ARNI in ADHF+LVEF<40%

1. Beka Aberra M.D
St Peter’s Cardiac Attachment
Moderator: Seifu Bacha, MD, Internist/Cardiologist
November, 2018

2. Introduction
Methodology
Results
Discussion
Conclusion
Critical appraisal
AHA Scientific Sessions

3.  Heart failure is a major public health issue. More than 5 million Americans have
heart failure (HF) & treatment costs for HF are approximately $31 billion annually.
Outcomes for patients after a hospitalization for HF remain disappointingly poor.
The 1-year mortality rate after a HF hospitalization is 20-30%, & this number has
been relatively unchanged over the past decade.
 The current state of treatments for patients hospitalized with acute heart failure is
focused on established guideline directed medical therapy, optimizing volume
status, & initiating beta-blockers if indicated. “Unfortunately, recent clinical trials
employing a variety of additional in-hospital interventions have failed to improve
post-discharge outcomes.”
 Thus, therapeutic options to improve post-discharge survival free of recurrent
HF hospitalizations for patients hospitalized for AHF are limited.

4.  This approach differs from the administration of Nesiritide (B-type natriuretic
peptide) in the setting of Acute HF, which did not improve clinical outcomes in the
ASCEND-HF trial.
 Activation of the RAAS plays a fundamental role in the Pathophysiology of HF, &
although therapies to block adverse neurohormonal activation are well established
& improve clinical outcomes in Chronic HF with reduced ejection fraction, they
have not been extensively tested among patients hospitalized with AHF.
 The PROTECT study was a small study ( N=151) that demonstrated that NTproBNP
guided therapy was superior to standard of care in reducing total cardiovascular
events, improved quality of life & impact on cardiac remodeling in patients with
chronic reduced ejection fraction.

5.  In the RELAX AHF trial, it was shown that patients that have a higher NTproBNP
level during an AHF hospitalization have a worse prognosis. Therefore, it is
important to evaluate therapeutic strategies that can lead to superior reductions
in NTproBNP in patients hospitalized due to an AHF episode.
 Sacubitril & valsartan combination tablet is an orally available, first in class,
combination of sacubitril, a neprilysin inhibitor, & valsartan, an angiotensin receptor
blocker that targets complementary pathways, RAAS inhibition via an Angiotensin II
receptor blockade & Natriuretic peptide [BNP] Augmentation via Neprilysin
Inhibition.
 Patients developing an AHF episode are known to have markedly elevated levels of
BNP & NTproBNP, which are reduced following adequate treatment & normalization
of their cardiac decompensation.

8.  Sacubitril & valsartan has been evaluated for safety & efficacy in patients with
chronic heart failure. The PARAMOUNT study was a randomized, double-blind,
active-controlled phase 2 trial of 308 patients with HF with preserved ejection
fraction (LVEF) ≥45%. NTproBNP levels were significantly reduced at 12 weeks in
the sacubitril & valsartan group compared with the valsartan group. The sacubitril
& valsartan combination was well tolerated & had a similar adverse effect profile
to valsartan.
 The PARAGON-HF trial is now enrolling 4300 similar patients with chronic HF with
preserved ejection fraction (LVEF ≥ 45%) to test whether the favorable effect of
sacubitril & valsartan combination tablet in reducing NTproBNP seen in PARAMOUNT
translates into a reduction in the composite end point of cardiovascular morbidity &
total (first & recurrent) HF hospitalizations.

