Is Hydroxychloroquine Harmful for the Heart?

Volume 16, Issue 5

Hydroxychloroquine is a unique medication. Its primary use is for patients with milder forms of rheumatoid arthritis (RA), where it works by suppressing activation of Toll-like receptors, which exist on the surface of endosomes and play a significant role in the innate immune response and autoimmune disease.

Unfortunately, hydroxychloroquine blocks the potassium channels, leading to prolongation of the QT interval, and this drug was approved prior to the now-mandatory evaluation of drugs for QTc prolongation risk. While postmarketing reports do not show an increased risk of QTc prolongation for this agent when used for RA, there were reports of higher rates of arrhythmias when it was used for COVID-19.

The cardiovascular safety of hydroxychloroquine remains understudied. In this week’s issue of Talking Therapeutics, we explore a new study published this week that compared hydroxychloroquine to methotrexate.

Point 1: No Signals for Harm in the General Population

The authors of this study used Medicare data from 2008 to 2016. The study included 54,462 propensity score-matched patients who were at least 65 years of age. Patients had rheumatoid arthritis and began treatment with either hydroxychloroquine or methotrexate. Their “primary outcomes were sudden cardiac arrest or ventricular arrythmia (SCA/VA) and major adverse cardiovascular event (MACE).” 

Overall, this study showed “hydroxychloroquine was not associated with risk of SCA/VA (HR: 1.03; 95% CI: 0.79-1.35) or MACE (HR: 1.07; 95% CI: 0.97-1.18) compared with methotrexate.”

Unfortunately, the median follow-up was 180 days for hydroxychloroquine and 228 days for methotrexate. This is relevant given that hydroxychloroquine does not reach a steady-state level for 6 months.

Furthermore, hydroxychloroquine accumulates in the lysosomes of cardiac myocytes in a dose and drug duration dependent manner, and adverse cardiovascular events occur rarely before 2 years of therapy and most frequently after 7 years. Hence the current study could have missed a treatment-related adverse event due to the relatively short follow-up period.

Point 2: Signals for Harm in Patients with Heart Failure

In those with history of heart failure, hydroxychloroquine initiators had greater risk of the following when compared to patients receiving methotrexate:

• MACE (HR: 1.30; 95% CI: 1.08-1.56);
• cardiovascular mortality (HR: 1.34; 95% CI: 1.06-1.70);
• all-cause mortality (HR: 1.22; 95% CI: 1.04-1.43);
• myocardial infarction (HR: 1.74; 95% CI: 1.25-2.42); and
• hospitalized heart failure (HR: 1.29; 95% CI: 1.07-1.54). 

Because this is a subgroup analysis of a retrospective study, these findings are purely hypothesis-generating. Future studies should be done to further characterize the potential for adverse cardiovascular effects of hydroxychloroquine in patients with heart failure.