Following the publication of the PARADIGM-heart failure trial,1 the angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan was included in the United States and European guideline recommendations for the reduction of morbidity and mortality in patients with chronic heart failure as it was more effective than previous treatments.2,3 Most drugs currently used for the treatment of heart failure induce a beneficial reverse remodeling in those patients with heart failure and a reduced ejection fraction (HFrEF).4–6 Switching therapy from an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to sacubitril/valsartan has been reported to further enhance this phenomenon.7,8 Whether the duration of heart failure might modify the effects of ARNI on cardiac structure and function is not yet known, as the PARADIGM-HF study did not present data on echocardiography at baseline apart from left ventricular (LV) ejection fraction (LVEF),1 and more recent studies focused on the possibility of treating acute heart failure in patients whose disease duration was not reported as a relevant variable.9,10 The current preliminary study describes the effects of sacubitril/valsartan on short-term cardiac remodeling in patients meeting the European guideline criteria for ARNI treatment,2 with the aim of analyzing whether these effects are correlated with the patients’ duration of heart failure.
Study design and patients
We present a retrospective analysis of clinical data collected from outpatients attending our heart failure clinic at the Istituto Auxologico Italiano IRCCS, Milan, Italy since March 2017 (when ARNI were approved for use in Italy). The study was approved by our local Ethics Committee. We included data regarding all the patients who had completed 12 months’ follow-up as of December 2019. Patients met the following criteria for treatment with sacubitril/valsartan according to the 2016 European Society for Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure2: New York Heart Association (NYHA) class II–III; therapy with an individual optimal dose of beta blocker, ACEI or ARB; an echocardiographic examination with LVEF less than 35%. At the time of their first visit (baseline visit), according to the policy of our research institute, all patients agreed to sign permission for the anonymous use of their clinical data for observational research. Subsequently, after verifying the criteria for ARNI treatment and the absence for contraindications, patients were prescribed sacubitril/valsartan at a low or intermediate dose (24/26 mg or 49/51 mg twice daily) and individual planning for titration was determined as detailed below (treatment). The first complete follow-up study visit was conducted 6 months after starting sacubitril/valsartan; the second follow-up visit was after 12 months’ treatment. As cardiac resynchronization therapy (CRT) per se can favorably influence ventricular structure,11,12 patients in whom a device (either CRT or CRT-defibrillator) had been implanted less than 6 months before drug initiation or during the follow-up period were excluded from the current analysis.
To date, 101 patients have started ARNI therapy in our center. Among those meeting the enrollment criteria, 69 patients completed both the 6-month and 12-month follow-up visits by the end of December 2019. Their baseline demographic and clinical characteristics, and information regarding pharmacological treatment and drug regimens are presented in Table 1.
The treatment and dosing of sacubitril/valsartan followed an individualized schedule. Patients were instructed to monitor blood pressure (BP) daily for the first 2 weeks; serum potassium was checked after 1 and 3 weeks. Thereafter, BP was measured weekly and potassium monthly for the first 6 months. A dedicated nurse involved in our institutional tele-monitoring service was in charge of routine drug titration; the cardiologist was involved whenever BP or serum potassium abnormalities were present, in order to revise the treatment schedule. After the 6 months’ follow-up visit, effort to further increase the dose of ARNI was made in patients still taking a low-to-intermediate dose showing adequate BP and potassium levels.