9.  The PARADIGM-HF study was a large randomized, double-blind, active-controlled
trial of 8442 patients with symptomatic, Chronic HF with reduced ejection fraction
(LVEF ≤ 40%). Patients receiving sacubitril & valsartan combination tablet, compared
to enalapril, were noted to have reduced risk of the primary outcome of composite
of death from cardiovascular causes or hospitalization for HF.
 The trial was stopped prematurely after a median follow-up of 27 months upon
the recommendation of the data safety monitoring board due to compelling
evidence in favor of sacubitril & valsartan.
 In PARADIGM-HF, 8385 patients had a baseline NTproBNP obtained. Results were
consistent with the primary composite endpoint regardless of whether the NTproBNP
was less than or equal to the median values compared to higher than median values.
Additionally, a subset of patients had biomarkers obtained at baseline, visit 3 (end
of enalapril run-in), visit 5 (end of sacubitril & valsartan combination tablet run-in),
4 weeks after randomization, & at 8 months after randomization

10.  The ratio of NTproBNP to baseline levels was 25% lower in the sacubitril &
valsartan combination tablet group compared to the enalapril group at 4 weeks
& 8 months post-randomization.
• Conversely, BNP levels were approximately 23% higher in the sacubitril & valsartan
combination tablet group compared to the enalapril group at 4 weeks & 8 months
post-randomization.
These findings are consistent with NTproBNP not being a substrate of neprilysin,
whereas BNP is a substrate of neprilysin; levels of BNP reflect the action of the
drug whereas NTproBNP levels reflect the effect of the sacubitril & valsartan
combination on the heart [Packer 2014].

11.  ENTRESTO™ (sacubitril & valsartan) received FDA approval on 07July2015. It is
indicated to reduce the risk of cardiovascular death & hospitalization for heart failure
in patients with chronic heart failure (NYHA class II-IV) & reduced ejection fraction.
The present study will be the first study to examine sacubitril & valsartan combination
tablet administration during AHF & whether it can safely mitigate the adverse neuro-
hormonal activation that persists & contributes to the unacceptably high adverse event
rate currently observed in the first months after hospitalization for AHF as determined
by the effect on NTproBNP in this patient population.

12. PURPOSE & RATIONALE OF THE PIONEER-HF STUDY
 The purpose of this study is to assess the effect of in hospital initiation of sacubitril & valsartan
tablets vs. enalapril on time averaged proportional change in NTproBNP in patients
hospitalized for acute decompensated heart failure (ADHF) & reduced ejection fraction (left
ventricular ejection fraction (LVEF) ≤ 40%).
 Hospitalization for acute decompensated heart failure identifies patients at increased risk of
death & re-hospitalization following discharge.
 This increased risk justifies intervention with novel treatment strategies initiated prior to
hospital discharge to improve patient outcomes.

13.  The Primary Objective of this study is to assess the effect of in hospital
initiation of sacubitril & valsartan tablets vs. enalapril on the time-averaged
proportional change of NTproBNP from baseline in patients who have been stabilized
following hospitalization for ADHF & left ventricular ejection fraction [LVEF] ≤ 40%.
Weeks 4 & 8 will be included in the analysis (primary analysis time point).
 The Secondary Objectives To examine the effect of sacubitril & valsartan
tablets vs. enalapril on change in:
The proportional change in NTproBNP from Baseline to Week 8
Incidence of symptomatic hypotension during 8 weeks of treatment
Incidence of hyperkalemia (Potassium >5.5 mEq/L) during 8 weeks of treatment
Incidence of angioedema during 8 weeks of treatment
Biomarkers: high sensitivity-Troponin (hs-Troponin), urinary cGMP at 4 & 8 weeks; &
BNP:NTproBNP ratio

14. STUDY DESIGN
This study will use a randomized, double-blind, double-dummy, active controlled,
parallel group design. Eligible patients hospitalized for ADHF will be randomized/
[48 hours—24 hrs] & up to [five days---10 days] of admission, while still hospitalized.
Patients randomized to sacubitril & valsartan will require a 36-hour wash-out from
prior ACEi/ARB treatment prior to first dose of active study treatment. At the time of
randomization, patients will have been stabilized, defined as
SBP ≥ 110 mg Hg for the preceding [24 hours,---6 hrs]
No Inc. in diuretics/ [24 hours---6hrs] prior to randomization, &
No inotropic drugs/24hrs
No vasodilators including nitrates/[24---6hrs] hours prior to randomization; &
meeting all other inclusion & none of the exclusion criteria.

