key: cord-0713124-1z7sm184 authors: Koh, Hui Moon; Chong, Pei Feng; Tan, Ju Nee; Chidambaram, Suresh Kumar; Chua, Hiu Jian title: QT prolongation associated with hydroxychloroquine and protease inhibitors in COVID‐19 date: 2021-03-25 journal: J Clin Pharm Ther DOI: 10.1111/jcpt.13356 sha: d95ef600f573010e4b3d8dc56bc55407bf7148ee doc_id: 713124 cord_uid: 1z7sm184 WHAT IS KNOWN AND OBJECTIVE: 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. METHODS: 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. RESULTS AND DISCUSSION: 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. WHAT IS NEW AND CONCLUSION: 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. Hydroxychloroquine (HCQ) and protease inhibitors (PI) were two of the most commonly repurposed drugs used as investigational therapeutics for COVID-19. Hydroxychloroquine possesses antiviral properties in vitro 1,2 by inhibiting ACE2-mediated viral entry (i.e. pre-infection prophylaxis) and has been postulated for having a role in attenuating the viral cytokine storm in severe COVID-19 patients. Due to the promising in vitro data, chloroquine or hydroxychloroquine had been extensively used in various countries as a COVID-19 treatment 3, 4 . Although exhibiting relatively favourable safety profiles, hydroxychloroquine blocks potassium channels and can potentially prolong corrected QT(QTc) intervals 5 , causing known risk of drug-induced torsades de pointes (DI-TdP) or drug-induced sudden cardiac death (DI-SCD). Several recent reviews have highlighted the risk of cardiac toxicity when used for the treatment of COVID-19 [6] [7] [8] . Commonly used boosted protease inhibitors in the treatment of COVID-19 include lopinavir/ritonavir 9 and atazanavir/ritonavir 10 . Similar to hydroxychloroquine, protease inhibitors do not independently prolong QTc intervals. However, the risk of QTc prolongation is increased with other risk factors such as multiple concurrent drugs that may prolong QTc and/or have multiple comorbidities 5 . Therefore, protease inhibitors when combined with hydroxychloroquine may potentiate DI-TdP. Lopinavir/ritonavir has possible TdP risk whereas atazanavir/ritonavir has conditional TdP risk when hypokalaemia is present or when taken with interacting drugs 11 . Concomitant pro-QT drugs or drugs that cause electrolyte disturbances such as diuretics and digoxin 12 can lead to pharmacokinetic and pharmacodynamic drug interactions. Each pro-QT drug is highly dependent on the circumstances of its use and on each patient's clinical characteristics. There were mainly three risk categories-known risk (KR), possible risk (PR) and conditional risk (CR) 11 . The known risk category encompasses drugs that prolong QT intervals and are clearly associated with a known risk of TdP, even when taken as recommended. The possible risk category encompasses drugs that can cause QT prolongation but currently lack evidence for a risk of TdP when taken as recommended, whereas the conditional risk category refers to drugs associated with TdP but only under certain conditions of their use (e.g. excessive doses, in patients with conditions such as hypokalemia or when taken with interacting drugs) or by creating conditions that facilitate or induce TdP (e.g. by inhibiting metabolism of a QT-prolonging drug or by causing an electrolyte disturbance that induces TdP). Additionally, QTc interval may be elevated by patient-related risk factors such as age, gender, hypokalemia, sepsis and presence of pre-existing comorbidities especially cardiovascular dysfunction 12 . National Health Services (NHS) UK defines cardiovascular dysfunction as conditions affecting the heart or blood vessels, and these conditions include coronary heart disease, stroke or transient ischaemic attack, peripheral arterial disease and aortic disease. Given the extensive but yet experimental use of these drugs in the treatment of COVID-19, our study aimed to investigate the incidence of QTc prolongation event and potential factors associated with its occurrence in the COVID-19 population. This study was also pivotal to provide an insight to targeted recommendation of 12-lead electrocardiogram (ECG) screening in patients on pro-QT COVID-19 therapy, especially in resource-limited settings. This study has been approved by the Medical Research and Ethics Committee Malaysia and registered with the National Medical Research Register (NMRR-20-798-54728). We established a retrospective study including 446 patients who pharmacotherapies used were interferon beta-1b and ribavirin. Patients who