PIONEER-HF Trial Research Articles

Sacubitril/Valsartan in Patients Hospitalized With Decompensated Heart Failure

BackgroundThe efficacy and safety of sacubitril/valsartan in patients hospitalized with heart failure (HF) across the spectrum of left ventricular ejection fraction (EF) has not been described. ObjectivesData from randomized trials of sacubitril/valsartan in HF patients with EF ≤40% (PIONEER-HF [Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode] trial) and >40% (PARAGLIDE-HF [Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF] trial) following recent worsening heart failure (WHF) were pooled to examine treatment effect across the EF spectrum. MethodsThe PIONEER-HF and PARAGLIDE-HF trials were double-blind, randomized trials of sacubitril/valsartan vs control therapy (enalapril or valsartan, respectively). All participants in the PIONEER-HF trial and 69.5% in the PARAGLIDE-HF trial were enrolled during hospitalization for HF after stabilization. The remainder in the PARAGLIDE-HF trial were enrolled ≤30 days after a WHF event. The primary endpoint of both trials was time-averaged proportional change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8. Adjudicated clinical endpoints were analyzed through the end of follow-up, adjusting for trial. ResultsThe pooled analysis included 1,347 patients (881 from PIONEER-HF, 466 from PARAGLIDE-HF). Baseline characteristics included median age 66 years, 36% women, 31% Black, 34% de novo HF, and median EF 30%. The reduction in NT-proBNP was 24% greater with sacubitril/valsartan vs control therapy (n = 1,130; ratio of change = 0.76; 95% CI: 0.69-0.83; P < 0.0001). Cardiovascular death or hospitalization for HF was reduced by 30% with sacubitril/valsartan vs control therapy (HR: 0.70; 95% CI: 0.54-0.91; P = 0.0077). This effect was consistent across the spectrum of EF ≤60%. Sacubitril/valsartan increased symptomatic hypotension (risk ratio: 1.35; 95% CI: 1.05-1.72). ConclusionsIn patients stabilized after WHF, sacubitril/valsartan led to a greater reduction in plasma NT-proBNP and improved clinical outcome compared with control therapy, in particular across the spectrum of EF ≤60%. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890; Changes in NT-proBNP, Safety, and Tolerability in HFpEF Patients With a WHF Event [HFpEF Decompensation] Who Have Been Stabilized and Initiated at the Time of or Within 30 Days Post-decompensation [PARAGLIDE-HF]; NCT03988634)

Effectiveness of sacubitril-varsartan versus angiotensin converting enzyme inhibitors in patients hospitalized for acute heart failure: a retrospective cohort study of the RICA registry.

Sacubitril-valsartan has been shown to reduce hospitalizations and mortality in patients with heart failure (HF) and reduced ejection fraction. The PIONEER-HF trial demonstrated that initiation of the drug during acute HF hospitalization reduced NT-proBNP levels and a post-hoc analysis of the trial found a reduction in HF hospitalizations and deaths. Real-life studies in the elderly population are scarce. The aim of our study was to assess the effectiveness of sacubitril-valsartan versus angiotensin converting enzyme inhibitors (ACEI) in elderly patients who initiate this treatment during hospitalization for acute HF. We conducted a retrospective cohort study using the Spanish acute heart failure registry (RICA) comparing rehospitalizations and deaths at 3 months and 1 year among patients aged 70 years or older who had initiated treatment with sacubitril-valsartan during hospitalization for acute HF versus those treated with ACEI. One hundred and ninety-nine patients hospitalized between October 2016 and November 2020 were included, with a median age of 82 years and high rate of comorbidity. Of these, 107 were treated with sacubitril-valsartan and 92 with ACEI. The adjusted OR for readmission for HF at 3 months was 0.906 (95% CI: 0.241-3.404) and for the combined variable readmission for HF or death at 3 months was 0.696 (95% CI: 0.224-2.167). The adjusted OR for HF readmission at one year was 0.696 (95% CI: 0.224 -2.167). and for the combined variable HF readmission or death at one year 0.724 (95% CI: 0.325-1.612). Treatment with sacubitril-valsartan initiated early in hospitalization for HF in elderly patients with high comorbidity was associated with a trend towards a reduction in readmissions and death due to HF compared to treatment with ACEI, which did not reach statistical significance either at 3 months or 1 year of follow-up.