15. Patients will be randomized to sacubitril & valsartan or enalapril. Initial dose
will be determined by the blood pressure at the time of randomization. Study
treatment will be titrated to the target dose of sacubitril & valsartan 97/103 mg
bid & enalapril 10 mg bid. Titration will be based on blood pressure at the time of
the visit. Dose adjustments will be allowed per protocol defined safety &
tolerability criteria. At the end of the 8-week treatment period, patients will
enter a 4-week follow up period on open label sacubitril & valsartan.

16. SETTING AND PARTICIPANTS OF STUDY
The study population will consist of male and female patients, ≥ 18 years of
age, admitted to hospital for acute decompensated heart failure. The goal is
to randomize a total of approximately [736—882] patients to sacubitril & valsartan
or enalapril in a 1:1 ratio in approximately [100—170] centers in the United States.
At the time of randomization, patients will have been stabilized.
Actual Study Start Date : April 29, 2016
Estimated Primary Completion Date : June 29, 2018
Estimated Study Completion Date : June 29, 2018

17. SAMPLE SIZE CALCULATION
Assuming a significance level of 0.05 and 85% power, a sample size of [736---882]
patients would be needed to detect an 18% reduction in the geometric mean of the
time-averaged proportional change from baseline (average of Weeks 4 and 8) in
NTproBNP for the sacubitril & valsartan treatment group assuming a value of 0.95
for the enalapril group, a common standard deviation of 0.85 and a 10% loss to
follow-up rate.
The estimates are based on the day 5 to day 14 data from the RELAX-AHF study. The
standard deviation estimate is supported by data from PARADIGM. The assumption of
a 18% reduction in the geometric mean for NTproBNP for the sacubitril and valsartan
treatment group vs. the enalapril group is consistent with NTproBNP results seen in
PARADIGM (26% and 25% relative reduction of sacubitril and valsartan vs. enalapril at Week
4 and Month 8 respectively),
PARAMOUNT (23% relative of sacubitril and valsartan vs. valsartan at Week 12) and
RELAX-AHF (19% relative reduction of serelaxin vs. placebo at Day 2).

18. SAMPLE SIZE CALCULATION

24. TRIAL PROCEDURES
Patients were randomly assigned to receive either sacubitril–valsartan or enalapril.
randomization was performed with the use of an Interactive Web-based response
system.
The initial dose of sacubitril–valsartan (either 24 mg/26 mg of sacubitril/valsartan or
49 mg/51 mg of valsartan as a fixed-dose combination) or enalapril (either 2.5 mg or
5 mg) was administered orally twice daily, with dosing selected on the basis of the
systolic blood pressure at randomization.
To ensure blinding, with each dose patients also received a placebo that resembled
the other trial drug. “Double Dummy”.
All the patients were monitored for a minimum of 6 hours after the third dose
was administered before they were discharged from the hospital.

25.  During the 8-week trial period, the dose of sacubitril–valsartan was adjusted with a
target of 97 mg/103 mg of Sacubitril/Valsartan twice daily, & the dose of
Enalapril was adjusted with a target of 10 mg twice daily.
 Dose adjustment was guided by an algorithm that was based on the systolic blood
pressure & by the investigator’s assessment of side effects.
 Follow-up visits were to be scheduled for weeks 1 & 2 & every 2 weeks thereafter.
Hematologic, chemical, & biomarker analyses of blood & urine samples were
performed at a central laboratory.
 The last dose of the assigned trial drug was administered on the morning of the
week 8 visit.

26. STATISTICAL ANALYSIS
All efficacy analyses were performed according to the Intention-to-Treat principle,
with the use of all available data through the 8-week trial period.
All analyses were performed with the use of SAS software, version 9.3 or higher
(SAS Institute).
The primary analysis of the proportional change in the NTproBNP concentration from
baseline on a logarithmic scale was performed with the use of an analysis of
covariance model, [ANCOVA] with adjustment for the baseline value. A similar
method was used to analyze the secondary biomarker outcomes.
The analyses included all enrolled patients except those who underwent
randomization inappropriately.

