No Significant Increase in Recurrent ICH When Restarting Antiplatelet Therapy

Rustam Al-Shahi Salman, PhD, MBBChir, FRCP

A follow-up of the Restart of Stop Antithrombotics Randomized Trial (RESTART; ISRCTN71907627) found no significant effect of antiplatelet therapy on recurrent intracerebral hemorrhage (ICH) or any major vascular events in patients with ICH that had taken antithrombotic therapy, allowing physicians to feel some reassurance about the use of antiplatelet therapy in this patient population. 

The prospective, open, blinded end point, parallel-group randomized clinical trial studied a total of 537 patients in 122 hospitals in UK from May 22, 2013, to May 31, 2018. During an extended follow-up through November 20, 2020, for a median total of 3 years (interquartile range [IQR], 2.0-5.0), investigators found that, of those randomized to start antiplatelet therapy (n = 268), 22 patients (8.2%) experienced the primary outcome of recurrent ICH, and of those randomized to avoid antiplatelet therapy (n = 269; 1 withdrawal), 25 patients (9.3%) experienced recurrent ICH, resulting in a nonsignificant difference (adjusted HR, 0.87 [95% CI, 0.49-1.55]; P = .64). 

When recurrent ICH occurred, 3 of the 22 patients in the start antiplatelet therapy group (13.6%) were not taking and antiplatelet agent, and 6 out of the 25 patients in the avoid antiplatelet group (24.0%) were taking an antiplatelet agent. 

The secondary outcome, a major vascular event, affected a total of 72 participants (26.8%) who received antiplatelet therapy and 87 participants (32.5%) who did not receive antiplatelet therapy (HR, 0.79 [95% CI, 0.58-1.08]; P = .14). While the amount of major vascular events in the group receiving antiplatelet therapy was lower, when compared to the group avoiding therapy, the difference was nonsignificant. 

“During extended follow-up of participants in RESTART for a median of 3 years, survivors of an ICH that occurred while they were receiving antithrombotic therapy who were assigned to start antiplatelet therapy experienced similar numbers of ICH recurrences compared with participants assigned to avoid antiplatelet therapy,” lead author Rustam Al-Shahi Salman, PhD, MBBChir, FRCP, professor of clinical neurology, Centre for Clinical Brain Sciences, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, et al wrote. “Effects on various secondary outcomes were not significant, but significantly fewer major vascular events occurred after allocation to start antiplatelet therapy after 1, 2, and 3 years.”

Patients included in the study had taken antithrombic therapy to prevent occlusive vascular disease after developing ICH. They had also discontinued antithrombotic therapy and then survived for 24 hours. The RESTART trial originally found that after ICH that occurred during antithrombotic therapy, the use of antiplatelet therapy was safe for up to 5 years. Patients had a median age of 76.0 years (interquartile range [IQR], 69.0-82.0) and a median time after ICH onset of 76.0 days (IQR, 29.0-146.0).

While no statistically significant differences were found between starting and avoiding antiplatelet therapy for all major vascular events, investigators did find significant differences in the cumulative risk of starting vs avoiding therapy after 1 year (cumulative risk difference, -7.0%; 95% CI, -12.6 to -1.4), 2 years (cumulative risk difference, -8.9%; 95% CI, -15.7 to -2.1), and 3 years (cumulative risk difference, -7.8%; 95% CI, -15.5 to -0.1).

“Our findings are consistent with the expected effects of antiplatelet therapy,” Al-Shahi Salman et al wrote. “However, extended follow-up in RESTART still lacked the power to detect these effects with precision, despite a 70% increase in the total person-years of follow-up from 1064 to 1805, a 34% increase in primary outcomes from 35 to 47, and a 45% increase in major vascular events from 110 to 159.”

The RESTART trial, which investigators stated is the only RCT comparing starting and avoiding antiplatelet therapy following ICH, also faced limitations, namely the smaller sample size and primarily male enrollment. A larger RCT will be necessary to address additional questions regarding antiplatelet therapy and ICH. 

REFERENCE

Al-Shahi Salman R, Dennis MS, Sandercock PAG, et al. Effects of antiplatelet therapy after stroke caused by intracerebral hemorrhage: Extended follow-up of the RESTART randomized clinical trial. JAMA Neurol. Published online September 3, 2021. doi:10.1001/jamaneurol.2021.2956