Open Access Research BMJ Open: first published as 10.1136/bmjopen-2015-009013 on 17 March 2016. Downloaded from Antiplatelet regimens in the long-term secondary prevention of transient ischaemic attack and ischaemic stroke: an updated network meta-analysis Peng-Peng Niu, Zhen-Ni Guo, Hang Jin, Ying-Qi Xing, Yi Yang To cite: Niu P-P, Guo Z-N, ABSTRACT et al Strengths and limitations of this study Jin H, . Antiplatelet Objective: To examine the comparative efficacy and regimens in the long-term safety of different antiplatelet regimens in patients with ▪ secondary prevention of Since the dose of aspirin ranged from 30 to prior non-cardioembolic ischaemic stroke or transient transient ischaemic attack 1500 mg daily, treatment with aspirin was and ischaemic stroke: an ischaemic attack. divided into four different regimens and treat- updated network meta- Design: Systematic review and network meta-analysis. ment with aspirin plus dipyridamole was divided analysis. BMJ Open 2016;6: Data sources: As on 31 March 2015, all randomised into two different regimens. e009013. doi:10.1136/ controlled trials that investigated the effects of ▪ Duration of follow-up was included in the model bmjopen-2015-009013 antiplatelet agents in the long-term (≥3 months) to perform the network meta-analysis. secondary prevention of non-cardioembolic transient ▪ Estimates from sensitivity analyses were compat- ▸ Prepublication history and ischaemic attack or ischaemic stroke were searched ible with the main analysis, except that cilostazol additional material is and identified. was not significantly more effective than clopido- available. To view please visit Outcome measures: The primary outcome measure grel and triflusal in preventing serious vascular the journal (http://dx.doi.org/ of efficacy was serious vascular events (non-fatal events when setting the prior on the variance 10.1136/bmjopen-2015- stroke, non-fatal myocardial infarction and vascular equal to a uniform (0, 1000). 009013). death). The outcome measure of safety was any ▪ Owing to the lack of data and consistent defini- bleeding. tions, we did not differentiate between different Results: A total of 36 randomised controlled trials degrees of bleeding. Received 8 June 2015 ▪ Revised 12 February 2016 (82 144 patients) were included. Network meta- Only four small trials including 2461 Asian Accepted 17 February 2016 analysis showed that cilostazol was significantly more patients were included for the treatment of cilos- http://bmjopen.bmj.com/ effective than clopidogrel (OR 0.77, 95% credible tazol, which decreases the confidence in the interval 0.60–0.98) and low-dose (75–162 mg daily) observed effect for cilostazol and means the aspirin (0.69, 0.55–0.86) in the prevention of serious effect of cilostazol may not be generalised to vascular events. Aspirin (50 mg daily) plus non-Asian populations. dipyridamole (400 mg daily) and clopidogrel reduced the risk of serious vascular events compared with low- dose aspirin; however, the difference was not INTRODUCTION statistically significant. Furthermore, low-dose aspirin Cerebrovascular disease is one of the leading was as effective as higher daily doses. Cilostazol was contributors to disease burden and results in on September 25, 2021 by guest. Protected copyright. associated with a significantly lower bleeding risk than nearly 10% of all deaths worldwide.1 most of the other regimens. Moreover, aspirin plus Ischaemic stroke is the most common form clopidogrel was associated with significantly more haemorrhagic events than other regimens. Direct of cerebrovascular disease. Patients who comparisons showed similar results as the network survive an ischaemic stroke or transient meta-analysis. ischaemic attack (TIA) are at increased risk Conclusions: Cilostazol was significantly more of experiencing another ischaemic stroke. effective than aspirin and clopidogrel alone in the long- On average, the annual risk for future ischae- term prevention of serious vascular events in patients mic stroke after an initial TIA or ischaemic with prior non-cardioembolic ischaemic stroke or stroke is approximately 3–4%.2 Moreover, a transient ischaemic attack. Cilostazol was associated Department of Neurology, recurrent stroke event is usually more devas- with a significantly lower bleeding risk than low-dose fi 3 Neuroscience Center, The tating than the rst stroke. Therefore, it is – First Hospital of Jilin aspirin (75 162 mg daily) and aspirin (50 mg daily) important to prevent the occurrence of University, Changchun, plus dipyridamole (400 mg daily). Low-dose aspirin future stroke among survivors of ischaemic was as effective as higher daily doses. However, Jilin, China stroke or TIA. further large, randomised, controlled, head-to-head Correspondence