Temporal Trends in Arrhythmogenicity Related to Treatment of COVID-19 Infection.

Hydroxychloroquine can cause corrected QT (QTc) interval prolongation but has been safely used for decades. Its novel use for coronavirus disease 2019 (COVID-19) infection, however, is controversial due to clinical equipoise regarding efficacy. Thus possible arrhythmogenicity in the context of COVID-19 treatment has led to safety concerns regarding its use without continuous cardiac rhythm monitoring.[1,2] It is often assumed that the duration for monitoring would be short, lasting only while the medication is being loaded. However, we have anecdotally observed patients who developed excessive QT prolongation following completion of a full course of hydroxychloroquine. Given that hydroxychloroquine has a long terminal half-life (30–60 days), a large volume of distribution and increased bioavailability in the setting of renal impairment, the proarrhythmic effects on repolarization may persist after completion of therapy and may potentially be exacerbated by additional QT-prolonging agents or impairment of renal function.[3-5] We thus sought to examine the time course of QTc prolongation in our database of patients with COVID-19 treated with hydroxychloroquine.

The data supporting the findings of this study are available from the corresponding author upon reasonable request. This retrospective cohort analysis of consecutive symptomatic patients admitted for treatment of COVID-19 was approved by the Yale University School of Medicine Human Investigation Committee. Hydroxychloroquine (400 mg orally twice daily for 1 day, followed by 200 mg twice daily for 4 days) and azithromycin (500 mg orally followed by 250 mg daily for the next 4 days) were administered. These drugs were not initiated in patients with baseline QTc >500 ms (or >550 ms with intraventricular conduction delay). Other QTc-prolonging medications were classified based on the Arizona Center for Education and Research on Therapeutics as high-risk drugs (ie, prolong the QTc and are associated with Torsades de Pointes [TdP]) or moderate-risk drugs (ie, prolong the QT but lack evidence of TdP).[6]

The QTc was calculated using the Bazett formula, and all automated measurements were overread and verified by a clinical cardiac electrophysiologist. Baseline QTc intervals were calculated from a 12-lead ECG before initiation of therapy. Subsequent QTc measurements were made either with daily 12-lead ECGs, or from a telemetry system that allows for recording of the 6 limb leads plus one precordial lead (V5) when the ECG was impractical due to constraints of isolation. If excessive QTc prolongation was observed on telemetry recordings, it was always confirmed with a 12-lead ECG. Excessive QTc prolongation was defined as an increase in baseline QTc of ≥60 ms and absolute QTc >500 ms narrow QRS (or 550 ms wide QRS). The temporal trend of QTc changes was examined.

The cohort consisted of 91 consecutive patients (age 63±15 years, 44% females). The mean baseline QTc for all patients was 437±25 ms and maximal QTc was 473±31 ms. Patients with excessive QTc prolongation had a longer baseline QTc compared with rest of cohort (459±27 versus 433±23, P<0.01). Excessive QTc prolongation occurred in 23% (n=21/91) including 18 patients with normal QRS duration (QTc prolonged to 500±40 ms) and 3 with wide QRS duration (QTc prolonged to 564±12 ms). The patients with excessive QTc prolongation were 43% females, age 70±15 years and with significant cardiovascular comorbidities (hypertension 58%; diabetes 38%; chronic kidney disease 24%; coronary artery disease 33%; and cerebrovascular disease 24%), and had severe COVID-19 infections (mechanical ventilation 48%; acute renal failure 38%; and mortality 43%).

The median time to peak QTc prolongation was 6 days (range 2–13). Of the patients with excessive QTc prolongation, 12/21 (57%) developed the QTc prolongation late, on or after day 6 of therapy (Figure [A]). In 4/21 (19%) patients the QTc prolongation occurred after day 9. In the 12 patients with late prolongation, only modest QTc prolongation was seen from baseline to day 5 (increase from baseline 23±20 ms), but the QTc prolonged by an additional 46±36 ms after day 5.

