Pardeep S JhundBHF Cardiovascular Research Centre

University of GlasgowScotland

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 peptidesBK, ADM

Subs-P, VIP, CGRPAngiotensin II

• Vasoconstriction• Sodium/water retention• Fibrosis/hypertrophyDegradation

products

Neprilysin AT1Receptor

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696

• Vasodilation• Natriuresis• Diuresis• Inhibition of pathologic

growth/fibrosis

LCZ696

sacubitril valsartan

Natriuretic peptidesBK, ADM

Subs-P, VIP, CGRPAngiotensin II

• Vasoconstriction• Sodium/water retention• Fibrosis/hypertrophyDegradation

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

0 2 4 6 80

100200300400500600700800900

10001100120013001400

0

50

100

150

200

250

300

350

400

450

500N

T-pr

oBN

P p

g/m

l

Months

BN

P p

g/m

l

LCZ696Enalapril

NT-proBNP

BNP

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

Pro BNP/NT proBNP

Pre- Post- Pre- Post-

BNP

Inhibition of 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 visitby visit

Cyclic GMP is the intracellular second messenger stimulated by natriuretic peptides and other vasoactive

substances including nitric oxide

Natriuretic peptidesBK, ADM

Subs-P, VIP, CGRPAngiotensin II

• Vasoconstriction• Sodium/water retention• Fibrosis/hypertrophyDegradation

products

Neprilysin AT1Receptor

Angiotensin Receptor Neprilysin Inhibition (ARNI): LCZ696

• Vasodilation• Natriuresis• Diuresis• Inhibition of pathologic

growth/fibrosis

LCZ696

sacubitril valsartan

Aldosterone6

mon

th m

orta

lity

(%) 80

60

40

20

0Below median

Abovemedian

Plasma aldosterone

P<0.001

CONSENSUS

Circulation. 1990;82:1730-1736

Raised plasma aldosteroneis associated with higher mortality

Circulation. 2003;108:1306-1309

Val-HeFTValsartan reduces aldosterone levels

100

120

140

160

180

200

220

240

260

280

300

LCZ696

EnalaprilPlas

ma

aldo

setr

one

(pm

ol/L

)

Randomization 1 month 8 monthsPrior 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 18 240

0.1

0.2

0.3

0.4

0.5

Months

Q4

Q3

Q2Q1C

umul

ativ

e m

orta

lityVal-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 monthsRandom-ization

Prior toRun-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

0

2

4

6

8

10

12

14

16

18

20

LCZ696Enalapril

ng/m

l

Randomization 1 month 8 monthsPrior to Run-in

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

Renal biomarkers and outcomes

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

LCZ696Enalapril

Randomization 1 month 8 monthsPrior to Run-in

mg/

L

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

Renal Outcomes

Renal progression: Protocol-defined endpoint

EndpointLCZ696n/N (%)

Enalapril n/N (%)

Hazard Ratio

(95% CI)P- value1-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 LCZ696n/N (%)

Enalapril n/N (%)

Hazard Ratio (95% CI)

P Value2-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

Hypotensionp = 0.38

0

2

4

6

8

10

12

14

Renal reasonsp = 0.002

Hyperkalaemiap = 0.56

Any adverse event p = 0.03

(%) Enalapril LCZ696

2929

3659

29 15 11

516

449

PARADIGM-HF: Renal safety

52

18

63

1.5

16

4

Cr ≥ 2.5 mg/dl

Cr ≥ 3.0 mg/dl

K+ > 5.5 mmol/l

K+ > 6.0 mmol/l

0

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 outcome though reduction in 50% decline eGFR/ESRD

· Less renal adverse events, even in the elderly

Thank you