Outpatient intensification of diuretics associated with increased mortality in heart failure

Intensification of diuretics in outpatients with heart failure may be linked to increased mortality, according to a recent Danish study.

Researchers in Denmark used nationwide data to identify patients diagnosed with heart failure from 2001 to 2016 who were alive four months later, received an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker within 120 days, and had not been hospitalized for heart failure since diagnosis. Patients were followed for five years or until the end of 2017, death, or relocation from Denmark. Diuretic intensification and heart failure hospitalization rates during follow-up were the two outcomes of interest, and the primary end point was all-cause mortality. Intensification was defined as a newly prescribed loop diuretic equivalent to a minimum of 80 mg of furosemide per day, a doubled dosage of furosemide equivalent compared with the initial dosage to a minimum of 160 mg/d, or a newly prescribed thiazide in addition to at least 160 mg of furosemide per day. Patients who had an intensification event or hospitalization were risk-set matched with two controls whose heart failure did not worsen. The results of the study were published July 14 by the Journal of the American Heart Association.

A total of 74,990 patients were included in the study. Median age was 71 years, and 36% were women. An association was seen between intensification events and a significant increase in mortality throughout follow-up. In-hospital mortality rates were 59.0% for patients with a hospitalization and 55.7% for those with an outpatient intensification event. One-year mortality rates were 18.0% after an intensification event, 22.6% after hospitalization for heart failure, and 10.4% for matched controls with neither of these risk factors. The hazard ratio for death at one year was 1.75 (95% CI, 1.66 to 1.85) after an intensification event and 2.28 (95% CI, 2.16 to 2.41) after hospitalization for heart failure in a multivariable Cox model adjusted for age, sex, ischemic heart disease, atrial fibrillation, chronic obstructive pulmonary disease, and diabetes.

The researchers noted that their study did not include data on left ventricular ejection fraction, clinical signs, and laboratory tests and that their results may not apply to patients who have an event soon after heart failure diagnosis, among other limitations. They concluded that in their study population, outpatient diuretic intensification events were common and were associated with a significantly higher risk for death. “Although HF [heart failure] hospitalization was associated with an even higher risk, patients with an outpatient intensification event should receive as careful a reevaluation for optimization of drug therapy and consideration of advanced options as patients who are hospitalized for worsening HF,” they wrote.

The study shows that increases in outpatient diuretics are “not a benign event” and that heart failure does not worsen only in the hospital setting, an accompanying editorial said. In addition, the editorialists said, the results indicate that oral diuretic intensification should be included in the definition of worsening heart failure in clinical trials, and the low rate of mineralocorticoid receptor antagonist therapy seen in the study, 32%, is in keeping with previous research indicating gaps in guideline-recommended medical therapy for heart failure.

“As the public health and financial burden of HF continues to increase, it is vital to recognize the entity of outpatient worsening HF, and to acknowledge an outpatient increase in oral diuretics as a high-risk clinical scenario,” the editorialists wrote. “Moreover, although HF hospitalizations have been the traditional focus for researchers, hospital systems, and clinicians, we must appreciate outpatient escalation of oral diuretics as common, potentially occurring more frequently than hospitalization, and a clear marker with poor prognosis.”