA yesterday approved the Alair Bronchial Thermoplasty System (Asthmatx), a medical device that uses electromagnetic energy to treat severe persistent asthma in adults. FDA based its approval on data from a clinical trial of 297 patients with severe persistent asthma that showed a reduction of severe asthma attacks with use of the Alair system. The agency said it is requiring a 5-year postapproval study of long-term safety and effectiveness of the device. Possible adverse effects during use of Alair may include asthma attacks, wheezing, chest tightness or pain, atelectasis, hemoptysis, anxiety, headaches, and nausea. The Alair system is designed to reduce the number of severe asthma attacks on a long-term basis. However, there is a risk of immediate asthma attacks during the course of the treatment. Several types of patients should not use Alair: those with a pacemaker, internal defibrillator, or other implantable electronic device; those with known sensitivities to lidocaine, atropine, or benzodiazepines; those with active respiratory infection, coagulopathy, or asthma exacerbations; and those whose corticosteroid regimen has changed in the past 14 days.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 29, 2010 * Vol. 17, No. 82
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
Apr. 29 issue of the New England Journal of Medicine (2010; 362).
Medication Adherence in Reformed Health Care: A Perspective article points to a number of lessons that can be learned from successful medication adherence efforts: financial barriers in the form of copayments, needed data and improvements in health information technology, shifting from a fee-for-service payment system, and proven screening and assessment tools (pp. 1553–5). The authors provide this description of one such success: “Community Care of North Carolina (CCNC), a loose affiliation of 14 physician networks serving Medicaid and uninsured patients, has launched the Pharmacy Home Project, a plan that pays participating physicians a monthly fee for coordination of care. Adherence is promoted through the use of case managers who are embedded throughout the networks and clinical pharmacists who serve multiple physician practices on a rotating basis and through the collection of data on patient medications from multiple sources including medical charts, claims records, and records of prescriptions filled to provide prescribers with complete and accurate data for use in reviewing medications. Under this program, CCNC has achieved a 5 to 7% increase in adherence rates.” (D. M. Cutler)
Physician Specialists & Medical Homes: Some cardiologists, endocrinologists, and pulmonologists function as primary care physicians, authors note, and thus might be able to establish medical homes needed under parts of the health care reform law (pp. 1555–8). The authors summarize results of a survey of 373 physicians in the above specialties who practice alone or in groups of up to 19 physicians: “A total of 81% of practices reported that their physicians serve as primary care physicians for 10% or less of their patients, only 12.5% that they serve as primary care physicians for more than 20% of their patients, and only 2.7% that they do so for more than 50% of their patients. Among the three types of specialists, endocrinologists were significantly more likely than the others to report serving as primary care physicians. In all three specialties, practices consisting of one or two physicians were significantly more likely than larger group practices to report serving as primary care physicians.” (L. P. Casalino)

>>>Diabetes Highlights
Source:
May issue of Diabetes Care (2010; 33).
Exenatide Plus Rosiglitazone in Type 2 Diabetes: Added to metformin in 137 patients with type 2 diabetes, exenatide plus rosiglitazone yielded better beta-cell function and insulin sensitivity than when rosiglitazone only was added, and the presence of exenatide prevented the weight gain seen with rosiglitazone (pp. 951–7). In a 20-week trial of EXE 10 mcg, ROSI 4 mg, or EXE plus ROSI twice daily and insulin-clamp studies of 73 patients, these results were noted: “A1C declined in all groups (P < 0.05), but decreased most with EXE+ROSI (EXE+ROSI, −1.3 ± 0.1%; ROSI, −1.0 ± 0.1%, EXE, −0.9 ± 0.1%; EXE+ROSI vs. EXE or ROSI, P < 0.05). ROSI resulted in weight gain, while EXE and EXE+ROSI resulted in weight loss (EXE, −2.8 ± 0.5 kg; EXE+ROSI, −1.2 ± 0.5 kg; ROSI, + 1.5 ± 0.5 kg; P < 0.05 between and within all groups). At week 20, 1st and 2nd phase insulin secretion was significantly higher in EXE and EXE+ROSI versus ROSI (both P < 0.05). Insulin sensitivity (M value) was significantly higher in EXE+ROSI versus EXE (P = 0.014).” (R. A. DeFronzo, albarado@uthscsa.edu)

>>>PNN NewsWatch
* Those in the pharmaceutical supply chain need to take additional steps to prevent cargo and warehouse thefts, FDA said yesterday. In a letter to manufacturer, wholesaler, pharmacy, device, and infant formula trade associations, the agency described the steps it would take when notified of large-scale thefts, outlined what firms should do, and emphasized the importance of notifying other members of the supply chain and the public after thefts occur.
*
Timothy R. Franson, a pharmacist and physician, last week was elected president of USP for the next 5 years, pharmacist.com reports. The vote took place at the organization’s quinquennial meeting in Washington, DC. With experience in industry and academia, Franson is senior vice president of B&D Consulting.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
Apr. 30, 2010 * Vol. 17, No. 83
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
May issue of Pharmacotherapy (2010; 30).
Adherence & Blood Pressure Control: While adherence to medications was unchanged after a physician–pharmacist collaboration in 584 patients with uncontrolled primary hypertension, blood pressures were significantly lowered among those in the intervention group, researchers report (pp. 432–41). Self-efficacy and social support were better among those receiving collaborative care, which included intensified hypertension management and drug adherence counseling. But these factors played a “minor role,” the authors conclude based on these results: “Self-reported adherence scores improved significantly in the control group (p = 0.0053) but not in the intervention group; however, adherence at baseline in both groups was high. There were small, but significant, improvements in self-efficacy (p < 0.04) and social support (p < 0.05) scores in the intervention group but not the control group at the end of the study. Social support and, to a lesser extent, self-efficacy improved as a function of duration of study participation (9-mo vs 6-mo intervention), regardless of whether the patient received the intervention. Blood pressure control in both groups improved significantly at the end of the study; however, mean blood pressure was significantly lower in the intervention group (129.7/76.6 mm Hg) compared with the control group (140.8/78.9 mm Hg; p < 0.0001 for systolic, p = 0.032 for diastolic).” (B. L. Carter, barry-carter@uiowa.edu)
An editorialist describes adherence improvements as “an emerging opportunity” in community and clinic pharmacy (
pp. 425–7): “There is a need for large, prospective, theory-based intervention studies that develop tools that standardize and assist with identifying adherence barriers (including intentional behavioral adherence issues), identify effective interventions, and can be replicated in the community setting. In addition, recent efforts should continue to support a fair reimbursement structure for clinicians choosing to address adherence issues. Finally, efforts need to be made to disseminate results and facilitate the incorporation of effective and efficient adherence interventions into community and clinic pharmacy practice settings. Pharmacists can and should take an active role in the development, assessment, dissemination, and delivery of effective and efficient adherence interventions. Changing behaviors is difficult, whether it is our own or our patients’ behaviors. Without taking an active evidence-based role, significant gains in improving drug adherence may not be realized for another 3 decades, or the opportunity for pharmacists may be missed permanently.” (D. R. Toucette, drtouche@uic.edu)
Clinical Pathway for Empiric Antibiotic Therapy: In patients with ventilator-associated pneumonia, use of a clinical pathway improved clinical and economic outcomes, compared with historical control patients managed through prescriber preference (pp. 453–62). Shorter duration of treatment, reduced hospital length of stay after onset of pneumonia, and lower hospital costs without any significant increase in antibiotic expenditures were observed in the study. (J. L. Kuti, jkuti@harthosp.org)

>>>PNN NewsWatch
* FDA calls it “cellular immunotherapy” and the lay media says it’s a “cancer vaccine.” But whatever name one uses, Dendreon Corp.’s sipuleucel-T (Provenge) product, approved for marketing yesterday, provides an innovative option for men with asymptomatic or minimally symptomatic metastatic, castrate-resistant (hormone-refractory) prostate cancer. Patient cells are collected through leukapheresis and shipped to a Dendreon manufacturing facility. There the cells are exposed to sipuleucel-T, a recombinant protein that functions as a prostate-cancer–associated antigen and immune cell activator. Activated cells are returned for infusion into the patient. In clinical trials, 512 patients with metastatic hormone-treatment refractory prostate cancer had an increase in overall survival of 4.1 months when treated with sipuleucel-T (median survival of 25.8 months, compared with 21.7 months with placebo). Almost all patients on the new therapy had adverse reactions. These included chills, fatigue, fever, back pain, nausea, joint ache, and headache that were mild or moderate in severity. About one-quarter of patients had serious adverse reactions, including acute infusion reactions and strokes.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 3, 2010 * Vol. 17, No. 84
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 1 issue of Lancet (2010; 375).
Whole-Genome Sequencing in Clinical Assessment: In a patient with family history of vascular disease and early sudden death, sequencing of the entire genome identified several clinically relevant variants, researchers report (pp. 1525–35). Using disease-specific mutation and pharmacogenomics databases, the investigators determined: “Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death—TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.” (E. A. Ashley, euan@stanford.edu)
Cardiovascular Risk with Lipoprotein-Associated Phospholipase A2: Activity of an inflammatory enzyme expressed in atherosclerotic plaques correlates with risk of coronary heart disease, according to an analysis of records of 79,036 participants in 32 prospective studies (pp. 1536–44). Magnitude of correlations of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were in the range of those of risk factors such as non-HDL cholesterol and systolic blood pressure, the investigators note, adding these data from a meta-analysis of within-study regressions: “Lp-PLA2 activity and mass were associated with each other (r = 0.51, 95% CI 0.47–0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA2 activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05–1.16) with Lp-PLA2 activity and 1.11 (1.07–1.16) with Lp-PLA2 mass for coronary heart disease; 1.08 (0.97–1.20) and 1.14 (1.02–1.27) for ischaemic stroke; 1.16 (1.09–1.24) and 1.13 (1.05–1.22) for vascular mortality; and 1.10 (1.04–1.17) and 1.10 (1.03–1.18) for non-vascular mortality, respectively. RRs with Lp-PLA2 did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA2mass. Adjusted RRs for coronary heart disease were 1.10 (1.02–1.18) with non-HDL cholesterol and 1.10 (1.00–1.21) with systolic blood pressure.” (Lp-PLA2 Studies Collaboration)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 340).
Student Risk Factors for Physician Misconduct: In medical students, male gender, lower socioeconomic background, and early academic difficulties are predictors of later professional misconduct, according to a case–control analysis from the U.K. (c2040). Comparing 59 physicians who had findings of serious professional misconduct with 236 matched controls, the researchers found: “Multivariable analysis showed that male sex (odds ratio 9.80, 95% confidence interval 2.43 to 39.44, P = 0.001), lower social class (4.28, 1.52 to 12.09, P = 0.006), and failure of early or preclinical examinations (5.47, 2.17 to 13.79, P < 0.001) were independently associated with being a case.” (J. Yates, janet.yates@nottingham.ac.uk)

>>>PNN NewsWatch
* On Saturday, FDA offered advice to consumers about a far-reaching recall of all unexpired lots of more than 40 liquid Tylenol, Motrin, Zyrtec, and Benadryl products by McNeil Consumer Healthcare. While no adverse effects have been directly linked with the products, the company cited quality shortcomings at its plants as the reason for the recall. Lay media reports state that some products may contain higher-than-labeled amounts of active ingredients.

>>>PNN JournalWatch
* MD-Logic Artificial Pancreas System: A Pilot Study in Adults with Type 1 Diabetes, in Diabetes Care, 2010; 33: 1072–6. (M. Phillip, mosheph@post.tau.ac.il)
* Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus, in
Pharmacotherapy, 2010; 30: 463–84. (J. J. Neumiller, jneumiller@wsu.edu)
* Identifying Medication Misadventures: Poor Agreement Among Medical Record, Physician, Nurse, and Patient Reports, in
Pharmacotherapy, 2010; 30: 529–38. (P. J. Kaboli, peter.kaboli@va.gov)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 4, 2010 * Vol. 17, No. 85
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and May 4 issue of the Annals of Internal Medicine (2010; 152).
ESAs in CKD: Risks of adverse clinical outcomes—probably including death, serious cardiovascular events, and end-stage renal disease—are higher in patients with chronic kidney disease who receive erythropoiesis-stimulating agents dosed to achieve higher target levels of hemoglobin (early release). In a systematic review of 27 trials of ESAs in 10,452 patients with CKD, investigators found: “A higher hemoglobin target was associated with increased risks for stroke (relative risk [RR], 1.51 [95% CI, 1.03 to 2.21]), hypertension (RR, 1.67 [CI, 1.31 to 2.12]), and vascular access thrombosis (RR, 1.33 [CI, 1.16 to 1.53]) compared with a lower hemoglobin target. No statistically significant differences in the risks for mortality (RR, 1.09 [CI, 0.99 to 1.20]), serious cardiovascular events (RR, 1.15 [CI, 0.98 to 1.33]), or end-stage kidney disease (RR, 1.08 [CI, 0.97 to 1.20]) were observed, although point estimates favored a lower hemoglobin target. Treatment effects were consistent across subgroups, including all stages of CKD.” (G. F. M. Strippoli, strippoli@negrisud.it)
Herpes Zoster Vaccine—Safety & Barriers: Two research papers examine the safety and barriers to use of herpes zoster vaccine.
A large study shows that herpes zoster vaccine is well tolerated in older, immunocompetent adults (
pp. 545–54). Among 38,546 patients aged 60 or older, 6,616 participated in an adverse events substudy at 22 U.S. academic centers. Single doses of herpes zoster vaccine produced these effects within 42 days: “After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1,604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients.” (M. S. Simberkoff, Mike.SimberkoffMD@va.gov)
Barriers, especially financial ones, are impeding physicians from providing more patients with herpes zoster vaccine, a second study shows (
pp. 555–60). Important among the factors is reimbursement, since Medicare reimburses the product under pharmacy-favorable Part D rather than B, the group reports based on a 2008 survey of internists and family medicine physicians: “Response rates were 72% in both specialties (301 general internists and 297 family medicine physicians). Physicians in both specialties reported similar methods for delivering vaccine, which included stocking and administering the vaccine in their offices (49%), referring patients to a pharmacy to purchase the vaccine and bring it back to the office for administration (36%), and referring patients to a pharmacy for vaccine administration (33%). Eighty-eight percent of providers recommend herpes zoster vaccine and 41% strongly recommend it, compared with more than 90% who strongly recommend influenza and pneumococcal vaccines. For physicians in both specialties, the most frequently reported barriers to vaccination were financial. Only 45% of respondents knew that herpes zoster vaccine is reimbursed through Medicare Part D. Of respondents who began administering herpes zoster vaccine in their office, 12% stopped because of cost and reimbursement issues.” (L. P. Hurley)
Growth Hormone in Recreational Athletes: Administered alone or with testosterone (in men), subcutaneous growth hormone 2 mg/d improved body composition and increased sprint capacity in 96 recreationally trained athletes, researchers report (pp. 568–77). Reduced fat mass and increased lean body mass were evident in those receiving active agents, but no performance measures other than sprinting improved significantly. (K. K. Y. Ho, k.ho@garvan.org.au)

>>>PNN NewsWatch
* Gonadotropin-releasing hormone agonists are being evaluated for diabetogenic effects, FDA said yesterday. GnRH agonists such as leuprolide and goserelin may increase risks of diabetes and serious cardiovascular events and diseases, according to seven cited studies.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 5, 2010 * Vol. 17, No. 86
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 5 issue of JAMA (2010; 303).
Cardiovascular Events & Pneumococcal Vaccine: Men older than 45 did not have a reduced risk of myocardial infarction or stroke after receiving pneumococcal vaccine, researchers report (pp. 1699–706). In a prospective cohort study of 84,170 Kaiser participants in the California Men’s Health Study in 2002–03, these trends were recorded: “During follow-up, there were 1,211 first MIs in 112,837 vaccinated person–years (10.73 per 1,000 person–years) compared with 1,494 first MI events in 246,170 unvaccinated person–years (6.07 per 1,000 person–years). For stroke, there were 651 events in 122,821 vaccinated person-years (5.30 per 1,000 person–years) compared with 483 events in 254,541 unvaccinated person–years (1.90 per 1,000 person–years). With propensity score adjustment, we found no evidence for an association between pneumococcal vaccination and reduced risk of acute MI (adjusted hazard ratio [HR], 1.09; 95% confidence interval [CI], 0.98–1.21) or stroke (adjusted HR, 1.14; 95% CI, 1.00–1.31). An inverse association was also not found in men of different age and risk groups. The results appeared to be consistent, because using more specific International Classification of Diseases, Ninth Revision codes for the outcome definition did not change the estimations.” (H. F. Tseng, hung-fu.x.tseng@kp.org)
Noting that a previous study had found the risk of cardiovascular events cut in half in those vaccinated against pneumococcal disease, editorialists provide this caveat (
pp. 1751–2): “Care should be taken in evaluating the potential effect of a vaccine for specific outcomes, such as cardiovascular events. In vaccine studies that use a case–control design, the morbidity and mortality benefits of vaccination are likely to be overestimated. The attributable risk might provide a more realistic estimate of the effect size than the odds ratio. When clinical trials are not feasible, observational studies that examine treatment outcomes should ensure careful selection of case and control groups, with proper matching, use of validated clinical data rather than billing data, use of a prospective design, stratification of study participants, and statistical adjustments for potential confounders and for propensity scores.” (M. Madjid, mmadjid@gmail.com)

>>>PNN NewsWatch
* Under an order from FDA, Baxter is recalling and destroying all Colleague Infusion Pumps still in use in the U.S. As many as 200,000 of the pumps remain in use despite years of wrangling between FDA and Baxter over numerous device flaws. In a news release, FDA said the problems dated back to 1999 and that “Colleague pumps have been the subject of several Class I recalls for battery swelling, inadvertent power off, service data errors, and other issues.” FDA obtained a consent decree of permanent injunction in 2006 that required Baxter to stop manufacturing and distributing the pumps until manufacturing deficiencies were corrected; FDA said in a news release that changes Baxter has made “have not corrected the product defect leading to the permanent injunction.” Under the consent decree, Baxter must provide refunds to customers or replace pumps at no cost. The company said it plans to offer to exchange its Sigma Spectrum infusion pumps for the Colleague model.
* Contamination of raw materials with gram-negative bacteria were among the litany of quality problems with
McNeil Consumer Healthcare liquid cough-and-cold products detailed to the media by FDA on Tuesday. After releasing the agency’s inspection report of the company’s Pennsylvania manufacturing facility, FDA officials told reporters that the contaminated Tylenol, Motrin, Zyrtec, and Benadryl products had potential potency variations, might contain black particles, and could have adulterated inactive ingredients in them. FDA Commissioner Margaret A. Hamburg, MD, advised consumers to talk with their pharmacists about the many generic products with the same active ingredients that consumers can give their children. She also reminded parents never to use adult medicines in children. McNeil has posted a list of frequently asked questions, including information on how consumers can get refunds for the products they are discarding.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 6, 2010 * Vol. 17, No. 87
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 6 issue of the New England Journal of Medicine (2010; 362).
Vitamin E, Pioglitazone in Nonalcoholic Steatohepatitis: In 247 adult patients with nonalcoholic steatohepatitis in adults without diabetes, vitamin E but not pioglitazone was superior to placebo for improving histologic features of the disease (pp. 1675–85). Participants received pioglitazone 30 mg daily, vitamin E 800 IU daily, or placebo for 96 weeks, with these results: “Vitamin E therapy, as compared with placebo, was associated with a significantly higher rate of improvement in nonalcoholic steatohepatitis (43% vs. 19%, P = 0.001), but the difference in the rate of improvement with pioglitazone as compared with placebo was not significant (34% and 19%, respectively; P = 0.04). Serum alanine and aspartate aminotransferase levels were reduced with vitamin E and with pioglitazone, as compared with placebo (P < 0.001 for both comparisons), and both agents were associated with reductions in hepatic steatosis (P = 0.005 for vitamin E and P < 0.001 for pioglitazone) and lobular inflammation (P = 0.02 for vitamin E and P = 0.004 for pioglitazone) but not with improvement in fibrosis scores (P=0.24 for vitamin E and P=0.12 for pioglitazone). Subjects who received pioglitazone gained more weight than did those who received vitamin E or placebo; the rates of other side effects were similar among the three groups.” (A. J. Sanyal, asanyal@mcvh-vcu.edu)
Impact of Bedside Bar Coding on Medication Errors: The bar-code electronic medication administration record is “an important intervention to improve medication safety,” researchers conclude based on a study showing the intervention substantially reduced the rate of errors in order transcription and medication administration, and decreased potential adverse drug events (pp. 1698–707). In a before-and-after, quasi-experimental study conducted at an academic medical center that was implementing the bar-code eMAR, these results were recorded: “We observed 14,041 medication administrations and reviewed 3,082 order transcriptions. Observers noted 776 nontiming errors in medication administration on units that did not use the bar-code eMAR (an 11.5% error rate) versus 495 such errors on units that did use it (a 6.8% error rate)—a 41.4% relative reduction in errors (P < 0.001). The rate of potential adverse drug events (other than those associated with timing errors) fell from 3.1% without the use of the bar-code eMAR to 1.6% with its use, representing a 50.8% relative reduction (P < 0.001). The rate of timing errors in medication administration fell by 27.3% (P < 0.001), but the rate of potential adverse drug events associated with timing errors did not change significantly. Transcription errors occurred at a rate of 6.1% on units that did not use the bar-code eMAR but were completely eliminated on units that did use it.” (E. G. Poon, epoon@partners.org)
Clinical Aspects of A/H1N1 Influenza Infection: A review article presents information on clinical aspects of infections of the pandemic 2009 influenza A/H1N1 virus (pp. 1708–19): “Major gaps exist in our understanding of viral transmission, pathogenesis of disease, genetic and other host factors related to susceptibility or disease severity, and optimal management of severe illness. The development of new antiviral regimens with improved effectiveness, combinations with targeted adjunctive therapies (i.e., immunodulators and neutralizing antibodies or immunotherapy), and improved management of influenza-associated [acute respiratory distress syndrome] are priorities, along with better prevention, recognition, and treatment of invasive bacterial coinfections. Available findings highlight the importance of early use of antiviral drugs and antibiotics in the treatment of serious cases and of the potential value of influenza-specific and pneumococcal vaccines for prevention. Both the gaps in knowledge and the experience to date underline the urgent need for better international collaboration in clinical research, particularly in the case of diseases with pandemic potential, for which rapid detection, investigation, and characterization of clinical syndromes are prerequisites for improved mitigation of their public health consequences.” (F. G. Hayden, fgh@virginia.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 7, 2010 * Vol. 17, No. 88
Providing news and information about medications and their proper use

