From the Department of Community Medicine and Epidemiology (W.S., H.S.R., O.B.-G., N.G., G.R.), Statistical Unit (O.B.-G.), Pharmacoepidemiology and Pharmacogenetics Unit (N.G.), and Department of Neurology (E.A.), Lady Davis Carmel Medical Center; Ruth and Bruce Rappaport Faculty of Medicine (W.S., G.R., E.A.), Technion-Israel Institute of Technology, Haifa; and Department of Neurology (J.M.), Tel-Aviv Sourasky Medical Center, Israel.
Neurology. 2018 Jul 31;91(5):e400-e409. doi: 10.1212/WNL.0000000000005907. Epub 2018 Jul 3.
To examine the association between statin exposure in a dose-dependent manner and intracerebral hemorrhage (ICH) in a large nationwide study.
The computerized database of the largest health care provider in Israel was used to identify diagnosed ICH among new users of statins, who started statin treatment between 2005 and 2010. We assessed a dose-response relationship between ICH and statins, using the average atorvastatin equivalent daily dose (AAEDD). Multivariable Cox proportional hazard regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio of ICH.
Of the 345,531 included patients, 1,304 were diagnosed with ICH during a median follow-up of 9.5 years (interquartile range 7.6-11.0). Overall, 75.3% of patients had AAEDD <10 mg/d, 19.0% had AAEDD 0-19.9 mg/d, and 5.7% had AAEDD ≥20 mg/d. The corresponding proportions were 81.0%, 15.0%, 4.0% among ICH cases, and 75.3%, 19.0%, 5.7% among non-ICH cases. Compared to those with AAEDD <10 mg/d (reference), the adjusted hazard ratio (HR) for ICH was 0.68 (95% confidence interval [CI] 0.58-0.79) in those with AAEDD 10-19.9 mg/d, and 0.62 (0.47-0.81) in those with AAEDD ≥20 mg/d. Compared to the lowest baseline total cholesterol quartile, the adjusted HR for ICH was 0.71 (95% CI 0.62-0.82), 0.55 (0.47-0.64), and 0.57 (0.49-0.67) in those in the second, third, and highest quartiles, respectively. The results were similar and robust among highly persistent statin users and after controlling for the change in cholesterol level.
This study confirms that the risk of ICH decreases with increasing cholesterol levels, but suggests that statin use might be associated with decreased risk of ICH.
在一项大型全国性研究中，以剂量依赖的方式研究他汀类药物暴露与脑出血（ICH）之间的关联。
利用以色列最大医疗保健提供者的计算机数据库，确定新使用他汀类药物的患者中ICH 的诊断，这些患者在 2005 年至 2010 年间开始使用他汀类药物治疗。我们使用阿托伐他汀等效日剂量（AAEDD）评估 ICH 与他汀类药物之间的剂量反应关系。多变量 Cox 比例风险回归模型，根据基线疾病风险评分进行调整，用于估计 ICH 的风险比。
在纳入的 345531 名患者中，有 1304 名患者在中位随访 9.5 年内（四分位距 7.6-11.0）被诊断为 ICH。总体而言，75.3%的患者 AAEDD<10mg/d，19.0%的患者 AAEDD 0-19.9mg/d，5.7%的患者 AAEDD≥20mg/d。ICH 病例中相应的比例分别为 81.0%、15.0%、4.0%，而非 ICH 病例中分别为 75.3%、19.0%、5.7%。与 AAEDD<10mg/d（参考）相比，AAEDD 为 10-19.9mg/d 的患者发生 ICH 的调整后危险比（HR）为 0.68（95%置信区间[CI]为 0.58-0.79），AAEDD≥20mg/d 的患者为 0.62（0.47-0.81）。与最低基线总胆固醇四分位组相比，ICH 的调整后 HR 分别为 0.71（95%CI 0.62-0.82）、0.55（0.47-0.64）和 0.57（0.49-0.67），在第二、第三和最高四分位数组中。在高度持续性他汀类药物使用者中，以及在控制胆固醇水平变化后，结果相似且稳健。
本研究证实，ICH 的风险随胆固醇水平的升高而降低，但提示他汀类药物的使用可能与 ICH 风险降低有关。