Narrative review in the current role of angiotensin receptor-neprilysin inhibitors.

Heart failure (HF) accounts for a tremendous burden on health care systems and the society. Since the landmark PARADIGM-HF trial, sacubitril/valsartan, the first in the class of angiotensin receptor neprilysin inhibitor (ARNI) showed superiority to enalapril in patients with HF with reduced ejection fraction (HFrEF). We performed a narrative literature review, hand-searched the reference lists of included articles and relevant reviews. Inhibition of neprilysin increases bradykinin, natriuretic peptides and adrenomedullin levels counteract the neurohormal activation that leads to sodium retention, vasoconstriction, and cardiac remodeling. In PARADIGM-HF the primary outcome of CV death or HF hospitalization was reduced 20% in the ARNI group (HR 0.80, P<0.001) similar to mortality due to cardiovascular cause (HR 0.80, P<0.001) in patients with HFrEF, rendering a number needed to treat of 21 patients. This effect was consistent across subgroups. The safety of starting ARNI inpatient once the acute decompensation of HF is stabilized was demonstrated in PIONEER-HF trial. With willingness-to-pay thresholds commonly acceptable in the United States, sacubitril/valsartan is likely to be cost effective, which might not be in other health systems. Although its safety has been reassured in some clinical trials, common side effects are hypotension, worsening kidney function, hyperkalemia and angioedema. In HFpEF (PARAGON-HF), sacubitril/valsartan showed decrease in the level of the cardiac biomarkers, with improve functional NYHA and decrease in hospitalizations, predominately in women and patients with borderline ejection fraction. Some ongoing studies aim to demonstrate the effects of ARNI in acute coronary syndrome, stable ischemic heart disease, advanced HF, mitral regurgitation, aortic impedance and pulmonary hypertension. In conclusion, sacubitril/valsartan has proven to be an effective addition to the HFrEF arsenal, with safety comparable to current standard of care. In HFpEF, it improves quality of life, particularly in women and in patients with borderline ejection fraction, with no effect on mortality.

Efficacy and Safety of Sacubitril/Valsartan in High-Risk Patients in the PIONEER-HF Trial.

In patients stabilized during hospitalization for acute decompensated heart failure (HF), initiation of sacubitril/valsartan compared with enalapril decreased the risk of cardiovascular death or rehospitalization for HF without increasing the risk of adverse events. It is unknown whether potentially high-risk subpopulations have a similar risk-benefit profile. PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP [N-terminal pro-B type natriuretic peptide] in Patients Stabilized From an Acute HF Episode) was a multicenter, randomized, double-blind trial of in-hospital initiation of sacubitril/valsartan (n=440) versus enalapril (n=441) in patients stabilized during hospitalization for acute decompensated HF. The composite of cardiovascular death or rehospitalization for HF was adjudicated. Safety outcomes included worsening renal function, symptomatic hypotension, and hyperkalemia. We evaluated heterogeneity in the effect of sacubitril/valsartan on these efficacy and safety outcomes in selected subgroups of clinical concern: patients with baseline systolic blood pressure ≤118 mm Hg (median; n=448), baseline NT-proBNP >2701 pg/mL (median; n=395), estimated glomerular filtration rate <60 mL/minute per 1.73 m2 (n=455), ≥1 additional hospitalization for HF within the prior year (n=343), admission to the ICU during the index hospitalization (n=96), inotrope use during the index hospitalization (n=68), and severe congestion (n=219). The relative risk reduction in cardiovascular death or rehospitalization for HF with sacubitril/valsartan versus enalapril was consistent across all high-risk subgroups (P interaction=non-significant [NS] for each). The risks of worsening renal function, symptomatic hypotension, and hyperkalemia with sacubitril/valsartan versus enalapril were also consistent in each high- versus low-risk subgroup (P interaction=NS for each). In high-risk subpopulations admitted for acute decompensated HF, treatment with sacubitril/valsartan after initial stabilization conferred a consistent reduction in cardiovascular death or rehospitalization for HF and was well tolerated.

