Lina Palaiodimou, MD

Murthy SB, Biffi A, Falcone GJ, Sansing LH, Torres Lopez V, Navi BB, et al. Antiplatelet Therapy After Spontaneous Intracerebral Hemorrhage and Functional Outcomes. Stroke. 2019

Initiation of antithrombotic therapy (antiplatelet or anticoagulant) after intracerebral hemorrhage (ICH) has long been a matter of conflict among clinicians dealing with stroke patients. Given that the treatment of ICH in the acute phase is mostly supportive, one can understand the anxiety of the clinicians who want to prevent an ICH recurrence. However, according to American Heart Association/American Stroke Association (AHA/ASA) guidelines, the recommendation that “anticoagulation after nonlobar ICH and antiplatelet monotherapy after any ICH might be considered, particularly when there are strong indications for these agents” is not well established (Class IIb) and is based on evidence derived from nonrandomized studies (Level of Evidence B). That is why studies aiming to shed light on this matter are more than welcome from the scientific community of stroke.

The study by Murthy et al. is an attempt to enrich the scarce data regarding the impact of antiplatelet therapy (APT) initiation after ICH on functional outcomes. For that reason, the authors separately analyzed data from 3 large cohort studies [ICH study at Massachusetts General Hospital (MGH), Virtual International Stroke Trials Archive-ICH (VISTA-ICH), ICH database of Yale University School of Medicine], consisting of 1801 ICH patients in total. Inclusion criteria were: diagnosis of primary ICH in CT-scan, age >18 years, and complete follow up at 90 days. Exclusion criteria were: previous history of ICH, secondary cause of ICH, and prior use of anticoagulants.

Study exposure was APT after ICH. For the analysis, APT was defined as a time varying covariate, since timing of APT initiation varied among different patients, and, in that way, the authors aimed to control immortal time bias. The primary endpoints were all-cause mortality at 3 months and a composite of death or major disability [modified Rankin Scale (mRS) 4-6] at 3 months. Secondary analyses were also performed regarding hematoma location (deep or lobar) and whether APT was resumed or started de-novo. Statistical analysis in each study was performed in univariate and multivariate models, adjusted for age, sex, GCS, hematoma volume, intraventricular hemorrhage, and hematoma location. 

Subsequently, the authors used a random-effects model (which is more conservative) to meta-analyze the results of each cohort, in order to calculate a polled hazard ratio (HR) for the outcomes. It should be highlighted that heterogeneity was not evident in any outcome.

The authors concluded that APT after ICH was not associated with mortality or the composite of death or major disability in neither of the individual cohorts or the meta-analysis of them. Similarly, in a secondary analysis, hematoma location did not interfere in the association between APT after ICH and mortality or mRS 4-6 in two of the cohorts (MGH and VISTA-ICH) and the meta-analysis of those two. Finally, a post-hoc analysis concluded that patients with a history of prior APT who restarted APT after ICH and patients who started APT for the first time after ICH had similar odds of outcome. History of prior APT did not seem to be an important confounding factor on the relationship between antiplatelet therapy after ICH and functional outcomes.

There are limitations of this study. First, duration of follow-up is limited, since the study population consists of ICH patients, whose recovery usually extends beyond 3 months. It is possible that a longer follow-up period could have displayed different outcomes between the APT and no-APT patient groups. In addition, data about pre-ICH mRS were not provided. Considering that 11.4% – 21.1% of patients included in the 3 cohorts had a history of prior ischemic stroke, pre-ICH mRS could have been a serious confounding factor. What was the disability status of those patients before the ICH? Furthermore, stroke severity was assessed clinically by GCS score only, and there is a lack of data regarding patients’ NIHSS score. Finally, although the definition of APT as a time varying covariate is a legitimate approach to mitigate the risk of immortal time bias, we should keep in mind that data regarding medication compliance and actual duration of APT were unavailable in this study.      

Despite the limitations, the study by Murthy et al. underscores that initiation of APT after ICH seems to be safe regarding all-cause mortality and major disability within a time frame of 3 months. Since this study is based on retrospectively collected observational data, the next step should be the design of large randomized-controlled trials in order to provide clinicians with strong evidence regarding safety of antithrombotic treatment in ICH patients.