Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage and Functional Outcomes

Discussion

In this multicenter cohort study, APT after ICH appeared safe and was not associated with all-cause mortality or functional outcome, regardless of hematoma location. The observed median times to starting APT ranged from 7 to 39 days across the studies.

There is a paucity of data on the relationship between APT after ICH and functional outcomes. Our study corroborates the results of prior studies. In the ERICH cohort study, restarting APT was initially associated with lower rates of good functional outcome at 90 days.^[12] However, no such adverse association was observed after adjusting for differences in baseline characteristics using propensity matching, and APT did not influence functional outcomes or overall quality of life. A multicenter Italian study of patients with warfarin-related ICH also reported no difference in mortality among patients after reinstatement of APT compared with those not on antithrombotic medications.^[16] One possible explanation for the lack of association between APT and disability is that more than half of the patients in our study had an mRS score of 4 to 6 at 90 days, which reflects the severity of disability these patients had as their new baseline following the ICH. Given that the trajectory for recovery after ICH continues beyond the traditionally used cut off of 90 days and extends well into the first year,^[17,18] it is possible that a longer time frame for assessment of ICH outcomes could more accurately capture the true benefits of APT.

Population studies have shown that APT used in the setting of primary prevention is associated with an increased risk of intracranial hemorrhage compared with subjects not on APT, particularly in the elderly population.^[19] Clinicians therefore are concerned about the heightened risk of ICH recurrence, should APT be started after ICH. The fact that recent nonrandomized studies have shown that reinstitution of oral anticoagulation therapy, a class of medications with a higher hemorrhagic risk than APT, was not associated with a heightened risk of recurrent ICH offers a countervailing observation.^[7,8,16] Furthermore, in a meta-analysis of observational studies, reinstatement of APT among ICH patients with atrial fibrillation did not increase the risk of recurrent ICH compared with patients not on APT.^[10] One possible explanation for this apparent conflict is the possibility that secondary blood pressure control is more robust post-ICH than in the care rendered for primary prevention of stroke.

We also observed a variation in the timing of APT after ICH where the median time to APT ranged from 7 to 39 days. This reflects the current evidence where the American Heart Association guidelines recommend consideration of antiplatelet monotherapy after ICH regardless of hematoma location but do not specify the optimal timeframe for APT resumption.^[20] In fact, this discrepancy in the timing of APT after ICH is also evident from prior studies. For instance, in the RESTART trial, the median time to resumption of APT was 76 days (IQR, 29–146),^[11] while in an observational study from Scotland reported the median time from ICH discharge to APT use was nearly 15 months.^[21] Similarly, a retrospective study from the Swedish Stroke Registry showed that rates of APT prescription were 43.6% and 17.5% within 1 year after ICH among patients with and without atrial fibrillation, respectively.^[22]

Our study has a few limitations. First, our study is subject to biases from the nonrandomized and retrospective design. Despite rigorous adjustment of baseline severity and comorbidities, our study is subject to confounding by indication in that clinicians were more likely to start APT in patients perceived to have modest to good outcome such as younger patients and those with smaller hematoma volumes. Moreover, specific indications that prompted use of APT were also not available, which likely also introduced bias in the study. We tried to partially address this issue including these factors as covariates in the Cox regression models. Second, to account for variation in the timing of APT, we used APT as a time varying covariate, to minimize immortal time bias. However, medication compliance could not be reliably assessed in our study and may have hampered our ability to accurately capture time on APT. Third, we did not have information on the specific cause of death, thrombotic events, or ICH recurrence. Finally, information on presence of cerebral microbleeds or amyloid angiopathy, which may have influenced decisions on starting APT, was not available in all cohorts.

In summary, APT after ICH was not associated with mortality or severe disability in our study. Furthermore, APT use appeared to be safe in both lobar and deep ICH. Large randomized controlled trials are warranted to better elucidate long-term beneficial and harmful effects of APT after ICH.

Stroke. 2019;50(11):3057-3063. © 2019 American Heart Association, Inc.