Efficacy versus safety: the dilemma of using novel platelet inhibitors for the treatment of patients with ischemic stroke and coronary artery disease

Figures & data

Figure 1 Cumulative incidence of survival free of stroke of any type in the clopidogrel plus aspirin (red lines) and aspirin (blue lines) groups.

Notes: Event rates are presented as Kaplan–Meier rate at 90 days and total number of events during the trial. From N Engl J Med, Wang Y, Wang Y, Zhao X, et al, Clopidogrel with aspirin in acute minor stroke or transient ischemic attack, 369(1), 11–19. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.³⁰

Table 1 Summary of all clopidogrel trials

Trial name	Patients	Randomized treatments	Primary endpoint	Main results	Key findings re stroke
CAPRIE^Citation21	N=19,185 patients with prior stroke, peripheral artery disease, or MI	75 mg clopidogrel versus325 mg aspirin	Ischemic stroke, MI, vascular death	RRR 8.7% (95% CI0.3–16.5); P=0.043	Primary EP in patients with previous stroke: RRR 7.3% (95% CI 5.7–18.7); P=0.26
PRoFESS^Citation22	N=20,333 patients with history of ischemic stroke or TIA (within 3 months)	25 mg aspirin + 200 mg dipyridamole versus 75 mg clopidogrel	Recurrent stroke of any type	HR 1.01 (95% CI0.92–1.11); P>0.05	Effect on ischemic stroke: HR 0.97 (95% CI 0.88–1.07); P=0.97 Effect on ICH: HR 1.42 (95% CI 1.11–1.83); P=0.006
MATCH^Citation23	N=7,599 patients with history of ischemic stroke or TIA (within 3 m)	75 mg clopidogrel + 75 mg aspirin versus 75 mg clopidogrel + matching placebo	Ischemic stroke, MI, vascular death, or rehospitalization for acute ischemic event	RRR 6.4% (95% CI−4.6–16.3); P=0.244	Effect on ischemic stroke: RRR 7.1% (95% CI –8.5–20.4); P=0.353 Effect on life-threatening bleeding: absolute difference 1.26 (95% CI 0.64–1.88); P<0.0001
CHARISMA^Citation24	N=15,603 patients with cardiovascular disease or multiple risk factors for coronary artery disease	75 mg clopidogrel + 75–162 mg daily aspirin versus 75–162 mg daily aspirin	Vascular death, MI, or stroke	RRR 0.93 (95% CI0.83–1.05); P=0.22	Effect on ischemic stroke: RRR 0.81 (95% CI 0.64–1.02); P=0.07 Effect on ICH: RRR 0.96 (95% CI 0.56–1.65); P=0.89
SPS3^Citation27	N=3,020 patients with symptomatic small subcortical brain infarcts	325 mg daily aspirin versus 75 mg clopidogrel + 325 mg daily aspirin	Recurrent stroke of any type (ischemic and hemorrhagic)	HR 0.92 (95% CI 0.72–1.16); P=0.48	Effect on ischemic stroke: HR 0.82 (95% CI 0.63–1.09); P=0.13 Effect on ICH: HR 1.65 (95% CI 0.83–3.31); P=0.15 Effect on major hemorrhages: HR 1.97 (95% CI 1.41–2.71); P<0.001 Effect on mortality: HR 1.52 (95% CI 1.14–2.04); P=0.004
CHANCE^Citation30	N=5,170 patients with history of high risk TIA or minor stroke in the previous 24 hours	300 mg loading dose and 75 mg/day clopidogrel for 90 days and 75 mg/day aspirin for 21 days versus placebo and 300 mg loading dose + 75 mg/day aspirin for 90 days	Stroke of any type	HR 0.68 (95% CI0.57–0.81); P<0.001	Effect on ischemic stroke: HR 0.67 (95% CI 0.56–0.81); P<0.001 Effect on hemorrhagic stroke: HR 1.01 (95% CI 0.38–2.70); P=0.98

Abbreviations: CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events; CHANCE, Clopidogrel in High-Risk Patients with Acute Non-Disabling Cerebrovascular Events; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CI, confidence interval; EP, endpoint; HR, hazard ratio; ICH, intracranial hemorrhage; m, months; MATCH, Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attacks or Ischemic Stroke; MI, myocardial infarction; PRoFESS, Prevention Regimen for Effectively Avoiding Second Strokes; RRR, relative risk reduction; SPS3, Secondary Prevention of Small Subcortical Strokes; TIA, transient ischemic attack.

Figure 2 Cumulative incidence of (A) the primary composite of cardiovascular death, myocardial infarction, and stroke; (B) mortality; and (C) major bleeding in the ticagrelor (solid lines) and clopidogrel (dotted lines) groups in patients with a history of prior stroke or transient ischemic attack (blue lines) and no previous stroke or transient ischemic attack (red lines) at baseline.

Notes: Event rates are presented as the Kaplan–Meier rate at 360 days and total number of events during the trial. Reproduced from James SK, Storey RF, Khurmi NS, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes and a history of stroke or transient ischemic attack. Circulation. 2012;125(23):2914–2921.³⁹

WangYWangYZhaoXClopidogrel with aspirin in acute minor stroke or transient ischemic attackN Engl J Med20133691111923803136

 PubMed Web of Science ®Google Scholar

CAPRIE Steering CommitteeA randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE)Lancet19963489038132913398918275

 PubMed Web of Science ®Google Scholar

DienerHCSaccoRLYusufSEffects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active, and placebo-controlled studyLancet Neurol200871087588418757238

 PubMed Web of Science ®Google Scholar

DienerHCBogousslavskyJBrassLMAspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trialLancet2004364943133133715276392

 PubMed Web of Science ®Google Scholar

BhattDLFoxKAHackeWClopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic eventsN Engl J Med2006354161706171716531616

 PubMed Web of Science ®Google Scholar

BenaventeORWhiteCLPearceLThe Secondary Prevention of Small Subcortical Strokes (SPS3) studyInt J Stroke20116216417521371282

 PubMed Web of Science ®Google Scholar

JamesSKStoreyRFKhurmiNSTicagrelor versus clopidogrel in patients with acute coronary syndromes and a history of stroke or transient ischemic attackCirculation2012125232914292122572911

 PubMed Web of Science ®Google Scholar