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valsartan for heart failure in adults with complex congenital heart disease
IJCA-27764; No of Pages 4 International Journal of Cardiology xxx (xxxx) xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Sacubitril/valsartan for heart failure in adults with complex congenital heart disease Susanne J. Maurer 1, Claudia Pujol Salvador 1, Sandra Schiele 1, Alfred Hager 1, Peter Ewert 1, Oktay Tutarel ⁎,1 Department of Congenital Heart Disease and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany
a r t i c l e
i n f o
Article history: Received 20 March 2019 Received in revised form 14 May 2019 Accepted 12 June 2019 Available online xxxx Keywords: Adult congenital heart disease Heart failure Sacubitril/valsartan
a b s t r a c t Background: Heart failure is an important cause of morbidity and mortality in adults with congenital heart disease (ACHD). Sacubitril/valsartan is an established treatment for heart failure with reduced ejection fraction due to acquired cardiovascular disease. Data in adults with complex congenital heart disease (CHD) is lacking. Methods: Retrospective study of ACHD patients with CHD of moderate/severe complexity and heart failure under treatment with sacubitril/valsartan. Clinical data was retrieved from medical records. Results: Altogether, 23 patients (mean age 41.2 ± 11.9 years, female 17.4%) were included. A systemic right ventricle was present in 12 pat. (52.2%), a single ventricle physiology in 4 (17.4%), and a systemic left ventricle in 7 (30.4%). During a median follow-up of 221 days [IQR 79–430], systemic ventricular function (p = 0.88) and functional status according to New York Heart Association class (p = 0.38) did not improve. While NT-proBNP levels did not change significantly under treatment (2561 ± 2042 ng/l vs. 1938 ± 1524 ng/l, p = 0.20), creatinine levels increased (1.14 ± 0.52 mg/dl vs. 1.35 ± 0.74 mg/dl, p = 0.002). Systolic (110 ± 15 mm Hg vs. 103 ± 14 mm Hg, p = 0.02) and diastolic blood pressures (68 ± 10 mm Hg vs. 61 ± 12 mm Hg, p = 0.01) were reduced under therapy. Five patients discontinued therapy, four of these due to side effects. Conclusion: In this small group of complex ACHD patients with heart failure, treatment with sacubitril/valsartan did not improve systemic ventricular function or functional status. Renal function needs close surveillance. © 2019 Elsevier B.V. All rights reserved.
1. Introduction Due to the advances in the care of children with congenital heart disease (CHD), the number of adults with congenital heart disease (ACHD) is increasing [1]. ACHD patients are burdened by significant morbidity and mortality, of which heart failure is the leading cause [2,3]. Furthermore, its incidence is increasing in ACHD patients [4]. In contrast to heart failure with reduced ejection fraction due to acquired cardiovascular disease, for which evidence-based guidelines exist, [5] treatment recommendations for ACHD patients are mainly based on expert consensus due to the lack of conclusive studies [3]. This is especially the case for drug therapy of heart failure. Sacubitril/valsartan has been established for the treatment of heart failure with reduced ejection fraction due to acquired cardiovascular disease [5,6]. Data regarding its use in ACHD patients is scarce. A case study of five patients with quite different underlying CHD and therefore, divergent pathophysiology was
⁎ Corresponding author at: Department of Congenital Heart Disease and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich, Lazarettstr. 36, 80636 Munich, Germany. E-mail address: [email protected] (O. Tutarel). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
published recently [7]. It reported an improvement in functional class during a short-term follow-up [7]. Another recent report of 15 ACHD patients including patients with less complex CHD reported symptomatic improvement in a proportion of patients (27%) during short-term follow-up, while the remaining patients reported no improvement [8]. Other studies are not available. Therefore, the aim of this study is to evaluate the use of sacubitril/ valsartan in ACHD patients with CHD of moderate/severe complexity and heart failure, and assess its efficacy and safety in this special patient group. 2. Methods From the database of our tertiary centre for ACHD, all patients (age ≫ 18 years of age) under a therapy with sacubitril/valsartan were identified. Demographic and clinical data (date of birth, gender, type of CHD and previous surgeries, date of begin with sacubitril/valsartan, date of last control or date of ending sacubitril/valsartan, laboratory results, imaging) as well as the indication for sacubitril/valsartan therapy were retrieved from the medical reports. Only patients with CHD of moderate or complex severity according to the Bethesda classification were included [9]. Systemic ventricular function was graded semiquantitatively
https://doi.org/10.1016/j.ijcard.2019.06.031 0167-5273/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
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S.J. Maurer et al. / International Journal of Cardiology xxx (xxxx) xxx
