key: cord-0693297-iy7bql20
authors: Padilla, Sergio; Telenti, Guillermo; Guillén, Lucía; García, José Alberto; García-Abellán, Javier; Ding, Carolina; Mora, Antonia; García-Pachón, Eduardo; Gutiérrez, Félix; Masiá, Mar
title: Predictive factors for cardiac conduction abnormalities with hydroxychloroquine-containing combinations for COVID-19
date: 2020-08-24
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2020.106142
sha: ca2bad662477575868653cd6eb88d151b54b7ad0
doc_id: 693297
cord_uid: iy7bql20

BACKGROUND: We aimed to assess the risk of QT-corrected (QTc) interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. METHODS: Longitudinal, prospective cohort. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval exceeding 470 ms in men or 480 ms in women. Patients were treated under strict cardiac supervision. RESULTS: One hundred and five adults, 56% male and median (Q1, Q3) age of 69 (57, 79), were included. All received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/RTV). Concomitant medications classified as having risk of developing Torsades de Pointes (TdP) were simultaneously used in 81 (77%) patients. In 14 (13%) subjects, a moderate-to-severe QTc prolongation was observed, mostly at days 3-5 from baseline, with 6 (6%) of them developing severe prolongation (> 500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/RTV to HCQ/AZM did not significantly prolong the QTc. Multivariable Cox regression revealed that comedications with known risk of TdP (HR 11.28, 95%CI 1.08–117.41), higher neutrophil-to-lymphocyte ratio (HR 1.10, 95%CI 1.03-1.18 per unit increase) and higher serum HS-cardiac troponin I (HR 4.09, 95%CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. CONCLUSIONS: In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacologic therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically a higher neutrophil-to-lymphocyte ratio, are conditions under which QTc interval monitoring should be particularly careful.

Since its emergence in late 2019, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has claimed the lives of more than 250,000 individuals worldwide (first week of May 2020) [1] . Although no proven effective therapies currently exist for the virus, there has been a worrying mass consumption of off-label and/or compassionate use drugs, with no demonstrated efficacy and with potential toxicity. Among toxicities, cardiac conduction abnormalities associated with certain commonly used drugs for the SARS-CoV-2 [2] [3] [4] [5] , such as chloroquine/hydroxychloroquine (CQ/HCQ) and azithromycin (AZM), are especially concerning. The three have been classified into the category of -known risk‖ of potentially fatal torsades de pointes (TdP) ventricular arrhythmias or sudden cardiac death [6] , and comprehensive evidence supports that concomitant administration of more than one QTcprolonging drug further increases the risk [7] [8] [9] [10] . Moreover, although the most common clinical presentation of the coronavirus disease 2019 (COVID- 19) involves the respiratory tract, cardiovascular manifestations are also being increasingly recognized [11] [12] [13] [14] , which might additionally contribute to exacerbate drug toxicity. A randomized clinical trial conducted in Brazil in patients with COVID-19 that compared high versus low doses of CQ, given in combination with AZM, and in most cases with oseltamivir, has been prematurely stopped due to a potential increase in mortality in the high-dose group [15] .The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently warned about serious potential adverse events with CQ/HCQ because of heart rhythm problems, especially at high doses or when combined with AZM or other QTc prolonging medicines [16, 17] .

In March 2020, the Spanish Agency of Medicines and Medical Devices granted an emergency-use authorisation for HCQ to treat patients with disease requiring hospital admission. Due to limited availability, health authorities recommended a dose of HCQ of 200 mg twice daily for 5 days, which is lower than doses used in several clinical trials worldwide for this indication [15, 18] . Based on data from an observational study suggesting a faster virological response [5] , in our setting HCQ was often prescribed in combination with AZM.

Our center developed specific guidelines for treating patients with COVID-19 with HCQcontaining regimens. The protocol included a close screening and monitoring of patients receiving this drug combination, and an investigation of the predictive factors for cardiac conduction abnormalities. In this article we describe the risk of QTc interval prolongation and its predicting factors. p=0.451). Table 2 shows factors associated with maximal QTc changes from baseline during follow-up.

