Association Between Systemic Amyloidosis and Intracranial Hemorrhage

Introduction: Isolated amyloid deposition in the brain is associated with intracranial hemorrhage. Whether systemic amyloidosis also increases the risk of intracranial hemorrhage is unclear. Methods: We evaluated the association between systemic amyloidosis and intracranial hemorrhage using claims data from a 5% national sample of Medicare beneficiaries from 2008-2015. The primary outcome was non-traumatic intracranial hemorrhage, defined as a composite of intracerebral hemorrhage, subarachnoid hemorrhage, and subdural hemorrhage. Secondary outcome were each hemorrhage type assessed separately. The exposure and outcomes were identified using previously validated ICD-9-CM diagnosis codes. We used Cox regression analysis adjusting for demographics and vascular risk factors to evaluate the association between systemic amyloidosis and intracranial hemorrhage. We also examined the risk of hip fracture (negative control). In sensitivity analyses, we excluded patients with cardiac amyloidosis, a subset most likely to be on antithrombotic therapy. Results: Among 1.8 million Medicare beneficiaries, 924 were diagnosed with systemic amyloidosis. During a median follow-up of 5.3 years (IQR, 2.8- 6.7), the cumulative incidence of intracranial hemorrhage was 19 per 1,000 patients per year among patients with amyloidosis, and 2 per 1,000 patients per year in those without amyloidosis. In adjusted Cox models, systemic amyloidosis was associated with an increased risk of intracranial hemorrhage (HR, 4.3; 95% CI, 2.9-6.3). The association persisted in a sensitivity analysis after excluding beneficiaries with cardiac amyloidosis (HR, 8.0; 95% CI, 5.0-12.7). In secondary analyses, systemic amyloidosis was associated with intracerebral hemorrhage (HR, 5.6; 95% CI, 3.6-8.7), subarachnoid hemorrhage (HR, 14.7; 95% 9.0-24.0), and subdural hemorrhage (HR, 3.6; 95% 2.0-6.2). There was no association between systemic amyloidosis and hip fracture (HR, 0.9; 95% CI, 0.6-1.4). Conclusions: In a large, heterogeneous national cohort of elderly patients, a diagnosis of systemic amyloidosis was associated with a 4-fold increased risk of intracranial hemorrhage, including intracerebral, subarachnoid, and subdural hemorrhages.