Keyword

Rationale for Renin–Angiotensin–Aldosterone System (RAAS) Inhibition in Heart Failure (HF)

According to the universal definition, HF is a complex clinical syndrome that comprises 3 elements: (1) structural or functional heart disease; (2) HF symptoms including dyspnea, fluid retention/edema, fatigue and exercise intolerance; (3) and objective signs commonly seen in HF [1]. The prevalence of HF increases with age up to 1–2% among adults [2, 3], however, taking into account unrecognized HF cases this number is presumably higher [4]. In addition, growing number of patients progress into a phase of advanced HF with persistent symptoms at rest and recurrent hospitalizations despite guideline-directed management and therapy (GDMT) [5,6,7]. HF is therefore a global challenge as prognosis remains poor with a 1-year mortality of 25–75% [8,9,10]. HF is classified based on left ventricular (LV) ejection fraction (EF) as follows: HF with reduced EF (HFrEF) with LV EF of ≤ 40%; HF with mildly reduced EF (HFmrEF) with LV EF of 41–49%; and HF with preserved EF (HFpEF) with LV EF of ≥ 50% [11, 12]. Moreover, those patients with HFrEF at baseline who show an increase at second measurement of LV EF of > 40% are referred to have HF with improved EF (HFimpEF) [1].

Distinct HF phenotypes reflect to different etiologies and complex pathophysiology of HF. Nonetheless, neurohormonal activation seems to be a common trigger in the development and progression of chronic HF. The adrenergic nervous system, the RAAS and the cytokine systems are initially activated as short-term compensatory mechanisms to maintain hemodynamic stability in a clinically asymptomatic patient. However, long-term maladaptive neurohormonal activation contributes to pathological LV remodeling and secondary end-organ damage with subsequent cardiac decompensation, collectively leading to symptomatic HF [13]. As a proof of concept, during the past decades, number of large, randomized clinical trials confirmed the efficacy of different RAAS inhibitors in the management of HF. Nonetheless, novel medications targeting the RAAS have been still proven in recent clinical HF studies. Accordingly, HF guidelines have been updated lately by the American College of Cardiology/American Heart Association (ACC/AHA), the Heart Failure Association of the European Society of Cardiology (HFA/ESC) and the Canadian Cardiovascular Society/Canadian Heart Failure Society (CCS/CHFS)—in part—to introduce pharmacological innovations of RAAS inhibition into GDMT of HF [11, 14, 15].

RAAS Inhibition is the Cornerstone of GDMT in HFrEF

Angiotensin-Converting Enzyme (ACE) Inhibitors

Unless contraindicated or not tolerated, ACE inhibitors are recommended in all—symptomatic and asymptomatic—patients with HFrEF to increase survival and improve symptoms [16,17,18,19]. ACE inhibitors should be initiated in low doses and thereafter uptitrated to the maximum tolerated recommended doses. Higher doses of ACE inhibitors are more effective than lower doses in preventing hospitalization. However, adjustment of the dose of diuretics may be necessary, because fluid retention can interfere with ACE inhibitory therapy and symptomatic hypotension can occur during the initiation of ACE inhibitors. ACE inhibitors act on the RAAS by inhibiting the enzyme that is responsible for the conversion of angiotensin I to the biologically active angiotensin II [20]. In addition, ACE inhibitors also inhibit kininase II and thereby may induce the upregulation of bradykinin, which may potentiate the effects of angiotensin suppression. All together, ACE inhibitors promote reverse LV remodeling and improve HF outcome.

