ACE Inhibitors/ ARB Therapy Several drug categories are considered pillars of therapy man- agement to reduce mortality in patients with HFrEF—Angioten- sin Converting Enzyme (ACE) Inhibitor and Angiotensin Receptor Blocker (ARB) therapy are two of those classes. The ACC/AHA HF guidelines recommend ACE Inhibitors as a class I/A agent. The evidence is based on clinical trials (e.g., AIRE, ATLAS, CONSENSUS, SOLVD, and SAVE) from various ACE inhibitors that reduce morbidity and mortality. Although data from landmark trials included captopril, enalapril, lisinopril, and ramipril, the benefit of ACE Inhibitors is considered a class effect. Table 2 lists the ACE inhibitors in the trials mentioned above for simplicity. Please refer to guidelines for a complete list of all drugs and targeted doses. Angiotensin Converting Enzyme Inhibitors work by blocking the conversion of angiotensin I to angiotensin II (a potent vasocon- strictor) in the RAAS system to prevent the downstream formation of aldosterone. As a result of direct and indirect effects of reduced aldosterone levels, hypotension, hyperkalemia, and elevated se- rum creatinine are apparent. Additionally, ACE inhibitors block the breakdown of bradykinin, which can produce a dry cough in patients. The incidence of cough ranges in literature, with some reports of up to 37% (mean of 10%) (Shim et al., 2020). Addition- ally, an uncommon (0.1-0.7%) but serious adverse effect of ACE Inhibitors is angioedema. This adverse effect manifests more fre- quently in African Americans, women, the elderly, smokers, and those with a history of drug allergies (Kostis et al., 2018). Due to the severity of this adverse event, reintroduction or use of another ACE Inhibitor is not recommended. An ARB can be used for patients who cannot tolerate an ACE Inhibitor. The ACC/AHA guidelines classify angiotensin Recep- tor Blockers as a class I/A agent per guidelines; however, only candesartan, losartan, and valsartan have this recommendation. Evidence supporting the use of these particular ARBs comes from the CHARM (candesartan), HEAAL (losartan), ValHeFT (valsartan), where a reduction in morbidity and mortality was observed (Yancy et al., 2017). Angiotensin Receptor Blockers inhibit angiotensin II by blocking the angiotensin II type-1 receptor to prevent vasoconstrictive ef- fects of this enzyme. The rates of angioedema with ARB are dif- ficult to determine in literature but appear to be half of that of ACE Inhibitors (Brown et al., 2017). Because ARBs do not inhibit the enzyme kininase, angioedema is less frequent. For patients intolerant to ACE Inhibitors due to angioedema, the guidelines recommend initiating an ARB (I/A) (Yancy et al., 2017). Further- more, the incidence of cough is less with ARB therapy than ACE inhibitors due to less interference of bradykinin metabolism (Chen et al., 2021). As with ACE Inhibitors, clinicians need to monitor blood pressure, Endogenous neuropeptides, such as natriuretic peptides, brady- kinin, and substance P, have beneficial properties in alleviating symptoms, including decreases in: sodium retention, vascular tone, and RAAS activation. Neprilysin is an enzyme that degrades these advantageous neuropeptides; understanding this process led to the development of sacubitril to block neprilysin. Unfortu- nately, neprilysin also degrades angiotensin II; therefore, blocking neprilysin leads to an increase in vasoconstriction. Adding valsar- tan to sacubitril allows for the blockade of both angiotensin II and neprilysin, resulting in an increase in natriuretic peptides without the unwanted effects of angiotensin II. This combination drug of sacubitril and valsartan is a novel agent in treating HFrEF and the first agent in the Angiotensin Receptor-Neprilysin Inhibitors (AR - NIs) class. renal function, and potassium levels with ARBs. Angiotensin Receptor-Neprilysin Inhibitors The ACC/AHA HF guidelines recommend sacubitril/valsartan as a I/B agent. Evidence for the use of this agent is based on the PAR- ADIGM-HF trial. In this trial, sacubitril/valsartan was compared to enalapril in 8,442 patients with NYHA class II-IV HF and an LVEF
