Comprehensive review of the heart failure management guidelines presented by the American College of Cardiology and the current supporting evidence

ACC/AHA/HFSA heart failure guidelines

The 2022 recommendations of the ACC/AHA/HFSA (Heart Failure Society of America) guideline for the management of heart failure and the 2024 treatment pathway for HFrEF are organized based on the disease’s staging. Stages A–D encompassed escalating levels of symptoms, structural defects, and lab values. Furthermore, the guideline incorporates the NYHA and the LVEF classifications to determine treatment based on patient symptoms and ventricular function. The NYHA classification is utilized for patients receiving treatment for either Stage C or D HF [8]. Stage C includes patients with HF symptoms, either presently or in the past [8]. Stage D involves patients with advanced HF that significantly affects their daily life [8]. The NYHA organizes patients into four classes that offer a progressive breakdown of symptom severity experienced by the patient (Table 1). Class I encompasses patients with no reduction in physical activity, Class II includes patients who experience some symptoms during regular physical activity, Class III involves patients with moderate levels of fatigue during daily activities, and Class IV pertains to patients with symptoms at rest [8]. The classification can change over the course of treatment as symptoms improve or worsen [8]. Finally, HF based on LVEF is classified as HFrEF, HFmrEF, and HFpEF. HFrEF is characterized by an LVEF of ≤40 %, HFmrEF corresponds to an LVEF ranging from 41 to 49 %, and HFpEF is defined as an LVEF ≥50 % [9]. This paper aims to summarize the pharmacological management of HF as it pertains to reduced EF, mildly reduced EF, and preserved EF.

Pharmacologic protocol for HFrEF

The initial recommended treatment for HFrEF involves the use of an angiotensin II receptor and neprilysin inhibitor (ARNi), which is recommended as a first-line therapy for patients with NYHA class II–IV symptoms [9, 10]. Sacubitril/valsartan is a novel medication belonging to the ARNi class that aims to mitigate the detrimental effects of the renin-angiotensin-aldosterone system (RAAS) [11]. Sacubitril functions by inhibiting neprilysin, which reduces the breakdown of natriuretic peptides, bradykinin, and angiotensin II [11]. The natriuretic peptides, including brain natriuretic peptitde (BNP) and N-terminal (NT)-pro BNP, released by the heart muscle, decrease sympathetic stimulation and blood pressure, while increasing vasodilation and reducing extracellular fluid volume through diuresis [11]. Along with the increase in favorable parameters, sacubitril increases the concentration of angiotensin II. Thus, valsartan, an angiotensin receptor blocker (ARB), must be co-administered to prevent the binding of angiotensin II to its AT1 receptor [11]. Adverse effects of ARNi include hypotension, hyperkalemia, renal failure, angioedema, and cough [11]. Finally, both sacubitril and angiotensin-converting enzyme inhibitors (ACEi) increase bradykinin levels, so concurrent administration with ACEi is contraindicated to minimize adverse effects such as dry cough and angioedema [11]. When switching from ACEi to ARNi, it is recommended that there is a 36 h delay prior to the new dose [9].

As of a recent update from the ACC, it is no longer recommended to proceed with a trial of ACEi or ARB prior to initiating treatment of ARNi [10]. ACEi and ARB are the subsequent classes of medications that can also be utilized as first-line therapy [9, 10]. ACEi block the angiotensin-converting enzyme (ACE) and prevent the formation of angiotensin II, thereby reducing blood pressure and promoting natriuresis [12]. Additionally, ACEi decreases afterload and preload, thus decreases wall stress and increases cardiac output [12]. An ACEi or ARNi are alternative options for patients who may not be able to afford or have access to ARNi [10].

The next class of agents is the mineralocorticoid receptor antagonists (MRAs), which are utilized for patients with NYHA class II–IV symptoms [9]. MRAs act by inhibiting the mineralocorticoid receptor, thereby preventing the binding of aldosterone to its receptor, and ultimately reducing blood pressure [13]. Spironolactone or eplerenone are recommended, which require an eGFR >30 mL/min/1.73 m² for proper excretion and a serum potassium <5.0 mEq/L [9]. Potassium levels and eGFR should be measured initially one week after starting a new or adjusted dose, then increased to four weeks, and subsequently every six months [9]. If a decline in kidney function or hyperkalemia occurs, the medication should be discontinued until a cause is determined [9]. It is important to note that eplerenone has a higher specificity to the aldosterone receptor, resulting in a decreased risk of gynecomastia and vaginal bleeding [9].

Sodium glucose transporter-2 inhibitors (SGLT2i) are recommended for patients with or without type 2 diabetes who have HF [9]. SGLT2i function by inhibiting the reabsorption of glucose at the proximal convoluted tubule, thereby promoting glucose excretion and diuresis [14]. These agents are associated with a 31 % reduction in HF hospitalization for patients with type 2 diabetes [9]. SGLT2i may have adverse effects in people with diabetes such as increased genital infection, euglycemic ketoacidosis, and soft tissue infections [9]. The 2024 guidelines recommend to continue use of these agents in patients with reduced eGFR levels due to the overall CV benefit seen in patients especially with dapagliflozin, sotagliflozin, and empagliflozin [10].

