Management of HFpEF :

Gaps in current treatment pattern

dr. Edrian Zulkarnain, Sp.JP-FIHA
5 years outcome in patients hospitalized with HFpEF and HFrEF
• Simillar outcome
HFrEF = HFpEF
• Data from the
GWTG-HF
• 39,982 patients
• 254 hospital
Regional Variation of Mortality:
Worst Outcome in Southeast Asian Patients for both HFpEF & HFrEF

HFrEF HFpEF

MacDonald et al., J Am Heart Assoc. 2020 Jan 7;9(1):e012199.

 HF with preserved EF in Asia (1204 patients)

South Asia
Northeast Asia

Southeast Asia

Southeast Asians are at higher risk of death or HF hospitalization at 1 year

[ HR: 2.68 (1.72–4.17) ]
Tromp et al. Eur J Heart Fail. 2019 Jan;21(1):23-36.
 Guideline recommendation for HFpEF treatment
Guidelines ESC 2016: AHA/ACC/HFSA Guidelines 2017:
Focus on symptom, well being & prognosis Focus on symptomatic relief, comorbidity management, modifying risk factors

ESC Guidelines 2016. Eur Heart J 2016;37:2129-2200 Yancy CW, et al. Circulation 2017; 136:e137–e161.
 Treatment options for HFpEF
“No treatment has yet been shown, convincingly, to reduce morbidity and mortality in patients with HFpEF”

The key mortality–morbidity trials with HFpEF:

#
STUDY Study drug Endpoint Outcome Publication
Patients
Yusuf S et al
CHARM- CV death or HF
Candesartan 3023 Lancet 2003
Preserved hospitalization

Cleland JG et al
Death or HF
PEP-CHF Perindopril 850 Primary Eur Heart J 2006
hospitalization
end-point
Death or HF not met Massie BN et al NEJM
I-Preserve Irbesartan 4128 hospitalization 2008

CV death, aborted
Pitt Bertram et al
TOPCAT Spironolactone 3445 cardiac arrest, or
NEJM 2014
HF hospitalization
Sacubitril/ HF Hospitalization Solomon SD, et al.
PARAGON 4,800 ???
Valsartan and CV Death JACC-Heart Fail 2017
 CHARM-Preserved Trial
In patients with HFpEF, candesartan does not significantly reduce CV death,
but does significantly reduce the rate of HF Hospitalization as compared with placebo

Candesartan vs Placebo in CHF with EF >40%

Candesartan Placebo Mean 3 years follow-up
N=1514 N=1509
adjusted HR 0.84;
333 366 HF hosp. or CV death (adjudicated 95%CI 0.70-1.00,
(22%) (24.3%) data) p=0.047
hazard ratio 0.89, p=0.12

330 371 HF hosp. or CV death (investigator

data)
hazard ratio 0.86, p=0.051
270 204 Higher rate of adverse events in the
(17.8%)  (13.5%) candesartan group, p=0.001

Using conventional primary endpoint

Insufficient evidence of treatment efficacy

Lancet 2003; 362:777-781

 TOPCAT Trial – Spironolactone in HFpEF
No significant difference in the primary composite outcome (CV death, aborted cardiac arrest, and HF hospitalization).
Post hoc analyses showed that spironolactone benefited patients in the Americas but not Russia or Georgia?

Spironolactone
Spironolactone Placebo level
Endpoint (%) of risk (%) vs placebo
HR (95%IC)

0.89 (0.77-1.04)
Primary Endpoint 18.6 20.4 P= 0.14

Americas
0.82 (0.69-0.98)
(USA, Canada, 27.3 31.8 P= 0.026
Brasil, Argentina)
1.10 (0.79-1.51)
Russia, Georgia 9.3 8.4 P= 0.576

 when the level of risk has an impact on the treatment effect

 it is difficult to conclude that the treatment is effective for the US
population based on this single study.

