Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin- converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF)
01 Sep 2013-European Journal of Heart Failure (Oxford University Press)-Vol. 15, Iss: 9, pp 1062-1073
TL;DR: The PARADIGM-HF trial as discussed by the authors evaluated the effect of angiotensin receptor neprilysin inhibitors (ARNIs) on the risk of heart failure in patients with chronic heart failure.
Abstract: Aims
Although the focus of therapeutic intervention has been on neurohormonal pathways thought to be harmful in heart failure (HF), such as the renin–angiotensin–aldosterone system (RAAS), potentially beneficial counter-regulatory systems are also active in HF. These promote vasodilatation and natriuresis, inhibit abnormal growth, suppress the RAAS and sympathetic nervous system, and augment parasympathetic activity. The best understood of these mediators are the natriuretic peptides which are metabolized by the enzyme neprilysin. LCZ696 belongs to a new class of drugs, the angiotensin receptor neprilysin inhibitors (ARNIs), which both block the RAAS and augment natriuretic peptides.
Methods
Patients with chronic HF, NYHA class II–IV symptoms, an elevated plasma BNP or NT-proBNP level, and an LVEF of ≤40% were enrolled in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortailty and morbidity in Heart Failure trial (PARADIGM-HF). Patients entered a single-blind enalapril run-in period (titrated to 10 mg b.i.d.), followed by an LCZ696 run-in period (100 mg titrated to 200 mg b.i.d.). A total of 8436 patients tolerating both periods were randomized 1:1 to either enalapril 10 mg b.i.d. or LCZ696 200 mg b.i.d. The primary outcome is the composite of cardiovascular death or HF hospitalization, although the trial is powered to detect a 15% relative risk reduction in cardiovascular death.
Perspectives
PARADIGM-HF will determine the place of the ARNI LCZ696 as an alternative to enalapril in patients with systolic HF. PARADIGM-HF may change our approach to neurohormonal modulation in HF.
Trial registration
NCT01035255
Citations
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TL;DR: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure and decreased the symptoms and physical limitations of heart failure.
Abstract: Background We compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods 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 LCZ696 (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. Results The trial was stopped early, according to prespecified rules, after a median followup of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 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, LCZ696 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 LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.)
4,727 citations
University of Texas Southwestern Medical Center1, University of Glasgow2, Harvard University3, Novartis4, Université de Montréal5, Medical University of South Carolina6, University of Iceland7, University of Western Ontario8, Charles University in Prague9, Saarland University10, Stellenbosch University11, University of Santiago de Compostela12, National Yang-Ming University13, Comenius University in Bratislava14, University of Latvia15, University of Gothenburg16, Universidad Autónoma de Santo Domingo17, University of Paris18, Nanjing Medical University19, Khon Kaen University20, Catholic University of Daegu21, Dokuz Eylül University22, National University of Cordoba23, Semmelweis University24, Central University of Venezuela25, Wrocław Medical University26, University of Eastern Finland27, University of São Paulo28, Aarhus University29, University of Porto30, University of Leicester31, Cleveland Clinic32, University of California, San Francisco33, Katholieke Universiteit Leuven34, Carol Davila University of Medicine and Pharmacy35
TL;DR: Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotens in-converting enzyme inhibition.
Abstract: Background—Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs ...
532 citations
TL;DR: In this article, the authors provide examples of some major unresolved clinical problems encountered in daily cardiovascular practice as we care for elderly patients, and summarize the current understanding of the mechanisms implicated in cardiovascular aging, and the potential for targeting novel pathways implicated in endothelial dysfunction, mitochondrial oxidative stress, chromatin remodeling, and genomic instability.
363 citations
TL;DR: LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths.
Abstract: Aims The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death.
Methods and results PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II–IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72–0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68–0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64–0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths.
Conclusions LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths.
Clinical Trial Registration , [NCT01035255][1].