28. TRIAL POPULATION
From May 2016 to May 2018, a total of 887
patients were enrolled at 129 participating
centers in the United States.
 A total of 6 patients (0.7%) underwent
randomization inappropriately; these patients did
not receive any doses of a trial drug & were
prospectively omitted from all analyses.
The efficacy analyses included 881 patients, of
whom 440 were randomly assigned to receive
sacubitril–valsartan & 441 to receive enalapril. The
trial database was locked on August 21, 2018.

29. The mean (±SD) age of the patients was 61±14 years; 635 patients (72.1%) were
male, & 316 (35.9%) were black.
The Index Hospitalization was for the first diagnosis of heart failure in 303
patients (34.4%). Of the 576 patients (65.4%) who had previously received a
diagnosis of heart failure, 343 (59.5%) had had at least one hospitalization for heart
failure during the previous year.
At the time of admission to the hospital, 459 patients (52.1%) were not receiving
treatment with an ACE inhibitor or ARB.
At screening, the median NTproBNP concentration was 4812 pg per milliliter
(interquartile range, 3050 to 8745) & the median BNP concentration was 1063 pg per
milliliter (interquartile range, 718 to 1743).
The median duration of the index hospitalization was 5.20 days (interquartile
range, 4.09 to 7.24)

30. TRIAL TREATMENT/FOLLOWUP
At least one dose of a trial drug was administered in 875 patients (439 in the
sacubitril–valsartan group & 436 in the enalapril group); these patients were
included in the safety analyses (i.e., analyses of adverse events). With the exclusion
of discontinuation owing to death, the trial drug was discontinued prematurely in
87 patients (19.6%) in the sacubitril–valsartan group & in 90 patients (20.3%) in
the enalapril group.
Data for the primary efficacy outcome were available through week 8 for 349
patients (79.3%) in the sacubitril–valsartan group & for 348 patients (78.9%) in the
enalapril group.

31. PRIMARY EFFICACY OUTCOME
The NTproBNP concentration decreased in both
treatment groups. The time-averaged reduction in
the NTproBNP concentration was significantly
greater in the sacubitril–valsartan group vs
enalapril group; the ratio of the geometric mean of
values obtained at weeks 4 & 8 to the baseline
value was 0.53 vs 0.75 in the sacubitril–valsartan
group vs the enalapril group.
Percent change, −46.7% vs.−25.3%; ratio
of change with sacubitril–valsartan vs. enalapril,
0.71; 95% confidence interval [CI], 0.63 to 0.81;
P<0.001)

32. SECONDARY EFFICACY OUTCOMES
The rates of worsening renal function,
hyperkalemia, & symptomatic hypotension
did not differ significantly between the
sacubitril–valsartan group & the enalapril
group.
The rate of permanent discontinuation of the
trial drug owing to any adverse event did not
differ significantly between the two
treatment groups.

33.  The PIONEER-HF trial was performed to evaluate the use of a neprilysin inhibitor
added to a renin–angiotensin system inhibitor, as compared with a renin–angiotensin
system inhibitor alone, in the treatment of patients who were hospitalized for acute
heart failure.
 The initiation of sacubitril–valsartan therapy after hemodynamic stabilization led to
a greater reduction in the NTproBNP concentration than enalapril therapy, a
difference that was evident by the first week. The beneficial effect of sacubitril–
valsartan on the concentration of NTproBNP, which is a biomarker of neurohormonal
activation, hemodynamic stress, & subsequent cardiovascular events, was
accompanied by a reduction in the concentration of HS cardiac troponin T, which is
a biomarker of myocardial injury associated with abnormalities of cardiac structure
& function & with a worse prognosis among patients with heart failure.

