Should Providers Prescribe Sacubitril/Valsartan Based on Trial Eligibility, Approval Indication, or Guideline Recommendations?

This article refers to ‘Sacubitril/valsartan eligibility and outcomes in the ESC-EORP-HFA Heart Failure Long-Term-Registry: bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM-HF trial, ESC guidelines, and real world’ by C.J. Kapelios et al., published in this issue on pages 1383–1397. The pivotal Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial demonstrated that sacubitril/valsartan (S/V), compared to enalapril, led to a 20% reduction in the relative risk of the composite of cardiovascular death or hospitalization for heart failure (HF) among ambulatory HF patients with an ejection fraction (EF) ≤ 40% and New York Heart Association (NYHA) functional class II–IV symptoms.1, 2 As a result of these data, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved S/V and the American College of Cardiology/American Heart Association/Heart Failure Society of America3 and the European Society of Cardiology (ESC)4 updated their recommendations to include initiating and/or switching HF with a reduced EF (HFrEF) patients from a conventional renin–angiotensin system antagonist (i.e. enalapril) to an angiotensin receptor–neprilysin inhibitor (ARNi) (i.e. S/V). However, there is substantial transatlantic variation in the stringency of interpreting the eligibility criteria of PARADIGM-HF resulting in key differences in U.S. and European clinical practice guidelines with respect to S/V.4, 5 In this issue of the Journal, Kapelios et al.6 leverage the ESC-EURObservational Research Programme (EORP)-Heart Failure Association (HFA) Heart Failure Long-Term (HF-LT) Registry to determine the potential scope of patients eligible for S/V based on the PARADIGM-HF trial, EMA/FDA approval indication, and the 2016 ESC guidelines. The ESC-EORP-HFA HF-LT Registry is a pan-European, prospective, multicentre observational study enrolling ambulatory and hospitalized patients aged ≥ 18 years presenting with HF.7, 8 Patients were considered eligible for S/V using PARADIGM-HF inclusion/exclusion criteria, regulatory approval indication, and clinical practice guidelines (Table 1). The final analytical cohort included 5443 ambulatory HFrEF patients with a mean age of 64 ± 13 years and 78% men. Subjects enrolled in the ESC-EORP-HFA HF-LT cohort were similar to PARADIGM-HF patients in terms of demographics, past medical history, and reported similar beta-blocker use but were less likely to be receiving an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) and more likely to be prescribed a mineralocorticoid receptor antagonist (MRA). Based on EMA/FDA labelling, more than 80% of ESC-EORP-HFA HF-LT Registry patients would be potentially eligible for S/V. However, if patients were required to be on a prior dose of an ACEi/ARB equivalent to ≥ 20 vs. ≥ 10 mg of enalapril daily according to PARADIGM-HF entry criteria and the 2016 ESC guideline recommendations, the proportion of potentially eligible patients would decrease to approximately 10% and 30%, respectively. For both the PARADIGM-HF trial and 2016 ESC guidelines, the individual and sequential impact of eligibility criteria was greatest for background medical therapy including current or prior treatment (i.e. in addition to a documented intolerance and/or contraindication) with an ACEi/ARB, beta-blocker, and/or MRA. The authors should be commended for performing a comprehensive post-hoc analysis of the ESC-EORP-HFA HF-LT Registry to determine the proportion of patients potentially eligible for ARNi therapy, yet their estimates range from a low of approximately 10% to a high of more than 80%, which generates uncertainty among practicing clinicians regarding the appropriate use of this drug in the setting of HFrEF. In essence, this question comes down to how strictly to interpret the inclusion/exclusion criteria of pivotal trials such as PARADIGM-HF. Broadly speaking, eligibility criteria serve three major purposes: (i) to identify the intended target population in order to evaluate efficacy (i.e. efficacy criteria); (ii) to ensure patient safety and a favourable ratio of benefit to harm (i.e. safety criteria); and (iii) to enrich the study population for the outcome of interest so that it is logistically feasible to design and conduct a well-powered trial based on the estimated sample size, duration of follow-up, event rate, and desired effect size (i.e. enrichment criteria). Hence, the main reason for incorporating elevated natriuretic peptide levels with or without a recent hospitalization for HF in the entry criteria of the PARADIGM-HF trial, both of which are known to be potent risk factors for HF-related morbidity and mortality, was to enrich the study population and ensure the trial was adequately powered to detect the pre-specified effect size. In fact, the landmark Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial, which evaluated the efficacy, safety, and tolerability of eplerenone in HFrEF patients with mild symptoms (i.e. NYHA functional class II), required participants to have had either a cardiovascular hospitalization within the past 6 months or an elevated natriuretic peptide level for this exact reason.9 However, despite deliberately incorporating enrichment criteria in the EMPHASIS-HF protocol, the 2016 ESC guidelines offer a class I, level of evidence A recommendation for the use of MRAs (i.e. spironolactone and eplerenone) in all patients who remain symptomatic (i.e. NYHA