Professional Documents
Culture Documents
Original Article
A BS T R AC T
BACKGROUND
Acute decompensated heart failure accounts for more than 1 million hospitalizations From the Section of Cardiovascular Med-
in the United States annually. Whether the initiation of sacubitril–valsartan therapy icine, Department of Internal Medicine,
Yale University School of Medicine, New
is safe and effective among patients who are hospitalized for acute decompensated Haven, CT (E.J.V.); the Thrombolysis in
heart failure is unknown. Myocardial Infarction Study Group, Car-
diovascular Division, Department of Med-
METHODS icine, Brigham and Women’s Hospital,
Harvard Medical School, Boston (D.A.M.,
We enrolled patients with heart failure with reduced ejection fraction who were E.B.); Duke Clinical Research Institute,
hospitalized for acute decompensated heart failure at 129 sites in the United States. Duke University, Durham, NC (A.D.D.);
After hemodynamic stabilization, patients were randomly assigned to receive sacu- Novartis Pharmaceuticals, East Hanover,
NJ (C.I.D., K.M., R.R.); and the Division
bitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) of Cardiology, Permanente Medical Group,
or enalapril (target dose, 10 mg twice daily). The primary efficacy outcome was the San Francisco, and the Division of Research,
time-averaged proportional change in the N-terminal pro–B-type natriuretic pep- Kaiser Permanente Northern California,
Oakland — both in California (A.P.A.).
tide (NT-proBNP) concentration from baseline through weeks 4 and 8. Key safety Address reprint requests to Dr. Velazquez
outcomes were the rates of worsening renal function, hyperkalemia, symptomatic at Yale University School of Medicine,
hypotension, and angioedema. P.O. Box 208017, New Haven, CT 06520-
8017, or at eric.velazquez@yale.edu.
RESULTS *A complete list of the PIONEER-HF inves-
Of the 881 patients who underwent randomization, 440 were assigned to receive tigators is provided in the Supplementary
sacubitril–valsartan and 441 to receive enalapril. The time-averaged reduction in Appendix, available at NEJM.org.
the NT-proBNP concentration was significantly greater in the sacubitril–valsartan This article was published on November 11,
group than in the enalapril group; the ratio of the geometric mean of values ob- 2018, and updated on February 13, 2019,
at NEJM.org.
tained at weeks 4 and 8 to the baseline value was 0.53 in the sacubitril–valsartan
group as compared with 0.75 in the enalapril group (percent change, −46.7% vs. N Engl J Med 2019;380:539-48.
DOI: 10.1056/NEJMoa1812851
−25.3%; ratio of change with sacubitril–valsartan vs. enalapril, 0.71; 95% confi- Copyright © 2018 Massachusetts Medical Society.
dence interval [CI], 0.63 to 0.81; P<0.001). The greater reduction in the NT-proBNP
concentration with sacubitril–valsartan than with enalapril was evident as early as
week 1 (ratio of change, 0.76; 95% CI, 0.69 to 0.85). The rates of worsening renal
function, hyperkalemia, symptomatic hypotension, and angioedema did not differ
significantly between the two groups.
CONCLUSIONS
Among patients with heart failure with reduced ejection fraction who were hospi-
talized for acute decompensated heart failure, the initiation of sacubitril–valsartan
therapy led to a greater reduction in the NT-proBNP concentration than enalapril
therapy. Rates of worsening renal function, hyperkalemia, symptomatic hypoten-
sion, and angioedema did not differ significantly between the two groups. (Funded
by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890.)
A
cute decompensated heart failure Me thods
accounts for more than 1 million hospi-
talizations in the United States annually.1 Trial Design
Rates of short-term unplanned rehospitalization Details of the trial design have been published
and death associated with acute decompensated previously.9 We conducted a multicenter, random-
heart failure are high (21% and 12%, respective- ized, double-blind, active-controlled trial of the
ly).2 Despite multiple trials of promising therapies, in-hospital initiation of sacubitril–valsartan ther-
the standard of care, which consists of deconges- apy, as compared with enalapril therapy, among
tion with intravenous diuretics and hemody- patients who had been admitted for acute decom-
namic support with vasodilators and inotropes, pensated heart failure with reduced ejection frac-
has remained largely unchanged during the past tion. The trial protocol (available with the full text
45 years.3-5 of this article at NEJM.org) was approved by eth-
Sacubitril–valsartan is an angiotensin recep- ics committees at participating centers. Novartis
tor–neprilysin inhibitor that is indicated for the was the sole sponsor and conducted the trial in
treatment of patients with symptomatic heart collaboration with the Duke Clinical Research In-
failure with reduced ejection fraction. In the stitute (DCRI) and the Thrombolysis in Myocardial
PARADIGM-HF (Prospective Comparison of Infarction (TIMI) Study Group.