Abstract 14302: Adoption of Sacubitril/Valsartan to Treat Acute Decompensated Heart Failure Improves Health System Finances Under Value-based Alternative Payment Models

Introduction: The PIONEER-HF trial demonstrated superior efficacy of sacubitril/valsartan over the angiotensin-converting-enzyme inhibitor (ACEi) enalapril in treating patients with acute decompensated heart failure (ADHF) after stabilization in the inpatient setting, but how medication choice affects health system finances is unknown. Measuring the financial impact is complicated as health systems are increasingly reimbursed through value-based alternative payment models (APM). Methods: A decision tree model was used to assess the financial impact of health system adoption of sacubitril/valsartan to treat ADHF under APM reimbursement. The model estimated differences in health care utilization and cost when treating hospitalized ADHF patients with ACEi or angiotensin-receptor blockers compared to sacubitril/valsartan using efficacy results from PIONEER-HF. The financial impact on health systems was assessed across three common APMs: Medicare Shared Savings Program (MSSP), Bundled Payments for Care Improvement (BPCI), and fee-for-service payments adjusted via the Hospital Readmission Reduction Program (HRRP). Results: Sacubitril/valsartan reduced re-hospitalizations after an ADHF admission by 46.3% for individuals aged 18-64 years and 23.4% for individuals aged ≥65 years. Health system financial benefit from adopting sacubitril/valsartan was $740 per ADHF case per year (PCPY). Savings were larger for patients aged ≥65 years ($803 PCPY) compared to those &lt;65 years ($653 PCPY). Adoption of sacubitril/valsartan improved health system finances under value-based APMs with the largest financial benefits under the HRRP ($1,190 financial gain PCPY), followed by BPCI ($645 financial gain PCPY) and MSSP ($253 financial gain PCPY). Conclusions: Adoption of sacubitril/valsartan to treat ADHF is expected to decrease hospitalizations and lead to a positive net financial impact on health systems under the commonly implemented APMs.

Angiotensin Receptor-Neprilysin Inhibition Based on History of Heart Failure and Use of Renin-Angiotensin System Antagonists

BackgroundThe PIONEER-HF (comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode) trial demonstrated the efficacy and safety of sacubitril/valsartan (S/V) in stabilized patients with acute decompensated heart failure (HF) and reduced ejection fraction. ObjectivesThe study sought to determine whether and how prior HF history and treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) affected the results. MethodsThe PIONEER-HF trial was a prospective, multicenter, double-blind, randomized clinical trial enrolling 881 patients with an ejection fraction ≤40%. Patients were randomly assigned 1:1 to in-hospital initiation of S/V (n = 440) versus enalapril (n = 441). Pre-specified subgroup analyses were performed based on prior HF history (i.e., de novo HF vs. worsening chronic HF) and treatment with an ACE inhibitor or ARB (i.e., ACE inhibitor or ARB-yes vs. ACE inhibitor or ARB-no) at admission. ResultsAt enrollment, 303 (34%) patients presented with de novo HF and 576 (66%) patients with worsening chronic HF. A total of 421 (48%) patients had been treated with an ACE inhibitor or ARB, while 458 (52%) had not been treated with an ACE inhibitor or ARB. N-terminal pro–B-type natriuretic peptide declined significantly in all 4 subgroups (p < 0.001), with greater decreases in the S/V versus the enalapril arm (p < 0.001). There was no interaction between prior HF history (p = 0.350) or ACE inhibitor or ARB treatment (p = 0.880) and the effect of S/V versus enalapril on cardiovascular death or rehospitalization for HF. The incidences of adverse events were comparable between S/V and enalapril across all 4 subgroups. ConclusionsAmong patients admitted for acute decompensated HF, S/V was safe and well tolerated, led to a significantly greater reduction in N-terminal pro–B-type natriuretic peptide, and improved clinical outcomes compared with enalapril irrespective of previous HF history or ACE inhibitor or ARB treatment. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect of NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890)

Efficacy and Safety of Sacubitril/Valsartan by Dose Level Achieved in the PIONEER-HF Trial

