The authors concluded that the addition of clopidogrel to aspirin slightly reduces all-cause and cardiovascular mortality in patients with ST-elevation myocardial infarction (STEMI), and modestly reduces myocardial infarction and stroke in patients with cardiovascular disease, but also increases bleeding. The review was generally well-conducted, but the lack of results data undermines the conclusion about the subgroup of STEMI patients. The other conclusions appear reliable.

To compare clopidogrel plus aspirin with aspirin alone for patients with established cardiovascular disease.

MEDLINE and the Cochrane CENTRAL Register were searched from 1996 to May 2006 for studies published in the English language; the search terms were reported. In addition, relevant journals and recently presented data at national cardiology conferences were screened, experts in the field and authors were contacted for details of further studies, and the Science Citation Index was used to track other relevant studies.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs) were eligible for inclusion in the review. The duration of follow-up ranged from 30 days or less to a mean of 28 months.

Specific interventions included in the review

Studies that compared clopidogrel plus aspirin with aspirin plus placebo were eligible for inclusion. The included studies evaluated between 75 and 325 mg/day aspirin. All but two studies evaluated a 300-mg loading dose of clopidogrel followed by 75 mg/day; two studies omitted the loading dose. Across studies, glycoprotein IIb/IIIa antagonists were used in between 0 and 39% of patients, fibrinolytics used in between 0 and 100%, and heparin used in between 0 and 80%.

Participants included in the review

Studies in patients with cardiovascular disease were eligible for inclusion. Although most patients in the included studies had an unstable coronary syndrome, some studies were in patients with ST-elevation myocardial infarction (STEMI) and others were in patients with non-ST–elevation acute coronary syndrome. Across studies, the mean age of the patients ranged from 57 to 64 years and the mean proportion of females ranged from 20 to 39%.

Outcomes assessed in the review

Inclusion criteria were not specified in terms of the outcomes, but it was clear that the review assessed all-cause mortality, cardiovascular mortality, myocardial infarction (MI), stroke and bleeding (major, fatal and haemorrhagic). The definitions of outcomes assessed in the review were reported. The review also assessed the composite outcome of all-cause mortality, MI or stroke.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Validity was assessed using the Jadad scale. The authors also reported on the baseline similarity of treatment groups and the comparability of concomitant medications between treatment groups. The authors did not state how the validity assessment was performed.

Three reviewers independently extracted the outcome data. Any disagreements were resolved through recourse to a fourth reviewer. For each treatment group in each study, numbers of patients with outcomes of interest were presented for each outcome. Where required, authors were contacted for missing data.

How were the studies combined?

Pooled odds ratios (ORs), risk differences (RDs) and 95% confidence intervals (CIs) were calculated for each outcome using fixed-effect (Mantel-Haenszel) and random-effects (DerSimonian and Laird) models. Corrections were made for cells with zero counts. Numbers-needed-to-treat or -to-harm to cause or prevent the outcome of interest were calculated. The potential for publication bias was assessed using Begg’s test.

How were differences between studies investigated?

Statistical heterogeneity was assessed using the Q statistic. Sensitivity analyses were apparently performed by repeating the analysis after excluding one large study (n>45,000) that only included patients with STEMI, and by excluding the two studies that reported the highest use of fibrinolytics (these analyses were referred to only in the discussion).

Five RCTs (n=79,624) were included.

All five studies scored 4 or more out of 5 on the Jadad scale. There were no significant differences between treatment groups with respect to baseline characteristics and concomitant medications.

The results reported below were obtained using the random-effects model.

Compared with aspirin alone, clopidogrel plus aspirin was associated with a significant reduction in all-cause mortality (6.3% versus 6.7%; OR 0.94, 95% CI: 0.89, 0.99, p=0.026; RD -0.0039, 95% CI: -0.0073, -0.00047, p=0.026), cardiovascular mortality (5.7% versus 5.9%; OR 0.94, 95% CI: 0.89, 1.00, p=0.044; RD -0.0033, 95% CI: -0.0066, -0.00019, p=0.05), MI (2.7% versus 3.3%; OR 0.82, 95% CI: 0.75, 0.89, p<0.0001; RD -0.0058, 95% CI: -0.0082, -0.0034, p<0.0001) and stroke (1.2% versus 1.4%; OR 0.82, 95% CI: 0.73, 0.93, p=0.002; RD -0.0025, 95% CI: -0.0041, -0.0097, p=0.002), and the composite outcome of cardiovascular mortality, MI or stroke.

There was no evidence of heterogeneity or publication bias for any outcome.

Clopidogrel plus aspirin was associated with a significant increase in the risk of bleeding compared with aspirin alone: 1.6% versus 1.3% (OR 1.26, 95% CI: 1.11, 1.41, p<0.0001; RD 0.0031, 95% CI: 0.0015, 0.0047, p<0.0001). There were no significant differences between treatments for fatal bleeds or haemorrhagic strokes.

In the text, the authors stated that the results for all-cause and cardiovascular mortality were sensitive to the exclusion of the largest study that only included patients with STEMI, but results data were not reported.

Compared with aspirin alone, clopidogrel plus aspirin resulted in a small reduction in all-cause mortality and cardiovascular mortality in patients with STEMI, and a modest reduction in MI and stroke in patients with cardiovascular disease. Bleeding was increased with dual therapy, but fatal bleeds and haemorrhagic stroke were not.

The review question was clear with respect to the participants, intervention, outcomes and study design. Several relevant sources were searched, some attempts were made to minimise publication bias, and the potential for publication bias was assessed and no evidence of it was found. However, no attempts were made to minimise language bias. Appropriate methods were used to minimise reviewer error and bias in the data extraction, but it is not clear whether similar steps were taken at the study selection and validity assessment stages. Validity was assessed using established criteria and the validity scores reported. Adequate information about the included studies was provided. Statistical heterogeneity was assessed and the studies appropriately pooled using meta-analysis.

The conclusions referring to the subgroup of patients with STEMI appear to have been based on the results of a sensitivity analysis that were only mentioned in the discussion and for which no results data were presented. It is not clear if the sensitivity analysis was determined in advance or why the analysis was not repeated with the inclusion of only the two studies in patients with STEMI, with results data reported. The review was generally well-conducted. However, basing part of the conclusions on a sensitivity analysis for which results data were not presented undermines the conclusion about mortality in the subgroup of STEMI patients. Conclusions for the other outcomes appear reliable.

Two of the authors have received financial contributions from pharmaceutical companies and one author was the primary investigator for an included study.

The authors did not state any implications for practice or further research.

Not externally funded.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.