Short- and long-term outcomes of intracoronary and endogenously mobilized bone marrow stem cells in the treatment of ST-segment elevation myocardial infarction: a meta-analysis of randomized control trials.

AIMS: Bone marrow stem cell (BMSC) treatment of ST-segment elevation myocardial infarction (STEMI) has been primarily via the intracoronary route or via endogenous mobilization using granulocyte colony-stimulating factor (G-CSF). Studies have provided conflicting results. We therefore performed a meta-analysis of these treatments, examining short- and long-term efficacy and safety. METHODS AND RESULTS: Randomized controlled trials (RCTs) of BMSC-based therapy for STEMI, delivered within 9 days of reperfusion, were identified by systematic search. Random effects models were used to calculate pooled effects of clinical outcomes, with meta-regression to assess dependence of the magnitude of effect sizes on study characteristics. Twenty-nine RCTs enrolling 1830 patients were included. Intracoronary BMSC therapy resulted in an overall improvement in left ventricular ejection fraction (LVEF) of 2.70% [95% confidence interval (CI) 1.48-3.92; P < 0.001] in the short term and 3.31% (95% CI 1.87-4.75; P < 0.001) longer term. Meta-regression suggested a dose-response relationship between quantity of CD34(+) cells delivered and increase in LVEF (P = 0.007). G-CSF treatment resulted in a trend towards similar benefits (P = 0.20). No significant differences were observed in pooled adverse outcome rates between intervention and control groups of either treatment approach, except for lower revascularization rates with intracoronary BMSC vs. control (odds ratio 0.68, 95% CI 0.47-0.97; P = 0.03). CONCLUSIONS: Intracoronary BMSC therapy post-STEMI improves LVEF beyond standard medical treatment, in both the short and longer term. G-CSF treatment shows positive but non-significant trends. Both treatments demonstrate safety comparable with conventional medical treatment.

Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? An updated meta-analysis.

BACKGROUND: Both COX-2 selective inhibitors (coxibs) and nonselective (ns)-NSAIDs elevate blood pressure (BP) and this may contribute to excess cardiovascular (CV) events. A number of recent large-scale randomized clinical trials (RCTs) comparing coxibs (including newer agents, lumiracoxib and etoricoxib) to both ns-NSAIDs and placebo have been reported, permitting an update to earlier BP analyses of these agents. DATA SOURCES/SYNTHESIS: Our search yielded 51 RCTs involving coxibs published before April 2008 with a total of 130 541 participants in which BP data were available. The Der Simonian and Laird random effects method for dichotomous variables was used to produce risk ratios (RR) for development of hypertension. RESULTS: For coxibs versus placebo, there was a RR of 1.49 (1.18-1.88, P = 0.04) in the development of new hypertension. For coxibs versus ns-NSAIDs, the RR was 1.12 (0.93-1.35, P = 0.23). These results were mainly driven by rofecoxib, with a RR of 1.87 (1.63-2.14, P = 0.08) versus placebo, and etoricoxib, with a RR of 1.52 (1.39-1.66, P = 0.01) versus ns-NSAID. CONCLUSION: On the basis of this updated meta-analysis, coxibs appear to produce greater hypertension than either ns-NSAIDs or placebo. However, this response was heterogeneous, with markedly raised BP associated with rofecoxib and etoricoxib, whereas celecoxib, valdecoxib and lumiracoxib appeared to have little BP effect. The relationship of this increased risk of hypertension to subsequent adverse CV outcomes requires further investigation and prospective RCTs.

Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials.

