Department of Pharmacy, Sungai Buloh Hospital, Ministry of Health, Sungai Buloh, Malaysia.
Department of Medicine and Infectious Disease, Sungai Buloh Hospital, Ministry of Health, Sungai Buloh, Malaysia.
J Clin Pharm Ther. 2021 Jun;46(3):800-806. doi: 10.1111/jcpt.13356. Epub 2021 Mar 25.
Hydroxychloroquine and protease inhibitors were widely used as off-label treatment options for COVID-19 but the safety data of these drugs among the COVID-19 population are largely lacking. Drug-induced QTc prolongation is a known adverse reaction of hydroxychloroquine, especially during chronic treatment. However, when administered concurrently with potential pro-arrhythmic drugs such as protease inhibitors, the risk of QTc prolongation imposed on these patients is not known. We aim to investigate the incidence of QTc prolongation events and potential factors associated with its occurrence in COVID-19 population.
We included 446 SARS-CoV-2 RT-PCR-positive patients taking at least one treatment drug for COVID-19 within a period of one month (March-April 2020). In addition to COVID-19-related treatment (HCQ/PI), concomitant drugs with risks of QTc prolongation were considered. We defined QTc prolongation as QTc interval of ≥470 ms in postpubertal males, and ≥480 ms in postpubertal females.
QTc prolongation events occurred in 28/446 (6.3%) patients with an incidence rate of 1 case per 100 person-days. A total of 26/28 (93%) patients who had prolonged QTc intervals received at least two pro-QT drugs. Multivariate analysis showed that HCQ and PI combination therapy had five times higher odds of QTc prolongation as compared to HCQ-only therapy after controlling for age, cardiovascular disease, SIRS and the use of concurrent QTc-prolonging agents besides HCQ and/or PI (OR 5.2; 95% CI, 1.11-24.49; p = 0.036). Independent of drug therapy, presence of SIRS resulted in four times higher odds of QTc prolongation (OR 4.3; 95% CI, 1.66-11.06; p = 0.003). In HCQ-PI combination group, having concomitant pro-QT drugs led to four times higher odds of QTc prolongation (OR 3.8; 95% CI, 1.53-9.73; p = 0.004). Four patients who had prolonged QTc intervals died but none were cardiac-related deaths.
In our cohort, hydroxychloroquine monotherapy had low potential to increase QTc intervals. However, when given concurrently with protease inhibitors which have possible or conditional risk, the odds of QTc prolongation increased fivefold. Interestingly, independent of drug therapy, the presence of systemic inflammatory response syndrome (SIRS) resulted in four times higher odds of QTc prolongation, leading to the postulation that some QTc events seen in COVID-19 patients may be due to the disease itself. ECG monitoring should be continued for at least a week from the initiation of treatment.
羟氯喹和蛋白酶抑制剂曾被广泛用作 COVID-19 的非适应证治疗选择，但 COVID-19 人群中这些药物的安全性数据在很大程度上缺乏。羟氯喹已知会导致 QTc 延长，尤其是在慢性治疗期间。然而，当与潜在的致心律失常药物（如蛋白酶抑制剂）同时给药时，这些患者的 QTc 延长风险尚不清楚。我们旨在调查 COVID-19 人群中 QTc 延长事件的发生率以及与 QTc 延长发生相关的潜在因素。
我们纳入了 446 例 SARS-CoV-2 RT-PCR 阳性患者，这些患者在一个月内（2020 年 3 月至 4 月）接受了至少一种 COVID-19 治疗药物。除 COVID-19 相关治疗（羟氯喹/蛋白酶抑制剂）外，还考虑了具有 QTc 延长风险的伴随药物。我们将 QTc 延长定义为青春期后男性 QTc 间期≥470ms，青春期后女性 QTc 间期≥480ms。
446 例患者中有 28 例（6.3%）发生 QTc 延长事件，发生率为每 100 人天 1 例。所有发生 QTc 延长的 28 例患者中，共有 26 例（93%）接受了至少两种致 QTc 药物。多变量分析显示，在控制年龄、心血管疾病、全身炎症反应综合征（systemic inflammatory response syndrome，SIRS）和除羟氯喹和/或蛋白酶抑制剂以外的同时使用致 QTc 药物后，羟氯喹和蛋白酶抑制剂联合治疗的 QTc 延长风险是羟氯喹单药治疗的五倍（比值比 5.2；95%置信区间，1.11-24.49；p=0.036）。无论药物治疗如何，SIRS 的存在使 QTc 延长的可能性增加了四倍（比值比 4.3；95%置信区间，1.66-11.06；p=0.003）。在羟氯喹-蛋白酶抑制剂联合治疗组中，同时使用致 QTc 药物使 QTc 延长的可能性增加了四倍（比值比 3.8；95%置信区间，1.53-9.73；p=0.004）。有 4 例 QTc 延长的患者死亡，但均与心脏无关。
在我们的队列中，羟氯喹单药治疗导致 QTc 间期延长的可能性较低。然而，当与可能或有条件风险的蛋白酶抑制剂同时使用时，QTc 延长的风险增加了五倍。有趣的是，独立于药物治疗，全身炎症反应综合征（systemic inflammatory response syndrome，SIRS）的存在使 QTc 延长的可能性增加了四倍，这表明 COVID-19 患者中出现的一些 QTc 事件可能是由疾病本身引起的。应在开始治疗后至少一周内继续进行心电图监测。
