Heart failure (HF) is the inability of the heart to pump an adequate supply of blood to meet the demands of the body. For centuries, the treatment of HF was essentially symptomatic using digitalis, mechanical removal of fluid from edematous extremities, diuretics, and others.1 The elucidation of the effects of the renin–angiotensin–aldosterone (RAAS) pathway and the sympathetic nervous system on the progression of HF lead to the development of angiotensin-converting enzyme inhibitors (ACEI), beta-adrenergic blockers, angiotensin receptor blockers (ARB), and aldosterone antagonists as cornerstone medical therapies for chronic HF with reduced ejection fraction (HFrEF).2 These drugs have been shown to reduce both morbidity and mortality.2 Despite the use of these medications and advances in device-based therapy, HF remains to be a leading cause of morbidity, mortality, and health care expenditures in the United States and worldwide.3,4 With the elucidation and understanding of the role of natriuretic peptide system (NPS) in HF, efforts were focused on exploiting the NPS in the treatment of HF. Although the idea seemed promising, lone neprilysin (NEP) inhibition failed to show significant clinical benefit in hypertensive and HF patients.5,6 Omapatrilat, a combination ACEI and NEP inhibitor (NEPI), was associated with an increased frequency of angioedema when compared with enalapril (an ACEI) in hypertensive patients.7 These findings stalled the further development of combined ACEI-NEPI as a therapy for HF. The newest addition to the drugs targeting the NPS in addition to the RAAS is sacubitril plus valsartan (Entresto; LCZ696; Novartis, Hanover, New Jersey). LCZ696 performed significantly better than enalapril in the PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) trial and was considered a major addition to the management of HFrEF.8 This article will discuss the limitations of this therapeutic innovation in the management of HF.
LCZ696 AND CLINICAL TRIALS
LCZ696 is a novel orally active first in-class angiotensin receptor–neprilysin inhibitor which combines valsartan (an ARB) and sacubitril in a 1:1 ratio.9 Sacrubitril (AHU377) is a prodrug, which upon ingestion is rapidly metabolized to an active NEPI moiety, LBQ657.9 This drug used an ARB in combination with an NEPI in an effort to prevent the increased frequency of angioedema as observed with omapatrilat. Phase I and II studies of LCZ696 showed that after oral administration of LCZ696, peak plasma concentrations were reached rapidly for valsartan (1.6–4.9 hours), sacutribil (0.5–1.1 hours), and its active moiety LBQ657 (1.8–3.5 hours).9 LCZ696 treatment was associated with increases in plasma atrial natriuretic peptide and cyclic guanosine monophosphate levels, diuresis, blood pressure reduction, increased renin concentration and activity, and increased angiotensin II levels, providing evidence for neprilysin inhibition and angiotensin receptor blockade.9,10 LCZ696 was considered safe and well tolerated, and data from these studies supported its further clinical development for hypertension and HF. Subsequent clinical trials of LCZ696 compared to valsartan in hypertensive subjects and in patients with New York Heart Association (NYHA) class II-IV HF with preserved ejection fraction showed greater reduction in blood pressure and significant reductions in N-terminal pro-B-type natriuretic peptide levels in the LCZ696 arm, respectively.11–13 LCZ696 was well tolerated in these trials and the encouraging results paved the way for the larger PARADIGM-HF trial.