BACKGROUND: There is uncertainty regarding which pharmacological agents most effectively prevent venous thromboembolism in hospitalized medical patients. We therefore performed a meta-analysis to determine this. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from 1950, 1966, and 1800, respectively, through June 30, 2006, for randomized controlled trials that involved medical patients comparing unfractionated heparin (UFH) or low-molecular-weight heparin or heparinoid (LMWH) with a control, LMWH with UFH, or selective factor Xa inhibitors with a comparator. Study selection, validity assessment, and data abstraction were performed by 2 independent reviewers (L.W. and S.W.). Data synthesis was undertaken by 1 blinded investigator (S.J.H.). RESULTS: Thirty-six studies were included. Compared with the control, UFH was associated with a reduced risk of deep venous thrombosis (DVT) (risk ratio [RR], 0.33; 95% confidence interval [CI], 0.26-0.42) and pulmonary embolism (RR, 0.64; 95% CI, 0.50-0.82), as was LMWH (RR, 0.56; 95% CI, 0.45-0.70; and RR, 0.37; 95% CI, 0.21-0.64, respectively). A UFH dosage of 5000 U 3 times daily was more effective in preventing DVT than a UFH dosage of 5000 U twice daily when compared with the control (RR, 0.27; 95% CI, 0.20-0.36; vs RR, 0.52; 95% CI, 0.28-0.96). Neither UFH nor LMWH reduced mortality. When directly compared with UFH, LMWH was associated with a lower risk of DVT (RR, 0.68; 95% CI, 0.52-0.88) and injection site hematoma (RR, 0.47; 95% CI, 0.36-0.62), but no difference was seen between the 2 agents in the risk of bleeding or thrombocytopenia. CONCLUSIONS: Both UFH and LMWH reduce venous thromboembolic risk in hospitalized medical patients, but neither agent alters mortality. When directly compared, LMWH is more effective in preventing DVT.

Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis.

BACKGROUND: Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim was to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease. METHODS: We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trial registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks. FINDINGS: We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01-1.35; p=0.031) and arteriovenous access thrombosis (1.34, 1.16-1.54; p=0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08-1.50; p=0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1.31, 0.97-1.78; p=0.075). The incidence of myocardial infarction was much the same in the two groups. INTERPRETATION: To target higher haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

Prognostic benefit of beta-blockers in patients not receiving ACE-Inhibitors.

AIMS: Beta-blockers (BBs) confer significant prognostic benefit in patients (pts) with systolic chronic heart failure (CHF). However, major trials have thus far studied BBs mainly in addition to ACE-Inhibitors or angiotensin receptor blockers (ARBs) as background therapy. The magnitude of the prognostic benefit of BBs in the absence of ACE-I or ARB has not as yet been determined. METHODS AND RESULTS: We performed a meta-analysis of all placebo-controlled BB studies in patients with CHF (n>200). Trials were identified via Medline literature searches, meeting abstracts, and contact with study organizations. Results for all-cause mortality and death or heart failure hospitalization were pooled using the Mantel-Haenszel (fixed effects) method. The impact of BB therapy on all-cause mortality in CHF, in the absence (4.8%) and presence (95.2%) of ACE-I (or ARB), was determined from six trials of 13 370 patients. The risk ratio (RR) for BBs vs. placebo was 0.73 [95% confidence interval (CI) 0.53-1.02] in the absence of ACE-I or ARB at baseline, compared with a RR of 0.76 (95% CI 0.71-0.83) in the presence of these agents. When ACE-Inhibitors were analysed in the same way (pre-BB), a RR of 0.89 (0.80-0.99) vs. placebo was observed in studies of >90 days. The impact of BB therapy on death or HF hospitalization in systolic CHF, in the absence and presence of ACE-I, was determined from three trials of 8988 patients. The RR for BBs vs. placebo was 0.81 (95% CI 0.61-1.08) in the absence of ACE-I or ARB at baseline, compared with a RR of 0.78 (95% CI 0.74-0.83) in the presence of these agents. When ACE-Is were analysed in the same way (pre-BB), a RR of 0.85 (95% CI 0.78-0.93) vs. placebo was observed in studies of >90 days. CONCLUSION: The magnitude of the prognostic benefit conferred by BBs in the absence of ACE-I appears to be similar to those of ACE-Is in systolic CHF. These data therefore suggest that either ACE-Is or BBs could be used as first-line neurohormonal therapy in patients with systolic CHF. Prospective studies directly comparing these agents are required to definitively address this issue.

Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure.