N Engl J Med 2014;370:1383-1392

JACC Heart Fail. 2020 March ; 8(3): 172–184.
doi:10.1016/j.jchf.2019.09.009
 PARAMOUNT HF - Phase II Results in HFpEF
Improvement in Several Domains

12-week randomized, double-blind, active-controlled study evaluating sacubitril/valsartan compared to valsartan

on changes in NT-proBNP, cardiac structure and function, and HF symptoms/signs in 301 HFpEF patients

Improvement in NT-proBNP Improvement in NYHA class Improvement in left atrial size

1000 Sac/val P=0.05 12 Weeks 36

Change in left atrial volume (mL)

Valsartan 100 P=0.11
900 Weeks
NT-proBNP (pg/mL)

90 2

Percent of patients
800 80 1
700 70 0
600 60 -1
50 -2
500 40
Week 4 Week 12 -3
400 30
P=0.063 P=0.005 Week 36 -4
300 20
P=0.20 -5 P=0.18
10 P=0.003
200 0 -6
0 5 10 15 20 25 35 Sac/Val Valsartan Sac/Val Valsartan
30 40 Sac/val
Week 12 Week 36
Weeks post-randomization Valsarta
Worsened Unchanged Improved
n

NT-proBNP: N-terminal pro-brain natriuretic peptide; NYHA: New York Heart Association
<<Solomon et al. Lancet 2012 380(9851):1387-1395>> 12
 PARAGON-HF: Trial Design
848 Sites in 43 Countries
Target patient population: ~4,800 patients with symptomatic HF (NYHA Class II–IV), LVEF ≥45%, LVH/LAE &
elevated NT-proBNP

Randomization 1:1 Double-blind treatment period

Active single-blind run-in

period

Sacubitril/ S
Eligibility Valsartan a
Valsartan
80 mg BID c
49/51 mg BID
Screening u
Valsartan 160 mg BID*
b
i
Valsartan
On top tof optimal background medications for co-
r
morbidities (excluding ACEi and ARB)
40 mg BID
i
l
1 – 4 weeks 2 – 4 weeks / ~35 months
* target doses, down-titration allowed for tolerability
V
<<Solomon SD, et al. JACC-Heart Fail 2017; 5(7):471-482.>>
a
13
l
PARAGON-HF: Endpoints

Composite Primary Endpoint Expanded Composite Endpoint

• Composite of CEC-confirmed: (Exploratory)
– Total (first and recurrent) HF • Composite of CEC-confirmed:
hospitalization – Total (first and recurrent) HF
– CV death hospitalization
– CV death
Urgent
– Urgent HFV HF visits* event reflecting morbidity
Secondary Endpoints is an important associated with
HF. The distinction between urgent HFV and HHF may predominantly
• NYHA functional classification at 8 months reflect local clinical practice with respect to the management of HF in
each hospitals or country or health insurance
• KCCQ Clinical Summary Score at 8 months
• Time to first occurrence of worsening renal function
• Time to all-cause mortality

14
Key Design Considerations: Recurrent Events
• HFpEF is characterized by frequent recurrent worsening HF events (HF hospitalization and Urgent HF visits)
• Each event is associated with worsening of long term prognosis
– In the CHARM program (candesartan) the risk of death increased with each additional HF hospitalization, with an
~30% cumulative incremental risk associated with 2nd or 3rd HF hospitalization
• This approach more accurately reflects the true burden of the illness on the patient and the healthcare system
• Commonly used in other diseases where recurrent encounters are common (e.g. asthma, multiple sclerosis) and included in
June 2019 FDA guidance “Treatment for Heart Failure: Endpoints for Drug Development”

Compensated

Recurrent
Clinical status

Worsening
Chronically Heart Failure
decompensated Event

Acutely
decompensated

Disease progression Death

<<Rogers et al. 2013>> 15

Key Inclusion & Exclusion Criteria
To Avoid Overlap with HFrEF Population and Ensure Certainty of HFpEF Diagnosis

