Management strategy in HF with ARNI - Recent updates

Management strategy in Heart
failure with ARNI -
Recent Updates
Dr. Praveen Nagula, MD, DM
Assistant Professor of Cardiology,
Osmania General Hospital,Hyderabad
drpraveennagula@gmail.com
Twitter: @kizashipraveen

1. The National Medical Journal of India, Vol 23, No.5, 2010 * The Indian Express: Published:June 30, 2015 3:33 am 2. Chaturvedi, et al.: Heart Failure In India: The INDUS Study J Pract Cardiovasc Sci 2016;2:28-35 4. . Bennett SJ, Huster GA, Baker SL, et al.
Characterization of the precipitants of hospitalization for heart failure decompensation. Am J Crit Care. 1998;7:168–74.
Uncontrolled Hypertension and IHD patients are the
key target population developing heart failure in India
Prevalence of HF ranges from 1.3 to 4.6 million,
with an annual incidence of 0.5 -1.8 million1.
*Parameters India US & Europe
Age 53 Yrs 65 - 75
EF 29.2% 34.4-39%
Death 30.8% 14-17%
Re-hospitalization 39.5% 24 -31%
Death post discharge 26.3% 5-15%
Incidences of Hospital admission due to HF are relatively
at younger age and with lower EF Treatment outcome are
poor compared to western countries.
Prevalence and Etiology of HF in India
The 3 main causes of hospitalizations due to chronic HF are sodium retention (55% of cases), ischaemic
episodes or myocardial infarction (25%) and arrhythmia (15%)4
Geographic distribution of Heart failure Etiology2

How are Indian HF patients different?
• The overall incidence is likely to
increase (in India) in the future owing
to the following factors:
• Aging population
• Rising CAD prevalence
• Epidemic rise of key risk factors such as
hypertension and DM
• Persistence of diseases such as RHD and
untreated congenital heart disease
• How are Indian HF patients different?
• Younger age at presentation
• Male to female ratio is also different in India
(70:30)
• RHD is also a major contributor
• DM is much more prevalent among Indians
• Prognosis of HF in Indian patients appears
to be worse than those in the West
• Strikes patients in the prime of their lives
Kidambi BR et al. J Pract Cardiovasc Sci 2019;5:2-11

Heart Failure is an increasingly prevalent syndrome and
a leading cause of both first hospitalization and readmissions.1
Heart Failure Rehospitalisation: An Unsolved Problem
1. Int J Cardiol. 2016 Nov 15;223:1035-1044 2. Maggioni et al. Eur J Heart Fail 2013;15:808–17; 3.. Ponikowski et al. ESC Heart Fail 2014;1:4-25; 4.. Kociol et al. Am Heart J 2013;165:987–94;5. Cleland et al. Eur
Heart J 2003;24:442–63 6. Indian Heart Journal 70S (2018) S85–S89
Nearly 44% of all HF patients are readmitted for any cause
within 1 year after discharge2
• Length of stay for HF hospitalization ranges between 5–10 days3
• In the USA, 30-day re-admission rates are >25%4
• In Europe, re-admission rates are ~24% at 12 weeks5
• In India re-hospitalization rate is 30% 6

TIMELINE OF
MANAGEMENT
OF HEART
FAILURE

Clinical Trajectory in Patients
Hollenberg et al. J Am Coll Cardiol 2019

Clinical Course of Heart Failure Graphic depiction of course of heart
failure admission
Writing Committee et al. J Am Coll Cardiol 2019;j.jacc.2019.08.001

Hospitalization is the Key
moment to optimized treatment

HEART FAILURE WITH REDUCED
EJECTION FRACTION
HFREF

Therapeutic algorithm for a patient with symptomatic HFREF
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. European Heart Journal (2016) 37, 2129–2200

Core therapy plus
other drugs for
the management
of HFrEF
S. Mishra et al. / Indian Heart Journal 70 (2018) 105–127

ARNI– A paradigm shift in the management of HF
ACEI- Angiotensin-converting enzyme inhibitor, ARB-Angiotensin receptor blockers
Sabe MA, et al. Cleveland Clinic J of Medicine 2015;82(10):693-701.
Sac/Val not only blocks the
renin angiotensin system, but
also enhances the activity of
vasoactive substances such as
the natriuretic peptides and
bradykinin

Positive Drug & device trials in HFrEF
2019
DAPA-HF

ARNI– A paradigm shift in the management of HF

Sacubitril/valsartan Doubles Effect on CV Death of
Current Inhibitors of the Renin-Angiotensin System
Presented at ESC HFA 2017, Paris by Prof. Dr. Adriaan Voors, Cardiologist University Medical Center
Groningen The Netherlands

