stopped due to the overwhelming benefit. Guidelines recom - mend the use of these agents in patients with an NYHA class II-IV, a potassium level of less than 5.0mEQ/L, a eGFR greater than 30 mL/min/1.73 m2, or creatinine less than 2.5 mg/dL in men and less than 2.0 mg/dL in women (Maddox et al., 2021). Both spironolactone and eplerenone curb the effects of the RAAS system by antagonizing aldosterone-specific mineralocorticoid receptors in the distal convoluted tubule. This process results in a decrease in sodium reabsorption and potassium retention. Due to the mechanism, clinicians should carefully monitor for hyper- kalemia. Additionally, gynecomastia occurs more frequently with spironolactone than with eplerenone. This is due to eplerenone’s higher binding affinity for mineralocorticoid receptors rather than androgen receptors. Furthermore, hypotension is not problem- atic with these agents in the HFrEF setting. In an analysis of the RALES and EMPHASIS-HF trial, the use of MRA for HFrEF treat- ment did not result in systolic blood pressure changes (Serenelli et al., 2020). According to the CHAMP-HF registry, of all eligible patients, 67% were not prescribed an MRA (Greene et al., 2018). Often unde- rutilized for concern of adverse events with MRAs, clinicians can play an essential role in ensuring these agents are added on and monitored in patients meeting criteria (Serenelli et al., 2020). Isosorbide Dinitrate/Hydralazine Combination The ACC/AHA HF guidelines recommend the combination of iso- sorbide dinitrate and hydralazine for patients who are intolerant to ACE Inhibitors, ARBs, or ARNIs (II/A COR/LOE). Additionally, guidelines recommend using the combination agent in African Americans still experiencing NYHA class III-IV symptoms despite receiving guideline-directed management and therapy (I/A). Evi- dence for use in patients of African American descent comes from the 2004 African-American Heart Failure Trial, where a significant improvement in mortality (p = .02) was observed amongst black patients with NYHA class III-IV receiving a fixed dose of isosorbide dinitrate and hydralazine plus standard therapy compared with standard therapy alone (Maddox et al., 2021; Yancy et al., 2017). As with MRAs, isosorbide dinitrate/hydralazine is underutilized in practice and represents a practice gap that clinicians should be aware of (Brewster, 2019). Isosorbide dinitrate stimulates cyclic GMP production, resulting in decreased vascular smooth muscle tone, while hydralazine is a peripheral vasodilator that decreases arterial resistance. The combination of the agents contributes to both a preload and afterload reduction. Due to the vasodilatory properties of this combination agent, headache, dizziness, and hypotension are common. Clinicians should be aware of rare adverse events with hydralazine, such as lupus erythematosus, nephritis, vasculitis, and hemolytic anemia (Herman et al., 2021). The fixed-dose combination is dosed three times daily, posing a problem to non-compliant patients. Additionally, the cost of the fixed-dose can prompt clinicians to order the medications sepa - rately, which can contribute to pill burden. Ivabradine The latest drug included in the 2017 ACC/AHA HF guidelines is ivabradine. Unlike beta-blockers, this novel therapeutic agent reduces heart rate without compromising blood pressure. It achieves this mechanism by inhibiting the If channel (sodium channel) in the sinoatrial node to slow depolarization and ulti- mately reduce heart rate. The guidelines give ivabradine a IIa/B recommendation for the reduction of HF-related hospitalization in individuals with: symptomatic HF (NYHA class II-III), an LVEF 35% or less, normal sinus rhythm with a heart rate of 70 bpm or greater, and receiving guideline-directed therapy including a beta-blocker at the maximally tolerated dose (Yancy et al., 2017). The recom- mendation comes from the SHIFT trial, where 6,558 patients were randomly assigned to ivabradine or placebo. According to this trial, compared with placebo, ivabradine significantly reduced the composite outcome of cardiovascular mortality or HF-related hospitalization (p < .0001). However, when analyzing outcomes