ARNI with ACEI to Determine Impact on Global The academic leadership committee (see the
Mortality and Morbidity in Heart Failure) trial,6,7 Supplementary Appendix, available at NEJM.org)
the use of sacubitril–valsartan resulted in a lower designed the protocol, identified the participat-
risk of death from cardiovascular causes or hos- ing centers, and oversaw implementation of the
pitalization for heart failure than the use of enala- protocol in conjunction with the trial sponsor.
pril in this population. Patients who were eligible United BioSource Corporation (UBC), a contract
for inclusion in the PARADIGM-HF trial were am- research organization, was involved in trial op-
bulatory outpatients who had received an angio- erations. All statistical analyses were completed
tensin-converting–enzyme (ACE) inhibitor or by UBC and were verified independently by the
angiotensin-receptor blocker (ARB), at stable DCRI and the sponsor. An independent data and
doses equivalent to a dose of enalapril of 10 mg safety monitoring board (see the Supplementary
daily, for a minimum of 4 weeks. In addition, Appendix) monitored safety data during the trial.
the trial had sequential run-in periods during The first draft of the manuscript was written by
which all patients received high-dose enalapril the first author, and all the authors critically re-
and sacubitril–valsartan before they underwent viewed and revised the manuscript at every stage
randomization. Patients with acute decompen- before acceptance. All the authors had full access
sated heart failure, which was defined by the to the data and vouch for the completeness and
presence of signs and symptoms that may lead accuracy of the data and for the fidelity of the
to the use of intravenous therapy, were excluded trial to the protocol.
from the trial.
Whether the initiation of sacubitril–valsartan Trial Patients
therapy is effective and safe among patients who Patients 18 years of age or older were eligible for
are hospitalized for acute decompensated heart inclusion in the trial if they had a left ventricular
failure is unknown.8 Therefore, we designed the ejection fraction of 40% or less and an N-terminal
PIONEER-HF (Comparison of Sacubitril–Valsar- pro–B-type natriuretic peptide (NT-proBNP) con-
tan versus Enalapril on Effect on NT-proBNP in centration of 1600 pg per milliliter or more or a
Patients Stabilized from an Acute Heart Failure B-type natriuretic peptide (BNP) concentration of
Episode) trial to assess the efficacy and safety of 400 pg per milliliter or more and had received a
the initiation of sacubitril–valsartan therapy, as primary diagnosis of acute decompensated heart
compared with enalapril therapy, after hemody- failure, including signs and symptoms of fluid
namic stabilization among patients who were overload. Patients were enrolled no less than 24
hospitalized for acute decompensated heart hours and up to 10 days after initial presentation
failure. to the hospital, while they were still hospitalized.
Before randomization, patients were required to thereafter. Hematologic, chemical, and biomarker
be hemodynamically stable, which was defined analyses of blood and urine samples were per-
by maintenance of a systolic blood pressure of at formed at a central laboratory. The last dose of
least 100 mm Hg for the preceding 6 hours, with the assigned trial drug was administered on the
no increase in the dose of intravenous diuretics morning of the week 8 visit.
and no use of intravenous vasodilators during
the preceding 6 hours and no use of intravenous Trial Outcomes
inotropes during the preceding 24 hours. A com- The primary efficacy outcome was the time-aver-
plete list of the inclusion and exclusion criteria aged proportional change in the NT-proBNP con-
is provided in Table S1 in the Supplementary Ap- centration from baseline through weeks 4 and 8.
