Agencia Española de Medicamentos y Productos Sanitarios (AEMPS), Madrid, Spain.
Eur J Clin Pharmacol. 2024 Oct;80(10):1503-1514. doi: 10.1007/s00228-024-03706-5. Epub 2024 Jun 22.
We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs).
A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before).
The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/10 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and 3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID.
Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.
我们旨在比较使用麦氨与非甾体抗炎药（NSAIDs）治疗时，麦氨导致粒细胞缺乏症的绝对（发生率）和相对（风险比；HR）风险。
使用 BIFAP（公共卫生系统药物流行病学研究数据库；西班牙）对麦氨和 NSAIDs 的新使用者进行了队列研究。在 2005 年至 2022 年期间，年龄≥2 岁的患者从第一次接受麦氨或 NSAID 配药后的第二天开始随访，直到治疗期结束，以确定因特发性粒细胞缺乏症住院的患者。假设粒细胞缺乏症的发病日期是住院日期（敏感性分析）或前 7 天（主要分析），估计麦氨和 NSAID 治疗粒细胞缺乏症的发病率（IR）和调整后的 HR。在次要分析中，我们使用了（1）阿片类药物-对乙酰氨基酚作为阴性对照和（2）任何住院中性粒细胞减少症作为结果（假设发病时间为前 7 天）。
队列包括 444972 名连续接受麦氨治疗、3814367 名 NSAID 和 3129221 名阿片类药物-对乙酰氨基酚的新使用者，中位治疗时间为 37-40 天。总体而言，26 名患者发生了 21 例住院粒细胞缺乏症，其中 5 例发生在第一周（主要分析中已排除），15 例在随后发生。粒细胞缺乏症的发病率分别为 14.20（N=5 例）和 8.52（N=3 例）、1.95（N=6 例）和 1.62（N=5 例）和 4.29（N=15 例）和 3.72（N=13 例）/10 人-周连续治疗，使用住院日期或前 7 天。在两个分析中，分别有 2 例、0 例和 2 例患者在每个队列中均有肿瘤。与 NSAID 相比，麦氨治疗粒细胞缺乏症的 HR 为 7.20[95%CI：1.92-26.99]和 4.40[0.90-21.57]，与阿片类药物-对乙酰氨基酚相比，HR 为 3.31[1.17-9.34]和 2.45[0.68-8.83]。与 NSAID 相比，麦氨治疗中性粒细胞减少症的 HR 为 2.98[1.57-5.65]。
粒细胞缺乏症非常罕见，但使用麦氨比其他镇痛药更为常见（超过 4 倍）。由于使用量较低，麦氨导致粒细胞缺乏症的药物影响不如对照药物精确，这使得在主要分析中无法发现统计学差异。麦氨治疗中性粒细胞减少症的风险增加支持了与粒细胞缺乏症严重程度的联系，尽管在随访期间无法发现触发因素（例如细胞毒性药物）。