Longer prolongations of the QTc were associated with higher levels of hs-cardiac troponin and of the neutrophil-to-lymphocyte ratio, with a graded increase with increasing ratio category, and with concomitant therapy with QTc-active drugs.

Multivariable Cox regression was performed to identify predictors of reaching a moderate-tosevere QTc prolongation ( 

arrhythmogenic potential, and therefore with a likely risk of developing complications. The

QTc-interval increased more than 60 ms in one fourth of patients, and in 13% of them it reached a moderate-to-severe QTc prolongation during treatment; however, severe prolongation of >500 ms occurred only in 6% of patients, and there were no episodes of TdP or death due to arrhythmia. We found that concomitant use of QTc-prolonging drugs, higher levels of hs-troponin, higher neutrophil-to-lymphocyte ratio and, to a lesser degree, lower levels of potassium, were predictors of moderate-to-severe QTc prolongations. Compared with therapy with HCQ plus AZM, there was a slight, non-significant increase in the QTc length when LPV/RTV was part of the combination.

To date, data from clinical studies evaluating the influence in the QTc of drug combinations including HCQ in the scenario of COVID-19 are very limited. We found no complication from QTc prolongation when daily doses of 400 mg of HCQ are used. This is a lower dose than the 600 mg or 800 mg doses employed in some ongoing clinical trials. Chorin et al have reported a QTc increase of >500 ms in 11% of 84 patients treated with HCQ/AZM [21] .

Although the dose of HCQ used in their study was the same, AZM was given at double dose (500 mg/daily) than in our study. Like HCQ, AZM is another drug with known risk of TdP, and this higher dose might have contributed to explain the higher frequency of severe QTc prolongation compared to our study, though in contrast to other macrolide drugs such as erythromycin or clarithromycin, azithromycin has the lowest risk of QTc prolongation [22] .

Interestingly, in our center most patients received LPV/RTV in addition to HCQ and AZM.

Although a marginally higher increase in the QTc was observed in these patients, there were not significant differences compared with therapy with HCQ and AZM. LPV/RTV is a mild inhibitor of cytochrome 2D6, which is involved in CQ/HCQ metabolism, and has been classified as a drug with -possible risk‖ of TdP, in contrast to the -known risk‖ of HCQ and AZM. Apart from the lower doses of HCQ and AZM, there could be additional reasons for the low rate of complications observed in our patients. As stated, we followed local institutional guidelines to manage all patients admitted with COVID-19, where clinical procedures and pharmacological therapy were pre-defined and programmed. The protocol included close monitoring of the patients, with baseline and follow-up ECGs, and stop rules when abnormal QTc intervals were reached, and/or more frequent ECGs if a prolonged interval was present at baseline. The protocol also contemplated a thorough review of concomitant medications with activity on the QTc, and their discontinuation when not considered as essential. Coprescribing QTc-prolonging-drugs has been associated with higher mortality rate and longer duration of hospitalization due to pharmacodynamic drug-drug interaction [7] . We found that co-administering QTc-prolonging drugs was associated with a higher increase in the QTc, and it turned out to be an independent predictor of reaching a moderate-to-severe QTc prolongation. This reinforces the importance of reviewing the patient's medical history, and of a closer monitoring of such patients. Although it did not remain as a significant factor in multivariate analysis, comorbidity measured by the Charlson index is a variable linked with a higher use of comedications, and patients with a higher index might also merit a greater supervision. Our analyses also found that low levels of potassium was associated with QTc prolongation, as previously described [23 ] .

Whether the QTc prolongation may simply be the result of pharmacological toxicity, or if the adverse drug event could be facilitated in a heart already damaged by the virus or the disease, remains unknown. Previous studies have found an increase in the concentrations of serum cardiac biomarkers in patients with COVID-19, such as cardiac troponin I [24 ] , whose increase has been associated with markedly higher mortality [25 ] . Interestingly, in our cohort higher levels of hs-troponin independently predicted moderate-to-severe QTc prolongation, suggesting that myocardial harm might also have contributed to drug toxicity.

