Biomarkers and renal function Pardeep S Jhund BHF Cardiovascular - - PowerPoint PPT Presentation

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

Results of PARADIGM-HF:

Biomarkers and renal function

Declaration of interest

Consulting: Novartis

Overview

· Biomarkers

– natriuretic peptides – aldosterone – hsTnT – galectin-3

· Renal

– cystatin C – Renal outcomes – Renal safety

Natriuretic peptides

BK, ADM

Subs-P, VIP, CGRP

Angiotensin II

• Vasoconstriction
• Sodium/water retention
• Fibrosis/hypertrophy

Degradation products

Neprilysin AT1Receptor

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696

• Vasodilation
• Natriuresis
• Diuresis
• Inhibition of pathologic

growth/fibrosis

LCZ696

sacubitril valsartan

Natriuretic peptides

BK, ADM

Subs-P, VIP, CGRP

Angiotensin II

• Vasoconstriction
• Sodium/water retention
• Fibrosis/hypertrophy

Degradation products

Neprilysin AT1Receptor

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696

• Vasodilation
• Natriuresis
• Diuresis
• Inhibition of pathologic

growth/fibrosis

LCZ696

sacubitril valsartan

NT pro BNP and BNP

Cardiomyocyte Blood

PARADIGM-HF: NT-proBNP and BNP

2 4 6 8 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 50 100 150 200 250 300 350 400 450 500

NT-proBNP pg/ml Months BNP pg/ml

LCZ696 Enalapril

NT-proBNP BNP

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

Pro BNP/ NT proBNP

Pre- Post- Pre- Post-

BNP

Inhibition

• f BNP

breakdown Reduced LV wall stress LCZ696 LCZ696

PARADIGM-HF: PARADIGM-HF: Geometric mean urinary Geometric mean urinary cyclic GMP concentration cyclic GMP concentration by visit by visit

Cyclic GMP is the intracellular second messenger stimulated by natriuretic peptides and other vasoactive substances including nitric oxide

Natriuretic peptides

BK, ADM

Subs-P, VIP, CGRP

Angiotensin II

• Vasoconstriction
• Sodium/water retention
• Fibrosis/hypertrophy

Degradation products

Neprilysin AT1Receptor

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696

• Vasodilation
• Natriuresis
• Diuresis
• Inhibition of pathologic

growth/fibrosis

LCZ696

sacubitril valsartan

Aldosterone

6 month mortality (%) 80 60 40 20

Below median Above median

Plasma aldosterone

P<0.001

CONSENSUS

• Circulation. 1990;82:1730-1736

Raised plasma aldosterone is associated with higher mortality

• Circulation. 2003;108:1306-1309

Val-HeFT

Valsartan reduces aldosterone levels

100 120 140 160 180 200 220 240 260 280 300

LCZ696 Enalapril

Plasma aldosetrone (pmol/L)

Randomization 1 month 8 months Prior to Run-in

* *

* p<0.05

PARADIGM-HF: Aldosterone

2-4 wk enalapril then 3 –6 wk LCZ696 both arms

Troponin and prognosis in HFREF

6 12 18 24 0.1 0.2 0.3 0.4 0.5 Months Q4 Q3 Q2 Q1 Cumulative mortality

Val-HeFT

HR per 0.05ng/mL increase 1.20 (95% CI 1.10-1.30)

• Circulation. 2007;116:1242-1249

PARADIGM-HF: median hs-TnT (µg/l) concentration by visit

4 weeks 8 months Random- ization Prior to Run-in

Randomization

PARADIGM-HF: hs-TnT (µg/l) by visit

Treatment Baseline (prior to run

• in)*

Random- ization 4 weeks 8 months Enalapril 58.2% 52.9% 58.0% 56.9% LCZ696 56.0% 50.8% 48.4% 48.1%

hs-TnT: % of patients >99th centile (>0.014 µg/l)

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 <LOD at baseline

PARADIGM-HF: Galectin-3 by visit

2 4 6 8 10 12 14 16 18 20

LCZ696 Enalapril ng/ml

Randomization 1 month 8 months Prior to Run-in 2-4 wk enalapril then 3 –6 wk LCZ696 both arms

Renal biomarkers and

• utcomes

Cystatin C

· Cysteine protease inhibitor · Less influenced by age, sex, or race · Low molecular weight · Freely filtered and neither secreted nor reabsorbed

Circulation: Heart Failure. 2012; 5: 602-609

· Sensitive measure of glomerular filtration · Higher levels associated with poorer prognosis

PARADIGM-HF: Cystatin C

1.06 1.08 1.1 1.12 1.14 1.16 1.18 1.2 1.22 LCZ696 Enalapril

Randomization 1 month 8 months Prior to Run-in

mg/L

2-4 wk enalapril then 3 –6 wk LCZ696 both arms

Renal Outcomes

Renal progression: Protocol-defined endpoint

Endpoint LCZ696 n/N (%) Enalapril n/N (%) Hazard Ratio (95% CI) P- value 1-sided Composite 94/4187 (2.2) 108/4212 (2.6) 0.86 (0.65, 1.13) 0.1424 (i) 50% decline in eGFR 32/4187 (0.8) 42/4212 (1.0) 0.75 (0.47, 1.19) 0.1118 (ii) >30 ml/min/1.73m2 decline in eGFR to <60 ml/min/1.73m2 77/4187 (1.8) 69/4212 (1.6) 1.11 (0.80, 1.53) 0.7283 (iii) Reaching ESRD 8/4187 (0.2) 16/4212 (0.4) 0.50 (0.21, 1.16) 0.0529

Renal progression: Conventional renal endpoint (post-hoc analysis)

Post-hoc analysis – based on conventional endpoint for renal disease progression (50% decline in eGFR or reaching ESRD) Endpoint LCZ696 n/N (%) Enalapril n/N (%) Hazard Ratio (95% CI) P Value 2-sided Composite 37/4187 (0.9) 58/4212 (1.4) 0.63 (0.42, 0.95) 0.0276 (i) 50% decline in eGFR 32/4187 (0.8) 42/4212 (1.0) 0.75 (0.47, 1.19) 0.2236 (iii) Reaching ESRD 8/4187 (0.2) 16/4212 (0.4) 0.50 (0.21, 1.16) 0.1057

Safety

“With regard to healing the sick, ……… I will take care that they suffer no hurt or damage” Hippocratic Oath

PARADIGM-HF: Adverse events leading to permanent study drug discontinuation

Hypotension p = 0.38

2 4 6 8 10 12 14

Renal reasons p = 0.002 Hyperkalaemia p = 0.56 Any adverse event p = 0.03

(%) Enalapril LCZ696

29

29

36 59 29 15 11 516 449

PARADIGM-HF: Renal safety

5 2 18 6 3 1.5 16 4 Cr ≥ 2.5 mg/dl Cr ≥ 3.0 mg/dl K+ > 5.5 mmol/l K+ > 6.0 mmol/l 5 10 15 20 (%) Enalapril LCZ696

P=0.007 P=0.10 P=0.15 P=0.007 (221 µmol/L) (265 µmol/L)

<55 years 55-64 years 65-74 years ≥75 years

P for interaction >0.05 for all events

PARADIGM-HF: Renal safety by age

Summary

Treatment with LCZ696 led to: · Lower NT-proBNP and higher BNP levels · Lower troponin · No change in galectin-3 and cystatin C · No difference in rates of the composite renal

• utcome though reduction in 50% decline

eGFR/ESRD · Less renal adverse events, even in the elderly

Thank you