Routine echocardiographic examination was performed by experienced operators (S.C., F.C., G.B., C.M.); it included Doppler and tissue Doppler imaging (TDI) analysis and was performed at baseline and at the two follow-up visits according to the American Society of Echocardiography and European Association of Cardiovascular Imaging guidelines.13 LVEF and estimated systolic pulmonary artery pressure (sPAP) were calculated according to our routine institution practice. Left ventricular end-diastolic and end-systolic volumes (LVEDV and LVESV) were recorded and normalized by body surface area. Trans-mitral and pulmonary venous flow velocities were recorded by pulsed Doppler in the apical four-chamber view. Tissue Doppler (TD) velocities were acquired at the septal and lateral annular sites. The following mitral inflow measurements were made: peak early (E) and peak late (A) velocities, E/A ratio, and deceleration time of E velocity. Pulmonary venous flow measurements were: peak systolic, diastolic and atrial reversal velocities, systolic filling fraction, and duration of atrial reversal. TD was used to measure the early diastolic (E′) velocity at the septal and lateral annular sites; the E/E′ ratio was calculated from the mean of septal and lateral E′ values. Diastolic function was evaluated according to a multiparametric array.13 The severity of mitral regurgitation was graded semiquantitatively on a four-point scale, from minimal (grade 1) to severe (grade 4), using color-flow Doppler images of the apical four-chamber view. Right ventricular (RV) function was described in a semiquantitative fashion using tricuspid annular plane systolic excursion (TAPSE, measured by M-mode tracing with 2D-echo guidance): TAPSE 15 mm or less was considered as an indication of severely abnormal RV function.14
Continuous variables were always expressed as the mean ± standard deviation (SD) and categorical variables as percentages. For statistical analysis we used a commercial statistical package (OriginPro 7.0, Northampton, Massachusetts, USA). The Student's t-test or the chi-square test was used for between-group comparisons of continuous variables (i.e. drug dosage, blood tests, LVEF, LV volumes and estimated pulmonary pressure) or categorical variables (i.e. prevalence of severe diastolic dysfunction and severe mitral regurgitation and abnormal RV function). Analysis of variance (ANOVA) for repeated measurements was used to compare treatment duration and treatment-related echocardiographic changes. A two-sided P less than 0.05 was considered statistically significant.
Laboratory and echocardiographic data were first analyzed for our entire study population; subsequently, we divided patients into two groups according to whether their disease duration (calculated from its first diagnosis) was shorter or longer than the mean disease duration of 8.5 years.
Sacubitril/valsartan titration and doses at follow-up
A first titration period of 11 ± 3 weeks allowed us to reach a mean sacubitril/valsartan dose of 278 ± 113 mg/day at the 6-month follow-up visit. At the 12-month visit, ARNI had been up-titrated to 348 ± 92 mg/day (P < 0.05 vs. the dose at 6 months). More in detail, after 6 months, 17 patients (24%) were treated with a low dose of sacubitril/valsartan (135 ± 24 mg/day), 19 patients (28%) were treated with an intermediate dose (200 mg/day) and 33 patients (48%) were treated with a high dose of the drug (344 ± 88 mg/day); after 12 months, fewer patients were taking a low ARNI dose (150 ± 25 mg/day; 14 patients, i.e. 20%) or an intermediate dose (200 mg/day; 16 patients, i.e. 23%), whereas the majority were taking a high dose (394 ± 24 mg/day; 39 patients, i.e. 57%). Due to the small number of observations in each group, no attempt was made to investigate dose-related effects on echocardiographic variables.
Table 2 shows the results of 6 and 12 months’ sacubitril/valsartan treatment on the laboratory, clinical and echocardiographic variables of interest in the entire study population. NYHA class significantly improved at 6 and 12 months from baseline; N-terminal-pro B type natriuretic peptide (NT-proBNP) levels were significantly decreased from baseline after 6 and 12 months’ treatment. No significant changes in hemoglobin levels, renal function and/or sodium and potassium levels were observed. Similar to recent reports,15 we documented a significant reduction in the furosemide daily dose at the 6 months’ follow-up; no further reduction of diuretic dose was observed after 12 months (Table 2).
