Vignan Yogendrakumar, MD, MSc
European Stroke Organisation Conference
September 1–3, 2021
Wrapping up our coverage of this year’s ESOC, the second round of results from major clinical trials!
APACHE-AF: Apixaban after Anticoagulation-Associated Intracerebral Hemorrhage In Patients with Atrial Fibrillation: A Randomized, Open-Label, Phase 2 Trial
APACHE-AF was a prospective, randomized, open-label clinical trial, recruiting adults with a history of atrial fibrillation and anticoagulation associated ICH. Following their ICH event (days 7-90 days post ICH event), participants were randomized to apixaban 5mg twice daily or to avoiding anticoagulation. Primary outcome was vascular death or non-fatal stroke and was evaluated using a Cox proportional hazards regression model. Between January 16, 2015 and July 6, 2020, 101 participants (46% female, median age 77 years) were recruited at a median of 46 (IQR 21-74) days after ICH in an intention to treat analysis. Participants were followed for a median of 1.9 (IQR 1.0-3.1) years. There were 10 patients who crossed over. For the primary outcome, comparing Apixaban to Avoiding Anticoagulation: Adjusted HR: 1.05 (0.48-2.31), indicating no major difference between the two groups. There were no major differences in subsequent ICH between the two groups.
SOSTART: Effects Of Long-Term Oral Anticoagulation For Atrial Fibrillation After Spontaneous Intracranial Hemorrhage: The Start Or Stop Anticoagulants Randomized Trial
SoSTART was a prospective, randomized, open-label, blinded endpoint, parallel-group pilot trial. Patients who survived for 24 hours after spontaneous intracranial hemorrhage, had AF, and CHA2DS2-VASc score ≥2 were randomized to avoid or start long-term (>1 year) full treatment dose OAC (either a direct oral anticoagulant [DOAC] or vitamin K antagonist, chosen by the patient’s physician before randomization). The primary outcome was recurrent symptomatic spontaneous ICH. 203 patients were randomized (101 Start OAC, 102 Avoid OAC). Median days to randomization: 115 days after ICH. Regarding hemorrhage events: Four events were noted in patients who avoided OAC, while 8 events were observed in those who started OAC (Adjusted HR: 2.42 [0.72-8.09]). Ischemic stroke events: 3 for the starting OAC and 19 for avoiding. Larger trials are required, but the results are promising — starting OAC may prevent major ischemic events with a minimal risk of recurrent hemorrhage.
RESTART: Effects of Antiplatelet Therapy after Stroke Due To Intracerebral Hemorrhage: Extended Follow-Up
RESTART was a prospective, randomized, open-label, blinded endpoint, parallel-group trial. Patients who were taking antithrombotic (antiplatelet/anticoagulant) therapy for the prevention of ischemic stroke when they developed ICH were randomized to start or avoid antiplatelet therapy. The main results of the trial reported follow-up for the primary outcome (recurrent ICH) and serious vascular events until November 2018. For these final results of RESTART, follow-up of all randomized participants until November 2020 was conducted using Cox proportional hazards regression using all available follow-up. Median follow-up was 3.5 years. At final follow-up, the number of patients with recurrent ICH was similar between the two groups (22 in starting vs. 25 in avoiding). No major interactions were noted in subgroup analysis. Serious vascular events were similar between the two groups in further follow-up. This is in contrast to the results of the original trial, where a difference in serious vascular events was noted (favoring starting antiplatelet therapy). As RESTART was a pilot trial, further data with larger trials is required to ensure consistency in findings.
Ischemic Benefit And Hemorrhage Risk Of Ticagrelor-Aspirin Vs. Aspirin In Patients With Acute Ischemic Stroke Or TIA: A re-analysis of the THALES trial
A re-examination of the THALES trial: a randomized, placebo-controlled, double-blind trial of patients with mild-to-moderate acute noncardioembolic ischemic stroke or high-risk TIA, where patients were randomized 1:1 within 24 hours after symptom onset to a 30-day regimen of either ticagrelor plus aspirin (ticagrelor-aspirin) or matching placebo plus aspirin. The original efficacy outcome was major ischemic events as the composite of ischemic stroke or non-hemorrhagic death. The original safety outcome, major hemorrhage, was defined as intracranial hemorrhage or hemorrhagic death. Net clinical impact was defined as the combination of these two endpoints and was primary outcome of interest for this re-analysis. Among 11,016 patients randomized, a major ischemic event occurred in 5.3% of patients in the ticagrelor-aspirin group and in 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 in 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%). Note: This analysis was not pre-planned.
NETS Trial: Neuroregeneration Enhanced By Transcranial Direct Current Stimulation (Tdcs) In Stroke
NETS is an investigator-initiated, interventional, prospective, randomized, double-blind, placebo-controlled trial and tested efficacy and safety of anodal tDCS (1mA, 20min) to the primary motor cortex of the lesioned hemisphere in the subacute phase (day 5-45) after cerebral ischemia. Stimulation was combined with standardized rehabilitative training and applied in 10 sessions over 2 weeks. After randomization of 123 patients, 119 patients entered the intention-to-treat (ITT) population. The primary outcome was upper-extremity function 1-7 days after the intervention period. The adjusted mean improvement of UEFMA from baseline was 9.07 in the placebo group and 8.76 with active stimulation (difference -0.31, 95% CI -2.97-2.35; p=0.820). Anodal tDCS did not enhance upper extremity recovery in a cohort of mild to moderately affected subacute stroke patients.
Timing Of Oral Anticoagulant Therapy In Acute Ischemic Stroke With Atrial Fibrillation: A Registry-Based Randomized Controlled Study
The TIMING study was a registry-based, randomized, non-inferiority, open-label, blinded endpoint study. The Swedish Stroke Register, with an integrated computerized randomization module, was used for enrolment and follow-up. Patients within 72 hours from stroke onset were randomized to early (≤4 days) or delayed (5-10 days) initiation of NOAC. Primary outcome was the composite of recurrent ischemic stroke, symptomatic intracerebral hemorrhage, or all-cause mortality within 90 days. An external validity cohort of non-randomized patients (observational) was also included in the analysis. From April 2017 to December 2020, 888 patients, 78 years (mean), 46% females, were randomized in TIMING, and 9,321 observational patients, 79 years (mean), 46% females, were registered. Of the 888 patients randomized in TIMING, baseline characteristics were similar between the two groups and were also similar to the observational group. 31/450 events vs. 38/438 events occurred in the early and delayed group, respectively. Early start was non-inferior to a delayed start of NOAC therapy but not superior. The majority of events related to the composite outcome appear to have occurred in the first 15 days. Zero patients in either arm experienced symptomatic ICH at 90 days.