Platelet function/reactivity testing and prediction of risk of recurrent vascular events and outcomes after TIA or ischaemic stroke: systematic review and meta-analysis.

S G Lim ,Vincent Thijs,Joan Montaner,Richard Perry,Gary A Ford,Dermot Cox,David J Werring,Jesse Dawson,Lina Zgaga,Bo Norrving,Lars Marquardt,Chika Offiah,Philip A Barber,Israel Fernández‐Cadenas ,Stephen J Murphy ,Su Yin Lim ,Călin I Prodan ,Philip M Bath ,Peter Kelly ,Dominick Mccabe

doi:10.1007/s00415-020-09932-y

Abstract

The prevalence of ex vivo 'high on-treatment platelet reactivity (HTPR)' and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear. A systematic review and meta-analysis was performed in accordance with the PRISMA statement. MEDLINE, EMBASE and Cochrane Library were searched for completed manuscripts until May 2019 on TIA/ischaemic stroke patients, ≥ 18years, treated with commonly-prescribed antiplatelet therapy, who had platelet function/reactivity testing and prospective follow-up data on recurrent stroke/TIA, myocardial infarction, vascular death or other cerebrovascular outcomes. Data were pooled using random-effects meta-analysis. Primary outcome was the composite risk of recurrent stroke/TIA, myocardial infarction or vascular death. Secondary outcomes were recurrent stroke/TIA, severe stroke (NIHSS > 16) or disability/impairment(modified Rankin scale ≥ 3) during follow-up. Antiplatelet-HTPR prevalence was 3-65% with aspirin, 8-56% with clopidogrel and 1.8-35% with aspirin-clopidogrel therapy. Twenty studies (4989 patients) were included in our meta-analysis. There was a higher risk of the composite primary outcome (OR 2.93, 95% CI 1.90-4.51) and recurrent ischaemic stroke/TIA (OR 2.43, 95% CI 1.51-3.91) in patients with vs. those without 'antiplatelet-HTPR' on any antiplatelet regimen. These risks were also more than twofold higher in patients with vs. those without 'aspirin-HTPR' and 'dual antiplatelet-HTPR', respectively. Clopidogrel-HTPR status did not significantly predict outcomes, but the number of eligible studies was small. The risk of severe stroke was higher in those with vs. without antiplatelet-HTPR (OR 2.65, 95% CI 1.00-7.01). Antiplatelet-HTPR may predict risks of recurrent vascular events/outcomes in CVD patients. Given the heterogeneity between studies, further prospective, multi-centre studies are warranted.

Highlights

An important proportion of patients with ischaemic cerebrovascular disease (CVD) are not protected from recurrent vascular events with commonly prescribed ‘non-monitored’ antiplatelet therapy
Our meta-analysis indicates that CVD patients with antiplatelet-HTPR on any regimen, based on HTPR definitions employed in individual studies, had at least 2-3 times the risk of experiencing the composite outcome or recurrent ischaemic cerebrovascular events alone during prospective follow-up compared with patients without antiplatelet-HTPR
Not all recurrent vascular events were recorded during prospective follow-up after HTPR testing by Fiolaki et al, which is a major strength or our current, more focused prospective meta-analysis, and the value of assessing HTPR status to predict the risk of the composite outcome of recurrent stroke, TIA, myocardial infarction or vascular death was not pre-planned or analysed in that prior study [23]

Summary

Introduction

An important proportion of patients with ischaemic cerebrovascular disease (CVD) are not protected from recurrent vascular events with commonly prescribed ‘non-monitored’ antiplatelet therapy. Monitoring the effects of antiplatelet therapy with reliable ex vivo platelet function/reactivity tests has the potential to facilitate precision-based medical treatment of CVD patients [4]. One meta-analysis found a higher incidence of stent thrombosis, myocardial infarction (MI) or death in patients with antiplatelet-HTPR compared with those with lower on-treatment platelet reactivity following percutaneous coronary intervention (PCI) on a device called the VerifyNow® which assesses platelet reactivity in whole blood ex vivo at low shear stress [16]. A subsequent meta-analysis of 10 randomized clinical trials (N = 4213 patients) revealed that intensifying antiplatelet therapy based on HTPR testing was associated with reduced cardiovascular mortality and stent thrombosis after PCI (P=0.02), with no difference in the risk of major haemorrhagic complications between ‘intensified’ and ‘standard treatment’ groups (P=0.44) [19]. The prevalence of ex-vivo ‘high on-treatment platelet reactivity (HTPR)’ and its relationship with recurrent vascular events/outcomes in patients with ischaemic cerebrovascular disease (CVD) is unclear

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Conclusion