Study Results Determine No Link Between Hydroxychloroquine and Heart Failure in Patients With Rheumatoid Arthritis

Hydroxychloroquine (HCQ), the controversial immunosuppressive therapy that made headlines earlier in the coronavirus disease 2019 (COVID-19) pandemic when it was floated as potential treatment option, has been a topic of interest for rheumatologists concerned about potential cardiovascular (CV) safety and risks associated with the drug. A recent study published in The Journal of Rheumatology,¹ however, found no association between hydroxychloroquine therapy and heart failure in patients with rheumatoid arthritis (RA) and other rheumatic diseases, such as systemic lupus erythematous (SLE).

HCQ, a popular disease-modifying anti-rheumatic drug (DMARD), lists cardiotoxicity as a rare, yet potentially life threatening, side effect. In this population-based study, investigators examined the relationship between this therapy and the risk of developing heart failure (HF) in patients with RA. This is of particular concern to rheumatologists because “the inflammatory burden characteristic of RA has been linked to the increase risk of CV disease, including HF. HF development in RA patients is multifactorial, with contribution from cardiovascular risk factors and RA disease-related factors. The relationship between HCQ and HF has been controversial, with one argument suggesting a cardioprotective effect of HCQ, while the counterargument supports a cardiotoxic role.”

Using data from the Rochester Epidemiology Project to perform the nested case-control study, investigators pulled cases of patients with RA who developed HF after diagnosis in Olmsted County, Minnesota, between 1980-2013. All patients were 18 years of age or older and fulfilled the American College of Rheumatology (ACR) classification criteria. Patients with HF were marked as “HF cases,” while those without HF were labeled as “non-HF controls.” Both groups were matched 1:1 for age, sex, and year of RA diagnosis. In order to calculate HCQ duration and cumulative dose, start/stop date data and dosage changes were collected from medical records and reviewed. Medical records also allowed investigators to dig deeper to discover potential CV risk factors, including age, smoking, hypertension, diabetes, and dyslipidemia. A patient’s glomerular filtration rate (GFR) was calculated from creatinine values obtained around the same time as the HF diagnosis within ±90 days.

Beginning with a cohort of 1078 patients with RA, the study focused on 143 RA HF cases (mean age 65.8 years, 62% female) and another 143 non-HF controls (mean age 64.5, 62% female). Both groups were matched for similar demographics and RA characteristics, with a multimorbidity of hypertension and diabetes mellitus being the most prevalent in the HF cases. A total of 71 HF cases and 69 non-HF controls used HCQ at some point prior to their HF diagnosis or index date. The age-adjusted logistic models confirmed that HCQ usage prior to index date did not increase a patient’s risk of developing HF.

Standard doses of HCQ for patients with RA ranged from 200 to 400 mg daily. The median (IQR) cumulative dose for patients prior to their index date/HF diagnosis was 371 g and 203 g, respectively. A cumulative dose of at least 300 g was similar for both HF cases and non-HF controls (55% and 54%, respectively). Investigators found that neither HCQ cumulative dose (<300 g or ≥300 g) was associated with HF. Additionally, taking HCQ prior to the index was not associated with an increased chance of developing HF.

The biggest limitation of this study was that it was a retrospective, and therefore could only use information attained in medical records to draw conclusions. However, investigators assure, “availability of complete medical records from all healthcare providers in the area and standardized case ascertainment likely minimized this bias.” Additionally, there were no follow-ups for patients after HCQ discontinuation and information on biological markers for HF and other cardiovascular statistics were not available. Further, cases of hypertension and diabetes mellitus were higher for patients with HF, which could lead to an imbalance of baseline characteristics. Investigators do not believe this is statistically significant, however, given the outcome of the study.

Although the results of the study are promising, more research is needed in order to understand the impact and safety of higher cumulative doses to determine whether HCQ can lead to the development of HF and cardiotoxicity in patients with RA and other rheumatic diseases. This information can help investigators further categorize and identify high-risk patients that may need cardiovascular screening before HCQ therapy is introduced.

Reference:

Sorour AA, Kurmann RD, Shahin YE, et al. Use of Hydroxychloroquine And Risk of Heart Failure in Patients With Rheumatoid Arthritis [published online ahead of print, 2021 Jan 15]. J Rheumatol. 2021;jrheum.201180. doi:10.3899/jrheum.201180