Understanding the early mortality benefit observed in the PARADIGM-HF trial: considerations for the management of heart failure with sacubitril/valsartan

Figures & data

Table 1 Morbidity and mortality benefits of pharmacologic therapies for heart failure

Pharmacological therapy	Mortality endpoint	Other key endpoints
β-blockers
Carvedilol vs placebo^Citation11	RR, 0.35; 95% CI, 0.20–0.61; P<0.001	Mortality or hospitalization for CV disease: RR, 0.62; 95% CI, 0.47–0.82; P<0.001
Metoprolol CR/XL vs placebo^Citation12	RR, 0.66; 95% CI, 0.53–0.81; P=0.00009	CV-related mortality: RR, 0.62; 95% CI, 0.50–0.78; P=0.00003
Bisoprolol vs placebo^Citation23	HR, 0.66; 95% CI, 0.54–0.81; P<0.0001	CV death or CV-related hospitalization: HR, 0.79; 95% CI, 0.69–0.90; P=0.0004
ACEIs
Enalapril vs placebo^Citation26	RR, 0.73; P=0.003	Mortality due to HF: RR, 0.50; P<0.001
Enalapril vs placebo^Citation15	RR, 0.84; 95% CI, 0.74–0.95; P<0.0072	Mortality or HFH: RR, 0.74; 95% CI, 0.66–0.82; P<0.001
ARBs
Losartan vs captopril^Citation14	HR; 1.13; 95.7% CI, 0.95–1.35; P=0.16	Mortality or hospitalization: HR, 1.07; 95% CI, 0.97–1.19; P=0.18
Valsartan vs placebo^Citation31	RR, 1.02; 98% CI, 0.88–1.18; P=0.80	Morbidity or mortality: RR, 0.87; 97.5 CI, 0.77–0.97; P=0.009
MRAs
Spironolactone vs placebo^Citation13	RR, 0.70; 95% CI, 0.60–0.82; P<0.001	Cardiac-related mortality or hospitalization: RR, 0.68; 95% CI, 0.59–0.78; P<0.001
Eplerenone vs placebo^Citation33	Adjusted HR, 0.76; 95% CI, 0.62–0.93; P=0.008	CV-related mortality or HFH: adjusted HR, 0.63; 95% CI, 0.54–0.74; P<0.001
Cardiac glycoside
Digoxin vs placebo^Citation34	RR, 0.99; 95% CI, 0.91–1.07; P=0.80	Hospitalization for worsening HF: RR, 0.72; 95% CI, 0.66–0.79; P<0.001
HCN channel blocker
Ivabradine vs placebo^Citation36	HR, 0.90; 95% CI, 0.80–1.02; P=0.092	CV death or hospitalization for worsening HF: HR, 0.82; 95% CI, 0.75–0.90; P<0.0001
ARNI
valsartan/valsartan vs enalapril^Citation45	HR, 0.84; 95% CI, 0.76–0.93; P<0.001	CV-related mortality or first HFH: HR, 0.80; 95% CI, 0.73–0.87; P<0.001
Sacubitril/valsartan vs enalapril^Citation64	HR, 0.66; 95% CI, 0.30–1.48; P not reported	Composite of serious clinical events:^a HR, 0.54; 95% CI, 0.37–0.79; P not reported

Notes: ^aThis endpoint included death, rehospitalization for heart failure, implantation of a left ventricular device, and inclusion on the list of patients eligible for heart transplantation.

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; CI, confidence interval; CR, controlled-release; CV, cardiovascular; HCN, hyperpolarization-activated cyclic nucleotide; HF, heart failure; HFH, heart failure hospitalization; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; RR, relative risk; XL, extended-release.

Figure 1 Rates of death by cause and treatment from PARADIGM-HF.

Note: Data from Desai et al.⁴⁸

Abbreviation: PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure.

Figure 2 Comparison of patient-reported symptoms over time between treatment groups in PARADIGM-HF.

Note: Data from Packer et al.⁵³

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARNI, angiotensin receptor-neprilysin inhibitor; KCCQ, Kansas City Cardiomyopathy Questionnaire; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure.

Figure 3 PARADIGM-HF Kaplan–Meier curves for the primary endpoint (A) and death from cardiovascular causes (B), according to study group.

Notes: From N Engl J Med, McMurray JJ, Packer M, Desai AS, et al, Angiotensin-neprilysin inhibition versus enalapril in heart failure, 371(11):993–1004. Copyright© (2014) Massachusetts Medical Society. Adapted with permission from Massachusetts Medical Society.⁴⁵

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARNI, angiotensin receptor-neprilysin inhibitor; CI, confidence interval; LCZ696, sacubitril/valsartan; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure.

Table 2 Identification of candidates for sacubitril/valsartan treatment

PARADIGM-HF patient characteristics, N=8442

Mean age: 64 years Predominantly male (78%) Less severe disease (70% NHYA class II) Majority with ischemic cardiomyopathy (60%) Hospitalized for HF (63%) Comorbid hypertension (71%) and diabetes mellitus (35%) On GDEM (recommended at the time) prior to enrollment, treated with an ACEI (77%), ARB (22%), or both Background therapy included β-blockers (93%), diuretics (80%), and MRAs (60%) Mean LVEF <30% High NT-proBNP levels (mean concentration=1608 pg/mL) Peripheral edema (21%) Poor self-reported quality of life, KCCQ OSS=73

Evidence-based support for treatment

Patients with HFrEF Patients with mild-to-moderate chronic HF, eg, NYHA class II-III Patients with stable HF already receiving guideline-directed therapy in other pharmacologic classes, as appropriate (β-blocker and MRA) Systolic blood pressure ≥100 mmHg eGFR ≥30 mL/min/1.73 m^2 Potassium ≤5.2 mmol/L

Evidence insufficient or not available to currently recommend treatment

Patients with HFpEF Patients with severe HF, eg, NYHA class IV Hospitalized patients with acute decompensated HF Patients with specific disease etiology or comorbidity

Contraindicated for treatment

History of angioedema related to previous ACEI or ARB therapy Concomitant use of ACEI or other ARB Concomitant use of aliskiren in patients with diabetes mellitus Severe hepatic impairment

Notes: ^aData from these studies.^7,8,39,45,60

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; eGFR, estimated glomerular filtration rate; GDEM, guideline-directed evaluation and management; HF, heart failure; HFpEF, HF with preserved ejection fraction; HFrEF, HF with reduced ejection fraction; KCCQ OSS, Kansas City Cardiomyopathy Questionnaire overall summary score; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association; PARADIGM-HF, Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure.

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