Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events - PubMed (original) (raw)

Review

Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events

Alessandro Squizzato et al. Cochrane Database Syst Rev. 2017.

Abstract

Background: Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease. This is an update to a previously published review from 2011.

Objectives: To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or were at high risk of atherothrombotic disease, but did not have a coronary stent.

Search methods: We updated the searches of CENTRAL (2017, Issue 6), MEDLINE (Ovid, 1946 to 4 July 2017) and Embase (Ovid, 1947 to 3 July 2017) on 4 July 2017. We also searched ClinicalTrials.gov and the WHO ICTRP portal, and handsearched reference lists. We applied no language restrictions.

Selection criteria: We included all randomised controlled trials comparing over 30 days use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in people with coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease. We excluded studies including only people with coronary drug-eluting stent (DES) or non-DES, or both.

Data collection and analysis: We collected data on mortality from cardiovascular causes, all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, major and minor bleeding. The overall treatment effect was estimated by the pooled risk ratio (RR) with 95% confidence interval (CI), using a fixed-effect model (Mantel-Haenszel); we used a random-effects model in cases of moderate or severe heterogeneity (I2 ≥ 30%). We assessed the quality of the evidence using the GRADE approach. We used GRADE profiler (GRADE Pro) to import data from Review Manager to create a 'Summary of findings' table.

Main results: The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry.Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence).There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence).However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence).Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively.

Authors' conclusions: The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence).

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Conflict of interest statement

AS: none

MB: none

AT: none

SM: reports grants and fees paid to her institution from GSK, BMS/Pfizer, Aspen, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Sanofi and Sanquin Blood Supply.

MPD: No relevant conflict of interest to declare for the work under consideration. I only declare that, for some congresses, the travel, accomodation and meeting expenses have been paid by different pharmaceutical companies.

Figures

1

1

Study flow diagram (PRISMA).

2

2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

3

3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

4

4

Funnel plot of comparison: 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, outcome: 1.2 All‐cause mortality. CABG: coronary artery bypass graft.

5

5

Funnel plot of comparison: 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, outcome: 1.5 Major bleeding. CABG: coronary artery bypass graft; PAD: peripheral arterial disease.

6

6

Funnel plot of comparison: 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, outcome: 1.6 Minor bleeding. CABG: coronary artery bypass graft; PAD: peripheral arterial disease.

1.1

1.1. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 1 Cardiovascular mortality.

1.2

1.2. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 2 All‐cause mortality.

1.3

1.3. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 3 Fatal and non‐fatal myocardial infarction.

1.4

1.4. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 4 Fatal and non‐fatal ischaemic stroke.

1.5

1.5. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 5 Major bleeding.

1.6

1.6. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 6 Minor bleeding.

1.7

1.7. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 7 Repeated revascularization for CABG.

1.8

1.8. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 8 Saphenous vein graft patency for CABG.

1.9

1.9. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 9 Amputation for people with PAD.

1.10

1.10. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 10 Sensitivity analysis ‐ random‐effects model: cardiovascular mortality.

1.11

1.11. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 11 Sensitivity analysis ‐ random‐effects model: fatal and non‐fatal myocardial infarction.

1.12

1.12. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 12 Sensitivity analysis ‐ random‐effects model: fatal and non‐fatal ischaemic stroke.

1.13

1.13. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 13 Sensitivity analysis ‐ random‐effects model: major bleeding.

1.14

1.14. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 14 Sensitivity analysis ‐ random‐effects model: minor bleeding.

1.15

1.15. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 15 Sensitivity analysis ‐ random‐effects model: repeated revascularization for people with CABG.

1.16

1.16. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 16 Sensitivity analysis ‐ random‐effects model: SVG patency for people with CABG.

1.17

1.17. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 17 Sensitivity analysis ‐ random‐effects model: amputation for people with PAD.

1.18

1.18. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 18 Sensitivity analysis ‐ low risk of bias (RoB): cardiovascular mortality.

1.19

1.19. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 19 Sensitivity analysis ‐ low RoB: all‐cause mortality.

1.20

1.20. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 20 Sensitivity analysis ‐ low RoB: fatal and non‐fatal myocardial infarction.

1.21

1.21. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 21 Sensitivity analysis ‐ low RoB: major bleeding.

1.22

1.22. Analysis

Comparison 1 Clopidogrel (Clo) plus aspirin (ASA) versus aspirin alone, Outcome 22 Sensitivity analysis ‐ low RoB: minor bleeding.

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References

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EXCELLENT 2012 {published data only}
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Geraghty 2010 {published data only}
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Jagroop 2004 {published data only}
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MATCH 2004 {published data only}
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ONSET/OFFSET 2010 {published data only}
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Pekdemir 2003 {published data only}
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PRODIGY 2012 {published data only}
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REAL‐LATE/ZEST‐LATE 2010 {published data only}
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RESET 2012 {published data only}
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Steinhubl 2006 {published data only}
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Suh 2011 {published data only}
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Thopte 2014 {published data only}
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Undas 2009 {published data only}
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Ussia 2011 {published data only}
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Wang 2015 {published data only}
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Willoughby 2014 {published data only}
    1. Willoughby SR, Luu L, Cameron JD, Nelson AJ, Schultz CD, Worthley SG, et al. Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease. Heart, Lung and Circulation 2014;23:534‐41. - PubMed
Wilson 2009 {published data only}
    1. Wilson AM, Brittenden J, Bachoo P, Ford I, Nixon GF. Randomized controlled trial of aspirin and clopidogrel versus aspirin and placebo on markers of smooth muscle proliferation before and after peripheral angioplasty. Journal of Vascular Surgery 2009;50(4):861‐9. - PubMed
Xydakis 2004 {published data only}
    1. Xydakis D, Papadogiannakis A, Sfakianaki M, Vakouti E, Papachristoforou K. The combination of clopidogrel and acetylsalicylic acid inhibits more effective the platelet activation in haemodialysis patients with acute coronary syndromes and high C reactive protein. 41st Congress of the European Renal Association. European Dialysis and Transplantation Association; 2004 May 15‐18; Lisbon, Portugal. 2004.
Yi 2014 {published data only}
    1. Yi X, Lin J, Wang C, Zhang B, Chi W. A comparative study of dual versus mono‐antiplatelet therapy in patients with acute large‐artery atherosclerosis stroke. Journal of Stroke and Cerebrovascular Diseases 2014;23:1975‐81. - PubMed
Zhao 2003 {published data only}
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References to ongoing studies

POINT {published data only}
    1. NCT00991029. Platelet‐oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design. clinicaltrials.gov/ct2/show/NCT00991029 Date first received: 7 October 2009.

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References to other published versions of this review

Squizzato 2011
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