>>>Pediatrics Highlights
Source:
May issue of Pediatrics (2010; 125).
Safety of Influenza Vaccine in Egg Allergy: Similar to other recent reports (see PNN, Apr. 16), researchers report that pediatric patients with egg allergies can safely receive influenza vaccine without a preliminary skin test when a two-dose, graded approach is used for vaccine administration (e1024–30). At a pediatric hospital, the skin test was used in 2002–2007, but the protocol was revised to eliminate the skin test and institute two graded doses of the vaccine. Retrospective chart review showed the following: “Two hundred sixty-one egg-allergic patients were evaluated for influenza vaccine administration, and 171 went on to receive the vaccine. Of the 56 patients who received the skin test before the influenza vaccine, 95% (exact 95% confidence interval [CI]: 85.1–98.9) tolerated the vaccine without a serious adverse reaction. This rate was unchanged after the vaccine skin test was removed from the protocol. Of the 115 patients who received the vaccine without a preceding skin test, 97% (exact 95% CI: 91.3–99.0) tolerated the vaccine without serious adverse reaction. The tolerance rate ratio was 1.01 (95% CI: 0.97–1.06).” (E. Y. Chung)
Suicidality & Antidepressant Use: FDA was correct when it included all antidepressants in suicidality warnings for children and adolescents, write authors of a 9-year cohort study that analyzed data from British Columbia (pp. 876–88): “Of 20,906 children who initiated antidepressant therapy, 16,774 (80%) had no previous antidepressant use. During the first year of use, we observed 266 attempted and 3 completed suicides, which yielded an event rate of 27.04 suicidal acts per 1,000 person–years (95% confidence interval [CI]: 23.9–30.5 suicidal acts per 1,000 person–years). There were no meaningful differences in the rate ratios (RRs) comparing fluoxetine with citalopram (RR: 0.97 [95% CI: 0.54–1.76]), fluvoxamine (RR: 1.05 [95% CI: 0.46–2.43]), paroxetine (RR: 0.80 [95% CI: 0.47–1.37]), and sertraline (RR: 1.02 [95% CI: 0.56–1.84]). Tricyclic agents showed risks similar to those of selective serotonin reuptake inhibitors (RR: 0.92 [95% CI: 0.43–2.00]).” (S. Schneeweiss)

>>>Psychiatry Report
Source:
May issue of the American Journal of Psychiatry (2010; 167).
Pharmacogenetics of Antidepressants: The “traditional candidates” for genetic markers of antidepressant effects failed to predict efficacy, according to the Genome-Based Therapeutic Drugs for Depression (GENDEP) project (pp. 555–64): “Drug-specific analyses revealed a genome-wide significant association between marker rs2500535 in the uronyl 2-sulphotransferase gene and response to nortriptyline. Response to escitalopram was best predicted by a marker in the interleukin-11 (IL11) gene.… An association with response to escitalopram was detected in the interleukin-6 gene, which is a close homologue of IL11.” (R. Uher)
>>>PNN NewsWatch
* The first four-phasic oral contraceptive was approved yesterday by FDA. Natazia (Bayer) is the first product to combine estradiol valerate with the progestin dienogest. The once-daily product provides four different doses of the two drugs over the 28-day menstrual cycle. Efficacy of Natazia was demonstrated in two studies of 1,867 women. Patients with obesity (BMI of 30 kg/m2 or more) were not included in the study. Safety risks include venous and arterial thrombotic and thromboembolic events (including myocardial infarction, thromboembolism, stroke), hepatic neoplasia, gallbladder disease, hypertension, ruptured ovarian cyst, and uterine leiomyoma. Bayer notes that the excess risk of thromboembolic events is highest during the first year of use of combination oral contraceptives such as Natazia.
* A Medication Guide for patients and revisions to the product labeling for
Vivitrol (naltrexone for extended-release injectable suspension) are now available, Alkermes and FDA announced yesterday. Language about injection-site reactions were strengthened last June, the company notes in a dear healthcare professional letter. The Med Guide replaces the patient package insert that was previously available.
*
Children’s Zyrtec Perfect Measure Grape has been added to the list of recalled children’s cough-and-cold product, McNeil Consumer Healthcare said. Health professionals may have samples of this product; these should be discarded.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 10, 2010 * Vol. 17, No. 89
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 8 issue of Lancet (2010; 375).
Triglycerides & Coronary Heart Disease: Data from 101 studies demonstrate a causal relationship between genetic changes affecting triglyceride-mediated pathways and development of coronary heart disease, researchers report (pp. 1634–9). The analysis focused on a promoter polymorphism of the apolipoprotein A5 (APOA5) gene, –1131T>C. These patterns were found among 20,842 patients with CHD, 35,206 controls with genetically raised triglyceride levels, 302,430 participants with no CHD, and 12,785 incident cases of CHD: “The minor allele frequency of –1131T>C was 8% (95% CI 7–9). –1131T>C was not significantly associated with several non-lipid risk factors or LDL cholesterol, and it was modestly associated with lower HDL cholesterol (mean difference per C allele 3.5% [95% CI 2.6–4.6]; 0.053 mmol/L [0.039–0.068]), lower apolipoprotein AI (1.3% [0.3–2.3]; 0.023 g/L [0.005–0.041]), and higher apolipoprotein B (3.2% [1.3–5.1]; 0.027 g/L [0.011–0.043]). By contrast, for every C allele inherited, mean triglyceride concentration was 16.0% (95% CI 12.9–18.7), or 0.25 mmol/L (0.20–0.29), higher (p = 4.4×10−24). The odds ratio for coronary heart disease was 1.18 (95% CI 1.11–1.26; p = 2.6×10−7) per C allele, which was concordant with the hazard ratio of 1.10 (95% CI 1.08–1.12) per 16% higher triglyceride concentration recorded in prospective studies. –1131T>C was significantly associated with higher VLDL particle concentration (mean difference per C allele 12.2 nmol/L [95% CI 7.7–16.7]; p = 9.3 × 10–8) and smaller HDL particle size (0.14 nm [0.08–0.20]; p = 7.0 × 10–5), factors that could mediate the effects of triglyceride.” (Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration)
Vitamin A & Maternal Survival: In study conducted in Ghana, provision of vitamin A supplementation to women of child-bearing age failed to significantly affect pregnancy or offspring outcomes (pp. 1640–9). Concluding that the evidence “does not support inclusion of vitamin A supplementation for women in either safe motherhood or child survival strategies,” the investigators provide these results: “544 clusters (104,484 women) were randomly assigned to vitamin A supplementation and 542 clusters (103,297 women) were assigned to placebo. The main reason for participant drop out was migration out of the study area. In the [intention-to-treat] analysis, there were 39,601 pregnancies and 138 pregnancy-related deaths in the vitamin A supplementation group (348 deaths per 100,000 pregnancies) compared with 39,234 pregnancies and 148 pregnancy-related deaths in the placebo group (377 per 100,000 pregnancies); adjusted odds ratio 0.92, 95% CI 0.73–1.17; p = 0.51. 1,326 women died in 292,560 woman-years in the vitamin A supplementation group (453 deaths per 100,000 years) compared with 1,298 deaths in 289,310 woman–years in the placebo group (449 per 100,000 years); adjusted rate ratio 1.01, 0.93–1.09; p = 0.85.” (B. R. Kirkwood, betty.kirkwood@lshtm.ac.uk)

>>>PNN NewsWatch
* Experts are not sure what to make of the presence of pig DNA in the two U.S. rotavirus vaccine products, but they don’t think the contaminant poses health hazards, the Los Angeles Times reports. On Friday, the FDA advisory committee on vaccines heard testimony from GlaxoSmithKline, whose Rotarix product remains suspended after porcine circovirus type 1 was found in it, and Merck, which revealed at the meeting that both PCV1 and PCV2 were found in its Rotateq product when highly sensitive assays were used. The latter product remains in use, and panelists supported return of Rotarix to use.

>>>PNN JournalWatch
* Percutaneous Endoscopic Gastrostomy (PEG) Feeding, in BMJ, 2010; 340: c2414. (M. Kurien, matthew.kurien@chesterfieldroyal.nhs.uk)
* Proteomic Strategies in the Search of New Biomarkers in Atherothrombosis, in
Journal of the American College of Cardiology, 2010; 55: 2009–16. (J. Tuñón, j.tunon@wanadoo.es)
* Tolerance and Withdrawal From Prolonged Opioid Use in Critically Ill Children, in
Pediatrics, 2010; 125: e1208–25. (K. J. S. Anand)
* Genetic Sensitivity to the Environment: The Case of the Serotonin Transporter Gene and Its Implications for Studying Complex Diseases and Traits, in
American Journal of Psychiatry, 2010; 167: 509–27. (A. Caspi)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 11, 2010 * Vol. 17, No. 90
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 10 issue of the Archives of Internal Medicine (2010; 170).
PPIs in Postmenopausal Women: Use of proton-pump inhibitors in postmenopausal women is associated with fractures of the spine, forearm, and wrist, researchers report (pp. 765–71). In nearly 162,000 women aged 50–79 years who participated in the Women’s Health Initiative, these relationships between medication use and self-reported fractures were observed: “During 1,005,126 person–years of follow-up, 1,500 hip fractures, 4,881 forearm or wrist fractures, 2,315 clinical spine fractures, and 21,247 total fractures occurred. The multivariate-adjusted hazard ratios for current PPI use were 1.00 (95% confidence interval [CI], 0.71–1.40) for hip fracture, 1.47 (95% CI, 1.18–1.82) for clinical spine fracture, 1.26 (95% CI, 1.05–1.51) for forearm or wrist fracture, and 1.25 (95% CI, 1.15–1.36) for total fractures. The BMD measurements did not vary between PPI users and nonusers at baseline. Use of PPIs was associated with only a marginal effect on 3-year BMD change at the hip (P = .05) but not at other sites.” (S. L. Gray, slgray@u.washington.edu)
Commenting on this and several other articles on PPIs in this issue (some of which are detailed below), an editorialist writes that these drugs may not provide enough benefit to justify their risks in many patients (
pp. 747–8): “Why are so many people treated with PPIs? One reason is that dyspepsia, a condition that leads to its use, is very common (25% of adults report dyspepsia), and PPIs are very effective at reducing the symptoms and have no immediate adverse effects that would dissuade patients from their use. Equally important, prescribing PPIs fits our medical model. The patient has a symptom; we give it a fancy name. We call persistent indigestion (without evidence of ulcer disease or esophagitis) ‘functional dyspepsia.’ We call heartburn ‘gastroesophageal reflux.’ Next, we treat the symptom with a medication, ideally one in pill form.…
“On a broader level, the over prescription of PPIs should also remind us to critically evaluate our own treatment paradigms: ‘more is better’ or ‘do no harm’?” (M. H. Katz,
mitch.Katz@sfdph.org)
PPIs & Recurrent Clostridrial Infections: Recurrence of antibiotic-associated Clostridium difficile infection was significantly more common among patients treated with proton-pump inhibitors, according to a retrospective cohort analysis of data from a VA center (pp. 772–8). Oral PPIs were used in 45% of 1,166 inpatients and outpatients with metronidazole- or vancomycin hydrochloride–treated incident CDI in 2003–08, with these results in comparison with those not receiving PPIs: “Recurrent CDI was more common in those exposed to PPIs than in those not exposed (25.2% vs 18.5%). Using Cox proportional survival methods, we determined that the adjusted HR of recurrent CDI was greater in those exposed to PPIs during treatment (1.42; 95% confidence interval [CI], 1.11–1.82). Risks among exposed patients were highest among those older than 80 years (HR, 1.86; 95% CI, 1.15–3.01) and those receiving antibiotics not targeted to C difficile during follow-up (HR, 1.71; 95% CI, 1.11–1.64).” (A. Linsky, Amy.Linsky@bmc.org)
Guidelines for PPIs in GI Bleeds: Reduced use of proton-pump inhibitors during hospitalization for prophylaxis against nosocomial upper gastrointestinal bleeding and on discharge was observed when standardized guidelines were implemented, researchers report (pp. 779–83). Investigators compared PPI use in the month before and after guideline implementation, with these results: “Among an overall cohort of 942 patients, 48% were prescribed PPIs while inpatients, and 41% were prescribed PPIs at hospital discharge. Univariate predictors of inpatient PPI use included age, length of hospital stay, history of gastroesophageal reflux disease or upper gastrointestinal tract bleeding, and outpatient PPI, aspirin, or glucocorticoid use. Among patients not on an outpatient regimen of PPIs at admission, implementation of guidelines resulted in lower rates of inpatient PPI use (27% before vs 16% after, P = .001) and PPI prescription at discharge (16% before vs 10% after, P = .03).” (P. S. Yachimski, patrick.yachimski@vanderbilt.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 12, 2010 * Vol. 17, No. 91
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 12 issue of JAMA (2010; 303).
Annual Vitamin D & Falls: In 2,256 community-dwelling women, annual high-dose oral vitamin D therapy was associated with an increased risk of falls and fractures, researchers report (pp. 1815–22). Patients received placebo or cholecalciferol 500,000 IU orally in autumn or winter for 5 years, with these results: “Women in the cholecalciferol (vitamin D) group had 171 fractures vs 135 in the placebo group; 837 women in the vitamin D group fell 2,892 times (rate, 83.4 per 100 person–years) while 769 women in the placebo group fell 2,512 times (rate, 72.7 per 100 person–years; incidence rate ratio [RR], 1.15; 95% confidence interval [CI], 1.02–1.30; P = .03). The incidence RR for fracture in the vitamin D group was 1.26 (95% CI, 1.00–1.59; P = .047) vs the placebo group (rates per 100 person–years, 4.9 vitamin D vs 3.9 placebo). A temporal pattern was observed in a post hoc analysis of falls. The incidence RR of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (test for homogeneity; P = .02). In the substudy, the median baseline serum 25-hydroxycholecalciferol was 49 nmol/L. Less than 3% of the substudy participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L. In the vitamin D group, 25-hydroxycholecalciferol levels increased at 1 month after dosing to approximately 120 nmol/L, were approximately 90 nmol/L at 3 months, and remained higher than the placebo group 12 months after dosing.” (K. Sanders, kerrie@barwonhealth.org.au)
Writing that high-dose vitamin D may have been “too much of a good thing,” editorialists question the current use of high loading doses in vitamin D–deficient patients (
pp. 1861–2): “The study by Sanders et al underscores the importance of simultaneously continuing to improve understanding of basic vitamin D physiology, particularly as it relates to the increased variety of supplement forms that have become available by prescription and over-the-counter. Specifically, the effect of dose size, route (intramuscular vs oral), and dosing interval on aspects of vitamin D metabolism including CYP24 activity and on local tissue-specific 1,25-dihydroxyvitamin D levels and actions should be investigated. It may also be necessary to reevaluate the risks and benefits of the current clinical practice of providing high loading doses of cholecalciferol to patients who are vitamin D deficient. In the meantime, it is important to reiterate that although vitamin D insufficiency is widespread, it can be safely corrected with a variety of existing supplement types and regimens and it should continue to be identified and treated in clinical practice.” (B. Dawson–Hughes, bess.dawson-hughes@tufts.edu)
Criteria for and Management of Food Allergies: In a Clinician’s Corner article, the need for better diagnositic criteria and management strategies for food allergies is discussed (pp. 1848–56). Based on data in 72 studies, the investigators estimate the prevalence of food allergies at more than 1% or 2% but less than 10%. Elimination diets are the “mainstay of therapy” for food allergies, the authors note, but these are “rarely studied.” They add, “Immunotherapy is promising but data are insufficient to recommend use. In high-risk infants, hydrolyzed formulas may prevent cow’s milk allergy but standardized definitions of high risk and hydrolyzed formula do not exist.” (J. J. Schneider Chafen, jjschnei@stanford.edu)

>>>PNN NewsWatch
* FDA wants the help of health professionals in identifying and reporting misleading or inaccurate promotions of pharmaceuticals. The Bad Ad Program aims to educate physicians, nurses, pharmacists, and others about ”their role in ensuring that prescription drug advertising and promotion is truthful, and not misleading,” the agency said in a news release. FDA plans to first engage health care providers at certain medical conventions and partner with specific medical societies to distribute educational materials, and then to expand those activities and update educational materials as needed. FDA added that health care professionals are encouraged to report a potential violations in drug promotions by pharmaceutical companies by e-mailing badad@fda.gov or calling 877-RX-DDMAC. Reports can be submitted anonymously, but FDA encourages inclusion of contact information.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 13, 2010 * Vol. 17, No. 92
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
May 13 issue of the New England Journal of Medicine (2010; 362).
Maternal Vitamin A & Offspring Lung Function: Rural Nepali children aged 9 to 13 years had better lung function when their mothers received vitamin A supplementation before, during, and after pregnancy, according to an update of a 1994–97 trial (pp. 1784–94). Mothers participated in a trial of vitamin A versus beta-carotene, and offspring showed these patterns when evaluated in pre-adolescence: “Of 1,894 children who were alive at the end of the original trial, 1,658 (88%) were eligible to participate in the follow-up trial. We performed spirometry in 1,371 of the children (83% of those eligible) between October 2006 and March 2008. Children whose mothers had received vitamin A had a forced expiratory volume in 1 second (FEV1) and a forced vital capacity (FVC) that were significantly higher than those of children whose mothers had received placebo (FEV1, 46 ml higher with vitamin A; 95% confidence interval [CI], 6 to 86; FVC, 46 ml higher with vitamin A; 95% CI, 8 to 84), after adjustment for height, age, sex, body-mass index, calendar month, caste, and individual spirometer used. Children whose mothers had received beta carotene had adjusted FEV1 and FVC values that were similar to those of children whose mothers had received placebo (FEV1, 14 ml higher with beta carotene; 95% CI, –24 to 54; FVC, 17 ml higher with beta carotene, 95% CI, –21 to 55).” (W. Checkley, wcheckl1@jhmi.edu)
The relationship between lung development and function and retinoid administration is summarized thusly by editorialists (
pp. 1829–31): “The results of the study by Checkley et al. and the endemic nature of vitamin A deficiency—including its occurrence in developed nations—among obese persons, and especially among women who have had multiple full-term pregnancies with a short interval between pregnancies, provide further rationale for the need for adequate and appropriate nutrition for everyone and for the need for health care providers in all nations, underdeveloped and developed, to be alert to the possibility of vitamin A deficiency.
“Beyond vitamin A, the article by Checkley et al. should prompt physicians to consider the effect of impaired anatomical development of the lung—whatever the cause—on disease-related loss of lung function. Persons with developmentally related low conducting-airway function, with fewer alveoli, or with both at the onset of a disease such as chronic obstructive pulmonary disease (which itself impairs airflow in conducting airways and destroys alveoli) would be expected to have an earlier onset of symptoms of respiratory insufficiency than would those without impaired anatomical development.” (D. Massaro)
Treating Gram-Negative Hospital-Acquired Infections: Combination therapy and monotherapy of hospital-acquired infections of gram-negative bacteria are evaluated in a review article (pp. 1804–13): “For empirical treatment, combination therapy improves the likelihood that a drug with in vitro activity against the suspected organism is being administered (often defined as appropriate therapy).… We recommend institution-tailored combination therapy for the empirical treatment of serious hospital-acquired gram-negative infections, followed by de-escalation to monotherapy once susceptibilities have been determined. Although clinicians have historically preferred dual therapy for serious pseudomonal infections, the data support single-agent therapy as long as an active beta-lactam can be chosen.” (A. Y. Peleg, apeleg@bidmc.harvard.edu)