pendix. All the patients provided written informed Key safety outcomes were the incidences of wors-
consent. ening renal function (an increase in the serum
creatinine concentration of ≥0.5 mg per deciliter
Trial Procedures [≥44 μmol per liter] and a decrease in the esti-
Patients were randomly assigned to receive either mated glomerular filtration rate of ≥25%), hy-
sacubitril–valsartan or enalapril. Randomization perkalemia (a serum potassium concentration of
was performed with the use of an interactive ≥5.5 mmol per liter), symptomatic hypotension,
Web-based response system. The initial dose of and angioedema. Any angioedema-like event that
sacubitril–valsartan (either 24 mg of sacubitril with was reported by a site investigator was reviewed
26 mg of valsartan or 49 mg of sacubitril with by an angioedema adjudication committee whose
51 mg of valsartan as a fixed-dose combination) members were unaware of the treatment assign-
or enalapril (either 2.5 mg or 5 mg) was admin- ments (see the Supplementary Appendix). Second-
istered orally twice daily, with dosing selected on ary biomarker outcomes included time-averaged
the basis of the systolic blood pressure at random- proportional changes in the high-sensitivity tro-
ization, according to a prespecified algorithm ponin T concentration, BNP concentration, and
(Fig. S1 in the Supplementary Appendix). To en- ratio of BNP to NT-proBNP. We also conducted
sure blinding, with each dose patients also re- analyses of exploratory clinical outcomes, includ-
ceived a placebo that resembled the other trial ing the incidence of a composite of death, rehos-
drug. Patients in the enalapril group received the pitalization for heart failure, implantation of a
assigned trial drug and placebo starting with the left ventricular assist device, inclusion on the list
first dose. Patients in the sacubitril–valsartan of patients eligible for heart transplantation, an
group received two doses of placebo alone (with unplanned visit for acute heart failure that led to
tablets that resembled both trial drugs), to en- the use of intravenous diuretics, an increase in the
sure a washout period of a minimum of 36 hours dose of diuretics of more than 50%, or the use of
before the initiation of sacubitril–valsartan, and an additional drug for heart failure.
then received the assigned trial drug and place-
bo starting with the third dose. All the patients Statistical Analysis
were monitored for a minimum of 6 hours after We calculated that a sample of 882 patients would
the third dose was administered before they were provide the trial with 85% power to detect an 18
discharged from the hospital. percentage-point greater time-averaged propor-
During the 8-week trial period, the dose of tional reduction in the NT-proBNP concentration,
sacubitril–valsartan was adjusted with a target of from the baseline value to the geometric mean
97 mg of sacubitril with 103 mg of valsartan of values obtained at weeks 4 and 8, in the sacu-
twice daily, and the dose of enalapril was adjusted bitril–valsartan group than in the enalapril group,
with a target of 10 mg twice daily. Dose adjustment at a two-sided significance level of 0.05. This
was guided by an algorithm that was based on calculation was based on the assumption of a
the systolic blood pressure and by the investiga- ratio of the NT-proBNP concentration at week 8
tor’s assessment of side effects (Fig. S1 in the as compared with baseline of 0.95 in the enala-
Supplementary Appendix). Follow-up visits were to pril group, a geometric standard deviation of the
be scheduled for weeks 1 and 2 and every 2 weeks log normal distribution of 0.85, and a rate at
which samples are missing or cannot be evalu- tial presentation to the hospital. At the time of
ated of 25%. randomization, signs and symptoms of heart fail-
All efficacy analyses were performed accord- ure were highly prevalent; 61.7% of the patients
ing to the intention-to-treat principle, with the had peripheral edema and 32.9% had rales on
use of all available data through the 8-week trial auscultation of the lungs. Baseline characteris-
period. The analyses were based on the likelihood tics of the patients are shown in Table 1, and in
method, with the assumption that data were miss- Table S2 in the Supplementary Appendix. The
ing at random. The analyses included all enrolled mean (±SD) age of the patients was 61±14 years;
patients except those who underwent random- 635 patients (72.1%) were male, and 316 (35.9%)
ization inappropriately. were black. The index hospitalization was for the
The primary analysis of the proportional change first diagnosis of heart failure in 303 patients
in the NT-proBNP concentration from baseline on (34.4%). Of the 576 patients (65.4%) who had
a logarithmic scale was performed with the use previously received a diagnosis of heart failure,
of an analysis of covariance model, with adjust- 343 (59.5%) had had at least one hospitalization
ment for the baseline value. A similar method was for heart failure during the previous year. At the
used to analyze the secondary biomarker out- time of admission to the hospital, 459 patients
comes. The incidences of worsening renal func- (52.1%) were not receiving treatment with an ACE
tion, hyperkalemia, symptomatic hypotension, and inhibitor or ARB.
angioedema were calculated along with relative At randomization, the median systolic blood
risks and associated 95% confidence intervals. pressure was 118 mm Hg (interquartile range,
Cumulative clinical-event rates were calculated 110 to 132), and 23.4% of the patients had a
according to the Kaplan–Meier method; the dif- systolic blood pressure of less than 110 mm Hg.
