Angiotensin receptor/neprilysin inhibitor—a breakthrough in chronic heart failure therapy: summary of subanalysis on PARADIGM-HF trial findings
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It is over 4 years since the Prospective Comparison of angiotensin receptor/neprilysin inhibitor (ARNI) with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial was published in New England Journal of Medicine. The PARADIGM-HF trial was the one that contributed to the official approval to use ARNI simultaneously with cardiac resynchronisation therapy (CRT) or implantable cardioverter-defibrillator (ICD) in patients who receive optimal medical treatment and still presented NYHA II-IV class symptoms according to the 2016 European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure. The aim of this article is to summarise current knowledge on the activity of ARNI in a selected group of patients with heart failure with reduced ejection fraction (HFrEF) based on a recent PARADIGM-HF subanalysis in the field of renal function in patients with and without chronic kidney disease, glycaemia control in patients with diabetes, ventricular arrhythmias and sudden cardiac death and health-related quality of life. This article includes also recently announced findings on the TRANSITION study which revealed that HFrEF therapy with ARNI might be safely initiated after an acute decompensated heart failure episode, including patients with heart failure de novo and ACEI/ARB naïve, both hospitalised or shortly after discharge, in contrary to the PARADIGM-HF trial, where patients had to be administered a stable dose of an ACEI/ARB equivalent to enalapril 10 mg a day for at least 4 weeks before the screening.
KeywordsChronic heart failure Angiotensin receptor/neprilysin inhibitor Angiotensin-converting enzyme PARADIGM-HF Diabetes Chronic kidney disease Sudden cardiac death Quality of life TRANSITION
In the course of time, subsequent analyses of the PARADIGM-HF trial reveal the ARNI effect to be more and more beneficial for patients with heart failure. The aim of this article is to summarise current knowledge on the influence of ARNI in a selected group of patients with HFrEF, based on a recent PARADIGM-HF subanalysis.
Effects of ARNI on renal function in patients with and without chronic kidney disease
Brenner et al. showed that RAAS inhibition reduces urinary albumin excretion and slows down the progression to end-stage renal disease, especially in patients without chronic kidney disease (CKD) or diabetes . Treatment with RAAS inhibitors becomes limited in patients with renal impairment or diabetes because the risk of serum creatinine increase or hyperkalemia is greater than in patients with HFrEF and without the abovementioned co-morbidities .
Packer et al. analysed again the PARADIGM-HF trial in the context of deterioration of renal function in patients with (3784 patients) and without concomitant diabetes (4615 patients). The deterioration of renal function was significantly lower in patients without diabetes than in diabetic patients (− 1.0 ml/min/1.73 m2/year [95% CI, − 1.2 to − 1.0] vs − 2.0 ml/min/1.73 m2/year [95% CI, − 2.1 to − 1.9], p < 0.0001) irrespective of the used treatment agent . According to Packer et al., the rate of decline in eGFR was lower in the sacubitril/valsartan than in the enalapril arm but the statistically obtained values differ from those obtained by Damman et al. because of different determined criteria (− 1.3 ml/min/1.73 m2/year vs − 1.8 ml/min/1.73 m2/year, p < 0.0001). It is pointed out that the benefit of using ARNI was greater in diabetic than in non-diabetic patients (difference 0.6 ml/min/1.73 m2/year [95% CI, 0.4–0.8] vs 0.3 ml/min/1.73 m2/year [95% CI, 0.2–0.5], p = 0.038).
The PARADIGM-HF study had several limitations, which makes it necessary to analyse the results particularly carefully. Firstly, patients were not randomised according to MRA use at baseline. Secondly, those who received MRAs were not monitored for dosing or compliance with MRAs during the study [22, 23]. Finally, the run-in period excluded patients who did not tolerate ARNI or ACEI or developed hyperkalemia during its administration. Due to residual differences between MRA-treated and MRA-naïve groups, some patients were excluded during the initial period of the trial. The true risk of hyperkalemia in both the groups randomised to the enalapril or sacubitril/valsartan arm may be underestimated and the hyperkalemia risk and the activity of ARNI, associated with the above risk, requires further investigation [22, 24].
