Mongkhon Pajaree, Singkham Noppaket, Ponok Kunyarat, Liamsrijan Natpatsorn, Phoosa Wipada, Phattanasobhon Sirayut, Fanning Laura, Senthong Vichai, Saokaew Surasak
Unit of Excellence on Cardiovascular Archive Research and Clinical Epidemiology, School of Pharmaceutical Sciences, University of Phayao, Phayao, 56000, Thailand.
Division of Social and Administrative Pharmacy (SAP), Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, 56000, Thailand.
Drug Saf. 2025 Jan;48(1):25-42. doi: 10.1007/s40264-024-01476-8. Epub 2024 Aug 30.
Off-label underdosed direct oral anticoagulants (DOACs) are commonly utilised in Asian patients with atrial fibrillation (AF) since they are prone to bleeding with OACs. However, the efficacy and safety of off-label underdosing DOACs are controversial. This study aimed to compare the effectiveness and safety of off-label underdosed DOACs in Asian patients with AF.
PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from 2010 to July 5, 2024, for randomised controlled trials or observational studies that compared off-label DOACs and on-label/warfarin in Asian patients with AF. The primary outcomes included ischaemic stroke or systemic embolism (ISSE) and major bleeding (MB), while secondary outcomes included all-cause death, gastrointestinal bleeding (GIB), intracranial haemorrhage (ICH), and myocardial infarction (MI). Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled using random-effects models.
Twenty observational studies were included. Seventeen studies compared off-label underdosed DOACs versus on-label DOACs, whereas five studies compared off-label underdosed DOACs versus warfarin. Off-label underdosed DOACs were associated with higher risk of ISSE (pooled HR [pHR] = 1.17; 95% CI: 1.00-1.38, p = 0.048) and ICH (pHR = 1.27; 95% CI: 1.06-1.52, p = 0.010) versus on-label. Subgroup analysis demonstrated increased ISSE risk with off-label underdosed rivaroxaban compared to on-label (pHR = 1.49; 95% CI: 1.07-2.08). Compared to warfarin, off-label underdosed DOACs were associated with decreased risk of MB (pHR = 0.46; 95% CI: 0.32-0.65, p < 0.001), GIB (pHR = 0.52; 95% CI: 0.29-0.93, p = 0.028), ICH (pHR = 0.60; 95% CI: 0.42-0.86, p = 0.005), and all-cause death (pHR = 0.70; 95% CI: 0.56-0.87, p = 0.001), while illustrating similar ISSE risk.
Off-label underdosed DOACs, particularly rivaroxaban, was associated with increased ISSE risk but did not decrease bleeding compared to on-label. Adherence to appropriate DOAC doses should be emphasised to achieve the best clinical outcomes for Asian patients with AF.
由于亚洲房颤（AF）患者使用口服抗凝药（OAC）时容易出血，因此非标签低剂量直接口服抗凝药（DOAC）在该群体中被广泛使用。然而，非标签低剂量使用DOAC的疗效和安全性存在争议。本研究旨在比较非标签低剂量DOAC在亚洲房颤患者中的有效性和安全性。
检索2010年至2024年7月5日期间的PubMed、Embase、Cochrane图书馆和ClinicalTrials.gov，查找比较非标签DOAC与标签上规定剂量的DOAC/华法林在亚洲房颤患者中的随机对照试验或观察性研究。主要结局包括缺血性中风或全身性栓塞（ISSE）和大出血（MB），次要结局包括全因死亡、胃肠道出血（GIB）、颅内出血（ICH）和心肌梗死（MI）。使用随机效应模型汇总95%置信区间（CI）的风险比（HR）。
纳入了20项观察性研究。17项研究比较了非标签低剂量DOAC与标签上规定剂量的DOAC，而5项研究比较了非标签低剂量DOAC与华法林。与标签上规定剂量的DOAC相比，非标签低剂量DOAC与更高的ISSE风险（合并HR [pHR] = 1.17；95% CI：1.00 - 1.38，p = 0.048）和ICH风险（pHR = 1.27；95% CI：1.06 - 1.52，p = 0.010）相关。亚组分析表明，与标签上规定剂量的利伐沙班相比，非标签低剂量利伐沙班的ISSE风险增加（pHR = 1.49；95% CI：1.07 - 2.08）。与华法林相比，非标签低剂量DOAC与更低的MB风险（pHR = 0.46；95% CI：0.32 - 0.65，p < 0.001）、GIB风险（pHR = 0.52；95% CI：0.29 - 0.93，p = 0.028）、ICH风险（pHR = 0.60；95% CI：0.42 - 0.86，p = 0.005）和全因死亡风险（pHR = 0.70；95% CI：0.56 - 0.87，p = 0.001）相关，同时显示出相似的ISSE风险。
非标签低剂量DOAC，尤其是利伐沙班，与更高的ISSE风险相关，且与标签上规定剂量的DOAC相比并未降低出血风险。应强调坚持使用适当的DOAC剂量，以实现亚洲房颤患者的最佳临床结局。