as normal, mildly, moderately, or severely impaired based on the results of routine transthoracic echocardiograms as described previously [10]. Concomitant diuretic therapy was adjusted individually by the treating physician during outpatient visits according to the clinical status of the patient. Statistical analysis was performed using MedCalc version 18.11.3 (MedCalc Software, Mariakerke, Belgium). Continuous variables are presented as mean ± standard deviation or median (interquartile range), whereas categorical variables are presented as number (percentage). N-terminal pro-B-type natriuretic peptide (NT-proBNP) values were analysed after logarithmic transformation. Comparison between groups was performed using the paired samples t-test or Wilcoxon test for paired samples (signed-rank test) for continuous and Chi-square test for categorical variables. All tests were performed two-sided and for all analyses, a pvalue ≪0.05 was considered statistically significant. This study complies with the Declaration of Helsinki, and the ethics committee of the Medical Faculty of the Technical University of Munich has approved the research protocol. The requirement for informed consent was waived by the ethics committee due to the retrospective nature of the study. 3. Results Altogether, 23 patients (mean age 41.2 ± 11.9 years, female 17.4%) were included. Indication for therapy was a reduced systemic ventricular function and/or heart failure symptoms. A systemic right ventricle (transposition of the great arteries or congenitally corrected transposition of the great arteries) was present in 12 pat. (52.2%), a single ventricle physiology in 4 pat. (17.4%), and a systemic left ventricle (tetralogy of Fallot, coarctation of the aorta, Ebstein's anomaly, complex shunts) in 7 pat. (30.4%). Systemic ventricular dysfunction was moderate in 10 pat., and severe in 10. For three pat. an echocardiogram at the beginning of therapy was not available since it was initiated in a different centre. Functional status according to New York Heart Association (NYHA) class was I in 7 pat. (31.8%), II in 8 (36.4%), and III in 7 (31.8%) at baseline. In one patient NYHA class at initiation of therapy was not available. In 17 pat. (73.9%) a device was already implanted at baseline. An implantable cardioverter-defibrillator was present in 9 pat., a pacemaker in 7, and a pacemaker with cardiac resynchronization in one. More detailed information regarding baseline characteristics is provided in Table 1. Tolerated maintenance dose was 24 mg/26 mg BID in 6 pat., 49/51 mg BID in 7, and 97/103 mg in 8; while 2 tolerated only a dose of 12/13 mg BID. During a median follow-up of 221 days [IQR 79–430], functional status according to NYHA class (p = 0.38) and systemic ventricular function (p = 0.88) did not improve (Fig. 1). N-terminal pro-B-type natriuretic peptide (NTproBNP) levels did not change significantly under treatment (2561 ± 2042 ng/l vs. 1938 ± 1524 ng/l, p = 0.20), while creatinine levels increased significantly (1.14 ± 0.52 mg/dl vs. 1.35 ± 0.74 mg/dl, p = 0.002) (Fig. 2 A/B). Potassium levels also increased under therapy (4.1 ± 0.5 mmol/l vs. 4.3 ± 0.4 mmol/l, p = 0.048). Systolic blood pressure (110 ± 15 mm Hg vs. 103 ± 14 mm Hg, p = 0.02) as well as diastolic blood pressure (68 ± 10 mm Hg vs. 61 ± 12 mm Hg, p = 0.01) were reduced under therapy. Five patients discontinued the therapy, two due to the development/worsening of severe renal dysfunction, one because of diarrhoea, one due to severe headaches and dizziness, and another one due to relocation to a different country. Considering the two patients who had to discontinue therapy with sacubitril/ valsartan due to worsening renal function, the first had a glomerular filtration rate (GFR) of 37 ml/min at the initiation of therapy. After six months of treatment with a dose of 24 mg/26 mg BID, GFR decreased to 19 ml/min. Therapy with sacubitril/valsartan was discontinued as well as the therapy with eplerenone. After
Table 1 Baseline characteristics. N (%) All Female Mean age (years) Systemic ventricle Left Right Single Systemic ventricular function* Moderately reduced Severe reduced New York Heart Association class* I II III Cardiac medication ACE inhibitors/Angiotensin II receptor blockers Beta-blockers Mineralocorticoid receptor antagonists Diuretics Digoxin and other digitalis glycosides Antiarrhythmic Device therapy Implantable cardioverter-defibrillator Pacemaker Pacemaker with cardiac resynchronization
23 (100) 4 (17.4) 41.2 ± 11.9 7 (30.4) 12 (52.2) 4 (17.4) 10 (50) 10 (50) 7 (31.8%) 8 (36.4) 7 (31.8) 14 (60.9) 17 (73.9) 17 (73.9) 18 (78.3) 8 (34.8) 6 (26.1) 9 (39.1) 7 (30.4) 1 (4.3)
In three patients, an echocardiogram at initiation of therapy and in one patient functional class was not available. In all patients due to therapy initiation in a different centres. ACE: angiotensin-converting enzyme.
two weeks GFR recovered to 35 ml/min. The other patient had a GFR of 23 ml/min at initiation of the therapy, which decreased to 15 ml/min after two weeks of therapy with a dose of 12/ 13 mg BID. The potassium level was 5.9 mmol/l. Sacubitril/ valsartan was discontinued, and GFR increased to 23 ml/min after a few days. Potassium levels were in the normal range. Both patients did not require dialysis, but were hospitalized.
