Results of PARADIGM-HF:

Biomarkers and renal function

Pardeep S Jhund BHF Cardiovascular Research Centre University of Glasgow Scotland UK

Declaration of interest Consulting: Novartis

Overview · Biomarkers – natriuretic peptides – aldosterone – hsTnT – galectin-3

· Renal – cystatin C – Renal outcomes – Renal safety

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696 LCZ696

valsartan

sacubitril

Natriuretic peptides

Angiotensin II

BK, ADM Subs-P, VIP, CGRP

• • • •

Vasodilation Natriuresis Diuresis Inhibition of pathologic growth/fibrosis

Neprilysin Degradation products

AT1Receptor • Vasoconstriction • Sodium/water retention • Fibrosis/hypertrophy

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696 LCZ696

valsartan

sacubitril

Natriuretic peptides

Angiotensin II

BK, ADM Subs-P, VIP, CGRP

• • • •

Vasodilation Natriuresis Diuresis Inhibition of pathologic growth/fibrosis

Neprilysin Degradation products

AT1Receptor • Vasoconstriction • Sodium/water retention • Fibrosis/hypertrophy

NT pro BNP and BNP Cardiomyocyte

Blood

PARADIGM-HF: NT-proBNP and BNP 500

LCZ696

1400

Enalapril

1300

450

1200

400

NT-proBNP

1000

350

900

300

800 250

700 600

200

BNP

500

150

400 300

100

200

50

100 0

0 0

2

4

Months

6

8

BNP pg/ml

NT-proBNP pg/ml

1100

Explaining the NT pro BNP and BNP changes with LCZ696 (schematic) Pro BNP/ NT proBNP

BNP Inhibition of BNP breakdown

Reduced LV wall stress PrePostLCZ696

PrePostLCZ696

PARADIGM-HF: Geometric mean urinary cyclic GMP concentration by visit Cyclic GMP is the intracellular second messenger stimulated by natriuretic peptides and other vasoactive substances including nitric oxide

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696 LCZ696

valsartan

sacubitril

Natriuretic peptides

Angiotensin II

BK, ADM Subs-P, VIP, CGRP

• • • •

Vasodilation Natriuresis Diuresis Inhibition of pathologic growth/fibrosis

Neprilysin Degradation products

AT1Receptor • Vasoconstriction • Sodium/water retention • Fibrosis/hypertrophy

6 month mortality (%)

Aldosterone 80

P0.014 µg/l) Treatment

Enalapril LCZ696

Baseline (prior to run -in)* 58.2%

Randomization

4 weeks

8 months

52.9%

58.0%

56.9%

56.0%

50.8%

48.4%

48.1%

LOD = 0.005 µg/l (5 pg/ml) LOQ = 0.013 µg/l (13 pg/ml) 99th centile = 0.0142 µg/l (14.2 pg/ml) *3.9% had values 30 ml/min/1.73m2 decline in eGFR to 5.5 mmol/l

K+ > 6.0 mmol/l

PARADIGM-HF: Renal safety by age P for interaction >0.05 for all events