Time course to development of excessive QT prolongation and its association with the number of additional QT-prolonging agents used. In A, the development of excessive QT prolongation peaks 5–6 d after initation of hydroxychloroquine (HCQ), although a significant number of patients prolonged even later, well after the drug was discontinued. In B, the incidence of excessive QT prolongation is shown to increase with each additional QT-prolonging agent administered.

An increased number of concurrent QTc-prolonging medications, as well as underlying chronic kidney disease or development of acute renal failure, was associated with excessive QTc prolongation (Figure [B]). High-risk drugs included amiodarone, azithromycin, chlorpromazine, escitalopram, haloperidol, moxifloxacin, ondansetron, and propofol. Moderate-risk drugs included aripiprazole, dexmedetomidine, lithium, lopinavir-ritonavir, mirtazapine, nicardipine, tramadol, and venlafaxine. The association of baseline renal dysfunction and acute renal failure was particularly evident in patients with late QTc prolongation, present in 5/12 (42%) of patients who prolonged after day 6 and in 3/4 (75%) of patients who prolonged after day 9. More than half (7/12) of patients with late QTc prolongation were mechanically ventilated.

Among patients with excessive QTc prolongation the median length of stay was 10 days (range 3–59) and 9 of the 21 patients (43%) died during the hospitalization. However, it is important to note that these patients developed severe decompensated COVID-19 infection and no patient died primarily from arrhythmia. One patient treated with combined hydroxychloroquine and azithromycin developed TdP. He had stable QTc ≈460 ms for the first 7 days of hospitalization. However, in the setting of acute renal failure and worsening glomerular filtration rate on day 8, the QTc increased to 591 ms on day 9 associated with the use of additional QTc-prolonging drugs, with development of TdP despite the fact that hydroxychloroquine and azithromycin had been stopped. He was successfully treated with magnesium repletion and intravenous lidocaine.

The major finding of this study is that QTc prolongation in patients with COVID-19 treated with hydroxychloroquine may occur following completion of the 5-day therapeutic course. Hydroxychloroquine has a large volume of distribution, resulting in a very long elimination half-life >30 days. Thus, steady-state concentrations are not immediately achieved, and drug concentrations remain elevated following discontinuation of the medication. Hence, drug-related effects on repolarization may accumulate beyond the initial few doses and may persist following termination of therapy. Late QTc prolongation with hydroxychloroquine is associated with the development of renal dysfunction and the use of additional QTc-prolonging drugs. Renal impairment results in decreased hydroxychloroquine clearance and increased bioavailability, thereby potentiating its proarrhythmic effects. Similarly, the concurrent use of other QTc-prolonging medications may also be expected to result in late QTc prolongation following discontinuation of hydroxychloroquine. Thus, it is important to recognize that patients with severe COVID-19 infection may be predisposed to late QTc prolongation in the setting of renal impairment and concurrent use of QTc-prolonging medications during prolonged hospitalizations.

This study is limited by small sample size and single-center retrospective design but a high rate of QTc prolongation was observed, consistent with other studies (1 and 2). We examined the timeline of onset of late QTc prolongation, however, the timeline for resolution of the prolonged QTc remains unknown. This study did not evaluate the long-term risk of proarrhythmia using ambulatory monitoring after hospital discharge. Thus, although the incidence of in-hospital TdP was low, it is unclear whether the patients were at higher risk of proarrhythmia after discharge.

This study demonstrates that QTc prolongation in hospitalized patients with COVID-19 infection is common and can occur very late, well after the initiation of therapy. Vigilance to minimize multiple concurrent drugs and careful monitoring of renal function and cardiac rhythm are required for hospitalized patients with COVID-19. This, however, should not be extrapolated to non-COVID-19 patients with no comorbidities and who are not using concurrent QT-prolonging medications.

Sources of Funding

None.

Disclosures

Dr Akar reports consulting for Biosense Webster. The other authors report no conflicts.