Does door-to-diuretic time matter?

Heart failure experts explain conflicting research about significance of speedy delivery of diuretics in an exacerbation.

Diuretics are important for treating acute heart failure exacerbations, but it's unclear whether starting them sooner improves clinical outcomes.

Image by Thinkstock
Image by Thinkstock

Two recent studies have produced contradictory results. A prospective observational cohort study of more than 1,200 patients with acute heart failure in Japan found lower in-hospital mortality among patients who received IV furosemide within 60 minutes of ED arrival (2.3% vs. 6.0% in those who received diuresis more than 60 minutes after presentation; P=0.002). These findings were published in the June 25, 2017, Journal of the American College of Cardiology. These findings persisted after the authors controlled for many possible confounders, such as heart failure risk score, age, sex, smoking status, blood pressure, heart rate, left ventricular ejection fraction, atrial fibrillation, and ischemic or valvular heart disease.

In contrast, in a prospective observational cohort study of more than 2,700 patients with acute decompensated heart failure in Korea, starting diuresis within 60 minutes of ED arrival was not associated with improved mortality in the hospital or at one month or one year after discharge. The results were published in the April 2018 JACC: Heart Failure.

Explaining the research

The differing findings might be explained by patient characteristics, according to some experts. In the first study, patients with shorter door-to-diuretic times had more prominent congestive symptoms, which could have triggered faster treatment, noted David H. Ellison, MD, a nephrologist and professor of medicine, physiology, and pharmacology at Oregon Health and Sciences University in Portland, Ore.

“Patients who present with more classical volume overload, with clearly congested lungs, elevated jugular venous distention, and more overall signs of rapid deterioration, would be likely to receive diuretics faster,” Dr. Ellison said. “But they also would be the patients who might benefit more from shorter door-to-diuretic time.”

Both studies enrolled patients consecutively, which tends to reduce the chances of selection bias and makes it easier to control for confounding. Nonetheless, “there may have been factors that differed between the patients in these two studies that we were not able to see from reading the papers,” said Dr. Ellison. “For example, we don't know the doctors' thought process that went into deciding how soon to start diuretics.”

Indeed, acute decompensated heart failure can be hard to recognize, especially when patients present atypically, said James L. Januzzi Jr., MD, a cardiologist and professor of medicine at Harvard Medical School in Boston.

Getting the diagnosis right is more important than rapid treatment, he added. “A sound history and physical examination is crucially important. Adjunctive testing is often very helpful but also can lead clinicians astray.” For example, chest radiography does not diagnose or exclude heart failure, and natriuretic peptides are highly sensitive but modestly less specific, he noted.

Dr. Januzzi said it hard to believe that early diuretic administration, which primarily provides relief from dyspnea, significantly affects hard clinical endpoints, such as mortality. In the studies that have found these links, shorter door-to-diuretic time could be a proxy for diagnostic acumen, he added, which could reasonably be expected to trigger a “cascade of interventions,” including titration of guideline-directed medical therapy, correct assessment of decongestion, and robust aftercare.

Slower progression

The study in Korea was among several to recently find that faster treatment does not improve clinical outcomes among patients with acute heart failure exacerbations.

In the TRUE-AHF (Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure) trial, for example, patients who received the parenteral natriuretic peptide ularitide within six hours of ED arrival had nearly identical cardiovascular mortality (21.7%) as those who received placebo (21%). The results of this trial were published in the May 18, 2017, New England Journal of Medicine.

Such null results probably reflect the slower progression of acute decompensated heart failure as compared with acute coronary syndrome (ACS), said Clyde W. Yancy, MD, MACP, chief of cardiology in the department of medicine at Northwestern University Feinberg School of Medicine in Chicago.

“The time stamp for an ACS event is mostly aligned with the onset of chest pain, and disease progression can be interrupted within hours,” Dr. Yancy said. “For heart failure, the onset of decompensation is now proven to begin days prior to emergency room presentation, with increases in continuously monitored [pulmonary artery] pressures occurring well before symptoms begin, and even longer before presentation.”

Thus, an “acute” heart failure exacerbation actually is a subacute process, said Dr. Yancy. This means that no matter how fast a patient receives IV diuretics, it's still quite late in the disease trajectory.

As a result, diuresis primarily improves symptoms, not clinical outcomes, Dr. Yancy said. “Tempting as it is to align door-to-diuretic time with door-to-balloon time for acute coronary syndromes, the data don't sync up as well as we would wish.”

Thus far, the only intervention that's been shown to improve outcomes in acute heart failure is optimizing guideline-directed medical therapy, Dr. Yancy emphasized. “We must fully respect the complexity of heart failure and not just extrapolate strategies that have proven successful in other types of heart disease.”

Sufficiency over speed

In acute heart failure, it's clear that sufficient diuresis is at least as important as rapid diuresis, the experts said.

For patients with established heart failure who are on loop diuretics and present with clear evidence of volume overload, the initial IV diuretic dose should be 2 to 2.5 times the home daily dose, they advised. “Diuresis should begin within 30 minutes [of IV diuretic treatment], and physicians can start assessing response at 90 minutes,” said Dr. Ellison.

Unfortunately, many physicians continue to under-diurese these patients, he said. “As a nephrologist, from what I see in consultation, the most common mistake that physicians make when treating patients with heart failure or volume overload is inadequate treatment, rather than overtreatment. We often see physicians waiting too long to give a diuretic or giving an inadequate dose.”

ED physicians often give too low an initial IV dose of diuretic, and hospitalists tend to wait too long to assess response and re-treat when needed, Dr. Ellison said. As a result, he sees patients with acute heart failure go “four, six, or even eight hours without adequate decongestion.”

Problems with handoffs are one reason. “Often, the emergency department physician gives a dose of loop diuretic and then moves the patient to the floor. The urine output during transfer may be difficult to track, impairing the accurate assessment of response.”

Most guidelines recommend 3 to 5 liters of diuresis per day for patients with acute heart failure exacerbations, and inadequate diuresis can be a factor in rehospitalization. Since diuresis often begins in the ED, “the handoff between the emergency department physician and the hospitalist is crucial,” Dr. Ellison said. That's because “there is no magical dose of diuretic. The magical dose is the dose that works.”