Key inclusion criteria Key exclusion criteria

• ≥ 50 years of age and LVEF ≥ 45% • Any prior measurement of LVEF < 40%
• Heart failure signs/symptoms (NYHA Class II–IV) • Current acute decompensated heart failure
requiring treatment with diuretic(s) for at least 30
• Alternative reason for signs and symptoms
days prior to enrollment
• Structural heart disease (LAE or LVH by • SBP < 110 or ≥ 180mm Hg (or > 150mm Hg if
echocardiography) patient not taking 3 or more antihypertensive
medications)
• Elevation in natriuretic peptides
• NT-proBNP 200 pg/ml if
hospitalized for HF within 9 months, and
300 pg/ml if not hospitalized; 3-fold
increase for patients in AF at enrollment

LAE: Left Atrial Enlargement; LVH: Left Ventricular Hypertrophy; SBP: Systolic Blood Pressure
<<Solomon SD, et al. JACC-Heart Fail 2017>>
16
 Baseline Demographics
Balanced Baseline Cardiovascular Profile
Sacubitril/Valsartan Valsarta
N=2,407 n
N=2,389
NYHA class at randomization Class I 3% 3%
Class II 78% 77%
Class III 19% 20%
Class IV 0.3% 0.5%
BMI – mean (SD) 30.2 (4.9) 30.3 (5.1)

Baseline mean SBP (SD) / mean DBP (SD) at randomization 130.5 (15.6) / 74.3 (10.6) 130.6 (15.3) / 74.3 (10.4)
Medical history Hypertension 96% 95%
Diabetes mellitus 43% 43%
Atrial fibrillation or flutter at screening ECG 32% 33%
Hospitalization for HF within 9 months 38% 39%
Medications
At screening ACEi or ARBs 86% 86%

At randomization Diuretics 95% 96%

MRA 25% 27%*
Beta blockers 80% 79%
Calcium channel blockers 34% 34%
Baseline characteristics balanced if not noted by *P<0.05.
<<Solomon SD et al. N Engl J Med 2019; 381:1609-1620 >>
17
PARAGON-HF Primary Composite Endpoint Results
Primary endpoint just missed significance

Primary endpoint:
• Clinically significant of
Mean cumulative events per 100 patients
Total HF hospitalizations and CV death
Primary Endpoints
55
but
50 Valsartan (n = 2389) • Not reach statistically
45 1009 events, 14.6 per 100 pt-years significant
40
35
30
25 Sacubitril/Valsartan (n = 2407)
20 894 events, 12.8 per 100 pt-years
15
10 Rate ratio 0.87 (95% CI 0.75, 1.01)
P = 0.059
5
0
0 1 2 3 4
Years
*Semiparametric LWYY method
18
 HF Hospitalizations and CV Death

HF hospitalizations* CV Death**
Events Patients
55 Valsartan 797 0.55 Valsartan 212 (8.9%)
50 Sacubitril/Valsartan 690 0.50 Sacubitril/Valsartan 204 (8.5%)
45 0.45
Rate ratio 0.85 (95% CI 0.72, 1.00) Hazard ratio 0.95 (95% CI 0.79, 1.16)
events per 100

