Table 2: Recommended HFrEF Treatment and Dosing Guideline ARB Candesartan I/A
4-8 mg daily
32 mg daily
ARB ARB
Losartan Valsartan
I/A I/A I/B
25-50 mg daily 20-40 mg BID 24/26 mg BIDa 49/51 mg BID 1.25 mg daily 3.125 mg BID
50-150 mg daily
160 mg BID
ARNI
Sacubitril/valsartan
97/103 mg BID
β -Blocker β -Blocker
Bisoprolol Carvedilol
I/A I/A
10 mg daily
25 mg BID or 50 mg BID (for ≥ 85 kg)
β -Blocker
Metoprolol succinate I/A
12.5-25 mg daily
200 mg daily 7.5 mg BID 50 mg daily
I f Channel inhibitor
Ivabradine Eplerenone
IIa/B
5 mg BID
MRA MRA
I/A I/A I/A
25 mg daily
Spironolactone
12.5-25 mg daily
25 mg daily or BID
NA
Isosorbide dinitrate/ hy- dralazine (Fixed- dose combination) Isosorbide dinitrate/hy- dralazine
20 mg isosorbide dini- trate/ 37.5 mg hydrala- zine TID 20–30 mg isosorbide dinitrate/ 25–50 mg hy- dralazine TID or QD
40 mg isosorbide dini- trate/ 75 mg hydralazine TID 40 mg isosorbide dini- trate TID with 100 mg hydralazine TID
NA
I/A b
SGLT2 Inhibitor SGLT2 Inhibitor
Empagliflozin Dapagliflozin
Not evaluated Not evaluated
10 mg every morning NA
10 mg daily NA Note . Drug Information and COR/LOE from: 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure, by C.W. Yancy, M Jessup, B Bozkurt, et al. JACC, 70(6), 776-803. Note . ACEI= Angiotensin Converting Enzyme Inhibitor; ARB= Angiotensin Receptor Blocker; BID= Twice a day; ARNI= Angiotensin Receptor- Neprilysin Inhibitors; COR/LOE= Class of Recommendation/Level of Evidence; NA= Not applicable; TID= Three times a day. a= de novo initiation; age ≥75, severe renal impairment, Child-Pugh class B, low dose ACE/ARB. b=Recommendation for African American patients on guideline-based therapy
Self-Assessment Quiz Question #1 Which of the following agents does NOT have evidence sup- porting a mortality benefit for patients with HFrEF?
a. Carvedilol. b. Lisinopril. c. Spironolactone. d. Digoxin. Heart failure with preserved ejection fraction
Unlike HFrEF with evidence-based treatment options, agents used to manage HFpEF have had limited success. While several trials have demonstrated HF-related hospitalization reduction, tri- als evaluating various agents have either unclear or no impact on mortality reduction. Due to the lack of successful pharmacological options in this setting, the ACC/AHA HF guidelines recommend initially treating comorbid conditions and managing symptoms. The latest guidelines give a 1/B recommendation to control sys- tolic and diastolic blood pressure to prevent morbidity in patients with HFpEF (Yancy et al., 2017). Additionally, the guidelines give a 1/C recommendation for the use of diuretics to reduce symptoms caused by volume overload. The discussion below describes the various agents investigated for managing hypertension and re- Evidence for using a mineralocorticoid receptor antagonist comes from the large international TOPCAT trial using spironolactone. This trial included patients with HF symptoms and an LVEF greater than 45%. Patients were randomly selected to receive either spi- ronolactone or placebo and evaluated for the composite primary endpoint of CV mortality, HF-related hospitalization, or aborted cardiac arrest. Despite the primary composite outcome not reach- ing statistical significance (p = .14), HF-related hospitalizations were significantly reduced with spironolactone compared with placebo (12% vs 14.2%, p= .04) (Kumbhani, 2021). A post hoc analysis revealed variations in event rates between testing centers in Russia and the Americas; treatment with spironolactone in the lieving symptoms in patients with HFpEF. Mineralocorticoid Receptor Antagonists
Americas improved efficacy, while efficacy rates did not improve in some Russian testing facilities. Furthermore, active metabolites for spironolactone were undetectable at some Russian sites, sug- gesting possible non-adherence to trial protocols and, therefore, skewing the primary outcome results in the TOPCAT trial (Yancy et al., 2017). Because of affordability and the ability to reduce HF-related hos- pitalizations, spironolactone remains a potential option in the treatment of HFpEF. The ACC/AHA guidelines recommend min- eralocorticoid receptor antagonists for HF-related hospitalizations in patients with: an LVEF of 45% or greater, elevated BNP levels, hospitalizations within one year, GFR above 30 ml/min, serum creatinine less than 2.5 mg/dL, and potassium levels less than 5mEQ/L (IIb, LOE B-R) (Yancy et al., 2017). ACE Inhibitors/ ARB Therapy In the last two decades, only a select few ACEI/ ARB agents have been studied in the HFpEF setting: candesartan (CHARMED- Preserved), irbesartan (I-Preserve), and perindopril (PEP-CHF). The data from these trials have been less than robust, with no impact on HF-related hospitalization. A secondary analysis from the CHARM-PRESERVED trial provides the best evidence sup- porting the use of an ARB (candesartan) in patients with an LVEF greater than 40%. Initially, the primary composite outcome for HF-related hospitalizations and CV mortality did not reach sta- tistical significance in the main CHARMED-PRESERVED trial (HR, 0.89 (95% CI, 0.77–1.03); P = 0.12). However, after adjusting for baseline characteristics in the secondary analysis, compared with
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