Best of heart failure

10 clear reasons, and they are stem. Recently, the advent inhibitor (ARNI) sacubi- rmacologic approach that al endopeptidase enzyme concomitantly blocks the ith valsartan). of ARNI with ACEI to rtality and Morbidity in tudy [ 31 ], a double-blind, patients with Class II–IV tion of 40% or less were itril/valsartan (at a dose of ectively) or enalapril (at a rimary outcome of death rt failure rehospitalization ARNI arm (21.8%) com- 01). Cardiovascular death % CI, 0.71; 0.89)) and risk n by 21% (HR 0.79 (95% lity was reduced by 16% HR 0.84 (95% CI, 0.76; y stopped because of the en compared to ACEI. ere reported in more than study, and these included gh, dizziness, and renal dema was also higher in pared to enalapril (0.5% in the black population). be encountered more fre- double-blind period of by a single-blind run-in ed if they could not toler- I. en tested in CHF patients . These include endothelin agents, and growth hor- terventions that modulate he neprilysin enzyme (in only proven treatment to patients with congestive t in treating patients with bradine, an HCN channel n normal sinus rhythm and or on maximum tolerable was tested in The Systolic inhibitor ivabradine Trial 505 patients with chronic bradine versus placebo on t. Patients had to be in rt rate of more or equal ss or equal 35%, and have N. W. Shammas 450 calcium overload [ 25 ], decreases myocardial mechanical efficiency, precipitates arrhythmias, increases myocardial oxygen co sumption and coronary blood flow requirements, and induc s left ventricular hypertrophy [ 26 ]. The SNS and the RAAS systems are therapeutic targets, and bl cking their activation has been shown to reduce mor- tality and morbidity in patients with CHF. Aldosterone is only partially produced as a result of angiotensin activation, and therefor , AII suppression [ 27 ] is not adequate to block its secretion. The addition of aldosterone blockers is, there- fore, eeded for optimal suppression of aldosterone, and it has been shown to provide additional reductions in mortality and morbidity in patients with CHF [ 28 , 29 ] (Fig. 24.2 ). Finally, beta adrenergic blockade also contributes in reduc- ing the activity of the RAAS [ 30 ]. The activation of the RAAS and the SNS is generally par- tially ounter-regulated by the production of vasoactive pep- tides including the natriuretic peptide (NP) system. These v soactiv peptides, particularly, brain natriuretic peptides (BNP) lead to vasodilation and increase sodium/water excretion. Also they inhibit aldosterone release and prevent cardiac and vascular fibrosis. In patients with heart failure, NP renal effects are blunted for unclear reasons, and they are also degraded by the neprilysin system. Recently, the advent of angiotensin receptor neprilysin inhibitor (ARNI) sacubi- tril/valsartan provided a novel pharmacologic approach that is capable of inhibiting the neutral endopeptidase enzyme neprilysin (with sacubitril) and concomitantly blocks the adverse effects of angiotensin II (with valsartan). In the Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study [ 31 ], a double-blind, randomized, multicenter trial, 8442 patients with Class II–IV heart failure and an ejection fraction of 40% or less were randomized to receive either sacubitril/valsartan (at a dose of 97/103 mg orally twice daily, respectively) or enalapril (at a dose of 10 mg twice daily). The primary outcome of death from cardiovascular causes or heart failure rehospitalization was significantly reduced in the ARNI arm (21.8%) com- pared to enalapril (26.5%) ( p < 0.001). Cardiovascular death was reduced by 20% (HR 0.80 (95% CI, 0.71; 0.89)) and risk of first heart failure hospitalization by 21% (HR 0.79 (95% CI, 0.71; 0.89)). Also total mortality was reduced by 16% (absolute risk reduction 2.8%) (HR 0.84 (95% CI, 0.76; 0.93)). The study was prematurely stopped because of the overwhelming benefit of ARNI when compared to ACEI. Adverse reactions of ARNI were reported in more than 5% of patients in the double-blind study, and these included hypotension, hyperkalemia, cough, dizziness, and renal failure. The incidence of angioedema was also higher in patients treated with ARNI compared to enalapril (0.5% versus 0.2% respectively; 2.4% in the black population). These adverse events are likely to be encountered more fre- quently in practice as the double-blind period of PARADIGM-HF was preceded by a single-blind run-in period where patients were excluded if they could not toler- ate the high dose of ARNI or ACEI. Several other therapies have been tested in CHF patients and have shown conflicting results. These include endothelin antagonists, immunomodulating agents, and growth hor- mone [ 32 ]. At the present time, interventions that modulate the SNS and RAAS and inhibit the neprilysin enzyme (in conjunction with ARB) remain the only proven treatment to reduce mortality and morbidity in patients with congestive heart failure. Another pharmacologic advent in treating patients with reduced EF and heart failure is ivabradine, an HCN channel blocker. It is indicated in patients in normal sinus rhythm and who are intolerant to beta blocker or on maximum tolerable dose of a beta blocker. Ivabradine was tested in The Systolic Heart failure treatment with the I f inhibitor ivabradine Trial (SHIFT) [ 33 ] which randomized 6505 patients with chronic heart failure and reduced EF to ivabradine versus placebo on top of optimal medical treatment. Patients had to be in normal sinus rhythm with a heart rate of more or equal 70 bpm, NYHC Class II–IV, EF less or equal 35%, and have Renin-angiotensin- aldosterone system Aldosterone antagonism + + + b -blockade ACE inhibition, ARB Ventricular remodeling Sympathetic nervous system Fig. 24.1 The renin–angiotensin–aldosterone system and the sympa- thetic nervous system promote ventricular remodeling, a process that can be reversed with aldosterone antagonism, ACEI, or ARB and beta blockade Angiotensin I Hypertrophy apoptosis Angiotensin II Aldosterone AT receptor antagonist ACE inhibitor Aldosterone antagonist Fig. 24.2 Interventions to block the renin–angiotensin–aldosterone system N. W. Shammas