What is the optimal approach to initiate quadruple therapy for heart failure?

From the Guidelines

The optimal approach to initiate quadruple therapy for heart failure is to start with an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) and then sequentially add a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and an SGLT2 inhibitor, with gradual uptitration of doses to target levels as tolerated, as recommended by the 2020 ACC/AHA clinical performance and quality measures for adults with heart failure 1.

Key Considerations

• The clinical strategy of inhibition of the renin-angiotensin system with ACE inhibitors or ARBs, in conjunction with evidence-based beta blockers and aldosterone antagonists, is recommended for patients with chronic heart failure with reduced ejection fraction (HFrEF) to reduce morbidity and mortality 1.
• ACE inhibitors should be started at low doses and titrated upward to doses shown to reduce the risk of cardiovascular events in clinical trials, with similar recommendations for ARBs 1.
• The 2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment provides guidance on the use of novel therapies, including ARNIs, and emphasizes the importance of gradual uptitration of doses to target levels as tolerated 1.

Sequential Initiation of Medications

• Start with an ACE-I or ARB, such as lisinopril 2.5-5mg daily or valsartan 40mg daily.
• After 1-2 weeks, add a beta-blocker, such as metoprolol succinate 12.5-25mg daily or carvedilol 3.125mg twice daily.
• Once these medications are tolerated for 2-4 weeks, introduce an MRA, such as spironolactone 12.5-25mg daily.
• Finally, add an SGLT2 inhibitor, such as empagliflozin 10mg daily or dapagliflozin 10mg daily.

Monitoring and Dose Adjustment

• Monitor blood pressure, heart rate, renal function, and electrolytes (particularly potassium) at each step before advancing.
• Doses should be gradually uptitrated to target doses as tolerated, with careful monitoring for adverse effects.
• The goal is to minimize the risk of hypotension, bradycardia, and electrolyte abnormalities while allowing for dose adjustments based on individual tolerance.

Rationale

• Each medication class works through different mechanisms to reduce cardiac workload, prevent adverse remodeling, decrease fluid retention, and improve cardiac metabolism, collectively reducing mortality and hospitalizations in heart failure patients with reduced ejection fraction.
• The sequential approach allows for careful monitoring and dose adjustment, reducing the risk of adverse effects and improving patient outcomes.

From the FDA Drug Label

The Systolic Heart Failure Treatment with the I f Inhibitor Ivabradine Trial (SHIFT) was a randomized, double-blind trial comparing ivabradine and placebo in 6,558 adult patients with stable New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction ≤ 35%, and resting heart rate ≥ 70 bpm Patients had to have been clinically stable for at least 4 weeks on an optimized and stable clinical regimen, which included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics, with fluid retention and symptoms of congestion minimized.

The optimal approach to initiate quadruple therapy for heart failure is to start with a stable and optimized clinical regimen that includes:

• Beta-blockers: at maximally tolerated doses
• ACE inhibitors or ARBs: as part of the regimen
• Spironolactone: as part of the regimen
• Diuretics: as part of the regimen Patients should be clinically stable for at least 4 weeks before initiating quadruple therapy. The dose of each medication should be titrated as tolerated to achieve the desired clinical effect, with careful monitoring for signs of hypotension, fluid retention, and other adverse effects 2.

From the Research

Optimal Approach to Initiate Quadruple Therapy for Heart Failure

The optimal approach to initiate quadruple therapy for heart failure involves considering various drug classes, including angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, angiotensin II receptor blockers (ARBs), and aldosterone antagonists.

• The cornerstone of therapy for patients with heart failure involving left ventricular dysfunction consists of ACE inhibitors and beta-blockers, which have been proven to decrease morbidity and mortality in patients with heart failure 3.
• Initiating therapy with a beta-blocker followed by an ACE inhibitor may be similarly efficacious to the opposite sequence in terms of combined mortality and all-cause hospitalization, with a trend towards better survival 4.
• ACE inhibitors have significantly decreased cardiovascular mortality, myocardial infarction, and hospitalizations for heart failure in patients with asymptomatic or symptomatic left ventricular systolic dysfunction, and should be titrated to the target dose achieved in clinical trials 5.
• The addition of ARBs, direct renin inhibitors, or aldosterone antagonists to conventional heart failure therapy, including ACE inhibitors, can further reduce the risk of cardiovascular events, with aldosterone antagonists being the most effective option 6.

Key Considerations

• Clinicians should consider results from clinical trials in specific patient populations, adverse-event profiles, tolerability, cost, and dosing regimens when selecting the most appropriate drug therapy for patients with heart failure 3.
• The use of ACE inhibitors, beta-blockers, and other drug classes should be guided by clinical judgment and individual patient needs, taking into account factors such as disease severity, comorbidities, and potential drug interactions 4, 5, 7.
• Close monitoring of renal function and serum potassium levels is necessary when using combination therapy, including ACE inhibitors and ARBs or aldosterone antagonists 5, 6.