>>>PNN NewsWatch
* Serious adverse effects are resulting from consumer ingestion of topical diphenhydramine topical gels, FDA said yesterday. Benadryl Extra Strength Itch Stopping Gel is one of several topical products marketed by McNeil Consumer Healthcare Division. Unconsciousness, hallucinations, and confusion have resulted when patients have mistakenly taken this gel orally rather than applying it to their skin as intended. The manufacturer is making several changes to the product’s packaging to help consumers avoid the error, including prominent statements of “For Skin Use Only” on the bottle’s label and cap. FDA notes that many pharmacies and grocers carry generic versions of this product that could be similarly misused and is encouraging manufacturers of these products to make similar changes.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 14, 2010 * Vol. 17, No. 93
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
May 18 issue of the Journal of the American College of Cardiology (2010; 55).
High-Dose Acetylcysteine in Contrast-Induced Nephropathy: In 251 patients undergoing primary angioplasty, high-dose N-acetylcysteine reduced indicators of oxidative stress but failed to affect contrast-induced nephropathy or myocardial reperfusion injury, researchers report (pp. 2201–9). Patients received the drug in doses of 1,200 mg/day for 2 days or placebo along with adequate hydration before angioplasty. Results showed: “The median volume of an iso-osmolar contrast agent during angiography was 180 ml (interquartile range [IQR] 140 to 230 ml) in the N-acetylcysteine and 160 ml (IQR 120 to 220 ml) in the placebo group (p = 0.20). The primary end point contrast-induced nephropathy occurred in 14% of the N-acetylcysteine group and in 20% of the placebo group (p = 0.28). The myocardial salvage index was also not different between both treatment groups (43.5; IQR 25.4 to 71.9 vs. 51.5; IQR 29.5 to 75.3; p = 0.36). Activated oxygen protein products and oxidized low-density lipoprotein as markers for oxidative stress were reduced by as much as 20% in the N-acetylcysteine group (p < 0.05), whereas no change was evident in the placebo group.” (H. Thiele, thielh@medizin.uni-leipzig.de)
Physicians Need to Improve Health Care System: A trio of physicians—including the CEO of the American College of Cardiology—call on physicians to address needed changes in the American health care system (pp. 2196–200). After addressing issues of appropriate services, “system professionalism” as provided through a medical team, need for a National Institute for Keeping People Healthy, coverage of the uninsured, and provision of access for all, the group concludes: “Jordan Cohen, the president of the [Association of American Medical Colleges], put it best: ‘We should not accept without challenge what we know to be abominable just because it appears to be inevitable.’ We all recognize that some parts of our system are abominable, but we must take the view that it is possible to work within it and in ways additional to the new legislation to help fix the system. We as physicians know the problems; we will likely have opinions on the solutions and should express them for our patients, for our country, and for ourselves. Our system must change. Exerting leadership to move medical practice and our entire health care system toward ever-improving, high-quality, and efficient care is best for the patient and for our profession.” (A. Garson, Jr., garson@virginia.edu)

>>>Circulation Report
Source:
May 11 issue of Circulation (2010; 121).
Triple Antithrombotic Therapy: Based on the case of a 76-year-old man who undergoes percutaneous coronary intervention with bare-metal stent placement, authors review optimal antithrombotic therapy in this clinical situation (pp. 2067–70). The authors conclude that triple therapy is best: “Because of the patient’s very high risk of recurrent stroke, he was treated with aspirin 81 mg once daily, clopidogrel 75 mg once daily, and warfarin, targeting an INR of 2.0 to 2.5 for 4 weeks, at which time clopidogrel was discontinued. The same patient receiving a drug-eluting stent instead of a bare-metal stent would continue with triple therapy for 3 or 6 months, at which time clopidogrel would be discontinued. Warfarin was managed by a specialist anticoagulation clinic, and the patient received acid-suppressive therapy to reduce his risk of gastrointestinal bleeding.” (J. S. Paikin, paikinjs@mcmaster.ca)
Stroke as CHD Risk Equivalent: Stroke should be included both as a risk equivalent in calculating coronary heart disease risk and as an outcome in the estimation of risk in primary and secondary prevention, authors argue (pp. 2071–8). “Excluding stroke as an outcome in risk calculation could have significant clinical implications because of an underestimation of risk and failure to treat patients who would otherwise qualify for preventive therapy,” the group writes. “For example, for an individual whose risk score when only coronary events are used puts him or her just below the threshold for treatment (10% over 10 years for aspirin or 20% over 10 years for statin therapy), inclusion of stroke in the outcome cluster would likely push him or her over the threshold.” (M. S. Dhamoon, msd2102@mail.cumc.columbia.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 17, 2010 * Vol. 17, No. 94
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
May 15 issue of Lancet (2010; 375).
Time to Treatment of Ischemic Stroke: Alteplase treatment of ischemic stroke improves outcomes up to 4.5 hours after stroke onset, but after that, risk may outweigh benefit, researchers report (pp. 1695–703). Onset to start of treatment (OTT) data from eight trials of nearly 3,700 patients showed these outcomes: “Treatment was started within 360 min of stroke onset in 3,670 patients randomly allocated to alteplase (n = 1,850) or to placebo (n = 1,820). Odds of a favourable 3-month outcome increased as OTT decreased (p = 0.0269) and no benefit of alteplase treatment was seen after around 270 min. Adjusted odds of a favourable 3-month outcome were 2.55 (95% CI 1.44–4.52) for 0–90 min, 1.64 (1.12–2.40) for 91–180 min, 1.34 (1.06–1.68) for 181–270 min, and 1.22 (0.92–1.61) for 271–360 min in favour of the alteplase group. Large parenchymal haemorrhage was seen in 96 (5.2%) of 1,850 patients assigned to alteplase and 18 (1.0%) of 1,820 controls, with no clear relation to OTT (p = 0.4140). Adjusted odds of mortality increased with OTT (p = 0.0444) and were 0.78 (0.41–1.48) for 0–90 min, 1.13 (0.70–1.82) for 91–180 min, 1.22 (0.87–1.71) for 181–270 min, and 1.49 (1.00–2.21) for 271–360 min.” (K. R. Lees, k.r.lees@clinmed.gla.ac.uk)
Adult Deaths a Priority Too: “Routine monitoring of adult deaths should be given much greater emphasis,” conclude investigators who studied worldwide mortality patterns, adding that “prevention of premature adult death is just as important for global health policy as the improvement of child survival” (pp. 1704–20). The probability of death between ages 15 and 60 years (45q15) was determined using 3,889 measurements of adult mortality from 187 countries from 1970 to 2010, with these results: “Adult mortality varied substantially across countries and over time. In 2010, the countries with the lowest risk of mortality for men and women are Iceland and Cyprus, respectively. In Iceland, male 45q15 is 65 (uncertainty interval 61–69) per 1,000; in Cyprus, female 45q15 is 38 (36–41) per 1,000. Highest risk of mortality in 2010 is seen in Swaziland for men (45q15 of 765 [692–845] per 1,000) and Zambia for women (606 [518–708] per 1,000). Between 1970 and 2010, substantial increases in adult mortality occurred in sub-Saharan Africa because of the HIV epidemic and in countries in or related to the former Soviet Union. Other regional trends were also seen, such as stagnation in the decline of adult mortality for large countries in southeast Asia and a striking decline in female mortality in south Asia.” (C. J. L. Murray, cjlm@u.washington.edu)

>>>BMJ Highlights
Source:
Early-release article from BMJ (2010; 340).
HIV Infectivity with Antiretroviral Therapy: Heterosexual couples in which one partner has HIV infection and is being treated with combination antiretroviral therapy rarely have seroconversion of the uninfected partner, a study shows (c2205). At an HIV clinic in Madrid, these data were recorded: “In 476 couples in which the index partner was not taking antiretroviral treatment, HIV seroprevalence at enrolment in non-index partners was 9.2% (n = 44), whereas in 149 couples in which the index partner was taking combined antiretroviral therapy no partner was infected (P < 0.001). During follow-up, the 341 serodiscordant couples in which the index partner was not taking antiretroviral treatment had about 11,000 acts of intercourse without condoms, 50 natural pregnancies, and five HIV seroconversions (0.0004 per unprotected intercourse; 95% confidence interval 0.0001 to 0.0010); 294 of these couples always used condoms, accounting for about 42,000 acts of intercourse, 136 risk exposures from condom failure, and one HIV seroconversion. The relative risk associated with condom use was 0.07 (0.01 to 0.58). In 144 couples the index partner was taking combined antiretroviral treatment; they accounted for over 7,000 unprotected acts of intercourse and 47 natural pregnancies but no HIV seroconversion (0 to 0.0005 per unprotected intercourse).” (J. Del Romero, jorgedelromero@gmail.com)

>>>PNN NewsWatch
* Use of Rotarix (rotavirus vaccine, GSK) can be resumed, FDA says.

>>>PNN JournalWatch
* Potential New Therapeutic Agents for Diabetic Kidney Disease, in American Journal of Kidney Diseases, 2010; 55: 928–40. (W. K. Bolton, wkb5s@virginia.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 18, 2010 * Vol. 17, No. 95
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and May 18 issue of the Annals of Internal Medicine (2010; 152).
Costs, Fractures, & Androgen Deprivation Therapy: In all but the highest risk men undergoing androgen deprivation therapy for prostate cancer, a bone mineral density screening test should be used to identify those needing alendronate, a cost-effectiveness analysis shows (pp. 621–9). Researchers applied published data to a hypothetical cohort of men aged 70 with locally advanced or high-risk localized prostate cancer. Incremental cost-effectiveness ratio (ICER), measured by cost per quality-adjusted life-year (QALY) gained, showed these 2-year results: “The ICERs for the strategy of a BMD test and selective alendronate therapy for patients with osteoporosis and universal alendronate therapy without a BMD test were $66,800 per QALY gained and $178,700 per QALY gained, respectively.” (K. Ito, itok1@mskcc.org)
New Markers for Coronary Artery Disease: Serum levels of fibroblast growth factor 23 (FGF23) and uncarboxylated matrix Gla protein (ucMGP) were independently associated with mortality and cardiovascular events in patients with stable coronary artery disease, researchers report (pp. 640–8). A third marker, fetuin-A, was not significantly correlated with outcomes, the study showed, providing these data on 833 outpatients with CAD: “During a median follow-up of 6.0 years, 220 participants died and 182 had CVD events. Compared with participants with FGF-23 levels in the lowest tertile, those in the highest tertile had 2-fold greater risk for mortality (hazard ratio [HR], 2.15 [95% CI, 1.43 to 3.24]) and CVD events (HR, 1.83 [CI, 1.15 to 2.91]) after adjustment for traditional CVD risk factors, C-reactive protein levels, and kidney function. The highest ucMGP tertile was associated with lower mortality risk (HR, 0.48 [CI, 0.31 to 0.75]) and showed a nonsignificant trend toward lower CVD event risk by tertile analysis (HR, 0.65 [CI, 0.40 to 1.05])—an association that was significant when modeled continuously (P = 0.029). No significant association of fetuin-A with mortality (HR, 0.84 [CI, 0.55 to 1.27]) or CVD events (HR, 0.99 [CI, 0.64 to 1.55]) was observed.” (J. H. Ix, joeix@ucsd.edu)
Perspective on Health Care Reform: An author provides insights into the recently enacted health care reform law (pp. 679–82): “The Patient Protection and Affordable Care Act (PPACA) of 2010 was signed into law by President Obama on March 23. This legislation has elicited much debate among policy experts and the public alike. No one knows exactly how this new complex law will play out, and objective evaluation of its effects is important. The American College of Physicians hopes that the legislation will advance key priorities on coverage, workforce, and payment and delivery system reform. The goal of the PPACA is to help provide affordable health insurance coverage to most Americans, improve access to primary care, and lower costs. This article discusses what the chances are that it will accomplish these objectives. It also explains many of the key provisions in the legislation and how they will affect both physicians and patients. Despite considerable uncertainty about the effects of this act, when compared with the status quo, it is an extraordinary achievement that will continue to evolve through its implementation.” (R. B. Doherty)
Dealing with Conflicts of Interest: A potential solution is offered to the “tension … between the competing goals of optimizing guideline quality by using the experience and insight of experts and ensuring that financial and intellectual conflicts of interest do not influence recommendations” (early release): “The executive committee of the American College of Chest Physicians’ Antithrombotic Guidelines has developed a strategy comprising 3 innovative aspects to address this tension: First, place equal emphasis on intellectual and financial conflicts and provide explicit criteria for both; second, a methodologist without important conflicts of interest should have primary responsibility for each chapter; and third, experts with important financial or intellectual conflicts of interest can collect and interpret evidence, but only panel members without important conflicts can be involved in developing the recommendation for a specific question. These strategies may help to achieve the benefits of expert input without conflicts of interest influencing recommendations.” (G. Guyatt, guyatt@mcmaster.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 19, 2010 * Vol. 17, No. 96
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
May 19 issue of JAMA, a theme issue on mental health (2010; 303).
Anxiety Management: Patients with a variety of anxiety disorders fared better when managed with Coordinated Anxiety Learning and Management (CALM) therapy, in comparison with usual care (UC), researchers report (pp. 1921–8). Under CALM, patients received cognitive–behavioral therapy (CBT), medications, or both. In 1,004 patients with panic disorder, generalized anxiety disorder, social anxiety disorder, or posttraumatic stress disorder, the interventions had these effects on patients’ Brief Symptom Inventory (BSI-12) anxiety and somatic symptoms score: “A significantly greater improvement for CALM vs UC in global anxiety symptoms was found (BSI-12 group mean differences of –2.49 [95% confidence interval {CI}, –3.59 to –1.40], –2.63 [95% CI, –3.73 to –1.54], and –1.63 [95% CI, –2.73 to –0.53] at 6, 12, and 18 months, respectively). At 12 months, response and remission rates (CALM vs UC) were 63.66% (95% CI, 58.95%–68.37%) vs 44.68% (95% CI, 39.76%–49.59%), and 51.49% (95% CI, 46.60%–56.38%) vs 33.28% (95% CI, 28.62%–37.93%), with a number needed to treat of 5.27 (95% CI, 4.18–7.13) for response and 5.50 (95% CI, 4.32–7.55) for remission.” (P. Roy–Byrne, roybyrne@u.washington.edu)
Behavior Therapy for Tourette Disorder: In 126 children with Tourette or chronic tic disorder, a comprehensive behavioral intervention was significantly more effective than supportive therapy and education, according to a trial conducted in 2004–07 (pp. 1929–37). Eight therapy sessions during a 10-week period produced these outcomes: “Behavioral intervention led to a significantly greater decrease on the Yale Global Tic Severity Scale (24.7 [95% confidence interval {CI}, 23.1–26.3] to 17.1 [95% CI, 15.1–19.1]) from baseline to end point compared with the control treatment (24.6 [95% CI, 23.2–26.0] to 21.1 [95% CI, 19.2–23.0]) (P < .001; difference between groups, 4.1; 95% CI, 2.0–6.2) (effect size = 0.68). Significantly more children receiving behavioral intervention compared with those in the control group were rated as being very much improved or much improved on the Clinical Global Impressions–Improvement scale (52.5% vs 18.5%, respectively; P < .001; number needed to treat = 3). Attrition was low (12/126, or 9.5%); tic worsening was reported by 4% of children (5/126). Treatment gains were durable, with 87% of available responders to behavior therapy exhibiting continued benefit 6 months following treatment.” (J. Piacentini, jpiacentini@mednet.ucla.edu)
Commenting on this and other papers in this theme issue on mental health, an editorialist writes (
pp. 1978–9): “It is disappointing that we did not receive any high-quality submissions for this theme issue on prevention of mental disorders, although JAMA has published such articles previously. This appears to be one aspect of the paucity of research, attention, and resources devoted to disease prevention and health promotion. It is certainly to be hoped that as parity for insurance coverage for mental disorders takes hold as part of US health care reform, and as the global mental health movement gains strength, the outlook for patients with mental disorders and their families will improve. However, an even better outcome would be the development of effective measures to prevent the onset and progression of these common and disabling disorders.” (R. M. Glass, richard.glass@jama-archives.org)
DSM-5 on the Way: Scheduled for publication in 2013, the fifth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5) needs to better address the “interface between psychiatry and general medicine,” editorialists write (pp. 1974–5): “A study group, implementing a psychiatry and general medical interface, was convened to address these issues. Co-occurrence of psychiatric and general medical symptoms also has implications for the assessment of disability because it is difficult for patients to separate the effects of their physical and mental symptoms on their overall activities of daily living. Accordingly, the DSM-5 disability assessment study group is considering methods to assess disability on a global level. This approach is consistent with that taken by the World Health Organization in its publication International Classification of Functioning, Disability, and Health.” (D. J. Kupfer, kupferdj@upmc.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 21, 2010 * Vol. 17, No. 98
Providing news and information about medications and their proper use

>>>JAPhA Highlights
Source:
May/June issue of the Journal of the American Pharmacists Assoc. (2010; 50).
Pharmacists’ MTM Recommendations: For 88 Medicaid patients, pharmacists’ medication therapy management recommendations produced annual savings of $9,444 and a net savings of $2,724 after MTM payments were considered (pp. 347–53). A retrospective analysis of records at 92 Kerr Drug locations in North Carolina showed these results: “Acceptance rate of pharmacist recommendations ranged from 42% to 60%. The rate at which the pharmacists’ accepted recommendations were implemented at Kerr Drug pharmacy ranged from 62% to 86% across the four quarterly reviews. Overall economic impact resulted in an average cost savings of $107 per beneficiary to North Carolina Medicaid per year. Quarterly economic impact results revealed that the highest impact occurred during the first quarterly review at $63 per beneficiary.” (N. M. Michaels, tmichaels@kerrhealth.com)
Compounding in Australian Pharmacies: Pharmacies in Australia that compound have distinctly different characteristics than those that do not, according to a survey conducted in 2006–07 (pp. 354–61). Using organization theory to assess the responses of 271 pharmacist proprietors and compounding pharmacists, the investigators determined: “Specialized compounding pharmacies were more likely to interact with a greater variety of prescribers of compounds and be located in a medical center/central business district setting. The majority of differences were found in the pharmacies’ organizational configuration. Specialized compounding staff were more likely to have undertaken further training in compounding and to prepare batches of product using specialized equipment and processes. A greater professional service orientation was apparent in specialized compounding pharmacies.” (J. A. Giam, jlee2941@uni.sydney.edu.au)
Privacy in Community Pharmacies: Most staff–patient interactions in community pharmacies occur while others are within 6 feet, a study shows, thereby potentially compromising protected health information (pp. 362–7). At 282 New York State pharmacies, observers collected data on the distances between staff–patient encounters and other patients in the pharmacy. Results from 597 encounters showed: “167 [interactions] occurred while a second patient was within 6 ft. Of the 282 pharmacies, pharmacy staff–patient conversations were audible to observers more than 6 ft away in 229 pharmacies; 142 could be heard more than 15 ft away.” (L-A McNutt, lamcnutt@gmail.com)
Continuing Professional Development Among Pharmacists: Adoption of continuing professional development as a replacement for pharmacy’s traditional continuing education system is unpopular, according to a survey of 471 Texas pharmacists (pp. 368–74). Not only did few pharmacists use elements of CPD—such as identification of areas of need and development of a plan to meet those needs—the majority believed that approach would not help them in maintaining professional competency: “The most common stimulants for learning were self-reflection, patients, literature, and regulatory requirements. The most highly rated sources of education were live followed by printed CE programs. Nearly one-third of respondents felt that a change to a CPD model would be beneficial to their professional development. More than one-half of respondents (53%) indicated that they were unsure of the benefits of CPD.” (R. A. Bellanger, bellange@uiwtx.edu)
Ensuring Pharmacist Competence: In an editorial, authors describe the rationale for better systems for ensuring pharmacists’ competence (pp. 343–6): “A coherent, well-designed, and accessible framework for professional credentialing is critical to the pharmacy profession’s future credibility. As members of a profession committed to patient-centered care, we should be held to the same societal expectations as other clinical disciplines (e.g., medicine). That is, the pharmacy profession should further evolve a rational, defensible credentialing system that documents the achievement and maintenance of competence across the spectrum of practitioners (from generalist to specialist to subspecialist). Anything less might cause health professional colleagues to doubt pharmacy’s commitment to ensuring competence as it extends its practice roles, thereby bringing into question its credibility as a caregiving profession.” (M. J. Rouse)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 24, 2010 * Vol. 17, No. 99
Providing news and information about medications and their proper use

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 340).
Vitamin B12 Testing During Metformin Therapy: Regular monitoring of serum concentrations of vitamin B12 should be considered during long-term metformin therapy, investigators conclude based on a study of 390 patients with type 2 diabetes (c2181). These results were obtained during 4.3 years of therapy with metformin 850 mg or placebo three times daily in patients also on insulin therapy: “Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B12 concentration of –19% (95% confidence interval –24% to –14%; P < 0.001) and in folate concentration of –5% (95% CI –10% to –0.4%; P = 0.033), and an increase in homocysteine concentration of 5% (95% CI –1% to 11%; P = 0.091).… The absolute risk of vitamin B12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P = 0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B12 concentration (150–220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P = 0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared with a mean homocysteine level of 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; P = 0.003) for patients with a low vitamin B12 concentration and 14.9 µmol/l (95% CI 14.3 to 15.5 µmol/l; P < 0.001 compared with vitamin B12 deficiency; P = 0.005 compared with low vitamin B12) for patients with a normal vitamin B12 concentration (>220 pmol/l).” (C. D. A. Stehouwer, cda.stehouwer@mumc.nl)
Claims of Benefits or Harm with Statins: A population-based cohort study quantifies adverse effects of statin therapy but fails to support various claims of benefits of statin therapy, except for a brief decrease in risk of esophageal cancer, researchers report (c2197). Among 2 million adults at 368 general practices in England and Wales, these findings were noted: “Individual statins were not significantly associated with risk of Parkinson’s disease, rheumatoid arthritis, venous thromboembolism, dementia, osteoporotic fracture, gastric cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer. Statin use was associated with decreased risks of oesophageal cancer but increased risks of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataract. Adverse effects were similar across statin types for each outcome except liver dysfunction where risks were highest for fluvastatin. A dose–response effect was apparent for acute renal failure and liver dysfunction. All increased risks persisted during treatment and were highest in the first year. After stopping treatment the risk of cataract returned to normal within a year in men and women. Risk of oesophageal cancer returned to normal within a year in women and within 1–3 years in men. Risk of acute renal failure returned to normal within 1–3 years in men and women, and liver dysfunction within 1–3 years in women and from three years in men.” (J. Hippisley–Cox, julia.hippisley-cox@ntlworld.com)
Antimicrobial Resistance from Primary Care Prescribing: Patients receiving antibiotics in primary care for urinary or respiratory infections develop bacterial resistance to the drug that can persist for 12 months, according to a systematic review and meta-analysis (c2096; A. Hay, alastair.hay@bristol.ac.uk)