ObjectivesThis study sought to evaluate the efficacy and safety of sacubitril/valsartan according to dose level achieved in the PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode) trial. BackgroundIn patients hospitalized for acute decompensated heart failure (ADHF), in-hospital initiation and continuation of sacubitril/valsartan as compared with enalapril is well tolerated, achieves a greater reduction in N-terminal pro–B-type natriuretic peptide (NT-proBNP), and reduces the risk of cardiovascular death or rehospitalization for HF through 8 weeks. However, not all patients achieve the target dose of sacubitril/valsartan, and its efficacy and safety in such patients are of interest. MethodsPIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan versus enalapril in 881 patients stabilized during hospitalization for ADHF. Blinded study medication was administered for 8 weeks, with initial dosing selected based on the systolic blood pressure at randomization and titrated toward a target of sacubitril/valsartan 97/103 mg twice daily, or enalapril 10 mg twice daily, with an algorithm based on systolic blood pressure and the investigator’s assessment of tolerability. ResultsAt 4 weeks, 199 (55%) patients allocated to sacubitril/valsartan and 211 (60%) patients allocated to enalapril were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. There was no heterogeneity across dose levels in the effect of sacubitril/valsartan on the reduction in NT-proBNP (pinteraction = 0.69), the reduction in cardiovascular death or rehospitalization for heart failure (pinteraction = 0.42), or the pre-specified adverse events of special interest through 8 weeks. ConclusionsIn hemodynamically stabilized patients with ADHF, the efficacy and safety of sacubitril/valsartan are generally consistent across dose levels. (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-proBNP in Patients Stabilized From an Acute Heart Failure Episode [PIONEER-HF]; NCT02554890)

Feasibility of sacubitril/valsartan initiation early after acute decompensated heart failure.

Despite significant diagnostic and therapeutic advances, heart failure (HF) is linked with high mortality and morbidity. Hospitalization for decompensated HF is still the most common cause of hospitalization in adults. What is more, a particularly high risk of hospitalization (even up to 50% of patients) is observed within a few months after a previous HF hospitalization. Sacubitril/valsartan, a first-in-class drug, contains a neprilysin inhibitor (sacubitril) and an angiotensin II receptor blocker (valsartan). In PARADIGM-HF trial investigators showed, that sacubitril/valsartan significantly reduced primary endpoint combined with cardiovascular death or HF hospitalization in patients with chronic, symptomatic HF (New York Heart Association class II-IV) with reduced ejection fraction (left ventricular ejection fraction [LVEF] ≤ 35-40%). Recently, results of the PIONEER-HF trial, which included HF patients with LVEF ≤ 40% who were hospitalized for acute decompensated HF were also published. The study proved that early, in-hospital, implementation of sacubitril/valsartan in these patients resulted in a substantially greater reduction of N-terminal prohormone B-type natriuretic peptide concentration and a lower rate of HF rehospitalizations with similar safety profile for enalapril.

Representativeness of the PIONEER-HF Clinical Trial Population in Patients Hospitalized With Heart Failure and Reduced Ejection Fraction.

In PIONEER-HF (Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on NT-pro BNP in Patients Stabilized From an Acute Heart Failure Episode), the in-hospital initiation of sacubitril/valsartan in patients hospitalized for acute decompensated heart failure (ADHF) was well-tolerated and led to improved outcomes. We aim to determine the representativeness of the PIONEER-HF trial among patients hospitalized for ADHF using real-world data. The study population was derived from all patients discharged alive for ADHF in the Get With The Guidelines-HF registry from 2006 to 2018 with HF with reduced ejection fraction (HFrEF; all HFrEF with ADHF). We then determined the proportion of patients meeting PIONEER-HF eligibility criteria (PIONEER-HF eligible) and those meeting a set of limited eligibility criteria (actionable cohort). Rates of HF readmissions and all-cause mortality were then compared between the all HFrEF with ADHF, PIONEER-HF eligible, and actionable cohorts using linked Medicare claims data. A total of 99 767 patients with HFrEF in Get With The Guidelines-HF were hospitalized for ADHF. PIONEER-HF inclusion criteria were met by 71 633 (71.8%) patients, and both inclusion and exclusion criteria were met by 20 704 (20.8%) patients. Further, 68 739 (68.9%) patients met the criteria for the actionable cohort. Among the Centers for Medicare and Medicaid-linked patients, the HF rehospitalization rate at 1 year was 35.1% (95% CI, 34.5-35.8) for all HFrEF with ADHF patients, 32.6% (95% CI, 31.3-33.9) for the PIONEER-HF eligible cohort, and 33.1% (95% CI, 32.3-33.9) for the actionable cohort. The 1-year all-cause mortality was 36.7% (95% CI, 36.1-7.4) for all HFrEF with ADHF patients, 31.6% (95% CI, 30.3-32.9) for the PIONEER-HF eligible cohort, and 32.2% (95% CI, 31.4-33.0) for the actionable cohort. Patient characteristics and clinical outcomes for patients eligible for PIONEER-HF only modestly differ when compared with those encountered in routine practice, suggesting that the in-hospital initiation of sacubitril/valsartan should be routinely considered for patients with HFrEF hospitalized for ADHF.

