P2Y12 Inhibitors Plus Aspirin Versus Aspirin Alone in Patients With Minor Stroke or High-Risk Transient Ischemic Attack
Background and purpose:
We performed a systemic review and meta-analysis to elucidate the effectiveness and safety of dual antiplatelet (DAPT) therapy with P2Y12 inhibitors (clopidogrel/ticagrelor) and aspirin versus aspirin monotherapy in patients with mild ischemic stroke or high-risk transient ischemic attack.
Following Preferred Reported Items for Systematic Review and Meta-Analysis standards for meta-analyses, Medline, Embase, Cochrane Central Register of Controlled Trials, and the Cochrane Library were searched for randomized controlled trials that included patients with a diagnosis of an acute mild ischemic stroke or high-risk transient ischemic attack, intervention of DAPT therapy with clopidogrel/ticagrelor and aspirin versus aspirin alone from January 2012 to July 2020. The outcomes included subsequent stroke, all-cause mortality, cardiovascular death, hemorrhage (mild, moderate, or severe), and myocardial infarction. A DerSimonian-Laird random-effects model was used to estimate pooled risk ratio (RR) and corresponding 95% CI in R package meta. We assessed the heterogeneity of data across studies with use of the Cochran Q statistic and I2 test.
Four eligible trials involving 21 493 participants were included in the meta-analysis. DAPT therapy started within 24 hours of symptom onset reduced the risk of stroke recurrence by 24% (RR, 0.76 [95% CI, 0.68–0.83], I2=0%) but was not associated with a change in all-cause mortality (RR, 1.30 [95% CI, 0.90–1.89], I2=0%), cardiovascular death (RR, 1.34 [95% CI, 0.56–3.17], I2=0%), mild bleeding (RR, 1.25 [95% CI, 0.37–4.29], I2=94%), or myocardial infarction (RR, 1.45 [95% CI, 0.62–3.39], I2=0%). However, DAPT was associated with an increased risk of severe or moderate bleeding (RR, 2.17 [95% CI, 1.16–4.08], I2=41%); further sensitivity tests found that the association was limited to trials with DAPT treatment duration over 21 days (RR, 2.86 [95% CI, 1.75–4.67], I2=0%) or ticagrelor (RR, 2.17 [95% CI, 1.16–4.08], I2=37%) but not within 21 days or clopidogrel.
In patients with noncardioembolic mild stroke or high-risk transient ischemic attack, DAPT with aspirin and clopidogrel/ticagrelor is more effective than aspirin alone for recurrent stroke prevention with a small absolute increase in the risk of severe or moderate bleeding.
von Weitzel-Mudersbach P, Andersen G, Hundborg HH, Johnsen SP. Transient ischemic attack and minor stroke are the most common manifestations of acute cerebrovascular disease: a prospective, population-based study–the Aarhus TIA study.Neuroepidemiology. 2013; 40:50–55. doi: 10.1159/000341696CrossrefMedlineGoogle Scholar
Coull AJ, Lovett JK, Rothwell PM; Oxford Vascular Study. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services.BMJ. 2004; 328:326. doi: 10.1136/bmj.37991.635266.44CrossrefMedlineGoogle Scholar
Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA.JAMA. 2000; 284:2901–2906. doi: 10.1001/jama.284.22.2901CrossrefMedlineGoogle Scholar
Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L,; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack.N Engl J Med. 2013; 369:11–19. doi: 10.1056/NEJMoa1215340CrossrefMedlineGoogle Scholar
Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, Kim AS, Lindblad AS, Palesch YY; Clinical Research Collaboration, Neurological Emergencies Treatment Trials Network, and the POINT Investigators. Clopidogrel and aspirin in acute ischemic stroke and high- risk TIA.N Engl J Med. 2018; 379:215–225. doi: 10.1056/NEJMoa1800410CrossrefMedlineGoogle Scholar
Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B,. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2019; 50:e344–e418. doi: 10.1161/STR.0000000000000211LinkGoogle Scholar
Wang Y, Zhao X, Lin J, Li H, Johnston SC, Lin Y, Pan Y, Liu L, Wang D, Wang C,; CHANCE investigators. Association between CYP2C19 loss-of- function Allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack.JAMA. 2016; 316:70–78. doi: 10.1001/jama.2016.8662CrossrefMedlineGoogle Scholar
Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin.Eur Heart J. 2006; 27:1038–1047. doi: 10.1093/eurheartj/ehi754CrossrefMedlineGoogle Scholar
Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, Wickens M, Emanuelsson H, Gurbel P, Grande P,. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes.J Am Coll Cardiol. 2007; 50:1852–1856. doi: 10.1016/j.jacc.2007.07.058CrossrefMedlineGoogle Scholar
Johnston SC, Amarenco P, Denison H, Evans SR, Himmelmann A, James S, Knutsson M, Ladenvall P, Molina CA, Wang Y; THALES Investigators. Ticagrelor and aspirin or aspirin alone in acute ischemic stroke or TIA.N Engl J Med. 2020; 383:207–217. doi: 10.1056/NEJMoa1916870CrossrefMedlineGoogle Scholar
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng HY, Corbett MS, Eldridge SM,. RoB 2: a revised tool for assessing risk of bias in randomised trials.BMJ. 2019; 366:l4898. doi: 10.1136/bmj.l4898CrossrefMedlineGoogle Scholar
Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM; FASTER Investigators. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial.Lancet Neurol. 2007; 6:961–969. doi: 10.1016/S1474-4422(07)70250-8CrossrefMedlineGoogle Scholar
Johnston SC, Easton JD, Farrant M, Barsan W, Battenhouse H, Conwit R, Dillon C, Elm J, Lindblad A, Morgenstern L,. Platelet-oriented inhibition in new TIA and minor ischemic stroke (POINT) trial: rationale and design.Int J Stroke. 2013; 8:479–483. doi: 10.1111/ijs.12129CrossrefMedlineGoogle Scholar
Pan Y, Elm JJ, Li H, Easton JD, Wang Y, Farrant M, Meng X, Kim AS, Zhao X, Meurer WJ,. Outcomes associated with clopidogrel- aspirin use in minor stroke or transient ischemic attack: a pooled analysis of clopidogrel in high- risk patients with acute non- disabling cerebrovascular events (CHANCE) and platelet- oriented inhibition in new TIA and minor ischemic stroke (POINT) Trials.JAMA Neurol. 2019; 76:1466–1473. doi: 10.1001/jamaneurol.2019.2531MedlineGoogle Scholar
Johnston SC, Elm JJ, Easton JD, Farrant M, Barsan WG, Kim AS, Lindblad AS, Palesch YY, Zurita KG, Albers GW,; POINT and Neurological Emergencies Treatment Trials Network Investigators. Time course for benefit and risk of clopidogrel and aspirin after acute transient ischemic attack and minor ischemic stroke.Circulation. 2019; 140:658–664. doi: 10.1161/CIRCULATIONAHA.119.040713LinkGoogle Scholar
Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment.N Engl J Med. 1988; 318:1728–1733. doi: 10.1056/NEJM198806303182605CrossrefMedlineGoogle Scholar
Barnett HJ, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL,. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators.N Engl J Med. 1998; 339:1415–1425. doi: 10.1056/NEJM199811123392002CrossrefMedlineGoogle Scholar
Spence JD. Antihypertensive drugs and prevention of atherosclerotic stroke.Stroke. 1986; 17:808–810. doi: 10.1161/01.str.17.5.808CrossrefMedlineGoogle Scholar
Chan FK, Ching JY, Hung LC, Wong VW, Leung VK, Kung NN, Hui AJ, Wu JC, Leung WK, Lee VW,. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding.N Engl J Med. 2005; 352:238–244. doi: 10.1056/NEJMoa042087CrossrefMedlineGoogle Scholar
Ding L, Peng B. Efficacy and safety of dual antiplatelet therapy in the elderly for stroke prevention: a systematic review and meta-analysis.Eur J Neurol. 2018; 25:1276–1284. doi: 10.1111/ene.13695Google Scholar
Hao Q, Tampi M, O’Donnell M, Foroutan F, Siemieniuk RA, Guyatt G. Clopidogrel plus aspirin versus aspirin alone for acute minor ischaemic stroke or high risk transient ischaemic attack: systematic review and meta-analysis.BMJ. 2018; 363:k5108. doi: 10.1136/bmj.k5108CrossrefMedlineGoogle Scholar
Huang Y, Li M, Li JY, Li M, Xia YP, Mao L, Hu B. The efficacy and adverse reaction of bleeding of clopidogrel plus aspirin as compared to aspirin alone after stroke or TIA: a systematic review.PLoS One. 2013; 8:e65754. doi: 10.1371/journal.pone.0065754Google Scholar
Liu Y, Fei Z, Wang W, Fang J, Zou M, Cheng G. Efficacy and safety of short-term dual- versus mono-antiplatelet therapy in patients with ischemic stroke or TIA: a meta-analysis of 10 randomized controlled trials.J Neurol. 2016; 263:2247–2259. doi: 10.1007/s00415-016-8260-7Google Scholar
Palacio S, Hart RG, Pearce LA, Anderson DC, Sharma M, Birnbaum LA, Benavente OR. Effect of addition of clopidogrel to aspirin on stroke incidence: meta-analysis of randomized trials.Int J Stroke. 2015; 10:686–691. doi: 10.1111/ijs.12050Google Scholar