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Antiplatelet Drugs for Secondary Prevention in Patients with Ischemic

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Antiplatelet Drugs for Secondary Prevention in Patients with Ischemic Del Giovane et al. BMC Neurology (2021) 21:319 https://doi.org/10.1186/s12883-021-02341-2 RESEARCH ARTICLE Open Access Antiplatelet drugs for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis Cinzia Del Giovane1,2, Giorgio B. Boncoraglio3, Lorenza Bertù4, Rita Banzi5 and Irene Tramacere4* Abstract Background: Antiplatelet drugs may prevent recurrent ischemic events after ischemic stroke but their relative effectiveness and harms still need to be clarified. Within this network meta-analysis we aimed to summarize the current evidence for using antiplatelet drugs for secondary stroke prevention. Methods: We searched MEDLINE, EMBASE and CENTRAL up to September 2020. Randomized controlled trials (RCTs) assessing antiplatelet drugs for secondary stroke prevention were included. We did pairwise meta-analyses and network meta-analyses using random-effects models. Primary outcomes were all strokes (ischemic or hemorrhagic) and all-cause mortality. Results: The review included 57 RCTs, 50 (n = 165,533 participants) provided data for the meta-analyses. Compared to placebo/no treatment, moderate to high-confidence evidence indicated that cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day significantly reduced the risk of all strokes (odds ratios, ORs and absolute risk difference, ARD): cilostazol 0.51 (95 % confidence interval, CI, 0.37 to 0.71; 3.6 % fewer), clopidogrel 0.63 (95 % CI, 0.49 to 0.79; 2.7 % fewer), dipyridamole + aspirin 0.65 (95 % CI, 0.55 to 0.78; 2.5 % fewer), ticagrelor 0.68 (95 % CI, 0.50 to 0.93; 2.3 % fewer), ticlopidine 0.74 (95 % CI 0.59 to 0.93; 1.9 % fewer), aspirin ≤ 150 mg/day 0.79 (95 % CI, 0.66 to 0.95; 1.5 % fewer). Aspirin > 150 mg/day and the combinations clopidogrel/aspirin, ticagrelor/aspirin, also decrease all strokes but increase the risk of hemorrhagic events. Only aspirin > 150 mg/day significantly reduced all-cause mortality (OR 0.86, 95 % CI 0.76 to 0.97; ARD 0.9 %, 95 %CI 1.5–0.2 % fewer, moderate confidence). Compared to aspirin ≤ 150 mg/day, clopidogrel significantly reduced the risk of all strokes, cardiovascular events, and intracranial hemorrhage outcomes. Cilostazol also appeared to provide advantages but data are limited to the Asian population. Conclusions: Considering the benefits and harms ratio, cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day appear to be the best choices as antiplatelet drugs for secondary prevention of patients with ischemic stroke or TIA. Systematic review registration: PROSPERO CRD42020159896. Keywords: Systematic review, Network meta-analysis, RCT, Stroke, Secondary prevention, Antiplatelet drugs * Correspondence: [email protected] 4Department of Research and Clinical Development, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Del Giovane et al. BMC Neurology (2021) 21:319 Page 2 of 10 Background two treatments, also those that have never been com- Despite a pronounced decrease in age-standardized mor- pared in a trial, by using direct and indirect evidence [9]. tality rates, stroke burden remains high. People living NMA also allows ranking drugs by benefits and harms with stroke in the European Union is estimated to in- [10], and thus are used in clinical guidelines to support crease by one third between 2017 and 2047. This shift in recommendations [11]. Current NMA on antiplatelet stroke burden from mortality to morbidity depends on drugs for secondary prevention of stroke focused only demographics change over time, implementation of pri- on a limited number of treatments and did not include a mary prevention strategies, and availability of better care thorough assessment of the confidence in the estimates and treatment both in the acute and long-term stages [12–17]. Therefore, we conducted a NMA to summarize after stroke [1]. the current evidence for using antiplatelet drugs for sec- The annual risk for future ischemic stroke after a ondary prevention in adult patients with ischemic stroke stroke or transient ischemic attack (TIA) is 3–5 %, ac- or TIA by estimating their relative efficacy and safety counting for 25–30 % of all strokes. These patients are and providing a clinically useful ranking to help clini- also at higher risk for subsequent myocardial infarction cians in their daily practice as well as informed clinical and death from vascular causes [2–5]. guidelines’ development. The risk of stroke is highest in the early period after the acute event. Prompt initiation of tailored prevention Methods strategies, e.g., referral to acute stroke units, immediate Protocol and registration antithrombotic drugs, early carotid revascularisation, is The systematic review protocol, registered in PROS- essential. In the longer term, optimal medical therapy, PERO (CRD42020159896) [18] was developed following including antiplatelet and statin therapy, and risk factor the Preferred Reporting Items for Systematic Review and modification, are recommended [4, 6]. The initiation or Meta-analysis Protocols (PRISMA-P) statement [19]. We resumption of antihypertensive therapy, accompanied by used the PRISMA-network meta-analysis extension to lifestyle modifications, may be beneficial for patients report the results [20]. with known hypertension [6]. Appropriate antithrombotic medication should be Search strategy and selection criteria carefully chosen considering the ischemic injury physio- We searched MEDLINE, EMBASE, and the Cochrane pathological mechanism: antiplatelet drugs are preferred Central Register of Controlled Trials (CENTRAL) elec- for lesions characterized by atherosclerosis and vascular tronic databases from inception date to September 2020, injury, whereas anticoagulant medications are indicated with no language restrictions. The full search strategies for cardioembolisms and thrombophilic conditions [7]. is available on PROSPERO [18]. We searched Clinical- Antiplatelet drugs are widely recommended for non- Trials.gov for ongoing studies (January 2016-December cardioembolic stroke. Different drugs are currently used 2020). as monotherapies or combination therapies for preven- tion of vascular events among patients with stroke or Eligibility criteria TIA, given their effect in reducing the risk of stroke, We included randomized controlled trials (RCTs) com- myocardial infarction and death [6, 8]. Historically, the paring any antiplatelet drug at any dose, as monotherapy role of aspirin in preventing any type of stroke among or combination therapy, with either a control (placebo/ patients with a recent stroke or TIA has been demon- no treatment) or another antiplatelet drug at any dose, strated, with a similar magnitude of benefit for doses as monotherapy or combination therapy, for secondary ranging from 75 to 1500 mg but a marked difference in prevention in adults (≥ 18 years old, both sexes) with is- toxicity. Platelet Adenine di-Phosphate receptor antag- chemic stroke or TIA in which hemorrhage had been onist, as ticlopidine and clopidogrel, and dual-therapies, ruled out. We included all settings of care (e.g., acute or as the combination of aspirin and dipyridamole were nursing homes, hospitals or ambulatory, etc.), as well as shown to be effective for secondary stroke prevention both acute and delayed treatments. We excluded RCTs [4]. Newer agents, such as ticagrelor, may offer pharma- comparing different doses of the same drug if no other cokinetics advantages over similar drugs. However, the eligible comparator was included, and those not provid- relative effectiveness of these approaches is unclear, and ing outcome data on a specific antiplatelet drug. We in- the different safety profile, costs, patient characteristics, cluded reports published in English or Italian. Two and preferences may affect the selection among agents authors independently performed study selection and for long-term secondary prevention. data extraction; any discrepancy was resolved by consen- Network meta-analysis (NMA) includes multiple inter- sus and arbitration by a third author. We excluded from ventions within a single analysis and allows researchers the statistical analyses studies with a total sample size < to estimate the relative treatment effect between each 100 participants because they are likely to produce Del Giovane
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