P13 Safety and efficacy of sacubitril-valsartan initiation during and after acute decompensated heart failure with reduced ejection fraction

Abstract Background The PIONEER-HF trial has demonstrated the safety of Sacubitril-Valsartan initiation during acute decompensated heart failure (ADHF) compared to Enalapril. The efficacy outcome was also addressed by the surrogate end point of reduction in NT-proBNP. However, the safety and efficacy of Sacubitril-Valsartan initiation during ADHF compared to initiation after ADHF was unknown. Objectives (1) To compare the safety and efficacy of Sacubitril-Valsartan initiation during ADHF(inpatient) to initiation after ADHF(outpatient). (2) To explore the echocardiogram parameters associated with Sacubitril-Valsartan initiation during ADHF(inpatient) versus after ADHF(outpatient). Methods We enrolled patients diagnosed with heart failure with reduced ejection fraction (HFrEF) initiated on Sacubitril-Valsartan from February 2017 to December 2018. The baseline characteristics, echocardiogram parameters (changes in LVEF and positive remodeling), composite safety outcomes (hypotension, interruption of Sacubitril-Valsartan and worsening of renal function), and efficacy outcomes (cardiac death, readmission for heart failure) were compared. Results Thirty-seven patients were identified out of which 21 patients started Entresto after ADHF (outpatient group) and 16 patients during ADHF (inpatient group). The median follow-up duration was 196 days (IQR: 105 to 328days). The baseline characteristics were similar between the 2 groups. Outpatient groups achieved a significantly higher maximally tolerable dose of Sacubitril-Valsartan compared to inpatient group (median 400mg/day versus 200mg/day, p = 0.008) despite a similar starting dose (median 100mg/day versus 100mg/day, p = 0.127). The composite efficacy outcomes were similar between the 2 groups (4.8% versus 18.8%, p = 0.296). The composite safety outcome was similar between the groups (18.8% versus 4.8%, HR5.70 p = 0.054, 95%CI 0.967 to 33.60). Both groups achieved a significant improvement in LVEF after initiation of Sacubitril-Valsartan therapy: mean LVEF 23.44 ± 7.88% to 34.30 ± 13.88% (p = 0.001) in outpatient group; mean LVEF 22.99 ± 11.31% to 38.81 ± 13.91% (p = 0.002) in inpatient group. Reverse remodeling (reduction of LVESV≥15%) was similar between the 2 groups (61.9% versus 50.0%, p = 0.506). Conclusions Among patients with HFrEF in ADHF, initiation of Sacubitril-Valsartan therapy during or after ADHF led to similar safety and efficacy. Overall, there was a significant improvement in LVEF and positive remodeling of the LV regardless of the timing of initiation of therapy.

Sacubitril-valsartan versus enalapril for acute decompensated heart failure: a cost-effectiveness analysis.

