Author + information
- Antonio L. Perez, MD, MBA,
- Veraprapas Kittipibul, MD,
- W.H. Wilson Tang, MD and
- Randall C. Starling, MD, MPH∗ ()
- Department of Cardiovascular Medicine, Kaufman Center for Heart Failure, Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio
- ↵∗Address for correspondence:
Dr. Randall C. Starling, Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, Ohio 44195.
- Food and Drug Administration
- heart failure
- heart failure with reduced ejection fraction
Evidence for Approval of Sacubitril/Valsartan
The approval of sacubitril/valsartan by the U.S. Food and Drug Administration (FDA) in July 2015 marked a significant advance in pharmacotherapy available for patients with heart failure (HF) with reduced ejection fraction (HFrEF) in the United States (1). The approval of this therapy was determined entirely on the basis of data from the pivotal global trial PARADIGM-HF (Prospective Comparison of ARNI [angiotensin receptor–nephrilysin inhibitor] with ACEI [angiotensin-converting enzyme inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), which enrolled 8,442 subjects with HFrEF and showed that sacubitril/valsartan reduced cardiovascular mortality rates by 20% when compared with enalapril. (2). The FDA approved sacubitril/valsartan for all patients in New York Heart Association (NYHA) functional class (FC) II to IV with reduced EF. The American College of Cardiology, American Heart Association, and Heart Failure Society of America (ACC/AHA/HFSA) in 2016 updated their HF guidelines to reflect the findings of the PARADIGM-HF trial and FDA drug approval, thus supporting the use of sacubitril/valsartan in patients with NYHA FC II to III HFrEF (Class I, Level of Evidence: B) (3). PARADIGM-HF, however, enrolled predominantly patients with NYHA FC II HFrEF (NYHA FC II, 70.1%; FC III, 23.9%; FC IV, 0.7%) and excluded those patients with severe reduction in renal function (estimated glomerular filtration rate [eGFR] ≤30 ml/min/1.73 m2), low blood pressure at rest (baseline systolic blood pressure ≤100 mm Hg), and mildly elevated baseline serum potassium (K) levels (K ≥5.2 mmol/l), as well as patients not currently receiving an ACEI or equivalent at a specified dose (enalapril, 10 mg/day). Therefore, sacubitril/valsartan is currently approved in the United States for use in a large population of patients with HF, with no clinical trial assessment of the drug combination’s safety and tolerability.
Eligibility for Sacubitril/Valsartan Determined on the Basis of Paradigm-HF Trial Criteria is Uncommon
We examined and compared the eligibility for sacubitril/valsartan therapy in real-world patients with HFrEF, who had been hospitalized for HF, on the basis of PARADIGM-HF criteria and FDA criteria, in effort to assess the proportion of patients who meet current FDA criteria (a group with very limited clinical trial data) (4). We believed that a gap existed, with no evidence, between the use of sacubitril/valsartan in the FDA-approved patient population and the population represented in the PARADIGM-HF trial. The medical records of all consecutive inpatient admissions from July to December 2014 to the HF services of the Cleveland Clinic in Cleveland, Ohio were reviewed (n = 549). We included all patients with HFrEF in NYHA FC II to IV who had at least 1 hospitalization during the study period who subsequently had at least 1 outpatient HF visit within 30 days of discharge. We recorded patients’ characteristics and 30-day all-cause readmission to any Cleveland Clinic Health System hospital. Initial N-terminal pro–B-type natriuretic peptide (NT-proBNP) measurement at the time of hospitalization was recorded. All patients who did not have follow-up appointments within 30 days of discharge and patients with a history of implantation of left ventricular assist device or cardiac transplantation were excluded from the study.
On the basis of the information obtained by chart review, eligibility for sacubitril/valsartan therapy was determined using FDA criteria and PARADIGM-HF enrollment criteria. FDA criteria were defined by the FDA-approved indications and use for the drug therapy: NYHA FC II to IV status with HFrEF (1). PARADIGM-HF enrollment criteria were determined on the basis of the clinical trial inclusion and exclusion criteria (2). We compared patients who met eligibility for sacubitril/valsartan on the basis of PARADIGM-HF criteria and those who met FDA eligibility criteria.
Majority of FDA-Eligible Patients Do Not Meet Paradigm-HF Inclusion Criteria and Have High-Risk Characteristics
A total of 463 patients in NYHA FC II to IV were admitted to the HF services of the Cleveland Clinic from July to December 2014. Of 210 patients who had post-discharge follow-up, 149 were eligible for sacubitril/valsartan therapy on the basis of FDA criteria. In comparison with patients who met PARADIGM-HF criteria, patients who did not meet these criteria had a higher NYHA FC, lower systolic blood pressure, higher NT-proBNP levels, and lower eGFR. In addition, compared with PARADIGM-HF–eligible patients, fewer ineligible patients were taking beta-blockers, ACEIs, or ARBs, and mineralocorticoid receptor antagonist, as expected (Table 1).
Among those patients ineligible for PARADIGM-HF enrollment (n = 95), the principal reasons for ineligibility as assessed at the time of outpatient follow-up visits within 30 days of discharge included the following: systolic blood pressure ≤100 mm Hg (39%); eGFR ≤30 ml/min/1.73 m2 (20%); not taking an ACEI or ARB (54%); not taking a beta-blocker (38%); and serum K ≥5.2 mmol/l (9.4%). Of these 95 patients, 59% were PARADIGM-HF ineligible because of systolic blood pressure ≤100 mm Hg, eGFR ≤30 ml/min/1.73 m2, or serum K ≥5.2 mmol/l.
