key: cord-0989342-nuw5nose
authors: Zhao, Wei; Gandhi, Nikhil; Affas, Saif; Szpunar, Susan; Mesiha, Nancy; Saravolatz, Louis
title: Predicting QT interval prolongation in patients diagnosed with the 2019 novel coronavirus infection
date: 2021-05-07
journal: Ann Noninvasive Electrocardiol
DOI: 10.1111/anec.12853
sha: 856b00b965e3c19daac97ccef89aa2aac5e834fc
doc_id: 989342
cord_uid: nuw5nose

INTRODUCTION: 2019 novel coronavirus (COVID‐19) patients frequently develop QT interval prolongation that predisposes them to Torsades de Pointes and sudden cardiac death. Continuous cardiac monitoring has been recommended for any COVID‐19 patient with a Tisdale Score of seven or more. This recommendation, however, has not been validated. METHODS: We included 178 COVID‐19 patients admitted to a non‐intensive care unit setting of a tertiary academic medical center. A receiver operating characteristics curve was plotted to determine the accuracy of the Tisdale Score to predict QT interval prolongation. Multivariable analysis was performed to identify additional predictors. RESULTS: The area under the curve of the Tisdale Score was 0.60 (CI 95%, 0.46–0.75). Using the cutoff of seven to stratify COVID‐19, patients had a sensitivity of 85.7% and a specificity of 7.6%. Risk factors independently associated with QT interval prolongation included a history of end‐stage renal disease (ESRD) (OR, 6.42; CI 95%, 1.28–32.13), QTc ≥450 ms on admission (OR, 5.90; CI 95%, 1.62–21.50), and serum potassium ≤3.5 mmol/L during hospitalization (OR, 4.97; CI 95%, 1.51–16.36). CONCLUSION: The Tisdale Score is not a useful tool to stratify hospitalized non‐critical COVID‐19 patients based on their risks of developing QT interval prolongation. Clinicians should initiate continuous cardiac monitoring for patients who present with a history of ESRD, QTc ≥450 ms on admission or serum potassium ≤3.5 mmol/L.

The 2019 novel coronavirus is increasingly recognized as a multi-organ infectious disease that goes far beyond the respiratory system. One of its common complications involves cardiac injuries in patients even without underlying heart conditions (Driggin et al., 2020) . This cardiac involvement can manifest as asymptomatic troponin elevation to catastrophic cardiac arrhythmia (Driggin et al., 2020) . In one study, arrhythmia was observed in 44.4% of COVID-19 patients admitted to the intensive care unit (ICU) and 6.9% of those managed on general wards (Wang et al., 2020a) . The increased risk of arrhythmia in COVID-19 patients can be explained by metabolic stress, a hypercoagulable state, direct myocardiocyte infection and cytokine storm (Lazzerini et al., 2020) . We are interested in identifying the subset of COVID-19 patients at high risk of developing QT interval prolongation during hospitalization. QT interval prolongation can deteriorate into Torsades de Pointes (TdP) and lead to sudden cardiac death (Yap & Camm, 2003) . In addition, it is also one of the few rhythm abnormalities that, if recognized early, can potentiallybeprevented.Anobservationalstudyfrommultiplehospitals inNewYorkfoundthat6. QT intervals greater than 500 ms on admission (Richardson et al., 2020) . In comparison, the incidence of QT intervals greater than 500msinthegeneralpopulationislessthanonepercent (Mizusawa & Wilde, 2013) . The higher risk of QT interval prolongation among COVID-19 patients is further complicated by the widespread use of QT-prolonging medications, including hydroxychloroquine and azithromycin(Chorinetal.,2020a;Mercuroetal.,2020),despitetheir ineffectiveness (Chen et al., 2020; Geleris et al., 2020; Wang et al., 2020b) . Therefore, identifying patients at high risk for QT interval prolongation is a critical step in managing COVID-19 patients.

