B-CONVINCED: Beta-blocker CONtinuation Vs. INterruption in patients with Congestive heart failure hospitalizED for a decompensation episode.

AIMS: Whether or not beta-blocker therapy should be stopped during acutely decompensated heart failure (ADHF) is unsure. METHODS AND RESULTS: In a randomized, controlled, open labelled, non-inferiority trial, we compared beta-blockade continuation vs. discontinuation during ADHF in patients with LVEF below 40% previously receiving stable beta-blocker therapy. 169 patients were included, among which 147 were evaluable. Mean age was 72 +/- 12 years, 65% were males. After 3 days, 92.8% of patients pursuing beta-blockade improved for both dyspnoea and general well-being according to a physician blinded for therapy vs. 92.3% of patients stopping beta-blocker. This was the main endpoint and the upper limit for unilateral 95% CI (6.6%) is lower that of the predefined upper limit (12.5%), indicating non-inferiority. Similar findings were obtained at 8 days and when evaluation was made by the patient. Plasma BNP at Day 3, length of hospital stay, re-hospitalization rate, and death rate after 3 months were also similar. Beta-blocker therapy at 3 months was given to 90% of patients vs. 76% (P < 0.05). CONCLUSION: In conclusion, during ADHF, continuation of beta-blocker therapy is not associated with delayed or lesser improvement, but with a higher rate of chronic prescription of beta-blocker therapy after 3 months, the benefit of which is well established.

A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?

The detection of hypoxia by the carotid bodies elicits a ventilatory response of utmost importance for tolerance to high altitude. Germline mutations in three genes encoding subunit B, C and D of succinate dehydrogenase (SDHB, SDHC and SDHD) have been associated with paragangliomas of the carotid body. We hypothesized that SDH dysfunction within the carotid body could result in low chemoresponsiveness and intolerance to high altitude. The frequency of polymorphisms of SDHs, hypoxia-inducible factor type 1 (HIF1alpha) and angiotensin converting enzyme (ACE) genes was compared between 40 subjects with intolerance to high altitude and a low hypoxic ventilatory response at exercise (HVRe < or = 0.5 ml min(-1) kg(-1); HVR- group) and 41 subjects without intolerance to high altitude and a high HVRe (> or = 0.80 ml min(-1) kg(-1); HVR+). We found no significant association between low or high HVRe and (1) the allele frequencies for nine single nucleotide polymorphisms (SNPs) in the SDHD and SDHB genes, (2) the ACE insertion/deletion polymorphism and (3) four SNPs in the HIF1alpha gene. However, a marginal significant association was found between the synonymous polymorphism c.18A>C of the SDHB gene and chemoresponsiveness: 8/40 (20%) in the HVR- group and 3/41 (7%) in the HVR+ group (p = 0.12). A principal component analysis showed that no subject carrying the 18C allele had both high ventilatory and cardiac response to hypoxia. In conclusion, no clear association was found between gene variants involved in oxygen sensing and chemoresponsiveness, although some mutations in the SDHB and SDHD genes deserve further investigations in a larger population.

Intensive cardiovascular risk factors therapy and prevalence of silent myocardial ischaemia in patients with type 2 diabetes.

BACKGROUND: Screening for silent myocardial ischaemia (SMI) is a controversial strategy undergoing intensive risk factor therapy. AIMS: To assess the prevalence of SMI and coronary artery disease (CAD) in asymptomatic type 2 diabetic patients at high cardiovascular risk (two additional risk factors or more) and undergoing long-term intensive risk factor therapy and tight glycaemic control. METHODS: SMI screening, using isotopic or echographic stress tests, was carried out in 122 asymptomatic type 2 diabetic patients at high cardiovascular risk and undergoing long-term intensive risk factor therapy. Coronary angiography was proposed if SMI was detected. Long-term follow-up data on death, myocardial infarction and revascularization were obtained by telephone call or clinical review. RESULTS: The mean age was 65+/-6 years and 74% of patients were men. The mean duration of diabetes was 15+/-9 years. The mean number of additional risk factors was 2.9, 32% of patients had microalbuminuria and 12% had peripheral arterial disease. SMI was detected in 20 (16%) patients. Seven (6%) patients had significant CAD treated successfully by angioplasty (n=6) or bypass surgery (n=1). The positive predictive value of the non-invasive screening test for the diagnosis of significant CAD (stenosis>50%) was 39%. The event rate was very low (1.6%) at 2-year follow-up. CONCLUSION: Long-term intensive risk factor therapy in high-risk patients with type 2 diabetes is associated with low prevalence of SMI and detected CAD. Optimal medical therapy and revascularization of significant CAD are associated with a low cardiovascular event rate at two years.