From Evidence to Guidelines to Implementation: The Necessity to Fill the Gap With Real-World Experience
In a single-center contemporary population of patients with HFrEF who were recently admitted with HF, we showed that that nearly two-thirds of patients who met criteria for sacubitril/valsartan therapy on the basis of the FDA-approved indication would have been excluded from PARADIGM-HF. Hence our findings identify an important evidence gap and highlight the need for additional clinical information regarding safety, tolerability, and clinical outcomes in patients not meeting PARADIGM-HF inclusion criteria but approved by the FDA for sacubitril/valsartan therapy. The tolerability of sacubitril/valsartan in most of the patients from this single-center cohort with FDA approval for the drug therapy is unknown. Patients in this cohort who did not meet PARADIGM-HF enrollment criteria were more ill (higher NYHA FC; lower systolic blood pressure; greater NT-proBNP level; lower eGFR; and lower beta-blocker, ACEI, and mineralocorticoid receptor antagonist use) than those patients who met enrollment criteria for the PARADIGM-HF trial. Patients not eligible for PARADIGM-HF enrollment who had an eGFR ≤30 ml/min/1.73 m2 had a significantly higher 30-day readmission rate than PARADIGM-HF-eligible patients (37% vs 9.3%; p = 0.03).
In summary, our analysis suggests that a major subset of recently hospitalized patients with HFrEF would not qualify for sacubitril/valsartan therapy on the basis of PARADIGM-HF criteria; therefore, no clinical trial evidence exists to support the use of sacubitril/valsartan in this population, despite a broad FDA approval indication. Because of the discrepancy between the patient population represented in PARADIGM-HF and the significantly broader population who have FDA approval for therapy with sacubitril/valsartan, the use of this drug therapy in patients recently hospitalized with HF, although it is often given with the intention of improving clinical outcomes, should be balanced against the potential risks and unclear benefits in a large portion of this population. Although the drug combination is superior to enalapril, the reference population in the PARADIGM-HF clinical trial represents a minority of patients with HFrEF. There is an evidence gap in patients with hypotension and reduced eGFR. Further experience and guidance on the tolerability and use of this drug therapy are required to maximize its use in expanded patient populations.
Since FDA approval of sacubitril/valsartan in July 2015, some investigators have strongly opined that caregivers should focus more on using this new therapy, which can provide a considerable mortality benefit in patients with HFrEF; we concur (5). Indeed, the strength of evidence for sacubitril/valsartan therapy in the large population represented in PARADIGM-HF (n = 8,442) is compelling. The cardiovascular mortality benefit in patients with NYHA FC II HFrEF, a group representing 70.5% of the trial population, is especially clear. However, the important patient groups we highlight were excluded from PARADIGM-HF: patients with systolic blood pressure ≤100 mm Hg; those with an eGFR ≤30 ml/min/1.73 m2; and those who were not previously taking at least equivalent doses of enalapril 10 mg daily and a stable dose of beta-blockers for at least 1 month. Despite these excluded groups, who have no clinical trial evidence of benefit from sacubitril/valsartan, the FDA has approved the use of sacubitril/valsartan in all patients with NYHA FC II to IV HFrEF who are not ARB intolerant. The ACC/AHA/HFSA guideline does not endorse the use of sacubitril/valsartan for patients in NYHA FC IV.
Our analysis shows that a large portion of real-world patients with HFrEF, and possibly a majority of patients with HFrEF who have been recently hospitalized for HF, were not represented in PARADIGM-HF. These findings highlight the importance of additional clinical experience to evaluate the use of sacubitril/valsartan on key patient populations excluded from PARADIGM-HF, including those patients with borderline systolic blood pressure, reduced renal function, and NYHA FC IV status. This information would be highly relevant to clinical practice and provide guidance for ACC/AHA/HFSA and European Society of Cardiology HF guidelines for refinement of the expanded use of sacubitril/valsartan.
Randomized clinical trials provide essential data regarding safety and efficacy of new treatments. Sacubitril/valsartan demonstrated a dramatic mortality benefit compared with enalapril in the PARADIGM-HF global trial. ACC/AHA/HFSA guidelines now endorse the use of sacubitril/valsartan. The important next step in deploying new therapies to expanded populations requires translation of the evidence to practical implementation so that patients receive important new evidence-based drugs. Structured registries to acquire necessary post-market approval tolerability and evidence will more rapidly inform caregivers and expand the use of newly approved medications. Critical steps in implementation include education, tolerability, initiation strategies, and compliance of both patients and caregivers. Clinicians’ skill in using and comfort with a new drug will evolve gradually as experience accumulates and barriers are overcome. Closing the gap between clinical trial evidence and real-world experience will facilitate acceptance, expanded use, and implementation of sacubitril/valsartan.
Dr. Starling has served has a consultant to Novartis without reimbursement. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received March 13, 2017.
- Accepted March 13, 2017.
- 2017 American College of Cardiology Foundation
- ↵U.S. Food and Drug Administration. FDA News Release: FDA Approves New Drug to Treat Heart Failure. Available at: https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm453845.htm. Accessed March 12, 2017.
- Yancy C.W.,
- Jessup M.,
- Bozkurt B.,
- et al.
- Perez A.,
- Kittipibul V.,
- Tang W.H.,
- Starling R.
- Packer M.
- Evidence for Approval of Sacubitril/Valsartan
- Eligibility for Sacubitril/Valsartan Determined on the Basis of Paradigm-HF Trial Criteria is Uncommon
- Majority of FDA-Eligible Patients Do Not Meet Paradigm-HF Inclusion Criteria and Have High-Risk Characteristics
- From Evidence to Guidelines to Implementation: The Necessity to Fill the Gap With Real-World Experience