Proportion
Mean cumulative

40 0.40
35 0.35
30 0.30
patients

25 0.25
20 0.20
15 0.15
10 0.10
5 0.05
0 0.00
0 1 2 3 4 0 1 2 3 4

Years Years

*HF Hospitalization = Joint frailty model

**CV death = Cox’s proportional hazard model 19
Pre-Specified Subgroups for Primary Endpoint
Evidence for Heterogeneity for Two Subgroups in Multivariable Analysis
No. of events Rate ratio No. of events Rate ratio
Subgroup /patients (95% CI) Subgroup /patients (95% CI)
Overall 1903/4796 0.87 (0.75−1.01) Diabetic
Age (years) Yes 1041/2069 0.89 (0.74−1.09)
Less than 65 years 276/825 0.99 (0.64−1.53) No 862/2727 0.84 (0.68−1.03)
LVEF*
65 years or older 1627/3971 0.85 (0.73−0.99)
at or below median 1048/2495 0.78 (0.64−0.95)
Age (years)
(57%) above median 855/2301 1.00 (0.81−1.23)
Less than 75 years 938/2597 0.82 (0.66−1.02) (57%)
75 years or older 965/2199 0.92 (0.76−1.11) History of AF 1140/2521 0.83 (0.69−1.00)
Sex* Yes 763/2275 0.94 (0.75−1.18)
Male 980/2317 1.03 (0.85−1.25) No
Female 923/2479 0.73 (0.59−0.90) Screening
708/2379
NT−proBNP 0.85 (0.67−1.08)
Race
at or below median (911 1183/2378 0.87 (0.73−1.05)
Caucasian 1542/3907 0.83 (0.71−0.97) pg/mL)
Black 89/102 0.69 (0.24−1.99) above median (911
pg/mL) 984/2450
Asian 237/607 1.25 (0.87−1.79) 0.88 (0.72−1.07)
Other 35/180 1.03 (0.47−2.28) Screening SBP 919/2344 0.86 (0.69−1.06)
at or below median (137
Region
mmHg)
Yes 545/1239 0.73 (0.56−0.95)
North America 478/559 0.80 (0.57−1.14) above median (137 mmHg)
No 1358/3557 0.94 (0.79−1.12)
Latin America 83/370 1.33 (0.75−2.36) MRA useeGFR
Baseline
Western Europe 544/1390 0.69 (0.53−0.89) <60 mL/min/1.73m2 1115/2341 0.79 (0.66−0.95)
Central Europe 466/1715 0.97 (0.76−1.24) >=60 mL/min/1.73m2 787/2454 1.01 (0.80−1.27)
Asia/Pacific 332/762 1.10 (0.79−1.52) NYHA class
I/II 1402/3843 0.90 (0.76−1.06)
III/IV 499/951 0.79 (0.59−1.06)

0.4 0.8 1.6 0.4 0.8 1.6

Rate ratio (95% CI) Rate ratio (95% CI)
*Multivariate interaction P < 0.05.
<<Solomon SD et al. N Engl J Med; 2019 >> 20
Treatment Effect by Gender
Primary Composite endpoint: Total HF hospitalizations and CV death

Including first and repeat hospitalizations

Women Men
Rate Ratio 0.73 (0.59, 0.90) Rate Ratio 1.03 (0.84, 1.25)

Valsartan Valsartan

Sac/val Sac/val
Treatment Effect by Ejection Fraction Quartiles
Primary Composite Total HF Hospitalizations and CV Death

No. of Rate Ratio

Subgroup Events/Patients (95% CI)
Overall EF 1903/4796 0.87 (0.75–1.01)

≤50 512/1208 0.82 (0.63–1.06)

>50–57 536/1287 0.77 (0.57–1.03)
>57–63 467/1202 0.91 (0.68–1.22)
>63 388/1099 1.09 (0.80–1.47)
0.4 0.6 0.8 1 1.2 1.4 1.6

Subgroup estimates are based on re-running the primary analysis model for each of the four subgroups defined by the by LVEF quartiles. 22
Treatment Effect for HFpEF Patients with
LVEF Below Median (≤57%)
Sac/Val Valsartan Rate Ratio
Endpoint N=1239 N=1256 (95% CI) Rate Ratio (95% CI)

Primary composite endpoint 457 591 0.78 (0.64 – 0.95)

Total HF hospitalizations 332 463 0.75 (0.60 – 0.95)

CV death 125 128 0.99 (0.77 – 1.26)

Expanded composite endpoint 480 622 0.78 (0.64 – 0.94)

Total Worsening HF* 355 494 0.74 (0.60 – 0.93)

