Experience With Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for QT Interval Monitoring

Abstract

Background Despite a lack of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected coronavirus disease 2019 ( COVID ‐19). Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation. Methods and Results We analyzed a case series of COVID ‐19–positive/suspected patients admitted between February 1, 2020, and April 4, 2020, who were treated with azithromycin, hydroxychloroquine, or a combination of both drugs. We evaluated baseline and postmedication QT interval (corrected QT interval [QTc]; Bazett) using 12‐lead ECG s. Critical QT c prolongation was defined as follows: (1) maximum QT c ≥500 ms (if QRS <120 ms) or QT c ≥550 ms (if QRS ≥120 ms) and (2) QT c increase of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated. Of 490 COVID ‐19–positive/suspected patients, 314 (64%) received either/both drugs and 98 (73 COVID ‐19 positive and 25 suspected) met study criteria (age, 62±17 years; 61% men). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QT c was 448±29 ms and increased to 459±36 ms ( P =0.005) with medications. Significant prolongation was observed only in men (18±43 ms versus −0.2±28 ms in women; P =0.02). A total of 12% of patients reached critical QT c prolongation. Changes in QT c were highest with the combination compared with either drug, with much greater prolongation with combination versus azithromycin (17±39 ms versus 0.5±40 ms; P =0.07). No patients manifested torsades de pointes. Conclusions Overall, 12% of patients manifested critical QT c prolongation, and the combination caused greater prolongation than either drug alone. The balance between uncertain benefit and potential risk when treating COVID ‐19 patients should be carefully assessed.

Effect of Triple Combination Therapy With Lopinavir-Ritonavir, Azithromycin, and Hydroxychloroquine on QT Interval and Arrhythmic Risk in Hospitalized COVID-19 Patients

“…Previous retrospective studies including different cohorts of COVID-19 patients showed that both AZT and cloroquine (CQ) or HQ increased the risk of QTc prolongation, with a incidence ranging from 10.7% to 36 % ( Bessiere et al, 2020 ; Mercuro et al, 2020 ; Ramireddy et al, 2020 ).…”

“…The association of CQ/HQ and AZT resulted in a significantly greater increase in the QTc interval when compared with monotherapy with either CQ or HQ ( Mercuro et al, 2020 ; Ramireddy et al, 2020 ; Saleh et al, 2020 ); however, though patients experienced QTc interval prolongation, especially when combination therapy was used, the risk of arrhythmic death and TdP were not increased ( Bun et al, 2020 ; Mercuro et al, 2020 ).…”

“…LPN/RTN causes the dose-dependent block of both human ether-a-go-go-related gene (HERG) potassium channels and delayed rectifier potassium current (IKr) channels predisposing to QT prolongation and torsade de pointes (TdP) ( Anson et al, 2005 ; Russo et al, 2020b ). Increased corrected QTc interval (QTc) has been reported in hospitalized COVID-19 patients treated with HQ/AZT ( Bun et al, 2020 ; Chorin et al, 2020 ; Cipriani et al, 2020 ; Hor et al, 2020 ; Mercuro et al, 2020 ; Ramireddy et al, 2020 ) alone or in combination, due the inhibitory effects on IKr channels. The concomitant use of three or more QT prolonging drugs twice increases the risk of QT prolongation in hospitalized patients on cardiology ward ( Khan et al, 2017 ); however, no data on the effect of triple combination therapy with LPN/RTN, HQ and AZT on corrected QT (QTc) interval and arrhythmic risk have been still provided.…”

Use of hydroxychloroquine for pre-exposure prophylaxis in COVID 19: debate and suggested future course

“…Instances of TdP have been observed in two studies [16,17]. However, in other study cohorts, it has been reported that while QT C prolongation occurred, it did not lead to arrythmias and drug discontinuation was rarely needed [19,20]. USFDA pharmacovigilance data reports 90 cases of serious cardiac events (17 fatal events) associated with HCQ including QT C prolongation, TdP, and other ventricular arrythmias [21].…”

Cardiotoxicity induced by the combination therapy of chloroquine and azithromycin in human embryonic stem cell-derived cardiomyocytes

“…Several reports have suggested a possible synergistic effect of the combination of HCQ and AZM, thereby prompting their use in combination ( 16 , 17 ). However, recent clinical studies have reported that the combination therapy of CQ/HCQ and AZM induces cardiotoxicity in patients ( 18 , 19 ). Although AZM itself does not usually lead to clinically significant prolongation of the corrected QT interval ( 20 ), studies have shown that AZM in combination with CQ/HCQ induced QT interval prolongation and torsades de pointes in patients ( 21 , 22 ).…”