Todung D.A. Silalahi
Cardiovascular Division, Department of Internal Medicine UKRIDA Faculty of Medicine
INTRODUCTION
Heart failure (HF) is a serious progressive disease with debilitating symptoms.
HF patients are at risk of a sudden worsening of the disease that requires urgent care in hospital and it is the number one reason for hospitalization in people over 65 years.1 Of the 26 million people worldwide living with HF, 83 percent of HF patients are hospitalized due to an acute HF episode at least once, and nearly half (43%) are hospitalized at least four times.2,3 Every year, there are approximately one million hospitalizations due to HF in the US and Europe, and on average, a HF patient remains in hospital for five to 10 days. Due to this, heart failure presents a major and growing health-economic burden that currently costs the world economy
$108 billion every year, which accounts for both direct and indirect costs.4,5 Neurohormonal pathways are thought to be fundamentally important in the pathophysiology of heart failure.6 The belief that sustained activation of certain neurohumoral pathways such as the renin”angiotensin”aldosterone system (RAAS) and sympathetic nervous system (SNS) is detrimental in heart failure underpins the basis of therapy. The crucial importance of the RAAS is supported by the beneficial effects of ACE inhibitors, ARBs, and mineralocorticoid receptor antagonists.
Likewise, the benefits of beta-blockers argue for a key role of the SNS.7 Although the focus of therapeutic intervention has been on blocking these pathways thought to be harmful in heart failure, potentially beneficial counter-regulatory systems are also activated in heart failure. These pathways variously promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and SNS, inhibit the release and actions of vasopressin, and augment the parasympathetic nervous system.8-10
The best understood mediators exerting these actions are the natriuretic peptides. The first of these to be described, A-type natriuretic peptide (ANP), is secreted in response to atrial distension, activates the ANPR-A receptor, increasing intracellular cyclic guanylate monophosphate (cGMP), and is cleared by the ANPR- C receptor and by the action of the enzyme neutral endopeptidase (NEP), also known as neprilysin. B-type natriuretic peptide,
secreted predominantly by the ventricles in response to increased wall stress, exerts similar actions and is cleared in the same way.11-13
PARADIGM-HF
PARADIGM-HF compared the angiotensin receptor”neprilysin inhibitor
PID X UKRIDA 50
sacubitril/valsartan with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either sacubitril/valsartan (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.7,12,14
The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with sacubitril/valsartan had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the sacubitril/valsartan group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the SACUBITRIL/VALSARTAN group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving sacubitril/valsartan and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio,0.80;95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, sacubitril/valsartan also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P = 0.001). The sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Sacubitril/valsartan was superior to enalapril in reducing the risks of death and of hospitalization for heart failure14.
PIONEER-HF
PIONEER-HF is a prospective, multicenter, double-blind, randomized, controlled trial designed to assess the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan compared with enalapril in appropriate, stable HFrEF patients who had been admitted for acute decompensation. NT-pro BNP is a biomarker commonly used to assess the severity and determine the prognosis of heart failure4. Levels of NT-pro BNP increase when heart muscle cells are subjected to stress (such as stretching) that occurs in people with heart failure. Studies suggest that HF patients with elevated NT-pro BNP are at an increased risk of CV death or HF hospitalization and that reducing levels of NT-proBNP in people with heart failure is associated with a lower risk of these negative clinical outcomes.
Entresto was also shown to reduce plasma NT-proBNP compared with enalapril in the PIONEER-HF and PARADIGM-HF trials. The study enrolled patients 18 years of age and older with ejection fraction (EF) ≤40% and an elevated amino terminal-pro b-type natriuretic peptide (NT-proBNP) ≥1600 pg/mL or b- type natriuretic peptide (BNP) ≥400 pg/mL, irrespective of both duration of
PID X UKRIDA 51
diagnosis or treatment with angiotensin converting-enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARB).
A total of 881 patients, with an average age of 61 years, were randomly assigned to in-hospital initiation of sacubitril/valsartan or enalapril twice daily, following stabilization. Patients were eligible for screening no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. All patients were treated with the objective to optimize therapy to the maximum tolerated dose based on an SBP-based algorithm. Patients were predominantly male (approximately 72%), and half of patients had a BMI>30 kg/m2. Notably, more than one-third of patients (36%) were African American. Approximately 34% of patients were newly diagnosed, having no prior history of heart failure, and slightly more than 50% of patients were not receiving ACEi/ARB therapy at the time of admission.15
The primary endpoint was the time-averaged proportional change in NT- proBNP from baseline through weeks 4 and 8. Patients treated with sacubitril/valsartan achieved a 47% reduction from baseline in time-averaged NT- proBNP, compared to a 25% reduction with enalapril, translating into a statistically significant 29% greater reduction with Entresto over the ACE inhibitor (95% CI:
0.63, 0.81; P<0.0001). Significant reductions in NT-proBNP were observed in sacubitril/valsartan patients as early as one week after treatment initiation1. Rates of serious adverse events occurring with a frequency of ≥0.5% were similar between sacubitril/valsartan and enalapril groups15.
REFERENCE
1. Bui et al. Nat Rev Cardiol 2011;8:30”41
2. Maggioni et al. Eur JHeart Fail 2013;15:808”17 3. Ponikowski et al. ESC Heart Fail 2014;1:4-25 4. Kociol et al. Am Heart J 2013;165:987”94 5. Cleland et al. Eur Heart J 2003;24:442”63 6. Levin et al. N Engl J Med 1998;339:321”8
7. Nathisuwan & Talbert. Pharmacotherapy 2002;22:27”42 8. Kemp&Conte.Cardiovascular Pathology 2012;365”371 9. Schrier et al. Kidney Int 2000;57:1418-25
10. Schrier & Abraham N Engl J Med 2009;341:577”85
11. Boerrigter, Burnett. Expert Opin Invest Drugs 2004;13:643”52 12. Ferro et al. Circulation 1998;97:2323”30
13. Brewster et al. Am J Med Sci 2003;326:15”24 14. McMurray JJ, et al. N.Engl.J.Med 2014
15. Velazquez E, Morrow D, DeVore, A, et al., N Engl J Med. 2018
PID X UKRIDA 52