had 12-lead ECG done within two weeks from the start of these drugs were included in the study. The ECG findings for QTc prolongation were reported by the attending physician 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. COVID-19, drug interaction, hydroxychloroquine, protease inhibitor, QTc prolongation either in actual time units or as prolonged or not in the EMR. We excluded patients whose ECG results were unavailable or unrecorded, patients whose ECG recorded prolonged QTc at baseline prior to starting drugs, patients who were recruited into the WHO Solidarity Trial, and pregnant women. We also excluded patients with underlying atrial fibrillation as QTc measures might be unreliable. After screening for eligibility, patients were screened for QTc prolongation events. Systemic inflammatory response syndrome (SIRS) was included as a potential risk factor for increasing QTC. SIRS was defined by two or more criteria, such as temperature >38.3˚C or <36˚C, heart rate of <90bpm, respiratory rate >20 breaths/min or PaCO2<32mmHg and white blood cell (WBC) >12,000 cells/mm 3 , <4000 cells/mm 3 or >10% immature bands 13 . Patients were observed for hospital outcome measures until discharge, death or up until 30 th May 2020. The primary outcome is the clinical documentation of QTc prolongation. All ECG data were directly recorded from the EMR. QTc prolongation was defined as any QTc interval exceeding 470 ms in postpubertal males, and 480 ms in postpubertal females, or a QTc increase of ≥ 60 ms from baseline. The interval has to be preceded by any pro-QT drug within 24 hours. In local practice, for QTc comparisons to be made, QTc was calculated from lead II of the 12-lead electrocardiogram and corrected for heart rate using Bazett's formula 14 . Dichotomous variables were expressed using proportions; continuous variables were expressed as medians with interquartile ranges (IQRs) and means with standard deviation (SD), where appropriate. The associations between QTc prolongation and potential risk factors were assessed using chi-square and logistic regression analysis. Variables for univariate analysis were chosen based on review of published literature. After univariate analysis, multivariate logistic regression was used to ascertain the relationship between risk factors and QT prolongation events. Multicollinearity among the independent variables was tested after recoding categorical variables into dummy variables. Statistical analyses were performed using SPSS version 22 (IBM). All levels of significance were set at 0.05. A total of 446 patients were included in the study (Figure 1 ). The baseline demographics and clinical characteristics of the study population are shown in Table 1 . In terms of COVID treatment drug regimens, 437/446 (98.0%) were put on HCQ-based treatment and about half of them were receiving PI in addition to HCQ. The median hospital stay duration was 9 days (IQR 6-13). The incidence of QTc prolongation events was 28/446 (6.3%) with a rate of 1 case per 100 person-days. The proportion of prolonged QTc events in the HCQ-only group, PI-only group, and F I G U R E 1 Study recruitment following eligibility according to inclusion and exclusion criteria. EMR: electronic medical records; RT-PCR: real-time reversetranscriptase polymerase chain reaction; AF: atrial fibrillation HCQ-PI combination group were 2/219 (0.9%), 2/9 (22%) and 24/218 (11%), respectively. Among the 24 patients who developed QTc prolongation while being put on the HCQ-PI combination, 13(54%) and 11 (45.8%) were receiving lopinavir/ritonavir and atazanavir/ritonavir respectively. Out of nine patients in the PI-only group, only one patient was on atazanavir/ritonavir and this patient was one of the two patients who had QTc prolongation. The estimated mean time from the commencement of HCQ or/and PI-based treatment to the development of QTc prolongation was 6 days (SD 3.3). All concurrent drugs that had known, possible or conditional risk of QTc prolongation were considered in the analyses ( Table 2) . We found that 237/446 (53.1%) were exposed to two or more QTcprolonging agents. Among the 28 patients who developed QTc prolongation, 19 (67.9%) had received concomitant QTc-prolonging drugs besides HCQ and/or PI,and 26 (92.9%) had received at least two pro-QT drugs be it HCQ, PI or other concomitant drugs ( Table 3) . The results for univariate and multivariate regression analyses are shown in Table 4 . In multivariate analysis, combination therapy containing both HCQ and PI was associated with five times higher