Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring

Abstract

1 Background: Despite a paucity of clinical evidence, hydroxychloroquine and 2 azithromycin are being administered widely to patients with verified or suspected 3 COVID-19. Both drugs may increase risk of lethal arrhythmias associated with QT 4 interval prolongation.5Methods: We performed a case series of COVID-19 positive/suspected patients admitted 6 between 2/1/2020 and 4/4/2020 who were treated with azithromycin, hydroxychloroquine 7 or a combination. We evaluated baseline and post-medication QT interval (QTc, Bazett's) 8 using 12-lead ECGs. Critical QTc prolongation was defined as: a) maximum QTc ≥500 ms 9 (if QRS <120 ms) or QTc ≥550 (if QRS ≥120 ms) and b) increased QTc of ≥60 ms. Tisdale 10 score and Elixhauser comorbidity index were calculated. 11 Results: Of 490 COVID-19 positive/suspected patients, 314 (64%) received either/both 12 drugs, and 98 (73 COVID-19 positive, 25 suspected) met study criteria (age 62±17 yrs, 13 61% male). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 14 62%. Baseline mean QTc was 448±29 ms and increased to 459±36ms (p=0.005) with 15 medications. Significant prolongation was observed only in men (18±43 ms vs -0.2±28 ms 16 in women, p=0.02). 12% of patients reached critical QTc prolongation. In a multivariable 17 logistic regression, age, sex, Tisdale score, Elixhauser score, and baseline QTc were not 18 associated with critical QTc prolongation (p>0.14). Changes in QTc were highest with the 19 combination compared to either drug, with many-fold greater prolongation with the 20 combination vs. azithromycin alone (17±39 vs. 0.5±40 ms, p=0.07). No patients 21 manifested torsades de pointes. 22. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)Conclusions: Overall, 12% of patients manifested critical QTc interval prolongation, 1 and traditional risk indices failed to flag these patients. With the drug combination, QTc 2 prolongation was several-fold higher compared to azithromycin alone. The balance 3 between uncertain benefit and potential risk when treating COVID-19 patients with 4 these drugs should be carefully assessed prior to use. 7 2/1/2020 and 4/4/2020 who received either AZ and/or HCQ as part of their medical 8 treatment. A detailed, retrospective chart review was then performed via the electronic 9 health record (Epic, Verona, WI) at our institution. Of the PUI and confirmed COVID-19 10 cases, we only included patients who had at least two 12-lead electrocardiograms 11 (ECGs) performed in our MUSE system between 1/1/2020 and 4/5/2020. Patients with 12 paced ventricular rhythms, atrial fibrillation, atrial flutter, supraventricular tachycardia, or 13 ECGs otherwise unsuitable for accurate QT interval measurement were excluded. 14 Additionally, patients without ECGs performed on day 2 of medication administration or 15 later were excluded (Figure 1). Our hospital policy states that daily ECGs sh...

Hydroxychloroquine in COVID-19: The predictors of QT Prolongation

“…In this study, we evaluated the effect of HCQ on QTc prolongation in patients with COVID-19. Critical QTc prolongation was detected in 12% of the population which is similar with two recent studies (Ramireddy et al, 2020;Saleh et al, 2020). However, in another one, critical QTc prolongation was reported as 20% (Mercuro et al, 2020).…”

“…Based on these cardiac events and insufficient evidence of efficacy, concerns and restrictions are increasing for its use in COVID-19 in all over the world. Serious adverse cardiac events related to HCQ use in treatment and prophylaxis were reported from recent studies (Ramireddy et al, 2020;Zengin R, 2020).…”

Harnessing adenosine A2A receptors as a strategy for suppressing the lung inflammation and thrombotic complications of COVID-19: Potential of pentoxifylline and dipyridamole

“…HCQ therapy often induces modest increases in QT interval, and concurrent administration of azithromycin can amplify this effect. Such increases can increase chances for dangerous torsade de pointes arrhythmias; studies examining ECGs in hospitalized COVID-19 patients treated with this combination reported 2 cases of torsade de pointes in 640 such patients [70][71][72][73]. Although it is very rare for these drugs to induce arrhythmias when used for their current indications, SARS-CoV-2 can directly attack the heart, and conceivably this could potentiate the pro-arrhythmic impact of HCQ [74,75].…”

<p>Hydroxychloroquine in COVID-19: The Study Points to Premature Decisions on Efficacy While Bells Ringing for Safety</p>

“…QT prolongation and de novo ventricular arrhythmia are reported by many studies. 7,21,27,29,30 In some studies, fewer adverse events are reported in the treatment group than the control group. 26 Six patients on HCQ were lost in follow-up in a study conducted by Gautret et al 16 In this regard, HCQ cannot be considered safe to use for COVID-19 patients without evaluating risk-benefit ratio.…”