>>>PNN JournalWatch
* Transmission of Pandemic A/H1N1 2009 Influenza on Passenger Aircraft: Retrospective Cohort Study, in BMJ, 2010; 340: c2424. (M. Baker, michael.baker@otago.ac.nz)
* “Kissing Bugs”: Potential Disease Vectors and Cause of Anaphylaxis, in
Clinical Infectious Diseases, 2010; 50: 1629–34. (S. A. Klotz, sklotz@u.arizona.edu)
* Combination Antibiotics as a Treatment for Chronic
Chlamydia-Induced Reactive Arthritis: A Double-Blind, Placebo-Controlled, Prospective Trial, in Arthritis & Rheumatism, 2010; 62: 1298–307. (J. D. Carter, jocarter@health.usf.edu)
* Guilt by Intimate Association: What Makes an Allergen an Allergen?, in
Journal of Allergy and Clinical Immunology, 2010; 125: 955–60. (C. L. Karp, chris.karp@cchmc.org)
* Medicare Beneficiaries’ Knowledge of and Choices Regarding Part D, 2005 to the Present, in
Journal of the American Geriatrics Society, 2010; 58: 950–66. (J. M. Polinski, jpolinski@partners.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 25, 2010 * Vol. 17, No. 100
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
May 24 issue of the Archives of Internal Medicine (2010; 170).
Beta-Blockers in COPD: Beta-blockers, usually avoided in patients with chronic obstructive pulmonary disease and cardiovascular disease, may actually be beneficial, a study shows (pp. 880–7). Investigators attributed their surprising findings to possible advantages of the drug’s dual cardiopulmonary protective properties. The data, collected in an observational cohort study at 23 general practices in the Netherlands, showed the following: “In total, the study included 2,230 patients 45 years and older with an incident or prevalent diagnosis of COPD between 1996 and 2006. The mean (SD) age of the patients with COPD was 64.8 (11.2) years at the start of the study, and 53% of the patients were male. During a mean (SD) follow-up of 7.2 (2.8) years, 686 patients (30.8%) died and 1,055 (47.3%) had at least 1 exacerbation of COPD. The crude and adjusted hazard ratios with Cox regression analysis of beta-blocker use for mortality were 0.70 (95% confidence interval [CI], 0.59–0.84) and 0.68 (95% CI, 0.56–0.83), respectively. The crude and adjusted hazard ratios for exacerbation of COPD were 0.73 (95% CI, 0.63–0.83) and 0.71 (95% CI, 0.60–0.83), respectively. The adjusted hazard ratios with the propensity score methods were even lower. Subgroup analyses revealed that patients with COPD but without overt cardiovascular disease had similar results.” (F. H. Rutten, F.H.Rutten@umcutrecht.nl)
Commenting on the “curious case” of beta-blockers in COPD, editorialists write (
pp. 849–50): “[This] study … provocatively suggests that the use of beta-blockers, contrary to classic teaching, is not only safe but also can prolong survival and reduce exacerbations in COPD, providing new hope for patients with COPD. However, before we can fully accept this notion, a large, well-conducted, randomized controlled trial will be needed to confirm these findings. Until then, the data by Rutten and colleagues provide a rationale for the practicing clinicians to use beta-blockers (even noncardioselective ones such as carvedilol) cautiously in their patients with COPD who also have a coexisting cardiovascular condition for which a beta-blocker is required. To this end, Rutten and coauthors’ study has turned the story of beta-blockers in COPD into a curious case of a foe becoming a potential friend to millions of patients with COPD worldwide.” (D. D. Sin, don.sin@hli.ubc.ca)
Academic Detailing & Thiazide Prescribing: In the ALLHAT/JNC7 Dissemination Project, academic detailing improved physician prescribing of thiazides and thereby made antihypertensive therapy more consistent with evidence, researchers report (pp. 851–8). Using data from a physician survey and pharmacy dispensing database, the investigators found these county-level correlations: “Academic detailing reached 18,524 physicians in 1,698 venues via 147 investigator-educators. We noted an association between ALLHAT/JNC7 academic detailing activities and increased prescribing of thiazide-type diuretics. Physician survey data showed that the percentage of hypertension visits where the physician recorded a thiazide-type diuretic increased the most in counties where academic detailing activity was the highest (an increase of 8.6%, from 37.9% to 46.5%) compared with counties where activity was moderate (an increase of 2%) or low (a decrease of 2%), or where there was none (an increase of 2%; P value for trend, <.05). Pharmacy dispensing data showed that thiazide-type diuretic prescribing increased by 8.7% in counties with Dissemination Project activities compared with 3.9% in those without activities (P < .001). Nationally, thiazide-type diuretic use did not increase between 2004 and 2008.” (S. L. Pressel, Sara.L.Pressel@uth.tmc.edu)

>>>PNN NewsWatch
* Questions and answers about approved pancreatic enzyme products have been updated on the FDA website, the agency said yesterday. Creon, Zenpep, and Pancreaze are the only FDA-approved PEPs currently available in the U.S.
* The supply of
recombinant thyroid stimulating hormone (Thyrogen, Genzyme) will be temporarily limited, FDA announced on Monday. Under the terms of a consent decree that resulted from manufacturing issues at a Genzyme plant, only patients for whom the agent has been certified as medically necessary can receive it. The company also gave up $175 million in “unlawful profits” under the decree.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 26, 2010 * Vol. 17, No. 101
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release article from and May 26 issue of JAMA (2010;303).
Managing Conflicts of Interest: Researchers with NIH grants have new rules for managing financial conflicts of interest (10.1001/jama.2010.774): “To grasp the rationale behind the proposed rule changes, it helps to consider the current regulations. Under this regulatory framework, most of the responsibility for disclosing significant financial interests that could pose possible FCOI lies with individual investigators, not their institutions. Specifically, investigators determine and disclose to their institutions any significant financial interest that would reasonably appear to be affected by the NIH-supported research, as well as any significant financial interest involving entities whose financial interests would reasonably appear to be affected by the research. Institutions, in turn, are required to manage, reduce, or eliminate the conflict; to report to NIH; and to assure NIH that this process has been followed for all identified FCOI that could have a significant and direct effect on NIH-funded research.” (F. S. Collins, collinsf@mail.nih.gov)
Patterns in Hypertension: Hypertension control has improved markedly since 2000, but just one-half of diagnosed patients are controlled, researchers report (pp. 2043–50). Data from the National Health and Nutrition Examination Survey (NHANES) for various 2-year time blocks show: “Rates of hypertension increased from 23.9% (95% confidence interval [CI], 22.7%–25.2%) in 1988–1994 to 28.5% (95% CI, 25.9%–31.3%; P < .001) in 1999–2000, but did not change between 1999–2000 and 2007–2008 (29.0%; 95% CI, 27.6%–30.5%; P = .24). Hypertension control increased from 27.3% (95% CI, 25.6%–29.1%) in 1988–1994 to 50.1% (95% CI, 46.8%–53.5%; P = .006) in 2007–2008, and BP among patients with hypertension decreased from 143.0/80.4 mm Hg (95% CI, 141.9–144.2/79.6–81.1 mm Hg) to 135.2/74.1 mm Hg (95% CI, 134.2–136.2/73.2–75.0 mm Hg; P = .02/P < .001). Blood pressure control improved significantly more in absolute percentages between 1999–2000 and 2007–2008 vs 1988–1994 and 1999–2000 (18.6%; 95% CI, 13.3%–23.9%; vs 4.1%; 95% CI, –0.5% to 8.8%; P < .001). Better BP control reflected improvements in awareness (69.1%; 95% CI, 67.1%–71.1%; vs 80.7%; 95% CI, 78.1%–83.0%; P for trend = .03), treatment (54.0%; 95% CI, 52.0%–56.1%; vs 72.5%; 95% CI, 70.1%–74.8%; P = .004), and proportion of patients who were treated and had controlled hypertension (50.6%; 95% CI, 48.0%–53.2%; vs 69.1%; 95% CI, 65.7%–72.3%; P = .006). Hypertension control improved significantly between 1988–1994 and 2007–2008, across age, race, and sex groups, but was lower among individuals aged 18 to 39 years vs 40 to 59 years (P < .001) and 60 years or older (P < .001), and in Hispanic vs white individuals (P = .004).” (B. M. Egan, eganbm@musc.edu)

>>>PNN NewsWatch
* Alglucosidase alfa (Lumizyme, Genzyme) has been approved by FDA for treatment of patients aged 8 years or older with late-onset (noninfantile) Pompe disease who do not have evidence of cardiac hypertrophy. The first agent approved in the U.S. for the late-onset form of this rare genetic disorder, alglucosidase alfa replaces the missing enzyme, allowing patients to metabolize glycogen more normally. A risk evaluation and mitigation strategy, or REMS, is being required for Lumizyme, and the product will be available only through a restricted distribution system. Genzyme markets this same agent as Myozyme, which is indicated for use in infants and children younger than 8 years. Myozyme has been in short supply because of limited manufacturing capacity. The new product can also be manufactured at a European plant, and this should improve the supply situation. However, the company and FDA emphasize that Lumizyme has not been studied in younger patients and should be used only in those aged 8 or older.
* Long-term or high-dose therapy with
proton-pump inhibitors is associated with increased risk of fractures, FDA warned yesterday. In language added to product labeling, results of epidemiologic studies are described. They note increased risk of fractures of the hip, wrist, and spine when PPIs are used for more than 1 year or in high doses. The risk has been noted primarily in people aged 50 years or older, but that is also the age range of most patients in the studies.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 27, 2010 * Vol. 17, No. 102
Providing news and information about medications and their proper use

>>>Gastroenterology Report
Source:
May issue of Gastroenterology (2010; 138).
Selenium Status & Cancer Risk: Patients with high levels of selenium have lower risks of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA), and some subgroups of patients have lower chances of developing esophageal adenocarcinoma (EAC), researchers report (pp. 1704–13). In the Netherlands Cohort Study, risk was assessed among 120,852 men and women aged 55–69 years through questionnaires and assays of toenail clippings in 1986. Over 16.3 years of follow-up, these results were noted: “In multivariable analyses of selenium status, we found an inverse association with ESCC (RR per standard unit increment, 0.80; 95% confidence interval [CI]: 0.67–0.96) and a borderline significant inverse association with GCA (RR, 0.91; 95% CI: 0.80–1.02). No overall association was observed for EAC (RR, 1.05; 95% CI: 0.95–1.15), but, for women and never smokers, significant inverse associations were found (RR per standard unit increment, 0.72; 95% CI: 0.61–0.84 and RR per standard unit increment, 0.74; 95% CI: 0.64–0.86, respectively).” (J. Steevens, Jessie.Steevens@epid.unimaas.nl)
Pentoxifylline in Advanced Cirrhosis: In a study of 335 patients with Child–Pugh class C cirrhosis, pentoxifylline therapy reduced complications but had no significant effect on short-term mortality (pp. 1755–62.e2). Three-times-daily 400-mg doses of the drug or placebo produced these results at 6 months: “By 2 months, 28 patients in the pentoxifylline group (16.5%) and 31 in the placebo group (18.2%) had died (P = .84). At 6 months, 50 patients in the pentoxifylline group (30.0%) and 54 in the placebo group (31.5%) had died (P = .75). The proportions of patients without complications (eg, bacterial infection, renal insufficiency, hepatic encephalopathy, or gastrointestinal hemorrhage) were higher in the pentoxifylline group than in the placebo group at 2 months (78.6% vs 63.4%; P = .006) and 6 months (66.8% vs 49.7%; P = .002). The probability of survival without complications was higher in the pentoxifylline group than in the placebo group at 2 and 6 months (P = .04). In multivariate analysis, the factors associated with death were age, the Model for End-Stage Liver Disease score, and presence of early-stage carcinoma. Treatment with pentoxifylline was the only factor associated with liver-related complications.” (D. Lebrec, didier.lebrec@inserm.fr)

Medical Care Highlights
Source:
June issue of Medical Care (2010; 48).
Financial Benefits of Medicare Part D: Medicare Part D and its low-income subsidy (LIS) have had limited effects on the more than half of Medicare families that spend more than 40% of their nonessential resources on health care costs, a study shows (pp. 503–9). Data from the Health and Retirement Study for 2,231 Medicare families in 2005 and 2006 showed the following: “In the year before Part D, more than half of Medicare families [56.0%; 95% confidence interval (CI): 55.3–59.9] experienced burdensome health care costs. Families in poor health allocated a median of 68.1% [interquartile range (IQR): 35.1–82.9] of nonessential resources to health care (compared with 34.0% median; IQR 11.9–52.2 among families in excellent health, P < 0.011). Most (64%) out-of-pocket health care spending was allocated to health insurance premiums and medications. As many as 26% of Medicare families had burdensome health care costs but were not eligible for LIS assistance.” (B. A. Briesacher)

>>>PNN NewsWatch
* Severe liver injury has been associated with use of both prescription and nonprescription formulations of orlistat, FDA said yesterday. In the U.S., one case occurred in a patient taking Alli, and outside this country, 12 cases have been reported with Xenical, the agency explained. Labeling is being changed for both products to warn of liver injury.
* Consumers who visit the drugs.com website or use its mobile applications will soon have also have access to
FDA patient health information. Through a new partnership, drugs.com will develop a joint online resource featuring at least 50 articles, videos, and photo slideshows. Visitors to the resource will also be able to click through to FDA’s full catalogue of consumer updates.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
May 28, 2010 * Vol. 17, No. 103
Providing news and information about medications and their proper use

>>>Diabetes Highlights
Source:
June issue of Diabetes Care (2010; 33).
Intensive Lifestyle Interventions in Type 2 Diabetes: A year of intensive lifestyle interventions (ILI) reduced medication use and costs and improved cardiovascular disease (CVD) risk factors in a study of 5,145 overweight or obese people with type 2 diabetes (pp. 1153–8). ILI used group and individual meetings to focus on weight loss and increased physical activity. Compared with a diabetes support and education (DSE) approach, ILI produced these results: “Participants randomized to an ILI had significantly greater improvements in CVD risk parameters and reduced medication use and cost compared with those assigned to DSE. At 1 year, average number of medications prescribed to treat CVD risk factors was 3.1 ± 1.8 for the ILI group and 3.6 ± 1.8 for the DSE group (P < 0.0001), with estimated total monthly medication costs of $143 and $173, respectively (P < 0.0001). DSE participants meeting optimal care goals at 1 year were taking an average of 3.8 ± 1.6 medications at an estimated cost of $194/month. ILI participants at optimal care required fewer medications (3.2 ± 1.7) at lower cost ($154/month) (P < 0.001).” (J. B. Redmon, redmo001@umn.edu)
Executive Functioning & Treatment Adherence: A study of 235 children with type 1 diabetes indicates that measures of executive function could provide a means of assessing adherence to antidiabetic treatments (pp. 1159–62). Skills such as planning, problem-solving, organization, and working memory were measured using the Behavior Rating Inventory of Executive Functioning. Its results correlated positively with treatment adherence as assessed with the Diabetes Self-Management Profile and glycemic control as reflected in A1C values. (D. Drotar, dennis.drotar@cchmc.org)
Ranolazine for Diabetes: The antianginal agent ranolazine—whose mechanism of action is unknown—lowered fasting plasma glucose and A1C levels in patients being treated for diabetes, researchers report (pp. 1163–8). Using 4-month data from the MERLIN-TIMI-36 study, the investigators found: “In patients with diabetes and A1C of ≥8–10% at randomization (n = 171), there was an absolute A1C reduction in the ranolazine group of 1.2% (95% CI −1.4 to −1.0), and the placebo-adjusted (n = 182) decrease in A1C by ranolazine was 0.59% (95% CI −0.99 to −0.20, P < 0.001). In patients with FPG of 150–400 mg/dl at randomization, ranolazine (n = 131) compared with placebo (n = 147) reduced FPG by 25.7 mg/dl (95% CI −43.3 to −8.1, P = 0.001). When changes in either A1C or FPG were correlated to A1C or FPG at randomization, the slopes were significantly steeper for ranolazine than placebo (A1C, P = 0.046; FPG, P < 0.001), indicating that lowering of A1C and FPG by ranolazine is related to hyperglycemia at randomization. Ranolazine, compared with placebo, was not associated with serious hypoglycemic events, associated with significant changes in concurrent antidiabetic therapy, or dependent on a history of angina.” (J. W. Chisholm, jeff.chisholm@gilead.com)
Testosterone & Obesity: Low free testosterone levels are common in middle-aged and older men with obesity, occurring in 40% of those without diabetes and 50% of those with the condition, a study reports (pp. 1186–92). The Hypogonadism In Males (HIM) study included 1,451 nondiabetic and 398 diabetic men older than 45, showing: “The prevalence of subnormal free testosterone concentrations in lean, overweight, and obese nondiabetic men was 26% (n = 275), 29% (n = 687), and 40% (n = 489), respectively (P < 0.001 for trend), and 44% (n = 36), 44% (n = 135), and 50% (n = 227), respectively, in diabetic men (P = 0.46 for trend within group and P < 0.05 compared with nondiabetic men).… The average decline of free testosterone concentrations was 7.8 pg/ml per decade in nondiabetic men and 8.4 pg/ml per decade in diabetic men.” (P. Dandona, pdandona@kaleidahealth.org)

>>>PNN NewsWatch
* Consumers should not purchase or use Arrow Brand Medicated Oil & Embrocation, FDA warned yesterday. The product contains methyl salicylate and camphor, poisons when taken internally. Sold primarily on the Internet and in shops catering to Latinos and Asians, the product is also marketed with Spanish and Chinese labels.
*
PNN will not be published on Mon., May 31, Memorial Day.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 1, 2010 * Vol. 17, No. 104
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
June 1 issue of the Annals of Internal Medicine (2010; 152).
Group Medical Clinics v. Usual Care: At VA facilities in North Carolina and Virginia, group medical clinics were significantly better than usual care for managing patients with hypertension, but clinical outcomes for those with diabetes were statistically similar with the two approaches (pp. 689–96). At GMCs, a medical team (primary care general internist, pharmacist, nurse or other certified diabetes educator) worked with patients in groups of 7 or 8. Compared with usual care, GMCs produced these differences: “Mean baseline systolic blood pressure and HbA1c level were 152.9 mm Hg (SD, 14.2) and 9.2% (SD, 1.4), respectively. At the end of the study, mean systolic blood pressure improved by 13.7 mm Hg in the GMC group and 6.4 mm Hg in the usual care group (P = 0.011 by linear mixed model), whereas mean HbA1c level improved by 0.8% in the GMC group and 0.5% in the usual care group (P = 0.159).” (D. Edelman, dedelman@duke.edu)
Managing Opioid-Dependent Patients with HIV Infection: Outcomes were better with a clinic-based buprenorphine–naloxone (BUP) strategy than with case management and referral to an opioid treatment program, researchers report (pp. 704–11). During a 1-year period at an HIV clinic in Baltimore, these results were noted with two approaches: “The average estimated participation in opioid agonist therapy was 74% (95% CI, 61% to 84%) for clinic-based BUP and 41% (CI, 29% to 53%) for referred treatment (P < 0.001). Positive test results for opioids and cocaine were significantly less frequent in clinic-based BUP than in referred treatment, and study participants receiving clinic-based BUP attended significantly more HIV primary care visits than those receiving referred treatment. Use of antiretroviral therapy and changes in HIV RNA levels and CD4 cell counts did not differ between the 2 groups.” (G. M. Lucas, glucas@jhmi.edu)

>>>Lancet Highlights
Source:
May 29 issue of Lancet (2010; 375).
Fibrates in CVD: Fibrates reduce the risk of cardiovascular disease, mostly by preventing coronary events, concludes a systematic review and meta-analysis of 18 studies (pp. 1875–84). The researchers conclude that the drugs “might have a role in individuals at high risk of cardiovascular events and in those with combined dyslipidaemia,” based on these findings: “Fibrate therapy produced a 10% RR reduction (95% CI 0–18) for major cardiovascular events (p = 0.048) and a 13% RR reduction (7–19) for coronary events (p < 0.0001), but had no benefit on stroke (–3%, –16 to 9; p = 0.69). We noted no effect of fibrate therapy on the risk of all-cause mortality (0%, –8 to 7; p = 0.92), cardiovascular mortality (3%, –7 to 12; p = 0.59), sudden death (11%, –6 to 26; p = 0.19), or non-vascular mortality (–10%, –21 to 0.5; p = 0.063). Fibrates reduced the risk of albuminuria progression by 14% (2–25; p = 0.028). Serious drug-related adverse events were not significantly increased by fibrates (17,413 participants, 225 events; RR 1.21, 0.91–1.61; p = 0.19), although increases in serum creatinine concentrations were common (1.99, 1.46–2.70; p < 0.0001).” (V. Perkovic, vperkovic@george.org.au)

>>>PNN NewsWatch
* Certain I.V. bags of metronidazole, ondansetron, and ciprofloxacin should not be used because of potential contamination, FDA is warning. Any such admixtures sold by Claris, Sagent Pharmaceuticals, Pfizer, and West-Ward Pharmaceuticals should pulled from inventory, FDA said, as it has received reports of white particulate matter in them. The products were all manufactured by Claris Lifesciences in Ahmedabad, India.

