Proposed algorithm for chronic reduced ejection fraction heart failure (HFrEF) by McMurray and Packer 2020

Proposed new algorithm for chronic heart failure in HFrEF (heart failure with reduced ejection fraction) in patients whom diuretic therapy has achieved euvolemia (1):

• Step 1: Simultaneous initiation of a beta-blocker and an sodium glucose transporter 2 inhibitor (SGLT2i)
  
  
• Step 2: Addition of sacubitril/valsartan, within 1-2 weeks of Step 1. If SBP <100 mmHG, it may be prudent to first evaluate tolerance with an ARB before switching to ARNI (angiotensin receptor-neprilysin inhibitor)
  
  
• Step 3: Addition of an mineraolocorticoid receptor antagonist (MRA), within 1-2 weeks of Step 2, if renal function is not severely impaired and serum potassium levels are normal. MRAs may also be initiated in Step 2 in patients with troublesome hypotension.

The algorithm can be individualized to specific circumstances and is most appropriate for outpatients.

Caution is required in hospitalized patients with decompensated HF.

This approach achieves treatment with beta-blocker, SGLT2i, ARNI and MRA within 4 weeks. Up-titration to target doses should be pursued after this period.

The new algorithm is based on five principles:

1) magnitude of the treatment benefit of each individual drug class is independent of the treatment benefits of other drug classes

2) foundational drugs are effective in reducing morbidity and mortality at low starting doses

3) addition of a new drug class to the treatment yields greater benefit than up-titrating existing drug classes - target doses are often only modestly more effective in comparison with starting doses in reducing risk of CV death

4) safety and tolerability can be improved by proper sequencing of drug classes

5) much of the benefit of foundational treatments can be seen within 30 days

Therapy with all four drug classes should therefore be achieved within 4 weeks.

The conventional approach assumes that clinical trials tested the efficacy and safety of each drug class in presence of all background therapies at target doses - however the majority of patients in heart failure trials were actually receiving sub-evidence based doses of recommended treatment (1,2). Also, if considering trials such as DAPA-HF and EMPEROR-reduced, then substantial proportion of patients were not treated with an MRA or ARNI.

McMurray and Packer expect that this will prevent HF death and HF hospitalizations and will enhance the tolerability of concurrently or subsequently administered treatments.

Reference:

• McMurray JJV and Packer M. How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction? A Redefinition of Evidence-Based Medicine. Circulation. 2020 doi: 10.1161/CIRCULATIONAHA.120.052926
• Packer M, Poole-Wilson PA, Armstrong PW, Cleland JG, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999; 100: 2312-2318.