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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