>>>PNN JournalWatch
* Genomic Medicine—An Updated Primer, in New England Journal of Medicine, 2010; 362: 2001–11. (W. G. Feero, feerow@mail.nih.gov)
* Aspirin for Primary Prevention of Cardiovascular Events in People with Diabetes [an official statement], in
Diabetes Care, 2010; 33: 1395–402. (M. S. Kirkman, skirkman@diabetes.org)
* Consensus Summary of Aerosolized Antimicrobial Agents: Application of Guideline Criteria. Insights from the Society of Infectious Diseases Pharmacists, in
Pharmacotherapy, 2010; 30: 562–84. (J. Le, jenle@ucsd.edu)
* Drug-Induced Black Hairy Tongue, in
Pharmacotherapy, 2010; 30: 585–93. (D. F. Thompson, dennis.thompson@swosu.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 2, 2010 * Vol. 17, No. 105
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 2 issue of JAMA (2010; 303).
Trends in Care of Heart Failure: Lengths of stay decreased over the past 14 years for hospitalized patients with heart failure, researchers report, but discharges to skilled nursing facilities were up and rehospitalization rates climbed (pp. 2141–7). These trends were observed among nearly 7 million fee-for-service Medicare patients hospitalized between 1993 and 2006: “Between 1993 and 2006, mean length of stay decreased from 8.81 days (95% confidence interval [CI], 8.79–8.83 days) to 6.33 days (95% CI, 6.32–6.34 days). In-hospital mortality decreased from 8.5% (95% CI, 8.4%–8.6%) in 1993 to 4.3% (95% CI, 4.2%–4.4%) in 2006, whereas 30-day mortality decreased from 12.8% (95% CI, 12.8%–12.9%) to 10.7% (95% CI, 10.7%–10.8%). Discharges to home or under home care service decreased from 74.0% to 66.9% and discharges to skilled nursing facilities increased from 13.0% to 19.9%. Thirty-day readmission rates increased from 17.2% (95% CI, 17.1%–17.3%) to 20.1% (95% CI, 20.0%–20.2%; all P < .001). Consistent with the unadjusted analyses, the 2005–2006 risk-adjusted 30-day mortality risk ratio was 0.92 (95% CI, 0.91–0.93) compared with 1993–1994, and the 30-day readmission risk ratio was 1.11 (95% CI, 1.10–1.11).” (H. M. Krumholz, harlan.krumholz@yale.edu)
NIH Support of CER: NIH officials describe the philosophy behind and nature of the organization’s support of comparative effectiveness research efforts mandated in the 2009 economic recovery act and the recently enacted health care reform law (pp. 2182–3): “One concern is whether in the process of conducting CER, the importance of individual responses to health interventions will be overlooked or minimized. Genomic sequencing, gene expression analysis, epigenetics, advanced proteomics, and other high-throughput technologies will give CER investigators the power to analyze effectiveness data at many different levels of resolution—ranging from the individual to subsets of patients to very large populations. Large-scale, randomized CER studies are needed to obtain well-validated answers about which interventions work best. But such studies must include assessment of individual differences in genetic risk factors and environmental exposures, or run the risk that subsets of individuals may have significantly different responses to an intervention than the group as a whole. Analyses of CER data sets must take these individual differences into account. Both CER and personalized medicine are essential parts of the equation for using science to improve health care.” (F. S. Collins, collinsf@mail.nih.gov)
Patient-Centered Medical Homes in Ontario: From a province where 75% of patients are seen in medical homes comes an analysis of this care model (pp. 2186–7): “Ontario’s medical homes are laudable in their innovation, scope, and workforce stabilization. They are a step forward in bringing change to a situation ‘exemplified by individuals making personal heroic efforts to compensate for the absence of systems and support.’ Political negotiations, however, resulted in policies that favored self-selection of healthier patients, disincentives in major cities, gaps for vulnerable groups, and suboptimal access to care. Improved primary care income is always welcome, but the lack of an open evaluation mechanism is troubling. Others may want to examine the Ontario blueprints for large-scale primary care reform. However, they will want to consider their political landscape, choose locally appropriate construction methods, and carefully select building materials for patient-centered medical homes in the United States.” (R. H. Glazier, rick.glazier@ices.on.ca)

>>>PNN NewsWatch
* FDA yesterday announced the approval of Amgen’s denosumab (Prolia) for treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. The drug is the first RANK-ligand inhibitor to reach the U.S. market. Approval was based on the Phase III FREEDOM study of 7,808 women. Every-6-month subcutaneous doses of denosumab 60 mg yielded significant reductions in vertebral, nonvertebral, and hip fractures. The agent is contraindicated in patients with hypocalcemia, and serious infections are a major concern with its use.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 3, 2010 * Vol. 17, No. 106
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 3 issue of the New England Journal of Medicine (2010; 362).
Sequential ACT in Early Breast Cancer: Sequential administration of four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT) proved advantageous in 5,351 patients with operable, node-positive, early-stage breast cancer, researchers report, but at a considerable cost in length of therapy and toxicity (pp. 2053–65). Compared with concurrent ACT (four cycles of doxorubicin, cyclophosphamide, and docetaxel) or four cycles of doxorubicin and docetaxel without docetaxel, sequential ACT provided these benefits: “At a median follow-up of 73 months, overall survival was improved in the sequential-ACT group (8-year overall survival, 83%) as compared with the doxorubicin–docetaxel group (overall survival, 79%; hazard ratio for death, 0.83; P = 0.03) and the concurrent-ACT group (overall survival, 79%; hazard ratio, 0.86; P = 0.09). Disease-free survival was improved in the sequential-ACT group (8-year disease-free survival, 74%) as compared with the doxorubicin–docetaxel group (disease-free survival, 69%; hazard ratio for recurrence, a second malignant condition, or death, 0.80; P = 0.001) and the concurrent-ACT group (disease-free survival, 69%; hazard ratio, 0.83; P = 0.01). The doxorubicin–docetaxel regimen showed noninferiority to the concurrent-ACT regimen for overall survival (hazard ratio, 0.96; 95% confidence interval, 0.82 to 1.14). Overall survival was improved in patients with amenorrhea for 6 months or more across all treatment groups, independently of estrogen-receptor status.” (S. W. Swain, sandra.m.swain@medstar.net)
Several “take-home lessons” are provided by an editorialist about taxane-based chemotherapy for node-positive breast cancer (
pp. 2122–4): “An overall survival advantage of 4 percentage points is only a modest gain in exchange for increasing the dose of chemotherapy agents, doubling the duration of therapy, and markedly increasing acute toxicity. It is therefore hard to escape the conclusion that this trial marks the end of the road for generic studies of combinations of anthracycline, taxane, and cyclophosphamide. Clinical investigators are currently considering an impressive array of targeted agents and new chemotherapeutic agents focused on the mitotic spindle. Researchers cannot afford to take the same time and have the same patient numbers that were required to optimize taxane-based therapy or they will not be able to fully take advantage of the many excellent opportunities being offered. In response to this challenge, smarter clinical trials must be designed that capture not only patient outcomes, but high-quality biologic samples before and during therapy. Study designs should be mechanism-based as much as possible and most critically focused on subgroups of patients with disease that is resistant to contemporary chemotherapy regimens. Finally, obtaining patient consent for whole-genome analysis to completely document the fundamental nature of the disease should be a new standard in clinical investigation.” (M. Ellis)
Incentives for Drug Development: The “curious case of colchicine” provides lessons in market exclusivity under the Orphan Drug Act, authors write (pp. 2045–7): “The manufacturer … received 7 years of market exclusivity for the use of Colcrys in the treatment of familial Mediterranean fever (FMF), a genetic inflammatory disorder that affects only about 100,000 patients worldwide.… The implications of market exclusivity for the public health can be substantial. After the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market and raised the price by a factor of more than 50, from $0.09 per pill to $4.85 per pill. These increased prices directly affect the availability of the drug to patients with gout or FMF who have long been using colchicine safely in an evidence-based manner. Exclusivity can also affect health care delivery more broadly. According to the Centers for Medicare and Medicaid Services, state Medicaid programs filled about 100,000 prescriptions of colchicine in 2007 and paid approximately $1 million for the drug. Use of the new brand-name colchicine could add as much as $50 million per year to these insurance programs’ budgets at a time when they are addressing the rising costs of health care by reducing some services or raising eligibility thresholds.” (A. S. Kesselheim)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 4, 2010 * Vol. 17, No. 107
Providing news and information about medications and their proper use

>>>Pharmacotherapy Report
Source:
June issue of Pharmacotherapy (2010; 30).
Statins & Adverse Muscular Events: A dose-dependent relationship is evident in patients taking statins and having muscle-related adverse effects (MAEs), researchers report (pp. 541–53). Use of lower-potency agents and drug discontinuation are reasonable approaches to managing MAEs, the authors write, adding these details on 354 adult patients with self-reported muscle-related symptoms during statin therapy: “Patients reported muscle pain (93%), fatigue (88%), and weakness (85%). Three hundred patients (85%) met literature criteria for probable or definite drug adverse-effect causality. Ninety-four percent of atorvastatin usages (240/255) generated MAEs versus 61% of lovastatin usages (38/62, p < 0.0001). Higher potency statins reproduced MAEs in 100% of 39 rechallenges versus 73% (29/40) with lower potency rechallenges (p < 0.01). Time course of onset after statin initiation varied (median 14 wks); some MAEs occurred after long-term symptom-free use. Recurrence with rechallenge had a significantly shorter latency to onset (median 2 wks). The MAEs adversely affected all assessed functional and [quality of life] domains. Most patients with probable or definite MAEs were in categories for which available randomized controlled trial evidence shows no trend to all-cause mortality benefit with statin therapy.” (B. A. Golomb, bgolomb@ucsd.edu)
Adjunctive CMV-IVIG in Stem-Cell Transplant: Trials of adjunctive cytomegalovirus intravenous immune globulin (CMV-IVIG) for probable or proven CMV disease are warranted in hematopoietic stem cell transplant (HSCT) recipients, conclude authors who conducted a retrospective cohort study (pp. 554–61). From 1999 through 2007, these outcomes were recorded for 35 patients who received at least one dose of CMV-IVIG: “Twenty-six patients (74%) had pneumonitis, nine (26%) had enteritis, and 29 (83%) had CMV viremia. All patients received concomitant antiviral therapy; 31 (89%) received ganciclovir, and 14 (40%) received foscarnet. All-cause mortality at hospital discharge was 49% (17 patients). Patient characteristics associated with mortality included requiring intubation for CMV pneumonia (11 [79%] of 14 nonsurvivors vs 3 (25%) of 12 survivors, p = 0.016) and earlier disease onset after HSCT (median 48 days for nonsurvivors vs 106 days for survivors, p < 0.001). In the multivariate analysis, only requiring intubation for CMV pneumonia remained a significant risk factor for increased mortality. A low rate of adverse events was attributed to CMV-IVIG, with mild hypertension (two patients [6%]) and erythema and chills (one patient [3%]) being the most common.” (L. M. Hladnik, lmh0275@bjc.org)
Pharmacists’ Educational Needs for Personalized Medicine: The ACCP Educational Affairs Committee proposes curricular requirements as the science of personalized medicine is applied by pharmacists (p. 626; 228e–35e): “The committee identified four key areas deemed essential components of a pharmacy curriculum related to advances in genomics: personalized medicine concepts and terminology, with a focus on genomics; genomic applications in basic and applied pharmaceutical sciences; biotechnology; and bioinformatics.… Material taught in each area should evolve with progress in the field, particularly for gene–drug response associations, biotechnology, and bioinformatics. As the areas of proteomics, metabolomics, and epigenetics evolve along with their implications for personalized drug therapy, they should also be incorporated into the curriculum. Self-directed learning behaviors should be encouraged, when possible, to better prepare students to advance their skills and knowledge with the science. Faculty development will likely be necessary for the widespread education of pharmacy students in personalized medicine.” (ACCP)

>>>PNN NewsWatch
* Teenagers abusing prescription medications accounted for 14.5% of emergency department visits in 2008 for nonmedical use of drugs, CDC reports in the 2009 National Youth Risk Behavior Survey. Combined with an issue brief issued in March, Unintentional Drug Poisoning in the United States, CDC officials said the nation has “a serious public health problem with nonmedical use of prescription drugs.” The new survey shows that 1 in 5 students in U.S. high schools has taken one or more legend medications without a prescription.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 7, 2010 * Vol. 17, No. 108
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 5 issue of Lancet (2010; 375).
Worldwide Childhood Mortality: Infectious diseases remain a major cause of mortality among children younger than 5, causing two-thirds of 8.8 million deaths in 2008, a study shows (pp. 1969–87). Pneumonia, diarrhea, and malaria were the most common infectious diseases involved in deaths, researchers report, adding that nearly one-half of deaths occurred in five countries: “Of the estimated 8.795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5.970 million), with the largest percentages due to pneumonia (18%, 1.575 million, uncertainty range [UR] 1.046 million–1.874 million), diarrhoea (15%, 1.336 million, 0.822 million–2.004 million), and malaria (8%, 0.732 million, 0.601 million–0.851 million). 41% (3.575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1.033 million, UR 0.717 million–1.216 million), birth asphyxia (9%, 0.814 million, 0.563 million–0.997 million), sepsis (6%, 0.521 million, 0.356 million–0.735 million), and pneumonia (4%, 0.386 million, 0.264 million–0.545 million). 49% (4.294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China.” (R. E. Black, rblack@jhsph.edu)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 340).
Hormone-Replacement Therapy & Stroke: Transdermal hormone-replacement therapy with low estrogen doses appears to avoid the increased risk of stroke seen with oral HRT, according to a population-based nested case–control study of 400 U.K. general practices that contribute to the General Practice Research Database (c2519). All women aged 50–79 years whose data were recorded for 1987–2006 were included in the analysis, which showed the following: “There were 15,710 cases of stroke matched to 59,958 controls. The rate of stroke in the cohort was 2.85 per 1,000 per year. The adjusted rate ratio of stroke associated with current use of transdermal HRT was 0.95 (95% CI 0.75 to 1.20) relative to no use. The risk of stroke was not increased with use of low oestrogen dose patches (rate ratio 0.81(0.62 to 1.05)) compared with no use, whereas the risk was increased with high dose patches (rate ratio 1.89 (1.15 to 3.11)). Current users of oral HRT had a higher rate of stroke than non-users (rate ratio 1.28 (1.15 to 1.42)) with both low dose and high dose.” (S. Suissa, samy.suissa@mcgill.ca)
Cost-Effectiveness of Pneumococcal Vaccination: At current prices and with the four-dose administration schedule, seven-valent pneumococcal conjugated vaccine is not cost-effective in the Netherlands, researchers report (c2509). An economic evaluation of PCV-7, PCV-10, and PCV-13 produced these conclusions about a model that included a cohort of 180,000 newborns who were followed to age 5 years: “The current Dutch infant vaccination programme of four doses of PCV-7 is not cost effective because of increases in invasive disease caused by non-vaccine serotypes, which reduces the overall direct effects of vaccination and offsets potential positive herd protection benefits in unvaccinated individuals. The 10 valent and 13 valent pneumococcal vaccines could have better net health benefits than PCV-7 through less replacement disease and increased herd protection. Both these effects could substantially reduce the incremental cost effectiveness ratio to possibly acceptable levels, if total programme costs can be lowered by reduced schedules, reductions in vaccine prices, or both.” (M. H. Rozenbaum, m.h.rozenbaum@rug.nl)

>>>PNN JournalWatch
* Mechanisms and Regulation of the Gene-Expression Response to Sepsis, in Pediatrics, 2010; 125: 1248–58. (T. T. Cornell)
* Emotion Modulation in PTSD: Clinical and Neurobiological Evidence for a Dissociative Subtype, in
American Journal of Psychiatry, 2010; 167: 640–7. (R. A. Lanius)
* Coprescription of Tamoxifen and Medications That Inhibit CYP2D6, in
Journal of Clinical Oncology, 2010; 28: 2768–76. (M. Goetz, goetz.matthew@mayo.edu)
* Future of Personalized Medicine in Oncology: A Systems Biology Approach, in
Journal of Clinical Oncology, 2010; 28: 2777–83. (A. M. Gonzalez-Angulo, agonzalez@mdanderson.org)
* Recent Advances in the Pathophysiology of Asthma, in
Chest, 2010; 137: 1417–26. (P. O’Byrne, byrnep@mcmaster.ca">obyrnep@mcmaster.ca)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 8, 2010 * Vol. 17, No. 109
Providing news and information about medications and their proper use

>>>Psychiatry Highlights
Source:
June issue of the American Journal of Psychiatry (2010; 167).
Sertraline plus Naltrexone for Depression, Alcohol Dependence: In patients with both depression and alcohol dependence, the addition of sertraline improves response to naltrexone therapy, researchers report (pp. 668–75). In a study of 170 such patients who were treated for 14 weeks, sertraline 200 mg/day, naltrexone 100 mg/day, both agents concomitantly, and double placebo produced these results: “The sertraline plus naltrexone combination produced a higher alcohol abstinence rate (53.7%) and demonstrated a longer delay before relapse to heavy drinking (median delay = 98 days) than the naltrexone (abstinence rate: 21.3%; delay = 29 days), sertraline (abstinence rate: 27.5%; delay = 23 days), and placebo (abstinence rate: 23.1%; delay = 26 days) groups. The number of patients in the medication combination group not depressed by the end of treatment (83.3%) approached significance when compared with patients in the other treatment groups. The serious adverse event rate was 25.9%, with fewer reported with the medication combination (11.9%) than the other treatments.” (H. M. Pettinati)
Risperidone Maintenance Doses: Fewer relapses occurred among patients who continued to receive the full risperidone dose used during acute episodes, compared with those who had dose reductions at 4 or 26 weeks, an open-label study shows (pp. 676–85). Patients who were clinically stabilized during the acute phase were randomized to a no-dose-reduction group (initial optimal therapeutic dose continued throughout the study), a 4-week group (initial optimal therapeutic dose continued for 4 weeks, followed by a 50% dose reduction that was maintained until the end of the study), or a 26-week group (initial optimal therapeutic dose continued for 26 weeks, followed by a 50% dose reduction until the end of the study), with these results: “Of the 404 patients who met the entry criteria and were randomly assigned, 374 completed the study. The estimated mean time from entry to relapse was 571 days in the 4-week group, 615 days in the 26-week group, and 683 days in the no-dose-reduction group, with estimated relapse rates of 30.5%, 19.5%, and 9.4%, respectively. Patients in the no-dose-reduction group experienced greater reduction in the severity of psychotic symptoms.” (C-Y Wang)

>>>Pediatrics Highlights
Source:
June issue of Pediatrics (2010; 125).
Changing Antibiotic Treatments of Staphylococci: As resistant strains of community-associated Staphylococcus aureus emerged as a clinical problem over the past 10 years, clindamycin became the most commonly prescribed antibiotic for infections with this organism in hospitalized children (e1294–300). That conclusion comes from a retrospective study that assessed the Pediatric Health Information Systems database for information about S. aureus infections at 25 U.S. children’s hospitals. From 1999 to 2008, these patterns were evident: “A total of 64,813 patients had a discharge diagnosis for S aureus infection. The incidence of methicillin-resistant S aureus (MRSA) infections during this period increased 10-fold, from 2 to 21 cases per 1,000 admissions, whereas the methicillin-susceptible S aureus infection rate remained stable. Among patients with S aureus infections, antibiotics that treat MRSA increased from 52% to 79% of cases, whereas those that treat only methicillin-susceptible S aureus declined from 66% to <30% of cases. Clindamycin showed the greatest increase, from 21% in 1999 to 63% in 2008. Similar trends were observed by using days of therapy per 1,000 patient–days.” (J. C. Herigon)
Vitamin D Levels in Adolescents: In a study conducted in the southeastern U.S., low vitamin D status was prevalent among adolescents, especially black youths (pp. 1104–11). Despite the “year-round sunny climate,” the investigators found that 559 adolescents had high respective prevalences of both vitamin D insufficiency (<75 nmol/L) and deficiency (≤ 50 nmol/L), with 56.4% and 28.8% of youths affected. Inverse correlations were observed between all measures of adiposity (BMI, waist circumference, total fat mass, percentage of body fat, visceral adipose tissue, and subcutaneous abdominal adipose tissue) and 25-hydroxyvitamin D levels. Positve correlations were noted between vitamin D status and vigorous physical exercise and cardiovascular fitness. (Y. Dong)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 9, 2010 * Vol. 17, No. 110
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 9 issue of JAMA (2010; 303).
Infection Control in Ambulatory Surgical Centers: Lapses in infection control procedures were common at 68 ambulatory surgical centers in Maryland, North Carolina, and Oklahoma, a study shows (pp. 2273–9). Inspections of a stratified sample of ASCs conducted by state agency surveyors showed these results in five areas of infection control (hand hygiene, injection safety and medication handling, equipment reprocessing, environmental cleaning, and handling of blood glucose monitoring equipment): “Overall, 46 of 68 ASCs (67.6%; 95% confidence interval [CI], 55.9%–77.9%) had at least 1 lapse in infection control; 12 of 68 ASCs (17.6%; 95% CI, 9.9%–28.1%) had lapses identified in 3 or more of the 5 infection control categories. Common lapses included using single-dose medication vials for more than 1 patient (18/64; 28.1%; 95% CI, 18.2%–40.0%), failing to adhere to recommended practices regarding reprocessing of equipment (19/67; 28.4%; 95% CI, 18.6%–40.0%), and lapses in handling of blood glucose monitoring equipment (25/54; 46.3%; 95% CI, 33.4%–59.6%).” (M. K. Schaefer, mschaefer@cdc.gov)
An editorialist, after describing similar findings by CDC in Nevada ASCs following a 2008 hepatitis C outbreak in that state and an 8.3% annual growth rate in number of ASCs in the U.S., notes these current developments (
pp. 2295–7): “Federal regulatory intervention is already occurring. Ambulatory surgical centers must now maintain infection control programs directed by a designated health care professional with training in infection control, and audited adherence will be conducted through a modified infection control tool, but programmatic sustainability after fiscal year 2010 is not assured when [American Recovery and Reinvestment Act] funding expires. Regardless, ASCs and practitioners are not absolved of individual and collective responsibility to do the right thing.” (P. S. Barie, pbarie@med.cornell.edu)
Linezolid-Resistant Staphylococcus aureus: A 2008 outbreak of linezolid- and methicillin-resistant Staphylococcus aureus (LRSA) in an intensive care department at a Madrid hospital was controlled through reduction in linezolid use and infection-control measures, researchers report (pp. 2260–4): “Between April 13 and June 26, 2008, 12 patients with LRSA were identified. In 6 patients, LRSA caused ventilator-associated pneumonia and in 3 patients it caused bacteremia. Isolates were susceptible to trimethoprim-sulfamethoxazole, glycopeptides, tigecycline, and daptomycin. Genotyping identified 1 predominant clone and 3 other types. Cfr-mediated linezolid resistance was demonstrated in all isolates. Potential hospital staff carriers and environmental samples were negative except for one. Six patients died, 5 of them in the intensive care unit, with 1 death attributed to LRSA infection. Linezolid use decreased from 202 defined daily doses in April 2008 to 25 defined daily doses in July 2008. Between July 2008 and April 2010, no new cases have been identified in the weekly surveillance cultures or diagnostic samples.” (M. Sánchez García, msanchezga.hcsc@salud.madrid.org)