The Comparison of Sacubitril-Valsartan versus Enalapril on Effect on NT-proBNP in Patients Stabilised from an Acute Heart Failure Episode (PIONEER-HF) trial demonstrated significant reductions in N-terminal pro-B-type natriuretic peptide. Our study explored the cost-effectiveness of the use of sacubitril-valsartan versus enalapril in acute decompensated heart failure from the Australian healthcare perspective. A Markov model was designed using data from the PIONEER-HF trial to model the clinical progress and costs of patients over a lifetime time horizon. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for acute decompensated heart failure' or 'dead'. Costs and utilities were estimated from published sources. The cost of sacubitril-valsartan (per the Australian pharmaceutical benefits schedule) was AU$7.08/day. Outcomes of interest were the incremental cost-effectiveness ratios in terms of cost per quality-adjusted life year gained and cost per year of life saved. Cost and benefits were discounted at 5.0% per annum. Compared to enalapril, sacubitril-valsartan was estimated to cost an additional AU$7464 (discounted) per person, but lead to 0.127 years of life saved (discounted) and 0.096 quality-adjusted life years gained (discounted) over a lifetime analysis. These equated to incremental cost-effectiveness ratios of AU$58,629/year of life saved (US$41,795, EU€58,629, GBP£32,001) and AU$77,889/quality-adjusted life year gained (US$55,526, EU€49,202, GBP£42,504). We have assumed a threshold of AU$50,000/quality-adjusted life year gained to suggest cost-effectiveness. At its current acquisition price, sacubitril-valsartan in comparison to enalapril is not likely to be cost-effective in the management of acute decompensated heart failure in Australia. A price reduction of more than 25% would confer cost-effectiveness.

1135Angiotensin receptor-neprilysin inhibition in patients with de novo acute decompensated heart failure: a prespecified subgroup analysis of the PIONEER-HF trial

Abstract Background The efficacy, safety, and tolerability of an angiotensin receptor-neprilysin inhibitor (ARNi) in patients presenting with de novo heart failure (HF) has not been previously well-defined. Methods The PIONEER-HF trial was a prospective, multicenter, double-blind, active-controlled, randomized clinical trial which enrolled 887 patients (pts) at 129 sites in the United States. Pts with or without a history of prior HF and an ejection fraction (EF) &lt;40% and a NT-proBNP &gt;1600 pg/mL or BNP &gt;400 pg/mL were eligible for participation no earlier than 24 hours while still hospitalized for acute decompensated HF (ADHF). Pts were randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan (S/V) titrated to 97/103 mg vs. enalapril titrated to 10 mg both by mouth twice daily for 8 weeks. We performed a pre-specified analysis in pts with de novo HF (i.e., defined as pts without a history of HF prior to the qualifying ADHF event). Results At the time of enrollment, 34% (N=303) had de novo HF. These pts experienced a similar improvement in NT-proBNP with S/V vs. enalapril (Ratio of geometric means 0.65, 95% Confidence Interval [CI] 0.53–0.81; p-value = 0.0002) compared to pts with worsening chronic HF (ratio 0.72 (0.63–0.83, p-value &lt;0.0001) (Figure). In addition, the incidence of worsening renal function, hyperkalemia, and hypotension was comparable with S/V vs. enalapril regardless of whether they were hospitalized for de novo or worsening chronic HF. Finally, there was no interaction (p-value = 0.350) between previous HF status and the effect of S/V on the composite of cardiovascular death or rehospitalization for HF (de novo HF: Hazard Ratio [HR] 0.34, 95% CI 0.11–1.05 vs. worsening chronic HF: HR 0.60, 95% CI 0.39–0.93). Conclusion Among patients admitted for ADHF, irrespective of prior HF history, in-hospital initiation of an ARNi led to a greater reduction in natriuretic peptide levels, a comparable safety profile, and a significant improvement in clinical outcomes. Acknowledgement/Funding Novartis

4331Safety and efficacy of sacubitril/valsartan by dose level in patients hospitalized with acute heart failure: Observations from PIONEER-HF

