Antithrombotic management options for acute ischemic large-vessel stroke: A meta-analysis of randomized clinical trials Background Stroke affects one in every 20 individuals in developed countries and its incidence has been steadily increasing worldwide over the past four decades 1. Most treatment options are time-dependent, with decreasing efficacy when started at later times from stroke onset 2, 3. One particular ischemic stroke subtype, large vessel atherosclerosis (LVA), has two unique characteristics that are relevant to early management: the highest early recurrence rate among all stroke subtypes 4 ; and potential interventions (surgical or endovascular) to potentially decrease recurrence risk. However, not all patients qualify for these interventions; and when invasive interventions are necessary, there may be a higher risk of complications from the procedures in the acute (<14-30 day) phase after stroke onset. Antithrombotics are frequently used in clinical practice after a LVA ischemic stroke. The main options include different combinations of heparin/heparinoids, single antiplatelet agents or dual antiplatelet agents. However, currently no consensus exists regarding which treatment option offers the best risk/benefit ratio 5. Although previous randomized studies in LVA stroke using transcranial Doppler microemboli detection as surrogate endpoint have suggested a relative efficacy of dual antiplatelet agents over single antiplatelet agents, their small sample size precluded testing efficacy on clinical endpoints 6, 7. Meanwhile, larger randomized trials with clinical endpoints have shown conflicting results, but were underpowered to examine different therapies in the particular subgroup of LVA 3, 8-10. We therefore aim to investigate, based on a meta-analysis of randomized clinical trials, whether heparin/heparinoids, single antiplatelet agents or dual antiplatelet agents are more effective in preventing early recurrence of LVA ischemic stroke. Meta-analysis format This meta-analysis will be prepared in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion Criteria 1. Study Design: Randomized controlled trial. 2. Population: Adult patients (> 18 years old) with ischemic stroke or TIA of presumed large vessel atherosclerotic origin, within 14 days of symptom onset. Patients with cardioembolic or small vessel atherosclerotic (lacunar) stroke will be excluded. 3. Interventions: Heparin/heparinoids versus single antiplatelet agents versus dual antiplatelet agents. 4. Outcomes: 1
Primary: o Combined outcome of any stroke (ischemic or hemorrhagic), death or severe bleeding at 30 or 90 days Secondary: o Recurrent stroke at 30 or 90 days o Intracranial hemorrhage at 30 or 90 days o Myocardial infarction at 30 or 90 days o Death from cardiovascular causes at 30 or 90 days o Death from any cause at 30 or 90 days o TIA at 30 or 90 days o Severe systemic bleeding at 30 or 90 days o Modified Rankin score at 30 or 90 days Key points for searching eligible articles Ischemic stroke within 14 days of symptom onset Trial reports large vessel atherosclerosis subtyping o TOAST criteria (interest in the first subtype below) or o Subgroup analysis in patients with carotid stenosis (>50%) or o Subgroup analysis in patients with intracranial stenosis (>50%) At least two comparison groups from treatments below o Heparin/heparinoids o Single antiplatelet agents o Dual antiplatelet agents Reporting of early outcomes (30 or 90 days) Search Strategy We will include all English and non-english articles, using the Cochrane Controlled Trials Register (CCTR), PubMed / MEDLINE and Embase, from the inception of all databases to March 12, 2014, as our primary search engines. Appropriate Medical 2
Subject Heading (MeSH) terms and title/abstract keywords will be used in our Medline search. Additionally, the same search terms will be used in BIOSIS and ClinicalTrials.org as sources of unpublished trials relevant to our search. We will evaluate existing reviews and supplement the collection of articles retrieved from references of the most relevant studies. We will also attempt to locate studies via personal communication with experts in the field. An experienced librarian assisted in the development of the following search strategies using sensitive terms for identifying relevant studies. Our Medline search strategy using MeSH terms and title/abstract (tiab] keywords: ( Stroke [Mesh] OR Intracranial embolism and Thrombosis [Mesh:NoExp] OR Intracranial Embolism [Mesh] OR Intracranial Thrombosis [Mesh:NoExp] OR Cerebral infarction [Mesh] OR Carotid Artery Thrombosis [Mesh] OR Brain ischemia [Mesh] OR Stroke*[ti] OR Cerebrovascular accident*[ti] OR Transient ischemic attack*[ti] OR CVA*[ti] OR TIA*[ti] OR Brain infarct*[ti] OR Brain isch*[ti] OR Cerebral infarct*[ti] OR Cerebral isch*[ti] OR Cerebral embol*[ti] OR Intracranial embol*[ti] OR Intracranial thromb*[ti] OR Brainstem infarct*[ti] OR Carotid artery thromb*[ti] OR Carotid thromb*[ti]) AND ( Platelet Aggregation Inhibitors [Mesh] OR Platelet Aggregation Inhibitors [Pharmacological Action] OR Anticoagulants [Pharmacological Action] OR Anticoagulants [Mesh] OR Aspirin[tiab] OR Clopidogrel[tiab] OR Ticlopidine[tiab] OR Cilostazol[tiab] OR Dipyridamole[tiab] OR Anti-platelet*[tiab] OR Antiplatelet*[tiab] OR Platelet aggregation inhibitor*[tiab] OR Heparin[tiab] OR warfarin[tiab] OR Dalteparin[tiab] OR Enoxaparin[tiab] OR Nadroparin[tiab]) AND Random*[tiab] NOT ( Animals [Mesh] NOT Humans [Mesh]) Our Embase search strategy: ('cerebrovascular accident'/de OR 'cardioembolic stroke'/de OR 'lacunar stroke'/de OR 'brain embolism'/de OR 'occlusive cerebrovascular disease'/exp OR 'carotid artery disease'/de OR 'carotid atherosclerosis'/de OR 'carotid artery obstruction'/exp OR 'brain ischemia'/de OR 'transient ischemic attack'/de OR 'brain infarction'/de OR 'brain stem infarction'/de OR 'cerebellum infarction'/de OR 'cerebral artery disease'/de) AND ('anticoagulant agent'/exp OR 'antithrombocytic agent'/exp) AND 'randomized controlled trial'/de Selection of studies Three authors will review the literature from the search strategy based on the prespecified eligibility criteria. Discrepancies regarding the decision of whether to exclude the titles, abstracts, or papers will be resolved by consensus. All reasons for exclusion will be systematically documented in a uniform log at the title, abstract, and paper level, with the potential to include excluded studies in subsequent sensitivity analyses. 3