• Sacubitril/Valsartan
• Consensus recommendation
- Sacubitril/valsartan is recommended as a replacement for ACE-I/ARBs to reduce the risk of
HF hospitalization and death in ambulatory patients with HFrEF who remain symptomatic
despite optimal medical treatment with an ACE-I, a beta-blocker and a MRA.
- Initiation of sacubitril/valsartan rather than an ACE-I or an ARB may be considered for
patients hospitalised with new-onset HF or decompensated CHF to reduce the short-term
risk of adverse events and to simplify management (by avoiding the need to titrate ACE-I first
and then switch to sacubitril/valsartan). Because these patients are already at high risk of
events, there is no need to check plasma concentrations of natriuretic peptides prior to
initiating sacubitril/valsartan. As indicated in the 2016 HF guidelines, ambulatory patients with
HFrEF should have an elevated plasma concentration of natriuretic peptides indicating
increased risk and the need for more effective therapy.
Eur J Heart Fail. 2019 May 26.

Acute Decompensated
Heart Failure

JAMA Cardiol. 2019 Dec 11. doi: 10.1001/jamacardio.2019.4665.
• Of 881 patients enrolled in PIONEER-HF, 832 (94%) participated in the open-label extension
study
• In this secondary analysis of PIONEER-HF, patients with ADHF were treated with either in-
hospital initiation of sacubitril/valsartan (titrated to target dose, 97mg of sacubitril with 103mg
of valsartan twice daily) continued for 12 weeks or in-hospital enalapril (titrated to target dose,
10mg twice daily) continued for 8 weeks followed by sacubitril/valsartan for 4 weeks.

• After ADHF, first-line initiation of sacubitril/valsartan in de novo HFrEF,
alongside the initiation of other guideline-directed therapies, is feasible
and is associated with a better risk–benefit profile than in patients with
prior HFrEF.
• Early intervention with sacubitril/valsartan may be considered to delay
disease progression in patients with de novo HFrEF.
Conclusion
Eur J Heart Fail, 22 (2), 303-312 Feb 2020

Results
Changes in N-terminal Pro–b-Type (NT-proBNP) From
Baseline Over 12Weeks
• Switching patients’ treatment from
Enalapril to Sacubitril/Valsartan at 8
weeks after randomization led to a
further 37% reduction in NT-
proBNP levels in patients with heart
failure with reduced ejection
fraction and a recent hospitalization
for ADHF.
JAMA Cardiol. 2019 Dec 11. doi: 10.1001/jamacardio.2019.4665.

• The study population of this post-hoc analysis comprised hospitalised patients divided into subgroups
based on HF history: newly diagnosed (de novo) HFrEF, or chronic HFrEF diagnosed prior to
enrolment in the study.
• Primary endpoint :
• To assess tolerability of treatment as the proportion of patients who achieved the target dose of 97/103
mg b.i.d. at the end of Week 10 after randomisation.
• Secondary endpoint :
• (i) Initiating sacubitril/valsartan shortly after hospitalisation in newly diagnosed (de novo) heart failure
patients (ii) the proportion of patients who received and maintained any dose of sacubitril/ valsartan for
≥2weeks leading up to Week 10; and (iii) the rates of permanent study drug discontinuations due to
adverse events

More de novo than prior HFrEF patients achieved target dose at Week 10
(56% vs. 45%; relative risk ratio 1.30, 95% confidence interval 1.12–1.52, P
<0.001), and fewer had SAEs and permanent treatment discontinuations.

De novo patients showed faster and greater decreases in N-terminal pro-B-type natriuretic
peptide and high-sensitivity troponin-T, and lower rates of HF and all-cause rehospitalisation
vs. prior HFrEF.

Prospective Comparison of ARNI With ARB Global Outcomes in HF With
Preserved Ejection Fraction - PARAGON-HF
Study design :
• A randomized, double-blind, active-comparator trial in which Patients with HFpEF were
randomized to sacubitril-valsartan 97/103 mg twice daily (n = 2,419) versus valsartan 160 mg
twice daily (n = 2,403).
Primary outcome :
• The primary outcome, rate of cardiovascular deaths or hospitalizations for HF, was 12.8
events per 100 patient-years in the sacubitril-valsartan group vs. 14.6 events per 100 patient-
years in the valsartan group (p = not significant).
Secondary outcomes:
• NYHA class improvement: 15.0% in the sacubitril-valsartan group vs. 12.6% in the valsartan
group (p < 0.05)
• Renal composite outcome: 1.4% in the sacubitril-valsartan group vs. 2.7% in the valsartan
group (p < 0.05)
Presented by Dr. Jonathan Cunningham at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 20

Primary and Secondary Outcomes
Presented by Dr. Jonathan Cunningham at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

Benefit of sacubitril-valsartan according to sex
Presented by Dr. Jonathan Cunningham at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 20
Sacubitril-valsartan hazard ratios (HRs) for the primary outcome according to sex:
Women: HR 0.73 (95% CI 0.59-0.90)
Men: HR 1.03 (95% CI 0.84-1.25) (p for interaction = 0.017)
As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of
heart
failure hospitalization more in women than in men.