Abstract Background In hemodynamically stabilized patients with acute decompensated heart failure (ADHF) enrolled in the PIONEER-HF trial, compared with enalapril, sacubitril/valsartan started in-hospital and continued for 8 weeks was well tolerated, achieved a greater reduction in NT-proBNP, and reduced cardiovascular death or rehospitalization for HF. Nearly 1/2 of patients achieved the target dose of blinded study drug. We performed an exploratory analysis of the safety and efficacy of sacubitril/valsartan according to the dose level dispensed at 4 weeks in PIONEER-HF Methods PIONEER-HF was a randomized, double-blind, active-controlled trial of sacubitril/valsartan vs. enalapril in 881 hospitalized ADHF pts following hemodynamic stabilization. Blinded study medication was administered for 8-weeks, with initial dosing selected based on the systolic blood pressure (SBP) at randomization (starting dose 24/26 or 49/51 mg twice daily vs 2.5 or 5 mg twice daily) and titrated toward a target of sacubitril/valsartan 97 mg/103 mg twice daily, or enalapril 10 mg twice daily with an algorithm using SBP along w/ the investigator's assessment of tolerability. Results At the week 4 visit, 199 patients (45.2%) in the sacubitril/valsartan group and 210 (47.6%) in the enalapril group were dispensed the target dose. Baseline characteristics were similar in the 2 treatment groups within each dose level. The prespecified adverse events of special interest were similar between sacubitril/valsartan and enalapril irrespective of dose level (Table) with no significant heterogeneity. In addition, there was no heterogeneity across dose levels in the favorable effect of sacubitril/valsartan on the change in NTproBNP by week 8 (Table, p-interaction=0.54) or the serious composite endpoint (p-interaction=0.71). Efficacy and Safety by Dose-Tier Conclusion In hemodynamically stabilized patients with ADHF, the safety and efficacy of sacubitril/valsartan appears generally consistent among patients at various dose levels. Acknowledgement/Funding Novartis Pharmaceuticals

Representativeness of the PIONEER-HF Clinical Trial Population in Patients Hospitalized with Heart Failure

Introduction In the PIONEER-HF trial, the in-hospital initiation of sacubitril/valsartan in patients hospitalized for acute decompensated heart failure (ADHF) was well-tolerated and led to a greater reduction in N-terminal pro-B natriuretic peptide compared with enalapril, and reduced HF hospitalizations. In this study, we aimed to: (1) determine eligibility for the PIONEER-HF trial among patients in a contemporary registry population with ADHF and HF with reduced ejection fraction (”all HFrEF”), (2) determine eligibility for sacubitril/valsartan using criteria most relevant to daily clinical practice (“actionable” cohort), and (3) compare long-term outcomes between the all HFrEF, PIONEER-HF trial eligible, and actionable cohorts using linked Medicare claims data. Methods The initial study population was derived from all patients discharged alive in the Get With The Guidelines-HF(GWTG-HF) registry between January 2006 and June 2018 with a left ventricular ejection fraction ≤40%. We derived cohorts meeting PIONEER-HF trial eligibility criteria and a set of clinically relevant criteria. Rates of HF-readmissions and all-cause mortality 1-year post index discharge were obtained linking the GWTG-HF registry with Medicare fee-for-service claims. Results Total of 99,767 patients in GWTG-HF were hospitalized for ADHF and HFrEF. PIONEER-HF inclusion criteria were met by 71,633 (71.8%) patients, and both inclusion and exclusion criteria were met by 20,704 (20.8%). 68,739 (68.9%) patients met the criteria for the actionable cohort (Figure). Among the CMS-linked patients, the 1-year all-cause mortality was 36.7% for all HFrEF patients, 32.2% for the actionable cohort and 31.6% for the PIONEER-HF trial eligible cohort (Log rank test P Conclusions Patient characteristics and clinical outcomes in participants enrolled in PIONEER-HF only modestly differ compared with those encountered in routine practice, suggesting the findings of this trial may be broadly generalizable.

Sacubitril/Valsartan Initiated in Black Patients Admitted for Acute Decompensated Heart Failure Reduced NT-proBNP, was Safe and Led to Improved Clinical Outcomes- A Secondary Analysis of the PIONEER-HF Trial

