Michel Cucherat

Clinical Effects of β-Adrenergic Blockade in Chronic Heart Failure A Meta-Analysis of Double-Blind, Placebo-Controlled, Randomized Trials

BACKGROUND beta-Blockers have improved symptoms and reduced the risk of cardiovascular events in studies of patients with heart failure, but it is unclear which end points are most sensitive to the therapeutic effects of these drugs. METHODS AND RESULTS We combined the results of all 18 published double-blind, placebo-controlled, parallel-group trials of beta-blockers in heart failure. From this combined database of 3023 patients, we evaluated the strength of evidence supporting an effect of treatment on left ventricular ejection fraction, NYHA functional class, hospitalizations for heart failure, and death. beta-Blockers exerted their most persuasive effects on ejection fraction and on the combined risk of death and hospitalization for heart failure. beta-Blockade increased the ejection fraction by 29% (P<10(-9)) and reduced the combined risk of death or hospitalization for heart failure by 37% (P<0.001). Both effects remained significant even if >90% of the trials were eliminated from the analysis or if a large number of trials with a neutral result were added to the analysis. In contrast, the effect of beta-blockade on NYHA functional class was of borderline significance (P=0.04) and disappeared with the addition or removal of only 1 moderate-size study. Although beta -blockade reduced all-cause mortality by 32% (P=0.003), this effect was only moderately robust and varied according to the type of ss-blocker tested, ie, the reduction of mortality risk was greater for nonselective beta-blockers than for beta1-selective agents (49% versus 18%, P=0.049). However, selective and nonselective beta-blockers did not differ in their effects on other measures of clinical efficacy. CONCLUSIONS These analyses indicate that there is persuasive evidence supporting a favorable effect of beta-blockade on ejection fraction and the combined risk of death and hospitalization for heart failure. In contrast, the effect of these drugs on other end points requires additional study.

Procalcitonin as a diagnostic test for sepsis in critically ill adults and after surgery or trauma: a systematic review and meta-analysis.

Objective:To quantify the accuracy of serum procalcitonin as a diagnostic test for sepsis, severe sepsis, or septic shock in adults in intensive care units or after surgery or trauma, alone and compared with C-reactive protein. To draw and compare the summary receiver operating characteristics curves for procalcitonin and C-reactive protein from the literature. Data Source:MEDLINE (keywords: procalcitonin, intensive care, sepsis, postoperative sepsis, trauma); screening of the literature. Study Selection:Meta-analysis of all 49 published studies in medical, surgical, or polyvalent intensive care units or postoperative wards. Children, medical patients, and immunocompromised patients were excluded. Data Extraction:Thirty-three studies fulfilled inclusion criteria (3,943 patients, 1,828 males, 922 females; mean age: 56.1 yrs; 1,825 patients with sepsis, severe sepsis, or septic shock; 1,545 with only systemic inflammatory response syndrome); eight studies could not be analyzed statistically. Global mortality rate was 29.3%. Data Synthesis:Global odds ratios for diagnosis of infection complicated by systemic inflammation were 15.7 for the 25 studies (2,966 patients) using procalcitonin (95% confidence interval, 9.1–27.1) and 5.4 for the 15 studies (1,322 patients) using C-reactive protein (95% confidence interval, 3.2–9.2). The summary receiver operating characteristics curve for procalcitonin was better than for C-reactive protein. In the 15 studies using both markers, the Q* value (intersection of summary receiver operating characteristics curve with the diagonal line where sensitivity equals specificity) was significantly higher for procalcitonin than for C-reactive protein (0.78 vs. 0.71, p = .02), the former test showing better accuracy. Conclusions:Procalcitonin represents a good biological diagnostic marker for sepsis, severe sepsis, or septic shock, difficult diagnoses in critically ill patients. Procalcitonin is superior to C-reactive protein. Procalcitonin should be included in diagnostic guidelines for sepsis and in clinical practice in intensive care units.