>>>PNN NewsWatch
* Accepting the Harvey A. K. Whitney Lecture Award last night at the ASHP2010 Summer Meeting in Tampa, pharmaceutical care pioneer Charles D. Hepler spoke of “A Dream Deferred”: “The people whom we have promised to take care of also have a dream. They dream of health care that is safe, timely, effective, efficient, equitable, and patient-centered. The professions have promised to provide that, and now the people seem to be demanding that we keep our promise. So we pharmacists share a dream with the people of the United States. We will succeed in reaching our dream to the extent that we help them reach their dream. Taking care of people is not only an ethical imperative—it is a political and social and economic imperative as well.” In the ASHP House, delegates passed numerous policies, including ones on health insurance coverage of U.S. residents, FDA recall authority, medication therapy management, quality consumer medication information, and “just culture” and reporting of medication errors. In a new business item, delegates asked the ASHP Board of Directors to look into situations involving medical marijuana in states where that is available.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 10, 2010 * Vol. 17, No. 111
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 10 issue of and early-release articles from New England Journal of Medicine (2010; 362).
Oseltamivir Ring Prophylaxis for H1N1 Containment: In four Singapore military camps, oseltamivir ring prophylaxis was effective in reducing outbreaks of 2009 A/H1N1 influenza early in the pandemic, researchers report (pp. 2166–74). Used with prompt identification and isolation of infected personnel, ring prophylaxis of those exposed to patients with the virus produced these results based on PCR assays and patient questionnaires: “A total of 1,175 personnel were at risk across the four sites, with 1,100 receiving oseltamivir prophylaxis. A total of 75 personnel (6.4%) were infected before the intervention, and 7 (0.6%) after the intervention. There was a significant reduction in the overall reproductive number (the number of new cases attributable to the index case), from 1.91 (95% credible interval, 1.50 to 2.36) before the intervention to 0.11 (95% credible interval, 0.05 to 0.20) after the intervention. Three of the four outbreaks showed a significant reduction in the rate of infection after the intervention. Molecular analysis revealed that all four outbreaks were derived from the New York lineage of the 2009 H1N1 virus and that cases within each outbreak were due to transmission rather than unrelated episodes of infection. Of the 816 personnel treated with oseltamivir who were surveyed, 63 (7.7%) reported mild, nonrespiratory side effects of the drug, with no severe adverse events.” (V. J. Lee, vernonljm@hotmail.com)
Commenting on this and an epidemiologic A/H1N1 influenza study (
pp. 2175–84; B. J. Cowling, bcowling@hku.hk), an editorialist notes that vaccination remains the primary prevention tool for influenza (pp. 2221–3): “Although the emergence of oseltamivir-resistant 2009 H1N1 virus infection that is associated with a His275Tyr mutation in viral neuraminidase has been rare to date, sporadic cases have occurred worldwide, including among persons receiving oseltamivir chemoprophylaxis. Practitioners who are considering the use of oseltamivir chemoprophylaxis for the control of outbreaks need to weigh the potential for the development of oseltamivir resistance. Limited transmission of oseltamivir-resistant strains has occurred among both previously healthy persons and severely immunosuppressed patients. Thus, appropriate antiviral management (zanamivir if available), the use of strict infection-control measures to prevent further transmission, and antiviral-resistance testing are especially important when oseltamivir resistance is suspected. If widespread prevalence of oseltamivir resistance develops in circulating 2009 H1N1 virus strains, zanamivir will be the remaining approved antiviral option for treatment and chemoprophylaxis. However, the best way to control influenza outbreaks is to prevent them from occurring as much as possible, and influenza vaccination is the primary prevention tool.” (T. M. Uyeki)
Valproic Acid in Early Pregnancy: Spina bifida and other severe congenital malformations are significantly more likely in women taking valproic acid during the first trimester of pregnancy, compared with either no drug therapy or use of other antiepileptic agents, a study shows (pp. 2185–93). Data from eight cohort studies of 1,565 pregnancies were grouped to make these determinations: “Exposure to valproic acid monotherapy was recorded for a total of 180 registrations, with 122 registrations in the case group, 45 in control group 1, and 13 in control group 2. As compared with no use of an antiepileptic drug during the first trimester (control group 1), use of valproic acid monotherapy was associated with significantly increased risks for 6 of the 14 malformations under consideration; the adjusted odds ratios were as follows: spina bifida, 12.7 (95% confidence interval [CI], 7.7 to 20.7); atrial septal defect, 2.5 (95% CI, 1.4 to 4.4); cleft palate, 5.2 (95% CI, 2.8 to 9.9); hypospadias, 4.8 (95% CI, 2.9 to 8.1); polydactyly, 2.2 (95% CI, 1.0 to 4.5); and craniosynostosis, 6.8 (95% CI, 1.8 to 18.8). Results for exposure to valproic acid were similar to results for exposure to other antiepileptic drugs.” (T. W. de Jong-van den Berg, l.t.w.de.jong-van.den.berg@rug.nl)
Next-Generation Kinase Inhibitors: Two early-release articles and a related editorial detail treatment of chronic myeloid leukemia with two next-generation BCR-ABL kinase inhibitors, dasatinib and nilotinib. Another study reports on survival with ipilimumab in patients with metastatic melanoma.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 11, 2010 * Vol. 17, No. 112
Providing news and information about medications and their proper use

>>>Cardiology Highlights
Source:
June 15 issue of the Journal of the American College of Cardiology (2010; 55).
Management of Drug Resistance in Patients with Stents: In patients with sirolimus-eluting stent (SES) restenosis, repeat SES yielded clinical outcomes similar to those paclitaxel-eluting stents (PES), researchers report (pp. 2710–6). In the ISAR-DESIRE 2 (Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis 2) study, 450 patients with stents and clinically significant restenosis were pretreated with clopidogrel 600 mg and randomly assigned to SES or PES implantation. Using a primary end point of late lumen loss at 6–8 months, the researchers found: “Regarding anti-restenotic efficacy, there were no differences between SES and PES in late loss (0.40 ± 0.65 mm vs. 0.38 ± 0.59 mm; p = 0.85), binary restenosis (19.6% vs. 20.6%; p = 0.69), or target lesion revascularization (16.6% vs. 14.6%; p = 0.52). In terms of safety outcomes, the rates of death/myocardial infarction (6.1% vs. 5.8%; p = 0.86) and stent thrombosis (0.4% vs. 0.4%; p > 0.99) were also similar.” (A. Kastrati, kastrati@dhm.mhn.de)
Feasibility of Autologous Delipidated HDL Infusions: Infusions of autologous HDL plasma that has been delipidated is clinically feasible and well tolerated in patients with acute coronary syndromes, a study shows (pp. 2727–35). Tested were serial infusions of selective HDL delipidated plasma, in which alpha-HDL has been converted to pre-beta-like HDL, “the most effective form of HDL for lipid removal from arterial plaques.” Seven weekly apheresis and reinfusions of HDL selective or control plasma produced these results in 28 patients: “All reinfusion sessions were tolerated well by all patients. The levels of pre-beta-like HDL and alpha-HDL in the delipidated plasma converted from 5.6% to 79.1% and 92.8% to 20.9%, respectively. The [intravascular ultrasound] data demonstrated a numeric trend toward regression in the total atheroma volume of –12.18 ± 36.75 mm3 in the delipidated group versus an increase of total atheroma volume of 2.80 ± 21.25 mm3 in the control group (p = 0.268).” (R. Waksman, ron.waksman@medstar.net)

>>>Circulation Highlights
Source:
June 8 issue of Circulation (2010; 121).
Sugar Intake & BP: Reduction in intake of sugar and sugar-sweetened beverages (SSBs) could be an effective strategy for reducing blood pressures, according to a study of 810 patients in the PREMIER trial (pp. 2398–406). The 18-month behavioral intervention trial measured blood pressure and dietary intake at 0, 6, and 18 months, finding these results when patients reduced their sugar intake: “At baseline, mean SSB intake was 0.9 ± 1.0 servings per day (10.5 ± 11.9 fl oz/d), and mean systolic BP/diastolic BP was 134.9 ± 9.6/84.8 ± 4.2 mm Hg. After potential confounders were controlled for, a reduction in SSB of 1 serving per day was associated with a 1.8-mm Hg (95% confidence interval, 1.2 to 2.4) reduction in systolic BP and 1.1-mm Hg (95% confidence interval, 0.7 to 1.4) reduction in diastolic BP over 18 months. After additional adjustment for weight change over the same period, a reduction in SSB intake was still significantly associated with reductions in systolic and diastolic BPs (P < 0.05). Reduced intake of sugars was also significantly associated with reduced BP. No association was found for diet beverage consumption or caffeine intake and BP. These findings suggest that sugars may be the nutrients that contribute to the observed association between SSB and BP.” (L. Chen, lchen@lsuhsc.edu)
Management of DM in Cardiovascular Disease: Based on findings from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial, authors describe optimal management of diabetes mellitus and cardiovascular risk factors in patients with diabetes mellitus (pp. 2447–9; A. B. Goldfine, Allison.Goldfine@Joslin.Harvard.Edu)

>>>PNN NewsWatch
* An earlier recall of Hospira’s Liposyn and propofol products has been expanded, FDA announced yesterday. Additional lots of the products may contain particulate contaminants, including subvisible inert stainless steel particles that could act as emboli and impede blood flow.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 14, 2010 * Vol. 17, No. 113
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 12 issue of Lancet (2010; 375).
Heterosexual HIV-1 Transmission During ART: Similar to a paper published last month in BMJ (see PNN, May 17), an article supports use of antiretroviral therapy in HIV-1–infected patients as a means of preventing infection of heterosexual partners (pp. 2092–8). The current report shows that low CD4 cell counts and high plasma HIV-1 concentrations can be used to guide optimal ART use, with 24 months of monitoring producing these results: “3,381 couples were eligible for analysis. 349 (10%) participants with HIV-1 initiated ART during the study, at a median CD4 cell count of 198 (IQR 161–265) cells per µL. Only one of 103 genetically-linked HIV-1 transmissions was from an infected participant who had started ART, corresponding to transmission rates of 0.37 (95% CI 0.09–2.04) per 100 person–years in those who had initiated treatment and 2.24 (1.84–2.72) per 100 person–years in those who had not—a 92% reduction (adjusted incidence rate ratio 0.08, 95% CI 0.00–0.57, p = 0.004). In participants not on ART, the highest HIV-1 transmission rate (8.79 per 100 person–years) was from those with CD4 cell counts lower than 200 cells per µL. In couples in whom the untreated HIV-1 infected partner had a CD4 cell count greater than 200 cells per µL, 66 (70%) of 94 transmissions occurred when plasma HIV-1 concentrations exceeded 50,000 copies per mL.” (D. Donnell, deborah@fhcrc.org)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 340).
Impact of Smoke-Free Laws on MI Hospitalizations: Within 15 months after smoke-free legislation took effect across England on July 1, 2007, hospital admissions for myocardial infarction were reduced significantly, researchers report (c2161). Noting that the decrease in MIs was somewhat less than in other countries after similar laws were implemented, the investigators note that secondhand exposure to smoke was fairly low in England before the law. These rates of primary diagnoses for MI were found among emergency admissions of adults in England for July 2002 through Sept. 2007: “After adjustment for secular and seasonal trends and variation in population size, there was a small but significant reduction in the number of emergency admissions for myocardial infarction after the implementation of smoke-free legislation (–2.4%, 95% confidence interval –4.06% to –0.66%, P = 0.007). This equates to 1,200 fewer emergency admissions for myocardial infarction (1,600 including readmissions) in the first year after legislation. The reduction in admissions was significant in men (3.1%, P = 0.001) and women (3.8%, P = 0.007) aged 60 and over, and men (3.5%, P < 0.01) but not women (2.5% P = 0.38) aged under 60.” (A. Gilmore, a.gilmore@bath.ac.uk)
Bevacizumab for Macular Degeneration: In 131 patients with neovascular age related macular degeneration, bevacizumab injections plus standard care improved visual acuity at week 54, compared with standard therapy alone, a study shows (c2459). Intravitreous bevaciumab 1.25 mg, administered as three loading injections at 6-week intervals followed by further treatment if needed, showed these effects with verteporfin or pegaptanib: “In the bevacizumab group, 21 (32%) patients gained 15 or more letters from baseline visual acuity compared with two (3%) in the standard care group (P < 0.001); the estimated adjusted odds ratio was 18.1 (95% confidence interval 3.6 to 91.2) and the number needed to treat was 4 (3 to 6). In addition, the proportion of patients who lost fewer than 15 letters of visual acuity from baseline was significantly greater among those receiving bevacizumab treatment (91% (59) v 67% (44) in standard care group; P < 0.001).” (A. Tufail, adnan.tufail@moorfields.nhs.uk)

>>>PNN NewsWatch
* Safety of olmesartan is under review at FDA based on increased mortality in the ROADMAP and ORIENT studies among patients with type 2 diabetes.

>>>PNN JournalWatch
* The Role of Viruses in Acute Exacerbations of Asthma, in Journal of Allergy and Clinical Immunology, 2010; 125: 1178–87. (D. J. Jackson, d.jackson@imperial.ac.uk)
* Genetic Testing in Pancreatitis, in
Gastroenterology, 2010; 138: 2202–6.e1. (S. D. Freedman, sfreedma@bidmc.harvard.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 15, 2010 * Vol. 17, No. 114
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release articles from and June 15 issue of the Annals of Internal Medicine (2010; 152).
Ribavirin for Chronic Hepatitis E: Case reports of two patients with chronic hepatitis E virus (HEV) infection responded to oral ribavirin therapy, indicating that this drug should be evaluated further, a brief communication notes (early release). The patients, one a kidney/pancreas transplant recipient and the other with idiopathic CD4* T lymphocytopenia, received ribavirin 12 mg/kg for 12 weeks, with these results: “Both patients had normalized liver function test results after 2 weeks of treatment and cleared HEV after 4 weeks of treatment. Hepatitis E virus RNA remained undetectable in the serum and stools throughout follow-up (3 months and 2 months for the first and second patient, respectively). Side effects were considered mild.” (V. Mallet, vincent.mallet@cch.aphp.fr)
Preventing Alzheimer Disease: An NIH state-of-the-science conference on prevention of Alzheimer disease and cognitive decline reached this conclusion about drug therapy and other strategies (early release): “Ongoing studies on antihypertensive medications, omega-3 fatty acids, physical activity, and cognitive engagement may provide new insights into the prevention or delay of cognitive decline or Alzheimer disease. This important research needs to be supplemented by further studies. Large-scale population-based studies and [randomized controlled trials (RCTs)] are critically needed to investigate strategies to maintain cognitive function in individuals at risk for decline, identify factors that may delay the onset of Alzheimer disease among persons at risk, and identify factors that may slow the progression of Alzheimer disease among persons in whom the condition is already diagnosed.” (NIH Consensus Development Program, www.consensus.nih.gov, 888/644-2667)
A systematic review on this topic and released at the conference makes these observations (
early release): “127 observational studies, 22 RCTs, and 16 systematic reviews were reviewed in the areas of nutritional factors; medical factors and medications; social, economic, or behavioral factors; toxic environmental exposures; and genetics. Few of the factors had sufficient evidence to support an association with cognitive decline. On the basis of observational studies, evidence that supported the benefits of selected nutritional factors or of cognitive, physical, or other leisure activities was limited. Current tobacco use, the apolipoprotein E e4 genotype, and certain medical conditions were associated with increased risk. One RCT found a small, sustained benefit from cognitive training (high quality of evidence) and a small RCT reported that physical exercise helps to maintain cognitive function.” (B. L. Plassman, brenda.plassman@duke.edu)
Extended Valganciclovir CMV Prophylaxis After Lung Transplantation: Nine months of valganciclovir therapy, added on to an initial 3-month regimen, reduces cytomegalovirus infection, disease, and disease severity in patients following lung transplant, researchers report (pp. 761–9). In 136 lung transplant recipients at 11 centers, oral valganciclovir and placebo produced these outcomes: “CMV disease occurred in 32% of the short-course group versus 4% of the extended-course group (P < 0.001). Significant reductions were observed with CMV infection (64% vs. 10%; P < 0.001) and disease severity (110 000 vs. 3,200 copies/mL, P = 0.009) with extended treatment. Rates of acute rejection, opportunistic infections, adverse events, CMV UL97 ganciclovir-resistance mutations, and laboratory abnormalities were similar between groups. During the 6 months after study completion, a low incidence of CMV disease was observed in both groups.” (S. M. Palmer, palme002@mc.duke.edu)
Racial Differences in A1c Levels: Blacks have higher glycosylated hemoglobin concentrations than do whites “across the full spectrum of glycemia,” authors write, adding that these findings indicate that utility of the indicator could therefore be limited (pp. 770–7). Using data on nearly 3,600 adults from two data sets, the investigators found that A1c levels were higher in blacks than whites in all groups, including those with normal glucose tolerance, prediabetes, and diabetes. “These findings could limit the use of [A1c] to screen for glucose intolerance, indicate the risk for complications, measure quality of care, and evaluate disparities in health,” the group concludes. (D. C. Ziemer)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 16, 2010 * Vol. 17, No. 115
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 16 issue of JAMA (2010; 303).
CER of Steroids in COPD: In hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease, low doses of oral corticosteroids produced outcomes similar to those with high intravenous doses of these drugs, according to a comparative effectiveness research report (pp. 2359–67). Using data from 414 hospitals where patients were in nonintensive-care settings, researchers obtained these results in a pharmacoepidemiologic cohort study: “Of 79,985 patients, 73,765 (92%) were initially treated with intravenous steroids, whereas 6,220 (8%) received oral treatment. We found that 1.4% (95% confidence interval [CI], 1.3%–1.5%) of the intravenously and 1.0% (95% CI, 0.7%–1.2%) of the orally treated patients died during hospitalization, whereas 10.9% (95% CI, 10.7%–11.1%) of the intravenously and 10.3% (95% CI, 9.5%–11.0%) of the orally treated patients experienced the composite outcome. After multivariable adjustment, including the propensity for oral treatment, the risk of treatment failure among patients treated orally was not worse than for those treated intravenously (odds ratio [OR], 0.93; 95% CI, 0.84–1.02). In a propensity-matched analysis, the risk of treatment failure was significantly lower among orally treated patients (OR, 0.84; 95% CI, 0.75–0.95), as was length of stay and cost. Using an adaptation of the instrumental variable approach, increased rate of treatment with oral steroids was not associated with a change in the risk of treatment failure (OR for each 10% increase in hospital use of oral steroids, 1.00; 95% CI, 0.97–1.03). A total of 1,356 (22%) patients initially treated with oral steroids were switched to intravenous therapy later in the hospitalization.” (P. K. Lindenauer, peter.lindenauer@bhs.org)
Editorialists note that CER efforts based on noninferiority clinical trials would be more actionable than with this retrospective study, especially in situations like that of steroids in COPD, where high-dose intravenous agents are overwhelming used in clinical care of hospitalized patients (
pp. 2409–10). Nevertheless, they note, the use of available data made possible through health information technology should be explored: “Here lies an opportunity for CER within linked registries, potentially enabling ongoing surveillance of care quality and patient outcomes. Large, representative, multisite registries, preferably enhanced in the future with clinical information derived from increased use of interoperative electronic medical and pharmacy records, can be used to track changes in practice, patient adherence, as well as benefits and harms in real-world settings. With sustained funding, CER within linked registries could further assess the harm to benefit profiles in various subgroups, including those typically underrepresented in efficacy research (eg, those with multiple comorbid conditions, race/ethnic minorities), document care delivery, and provide quality measurement that can assist ongoing efforts to enhance care. These activities can serve to reassure improvements in health care delivery and outcomes with lower oral doses of corticosteroids and identify the need to modify or halt the implementation of such a strategy in one or more patient subgroups.” (J. A. Krishnan, jkrishna@medicine.bsd.uchicago.edu)
MRSA & Survival in Cystic Fibrosis: Patients with cystic fibrosis who have methicillin-resistant Staphylococcus aureus in their respiratory tracts are more likely to die, according to a cohort study of 19,833 children, adolescents, and adults (pp. 2386–92). The patients, aged 6–45 years and seen at accredited CF centers, were initially seen in 1996–2006 and followed through the end of 2008. Results showed: “In 137,819 patient–years of observation (median, 7.3 years/patient), 2,537 CF patients died and 5,759 patients had MRSA detected. The mortality rate was 18.3 deaths (95% confidence interval [CI], 17.5–19.1) per 1,000 patient–years in patients without MRSA and 27.7 deaths (95% CI, 25.3–30.4) per 1,000 patient–years in those with MRSA. Among those with MRSA, the attributable risk percentage of death associated with MRSA was 34.0% (95% CI, 26.7%–40.4%). The unadjusted hazard ratio associated with MRSA was 1.47 (95% CI, 1.32–1.62). After adjustment for time-varying covariates associated with severity of illness, MRSA remained associated with a higher risk of death (1.27; 95% CI, 1.11–1.45).” (E. C. Dasenbrook, ecd28@case.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 17, 2010 * Vol. 17, No. 116
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 17 issue of the New England Journal of Medicine (2010; 362).
Antiretroviral Drugs During Breast-feeding, Pregnancy: Two studies and an editorial provide clinicians with useful information on ways to prevent HIV transmission from mothers to infants during pregnancy and breast-feeding.
Transmission of HIV-1 during breast-feeding was reduced by a maternal antiretroviral regimen and infant doses of nevirapine, researchers report (
pp. 2271–81). Among 2,369 HIV-1–positive mothers with CD4+ lymphocyte counts of 250 cells/cu mm or more, perinatal prophylaxis was provided to all mothers and infants. They were then assigned to a maternal antiretroviral regimen, infant nevirapine, or no extended postnatal antiretroviral regimen (control group). Kaplan–Meier estimation of cumulative transmission risk or death by 28 weeks among infants who were HIV-1 negative 2 weeks after birth showed these patterns: “Among mother–infant pairs, 5.0% of infants were HIV-1–positive at 2 weeks of life. The estimated risk of HIV-1 transmission between 2 and 28 weeks was higher in the control group (5.7%) than in either the maternal-regimen group (2.9%, P = 0.009) or the infant-regimen group (1.7%, P < 0.001). The estimated risk of infant HIV-1 infection or death between 2 and 28 weeks was 7.0% in the control group, 4.1% in the maternal-regimen group (P = 0.02), and 2.6% in the infant-regimen group (P < 0.001). The proportion of women with neutropenia was higher among those receiving the antiretroviral regimen (6.2%) than among those in either the nevirapine group (2.6%) or the control group (2.3%). Among infants receiving nevirapine, 1.9% had a hypersensitivity reaction.” (C. M. van der Horst, cvdh@med.unc.edu)
An overall 1.1% HIV-1 transmission rate to infants resulted from use of highly active antiretroviral therapy (HAART) in pregnant and breast-feeding women, a study shows (
pp. 2282–94). Study participants, 560 HIV-1–infected pregnant women with CD4+ counts of 200 cells/cu mm or more, received coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir–ritonavir plus zidovudine–lamivudine (the protease-inhibitor group) from 26 to 34 weeks’ gestation through planned weaning by 6 months postpartum, with these results: “The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group.” (R. L. Shapiro, rshapiro@hsph.harvard.edu)
Clinicians have the needed tools to “protect the next generation,” an editorialist writes in response to these studies (
pp. 2316–8): “Debate about which intervention is optimal and most effective should not be used to justify inaction. Success will be tied less to what regimen is provided than to the integration of services for the identification, care, and treatment of women with HIV-1 infection and their infants. The implementation of these new options for the perinatal prevention of HIV-1 infection in resource-limited countries offers a unique opportunity to link prevention and treatment efforts, rather than view these as competing efforts. We now have the tools to make a considerable difference in controlling the pediatric HIV-1 epidemic. A generation of children awaits our actions.” (L. M. Mofenson)

