This review found potentially relevant differences in efficacy and bleeding risk between antiplatelet drugs prasugrel, ticagrelor and high-dose clopidogrel in patients undergoing percutaneous coronary interventions, but that these conclusions were not definitive as they were not based on direct comparisons of treatments. Despite some limitations, the authors' conclusions reflect the evidence and are likely to be reliable.

To compare the efficacy and safety of prasugrel, ticagrelor, and clopidogrel (new anti-platelet treatments) at high and standard doses in patients scheduled for percutaneous coronary interventions.

EMBASE and MEDLINE were searched up to May 2011 with no language restrictions; search terms were reported. Reference lists of included articles, relevant reviews and selected cardiovascular journals were searched to identify further studies. Reviews for the advisory committee of the American Food and Drug Administration, Division of Cardiovascular and Renal Products and clinicaltrials.gov were scanned for additional studies.

Randomised controlled trials (RCTs) of aspirin in patients scheduled for and/or undergoing percutaneous coronary interventions were eligible for inclusion if aspirin was administered with high- and/or standard-dose clopidogrel, prasugrel, or ticagrelor. Trials were required to have a minimum duration of follow-up of two weeks. High-dose clopidogrel was stated to be a maintenance dose of clopidogrel that was at least twice the standard dose of 75mg.

The primary efficacy outcome was all-cause death; other efficacy outcomes were cardiovascular death, myocardial infarction, stroke and stent thrombosis. Major bleeding was the primary bleeding outcome; minor bleeding data were also evaluated. When possible, bleeding results were classified according to Thrombolysis in Myocardial Infarction criteria.

In most included trials, all the patients were undergoing percutaneous coronary interventions; in other trials, the percentage of patients undergoing percutaneous coronary interventions ranged from 55% to 99%. Prasugrel was administered at doses from loading doses of 60mg, followed by daily maintenance doses of 10mg. A loading dose of 180mg to 270mg ticagrelor was given prior to maintenance treatment of 180mg for 12 months. High-dose clopidogrel was administered at doses from a loading dose of 300mg to 600mg, followed by maintenance doses of 150mg. Standard-dose clopidogrel was given as a loading dose of 300mg in most trials, followed by maintenance doses of 75mg for the trial duration. Treatment duration ranged from seven days to 15 months; most trials treated patients for 30 days.

The reviewers did not state how many reviewers performed the study selection.

Methodological quality was assessed by two reviewers using the Cochrane Risk of Bias assessment tool for randomisation, allocation concealment, blinding of patients, personnel and outcome assessors, completeness of outcome data, selective reporting, and the presence of other biases.

Two reviewers independently extracted data on an intention-to-treat basis to calculate odds ratios and 95% confidence intervals for the outcomes for each trial and comparison. Trial authors were contacted when necessary for additional information.

Pooled odds ratios and 95% confidence intervals were calculated for the differences in outcomes for each comparison. Statistical heterogeneity was evaluated using Ι²; Ι² values of 25% indicate low heterogeneity, 50% moderate heterogeneity, and 75% high heterogeneity. The results were combined using Mantel-Haenszel fixed-effect model.

For the network meta-analyses, a regression model was separately fitted for each outcome to combine direct and indirect comparisons. The results were adjusted for mean length of follow-up and validated using a mixed treatment comparison.

Fourteen RCTs (48,982 patients) were included in the review. Sample sizes ranged from 40 to 17,263 patients. High-dose clopidogrel was compared with low-dose clopidogrel in nine trials. Two trials evaluated prasugrel compared with standard-dose clopidogrel. Two trials compared prasugrel with high-dose clopidogrel. One trial compared ticagrelor with standard-dose clopidogrel. All trials adequately reported adequate sequence generation. The overall risk of bias was low. Follow-up ranged from 30 days to 15 months.

Ticagrelor versus low-dose clopidogrel (direct comparison): Statistically significant reductions were observed with ticagrelor for all-cause death (OR 0.80, 95% CI 0.67 to 0.94), cardiovascular death (OR 0.81, 95% CI 0.67 to 0.97), myocardial infarction (OR 0.79, 95% CI 0.68 to 0.92) major adverse cardiac events (OR 0.83, 95% CI 0.74 to 0.93), and for stent thrombosis (OR 0.72, 95% CI 0.56 to 0.93) compared with low-dose clopidogrel.

