Untreated brain arteriovenous malformation: patient-level meta-analysis of hemorrhage predictors

Abstract

Objective: To identify risk factors for intracranial hemorrhage in the natural history course of brain arteriovenous malformations (AVMs) using individual patient data meta-analysis of 4 existing cohorts.

Methods: We harmonized data from Kaiser Permanente of Northern California (n = 856), University of California San Francisco (n = 787), Columbia University (n = 672), and the Scottish Intracranial Vascular Malformation Study (n = 210). We censored patients at first treatment, death, last visit, or 10-year follow-up, and performed stratified Cox regression analysis of time-to-hemorrhage after evaluating hemorrhagic presentation, sex, age at diagnosis, deep venous drainage, and AVM size as predictors. Multiple imputation was performed to assess impact of missing data.

Results: A total of 141 hemorrhage events occurred during 6,074 patient-years of follow-up (annual rate of 2.3%, 95% confidence interval [CI] 2.0%-2.7%), higher for ruptured (4.8%, 3.9%-5.9%) than unruptured (1.3%, 1.0%-1.7%) AVMs at presentation. Hemorrhagic presentation (hazard ratio 3.86, 95% CI 2.42-6.14) and increasing age (1.34 per decade, 1.17-1.53) independently predicted hemorrhage and remained significant predictors in the imputed dataset. Female sex (1.49, 95% CI 0.96-2.30) and exclusively deep venous drainage (1.60, 0.95-2.68, p = 0.02 in imputed dataset) may be additional predictors. AVM size was not associated with intracerebral hemorrhage in multivariable models (p > 0.5).

Conclusion: This large, individual patient data meta-analysis identified hemorrhagic presentation and increasing age as independent predictors of hemorrhage during follow-up. Additional AVM cohort data may further improve precision of estimates, identify new risk factors, and allow validation of prediction models.

Figure 1. Survival curves of time-to-hemorrhage in patients with untreated brain AVM, by MARS cohort

The y-axis shows the proportion of subjects who remain hemorrhage-free. The x-axis shows follow-up time after AVM diagnosis in years. The table below shows the number at risk at each follow-up time interval. AVM = arteriovenous malformation; COL = Columbia; KPNC = Kaiser Permanente of Northern California; MARS = Multicenter AVM Research Study; SIVMS = Scottish Intracranial Vascular Malformation Study; UCSF = University of California San Francisco.

Figure 2. Forest plots of multivariable-adjusted predictors by cohort and combined IPDMA

(A) Initial hemorrhagic presentation. (B) Exclusively deep venous drainage. (C) Age at diagnosis. (D) Sex. The x-axis shows the HR with the vertical black line at 1.0 (no association) and the vertical red line indicating the overall estimate from IPDMA. CI = confidence interval; COL = Columbia; HR = hazard ratio; IPDMA = individual patient data meta-analysis; KPNC = Kaiser Permanente of Northern California; SIVMS = Scottish Intracranial Vascular Malformation Study; UCSF = University of California San Francisco.