In this large cohort of RA and SLE patients, HCQ use was not associated with QTc length when adjusted for potential confounders such as age and other medications affecting QTc length. The adjusted QTc length was comparable between HCQ users and non-users (438 ms vs 437 ms). Although up to 44% of the combined cohort had a QTc\(\ge\)440 ms, HCQ use was not a predictor of prolonged QTc.
QTc length as an outcome remains of paramount interest, since in the general population and in selected subpopulations (i.e. the elderly, patients with coronary artery disease, and the critically ill), prolonged QTc length (defined in those studies as > 450 ms in men and > 470 ms in women) independently predicts sudden cardiac death(17, 18). In fact, even moderate QTc prolongation between 420–440 ms has been associated with all-cause mortality(19). In a retrospective cohort study of RA patients, idiopathic QTc prolongation(20) was associated with an almost 30% increase in all-cause mortality (HR: 1.28; 95% CI: 0.91–1.81, p = 0.16). Furthermore, in a prospective cohort of RA patients, a 50-ms increase in QTc interval was independently associated with a two-fold risk of mortality (HR = 2.18, 95% CI 1.09, 4.35), but this association was lost when CRP was added to the final model (HR = 1.73; 95% CI 0.83, 3.62; p = 0.143)(8). In our study, prednisone use was associated with a lower QTc length in the combined RA + SLE cohort, in addition to being a negative predictor of QTc\(\ge\)440 ms, further signaling a possible interplay between inflammation and arrhythmogenic potential.
HCQ-associated QTc prolongation and subsequent arrhythmia development received considerable attention during its widespread use in COVID-19 patients. In an uncontrolled study of COVID-19 patients receiving HCQ alone or HCQ and azithromycin for associated pneumonia(6), baseline to treatment change in QTc was higher in the HCQ + azithromycin group vs HCQ alone. It is also worthwhile noting that in the prior study, up to 19% of those receiving HCQ alone had a QTc > 500 ms (and 21% in combination group) and 8% had a clinically significant increase > 60 ms, with one episode of torsades de pointes reported. However, independent effects of COVID-19 infection on the cardiac conduction system(7) and indication bias (severe COVID-19 patients more likely to receive HCQ) must be considered in interpretation of these data. Similarly, Ramireddy et al(21) reported a significantly higher change in QTc from baseline to treatment in the HCQ and azithromycin group vs HCQ alone (17 ± 39 ms vs 0.5 ± 40 ms; p = 0.07). More concerning, up to 12% of total patients in this study (receiving HCQ alone, azithromycin alone, or both), had critical QTc prolongation (defined as maximum QTc ≥ 500 ms (if QRS < 120 ms) or QTc ≥ 550 ms (if QRS ≥ 120 ms) and QTc increase of ≥ 60 ms), however no torsades de pointes was documented. The results of a more recent randomized controlled trial (22) were more reassuring in that, in 1,561 COVID patients randomized to the HCQ arm and loaded with high doses of HCQ (800 mg x 2 doses followed by 400 mg every 12 hours for 9 days or until discharge), there were no significant differences in terms of frequency of arrhythmias compared to the usual care group.
As for rheumatologic patients, SLE patients treated with high cumulative doses (700g-1300g) of anti-malarials from several months to decades, demonstrated bundle branch block and third degree AV block (with some leading to Torsades de Pointes)(23–26). However, interpretation from these case reports is limited due to absence of controls. It is also important to note that current trends in HCQ dosing have become more conservative due to heightened awareness of retinal toxicity. More recently, Lane et al(27) reported no increased risk of cardiac arrhythmias (calibrated HR 0.90; 95% CI 0.78–1.03; p < 0.01) in HCQ users (400 mg/day for 30 days) vs sulfasalazine users in a retrospective review of 14 multinational databases of RA patients. Liu et al(28) reported a lower risk of CV disease including sudden cardiac arrest/death in HCQ/chloroquine (CQ) users vs non-users (RR 0.72; 95% CI 0.56–0.94; p = 0.013) in a meta-analysis of various rheumatologic patients. Various cardioprotective (thromboprotective and cholesterol reducing) effects of HCQ/CQ(29, 30) may partially explain this finding but the absence of clinical trial data and CV/metabolic parameters limit interpretation. In another prospective study(31) of RA patients, incidence of long QT syndrome or arrhythmia related hospitalizations were comparable between HCQ use vs non-HCQ disease modifying anti-rheumatic drug (DMARD) use.
Specifically, the lack of association of HCQ use with overall QTc length in our results is consistent with prior publications in RA and SLE patients(8–11, 20). The main strength of our study is its sample size as it represents one of the largest multiethnic studies inclusive of both SLE and RA patients. Importantly, we accounted for the concurrent use of a wide variety of QTc prolonging or arrhythmogenic medications, which was not consistently done in previous literature. Although SLE data were obtained retrospectively via ICD 9/10 codes on EMR review, we restricted analyses to SLE patients who demonstrated consistent care at our institution (≥ 2 visits). For both the SLE and RA cohorts, QTc length was calculated by standardized Bazett’s formula and confirmed by a blinded, trained cardiac electrophysiologist (PP). The main limitations of our study include the lack of data on HCQ adherence (i.e. via patient report, and/or metabolite levels), as well as cumulative dosage or length of therapy. In addition, we did not obtain or analyze pre-HCQ ECGs (determined only at the time of HCQ use for both SLE and RA cohorts) and therefore, cannot make conclusions about pre and post exposure change in QTc length. Finally, although we excluded patients with clinical CVD and our findings may not directly apply to those patients, our patients likely had underlying, subclinical CVD given the prevalence of associated risk factors (hypertension, diabetes).