The effectiveness of ACE inhibitors has been consistently reported in clinical trials including broad varieties of symptomatic and asymptomatic patients as well as causes and severity of LV dysfunction. Studies of Left Ventricular Dysfunction (SOLVD prevention) [21], Survival and Ventricular Enlargement (SAVE) [22] and Trandolapril Cardiac Evaluation (TRACE) [23] clinical studies demonstrated that ACE inhibitors limit the progression to symptomatic HF and the need of hospitalization in asymptomatic patients with LV dysfunction. Likewise, ACE inhibitors showed similar benefit for patients with symptomatic LV dysfunction. Moreover, all the three placebo-controlled chronic HF trials demonstrated a reduction in mortality [16, 19, 21]. Although placebo-controlled mortality trials have been conducted only with enalapril in patients with chronic HF, ACE inhibitors reduce mortality in direct relation to the degree of severity of chronic HF. Indeed, among HF patients with NYHA class IV, the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) [16] had a much larger effect size than the SOLVD treatment trial on mild congestive HF [19], which in turn had a larger effect size than the SOLVD prevention trial on asymptomatic LV dysfunction [21]. In line, enalapril improves HF with a mechanism independent of vasodilation, and this positive effect is related to the extent of neurohormonal activation as a prognostic factor for patients with HF. Accordingly, in the Vasodilator Therapy of Heart Failure II (V-HeFT-II) trial enalapril had significantly lower mortality as compared with the vasodilatory combination of hydralazine plus isosorbide dinitrate—with no direct action on the neurohormonal systems [24]. Beyond enalapril, multiple ACE inhibitors have been proven in myocardial infarction (MI) trials. ACE inhibitors including captopril, trandolapril and ramipril similarly improve both survival and functional NYHA class in HFrEF patients following acute MI [22, 23, 25]. Use of ACE inhibitors—or ARBs—are therefore recommended as soon as safely possible after MI in hemodynamically stable patients with HF or an LV EF < 40% [11, 14, 15]. In conclusion, the effects of ACE inhibitors on the natural history, development and progression of HF and post-MI LV systolic dysfunction represent “class effects” of these agents. Nonetheless, the effectiveness of ACE inhibitors is less well established in HFrEF patients with hypotension and impaired renal function.

Over the past decades, number of experimental and clinical studies have provided evidence that ACE inhibitors promote reverse cardiac remodeling as shown by reduced LV volumes and increased LV EF [26]. As a matter of fact, one of the first treatments among RAAS inhibitors shown to reverse cardiac remodeling was ACE inhibition [27]. Considering that both plasma and cardiac RAAS are activated in infarcted animals to promote angiotensin II formation, in pioneer works by Pfeffer et al. treatment with captopril could reduce chamber dilatation and infarction size, as well as improve survival in post-MI rats [28, 29]. Following experimental studies with ACE inhibitors and ARBs on post-MI rats have shown enhancement in intracellular Ca2+ handling, cellular and membrane protein expression and gene expression levels [30]. ACE inhibition can also enhance cardiac NO production and attenuate beta adrenergic signaling [31]. Afterwards, reverse remodeling due to ACE inhibitory therapy was demonstrated in the human SAVE trial [22]. Likewise, in the SOLVD trial enalapril reduced LV volumes regardless of symptomatic status and improved EF as these effects were related to reverse LV remodeling [32].

ACE inhibitors are contraindicated in cardiogenic pre-shock/shock and with history of angioedema, bilateral renal artery stenosis, pregnancy and known adverse (e.g. allergic) reaction. Majority of the adverse effects of ACE inhibitors are related to suppression of the RAAS. Significant hyperkalemia (>5.0 mM/L), significant renal dysfunction [creatinine > 221 µM/L (>2.5 mg/dL) or eGFR < 30 mL/min/1.73 m2], symptomatic or severe asymptomatic hypotension (systolic blood pressure < 90 mmHg) need caution. Light hypotension and mild azotemia are often seen during the initiation of therapy and well tolerated. Blood chemistry (serum potassium level, creatinine, urea/BUN) needs to be monitored in 1–2 weeks after initiation, then in 1–2 weeks after final dose titration and 4-monthly thereafter. Side effects of ACE inhibitors including bothersome nonproductive cough (10%), skin rash or angioedema (<1%) are related to kinin potentiation. In such patients, angiotensin receptor blockers (ARBs) are the recommended alternative line of therapy. Except serious complications (e.g. angioedema, hyperkalemia) occur, abrupt withdrawal of an ACE inhibitor should be avoided as it may cause clinical deterioration [11, 14, 15].

