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John McMurrayBHF Cardiovascular Research Centre
University of GlasgowScotland
UK
PARADIGM-HF: Causes of death
LCZ696 200 mg BID (n=4187)
Enalapril 10 mg BID (n=4212)
Outcome driven (CV death): Stopped early for benefitMedian follow-up = 27 months
1-2 weeks
Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid
1-2 weeks 2 weeks
Prior ACEi/ARB use discontinued
Single-blind period Double-blind period
N = 8442 (1:1 randomization)
PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
• Age ≥18 years. NYHA class II-IV. LVEF ≤0.40 (amended to ≤0.35). • BNP ≥150 pg/ml (NTpro-BNP ≥600 pg/ml) or if HF hosp. within12 mo. BNP
≥100 pg/ml (NTpro-BNP ≥400 pg/ml) • Background RAS blocker therapy equivalent to enalapril ≥10 mg/d• Beta-blocker and MRA as recommended by guidelines• SBP ≥100 mmHg run-in/ ≥95 mmHg at randomization• eGFR ≥30 ml/min/1.73m2 /no decrease >25% (amended to 35%) • Potassium ≤5.2 mmol/l run-in/ ≤5.2 mmol/l at randomization
LCZ696(n=4187)
Enalapril(n=4212)
Age (years) 63.8 ± 11.5 63.8 ± 11.3Women (%) 21.0% 22.6%Ischemic cardiomyopathy (%) 59.9% 60.1%LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9%Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15Heart rate (beats/min) 72 ± 12 73 ± 12N-terminal pro-BNP (pg/ml) 1631 (885-3154) 1594 (886-3305)B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)History of diabetes 35% 35%Digitalis 29.3% 31.2%Beta-adrenergic blockers 93.1% 92.9%Mineralocorticoid antagonists 54.2% 57.0%CRT 7.0% 6.7%ICD 15% 15%
PARADIGM-HF: Baseline Characteristics
PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function
PARADIGM-HF: Primary outcome Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
At riskEnalapril: 4212 3883 3579 2922 2123 1488 853 236
LCZ696: 4187 3922 3663 3018 2257 1544 896 249
Cum
ulative Propo
rtion
of P
atients
with
Prim
ary End
Point (%
)
Days after Randomization
0
10
20
30
40
0 180 360 540 720 900 1080 1260
HR: 0.80 (0.73, 0.87)p = 0.0000004 1117Enalapril
(n=4212)
LCZ696(n=4187)
914
PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function
PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
Death from CV causes20% risk reduction
HF hospitalization21% risk reduction
693
558
658
537
McMurray, Packer et al NEJM 2014
P = 0.00008 P = 0.00008
PARADIGM-HF: Pre-specified endpoints
· Primary: Cardiovascular death or heart failure hospitalization
– Cardiovascular death
– Heart failure hospitalization
· Secondary:
– Death from any cause
– KCCQ (CSS - symptoms and physical limitations)
– New onset atrial fibrillation
– Decline in renal function
PARADIGM-HF Prospective comparison of ARNI with ACEI to Determine Impact on
Global Mortality and morbidity in Heart Failure trial
Death from any cause
0
10
20
30
40
0 180 360 540 720 900 1080 1260
16% risk reduction
Enalapril(n=4212)
835
LCZ696(n=4187)
711
Days after Randomization
Cum
ulative Propo
rtion
of P
atients
Who
Died fro
m Any
Cau
se (%
)
HR: 0.84 (0.76, 0.93)P = 0.0009
PARADIGM-HF: cause/mode of death
0.800.00004
835
693
311
184
711
558
250147
0100200300400
500600700800900
0.800.008
0.790.034
0.84< 0.001
Num
ber
EnalaprilLCZ696
HRp =
All causes CV causes Worsening HFSudden
0.800.00008
Sudden death or resuscitated sudden death (RSD)
LCZ696 vs Enalapril
Outcome LCZ696n/N (%)
Enalapriln/N (%)
Hazard ratio
(95% CI)
P-value(2-sided)
Sudden death or 1st RSD
266/4187 (6.35)
338/4212 (8.02)
0.78( 0.66, 0.92)
0.0025
Sudden death* 250/4187 (5.97)
311/4212 (7.38)
0.80( 0.68, 0.94)
0.0082
1st RSD 16/4187 (0.38)
28/4212 (0.66)
0.56( 0.31, 1.04)
0.0681
*Last contact: <1 hour 167 vs. 213 1-24 hours 83 vs. 98
PARADIGM-HF: Adjudicated causes of cardiovascular death
LCZ696N=4187 n (%)*
EnalaprilN=4212 n (%)*