In a recent case series of ST-elevations in patients with COVID-19, some patients had non-obstructive disease on coronary angiography, which indicates non-coronary myocardial injury [26 ] . Angiotensin-converting enzyme 2, the host cellular receptor for SARS-CoV-2 virus spike protein, is highly expressed in the pericytes of adult human hearts. Binding of the virus might induce subsequent capillary endothelial cell dysfunction and microcirculation disorder [27 ] . An imbalance between infection-induced increase in metabolic demand and reduced cardiac reserve, coinciding with an accentuated inflammatory response, are some of the theories proposed to explain the cardiovascular involvement in COVID-19 [26 , 28 ] . Inflammation associated with cytokine storm is a recognized characteristic feature of COVID-19. In support of inflammation as a potential pathogenic mechanism, we observed that moderate-to-severe prolongation of the QTc in our study was associated with higher neutrophil-to-lymphocyte ratio, a marker of the inflammatory status and severity of disease [29 ] . The endomyocardial biopsy of patients with COVID-19 and cardiogenic shock has shown viral particles in interstitial cytopathic macrophages, where they might have activated an exaggerated inflammatory response leading to myocardial injury [30 ] . This damaged myocardium may, at the same time, heighten drug toxicity.

Limitations of the study include those inherent to the observational nature; the absence of a concurrent control group receiving higher doses of HCQ and AZM to assess whether different changes occurred on the QTc; some patients received tocilizumab and/or interferon-β-1b, which might also have a contribution to the QTc prolongation; and the individual effect on the QTc of HCQ and AZM cannot be established. Strengths are the homogeneity of the procedures and treatment applied to all patients under strict supervision, and the novelty of providing data about QTc with a combination including also LPV/RTV.

In summary, combined therapy including HCQ, AZM and LPV/RTV for COVID-19, when given at low doses and under close screening and cardiac monitoring, was not associated with incident TdP or sudden cardiac death . In addition to drug toxicity, disease-related myocardial damage and inflammation might be implicated in the pathogenesis of cardiac conduction abnormalities in patients with COVID-19. Therefore, evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically a higher neutrophil-to-lymphocyte ratio and increased IL-6, warrants careful QTc interval monitoring.

Additional predictive factors for developing cardiac conduction abnormalities were comedications and low serum potassium levels, which should be taken into account to reduce the risk of serious complications, especially in patients with altered myocardial enzymes and enhanced inflammatory response. # Drugs classified as "Known, possible or conditional risk of Torsades de Pointes (TdP)" in CredibleMeds [6] taken simultaneously with COVID-19 therapy. If drugs from more than one category were taken in a patient simultaneously, that patient was assigned to the higher risk category. & Median (Q1, Q3) maximal QTc rise throughout follow-up. QTc, heart ratecorrected QT interval (Bazett formula, [19] ); HS, High-sensitivity; eGFR, Estimated glomerular filtration rate using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula; ms, milliseconds; Q1, 1st quartile; Q3, 3rd quartile; HCQ, Hydroxychloroquine; AZM, azithromycin; LPV/RTV, lopinavir/ritonavir. 

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If drugs from more than one category were taken in a patient simultaneously, that patient was assigned to the higher risk category. $ Baseline QTc values categories, Normal <430 in males & <450 in females; Borderline 431-450 in males & 451-470 in females; Prolonged >450 in males & >470 in females (19). & Median (Q1, Q3) maximal QTc rise throughout follow-up. ms, milliseconds; IQR

QTc, heart ratecorrected QT interval (Bazett formula

Multivariate analysis were also adjusted for sex and age and therapy with interferon-β-1b. # Drugs classified as "Known risk of Torsades de Pointes" in CredibleMeds [6] taken simultaneously with Covid-19 therapy. QTc, heart rate-corrected QT interval (Bazett formula [19] ); BL, Baseline; HS, High-sensitivity; HR, Hazard ratio; CI, Confidence interval; ms, milliseconds. eGFR, Estimated glomerular filtration rate using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula; HCQ, Hydroxychloroquine; AZM, azithromycin; LPV/RTV, lopinavir/ritonavir.