key: cord-270723-cjfglili authors: Fteiha, Bashar; Karameh, Hani; Kurd, Ramzi; Ziff‐Werman, Batsheva; Feldman, Itamar; Bnaya, Alon; Einav, Sharon; Orlev, Amir; Ben‐Chetrit, Eli title: QTc prolongation among hydroxychloroquine sulfate‐treated COVID‐19 patients: An observational study date: 2020-10-15 journal: Int J Clin Pract DOI: 10.1111/ijcp.13767 sha: doc_id: 270723 cord_uid: cjfglili BACKGROUND: The liberal administration of hydroxychloroquine‐sulphate (HCQ) to COVID‐19 patients has raised concern regarding the risk of QTc prolongation and cardiac arrhythmias, particularly when prescribed with azithromycin. We evaluated the incidence of QTc prolongation among moderately and severely ill COVID‐19 patients treated with HCQ and of the existence of concomitant alternative causes. METHODS: All COVID‐19 patients treated with HCQ (between Mar 1 and Apr 14, 2020) in a tertiary medical center were included. Clinical characteristics and relevant risk factors were collected from the electronic medical records. Individual patient QTc intervals were determined before and after treatment with HCQ. The primary outcome measure sought was a composite endpoint comprised of either an increase ≥ 60 milliseconds (ms) in the QTc interval compared with pretreatment QTc, and/or a maximal QTc interval >500 ms. RESULTS: Ninety patients were included. Median age was 65 years (IQR 55‐75) and 57 (63%) were male. Thirty‐nine patients (43%) were severely or critically ill. Hypertension and obesity were common (n=23 each, 26%). QTc prolongation evolved in fourteen patients (16%). Age > 65 years, congestive heart failure, severity of disease, C‐reactive protein level, hypokalemia and furosemide treatment, were all associated with QTc prolongation. Adjusted analysis showed that QTc prolongation was five times more likely with hypokalemia [OR 5, (95% CI, 1.3‐20)], and three times more likely with furosemide treatment [ OR 3 (95% CI, 1.01‐13.7)]. CONCLUSION: In patients treated with HCQ, QTc prolongation was associated with the presence of traditional risk factors such as hypokalemia and furosemide treatment. The emerging outbreak of Corona virus disease 2019 (COVID- 19) due to the novel beta corona virus SARS-CoV-2 has spread globally at an alarming rate. In search of effective treatments, one strategy was drug repurposing of an approved drug for a different disease than that for which it was originally developed. Among other options, the anti-malarial drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have resurfaced as promising drugs for the treatment of patients with COVID-19 disease 1,2 .The accumulated long-term experience with these drugs with regards to dosage, safety, adverse effects and drug interactions provided the leeway required for off-label use in the setting of the new pandemic. Pressured to provide antiviral treatment options in the midst of the pandemia, the FDA had approved the use of CQ and HCQ for treating COVID-19 disease 3 . An open-label nonrandomized (nowadays controversial) trial also showed that HCQ treatment was associated with a significant reduction in viral shedding, an effect reportedly accentuated by concomitant treatment with azithromycin in six patients 4 . Despite the small sample studied and the major methodological limitations of the study, it had garnered substantial attention in the media and scientific community. This led to liberal use of HCQ in hospitals overwhelmed with the SARS-CoV-2 pandemic despite the paucity of evidence. In the wake of the widespread use of HCQ, several authors have raised concerns regarding the potential for inducing cardiac arrhythmias. Significant QTc prolongation was attributed to treatment with HCQ in several papers, albeit mainly in patients receiving combined HCQazithromycin treatment 5-7 . Resultantly it has been proposed that frequent electrocardiographic (ECG) monitoring be mandatory for patients with COVID-19 who receive treatment with HCQ. This article is protected by copyright. All rights reserved As similar monitoring has not been previously recommended in other chronic illnesses such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) where HCQ is prescribed for months, this raises a major question regarding the actual risk of arrhythmias in this patient cohort. This study aimed to quantify the evolution of ECG changes potentially attributable to HCQ among moderate and severely ill COVID-19 patients and to seek concomitant causes. We hypothesized that QTc prolongation may be induced by the combination of severe acute illness and severe inflammation (reported in in addition to medications. Following receipt of Institutional Review Board approval (0154-20-SZMC) with waiver of informed consent, data collection was performed during patient admission for the purpose of this observational study. Clinical setting: The Shaare Zedek Medical Center (SZMC) is a tertiary 1000-bed teaching hospital. As the SARS-CoV-2 pandemic reached Jerusalem in March 2020, six departments were established to treat patients with COVID19 in the SZMC. These departments were isolated and set up with telemedicine and monitoring technologies to enable constant observation and monitoring of patients. Patients were admitted to these departments only after