Evidence of cardiac remodeling was observed already at the first follow-up visit (Table 2); mean LVEF values increased and the proportion of patients with grade 3 diastolic dysfunction decreased compared with baseline. Moreover, the mean LVEDV, LVESV and sPAP values were significantly lower at 6 months than at baseline (all P < 0.05). These significant improvements were maintained at 12 months for LVEF, diastolic dysfunction and sPAP. As a matter of fact, cardiac remodeling was more evident after 12 months of treatment, when we observed a significantly lower LVESV value and a further significant reduction in sPAP compared with the values observed at baseline and after 6 months. The proportion of patients with functional grade 3–4 mitral regurgitation was also significantly lower at 6 and 12 months than at baseline (Table 2). No significant changes in right ventricular function were observed in the whole group of 69 patients.
Effect of heart failure duration on treatment outcomes
As shown in Table 3, the appearance and persistence of the ventricular remodeling induced by sacubitril/valsartan seemed to be related to the duration of heart failure. The subgroup of patients with a disease duration shorter than the mean of 8.5 years (n = 40, mean heart failure duration 4.1 ± 2.9 years) had a significantly and sustained improvement in all variables considered (Table 3): mean LVEF values were significantly higher, whereas LVEDV, LVESV and sPAP values were significantly lower, at 6 and 12 months than at baseline. Moreover, the proportion of patients with grade 3 diastolic dysfunction or grade 3–4 functional mitral regurgitation was significantly lower at 6 and 12 months than at baseline. Finally, in this group, we observed a gradual reduction in the proportion of patients with severe RV dysfunction as assessed by TAPSE: of note, after 12 months of treatment, this change became significant compared with baseline (Table 3 and Fig. 1). In the subgroup of patients with disease duration of at least 8.5 years (n = 29, mean heart failure duration 15.5 ± 9.6 years), only LVEF and the proportion of patients with grade 3–4 functional mitral regurgitation showed a significant favorable change compared with baseline, and only after 12 months of treatment (Table 3). No changes were observed in other echocardiographic variables (LV volumes, sPAP and RV function did not improve). Nonetheless, we still observed a significant improvement from baseline in NYHA class at 6 and 12 months, and a decrease in the mean NT-proBNP values similar to that observed with the shorter disease duration subgroup.
We believe that a preliminary acknowledgement of the limitations of the current study is fair. First, this is a single-center observational report on a small number of patients, without a control group; all the results are therefore hypothesis-generating. Moreover, echocardiograms were performed by expert operators following guideline-recommended procedures, but only by 2D routine examinations, without any attempt to explore LV and RV function with more advanced imaging (bi-ventricular and bi-atrial speckle tracking, 3D echo).16,17 However, to our knowledge, this is the first study to examine so far the possible relationship between heart failure duration and the cardiac remodeling effects of ARNI therapy, and as such was of sufficient duration (12 months) to discern such effects even in a small population and with routine imaging techniques.
The peculiar mechanism of action of sacubitril/valsartan [amplification of natriuretic peptide activity combined with rennin–angiotensin–aldosterone system (RAAS) inhibition] led to the remarkable results of the PARADIGM-HF study, in which sacubitril/valsartan significantly reduced the risks of mortality and of hospitalization for heart failure compared with enalapril.1 As a result, sacubitril/valsartan is now recommended for use in patients with HFrEF who, despite optimal treatment, remain in NYHA class II or III.2,3 More recently, favorable reverse ventricular remodeling has been described with ARNI treatment.7,8 A variety of mechanisms explain this finding. Vasodilation reduces cardiac afterload and mechanical stress and activation of the natriuretic peptide system affects ventricular geometry,9 whereas RAAS inhibition and the autonomic nervous system neutralize pro-apoptotic and pro-fibrotic pathways.18–20