Association of sacubitril-valsartan initiation from HF
hospitalization and benefit
• Sacubitril-valsartan vs. placebo was associated with an absolute 6.4%
reduction in cardiovascular death or hospitalization for HF when initiated <30
days from index hospitalization, 4.6% when initiated 30-90 days after index
hospitalization, 3.4% when initiated 91-180 days after index hospitalization,
and no benefit when initiated >180 days after index hospitalization (p for
interaction = 0.05).
• There was possible enhanced benefit when sacubitril-valsartan was initiated
in close proximity to the index hospitalization event; however, this finding
deserves prospective validation.
Presented by Dr. Jonathan Cunningham at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 30, 2020.

Effect Of Sacubitril/Valsartan On NT-proBNP In Patients
With Heart Failure And Preserved Ejection Fraction
J Am Coll Cardiol HF 30 March 2020
• The prognostic significance of baseline NT-proBNP was evaluated ,
whether NT-proBNP modified the treatment response to sacubitril/valsartan,
and the treatment effect of sacubitril/valsartan on NT-proBNP overall and in
key subgroups.
• NT-proBNP was measured at screening in all patients and at 5 subsequent
times in >2,700 patients: before, between, and after sequential valsartan
and sacubitril/valsartan run-in periods, and 16 and 48 weeks post-
randomization.

Association Between Screening Visit NT-proBNP and Primary Endpoint
Event Rate in Patients With/Without AF and Obesity
• NT-proBNP was associated
with the primary endpoint,
total HF hospitalizations and
cardiovascular death (rate
ratio [RR] 1.68 per log
increase in NT-proBNP, p <
0.001).
• This relationship was stronger
with atrial fibrillation (p for
interaction < 0.001) and
weaker with obesity (p for
interaction < 0.001).
• Sacubitril/valsartan compared

Variation in Primary Endpoint Event Rate and Sacubitril/Valsartan Treatment
Effect by Screening Visit NT-proBNP
• Baseline NT-proBNP did
not modify the treatment
effect of sacubitril-
valsartan compared with
valsartan (p for
interaction = 0.96).

• Thirty patients with New York Heart Association class II–III HFrEF were treated
with ARNI and monitored using standard echocardiographic examination and
GLS measurements at baseline, 3 months, and 6 months.
• Sacubitril/valsartan has been shown to be a well tolerated drug in the population
with HFrEF, and it was possible to titrate the ARNI to the maximum dose (97/103
mg bid) in 69% of patients.
ESC Heart Fail. 2020 Mar 31. doi: 10.1002/ehf2.12656

Global longitudinal strain at baseline and after 3 and 6 months of follow-up
• There is a progressive
improvement of all strain
parameters that becomes
statistically significant already at 3
months for most of the parameters
considered.
• This improvement maintained
statistical significance even at 6
months, showing a progressive
trend over time.

Example of evaluation of the systolic peak of strain on 16 segments model at baseline (pre-treatment) and after 6
months of angiotensin receptor neprilysin inhibitor therapy.
• Sacubitril/valsartan induces an early benefit on left ventricular remodelling, which is
captured by myocardial strain and not by standard echocardiography.
• Strain method represents a practical tool to assess early and minimal variations of left
ventricular systolic function.

• A total of 105 patients with heart failure with reduced ejection fraction, who were
candidates for sacubitril/valsartan treatment, were included in this prospective,
observational, multicentre, and international study.
Neprilysin inhibition, endorphin dynamics, and early
symptomatic improvement in heart failure: a pilot study
ESC Heart Failure (Feb 2020) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12607
Patients flow
diagram• Serum endorphin levels –levels of α
Endorphin- (α-EP), γ-Endorphin (γ-EP), and
soluble NEP (sNEP) were measured using
enzyme-linked immunoassays.
• New York Heart Association (NYHA)
functional class was used as an indicator
of patient’s functional status.
• Patients were reevaluated at 30 days after
the start of sacubitril/valsartan.