4. Discussion In this small cohort of ACHD patients with heart failure and underlying complex CHD, therapy with sacubitril/valsartan did not improve NYHA class or systemic ventricular function. Furthermore, NT-proBNP levels were also not significantly changed. In the Prospective Comparison of ARNI (Angiotensin ReceptorNeprilysin Inhibitor) with ACEI (Angiotensin-Converting-Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF), a therapy with sacubitril/ valsartan was superior to enalapril in reducing the risks of death and of hospitalization for heart failure due to acquired cardiovascular diseases [6]. Around 60% of these patients had ischemic cardiomyopathy. Patients with complex CHD were not included. Regarding concomitant cardiac medications, the use of diuretics and digoxin was at a similar rate compared to our cohort. However, the PARADIGM-HF trial had a higher proportion of patients with beta-blockers, while in our study cohort the proportion of patients using mineralocorticoid receptor antagonists was higher. Interestingly, only 15% of patients in the PARADIGM-HF trial had an implantable cardioverter-defibrillator, while this number was around 40% in our cohort. Therefore, the severity of heart failure was comparable, but the pathophysiology is quite different between both cohorts considering the high number of patients with a systemic right ventricle – where the morphological right ventricle supports the systemic circulation – as well as patients with a single ventricle physiology in our study cohort. Therefore,
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
S.J. Maurer et al. / International Journal of Cardiology xxx (xxxx) xxx
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Fig. 1. New York Heart Association class at initiation of therapy and at follow-up.
an extrapolation of the results of the PARADIGM-HF trial to ACHD patients with complex CHD is not possible. Appadurai and colleagues reported the results of a case series of five ACHD patients with heart failure under a therapy with sacubitril/valsartan [7]. Out of the five patients, two had a systemic right ventricle and three a systemic left ventricle. While the patients reported some symptomatic improvement, cardiopulmonary exercise testing (CPET) – which was available in two patients – showed an improvement in one patient and a decline in the other patient. Unfortunately, CPET at initiation of therapy and follow-up was only available in one patient in our cohort. In this case, peak oxygen uptake decreased under therapy. While all patients in the case series of Appadurai and colleagues reported heart failure symptoms, some patients in our cohort were in NYHA class I, and therapy with sacubitril/valsartan was initiated for reduced systemic ventricular function. Therefore, one could speculate that symptomatic patients may have a greater benefit. Especially, since around 95% of patients in the PARADIGM-HF trial were in NYHA class II-IV [6]. These reported an improvement in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire [6]. However, the majority of our patients was also symptomatic (n = 15), and only two of these reported an improvement in functional class. Moreover, in Lluri and colleagues' report, all 15 ACHD patients had heart failure symptoms, but only 27% reported some symptomatic improvement under a therapy with sacubitril/valsartan [8]. Unfortunately, both previous studies did not report data regarding systemic ventricular function or NT-proBNP levels under therapy [7,8]. In our cohort, there was
no significant improvement of either. Furthermore, while 60% of patients in the case series had a systemic left ventricle, [7] as well as 53% of patients reported by Lluri and colleagues, [8] this was the case in only 30% of our cohort. The remaining patients had a systemic right ventricle or a single ventricle physiology. Both have a quite different pathophysiology compared to the failure of a systemic left ventricle, [11] which could explain the different outcome in the current study. Not all of our patients reached the target dose for sacubitril/valsartan. However, we observed a significant decrease in systolic and diastolic blood pressure levels in our study as reported in the PARADIGM-HF trial [6]. Therefore, we can safely assume that sacubitril/valsartan showed a therapeutic effect despite the fact that not all of our patients reached the target dose. Five patients in our study cohort discontinued the therapy, four (17.4%) due to side-effects. In the PARADIGM-HF trial sacubitril/ valsartan was discontinued in 10.7% because of an adverse event. This number was higher for the control group with enalapril [6]. The higher number in our study cohort could be due to the small number of patients included. Another explanation would be that ACHD patients with their divergent pathophysiology are more susceptible to side effects of the therapy. In our cohort, two patients developed severe renal dysfunction. Likewise, one patient in Lluri and colleagues' report discontinued medication due to continued worsening of renal function [8]. This was also common in the PARADIGM-HF trial [6]. Furthermore, creatinine levels increased significantly in our cohort, while this was not the case in the previous report [8]. A possible explanation is the
Fig. 2. NT-proBNP and creatinine levels at initiation of therapy and at follow-up. Circles represent individual observations.