* Total worsening HF events include HF hospitalizations and urgent HF visits

0.5 0.6 0.7 0.8 0.9 1 1.1 1.3

Sac/Val Better Val Better

23
Expanded Composite Endpoint
Criteria of HF hospitalization and Urgent HF Visit

Strict CEC definition for adjudicating HF hospitalizations and Urgent HF visits, consistent with
the Standardized Data Collection for Cardiovascular Trials Initiative (SCTI) (Hicks et al
2018), all of the below required from source documentation:

Criteria HF Hospitalization Urgent HF Visit

Unplanned presentation with HF exacerbation  

Stay traversing change in calendar date  Not required

At least one symptom of worsening HF  

At least two signs of worsening HF  

Qualified treatments directed at treating HF   + must include IV HF

treatment

<<Hicks et al. Circulation 2018 137(9):961-972>>

24
 Expanded Composite Endpoint
CV Death, Total HF Hospitalizations and Urgent HF Visits
Prospectively CEC-adjudicated Pre-Specified Exploratory Endpoint

Expanded composite endpoint includes 95 additional events (40 events in sacubitril/valsartan and 55 events
in valsartan)
Sacubitril/Valsartan Valsartan Rate Ratio/ P-Value
N=2407 N=2389 Hazard Ratio (2-sided)
(95% CI)
n Rate per 100 pt yr n Rate per 100 pt yr
(95% CI) (95% CI)
CEC-confirmed 12.8 14.6 0.87
Primary Endpoint 894 1009 (0.75 –1.01)
0.059
(12.0 – 13.7) (13.7 – 15.6)
Expanded Composite 13.4 15.4 0.86
Endpoint 934 1064 (0.75 – 0.99)
0.040
(12.6 – 14.3) (14.5 – 16.4)
10.5 12.4 0.84
Total worsening HF* 730 852 (0.71 – 0.98)
0.031
(9.7 – 11.3) (11.5 – 13.2)
* Total worsening HF events include HF hospitalizations and urgent HF visits

Vaduganathan, Muthiah et al. JACC: HEART FAILURE 2021;9(5):374–82

25
Benefits of initiating sacubitril/valsartan ≤30 days after HFpEF hospitalization

 Recent HF hospitalization represents a

risk predictor of recurrent clinical events

 Patients recently hospitalized for

decompensated HFpEF may benefit
from sacubitril/valsartan to decrease the
risks of another hospitalization and CV
death.
Total HF Hospitalizations and CV Death by LVEF
(PARAGON-HF and PARADIGM-HF)

LVEF Septile Entresto Comparator Rate Ratio Rate Ratio

EAR EAR Estimate (95% CI) Estimate (95% CI)
≤ 25% 18.8 23.0 0.816 (0.684, 0.973)
>25% to ≤ 30% 14.9 20.7 0.720 (0.590, 0.878)
>30% to ≤ 33% 14.6 18.9 0.767 (0.575, 1.023)
>33% to ≤ 36% 12.9 16.7 0.759 (0.589, 0.978)
>36% to ≤ 50% 13.1 15.1 0.878 (0.708, 1.087)
>50% to ≤ 60% 12.4 15.4 0.794 (0.632, 0.996)
> 60% 13.3 11.8 1.117 (0.855, 1.458)