In 2013, Tisdale et al reported a risk model to predict QT interval prolongation in critically ill patients admitted to the cardiac critical care unit (Tisdale et al., 2013) . It incorporates nine variables and stratifies patients into low-, medium-or high-risk groups dependingontheircumulativescores.ExpertssuggestthataTisdaleScore of seven or more in COVID-19 patients indicates the need for continuouscardiacmonitoringofcatastrophiccardiacevents (Simpson etal.,2020) .GeneralizationoftheperformanceoftheTisdaleScore in a critically ill population with severe underlying heart conditions to COVID-19 patients, however, may overestimate the risk of QT interval prolongation. Therefore, the performance of the Tisdale ScoreremainstobeevaluatedinhospitalizedCOVID-19patients.In additiontotheTisdaleScore,otherpotentialriskfactorsshouldbe evaluated to determine their usefulness in stratifying hospitalized COVID-19 patients based on their risks of developing QT interval prolongation.

Our study aims to answer a question that every clinician faces in the middle of COVID-19 pandemic: which COVID-19 patients will benefit from continuous cardiac monitoring and what we can offer to minimize the risk of QT interval prolongation? We focused on the non-critical patients for whom decisions on initiating continuous cardiac monitoring need to be made. Reliably identifying COVID-19 patients who will or will not benefit from continuous cardiac monitoring should help achieve better patient care and prioritize medical resources.

We conducted a single-center retrospective study evaluating adults with confirmed COVID-19 infection by nasopharyngeal reverse transcriptase-polymerase chain reaction (RT-PCR) who were admitted to a non-ICU setting of Ascension St. John Hospital, Detroit, MichiganfromMarch1,2020,toApril30,2020.Thisstudywasap-provedbyAscensionSt.JohnHospitalInstitutionalReviewBoard.

Inclusion criteria were confirmed COVID-19 infection, the corrected QT interval (QTc) less than 500 ms on admission, at least one followup electrocardiogram (EKG) during hospitalization, and admission to a non-ICU setting. Exclusion criteria were QTc equal or more than 500 ms on admission, no follow-up EKG, discharge from emergency room, or admission to ICU. Electronic medical records were reviewed to collect demographic and clinical data, including age, sex, race, comorbidities, medications received during the hospitalization, laboratoryresultsandserialEKGs.TheTisdaleScorewasretrospectively calculated for each included patient. The standard regimen of azithromycin, if used, was 500 mg daily on day one followed by 250 mg daily on days two to five. The standard regimen of hydroxychloroquine, if used, was 400 mg twice daily on day one followed by 200 mg twice daily on days two to five. QT-prolonging medications were further classified into low risk, moderate risk or high risk according to their potential to cause QT interval prolongation (Table 1) .

Each 12-lead EKG was reviewed by at least one investigator (WZ, Our outcome of interest was newly developed QT interval prolongationduringhospitalization,definedasacorrectedQTc≥500msor anincreaseinQTc≥60mscomparedwiththebaselineQTc.

Descriptive statistics were calculated to characterize the study groups. Continuous variables were described as the mean with TA B L E 1 ClassificationofQTprolonging medications based on their risks of causing QT interval prolongation standarddeviation(SD)orthemedianwithinterquartilerange(IQR).

Categorical variables were described as frequency distributions.

Receiver operating characteristic (ROC) curves were generated, and the area under the curve (AUC) was used to assess the ability of theTisdaleScoretopredicttheoutcomeofinterest.Sensitivityand specificity were computed based on different cutoffs of the Tisdale Score.UnivariableanalysiswasdoneusingStudent'st test, the chisquaredtest,andtheMann-WhitneyU test. Variables with a p-value less than 0.05 were selected to enter a multivariable logistic regressionmodelusingbackwardlikelihoodratiotest(LRT)algorithm.All data were analyzed using SPSS (v 27.0) and R (version 4.00). A pvalue less than .05 was considered to indicate statistical significance.

We included 178 non-critical COVID-19 patients who were admitted to a non-ICU setting following laboratory confirmation of their TheAUCoftheTisdaleScorewas0.60(CI95%,0.46-0.75).These results collectively showed that using the Tisdale Score was inadequate to identify the hospitalized non-critical COVID-19 patients who were at increased risk of developing QT interval prolongation.