separately, ivabradine had little impact on all-cause mortality or cardiovascular mortality; the composite outcome was primarily driven by a significant reduction in HF-related hospitalizations (Yancy et al., 2017). In the SHIFT trial, symptomatic bradycardia and transient vision changes were reported more commonly in the ivabradine group than in the placebo group. Real-world data began to surface with an increased risk of atrial fibrillation after initiating ivabradine. Ac - cording to a recent meta-analysis consisting of thirteen trials and 37,533 patients, a significantly higher incidence of atrial fibrilla - tion was associated with ivabradine than with placebo (OR 1.23; 95% CI, 1.08-1.41) (Wang et al., 2021). Therefore, ivabradine is contraindicated in patients with atrial fibrillation. The initial dose of ivabradine is 5 mg twice daily; however, a lower dose of 2.5 mg twice daily is recommended for individuals with a history of conduction defects or those at risk of hemodynamic compromise. Titration is based on the patient’s heart rate. If the heart rate remains above 60 bpm and the patient is asymptom- atic, the dose can be increased to the goal of 7.5 mg twice daily. If not already at the target dose and the patient’s heart rate is between 50 to 60 bpm, a dose increase is not warranted, and the patient should remain on the current dose. Lastly, if the pa- tient’s heart rate falls below 50 bpm or experiences bradycardia symptoms, the dose should be reduced to 2.5 mg twice daily un- less the patient is already at the lowest dose, which would require discontinuation. Sodium-Glucose Cotransporter-2 Inhibitors Patients with HF have a four-fold higher prevalence of T2DM than those without HF (Maack et al., 2018). Until recently, limited phar- macological options existed to treat both highly correlated con- ditions. Furthermore, some T2DM agents, such as pioglitazone and saxagliptin, increase the risk of HF development and hospi- talization. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic agents that reduce both cardiovascu- lar- related events and diabetic outcomes. Clinical trials of SGLT2 inhibitors have shown a class effect in reducing HF-related hospitalization in patients with and with- out T2DM. This serendipitous finding led researchers to look for plausible mechanisms. Unfortunately, the mechanism of ac- tion for benefit in HF is complex and elusive. A leading theory is that SGLT2 inhibitors potentially cause a preload and afterload reduction. Sodium-glucose cotransporter 2 is a protein found mainly in the proximal convoluted tubule and is responsible for reabsorbing glucose via an electrochemical gradient with sodium. Sodium-glucose cotransporter-2 inhibitors work by blocking the endogenous protein and allowing for sodium and glucose to be excreted. An osmotic diuretic effect occurs by eliminating sodium (natriuresis), which contributes to a preload reduction (Verma & McMurray, 2018). An afterload reduction might be plausible by regulating the renal afferent nerve activity, which blunts the cen- tral reflex mechanism to activate the sympathetic nervous system. The result is a decrease in catecholamines that would otherwise increase vascular resistance (Sano, 2018). Data from large randomized controlled trials involving SGLT2 in- hibitors were published after the 2017 ACC/AHA HF guidelines. However, the 2021 ACC Expert Consensus Pathway for Optimiza- tion of HF document recommends empagliflozin or dapagliflozin for patients with NYHA class II-IV and adequate renal function (Maddox et al., 2021). In addition, the American Diabetes Asso- ciation Standards of Medical Care do not specify a specific SGLT2 inhibitor but recommend the use in patients with T2DM when HFrEF predominates (American Diabetes Association, 2021). Evidence supporting the empagliflozin recommendation comes from the EMPEROR-REDUCED trial (Packer et al., 2020). This tri- al included 3,730 adult patients with or without T2DM, an LVEF of 40% or less, and an NYHA class II-IV that were randomly as- signed to empagliflozin 10 mg or placebo. The empagliflozin group, compared with placebo, had a 25% risk reduction in the composite outcome of cardiovascular death or first hospitaliza - tion for decompensated HF (HR 0.75; 95% CI 0.65 to 0.86; p <
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