Microvessel Density as a Prognostic Factor in Women with Breast Cancer: A Systematic Review of the Literature and Meta-Analysis

We performed a meta-analysis of all 87 published studies linking intratumoral microvessel density (MVD), reflecting angiogenesis, to relapse-free survival (RFS) and overall survival (OS). With median MVD as cutoff, MVD impact was measured by risk ratio (RR) between the two survival distributions. Seventeen studies did not mention survival data or fit inclusion criteria. Twenty-two were multiple publications of the same series, leaving 43 independent studies (8936 patients). MVD was assessed by immunohistochemistry, using antibodies against factor VIII (27 studies; n = 5262), CD31 (10 studies; n = 2296), or CD34 (8 studies; n = 1726). MVD might be a better prognostic factor when assessed by CD31 or CD34 versus factor VIII (P = 0.11). For RFS, statistical calculations were performed in 25 studies (6501 patients). High MVD significantly predicted poor survival [RR = 1.54 for RFS and OS with the same 95% confidence interval (CI), 1.29-1.84]. Twenty-two studies analyzed separately lymph node-negative patients (n = 3580), for whom predictors of poor survival are requested. This latter meta-analysis included 15 studies for RFS (2727 patients) and 11 for OS (1926 patients). High MVD significantly predicted poor survival [RR = 1.99 for RFS (95% CI, 1.33-2.98) and RR = 1.54 for OS (95% CI, 1.01-2.33)]. Between-study variations could result from patient selection criteria, techniques to stain and count microvessels, and cutoff selection. MVD was a significant although weak prognostic factor in women with breast cancer. Standardization of MVD assessment is needed.

Microvessel density and VEGF expression are prognostic factors in colorectal cancer. Meta-analysis of the literature

We performed a meta-analysis of all published studies relating intratumoural microvessel density (MVD) (45 studies) or vascular endothelial growth factor (VEGF) expression (27 studies), both reflecting angiogenesis, to relapse free (RFS) and overall survival (OS) in colorectal cancer (CRC). For each study, MVD impact was measured by risk ratio between the two survival distributions with median MVD as cutoff. Eleven studies did not mention survival data or fit inclusion criteria, six were multiple publications of same series, leaving 32 independent studies for MVD (3496 patients) and 18 for VEGF (2050 patients). Microvessel density was assessed by immunohistochemistry, using antibodies against factor VIII (16 studies), CD31 (10 studies) or CD34 (seven studies). Vascular endothelial growth factor expression was mostly assessed by immunohistochemistry. Statistics were performed for MVD in 22 studies (the others lacking survival statistics) including nine studies (n=957) for RFS and 18 for OS (n=2383) and for VEGF in 17 studies, including nine studies for RFS (n=1064) and 10 for OS (n=1301). High MVD significantly predicted poor RFS (RR=2.32 95% CI: 1.39–3.90; P<0.001) and OS (RR=1.44; 95% CI: 1.08–1.92; P=0.01). Using CD31 or CD34, MVD was inversely related to survival, whereas it was not using factor VIII. Vascular endothelial growth factor expression significantly predicted poor RFS (RR=2.84; 95% CI: 1.95–4.16) and OS (RR=1.65; 95% CI: 1.27–2.14). To strengthen our findings, future prospective studies should explore the relation between MVD or VEGF expression and survival or response to therapy (e.g. antiangiogenic therapy). Assessment of these angiogenic markers should be better standardised in future studies.

Efficacy of pneumococcal polysaccharide vaccine in immunocompetent adults: a meta-analysis of randomized trials.

The use of pneumococcal polysaccharide vaccine (PPV) is low in some countries, maybe because of doubts regarding its efficacy. This meta-analysis aims at combining evidence from randomized trials of PPV assessing its efficacy in preventing Streptococcus pneumoniae related diseases in immunocompetent adults. In the fourteen trials totalling 48,837 patients retrieved, PPV prevents definite pneumococcal pneumonia by 71%, presumptive pneumococcal pneumonia by 40%, and mortality due to pneumonia by 32%, but not all-cause pneumonia or death. No preventive effect was seen in the subgroup of patients aged 55 years or more, possibly due to a lack of statistical power.