PARADIGM-HF was a phase III double-blind trial that randomized 8442 patients with NYHA class II–IV HF and an ejection fraction of ≤40% (later amended to ≤35%) to receive twice daily dosing of either 200 mg of LCZ696 or 10 mg of enalapril in addition to standard medical therapy for HF (Table 1).8 The primary end point was a composite of death from cardiovascular causes or hospitalization for HF. At 27-month follow-up, LCZ696 was associated with a 20% decrease in the primary end point compared with enalapril. When compared to enalapril, LCZ696 reduced death from any cardiovascular cause by 20%, first hospitalization for worsening HF by 21%, all-cause mortality by 16%, and improved the symptoms and quality of life as measured on the Kansas City Cardiomyopathy Questionnaire. Although 14% of patients receiving LCZ696 experienced hypotension compared to 9% in the enalapril group (P < 0.001), the number of patients who discontinued therapy because of hypotension was not significantly different between the 2 groups (0.9% in the LCZ696 group vs. 0.7% in the enalapril group). Nonserious angioedema occurred more frequently in the LCZ696 group although the difference was not significant (19 cases vs. 10 cases in the enalapril group). Significantly fewer patients developed cough, elevated serum potassium >6.0 mmol/L, or elevated serum creatinine ≥2.5 mg/dL in the LCZ696 group (Table 1). A putative placebo analysis of LCZ696 using results from previous landmark placebo controlled trials showed larger reductions in cardiovascular death, HF hospitalization, and all-cause mortality with LCZ696.14 Secondary analysis of the results from the PARADIGM-HF trial favored LCZ696 over enalapril across multiple variables and clinical end points.15–21
CURRENT ROLE OF LCZ696 IN HF
The results from the above-mentioned studies generated a lot of excitement in the medical community who have been eagerly waiting for newer medical therapies in the management of HF. The United States Food and Drug Administration reviewed LCZ696 under the priority review program with a fast track designation and approved LCZ696 for the treatment of HF. Although the drug is not yet approved for clinical use in Canada, the Canadian HF guidelines recommend the use of LCZ696 in place of an ACEI or an ARB in patients with mild to moderate HF, an ejection fraction <40%, an elevated natriuretic peptide level or hospitalization for HF in the past 12 months, a serum potassium <5.2 mmol/L, and an estimated glomerular filtration rate ≥30 mL/min treated with guideline-directed medical therapy, with close surveillance of serum potassium and creatinine (conditional recommendation; high-quality evidence).22 Further trials are on the horizon testing LCZ696 in more selective populations including HF patients with preserved ejection fraction and HF patients with proteinuric chronic kidney disease.23 Encouraged by the results of PARADIGM-HF, clinicians have started using this therapeutic innovation in patients with HFrEF. But is one trial enough to change guidelines and recommendations? Does PARADIGM-HF truly establish the superiority of LCZ696 over current standard therapy for HFrEF? Are the additional costs associated with LCZ696 truly justified based on this trial? Does the sacubitril moiety in the LCZ696 actually work? Many questions remain to be answered.
CRITICISM OF THE PARADIGM-HF TRIAL AND LIMITATIONS OF LCZ696
To understand the limitations of LCZ696 in the management of HF, let us closely look at the study design of the PARADIGM-HF. PARADIGM-HF compared enalapril with the combination sacubitril and valsartan.8 Little is known about the effects and adverse events associated with sacubitril alone as there are no clinical trials that tested sacubitril in patients with HF. The patient population in the PARADIGM-HF was previously exposed to RAAS inhibition with either an ACEI or an ARB.8 The possibility of safe initiation of LCZ696 therapy in HFrEF patients naive to RAAS inhibition was not answered by this trial.
This trial randomized the study population to receive twice daily dosing of either 200 mg of LCZ696 (160 mg of valsartan) or 10 mg of enalapril in addition to standard medical therapy for HF.8 During the study period, the administered mean doses of LCZ696 and enalapril were 375 ± 71 mg and 18.9 ± 3.4 mg, respectively. The administered dose of LCZ696 provides around 320 mg of valsartan daily which is the maximum recommended dose of valsartan in HF, whereas the administered dose of enalapril is far less than the maximal recommended dose of 40 mg daily. The mean dose of enalapril achieved in many HF trials was between 15 mg/d and 20 mg/d, but the prespecified target dose of enalapril in these trials was only 20 mg daily and not 40 mg daily.24–26 However, it is unclear whether the maximal dose of valsartan produced more RAAS blockade leading to better clinical outcomes compared with the moderate dose of enalapril as there were no trials with head-to-head comparison of the study doses of valsartan and enalapril as used in the PARADIGM-HF.
The observed higher frequency of hypotension in the LCZ696 group might support this hypothesis of a higher degree of RAAS blockade. There were no trials with head-to-head comparison of the study doses of valsartan and enalapril as used in the PARADIGM-HF. The ATLAS (Assessment of Treatment with Lisinopril And Survival) trial compared the effects of low and high doses of lisinopril (an ACEI) on morbidity and mortality in HF patients.27 Although the study found no statistically significant difference in all-cause mortality, high-dose lisinopril significantly reduced the composite end point of all-cause mortality and hospitalization for HF (55.1% vs. 60.4%; P < 0.001).27 Although the Val-HeFT (Valsartan Heart Failure Trial) and the VALIANT (Valsartan in Acute Myocardial Infarction) trial did not show a mortality benefit of valsartan over placebo and captopril, respectively, these trials used lower mean doses of valsartan (254 mg/d in the Val-HeFT trial and 247 mg/d in the VALIANT trial) compared with 320 mg/d used in the PARADIGM-HF trial.28,29
It is important to consider the high dropout rate of more than 10% of the study population who entered the LCZ696 run-in phase of the study.8 Of the 9419 persons who entered the LCZ696 run-in period, 977 (10.4%) discontinued the study and 547 (5.8%) of these persons had an unspecified adverse event. This dropout rate might have biased downward the prevalence of adverse effects because of LCZ696 and may reduce the generalizability of the study to the target patient population. Physicians should therefore be cautious in selecting patients for treatment with LCZ696 as a significant number of HF patients may not be able to tolerate the drug, and a run-in period is not always feasible in regular clinical practice.