BACKGROUND: Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and are associated with blood pressure (BP) elevation. The development of selective cyclooxygenase-2 inhibitors (coxibs) raises the issue of the magnitude of BP response compared with nonselective NSAIDs. We therefore performed a meta-analysis comparing the effects of coxibs with placebo, nonselective NSAIDs, and each other on BP elevation and hypertension. METHODS: Nineteen randomized controlled trials involving coxibs were published before May 2004, with a total of 45 451 participants in which BP data were available. The Cohen method statistically combined weighted mean difference (WMD). The Der Simonian and Laird method pooled results concerning the relative risk (RR) of developing hypertension and the RR of clinically important BP elevations. RESULTS: Among the trials analyzed, coxibs caused a WMD point estimate increase in systolic and diastolic BP compared with placebo (3.85/1.06 mm Hg) and nonselective NSAIDs (2.83/1.34 mm Hg). Cyclooxygenase-2 inhibitors were associated with a nonsignificantly higher RR of causing hypertension compared with placebo (RR, 1.61; 95% confidence interval [CI], 0.91-2.84; P = .10) and nonselective NSAIDs (RR, 1.25; 95% CI, 0.87-1.78; P = .23). Rofecoxib induced a WMD point estimate increase in systolic BP (2.83 mm Hg) and a nonsignificantly higher risk of developing clinically important systolic BP elevation (RR, 1.50; 95% CI, 1.00-2.26; P = .05) compared with celecoxib. CONCLUSIONS: Cyclooxygenase-2 inhibitors were associated with a point-estimate BP elevation compared with placebo and nonselective NSAIDs. There was a nonsignificantly higher incidence of developing hypertension compared with nonselective NSAIDs, as was observed with rofecoxib compared with celecoxib. These BP elevations may be clinically significant in relation to increased cardiovascular risk.

Are beta-blockers as efficacious in patients with diabetes mellitus as in patients without diabetes mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials.

BACKGROUND: Diabetes mellitus is a frequent comorbid condition in patients with chronic heart failure (CHF) and confers a worse prognosis. Furthermore, although patients with CHF derive considerable benefit from beta-blockers, these agents are thought by many physicians to be contraindicated in patients with diabetes mellitus. Most published studies on beta-blockers in CHF have been unable to reach definitive conclusions about the mortality benefits of these agents in patients with diabetes mellitus. We therefore performed a meta-analysis of beta-blocker trials that reported mortality outcomes in patients with diabetes mellitus who had CHF to pool all available trial evidence on the benefits (or otherwise) of these agents in this setting. METHODS: All-cause mortality data on patients with diabetes mellitus were obtained from all completed beta-blocker CHF randomized placebo-controlled trials involving >100 patients exposed to beta-blockers, in which outcomes in patients with diabetes mellitus were described. When events were not directly reported, risk ratios (RRs) were derived from analysis of figures and other manuscript data. Results were pooled with the Mantel-Haenszel method. RESULTS: A total of 24.6% of patients were reported to have diabetes mellitus in the 6 studies analyzed (Australia and New Zealand [ANZ]-Carvedilol, Beta-blocker Evaluation of Survival Trial [BEST], Carvedilol US Trials, Cardiac Insufficiency Bisoprolol Study [CIBIS-II], Carvedilol Prospective Randomized Cumulative Survival Trial [COPERNICUS], and Metoprolol Controlled-release Randomized Intervention Trial in Heart Failure [MERIT-HF]). Patients with diabetes mellitus had increased mortality rates overall compared with subjects without diabetes mellitus (RR, 1.25; 95% CI, 1.15-1.36; P <.001). Compared with placebo, beta-blocker therapy for CHF was beneficial in patients with diabetes mellitus (RR, 0.84; 95% CI, 0.73-0.96; P =.011) and in subjects without diabetes mellitus (RR, 0.72; 95% CI, 0.65-0.79; P <.001). The absolute risk reduction in mortality with beta-blocker therapy was greater in patients with heart failure but without diabetes mellitus than in patients with diabetes mellitus (P =.023). CONCLUSIONS: Patients with diabetes mellitus and CHF appear to derive prognostic benefit from beta-blocker therapy, although the magnitude of that benefit is somewhat less than that observed in subjects without diabetes mellitus.