Evolving Approaches to Antithrombotics in Stroke Prevention and Treatment

Vijayakumar Javalkar, MD, MCh; Okkes Kuybu, MD; Abdallah Amireh, MD; Roger E. Kelley, MD


South Med J. 2020;113(11):585-592. 

In This Article

Short-term Dual Antiplatelet Therapy

Two RCTs have explored the efficacy and safety of short-term DAPT. In the CHANCE trial (Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack),[47] clopidogrel, at an initial dose of 300 mg, followed by 75 mg/day for 90 days plus aspirin at a dose of 75 mg/day for the first 21 days (DAPT for 3 weeks) was compared with placebo plus aspirin at 75 mg/day for 90 days. The primary outcome was stroke (ischemic or hemorrhagic) during the 90-day follow-up. It was reported that the combination of clopidogrel and aspirin for 3 weeks, followed by clopidogrel alone for the remainder of the 90 days, was superior to aspirin alone for reducing the risk of stroke in the first 90 days and did not increase the risk of hemorrhage.

In the POINT (International Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial,[48] patients with minor stroke (National Institutes of Health Stroke Scale score <3) and higher risk TIA patients (ABCD2 score >4) were included. Patients received either a 600-mg loading dose of clopidogrel on day 1, followed by 75 mg/day plus aspirin at a dose of 50 to 325 mg/day from days 2 to 90 or the same ranges of aspirin dosing alone. The primary efficacy outcome of ischemic stroke, myocardial infarction (MI), or death from vascular causes was 5% for combined therapy versus 6.5% for aspirin (P = 0.02). The secondary outcome of ischemic stroke was 4.6% for combined therapy versus 6.3% for aspirin alone (P = 0.01). Major hemorrhage was 0.9% in the combined group versus 0.4% for aspirin alone (P = 0.02). Minor hemorrhage was 1.6% in the combined group versus 0.5% for aspirin alone (P < 0.001). The benefit for the combination was greatest at 7 days (P = 0.04) and 30 days (P = 0.02) than at 90 days, with a lower risk of hemorrhage noted during the first 7 days versus days 8 to 90 (P = 0.04).

Although both CHANCE and POINT trials confirmed that short-term DAPT for minor stroke or high-risk TIA is beneficial, the risk of major and minor hemorrhage is increased with DAPT for the 3 months of treatment. Per the POINT trial, the benefit of DAPT was greatest in the first 30 days. Reviews and analyses of the POINT and CHANCE trials suggest that the benefit of DAPT appears to be most favorable for the first 21 days without significantly increasing the risk of bleeding.[49,50]

Dual antiplatelet therapy also was used in the SAMMPRIS (Aggressive Medical Treatment with or without Stenting in High-Risk Patients with Intracranial Artery Stenosis) trial,[51] in which patients were enrolled who had a recent TIA or ischemic stroke attributed to stenosis of 70% to 99% of a major intracranial artery. In one group, aspirin at a daily dose of 325 mg/day and clopidogrel at 75 mg/day were given for 90 days along with aggressive management of vascular risk factors. The other group received the same aggressive medical therapy and underwent percutaneous transluminal angioplasty and stenting. Aggressive medical therapy alone had a lower than expected risk of stroke and was superior to angioplasty and stenting. The early benefit of aggressive medical management over stenting persisted over extended follow-up.[52]

Triple Antiplatelet Therapy

The TARDIS (Triple Antiplatelets for Reducing Dependency after Ischemic Stroke) study[53] examined the potential for triple therapy to provide additional protection against acute cerebral ischemia in subjects treated within 48 hours of presentation with cerebral infarct or TIA. The study groups included those who received loading doses and then were continued on a combination of aspirin 75 mg/day, clopidogrel 75 mg/day, and dipyridamole 200 mg twice daily versus clopidogrel alone or combined aspirin and dipyridamole. The rate and severity of recurrent stroke did not differ between groups; the trial was stopped early because of the adjusted odds ratio of 2.54 (95% CI 2.05–3.16, P < 0.001) for more severe bleeding with triple antiplatelet therapy.