placebo, candesartan had a significant decrease in the composite of HF-related hospitalizations and cardiovascular death (p = .051) (Kjeldsen et al., 2020). Based on this trial, current guidelines give a IIb/B recommendation for using ARBs to decrease HF hospital- ization (Yancy et al., 2017). Unfortunately, efficacy for the use of irbesartan could not be duplicated in the I-PRESERVE trial. In this trial, no significant difference was observed in patients with an LVEF 45% or greater taking irbesartan 300 mg daily or placebo in terms of all- cause mortality or cardiovascular-related hospitaliza- tion after a 50 month mean follow-up (Kjeldsen et al., 2020). In the PEP-HF trial, perindopril (4 mg/day), compared with placebo, failed to show a difference in the composite outcome of all-cause mortality or HF-related hospitalization (Kjeldsen et al., 2020). Angiotensin Receptor-Neprilysin Inhibitors In early 2021, the FDA approved sacubitril/valsartan for the treat- ment of HFpEF based on the results of the PARAGON-HF trial; this marks the first time a medication received approval, specifi - cally the treatment of HFpEF. This study included 4,822 patients older than 50 years, with NYHA class II-IV symptoms, an LVEF of 45% or greater, structural heart disease, and elevated NT-proBNP. Patients were randomly assigned to receive sacubitril/valsartan (dose targeted to 97 mg/103 mg twice daily) or valsartan alone (dose targeted to 160 mg twice daily). The combination of sacu- bitril/valsartan, compared with valsartan alone, clinically reduced the risk of the composite of HF-related hospitalizations and car- diovascular death by 13% (RR, 0.87; 95% CI, 0.75 to 1.01; p = .06), but failed to achieve statistical significance (Solomon et al., 2019). Despite sacubitril/valsartan narrowly not meeting the statistical significance for the primary outcome, the FDA advisory commit - tee discussed a favorable safety profile and positive evidence in the PARADIGM-HF in the decision for drug approval (FDA Advi- sory Committee, 2020). Beta-Blockers The ACC/AHA HF guidelines mention beta-blockers in conjunc- tion with an ACE inhibitor/ARB therapy as a class IIa/C recom- mendation in patients with HFpEF. Like evidence with ACE in- hibitors/ARBs, data are sparse regarding beta-blockers in the HFpEF setting. According to a meta-analysis of eleven trials, no morbidity or mortality benefit existed using various beta- blockers in a small group of patients with an EF of 50% or greater (N=73) (Cleland et al., 2018). More recently, according to a secondary analysis of the TOPCAT Trial, beta-blockers were associated with an increased risk of HF-related hospitalization in 1,567 patients with an EF greater than 50%; however, there was not a significant associated risk of CV mortality in this population (Silverman et al., 2019). While evidence supports a mortality benefit in patients with HFrEF, the use of beta-blockers in HFpEF may be better used as an agent for rate control for atrial fibrillation management. Diuretics Current ACC/AHA HF guidelines recommend diuretics to provide symptom relief in patients with volume overload in HFrEF and the HFpEF setting (class IC). In combination with sodium and fluid re - striction, loop diuretics (e.g., bumetanide, furosemide, torsemide) are typically used for diuresis, where dose and route are based on the severity of volume overload. The pharmacokinetics of loop di- uretics may influence clinical decisions. For example, furosemide has a variable bioavailability (10-90%) that is influenced by food, which affects drug absorption. Meanwhile, the bioavailability of torsemide and bumetanide is larger, less variable (80-90%), and has a longer half-life (3-4 hours) than furosemide (1-1.5 hours) (Gupta et al., 2019; Oh & Han, 2015). Therefore, patients refrac- tory to furosemide may have more success with a different loop diuretic. Adverse effects of loop diuretics may include but are not limited to electrolyte imbalances, hypovolemia, and ototoxicity; therefore, clinicians need to be cautious in aggressive diuresis. In patients that are refractory to loop diuretics, thiazide or thi- azide-like diuretics (e.g., metolazone) can be used to augment management. Thiazide and thiazide-like diuretics work to prevent the reabsorption of sodium in the distal convoluted tubule, as well as potassium. As such, adverse events of electrolyte imbalances, hyperuricemia, and orthostatic hypotension may occur.