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
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shorter follow-up duration in the latter study with a median follow-up of 69 days in comparison to 221 days in our study. Hypotension, another common side effect of sacubitril/valsartan, did occur in only one patient in our study cohort. Previous studies with established heart failure medications like ACE-inhibitors or beta-blockers in patients with CHD were also negative. For example, a randomized controlled trial of the angiotensin II receptor blocker valsartan in adult patients with a systemic right ventricle failed to show a significant treatment effect of valsartan on right ventricular ejection fraction, exercise capacity, or quality of life [12]. In a trial in children and adolescents with symptomatic systolic heart failure including patients with CHD, carvedilol did not significantly improve clinical heart failure outcomes [13]. While there was a beneficial trend in patients with a systemic left ventricle, this was not the case in those whose systemic ventricle was not a left ventricle [13]. The reasons for these negative study results are a matter of debate. While without doubt the small number of patients included in these studies compared to the landmark trials in the treatment of heart failure with reduced ejection fraction due to acquired cardiovascular disease plays an important role, some other aspects may also be of importance. One could speculate that neurohormonal activation is less pronounced in ACHD patients. However, a study of 53 ACHD patients reported that the level of neurohormonal activation beared the hallmarks of chronic heart failure, relating to symptom severity and ventricular dysfunction [10]. Another possible explanation could be the different myocardial substrate in patients with CHD compared to patients with acquired cardiovascular disease. Often we are not dealing with a systemic left ventricle, but a systemic right ventricle or a single ventricle physiology. This is of importance, because even the orientation of the cardiomyocytes differs between the left and right ventricle [14]. Furthermore, repeated surgeries from early childhood leading to myocardial damage in the perioperative period and a geometry of the right ventricle, which makes it less suitable to handle the constant pressure overload of the systemic circulation, need to be considered [15]. When designing future drug studies in ACHD patients, we have to decide which would be the best outcome markers. Maybe a combination of surrogate markers like NT-proBNP and improved performance on cardiopulmonary exercise testing could be helpful. Alternatively, we have to identify new biomarkers, which better resemble the clinical status of ACHD patients. However, ideally we should focus on hard clinical endpoints like mortality. To achieve such a goal, we need to conduct multicentre studies with a much longer study duration. A limitation of our study is its retrospective nature with all inherent limitations. In some patients, variables like NYHA class were missing. Furthermore, CPET as an objective measure of exercise capacity was not regularly performed. Additionally, despite being the largest study with the longest follow-up duration reported so far for ACHD patients with complex CHD under sacubitril/valsartan therapy, the number of patients is still low compared to studies in acquired cardiovascular disease, a common problem in studies with ACHD patients. Even a multicentre trial studying the effect of valsartan on systemic right ventricular function did include only 78 patients (38 with valsartan, 40 with placebo) [12]. This trial also showed no significant treatment effect of valsartan on systemic right ventricular function, exercise capacity or quality of life.
While the current study showed no benefit of sacubitril/valsartan in a cohort of ACHD patients with complex disease, further studies in larger cohorts are necessary for a final verdict. Ideally, a double blind, randomized controlled trial should be performed. Furthermore, a multicentre, international registry needs to be established, which is currently in the making. Until these studies are available, sacubitril/ valsartan should only be used on an individual basis for ACHD patients with complex disease. Renal function needs close surveillance. Declaration of Competing Interest None. Acknowledgements None. References [1] P. Khairy, R. Ionescu-Ittu, A.S. Mackie, M. Abrahamowicz, L. Pilote, A.J. Marelli, Changing mortality in congenital heart disease, J. Am. Coll. Cardiol. 56 (2010) 1149–1157. [2] C.C. Engelings, P.C. Helm, H. Abdul-Khaliq, B. Asfour, U.M. Bauer, H. Baumgartner, et al., Cause of death in adults with congenital heart disease - an analysis of the German National Register for Congenital Heart Defects, Int. J. Cardiol. 211 (2016) 31–36. [3] W. Budts, J. Roos-Hesselink, T. Radle-Hurst, A. Eicken, T.A. McDonagh, E. Lambrinou, et al., Treatment of heart failure in adult congenital heart disease: a position paper of the Working Group of Grown-Up Congenital Heart Disease and the Heart Failure Association of the European Society of Cardiology, Eur. Heart J. 37 (2016) 1419–1427. [4] K. Norozi, A. Wessel, V. Alpers, J.O. Arnhold, S. Geyer, M. Zoege, et al., Incidence and risk distribution of heart failure in adolescents and adults with congenital heart disease after cardiac surgery, Am. J. Cardiol. 97 (2006) 1238–1243. [5] P. Ponikowski, A.A. Voors, S.D. Anker, H. Bueno, J.G.F. Cleland, A.J.S. Coats, et al., 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). Eur. Heart J. 37 (2016) 2129–2200. [6] J.J. McMurray, M. Packer, A.S. Desai, J. Gong, M.P. Lefkowitz, A.R. Rizkala, et al., Angiotensin-neprilysin inhibition versus enalapril in heart failure, N. Engl. J. Med. 371 (2014) 993–1004. [7] V. Appadurai, J. Thoreau, T. Malpas, M. Nicolae, Sacubitril/valsartan in adult congenital heart disease patients with chronic heart failure - a single centre case series and call for an international registry, Heart Lung Circ. (2019)https://doi.org/10.1016/j. hlc.2018.12.003. [8] G. Lluri, J. Lin, L. Reardon, P. Miner, K. Whalen, J. Aboulhosn, Early experience with sacubitril/valsartan in adult patients with congenital heart disease, World J. Pediatr. Congenit Heart Surg. 10 (2019) 292–295. [9] C.A. Warnes, R. Liberthson, G.K. Danielson, A. Dore, L. Harris, J.I. Hoffman, et al., Task force 1: the changing profile of congenital heart disease in adult life, J. Am. Coll. Cardiol. 37 (2001) 1170–1175. [10] A.P. Bolger, R. Sharma, W. Li, M. Leenarts, P.R. Kalra, M. Kemp, et al., Neurohormonal activation and the chronic heart failure syndrome in adults with congenital heart disease, Circulation. 106 (2002) 92–99. [11] O. Tutarel, S. Dangwal, J. Bretthauer, M. Westhoff-Bleck, P. Roentgen, S.D. Anker, et al., Circulating miR-423_5p fails as a biomarker for systemic ventricular function in adults after atrial repair for transposition of the great arteries, Int. J. Cardiol. 167 (2013) 63–66. [12] T. van der Bom, M.M. Winter, B.J. Bouma, M. Groenink, H.W. Vliegen, P.G. Pieper, et al., Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial, Circulation. 127 (2013) 322–330. [13] R.E. Shaddy, M.M. Boucek, D.T. Hsu, R.J. Boucek, C.E. Canter, L. Mahony, et al., Carvedilol for children and adolescents with heart failure: a randomized controlled trial, JAMA. 298 (2007) 1171–1179. [14] L. Lopez, M.S. Cohen, R.H. Anderson, A.N. Redington, D.G. Nykanen, D.J. Penny, et al., Unnatural history of the right ventricle in patients with congenitally malformed hearts, Cardiol. Young 20 (Suppl. 3) (2010) 107–112. [15] M.M. Winter, B.J. Bouma, M. Groenink, T.C. Konings, J.G. Tijssen, D.J. van Veldhuisen, et al., Latest insights in therapeutic options for systemic right ventricular failure: a comparison with left ventricular failure, Heart. 95 (2009) 960–963.