ferences in clinical outcomes between the two At screening, the median NT-proBNP concentra-
treatment groups were assessed with the log- tion was 4812 pg per milliliter (interquartile
rank test, and hazard ratios and associated 95% range, 3050 to 8745) and the median BNP concen-
confidence intervals were calculated with a Cox tration was 1063 pg per milliliter (interquartile
proportional-hazards model. Confidence intervals range, 718 to 1743). During the index hospital-
for all outcomes except the primary efficacy out- ization and before randomization, 814 patients
come have not been adjusted for multiple com- (93.0%) received intravenous furosemide, 97 (11.0%)
parisons, and therefore, inferences drawn from received care in an intensive care unit, and 68
these intervals may not be reproducible. The con- (7.7%) received an intravenous inotrope. The me-
sistency of treatment effect was examined across dian duration of the index hospitalization was
six prespecified subgroups and six additional ex- 5.20 days (interquartile range, 4.09 to 7.24).
ploratory subgroups. All analyses were performed
with the use of SAS software, version 9.3 or Trial Treatments and Follow-up
higher (SAS Institute). At least one dose of a trial drug was administered
in 875 patients (439 in the sacubitril–valsartan
group and 436 in the enalapril group); these
R e sult s
patients were included in the safety analyses
Trial Population (i.e., analyses of adverse events). With the exclu-
From May 2016 to May 2018, a total of 887 pa- sion of discontinuation owing to death, the trial
tients were enrolled at 129 participating centers drug was discontinued prematurely in 87 patients
in the United States. A total of 6 patients (0.7%) (19.6%) in the sacubitril–valsartan group and in
underwent randomization inappropriately; these 90 patients (20.3%) in the enalapril group (Ta-
patients did not receive any doses of a trial drug ble S3 in the Supplementary Appendix). A total
and were prospectively omitted from all analy- of 4 patients (3 in the sacubitril–valsartan group
ses. The efficacy analyses included 881 patients, and 1 in the enalapril group) were lost to follow-
of whom 440 were randomly assigned to receive up, with no data on vital status at 8 weeks; data
sacubitril–valsartan and 441 to receive enalapril for these patients were censored at a median of
(Fig. 1). The trial database was locked on August 37 days (Fig. 1). By the week 8 visit, 243 patients
21, 2018. (55.2%) in the sacubitril–valsartan group and 268
Patients were enrolled in the trial a median of (60.8%) in the enalapril group were receiving the
68 hours (interquartile range, 48 to 98) after ini- target dose of the assigned trial drug. Data for
443 Were assigned to receive sacubitril–valsartan 444 Were assigned to receive enalapril
3 Were excluded from analyses owing to 3 Were excluded from analyses owing to
randomization error randomization error
440 Were included in efficacy analysis 441 Were included in efficacy analysis
379 Had data for primary efficacy outcome 374 Had data for primary efficacy outcome
at baseline and at week 4 or 8 (or both) at baseline and at week 4 or 8 (or both)
439 Were included in safety analysis 436 Were included in safety analysis
1 Was excluded (did not receive trial drug) 5 Were excluded (did not receive trial drug)
the primary efficacy outcome were available greater in the sacubitril–valsartan group than in
through week 8 for 349 patients (79.3%) in the the enalapril group; the ratio of the geometric
sacubitril–valsartan group and for 348 patients mean of values obtained at weeks 4 and 8 to the
(78.9%) in the enalapril group. baseline value was 0.53 in the sacubitril–valsar-
tan group as compared with 0.75 in the enalapril
Primary Efficacy Outcome group (percent change, −46.7% vs. −25.3%; ratio
The NT-proBNP concentration decreased in both of change with sacubitril–valsartan vs. enalapril,
treatment groups. The time-averaged reduction in 0.71; 95% confidence interval [CI], 0.63 to 0.81;
the NT-proBNP concentration was significantly P<0.001) (Fig. 2, and Table S4 in the Supplemen-
Change in NT-proBNP
−10
dose of intravenous diuretics and no use of intra- 8 weeks, in most cases because of an adverse event.
venous vasodilators during the preceding 6 hours Taken together, these considerations suggest that
and no use of intravenous inotropes during the the initiation of any neurohormonal agent in
preceding 24 hours. Sacubitril–valsartan therapy this population should be performed cautiously.
