Hu Yuqi, Gao Le, Zhou Lingyue, Liu Wenlong, Wei Cuiling, Liu Boyan, Sun Qi, Tian Wenxin, Chu Rachel Yui Ki, Song Song, Cheng Franco Wing Tak, Chan Joe Kwun Nam, Ng Amy Pui Pui, Lo Heidi Ka Ying, Lee Krystal Chi Kei, Chang Wing Chung, Wong William Chi Wai, Chan Esther Wai Yin, Wong Ian Chi Kei, Chai Yi, Lai Francisco Tsz Tsun
Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR.
Department of Pharmacy Administration, School of Pharmacy, Xi'an Jiaotong University, Shaanxi, China.
PLoS Med. 2024 Dec 5;21(12):e1004457. doi: 10.1371/journal.pmed.1004457. eCollection 2024 Dec.
Clozapine is widely regarded as a highly efficacious psychotropic drug that is largely underused worldwide. Recent disproportionality analyses and nationwide case-control studies suggested a potential association between clozapine use and hematological malignancy (HM). Nevertheless, the absolute rate difference is not well-established due to the absence of analytic cohort studies. The clinical significance of such a potential risk remains unclear.
We extracted data from a territory-wide public healthcare database from January 2001 to August 2022 in Hong Kong to conduct a retrospective cohort study of anonymized patients aged 18+ years with a diagnosis of schizophrenia who used clozapine or olanzapine (drug comparator with highly similar chemical structure and pharmacological mechanisms) for 90+ days, with at least 2 prior other antipsychotic use records within both groups. Weighted by inverse probability of treatment (IPTW) based on propensity scores, Poisson regression was used to estimate the incidence rate ratio (IRR) of HM between clozapine and olanzapine users. The absolute rate difference was also estimated. In total, 9,965 patients with a median follow-up period of 6.99 years (25th to 75th percentile: 4.45 to 10.32 years) were included, among which 834 were clozapine users. After IPTW, the demographic and clinical characteristics of clozapine users were comparable to those of olanzapine users. Clozapine users had a significant weighted IRR of 2.22 (95% confidence interval (CI) [1.52, 3.34]; p < 0.001) for HM compared to olanzapine users. The absolute rate difference was estimated at 57.40 (95% CI [33.24, 81.55]) per 100,000 person-years. Findings were consistent across subgroups by age and sex. Sensitivity analyses all supported the robustness of the results and showed good specificity to HM but no other cancers. The main limitation of this observational study is the potential residual confounding effects that could have arisen from the lack of randomization in clozapine or olanzapine use.
Absolute rate difference in HM incidence associated with clozapine is small despite a 2-fold elevated rate. Given the rarity of HM and existing blood monitoring requirements, more restrictive indication for clozapine or special warnings may not be necessary.
氯氮平被广泛认为是一种高效的精神药物，但在全球范围内大多未得到充分使用。最近的不成比例分析和全国性病例对照研究表明，氯氮平的使用与血液系统恶性肿瘤（HM）之间可能存在关联。然而，由于缺乏分析性队列研究，绝对率差尚未明确确立。这种潜在风险的临床意义仍不清楚。
我们从香港2001年1月至2022年8月的全地区公共医疗数据库中提取数据，对年龄在18岁及以上、诊断为精神分裂症、使用氯氮平或奥氮平（化学结构和药理机制高度相似的药物对照）90天以上且两组内均至少有2次先前使用其他抗精神病药物记录的匿名患者进行回顾性队列研究。基于倾向评分采用治疗逆概率加权法（IPTW），使用泊松回归估计氯氮平和奥氮平使用者中HM的发病率比（IRR）。还估计了绝对率差。总共纳入了9965名患者，中位随访期为6.99年（第25至75百分位数：4.45至10.32年），其中834名是氯氮平使用者。经过IPTW后，氯氮平使用者的人口统计学和临床特征与奥氮平使用者相当。与奥氮平使用者相比，氯氮平使用者发生HM的加权IRR显著为2.22（95%置信区间[CI][1.52, 3.34]；p < 0.001）。绝对率差估计为每10万人年57.40（95% CI [33.24, 81.55]）。按年龄和性别划分的亚组结果一致。敏感性分析均支持结果的稳健性，对HM具有良好的特异性，但对其他癌症无特异性。这项观察性研究的主要局限性是氯氮平或奥氮平使用缺乏随机化可能产生的潜在残余混杂效应。
尽管氯氮平相关的HM发病率升高了2倍，但其绝对率差较小。鉴于HM的罕见性以及现有的血液监测要求，可能无需对氯氮平采取更严格的适应证或特殊警告。