Angiotensin Receptor Blockade

ARBs are recommended and well tolerated in symptomatic and asymptomatic patients with reduced EF who are intolerant of ACE inhibitors for reasons other than hyperkalemia or renal insufficiency such as cough, skin rash, and angioedema. Like ACE inhibitors, ARBs have similar rates of hypotension, hyperkalemia or renal dysfunction. ARBs inhibit RAAS through the angiotensin type 1 (AT1) receptor that mediates majority of relevant adverse effects of angiotensin II on cardiac remodeling. Similar to ACE inhibitors, ARBs exert their beneficial effects on reverse LV remodeling by reducing LV dimensions and improving LV EF [33] as this process is predictive of a long-term prognosis [34]. ARBs including candesartan, valsartan and losartan have been evaluated in placebo-controlled HF trials [33, 35,36,37]. Candesartan significantly reduced all-cause mortality in the Candesartan Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM-Alternative) trial [35], irrespective of background ACE inhibitor or beta blocker therapy. Valsartan had a similar favorable effect on survival in patients not receiving an ACE inhibitor in the Valsartan Heart Failure Trial (Val-HeFT) [33]. The Losartan Heart Failure Survival Study (ELITE II) was designed to directly compare the ARB losartan with the ACE inhibitor captopril on survival and tolerability of NYHA II-IV class HFrEF patients. There were no significant differences in all-cause mortality or sudden death between the two treatment groups, but losartan was significantly better tolerated [38]. Afterwards, two captopril-controlled trials aimed to compare an ARB and an ACE inhibitor in post-ST elevation MI patients with subsequent LV systolic dysfunction or HF. In the Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) study losartan (18%) was not as effective as captopril (16%) on all-cause mortality [39]. Conversely, in the Valsartan in Acute Myocardial Infarction Trial (VALIANT) on 14703 patients with acute MI valsartan was shown to be noninferior to captopril on all-cause mortality (valsartan 19.9%, captopril 19.5%) [40]. However, the combination of captopril and valsartan increased the number of adverse events with no further reduction in mortality (19.3%) in VALIANT. Valsartan (80 mg twice daily) therefore represents an alternative to ACE inhibitors. As a matter of fact, when complement ARBs were tested on top of ACE inhibitory therapies, neither candesartan in the CHARM-Added trial [36], nor valsartan in the Val-HeFT trial [33] added significant positive effect on mortality. Based on the results of the Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) trial comparing high-dose versus low-dose ARB effect on all-cause death and HF admissions [37], ARBs should be initiated with the starting doses and thereafter uptitrated to the recommended doses [11, 14, 15]. Nevertheless, ACE inhibitors remain first-line options in the GDMT of HF, while ARBs are recommended for ACE-intolerant patients [11, 14, 15]. As with ACE inhibitors, blood pressure, renal function and potassium should be reassessed within 1–2 weeks after initiation of ARBs and monitored closely after changes in doses. Side effect profile of ARBs is similar to those of ACE inhibitors in terms of hyperkalemia or renal insufficiency.

There is lack of strong evidence regarding ACE inhibitors and ARBs in the early management of acute or worsening HF [15]. Observational data are available from the Get With The Guidelines-HF Registry (n = 16052) showing lower mortality and first year readmission rates in patients treated with ACE inhibitor/ARB treatment before discharge [41]. Indeed, a matched-cohort analysis showed that all-cause mortality was lower in patients who initiated in-hospital ACE inhibitor/ARB treatment compared with those for whom ACE inhibitor/ARB treatment was discontinued [42]. At the same time, in such patients hospitalized for HFrEF hemodynamic instability and/or worsening renal function much interfere with the otherwise optimal GDMT [43,44,45]. Important to note, a preventive reduction or withdrawal of ACE inhibitor/ARB therapy is carried out in a significant portion of patients with no documented impairment of renal function [46].

Dual Angiotensin Receptor and Neprilysin Inhibition

The Prospective Comparison of ARNi With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial [47] was the first multicentre, randomized, double-blind trial to evaluate the efficacy and safety of LCZ696 (200 mg twice daily) versus enalapril (10 mg twice daily)—in addition to recommended therapy—on morbidity and mortality in HFrEF. It is noteworthy that the trial was stopped early, because of the overwhelming benefit on the LCZ696 arm. Among 8442 HFrEF patients with NYHA class II-IV LCZ696 was superior to enalapril in the primary composite endpoint (death from cardiovascular causes or first hospitalizations for HF) forasmuch that occurred in 21.8% in the LCZ696 group and 26.5% in the enalapril group (P < 0.001). Similar efficacy was observed with LCZ696 as compared with enalapril in death from any cause, death from cardiovascular causes and risk of hospitalization (all P < 0.001). In addition, LCZ696 significantly decreased the symptoms and physical limitations of HF (P = 0.001). Although the LCZ696 group had higher proportions of patients with hypotension and non-serious angioedema than the enalapril group, but had a simultaneous reduction in the decline in eGFR [48], in hyperkalemia [49], in the incidence of diabetes requiring insulin treatment [50], cough and even loop diuretic requirement [51]. Patients developing symptomatic hypotension also gained clinical benefits from LCZ696 therapy [52].

