New algorithm to sequence drugs for heart failure

Management of heart failure with reduced ejection fraction (HFrEF) has witnessed some major developments in the past 2 decades with the addition of neprilysin inhibitors and lately SGLT2i to the therapeutic armamentarium. However, the approach to defining the sequence of adding different drugs while managing a patient has not been revised for long. Cardiologists continue to prescribe the conventional sequence of ACE-inhibitors or ARBs followed by beta-blockers and then mineralocorticoid antagonists (MRAs). If a patient doesnot improve on these conventional regimens then neprilysin inhibitors or SGLT2i are added.

In the current issue of Circulation journal, McMurray et al have highlighted the shortcomings of this approach and proposed an algorithm that redefines the management of HFrEF.

The current approach suffers from many important limitations:

1. It assumes that our most effective and well-tolerated treatments were developed first. However, the evidence from the oldest drug in this regard- digoxin disproves this statement.

2. It assumes that foundational treatments are effective only when titrated to target doses. Yet, low doses of drugs for HFrEF yield important benefits to reduce morbidity and mortality, and target doses are often only modestly more effective than low starting doses in reducing the risk of cardiovascular death. In fact, addition of new drug like SGLT2i causes more increment of benefit rather than simply up-titrating betablockers over weeks.

3. It assumes that the efficacy and safety of each drug class were tested in clinical trials that required patients to be receiving all background therapy at target doses. However, a close scrutiny of the trial data reveals that most patients in these trials were on sub-maximal doses while they continued to achieve spectacular benefits.

The current approach to the sequencing of drug treatments has had adverse consequences on the adoption of disease-modifying therapies for HFrEF. If physicians prioritize the achievement of target doses of each drug class before initiating treatment with the next, it may take ≥6 months to prescribe all recommended treatments.

More importantly, even if the current guideline-recommended approach was fully adopted, a delay of 6 months is unacceptable, because each of the foundational drugs has been shown to reduce morbidity and mortality within 30 days of initiating treatment. With every passing visit, the absence of ≥1 therapy results in unnecessary hospitalizations and deaths.

The proposed "new sequence" algorithm (Figure) involves 3 steps, to be initiated in a patient in whom diuretics has achieved clinical euvolemia.

Step 1 is simultaneous initiation of treatment with a β-blocker and an SGLT2i. SGLT2is have a striking effect to reduce the risk of hospitalizations for heart failure, and this benefit (potentially acting in concert with their early diuretic action) may mitigate the short-term risk of worsening heart failure that may occur after a β-blocker is started.

Step 2 is addition of sacubitril/valsartan, within 1 to 2 weeks of step 1. Any hypotensive effects commonly resolve with repeated dosing or with adjustment of the dose of concurrently administered diuretics.

Step 3 is the addition of an MRA, within 1 to 2 weeks of step 2, if serum potassium is normal and renal function is not severely impaired. The favorable effects of neprilysin inhibitors and SGLT2i to improve renal function and potassium homeostasis may increase the tolerability of MRAs.

Used in appropriate patients, the approach outlined achieves treatment with all 4 foundational treatments within 4 weeks. Up-titration to target doses should be pursued thereafter. This sequencing maximizes the likelihood that highly effective therapies will be implemented in a manner that rapidly prevents deaths and hospitalizations and enhances the tolerability of concurrently or subsequently administered treatments.

Source: Circulation Journal: https://doi.org/10.1161/CIRCULATIONAHA.120.052926Circulation. 2021;143:875–877