functional class II–IV symptoms) despite treatment with an ACEi/ARB and a beta-blocker without any additional caveats.4 Therefore, it seems reasonable to offer ARNi therapy to all symptomatic HFrEF patients in the absence of additional risk factors (i.e. elevated natriuretic peptide levels with or without a recent HF hospitalization), recognizing that HF is a chronic and progressive condition and this subset of patients may derive a comparable lifetime benefit. Similarly, there is little reasonable justification to restrict the use of S/V to HF patients with an EF ≤ 35%. Although the initial eligibility requirement for PARADIGM-HF was an EF ≤ 40%, it was changed to an EF ≤ 35% by an amendment to the protocol on 15 December 2010.2 This controversial decision was again made to enrich the study population for the outcome of interest given the concern that the completion of EMPHASIS-HF, which occurred midway through the enrolment for PARADIGM-HF, might potentially lead to more widespread use of MRAs in HF patients with NYHA functional class II symptoms and further reduce the anticipated event rate and the statistical power to detect a clinically meaningful between-group difference in clinical outcomes. However, prior to changing the EF cutoff in the PARADIGM-HF trial, a substantial number of patients had already been enrolled with an EF between 35% and 40% and in aggregate these patients represented nearly 25% of the enrolled cohort.10 Furthermore, S/V vs. enalapril led to a greater reduction in the primary composite endpoint (i.e. cardiovascular mortality and hospitalization for HF) across the EF spectrum and no heterogeneity was observed in the findings when EF was modelled either as a categorical or as a continuous variable. Thus, there is ample evidence to support a frontline role for S/V in patients with an EF between 35% and 40% and there is no valid reason for withholding this potentially life-prolonging therapy in patients with a moderately reduced EF. Finally, it has also been suggested that patients not already receiving optimal medical therapy should not be initiated or switched to ARNi therapy prior to receiving maximally-tolerated doses of an ACEi/ARB, a beta-blocker, and an MRA. Indeed, the objective in evaluating novel drugs and/or devices for HF is to demonstrate superior efficacy and comparable safety on top of maximally tolerated background medical therapy. For instance, in the PARADIGM-HF trial, eligible participants had to be tolerating an ACEi/ARB equivalent to ≥ 10 mg of enalapril daily at the start of the run-in phase and 93% and 56% of randomized patients were receiving a beta-blocker and an MRA, respectively. However, the magnitude of the benefit of S/V vs. enalapril on the primary composite endpoint was fundamentally unchanged based on beta-blocker dose (i.e. ≥ 50% vs. < 50% of target dose) and/or treatment with an MRA (i.e. yes vs. no).11 Finally, the more recently published Comparison of Sacubitril-Valsartan veersus Enalapril on Effect on NT-proBNP in Patients Stabilized from an Acute Heart Failure Episode (PIONEER-HF) trial showed that in-hospital initiation of S/V vs. enalapril was safe and well tolerated, achieved an approximately 30% reduction in N-terminal pro-B-type natriuretic peptide levels, and reduced cardiovascular death or rehospitalization for HF within 8 weeks of discharge.12-14 Notably, since upwards of 35% of the patients enrolled in PIONEER-HF presented with de novo HF (i.e. as opposed to worsening chronic HF), only approximately 50%, 60%, and 10% of patients, respectively, were receiving an ACEi/ARB, a beta-blocker, and/or an MRA prior to enrolment. More importantly, the early and sustained benefit of S/V, compared to enalapril, on natriuretic peptide levels and the corresponding short-term improvement in clinical outcomes were consistent regardless of duration of diagnosis (i.e. de novo vs. chronic HF) and/or prior ACEi/ARB exposure (i.e. renin–angiotensin system naïve vs. previous treatment). Thus, these findings strongly suggest that S/V should be preferentially considered in patients with a new or recent diagnosis of HF as part of a synergistic strategy to implement optimal medical therapy. In conclusion, using the ESC-EORP-HFA HF-LT Registry, Kapelios and colleagues applied the PARADIGM-HF entry criteria, EMA/FDA approval indication, and the 2016 ESC guidelines to estimate that a broad range between 10% and 85% of ambulatory HFrEF patients would potentially be eligible for ARNi therapy. Despite this finding, a deeper delve into the PARADIGM-HF inclusion/exclusion criteria reveals that the reasons for ineligibility predominantly stem from requiring an elevated natriuretic peptide level with or without a recent hospitalization for HF, concerns regarding the modification of the EF cutoff midway through the trial, and employing a rigorous and possibly onerous definition of ‘optimal medical therapy’. However, given the preponderance of evidence based on the PARADIGM-HF and PIONEER-HF trials, it becomes clear that the potential scope and clinical application of ARNi therapy in routine practice is likely most in line with the EMA/FDA approval indication and S/V should be considered first-line in all symptomatic HFrEF patients without documented safety concerns. Conflict of interest: A.P.A. reports having received reimbursement from Novartis Pharmaceuticals Corporation (East Hanover, NJ) for travel expenses related to the PIONEER-HF trial. All other authors have no relevant conflicts of interest to declare.