The review concluded that triple antiplatelet therapy based on intravenous glycoprotein IIb/IIIa inhibitors reduced vascular events compared with aspirin-based dual therapy in patients with non-ST elevation with acute coronary and ST elevation with myocardial infarction, but increased minor bleeding in some specified subgroups. Limited assessment of trial quality makes it difficult to judge the strength of these conclusions.

To compare the safety and efficacy of triple antiplatelet therapy with dual therapy in reducing recurrent vascular events.

MEDLINE, EMBASE, the Cochrane Library and Science Citation Index were searched in October 2009 for studies in any language. Search terms were reported. Reference lists of identified studies and reviews were screened.

Completed randomised controlled trials (RCTs) were eligible if they compared triple antiplatelet therapy with dual antiplatelet therapy in adults at high risk of ischaemic vascular events. These were defined as non-ST elevation with acute coronary syndromes (NSTE-ACS), ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI), acute ischaemic stroke/transient ischaemic attack, peripheral vascular disease, previous myocardial infarction or coronary artery disease, and peripheral arterial disease.

The primary review outcome was composite vascular events (non-fatal stroke, non-fatal myocardial infarction or death). Secondary outcomes were myocardial infarction, ischaemic stroke, death, major and minor bleeding, intracranial bleeding, blood transfusions and thrombocytopenia.

Included trials involved patients with NSTE-ACS, STEMI and elective PCI. The mean age of participants ranged from 56 to 69 years; most were male (range 58 to 87%). None of the trial included patients with previous stroke or peripheral vascular disease. Most trials evaluated intravenous glycoprotein IIb/IIIa receptor antagonist (tirofiban, abciximab and eptifibatide) as the additional antiplatelet agent; other studies used clopidogrel or cilostazol as the additional agent. Most dual therapy regimens included aspirin and thienopyridine. Most trials administered heparin in both treatment groups. The duration of treatment in NSTE-ACS and STEMI studies was mostly 12 hours. Treatment duration for elective PCI studies ranged from 12 hours to six months.

Two reviewers selected studies. One reviewer resolved disagreements by discussion.

Quality was assessed using randomisation and allocation concealment.

The authors did not explicitly state how many reviewers assessed validity.

Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.

Two reviewers extracted data onto specified software. One reviewer resolved disagreements by discussion.

Trials were grouped by medical condition and additional drug. Pooled odds ratios and 95% confidence intervals were calculated using a random-effects model. Heterogeneity was assessed using X² and I². Absolute event rates were calculated for the composite outcome and bleeding (details were reported).

The possibility of publication bias was explored using Egger’s test and Begg’s funnel plot.

Twenty-five RCTs were included in the review (n=17,383 patients). Sample size ranged from 31 to 2,159 patients. Seventeen trials had adequate allocation concealment. Duration of follow-up ranged from 48 hours to 12 months.

Non-ST elevation with acute coronary syndromes (NSTE-ACS; four RCTs): Compared with aspirin-based dual therapy, triple therapy using intravenous glycoprotein IIb/IIIa inhibitors was associated with a statistically significant reduction in composite vascular events (OR 0.69, 95% CI 0.55 to 0.86; four RCTs) and myocardial infarction (OR 0.70, 95% CI 0.56 to 0.88; four RCTs). There was no statistically significant difference between intravenous glycoprotein IIb/IIIa inhibitor based triple therapy and dual therapy for death (four RCTs) or measures of bleeding. There was no evidence of statistical heterogeneity, although results were not reported for bleeding.

ST-segment elevation myocardial infarction (STEM; eight RCTs): Compared with dual therapy, triple therapy using intravenous glycoprotein IIb/IIIa inhibitor was associated with a statistically significant reduction in composite vascular events (OR 0.39, 95% CI 0.30 to 0.51; six RCTs), myocardial infarction (OR 0.26, 95% CI 0.17 to 0.38; five RCTs) and death (OR 0.69, 95% CI 0.49 to 0.99; six RCTs)and a significant increase in minor bleeding (OR 2.73, 95% CI 1.15 to 6.46). There was no evidence of statistical heterogeneity although results were not reported for bleeding.

Elective percutaneous coronary intervention (PCI; 13 RCTs): There was no statistically significant difference between triple therapy with intravenous glycoprotein IIb/IIIa inhibitor and dual therapy for composite vascular events (five RCTs; I²=68.7%), myocardial infarction (six RCTs; I²=61.2%) or death (five RCTs; I²=0%). Triple therapy using intravenous glycoprotein IIb/IIIa inhibitor was associated with a statistically significant increase in minor bleeding (OR 1.60, 95% CI 1.16 to 2.21), blood transfusions (OR 1.79, 95% CI 1.14 to 2.79) and thrombocytopenia (OR 8.04, 95% CI 1.82 to 35.59).

There were insufficient data to evaluate treatment effects on stroke events.

Other results were also reported.

There was no evidence of publication bias.

Triple antiplatelet therapy (based on intravenous glycoprotein IIb/IIIa inhibitors) was more effective than aspirin-based dual therapy in reducing vascular events in patients with ST-segment elevation myocardial infarction and non-ST elevation with acute coronary syndromes. Minor bleeding was increased in patients with ST-segment elevation myocardial infarction and patients undergoing elective percutaneous coronary intervention. In patients undergoing percutaneous coronary intervention, triple therapy had no beneficial effect and was associated with an 80% increase in transfusions and an eightfold increase in thrombocytopenia.

The review question was clearly stated and inclusion criteria were appropriately defined. Several relevant sources were searched. No language restrictions were applied, but no attempts were made to minimise publication bias; no evidence of publication bias was found. Methods were used to minimise reviewer errors and bias in the selection of studies and extraction of data, but it was not clear whether similar steps were taken in the assessment of quality.

The limited quality assessment made it difficult to judge the quality of the evidence. Relevant information was provided about interventions and participants. Trials were grouped appropriately and pooled using meta-analysis. Forest plots were presented. Heterogeneity was assessed. Results were based on a small number of trials with short duration of treatment and follow-up. There was some evidence of statistical heterogeneity for the percutaneous coronary intervention trials. Trials with zero events were not taken into account. The authors acknowledged that the effect of heparin on outcomes was unclear.

Evidence appeared to support the authors’ conclusions, but the limited assessment of trial quality makes it difficult to judge the strength of this evidence.

Practice: The authors stated that the superiority of intravenous glycoprotein IIb/IIIa inhibitors should only be considered in the short-term.

Research: The authors stated that there is a need for studies to compare the effects of triple versus dual antiplatelet therapy in patients with chronic ischaemic heart disease, acute and chronic stroke and peripheral artery disease.

The employer (Division of Stroke, University of Nottingham) of one author received core funding from The Stroke Association (UK).

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.