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Platelet function-guided modification in antiplatelet therapy after acute ischemic stroke is associated with clinical outcomes in patients with aspirin nonresponse.

ABSTRACT: To investigate the association of clinical outcomes with platelet function-guided modification in antiplatelet therapy in patients with ischemic stroke.Among 812 patients, 223 patients had aspirin nonresponse, 204 patients was modified in antiplatelet therapy after platelet function testing. Mean follow-up period was 4.8 ± 1.7 years (ranged from 1 to 6.4 years). The incidence rates of ischemic events, death, or bleeding events were not significantly different between the patients with and without antiplatelet therapy modification. However, in patients with aspirin nonresponse, antiplatelet therapy modification was associated with decreased ischemic events (hazard ratio, 0.67; 95% confidence interval [CI], 0.62-0.97; P = 0.01) and ischemic stroke (hazard ratio, 0.70; 95% CI, 0.63-0.98; P = 0.03) compared with no modification in antiplatelet therapy.In patients with aspirin nonresponse, platelet function-guided modification in antiplatelet therapy after an ischemic stroke was associated with significantly lower rate of ischemic events. The platelet function testing may be useful to guide antiplatelet therapy modification.This is a retrospective, multicentre study. From August 2010 to December 2014, 812 patients with ischemic stroke underwent platelet function testing using platelet aggregation. Antiplatelet therapy modification was defined as any change in antiplatelet therapy after testing, including increasing aspirin dosage, adding an additional antiplatelet agent to aspirin, or switching to a more potent antiplatelet agent. The primary outcome was ischemic events. Secondary outcomes included death and bleeding events. Clinical outcomes were compared between patients with and without antiplatelet therapy modification using univariate and propensity score-adjusted analyses.

SUBMITTER: Yi X

PROVIDER: S-EPMC5739731 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Platelet function-guided modification in antiplatelet therapy after acute ischemic stroke is associated with clinical outcomes in patients with aspirin nonresponse.

Yi Xingyang X Lin Jing J Wang Chun C Huang Ruyue R Han Zhao Z Li Jie J

Oncotarget 20171107 63

<h4>Purpose</h4>To investigate the association of clinical outcomes with platelet function-guided modification in antiplatelet therapy in patients with ischemic stroke.<h4>Results</h4>Among 812 patients, 223 patients had aspirin nonresponse, 204 patients was modified in antiplatelet therapy after platelet function testing. Mean follow-up period was 4.8 ± 1.7 years (ranged from 1 to 6.4 years). The incidence rates of ischemic events, death, or bleeding events were not significantly different betw ...[more]

PMID: 29290946

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Project description:Background and purposeIn patients with acute mild-moderate ischemic stroke or high-risk transient ischemic attack, the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and Aspirin for Prevention of Stroke and Death) demonstrated that when added to aspirin, ticagrelor reduced stroke or death but increased risk of severe hemorrhage compared with placebo. The primary efficacy outcome of THALES included hemorrhagic stroke and death, events also counted in the primary safety outcome. We sought to disentangle risk and benefit, assess their relative impact, and attempt to identify subgroups with disproportionate risk or benefit.MethodsIn a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk transient ischemic attack, patients were randomized within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin or matching placebo plus aspirin. For the present analyses, we defined the efficacy outcome, major ischemic events, as the composite of ischemic stroke or nonhemorrhagic death, and defined the safety outcome, major hemorrhage, as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these 2 end points.ResultsIn 11 016 patients (5523 ticagrelor-aspirin and 5493 aspirin), a major ischemic event occurred in 294 patients (5.3%) in the ticagrelor-aspirin group and in 359 patients (6.5%) in the aspirin group (absolute risk reduction 1.19% [95% CI, 0.31%–2.07%]). Major hemorrhage occurred in 22 patients (0.4%) in the ticagrelor-aspirin group and 6 patients (0.1%) in the aspirin group (absolute risk increase 0.29% [95% CI, 0.10%–0.48%]). Net clinical impact favored ticagrelor-aspirin (absolute risk reduction 0.97% [95% CI, 0.08%–1.87%]). Findings were similar when different thresholds for disability were applied and over a range of predefined subgroups.ConclusionsIn patients with mild-moderate ischemic stroke or high-risk transient ischemic attack, ischemic benefits of 30-day treatment with ticagrelor-aspirin outweigh risks of hemorrhage.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT03354429.

Project description:Stroke is one of the world's leading causes of disability and death. Antiplatelet agents are administered to acute ischemic stroke patients as secondary prevention. Clopidogrel involves biotransformation by cytochrome P450 (CYP) enzymes into an active metabolite, and single nucleotide polymorphisms (SNPs) can influence the efficacy of this biotransformation. Despite the therapeutic advantages of aspirin, there is significant inter-individual heterogeneity in response to this antiplatelet drug. In this clinical review, the recent advances in the biomarkers of antiplatelet agents in acute ischemic stroke are discussed. The studies reviewed herein highlight the clinical relevance of antiplatelet resistance, pharmacotherapy of antiplatelet agents predicting drug response, strategies for identifying aspirin resistance, pharmacogenetic variants of antiplatelet agents, miRNAs, and extracellular vesicles (EVs) as biomarkers toward the personalized approach in the management of acute ischemic stroke. The precise pathways contributing to antiplatelet resistance are not very well known but are presumably multi-factorial. It is essential to understand the clinical relevance of clopidogrel and aspirin-related single nucleotide polymorphism (SNPs) as potential predictive and prognostic biomarkers. Prasugrel is a next-generation antiplatelet agent that prevents ADP-platelet activation by binding irreversibly to P2Y12 receptor. There are sporadic reports of prasugrel resistance and polymorphisms in the Platelet endothelial aggregation receptor-1 (PEAR1) that may contribute to a change in the pharmacodynamics response. Ticagrelor, a direct-acting P2Y12-receptor antagonist, is easily absorbed and partly metabolized to major AR-C124910XX metabolite (ARC). Ticagrelor's primary active metabolite, ARC124910XX (ARC), is formed via the most abundant hepatic cytochrome P450 (CYP) enzyme, CYP3A4, and CYP3A5. The integration of specific biomarkers, genotype as well as phenotype-related data in antiplatelet therapy stratification in patients with acute ischemic stroke will be of great clinical significance and could be used as a guiding tool for more effective, personalized therapy.

Project description:BACKGROUND:Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS:In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS:A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P=0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P=0.02). CONCLUSIONS:In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029 .).

Dataset Information

Platelet function-guided modification in antiplatelet therapy after acute ischemic stroke is associated with clinical outcomes in patients with aspirin nonresponse.

Publications

Platelet function-guided modification in antiplatelet therapy after acute ischemic stroke is associated with clinical outcomes in patients with aspirin nonresponse.

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