Effects of ARNI on glycaemia control in patients with diabetes
Diabetes mellitus is a comorbidity frequently accompanying chronic heart failure and is an independent risk factor for heart failure progression [25, 26]. Findings of Kristensen et al. reveal that approximately 1 in 5 patients with HFrEF without a confirmed history of diabetes suffers from undiagnosed diabetes and 1 patient in 3 has actually pre-diabetes. The authors have divided all patients without history of diabetes into 3 groups, according to the concentration of glycated heamoglobin (HbA1c), measured at screening: normal < 6.0%, pre-diabetes 6.0–6.4% (2103 patients) and undiagnosed diabetes ≥ 6.5% (1106 patients); patients diagnosed previously with diabetes (2907 patients) were considered to have diabetes irrespective of HbA1c concentration . An analysis showed that patients with a history of diabetes had a higher risk of the primary composite outcome of hospitalization due to heart failure or cardiovascular mortality, compared with those without a history of diabetes (HR 1.38 [95% CI, 1.25 to 1.52], p < 0.001); a higher risk was also observed in patients with undiagnosed diabetes and diagnosed diabetes, compared with those with normal HbA1c (HR 1.39 [95% CI, 1.17–1.64], p < 0.001 vs HR 1.64 [1.43–1.87], p < 0.001, respectively) and patients with pre-diabetes compared with those with normal HbA1c (HR 1.27 [95% CI, 1.10–1.47], p < 0.001).
Effects of ARNI on all-cause mortality including sudden cardiac death
The impact of administration of sacubitril/valsartan on decrease in the number of cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the PARADIGM-HF trial, is incontestable. Desai et al. examined the data from the trial to better understand the mode of death . According to the authors, most of the deaths were due to cardiovascular disorders (80.9%), and among them, the majority of cases were sudden cardiac deaths (44.8%) followed by worsening heart failure (26.5%) . The risk of cardiovascular death was significantly reduced in the sacubitril/valsartan arm (HR 0.80 [95% CI, 0.72–0.89], p < 0.001) compared with enalapril and in deaths due to cardiovascular reasons; the reduction in mortality with sacubitril/valsartan was greater in comparison to enalapril and similar for both sudden cardiac deaths (HR 0.80 [95% CI 0.68–0.94], p = 0.008) and deaths due to increasing heart failure (HR 0.79 [95% CI 0.64–0.98], p = 0.034).
The precise mechanism of reduced mortality and sudden cardiac death in the group of sacubitril/valsartan remains unclear. However, Sarrias and Bayes-Genis suggest a direct involvement of neprilysin inhibition in the process . Increase in natriuretic peptide concentration leads to molecular cascade, which in turn, reduces cardiac inflammation, myocyte death, hypertrophy and fibrosis; all these 4 factors are beneficial for patients with HFrEF as they reverse or reduce left ventricular remodeling. By inducing an antiarrhythmic effect with enkephalins, endorphins and bradykinin, they reduce the rate of ventricular tachyarrhythmias and ventricular premature beats which results in a decline of the rate of sudden cardiac death.
The beneficial effects of ARNI application, compared with ACEI on reduction of appropriate shocks, non-sustained ventricular tachycardia (nsVT) and premature ventricular contraction (PVC), were shown by de Diego et al. in a prospective, non-randomised trial which included 120 patients with HFrEF and implanted ICDs who were initially treated with ACEI or ARB within the first 9 months and then ACEI or ARB was subsequently changed to ARNI for the next 9 months of the follow-up . ARNI, compared with ACEI or ARB, significantly decreased: nsVT episodes (5.4 ± 0.5 vs 15 ± 1.7, p < 0.002), sVT and appropriate ICD shocks (0.8% vs 6.7%, p < 0.02), PVCs per hour (33 ± 12 vs 78 ± 15, p < 0.0003) and increased biventricular pacing percentage (from 95% ± 6% to 98.8% ± 1.3%, p < 0.02). Such types of original studies provoke questions whether we still need ICDs if we have ARNI , but the answer is nowadays not obvious and the potential antiarrhythmic activity of ARNI needs further studies.
Effects of ARNI on health-related quality of life
The design of the PARADIGM-HF trial included not only objective and measureable data collection but also but also allowed patients to make a subjective analysis of their health-related quality of life (HRQL) when they used ARNI or ACEI, evaluated with the Kansas City Cardiomyopathy Questionnaire (KCCQ) completed, at randomisation and after 4, 8, 12, 24 and 36 months . KCCQ includes both question about clinical status (i.e. extremities swelling, fatigue or shortness of breath) and social or physical activity (i.e. showering/bathing, hurrying/jogging or working/doing household chores).
This subanalysis performed by Lewis et al. showed that KCCQ clinical summary scores and KCCQ overall summary scores at 8 months were better in patients treated with sacubitril/valsartan compared with those treated with enalapril (+ 0.64 vs − 0.29, p = 0.008, for clinical summary scores and + 1.13 vs − 0.14, p < 0.001, for overall summary scores, respectively) .
