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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials

EP Navarese, M Verdoia, A Schaffer, P Suriano, M Kozinski, F Castriota, S de Servi, J Kubica, and G de Luca.

Review published: 2011.

CRD summary

The review concluded that new oral antiplatelet regimens to block platelet adenosine diphosphate (ADP)-receptors for patients with acute coronary syndromes were associated with a reduction in mortality, myocardial reinfarction and in-stent thrombosis without any increase in bleeding. The uncertain trial quality and limitations in review reporting mean that the reliability of the authors' conclusions is unclear.

Authors' objectives

To determine the efficacy of new oral antiplatelet regimens to block platelet adenosine diphosphate (ADP) receptors compared with standard-dose clopidogrel on ischaemic and bleeding complications.

Searching

MEDLINE and Cochrane Central Registry of Controlled Trials (CENTRAL) were searched from January 1990 to January 2010 with no language restriction. Search terms were reported. Conference abstracts (Circulation, Journal of the American College of Cardiology, European Heart Journal and American Journal of Cardiology) were searched from January 1990 to January 2011. Five relevant websites were also searched (January 2002 to January 2011).

Study selection

Randomised controlled trials (RCTs) that compared new oral antiplatelet regimens (to block platelet ADP-receptors) with a standard dose of clopidogrel in patients with acute coronary syndromes were eligible for inclusion in the review. Eligible trials had to include complete clinical data. Trials with follow-up data in less than 90% of the patients, on-going trials or trials with irretrievable data, and trials of intravenous therapy with periprocedural but not chronic administration were excluded. The primary outcome was mortality. Secondary outcomes included myocardial infarction and definite in-stent thrombosis. Major bleeding complications were assessed as safety endpoint.

In included trials, interventions included new antiplatelet regimens of ticagrelor (loading dose of 90mg or 180mg followed by 90mg or 180mg twice daily) or prasugrel (loading dose of 60mg followed by 10mg daily), or high-dose clopidogrel (loading dose 600mg or 900mg followed by 75mg to 150mg daily). The comparator intervention was standard-dose clopidogrel (loading dose 300mg followed by 75mg daily).

Acute coronary syndromes included non-ST-segment elevation acute coronary syndrome, ST-segment elevation myocardial infarction, and thrombolysis in myocardial infarction. Most patients underwent percutaneous coronary intervention. Most trials defined major bleeding according to Thrombolysis In Myocardial Infarction (TIMI) classification; one trial used the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) classification.

The authors did not state how many reviewers selected trials for the review.

Assessment of study quality

The authors did not state whether the quality of the included trials was formally assessed.

Data extraction

Data used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) were independently extracted by two reviewers and any disagreements were resolved by consensus. Data were extracted on an intention-to-treat basis. Where there was incomplete or unclear data, authors of the original trials were contacted.

Methods of synthesis

Summary odds ratios and their associated 95% confidence intervals were calculated using fixed-effect and random-effects models. Statistical heterogeneity was assessed using Χ² and Ι².

Subgroup analyses according to new antiplatelet drugs (prasugrel and ticagrelor), high-dose clopidogrel (600mg), and patients undergoing percutaneous coronary intervention were prespecified.

Potential publication bias was examined by construction of a funnel plot for all-cause mortality.

Results of the review

Seven RCTs were included in the review (58,591 patients). Follow-up ranged from 0.9 to 15 months.

A significant reduction in all-cause mortality (OR 0.87, 95% CI 0.79 to 0.95; Ι²=15%; seven RCTs), recurrent myocardial infarction (OR 0.80, 95% CI 0.74 to 0.87; Ι²=38%; six RCTs) and definite in-stent thrombosis (OR 0.52, 95% CI 0.43 to 0.63; Ι²=0%; four RCTs) was found with new antiplatelet regimens compared with standard-dose clopidogrel. No between group difference was found for major bleeding complications.

In subgroup analyses, a significant reduction in all-cause mortality was found for new antiplatelet drugs (OR 0.83, 95% CI 0.74 to 0.92; Ι²=36%; three RCTs) and for patients who underwent percutaneous coronary intervention (OR 0.88, 95% CI 0.78 to 0.99; Ι²=12%; four RCTs), but not for high-dose clopidogrel (600mg). A significant reduction in myocardial infarction was found for new antiplatelet drugs (OR 0.79, 95% CI 0.72 to 0.86; Ι²=55%; three RCTs) and patients who underwent percutaneous coronary intervention (OR 0.73, 95% CI 0.67 to 0.80; Ι²=30%; three RCTs), but for not high-dose clopidogrel. High-dose clopidogrel was associated with a higher rate of bleeding complications (OR 1.25, 95% CI 1.02 to 1.53; Ι²=0%; four RCTs) compared with standard dose clopidogrel. No between group differences were found for new antiplatelet drugs or percutaneous coronary intervention and 300mg clopidogrel.

No evidence of publication bias was found in the funnel plot for all-cause mortality.

Authors' conclusions

New oral antiplatelet regimens that blocked platelet ADP-receptors were associated with a reduction in mortality, myocardial reinfarction and in-stent thrombosis without an increase of major bleeding in acute coronary syndromes patients.

CRD commentary

Inclusion criteria were clearly defined for study design and outcomes, but those for population, interventions amd comparators were not; these were deduced from other information. Two relevant databases were searched with no language restriction and some attempt was made to identify unpublished trials, which minimised the possibility of publication and language bias. Appropriate steps were reported to minimise the likelihood of reviewer error and bias for data extraction but it was not clear whether similar procedures were undertaken for trial selection.

The authors did not state that they formally assessed the quality of the included trials, so the reliability of the estimates was unclear. Trials were pooled using standard meta-analytic methods. Statistical heterogeneity was assessed. Although the trials included three different antiplatelet regimens, pre-specified subgroup analyses based on regimen type was performed.

The uncertain trial quality and limitations in review reporting mean that the reliability of the authors' conclusions is unclear.

Implications of the review for practice and research

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

Funding

Partially supported by a European Association of Percutaneous Cardiovascular Interventions (EAPCI) international cardiology fellowship grant.

Bibliographic details

Navarese EP, Verdoia M, Schaffer A, Suriano P, Kozinski M, Castriota F, de Servi S, Kubica J, de Luca G. Ischaemic and bleeding complications with new, compared to standard, ADP-antagonist regimens in acute coronary syndromes: a meta-analysis of randomized trials. QJM 2011; 104(7): 561-569. [PubMed: 21572108]

Indexing Status

Subject indexing assigned by NLM

MeSH

Acute Coronary Syndrome /complications /drug therapy /mortality; Adenosine /adverse effects /analogs & derivatives; Administration, Oral; Hemorrhage /chemically induced; Humans; Ischemia /chemically induced; Piperazines /adverse effects; Platelet Aggregation Inhibitors /adverse effects; Randomized Controlled Trials as Topic; Thiophenes /adverse effects; Ticlopidine /adverse effects /analogs & derivatives

AccessionNumber

12011004127

Database entry date

17/08/2012

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21572108

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