High-dose versus low-dose clopidogrel (direct comparison): Statistically significant differences favouring high-dose clopidogrel treatment were found for myocardial infarction (OR 0.78, 95% CI 0.65 to 0.94), major adverse cardiac events (OR 0.82, 95% CI 0.72 to 0.95), and stent thrombosis (OR 0.66, 95% CI 0.53 to 0.82). High-dose clopidogrel was associated with increased minor bleeding (OR 1.23, 95% CI 1.08 to 1.39) and minor or major bleeding (OR 1.22, 95% CI 1.09 to 1.37).

Prasugrel versus low-dose clopidogrel (direct comparison): Significant benefits favouring prasugrel were observed for major adverse cardiac events (OR 0.80, 95% CI 0.72 to 0.89), stent thrombosis (OR 0.46, 95% CI 0.35 to 0.62) and myocardial infarction (OR 0.75, 95% CI 0.66 to 0.85) compared with low-dose clopidogrel. Prasugrel was significantly associated with increased major bleeding (OR 1.45, 95% CI 1.14 to 1.83), increased major or minor bleeding (OR 1.33, 95% CI 1.11 to 1.58), and increased non-coronary artery bypass graft-related major bleeding (OR 1.31, 95% CI 1.02 to 1.67).

Prasugrel versus high-dose clopidogrel (indirect comparison): No statistically significant differences were found between prasugrel and high-dose clopidogrel for any of the outcomes in the direct comparisons. Indirect comparisons found a lower chance of stent thrombosis with prasugrel (0.68, 95% CI 0.48 to 0.97).

Ticagrelor versus high-dose clopidogrel (indirect comparison): Treatment with ticagrelor was associated with a significantly reduced chance of major or minor bleeding (OR 0.81, 95% CI 0.69 to 0.96) compared with high-dose clopidogrel.

Ticagrelor versus prasugrel (indirect comparison): Although prasugrel was associated with statistically significant reductions in stent thrombosis (OR 0.63, 95% CI 0.43 to 0.93), it was also associated with significantly higher odds of major bleeding (OR 1.45, 95% CI 1.10 to 1.90) and major or minor bleeding (OR 1.37, 95% CI 1.11 to 1.68) compared with ticagrelor.

There was no evidence of heterogeneity for any of the direct comparisons (Ι²<50%).

Result details were given in separate online supplementary material. Further results of indirect comparisons and subgroup analyses were reported.

The new antiplatelet treatments, high-dose clopidogrel, ticagrelor and prasugrel, significantly reduced non-fatal cardiac endpoints compared with standard-dose clopidogrel; only ticagrelor showed reduced mortality and did not increase bleeding risks compared with standard-dose clopidogrel. Indirect comparisons between novel antiplatelet agents suggested that ticagrelor showed the most favourable bleeding profile, although this should be confirmed by further randomised trials directly comparing the new antiplatelet treatments.

The review addressed a clear question. Criteria for the inclusion of studies were clearly defined. Appropriate databases were searched with no language restrictions. There were attempts to identify unpublished trials. Steps were taken to minimise reviewer errors and biases for data extraction and the assessment of methodological quality, but were not reported for the selection of studies review process.

Methodological quality was assessed; the quality of the included trials was considered at low risk of bias. The authors decision to combine the results in meta-analyses appeared to be justified, although there may be an increased risk of false positive results with the large number of analyses performed. Potential differences amongst subgroups were explored. The authors acknowledged some of the limitations of the review in the validity of indirect comparisons, the possible confounding effects of aspirin, and the varying definitions of bleeding events.

The authors' conclusions reflect the review findings and are likely to be reliable.

Practice: The authors stated that high-dose clopidogrel was more effective than standard-dose clopidogrel and represented an alternative for patients, particularly in light of economic constraints and increasing availability of generic clopidogrel.

Research: The authors stated that definitive conclusions about the superiority of one anti-platelet drug over another were not clear, so further RCTs of direct comparisons between the drugs were required.

One author was supported by the Erwin Schroedinger-Fellowship of the Austrian Science Fund.

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.