Restarting Antiplatelet After ICH Cuts Recurrence Risk in Half

Damian McNamara

May 23, 2019

MILAN — Despite expectations that restarting aspirin or clopidogrel (Plavix, Sanofi-Aventis) following an intracranial hemorrhage (ICH)–associated stroke might increase risk for a recurrent brain hemorrhage, researchers have found the opposite.

Restarting antiplatelet therapy was associated with a 49% reduction in risk of experiencing a subsequent ICH over an average of 2 years.

Dr Rustam Al-Shahi Salman

"So there was a halving of the risk," Rustam Al-Shahi Salman, PhD, professor of clinical neurology and researcher at the Center for Clinical Brain Sciences at Edinburgh University in Scotland, United Kingdom, said during a media briefing here at the 5th European Stroke Organisation Conference (ESOC) 2019.

"The effects we found on brain hemorrhage happening again was very reassuring," he added. The findings were simultaneously published online May 22 in the Lancet.

The prospective Restart or Stop Antithrombotics Randomised Trial (RESTART) also found no significant increase in risk for bleeding associated with restarting antiplatelet therapy. "I am completely relieved," Salman said. "I was really worried we might harm patients, and I'm utterly relieved we are not."

Previous studies were observational in nature. A meta-analysis that combined observational data for more than 5000 patients showed a lower risk for thromboembolic events and no apparent heightened risk for ICH recurrence.

"In the observational studies, we just look at what happens when the doctors choose to restart antiplatelet therapy," Salman told Medscape Medical News. However, the characteristics of those patients could potentially confound the results, he noted. RESTART is the first trial that randomly assigned people who were taking antiplatelet therapy at the time of an ICH to receive either antiplatelet treatment or no antiplatelet treatment in an open-label fashion.

All participants were adults who had survived their stroke for at least 24 hours. They were recruited from one of 122 hospitals in the United Kingdom between May 2013 and May 2018.

The primary outcome was recurrence of ICH. Of the 268 people randomly assigned to restart antiplatelet therapy, 12 experienced another brain hemorrhage. In contrast, 23 of the 269 people who were randomly assigned to not restart aspirin or clopidogrel therapy (the avoid-therapy group) experienced a recurrent brain hemorrhage. One person dropped out of the avoid-therapy group, so the number of patients in each group was equal.

This finding translates to a rate of a subsequent brain hemorrhage in the restart-therapy group of 4.5%, vs 8.6% in the avoid-therapy group (adjusted hazard ratio, 0.51; P = .60).

The investigators monitored blood pressure during the study because "it influences brain hemorrhage," Salman said. Average systolic blood pressure was 130 mmHg on annual assessments, which is the target in UK guidelines for blood pressure in this population. "This doesn't explain the difference we found, so it was also reassuring," Salman said.

Clinical Conundrum

The study "addresses a question we have struggled with for years in stroke medicine," he said. "We know drugs that stop blood clotting are effective...and beneficial despite increasing risk of bleeding a little bit.

"What we don't know if it's safe to use those drugs in the type of stroke caused by bleeding in the brain — intracranial hemorrhage."

Salman said that in most clinical settings, 4 of 5 patients do not restart antiplatelet therapy after experiencing an ICH.

When asked by Medscape Medical News if this is potentially a practice-changing trial, Salam said, "I hope so." A survey of his collaborators indicated that 100% believe it will be practice changing, he added. He and his colleagues encourage others to comment on the relevance of their findings through an online survey on the RESTART Trial website.

The study population of 537 participants was not large enough to allow subgroup analyses to be conducted. Therefore, the investigators could not determine which patient characteristics might be more favorable with regard to restarting or not restarting therapy. That could be the focus of future research, he said.

The current findings contrast with major aspirin trials and guidelines published in the past year that indicate that there is no benefit for primary prevention of cardiovascular events. "The important distinction is those were primary prevention trials, asking if an aspirin a day keeps the doctor away in people who have not had a heart attack or stroke." In comparison, he added, the current study involved patients who had had a heart attack or stroke in the past and who had had a brain hemorrhage as well, "which means they really have something wrong with the blood vessels in their head.

"Aspirin does seem more appropriate for people with brain hemorrhage and a history of heart attack or stroke," he said.

More Objective Evidence

"It certainly is a good study, and very reassuring," session co-moderator Jesse Dawson, MD, of the Institute of Cardiovascular and Medical Sciences at the University of Glasgow, United Kingdom, told Medscape Medical News

Selection bias as to whether or not to prescribe antiplatelet therapy is "the main concern we have in this area," he said. "In our clinical practice, we might say, 'This person has had six heart attacks and one hemorrhage, but we can control their blood pressure, so I might give them antiplatelets,' or 'This person's scan might look like they have another hemorrhage, and I'm not going to give them antiplatelets.'

"The randomization in this trial has removed all those selection biases, so I think it's the most objective data we have," he said. "And it reassures us that we are very, very unlikely to do harm by restarting."

The study was funded by the British Heart Foundation. Salman and Dawson have disclosed no relevant financial relationships.

Lancet. Published online May 22, 2019. Full text

5th European Stroke Organisation Conference (ESOC) 2019: Presented May 22, 2019.

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