testing positive in a polymerase-chain reaction (PCR) nasopharyngeal swab specimen for SARS-CoV-2. Patients were classified as having mild to moderate illness defined as mild respiratory symptoms (no oxygen support) up to mild pneumonia. Severe disease was defined as hypoxia, diffuse bilateral infiltrates on imaging, requirement of high-flow nasal cannula or non-invasive ventilation. Critically ill patients were those who required mechanical ventilation with or without multi-organ failure. Treating physicians were allowed to administer HCQ to any patient with confirmed COVID-19 of moderate severity or worse unless contraindicated (QTc > 500 ms, known allergy to HCQ, significant liver disease). The treatment dose of HCQ was 400 mg twice daily on day 1, and 200 mg twice daily thereafter for 5 to 10 days. The dose was reduced by 50% in patients with creatinine clearance less than 30 ml/min. In cases where QTc interval increased by more than 60 ms or prolonged > 500 ms, HCQ was withdrawn. Inclusion/exclusion criteria: The EMRs of all adult patients admitted for treatment of confirmed COVID-19 and treated with HCQ were screened (Mar-1-2020 to Apr14-2020). Inclusion was confirmed following manual verification of a positive PCR nasopharyngeal swab specimen tested This article is protected by copyright. All rights reserved for SARS-CoV-2 and receipt of >2 days of HCQ and at least one follow-up ECG post-treatment ( Figure 1 ). Patients with known arrhythmias such as atrial fibrillation or conduction blocks were not excluded from the analysis. Data collection and variables: All relevant demographic, clinical and laboratory data (including additional medications which could potentially prolong QTc interval, prescribed throughout hospitalization and overlapped with HCQ treatment) were collected from the electronic medical record (EMR). HCQ was defined as a QT prolonging agent. In-line with the 2011 American Heart Association/American College of Cardiology scientific statement on prevention of TdP in hospital settings, a QTc of >470 ms for men, and >480 ms for women was considered prolonged. A QTc >500 ms was considered highly abnormal for both men and women 8 . Drug-induced QT prolongation was defined as a QTc of 500 ms or greater or an increase of 60 ms or greater in the QT interval compared with the premedication baseline interval 8 QTc calculation -The calculation of QTc in all patients was performed in accordance with a special QTc calculation protocol written by a team of senior electrophysiologists based on the guidelines recommended in the literature. The QT was measured manually using the "tangent" method, looking mainly at leads II and V5 9 . A tangent was drawn to the steepest last limb of the presumed T wave to define the end of the T wave as the intersection of this tangent with the baseline. The QTc interval was calculated from the QT and R-R intervals using Bazett's formula. The QRS interval was measured from the onset of the Q wave, or the R wave if no Q wave was visible, to the J point. The JTc interval was calculated by subtracting the QRS duration from the QTc interval (QTc interval -QRS duration). The protocol also accounts for the two special cases of atrial fibrillation and patients with wide complexes such as CLBBB -in cases of atrial fibrillation the average of QT interval and RR intervals for 5 to 10 beats was calculated, and QTc was then calculated according to Bazett's formula. in case of CLBBB or pacemaker rhythm, QTc was calculated by subtracting 50 ms from the corrected QT when QRS width was more than 100 ms, or subtracting 50 ms from the original value in a pacemaker provided the pacing rate is around 60 beats per second. ECG was repeated at the convenience of the treating physician in order to reduce unnecessary contact with patients. The maximal QTc measurement observed in all follow-up electrocardiograms was documented for each patient. This article is protected by copyright. All rights reserved Outcome measures: The primary outcome measure was a composite endpoint consisting of either an increase  60 ms of the QTc interval post HCQ treatment (as compared with baseline QTc prior to treatment) and/or a maximal QTc interval longer than 500 ms. The secondary outcome was the adjusted association of the occurrence of QT prolongation (yes/no) with HCQ treatment combinations. All data were inserted to -a Microsoft Excel (version 16 Two hundred and ninety-seven patients with confirmed COVID-19 disease were screened during the 45-day study period. Among these patients, overall 149 were treated with HCQ during admission. One patient was initially treated with CQ but this treatment was replaced with HCQ three days later due to hallucinations. Overall ninety patients met inclusion criteria. The rest were excluded due to lack of serial ECG recordings, missing data or completion of less than 2 days of treatment ( Figure 1 ). HCQ was prescribed for a median of 7 days (IQR 6-8). The demographic and clinical characteristics of the study cohort are presented in Table 1 . The median age of the patients was 65 (IQR 55-75) years and 57 (63 %) were male. Fifty-one patients (57%) had mild to moderate disease and 39 (43%) had severe or critical illness. The mean CRP level was 