|Impact of clopidogrel and potent P2Y12-inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention: a systematic review and meta-analysis
|Aradi D, Komocsi A, Vorobcsuk A, Serebruany VL
This review concluded that higher potency P2Y12-receptor inhibition (using prasugrel/tricagrelor anticoagulants) was associated with decreased risk of cardiovascular death and myocardial infarction, but not stroke, compared with clopidogrel. Given the unknown risk of bias of the included trials, the substantial clinical variability across the trials, and concerns about the analysis, the authors' conclusions should be treated with caution.
To evaluate the influence of P2Y12-receptor inhibition of different potency on major cardiovascular outcomes in patients with acute coronary syndrome or undergoing a percutaneous coronary intervention.
PubMed, SCOPUS, and ClinicalTrials.com were searched with no language restrictions from 1975 up to March 2012; search terms were reported. Reference lists of included studies, reviews editorials, and letters, and conference abstracts (related associations not reported), were also searched.
Randomised controlled trials (RCTs) that compared clopidogrel (moderate P2Y12-receptor inhibitor) versus placebo or prasugrel, ticagrelor or elinogrel (potent new P2Y12-receptor inhibitors), in at least 500 patients, were eligible for inclusion. Trails that evaluated clopidogrel plus aspirin were excluded. RCTs conducted in patients who had a stroke, or who had multiple risk factors for cardiovascular, cerebrovascular or peripheral artery disease, were excluded.
The included RCTs compared clopidogrel with placebo or with prasugrel/ticagrelor. Across the trials, patients' mean age ranged from 57 to 66 years, the proportion of women from 20% to 39%, diabetes from 16% to 38%, prior myocardial infarction from 8% to 43%, and prior stroke from 0% to 7% (where reported). At least 94% of patients took concomitant aspirin; 7% to 71% of patients took glycoprotein IIb/IIIa inhibitors (where reported). Patients who received fibrinolytics were excluded from trials that evaluated different P2Y12-receptor inhibitors; their use ranged from 2% to 99.7% in placebo controlled trials (where reported). The incidence of percutaneous coronary intervention ranged from 0% to 99%.
Three independent reviewers selected studies for the review; disagreements were resolved by discussion.
Assessment of study quality
There did not appear to be an assessment of trial quality.
Three independent reviewers extracted data to calculate odds ratios and 95% confidence intervals; disagreements were resolved by discussion.
Methods of synthesis
Pooled odds ratios with 95% confidence intervals were calculated using fixed-effect and random-effects models; results for the random-effects model were presented. Heterogeneity was assessed using Ι² and Χ². Publication bias was investigated using funnel plots.
Results of the review
Nine RCTs met the inclusion criteria (107,467 patients; range 904 to 45,852); seven were phase III RCTs and two were phase II RCTs. Evidence for publication bias was not observed. Follow-up ranged from 28 days to 17.1 months.
Clopidogrel versus placebo (four RCTs): Compared with placebo, clopidogrel significantly reduced the incidence of cardiovascular death (OR 0.93, 95% CI 0.87 to 0.99; four RCTs), myocardial infarction (OR 0.80, 95% CI 0.74 to 0.88; four RCTs), stroke (OR 0.84, 95% CI 0.72 to 0.97; four RCTs), and the composite outcome of cardiovascular death/myocardial infarction/stroke (OR 0.84, 95% CI 0.76 to 0.93), but not haemorrhagic stroke (three RCTs). No statistical heterogeneity was observed (Ι²=0%).
Prasugrel/ticagrelor versus clopidogrel (five RCTs): Compared with clopidogrel, prasugrel or ticagrelor significantly reduced the incidence of cardiovascular death (OR 0.86, 95% CI 0.78 to 0.94; Ι²=0%; five RCTs), myocardial infarction (OR 0.83, 95% CI 0.74 to 0.93; Ι²=43%; five RCTs) and the composite of cardiovascular death/myocardial infarction/stroke (OR 0.85, 95% CI 0.79 to 0.92), but not stroke (five RCTs) or intracranial haemorrhage (four RCTs). An inverse, linear association was observed between the potency of the P2Y12-receptor inhibitor and the risk of myocardial infarction, and cardiovascular mortality, but not stroke.
Higher potency P2Y12-receptor inhibition (prasugrel/ticagrelor) was associated with a lower risk of cardiovascular death and myocardial infarction, but not stroke, when compared with clopidogrel (moderate potency P2Y12-receptor inhibition).
The review addressed a clear question supported by reproducible inclusion criteria. Relevant sources were searched with no language restrictions; attempts were made to locate unpublished studies. The potential for publication bias was investigated, but (as the authors acknowledged) the value of this assessment was limited due to the low number of trials included. Study selection and data extraction were conducted in duplicate, which reduced the risk of error and bias.
The quality of the included RCTs was not assessed, so it was unclear whether they were subject to bias, which would reduce confidence in the reliability of the results derived from them. The results of the random-effects model were presented, but most of the analyses had four or fewer RCTs included, which may have not been sufficient to inform the distribution of effects within the model. However, the authors stated that the results from the fixed-effect model were not different. There was substantial clinical heterogeneity across the trials, which made the reliability and generalisability of the pooled estimates uncertain. The combining of trials evaluating prasugrel and ticagrelor presumed a class effect and similar potency; if this was not the case, the uncertainty surrounding the reliability and generalisability of the pooled estimates would be increased. The conclusion on the impact of P2Y12-receptor inhibitor potency was based on indirect comparisons of results from different meta-analyses. The more robust network meta-analytical models available should have been used if placebo-controlled trials of prasugrel, ticagrelor and elinogrel, and direct comparisons of these higher potency inhibitors were sought. One of the authors of the review was listed as the inventor of prasugrel and ticagrelor.
Given the concerns outlined, the authors' conclusions should be treated with caution.
Implications of the review for practice and research
Practice: The authors stated that the observed mortality benefit with potent P2Y12-receptor inhibition compared with clopidogrel justified the use of prasugrel/ticagrelor in patients with acute coronary syndrome and after percutaneous coronary intervention.
Research: The authors did not stated any implications for further research.
Aradi D, Komocsi A, Vorobcsuk A, Serebruany VL. Impact of clopidogrel and potent P2Y12-inhibitors on mortality and stroke in patients with acute coronary syndrome or undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Thrombosis and Haemostasis 2013; 109(1): 93-101
Subject indexing assigned by NLM
Acute Coronary Syndrome /blood /complications /drug therapy /mortality; Adenosine /analogs & Aged; Coronary Thrombosis /blood /etiology /mortality /prevention & Female; Humans; Intracranial Hemorrhages /chemically induced; Male; Middle Aged; Myocardial Infarction /etiology /mortality /prevention & Odds Ratio; Percutaneous Coronary Intervention /adverse effects /mortality; Piperazines /therapeutic use; Platelet Aggregation Inhibitors /adverse effects /therapeutic use; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists /adverse effects /therapeutic use; Receptors, Purinergic P2Y12 /blood /drug effects; Risk Assessment; Risk Factors; Stroke /blood /etiology /mortality /prevention & Thiophenes /therapeutic use; Ticlopidine /adverse effects /analogs & Treatment Outcome; control; control; control; derivatives /therapeutic use; derivatives /therapeutic use
Date bibliographic record published
Date abstract record published
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.