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Review
. 2014 Oct 24:349:g6269.
doi: 10.1136/bmj.g6269.

Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis

Anne Bellemain-Appaix  1 , Mathieu Kerneis  2 , Stephen A O'Connor  2 , Johanne Silvain  2 , Michel Cucherat  3 , Farzin Beygui  2 , Olivier Barthélémy  2 , Jean-Philippe Collet  2 , Laurent Jacq  4 , François Bernasconi  4 , Gilles Montalescot  5 ; ACTION Study Group
Affiliations
Review

Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis

Anne Bellemain-Appaix et al. BMJ. .

Abstract

Objective: To investigate the effect of pretreatment with P2Y12 receptor inhibitors compared with no pretreatment on efficacy and safety of treatment of non-ST elevation acute coronary syndrome (ACS).

Data sources: Two reviewers independently searched Medline, Embase, Cochrane Controlled Trials, and BioMed Central databases for randomized placebo controlled trials and observational studies from August 2001 to March 2014.

Study eligibility: Studies must have reported both all-cause mortality (primary efficacy endpoint) and major bleeding (safety endpoint) outcomes.

Data extraction: Data on sample size, characteristics, drug dose and delay of administration, and outcomes were independently extracted and analyzed.

Data synthesis: A random-effect model was applied. The analysis was performed (i) in all patients independently of the management strategy and (ii) only in patients undergoing percutaneous coronary intervention.

Results: Of the 393 titles identified, seven (four randomized controlled trials, one observational analysis from a randomized controlled trial, and three observational studies) met the inclusion criteria. No study was identified for ticagrelor or cangrelor, and analyses were thus limited to thienopyridines. A total of 32,383 non-ST elevation ACS patients were included, 18,711 coming from randomized controlled trials. Of these, 55% underwent percutaneous coronary intervention (PCI). Pretreatment was not associated with a significant lower risk of mortality in all patients (odds ratio 0.90 (95% confidence interval 0.75 to 1.07), P=0.24), in particular when considering only the randomized controlled trials (odds ratio 0.90 (0.71 to 1.14), P=0.39). Similar results were observed in the cohort of patients undergoing PCI. A significant 30-45% excess of major bleeding was consistently observed in all patients (odds ratio 1.32 (1.16 to 1.49), P<0.0001) and in those undergoing PCI, as well as in the subset analyses of randomized controlled trials of these two cohorts of patients. There was a reduction in major adverse cardiovascular events in the analysis of all patients (odds ratio 0.84 (0.72 to 0.98), P=0.02), driven by the old clopidogrel studies (CURE and CREDO), but the difference was not significant for the cohort of patients undergoing PCI. Stent thrombosis, stroke, and urgent revascularization did not differ between groups (pretreatment v no pretreatment). The results were consistent for both thienopyridines and confirmed in sensitivity analyses.

Limitations: Analysis was not performed on individual patient's data.

Conclusion: In patients presenting with non-ST elevation ACS, pretreatment with thienopyridines is associated with no significant reduction of mortality but with a significant excess of major bleeding no matter the strategy adopted, invasive or not. Our results do not support a strategy of routine pretreatment in patients with non-ST elevation ACS.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

GM has received consulting fees from Bayer, Boehringer-Ingelheim, CFR, Europa, GLG, Iroko Cardio International, Lead-Up, LLC, Luminex, Mc Kinsey, Remedica, Servier, TIMI Group, WebMD, and Wolters; consulting fees and grant support from Bristol-Myers Squibb, AstraZeneca, Biotronik, Eli Lilly, The Medicines Company, Medtronic, Menarini, Sanofi-Aventis, Pfizer, and Accumetrics; and grant support from Abbott Vascular, Daiichi-Sankyo, Nanospheres, and Stentys. JPC has received research grants from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centocor, Fondation de France, INSERM, Federation Francaise de Cardiologie, and Société Française de Cardiologie; consulting fees from Sanofi-Aventis, Eli Lilly, and Bristol-Myers Squibb; and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, and Eli Lilly. ABA has received research grants from Daiichi-Sankyo, Eli Lilly, Fédération Française de Cardiologie and Société Française de Cardiologie and lecture fees from AstraZeneca, Servier, and Daiichi-Sankyo. JS reports receiving research grants from Sanofi-Aventis, Daiichi-Sankyo, Eli Lilly, Brahms, INSERM, Fédération Française de Cardiologie and Société Française de Cardiologie; consulting fees from Daiichi-Sankyo, Eli Lilly and speaker honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly, Iroko Cardio and Servier. SAO’C has received grants from A Menarini and the European Society of Cardiology. MC has received research grants from Bristol-Myers Squibb, AstraZeneca, Bayer, Haute Autorité de Santé; consulting fees from Bayer, Bristol-Myers Squibb; and speaker honoraria from Bristol-Myers Squibb.

Figures

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Fig 1 Flow chart of study selection
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Fig 2 All cause death for all patients with non-ST elevation acute coronary syndrome (ACS) (top) and those who underwent percutaneous coronary intervention (PCI) (bottom) comparing pretreatment with P2Y12 inhibitors versus no pretreatment. Death was considered at shortest follow-up available in each study which was 7 or 30 days unless indicated otherwise.
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Fig 3 Major bleeding for all patients with non-ST elevation acute coronary syndrome (ACS) (top) and those who underwent percutaneous coronary intervention (PCI) (bottom) comparing pretreatment with P2Y12 inhibitors versus no pretreatment. Major bleeding was considered at shortest follow-up available in each study which was 7 or 30 days unless indicated otherwise
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Fig 4 Main composite ischemic endpoint for all patients with non-ST elevation acute coronary syndrome (ACS) (top) and those who underwent percutaneous coronary intervention (PCI) (bottom) comparing pretreatment with P2Y12 inhibitors versus no pretreatment. The composite ischemic endpoint was considered at shortest follow-up available in each study which was 7 or 30 days unless indicated otherwise
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Fig 5 Main ischemic and hemorrhagic endpoints in randomized controlled trials only for all patients with non-ST elevation acute coronary syndrome (ACS) (top) and those who underwent percutaneous coronary intervention (PCI) (bottom) comparing pretreatment with P2Y12 inhibitors versus no pretreatment. All endpoints were considered at shortest follow-up available in each study which was 7 or 30 days unless indicated otherwise
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