Prospective Study of Biomarkers, Symptom Improvement and Ventricular

Remodeling During Entresto Therapy for Heart Failure

(PROVE-HF; NCT02887183)

Improvement of Health Status Following

Initiation of Sacubitril/Valsartan in Patients With
Heart Failure and Reduced Ejection Fraction
Ileana L. Piña MD MPH1, Alexander Camacho PhD2, Nasrien Ibrahim MD2, G.
Michael Felker MD MHS3, Javed Butler MD MPH MBA4, Alan S. Maisel MD5,
Margaret F. Prescott PhD6, Kristin M. Williamson PharmD6, Scott D. Solomon
MD7, James L. Januzzi MD2,8, on behalf of the PROVE-HF Investigators
1
Wayne State Medical School, Detroit MI; 2Massachusetts General Hospital, Boston, MA;
3
Duke University Medical Center and Duke Clinical Research Institute, Durham, NC;
4
University of Mississippi Medical Center, Jackson, MS; 5University of California, San Diego
School of Medicine, San Diego, CA; 6Novartis Pharmaceuticals, East Hanover, NJ; 7Brigham
and Women’s Hospital, Boston, MA; 8Baim Institute for Clinical Research, Boston, MA, USA
1
 Disclosures

• The PROVE-HF Study was Sponsored by Novartis Pharmaceuticals, Inc.

• Dr. Pina reports consulting income from Relypsa and Novartis.

• Dr. Felker has received research grants from NHLBI, American Heart Association, Amgen, Merck, Cytokinetics, and Roche Diagnostics;
he has acted as a consultant to Novartis, Amgen, BMS, Medtronic, Cardionomic, Relypsa, V-Wave, Myokardia, Innolife, EBR Systems,
Arena, Abbott, Sphingotec, Roche Diagnostics, Alnylam, LivaNova, and SC Pharma.

• Dr. Butler has received research support from the NIH, PCORI, and the European Union. He serves as a consultant for Abbott,
Adrenomed, Amgen, Array, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squib, CVRx, G3 Pharmaceutical, Innolife,
Janssen, LinaNova, Luitpold, Medtronic, Merck, Novartis, NovoNordisk, Relypsa, Roche, Sanofi, V-Wave Limited, and Vifor. 

• Dr. Maisel has received consulting income from Abbott Vascular, Ortho Clinical Diagnostics and Novartis.

• Dr. Prescott and Dr. Williamson are employees of Novartis Pharmaceuticals, Inc.
• Dr. Solomon has received research grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos,
Gilead, GSK, Ionis, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Novartis, Sanofi Pasteur, Theracos,  and has consulted for
Akros, Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardior, Corvia, Cytokinetics, Gilead, GSK, Ironwood, Merck, Myokardia,  Novartis,
Roche, Takeda, Theracos, Quantum Genetics,  Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya.

• Dr. Januzzi is a Trustee of the American College of Cardiology, is a Board member of Imbria Pharmaceuticals, has received grant
support from Novartis, Roche Diagnostics, Abbott, Singulex and Prevencio, and consulting income from Abbott, Janssen, Novartis,
Pfizer, Merck, and Roche Diagnostics.
2
 Introduction

• Studies suggest that sacubitril/valsartan (S/V) leads to significant decreases in N-

terminal pro-B type natriuretic peptide (NT-proBNP) and improvements in Clinical (CS)
and Overall Summary (OS) scores of the Kansas City Cardiomyopathy Questionnaire
(KCCQ)
– A link between the timing and extent of changes in circulating levels of NT-proBNP and KCCQ scores has
not been clearly established

• In the PROVE-HF Study1, patients with heart failure with reduced ejection fraction
(HFrEF) were treated with S/V. Comprehensive KCCQ data was collected following
initiation and through 12 months of treatment

