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Evevident
Original paper
2014NEJMCardiology

PARADIGM-HF

Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure

RCTHeart Failure

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Overview

Sacubitril/valsartan beat enalapril for cardiovascular death and heart-failure hospitalization in HFrEF.

Clinical takeaway

PARADIGM-HF showed that the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan was superior to the ACE inhibitor enalapril in reducing cardiovascular death and heart-failure hospitalization in HFrEF.

Key result

Primary composite: HR 0.80 (95% CI 0.73-0.87), p<0.001.

Practice impact

Established ARNI therapy over ACE inhibitor therapy as a cornerstone of HFrEF treatment.

Evidence

Study design

Randomized, double-blind, active-controlled trial

Enrollment

8,442

Follow-up

Median 27 months

Geography

Multinational

Clinical question

In patients with symptomatic HFrEF, is sacubitril/valsartan superior to enalapril in reducing cardiovascular death or heart-failure hospitalization?

Population

  • HFrEF with LVEF <= 40% (later amended to <= 35%)
  • NYHA class II-IV with elevated natriuretic peptides
  • Tolerated run-in of both enalapril and sacubitril/valsartan

Intervention

Sacubitril/valsartan (LCZ696) 200 mg twice daily

Comparator

Enalapril 10 mg twice daily

Primary outcome

Composite of cardiovascular death or heart-failure hospitalization

Sacubitril/valsartan reduced cardiovascular death or heart-failure hospitalization compared with enalapril.

HR / 0.8 / CI 0.73-0.87 / p=<0.001

Key results

  • Primary composite: HR 0.80 (95% CI 0.73-0.87), p<0.001
  • Cardiovascular death: HR 0.80 (0.71-0.89)
  • All-cause mortality reduced; trial stopped early for benefit
  • More symptomatic hypotension, but less renal impairment, hyperkalemia, and cough versus enalapril

Harms

  • More symptomatic hypotension with sacubitril/valsartan.
  • Less renal impairment, hyperkalemia, and cough compared with enalapril in the seed data.

Clinical Use

When to cite

  • When explaining why ARNI is preferred over ACE inhibitor therapy in eligible HFrEF patients
  • When discussing foundational HFrEF guideline-directed medical therapy

Practice impact

  • Established ARNI as preferred over ACE inhibitor or ARB in HFrEF
  • Became a class I guideline recommendation
  • One of the four foundational pillars of HFrEF therapy

Applicability

  • Most applicable to symptomatic HFrEF patients who can tolerate ARNI therapy
  • Useful when discussing replacement of ACE inhibitor or ARB therapy in HFrEF

Limitations

  • Active-comparator run-in selected for patients who tolerated ARNI
  • Enalapril, not higher ACE inhibitor doses, was the comparator
  • Requires 36-hour washout from ACE inhibitor to avoid angioedema

Common misinterpretations

  • Do not overlap sacubitril/valsartan with an ACE inhibitor; allow a 36-hour washout to reduce angioedema risk.

Related evidence

DAPA-HF - Same DiseaseEMPHASIS-HF - Context

Citation

McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004. doi:10.1056/NEJMoa1409077