The major finding from this prospective cohort study is that lobar ICH is associated with a high rate of recurrent hemorrhage and that severity of white matter disease and cerebral microbleeds independently increase this risk. The use of antithrombotic agents in CAA after lobar ICH may also increase this risk when the analysis is controlled for baseline microbleed count.
Although the association between aspirin exposure, microbleeds, and symptomatic ICH was previously reported in case-control studies,21,22
prospective data on the influence of aspirin on lobar ICH recurrence have been lacking. This analysis of prospectively followed patients with CAA associates aspirin use with recurrent hemorrhage when adjusting for baseline predictors of recurrent ICH.
Several mechanisms might be implicated in the effect of aspirin exposure in patients with CAA. Recently published data on a cross-sectional population study of microbleeds prevalence suggest that exposure to aspirin may be associated with increased prevalence of lobar microbleeds, one of the hallmarks of CAA.23
Antiplatelet agents might therefore increase the risk of recurrent ICH by substantially increasing the number of microbleeds at risk for conversion into clinically manifest macrobleeds. Antiplatelet therapy might also act on preexisting and new spontaneous microbleeds by increasing the risk of evolution into clinically symptomatic ICH.
Although our analysis was not adequately powered to explore this mechanism in regard to warfarin, anticoagulation therapy might also influence ICH recurrence based on microbleed burden. Limited evidence supporting this hypothesis has been recently provided in a small case-control series.24
Additional studies with larger numbers of ICH survivors taking warfarin will be needed to better determine the risk of anticoagulation in ICH survivors.
We identified the presence of CT-WMH in posterior brain regions as a predictor of lobar ICH recurrence. Although previous evidence suggests that the presence of CT-WMH correlates with lobar ICH recurrence,13
in that study we did not examine the location of CT-WMH. Here we extend those results by showing that the location as well as extent of white matter damage might be relevant in predicting ICH recurrence in CAA. These results contrast somewhat with a voxel-wise MRI-based analysis of white matter lesions, which found no major differences in location between patients with CAA, AD, and normal aging.25
Posterior CT-WMH may be a stronger marker of underlying CAA than overall WMH burden. Consistent with this hypothesis, the correlation of number of microbleeds with posterior CT-WMH was stronger than with overall CT-WMH. Microbleeds in patients with CAA have been shown to have a posterior predominance.26
Further studies are required to determine the relationship between CT-WMH and MRI-based measures to better determine whether white matter damage may also have a posterior predominance in patients with CAA.
We did not identify APOE
alleles ε2 and ε4 as risk factors for lobar ICH recurrence, but we observed mild multicollinearity with other predictors in our Cox model. This can be explained by the association of APOE
alleles with presence of lobar microbleeds14,15
and white matter disease.27
The extremely high predictive power of these imaging variables is likely to obscure the relatively weaker effects of correlated APOE
Our results have potential implications for patients with CAA at high risk for ischemic cardiovascular and cerebrovascular diseases. Previous studies have suggested that antiplatelet therapy might be used in selected ICH survivors without a substantial increase in the risk of rebleeding.6,28
These studies, however, were not limited to patients with CAA and complete data regarding the cerebral microbleeds were not available. Our results suggest that there may be an increased risk of recurrent ICH in patients with CAA treated with aspirin. However, baseline predictors of ICH recurrence (microbleeds in particular) likely play an important role in the overall risk of hemorrhage recurrence in these patients. As data continue to accumulate on predicting future risk of ICH, clinicians should cautiously weigh the risks and benefits of antiplatelet treatment in individuals diagnosed with CAA.
This study has limitations. Although we were able to develop a powerful predictive model for lobar ICH recurrence (Harrell's C = 0.84 for lobar ICH), predictive performance evaluation in a separate cohort is required. In this study, all subjects were exposed to aspirin as the antiplatelet agent. The effect of nonaspirin antiplatelet agents or the combination of such agents cannot be assessed using these results. Although our results could suggest that the risk of recurrent ICH with aspirin use in CAA is moderated by microbleed burden, we had insufficient statistical power to answer this question definitively by testing for an interaction. Patients with CAA who did not undergo MRI were excluded from the current study. However, as we did not find any difference in baseline characteristics between subjects in the study and excluded subjects, it is unlikely to introduce significant bias. Finally, aspirin use was not randomly assigned, but rather resulted from each individual patient and physician decisions. Indeed, the effect of antiplatelet therapy on ICH recurrence became apparent only when controlling for some of the baseline factors that may have influenced this decision.