When is the moment for ARNI initiation? TRANSITION study
TRANSITION (Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event) is a randomised, simultaneous, open-label study which aimed at comparing pre- and post-discharge (1–14 days) initiation of sacubitril/valsartan in patients with HFrEF, LVEF ≤ 40% and NYHA class II–IV following hemodynamic stabilisation (defined as no need for intravenous diuretics in 24 h prior to screening and systolic blood pressure > 110 mmHg for at least 6 h prior to randomisation), after an episode of acute decompensated heart failure (ADHF), including patients with newly diagnosed HF and also ACEI/ARB naïve (no ACEI/ARB for ≥ 4 weeks before hospitalisation). In contrast, all patients of PARADIGM-HF were administered a stable dose of an ACEI/ARB equivalent to enalapril 10 mg/day for at least 4 weeks before the screening.
The primary endpoint was the proportion of patients achieving 200 mg sacubitril/valsartan twice a day at 10 weeks’ post-randomisation, and it was reached by 45.0% of 493 patients in the pre-discharge arm and 50.4% of 490 patients in the post-discharge arm (relative risk ratio [RRR] 0.893; [95% CI, 0.783–1.019], p = 0.092) [42, 43].
As the incidence of adverse events of sacubitril/valsartan and their discontinuations was similar in pre- and post-discharge groups, it is concluded that HFrEF therapy with ARNI might be safely initiated after an ADHF episode, including patients with new-onset and ACEI/ARB naïve, both in-hospital or shortly after discharge.
The PARADIGM-HF was a well-designed clinical trial that confirmed benefits due to initiation of sacubitril/valsartan in patients diagnosed with HFrEF, LVEF ≤ 35% and NYHA II–IV symptoms despite optimal medical treatment accompanied by cardiac resynchronisation therapy (CRT) or implantable cardioverter-defibrillator (ICD). Although, we do not understand all mechanisms of ARNI activity and the way it decreases HF symptoms, some of the subanalyses provide us invaluable experience on how ARNI reduce the decline in eGFR and risk of hyperkalemia in patients with and without chronic kidney disease, improve glycaemia control in diabetic patients, prevent ventricular arrhythmias or sudden cardiac death and ameliorate health-related quality of life. The new TRANSITION study results, where sacubitril/valsartan is initiated earlier than previously, suggest that ARNI will be used more frequently soon. It brings a hope for patients, affected by HF and who have not responded really positively to a conventional therapy.
Compliance with ethical standards
Conflict of interest
Małgorzata Lelonek participated in clinical trials with molecule LCZ696. Marcin Książczyk declares that there is no conflict of interest.
- 1.McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR, PARADIGM-HF Investigators and Committees (2014) Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371:993–1004. https://doi.org/10.1056/NEJMoa1409077 CrossRefPubMedGoogle Scholar
- 2.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force Members, Document Reviewers (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 18(8):891–975. https://doi.org/10.1002/ejhf.592 CrossRefPubMedGoogle Scholar
- 3.Claggett B, Packer M, McMurray JJ, Swedberg K, Rouleau J, Zile MR, Jhund P, Lefkowitz M, Shi V, Solomon SD, PARADIGM-HF Investigators (2015) Estimating the long-term treatment benefits of sacubitril-valsartan. N Engl J Med. 373(23):2289–2290. https://doi.org/10.1056/NEJMc1509753 CrossRefPubMedGoogle Scholar
- 11.Dalzell JR, Seed A, Berry C et al (2014) Effects of neutral endopeptidase (neprilysin) inhibition on the response to other vasoactive peptides in small human resistance arteries: studies with thiorphan and omapatrilat. Cardiovasc Ther 32:13–18. https://doi.org/10.1111/1755-5922.12053 CrossRefPubMedGoogle Scholar
- 13.Myhre PL, Vaduganathan M, Claggett B, Packer M, Desai AS, Rouleau JL, Zile MR, Swedberg K, Lefkowitz M, Shi V, McMurray J, Solomon SD (2019) B-Type natriuretic peptide during treatment with sacubitril/valsartan: the PARADIGM-HF trial. J Am Coll Cardiol. 73(11):1264–1272. https://doi.org/10.1016/j.jacc.2019.01.018 CrossRefPubMedGoogle Scholar
- 14.Ibrahim NE, McCarthy CP, Shrestha S, Gaggin HK, Mukai R, Szymonifka J, Apple FS, Burnett JC Jr, Iyer S, Januzzi JL Jr (2019) Effect of neprilysin inhibition on various natriuretic peptide assays. J Am Coll Cardiol. 73(11):1273–1284. https://doi.org/10.1016/j.jacc.2018.12.063 CrossRefPubMedGoogle Scholar