LCZ696 is the first-in-class drug with dual angiotensin receptor and neprilysin inhibition (ARNi) as a novel therapeutic strategy in HF [53]. LCZ696 is a salt complex that comprises two active components, i.e. the pro-drug sacubitril and the ARB valsartan [54], and thereby delivers simultaneous neprilysin inhibition and AT1 receptor blockade [55]. Sacubitril is further metabolized to the neprilysin inhibitor LBQ657. In the failing heart natriuretic peptide release from the heart (ANP and BNP) and the vasculature (CNP) have potential beneficial actions on the regulation of blood pressure and volume [56,57,58]. Furthermore, preclinical studies indicate that natriuretic peptides also exert potent cardiac antihypertrophic and antifibrotic effects [59, 60]. Since the endopeptidase neprilysin is responsible for natriuretic peptide degradation, targeting neprilysin appears a reasonable therapeutic approach in HF. Nonetheless, neprilysin metabolizes angiotensin I and II via several pathways, inhibition of neprilysin alone is therefore insufficient as it is associated with an increase in angiotesin II levels, counteracting the potential benefits of neprilysin inhibition [61]. For this reason, neprilysin inhibition must be accompanied by simultaneous RAAS blockade (e.g. AT1 receptor blockade). ARNi prevents both the counterproductive RAAS activation seen with neprilysin inhibition alone and the increase in bradykinin seen with neprilysin inhibition plus ACE inhibitor [61, 62]. Complementary effects of simultaneous inhibition of neprilysin and suppression of the RAAS with ARNi lead to enhancing cGMP-mediated benefical effects of natriuretic peptides and suppressing RAAS-mediated detrimental effects [63]. Natriuretic peptide levels are diagnostic and prognostic biomarkers in HF. Unlike BNP, NT-proBNP is not a substrate for neprilysin, consequently, NT-proBNP remains a useful biomarker of therapeutic effect and prognosis during neprilysin inhibition [47, 53]. Bradykinin is a substrate of neprilysin and other vasopeptidases and its elevation has been associated with cough and angioedema. However, LCZ696 opens alternative degradation pathways for bradykinin in accordance with a lower incidence of cough and a higher proportion of non-serious angioedema in patients treated with LCZ696 versus enalapril in PARADIGM-HF.

Growing evidence suggests that ARNi can also reverse LV remodeling in the failing heart. In rodent models of MI or ischemia–reperfusion injury ARNi could attenuate LV remodeling by reducing cardiac fibrosis and hypertrophy [64, 65]. Likewise in HFrEF patients, ARNi leads to a dose-dependent reverse remodeling involving both systolic and diastolic LV function [66, 67]. In addition, two trials on patients with HFrEF have been presented lately that support the role of ARNi in cardiac reverse remodeling. The Study of Effects of Sacubitril/Valsartan versus Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction (EVALUATE-HF) trial demonstrated reduction in both atrial and ventricular volumes, improvement in diastolic function and reduction in NT-proBNP after 3 months of treatment with ARNi as compared to enalapril [68]. The Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF trial) demonstrated similar improvements in LV EF, as well as reduction in left atrial and LV volume indicies [69]. Finally, a sub-study of PROVE-HF established a strong predictive value of the rise in ANP concentration on later improvements in LV EF and reductions in left atrial volume index [70]. This observation was later proven single-centre retrospective study of patients with HFrEF showing ARNi had greater influence on left atrial reverse remodeling and was associated with a better prognosis compared with ACE inhibitor/ARB use [71]. However, the mode of action of ARNi on reverse remodeling warrants further mechanistic studies.

