What is wrong with meta-analysis? The importance of clinical heterogeneity in myocardial regeneration research.

The author discusses the significance and potential pitfalls in performing a meta-analysis underscoring the importance of a usual forgotten issue in meta-analysis called clinical heterogeneity. Clinical heterogeneity can mislead results and misinform clinicians. Practical examples from the literature are given, and the results of meta-analyses are compared with the results of subsequent large randomised clinical trials addressing similar questions from a historical and contemporary point of view, highlighting clinical heterogeneity. The contemporary aspect culminates with the presentation of a meta-analysis evaluating myocardial cell regeneration with an emphasis in clinical heterogeneity, helping clinicians to understand the issue and better appraise future meta-analyses.

The effects of angiotensin-receptor blockers on mortality and morbidity in heart failure: a systematic review.

BACKGROUND: Trials evaluating angiotensin-receptor blockers in heart failure (HF) have shown inconsistent results. OBJECTIVE: To evaluate the effect of angiotensin II (AII) receptor blockers in HF patients on total mortality and HF hospitalisations. METHODS: Systematic search of the literature through MEDLINE (1980-2007) and abstracts of major cardiovascular congresses from 2002 to 2007. ELIGIBILITY CRITERIA: (i) randomised controlled trials with more than 500 patients and follow up > 6 months, (ii) availability of total mortality and/or (iii) availability of hospital admission because of worsening HF. Data retrieved by two independent reviewers. DerSimonian random effects model was used. RESULTS: Mortality data were available from 27,495 patients. When AII receptor blockers plus angiotensin-converting enzyme inhibitors (ACE-I) were compared with ACE-I in chronic HF trials, the relative risk (RR) for death was 0.98 (95% CI: 0.84-1.15). When AII receptor blockers were compared with ACE-I the RR for death was 1.06 (95% CI: 0.56-1.62). Similar results were found for postmyocardial infarction trials. The effects on hospital admission revealed a RR of 0.83 (95% CI: 0.71-0.97) and 1.09 (95% CI: 0.74-1.60) respectively. CONCLUSION: Angiotensin II receptor blockers did not show any beneficial effect on mortality when used in combination with ACE-I or when compared with ACE-I alone. A 17% reduction in hospital admissions was observed.

Long term prognosis of heart failure after acute coronary syndromes without ST elevation.

BACKGROUND: Information about long term outcomes of patients with acute coronary syndromes (ACS) who have clinically diagnosed heart failure is scarce. METHODS: In a UK registry, this study evaluated patients with non-ST elevation ACS, recording treatment, and clinical outcomes for six months. In a subgroup, a four year mortality follow up was performed to estimate the impact of the clinical diagnosis of heart failure on survival. RESULTS: Of 1046 patients, 139 (13%) had a history of clinically diagnosed heart failure. At discharge, ACE inhibitors were prescribed for 58% and 28%, of those with and without a history of heart failure respectively (p<0.001). Rates of angiography, percutaneous intervention, and coronary artery bypass graft were 17.3% and 29.2% (p = 0.003), 5.0% and 8.4% (p = 0.17), and 5.0% and 7.5% (p = 0.3) for these groups respectively. Death or new myocardial infarction at six months occurred in 22% and 10% (p<0.001) and at four years death occurred in 60% and 20% of these groups respectively (p<0.001). In a multivariate analysis prior heart failure carried an odds ratio of 2.0 (p = 0.001) for death or myocardial infarction at six months and 2.4 (p<0.001) for death over four years. New heart failure was associated with an increased risk of death at six months (20% compared with 5%, p<0.001). CONCLUSION: A clinical history of heart failure carries a substantial risk of death in patients admitted with ACS without ST elevation. Nearly 60% of those with prior heart failure are dead after four years. After adjustment for confounding factors, prior heart failure more than doubles the risk compared with those with no history.

Diabetic patients with acute coronary syndromes in the UK: high risk and under treated. Results from the prospective registry of acute ischaemic syndromes in the UK (PRAIS-UK).

OBJECTIVES: Short-term randomised trials suggest that patients with diabetes mellitus (DM), admitted with acute coronary syndromes (ACS) are at increased risk of subsequent adverse events. We tested whether this hypothesis was true for an unselected population of ACS patients with and without DM admitted with non-ST elevation MI or unstable angina, in a non-trial setting over a longer term of follow-up. METHODS: Prospective, centrally, coordinated multicenter registry involving 56 centers throughout the UK (half having angiographic facilities). Consecutive patients admitted with ACS without ST elevation on the presenting ECG were followed up to 6 months. A sub-group of patients were flagged with the UK Office for National Statistics and followed-up for death over 4 years. RESULTS: Data were collected on 1046 ACS patients of whom 170 (16%) had a prior diagnosis of DM. DM patients had higher baseline co-morbidities and unadjusted mortality rates at 6 months (11.8% vs. 6.4%, p=0.01). After correcting for clinical variables such as age, gender, smoking status and chest pain/ischaemic ECG changes on admission, prior history of any of myocardial infarction, heart failure, hypertension, hypercholesterolemia (on treatment), stroke or coronary revascularisation (PTCA or CABG), mortality rates for DM patients were no longer significantly raised (hazard ratio 1.35, 95% CI: 0.79-2.30; p=0.27 at 6 months and 1.15, 95% CI 0.72-1.83 at 4 years). 30% of diabetics were dead after 4 years of follow-up. Patients with DM were more likely to have been revascularised at 6 months and were more likely to receive ACE inhibitors. Based on the rate of recruitment and the population covered in the study, about 21,000 patients with DM will be admitted with non-ST elevation ACS each year in the UK. CONCLUSIONS: DM is common amongst patients admitted with ACS without ST elevation and is associated with significant morbidity and mortality: approximately 1 in 8 will not survive up to 6 months and 1 in 3 to 4 years. DM patients should be managed aggressively to reduce their risk of future complications.

Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure.

Heart failure is a common condition that carries a high burden of mortality and morbidity. Several randomised trials have evaluated the effects of beta blockers in heart failure. This paper gives a systematic overview of published randomised trials of beta blockers in heart failure using standard methods. In all, 22 randomised controlled trials were identified with a total of 10480 patients, and an average of 11 months of treatment. The average age was 61 years and 4% were female. Most studies excluded patients with severe heart failure. Death rates in patients randomised to receive beta blockers compared to controls were 458/5657 (8.0%) and 635/4951 (12.8%) respectively, odds ratio 0.63, 95% CI 0.55-0.72, P<0.00001. Similar reductions were observed for hospital admissions for worsening heart failure (11.3 vs. 17.1%, respectively, odds ratio 0.63) and for the composite outcome of death or heart-failure hospital admission (19.4 vs. 26.9%, respectively, odds ratio 0.66). These results show that beta blockers reduce the risk of mortality or the need for heart-failure hospital admission by approximately one third. Absolute reductions of 5-6% in event rates were observed over approximately 1 year of treatment period. These important benefits should be implemented as a priority, since treatment with beta blockers is inexpensive and heart failure carries a high risk of death and disability. Further information on the effect of beta blockers in elderly patients and women would be helpful.