From the Guidelines
Quadruple therapy for heart failure with reduced ejection fraction (HFrEF) in patients with severe hypertension should include an angiotensin receptor-neprilysin inhibitor (ARNI) like sacubitril/valsartan (Entresto) 24/26 mg twice daily titrated to 97/103 mg twice daily as tolerated, a beta-blocker such as carvedilol 3.125 mg twice daily titrated to 25 mg twice daily, a mineralocorticoid receptor antagonist (MRA) like spironolactone 25 mg daily, and an SGLT2 inhibitor such as empagliflozin 10 mg daily or dapagliflozin 10 mg daily, as this regimen has demonstrated mortality benefits and improved quality of life in HFrEF patients while effectively managing blood pressure in hypertensive patients 1.
Key Components of Quadruple Therapy
- An angiotensin receptor-neprilysin inhibitor (ARNI) like sacubitril/valsartan, which has been shown to reduce morbidity and mortality in patients with HFrEF 1
- A beta-blocker such as carvedilol, which reduces sympathetic drive and myocardial oxygen demand
- A mineralocorticoid receptor antagonist (MRA) like spironolactone, which blocks aldosterone's adverse effects
- An SGLT2 inhibitor such as empagliflozin or dapagliflozin, which provides cardiorenal protection through multiple mechanisms
Initiation and Monitoring of Quadruple Therapy
This regimen should be initiated sequentially with careful monitoring of blood pressure, renal function, and electrolytes. Start with lower doses and titrate upward every 2-4 weeks as tolerated. For severe hypertension, additional antihypertensives like amlodipine 5-10 mg daily may be needed. Diuretics such as furosemide 20-80 mg daily should be used as needed for volume management.
Rationale for Quadruple Therapy
This comprehensive approach targets multiple pathophysiological pathways, providing a synergistic effect on reducing morbidity and mortality in HFrEF patients while effectively managing blood pressure in hypertensive patients. The use of an ARNI like sacubitril/valsartan is supported by recent guidelines, which recommend its use as a replacement for ACEI/ARB in patients with symptomatic HFrEF 1. The addition of a beta-blocker, MRA, and SGLT2 inhibitor provides further benefits in reducing the risk of HF hospitalization and death, as recommended by previous guidelines 1.
From the FDA Drug Label
The FDA drug label does not answer the question.
From the Research
Quad Therapy for Heart Failure with Reduced Ejection Fraction (HFrEF) and Severe Hypertension (HTN)
The quad therapy for HFrEF with severe HTN typically involves a combination of medications, including:
- Beta-blockers
- Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs)
- Angiotensin Receptor Neprilysin Inhibitors (ARNIs)
- Mineralocorticoid receptor antagonists
Key Components of Quad Therapy
The key components of quad therapy are:
- Beta-blockers to reduce heart rate and blood pressure 2, 3, 4, 5, 6
- ACE inhibitors or ARBs to reduce blood pressure and decrease the heart's workload 2, 3, 4, 5, 6
- ARNIs, such as sacubitril/valsartan, to further reduce mortality and morbidity in patients with HFrEF 3, 4, 5
- Mineralocorticoid receptor antagonists to reduce fluid retention and blood pressure 2, 3, 4
Additional Therapies
Additional therapies that may be considered in patients with HFrEF and severe HTN include:
- Ivabradine to reduce heart rate 2, 3, 4
- Hydralazine/isosorbide dinitrate to reduce blood pressure and improve symptoms 4
- Sodium-glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular and all-cause mortality 3, 4, 5
- Vericiguat, a soluble guanylate cyclase stimulator, to reduce heart failure hospitalization in high-risk patients with HFrEF 4
Device Therapies
Device therapies, such as cardiac resynchronization therapy (CRT) and implantable cardiac defibrillators (ICDs), may also be considered in patients with HFrEF and severe HTN, particularly those with interventricular dyssynchrony or severe left ventricular dysfunction 2, 4