Safety and Effectiveness of Hydroxychloroquine and Azithromycin Combination Therapy for Treatment of Hospitalized Patients with COVID-19: A Propensity-Matched Study

The major findings of this study were (1) there was no significant difference in in-hospital mortality, incidence of PEA arrest, or non-lethal arrhythmias between HCQ-AZM treated and propensity-matched control groups; (2) mean length of hospital stay and peak C-reactive protein levels were higher for the HCQ-AZM treated group; (3) despite a higher degree of QTc prolongation in the HCQ-AZM group than the control group (6.2% vs. 2.5% increase), drug-related TdP remained rare (0.6%); and (4) patients with greater changes in QTc interval (> 60 ms) were more likely to have electrolyte abnormalities after starting HCQ-AZM therapy.

Despite limited evidence of its effectiveness, HCQ (with or without AZM) remains under investigation for empiric treatment and prophylaxis for treatment of COVID-19 [16, 17]. A potentially clinically important side effect of HCQ administration is the risk for QT interval prolongation and development of lethal ventricular arrhythmias such as TdP. Further, QT interval prolongation can be exacerbated by electrolyte derangements (in particular, depletion of serum potassium or magnesium levels) and co-prescribed medications such as azithromycin which have also been used in the treatment of SARS-CoV-2.

Progression from the early symptomatic phase to acute respiratory distress syndrome and resultant hypoxic respiratory failure may be secondary to uncontrolled release of cytokines. Given HCQ’s clinical use as an anti-inflammatory medication for patients with autoimmune disease [12], HCQ may inhibit cytokine storm by suppressing T cell activation and reduce severity of mortality and morbidity of patients with COVID-19 [6‐10]. However, the evidence for the clinical efficacy of HCQ for treatment of SARS-CoV-2 remains limited and there is also debate regarding the optimal therapeutic dosage and duration for treatment. Gautret et al. reported that a combination of HCQ and AZM may be more effective in reducing viral load than HCQ alone [10]. In a recently published study, hospitalized patients with COVID-19 who were treated using a high-dose CQ protocol (600 mg twice daily for 10 days) were more likely to experience QT prolongation and had higher in-hospital mortality than patients treated with low-dose CQ protocol (450 mg twice daily for one day and once daily for 9 more days) (mortality at 13 days 39% vs. 14%). The randomized trial, which was intended to include 440 patients, was stopped prematurely after enrolling only 81 patients because of the high rate of major adverse events [18].

In the current study, we compared in-hospital outcomes between 173 patients treated with a combination of HCQ-AZM for 5 days and 173 propensity-matched controls who did not receive HCQ-AZM during their index hospitalization for COVID-19. We observed no difference in mortality or in-hospital PEA arrest between HCQ-AZM treated and matched control patients (15.0% vs. 10.4% deaths; p = 0.2). Despite similar age, sex, comorbidities, LVEF, and BMI between groups, we found that length of hospital stay was significantly higher for patients treated with HCQ-AZM therapy (10.5 ± 7.4 days vs. 5.8 ± 6.1 days; p < 0.001) than matched control patients. Altogether, the lack of demonstrated clinical effectiveness, requirement for QT monitoring, and longer hospital stay associated with HCQ-AZM may be important considerations for its potential use in patients with COVID-19, especially given strained healthcare resources and limited bed availability needed for critically ill patients in the pandemic.

Although it has been postulated that HCQ may play a beneficial role for treatment of SARS-CoV-2 by inhibiting cytokine release and controlling inflammation, we did not observe any significant reduction in commonly tested, serially drawn inflammatory biomarkers in the HCQ-AZM treatment group versus the matched control group. In fact, peak hospital C-reactive protein levels remained significantly higher in the HCQ-AZM arm of the study despite treatment. CQ is believed to inhibit T cell proliferation by reducing IL-2 production and IL-2 responsiveness [19]. However T_H2 cell response may play a role in suppressing inflammation in SARS-CoV-2 infection, and therefore it remains possible that administration of CQ/HCQ could negatively impact the immune response to viral infection [3, 20]. Although patients groups were propensity score matched for baseline covariates in this study, treatment of more severely ill patients in the HCQ-AZM group cannot be completely excluded.

From a cardiovascular standpoint, an interesting finding of the study was the relatively low incidence of elevated serum troponin in the study cohort (77% of patients troponin I level within our hospital’s reference range), despite the high prevalence of critically ill patients and incidence of both acute kidney injury (AKI) and circulatory shock. The incidence of atrial and ventricular tachyarrhythmias was similar between study groups with the most common atrial arrhythmia being atrial fibrillation (Table 2). The incidence of sustained or hemodynamically unstable ventricular arrhythmias was low and statistically similar between groups. One patient in the HCG-AZM treated group developed PVC-induced TdP in the setting of drug-induced QT prolongation. After discontinuation of HCQ, the patient’s QTc interval returned to baseline and the patient did not have further ventricular arrhythmias. The incidence of bradyarrhythmias was 4.2%, although none of the patients in the study required temporary or permanent pacemaker implantation.

Since the start of the COVID-19 pandemic, the widespread usage of CQ and HCQ in the acute hospital setting has been unprecedented. While QT interval prolongation is a known side effect of HCQ administration and has been demonstrated in patients treated with HCQ-AZM combination therapy [12, 18, 21], the degree of QT interval prolongation is variable among patients and may also be modulated by electrolyte abnormalities, myocarditis, and medications exerting QT-prolonging effects on ventricular repolarization. Although HCQ is structurally similar to quinidine and the incidence of TdP has been well established for other potassium channel IKr (hERG/KV11.1) blocking medications [22‐24], the risk of TdPs in patients taking HCQ at treatment dosages for COVID-19 remains unknown.

The results of the current study confirm that a significant increase in QTc intervals occurs following administration of a moderate HCQ-AZM dosing protocol (HCQ: 400 mg twice day 1, then 200 mg twice daily for 4 days; AZM: 500 mg day 1, then 250 mg per for next 4 days) versus matched controls [18]. In total, HCQ-AZM was stopped prior to completion of the dosing regimen in a minority of patients (6%) because of significant QTc prolongation (QTc interval above 500 ms or total increase in QTc interval > 60 ms) and in one patient because of drug-related polymorphic ventricular arrhythmia. In a subgroup analysis of patients treated with HCQ-AZM, we found that patients with significant increment in QT interval (∆ > 60 ms) were more likely to have hypokalemia (< 3.3 mmol/mL) in hospital. Hypokalemia has been known to potentiate QT prolongation and dispersion of ventricular repolarization, both increasing vulnerability for TdP. Thus, monitoring and correction of electrolyte abnormalities is paramount in patients receiving HCQ or HCQ-AZM combination therapy for treatment of COVID-19 in the hospital.