Evidence of clinical efficacy of homeopathy

AbstractObjective: To establish, using a systematic review and meta-analysis, whether there is any evidence from randomised controlled clinical trials of the efficacy of homeopathic treatment in patients with any disease. Data sources: Published and unpublished reports of controlled clinical trials available up to June 1998, identified by searching bibliographic databases (Medline, Embase, Biosis, PsychInfo, Cinahl, British Library Stock Alert Service, SIGLE, Amed), references lists of selected papers, hand searching homeopathic journals and conference abstracts, and contacting pharmaceutical companies. Trials selection: Trials were selected using an unblinded process by two reviewers. The selection criteria were randomised, controlled trials in which the efficacy of homeopathic treatment was assessed relative to placebo in patients using clinical or surrogate endpoints. Prevention trials or those evaluating only biological effects were excluded. One hundred and eighteen randomised trials were identified and evaluated for inclusion. Sixteen trials, representing 17 comparisons and including a total of 2617 evaluated patients, fulfilled the inclusion criteria. Data extraction: Data were extracted by two reviewers independently, using a summary form. Disagreements were resolved by a third person. Data synthesis: The evidence was synthesised by combining the significance levels (P values) for the primary outcomes from the individual trials. The combined P value for the 17 comparisons was highly significant P=0.000036. However, sensitivity analysis showed that the P value tended towards a non-significant value (P=0.08) as trials were excluded in a stepwise manner based on their level of quality. Conclusions: There is some evidence that homeopathic treatments are more effective than placebo; however, the strength of this evidence is low because of the low methodological quality of the trials. Studies of high methodological quality were more likely to be negative than the lower quality studies. Further high quality studies are needed to confirm these results.

Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials

BACKGROUND Sudden unexpected death in epilepsy (SUDEP) represents the main cause of death in patients with refractory epilepsy. No evidence-based intervention to prevent SUDEP exists. We postulated that pooling data from randomised placebo-controlled trials in patients with refractory epilepsy might show a lower incidence of SUDEP in patients receiving antiepileptic drugs (AEDs) at efficacious doses than in those receiving placebo. METHODS We searched Medline and the Cochrane Library for randomised trials investigating any AED in the add-on treatment of drug-resistant epilepsy in adults. We extracted the number and causes of death in patients allocated to AEDs at doses that were more efficacious than placebo against seizures, AEDs at non-efficacious doses, and placebo. In our primary analysis, we compared the occurrence of definite or probable SUDEP between patients given efficacious AED doses and those given placebo using the Mantel-Haenszel method, with exclusion of trials with no event. FINDINGS Data of 33 deaths, including 20 deemed as SUDEP, were extracted from 112 eligible randomised trials. 18 deaths were classified as definite or probable SUDEP and two as possible SUDEP. Definite or probable SUDEP, all SUDEP, and all causes of death were significantly less frequent in the efficacious AED group than in the placebo group, with odds ratios of 0·17 (95% CI 0·05-0·57, p=0·0046), 0·17 (0·05-0·57, p=0·0046), and 0·37 (0·17-0·81, p=0·0131), respectively. Rates of definite or probable SUDEP per 1000 person-years were 0·9 (95% CI 0·2-2·7) in patients who received efficacious AED doses and 6·9 (3·8-11·6) in those allocated to placebo. INTERPRETATION Treatment with adjunctive AEDs at efficacious doses may have reduced the incidence of definite or probable SUDEP by more than seven times compared with placebo in patients with previously uncontrolled seizures. This result provides evidence in favour of active treatment revision for patients with refractory epilepsy. FUNDING None.