15 (± 11) mg/dl. Twenty-six patients (29%) were treated with HCQ alone and 31 patients (34%) were treated with HCQ and azithromycin. Thirty-three patients were treated with This article is protected by copyright. All rights reserved HCQ and other QTc prolonging medications including 7 patients who were treated with levofloxacin ( Table 1 ). The mortality rate in the study cohort was 12.2% (11 patients), all were critically ill. Nine patients had atrial fibrillation. Two had a pacemaker and one had CLBBB. The Table 1) . A significant QTc prolongation of more than 60 ms was noted in 11 (12%) patients. QTc prolongation greater than 500 ms was identified in 7 (7.8%) patients. The overall composite endpoint was identified in overall 14 patients (16%). The increase in the QTc interval seemed somewhat higher among patients treated with combination therapy as compared to HCQ treatment only but the difference was not found to be statistically significant (Supplemental figure) . Overall, 11 patients died. The median age of non-survivors was 86 (IQR 79-90). Median BMI and CRP was 30 (IQR 21-33) and 24 (9-35), respectively. Five had CHF, 6 had atrial fibrillation. Nine were treated with multiple QTc prolonging agents including azithromycin, ciprofloxacin, and antipsychotics. Six had met the composite endpoint. Two had an increase of more than 60 ms in the QTc interval, three had a maximal QTc longer than 500 ms, and in one patient both endpoints were reached. In all patients HCQ was withdrawn. Three of the patients had hypokalemia. Five were treated with multiple QT prolonging drugs. Sudden clinical deterioration and asystole was documented in a 71-year-old morbidly obese male patient with diabetes. A 90-year-old female patient with congestive heart failure, atrial fibrillation and hyperkalemia had ventricular tachycardia. Ventricular fibrillation occurred in one 79-year-old patient with multiple co-morbidities (IHD, diabetes, end-stage kidney disease) not meeting the composite endpoint. This article is protected by copyright. All rights reserved Univariate analysis revealed that in COVID-19 patients treated with HCQ, age above 65 years, severe or critical illness, congestive heart failure, hypokalemia, furosemide treatment and increased CRP level were all significantly associated with the composite endpoint (Table 2) . Hypomagnesemia was not detected in any of the patients. Co-linearity testing showed a strong interaction between furosemide treatment, CRP and severe or critical disease. Although CRP had a strong correlation with meeting the composite endpoint (p=0.01), the OR was not as significant as that of furosemide -OR 1.06 (95% CI 1.01-1.1), vs. Multivariate analysis revealed that hypokalemia and furosemide therapy were strongly associated with QTc prolongation (Table 2 ). The current study reports significant QTc interval prolongation in 16% of the patients treated with HCQ with/without other agents. However, multivariate analysis in this small dataset also suggested that in COVID-19 patients treated with HCQ, concomitant hypokalemia and furosemide treatment were strongly associated with QTc prolongation. Our study findings support those of previous studies that showed a mild increase in the QTc interval among patients treated with HCQ and azithromycin and to a higher degree with quinolones 7 . In our cohort QTc prolongation was not significantly higher in patients receiving HCQ in combination with other drugs than with HCQ treatment alone but our study was not powered to seek this outcome. Similarly, a recent multicenter randomized controlled trial conducted in Brazil reported more frequent events of QTc interval prolongation among patients who received HCQ, either with azithromycin or alone, than patients who did not receive either agent 10 . This article is protected by copyright. All rights reserved The presence of hypokalemia did not correlate with furosemide treatment. Hypokalemia may be a common finding in COVID-19 patients, a finding that has been mainly attributed to urinary potassium loss secondary to angiotensin converting enzyme 2 (ACE2) degradation in recent reports 11 . Gastrointestinal loss of potassium may also play and important role in inducing hypokalemia as diarrhea may occur in 2% to 50% of COVID-19 patients 12 . The use of loop diuretics is an independent risk factor for QTc prolongation 13 . It is also one of the variables comprising the Tisdale Risk Score which predicts the risk of QT prolongation > 500 ms in hospitalized patients 14 . A similar finding was demonstrated in a recent report 7 . Furosemide was often administered to patients in our cohort, most often to those who were severely ill. Diuretics may be appropriate in ARDS and are the mainstay of treatment of heart failure. The pulmonary infiltrates that are almost pathognomonic of COVID-19 disease tempt clinicians treating these complex patients, particularly those who have been trained to treat these diseases, to administer diuretics. However, our findings suggest that treatment with loop diuretics is not harmless in this scenario and that administration of such treatment, particularly when combined with HCQ, should not be empirical. Testing for beta natriuretic factor levels and performing an