odds of QTc prolongation events as compared to HCQ-only therapy after Our study reported a 0.9% incidence of QTc prolongation in patients taking onlyhydroxychloroquine. This is in line with the study by Gerard et al. which reported an estimated incidence of 0.77% to 1.54% for cardiac adverse drug reaction secondary to hydroxychloroquine, with prolonged QTc being the commonest cause 16 . However, there were differences in the study populations in which our study population was of a younger age group ( Similarly, hydroxychloroquine is also a hERG-K blocker and drugdrug interaction occurring with the combination of both therapies could explain the result of this finding 22 . This is supported by another study which reported that HCQ given together with PIs significantly increase QTc interval of >500ms with an increase of >40ms by day 3 of therapy 20 . However, PIs do not appear to independently predispose patient to QTc prolongation 23, 24 . Our study showed no difference in the occurrence of QTc event between the different PIbased regimens, similar to the findings in the SMART study 24 . Our study has shown that HCQ and/or PI-based treatments with other concomitant pro-QT drugs had a higher chance of causing QTc prolongation when compared to those patients on treatments with no other concomitant pro-QT drugs. The increase in risk has been highlighted in other studies whereby the concurrent usage of a pro-QT drug like azithromycin increased the risk of QTc prolongation by 3% to 28% as compared to treatments with HCQ alone 17, 18 . In critically ill patients, concurrent pro-arrhythmic drugs given together such as macrolides, fluoroquinolones, typical and atypical antipsychotics were associated with QTc prolongation 25 . This explains the association of QTc prolongation with some of the concomitant pro-arrhythmic drugs given in our study in Table 2 . QTc prolongation was likely due to the drugs' mechanism of action or through the interaction with other drugs which prolongs the repolarization phase. Moreover, the wide extent of underlying clinical conditions predisposes patients to higher risk of developing TdP, especially in the critically ill. This underscores the importance of drug reconciliation to enable early identification of QTc-prolonging drugs that patients have been taking and discontinuation of them if deemed unnecessary prior to the initiation of pro-QT drugs used for COVID-19 treatments. Interestingly, we found that systematic inflammatory response (SIRS) is an independent factor/variable in prolonging QTc. COVID-19 is known to cause an accentuated immune response in some individuals resulting in a more severe disease 26 . This explains that COVID-19 patients reportedly have a longer baseline QTc due to metabolic and physiological sequelae of the illness 20 . Additionally, critically ill from ongoing large randomized trials is anticipated 7, 8 . Despite having the highest number of admissions for COVID-19 in the country, single-centred studies such as ours lacked external validity. There were no cardiac-related morbidity and mortality in our cohort, which warrants a further validation through multi-centred, controlled trials. Another limitation to our study was the absence and non-feasibility of continuous ECG monitoring. Ill patients were monitored daily whereas fitter patients were monitored periodically within the treatment period. This means the actual start time of QTc prolongation was not known. In this cohort, HCQ-only regimens had low potential for QTc prolongation but the risk was increased with combined use of QTcprolonging drugs. ECG monitoring for QTC prolongation should be done periodically for at least a week from the initiation of treatment. Drug reconciliation is essential to avoid overlapping toxicities. This study has been approved by the Medical Research and Ethics Committee Malaysia and registered with the National Medical Research Register (NMRR-20-798-54728). Due to the nature of the retrospective chart review, the need for informed consent from individual patients was waived. All authors accept the terms and conditions of the editorial for publication. We would like to thank the Director General of Health Malaysia for his permission to publish this article. We would also like to record our deepest gratitude to our Pharmacy Head of Department, Dr permission to allow the research to be conducted in this facility. No conflicts of interest have been declared. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. 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