Aspirin and recurrent intracerebral hemorrhage in cerebral amyloid angiopathy

Abstract

Objective: To identify and compare clinical and neuroimaging predictors of primary lobar intracerebral hemorrhage (ICH) recurrence, assessing their relative contributions to recurrent ICH.Methods: Subjects were consecutive survivors of primary ICH drawn from a single-center prospective cohort study. Baseline clinical, imaging, and laboratory data were collected. Survivors were followed prospectively for recurrent ICH and intercurrent aspirin and warfarin use, including duration of exposure. Cox proportional hazards models were used to identify predictors of recurrence stratified by ICH location, with aspirin and warfarin exposures as time-dependent variables adjusting for potential confounders.Results: A total of 104 primary lobar ICH survivors were enrolled. Recurrence of lobar ICH was associated with previous ICH before index event (hazard ratio [HR] 7.7, 95% confidence interval [CI] 1.4 -15.7), number of lobar microbleeds (HR 2.93 with 2-4 microbleeds present, 95% CI 1.3-4.0; HR ϭ 4.12 when Ն5 microbleeds present, 95% CI 1.6 -9.3), and presence of CTdefined white matter hypodensity in the posterior region (HR 4.11, 95% CI 1.01-12.2). Although aspirin after ICH was not associated with lobar ICH recurrence in univariate analyses, in multivariate analyses adjusting for baseline clinical predictors, it independently increased the risk of ICH recurrence (HR 3.95, 95% CI 1.6 -8.3, p ϭ 0.021). Conclusions:Recurrence of lobar ICH is associated with previous microbleeds or macrobleeds and posterior CT white matter hypodensity, which may be markers of severity for underlying cerebral amyloid angiopathy. Use of an antiplatelet agent following lobar ICH may also increase recurrence risk. Neurology ® 2010;75:693-698 GLOSSARY CAA ϭ cerebral amyloid angiopathy; CI ϭ confidence interval; CT-WMH ϭ CT-defined white matter hypodensity; HR ϭ hazard ratio; ICH ϭ intracerebral hemorrhage; VIF ϭ variance inflation factor.Intracerebral hemorrhage (ICH), although accounting for only 15% of acute strokes in the United States, 1 carries the worst prognosis of all acute cerebrovascular diseases. 2,3 Lobar ICH location (selective involvement of the cerebral cortex and underlying white matter) is associated with greater risk for recurrence than deep ICH location [4][5][6] and is associated with different clinical features and risk factors. 7,8 Nonfamilial cerebral amyloid angiopathy (CAA), caused by ␤-amyloid deposition in cerebral arteries and arterioles, is a major cause of lobar ICH but not deep ICH, as shown by autopsy investigations, 9 as well as studies linking lobar ICH with several hallmarks of CAA, such as the APOE ⑀2 and ⑀4 alleles, 5,9,10 asymptomatic microbleeds detected on gradient-echo MRI, 11,12 and white matter lesions. 13 Based on recent evidence, there is some suggestion that asymptomatic CAA may be highly prevalent in the elderly. 14,15 Although several predictors of lobar ICH recurrence have been described, little is known regarding the relative contribution or interaction of each of these predictors. For examp...

APOE ε4 and lipid levels affect risk of recurrent nonlobar intracerebral hemorrhage

“…3,5 A recent, large meta-analysis of case-control studies conclusively demonstrated that APOE e2 and e4 increase risk of ICH in the lobar brain regions. 6 An intriguing preliminary finding that emerged as well was an association between APOE e4, but not e2, and nonlobar ICH.…”

“…2 Previous studies demonstrated that survivors of ICH in the lobar brain regions are at higher risk of recurrence, and multiple predictors of recurrent lobar ICH have been identified. 3,4 Among these, the e2/e4 variants of the APOE gene are presumed to modify lobar ICH recurrence risk via their role in small vessel disease associated with cerebral amyloid angiopathy (CAA). 3,5 A recent, large meta-analysis of case-control studies conclusively demonstrated that APOE e2 and e4 increase risk of ICH in the lobar brain regions.…”

“…3,4 Among these, the e2/e4 variants of the APOE gene are presumed to modify lobar ICH recurrence risk via their role in small vessel disease associated with cerebral amyloid angiopathy (CAA). 3,5 A recent, large meta-analysis of case-control studies conclusively demonstrated that APOE e2 and e4 increase risk of ICH in the lobar brain regions. 6 An intriguing preliminary finding that emerged as well was an association between APOE e4, but not e2, and nonlobar ICH.…”

Antithrombotic medications and the etiology of intracerebral hemorrhage

“…It is likely that these abnormalities might render cortical-subcortical vessels more vulnerable to rupture and with less potential for tamponade compared to deep perforating arteries in the presence of excessive anticoagulation. 17,18 In addition, evidence supporting a link between CAA and OAC-ICH includes the demonstration that the APOE e2 allele, a known genetic risk factor of CAA-related lobar ICH, 19,20 is more common in warfarin-associated ICH than in control patients on warfarin without ICH, 8 and that individual cases of ICH following anticoagulation or coronary thrombolysis revealed advanced CAA on autopsy. 21,22 Our findings are in apparent disagreement with those derived from the PITCH study by DequatrePonchelle et al 12 who found no influence of OACs on the anatomical distribution of ICH but a significant effect of these compounds on the volume of deep brain hematomas.…”

Update on Amyloid-associated Intracerebral Hemorrhage

“…The microbleed burden could have significant implications for anti-platelet treatment in patients with CAA. 47 A subanalysis of the Perindopril protection against recurrent stroke study (PROGRESS) suggests that blood pressure control reduces the risk of CAA-related ICH and blood pressure lowering could be preventive against multiple causes of ICH. 48 Animal studies in mice suggest that AB immunotherapy could theoretically slow or stop the development of CAA; however, it remains unclear if these findings are applicable in humans.…”