Beta blockers are added to the ARNi or ACEi/ARB treatment to decrease hospitalizations and risk of death [9]. Beta blockers act by inhibiting catecholamine beta 1 and beta 2 receptors, which respond to sympathetic stimulation [15]. Beta 1 blockers slow down the heart rate via sinoatrial (SA) and atrioventricular nodes (AV), reduce heart contractility and inhibit renin release from the kidney; beta-2 blockers increase vasodilation [16, 17]. Three beta blockers are recommended: Carvedilol, sustained-release metoprolol succinate, and bisoprolol [9]. These three beta blockers have been shown to have a significant improvement on the survival of HF patients with carvedilol being first line, followed by bisoprolol and extended-release metoprolol [18]. The agents improve the LVEF and provide symptomatic relief and should be continued even with improvement of symptoms and LVEF [9]. Multiple randomized controlled trials (RCTs) have demonstrated that patients with comorbidities such as coronary artery disease and diabetes benefit from the use of beta blockers [9]. In conclusion, ARNi/ACEi/ARB, beta blockers, MRAs, and SGLT2i therapies form the basic cornerstone of therapy.

Loop diuretic agents can be added to the guideline-directed medical therapy (GDMT) for patients with NYHA class II–IV HF experiencing volume overload [10]. Additionally, a combination of hydralazine and isosorbide dinitrate treatment may be used for African American patients who have NYHA class III–IV symptoms. This treatment may be used as an add-on or as an alternative to ARNi, ACEi, or ARB therapy if it is not tolerated by the patient or if the patient experiences hypotension and renal insufficiency [9]. Hydralazine acts by vasodilating arterioles, and isosorbide dinitrate releases nitric oxide (NO), which signals the endothelium of blood vessels to dilate [19, 20].

Agents such as ivabradine and soluble guanylyl cyclase stimulators are recommended as an addition to the GDMT [10]. Ivabradine, an If channel inhibitor, is recommended for patients not responding to the GDMT, who have a normal sinus rhythm, a heart rate greater than or equal to 70 bpm, and NYHA II-III symptoms [9, 21]. The goal heart rate with this agent is 50–60 bpm to reduce negative outcomes such as HF hospitalizations [10]. Next, vericiguat, which stimulates soluble guanylate cyclase production, has been shown to also reduce hospitalizations in worsening HF [9]. The agents increases vasodilation, reduces fibrosis of the heart, and improves endothelial function, which has been shown to decrease HF hospitalizations and CV death [10]. The use of these additional medications beyond the four cornerstones of therapy requires clinical judgment (Tables 2 and 3).

Pharmacological protocol for HFmrEF

The pharmacological management protocol for patients with HFmrEF is based on analyses of RCTs that have included participants with an ejection fraction (EF) ranging from 41 to 49 % [9]. Due to limited research in this category, patients are treated similarly to those with HFrEF. The ACC guidelines recommend the use of SGLT2i, specifically empagliflozin, to reduce hospitalization and the risk of CV death in symptomatic patients with LVEF >40 % [9]. The administration of ACEi/ARB/ARNi, beta-blockers, and MRAs is recommended next. Candesartan has been shown to reduce hospitalizations and CV death in this subgroup [9]. Spironolactone is recommended in patients with HFmrEF and uncontrolled hypertension [9]. Finally, the use of loop diuretics should be utilized to reduce edema if necessary [9].

Pharmacological protocol for HFpEF

Patients with HFpEF are also treated similarly to those with HFrEF, with a few exceptions [22]. As of 2023, the ACC recommends treatment that includes SGLT2i, MRAs, and ARNi/ARB [22]. To begin, SGLT2i are recommended as the first-line therapy to which MRAs and ARNi can be added too [22]. SGLT2i such as empagliflozin have been shown to reduce the need for MRAs, decrease the risk of hyperkalemia, and reduce congestion in the body [22]. Next, MRA agents such as spironolactone improve diastolic function and reduces hospitalizations in patients with HFpEF [22]. Additionally, this class of drugs helps to maintain fluid balance and control hypertension [22]. Monitoring of potassium levels and overall kidney function is important in patients receiving this therapy [22]. Additionally, sacubitril-valsartan can be added to the treatment if needed [22]. It also important to note that ARNi and spironolactone have demonstrated effectiveness in female patients across the entire range of LVEF [22]. Finally, ARB may be used as an alternative to the ARNi therapy [22]. ACEi are not considered a reasonable alternative due to the lack of benefit [22].

Evidence review of pharmacological agents