Accordingly, ARNi (sacubitril/valsartan) is recommended as a replacement for ACE inhibitor/ARB therapy in symptomatic HFrEF patients despite optimal GDMT (strong recommendation). A candidate for sacubitril/valsartan therapy should be hemodynamically stable and have an adequate blood pressure and an eGFR ≥ 30 mL/min/1.73 m2. A washout period of at least 36 h after ACE inhibitor therapy is required in order to minimize the risk of angioedema. Nevertheless, 36 h washout period is not necessary for those receiving ARB therapy at the time of hospitalization [11, 14, 15]. Recently, two studies have examined the safety and efficacy of ARNi in patients hospitalized with acute HF, including de novo HF, with or without previous exposure to RAAS inhibition. The Comparison of Pre-discharge and Post-Discharge Treatment Initiation With LCZ696 in Heart Failure Patients With Reduced Ejection-Fraction Hospitalized for an Acute Decompensation Event (TRANSITION) study [72] showed the safety of initiating ARNi in HFrEF patients with decompensated HF compared with initiation of ARNi after discharge. In addition, patients with newly diagnosed HF were shown to be more likely to achieve target dose of sacubitril/valsartan at 10 weeks with fewer serious adverse reactions in TRANSITION [73]. Patients with de novo HFrEF who started ARNi therapy had a greater decrease in NT-proBNP and lower rates of rehospitalization without compromising up-titration of other GDMT. Likewise, in-hospital initiation of sacubitril/valsartan was compared with enalapril for 8 weeks in hemodinamically stable HFrEF patients (n = 881) hospitalized with acute decompensated HF and resulted in a significantly greater proportional reduction in NT-proBNP in the Comparison of Sacubitril/Valsartan Versus Enalapril on Effect on Nt-Pro-Bnp in Patients Stabilized From an Acute Heart Failure Episode (PIONEER-HF) trial [74]. This change was consistent across all subgroups, irrespective of previous HF or RAAS inhibition. When in-hospital initiation of sacubitril/valsartan and switch from enalapril to sacubitril/valsartan were followed-up for an additional 4 weeks, a further 17.2% and 37.4% reduction in NT-proBNP was observed, respectively [75]. ARNi as an in-hospital first choice therapy resulted in a lower incidence of HF rehospitalization or cardiovascular mortality over the entire 12-week trial period compared with the conversion of enalapril to ARNi after the first 8 weeks (13.0% versus 18.1%; P = 0.03) [75]. A recent additional analysis has shown that in hemodynamically stabilized patients with acute decompensated HF the efficacy and safety of sacubitril/valsartan are generally consistent across dose levels, even in patients who might not tolerate early up-titration to target dose [76]. In summary, first-line ARNi therapy as an alternative to either an ACE inhibitor or ARB may be considered with a new diagnosis of HFrEF (weak recommendation) [11, 14, 15]. ARNi might reduce diuretic requirements and diuretic dosing should be carefully evaluated when starting ARNi therapy. Initial dosing and titration schedule should be individualized. Drug tolerability, side effects, and laboratory follow-up (renal function and serum potassium level) of ARNi is similar to that of ACE inhibitors or ARBs, and essential after discharge to monitor for adverse events [11, 14, 15]. Last but not least, important lacking clinical information has been reported lately on the utility of ARNi in patients with acute MI complicated by HF. The Prospective ARNI versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) trial aimed to compare sacubitril/valsartan (200 mg twice daily) with ramipril (5 mg twice daily) treatment early after high-risk MI (12 h to 7 days) on the composite endpoint of cardiovascular death or incident HF [77]. A total of 5661 patients were involved for a median of 22 months. Of note, a primary outcome event occurred with a similar rate in the sacubitril/valsartan group (11.9%) and in the ramipril group (13.2%). Accordingly, ARNi and ACE inhibiton show comparable outcome on the incidence of death from cardiovascular causes or incident HF among patients with acute MI [78].