In clinical practice, HF medications are usually titrated as tolerated to achieve target doses. LCZ696 was successfully uptitrated to its target dosing of 200 mg twice daily in the PARADIGM-HF trial. However, the study population in the PARADIGM-HF is relatively young with a mean age of 64 years. The LCZ696 arm had a 14% incidence of hypotension which was significantly higher than the enalapril arm.8 Low blood pressure limiting uptitration of HF medications is a common problem in the elderly, and lower blood pressure in the elderly has been associated with worse outcomes.30 The successful uptitration of LCZ696 to its target dose in addition to other essential HF medications in the elderly HF population might be challenging in clinical practice. The black population in the PARADIGM-HF trial was only 5%.8 In the OCTAVE (Omapatrilat Cardiovascular Treatment vs. Enalapril) trial, black patients had an increased frequency of angioedema with omapatrilat.7 The lower proportion of black patients in the PARADIGM-HF trial may have limited the ability of this trial to detect a significant difference in the frequency of angioedema with LCZ696.
The study population in this trial was predominantly white (66%), male (78%), NYHA functional class II HF (70%), mean age of 64 years, and 60% of the subjects with ischemic cardiomyopathy.8 Only 60 patients (<1%) had NYHA functional class IV HF at baseline, and only 5% of the study population was black.8 These factors might reduce the generalizability of the data from the trial as HF patients are usually older individuals with varying NYHA functional class. In the US population, non-Hispanic black patients have a higher rate of HF-related mortality as than other races.31 The lower proportion of black subjects reduces the power of this trial to assess the clinical benefit of LCZ696 in this particular population with higher HF-related mortality.
Patients who had an acute coronary event within the last 3 months were excluded from the trial.8 This key exclusion does not support the use of LCZ696 in patients with new onset HFrEF after an acute coronary syndrome at least until 3 months after the event. Physicians should be cautious when prescribing LCZ696 to patients with severe pulmonary disease and in patients with hepatic disease as such patients were excluded from the PARADIGM-HF trial.8 Despite a few underrepresented groups, the PARADIGM-HF is the largest published trial in HFrEF and will hold strong clinical implications. Clinicians should be aware of these deficiencies while prescribing this medication to make appropriate decisions in regular clinical practice.
Neprilysin plays a critical role in maintaining the homeostasis of amyloid-β peptide (Aβ) in the brain.32 NEPI might lead to accumulation of Aβ in the brain, favoring the development of Alzheimer dementia.33 Although the incidence of cognition-related adverse effects was not increased by LCZ696 in the PARADIGM-HF trial, the duration of the trial was not long enough to assess this problem.8 The mean patient age in the PARADIGM-HF trial was 64 years, but HF population in the community are typically older individuals who are at a risk for cognitive impairment. The possibility of any such neurological adverse events would limit the use of this combination in the elderly patient population with higher HF prevalence. Although the association between LCZ696 and dementia is currently not supported by data from randomized trials, the PARAGON-HF (Prospective comparison of angiotensin receptor-neprilysin inhibitor with ARB Global Outcomes in HF with preserved ejection fraction) trial (NCT01920711) that includes serial cognitive function testing in its design should provide more information. In addition, phase IV safety data of LCZ696 might shed more light on this association.
Although the PARADIGM-HF trial projected LCZ696 as a major advancement in the treatment of HFrEF compared to the current treatment with ACEI, the results of this trial should be interpreted carefully for the reasons mentioned above. The benefit of this combination is most apparent when initiated early in the course of HF in patients with mild to moderate symptoms. It is unclear whether LCZ696 will benefit patients with severe symptomatic HF as such patients were underrepresented in this study. The tolerability of sacubitril–valsartan in the community based HF population is to be tested in clinical practice. More appropriately designed trials comparing the combination sacubitril and valsartan with valsartan alone in the typical HF population will provide more information about the beneficial and adverse effects of the sacubitril moiety in this combination.
1. Davis RC, Hobbs FD, Lip GY. ABC of heart failure: history and epidemiology. BMJ. 2000;320:39–42.
2. Yancy CW, Jessup M, Bozkurt B, et al 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American heart association Task Force on practice guidelines. Circulation. 2013;128:1810–1852.
3. Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385:812–824.
4. Mozaffarian D, Benjamin EJ, Go AS, et al Heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation. 2016;133:e38–e360.
5. Bevan EG, Connell JM, Doyle J, et al Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension. J Hypertens. 1992;10:607–613.