to trials are needed, especially in non-Asian ethnic Antiplatelet therapy is one of the major Professor Yi Yang; groups. strategies used for preventing recurrent [email protected] stroke in patients who have previously Niu P-P, et al. BMJ Open 2016;6:e009013. doi:10.1136/bmjopen-2015-009013 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2015-009013 on 17 March 2016. Downloaded from experienced ischaemic stroke or TIA of non- duplicate publications, we included papers with the cardioembolic aetiology. Aspirin is currently the most largest sample size or the most complete information. widely tested antiplatelet agent and, hence, it has the Any disagreements were resolved through a discussion most extensive evidence concerning its benefits in between the reviewers. patients with prior ischaemic stroke and TIA.4 In add- Studies were included if they met the following inclu- ition to aspirin, there are three other antiplatelet regi- sion criteria: randomised, placebo-controlled or mens that have been approved by the US Food and head-to-head trials; trials that investigated the efficacy of Drug Administration for the secondary prevention of antiplatelet agents for the secondary prevention of non- ischaemic stroke (ie, clopidogrel, ticlopidine, and a com- cardioembolic TIA or ischaemic stroke; trials that bination of aspirin and dipyridamole). Newer antiplate- assessed the following antiplatelet agents: aspirin, clopi- let agents, including triflusal and cilostazol, are also dogrel, ticlopidine, dipyridamole, cilostazol or triflusal; potentially effective in the secondary prevention of TIA trials with a long-term follow-up (≥3 months); and trials or ischaemic stroke.56However, no direct comparisons with at least 100 patients per trial arm.9 We excluded have been made among some of the antiplatelet studies that investigated the effects of other antiplatelet regimens. agents. However, for multiarm trials (≥3 arms) that Network meta-analysis can assess the relative effective- involved the above antiplatelet agents and other antipla- ness of two treatments in cases where they have not telet agents, if we can extract two or more comparison been compared directly in a trial, but have instead each arms that meet the criteria (including placebo), the been compared with other interventions.7 We, therefore, trials will be included and the data of other antiplatelet performed a systematic review by using such an analytic agents will be ignored. approach to provide an up-to-date summary of the ran- domised controlled trials (RCTs) that have evaluated Data extraction and quality assessment common antiplatelet agents for the secondary preven- Data from the included articles were extracted by two tion of non-cardioembolic TIA or ischaemic stroke, and independent reviewers (ZNG and HJ). The following to provide an informative comparison of the relative effi- information was extracted from each study: acronym of cacies and bleeding risk of different antiplatelet the study or last name of the first author; publication regimens. year; country or geographical origin of the investigation; baseline characteristics of the patients; variables related to the interventions, including drug, dose and follow-up METHODS duration; number of patients in each group; and We followed the guidelines for conducting and report- 8 outcome data in each group. Discrepancies were ing systematic reviews and meta-analyses. No protocol resolved through a discussion between the two reviewers. for this study was registered or published. Data from the intention-to-treat analysis were used. http://bmjopen.bmj.com/ Aspirin was the main comparison arm for many of the Data sources and searches studies, and its dose ranged from 30 to 1500 mg daily; We systematically searched the EMBASE and PubMed treatment with aspirin was divided into the following databases for articles published up to 31 March 2015, four regimens, which were similar to those described by without language or publication-type restrictions. The the Antithrombotic Trialists’ Collaboration:4 aspirin 30– search was limited to studies involving human subjects. 50 mg daily (very low dose), aspirin 75–162 mg daily The search strategy (see online supplementary appendix (low dose), aspirin 283–330 mg daily (median dose) and 1) combined the terms ‘aspirin’, ‘clopidogrel’, ‘ticlopi- aspirin 500–1500 mg daily (high dose). Treatment with on September 25, 2021 by guest. Protected copyright. dine’, ‘dipyridamole’, ‘cilostazol’,or‘triflusal’ and aspirin plus dipyridamole was classified into two differ- ‘ischemic stroke’ or ‘transient ischemic attack’. Two of ent regimens: aspirin (50 mg) plus dipyridamole the authors (ZNG and HJ) independently performed (400 mg) daily and aspirin (990–1300 mg) plus dipyrid- the