Aldosterone Antagonists

Mineralocorticoid receptor antagonists (MRAs: spironolactone or eplerenone) are recommended, in addition to an ACE inhibitor and a beta blocker, in all patients with HFrEF to reduce mortality and the risk of HF hospitalization, as well as to improve symptoms [79, 80]. As a matter of fact, aldosterone levels are not reduced by long-term treatment with ACE inhibitors [81]. MRAs are classified as potassium-sparing diuretics with additional benefits independently of the effects of these agents on sodium balance. MRAs block receptors that bind aldosterone and, with different degrees of affinity, other steroid hormone receptors (e.g. corticosteroid and androgen). In contrast to spironolactone as a competitive aldosterone antagonist, eplerenone is a selective aldosterone inhibitor, and thereby causes less gynaecomastia [82, 83].

More than two decades ago spironolactone produced a positive outcome on survival in the Randomized Aldactone Evaluation Study (RALES) trial, which evaluated the spironolactone versus placebo in HFrEF patients with NYHA class III-IV and ongoing ACE inhibitor, loop diuretic and typically digoxin therapy [79]. The trial was stopped prematurely, because spironolactone resulted in 30% reduction in total mortality and 35% reduction in hospitalization for worsening HF as compared to placebo (both P < 0.001). In addition, spironolactone also improved symptoms of HF (P < 0.001), although gynecomastia was significantly higher in men who were treated with spironolactone (10%) versus placebo (1%; P < 0.001). Actions of aldosterone are mediated through the mineralocorticoid receptor, and lead to myocardial fibrosis [84] and ventricular arrhythmias [85]. Thus, the beneficial effect of spironolactone seen in RALES might be attributable to the prevention of extracellular matrix remodeling and increasing potassium levels. Thereinafter, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial demonstrated an unambiguous positive effect of eplerenone (titrated to 50 mg daily) over placebo on composite of death from cardiovascular causes or hospitalization for HF in HFrEF patients (eplerenone: 18.3% versus placebo: 25.9%; hazard ratio, 0.63; 95% confidence interval, 0.54 to 0.74; P < 0.001) [80]. Similarly, eplerenone also resulted in significant decreases in all-cause death (24%), cardiovascular death (24%), all-cause hospitalization (23%) and HF hospitalizations (43%). Of importance, in contrast with the RALES trial, which was conducted before the widespread adoption of beta blockers, the background therapy for EMPHASIS-HF included ACE inhibitors/ARBs and beta blockers.

The findings in RALES and EMPHASIS-HF are consistent with those in randomized clinical trials in patients with acute MI and LV dysfunction. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival (EPHESUS) study evaluated the effect of eplerenone (titrated to 50 mg daily) on morbidity and mortality among patients with acute MI complicated by LV dysfunction and HF [86]. Treatment with eplerenone led to a 15% decrease in all-cause death in EPHESUS.

Although the aldosterone receptor is upregulated in failing human hearts, reverse remodeling was also shown with aldosterone antagonists [87]. Under experimental settings MRAs (spironolactone and eplerenone) were shown to restore endothelium-dependent vasodilation [88], reduce post-MI fibrosis [89,90,91] and normalize echocardiographic and hemodynamic parameters of diastolic function [92]. Moreover, the combination of eplerenone with the ACE inhibitor trandolapril in post-MI rats further improved LV remodeling and neurohormonal activation [93]. As a matter of fact, electrical remodeling of the myocardium precedes myocyte hypertrophy following experimental MI, but appears to be attenuated by mineralocorticoid receptor antagonism [94]. Aldosterone blockade is therefore likely to attribute to the prevention of sudden cardiac death after MI. As a proof of principle, cardiac remodeling (e.g. fibrosis) was prevented with spironolactone after MI in human patients [95].

On the basis of the results of the RALES and EMPHASIS-HF trials [96], MRAs currently are recommended for all patients with HFrEF in addition to a RAAS inhibitor (ACE inhibitor/ARB/ARNi) and a beta blocker to increase survival, reduce the risk of HF hospitalization and improve symptoms [11, 14, 15]. Spironolactone should be initiated at a dose of 12.5–25 mg/day and uptitrated to 25–50 mg/day, whereas eplerenone should be initiated at a dose of 25 mg/day and increased to 50 mg/day. Important to note, MRAs are not recommended in significant hyperkaleamia and kidney failure, therefore caution is needed with high serum potassium levels (>5.0 mM/L) or renal dysfunction [creatinine > 221 µM/L (> 2.5 mg/dL) or eGFR < 30 mL/min/1.73 m2] to avoid life-threatening hyperkalemia as the main concern. Worsening renal function might lead to dose reduction or discontinuation of MRA therapy, as well as adjustment of potassium supplementation if any. Monitoring of serum creatinine and potassium should be repeated within 1 week of initiation or dose change. Switching to eplerenone should be considered because of breast discomfort or gynaecomastia in ca. 10–15% of male patients who use spironolactone. MRAs, when used for HF, have very little effect on BP.