echocardiograph may be of value. Treatment should be accompanied by appropriate monitoring of blood potassium and magnesium levels as well as periodic ECGs. Severely ill patients are at increased risk of QTc prolongation due to multiple risk factors [12 15 ]. These patients are often treated with QTc prolonging drugs other than loop diuretics (e.g. amiodarone, anti-emetics and anti-psychotics). Acute delirium is common among patients with COVID-19 disease 16 .In our cohort 16 patients (18%) received anti-psychotic medications (table 1, footnote). Although we did not identify an association between such treatment and QTc prolongation, our cohort may have been too small to detect it Mercuro et al. also showed an association between QTc prolongation > 500 ms and severe COVID-19 infection with more than two inflammatory systemic response syndrome criteria 7 Other studies have also suggested that critically-ill patients with increased levels of IL-1, IL-6, TNF-ɑ and CRP are prone to arrhythmia 17-19 . We also found that severely ill patients had a higher mean CRP than did mild to moderately ill patients (20±13.8 versus 11±6.4, respectively, p value <0.01) and higher values were significantly associated with the composite endpoint (Table 2) . This article is protected by copyright. All rights reserved Among the study patients eleven died. All were elderly, severely ill patients with markedly elevated CRP and a high BMI. It is difficult to delineate the cause of death as in most cases it is multi-factorial (multiple co-morbidities, respiratory insufficiency, renal failure, secondary infections) and this was not the aim of our study. However, QTc prolongation is a risk factor for cardiac death and indeed, six patients who did not survive had met the composite endpoint of the study. Although fatal arrhythmia was documented in only two, most of the cohort patients were not continuously monitored, thus, the likelihood of under-diagnosis of severe arrhythmias was high. Our study has several limitations, including the inherent limitations of a retrospective design, a single center study, and its small sample size. However, similar observations have been reported elsewhere 5,7 . Some patients had only one follow-up ECG reflecting the initial technical difficulties of many medical teams that were learning to manage mass isolation at the outset of the pandemic. In addition, patients excluded from the study due to missing serial ECGs may have had mild cardiac disease and this may have contributed to selection bias. Finally, the lack of a control group of patients without HCQ treatment makes it difficult to ascertain whether the QTc prolongation is related to treatment with HCQ or is a consequence of the disease itself. Nevertheless, serial electrocardiograms with successive QT measurements are not routinely performed for COVID-19 patients which makes creating a control group a rather difficult task. In conclusion, our study shows that QTc prolongation among HCQ-treated patients was associated with traditional, modifiable risk factors such as hypokalemia and furosemide treatment which are both commonly observed in COVID-19 patients. Importantly, the present study was based on data from patients admitted during the first weeks of the pandemia in Israel, when treatment guidelines were based on preliminary reports from China and Italy suggesting HCQ to be beneficial. Since then, accumulating data based on better-designed studies, do not support the use of this drug 21, 22 . In our institute, HCQ is no longer recommended in COVID-19. Table 2 . Univariate analysis and adjusted multivariate regression analysis of variables associated with QT prolongation > 60 ms and/or QT prolongation > 500 ms post-treatment with HCQ (the composite endpoint). This article is protected by copyright. All rights reserved In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Request for emergency use authorization for use of chloroquine phosphate or hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of 2019 Coronavirus disease United States Food and Drug Administration Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label nonrandomized clinical trial Ventricular Arrhythmia Risk Due to Hydroxychloroquine-Azithromycin Treatment For COVID-19 Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19) Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation Determination and Interpretation of the QT Interval Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19 Hypokalemia and Clinical Implications in Patients with Coronavirus Disease infection: pathogenesis, epidemiology, prevention and management Risk factors for QTc interval prolongation Development and validation of a risk score to predict QT interval prolongation in hospitalized patients QTc interval prolongation in critically ill patients: Prevalence, risk factors and associated medications Accepted Article QT interval and inflammatory cytokines in rheumatoid arthritis An Emerging Role for Inflammation and Immunity Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment COVID-19 and the cardiovascular system Hydroxychloroquine in Hospitalized Patients with Covid-19 Electrocardiographic features, median (IQR) Highest CRP during HCQ treatment, mg/dL 15.2 (11.1)