Day: 04/26/2011

CABG for Patients with Coronary Disease and Markedly Reduced Ejection Fraction?

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In a randomized trial, coronary artery bypass grafting — compared with good medical therapy — did not lower mortality at 5 years.

Does coronary artery bypass grafting (CABG) lower medium-term mortality in patients with substantially reduced left ventricular ejection fraction (LVEF) and coronary artery disease suitable for CABG? To answer this question, researchers randomized 1200 patients with coronary disease and LVEF 35% either to optimal medical therapy alone or medical therapy plus CABG. Most patients had two- or three-vessel disease; patients with left main stenosis and severe angina were excluded. During the trial, 17% of medical-therapy patients crossed over to CABG.

After average follow-up of almost 5 years, all-cause mortality (the primary outcome) was similar in the CABG and medical therapy groups (36% and 41%; P=0.12). Early mortality was higher in the CABG group than in the medical-therapy group, owing to perioperative death (4% vs. 1% at 30 days); after 2 or 3 years, the death rate was slightly lower in the CABG group. Several secondary endpoints (combinations of mortality and hospitalization or additional coronary revascularization) favored the CABG group. Interestingly, assessment of myocardial viability (using noninvasive imaging) did not predict which patients would benefit from CABG.

Comment: In this study of patients with LVEF 35% and coronary artery disease, but without left main disease, who received aggressive medical management, addition of CABG conferred no significant mortality benefit. Medical management of such patients is appropriate unless coronary revascularization is required for other reasons, such as uncontrolled angina.

Source: Journal Watch General Medicine

Clusterin and Alzheimer Disease

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Elevated plasma levels of the protein clusterin were associated with AD prevalence and severity, but they did not predict AD incidence or distinguish between AD and vascular dementia.

Plasma clusterin has been reported to be associated with baseline severity of Alzheimer disease (AD) and with the speed of AD progression and brain atrophy. Furthermore, the locus of the gene that encodes for this protein has been implicated in AD.

To assess the value of plasma clusterin as an AD biomarker, researchers analyzed data from a randomly selected subcohort of 926 participants in the large, prospective, population-based Rotterdam Study. Each participant had undergone brief cognitive screening with the Mini-Mental State Examination and the Geriatric Mental State Schedule; subsequent neuropsychological testing was conducted in those with an MMSE score <26 or a GMSS organic level above zero.

During a mean follow-up of 7.2 years, 61 of the 926 participants in the subcohort were diagnosed with dementia according to standard criteria. To these 61, the researchers added 178 people from the larger cohort who developed dementia during follow-up and another 77 who had a dementia diagnosis upon study entry. After adjustment for multiple dementia risk factors (e.g., older age, less education, apolipoprotein E 4 carrier status, vascular risk factors), no clear association between incident dementia and plasma clusterin levels was found. Plasma clusterin also did not discriminate effectively between AD and vascular dementia. Elevated plasma clusterin levels were, however, significantly associated with AD diagnosis at the time of study entry (i.e., with AD prevalence) and with greater AD severity.

Comment: The authors acknowledge that, given their data, plasma clusterin is not a useful biomarker for predicting the development of AD. However, the current findings point to a possible neuroprotective role of clusterin in dementia. Harnessing clusterin in AD therapy may warrant exploration.

Source: Journal Watch Neurology

Off-Label Use of Recombinant Factor VIIa

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Usage soars despite safety risks for some indications and a lack of efficacy in reducing mortality.

Recombinant factor VIIa (rFVIIa) is a potent procoagulant that directly activates factor X on the platelet surface, bypassing the requirement for factor VIII and several other factors in the coagulation cascade. It is FDA approved for the treatment of bleeding due to FVIII inhibitors but has been used off-label to control hemorrhage in many other clinical situations. Now, researchers have conducted two studies to determine patterns and efficacy of off-label rFVIIa use.

In the first study, investigators reviewed 12,644 discharge records of patients who received rFVIIa at 615 hospitals from 2000 through 2008. During that period, off-label use of rFVIIa increased more than 140-fold. During 2008, 97% of all uses were for off-label indications; the most common of these were adult cardiovascular surgery (27%), body trauma (18%), and intracranial hemorrhage (11%). The researchers cited prior randomized and observational studies showing that the use of rFVIIa for these indications had no effect on mortality, but that it increased the rate of thromboembolic events in adult cardiac surgery and intracranial hemorrhage.