NYHA class changes after sacubitril/valsartan initiation
• After 30 days treatment with
sacubitril/valsartan, a
significant improvement in
NYHA class was found with 36
(34.3%) patients experiencing
improvement by at least one
NYHA class category.
• Before sacubitril/valsartan
treatment 8.6% of the patients
were in NYHA class I, while
after the treatment the
percentage of patients in
NYHA class I was 32.4%.

endorphin dynamics and NYHA
class at 30 days
• After forcing the three markers in the
statistical model, Δα-EP and ΔsNEP showed
to be significantly associated with NYHA
class after 30 days of treatment. (P = 0.014
and P < 0.001, respectively).
• For Δα-EP, the association was linear and
negative. On the other hand, ΔsNEP was
positive and linearly associated with higher
NYHA30-d class.
• Δα-EP showed to be significantly associated
with NYHA class improvement.
• These data suggest that beyond the
haemodynamic benefits achieved with
sacubitril/valsartan, the altered cleavage of
endorphin peptides by NEP inhibition may
participate in patients’ symptoms
improvement.

Sacubitril-Valsartan in a routine community population: attention to volume
status critical to achieving target dose
• A retrospective single-centre review of patients switched from angiotensin-
converting enzyme inhibitors/angiotensin receptor blockers to sacubitril-
valsartan between May 2016 and August 2018.
• The patients’ volume status was closely monitored , paying particular
attention to the need for diuretic dose adjustment, based on the
observation of a need for a reduction in diuretic strength in a significant
number of patients in the PARADIGM-HF population.
ESC Heart Failure (Feb 2020) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI:
10.1002/ehf2.12547

OTHER SUBSETS OF HEART FAILURE

Beneficial Acute Hemodynamic Effects of Sacubitril-Valsartan in Patients with
Low-Cardiac Output Including Significant Improvement in PAPi
The Journal of Heart and Lung Transplantation Volume 39, Issue 4, Supplement, April 2020, Page S54

• Sixty consecutive patients with chronic heart failure and NYHA class II-III enrolled in the
Daunia Heart Failure Registry were followed up for 12 months after therapy with
sacubitril/valsartan. Left and (RV) function was assessed at baseline and after 12 months
of therapy.
• At 12-month control, therapy with sacubitril/valsartan was associated with a significant
improvement in a series of echo parameters: LVEF (p < 0.05), LV end-systolic volume (p
< 0.01), left atrium area (p < 0.05).
M. Correale et al. / IJC Heart & Vasculature 27 (2020) 100486

Differences between baseline and follow-up
parameters • Right ventricular echo parameters
were also improved after
sacubitril/valsartan therapy
• Improvement in PAsP and TAPSE
were independent of left ventricular
improvements except for PAsP and
end-systolic volumes (r 0.44, p < 0.01).
• In a real world scenario,
sacubitril/valsartan was associated
with an improved RV function.
M. Correale et al. / IJC Heart & Vasculature 27 (2020) 100486

• 37 consecutive patients with advanced HF were treated with
sacubitril/valsartan.
• Patients were followed up until HT, device implant, or last follow-up visit
after 2 years of follow-up.

Comparison of physical frailty domain before and
after the start of sacubitril/valsartan
Comparison of the analytical and clinical
characteristics before and after the start of
sacubitril/valsartan
• There was a rapid improvement in physical frailty( PF) in HT waiting list patients treated with
sacubitril/valsartan.
• The improvement in all PF domains was paralleled by VO2 and 6MWT increase and together
with an NT-pro-BNP reduction

(A) Reasons for failure to tolerate sacubitril-valsartan and
(B) Preventing patients reaching target dose

Diuretic dose change patterns in the cohort
• Diuretic dose decrease was achieved
in 37.2% of patients with a mean
reduction of 10 ± 38 mg furosemide
equivalent across the entire
population., and this was the strongest
independent predictor of achieving TD
(odds ratio = 2.1; 95% confidence
interval [1.16, 3.8]; P = 0.014).

Clinical insights
• Sacubitril-valsartan was well tolerated.
• Achievement of TD was possible in the majority of the cohort and was
linked to response metrics.
• Reduction in diuretic was required in a large percentage of the population
and was the strongest predictor of attaining TD.
• Therefore, careful clinical attention to volume status assessment is
essential to maximising the benefits of sacubitril-valsartan.

Gaps between the guidelines and the real life
 Lack of awareness in general population
 Lack of access to NP testing
 Need a better screening of HF patients with the implementation of HF
screening program
 Need a better education of HF patients & their relatives
 Under-optimization of drug regimen
 Under adherence to the guidelines
 Access to HF centres and cardiac rehabilitation program

Novel considerations in optimizing care for patients with heart failure

Management strategy in HF with ARNI - Recent updates

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