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

  1. Archana Ramireddy
  2. Harpriya Chugh
  3. Kyndaron Reinier
  4. Joseph Ebinger
  5. Eunice Park
  6. Michael Thompson
  7. Eugenio Cingolani
  8. Susan Cheng
  9. Eduardo Marban
  10. Christine M. Albert
  11. Sumeet S. Chugh

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Abstract

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.

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  1. Version published to 10.1161/jaha.120.017144
  2. ScreenIT

    SciScore for 10.1101/2020.04.22.20075671: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: Patient Population: This study was approved by the Cedars-Sinai Institutional Review Board.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableThe Tisdale score consists of age ≥ 68 yrs, female sex, use of loop diuretics, potassium level ≤ 3.5 mEq/L, baseline QTc ≥ 450 ms, acute MI, number of QT prolonging medications, sepsis, and heart failure and has been developed as a risk score for QTc interval prolongation.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Of the PUI and confirmed COVID-19 cases, we only included patients who had at least two 12-lead electrocardiograms (ECGs) performed in our MUSE system between 1/1/2020 and 4/5/2020.
    MUSE
    suggested: (Muse, RRID:SCR_014418)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Limitations: The variation in dosing patterns and duration of treatment for each medication are important to note as this can potentially influence when the ECG with the longest QTc may be observed. Due to inconsistency in obtaining daily ECGs during medication administration, we believe that the 12% of patients who experienced critical QTc prolongation was likely an under-estimation. Furthermore, variability in heart rates, especially in the setting of sepsis, can affect QT interval correction. We reported the QTc using Bazett’s correction, which is consistent with the majority of the published literature as well as ECG recording machines in typical use. The relatively small sample size does not allow for assessment of torsades des pointes risk with these agents.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.04.22.20075671v1 on medRxiv