Introduction There is a disproportionate burden and severity of heart failure (HF) among black patients (pts) who may be less responsive to treatment with an ACEi/ARB than other racial/ethnic groups. How black pts with HF respond to sacubitril/valsartan (S/V), an angiotensin receptor neprilysin inhibitor, has not been fully explored. Methods The PIONEER-HF trial was a prospective, multicenter, double-blind, active-controlled, randomized trial which enrolled 881 pts at 129 sites in the United States. Pts with or without a history of prior HF and an EF ≤40% and an NT-proBNP ≥1600 pg/mL or BNP ≥400 pg/mL were eligible for participation no earlier than 24 hours and after hemodynamic stabilization while hospitalized for acute decompensated HF (ADHF). Pts were randomly assigned 1:1 to in-hospital initiation of S/V (N = 440) vs. enalapril (E, N = 441) for 8 weeks. We performed a pre-specified subgroup analysis by self-reported race (i.e., black vs. other). Results The study population was 316 (35.9%) black, 515 (58.5%) white, and 50 (5.7%) other. Black pts (Ratio of change [ROC] 0.72, 95% CI 0.57-0.89) experienced a similar improvement in NT-proBNP with S/V vs. E compared to white pts (ROC 0.68, 95% CI 0.58-0.80; p-value for interaction = 0.13). There was no statistical interaction between race and the effect of S/V on the composite of CV death or rehospitalization for HF (black: HR 0.47, 95% CI 0.24-0.94 vs. white: HR 0.60, 95% CI 0.35-1.01) (Figure). The incidence of worsening renal function, hyperkalemia, and symptomatic hypotension was comparable with S/V vs. E regardless of race. There was one confirmed angioedema event in the S/V arm (in a white pt), while there were six in the enalapril arm (all in black pts) (p-value = NS). Conclusion Among black pts admitted for ADHF, in-hospital initiation of S/V resulted in a greater reduction in natriuretic peptide levels, was safe and well-tolerated, and led to a significant improvement in clinical outcomes compared to enalapril. The effect of S/V vs. E on these outcomes did not differ by race. No angioedema event with S/V was observed in a black patient.

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Should providers prescribe sacubitril/valsartan based on trial eligibility, approval indication, or guideline recommendations?

Cardiovascular biomarkers in patients with acute decompensated heart failure randomized to sacubitril-valsartan or enalapril in the PIONEER-HF trial.

AimsCirculating high-sensitivity cardiac troponin (hsTn) and soluble ST2 (sST2) reflect myocardial stress in patients with heart failure (HF). Production of cyclic guanosine 3′5′ monophosphate (cGMP) in response to activation of natriuretic peptide receptors reduces cardiac afterload and preload. We assessed the effects of sacubitril/valsartan on these biomarkers in patients with reduced ejection fraction and acute decompensated HF (ADHF).Methods and resultsPIONEER-HF was a randomized, double-blind trial of sacubitril/valsartan vs. enalapril in hospitalized patients with ADHF following haemodynamic stabilization. We measured circulating hsTnT, sST2, and urinary cGMP at baseline, 1, 2 (sST2, cGMP), 4, and 8 weeks (n = 694 with all baseline biomarkers). Ratios of geometric means (timepoint/baseline) were determined and compared as a ratio for sacubitril/valsartan vs. enalapril. Compared with enalapril, sacubitril/valsartan led to a significantly greater decline in hsTnT and sST2. This effect emerged as early as 1 week for sST2 and was significant for both at 4 weeks with a 16% greater reduction in hsTnT (P < 0.001) and 9% greater reduction in sST2 (P = 0.0033). Serial urinary cGMP increased with sacubitril/valsartan compared with enalapril (P < 0.001, 1 week). The significant differences between treatment groups for each biomarker were sustained at 8 weeks. In an exploratory multivariable-adjusted analysis of cardiovascular death or HF-rehospitalization, the concentrations of hsTnT, sST2 at week 1 were significantly associated with subsequent outcome.ConclusionBiomarkers of myocardial stress are elevated in patients with ADHF and associated with outcome. Compared with enalapril, sacubitril/valsartan reduces myocardial injury and haemodynamic stress as reflected by biomarkers, with an onset that is apparent within 1–4 weeks.Clinical trials registrationNCT 02554890 clinical.trials.gov

PRIOR EXPOSURE TO A CONVENTIONAL RENIN-ANGIOTENSIN SYSTEM ANTAGONIST AND ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITION IN ACUTE DECOMPENSATED HEART FAILURE: A PRESPECIFIED SUBGROUP ANALYSIS OF THE PIONEER-HF TRIAL

There are limited data on the efficacy, safety, and tolerability of sacubitril/valsartan (S/V) in heart failure with a reduced ejection fraction (HFrEF) patients not previously treated with an angiotensin converting-enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB). The PIONEER-HF trial

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial

ObjectiveThe objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. BackgroundSacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. MethodsPIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. ConclusionThe PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.