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Sacubitril/valsartan for heart failure in adults with complex congenital heart disease Susanne J. Maurer 1, Claudia Pujol Salvador 1, Sandra Schiele 1, Alfred Hager 1, Peter Ewert 1, Oktay Tutarel ⁎,1 Department of Congenital Heart Disease and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich, Munich, Germany
a r t i c l e
i n f o
Article history: Received 20 March 2019 Received in revised form 14 May 2019 Accepted 12 June 2019 Available online xxxx Keywords: Adult congenital heart disease Heart failure Sacubitril/valsartan
a b s t r a c t Background: Heart failure is an important cause of morbidity and mortality in adults with congenital heart disease (ACHD). Sacubitril/valsartan is an established treatment for heart failure with reduced ejection fraction due to acquired cardiovascular disease. Data in adults with complex congenital heart disease (CHD) is lacking. Methods: Retrospective study of ACHD patients with CHD of moderate/severe complexity and heart failure under treatment with sacubitril/valsartan. Clinical data was retrieved from medical records. Results: Altogether, 23 patients (mean age 41.2 ± 11.9 years, female 17.4%) were included. A systemic right ventricle was present in 12 pat. (52.2%), a single ventricle physiology in 4 (17.4%), and a systemic left ventricle in 7 (30.4%). During a median follow-up of 221 days [IQR 79–430], systemic ventricular function (p = 0.88) and functional status according to New York Heart Association class (p = 0.38) did not improve. While NT-proBNP levels did not change significantly under treatment (2561 ± 2042 ng/l vs. 1938 ± 1524 ng/l, p = 0.20), creatinine levels increased (1.14 ± 0.52 mg/dl vs. 1.35 ± 0.74 mg/dl, p = 0.002). Systolic (110 ± 15 mm Hg vs. 103 ± 14 mm Hg, p = 0.02) and diastolic blood pressures (68 ± 10 mm Hg vs. 61 ± 12 mm Hg, p = 0.01) were reduced under therapy. Five patients discontinued therapy, four of these due to side effects. Conclusion: In this small group of complex ACHD patients with heart failure, treatment with sacubitril/valsartan did not improve systemic ventricular function or functional status. Renal function needs close surveillance. © 2019 Elsevier B.V. All rights reserved.
1. Introduction Due to the advances in the care of children with congenital heart disease (CHD), the number of adults with congenital heart disease (ACHD) is increasing [1]. ACHD patients are burdened by significant morbidity and mortality, of which heart failure is the leading cause [2,3]. Furthermore, its incidence is increasing in ACHD patients [4]. In contrast to heart failure with reduced ejection fraction due to acquired cardiovascular disease, for which evidence-based guidelines exist, [5] treatment recommendations for ACHD patients are mainly based on expert consensus due to the lack of conclusive studies [3]. This is especially the case for drug therapy of heart failure. Sacubitril/valsartan has been established for the treatment of heart failure with reduced ejection fraction due to acquired cardiovascular disease [5,6]. Data regarding its use in ACHD patients is scarce. A case study of five patients with quite different underlying CHD and therefore, divergent pathophysiology was
⁎ Corresponding author at: Department of Congenital Heart Disease and Paediatric Cardiology, German Heart Centre Munich, Technical University of Munich, Lazarettstr. 36, 80636 Munich, Germany. E-mail address: [email protected] (O. Tutarel). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
published recently [7]. It reported an improvement in functional class during a short-term follow-up [7]. Another recent report of 15 ACHD patients including patients with less complex CHD reported symptomatic improvement in a proportion of patients (27%) during short-term follow-up, while the remaining patients reported no improvement [8]. Other studies are not available. Therefore, the aim of this study is to evaluate the use of sacubitril/ valsartan in ACHD patients with CHD of moderate/severe complexity and heart failure, and assess its efficacy and safety in this special patient group. 2. Methods From the database of our tertiary centre for ACHD, all patients (age ≫ 18 years of age) under a therapy with sacubitril/valsartan were identified. Demographic and clinical data (date of birth, gender, type of CHD and previous surgeries, date of begin with sacubitril/valsartan, date of last control or date of ending sacubitril/valsartan, laboratory results, imaging) as well as the indication for sacubitril/valsartan therapy were retrieved from the medical reports. Only patients with CHD of moderate or complex severity according to the Bethesda classification were included [9]. Systemic ventricular function was graded semiquantitatively
https://doi.org/10.1016/j.ijcard.2019.06.031 0167-5273/© 2019 Elsevier B.V. All rights reserved.
