Tools for Practice


#191 Sacubitril/Valsartan: Getting to the Heart of This Novel Therapy


CLINICAL QUESTION
Is sacubitril/valsartan (Entresto®) effective for systolic heart failure (HF)?


BOTTOM LINE
Based on one randomized controlled trial (RCT), for every 36 patients with heart failure switched from ACE inhibitors to sacubitril/valsartan, one fewer will die and one fewer will be admitted for heart failure over 27 months. Beta-blockers and aldosterone antagonists should be offered first and continued concurrently.   



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EVIDENCE
One RCT (PARADIGM-HF):1 8,399 patients with systolic HF, mean age 64, ~94% Class II/IIIB-type natriuretic peptide (BNP) ~250 pg/mL, ~7% North AmericanPatients switched from their ACE inhibitor to sacubitril/valsartan 200 mg (97 mg/103 mg) BID or enalapril 10 mg BID.  
  • At 27 monthssacubitril/valsartan significantly reduced: 
    • Cardiovascular death or HF hospitalization: 22% versus 27%, Number Needed to Treat (NNT)=22. 
    • Cardiovascular death: 13% versus 17%, NNT=32.  
    • HF hospitalization13% versus 16%, NNT=36.  
    • All-cause mortality17% versus 20%, NNT=36. 
    • Mean blood pressure ~3 mmHg lower. 
    • Fewer discontinuations for renal impairment: 0.7% versus 1.4%, NNT=143. 
  • Adverse EffectsOverall fewer with sacubitril/valsartan, 10.7% versus 12.3%, NNT=63. But increased: 
    • Symptomatic hypotension: 14% versus 9.2%, Number Needed to Harm (NNH)=20.  
    • Angioedema cases: 19 versus 10.  
  • Limitations: ~20% withdrew during run-in, stopped early (which can overestimate benefit and underestimate harm), and industry sponsored. 
Context: 
  • The usefulness of initiating therapy based on BNP levels is unknown as most heart failure patients have elevated BNP.2 
  • Concurrent therapy in PARADIGM-HF:1 
    • ~93% taking beta-blockers.  
    • ~Half taking aldosterone antagonists. 
  • ACE inhibitors, beta-blockers, and aldosterone antagonists each reduce all-cause mortality by ~20-30% versus placebo.3 
  • Based on PARADIGM-HF,1 guidelines recommend replacing ACE inhibitor/angiotensin receptor blockers with sacubitril/valsartan if on ACE inhibitors, beta-blockers and aldosterone antagonists with elevated natriuretic peptides or hospitalization for heart failure in the previous 12 months.4,5 
  • Starting dose is 50 mg (24 mg/26 mg) to 100 mg (49 mg/51 mg) BID with possible titration to 200 mg in 2-4 weeks.6 
    • ~40% of patients will need a dose reduction (but 1/3 will be able to go back to full dose).7 
  • Although not currently covered by many insurance plans, it is a recommended benefit.8 
    • Cost ~$250/month. 


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Author(s):

  • Adrienne J Lindblad BSP ACPR PharmD
  • Evan Sehn BScPharm PharmD Candidate
  • Terrence McDonald MD MSc CCFP (SEM) Dip. Sport Med.

1. McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014; (11):993-1004.

2. Latour-Pérez J, Coves-Orts FJ, Abad-Terrado C, et al. Eur J Heart Fail. 2006; 8(4):390-9.

3. Lindblad AJ, Allan GM. Can Fam Physician. 2014; 60:e104.

4. Moe GW, Ezekowitz JA, Lepage S, et al. Can J Cardiol. 2015; 31:3-16.

5. Howlett JG, Chan M, Ezekowitz JA, et al. Can J Cardiol. 2016; 32:296-310.

6. Novartis Pharmacueticals Canada Inc. ENTRESTO® Product Monograph. Available from: https://www.ask.novartispharma.ca/download.htm?res=entresto_scrip_e.pdf&resTitleId=1137. Last Accessed: March 28, 2017.

7. Vardeny O, Claggett B, Packer M, et al. Eur J Heart Fail. 2016; 18:1228-34.

8. Canadian Agency for Drugs and Technologies in Health. CADTH Canadian Drug Expert Committee Final Recommendation: sacubitril/valsartan. Available from: https://www.cadth.ca/sites/default/files/cdr/complete/SR0447_complete_Entresto-Mar-22_e.pdf. Last Accessed: June 7, 2017.

Authors do not have any conflicts of interest to declare.