PARADIGM-HF: Causes of death John McMurray BHF Cardiovascular Research Centre University of Glasgow Scotland UK
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/1.73m 2 /no decrease >25% (amended to 35%) • Potassium ≤5.2 mmol/l run-in/ ≤5.2 mmol/l at randomization Double-blind period Single-blind period LCZ696 200 mg BID (n=4187) Enalapril 5-10 mg bid LCZ 100 mg bid LCZ 200 mg bid N = 8442 (1:1 randomization) Enalapril 10 mg BID (n=4212) 1-2 weeks 1-2 weeks 2 weeks Outcome driven (CV death): Stopped early for benefit Median follow-up = 27 months Prior ACEi/ARB use discontinued
PARADIGM-HF: Baseline Characteristics LCZ696 Enalapril (n=4187) (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: 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 40 HR: 0.80 (0.73, 0.87) p = 0.0000004 1117 Cumulative Proportion of Patients Enalapril (n=4212) with Primary End Point (%) 30 914 LCZ696 (n=4187) 20 10 0 0 180 360 540 720 900 1080 1260 Days after Randomization At risk Enalapril: 4212 3883 3579 2922 2123 1488 853 236 LCZ696: 4187 3922 3663 3018 2257 1544 896 249
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 HF hospitalization 20% risk reduction 21% risk reduction P = 0.00008 P = 0.00008 693 658 558 537 McMurray, Packer et al NEJM 2014
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 16% risk reduction 40 HR: 0.84 (0.76, 0.93) Cumulative Proportion of Patients P = 0.0009 Who Died from Any Cause (%) 30 835 Enalapril (n=4212) 711 20 LCZ696 (n=4187) 10 0 0 180 360 540 720 900 1080 1260 Days after Randomization
PARADIGM-HF: cause/ mode of death All causes CV causes Sudden Worsening HF 900 835 800 Enalapril 711 693 700 LCZ696 558 600 Number 500 400 311 250 300 184 147 200 100 0 0.84 0.80 0.80 HR 0.80 0.79 < 0.001 0.00004 0.00008 p = 0.008 0.034
Sudden death or resuscitated sudden death (RSD) LCZ696 vs Enalapril Outcome LCZ696 Enalapril Hazard P-value n/N (%) n/N (%) ratio (2-sided) (95% CI) Sudden death or 1 st 266/4187 338/4212 0.78 0.0025 RSD (6.35) (8.02) ( 0.66, 0.92) Sudden death* 250/4187 311/4212 0.80 0.0082 (5.97) (7.38) ( 0.68, 0.94) 1 st RSD 16/4187 28/4212 0.56 0.0681 (0.38) (0.66) ( 0.31, 1.04) *Last contact: <1 hour 167 vs. 213 1-24 hours 83 vs. 98
PARADIGM-HF: Adjudicated causes of cardiovascular death LCZ696 Enalapril N=4187 N=4212 n (%)* 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 LCZ696 Enalapril N=4187 N=4212 n (%)* 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) Cardiovascular death LVEF LCZ696 Enalapril Hazard ratio tertile n/m (%) n/m (%) (95% CI) LCZ696 vs. enalapril Tertile 1 (<28%) 212/1349 438/1432 0.82 (15.7) (19.0) (0.68,0.98) Tertile 2 (28- <33%) 156/1274 313/1221 0.76 (12.2) (16.2) (0.62,0.94) Tertile 3 (≥33%) 190/1564 366/1558 0.83 (12.2) (14.3) (0.68,1.00) Subgroup by treatment interaction p=0.83
PARADIGM-HF: Effect of LCZ696 according to age category LCZ696 Enalapril 14 CV death 14 All-cause death 12 12 Rate per 100 patient years Rate per 100 patient years 10 10 8 8 6 6 4 4 2 2 0 0 < 55 55-64 65-74 ≥ 75 < 55 55-64 65-74 ≥ 75 Age (years) Age (years)
Incremental benefit • Baseline MRA treatment • ICD/CRT-D
PARADIGM-HF: Baseline mineralocorticoid receptor (aldosterone) antagonist (MRA) use Enalapril Cardiovascular death LCZ696 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 - Yes MRA - No *Interaction p = 0.32
PARADIGM-HF: Baseline ICD/CRT-D use (post hoc analysis) Enalapril Cardiovascular death (%) LCZ696 HR 0.80 (0.71, 0.89); p <0.0001 HR 0.80 (0.71, 0.90)* HR 0.76 (0.55, 1.05)* ICD - Yes ICD - No *Interaction p = 0.92
PARADIGM-HF: Incremental benefit of LCZ696 on CV death Enalapril n/N LCZ696 HR Interaction (%) n/N (%) (95% CI) p-value Beta-blocker target dose* ≥50% 266/1848 (14.4) 249/1919 (13.0) 0.89 (0.75,1.05) <50% 338/2027 (16.7) 266/1948 (13.7) 0.81 (0.69,0.96) 0.49 MRA use No 304/1812 (16.8) 234/1916 (12.7) 0.75 (0.63,0.89) Yes 389/2400 (16.2) 315/2271 (13.9) 0.84 (0.74,0.97) 0.32 Digoxin use No 431/2896 (14.9) 370/2964 (12.5) 0.82 (0.72,0.95) Yes 262/1316 (19.9) 188/1223 (15.4) 0.76 (0.63,0.92) 0.54 ICD/CRT-D No 609/3592 (17.0) 491/3564 (13.8) 0.80 (0.71,0.90) Yes 84/620 (13.6) 67/623 (10.8) 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
Imputed placebo analysis - comparison network LCZ696 PARADIGM-HF imputed SOLVD-T Enalapril Placebo SOLVD-T LCZ696 PARADIGM-HF imputed CHARM- Alternative Candesartan Placebo CHARM-Alternative
CV mortality in SOLVD-T, CHARM- Alternative and PARADIGM-HF Hazard Ratio for Mortality HR: 0.83 (0.73,0.95) SOLVD-T p = 0.008 HR: 0.85 (0.71,1.02) CHARM-Alt. p = 0.072 PARADIGM-HF imputed placebo HR: 0.66 (0.56,0.79) from SOLVD-T p < 0.0001 HR: 0.68 (0.55,0.84) from CHARM-Alt. p < 0.0001 0.5 1 2 Favours Favours Active Drug Placebo
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.
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