- 20.Damman K, Gori M, Claggett B, Jhund PS, Senni M, Lefkowitz MP, Prescott MF, Shi VC, Rouleau JL, Swedberg K, Zile MR, Packer M, Desai AS, Solomon SD, McMurray J (2018) Renal effects and associated outcomes during angiotensin-neprilysin inhibition in heart failure. JACC Heart Fail. 6(6):489–498. https://doi.org/10.1016/j.jchf.2018.02.004 CrossRefPubMedGoogle Scholar
- 21.Packer M, Claggett B, Lefkowitz MP, McMurray J, Rouleau JL, Solomon SD, Zile MR (2018) Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the ennin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 6(7):547–554. https://doi.org/10.1016/S2213-8587(18)30100-1 CrossRefPubMedGoogle Scholar
- 22.Desai AS, Vardeny O, Claggett B et al (2017) Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril. A secondary analysis of the PARADIGM-HF Trial. JAMA Cardiol. 2(1):79–85. https://doi.org/10.1001/jamacardio.2016.4733 CrossRefPubMedGoogle Scholar
- 23.Masoudi FA, MD, MSPH, FACC, FAHA reviewing Desai AS et al. JAMA Cardiol 2016 Nov 14 Ezekowitz JA. JAMA Cardiol 2016 Nov 14 Does sacubitril/valsartan reduce hyperkalemia in HFrEF patients taking MRAs? https://www.jwatch.org/na42871/2016/12/20/does-sacubitril-valsartan-reduce-hyperkalemia-hfref. Accessed 28 Aug 2019
- 26.Seferovic JP, Claggett B, Seidelmann SB et al (2017) Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 5(5):333–340. https://doi.org/10.1016/S2213-8587(17)30087-6 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Kristensen SL, Preiss D, Jhund PS et al (2016) 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 9(1). https://doi.org/10.1161/cirheartfailure.115.002560
- 29.Heinisch BB, Vila G, Resl M, Riedl M, Dieplinger B, Mueller T, Luger A, Pacini G, Clodi M B-type natriuretic peptide (BNP) affects the initial response to intravenous glucose: a randomised placebo-controlled cross-over study in healthy men. Diabetologia. 55(5):1400–1405. https://doi.org/10.1007/s00125-011-2392-1 CrossRefGoogle Scholar
- 30.Engeli S, Birkenfeld AL, Badin PM, Bourlier V, Louche K, Viguerie N, Thalamas C, Montastier E, Larrouy D, Harant I, de Glisezinski I, Lieske S, Reinke J, Beckmann B, Langin D, Jordan J, Moro C (2012) Natriuretic peptides enhance the oxidative capacity of human skeletal muscle. J Clin Invest. 122(12):4675–4679. https://doi.org/10.1172/JCI64526 CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Desai AS, McMurray J, Packer M, Swedberg K, Rouleau JL, Chen F, Gong J, Rizkala AR, Brahimi A, Claggett B, Finn PV, Hartley LH, Liu J, Lefkowitz M, Shi V, Zile MR, Solomon SD (2015) Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 36(30):1990–1997. https://doi.org/10.1093/eurheartj/ehv186 CrossRefPubMedGoogle Scholar
- 37.de Diego C, González-Torres L, Núñez JM, Centurión Inda R, Martin-Langerwerf DA, Sangio AD, Chochowski P, Casasnovas P, Blazquéz JC, Almendral J (2018) Effects of angiotensin-neprilysin inhibition compared to angiotensin inhibition on ventricular arrhythmias in reduced ejection fraction patients under continuous remote monitoring of implantable defibrillator devices. Heart Rhythm. 15(3):395–402. https://doi.org/10.1016/j.hrthm.2017.11.012 CrossRefPubMedGoogle Scholar
- 40.Lewis EF, Claggett BL, McMurray JJV et al (2017) Health-related quality of life outcomes in PARADIGM-HF. Circ Heart Fail 10(8). https://doi.org/10.1161/circheartfailure.116.003430
- 41.Chandra A, Lewis EF, Claggett BL, Desai AS, Packer M, Zile MR, Swedberg K, Rouleau JL, Shi VC, Lefkowitz MP, Katova T, McMurray J, Solomon SD (2018) Effects of sacubitril/valsartan on physical and social activity limitations in patients with heart failure: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 3(6):498–505. https://doi.org/10.1001/jamacardio.2018.0398 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in hospitalized patients with HFrEF after hemodynamic stabilization: Baseline characteristics of the TRANSITION study compared with TITRATION and PARADIGM-HF. Poster P6531 presented at ESC congress, Munich, Germany, 25-29 August 2018Google Scholar
- 43.Wachter R, Senni M, Belohlavek J, et al. Initiation of sacubitril/valsartan in hospitalized patients with heart failure with reduced ejection fraction after hemodynamic stabilization: Primary results of the TRANSITION study. Poster P886 presented at ESC Congress, Munich, Germany, 25-29, 2018 August, 2018Google Scholar
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