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CHICAGO -- Starting sacubitril/valsartan (Entresto) during hospitalization for acute decompensation in heart failure with reduced ejection fraction (HFrEF) safely improved a key prognostic biomarker, with a possible halving of rehospitalizations too, the PIONEER-HF trial showed.

The time-averaged reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration from baseline to weeks 4 and 8 was 46.7% with sacubitril/valsartan versus 25.3% with enalapril alone (the ratio of the geometric mean 0.53 vs 0.75, ratio of change 0.71, P<0.001).

That primary endpoint benefit in a fairly all-comer HfrEF population after hemodynamic stabilization supports broad generalizability, Eric Velazquez, MD, of Yale University in New Haven, Connecticut, reported here at the American Heart Association (AHA) annual meeting and online in the .

The biomarker change was confirmatory of what has been seen in the chronic HFrEF setting in the pivotal PARADIGM-HF trial, commented Mary Norine Walsh, MD, of St. Vincent Heart Center in Indianapolis and immediate past-president of the American College of Cardiology.

More important was the safety seen in early administration in the hospital, she argued.

PARADIGM-HF had a run-in period before randomization to sacubitril/valsartan that was longer than most hospitalizations, and there had been concerns that acute cases might particularly struggle with hypotension and angioedema, Walsh noted.

The beneficial effect on that "biomarker of neurohormonal activation, hemodynamic stress, and subsequent cardiovascular events, was accompanied by a reduction in the concentration of high-sensitivity cardiac troponin T, which is a biomarker of myocardial injury," reported Eric Velazquez, MD, of Yale University in New Haven, Connecticut, and colleagues.

Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema were all similar between groups in the findings presented here at the American Heart Association (AHA) annual meeting and online in the .

Safety was the key concern, commented Mary Norine Walsh, MD, of St. Vincent Heart Center in Indianapolis and immediate past-president of the American College of Cardiology.

The biomarker change was confirmatory of what has been seen in the chronic HFrEF setting, but safety of early administration in the hospital had been a question because the pivotal PARADIGM-HF trial had a run-in period before randomization to sacubitril/valsartan that was longer than most hospitalizations, she noted.

PIONEER-HF actually even showed numerically less angioedema confirmed by blinded adjudication, with one case in a white patient on sacubitril/valsartan compared with six cases in black patients on enalapril. Almost 36% of participants in the trial were African Americans.

Only about 14% of patients had hypotension, with a less than 2% difference between groups, highlighted AHA discussant Larry Allen, MD, of the University of Colorado in Aurora.

However, the most "compelling" part was the potential effect on readmissions, said Gregg Fonarow, MD, of the University of California Los Angeles and a member of the PIONEER-HF data safety monitoring board.

While composite clinical events (ranging from death to a more than 50% increase of diuretic dose) were similar between treatment arms in the exploratory secondary outcome analysis, rehospitalization for heart failure at 8 weeks was 46% less common with sacubitril/valsartan (8.0% vs 13.8%, P=0.005).

"That is a phenomenal magnitude," Fonarow said. "The entire impact of the billions of dollars of penalties from CMS [Centers for Medicare & Medicaid] has not even come close to that."

Velazquez also highlighted the exploratory composite of death, heart failure rehospitalization, left ventricular assist device use, and transplant listing, which had a hazard ratio of 0.54 (95% CI 0.37-0.79) for a number needed to treat of 13.

AHA press conference moderator Donald Lloyd-Jones, MD, of Northwestern University in Chicago, also called the findings “extremely promising looking,” although he cautioned that the numbers of events were small.

“There could be some chance at play here, perhaps not in the overall effect but in the size of that effect,” he said. “We’re going to want larger trials to nail down exactly what the size of effect is.”

Sacubitril/valsartan is already a standard of care medication for these patients, but clinical inertia has left rates of use low, said Allen.

This simpler strategy of just starting patients on the drug as an inpatient, rather than putting patients on an ACE inhibitor in the hospital and waiting for the outpatient care team to start sacubitril/valsartan, is better for clinicians and better for patients, he said.

“I do think it will change practice,” Allen said. “It simplifies that algorithm — if somebody comes into the hospital and they are a captive audience, I can get them on what I think is best therapy more directly and discharge them on that therapy. … Yes, there are other barriers but I do think this takes down one of the major barriers and will help.”

That early initiation is important, Fonarow agreed, noting it appeared to be equally beneficial whether patients were initiated sooner or later in their index admission.

Patients were enrolled in the hospital from 24 hours to 10 days after initial presentation, with a median of 68 hours.

After hemodynamic stabilization, 881 U.S. patients with HFrEF hospitalized for acute decompensated heart failure patients were randomly assigned to get sacubitril/valsartan (target dose 97 and 103 mg, respectively, twice daily) or enalapril (target dose 10 mg twice daily).

Notably, systolic blood pressure had to be at least 100 mm Hg for the preceding 6 hours, and median systolic pressure was 118 mm Hg at randomization. Only 23.4% of the patients had a systolic blood pressure under 110 mm Hg.

Those blood pressure characteristics have to be a consideration before people apply the findings liberally, Walsh noted.

It was notable that 34% were first diagnosed with heart failure at the index hospitalization. And fully 52% of participants were not on an ACE inhibitor or angiotensin receptor blocker at admission. "On the front end, it wasn't an ideally-treated patient population by any means," Walsh noted.

But even if some patients discontinue sacubitril/valsartan after being started on it in the hospital, "there's evidence in multiple studies showing any drug started in hospital is more likely to be continued by the patient," she pointed out.

PIONEER-HF may even provide enough evidence that hospital systems should think about adding a flag to the electronic health record to start sacubitril/valsartan for appropriate patients, Walsh suggested.

"It's already consistent with guidelines to do this, but it gives a more compelling reason that initial drug...of your three choices will be your strongly preferred choice," Fonarow concluded. "It's a win, win, win."

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