In the second study, researchers conducted a meta-analysis of 64 randomized and observational studies to evaluate potential benefits and harms of five off-label uses of rFVIIa. The findings confirmed that use of rFVIIa in adult cardiac surgery, body trauma, and intracranial hemorrhage did not affect mortality and that it increased the rate of thromboembolic events in adult cardiac surgery and intracranial hemorrhage. In addition, rFVIIa use in liver transplantation did not affect mortality or thromboembolic events, and a small study of patients undergoing prostatectomy did not provide sufficient evidence for analyses of mortality or thrombosis.

Comment: The pathophysiology of bleeding is complex and most often reflects a loss of vascular integrity; thus, the lack of efficacy of rFVIIa in reducing mortality is not surprising. Also, the predisposition for thromboembolic events is much greater in patients with cardiovascular disease than in those with hemophilia. Unfortunately, the use of rFVIIa has been driven by the misguided perception that it would be a panacea for severe bleeding, rather than by solid evidence of safety and effectiveness.

Source:Journal Watch Oncology and Hematology

Diagnostic accuracy of echocardiography for pulmonary hypertension: a systematic review and meta-analysis.

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Context Right heart catheterisation is the gold standard for the diagnosis of pulmonary hypertension. However, echocardiography is frequently used to screen for this disease and monitor progression over time because it is non-invasive, widely available and relatively inexpensive. Objective To perform a systematic review and quantitative meta-analysis to determine the correlation of pulmonary pressures obtained by echocardiography versus right heart catheterisation and to determine the diagnostic accuracy of echocardiography for pulmonary hypertension. Data sources MEDLINE, EMBASE, PapersFirst, the Cochrane collaboration and the Cochrane Register of controlled trials were searched and were inclusive as of February 2010. Study selection Studies were only included if a correlation coefficient or the absolute number of true-positive, false-negative, true-negative and false-positive observations was available, and the `reference standards` were described clearly. Data extraction Two reviewers independently extracted the data from each study. Quality was assessed with the quality assessment for diagnostic accuracy studies. A random effects model was used to obtain a summary correlation coefficient and the bivariate model for diagnostic metaanalysis was used to obtain summary sensitivity and specificity values.

source: Heart

Phyllanthus species for chronic hepatitis B virus infection.

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Phyllanthus species for patients with chronic hepatitis B virus (HBV) infection have been assessed in clinical trials, but no consensus regarding their usefulness exists.
OBJECTIVES: To evaluate the benefits and harms of phyllanthus species for patients with chronic HBV infection.
SEARCH STRATEGY: Searches were performed in The Cochrane Hepato-Biliary Gorup Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and the Chinese Biomedical CD Database, China Network Knowledge Information, Chinese Science Journal Database, TCM Online, and Wanfang Database. Conference proceedings in Chinese were handsearched. All searches were conducted until October 2010.
SELECTION CRITERIA: Randomised clinical trials comparing phyllanthus species with placebo or no intervention for patients with chronic HBV infection. Co-interventions were allowed if all comparison groups had received the same co-interventions. We included trials irrespective of blinding, publication status, or language.
DATA COLLECTION AND ANALYSIS: Two authors selected the trials and extracted the data independently. The RevMan software was used for statistical analysis of dichotomous data with risk ratio (RR) with 95% confidence intervals (CI). Risk of bias was assessed to control for systematic errors. Trial sequential analysis was used in order to control for random errors.
MAIN RESULTS: A total of 16 randomised trials with 1326 patients were included. One trial with 42 participants compared phyllanthus with placebo. The trial found no significant difference in HBeAg seroconversion after the end of treatment (RR 0.9; 95% CI 0.73 to 1.25) or follow-up (RR 1.00; 95% CI 0.63 to 1.60). No other outcomes could be assessed. Fifteen trials compared phyllanthus plus an antiviral drug like interferon alpha, lamivudine, adefovir dipivoxil, thymosin, vidarabine, or conventional treatment with the same antiviral drug alone. Phyllanthus did significantly affect serum HBV DNA (RR 0.69; 95% CI 0.52 to 0.91, P = 0.008; I(2) = 71%), serum HBeAg (RR 0.70; 95% CI 0.60 to 0.81, P < 0.00001; I(2) = 68%), and HBeAg seroconversion (RR 0.77; 95% CI 0.63 to 0.92, P = 0.005; I(2) = 78%), but the heterogeneity was substantial. The result obtained regarding serum HBV DNA was not supported by trial sequential analysis. None of the trials reported mortality and hepatitis B-related morbidity, quality of life, or liver histology. Only two trials reported adverse events with numbers without significant differences. No serious adverse events were reported.
AUTHORS’ CONCLUSIONS: There is no convincing evidence that phyllanthus compared with placebo benefits patients with chronic HBV infection. Phyllanthus plus an antiviral drug may be better than the same antiviral drug alone. However, heterogeneity, systematic errors, and random errors question the validity of the results. Clinical trials with large sample size and low risk of bias are needed to confirm our findings. Species of phyllanthus should be reported in future trials, and a dose-finding design is warranted.