However, despite established guideline recommendations to initiate MRAs as part of standard therapy, a report of the US CHAMP-HF registry [97] showed that MRA was used in only 33.4% of patients with HFrEF without documented contraindication. Likewise in the more recent PARADISE-MI trial (with ARNi in post-MI HF), in which only 42% of patients were treated with MRAs almost 20 years after the randomized control trial evidence (EPHESUS) [98]. Randomized controlled trial data regarding in-hospital initiation of MRA therapy among patients with HFrEF is limited to the EPHESUS trial. In the PIONEER-HF study (with ARNi in acute decompensated HF) it was noted that in patients admitted with acute decompensated HFrEF, 65% had a history of HF but only 10% were receiving an MRA at the time of admission [74]. It appears that GDMT—at least regarding MRAs—is sub-optimal in the clinical practice and should be revised and improved to achieve better overall outcome for HF patients. Taken together, CCS/CHFS now recommend MRA treatment for patients with acute MI and LV EF ≤ 40%, and HF symptoms or diabetes, to reduce mortality and hospitalization for cardiovascular events (strong recommendation) [15].

Concerns and Limitations of RAAS Inhibition in HF

Renin Inhibition

Aliskiren, an orally active direct renin inhibitor appeared to suppress the RAAS as effectively as the ACE inhibitor ramipril in the short term [99]. The concept of renin inhibition has been encouraged by the phenomenon of “RAAS escape” that means a counterproductive increase in renin and downstream intermediaries of the RAAS upon ACE inhibitor and ARB therapy [81]. In the Aliskiren Observation of Heart Failure Treatment (ALOFT) trial HFrEF patients with NYHA class II-IV (n = 302) were randomized to test the addition of aliskiren to an ACE inhibitor/ARB and beta blocker [100]. After 3 months of treatment plasma NT-proBNP and urinary aldosterone were reduced by aliskiren in ALOFT. Despite these promising early results, however, the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) study did not reach the primary endpoint in HFrEF patients following an episode of acute decompensation [101]. No significant difference in cardiovascular death or HF rehospitalization at 6 months was observed in patients treated with aliskiren versus standard medical therapy for HF. However, hyperkalemia, hypotension and renal impairment/failure were more frequent in the aliskiren group than in the placebo group. Subsequently, the Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbi-mortality in Patients with Chronic Heart Failure (ATMOSPHERE) study was designed to compare enalapril (n = 2336) with aliskiren (n = 2340) and with the combination of the two treatments (n = 2340) in NYHA class II-IV HFrEF patients [102]. Nonetheless, the addition of aliskiren to enalapril led to more adverse events, while neither an increase in benefit, nor noninferiority was shown for aliskiren as compared with enalapril. Therefore, aliskiren has not been introduced to GDMT of HF.

HFmrEF

There are no specific trials of RAAS inhibitors in patients with HFmrEF. However, limited data are available from retrospective and group analyses of large clinical studies on HFpEF with LV EF > 40%. Accordingly, treatment with ACE inhibitors, ARBs, ARNi and MRAs may be considered in patients with HFmrEF. As a matter of fact, many patients with HFmrEF receive an ongoing RAAS inhibitor therapy because of ischemic heart disease and co-morbidities. Moreover, in contrast to HFpEF, it seems that guidelines recommend to treat and manage HFmrEF more similar to HFrEF [11, 14, 15].