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
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as normal, mildly, moderately, or severely impaired based on the results of routine transthoracic echocardiograms as described previously [10]. Concomitant diuretic therapy was adjusted individually by the treating physician during outpatient visits according to the clinical status of the patient. Statistical analysis was performed using MedCalc version 18.11.3 (MedCalc Software, Mariakerke, Belgium). Continuous variables are presented as mean ± standard deviation or median (interquartile range), whereas categorical variables are presented as number (percentage). N-terminal pro-B-type natriuretic peptide (NT-proBNP) values were analysed after logarithmic transformation. Comparison between groups was performed using the paired samples t-test or Wilcoxon test for paired samples (signed-rank test) for continuous and Chi-square test for categorical variables. All tests were performed two-sided and for all analyses, a pvalue ≪0.05 was considered statistically significant. This study complies with the Declaration of Helsinki, and the ethics committee of the Medical Faculty of the Technical University of Munich has approved the research protocol. The requirement for informed consent was waived by the ethics committee due to the retrospective nature of the study. 3. Results Altogether, 23 patients (mean age 41.2 ± 11.9 years, female 17.4%) were included. Indication for therapy was a reduced systemic ventricular function and/or heart failure symptoms. A systemic right ventricle (transposition of the great arteries or congenitally corrected transposition of the great arteries) was present in 12 pat. (52.2%), a single ventricle physiology in 4 pat. (17.4%), and a systemic left ventricle (tetralogy of Fallot, coarctation of the aorta, Ebstein's anomaly, complex shunts) in 7 pat. (30.4%). Systemic ventricular dysfunction was moderate in 10 pat., and severe in 10. For three pat. an echocardiogram at the beginning of therapy was not available since it was initiated in a different centre. Functional status according to New York Heart Association (NYHA) class was I in 7 pat. (31.8%), II in 8 (36.4%), and III in 7 (31.8%) at baseline. In one patient NYHA class at initiation of therapy was not available. In 17 pat. (73.9%) a device was already implanted at baseline. An implantable cardioverter-defibrillator was present in 9 pat., a pacemaker in 7, and a pacemaker with cardiac resynchronization in one. More detailed information regarding baseline characteristics is provided in Table 1. Tolerated maintenance dose was 24 mg/26 mg BID in 6 pat., 49/51 mg BID in 7, and 97/103 mg in 8; while 2 tolerated only a dose of 12/13 mg BID. During a median follow-up of 221 days [IQR 79–430], functional status according to NYHA class (p = 0.38) and systemic ventricular function (p = 0.88) did not improve (Fig. 1). N-terminal pro-B-type natriuretic peptide (NTproBNP) levels did not change significantly under treatment (2561 ± 2042 ng/l vs. 1938 ± 1524 ng/l, p = 0.20), while creatinine levels increased significantly (1.14 ± 0.52 mg/dl vs. 1.35 ± 0.74 mg/dl, p = 0.002) (Fig. 2 A/B). Potassium levels also increased under therapy (4.1 ± 0.5 mmol/l vs. 4.3 ± 0.4 mmol/l, p = 0.048). Systolic blood pressure (110 ± 15 mm Hg vs. 103 ± 14 mm Hg, p = 0.02) as well as diastolic blood pressure (68 ± 10 mm Hg vs. 61 ± 12 mm Hg, p = 0.01) were reduced under therapy. Five patients discontinued the therapy, two due to the development/worsening of severe renal dysfunction, one because of diarrhoea, one due to severe headaches and dizziness, and another one due to relocation to a different country. Considering the two patients who had to discontinue therapy with sacubitril/ valsartan due to worsening renal function, the first had a glomerular filtration rate (GFR) of 37 ml/min at the initiation of therapy. After six months of treatment with a dose of 24 mg/26 mg BID, GFR decreased to 19 ml/min. Therapy with sacubitril/valsartan was discontinued as well as the therapy with eplerenone. After
Table 1 Baseline characteristics. N (%) All Female Mean age (years) Systemic ventricle Left Right Single Systemic ventricular function* Moderately reduced Severe reduced New York Heart Association class* I II III Cardiac medication ACE inhibitors/Angiotensin II receptor blockers Beta-blockers Mineralocorticoid receptor antagonists Diuretics Digoxin and other digitalis glycosides Antiarrhythmic Device therapy Implantable cardioverter-defibrillator Pacemaker Pacemaker with cardiac resynchronization
23 (100) 4 (17.4) 41.2 ± 11.9 7 (30.4) 12 (52.2) 4 (17.4) 10 (50) 10 (50) 7 (31.8%) 8 (36.4) 7 (31.8) 14 (60.9) 17 (73.9) 17 (73.9) 18 (78.3) 8 (34.8) 6 (26.1) 9 (39.1) 7 (30.4) 1 (4.3)
In three patients, an echocardiogram at initiation of therapy and in one patient functional class was not available. In all patients due to therapy initiation in a different centres. ACE: angiotensin-converting enzyme.
two weeks GFR recovered to 35 ml/min. The other patient had a GFR of 23 ml/min at initiation of the therapy, which decreased to 15 ml/min after two weeks of therapy with a dose of 12/ 13 mg BID. The potassium level was 5.9 mmol/l. Sacubitril/ valsartan was discontinued, and GFR increased to 23 ml/min after a few days. Potassium levels were in the normal range. Both patients did not require dialysis, but were hospitalized.