source: cochrane database

Surgery for stress urinary incontinence due to presumed sphincter deficiency after prostate surgery.

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Incontinence after prostatectomy for benign or malignant disease is a well known and often a feared outcome. Although small degrees of incidental incontinence may go virtually unnoticed, larger degrees of incontinence can have a major impact on a man`s quality of life.Conceptually, postprostatectomy incontinence may be caused by sphincter malfunction and/or bladder dysfunction. The majority of men with post-prostatectomy incontinence (60 to 100%) have stress urinary incontinence, which is the complaint of involuntary urinary leakage on effort or exertion, or on sneezing or coughing. This may be due to intrinsic sphincter deficiency and may be treated with surgery for optimal management of incontinence. Detrusor dysfunction is more common after surgery for benign prostatic disease.
OBJECTIVES: To determine the effects of surgical treatment for urinary incontinence related to presumed sphincter deficiency after prostate surgery for either benign LUTS secondary to BPH (transurethral resection of prostate (TURP), photo vaporization of the prostate, laser enucleation of the prostate and open prostatectomy) or radical prostatectomy for prostate cancer (retropubic, perineal, laparoscopic, or robotic).
SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Register (searched 28 June 2010), MEDLINE (January 1966 to January 2010), EMBASE (January 1988 to January 2010), LILACS (January 1982 to January 2010) and the reference lists of relevant articles, handsearched conference proceedings and contacted investigators to locate studies.
SELECTION CRITERIA: Randomised or quasi-randomised trials that include surgical treatments of urinary incontinence after prostate surgery.
DATA COLLECTION AND ANALYSIS: Two authors independently screened the trials identified, appraised quality of papers and extracted data.
MAIN RESULTS: Only one study with 45 participants met the inclusion criteria. Men were divided in two subgroups (minimal or total incontinence) and each group was randomized to artificial urethral sphincter (AUS) implantation or Macroplastique injection. Follow-up ranged from six to 120 months. In the trial as a whole, the men treated with AUS were more likely to be dry (18/20, 82%) than those who had the injectable treatment (11/23, 46%) (OR 5.67, 95% CI 1.28 to 25.10). However, this effect was only statistically significant for the men with more severe (`total`) incontinence (OR 8.89, 95% CI 1.40 to 56.57) and the confidence intervals were wide. There were more severe complications in the group undergoing AUS, and the costs were higher.
AUTHORS’ CONCLUSIONS: The evidence available at present is limited because only one small randomised clinical trial was identified. Although the result is favourable for the implantation of AUS in the group with severe incontinence, this result should be considered with caution due to the small sample size and uncertain methodological quality of the study found.

source: cochrane database

Meningococcal Vaccine Approved for Infants and Toddlers

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The FDA has approved use of the meningococcal vaccine Menactra in children as young as age 9 months.

The vaccine had already been approved for use in children 2 years and older. In announcing its action on Friday, the agency noted that the highest rates of meningococcal disease occur in children under 1 year of age. With the new approval, the vaccine can be given in two doses, 3 months apart.