HFpEF

Unlike in HFrEF, clinical studies on RAAS inhibition have failed to achieve their primary endpoints in HFpEF. These large, randomized, controlled trials include The perindopril in elderly people with chronic heart failure (PEP-CHF) [103], the CHARM-Preserved study [104], the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE) [105], the Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function (TOPCAT) [106] and the Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) [107], all with neutral outcomes on survival. Of note, hospitalizations for HF were reduced by candesartan and spironolactone, and there was a trend towards reduction with sacubitril/valsartan. In addition, subgroups of patients such as women and individuals with a lower LV EF may gain benefit with ARNi. As a matter of fact, because of similar reasons seen in HFmrEF, many HFpEF patients are already treated with RAAS inhibitors. In the recent Effect of Sacubitril/Valsartan versus Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction (PARALLAX) study the effect of sacubitril/valsartan was compared with that of a RAAS inhibitor (ACE inhibitor/ARB) or placebo in HF patients (n = 2572) with LV EF of > 40% including both HFmrEF and HFpEF [108]. Sacubitril/valsartan treatment versus standard RAAS inhibitor or placebo resulted in a greater decrease in plasma NT-proBNP levels at 12 weeks but failed to improve 6-min walk distance at 24 weeks. Taken together, none of the RAAS inhibitory compounds met clinical significance, and thereby evidence-based recommendation in HFpEF [11, 14, 15, 109]. To date, only the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has been proven in HFpEF [110], and supposed to be incorporated into future HFpEF guidelines.

Coronavirus Disease 2019 (COVID-19)

Lately, COVID-19 has spread and been responsible for vast majority of morbidity and mortality as well as of HF decompensation worldwide. HF is an important risk factor for death in COVID-19 [111]. COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) through a RAAS-mediated mechanism. Although angiotensin II is generated by ACE, it is eliminated by the so-called ACE2 isoform [112]. Important to note, ACE2 is not only responsible for the breakdown of angiotensin II but the cellular binding site for the SARS-CoV-2 [113, 114]. For this reason, uncertainties have arisen regarding the use of RAAS inhibitory medications in the management of COVID-19 infection.

An early prospective cohort study on 8.3 million patients aged 20–99 years reported that neither ACE inhibitors, nor ARBs were associated with increased risk of COVID-19 disease or receiving intensive care unit [115]. It appears that discontinuation versus continuation of RAAS inhibition in COVID-19 has no significant influence on the seriousness of COVID-19 [116]. In patients hospitalized for COVID-19, however, ACE inhibitor or ARB use is associated with lower levels of inflammation and lower risk of in-hospital outcomes [117]. On the basis of the data of two randomized clinical trials, namely the Randomized Elimination or ProLongation of Angiotensin Converting Enzyme inhibitors and angiotensin receptor blockers in Coronavirus Disease 2019 (REPLACE COVID trial) [118] and Angiotensin Receptor Blockers and Angiotensin-converting Enzyme Inhibitors and Adverse Outcomes in Patients With COVID19 (BRACE-CORONA) [119], RAAS inhibitors can be safely continued in patients admitted to hospital with COVID-19. Nonetheless, both studies predominantly evaluated patients with previously receiving ACE inhibitors or ARBs, whilst HF was an important exclusion criterion. Unlike the 1.4 million nationwide cohort from the Swedish National Patient Registry, in which patients with hypertension, HF, diabetes, kidney disease or ischemic heart disease were included, and was found that use of RAAS inhibition was not associated with increased risk of hospitalization for or death from COVID-19 [120]. On the contrary, the withdrawal of GDMT (e.g. ACE inhibitor/ARBs and MRAs) is associated with a significant increase of in-hospital mortality [111]. Moreover, it turned out that discontinuation of RAAS inhibitory medication worsens cardiovascular status without affecting ACE2 levels [112] (Tables 19.1, 19.2 and 19.3)..

Table 19.1 Clinical trials with RAAS inhibitors in HFrEF
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Table 19.2 Clinical trials with RAAS inhibitors in HFpEF
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Table 19.3 Actions of RAAS inhibition on reverse remodeling in HF
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Summary

In summary, RAAS inhibition remains the cornerstone of GDMT in HF. Although there is clear evidence of targeting RAAS in the failing heart, mechanistic gaps and practical insufficiencies still require attention. On the one hand, research should be encouraged on novel RAAS inhibitory therapies (e.g. ARNi) regarding their mechanism of action and contribution to reverse cardiac remodeling. On the other hand, clinical practice should be improved to achieve maximal optimal therapy for HF patients. Finally, ongoing experimental and clinical studies presumably provide further evidence on broader indications of ARNi.