HCQ in Lupus: No Heart Worries With Higher Doses

Patients with systemic lupus erythematosus (SLE) who received higher than normal doses of hydroxychloroquine (HCQ) to control their disease did not experience increased rates of serious cardiovascular events, researchers found in a retrospective study.

Compared with lupus patients taking HCQ at 5 mg/kg/day or less — the dosage level recommended in current guidelines — those taking more experienced a composite endpoint of life-threatening arrhythmias, heart failure with reduced ejection fraction (HFrEF), or cardiovascular death at substantially the same rates, according to Alejandra Londono Jimenez, MD, MSc, of McFarland Clinic in Ames, Iowa, and colleagues.

In fact, rates of these adverse outcomes were actually lower with the higher HCQ doses when results were adjusted for age, comorbidities, and body mass index, the researchers reported in Arthritis Care & Research.

With median follow-up of 7.9 years, each 1-mg/kg increment in HCQ dose was associated with reductions of 38% in the composite endpoint among nonsmokers (HR 0.62, 95% CI 0.41-0.92) and 15% among smokers (HR 0.85, 95% CI 0.53-1.34).

Jimenez and colleagues undertook the study to examine the degree to which long-term HCQ dosing may exacerbate or ameliorate cardiovascular risk. Short-term studies have indicated that the drug “can interfere with ventricular repolarization, and some with longer follow-up have suggested increased risk for cardiomyopathy.” One recent analysis among veterans found a slight increase in arrhythmias, which remained rare.

Meanwhile, the group explained, many other studies have demonstrated reduced risks for all-cause mortality, coronary artery disease, and major cardiovascular events. Lupus itself can damage the heart and HCQ’s ability to control the disease is hypothesized to weigh in the drug’s favor. The guideline-recommended dosing limits are mainly meant to prevent ocular toxicity.

The new study involved 294 patients seen at Montefiore Medical Center in the Bronx, New York (where Jimenez was a trainee during the research), of whom 159 were taking more than 5 mg/kg/day of HCQ. Reasons for the higher-than-recommending dosing were not clear, although HCQ is dispensed primarily as 200-mg tablets that do not allow for full adherence to a weight-based maximum while maintaining optimal efficacy. The authors did not report actual doses, other than to note that those experiencing the composite endpoint were taking a median of 4.9 mg/kg, while median dosing was 5.2 mg/kg in those avoiding the adverse events.

Jimenez and colleagues also identified 99 pairs of patients, one each from the lower- and higher-dosing groups, matched according to propensity for the endpoint events. Regression analysis indicated that the higher doses did not confer greater risk for the events (HR 0.68, P=0.3).

The researchers did not overtly call for a revision to the HCQ dosing guidelines. Rather, they wrote, “our results suggest that the potential cardiac benefits derived from higher HCQ doses need to be weighted carefully with the risk of other toxicities when deciding on appropriate HCQ dosing.”

They called for additional studies with “more precise measurements of HCQ exposure” and that also “account for interindividual differences in adherence and metabolism.” The current study, they acknowledged, came with a number of substantial limitations, including lack of comprehensive information on individual patients’ cardiovascular risk factors, medication compliance, and drug blood levels. Also, HFrEF was diagnosed via echocardiography, such that the results “may only be generalized to SLE patients with clinically indicated echocardiograms,” the researchers said.