From the UMC Utrecht Brain Center (J.P.K., Y.M.R.), Department of Neurology and Neurosurgery, University Medical Center Utrecht; Julius Center for Health Sciences and Primary Care (J.P.K., O.H.K., M.I.G.), University Medical Center Utrecht, and Division of Pharmacoepidemiology and Clinical Pharmacology (S.A., O.H.K.), Utrecht Institute for Pharmaceutical Sciences, Utrecht University, the Netherlands; Infection Medicine (C.S.), Edinburgh Medical School, The University of Edinburgh, United Kingdom; Department of General Practice (M.I.G.), Amsterdam UMC, location University of Amsterdam; Amsterdam Public Health, Aging & Later Life, and Personalized Medicine (M.I.G.); and Amsterdam Neuroscience, Neurodegeneration, and Mood, Anxiety, Psychosis, Stress, and Sleep (M.I.G.), the Netherlands.
Neurology. 2024 Jun 25;102(12):e209479. doi: 10.1212/WNL.0000000000209479. Epub 2024 Jun 5.
Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial aneurysms thus remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing. We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence.
We defined all aSAH cases between 2000 and 2020 using codes from the Secure Anonymised Information Linkage databank. Each case was matched with 9 controls based on age, sex, and year of database entry. We investigated commonly prescribed drugs (>2% in study population) and defined 3 exposure windows relative to the most recent prescription before index date (i.e., occurrence of aSAH): current (within 3 months), recent (3-12 months), and past (>12 months). A logistic regression model was fitted to compare drug use across these exposure windows vs never use, controlling for age, sex, known aSAH risk factors, and health care utilization. The family-wise error rate was kept at < 0.05 through Bonferroni correction.
We investigated exposure to 205 commonly prescribed drugs between 4,879 aSAH cases (mean age 61.4, 61.2% women) and 43,911 matched controls. We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril odds ratio [OR] 0.63, 95% CI 0.44-0.90, amlodipine OR 0.82, 95% CI 0.65-1.04) and an increased aSAH risk for recent use (lisinopril OR 1.30, 95% CI 0.61-2.78, amlodipine OR 1.61, 95% CI 1.04-2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). By contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35, 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15, 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56).
We identified several drugs associated with aSAH, of which 5 drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased aSAH risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence.
This study provides Class III evidence that some commonly prescribed drugs are associated with subsequent development of aSAH.
目前，侵入性颅内动脉瘤治疗预防蛛网膜下腔出血（aSAH）的益处很少超过治疗风险。因此，大多数颅内动脉瘤未得到治疗。常用于降低 aSAH 发生率的药物可能为药物再利用提供线索。我们进行了一项广泛的药物关联研究（DWAS），以系统地研究常用药物与 aSAH 发生率之间的关联。
我们使用 Secure Anonymised Information Linkage 数据库中的代码，在 2000 年至 2020 年间定义了所有的 aSAH 病例。每个病例都根据年龄、性别和数据库录入年份与 9 名对照匹配。我们研究了常用药物（研究人群中>2%），并定义了与索引日期（即 aSAH 发生）最近的处方相对的 3 个暴露窗口：当前（3 个月内）、近期（3-12 个月）和过去（>12 个月）。我们拟合了一个逻辑回归模型，比较了这些暴露窗口与从未使用药物之间的药物使用情况，控制了年龄、性别、已知的 aSAH 风险因素和医疗保健利用情况。通过 Bonferroni 校正，将错误发现率保持在<0.05。
我们在 4879 例 aSAH 病例（平均年龄 61.4 岁，61.2%为女性）和 43911 名匹配对照中，研究了 205 种常用药物的暴露情况。我们发现赖诺普利和氨氯地平的趋势相似，当前使用降低了 aSAH 的风险（赖诺普利比值比[OR]0.63，95%置信区间[CI]0.44-0.90，氨氯地平 OR 0.82，95%CI 0.65-1.04），而近期使用增加了 aSAH 的风险（赖诺普利 OR 1.30，95%CI 0.61-2.78，氨氯地平 OR 1.61，95%CI 1.04-2.48）。我们还发现，当前使用辛伐他汀（OR 0.78，95%CI 0.64-0.96）、二甲双胍（OR 0.58，95%CI 0.43-0.78）和坦索罗辛（OR 0.55，95%CI 0.32-0.93）也降低了 aSAH 的风险。相比之下，当前使用华法林（OR 1.35，95%CI 1.02-1.79）、文拉法辛（OR 1.67，95%CI 1.01-2.75）、丙氯拉嗪（OR 2.15，95%CI 1.45-3.18）和可待因（OR 1.31，95%CI 1.10-1.56）则增加了 aSAH 的风险。
我们发现了一些与 aSAH 相关的药物，其中 5 种药物（赖诺普利和可能的氨氯地平、辛伐他汀、二甲双胍和坦索罗辛）降低了 aSAH 的风险。未来的研究应在此基础上进一步评估这些药物降低 aSAH 发生率的有效性。
本研究提供了 III 级证据，表明一些常用药物与随后发生的 aSAH 有关。
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