Simultaneous or Rapid Initiation of Combination Therapy for Heart Failure With Preserved Ejection Fraction

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  Central Illustration. The Roles of Steroidal and Nonsteroidal MRAs in HF Management and Key Considerations to Optimize Treatment ∗The MR is expressed in the heart and blood vessels.11†Overactivation of the MR in the circulatory system is responsible for adverse cardiovascular effects, such as endothelial dysfunction, vasoconstriction, increased inflammation and oxidative stress, increased thrombosis, atherogenesis, myocardial hypertrophy, apoptosis, and fibrosis.11‡Spironolactone and eplerenone. CKM = cardiovascular–kidney–metabolic; FDA = U.S. Food and Drug Administration; GDMT = guideline-directed medical therapy; HF = heart failure; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; LVEF = left ventricular ejection fraction; MR = mineralocorticoid receptor; MRA = mineralocorticoid receptor antagonist; nsMRA = nonsteroidal MRA; sMRA = steroidal MRA.

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  Figure 1. Initiation and Dose Adjustment Protocols for Spironolactone,∗ Eplerenone,† and Finerenone‡,22,41,43 ∗Approved by the FDA for HFrEF, hypertension, edema, and primary hyperaldosteronism; †approved by the FDA for HFrEF after acute myocardial infarction and hypertension; ‡approved by the FDA for HF with LVEF ≥40% and CKD with T2D; §when potassium levels are <5.5 mEq/L; ¶for CKD with T2D, the target daily dose is 20 mg; the dose can be increased from 10 mg qd if eGFR has decreased by ≤30%. For HF with LVEF ≥40%, the target daily dose is 20 mg or 40 mg if eGFR at initiation is ≥25 to <60 mL/min/1.73 m2 or ≥60 mL/min/1.73 m2, respectively; dose can be increased to the target dose provided eGFR has decreased by ≤30%; #for CKD with T2D, consider restarting at 10 mg qd when serum [K+] ≤5.0 mEq/L. For HF with LVEF ≥40%, if repeated serum [K+] measurements are ≥5.5 mEq/L, restart at 10 mg qd when serum [K+] <5.0 mEq/L. CKD = chronic kidney disease; CrCl = creatinine clearance; eGFR = estimated glomerular filtration rate; FDA = U.S. Food and Drug Administration; HF, heart failure; HFrEF = heart failure with reduced ejection fraction; [K+] = potassium concentration; LVEF = left ventricular…

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  Figure 2. Finerenone Dosing for Patients With HF With LVEF ≥40%, CKD and T2D, or HF With LVEF ≥40% Plus CKD and T2D ∗Compared with previous measurement and provided serum potassium levels are ≤4.8 mEq/L for a primary indication of CKD and T2D or <5.0 mEq/L for a primary indication of HF with LVEF ≥40%. The dose adjustment schedule should be followed based on serum potassium levels if these thresholds are exceeded (Figure 1F). †The target dose should be selected based on the primary indication. In the absence of a specific label or guideline direction on dose selection, when both indications coexist, we suggest that for patients who meet the HF with mildly reduced or preserved ejection fraction indication, the HF indication should be regarded as the primary indication. ‡Measure eGFR periodically during maintenance treatment in patients with HF. Consider delaying uptitration or interrupting treatment with finerenone in patients with HF who develop clinically significant worsening of kidney function. HFpEF = heart failure with preserved ejection fraction; other abbreviations as in Figure 1.

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  Figure 3. Serum Potassium Monitoring Requirements for Spironolactone,∗ Eplerenone,† and Finerenone‡,22,41,43 ∗Spironolactone is approved by the FDA for HFrEF, hypertension, edema, and primary hyperaldosteronism. †Eplerenone is approved by the FDA for HFrEF after acute myocardial infarction and hypertension. ‡Finerenone is approved by the FDA for patients with HF with ≥40% LVEF and patients with CKD and T2D. ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CYP3A = cytochrome P450, family 3, subfamily A; NSAID = nonsteroidal anti-inflammatory drug; PI = prescribing information; other abbreviations as in Figure 1.

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  Figure 4. Estimated Absolute Event-Free Survival Gains in an Actuarial Analysis of HF With Mildly Reduced or Preserved Ejection Fraction With Comprehensive Medical Therapy of an SGLT-2i and Finerenone Data are from an indirect comparison of cross-trial data from DELIVER, FINEARTS-HF, and PARAGON-HF trials (N = 6,263, N = 6,001, and N = 4,796, respectively). Kaplan-Meier estimated curve for patients starting at 65 years of age for survival free from the primary endpoint (cardiovascular death or worsening HF event) in the overall HF with mildly reduced or preserved ejection fraction population. SGLT-2i = sodium–glucose cotransporter-2 inhibitor.

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  Figure 5. Pillars of Treatment for HFmrEF/HFpEF29,93, 94, 95 ARNi = angiotensin receptor–neprilysin inhibitor; GLP-1RA = glucagon-like peptide-1 receptor agonist; HFmrEF/HFpEF = heart failure with mildly reduced or preserved ejection fraction; nsMRA = nonsteroidal mineralocorticoid receptor antagonist; other abbreviations as in Figures 1 and 4.

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  Figure 6. Overlapping Disorders in CKM Syndrome100, 101, 102 AF = atrial fibrillation; AS = aortic stenosis; CKD = chronic kidney disease; CKM = cardiovascular–kidney–metabolic; HF = heart failure; MASH = metabolic dysfunction-associated steatohepatitis; MASLD = metabolic dysfunction-associated steatotic liver disease; MI = myocardial infarction; T1D = type 1 diabetes; T2D = type 2 diabetes.