A 55-year-old man with hypertension, diabetes mellitus and recent drug eluting stent placement to left anterior descending (LAD) artery after suffering a myocardial infarction comes to your clinic after being discharged from the hospital. He is able to carry out daily activities with ease but reports getting short of breath on climbing 2 sets of stairs. An echocardiogram done during the hospitalization revealed an left ventricular ejection fraction (LVEF) of 35%-39% with wall motion abnormalities in LAD territory. He mentions compliance with his regimen of Aspirin 81 mg once daily, Clopidogrel 75 mg once daily, Amlodipine 5 mg, Atorvastatin 80 mg and Furosemide 20 mg once daily. On examination his blood pressure is 147/87 and heart rate 76 beats per minute, he appears in no acute distress, JVP is 7 cm H2O, lungs are clear, heart sounds are regular with no murmurs and no lower extremity edema is noted. He asks about additional therapies to help recover improve his heart function and quality of life.

NEUROHORMONAL BLOCKADE IN HEART FAILURE

Understanding the pathophysiological role of the neurohormonal axis in heart failure (HF) has been a key driver of the paradigm shift of the management of HF from one of only symptom management to that involving strategies aimed at modulating pathologic left ventricular (LV) remodeling and HF-related mortality.

THE NEUROHORMONAL SYSTEM IN HEART FAILURE

A reduction in myocardial function, stemming from any insult, leads to a decrease in cardiac output and blood pressure and, via activation of baroreceptors, leads to activation of the sympathetic nervous system (SNS) and renal hypoperfusion. The SNS primarily mediates its effects via catecholamines.¹ Via stimulation from the SNS as well as intrinsic renal mechanisms, the renin angiotensin and subsequently aldosterone system are activated, collectively referred to as the renin-angiotensin-aldosterone system (RAAS). The combined effect of the 2 systems leads to increased inotropy, chronotropy, sodium and water retention (leading to an increase in preload), and vasoconstriction (causing an increase in afterload). Over the short term, the above compensation helps maintain cardiac output (CO) and blood pressure (BP); however, chronic activation of the same compensatory mechanisms leads to pathologic remodeling of the ventricular myocardium (Figure 28-1).² Although described more extensively in patients with HF with reduced ejection fraction (HFrEF), regardless of the etiology, similar mechanisms may play a role in HF with preserved ejection fraction (HFpEF).

RENIN-ANGIOTENSIN-ALDOSTERONE RECEPTOR BLOCKADE

Therapies aimed at blocking various steps in the RAAS pathway help to mitigate the effect of the chronically overactivated system, and have demonstrated definitive beneficial effects on morbidity and mortality in HFrEF.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

Angiotensin-converting enzyme (ACE) inhibitors exert their effect via inhibition of the ACE. The ACE, in addition to its role in converting angiotensin I to angiotensin II, also facilitates the degradation of bradykinin and substance P, both of which are potent vasodilators (Figure 28-2). ACE inhibitor therapy has short-term benefits including improvement of cardiac output, enhancement of natriuresis, and vasodilation, and long-term effects including prevention or delay of LV remodeling as well as causing favorable LV reverse remodeling.³

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS IN HEART FAILURE WITH REDUCED EJECTION FRACTION

ACE inhibitors have been evaluated in multiple clinical trials in patients with symptomatic HF, in patients with asymptomatic LV systolic dysfunction, and in patients with post myocardial infarction (MI) HF, with favorable effects. Enalapril and captopril are the best studied ACE inhibitors; however, similar benefits have been observed with other ACE inhibitors as well. Garg and Yusuf conducted a meta-analysis of 32 trials comparing various ACE inhibitors versus placebo in 7105 symptomatic HFrEF patients of ischemic and nonischemic etiology (Table 28-1). A significant reduction in odds of developing the combined endpoint of death or hospitalization for HF, as well as of death—primarily due to a substantial reduction in deaths attributable to progressive HF—was observed with ACE inhibitor use as compared with placebo.⁴ The greatest benefit was seen during the first3 months, but additional benefit was observed during longer-term treatment. Moreover, the lower the EF, the more the benefit observed. An improvement in exercise capacity in patients with HFrEF was noted by Narang et al in their meta-analysis of 33 studies.⁵

In addition, patients with asymptomatic LV dysfunction comprise a cohort that is at high risk for development of HF and mortality.⁶ The Studies of Left Ventricular Dysfunction (SOLVD) prevention trial examined the effect of enalapril on morbidity, mortality, and development of HF in patients with asymptomatic LV systolic dysfunction. Compared with placebo, enalapril significantly reduced the rate of hospitalization for HF and showed a trend toward lower mortality.⁷ The salient results from 3 of the landmark clinical trials^7-9 of ACE inhibitors in HFrEF or asymptomatic LV systolic dysfunction are shown in Figure 28-3.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