To identify the predictors for QT interval prolongation in hospitalized non-critical COVID-19 patients, we performed univariable 

The incidence of QT interval prolongation in COVID-19 patients who were admitted to a non-ICU setting of our hospital was 11.8%. To help stratify the COVID-19 patients based on their risks of developing QT interval prolongation during hospitalization, potentially contributing variables were evaluated in our study. We found that the risk of developing QT interval prolongation was independently asso-ciatedwithahistoryofESRD,QTcinterval≥450msonadmissionand serum potassium ≤3.5 mmol/L during hospitalization. Interestingly,

QT interval prolongation, whereas those who developed acute kidney injury(AKI)arenotatrisk.Thisfindingsupportsthatchroniccardiac ion channel remodeling induced by long-standing renal insufficiency rather than metabolic derangement predominantly contributes to car-diacrepolarizationabnormalitiesinhospitalizedCOVID-19patients.A possible molecular mechanism involves a progressive reduction of the naturally redundant potassium channels and a concomitant increase in sensitivity of the remaining potassium channels to pharmaceutical inhibition (Gussak & Gussak, 2007 Nevertheless, the use of hydroxychloroquine or azithromycin has been taking the most blame. One retrospective study showed that 21% of COVID-19 patients who received both hydroxychloroquine and azithromycin developed prolonged QTc exceeding 500 ms, and 13%ofpatientshadanincreaseinQTcbymorethan60ms (Mercuro et al., 2020) . Another retrospective study showed that the mean 

We are aware of the limitation that our study has as a retrospec- 

A history of ESRD, QTc ≥450 ms on admission, and serum potas-sium≤3.5mmol/Lwereidentifiedinourstudyassignificantpredictors for developing QT interval prolongation in hospitalized non-ICU COVID-19 patients. Any patient who presents withthese features requires preventative measures, including continuous cardiac monitoring, potassium replacement and, if possible, avoiding high-risk QT-prolonging medications.

Authorshavenoconflictstodisclose. 

This study conforms to the Declaration of Helsinki and was ap-provedbyAscensionSt.JohnHospitalInstitutionalReviewBoard.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Wei Zhao https://orcid.org/0000-0001-5501-3384

Chronic hydroxychloroquine use associated with QT prolongation and refractory ventricular arrhythmia

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Riskevaluation of azithromycin-induced QT prolongation in real-world practice

The QT interval in patients with COVID-19 treated with hydroxychloroquine and azithromycin

QTintervalprolongation and torsade De pointes in patients with COVID-19 treated with Hydroxychloroquine/azithromycin

Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic

Observational study of hydroxychloroquine in hospitalized patients with Covid-19

Sudden cardiac death in nephrology: Focus on acquired long QT syndrome

COVID-19,arrhythmicriskandinflammation:Mindthegap!

QT interval: Metric for cardiac prognosis?

Association of QT interval with mortality by kidney function: ResultsfromtheNationalHealthandNutritionExaminationSurvey (NHANES)

RiskofQTintervalprolongationassociated with use of hydroxychloroquine with or without concomitant azithromycin among hospitalized patients testing positive for coronavirus disease 2019 (COVID-19)

QT prolongation and mortality in hospital settings: Identifying patients at high risk

Hydroxychloroquine/azithromycin therapy and QT prolongation in hospitalized patients with COVID-19

Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in theNewYorkCityarea

Ventricular arrhythmia risk due to hydroxychloroquine-azithromycin treatment for COVID-19

Developmentandvalidation of a risk score to predict QT interval prolongation in hospitalized patients

Liver cirrhosis-effect on QT interval and cardiac autonomic nervous system activity

GW26-e0739a new formula for calculating the QT interval in left bundle branch block

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

DruginducedQTprolongationandtorsades de pointes

PredictingQTinterval prolongation in patients diagnosed with the 2019 novel coronavirus infection