[1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01035255&atom=%2Fehj%2Fearly%2F2015%2F05%2F27%2Feurheartj.ehv186.atom
329 citations
Brigham and Women's Hospital1, Baylor University Medical Center2, Imperial College London3, Medical University of South Carolina4, United States Department of Veterans Affairs5, University of Gothenburg6, Montreal Heart Institute7, Karolinska University Hospital8, Copenhagen University Hospital9, University of Minnesota10, University of Arizona11, Semmelweis University12, Carol Davila University of Medicine and Pharmacy13, National Yang-Ming University14, Novartis15, British Heart Foundation16
TL;DR: The therapeutic effects of sacubitril/valsartan, compared with a renin-angiotensin-aldosterone–system inhibitor alone, vary by LVEF with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction.
Abstract: Background: While disease-modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF...
291 citations
References
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Journal Article•
12,135 citations
TL;DR: The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.
Abstract: Background Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35. Methods Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-bind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months. Results There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P less than 0.0001). Conclusions The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.
7,460 citations
TL;DR: The addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms, and the effect seems to be due to a reduction in death from progression of heart failure.
Abstract: To evaluate the influence of the angiotensin-converting enzyme inhibitor, enalapril (2.5 to 40 mg/day), on the prognosis of severe congestive heart failure, defined as New York Heart Association functional class IV, a double-blind study was undertaken in which 253 patients were randomized to receive either placebo (n = 126) or enalapril (n = 127) in addition to conventional treatment, including vasodilators. Follow-up averaged 188 days (range 1 day to 20 months). The reduction in crude mortality within 6 months (primary objective) was 40% in the enalapril-treated group (from 44 to 26%, p = 0.002) and within 1 year 31% (p = 0.001). By the end of the study, 68 subjects in the placebo group and 50 in the enalapril group had died--a reduction of 27% (p = 0.003). The entire reduction in total mortality (50%) was found in patients dying from progressive heart failure, whereas no difference was seen in the incidence of sudden cardiac death. There was a significant improvement in New York Heart Association classification in the enalapril group, together with a reduction in heart size and a reduced requirement for other heart failure medication. It is concluded that the addition of enalapril to conventional therapy in patients with severe congestive heart failure can reduce mortality and improve symptoms. The effect seems to be due to a reduction in death from progression of heart failure.
4,328 citations
TL;DR: The angiotensin-converting--enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction.
Abstract: Background It is not known whether the treatment of patients with asymptomatic left ventricular dysfunction reduces mortality and morbidity. We studied the effect of an angiotensin-converting--enzyme inhibitor, enalapril, on total mortality and mortality from cardiovascular causes, the development of heart failure, and hospitalization for heart failure among patients with ejection fractions of 0.35 or less who were not receiving drug treatment for heart failure. Methods Patients were randomly assigned to receive either placebo (n = 2117) or enalapril (n = 2111) at doses of 2.5 to 20 mg per day in a double-blind trial. Follow-up averaged 37.4 months. Results There were 334 deaths in the placebo group, as compared with 313 in the enalapril group (reduction in risk, 8 percent by the log-rank test; 95 percent confidence interval, -8 percent [an increase of 8 percent] to 21 percent; P = 0.30). The reduction in mortality from cardiovascular causes was larger but was not statistically significant (298 deaths in the placebo group vs. 265 in the enalapril group; risk reduction, 12 percent; 95 percent confidence interval, -3 to 26 percent; P = 0.12). When we combined patients in whom heart failure developed and those who died, the total number of deaths and cases of heart failure was lower in the enalapril group than in the placebo group (630 vs. 818; risk reduction, 29 percent; 95 percent confidence interval, 21 to 36 percent; P less than 0.001). In addition, fewer patients given enalapril died or were hospitalized for heart failure (434 in the enalapril group; vs. 518 in the placebo group; risk reduction, 20 percent; 95 percent confidence interval, 9 to 30 percent; P less than 0.001). Conclusions The angiotensin-converting--enzyme inhibitor enalapril significantly reduced the incidence of heart failure and the rate of related hospitalizations, as compared with the rates in the group given placebo, among patients with asymptomatic left ventricular dysfunction. There was also a trend toward fewer deaths due to cardiovascular causes among the patients who received enalapril.
3,554 citations
TL;DR: It is concluded that the atrial extract contained an extremely powerful inhibitor of renal tubular NaCl re absorption, which caused a rapid, more than 30-fold increase of sodium and chloride excretions, while urine volume and potassium excretion doubled.
3,051 citations