When managing fluid status, clinicians should carefully examine changes in electrolyte levels, renal function, daily weight (reduc- tion of 1 kg/day), and blood pressure. Sodium-Glucose Cotransporter-2 Inhibitors As previously mentioned, SGLT2 inhibitors reduce the risk of HF hospitalizations; however, data from these landmark trials enrolled a small number of patients with HF or did not stratify patients ac- cording to HF subtype. As a result, these trials had mixed results with the use of SGLT2 inhibitors for patients with HFpEF (Cosen- tino et al., 2020; Januzzi, 2019; Kato et al., 2019). The EMPEROR-PRESERVED trial was the first clinical trial dedi - cated to investigating patients with HFpEF, which used the SGLT2 inhibitor empagliflozin (Anker et al., 2021). In this study, 5,988 patients (with or without T2DM), having an LVEF above 40% and classified as an NYHA class II to IV, were randomly assigned to re - ceive empagliflozin 10 mg daily or placebo. The primary outcome of the composite of hospitalization for heart failure or cardio- vascular death occurred in 13.8% (n = 415) of patients receiving empagliflozin and 17.1% (n = 511) of patients receiving placebo (6.9 vs. 8.7 events per 100 patient-years, respectively; HR 0.79; 95% CI, 0.69 to 0.90; p < .001). Separating the components of the primary outcome, a reduction in cardiovascular mortality rates was not statistically significant. Nevertheless, based on the re - sults from this trial, the FDA granted empagliflozin breakthrough therapy designation status as an investigational treatment option for HFpEF. Breakthrough designation status signifies that a drug improves outcomes over other therapeutic agents on at least one clinical endpoint. Additionally, FDA expedites the review and drug development process for this agent. The DELIVER trial (NCT03619213) is another dedicated HFpEF trial with SGLT2 inhibitors that is currently underway. This trial is currently evaluating dapagliflozin 10 mg compared to placebo for the primary composite outcome of HF events and cardiovascular death (Solomon et al., 2021). Included in the trial were patients with an LVEF greater than 40%, elevated natriuretic peptides, and HF signs and symptoms. Results from the DELIVER Trial are ex- pected in 2022. Trials evaluating sotagliflozin, an investigational SGLT2 inhibitor, provide further information with SGLT2 inhibitors’ use in patients with HFpEF. According to the SOLOIST WHF and SCORED Trials, the primary outcome of the composite of cardiovascular mortality and hospitalizations or urgent outpatient care visits related to HF was reduced by 33% with sotagliflozin when compared with pla - cebo. Unfortunately, these trials ended prematurely due to a loss of funding, and this trial included a small sample of patients with HFpEF (N = 1,931) (Bhatt, 2021). Because data from trials evaluating patients with HFpEF dedi- cated trials are still pending or resulted after the 2017 ACC/AHA HF guidelines, no recommendation exists for the use of SGLT2 inhibitors in this setting. The Paragon-HF study and the dedicated HFpEF trials with SGLT2 inhibitors included patients with an LVEF less than 50%; this may have confounded results by including HFmrEF patients by definition. The next update to the HF guide - lines should address this and make recommendations on these two novel drug classes for HFpEF Other Therapeutic Options The 2017 ACC/AHA guidelines do not recommend other agents at this time, such as nitrates, phosphodiesterase-5 inhibitors (e.g., sildenafil), or nutritional supplements due to insufficient evidence (Yancy et al., 2017). Self-Assessment Quiz Question #2 Which of the following therapeutic agents has both FDA ap- proval AND is recommended per HF guidelines for the treat- ment of HFpEF? a. Sacubitril/valsartan.
b. Empagliflozin. c. Dapagliflozin. d. None of the above.
EliteLearning.com/Pharmacy
Book Code: RPTX3024
Page 96
Powered by FlippingBook