34.  The results of the PIONEER-HF trial extend the evidence base regarding the use of
sacubitril–valsartan to populations for which there had been limited or no data,
including patients who are hospitalized for ADHF, patients who have new heart
failure, patients who have not been exposed to high doses of guideline-directed
medications for heart failure, & patients who are not receiving conventional renin–
angiotensin system inhibitors.
 In addition, 35.9% of the patients in our trial identified as black, & there is
limited evidence from previous clinical studies regarding the use of sacubitril–
valsartan among black patients.

35.  Results from previous trials of sacubitril–valsartan, most notably the PARADIGM-
HF trial, were limited to ambulatory outpatients who had received established high
doses of an ACE inhibitor or ARB, as well as the highest doses of enalapril &
sacubitril–valsartan during sequential single-blind run-in periods before
randomization.
 The PIONEER-HF trial made use of the lowest starting dose of sacubitril–valsartan
(24 mg/26mg of sacubitril/valsartan), with which there was less experience. The
PIONEER-HF trial set specific requirements or the in-hospital initiation of sacubitril–
valsartan therapy. [Inclusion Criteria]
 There are several limitations of our trial. The in-hospital initiation phase, which
included the provision of placebo alone for the first two doses in the sacubitril–
valsartan group & then mandatory observation for 6 hours after the third dose, may
have prolonged the length of stay.

36. Among patients with Heart failure with reduced ejection fraction who
were hospitalized for Acute Decompensated Heart Failure, the
initiation of sacubitril–valsartan therapy led to a greater reduction
in the NTproBNP concentration than enalapril therapy.
Rates of worsening renal function, hyperkalemia, symptomatic
hypotension, & angioedema did not differ significantly between the
two groups.
(Funded by Novartis; PIONEER-HF ClinicalTrials.gov number, NCT02554890.)

37. 37
1. Was the Study design Appropriate?
Yes; It was Clinical Trial, Experimental study of sacubitril–valsartan therapy, as compared
with enalapril therapy for ADHF; LVEF<40%. It was Multicenter, randomized, double blinded,
double dummy, active controlled trial.
2. Were all patients who entered the trial properly accounted for at its conclusion?
[Losses to follow-up should be < 20% ]and reasons for drop out?
Yes, there were 187 premature treatment discontinuations, Loss to follow-up was 16 [2%];
Reasons for drop out>>See PREV FLOW [S/R/F] CHART
3. Was follow-up Long enough?
 Yes, It spanned from April 29, 2016- June 29, 2018.

38. 38
4. Were the recruited patients representative of the target population?
Yes, Screening of Patients with strict Inclusion criteria addressed Desired Patients [ADHF;
LVEF<40%]. It was active controlled study thereby wrong patients that were entered were
removed thereby preventing Selection bias.
5. Was the allocation (assignment) of patients to treatment randomized and concealed?
Were patients, health workers, and study personnel “Blind” to treatment?
Yes, It was Randomized but without stratification. Masking was Quadruple (Participant, Care
Provider, Investigator, Outcomes Assessor). It was Double Blinded/ Double Dummy thereby
reducing observer/ experimenter’s bias.
6. Were patients analyzed in the groups to which they were randomized?
Yes, See PREV FLOW [S/R/F] CHART

39. 7. Were all randomized patient data analyzed? If not, was a sensitivity or “Worst
case scenario” analysis done?
Yes, It was an Intention to Treat Analysis meaning everyone who is randomized considered to
be part of trial, and is analyzed. See PREV FLOW [S/R/F] CHART
8. Were groups similar at the start of the trial?
Yes, See Demographic Distribution Chart @ baseline.
9. Aside from the experimental intervention, were the groups treated equally?
Yes, See PREV FLOW [S/R/F] CHART
10. Are the sources of support and other potential conflicts of interest
acknowledged and addressed?
Yes, The Corresponding Author and Researchers have put out disclosure forms of links with
sponsor NOVARTIS. All personal Fees, Grants, other Nonfinancial supports have been
submitted to the ICMJE [International Committee of Medical Journal Editors]