>>>PNN NewsWatch
* Parents and caregivers should be alert for droppers packaged with some vitamin D supplements that can deliver to infants more than the recommended 400 IU of this nutrient. In addition to issuing this warning, FDA is recommending that manufacturers use droppers in these infant formulations that deliver no more than 400 IU.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 18, 2010 * Vol. 17, No. 117
Providing news and information about medications and their proper use

>>>Allergy/Immunology Report
Source:
June issue of the Journal of Allergy and Clinical Immunology (2010; 125).
Montelukast & Early Immunotherapy in Childhood Asthma: While benefits were expected, montelukast instead decreased the effectiveness of allergen-specific immunotherapy (SIT) in 36 children with asthma and allergy to house dust mites, a study shows (pp. 1220–7). Patients received inhaled budesonide 400–800 mcg/day during a 7-month run-in phase, followed by allocation to montelukast 5 mg daily or placebo with inhaled corticosteroids for 3 months. The researchers noted the following during maintenance SIT: “After 12 months of SIT, a reduction of the median daily ICS dose, necessary to control asthma symptoms, was 16.7% grater in patients from the placebo group than in patients from the montelukast group. Intervention with montelukast significantly impaired the induction of regulatory T lymphocytes. During the build-up phase of SIT, patients in the placebo group frequently experienced an increase in asthma symptoms leading to exclusions from the per protocol population.” (I. Stelmach, alergol@kopernik.lodz.pl)
Mometasone & Ocular Symptoms of Seasonal Allergic Rhinitis: Mometasone furoate nasal spray (MFNS) reduced ocular symptoms of seasonal allergic rhinitis in a study of 429 adolescents and adults, researchers report (pp. 1247–53.e5). The 15-day trial compared MFNS 200 mcg once daily or placebo, with effects measured using total ocular symptom scores (TOSSs) and total nasal symptom scores (TNSSs): “MFNS treatment yielded significant reductions from baseline versus placebo in instantaneous TOSSs (−0.34, P = .026, coprimary end point), instantaneous TNSSs (−0.88, P < .001, coprimary end point), reflective TOSSs (−0.44, P = .005), and reflective TNSSs (−1.06, P < .001). Significant decreases in all individual reflective ocular symptoms and instantaneous eye itching/burning and eye watering/tearing were observed for MFNS versus placebo (P < .05). Numeric improvements in instantaneous eye redness were seen but did not reach statistical significance. Improvements in Rhinoconjunctivitis Quality of Life Questionnaire total scores and individual symptom domains were achieved with MFNS treatment versus placebo (P < .001). MFNS was well tolerated.” (B. M. Prenner, prenner@aaamg.com)

>>>PNN NewsWatch
* A new agent for use with prednisone in men with metastatic hormone-refractory prostate cancer (mHRPC), cabazitaxel (Jevtana, Sanofi-Aventis), was approved yesterday by FDA following a priority review. The microtubule inhibitor was studied in the Phase III TROPIC trial of 755 patients with mHRPC who had been treated previously with docetaxel-containing regimens. Compared with an active chemotherapy regimen of mitoxantrone and prednisone, cabazitaxel plus prednisone reduced mortality by a significant 30% (median overall survival, 15.1 months versus 12.7 months). The most common adverse reactions occurring in at least 10% of patients were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia. The agent will be available this summer.
* A fraudulent formulation is being sold on the Internet as
“Generic Tamiflu,” FDA warned yesterday. Purchased by the agency without a prescription from a now-defunct site, the product contained cloxacillin rather than the expected oseltamivir. FDA cautioned that penicillin-sensitive patients could have serious reactions if they used the product.
* Summaries of
FDA safety analyses of recently approved products are now being posted on FDA’s website along with a brief discussion of the steps the agency is taking to address any identified safety issues. Under the Food and Drug Administration Amendments Act of 2007, FDA is required to prepare safety summaries within 18 months after a product’s approval or after the agent has been used by 10,000 patients, whichever comes later. Included in the summaries is information on potentially serious, previously unidentified risks, if any are found during the review, as well as known adverse events that occur more often than they did during clinical studies. The summaries will also include a brief discussion of any steps FDA is taking to address safety issues.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 21, 2010 * Vol. 17, No. 118
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 19 issue of Lancet (2010; 375).
High-Dose Allopurinol, Exercise, & Angina: In a group of 65 patients with chronic stable angina, high-dose allopurinol was an effective antiischemic agent during exercise, researchers report (pp. 2161–7). Based on previous studies indicating the xanthine oxidase inhibitors reduce myocardial oxygen consumption in particular stroke volumes, the investigators tested allopurinol 600 mg/day using a primary endpoint of ST depression and secondary indicators of total exercise time and time to chest pain. Results showed: “In the first treatment period, 31 patients were allocated to allopurinol and 28 were analysed, and 34 were allocated to placebo and 32 were analysed. In the second period, all 60 patients were analysed. Allopurinol increased the median time to ST depression to 298 s (IQR 211–408) from a baseline of 232 s (182–380), and placebo increased it to 249 s (200–375; p = 0.0002). The point estimate (absolute difference between allopurinol and placebo) was 43 s (95% CI 31–58). Allopurinol increased median total exercise time to 393 s (IQR 280–519) from a baseline of 301 s (251–447), and placebo increased it to 307 s (232–430; p = 0.0003); the point estimate was 58 s (95% CI 45–77). Allopurinol increased the time to chest pain from a baseline of 234 s (IQR 189—382) to 304 s (222–421), and placebo increased it to 272 s (200–380; p = 0.001); the point estimate was 38 s (95% CI 17–55). No adverse effects of treatment were reported.” (A. D. Struthers, a.d.struthers@dundee.ac.uk)

>>>BMJ Highlights
Source:
Early-release articles from BMJ (2010; 340).
Postoperative Pneumonia & Acid Suppressants: No increased risk of postoperative pneumonia was found in elderly patients undergoing elective surgery in a large Canadian study (c2608). In a populationwide retrospective cohort analysis of consecutive patients older than 65 who were admitted for elective surgery to acute-care hospitals in 1992–2008, researchers found: “A total of 593,265 patients were included, of whom about 21% were taking an acid suppressant (most commonly omeprazole or ranitidine). Overall, 6,389 patients developed postoperative pneumonia, with a rate significantly higher for those taking acid suppressants (13 per 1,000) than controls (10 per 1,000), equivalent to a 30% increase in frequency (odds ratio 1.30 (95% confidence interval 1.23 to 1.38), P < 0.001). However, no increase in risk was observed after adjustment for duration of surgery, site of surgery, and other confounders (odds ratio 1.02 (0.96 to 1.09), P = 0.48). The general safety of acid suppressants extended to those patients prescribed proton pump inhibitors, experiencing long term treatment, receiving high doses, and undergoing high risk procedures.” (D. A. Redelmeier, dar@ices.on.ca)
Rotavirus Vaccine & Childhood Diarrhea: Tested at seven hospitals in El Salvador, a monovalent rotavirus vaccine was effective in reducing admissions for diarrhea in children younger than 2 years, a study shows (c2825). The vaccine’s effects persisted into subsequent years, investigators note, reporting these results for 323 children admitted for rotavirus diarrhea (cases) and 969 healthy controls: “Effectiveness of two doses of vaccination against diarrhoea requiring hospital admission was 76% (95% confidence interval 64% to 84%). Protection was significantly lower (P = 0.046) among children aged 12 months or more (59%, 27% to 77%) compared with children aged 6–11 months (83%, 68% to 91%). One dose of vaccine was 51% (26% to 67%) effective. At the sentinel hospitals, all admissions for diarrhoea among children under 5 declined by 40% in 2008 and by 51% in 2009 from the prevaccine year 2006.” (M. Patel, aul3@cdc.gov)

>>>PNN JournalWatch
* Zoster Vaccine: Current Status and Future Prospects, in Clinical Infectious Diseases, 2010; 51:197–213. (M. N. Oxman, mnoxman@ucsd.edu)
* New Perspectives in the Natural History of Multiple Sclerosis, in
Neurology, 2010; 74: 2004–15. (H. Tremlett, tremlett@interchange.ubc.ca)
* Reappraisal of the Impact of Race on Survival in Patients on Dialysis, in
American Journal of Kidney Diseases, 2010; 55: 1102–10. (B. I. Freedman, bfreedma@wfubmc.edu)
* How Medicare’s Payment Cuts For Cancer Chemotherapy Drugs Changed Patterns Of Treatment, in
Health Affairs, 2010; 10.1377/hlthaff.2009.0563. (M. Jacobson, mjacobso@rand.org)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 21, 2010 * Special Alert
Providing news and information about medications and their proper use

FDA announced today that Pfizer is voluntarily withdrawing its brand of gemtuzumab ozogamicin from the U.S. market. Mylotarg had been indicated for treatment of patients aged 60 years or older with recurrent acute myeloid leukemia. FDA requested that Pfizer take this action because of safety concerns and lack of efficacy, as demonstrated in a recent trial conducted as a condition of the agent’s accelerated approval in 2000. Patients already on Mylotarg may complete their therapy if they choose to do so after consultation with their health professional. FDA added that “Mylotarg will not be commercially available to new patients” as a result of the market withdrawal. More information will be in tomorrow's PNN.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 22, 2010 * Vol. 17, No. 119
Providing news and information about medications and their proper use

>>>Rheumatology Highlights
Source:
June issue of Arthritis & Rheumatism (2010; 62).
Rising Incidence of RA in Women: Evidence for an increasing incidence of rheumatoid arthritis in women comes from a study conducted in Olmsted County, MN, from 1955 through 2007 (pp. 1576–82). Researchers used a pre-existing cohort of patients with RA to assemble a population-based incidence cohort of adults who first fulfilled diagnostic criteria in 1994–2007 and a cohort of patients with prevalent RA on Jan. 1, 2005. Incidence and prevalence rates showed these patterns: “The 1995–2007 incidence cohort comprised 466 patients (mean age 55.6 years), 69% of whom were female and 66% of whom were rheumatoid factor positive. The overall age- and sex-adjusted annual RA incidence was 40.9/100,000 population. The age-adjusted incidence in women was 53.1/100,000 population (versus 27.7/100,000 population in men). During the period of time from 1995 to 2007, the incidence of RA increased moderately in women (P = 0.02) but not in men (P = 0.74). The increase was similar among all age groups. The overall age- and sex-adjusted prevalence on January 1, 2005 was 0.72% (95% confidence interval [95% CI] 0.66, 0.77), which is an increase when compared with a prevalence of 0.62% (95% CI 0.55, 0.69) in 1995 (P < 0.001). Applying the prevalence on January 1, 2005 to the U.S. population in 2005 showed that an estimated 1.5 million U.S. adults were affected by RA. This is an increase from the previously reported 1.3 million adults with RA in the U.S.” (S. E. Gabriel, gabriel.sherine@mayo.edu)
NSAID Risk of GI Bleeds: NSAIDs with long half-lives, formulated for slow release, and/or inhibitors of both COX isoenzymes have a greater risk of causing upper gastrointestinal bleeding and perforation, researchers report (pp. 1592–601). Based on a systematic review of observational studies of NSAID use and upper GI bleeding/perforation published in 2000–08, the authors found: “The RR of upper GI bleeding/perforation was 4.50 (95% confidence interval [95% CI] 3.82–5.31) for traditional NSAIDs and 1.88 (95% CI 0.96–3.71) for coxibs. RRs lower than that for NSAIDs overall were observed for ibuprofen (2.69 [95% CI 2.17–3.33]), rofecoxib (2.12 [95% CI 1.59–2.84]), aceclofenac (1.44 [95% CI 0.65–3.2]), and celecoxib (1.42 [95% CI 0.85–2.37]), while higher RRs were observed for ketorolac (14.54 [95% CI 5.87–36.04]) and piroxicam (9.94 [95% CI 5.99–16.50). Estimated RRs were 5.63 (95% CI 3.83–8.28) for naproxen, 5.57 (95% CI 3.94–7.87) for ketoprofen, 5.40 (95% CI 4.16–7.00) for indomethacin, 4.15 (95% CI 2.59–6.64) for meloxicam, and 3.98 (95% CI 3.36–4.72) for diclofenac. The degree of inhibition of whole blood COX-1 did not significantly correlate with RR of upper GI bleeding/perforation associated with individual NSAIDs (r2 = 0.34, P = 0.058), but a profound and coincident inhibition (>80%) of both COX isozymes was associated with higher risk. NSAIDs with a long plasma half-life and with a slow-release formulation were associated with a greater risk than NSAIDs with a short half-life.” (L. A. García Rodríguez, lagarcia@ceife.es)

>>>PNN NewsWatch
* No new patients should be started on Mylotarg, Pfizer’s brand of gemtuzumab ozogamicin for injection, the company recommended yesterday as it announced the voluntary Oct. 15 withdrawal of the product from the U.S. market. When FDA approved gemtuzumab in 2000 under accelerated approval regulations based on three noncomparative studies, it required the company to conduct a postapproval study. SWOG S0106 showed no increase in survival with the drug, compared with chemotherapy alone, in patients with previously untreated acute myeloid leukemia. Additionally, among all patients evaluable for early toxicity, the fatal induction toxicity rate was significantly higher in the daunorubicin and cytosine arabinoside + gemtuzumab arm than in the daunorubicin and cytosine arabinoside arm (16/283 = 5.7% vs. 4/281 = 1.4%). Hepatotoxicity, including severe hepatic veno-occlusive disease, has been reported in association with the use of gemtuzumab as a single agent, as part of a combination chemotherapy regimen, and in patients without a history of liver disease or hematopoietic stem-cell transplant. Patients who are currently taking Mylotarg and those patients who have been prescribed Mylotarg may continue their course of therapy, in consultation with their physicians, the company and FDA said.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 23, 2010 * Vol. 17, No. 120
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
June 23 issue of JAMA (2010; 303).
Lack of Clinical Effects of Homocysteine Lowering: Long-term reductions in serum homocysteine levels failed to produce significant improvements in vascular outcomes among 12,064 survivors of myocardial infarction, according to a report from the 7-year Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group (pp. 2486–94). The reductions were achieved through daily use of folic acid 2 mg and vitamin B12 1 mg, and while concern has been expressed about carcinogenesis with folate, no increases in incidence of cancer were found in this trial: “Allocation to the study vitamins reduced homocysteine by a mean of 3.8 µmol/L (28%). During 6.7 years of follow-up, major vascular events occurred in 1,537 of 6,033 participants (25.5%) allocated folic acid plus vitamin B12 vs 1,493 of 6,031 participants (24.8%) allocated placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97–1.12; P = .28). There were no apparent effects on major coronary events (vitamins, 1,229 [20.4%], vs placebo, 1,185 [19.6%]; RR, 1.05; 95% CI, 0.97–1.13), stroke (vitamins, 269 [4.5%], vs placebo, 265 [4.4%]; RR, 1.02; 95% CI, 0.86–1.21), or noncoronary revascularizations (vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18; 95% CI, 0.95–1.46). Nor were there significant differences in the numbers of deaths attributed to vascular causes (vitamins, 578 [9.6%], vs placebo, 559 [9.3%]) or nonvascular causes (vitamins, 405 [6.7%], vs placebo, 392 [6.5%]) or in the incidence of any cancer (vitamins, 678 [11.2%], vs placebo, 639 [10.6%]).” (J. M. Armitage, search@ctsu.ox.ac.uk)
Legal Challenges to Health Care Reform: In a commentary that assesses the impact on health care reform on social policy in the U.S., authors assess prospects for judicial challenges to the Affordable Care Act (pp. 2521–2): “State attorneys general have launched constitutional challenges, claiming the federal government lacks the power to impose tax penalties against individuals who choose not to purchase insurance. This argument is likely to fail because the federal government has a broad power to regulate commerce. Health care has a substantial national economic impact and is not restricted to intrastate business. Furthermore, because the mandate is enforced through a tax penalty, the federal government can also rely on its taxing power.
“State attorneys general similarly argue that the federal government cannot compel states to create insurance exchanges. The act, however, does not create a requirement for states to establish exchanges. Instead, states can either create an exchange or opt for the Secretary of Health and Human Services to set up and operate the exchange. This conforms to Supreme Court precedent. The Supremacy Clause, moreover, holds that federal law supersedes state law—if state and federal law conflict, federal requirements prevail.” (L. O. Gostin,
gostin@law.georgetown.edu)
Genomic Analysis of Mental Illness: The complicated search for genetic contributors to schizophrenia and other complex neuropsychiatric disorders is reviewed in a commentary article (pp. 2523–4). After noting the effects of rare alleles that have severe psychiatric effects and results of genome-wide association studies, the authors conclude: “Psychiatric illnesses are characterized by substantial locus and allelic heterogeneity. Many apparent disease-causing mutations either are de novo or occurred in recent generations. The human genome has a vast number of genes and regulatory mechanisms related to brain development, any one of which can be disrupted by a variety of mutational mechanisms. Contributions from somatic mutation, epigenetic dysregulation, and environmental influences further add to etiologic complexity.
“The goal is to identify and characterize neurobiological processes disrupted in individuals with mental disorders, regardless of cause. Even if most affected persons harbor different mutations in different genes, many events likely disrupt the same or related components of brain circuitry. Characterizing critical pathways will contribute substantially to understanding psychopathology and provide important targets for treatment.” (J. McClellan,
drjack@uw.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 24, 2010 * Vol. 17, No. 121
Providing news and information about medications and their proper use