6. Cleland JG, Swedberg K. Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. Lancet. 1998;351:1657–1658.
7. Kostis JB, Packer M, Black HR, et al Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17:103–111.
8. McMurray JJ, Packer M, Desai AS, et al Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.
9. Gu J, Noe A, Chandra P, et al Pharmacokinetics and pharmacodynamics of LCZ696
, a novel dual-acting angiotensin receptor—neprilysin inhibitor
(ARNi). J Clin Pharmacol. 2010;50:401–414.
10. Hegde LG, Yu C, Madhavi C, et al Comparative efficacy of AHU-377, a potent neprilysin inhibitor
, in two rat models of volume-dependent hypertension. BMC Pharmacol. 2011;11:P33.
11. Ruilope LM, Dukat A, Bohm M, et al Blood-pressure reduction with LCZ696
, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255–1266.
12. Kario K, Sun N, Chiang FT, et al Efficacy and safety of LCZ696
, a first-in-class angiotensin receptor neprilysin inhibitor
, in asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014;63:698–705.
13. Solomon SD, Zile M, Pieske B, et al The angiotensin receptor neprilysin inhibitor LCZ696
in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–1395.
14. McMurray J, Packer M, Desai AS, et al A putative placebo analysis of the effects of LCZ696
on clinical outcomes in heart failure. Eur Heart J. 2015;36:434–439.
15. Packer M, McMurray JJ, Desai AS, et al Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131:54–61.
16. Desai AS, McMurray JJ, Packer M, et al Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696
compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015;36:1990–1997.
17. Kristensen SL, Preiss D, Jhund PS, et al Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction
: insights from prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial. Circ Heart Fail. 2016;9:e002560.
18. Solomon S, Packer M, Zile M, et al The angiotensin receptor neprilysin inhibitor LCZ696
is effective across the spectrum of ejection fraction in heart failure with reduced ejection fraction
. J Card Fail. 2015;21:S45–S46.
19. Simpson J, Jhund PS, Silva Cardoso J, et al Comparing LCZ696
with enalapril according to baseline risk using the MAGGIC and EMPHASIS-HF risk scores: an analysis of mortality and morbidity in PARADIGM-HF. J Am Coll Cardiol. 2015;66:2059–2071.
20. Böhm M, Refsgaard J, Ramires FJA. Effect of angiotensin receptor neprilysin inhibitor LCZ696
compared with enalapril according to systolic blood pressure in PARADIGM-HF. Eur J Heart Fail. 2015;17(suppl 1):393.
21. Jhund PS, Fu M, Bayram E, et al Efficacy and safety of LCZ696
(sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J. 2015;36:2576–2584.
22. Moe GW, Ezekowitz JA, O'Meara E, et al The 2014 Canadian Cardiovascular Society Heart Failure Management Guidelines Focus Update: anemia, biomarkers, and recent therapeutic trial implications. Can J Cardiol. 2015;31:3–16.
23. Judge P, Haynes R, Landray MJ, et al Neprilysin inhibition in chronic kidney disease. Nephrol Dial Transpl. 2015;30:738–743.
24. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
25. Packer M, Califf RM, Konstam MA, et al Comparison of omapatrilat and enalapril in patients with chronic heart failure: the omapatrilat versus enalapril randomized trial of Utility in reducing events (OVERTURE). Circulation. 2002;106:920–926.
26. Willenheimer R, van Veldhuisen DJ, Silke B, et al Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005;112:2426–2435.
27. Packer M, Poole-Wilson PA, Armstrong PW, et al Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor
, lisinopril, on morbidity and mortality in chronic heart failure. Circulation. 1999;100:2312–2318.
28. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675.
29. Pfeffer MA, McMurray JJ, Velazquez EJ, et al Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893–1906. [Erratum, N Engl J Med. 2004;350:203.].
30. Boshuizen HC, Izaks GJ, van Buuren S, et al Blood pressure and mortality in elderly people aged 85 and older: community based study. BMJ. 1998;316:1780–1784.
31. Ni H, Xu J. Recent Trends in Heart Failure-Related Mortality: United States, 2000–2014. NCHS Data Brief, No 231. Hyattsville, MD: National Center for Health Statistics; 2015.
32. Nalivaeva NN, Belyaev ND, Kerridge C, et al Amyloid-clearing proteins and their epigenetic regulation as a therapeutic target in Alzheimer's disease. Front Aging Neurosci. 2014;6:235.
33. Vodovar N, Paquet C, Mebazaa A, et al Neprilysin, cardiovascular, and Alzheimer's diseases: the therapeutic split? Eur Heart J. 2015;36:902–905.