causes of death paradigm-hf · pdf file0 180 360 540 720 900 1080 1260 16% risk reduction...

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


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





· Secondary:







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





· Secondary:







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

Subgroups• LVEF• Age

PARADIGM-HF: Sub-group analysis (primary endpoint and CV death)

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

Incremental benefit• Baseline MRA treatment• ICD/CRT-D

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 vs.placebo?• Imputed/putative placebo analysis• Indirect comparison with placebo

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.

causes of death paradigm-hf · pdf file0 180 360 540 720 900 1080 1260 16% risk reduction...

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