There is no convincing evidence to show that ACE inhibitor therapy improves hard endpoints in patients with HFpEF. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial studied perindopril in 850 patients with HFpEF and failed to show a significant improvement in the primary outcome (composite of all-cause mortality and unplanned HF-related hospitalization). However, significant improvements were observed favoring ACE inhibitor therapy in some other secondary endpoints, including the proportion of patients in NYHA functional class I and change in 6-minute walk test (6MWT) at 1 year.¹⁰

OPTIMAL DOSING OF ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial compared the efficacy and safety of low-dose versus high-dose ACE inhibition on mortality and morbidity in chronic symptomatic heart failure with either low-dose (target 2.5-5.0 mg daily) or high-dose (target 32.5-35 mg daily) lisinopril. Compared with the low-dose group, patients in the high-dose group had a nonsignificant 8% lower risk of death (p = 0.128) but a significant 12% lower risk of death or hospitalization for any reason(p = 0.002) and 24% fewer hospitalizations for HF (p = 0.002).¹¹

ANGIOTENSIN RECEPTOR BLOCKERS IN HEART FAILURE

Angiotensin II, through its actions on the angiotensin II type I (AT-1) receptor, is a major mediator of vasoconstriction, hemodynamic derangements, adverse remodeling, and symptoms in HF (Figure 28-2).¹² ACE inhibition results in only a partial decrease in the production of angiotensin II, which can also be produced through non-ACE-dependent pathways (Figure 28-2).¹³ Angiotensin receptor blockers (ARBs), which block the AT-1 receptor, could theoretically produce more complete blockade of the effects of angiotensin II and could potentially have more favorable effects in HF compared with ACE inhibitors. Moreover, compared to ACE inhibitors, ARBs do not inhibit the breakdown of bradykinin, the substance that causes the adverse effects of cough associated with ACE inhibitor use. ARBs may therefore be better tolerated than ACE inhibitors. Furthermore, it had been hypothesized that concomitant use of ACE inhibitors and ARBs may lead to synergistic effects of RAAS antagonism and could potentially lead to better clinical outcomes. Therefore, several trials evaluated the effects of ARBs compared with ACE inhibitors in HFrEF, as well as the effects of both ACE inhibitors and ARBs used in combination.

ANGIOTENSIN RECEPTOR BLOCKERS IN HEART FAILURE WITH REDUCED EJECTION FRACTION

A head-to-head comparison of ARBs and ACE inhibitors was conducted in New York Heart Association class II to IV HF (LVEF ≤40%) patients in Evaluation of Losartan In The Elderly II (ELITE II) and in high-risk patients after acute MI in the Optimal Trial In Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) trials, which compared losartan 50 mg daily with captopril 50 mg 3 times daily.^14,15 There was no evidence of superiority of the ARB over the ACE inhibitor. In fact, there was even a trend for better outcomes with the ACE inhibitor in some endpoints. Going 1 step further, the Valsartan in Acute Myocardial Infarction Trial (VALIANT) compared valsartan 160 mg daily, captopril 50 mg 3 times daily, and valsartan 160 mg daily + captopril 50 mg 3 times daily in a 1:1:1 fashion in patients within 10 days post-MI with LV systolic dysfunction and HF.¹⁶ The ACE inhibitor and the ARB were equivalent in terms of the overall mortality as well as fatal and nonfatal cardiovascular (CV) outcomes. Furthermore, VALIANT showed that combined therapy of ACE inhibitor and ARB soon after MI resulted in an increase in adverse events without improving overall survival. Adverse events were less common for monotherapy, with hypotension and renal dysfunction being more common in the ARB group and cough, skin rash, and taste disturbance more common in the ACE inhibitor group.

COMBINED ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AND ANGIOTENSIN RECEPTOR BLOCKER THERAPY IN CHRONIC HEART FAILURE WITH REDUCED EJECTION FRACTION

The Valsartan Heart Failure Trial (Val-HeFT) and the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Added trials evaluated whether the combination of ACE inhibitors and ARBs would be more beneficial than ACE inhibitors alone in symptomatic patients with chronic HFrEF.^17,18 Although a significant decrease in CV mortality and a reduction in HF hospitalization were seen in the CHARM-Added trial with candesartan, Val-HeFT demonstrated only a decrease in HF hospitalizations in the valsartan group. Notably, in Val-HeFT and the CHARM-Added, as well as other studies that have studied concomitant use of ACE inhibitors and ARBs, a higher incidence of hypotension, hyperkalemia, and renal dysfunction has been seen with combination therapy. Therefore, ARBs may be considered in patients who appear to have continuing symptoms of progressive HF and hospitalizations despite therapy with target doses of ACE inhibitors and beta blockers when aldosterone antagonists are not tolerated. However, there is no role for routine combined use of ACE inhibitors, aldosterone antagonists, and ARBs (ACC/AHA Guidelines Class III recommendation).¹⁹