Epilepsy in autism is associated with intellectual disability and gender: evidence from a meta-analysis.

BACKGROUND: The association between epilepsy and autism is consistently reported, with a wide range of prevalence rates. This may be attributed to the heterogeneity of the samples with respect to age, comorbidity, sex, and intellectual disability (ID). We aimed to compare the prevalence of epilepsy 1) among autistic patients with ID versus autistic patients without ID and 2) among male versus female autistic patients. METHODS: We reviewed all data available from published reports (1963-2006) on autism and epilepsy and conducted a meta-analysis of 10 and 14 studies, respectively, to assess the relative risk (RR) of epilepsy in autism according to ID and gender. The pooled groups included 2112 (627 with IQ > or = 70, 1485 with IQ < 70) and 1530 (1191 male, 339 female) patients, respectively. RESULTS: There was a strong discrepancy in relative risk (RR) according to IQ, with more autistic patients with ID having epilepsy (RR = .555; 95% confidence interval [CI]: .42-.73; p < .001). The pooled prevalence of epilepsy was 21.5% in autistic subjects with ID versus 8% in autistic subjects without ID. There was a strong discrepancy in RR according to sex, favoring comorbidity of epilepsy in autistic girls (RR = .549; 95% CI: .45-.66; p < .001). The male:female ratio of autism comorbid with epilepsy was close to 2:1 whereas the male:female ratio of autism without epilepsy was 3.5:1. CONCLUSIONS: The results of this meta-analysis indicate that risk for epilepsy in autism is a function of ID severity and distinguishes autism associated with epilepsy as a subgroup of autism by its male-female ratio.

Comorbidity with ADHD decreases response to pharmacotherapy in children and adolescents with acute mania: evidence from a metaanalysis.

OBJECTIVE: To assess whether comorbid attention-deficit hyperactivity disorder (ADHD) influences response to treatment in young patients with acute mania. METHODS: We conducted a metaanalysis of 5 open trials of 100, 35, 41, 60, and 37 children and adolescents. The pooled group included 273 children and adolescents with bipolar disorder (BD), divided into 2 subgroups: those with (n = 132), and those without (n = 141), ADHD comorbidity. RESULTS: There was a moderate and significant reduction in relative risk (RR) favouring treatment response in children and adolescents with BD but without ADHD comorbidity (RR 0.822; 95% CI, 0.69 to 0.97; P = 0.021). The negative effect of ADHD comorbidity on treatment response was more significant in studies including adolescents only or subjects with BD I only. CONCLUSION: These findings suggest that children and adolescents with BD and ADHD tend to be less responsive to drugs used in treatment of acute mania.

A meta-analysis to assess the efficacy of oral antiviral treatment to prevent genital herpes outbreaks.

BACKGROUND: Efficacy of oral antiviral therapies, ie, acyclovir, valacyclovir (VACV), and famciclovir, for suppression of recurrent genital herpes was studied at different doses and regimens. OBJECTIVE: We sought to compare the clinical efficacies of the different oral antiviral drugs prescribed prophylactically to suppress recurrent genital herpes. METHODS: MEDLINE and EMBASE databases were searched for articles on genital herpes and selected antiviral drugs. The selected trials were: parallel randomized clinical trials testing prophylactic oral antiviral treatment of genital herpes versus placebo in immunocompetent and nonpregnant patients. RESULTS: Fourteen randomized clinical trials were selected, including a total of 6158 patients. The global relative risk of developing at least one recurrence during the study was reduced by 47% (95% confidence interval 45%-49%) in antiviral drug groups compared with the placebo. The best evaluated regimens, with comparable efficacies, were given twice daily, ie, acyclovir (400 mg twice daily), VACV (250 mg twice daily), and famciclovir (250 mg twice daily), or once daily (VACV 500 mg). LIMITATIONS: The only end point available for all the studies was the number of patients presenting at least one recurrence of genital herpes during the observation period. CONCLUSION: The results of this first meta-analysis confirmed the high clinical efficacy of oral acyclovir, VACV, or famciclovir for prophylaxis against recurrent genital herpes.

Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: a meta-analysis.

AIMS: Atrial fibrillation (AF) is an important morbidity-mortality risk factor, especially in patients with heart failure (HF). Beta-blockers reduce morbidity and mortality in HF. The study was designed to estimate the preventive efficacy of beta-blocker treatment on AF occurrence in patients with HF. METHODS AND RESULTS: A systematic review of the literature was performed to identify all clinical trials evaluating beta-blockers' efficacy in HF. Eligible studies had to be randomized, placebo-controlled and providing information on the incidence of AF during follow-up among those with sinus rhythm at baseline. A total of seven studies which included 11 952 patients receiving a background treatment with angiotensin-converting enzyme-inhibitors could be found. Overall, beta-blockers significantly reduced incidence of onset of AF from 39 to 28 per 1000 patient-years: relative risk reduction=27% (95% confidence interval 14-38, P<0.001); heterogeneity test: P=0.096. A same trend of efficacy was observed in all trials except the SENIORS study. In this trial which included aged patients (>70 years) with systolic or diastolic HF, a higher prevalence of AF at baseline (35%) was observed compared with the mean baseline prevalence (13%). CONCLUSION: Beta-blockers appear to effectively prevent occurrence of AF in patients with systolic HF.

Low-molecular-weight heparin vs. unfractionated heparin in percutaneous coronary intervention: a combined analysis.

This meta-analysis assessed the rates of the efficacy and safety endpoints with intravenous low-molecular-weight heparin (LMWH) compared with unfractionated heparin (UFH) in patients undergoing percutaneous coronary intervention (PCI). Subcutaneous LMWH has compared favorably with UFH, but limited experience exists with intravenous LMWH for immediate anticoagulation in PCI. The meta-analysis included data from eight randomized trials in which patients received LMWH (n = 1,037) or UFH (n = 978) during PCI. Seven additional nonrandomized studies/registries were analyzed to assess the efficacy and safety of LMWH during PCI. Efficacy endpoints were ischemic events (usually a composite of death, myocardial infarction, and urgent revascularization) and the safety endpoint was bleeding (major, minor, or all bleeding). In the randomized studies, LMWH was comparable with UFH in terms of efficacy (6.2% vs. 7.5%) and major bleeding (0.9% vs. 1.8%). The analysis of pooled data, randomized or not, suggests potential improved efficacy (5.8% vs. 7.6%) and reduced major bleeding (0.6% vs. 1.8%) with LMWH (n = 3,787) compared with UFH (n = 978). During PCI, intravenous LMWH without coagulation monitoring has the potential to be at least as safe and efficacious as intravenous UFH. Further studies of LMWHs in PCI are therefore required.

Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment.

The use of weight-adjusted enoxaparin dosage in patients with renal failure results in increased bleeding complications. The authors investigated the impact of patient-related factors such as renal function on the pharmacokinetics of enoxaparin. Anti-Xa activity was measured in the blood of 60 patients (74 +/- 10 years, body weight 72 +/- 15 kg, men 60%, creatinine clearance 56 +/- 24 mL/min) with acute coronary syndromes receiving subcutaneous administration of enoxaparin. A population-based approach with limited sampling strategy was used. A 1-compartment model with first-order absorption and elimination best fitted the data. The mean clearance (CL/F) and distribution volume (V/F) were 0.72 L/h and 6.65 L, respectively. V/F was influenced by body weight. CL/F was mainly related to the renal function, decreasing with increasing levels of serum creatinine, and lower in women than in men. The elimination half-life was thus estimated to be 6.4 and 9.2 hours in male and female patients, respectively. The final covariate submodel was then: [Equation included in full-text article]. Maximal anti-Xa activity was predicted to rise above 1.5 IU/mL in case of mild elevation of serum creatinine according to gender and body weight. Renal function is the main factor affecting enoxaparin pharmacokinetics. In patients with decreased renal function, enoxaparin dose should be adjusted on the basis of body weight, serum creatinine, and gender to reach a target anticoagulation level assessed by maximal anti-Xa activity in steady-state conditions.

[Antilipemics and prevention of cerebrovascular accidents. Meta-analysis]. / Hypolipémiants et prévention des accidents vasculaires cérébraux. Méta-analyse.