of 40% or less. Sacubitril/valsartan, compared with enalapril, sig- nificantly reduced the risk of the composite outcome of cardio - vascular mortality or HF-related hospitalizations by 20% (p < .001) (Yancy et al., 2017). Due to this trial, the ACC/AHA guidelines recommend, for those patients currently tolerating an ACE inhibi- tor or an ARB, changing to sacubitril/valsartan for further morbid- ity/mortality benefits (I/B)(Yancy et al., 2017). The recommended dose of sacubitril/valsartan is 24/26 mg twice daily for patients on low-dose ACE inhibitors/ARB therapy (enalapril equivalent of 10 mg/day or less or valsartan equivalent of 160 mg/day or less). Additionally, patients with an eGFR <30ml/min/1.732, Child-Pugh Class B, and individuals 75 years or older require a lower initial dose of 24/26 mg twice daily. The recommended sacubitril/valsar- tan dose is 49/51 mg twice daily for patients currently taking mod- erate to high ACE inhibitor/ARB doses. A 36-hour washout period is necessary when converting from an ACE Inhibitor to an ARNI to help prevent the development of angioedema. If angioedema previously occurred with an ACE inhibitor, sacubitril/valsartan is contraindicated. Furthermore, a monitoring period of two to four weeks is necessary to observe patients for hyperkalemia, hypo- tension, and decreased renal function before doubling to the next dose (target goal of 97/103 mg)(Maddox et al., 2021). Patients in the PARADIGM-HF experienced significantly more symptomatic hypotensive events with sacubitril/valsartan than enalapril, but this did not affect discontinuation rates. Because of clinical trial exclusion criteria, initial concerns existed for using sacubitril/valsartan in de novo HFrEF (new-onset acute HF) or in patients not previously taking an ACE inhibitor or ARB; however, in light of new data, the 2021 ACC Expert Consensus document now recommends a direct-to-ARNI approach using 24/26 mg twice daily with monitoring for blood pressure, renal function, and electrolytes for individuals naïve to ARNI therapy (Maddox et al., 2021). Beta-Blockers Beta-blockers are considered a cornerstone of HFrEF manage- ment; ACC/AHA guidelines recommend using an evidence-based beta-blocker in conjunction with an ACE Inhibitor, ARB, or ARNI (I/A) (Yancy et al., 2017). Because of mortality-reducing evidence from CIBIS-II (bisoprolol), COMET (Carvedilol), and MERIT (meto- prolol succinate), only these three cardioselective agents are rec- ommended per guidelines (Yancy et al., 2017). Little evidence ex- ists regarding the efficacy between these agents, and the choice may depend on compliance and the cost of the medication. By negating the effects of the compensatory sympathoadren- ergic system in HF, beta-blockers improve systolic and diastolic dysfunction, reverse cardiac remodeling, and prevent or control arrhythmias. To negate some of the adverse effects of beta-block- ers, clinicians should initiate at the lowest dose when patients are volume stable due to the possibility of initial fluid retention with these agents. Additionally, titrating to the recommended goal should be done every two weeks to assess worsening HF symp- toms. Clinicians should not suddenly discontinue beta-blockers because of withdrawal effects, such as tachycardia and rebound hypertension. Other adverse effects to monitor with beta-blockers include bra- Spironolactone and eplerenone are mineralocorticoid (aldoste- rone) receptor antagonists (MRAs) with a I/A recommendation per ACC/AHA HF guidelines for specific individuals. Evidence supporting these agents is based on the RALES (spi- ronolactone) and EMPHASIS-HF (eplerenone) trials. According to the RALES trial, spironolactone, compared with placebo, de- creased mortality by 30%, hospitalization by 35%, and significant - ly improved HF symptoms in patients with an NYHA class III and above. In the EMPHASIS trial, eplerenone also reduced the risk of the composite outcome of mortality and HF-related hospital- izations by 37% in patients with NYHA class II-IV (Ferreira et al., 2019). Both the RALES and EMPHASIS-HF trials were prematurely dycardia, fatigue, dizziness, and hypotension. Mineralocorticoid Receptor Antagonists
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