tion for decompensated HF (HR 0.75; 95% CI 0.65 to 0.86; p < .001). The primary composite outcome benefit was mainly from a 31% reduction in HF hospitalization. When analyzed separately, empagliflozin, compared to placebo, did not significantly reduce cardiovascular mortality (HR, 0.92; 95% CI, 0.75 to 1.12). The HFrEF dosing of empagliflozin is 10 mg by mouth every morning. While this agent is contraindicated with an eGFR less than 30 ml/min/1.732 for a T2DM indication, empagliflozin can be initiated in adults with HFrEF at an eGFR as low as 20 ml/ min/1.732. From clinical trials, genital infections were a statisti- cally significant adverse event; this adverse event can be treated with antifungal agents and does not warrant discontinuation of the SGLT2 inhibitor. Other adverse effects are urinary tract infec- tions, diabetic ketoacidosis, volume depletion, and hypotension. The ACC Expert Consensus Pathway for HF also supports dapa- gliflozin in the HFrEF. The evidence for this decision comes from the DAPA-HF Trial (McMurray et al., 2019). This trial consisted of 4,744 adult patients with HFrEF (regardless of T2DM status) with an LVEF of 40% or less, NYHA II-IV symptoms, and elevated NT- proBNP levels. Like empagliflozin in the EMPEROR- REDUCED trial, dapagliflozin reduced the risk of the composite outcome of cardiovascular death and the initial episode of worsening heart failure by 26% (HR, 0.74; 95% CI, 0.65 to 0.85%; p < .001). This significant outcome was also driven primarily by a risk reduction in HF-related hospitalizations (30%). Currently, dapagliflozin has the FDA approvals for glycemic con - trol in T2DM patients; HF risk reduction in patients with or with- out T2DM; and risk reduction for renal decline, end-stage kidney disease, cardiovascular death, and hospitalization in patients with HFrEF and chronic kidney disease. The current dose for HFrEF patients is 10 mg daily in patients with an eGFR greater than 30 ml/min/1.73m2. Genital infections and diabetic ketoacidosis were significantly greater in patients taking dapagliflozin compared with placebo in clinical trials. Patients can also experience urinary tract infections, volume depletion, and hypotension while taking this medication. To date, dedicated HF trials involving other SGLT2 inhibitors (cana- gliflozin and ertugliflozin) are not available. Unfortunately, clinical trials that brought these agents to market had a low percentage of patients with a history of heart failure. For that reason, these two SGLT2 inhibitors do not have an FDA indication for HFrEF. Digoxin Atrial fibrillation is a concomitant condition associated with HF, where the prevalence reaches nearly 25% (Carlisle et al., 2019). Controversy exists with the role of digoxin therapy in the HFrEF setting to treat both conditions despite this agent being nearly a century old. Conflicting data exist regarding whether digoxin increases mortality risk due to older clinical trials having incon- sistent baseline criteria and definitions. According to the DIG trial, patients with an LVEF of 45% or less had no improvement in mortality but had decreased symptoms and a reduction in hospi- talization. The trial is from 1997, and guideline-directed therapy has since evolved, which questions the efficacy of digoxin today. Meta-analyses that try to reconcile data over the years have led to mixed results on mortality. The 2021 ACC/AHA consensus up- date states digoxin lacks any new compelling data to change the IIa/B recommendation from the previous guidelines (Maddox et al., 2021). Currently, digoxin may be used to reduce hospitaliza- tions in patients with HFrEF. Alternatively, guidelines suggest the consideration of digoxin in patients with atrial fibrillation for heart
rate reduction when other agents are not appropriate. The start- ing dose of digoxin is 0.125 to 0.25 mg daily with dose adjust- ments for renal insufficiency, drug interactions (e.g., amiodarone and macrolide antibiotics), and drug levels. The mortality risk is independently associated with a digoxin level of 1.2ng/mL or greater in patients with atrial fibrillation; therefore, a lower target of 0.5-0.9 ng/mL is recommended in the HFrEF set- ting (Lopes et al., 2018). Drug toxicity leads to conduction abnor- malities, hallucinations, intestinal ischemia, and potentially death. Common reactions of the drug may include dizziness, headache, nausea, anorexia, and abdominal pain. Diuretics Diuretics will be discussed in a subsequent section. Other Therapeutic Options: Vericiguat The latest HF medication to receive FDA approval for HFrEF is vericiguat, based on the results from the VICTORIA trial. Vericiguat is an agent classified as an oral guanylate cyclase stim - ulator. Guanylate cyclase is an enzyme that works in tandem with nitric oxide to stimulate cyclic guanosine monophosphate. Intra- cellularly, cyclic guanosine monophosphate facilitates systemic and pulmonary vasodilation, prevents cardiac hypertrophy, and reduces the harmful effects of catecholamines. Vericiguat, compared to placebo, reduced the risk of the primary composite outcome of cardiovascular mortality and HF-related hospitalizations by 10% (HR, 0.90; 95% CI, 0.82 to 0.98; p = .02) according to results from the VICTORIA trial (Armstrong et al., 2020). In a secondary analysis that separated the primary out- come components, HF-related hospitalizations were statistically significant; however, CV mortality was not. The authors of this study stated that the risk reduction of vericiguat, compared to other novel HFrEF agents, was not as substantial-potentially due to a more advanced HF population (41% with NYHA class III-IV) included within the VICTORIA trial. Vericiguat is FDA approved for HFrEF with an LVEF of 45% or less and for patients recently hospitalized or receiving outpatient intravenous diuretics. This agent should be dosed at 2.5 mg by mouth daily with food and titrated as tolerated to 10 mg by mouth daily. The adverse ef- fects of vericiguat were not statistically different from placebo in the VICTORIA trial. However, vericiguat had a numerically higher number of symptomatic hypotensive cases. Additionally, this drug has a contraindication for use in pregnancy due to associated fetal toxicity. Since the FDA approved vericiguat in early 2021, the 2017 ACC/ AHA HF guidelines do not mention this agent. Given the novelty of this agent, the place in HFrEF therapy is unknown at this time. However, it can be considered an add-on agent for those already taking guideline- directed therapy. In addition, the daily cost of vericiguat is $14.57, which may affect clinical decisions (Alsumali et al., 2021). Healthcare Professional Consideration: With newer agents available for the treatment of HFrEF and HFpEF, affordability may be a factor for many patients. However, socioeconomic sta- tus should not preclude patients from receiving beneficial treat - ment. Clinicians should be aware if a drug manufacturer has a savings card that can be used together with health insurance to reduce the monthly cost of the medication. Additionally, drug manufactures may have a patient assistance program for unin- sured or underinsured individuals to receive the medication at no additional cost.
Table 2: Recommended HFrEF Treatment and Dosing Guideline Class Drug COR/LOE
Initial Dosing 6.25 mg TID 2.5 mg BID 2.5-5 mg daily
Maximum Dose
ACEI ACEI ACEI ACEI
Captopril Enalapril Lisinopril Ramipril
I/A I/A I/A I/A
50 mg TID
10-20 mg BID 20-40 mg daily
1.25-2.5 mg daily
10 mg daily
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