0.4 0.6 0.8 1 1.2 1.4 1.6

Favors Sac/Val Favors ACEi/ARB

EAR: exposure-adjusted rate

27
 Treatment Effect by LVEF and Sex
Benefit Extends to Higher LVEF in Women (PARAGON-HF and PARADIGM-HF)

Total HF Hospitalizations and CV Death

Red: women
RASi better
Blu: men

S/V better

<<Solomon et al. Circulation. 2020;141:352–361>>

28
Sacubitril/Valsartan Reduced the Risk of the Composite Renal Endpoint

Lower Incidence of ≥50% Reduction in eGFR

0.10
valsartan
sacubritril/valsartan
Proportion of Patients

0.08 Sacubitril/
Valsartan Valsartan
Composite N=2407 N=2389
n (%) n (%)
0.06
HR 0.50 (95% Cl 0.33 – 0.77), p = Composite renal endpoint 33 64
0.001 (1.4) (2.7)
0.04
(i) Renal death 1 1
(ii) Reaching ESRD 7 12
0.02
(iii) ≥50% decline in 27 60
eGFR relative to
baseline
0.00
0 1 2 3 4
Number at Risk Years
valsartan 2389 2273 2145 1033 135
2407 2320 2195 1049 129
sacubitril/valsartan

Similar effect seen in PARADIGM-HF with lower risk of the same renal composite endpoint with sacubitril/valsartan compared with enalapril
29
Change in NYHA FC and KCCQ CSS Favors
Sacubitril/Valsartan
Effect Size P-value
Sac/Val Valsartan (95% CI) (2-sided)
NYHA class favorable change at 8 months – n 2316 2302
Improved 15.0% 12.6%
Unchanged 76.3% 77.9% OR, 1.45 (1.13 – 1.86) 0.004
Worsened* 8.7% 9.6%

KCCQ clinical summary score at 8 months – n 2250 2226

LSM of change from baseline (SE) -1.5 (0.4) -2.5 (0.4) Difference, 1.0 (0.0 – 2.1) 0.051

≥5 point Improvement 33.0% 29.6% 0.019

≥5 point Deterioration 33.5% 34.5% 0.467

Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) based on the physical limitation and total symptom score domains
LSM: least square mean; OR: odds ratio
*Patients who died were included in the worsened category 30
 Safety endpoints
Adverse event Sacubitril/valsartan
(N = 2407)
Valsartan
(N = 2389)
P-value

Hypotension with SBP < 100 mm Hg 15.8% 10.8% <0.0001

Elevated serum creatinine ≥ 2.0 mg/dl 10.8% 13.7% 0.002
≥ 2.5 mg/dl 4% 4.6% 0.36
≥ 3.0 mg/dl 1.6% 1.7% 0.79
Elevated serum potassium > 5.5 mmol/liter 13.2% 15.3% 0.05
> 6.0 mmol/liter 3.1% 4.3% 0.04

Angioedema* 0.6% 0.2% 0.02

*Adjudicated
Sacubitril/valsartan is ONLY indicated in adult patients for treatment of symptomatic chronic heart failure with reduced ejection fraction.
Sacubitril/valsartan is NOT APPROVED for treatment of HF patients with mid-range or preserved ejection fraction.
 From: COVID-19 and Heart Failure With Preserved Ejection Fraction

JAMA. 2020;324(15):1499-1500. doi:10.1001/jama.2020.17445

Figure Legend:
The Potential Intersection of Acute and Chronic Phases of COVID-19 and Risk of Heart Failure With Preserved Ejection
FractionCOVID-19 indicates coronavirus disease 2019; LDH, lactate dehydrogenase; PAI-1, plasminogen activator inhibitor 1; TNF,
tumor necrosis factor.

Date of download: Copyright © 2012 American Medical

mm/dd/yyyy Association. All rights reserved.
 Take Home Massage
• HFpEF have a similar outcome compare to HFrEF, worst outcome in SEA patients especially in
Indonesia (younger but sicker!)
• Both ACC/AHA and ESC recommend screening for, and treatment of, aetiologies, and
cardiovascular and non-cardiovascular comorbidities , with no specific treatment (“one pill for all”)
• ARNI despite narrowly missing statistical significance for primary endpoint, we observed

– a ~13% reduction in the primary outcome overall, which was driven mainly by a
reduction in first and recurrent HF hospitalizations

– Secondary efficacy endpoints (NYHA, KCCQ and renal composite endpoint) consistently
favor sacubitril/valsartan

– greater benefit in women and in individuals with lower LVEF

• Make sure ur HF patients already take the vaccine jab!

33