Antiplatelet therapy shows “reassuring effects” on the risk of recurrent intracerebral haemorrhage

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“Starting antiplatelet therapy after intracerebral haemorrhage associated with antithrombotic drug use demonstrated reassuring effects on the risk of recurrent haemorrhage,” said Rustam Al-Shahi Salman (University of Edinburgh, Edinburgh, Scotland) while concluding the results of the RESTART trial at the European Stroke Organisation Conference (ESOC; 22–24 May, Milan, Italy).

Specifically, he stated that of the 537 participants randomised, 12 (4%) that were allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage, compared to 23 (9%) of those allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). Moreover, 18 (7%) of participants allocated to the former experienced major haemorrhagic events, compared with 25 (9%) participants allocated to avoid antiplatelet therapy.

With these findings in mind, he later acknowledged in an ESO interview, “I think this is a reassuring and permissive finding for clinical practice. I think it would be good for this result to be replicated in other randomised controlled trials [RCTs] that are underway. And, I think that it would also be interesting to pursue the hypothesis that the underlying cause of recurrent brain haemorrhage may be thrombosis in the first instance, by doing a much larger RCT, imaging and other mechanistic studies.”

The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial carried out between May 2013 and November 2018. The study investigators recruited adults who were taking antithrombotic (either antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived 24 hours.

“The RESTART trial was addressing a common question nowadays about survivors of stroke due to brain haemorrhage. About a third to a half of these patients in high income countries are taking antithrombotic drugs at the time they have a brain haemorrhage because of a past history of a heart attack or ischaemic stroke,” said Al-Shahi Salman. He added, “In our clinical practice, we usually stop these drugs as soon as intracerebral haemorrhage is diagnosed. In survivors, we are left with the uncertainty about whether we should start an antiplatelet drug, or whether to avoid it. The RESTART trial was an RCT at 122 hospitals in the UK that set out to answer this question.”

By using a computerised randomisation system that incorporated minimisation and allocated participants 1:1 to start or avoid antiplatelet therapy, Al-Shahi Salman and team were able to follow participants to assess the difference in: primary outcome (recurrent symptomatic intracerebral haemorrhage), secondary outcomes (all major vascular events), and other serious adverse events for up to five years. Participants were recruited a median of 76 days following intracerebral haemorrhage onset and followed for a median of two years subsequent to this. Al-Shahi Salman analysed treatment effects using intention-to-treat analyses and Cox proportional hazards regression, adjusted for minimisation covariates.

In terms of major adverse events, Al-Shahi Salman reported that 39 (15%) of participants allocated to avoid antiplatelet therapy had major occlusive vascular events, compared to 38 (14%) allocated to no antiplatelet therapy (1.02 [0.65–1.60]; p=0.92).

He put to the audience: “So, in summary […], the effect we observed was much lower than the increase in risk expected [RR=1.67]. Now, we raise the surprising hypothesis that antiplatelet therapy might reduce the risk of recurrent intracerebral haemorrhage. Any risk encompassed by the upper 95% confidence interval of the adjusted hazard ratio (1·03) seems too small to exceed the established of antiplatelet therapy.”

Although Al-Shahi Salman noted that there was no heterogeneity found in sub-groups, he alluded to the fact that trial was small. “But this is why we need to carry on recruiting to ongoing trials [such as RESTART-Fr in France and STATICH in the Nordic countries] and go on to test the hypothesis that antiplatelet therapy helps these patients in a larger definitive trial,” he summarised.

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