PARADIGM-HF - Sacubitril/valsartan vs enalapril in HFrEF (short)

McMurray JJV, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.

Bottom-line: In patients with compensated HFrEF without symptomatic hypotension on an ACEI/ARB at a dose equivalent to enalapril 10 mg/d or greater, sacubitril-valsartan reduced the risk of death (NNT 36) and serious adverse events (NNT 23), including CV death or HF hospitalization (NNT 22) compared to enalapril at 2.3 years.

 

Context:

  • Medical therapy in heart failure focuses on blocking the compensatory mechanisms that eventually lead to morbidity and mortality, such as the renin-angiotensin-aldosterone system (RAAS)
    • ACEIs, ARBs and mineralocorticoid antagonists reduce HF-related morbidity and mortality
  • The natriuretic peptide pathway is a newer molecular target for HF treatment that largely performs opposite functions to the RAAS
    • Natriuretic peptides directly induce natriuresis, diuresis, peripheral vasodilation, inhibit cardiac remodelling, leading to decreased preload and afterload. Additionally, natriuretic peptides suppress the RAAS axis and adrenergic outflow
    • Neprilysin is an enzyme that degrades natriuretic peptides, though it also degrades "off-target" hormones such as angiotensin II, bradykinin and vasopressin
  • The selection of combination of sacubitril/valsartan was based on lack of benefit with neprilysin inhibition alone, and harm with a neprilysin inhibition/ACEI combo
    • Neprilysin inhibition alone: No effect on HF outcomes; postulated to result the effect of increased natriuretic peptides being offset by increased angiotensin II
    • Neprilysin + ACE inhibition: Increased risk of angioedema, likely a result of the dual inhibition of bradykinin by neprilysin and ACE inhibition

Patients (n=8442)

  • Multicenter (1043 centres in 47 countries)
  • Inclusion:
    • Adults with HFrEF
      • NYHA class II-IV
      • EF <40% (<35% after 2010 protocol change)
      • BNP 150+ pg/mL (NT-proBNP 600+ pg/mL) or hospitalized within 1 year + BNP 100+ pg/mL (NT-proBNP 400+ pg/mL)
    • Stable dose of beta-blocker + ACEI/ARB dose equivalent to enalapril 10+ mg/day
  • Exclusion
    • Current
      • Acutely decompensated HF
      • Symptomatic hypotension
      • Hemodynamically significant mitral or aortic valve disease (except MR 2o to LV dilatation)
      • SBP <100 mmHg at screening (SBP <95 mmHg at randomization)
      • GFR <30 or GFR decrease >25% (later amended to >35%) between screening & randomization visit
      • K >5.2 at screening (>5.4 at randomization)
    • PMHx
      • ACS, stroke/TIA, major CV surgery or PCI within 3 months
      • Coronary or carotid artery disease likely to require surgical/percutaneous intervention within 6 months
      • Hx angioedema
  • 10,521 underwent run-in phase -> 8442 randomized
  • Average patient
    • Age 64
    • Female 21%
    • White 66%
    • Geography - North America 7%
    • PMHx
      • AF 36%
      • MI 43%
    • HF characteristics
      • Ischemic CM 60%
      • Hospitalization for HF 63%
      • NYHA: 1 (4%), 2 (70%), 3 (24%), 4 (<1%)
      • Mean LVEF ~30%
      • Median BNP 255 (NT-proBNP 1631)
    • HF tx
      • Diuretic 80%
      • Digoxin 30%
      • Beta-blocker 93%
      • Mineralocorticoid antagonist 55%
      • ICD 15%, CRT 7%
    • P/E & labs
      • SBP 122
      • HR 72
      • BMI 28
      • SCr 100 umol/L

Interventions

  • I: Sacubitril-valsartan 200 mg PO BID
    • Mean dose at last assessment: 375 mg/day
    • 17.8% discontinued 
  • C: Enalapril 10 mg PO BID
    • Mean dose at last assessment: 18.9 mg/day
    • 19.8% discontinued
  • Co-interventions common to both groups:
    • Dose reduction if unacceptable side-effects at target doses

Results @ median 2.3 years

  • Statistically significantly lower risk of primary outcome (CV death or HF hospitalization) with sacubitril-valsartan: Hazard ratio 0.80, 0.73-0.87
    • Sacubitril-valsartan 21.8% versus enalapril 26.5% (NNT 22)
  • Secondary efficacy outcomes, statistically significant differences:
    • Death: 17.0% vs 19.8% (NNT 36)
    • Serious adverse events: 46.1% versus 50.6% (NNT 23) 
    • HF hospitalization: 12.8% vs 15.6% (NNT 36)
    • Kansas City Cardiomyopathy Questionnaire (KCCQ) score difference: 1.64 (/100) better with sacubitril-valsartan
  • Safety outcomes, statistically significant difference
    • Symptomatic hypotension: 14.0% vs 9.2% (NNH 22)
      • With SBP <90: 2.7% vs 1.4% (NNH 77)
    • Cough: 11.3% vs 14.3% (NNT 34)
  • Safety outcomes, no difference
    • Angioedema: <0.05% in both groups
    • New-onset AF: 3.1% in both groups
    • Decline in renal function: 2.2% vs 2.6% (p=0.28)
      • Serum creatinine 221 umol/L or greater: 3.3% vs 4.5%
    • K elevation
      • >5.5: 16.1% vs 17.3%
      • >6.0 4.3% vs 5.6% (NNT 77)

Issue with internal validity?

  • No: Allocation-concealed, double-blind RCT with blinded outcome adjudication, with <1% loss-to-follow-up, analyzing the intention-to-treat population
    • Low risk of allocation, performance, detection or attrition bias
    • Trial stopped early after 3rd interim analysis. This may lead to an exaggerated estimate of benefit
    • Run-in period before randomization:
      1. Switched from previous ACEI/ARB to enalapril 10 mg BID x2 weeks
      2. Enalapril then D/Ced x1 day, then started on sacubitril-valsartan x4-6 weeks (started at 100 mg BID & increased to 200 mg BID)

Additional publications of PARADIGM-HF