4. Discussion In this small cohort of ACHD patients with heart failure and underlying complex CHD, therapy with sacubitril/valsartan did not improve NYHA class or systemic ventricular function. Furthermore, NT-proBNP levels were also not significantly changed. In the Prospective Comparison of ARNI (Angiotensin ReceptorNeprilysin Inhibitor) with ACEI (Angiotensin-Converting-Enzyme Inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM-HF), a therapy with sacubitril/ valsartan was superior to enalapril in reducing the risks of death and of hospitalization for heart failure due to acquired cardiovascular diseases [6]. Around 60% of these patients had ischemic cardiomyopathy. Patients with complex CHD were not included. Regarding concomitant cardiac medications, the use of diuretics and digoxin was at a similar rate compared to our cohort. However, the PARADIGM-HF trial had a higher proportion of patients with beta-blockers, while in our study cohort the proportion of patients using mineralocorticoid receptor antagonists was higher. Interestingly, only 15% of patients in the PARADIGM-HF trial had an implantable cardioverter-defibrillator, while this number was around 40% in our cohort. Therefore, the severity of heart failure was comparable, but the pathophysiology is quite different between both cohorts considering the high number of patients with a systemic right ventricle – where the morphological right ventricle supports the systemic circulation – as well as patients with a single ventricle physiology in our study cohort. Therefore,
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
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Fig. 1. New York Heart Association class at initiation of therapy and at follow-up.
an extrapolation of the results of the PARADIGM-HF trial to ACHD patients with complex CHD is not possible. Appadurai and colleagues reported the results of a case series of five ACHD patients with heart failure under a therapy with sacubitril/valsartan [7]. Out of the five patients, two had a systemic right ventricle and three a systemic left ventricle. While the patients reported some symptomatic improvement, cardiopulmonary exercise testing (CPET) – which was available in two patients – showed an improvement in one patient and a decline in the other patient. Unfortunately, CPET at initiation of therapy and follow-up was only available in one patient in our cohort. In this case, peak oxygen uptake decreased under therapy. While all patients in the case series of Appadurai and colleagues reported heart failure symptoms, some patients in our cohort were in NYHA class I, and therapy with sacubitril/valsartan was initiated for reduced systemic ventricular function. Therefore, one could speculate that symptomatic patients may have a greater benefit. Especially, since around 95% of patients in the PARADIGM-HF trial were in NYHA class II-IV [6]. These reported an improvement in the clinical summary score on the Kansas City Cardiomyopathy Questionnaire [6]. However, the majority of our patients was also symptomatic (n = 15), and only two of these reported an improvement in functional class. Moreover, in Lluri and colleagues' report, all 15 ACHD patients had heart failure symptoms, but only 27% reported some symptomatic improvement under a therapy with sacubitril/valsartan [8]. Unfortunately, both previous studies did not report data regarding systemic ventricular function or NT-proBNP levels under therapy [7,8]. In our cohort, there was
no significant improvement of either. Furthermore, while 60% of patients in the case series had a systemic left ventricle, [7] as well as 53% of patients reported by Lluri and colleagues, [8] this was the case in only 30% of our cohort. The remaining patients had a systemic right ventricle or a single ventricle physiology. Both have a quite different pathophysiology compared to the failure of a systemic left ventricle, [11] which could explain the different outcome in the current study. Not all of our patients reached the target dose for sacubitril/valsartan. However, we observed a significant decrease in systolic and diastolic blood pressure levels in our study as reported in the PARADIGM-HF trial [6]. Therefore, we can safely assume that sacubitril/valsartan showed a therapeutic effect despite the fact that not all of our patients reached the target dose. Five patients in our study cohort discontinued the therapy, four (17.4%) due to side-effects. In the PARADIGM-HF trial sacubitril/ valsartan was discontinued in 10.7% because of an adverse event. This number was higher for the control group with enalapril [6]. The higher number in our study cohort could be due to the small number of patients included. Another explanation would be that ACHD patients with their divergent pathophysiology are more susceptible to side effects of the therapy. In our cohort, two patients developed severe renal dysfunction. Likewise, one patient in Lluri and colleagues' report discontinued medication due to continued worsening of renal function [8]. This was also common in the PARADIGM-HF trial [6]. Furthermore, creatinine levels increased significantly in our cohort, while this was not the case in the previous report [8]. A possible explanation is the
Fig. 2. NT-proBNP and creatinine levels at initiation of therapy and at follow-up. Circles represent individual observations.