40.  Published on NEJM; Impact Factor 72.6
[2018]
 Clear Title
 Randomized, Controlled trial; Multicenter
 Clear Inclusion and Exclusion criteria
 Adequate Sample Size; With Power of 85%
 Loss to follow up [2%]
 Comparable Baseline Popn. characteristics;
Moreover 36% were Black a group with
little evidence for use of LCZ696.
 Final result had Narrow CI, high precision
rate, high reliability, adequate sample.
 Novartis participated in funding, design
 African Country not represented
 Local applicability (availability, expense,
experience)
 Intention to treat Analysis risk of Validity
 Not Stratified Sampling risk of confounders
 NTproBNP Concentration at Randomization
Were different b/n the groups [p=0.04]
 Risk of Recall Bias long duration for study
participants
 Unnecessary hospital stay 6hrs after 3rd
dose
11. Notable Study Strengths vs. Weaknesses/Concerns?

41. 12. How Serious are the threats to validity & in what direction could
they bias the study outcomes?
Not that serious, The study was able to scientifically answer the question it intended
to answer.
13. Clinical Importance of Study?
How large was the treatment effect? The time-averaged reduction in the
NTproBNP concentration was significantly greater in the sacubitril–valsartan group
than in the enalapril group the ratio of the geometric mean of values obtained at
weeks 4 and 8 to the baseline value was 0.53 vs 0.75 in the sacubitril–valsartan
group as compared with enalapril group (percent change, −46.7% vs. −25.3%)
How precise was the treatment effect?
0.71; 95% confidence interval [CI], 0.63 to 0.81; P<0.001)

42.  CHICAGO — Patients with acute decompensated HF had greater reduction
in N-terminal pro-B-type natriuretic peptide when assigned
sacubitril/valsartan than treatment with enalapril, according to the
results of the PIONEER-HF trial presented at the American Heart
Association Scientific Sessions.
 Sacubitril/valsartan (Entresto, Novartis) was also superior to enalapril
for a secondary serious composite clinical endpoint of death, HF
rehospitalization, left ventricular assist device implantation or
transplant listing at 8 weeks.
 “The outlook for patients in first 30 days following HF hospitalization is
poor, with up to one in five readmitted during this vulnerable period and
up to 10% likely to die,” he said. “We conducted PIONEER-HF to give the
medical community greater insight into the safety of sacubitril/valsartan
versus a standard HF medicine in this vulnerable time period. Additionally,
we ensured that PIONEER-HF included populations typically
underrepresented in HF studies.”
 Eric J. Velazquez, MD Professor of Cardiology; Yale University School of
Medicine. Eric J. Velazquez, MD

43.  “..a major gap existed with respect to administration of sacubitril/valsartan
in patients with Acute HF.…PARADIGM-HF, patients were gradually titrated up
in a stable state. It left a very large question about the safety and
tolerability of sacubitril/valsartan in patients that are more
decompensated…The takeaways of PIONEER-HF are that the primary
endpoint of the trial showed a rapid reduction in NT pro-BNP, in patients
assigned sacubitril/valsartan; this is an important outcome. In addition, we
saw that initiation and titration of sacubitril/valsartan was safe and well-
tolerated without an excess in hypotension, kidney complications and
hyperkalemia; strikingly, only one patient had angioedema from the drug vs.
six in the enalapril group, and one might have expected that to be the other
way around, given that neprilysin inhibition is supposedly associated with
higher risk for angioedema. Lastly, although the trial was not designed to
show it, there was a reduction in CV events with sacubitril/valsartan
 I envision that this will lead to a change in current consensus documents,
as well as to the guidelines the next time they are redrafted.
 James L. Januzzi Jr., MD Professor of Medicine Harvard Medical School