Although the typical, direct effects of neprilysin inhibition are vasodilation and natriuresis, which would be expected to occur in any treated patient, the effects resulting from an interaction with the pro-fibrotic and pro-apoptotic regulatory systems20 might appear only when heart failure is in a less advanced and more adaptable phase. On the basis of this reasoning, in long-lasting disease, ventricular fibrosis would be too advanced to be entirely responsive to the whole spectrum of ARNI effects.18–20
Of interest is the effect of sacubitril/valsartan on systolic pulmonary pressure that appeared after 1 year of treatment in patients with short-lasting disease. The so-called left sided or type II pulmonary hypertension21 is almost entirely dependent on the LV filling pressure, and may react positively to the modulation of load conditions. Of note, a similar striking reduction in pulmonary pressure has been recently reported in two patients with a recent onset of heart failure (<5 years).22 The reversal of an unfavorable right hemodynamic load could also explain the slight improvement in RV function observed in these patients after prolonged ARNI treatment. As already mentioned above, our clinical estimate of RV function was obtained only by the simple measurement of TAPSE; therefore, the latter finding should be confirmed by using newer imaging techniques that specifically and more precisely assess RV function.16,17,23
Despite the lack of remodeling observed in the group of patients who started ARNI after many years of illness, the powerful vasodilation induced by sacubitril/valsartan was still able to attenuate the severity of functional mitral regurgitation and slightly improve the LV ejection fraction. Our results are in agreement with the recently published results from the PRIME study,24 in which sacubitril amplified the vasodilating properties of valsartan by increasing the natriuretic peptide activity, resulting in a stronger modulation of cardiac preload and afterload (i.e. the main determinants of functional mitral regurgitation).24,25
Sacubitril/valsartan is well tolerated in ambulatory patients with heart failure and does not significantly modify the plasma levels of electrolytes or renal function. Favorable LV and pulmonary circulation remodeling was observed in patients with a relatively short duration of heart failure, while in patients with longer lasting disease, the clinically favorable effect of this combination seemed mostly linked to a powerful and sustained vasodilation, as demonstrated by the reduction in the severity of mitral regurgitation.
The timing of the initiation of ARNI therapy is conceptually different between European and US guidelines. Although the European guidelines consider sacubitril/valsartan to be a second-line therapy option,2 the US guidelines allow ARNI use in patients with HFrEF, even in the early stage of disease, and as a first-line therapy.3 Our study is the first to examine the relationship between heart failure duration and the antiremodeling effects of ARNI, as heart failure duration at randomization was not reported for patients in the PARADIGM study.1 In the TRANSITION9 and PIONEER10 trials, ARNI was effective when administered shortly after an acute episode of heart failure, even in patients not receiving ACE-inhibitors9,10; a recent meta-analysis also supports the concept of using sacubitril/valsartan early in the course of heart failure.26 These data inspired a recent consensus document of the European Heart failure Association, suggesting that ‘initiation of sacubitril/valsartan rather than an ACEI or an ARB may be considered for patients hospitalized with new-onset heart failure or decompensated chronic heart failure to reduce the short-term risk of adverse events and to simplify management’.27 The ongoing PARADISE-MI study is evaluating whether adding sacubitril/valsartan treatment soon after a myocardial infarction, in addition to conventional postacute myocardial infarction treatment, reduces the risk of death and hospitalizations for heart failure.28 As drug-induced LV reverse remodeling is a crucial pathophysiological issue in the clinical management of patients with HFrEF, the results of the latter study might shift the interpretation of ARNI treatment to that of a disease-modifying drug.
The authors are grateful to Elena Bressan RN, for her help in collecting patients’ data for this study. The authors also thank Tracy Harrison and Sarah Greig, PhD, of inScience Communications, Springer Healthcare, who provided English and technical editing assistance. This assistance was funded by Novartis Farma, Italy.
Funding: No funding was received for this study. Editorial assistance was funded by Novartis Farma, Italy.
Conflicts of interest
There are no conflicts of interest.
1. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med
2. Ponikowski P, Voors AA, Anker SD, et al. Authors/Task Force Members; Document Reviewers. 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
3. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation
4. Chan AK, Sanderson JE, Wang T, et al. Aldosterone receptor antagonism induces reverse remodeling when added to angiotensin receptor blockade in chronic heart failure
. J Am Coll Cardiol
5. Doughty RN, Whalley GA, Walsh HA, Gamble GD, López-Sendón J, Sharpe N, et al. CAPRICORN Echo Substudy Investigators. Effects of carvedilol on left ventricular remodeling
after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation
6. Konstam MA, Patten RD, Thomas I, et al. Effects of losartan and captopril on left ventricular volumes in elderly patients with heart failure: results of the ELITE ventricular function substudy. Am Heart J
7. Almufleh A, Marbach J, Chih S, et al. Ejection fraction improvement and reverse remodeling achieved with sacubitril/valsartan
in heart failure with reduced ejection fraction patients. Am J Cardiovasc Dis
8. Martens P, Belien H, Dupont M, Vandervoort P, Mullens W. The reverse remodeling response to sacubitril/valsartan
therapy in heart failure with reduced ejection fraction. Cardiovasc Ther
9. Wachter R, Senni M, Belohlavek J, et al. TRANSITION Investigators. Initiation of sacubitril/valsartan
in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail
10. Velazquez EJ, Morrow DA, DeVore AD, et al. PIONEER-HF Investigators. Angiotensin-neprilysin inhibition in acute decompensated heart failure. N Engl J Med
11. Kutyifa V, Vermilye K, Solomon SD, McNitt S, Moss AJ, Daimee UA. Long-term outcomes of cardiac resynchronization therapy by left ventricular ejection fraction. Eur J Heart Fail
12. Malfatto G, Facchini M, Branzi G, et al. Reverse ventricular remodeling
and improved functional capacity after ventricular resynchronization in advanced heart failure. Ital Heart J
13. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging
14. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography. J Am Soc Echocardiogr
15. Vardeny O, Claggett B, Kachadourian J, et al. Reduced loop diuretic use in patients taking sacubitril/valsartan
compared with enalapril: the PARADIGM-HF trial. Eur J Heart Fail
16. Addetia K, Muraru D, Badano LP, Lang RM. New directions in right ventricular assessment using 3-dimensional echocardiography. JAMA Cardiol
2019; 24[Epub ahead of print].
17. Muraru D, Badano LP, Nagata Y, et al. Development and prognostic validation of partition values to grade right ventricular dysfunction severity using 3D echocardiography. Eur Heart J Cardiovasc Imaging
18. Januzzi JL Jr, Prescott MF, Butler J, et al. PROVE-HF Investigators. Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA
2019; [Epub ahead of print].
19. Singh JSS, Burrell LM, Cherif M, Squire IB, Clark AL, Lang CC. Sacubitril/valsartan
: beyond natriuretic peptides. Heart
20. Zile MR, O’Meara E, Claggett B, et al. Effects of sacubitril/valsartan
on biomarkers of extracellular matrix regulation in patients with HFrEF. J Am Coll Cardiol
21. Galie N, Humbert M, Vachiery JL, et al. ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J
22. De Simone V, Guarise P, Zanotto G, Morando G. Reduction in pulmonary artery pressures with use of sacubitril/valsartan
. J Cardiol Cases
23. Dutta T, Aronow WS. Echocardiographic evaluation of the right ventricle: clinical implications. Clin Cardiol
24. Kang DH, Park SJ, Shin SH, et al. Angiotensin receptor neprilysin inhibitor for functional mitral regurgitation. Circulation
25. Mullens W, Martens P. Sacubitril/valsartan
to reduce secondary mitral regurgitation. Circulation
26. Wang Y, Zhou R, Lu C, Chen Q, Xu T, Li D. Effects of the angiotensin-receptor neprilysin inhibitor on cardiac reverse remodeling: meta-analysis. J Am Heart Assoc
27. Seferovic PM, Ponikowski P, Anker SD, et al. Clinical practice update on heart failure 2019: pharmacotherapy, procedures, devices and patient management. An expert consensus meeting report of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail
28. ClinicalTrials.gov. Prospective ARNI vs ACE inhibitor trial to determine superiority in reducing heart failure events after MI (PARADISE-MI). 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT02924727
. [Accessed 20 September 2019]