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Can ICH Survivors Safely RESTART Antiplatelet Therapy?

December 30, 2021

While treatment with antiplatelet therapy lessens the risks of subsequent occlusive vascular events, it may increase the risk of recurrent intracerebral hemorrhage (ICH) in patients with a history of ICH. In the REstart or STop Antithrombotics Randomised Trial (RESTART), researchers sought to determine if patients could safely be placed back on antiplatelet therapy after experiencing a ICH, finding that a modest increase in the risk of recurrent ICH with antiplatelet therapy.

That risk is "probably too small" to exceed the benefits of secondary prevention of occlusive vascular disease, lead author Rustam Al-Shahi Salman, PhD, from the Centre for Clinical Brain Sciences at the University of Edinburgh, and investigators wrote in The Lancet. These results "provide reassurance about the use of long-term antiplatelet therapy in a range of patients after ICH associated with antithrombotic therapy," they added.

RESTART is a prospective, randomized, open-label trial conducted at 122 hospitals in the U.K. between May 2013 and May 2018. The trial enrolled a total of 537 adults who had been taking antithrombotic (anti-platelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they experienced a spontaneous ICH. Therapy was then discontinued.

Participants were randomized 1:1 to start antiplatelet therapy (n=268) or avoid antiplatelet therapy (n=269) and followed for five years or until recurrent symptomatic ICH (the study's primary endpoint).

At baseline, patient characteristics were similar between the two treatment groups. The median age of patients was 76 years (range = 69-82 years), and most (88%) had one or more previous occlusive vascular diseases, such as ischemic heart disease, ischemic stroke, or transient ischemic attack. At the onset of ICH, the most common antithrombotic therapy was aspirin, followed by clopidogrel or an oral anticoagulant.

During a median follow-up of two years (range = 1-3 years), one patient in the avoid-therapy group withdrew from the trial. Of the remaining 536 participants, the proportion of patients who experienced a recurrent ICH was doubled in the group who did not restart antiplatelet therapy:

  • 4% (n=12/268) in the group allocated to start antiplatelet therapy
  • 9% (n=23/269) participants who did not start therapy

This increase had a trend toward being statistically significant (adjusted hazard ratio = 0.51 (95% CI 0.25-1.03; p=0.06).

The proportion of patients who died within 30 days of the recurrent ICH was similar between both groups: 42% (n=5/12) of participants starting antiplatelet therapy and 39% (n=9/23) of those avoiding antiplatelet therapy (p value not reported).

For the composite secondary outcomes of major hemorrhagic events or major occlusive vascular events, participants allocated to start antiplatelet therapy experienced fewer events, although again, these findings were not statistically significant (TABLE).

Overall, during follow-up, 104 participants (19%) died due to noncardiovascular causes (n=57; 55%), primary or secondary outcome events (n=29; 28%), other cardiovascular deaths (n=16; 15%), or undetermined causes (n=2; 2%).

"Starting antiplatelet therapy might have reduced the risk of recurrent symptomatic ICH, but the results exclude all but a very modest increase in the risk of recurrent ICH with antiplatelet therapy," the authors wrote. "Therefore, starting antiplatelet therapy seems to be safe and might be beneficial in patients who survived [an] ICH, most of whom had good functional ability at baseline."

Limitations of this analysis include lower-than-intended recruitment and the possibility that patients were not adherent to their allocated treatment, according to the researchers. The study also was not blinded to treatment. They added that ongoing, adequately powered randomized trials are needed to confirm or refute the effects of antiplatelet therapy seen in RESTART.

The authors report no relevant conflicts of interest.


Al-Shahi Salman R, Dennis MS, Sandercock P, et al. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial. Lancet. 2019;393:2613-23.


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