Data Extraction We designed a standardized data extraction instrument. Two investigators (LB, MB) extracted the data and a third one adjudicated discrepancies (YS). The following data was extracted: General information: Extractor s initials, date of data collection Study ID First author Title Citation Country of origin Source of funding Participant characteristics: Demographic information (age, sex) Number of subjects in each treatment arm Comorbidities: diabetes, hypertension, body mass index, history of previous strokes, transient ischemic events, cardiovascular disease, cholesterol levels, smoking. Study Characteristics: Objectives Study design Recruitment procedures Inclusion/exclusion criteria o Randomization o Allocation concealment o Blinding o Attrition Unit of allocation Treatment characteristics: Time from symptom onset to treatment initiation Name of medication, duration and dose Previous treatment with alteplase (tpa) Outcome measures: Definitions of outcomes (primary and secondary) in the study at 30 and 90 days: o Any stroke - ischemic or hemorrhagic o Transient ischemic attack o Myocardial infarction o Death o Severe bleeding For each intervention: o Number of participants in each treatment group, number analyzed and number withdrawn. Statistical analyses and effect measures (OR, RR, RD, CI, p-value) Data Analysis Effect measure for summary statistic We will give preference to risk ratios as the a priori effect measure of choice. When not readily available in the published data, corresponding authors for each trial will be contacted to access the primary data. STATA version 13.0 will be used for all analyses. Weighting method for pooled estimate 4
We expect some heterogeneity between studies arising from different drug regimens and doses and therefore chose a random-effects model for the pooled analysis. Forest plots of the relative risks of each pre-specified outcome for each treatment category will be constructed. We will adopt the Knapp-Hartnung random-effects estimator based on small-sample adjustments, which has been shown to provide an unbiased and more conservative estimate when compared to the DerSimonian Laird method 11. Assessment of heterogeneity Initial assessment of heterogeneity will involve visual inspection of the forest plots, based on an overlap between the confidence intervals for each study and the pooled effect estimate. Additionally, we will formally test for heterogeneity using Cochran Q-statistic and the I 2 statistic. The Q-statistic determines whether an individual study effect deviated from the pooled effect beyond what is expected by chance alone, while the I 2 statistic expresses the proportion of total variance due to between-study variability. We will consider significant heterogeneity if the p-value < 0.05 for the Q- statistic or if the I 2 statistic > 40% 12. An alpha level < 0.05 will be considered statistically significant. Exploring heterogeneity The sources of heterogeneity, if present, will be explored using stratified metaanalysis and meta-regression. We planned the following subgroup analyses a priori, which are expected to explain some of the study heterogeneity: 1. Treatment choices o Clopidogrel/aspirin vs aspirin/dypiridamol vs cilostazol/aspirin vs aspirin o Heparin vs any antiplatelet 2. Time between symptom onset and treatment vs outcome 3. Dose of antiplatelet agents vs outcome 4. Combined vs single outcome L Abbé plots will be used to identify further stratification variables or covariates for meta-regression. Identification of such variables may provide further insights into the causes of heterogeneity and guide future studies in the field. The following studyspecific characteristics will also be tested in meta-regression, which may be responsible for heterogeneity: 1. Year of publication 2. Location 3. Study design 4. Length of follow-up Publication bias assessment 5
We will visually inspect funnel plots to evaluate potential publication bias. Additionally, Egger s linear regression approach will be used to formally test for publication bias. We will apply sensitivity analyses where appropriate for studies with very discordant results from the pooled estimate. If a significant publication bias is detected on Egger s test, we will also perform sensitivity analyses using the failsafe number of studies approach, where we will simulate how many small studies with an inverse result would be required to change the overall meta-analysis result. Acknowledgements The authors gratefully acknowledge Ms. Carol Mita at the Countway Medical Library of Harvard Medical School for her assistance with electronic database searches and document retrieval. References: 1. Feigin VL, Lawes CM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet neurology 2009;8:355-369. 2. Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet neurology 2007;6:961-969. 3. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:331-337. 4. Ay H, Gungor L, Arsava EM, et al. A score to predict early risk of recurrence after ischemic stroke. Neurology 2010;74:128-135. 5. Stoner MC, Defreitas DJ. Process of care for carotid endarterectomy: perioperative medical management. Journal of vascular surgery 2010;52:223-231. 6. Hankey GJ, Hacke W, Easton JD, et al. Effect of clopidogrel on the rate and functional severity of stroke among high vascular risk patients: a prespecified substudy of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial. Stroke; a journal of cerebral circulation 2010;41:1679-1683. 7. Markus HS, Droste DW, Kaps M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation 2005;111:2233-2240. 8. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. The New England journal of medicine 2008;359:1238-1251. 6
9. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. The New England journal of medicine 2006;354:1706-1717. 10. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. The New England journal of medicine 2013;369:11-19. 11. Knapp G, Hartung J. Improved tests for a random effects meta-regression with a single covariate. Statistics in medicine 2003;22:2693-2710. 12. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org. 2011. 7