In safety studies, the most common adverse events among children ages 9 and 12 months were injection-site tenderness and irritability.

Source: FDA

HIV PrEP Trial in Women Halted

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Preliminary data from the FEM-PrEP trial show equal numbers of HIV infection in women taking Truvada as oral pre-exposure prophylaxis and those taking placebo.

A large trial of HIV pre-exposure prophylaxis (PrEP) has been stopped early, because it is “highly unlikely” to demonstrate that Truvada (tenofovir disoproxil fumarate/FTC) protects women against HIV infection.

In this phase III trial (called FEM-PrEP), 1951 HIV-negative, high-risk women in Africa were randomized to take Truvada or placebo orally once daily. All the women received monthly risk-reduction counseling, free condoms, and free treatment for sexually transmitted infections; they were also tested monthly for HIV infection and pregnancy.

Preliminary data from approximately 1100 person-years of follow-up indicate that 56 infections occurred during the trial, with exactly half in the Truvada group and half in the placebo group. This finding stands in stark contrast to the results of both the iPrEx trial, which showed a protective effect for once-daily oral Truvada among men who have sex with men, and the CAPRISA 004 trial, which showed a significant risk reduction among women who used a vaginal 1% tenofovir gel before and after sex. In both of those trials, the efficacy of PrEP was directly related to adherence. In the FEM-PrEP trial, preliminary data indicate that self-reported adherence levels were very high (around 95%) for visits where tablets were dispensed.

Another surprise finding in the FEM-PrEP study was a high pregnancy rate in the Truvada group compared with the placebo group. Nearly all participants (96%) were using hormonal contraceptives at study enrollment, raising questions about whether a previously unknown interaction might exist between these contraceptives and the antiretrovirals used in the study. Differential adherence to contraception might have also played a role, as indicated by the higher pregnancy rates seen among women who used oral versus injectable contraceptives.

Final, in-depth analyses of FEM-PrEP data will be conducted once follow-up is complete. In the meantime, several other PrEP trials are ongoing, with the VOICE trial being the most notable. In that study, 5000 women are being randomized to one of five study treatments, to be used daily: oral tenofovir, Truvada, oral placebo, tenofovir gel, or placebo gel.

Comment: While disappointing, the results of the FEM-PrEP trial are clear — they show zero effectiveness after 56 endpoints (75% of the target endpoints) were reached. The independent data monitoring committee determined that, under these circumstances, continuing the study to its target of 74 endpoints in an attempt to demonstrate Truvada’s efficacy would be futile. Why the trial did not produce positive results, as highly anticipated, is unclear. We do not yet know whether trial design and conduct (e.g., low adherence, tolerability) played a role in the findings, whether Truvada is ineffective at preventing HIV infection only in this study population, or whether it is generally ineffective in women. Detailed analyses from the trial, including data on drug levels in the blood and genital tract, are keenly awaited. Other, ongoing PrEP studies, which are being conducted in different populations with different approaches, might also provide valuable clues to interpreting the FEM-PrEP results.

Source: Journal Watch HIV/AIDS Clinical Care

Longer Varenicline Preloading Might Enhance Smoking Cessation Rates

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Extending the varenicline (Chantix) preloading period from 1 week to 4 before the target quit date may enhance smoking cessation rates, according to a preliminary, industry-funded study in the Archives of Internal Medicine.

Some 100 adult smokers were randomized to take varenicline for 4 weeks before their target quit date, or to take placebo for 3 weeks and then varenicline for 1 week before the quit date (the drug’s prescribing information recommends 1 week of preloading). Both groups also received varenicline for up to 12 weeks after quitting.

Longer varenicline preloading was associated with decreased smoking and less smoking enjoyment before quitting, although it had no effect on withdrawal symptoms after quitting. In addition, the smoking cessation rate at 12 weeks was significantly higher with 4 weeks of preloading than with just 1 week (36% vs. 15%).

The authors conclude that the “prequit dosaging recommended per the current varenicline labeling is likely to be too short.”

Source:Archives of Internal Medicine