BACKGROUND: Previous overviews have suggested that the HMG-CoA reductase inhibitors (statins), but not other lipid lowering therapies (LLTs), may reduce stroke incidence in coronary patients. Our objective was to investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: A literature search was performed from 1966-2001 to identify all English-language published trials testing LLT. We then conducted a meta-analysis including randomised primary and secondary coronary heart disease prevention trials, which tested statins, nonstatins, diet or other interventions, and providing data on stroke incidence. RESULTS: The overall meta-analysis (38 individual trials, 83,161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLTs of 17% (p < 0.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary prevention) or type of LLT. Most demonstrative effects was obtained however with statins (RRR = 26%). Effect model analysis showed that the treatment benefits appeared constant whatever the risk of stroke, suggesting that LLTs may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between the RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol level allowed a clear separation between benefit (RRR > 0) and no effect (RRR < 0) of LLTs on stroke incidence, with a cut-off for benefit of 6.0 mmol/L. CONCLUSION: LLTs reduce stroke incidence in coronary patients, especially when total cholesterol is under 6.0 mmol/L, this explains the better results obtained with statins.

Beta-blocker benefit according to severity of heart failure.

BACKGROUND AND AIMS: Beta-blockers are an established treatment for chronic heart failure. However, the relationship between their benefit and the severity of the disease remains to be determined. METHODS AND RESULTS: We studied the relationship between amplitude of benefit of beta-blockers and severity of chronic heart failure, based on data for mortality and hospitalizations for worsening heart failure, using a meta-analysis of randomized controlled trials, complementary subgroup analyses and analysis of individual data from the CIBIS II trial. In the meta-analysis, mortality was reduced by 22% (95%CI: 16 to 28) and hospitalizations for worsening heart failure by 24% (95%CI: 20 to 29). Benefit was similar with metoprolol, bisoprolol and carvedilol. After exclusion of bucindolol trials, due to the heterogeneity of results for mortality, the reduction in mortality was similar according to the severity of heart failure, assessed either by left ventricular ejection fraction or by New York Heart Association classification. In CIBIS II, beta-blockers induced a significant reduction in mortality of 45% (95%CI: 9 to 66), 41% (95%CI: 17 to 59) and 23% (95%CI: 1 to 40) in the low, intermediate and high risk groups, respectively. Hospitalizations were reduced by 35% (95%CI: 2 to 57), 41% (95%CI: 18 to 58) and 23% (95%CI: 0 to 41), there was no significant difference between the three score groups. CONCLUSION: We conclude that the amplitude of benefit of the beta-blockers carvedilol, metoprolol and bisoprolol on mortality and morbidity is similar, regardless of the severity of chronic heart failure.

Differential effects of lipid-lowering therapies on stroke prevention: a meta-analysis of randomized trials.

BACKGROUND: Previous overviews suggested that hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins), but not other lipid-lowering therapy (LLT), may reduce stroke incidence in coronary patients. OBJECTIVE: To investigate the amplitude and sources of heterogeneity of LLT effects on stroke prevention. METHODS: We searched the literature from 1966 to 2001 and then conducted a meta-analysis including randomized trials of primary and secondary coronary heart disease prevention, testing statins, nonstatin drugs, diet, or other interventions and providing data on stroke incidence. RESULTS: The meta-analysis (38 trials, 83 161 patients, mean follow-up of 4.7 years) showed a significant relative risk reduction (RRR) of strokes by LLT of 17% (P<.001), without significant heterogeneity between trials and between subgroups according to either the type of prevention (primary or secondary) or the type of LLT. The most substantial effects were obtained, however, with statins (RRR, 26%). Effect model analysis showed that treatment benefit appeared constant whatever the risk of stroke, suggesting that LLT may be effective in a population with a higher risk of stroke. Weighted regression showed a significant correlation between RRR of stroke and total cholesterol levels (baseline, final, and change). Only final cholesterol allowed clear separation between benefit (RRR>0) and no effect (RRR<0) of LLT on stroke incidence, with a cutoff for benefit of 232 mg/dL (6.0 mmol/L). CONCLUSION: Lipid-lowering therapy reduces stroke incidence in coronary patients, especially when total cholesterol level is lowered to less than 232 mg/dL (6.0 mmol/L), which explains the best results being obtained with statins.