PARADIGM-HF: Causes of death John McMurray BHF Cardiovascular - - PowerPoint PPT Presentation

John McMurray BHF Cardiovascular Research Centre University of Glasgow Scotland 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 benefit Median 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 ± 11.3 Women (%) 21.0% 22.6% Ischemic cardiomyopathy (%) 59.9% 60.1% LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3 NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9% Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15 Heart rate (beats/min) 72 ± 12 73 ± 12 N-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 risk

Enalapril: 4212 3883 3579 2922 2123 1488 853 236 LCZ696: 4187 3922 3663 3018 2257 1544 896 249

Cumulative Proportion of Patients with Primary End Point (%) Days after Randomization 10 20 30 40 180 360 540 720 900 1080 1260 HR: 0.80 (0.73, 0.87) p = 0.0000004 1117 Enalapril (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 causes 20% risk reduction HF hospitalization 21% 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

10 20 30 40 180 360 540 720 900 1080 1260

16% risk reduction

Enalapril (n=4212) 835 LCZ696 (n=4187) 711 Days after Randomization Cumulative Proportion of Patients Who Died from Any Cause (%) HR: 0.84 (0.76, 0.93) P = 0.0009

PARADIGM-HF: cause/ mode of death

0.80 0.00004

835 693 311 184 711 558 250 147

100 200 300 400 500 600 700 800 900

0.80 0.008 0.79 0.034 0.84 < 0.001

Number

Enalapril LCZ696

HR p =

All causes CV causes Worsening HF Sudden

0.80 0.00008

Sudden death or resuscitated sudden death (RSD)

LCZ696 vs Enalapril Outcome LCZ696 n/N (%) Enalapril n/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

LCZ696 N=4187 n (%)* Enalapril N=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

• f non-cardiovascular death

LCZ696 N=4187 n (%)* Enalapril N=4212 n (%)* 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 LCZ696 n/m (%) Enalapril n/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 ≥ 75 2 4 6 8 10 12 14 Age (years) Rate per 100 patient years

CV death

< 55 55-64 65-74 ≥ 75 2 4 6 8 10 12 14 Age (years) Rate per 100 patient years

LCZ696 Enalapril

Incremental benefit

• Baseline MRA treatment
• ICD/CRT-D

PARADIGM-HF: Baseline mineralocorticoid receptor (aldosterone) antagonist (MRA) use

Cardiovascular death

HR 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 (%) Enalapril LCZ696

*Interaction p = 0.32

PARADIGM-HF: Baseline ICD/CRT-D use (post hoc analysis)

ICD - No Enalapril LCZ696 ICD - Yes

Cardiovascular death

HR 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 use No Yes 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 use No Yes 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-D No Yes 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 Placebo

SOLVD-T PARADIGM-HF imputed

LCZ696 Candesartan Placebo

CHARM-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 Favours Placebo

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 placebo from 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.