was initiated at a low dose among patients with There are several limitations of our trial. The
lower systolic blood pressure, and the dose was in-hospital initiation phase, which included the
adjusted according to a prespecified algorithm. provision of placebo alone for the first two
A washout period of 36 hours was used to ensure doses in the sacubitril–valsartan group and then
that patients who had previously been taking an mandatory observation for 6 hours after the third
ACE inhibitor or ARB did not have any overlap- dose, may have prolonged the length of stay. These
ping medication effects. Despite these precau- elements of the protocol were necessary to preserve
tions, approximately 20% of the patients in each blinding, maintain protocol consistency, and en-
treatment group had discontinued treatment by sure patient safety. In addition, approximately
0.5% of the patients were lost to follow-up and to the rates of renal insufficiency, hyperkalemia,
15% had missing data on the NT-proBNP concen- symptomatic hypotension, and angioedema.
tration, although the results for the primary ef- Supported by Novartis.
ficacy outcome remained significant in an analy- Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
sis with multiple imputation. A data sharing statement provided by the authors is available
In conclusion, among patients who were hospi- with the full text of this article at NEJM.org.
talized for acute decompensated heart failure, the We thank Stacy Sabo, Eugene Patin, Lesley Schofield, and
Amy Starinsky (Novartis), Layle Gurrieri (United BioSource
initiation of sacubitril–valsartan therapy resulted in Corporation), Mary Ann Sellers and Patricia Daraugh (Duke
a significantly greater reduction in the NT-proBNP Clinical Research Institute), and Laura Grip (Thrombolysis in
concentration than enalapril therapy. There were no Myocardial Infarction Study Group) for assistance with trial
operations; Elizabeth Cook (Duke Clinical Research Institute)
significant differences between the sacubitril–val- for assistance with preparation of an earlier version of the
sartan group and the enalapril group with regard manuscript; and the patients for their participation in the trial.
References
1. Ambrosy AP, Fonarow GC, Butler J, et 5. Ponikowski P, Voors AA, Anker SD, et sus enalapril in heart failure. N Engl J
al. The global health and economic bur- al. 2016 ESC guidelines for the diagnosis Med 2014;371:993-1004.
den of hospitalizations for heart failure: and treatment of acute and chronic heart 8. Ambrosy AP, Mentz RJ, Fiuzat M, et al.
lessons learned from hospitalized heart failure: the Task Force for the diagnosis The role of angiotensin receptor-neprily-
failure registries. J Am Coll Cardiol 2014; and treatment of acute and chronic heart sin inhibitors in cardiovascular disease-
63:1123-33. failure of the European Society of Cardiol- existing evidence, knowledge gaps, and
2. Report to the Congress:Medicare and ogy (ESC) developed with the special con- future directions. Eur J Heart Fail 2018;
the health care delivery system — mandat- tribution of the Heart Failure Association 20:963-72.
ed report:the effects of the Hospital Read- (HFA) of the ESC. Eur Heart J 2016;37: 9. Velazquez EJ, Morrow DA, DeVore AD,
missions Reduction Program. Washington, 2129-200. et al. Rationale and design of the com-
DC:Medicare Payment Advisory Commis- 6. McMurray JJ, Packer M, Desai AS, et ParIson Of sacubitril/valsartaN versus
sion, June 2018 (http://www.medpac.gov/). al. Dual angiotensin receptor and neprily- Enalapril on Effect on nt-pRo-bnp in pa-
3. Ramírez A, Abelmann WH. Cardiac sin inhibition as an alternative to angio- tients stabilized from an acute Heart
decompensation. N Engl J Med 1974;290: tensin-converting enzyme inhibition in Failure episode (PIONEER-HF) trial. Am
499-501. patients with chronic systolic heart fail- Heart J 2018;198:145-51.
4. Yancy CW, Jessup M, Bozkurt B, et al. ure: rationale for and design of the Pro- 10. Senni M, McMurray JJ, Wachter R, et
2017 ACC/AHA/HFSA focused update of the spective comparison of ARNI with ACEI al. Initiating sacubitril/valsartan (LCZ696)
2013 ACCF/AHA guideline for the manage- to Determine Impact on Global Mortality in heart failure: results of TITRATION,
ment of heart failure: a report of the Ameri- and morbidity in Heart Failure trial a double-blind, randomized comparison
can College of Cardiology/American Heart (PARADIGM-HF). Eur J Heart Fail 2013; of two uptitration regimens. Eur J Heart
Association Task Force on Clinical Practice 15:1062-73. Fail 2016;18:1193-202.
Guidelines and the Heart Failure Society of 7. McMurray JJV, Packer M, Desai AS, et Copyright © 2018 Massachusetts Medical Society.
America. Circulation 2017;136(6):e137-e161. al. Angiotensin–neprilysin inhibition ver-