CRD summary

This review of 15 studies concluded that in patients scheduled for percutaneous coronary intervention clopidogrel pretreatment did not lower mortality but lowered the risk of major coronary events. The review was well conducted and the result is probably reliable despite limitations in the available evidence that require further corroborative studies to reduce uncertainty.

Authors' objectives

To evaluate the association of clopidogrel pretreatment versus no treatment with mortality and major bleeding among patients who underwent percutaneous coronary intervention (PCI).

Searching

MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) (January 1980 to September 2012) were searched using specified search terms and without language restrictions. References from reviews and selected articles were searched.

Study selection

Inclusion criteria were defined as: patients with coronary artery disease who underwent catheterisation, PCI or both; controlled comparison between clopidogrel pretreatment and no pretreatment; and data on clopidogrel loading dose with at least mortality and bleeding outcomes reported. Pretreatment was defined as administration of clopidogrel before PCI or catheterisation. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary end points included major cardiac events. Primary analysis was based only on randomised controlled trials (RCTs) but additional analyses included comparative controlled studies.

For the main analysis of RCTs, three-quarters of the patients had acute coronary syndromes (including those with ST-elevation myocardial infarction) and the rest had elective PCI. Follow-up varied from the time patients were in the hospital to a maximum of one year (mean 192 days, range seven to 365 days). Details of interventions received by each trial arm were reported.

Two reviewers assessed study eligibility independently.

Assessment of study quality

Study quality was assessed independently by two reviewers who used the Ottawa Scale (non-randomised studies) and Jadad scale (randomised controlled trials).

Data extraction

Binary outcome data were extracted to enable calculation of absolute risks, odds ratios (OR) and associated 95% confidence intervals (CI).

Results were independently extracted by two reviewers. Disagreements were resolved by consensus.

Methods of synthesis

Random-effects models were used to pool studies with fixed-effect Mantel-Haenszel models as sensitivity analyses to avoid over-weighting of small studies. The main analysis was performed on RCTs and confirmed by observational analyses and observational studies. Prespecified subgroups based on clinical presentation and clopidogrel loading dose were analysed. Heterogeneity was tested using Χ² and quantified using Ι². Publication bias was assessed by visual inspection of funnel plots and use of trim-and-fill.

Results of the review

Fifteen studies (37,814 patients) were included in the review: seven studies were randomised controlled trials (8,608 patients); two studies were observational analyses of RCTs (10,945 patients); and six studies were observational studies (18,261 patients). Most RCTs were high quality (four scored 5 on the Jadad scale and two scored 3). Observational data were similarly robust (8 or 9 on the Newcastle-Ottawa scale).

Analysis of RCTs showed that clopidogrel pretreatment was not associated with a reduction of risk of death (absolute risk 1.54% versus 1.97% and OR 0.80, 95% CI 0.57 to 1.11) but was associated with a lower risk of major cardiac events (absolute risk 9.83% versus 12.35% and OR 0.77, 95% CI 0.66 to 0.89). There was no significant association between pretreatment and major bleeding (absolute risk 3.57% versus 3.08% and OR 1.18, 95% CI 0.93 to 1.50). Analyses from observational analyses of RCTs and observational studies were consistent for all results.

Heterogeneity was not statistically significant in analyses based on RCTs and there was no evidence of publication bias.

Additional results based on subgroup analyses were reported.

Authors' conclusions

Among patients scheduled for percutaneous coronary intervention, clopidogrel pretreatment was not associated with lower mortality but was associated with a lower risk of major coronary events.

CRD commentary

The review addressed a clear question. The authors used appropriate methods to minimise bias in searching, selecting and appraising studies. Standard methods were used to pool studies. There was no evidence of either important heterogeneity or publication bias but this may have been due to a lack of power to detect differences rather than robust evidence of consistency.

The lack of effect on mortality was strongly dependent on a single randomised trial and the absolute difference in reduced risk of major coronary events was small (2.5%). However, the stratified inclusion of non-randomised evidence demonstrated consistent overall effects irrespective of type of primary information and increased the strength of inferences based on randomised evidence alone.

The authors' conclusions that clopidogrel pretreatment was not associated with lower mortality but was associated with a lower risk of major coronary events reflect the evidence and are probably reliable. The authors assessment of future research needs seems particularly judicious in light of the limits in the current evidence base.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that the value of pretreatment, including with new antiplatelet agents, needed to be assessed in large prospective studies.

Funding

No external funding.

Bibliographic details

Bellemain-Appaix A, O'Connor SA, Silvain J, Cucherat M, Beygui F, Barthelemy O, Collet JP, Jacq L, Bernasconi F, Montalescot G, Allies in Cardiovascular Trials Initiatives and Organized Networks Group. Association of clopidogrel pretreatment with mortality, cardiovascular events, and major bleeding among patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. JAMA 2012; 308(23): 2507-2517. [PubMed: 23287889]

Original Paper URL

http://jama.jamanetwork.com/article.aspx?articleid=1486836

Indexing Status

Subject indexing assigned by NLM

MeSH

Acute Coronary Syndrome /therapy; Coronary Artery Disease /therapy; Endpoint Determination; Hemorrhage /prevention & control; Humans; Myocardial Infarction /prevention & control; Percutaneous Coronary Intervention /adverse effects /mortality; Platelet Aggregation Inhibitors /administration & dosage; Preoperative Care; Randomized Controlled Trials as Topic; Registries; Stroke /prevention & control; Ticlopidine /administration & dosage /analogs & derivatives; Treatment Outcome

AccessionNumber

12012058168

Database entry date

08/01/2013

Record Status

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.