Risk in HFpEF Varies With Normal vs High Natriuretic Peptides

Although elevated natriuretic peptides (NP) aren't needed for a heart failure (HF) diagnosis, in practice they can sometimes be seen that way. But using NP assays as a rule-out test could miss the diagnosis in some patients with normal levels who have bona fide HF with preserved ejection fraction (HFpEF).

Such patients would then miss out on new options for therapy and their potential benefits, perhaps with consequences. Symptomatic patients with normal NPs found to have HFpEF at invasive exercise hemodynamic testing are at greater risk for death or HF events compared with those whose symptoms are not due to HF, new research suggests.

Also, patients with HFpEF and normal NPs in the observational study had cardiac structural and exercise hemodynamic abnormalities as well as clinical outcomes that mirrored, though with less severity, what was seen in its HFpEF patients with elevated NPs.

"To our knowledge, the present study shows for the first time that patients with HFpEF and normal NP display an increased risk of adverse outcome compared with controls with noncardiac dyspnea. This is important because these two patient groups are difficult to distinguish by NP levels or echocardiography," states a report published February 9 in the European Heart Journal, with lead author Frederik H. Verbrugge, MD, PhD, Mayo Clinic, Rochester, Minnesota.

Elevated NPs are common in HF with reduced ejection fraction (HFrEF), so — more often in general practice or primary care — it "has sort of been assumed that we can just apply this logic to the everyday evaluation of people with possible HFpEF," senior author Barry A. Borlaug, MD, told theheart.org | Medscape Cardiology.

At least 30% of patients with HFpEF have normal NPs, estimated Borlaug, also of the Mayo Clinic. "So, if you use it as a rule-out test, you are basically missing a lot of patients and falsely reassuring them that they don't have HFpEF." The current study, he said, "hopefully will be eye-opening" for many clinicians.

How HF Is Defined

An HF diagnosis, as described in the recently unveiled "universal definition of heart failure," requires patients with the characteristic symptoms to also have structural or functional cardiac abnormalities marked by either elevated NPs or "objective evidence of cardiogenic pulmonary or systemic congestion at rest or exercise," observed Gregg C. Fonarow, MD, University of California Los Angeles Medical Center.

The current study "nicely demonstrates that [patients with] HFpEF with elevated NP levels have the worse prognosis, but patients with HFpEF with normal NP levels have evidence of cardiac structure, function, and hemodynamics that are included the definition of heart failure and have a prognosis less favorable" than its control group, he told theheart.org | Medscape Cardiology.

The findings therefore "further reinforce" the universal definition, said Fonarow, who was a member of the universal definition writing group but did not participate in the current analysis.

Thin Evidence Base for Drug Therapy

The large HFpEF drug-therapy trials have generally included elevated NPs among their eligibility criteria, in part to help exclude patients who appear to but don't actually have the disorder, both Borlaug and Fonarow observed.

For example, elevated NPs were required for entry to the EMPEROR-Preserved trial, with its groundbreaking win for empagliflozin (Jardiance, Boehringer Ingelheim), and PARAGON-HF, which hinted at benefit from sacubitril/valsartan (Entresto, Novartis). Both trials entered patients with HF with either preserved or midrange ejection fractions and excluded those with HFrEF.

But the current study challenges such requirements. In the future, the authors recommend, HFpEF drug-therapy trials "should consider use of normal and high NP to help guide tailoring of treatment to underlying pathophysiology."

"This and other studies show that NP entry requirements exclude a significant proportion of patients with HFpEF," Fonarow noted. "Nevertheless, there would be logistical challenges to requiring exercise hemodynamics for large-scale randomized clinical trials."

Instead, he proposed, "a staged approach could be considered, where select patients can be entered despite no elevation in NP so long as other objective criteria are demonstrated."

Impact of NP Elevations in HFpEF

The analysis included 581 consecutive patients with HF-like symptoms and a left ventricular (LV) ejection fraction greater than 50% who underwent cardiac catheterization with cardiopulmonary exercise testing over about 12 years at a major center, and who had been tested for N-terminal pro-brain natriuretic peptide (NT-proBNP) at about the same time. Their average LV ejection fraction was about 65%.

Baseline NT-proBNP averaged 65 ng/L in the 157 patients with hemodynamically defined HFpEF and normal NP levels (that is, less than 125 ng/L), comparable to the 73 ng/L average among 161 control participants in whom HFpEF was ruled out.

But HFpEF patients with normal NT-proBNP, compared to the controls, showed significantly more severe LV hypertrophy, higher LV filling pressures, and poorer diastolic function but comparable right ventricular function, the report notes. At exercise, the HFpEF group showed reduced cardiac output and increased measures of LV preload and pulmonary artery pressure.

For the comparison of patients with HFpEF with normal vs elevated (at least 125 ng/L) baseline NT-proBNP levels, the 263 with high levels (average, 790 ng/L) showed significantly greater LV mass, worse cardiac output, and more right ventricular remodeling and dysfunction, systemic and pulmonary vascular disease, and secondary mitral and tricuspid regurgitation.

The risk of death or HF hospitalization for patients with HFpEF and normal NT-proBNP levels was sharply higher than in the control group at a median of 32 months, but significantly lower than in HFpEF patients with elevated biomarker levels in adjusted analysis. The hazard ratios (95% CI) were:

2.74 (1.02 - 7.32), P = .045 vs the control group
0.41 (0.24 - 0.72), P = .002 vs HFpEF and elevated NT-proBNP

The cardiac structural, functional, and hemodynamic findings for the two HFpEF groups may suggest that their NT-proBNP levels tracked with HF severity, in that they seemed consistently worse in those with elevations. But the baseline levels used in the analysis can't shed light on how NT-proBNP levels may change with disease progression, Borlaug observed.

Another possible interpretation, he noted, is that normal NP levels may characterize a distinct HFpEF phenotype with its own management and prognostic implications.

"We don't really have a good handle on this. Is it a fundamentally different disease, or is it an earlier stage of heart failure that's less advanced? That's a really important unanswered question right now."

Verbrugge, Borlaug, and the other authors have disclosed no relevant financial relationships. Fonarow disclosed consulting for AstraZeneca and Novartis.

Eur Heart J. 2022; ehab911. Full text

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