Clinical Challenges: Managing the New Heart Failure Categories

An update to heart failure (HF) guidelines introduced new categories for heart failure with intermediate and improved ejection fraction, which should help with management decisions for these unique patient groups.

The guideline update from the American College of Cardiology (ACC), American Heart Association, and Heart Failure Society of America, which launched on the eve of the ACC meeting in Washington, D.C. in early April, included two new categories from the prior 2013 guidelines:

• HF with improved ejection fraction (HFimpEF): left ventricular ejection fraction (LVEF) previously ≤40% but >40% on follow-up
• HF with mildly reduced ejection fraction (HFmrEF): LVEF 41% to 49% and increased LV filling pressures

These changes followed the universal definition of HF proposed last year in conjunction with other global organizations, including the European Society of Cardiology.

How to divide up the categories of heart failure beyond the 40% threshold for heart failure with reduced ejection fraction (HFrEF) has been an area of ongoing discussion, challenges, and growth, noted David Dudzinski, MD, JD, of Massachusetts General Hospital in Boston.

“This is a theme throughout all of medicine, the ‘lumpers and splitters,'” he told MedPage Today. “Do you put diseases together or do you phenotype with granularity and try to get specific outcomes and therapies for individual and really narrowly defined subgroups? The guidelines that just came out really emphasize well that there’s this temporal nature and that patients are improving or not improving, and they’re probably all different.”

The previous U.S. guideline labeled patients with an ejection fraction in the 41% to 49% range as “HFpEF [heart failure with preserved ejection fraction], borderline, a term with limited utility for diagnosis and management,” wrote Michelle Kittleson, MD, PhD, of the Smidt Heart Institute in Los Angeles, in an editorial accompanying the guideline in the Journal of Cardiac Failure (co-published in Circulation and the Journal of the American College of Cardiology).

The dynamic trajectory of patients improving from HFrEF or deteriorating from HFpEF is clinically meaningful, she wrote. “This distinction is important: based on a landmark trial in patients with HFimpEF, there is now a class I indication that in patients with HFimpEF after treatment, GDMT [guideline-directed medical therapy] should be continued to prevent relapse of HF and left ventricular dysfunction, even in patients who may become asymptomatic.”

That trial, TRED-HF, showed that randomization to withdrawal of heart failure medication for patients with dilated cardiomyopathy whose ejection fraction had improved from less than 40% to at least 50% often led to relapse. The rate was 44% over the first 6 months compared with none of those assigned to continue treatment. When those initially assigned to continue treatment attempted to discontinue it after 6 months, 36.0% relapsed.

That was “clear evidence,” emphasized guideline writing committee chair Paul Heidenreich, MD, of Stanford University in California.

“There is a very rare patient who truly normalizes their heart function and whatever toxin or thing they had onboard is gone,” he said. “Those are very rare. Putting those aside, the rest should continue with whatever treatment got them to that improved ejection fraction.”

“Patients often want to stop, especially if they see a number improving. They like to say, ‘Hey, does that mean I can stop my medication now that my ejection fraction has improved?’ Our answer would be no. You don’t necessarily need to escalate therapy, like you now potentially wouldn’t need a defibrillator, whereas you might have if your ejection fraction remained where it was,” he added.

One reason is that ejection fraction may not tell the whole story for HFimpEF patients, Dudzinski pointed out. “They may still have abnormalities in cardiac chamber size and diastolic function.”

While the guidelines came down solidly in favor of continued treatment for HFimpEF patients, the best strategy for the HFmrEF group was less well defined.

“There is limited evidence to guide treatment for patients who improve their LVEF from mildly reduced (41%-49%) to ≥50%. It is unclear whether to treat these patients as HFpEF or HFmrEF,” according to the guidelines.

For HFmrEF patients, the guidelines gave SGLT2 inhibitors a class IIa recommendation in decreasing HF hospitalizations and cardiovascular mortality. Other classes of medications — beta-blockers for HFrEF, angiotensin receptor-neprilysin inhibitors, ACE inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists — got a IIb “may be considered” recommendation, “particularly among patients with LVEF on the lower end of this spectrum.”

The higher recommendation for SGLT2 inhibitors was based on the EMPEROR-Preserved trial. Although there was no significant interaction by LVEF subgroups, the largest benefit was seen in those at the lowest ejection fraction end of the enrolled population — 40% to 49%, with a hazard ratio of 0.71 (95% CI 0.57-0.88) for the primary composite endpoint of cardiovascular death or HF hospitalization — compared with those in the 50% to 59% or 60% and above subgroups.

It was the first time a medication was shown to improve the primary outcome for patients with an ejection fraction over 40%, Heidenreich noted.

“In looking at the trial data for all four pillars of therapy, there is a clear relationship with the ejection fraction, such that you get more benefit from treatment if your ejection fraction is lower,” he said. “For that reason, we separated out mildly reduced from HFpEF, which would be an ejection fraction of 50% or greater.”

However, there’s room for better evidence, Dudzinski acknowledged.

“What’s notable is that the guidelines give us a lot of gaps, a lot of areas for future research and among them are, ‘Are these the right definitions?'” he said in an interview. “That’s actually the first gap listed in the last table in the guideline paper. What is the consensus, and what should the specific classifications and categories be? A few lines down from that is, ‘What are specific evidence-based strategies for this mildly reduced EF category?’ Some of the data come from post-hoc analyses. So we don’t exactly know what to do for that specific category.”

Additional trials with SGLT2 inhibitors have the potential to move up their recommendation to class I, Heidenreich pointed out.

Another implication from the new categories is the need for serial assessment, Dudzinski added.

“Part of the theme here is heart failure is not a static, but is a dynamic, process,” he said. “The implication is that the cardiologist and care team will be surveilling the ejection fraction over time.”

A class I recommendation was given for repeat cardiac imaging to follow ejection fraction, degree of structural remodeling, and valvular function if there is a significant clinical change or with consideration for invasive procedures or device therapy. The guidelines also gave a class IIa recommendation to serial use of risk assessment with validated tools and noted that changes in clinical condition or treatment can mean repeating pertinent laboratory tests as well, such as those to monitor renal function or electrolytes with diuretics.