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KSR Number: KSRA111175

Optimal duration of aspirin plus clopidogrel after ischemic stroke or transient ischemic attack

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

This well conducted review, of patients who had experienced an ischaemic stroke or transient ischaemic attack, found that aspirin plus clopidogrel reduced recurrent stroke and major adverse cardiovascular events in the initial three months. Long-term aspirin plus clopidogrel treatment did not show benefit and also increased the bleeding risk compared with aspirin monotherapy, but this should be further investigated in further sufficiently large clinical trials.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

No information was provided on the number of reviewers involved in the risk of bias assessment. However, as all other stages of the review were performed in duplicate, it is likely that this stage also involved two reviewers. The remainder of the review was judged at low risk of bias. The relevance of identified studies to the review's research questions were appropriately considered. Results were not emphasised based on their statistical significance.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Probably yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Probably yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Low

Details of Review

Number of studies 10
Number of participants 15,434
Last search date 31 June 2018
Review type Intervention
Objective To establish the optimal period of efficacy and safety of aspirin plus clopidogrel therapy compared to aspirin monotherapy.
Population Adult patients with non-cardioembolic acute ischaemic stroke (IS) or transient ischaemic attack (TIA)
Interventions Aspirin plus clopidogrel.
Comparator Aspirin monotherapy.
Outcome Primary outcomes: recurrent ischaemic stroke and major bleeding.

Secondary outcomes: major adverse cardiovascular events (composite stroke, myocardial infarction, and cardiovascular mortality) and all-cause mortality.
Study design Randomised controlled trials.

Results

Aspirin plus clopidogrel (A+C) therapy reduced the risk of recurrent IS at both short-term; ≤1 month (relative risk [RR], 0.53; 95% CI, 0.37 to 0.78) and intermediate-term; ≤3 months (RR, 0.72; 95% CI, 0.58 to 0.90) duration compared to aspirin monotherapy. However, there was no difference between the groups at long-term; >3 months (RR, 0.81; 95% CI, 0.63 to 1.04).

Aspirin plus clopidogrel therapy increased the risk of bleeding at both intermediate-term (RR, 2.58; 95% CI, 1.19 to 5.60) and long-term (RR: 1.87; 95% CI, 1.36 to 2.56). At short-term duration, A+C therapy was comparable to aspirin monotherapy (RR, 1.82; 95% CI, 0.91 to 3.62).

In terms of major adverse cardiovascular events, A+C therapy was superior to aspirin monotherapy at both short-term (RR, 0.68; 95% CI, 0.60 to 0.78) and intermediate-term (RR, 0.76; 95% CI, 0.61 to 0.94) duration. Long-term A+C therapy did not provide an efficacy benefit (RR, 0.87; 95% CI, 0.71 to 1.07).

All-cause mortality was increased by long-term A+C therapy (RR, 1.45; 95% CI, 1.10 to 1.93) as opposed to short-term (RR, 1.15; 95% CI, 0.53 to 2.48) and intermediate-term (RR, 1.56; 95% CI, 0.77 to 3.18) therapy.

Full Risk of Bias Assessment

The research objective was clearly stated and appropriate inclusion criteria were defined. No restrictions were applied to eligibility criteria based on study characteristics and sources of information.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Probably yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Probably yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably yes
Concerns regarding specification of study eligibility criteria Low

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched. In addition, bibliographies of the relevant articles were reviewed for additional relevant studies. The search strategy appeared to be appropriate. There were no restrictions based on date, publication format, or language. Two reviewers independently judged study eligibility, a third reviewer supervised the process and disagreements were resolved by consensus.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably yes
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably yes
2.4 Were restrictions based on date, publication format, or language appropriate? Probably yes
2.5 Were efforts made to minimise error in selection of studies? Probably yes
Concerns regarding methods used to identify and/or select studies Low

Data extraction was performed by two reviewers independently. Individual study characteristics and study results were appropriately reported. Quality assessment of the included studies was performed using the Cochrane risk of bias assessment tool, no information was provided on the number of reviewers involved in this process.

3.1 Were efforts made to minimise error in data collection? Probably yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Probably yes
3.3 Were all relevant study results collected for use in the synthesis? Probably yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Probably yes
3.5 Were efforts made to minimise error in risk of bias assessment? No information
Concerns regarding methods used to collect data and appraise studies Unclear

The synthesis included all eligible studies. The method of analysis was explained and appeared appropriate. The quality of individual studies was considered in the synthesis.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Probably yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low

Abstract

Background and Purpose- The role of aspirin plus clopidogrel (A+C) therapy compared with aspirin monotherapy in patients presenting with acute ischemic stroke (IS) or transient ischemic attack remains uncertain. We conducted this study to determine the optimal period of efficacy and safety of A+C compared with aspirin monotherapy. Methods- Ten randomized controlled trials (15 434 patients) were selected using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) (inception June 2018) comparing A+C with aspirin monotherapy in patients with transient ischemic attack or IS. The primary efficacy outcome was recurrent IS, and the primary safety outcome was major bleeding. The secondary outcomes were major adverse cardiovascular events (composite of stroke, myocardial infarction, and cardiovascular mortality) and all-cause mortality. We stratified analysis based on the short- (</=1 month), intermediate- (</=3 month), and long-term (>3 month) A+C therapy. Effects were estimated as relative risk (RR) with 95% CI. Results- A+C significantly reduced the risk of recurrent IS at short-term (RR, 0.53; 95% CI, 0.37-0.78) and intermediate-term (RR, 0.72; 95% CI, 0.58-0.90) durations. Similarly, major adverse cardiovascular event was significantly reduced by short-term (RR, 0.68; 95% CI, 0.60-0.78) and intermediate-term (RR, 0.76; 95% CI, 0.61-0.94) A+C therapy. However, long-term A+C did not yield beneficial effect in terms of recurrent IS (RR, 0.81; 95% CI, 0.63-1.04) and major adverse cardiovascular events (RR, 0.87; 95% CI, 0.71-1.07). Intermediate-term (RR, 2.58; 95% CI, 1.19-5.60) and long-term (RR, 1.87; 95% CI, 1.36-2.56) A+C regimens significantly increased the risk of major bleeding as opposed to short-term A+C (RR, 1.82; 95% CI, 0.91-3.62). Excessive all-cause mortality was limited to long-term A+C (RR, 1.45; 95% CI, 1.10-1.93). Conclusions- Short-term A+C is more effective and equally safe in comparison to aspirin alone in patients with acute IS or transient ischemic attack.