Association of Clopidogrel Pretreatment With Mortality, Cardiovascular Events, and Major Bleeding Among Patients Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis

CONTEXT Clopidogrel pretreatment is recommended for patients with acute coronary syndromes (ACS) and stable coronary artery disease who are scheduled for percutaneous coronary intervention (PCI), but whether using clopidogrel as a pretreatment for PCI is associated with positive clinical outcomes has not been established. OBJECTIVE To evaluate the association of clopidogrel pretreatment vs no treatment with mortality and major bleeding after PCI. DATA SOURCES MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and reference lists of qualifying articles. STUDY SELECTION Studies reporting clinical data on mortality and major bleeding were included. Of the 392 titles identified, 15 articles published between August 2001 and September 2012 met the inclusion criteria: 6 randomized controlled trials (RCTs), 2 observational analyses of RCTs, and 7 observational studies. DATA EXTRACTION Quality of studies was assessed with the Ottawa Scale and the Jadad Score as appropriate. Results were independently extracted by 2 reviewers. A random-effect model was applied. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization. The main analysis was performed on RCTs and confirmed by observational analyses and observational studies. Prespecified subgroups--clinical presentation and clopidogrel loading dose--were analyzed. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary end points included major cardiac events. RESULTS Of the 37 814 patients included in the meta-analysis, 8608 patients had participated in RCTs; 10,945, in observational analyses of RCTs; and 18,261, in observational studies. Analysis of RCTs showed that clopidogrel pretreatment was not associated with a reduction of death (absolute risk, 1.54% vs 1.97%; OR, 0.80; 95% CI, 0.57-1.11; P = .17) but was associated with a lower risk of major cardiac events (9.83% vs 12.35%; OR, 0 .77; 95% CI, 0.66-0.89; P < .001). There was no significant association between pretreatment and major bleeding overall (3 .57% vs 3.08%; OR, 1.18; 95% CI, 0.93-1.50; P = .18). Analyses from observational analyses of RCTs and observational studies were consistent for all results. CONCLUSIONS Among patients scheduled for PCI, clopidogrel pretreatment was not associated with a lower risk of mortality but was associated with a lower risk of major coronary events.

Reappraisal of Metformin Efficacy in the Treatment of Type 2 Diabetes: A Meta-Analysis of Randomised Controlled Trials

Catherine Cornu and colleagues performed a meta-analysis of randomised controlled trials of metformin efficacy on cardiovascular morbidity or mortality in patients with type 2 diabetes and showed that although metformin is considered the gold standard, its benefit/risk ratio remains uncertain.

Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta‐analysis

Summary.  Background: The benefit‐to‐risk ratio of vitamin K antagonists (VKA), relative to active comparators, especially low‐molecular‐weight heparins (LMWH), for preventing venous thromboembolism in patients undergoing major orthopedic surgery is debated. Objectives: We performed a meta‐analysis of all randomized trials in orthopedic surgery comparing adjusted doses of VKA to control treatments. Patients and methods: An exhaustive literature search, both manual and computer‐assisted, was performed. Studies were selected on the basis of randomization procedure (VKA vs. a control group). At least one of the following outcome measures was to be evaluated: deep vein thrombosis (DVT), pulmonary embolism (PE), death, major hemorrhage or wound hematoma. Four reviewers assessed each article to determine eligibility for inclusion and outcome measures. Results: VKAs were more effective than placebo or no treatment in reducing DVT [567 patients, relative risk (RR) = 0.56, 95% confidence interval (CI) 0.37, 0.84, P < 0.01] and clinical PE (651 patients, RR = 0.23, 95% CI 0.09, 0.59, P < 0.01). These results were obtained at the cost of a higher rate of wound hematoma (162 patients, RR = 2.91, 95% CI 1.09, 7.75, P = 0.03). VKAs were also more effective than intermittent pneumatic compression (534 patients, RR = 0.46, 95% CI 0.25, 0.82, P = 0.009) in preventing proximal DVT. In contrast, VKAs were less effective than LMWH in preventing total DVT and proximal DVT (9822 patients, RR = 1.51, 95% CI 1.27, 1.79, P < 0.001; and 6131 patients, RR = 1.51, 95% CI 1.04, 2.17, P = 0.028, respectively). The differences between VKA and LMWH in major hemorrhage and wound hematoma were not significant. Conclusions: In patients undergoing major orthopedic surgery, VKAs are less effective than LMWH, without any significant difference in the bleeding risk.