AHA 2018 – Chicago, IL, USA

Angiotensin Receptor-Neprilysin Inhibition in Patients Hospitalized With Acute Decompensated Heart Failure: Primary Results of the PIONEER-HF Randomized Controlled Trial

Presented at the AHA congress 2018 by: Eric J Velazquez (New Haven, CT, USA)

Introduction and methods

Acute decompensated heart failure (ADHF) accounts for over a million hospitalizations in the US annually. Guideline-directed therapy for ADHF is limited. Decongestion with diuretics and hemodynamic support with vasodilators remain the standards of care.

In the PARADIGM-HF trial in chronic HF with reduced ejection fraction (HFrEF), treatment with sacubitril/valsartan lowered CV death or HF hospitalization (HHF), as compared with enalapril. In PARADIGM-HF, patients with ADHF requiring intravenous (IV) therapy were excluded. Moreover, enrolled patients had stable HF therapy with adequate doses for at least 4 weeks and there was a sequential run-in with high dose enalapril and subsequently sacubitril/valsartan before randomization. Thus, it is unknown if in-hospital initiation of sacubitril/valsartan compared to enalapril is safe and effective in ADHF.

The PIONEER-HF therefore evaluated sacubitril/valsartan in patients hospitalized with ADHF (HFrEF), who, once stabilized, were randomized to sacubitril/valsartan or enalapril. A blood pressure-based titration algorithm was followed over 8 weeks to reach target dose. Eligible patients had signs and symptoms of fluid overload, LVEF ≤40% within the last 6 months, NT-proBNP ≥1600 pg/mL or BNP≥400 pg/mL. Patients were stabilized while still hospitalized, meaning in the prior 6 hours: SBP ≥100 mmHg, no symptomatic hypotension, no increase in IV diuretics, no IV vasodilators, and in the prior 24 hours: no IV inotropes.

Main results

• The primary endpoint of proportional change in NT-proBNP from baseline to the mean of weeks 4 and 8 showed a 29% greater reduction with sacubitril/valsartan as compared with enalapril (95%CI: 19-37, P<0.0001).
• No significant differences were seen between treatment groups in safety endpoints worsening of renal function (13.6% vs. 14.7%, RR: 0.93, 95%CI: 0.67-1.28), hyperkalemia (11.6% vs. 9.3%, RR: 1.25, 95%CI: 0.84-1.84), symptomatic hypotension (15.0% vs. 12.7%, RR: 1.18, 95%CI: 0.85-1.64) and angioedema events (0.2% vs. 1.4%, RR: 0.17, 95%CI: 0.02-1.38).
• The serious composite clinical endpoint of death, HF rehospitalization, LVAD and transplant listing was reduced with sacubitril/valsartan as compared with enalapril (HR: 0.54, 95%CI: 0.37-0.79, P=0.001, NNT=13).
• The benefit seen for the serious composite clinical endpoint was mostly driven by rehospitalization for HF (8.0 vs. 13.8%, HR: 0.56, P=0.005 as an exploratory endpoint).
• No differences in the treatment effect of sacubitril/valsartan was seen in 12 subgroup analyses.

Conclusion

These results show that among hemodynamically stabilized acute heart failure patients

with reduced EF, compared with enalapril, sacubitril/valsartan administered over 8 weeks led to greater reduction in NT-proBNP, reduced rehospitalization for HF and sacubitril/valsartan was well tolerated with comparable rates of worsening renal function, hyperkalemia, symptomatic hypotension and angioedema. These results support the in-hospital initiation of sacubitril/valsartan in stabilized patients with acute decompensated heart failure and reduced EF, irrespective of prior ACEi/ARB use, or prior HF diagnosis.

Discussion

The discussant Larry Allen highlighted the need for a study like this, because there is such a difference between ambulatory and hospitalized clinical HF situations. While in ambulatory setting, several proven treatment options exist, in hospitalized setting various treatment strategies have failed to show a benefit. 70% of HF care takes place in hospital setting, and while the data are mostly available in ambulatory setting, the action takes place in the hospital.

While the results of PARADIGM-HF were very positive, its limitations included that it was performed only in stable ambulatory patients, with a run-in phase, and less than 2% of patients had severe disease (NYHA IV). Moreover, there were concerns about hypotension. A real-world registry has revealed that less than 15% of patients (in CHAMP) would have been eligible for PARADIGM-HF and consequently, the use of sacubitril/valsartan is low in clinical practice. Reasons may include that physicians do not trust a single trial as evidence for a new drug, they may find switching complicated, or the background therapy, or costs might be involved, or it may boil down to clinical inertia.

In this setting, PIONEER comes in as a major success. First of all, it was safe, and also effective, with a reduction of NT-proBNP of 29% and an almost halfing of serious events at 8 weeks. When interpreting the results, one should keep in mind that the population was relatively young, but reasonably diverse: about 30% women and 36% blacks. Few patients had stage D disease though, and they were excluded if SBP <100 mmHg. Also, a surrogate was used as primary endpoint, namely NT-proBNP. The changes in this biomarker were, however, backed by impressive secondary endpoints, which were consistent with PARADIGM-HF results.

During the discussion, it was pointed out that these ADHF patients do not reflect emergency situations, as the study applied an inclusion criterium that patients needed to be hemodynamically stable for enrollment. Thus, they had acute HF that was stabilized. It was acute on presentation, and about two thirds of patients experienced an acute situation on chronic HF, and one third had acute incident HF.

Allen concluded by saying that a simpler algorithm may be appropriate for inpatient and subsequent outpatient HFrEF management, which is better for clinicians and better for patients.

- Our reporting is based on the information provided at the AHA Scientific Sessions -

The PIONEER-HF resutls were simultaneously published in NEJM View our video about PIONEER-HF