ANGIOTENSIN RECEPTOR BLOCKERS INACE-INTOLERANT PATIENTS

The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial addressed the role of ARBs in HF patients intolerant of ACE inhibitors by comparing candesartan with placebo and showing a significant 23% reduction in the composite outcome of CV mortality or HF hospitalizations. Interestingly, the margin of benefit observed with ARBs in the CHARM-Alternative trial was similar to that observed with ACE inhibitors compared to placebo.²⁰ Therefore, ARBs are now considered to provide equivalent benefit to ACE inhibitors in patients with HFrEF and are often used when patients are unable to tolerate ACE inhibitors due to cough or angioedema.

ANGIOTENSIN RECEPTOR BLOCKERS IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

The effect of ARBs on outcome in HFpEF has been best studied in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved and the Irbesartan in Heart Failure with Preserved Ejection Fraction (I–PRESERVE) trials.^21,22 A trend toward lower incidence of the primary composite endpoint of CV death or hospital admission for HF was seen in the candesartan arm, driven primarily by a reduction in hospitalizations for HF in CHARM-Preserved. However, the larger I-PRESERVE trial (4128 patients with HFpEF) showed no significant difference in the occurrence of death from any cause or hospitalization for a CV cause (Figure 28-4). Hence, no conclusive data exist to support routine use of ARBs in patients with HFpEF to improve mortality or morbidity outcomes.

ALDOSTERONE ANTAGONISTS

Aldosterone is secreted by the adrenal cortex in response to angiotensin II and other non-RAAS factors, the most potent of which is serum potassium. As the role of ACE inhibitors and ARBs became more prevalent in HF, aldosterone escape, a phenomenon resulting from only partial inhibition of aldosterone by inhibitors of the RAAS and non-RAAS activation of aldosterone, was described.²³ HF is characterized by excess sodium and fluid retention, both of which are enhanced by aldosterone. Moreover, aldosterone increases myocardial and vascular fibrosis and LV hypertrophy (Figure 28-5). As higher levels of circulating aldosterone were found in patients with HF, the role of mineralocorticoid receptor antagonists (MRA) in HF emerged.

ALDOSTERONE ANTAGONISTS IN HEART FAILURE WITH REDUCED EJECTION FRACTION

The Randomized Aldactone Evaluation Study (RALES) examined the efficacy of spironolactone 25 mg (titrated to 50 mg daily as tolerated) compared with placebo on a background of standard HF therapy, which at the time of the trial did not routinely use beta blockers in patients with severe HF (NYHA class III-IV).²⁴ The trial was terminated early when a 30% relative risk reduction in all-cause mortality (95% confidence interval [CI], 0.60-0.82; P <0.001) as well as 29% reduction in sudden death was observed. Incidence of gynecomastia was 10% in the male population and was the major adverse event although leading to discontinuation of the medication in only a very small proportion of patients; but importantly the incidence of serious hyperkalemia (serum potassium ≥6 meq/L) was not significantly higher in the spironolactone group under close potassium-monitoring strategies of the trial. The Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) trial studied eplerenone, a more specific aldosterone antagonist, in patients with LV systolic dysfunction and HF post-MI.²⁵ Again, a significant reduction in mortality by 15% (P = 0.008) and CV deaths or hospitalizations by 13% (P = 0.002) was observed in the eplerenone group. As expected, incidence of gynecomastia was not higher in the eplerenone group. As aldosterone receptor antagonist use became more prevalent in patients with moderate to severe HF, the Eplerenone in Mild Patients Hospitalization And Survival Study in Heart Failure (EMPHASIS-HF) trial enrolled patients with mild chronic HFrEF on a background of optimal concomitant therapy with nearly 90% of patients being on both beta blockers and ACE inhibitors or ARBs.²⁶ Once again, results overwhelmingly favored eplerenone. The primary composite outcome of death from CV causes or hospitalization for HF and overall mortality was reduced by 37% (hazard ratio [HR], 0.63; 95% CI, 0.54-0.74; P <0.001) and 24% (HR, 0.76; 95% CI, 0.61-0.94;P = 0.01) in the eplerenone group compared to placebo, respectively. Importantly, incidence of hyperkalemia was not significantly different with eplerenone or placebo (Figures 28-6 and 28-7).