>>>NEJM Highlights
Source:
June 24 issue of the New England Journal of Medicine (2010; 362).
Poliovirus Vaccine: Two studies and a commentary explore poliovirus immunization and eradication.
Using fractional doses of poliovirus vaccine results in rates of seroconversion similar to those of full doses, but the titers are much lower with the antigen-sparing approach, a study shows (
pp. 2351–9). In Oman, poliovirus vaccine was administered to infants in fractional doses of 0.1 mL given intradermally using a needle-free jet injector device or full (0.5 mL) doses given intramuscularly at 2, 4, and 6 months, with these results: “A total of 400 infants were randomized, of whom 373 (93.2%) fulfilled the study requirements. No significant baseline differences between the groups were detected. Thirty days after completion of the three-dose schedule, the rates of seroconversion to types 1, 2, and 3 poliovirus were 97.3%, 95.7%, and 97.9%, respectively, in the fractional-dose group, as compared with 100% seroconversion to all serotypes in the full-dose group (P = 0.01 for the comparison with respect to type 2 poliovirus; results with respect to types 1 and 3 poliovirus were not significant). The median titers were significantly lower in the fractional-dose group than in the full-dose group (P < 0.001 for all three poliovirus serotypes). At 7 months, 74.8% of the infants in the fractional-dose group and 63.1% of those in full-dose group excreted type 1 poliovirus (P=0.03). Between birth and 7 months, 42 hospitalizations were reported, all related to infectious causes, anemia, or falls, with no significant difference between vaccination groups.” (R. W. Sutter, sutterr@who.int)
In devising eradication strategies, public health officials must have plans to deal with vaccine-derived poliovirus that is just as virulent and pathogenic wild-type poliovirus (WPV), researchers report based on experiences in Nigeria (
pp. 2360–9). The largest recorded outbreak of circulating vaccine-derived poliovirus (cVDPV) provided this information: “No significant differences were found in the clinical severity of paralysis among the 278 cases of type 2 cVDPV, the 2,323 cases of type 1 WPV, and the 1,059 cases of type 3 WPV. The estimated average annual clinical attack rates of type 1 WPV, type 2 cVDPV, and type 3 WPV per 100,000 susceptible children under 5 years of age were 6.8 (95% confidence interval [CI], 5.9 to 7.7), 2.7 (95% CI, 1.9 to 3.6), and 4.0 (95% CI, 3.4 to 4.7), respectively. The estimated effectiveness of trivalent oral polio vaccine against paralysis from type 2 cVDPV was 38% (95% CI, 15 to 54%) per dose, which was substantially higher than that against paralysis from type 1 WPV (13%; 95% CI, 8 to 18%), or type 3 WPV (20%; 95% CI, 12 to 26%). The more frequent use of serotype 1 and serotype 3 monovalent oral polio vaccines has resulted in improvements in vaccine-induced population immunity against these serotypes and in declines in immunity to type 2 cVDPV.” (H. E. Jenkins, jenkins.helen@gmail.com)
A commentary author writes of “reasons for hope” on “the bumpy road to polio eradication” (
pp. 2346–9): “Widened use of monovalent and bivalent type 1 and 3 [oral poliovirus vaccine (OPV)] formulations that are more immunogenic than [trivalent] OPV markedly reduced wild-type disease in Nigeria and India in 2009; only two cases of wild-type poliomyelitis have been reported in India since early February 2010. Overall, according to the WHO, about half as many cases of wild-type polio have been reported globally in 2010 as during the same period last year. The Bill and Melinda Gates Foundation has entered the fray, contributing $700 million, and Mr. Gates traveled to Nigeria in 2009 to meet with governmental and religious leaders to support the eradication program. The [Global Poliomyelitis Eradication Initiative of the World Health Organization] team has developed a new strategic plan designed to align polio eradication with other global health priorities and continues to apply new insights from laboratory advances, epidemiologic studies, and disease modeling. This team’s extraordinary dedication and determination to succeed should not be underestimated.” (J. F. Modlin)
Gefitinib in Non–Small-Cell Lung Cancer: In a planned interim analysis of 200 patients with non–small-cell lung cancer with sensitive mutations of the epidermal growth factor receptor (EGFR), first-line gefitinib improved progression-free survival, compared with standard chemotherapy. (pp. 2380–8; A. Inoue, akinoue@idac.tohoku.ac.jp)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 25, 2010 * Vol. 17, No. 122
Providing news and information about medications and their proper use

>>>Health Affairs Report
Source:
Early-release article from Health Affairs (2010; 29).
Payment-Driven Changes in Chemotherapy Use: Payment reforms enacted as part of the Medicare Modernization Act of 2003 likely changed the way physicians treated lung cancer, with unknown effects on patients, researchers report (doi: 10.1377/hlthaff.2009.0563). Substantial reductions in payment rates for outpatient chemotherapy drugs were made in 2005, the group notes, adding: “Contrary to concerns about access, we found that the changes actually increased the likelihood that lung cancer patients received chemotherapy. The type of chemotherapy agents administered also changed. Physicians switched from dispensing the drugs that experienced the largest cuts in profitability, carboplatin and paclitaxel, to other high-margin drugs, like docetaxel. We do not know what the effect was on cancer patients, but these changes may have offset some of the savings projected from passage of the legislation. The ultimate message is that payment reforms have real consequences and should be undertaken with caution.” (M. Jacobson, mjacobso@rand.org)

>>>Medical Care Highlights
Source:
July issue of Medical Care (2010; 48).
Partnership Research in a Depression Study: Translational research—which involves T1 (translation studies of bench to bedside), T2 (effectiveness trials), and T3 (implementation studies)—is working well among academic health centers in Minnesota, a report notes (pp. 576–82). A depression initiative and study has been successful under a partnership-research model, which is important as health centers seek to meet requirements of NIH funding. The authors explain: “The Depression Improvement Across Minnesota: Offering a New Direction study was developed in an ongoing partnership with the Initiative leaders from 7 health plans, 85 clinics, and a regional quality improvement collaborative to evaluate the implementation and its impacts on patients and other stakeholders. We agreed on a staggered implementation, multiple baseline research design, using the concepts of practical clinical trials and engaged scholarship and have collaborated on all aspects of conducting the study, including joint identification of patient and clinic survey recipients.
“Complex study methods have worked well through 20 months because of the commitment of all stakeholders to both the Initiative and the Study. Over 1,500 subjects have been recruited from health plan information delivered weekly, and 99.7% of 316 physicians and administrators from all participating clinical organizations have completed the Study surveys.” (L. I. Solberg)
Aggregated Z-Score in Monitoring Diabetes Care: Researchers developed a tool that uses a composite end point of blood pressure, lipids, and glycemia to detect improvements in diabetes care among populations (pp. 589–95). While noting that the aggregated Z-score cannot be used to compare physicians, the authors note that “this scoring system is useful to picture practice populations with diabetes who are at high cardiovascular risk because of modifiable risk factors.” They explain: “We created an aggregated zA-score, calculated as the average of 3 z-scores testing whether the mean practice values of hemoglobin A1c, low density lipoprotein cholesterol, and systolic blood pressure are significantly higher than the corresponding ADA-target (respectively 7%, 100 mg/dL, and 130 mm Hg). This score was used with 100 general practitioners who participated in a Quality Improvement Program. We defined the cut-off value (COV) to determine ‘Practices Requiring Support’ (zA Results showed the following: “The COV was −1.22 and was valid to discriminate between practices at higher risk from practices at lower CHD risk (24% ± 4% vs. 19% ± 4%). The correlation coefficient was −0.515 (P = 0.001). The average z-score increased from −1.21 ± 0.97 at baseline to 0.49 ± 1.01 after the intervention (P < 0.001).” (G. Goderis)

>>>PNN NewsWatch
* FDA this week notified CDC of termination of the emergency use authorization for antiviral agents, an action taken during the 2009 A/H1N1 influenza pandemic. Postings detail the action with regard to oseltamivir, zanamivir, and peramivir.

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 28, 2010 * Vol. 17, No. 123
Providing news and information about medications and their proper use

>>>Lancet Highlights
Source:
June 26 issue of Lancet, a theme issue on diabetes that coincides with the American Diabetes Assoc. Scientific Sessions (2010; 375).
Dapagliflozin in Type 2 Diabetes: The selective sodium-glucose cotransporter-2 inhibitor dapagliflozin provides a new option for use in patients with type 2 diabetes who have inadequate glycemic control with metformin alone, a Phase III trial shows (pp. 2223–33). In 546 adult patients, dapagliflozin 2.5, 5, or 10 mg produced these outcomes in combination with prestudy doses of metformin: “At week 24, mean HbA1c had decreased by −0.30% (95% CI −0.44 to −0.16) in the placebo group, compared with −0.67% (−0.81 to −0.53, p = 0.0002) in the dapagliflozin 2.5 mg group, −0.70% (−0.85 to −0.56, p < 0.0001) in the dapagliflozin 5 mg group, and −0.84% (−0.98 to −0.70, p < 0.0001) in the dapagliflozin 10 mg group. Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin (2—4%) and placebo groups (3%). Signs, symptoms, and other reports suggestive of genital infections were more frequent in the dapagliflozin groups (2.5 mg, 11 patients [8%]; 5 mg, 18 [13%]; 10 mg, 12 [9%]) than in the placebo group (seven [5%]). 17 patients had serious adverse events (four in each of the dapagliflozin groups and five in the placebo group).” (C. J. Bailey, c.j.bailey@aston.ac.uk)
Once-Weekly Exenatide: Among 456 patients whose type 2 diabetes was inadequately controlled by maximal doses of hypoglycemic agents for 3 months or longer, exenatide given once weekly provided better outcomes than daily doses of insulin glargine, researchers report (pp. 2234–43): “Change in HbA1c at 26 weeks was greater in patients taking exenatide (n = 228; −1.5%, SE 0.05) than in those taking insulin glargine (n = 220; −1.3%, 0.06; treatment difference −0.16%, 0.07, 95% CI −0.29 to −0.03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p = 0.012). A planned extension period (up to 2.5 years’ duration) is in progress.” (M. Diamant, m.diamant@vumc.nl)
Prandial Inhaled Insulin in Type 2 Diabetes: Glycemic control was similar with prandial doses of Technosphere inhaled insulin and a twice-daily insulin formulation, but those in the inhalation group had more coughing and changes in pulmonary function, a study shows (pp. 2244–53). The inhaled insulin powder was administered with meals (patients received insulin glargine at bedtime), and the regimen provided these outcomes in comparison with twice-daily biaspart insulin (70% insulin aspart protamine suspension and 30% insulin aspart of rDNA origin): “Change in HbA1c with inhaled insulin plus insulin glargine (−0.68%, SE 0.077, 95% CI −0.83 to −0.53) was similar and non-inferior to that with biaspart insulin (−0.76%, 0.071, −0.90 to −0.62). The between-group difference was 0.07% (SE 0.102, 95% CI −0.13 to 0.27). Patients had significantly lower weight gain and had fewer mild-to-moderate and severe hypoglycaemic events on inhaled insulin plus insulin glargine than on biaspart insulin. The safety and tolerability profile was similar for both treatments, apart from increased occurrence of cough and change in pulmonary function in the group receiving inhaled insulin plus insulin glargine.” (J. Rosenstock, juliorosenstock@dallasdiabetes.com)
Lancet editors comment on the lack of study of ways to prevent diabetes (p. 2193): “Diabetes need not be an inevitable consequence of urbanisation or social inequity, nor should future generations be condemned to perpetuate diabetogenic lifestyles. The fact that type 2 diabetes, a largely preventable disorder, has reached epidemic proportion is a public health humiliation. A strong, integrated, and imaginative response is required, in which the limits of drug treatment and the opportunities of civil society are recognised. The ADA meeting offers world leaders in diabetes an opportunity to reflect on the above challenges and initiate debate on a more inclusive and effective strategy to control diabetes.”

>>>PNN JournalWatch
* Management of People with Diabetes Wanting To Fast During Ramadan, in BMJ, 2010; 340: c3053. (D. Devendra)

* Chronic Obstructive Pulmonary Disease Diagnosis and Management in Older Adults, in
Journal of the American Society of Geriatrics, 2010; 58: 1153–62. (N. S. Gooneratne, ngoonera@mail.med.upenn.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 29, 2010 * Vol. 17, No. 124
Providing news and information about medications and their proper use

>>>Internal Medicine Report
Source:
Early-release article from and June 28 issue of the Archives of Internal Medicine (2010; 170).
Rosiglitazone Risks: Posted in advance of a July 13–14 FDA hearing on the cardiovascular safety of rosiglitazone, a meta-analysis of 56 trials with 34,531 patients links the drug with an increased risk of myocardial infarction but not cardiovascular or all-cause mortality (doi:10.1001/archinternmed.2010.207). The report concludes, “The current findings suggest an unfavorable benefit to risk ratio for rosiglitazone,” adding these details: “Rosiglitazone therapy significantly increased the risk of MI (OR, 1.28; 95% confidence interval [CI], 1.02–1.63; P = .04) but not CV mortality (OR, 1.03; 95% CI, 0.78–1.36; P = .86). Exclusion of the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) trial yielded similar results but with more elevated estimates of the OR for MI (OR, 1.39; 95% CI, 1.02–1.89; P = .04) and CV mortality (OR, 1.46; 95% CI, 0.92–2.33; P = .11). An alternative analysis pooling trials according to allocation ratios allowed inclusion of studies with no events, yielding similar results for MI (OR, 1.28; 95% CI, 1.01–1.62; P = .04) and CV mortality (OR 0.99; 95% CI, 0.75–1.32; P = .96).” (S. E. Nissen, nissens@ccf.org)
Statins in Primary Prevention: Two articles and an editorial evaluate the utility of statins in primary prevention.
No benefit was found in a meta-analysis of statins used in intermediate- to high-risk patients without cardiovascular disease, researchers report (
pp. 1024–31). Assessing trials that included details or data on all-cause mortality, the analysis showed: “Data were combined from 11 studies and effect estimates were pooled using a random-effects model meta-analysis, with heterogeneity assessed with the I2 statistic. Data were available on 65,229 participants followed for approximately 244,000 person–years, during which 2,793 deaths occurred. The use of statins in this high-risk primary prevention setting was not associated with a statistically significant reduction (risk ratio, 0.91; 95% confidence interval, 0.83–1.01) in the risk of all-cause mortality. There was no statistical evidence of heterogeneity among studies (I2 = 23%; 95% confidence interval, 0%–61% [P = .23]).” (K. K. Ray, koshray@gmail.com)
Authors re-evaluating the JUPITER (Justification for the Use of Statins in Primary Prevention) trial reach a disconcerting conclusion: “The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors” (
pp. 1032–6). After “careful review of both results and methods used in the trial and comparison with expected data,” the writers report: “The trial was flawed. It was discontinued (according to prespecified rules) after fewer than 2 years of follow-up, with no differences between the 2 groups on the most objective criteria. Clinical data showed a major discrepancy between significant reduction of nonfatal stroke and myocardial infarction but no effect on mortality from stroke and myocardial infarction. Cardiovascular mortality was surprisingly low compared with total mortality—between 5% and 18%—whereas the expected rate would have been close to 40%. Finally, there was a very low case-fatality rate of myocardial infarction, far from the expected number of close to 50%. The possibility that bias entered the trial is particularly concerning because of the strong commercial interest in the study.” (M. de Lorgeril, michel.delorgeril@ujf-grenoble.fr)
Discussing the above trials in the context of how there is “still much we don’t know,” an editorialist concludes (
pp. 1007–8): “As the American humorist Josh Billings (Henry Wheeler Shaw, 1818–1885) pointed out, ‘It ain’t what folks don’t know that’s the problem, it’s what they know that ain’t so.’ So what do we, the physicians who are responsible for giving the best evidence-based advice to our patients, really know about pharmacological lipid lowering for coronary primary prevention? Ray and colleagues’ meta-analysis makes it clear that in the short term, for true primary prevention, the benefit, if any, is very small. In the long term, although sincere advocates on both sides will try to convince us otherwise, we really must admit that we do not know. We need good research to find out, and, as de Lorgeril and colleagues point out, that research must be free of incentives to find any particular desired answer.” (L. A. Green, greenla@umich.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.

PNN Pharmacotherapy Line
June 30, 2010 * Vol. 17, No. 125
Providing news and information about medications and their proper use

>>>JAMA Highlights
Source:
Early-release articles from and June 30 issue of JAMA (2010; 303).
More on Rosiglitazone: Adding to the evidence noted in yesterday’s PNN, a research study finds that rosiglitazone use is associated with increased risk of stroke, heart failure, and all-cause mortality and an increased risk of a composite end point of acute myocardial infarction (AMI), stroke, heart failure, or all-cause mortality in patients 65 years or older (doi:10.1001/jama.2010.920). Among nearly 228,000 Medicare Part D beneficiaries who received rosiglitazone or pioglitazone in 2006–09, these patterns were noted over 3 years of follow-up: “A total of 8,667 end points were observed during the study period. The adjusted hazard ratio for rosiglitazone compared with pioglitazone was 1.06 (95% confidence interval [CI], 0.96–1.18) for AMI; 1.27 (95% CI, 1.12–1.45) for stroke; 1.25 (95% CI, 1.16–1.34) for heart failure; 1.14 (95% CI, 1.05–1.24) for death; and 1.18 (95% CI, 1.12–1.23) for the composite of AMI, stroke, heart failure, or death. The attributable risk for this composite end point was 1.68 (95% CI, 1.27–2.08) excess events per 100 person-years of treatment with rosiglitazone compared with pioglitazone. The corresponding number needed to harm was 60 (95% CI, 48–79) treated for 1 year.” (D. J. Graham, david.graham1@fda.hhs.gov)
While FDA may elect to await further trials of rosiglitazone after its hearing on the drug in July, an editorialist argues that safety should trump certainty (
doi:10.1001/jama.2010.954): “The epilogue of the rosiglitazone story has yet to be written, but a few observations can now be made with confidence. First, there is no direct evidence that rosiglitazone prevents vascular events in patients with diabetes. Second, converging lines of evidence suggest that rosiglitazone is less safe than pioglitazone, whereas no data suggest that the converse might be true. Third, because the evidence to date is not conclusive, differing views have emerged on how to proceed in the face of uncertainty. A consensus panel of the American Heart Association and the American College of Cardiology Foundation has called for more controlled clinical trials, whereas the American Diabetes Association and its European counterpart have advised against the use of rosiglitazone. The latter view incorporates a simple fact that has frequently gone overlooked: rosiglitazone confers no therapeutic advantage over pioglitazone. Whether rosiglitazone and pioglitazone really do have different cardiovascular safety profiles is an intriguing question but one with a misplaced focus. Accumulating concerns about rosiglitazone make it difficult to advance a cogent argument regarding why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative.” (D. N. Juurlink, dnj@ices.on.ca)
Adiposity & Diabetes: Weight gain and central and overall adiposity in later years of life do increase the diabetes risk, a prospective cohort study confirms (pp. 2504–12). Among 4,193 adults in the Cardiovascular Health Study in 1989–2007, these associations were made: “Over median follow-up of 12.4 years (range, 0.9–17.8 years), 339 cases of incident diabetes were ascertained (7.1/1000 person–years). The adjusted hazard ratio (HR) (95% confidence interval [CI]) of type 2 diabetes for participants in the highest quintile of baseline measures compared with those in the lowest was 4.3 (95% CI, 2.9–6.5) for body mass index…, 3.0 (95% CI, 2.0–4.3) for BMI at 50 years of age, 4.2 (95% CI, 2.8–6.4) for weight, 4.0 (95% CI, 2.6–6.0) for fat mass, 4.2 (95% CI, 2.8–6.2) for waist circumference, 2.4 (95% CI, 1.6–3.5) for waist-hip ratio, and 3.8 (95% CI, 2.6–5.5) for waist-height ratio. However, when stratified by age, participants 75 years of age and older had HRs approximately half as large as those 65 to 74 years of age. Compared with weight-stable participants (±2 kg), those who gained the most weight from 50 years of age to baseline (9 kg), and from baseline to the third follow-up visit (6 kg), had HRs for type 2 diabetes of 2.8 (95% CI, 1.9–4.3) and 2.0 (95% CI, 1.1–3.7), respectively. Participants with a greater than 10-cm increase in waist size from baseline to the third follow-up visit had an HR of type 2 diabetes of 1.7 (95% CI, 1.1–2.8) compared with those who gained or lost 2 cm or less.” (M. L. Biggs, mlbiggs@u.washington.edu)

PNN Pharmacotherapy Line is published via e-mail each business day except for federal holidays by PNN Pharmacotherapy News Network, P.O. Box 6565, Athens, GA 30604; 706/613-0100 or 706/613-0200 (fax). Copyright © 2010, Pharmacy Editorial & News Services, Inc. All rights reserved. L. Michael Posey, Editor and Publisher. E-mail PNNInfo@mac.com or call 706/613-0100 to request missing copies of PNN.