Less Is More: Loop Diuretic Withdrawal May Be Safe in Selected Heart Failure Outpatients

May 28, 2019

Selected patients with heart failure who are doing well on optimal guideline-directed medical therapy, including furosemide, may be safely taken off loop diuretics without raising their risk for dyspnea, decompensation, or other ill effects, suggests a randomized study.

Importantly, the study entered patients with a history of hospitalization for acute HF who were consistently stable on good medical therapy. In fact, about 60% of the 188 patients were in NYHA functional class 1 when they were randomly assigned to either go off or continue their maintenance doses of furosemide.

"This was a very low-risk group. They had no recent admissions and were optimized on drugs, and they tended to be younger than we see in some trials of decompensated heart failure," said Andréia Biolo, MD, ScD, Hospital de Clinicas de Porto Alegre, Brazil. The mean age for patients in both groups was 59 years.

That means their prognosis was "fairly favorable" and their prospects for living many more years were quite good. Such patients would likely welcome the opportunity to take one fewer medication among the many generally prescribed in heart failure, she told theheart.org | Medscape Cardiology after presenting the first Brazilian Research Network in Heart Failure (ReBIC-1) study here at European Society of Cardiology Heart Failure 2019.

There are also good clinical reasons why furosemide withdrawal, when safely possible, may be a prudent idea, Biolo observed. Intensive loop diuretic therapy can cause neurohormonal activation and compromise renal function, among other potential adverse effects, and possible long-term risks of lower maintenance doses aren't well understood.

The current study asked whether it is safe to withdraw loop diuretics in low-risk stable patients with heart failure, "and we know safety trials, to be definitive, actually require a very large sample size," noted G. Michael Felker, MD, MHS, Duke University, Durham, North Carolina, as invited discussant after the ReBIC-1 presentation.

"I think smaller trials can give a clue and a suggestion that a treatment or process of care might be safe, but I don't think they're able to provide definitive evidence of safety."

However, for lower-risk stable, medically well-managed patients like those in the study, "I think these data definitely support the concept of a trial of furosemide withdrawal as part of an overall strategy of optimizing care," he said.

"Most of what we do in heart failure care is to focus on increasing intensity of treatment," Felker noted. "But when we think about optimization, it doesn't always mean increasing doses. It means having people on the right regimen. For drugs like diuretics that are focused on symptomatic management of congestion, maybe the correct dose is a lower dose."

It may be relatively few patients with a history of HF decompensation that the current findings apply to, cautioned Martin Schulz, PhD, professor of pharmacy, Freie Universität Berlin, who wasn't involved in ReBIC-1.

The trial's inclusion and exclusion criteria produced a population that was well treated, with literally everyone on beta blockers and 90% on ACE inhibitors or angiotensin receptor blockers, and with strikingly high usage of other guideline-based medications, he told theheart.org | Medscape Cardiology.

That in itself suggests the population was unusual, given the typically high rates of undertreatment and noncompliance in such patients.

Clinical trial populations, he noted, often don't well represent broad clinical practice. "Probably in the real world, they would be higher risk" and wouldn't respond as well to furosemide withdrawal.

Biolo said in an interview that probably fewer than half of patients with a history of heart-failure hospitalization resemble those in ReBIC-1.

The trial entered patients in NYHA class 1 or 2 with a left ventricular ejection fraction (LVEF) ≤45% who had been stable on optimal medical therapy, including furosemide at 40 to 80 mg/d, for at least 6 months.

It excluded patients with severe valvular, renal, pulmonary, or liver disease; and those with acute coronary syndromes, stroke, or coronary revascularization in the previous 3 months.

The 95 assigned to furosemide withdrawal and 93 to maintenance furosemide were similar with respect to LVEF, which averaged 32% for both groups, and in distribution of NYHA class; three-fourths of both groups were male.

There were no differences between the groups in dyspnea symptoms, self-assessed using a visual analog scale (P = .50), one of the two primary end points, throughout the 90-day follow-up.

Nor was there a significant difference (P = .16) in re-initiation or intensification of furosemide, the other primary end point, which was decided by clinicians blinded to patients' assigned group in accordance with predefined criteria. They included worsening symptoms or NYHA functional class and a weight gain of more than 2 kg.

A blinded adjudication committee decided whether any furosemide change qualified as a primary end point, which was defined as any temporary IV loop diuretic administration or any oral loop diuretic given for more than 4 days.

There were five hospitalizations in the withdrawal group and three in the maintenance group (5.3% and 3.2%, respectively), no deaths in the withdrawal group, and two deaths in the maintenance group. None of the differences came close to significance in the study that, at any rate, was underpowered for clinical outcomes.

Nor were there significant 90-day differences in change in natriuretic peptide levels, 6-minute walk distance, or body weight.

Biolo proposed that a side benefit of furosemide withdrawal for patients, in addition to a less daunting pill regimen and less discomfort from the drug's effects, may be improved tolerance, allowing greater optimization, of renin-angiotensin-system-inhibiting agents, "the life-saving drugs that they must use."

Biolo and Schulz had no disclosures. Felker has previously disclosed receiving research grants from Johnson & Johnson, Roche Diagnostics, Critical Diagnostics, and BG Medicine.

European Society of Cardiology Heart Failure (ESC-HF) 2019: Abstract 646. Presented May 26, 2019.

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