Number of patients who died 711 (100) 835 (100)Cardiovascular death 558 (78.5) 693 (83.0)
Pump failure 147 (20.7) 184 (22.0)Sudden death 250 (35.2) 311 (37.2)Presumed sudden death 26 (3.7) 23 (2.8)Myocardial infarction 24 (3.4) 33 (4.0)Stroke 30 (4.2) 34 (4.1)Presumed CV Death 67 (9.4) 95 (11.4)Other causes 14 (2.0) 13 (1.6)
* % of all deaths
PARADIGM-HF: Adjudicated causes of non-cardiovascular death
LCZ696N=4187n (%)*
EnalaprilN=4212n (%)*
Number of patients who died 711 (100) 835 (100)Non-Cardiovascular death 120 (16.9) 109 (13.1)
Infection 36 (5.1) 34 (4.1)Malignancy 41 (5.8) 41 (4.9)Gastrointestinal 16 (2.3) 9 (1.1)Accidental 13 (1.8) 6 (0.7)Pulmonary 7 (1.0) 13 (1.6)Renal 1 (0.1) 1 (0.1)Other Non-CV 6 (0.8) 5 (0.6)
Unknown 33 (4.6) 33 (4.0)* % of all deaths
PARADIGM-HF: Subgroup analysis according to baseline LVEF (tertiles)
LVEF tertile
LCZ696n/m (%)
Enalapriln/m (%)
Hazard ratio(95% CI)
LCZ696 vs.enalapril
Tertile 1 (<28%) 212/1349 (15.7)
438/1432 (19.0)
0.82(0.68,0.98)
Tertile 2 (28- <33%) 156/1274(12.2)
313/1221 (16.2)
0.76 (0.62,0.94)
Tertile 3 (≥33%) 190/1564 (12.2)
366/1558(14.3)
0.83(0.68,1.00)
Subgroup by treatment interaction p=0.83
Cardiovascular death
PARADIGM-HF: Effect of LCZ696 according to age category
All-cause death
< 55 55-64 65-74 ≥ 750
2
4
6
8
10
12
14
Age (years)
Rate
per
100
pat
i ent
yea
rs
CV death
< 55 55-64 65-74 ≥ 750
2
4
6
8
10
12
14
Age (years)
Rate
per
100
pat
ient
yea
r s
LCZ696Enalapril
PARADIGM-HF: Baseline mineralocorticoid receptor (aldosterone) antagonist (MRA) use
Cardiovascular deathHR 0.80 (0.71, 0.89); p <0.0001
HR 0.75 (0.63, 0.89)* HR 0.84 (0.73, 0.98)*
MRA - No MRA - Yes
(%)
EnalaprilLCZ696
*Interaction p = 0.32
PARADIGM-HF: Baseline ICD/CRT-D use(post hoc analysis)
ICD - No
EnalaprilLCZ696
ICD - Yes
Cardiovascular deathHR 0.80 (0.71, 0.89); p <0.0001
HR 0.80 (0.71, 0.90)* HR 0.76 (0.55, 1.05)*
*Interaction p = 0.92
(%)
PARADIGM-HF: Incremental benefit of LCZ696 on CV death
Enalapril n/N
(%)
LCZ696
n/N (%)
HR
(95% CI)
Interaction
p-value
Beta-blocker target dose*≥50%<50%
266/1848 (14.4)338/2027 (16.7)
249/1919 (13.0)266/1948 (13.7)
0.89 (0.75,1.05)0.81 (0.69,0.96)
0.49 MRA useNoYes
304/1812 (16.8)389/2400 (16.2)
234/1916 (12.7)315/2271 (13.9)
0.75 (0.63,0.89)0.84 (0.74,0.97)
0.32
Digoxin useNoYes
431/2896 (14.9)262/1316 (19.9)
370/2964 (12.5)188/1223 (15.4)
0.82 (0.72,0.95)0.76 (0.63,0.92)
0.54
ICD/CRT-DNoYes
609/3592 (17.0)84/620 (13.6)
491/3564 (13.8)67/623 (10.8)
0.80 (0.71,0.90)0.76 (0.55,1.05)
0.92
* Among 588 patients (7.0%) not taking beta-blockers, enalapril:LCZ696 HR 0.47 (0.32,0.69)
LCZ696
Enalapril PlaceboSOLVD-T
PARADIGM-HF imputed
LCZ696
Candesartan PlaceboCHARM-Alternative
PARADIGM-HF imputed
SOLVD-T
CHARM-Alternative
Imputed placebo analysis - comparison network
CV mortality in SOLVD-T, CHARM-Alternative and PARADIGM-HF
Hazard Ratio for Mortality
Favours Active Drug
FavoursPlacebo
HR: 0.83 (0.73,0.95)p = 0.008
HR: 0.85 (0.71,1.02)p = 0.072
HR: 0.66 (0.56,0.79)p < 0.0001
0.5 1 2
SOLVD-T
CHARM-Alt.
PARADIGM-HF imputed placebofrom SOLVD-T
from CHARM-Alt. HR: 0.68 (0.55,0.84)p < 0.0001
PARADIGM-HF: Summary of causes of death
· In PARADIGM-HF, most deaths were cardiovascular (78% in enalapril group).
· Among cardiovascular deaths, more were sudden (45% of CV deaths in the enalapril group) than due to worsening pump failure (27%).
· Compared with enalapril, LCZ696 reduced cardiovascular death by 20% (558 vs 693 deaths).
· There were fewer non-CV deaths in the LCZ696 group (109 vs. 120 in the enalapril group).
· Compared with enalapril, LCZ696 reduced death from any cause by 16% (558 vs 693 deaths).
· The mortality benefit of LCZ696 over enalapril was consistent across all sub-groups.