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Prolonging the Controversy of Hydroxychloroquine

Since the start of the pandemic, hydroxychloroquine (HCQ) was forced into the limelight for the prevention/treatment of COVID-19. When it was found to be ineffective for COVID-19 and might cause potential harm, the drug came under closer scrutiny for its safety profile.

One of the key issues that surfaced is whether HCQ increases cardiovascular (CV) mortality, especially when used with other medications that can potentially prolong the QTc interval. In 2020, Lane et al. published a retrospective review of new users of the drug in rheumatoid arthritis (RA) and compared patients initiating HCQ with those who were started on sulfasalazine (SSZ). The study analyzed cardiovascular mortality between the two groups and looked at HCQ in combination with azithromycin or amoxicillin. The authors concluded HCQ had no increased risk for short term mortality in RA, but it appears associated with excess CV mortality (HR 1.65, CI 1.12-2.44) especially in the setting of azithromycin (HR2.19, 95% 1.22-3.95) (1).  

Hydroxychloroquine is considered one of the safest disease modifiers available, but rheumatologists started to question if routine electrocardiograms (ECGs) should be performed on all patients who are taking HCQ and whether to risk stratify patients before prescribing treatment. Pharmacists were calling physicians alerting them to potential drug interactions with antidepressants, antibiotics, and other medications that can prolong the QTc. Is this concern justified or is it overblown? 

Several abstracts at the American College of Rheumatology (ACR) 2021 Convergence meeting addressed the topic of HCQ and cardiovascular safety: 

Abstract # 0871: Jimenz at al. conducted a retrospective cohort study of systemic lupus erythematosus (SLE) patients on HCQ who had at least 1 ECG. Primary outcomes including heart failure with reduced ejection fraction (HF), life threatening arrhythmias or cardiac deaths were evaluated. 296 patients had a median of 7 years of follow-up. After a multivariable analysis adjusted for age, renal disease, and diabetes, HCQ was found to reduce the risk for HF (HR 0.72, 95%CI 0.53, 0.98), p=0.03. The incidence of cardiovascular outcomes was lowest in patients with higher HCQ dose > 5 mg/kg/day. The authors concluded that higher HCQ doses were associated with lower risk for HF, life-threatening arrhythmias, or cardiac deaths among SLE patients.  

Abstract #L11: In this late breaking abstract, D’Andrea et al. evaluated Medicare claims data comparing the safety of HCQ with MTX for patients with RA. Primary outcomes were sudden cardiac arrest or ventricular arrhythmias (SCA/VA), and major adverse cardiovascular event (MACE). Secondary outcomes were CV mortality, all-cause mortality, heart failure, stroke, myocardial infarction. Of 54,462 propensity score matched pairs of RA patients initiating HCQ or MTX, primary analysis did not find an association between HCQ and risk for SCA/VA or MACE compared to MTX. However, in secondary analyses, HCQ use was associated with increased risks of hospitalized heart failure (HR 1.41, 95% CI 1.24-1.61), and for patients with a history of heart failure, CV mortality (HR 1.21, 95% CI 1.00-1.48), and all-cause mortality (HR 1.19, 95% CI 1.05-1.36) significantly increases. 

Abstract #1705: Antivalle et al studied the impact of age and drug to drug interactions on the QT interval in chronic HCQ users. The study evaluated ECGs in 355 patients with SLE, RA, or other connective tissue disease patients who are taking HCQ and concomitant medications including statins, ACE inhibitors, vitamin D, calcium channel blockers (CCBs), ;selective serotonin reuptake inhibitors (SSRIs), proton pump inhibitors (PPIs), gabapentinoids, glucocorticoids, and biologics. Patients on average had 5 concomitant medications. QTc prolongation was seen with older age, especially with addition of vitamin D, PPIs, and CCBs but not with other medications.  

Abstract # 1762: ;A New York study looked at risk for prolonged QTc in HCQ alone without other QTc prolonging medications. 3917 patients were on HCQ alone of which 1036 patients had at least 1 ECG. No significant differences in QTc were seen with HCQ after they were started on treatment 

Recently, a white paper on HCQ and cardiac toxicity was published by the ACR recommending clinicians be aware of the small effect that HCQ has on QTc prolongation affecting cardiac repolarization and long-term use may lead to cardiomyopathy associated with arrhythmias and heart failure. While the Food and Drug Administration label warns and recommends monitoring, the ACR working group of experts noted, "ECG monitoring is not part of the current standard of practice when HCQ/CQ is prescribed for the treatment of rheumatologic or dermatologic conditions, and there is currently insufficient evidence on which to base specific monitoring recommendations across all patient populations prescribed HCQ/CQ (2)."

The white paper suggests clinician can consider a baseline ECG in patients with additional QT prolonging risk factors (e.g, using > 1 QTc prolonging meds, older age >68 years old, severe acute illness, recent MI, CHF, alcoholic liver disease, electrolyte abnormalities), ;and providers should maintain a high index of suspicion for cardiomyopathy in patients who have had long-term HCQ treatments with new cardiac symptoms. While the debate continues, what will you do? Will you obtain baseline ECGs in high-risk patients? Would you avoid HCQ in patients with heart failure?  


  1. Lane, J. C. E. et al. Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study. Lancet Rheumatol. (2020). 
  1. American College of Rheumatology White Paper on Antimalarial Cardiac Toxicity October 2021 



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