• A pre-specified endpoint of the PROVE-HF Study was to evaluate change in KCCQ

scores following initiation of sacubitril/valsartan

1. Januzzi JL, et al. JAMA 2019; 322(11):1085–1095. 3

 Methods
• Change in Overall Summary (OS) score
among all subjects during course of
PROVE-HF was evaluated
• Parallel Process Latent Growth Curve
Models were used to evaluate associations
between rate of changes in KCCQ Total
Symptom (TS), Clinical Summary (CS),
and Overall Summary (OS) scores and
circulating NT-proBNP concentrations over
a 12-month period
• A total of 681 patients had data for all
time points; missing values (<5%) were
replaced with the cohort mean before
modeling
• KCCQ Scores Analyzed:
– Total Symptom (TS) Score (frequency,
burden)
– Clinical Summary (CS) Score (total
symptom and physical function)
– Overall Summary (OS) Score (total
symptom, physical function, social
limitations,QOL) 
4
 Results: Patient Characteristics
Complete KCCQ Cohort Main PROVE-HF Cohort
Characteristic
(N=681) (N=794)
Age, years; median (IQR) 65.0 (57.0,74.0) 66.0 (57.0, 74.0)
Black race 156 (22.9%) 180 (22.7%)
NYHA symptom severity    
II 496 (72.8%) 558 (70.3%)
III 175 (25.7%) 222 (27.9%)
IV 10 (1.5%) 14 (1.8%)
Medical history     Patients with complete
Diabetes 309 (45.4%) 361 (45.5%) KCCQ data were similar
Hypertension 597 (87.7%) 699 (88.0%) to the PROVE-HF study
Myocardial Infarction 279 (41.0%) 329 (41.4%) participants as a whole
Atrial Fibrillation/Atrial Flutter 240 (35.2%) 280 (35.3%)
New-onset HF and/or ACEi/ARB naïve 99 (14.5%) 118 (14.9%)
BNP/NT-proBNP <PARADIGM inclusion 269 (39.5%) 292 (36.7%)
Baseline NT-proBNP, pg/mL; median, IQR 780 (329, 1754) 816 (332, 1822)
LVEF, %; median (IQR) 28.3 (23.8, 32.8) 28.2 (24.5, 32.7)
Kansas City Cardiomyopathy Questionnaire    
Total Symptom Score 75.0 75.0
Clinical Summary Score 71.9 64.8
Overall Summary Score 67.0 69.8

IQR denotes: interquartile range; ACEi denotes: angiotensin converting enzyme inhibitor; ARB denotes: angiotensin II receptor blocker; BNP denotes: B-type natriuretic peptide; NT-proBNP denotes: N-terminal pro-BNP; LVEF denotes: left ventricular ejection fraction 5
 Complete PROVE-HF Cohort:
Rapid and Substantial Change in KCCQ Overall Score

80
Δ from BL: 5.98* 7.53* 9.09* 9.01* 9.39* 9.34* 9.32*
(25th, 75th) (-0.50, 12.5) (-0.60, 16.10) (0.00, 17.7) (-0.50, 19.0) (0.00, 19.7) (0.00, 20.30) (-0.30, 20.8)
KCCQ-23 Overall Summary Score

*P <.001
75

70

65

Baseline Day 14 Day 30 Month 2 Month 3 Month 6 Month 9 Month 12

Visit
Total N 756 749 742 697 715 705 655 640
6
 Complete PROVE-HF Cohort:
Change of Clinical Score in Pre-specified Subgroups
Improvement in KCCQ CS* by 12 months was similar in pre-specified sub-groups

New-onset HF/ACEi-ARB naïve? BNP/NT-proBNP <PARADIGM IC? Not reaching target S/V dose?
8 8 8

Change in CS from baseline to 12-months

Change in CS from baseline to 12-months

Change in CS from baseline to 12-months

7 7 7

6 6 6

5 5 5

4 4 4

3 3 3

2 2 2

1 1 1

0 0 0
Yes No Yes No Yes No
(n=112) (n=644) (n=280) (n=446) (n=266) (n=490)

*CS: KCCQ-23 Clinical Summary Score 7

 KCCQ in Patients With
Complete Data (n=681)

80.0

77.5

75.0
Value

72.5

70.0

67.5
KCCQ Scores
Total Symptom Score
65.0
Overall Summary Score
Clinical Summary Score

Baseline 14 days 30 days 2 months 3 months 6 months 9 months 12 months

Total Symptom Score 75 79.2 83.3 83.3 84.4 85.4 83.3 85.4
Clinical Summary Score 71.9 76 78.1 80.2 80.2 81.2 80.7 81.3
Overall Summary Score 67 72.7 74.5 77.6 78.1 78.9 78.9 79.2
8
 Parallel Rates of Change

• Latent intercepts
7 – NT-proBNP: 706 pg/mL
– KCCQ CS: 70.19
6
– KCCQ OS: 65.79
5 – KCCQ TS: 72.28
• Latent Slopes
Natural log scale

4
– KCCQ CS: 5.41
3 – KCCQ OS: 6.92
– KCCQ TS: 6.51
2
• Correlations Between Slopes
1
KCCQ: 95% CI (Lower) KCCQ: Average KCCQ: 95% CI (Upper)
– NT-proBNP and TS: r = -0.51; P<.001
NT-proBNP: 95% CI (Lower) NT-proBNP: Average NT-proBNP: 95% CI (Upper)
– NT-proBNP and CS: r = -0.70; P<.001
0
Baseline Month 3 Month 6 Month 9 Month 12 – NT-proBNP and OS: r = -0.08; P<.001
Study visit

9
 Conclusions

• Following initiation of S/V, improvement in KCCQ

KCCQ Overall Score
scores occurred early (within 2 weeks) and were
Baseline versus 12 months
statistically significant over a 12-month follow-up
100
– Average change >5 point increase every 90 days 90

• Changes in KCCQ summary scores inversely 80

associated with changes in circulating NT- 70

KCCQ Score
proBNP concentrations 60

50
– Rate of change in KCCQ TS and CS scores was related to
40
the rate of change in circulating NT-proBNP
30
• For some patients, there may be a lag effect 20
between changes in NT-proBNP and changes in 10
KCCQ summary scores 0

• Further analyses regarding changes in health Patient

status relative to LV remodeling will be explored Baseline Visit 10

10