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031
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shorter follow-up duration in the latter study with a median follow-up of 69 days in comparison to 221 days in our study. Hypotension, another common side effect of sacubitril/valsartan, did occur in only one patient in our study cohort. Previous studies with established heart failure medications like ACE-inhibitors or beta-blockers in patients with CHD were also negative. For example, a randomized controlled trial of the angiotensin II receptor blocker valsartan in adult patients with a systemic right ventricle failed to show a significant treatment effect of valsartan on right ventricular ejection fraction, exercise capacity, or quality of life [12]. In a trial in children and adolescents with symptomatic systolic heart failure including patients with CHD, carvedilol did not significantly improve clinical heart failure outcomes [13]. While there was a beneficial trend in patients with a systemic left ventricle, this was not the case in those whose systemic ventricle was not a left ventricle [13]. The reasons for these negative study results are a matter of debate. While without doubt the small number of patients included in these studies compared to the landmark trials in the treatment of heart failure with reduced ejection fraction due to acquired cardiovascular disease plays an important role, some other aspects may also be of importance. One could speculate that neurohormonal activation is less pronounced in ACHD patients. However, a study of 53 ACHD patients reported that the level of neurohormonal activation beared the hallmarks of chronic heart failure, relating to symptom severity and ventricular dysfunction [10]. Another possible explanation could be the different myocardial substrate in patients with CHD compared to patients with acquired cardiovascular disease. Often we are not dealing with a systemic left ventricle, but a systemic right ventricle or a single ventricle physiology. This is of importance, because even the orientation of the cardiomyocytes differs between the left and right ventricle [14]. Furthermore, repeated surgeries from early childhood leading to myocardial damage in the perioperative period and a geometry of the right ventricle, which makes it less suitable to handle the constant pressure overload of the systemic circulation, need to be considered [15]. When designing future drug studies in ACHD patients, we have to decide which would be the best outcome markers. Maybe a combination of surrogate markers like NT-proBNP and improved performance on cardiopulmonary exercise testing could be helpful. Alternatively, we have to identify new biomarkers, which better resemble the clinical status of ACHD patients. However, ideally we should focus on hard clinical endpoints like mortality. To achieve such a goal, we need to conduct multicentre studies with a much longer study duration. A limitation of our study is its retrospective nature with all inherent limitations. In some patients, variables like NYHA class were missing. Furthermore, CPET as an objective measure of exercise capacity was not regularly performed. Additionally, despite being the largest study with the longest follow-up duration reported so far for ACHD patients with complex CHD under sacubitril/valsartan therapy, the number of patients is still low compared to studies in acquired cardiovascular disease, a common problem in studies with ACHD patients. Even a multicentre trial studying the effect of valsartan on systemic right ventricular function did include only 78 patients (38 with valsartan, 40 with placebo) [12]. This trial also showed no significant treatment effect of valsartan on systemic right ventricular function, exercise capacity or quality of life.
While the current study showed no benefit of sacubitril/valsartan in a cohort of ACHD patients with complex disease, further studies in larger cohorts are necessary for a final verdict. Ideally, a double blind, randomized controlled trial should be performed. Furthermore, a multicentre, international registry needs to be established, which is currently in the making. Until these studies are available, sacubitril/ valsartan should only be used on an individual basis for ACHD patients with complex disease. Renal function needs close surveillance. Declaration of Competing Interest None. Acknowledgements None. References [1] P. Khairy, R. Ionescu-Ittu, A.S. Mackie, M. Abrahamowicz, L. Pilote, A.J. Marelli, Changing mortality in congenital heart disease, J. Am. Coll. Cardiol. 56 (2010) 1149–1157. [2] C.C. Engelings, P.C. Helm, H. Abdul-Khaliq, B. Asfour, U.M. Bauer, H. Baumgartner, et al., Cause of death in adults with congenital heart disease - an analysis of the German National Register for Congenital Heart Defects, Int. J. Cardiol. 211 (2016) 31–36. [3] W. Budts, J. Roos-Hesselink, T. Radle-Hurst, A. Eicken, T.A. McDonagh, E. Lambrinou, et al., Treatment of heart failure in adult congenital heart disease: a position paper of the Working Group of Grown-Up Congenital Heart Disease and the Heart Failure Association of the European Society of Cardiology, Eur. Heart J. 37 (2016) 1419–1427. [4] K. Norozi, A. Wessel, V. Alpers, J.O. Arnhold, S. Geyer, M. Zoege, et al., Incidence and risk distribution of heart failure in adolescents and adults with congenital heart disease after cardiac surgery, Am. J. Cardiol. 97 (2006) 1238–1243. [5] P. Ponikowski, A.A. Voors, S.D. Anker, H. Bueno, J.G.F. Cleland, A.J.S. Coats, et al., 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). Eur. Heart J. 37 (2016) 2129–2200. [6] J.J. McMurray, M. Packer, A.S. Desai, J. Gong, M.P. Lefkowitz, A.R. Rizkala, et al., Angiotensin-neprilysin inhibition versus enalapril in heart failure, N. Engl. J. Med. 371 (2014) 993–1004. [7] V. Appadurai, J. Thoreau, T. Malpas, M. Nicolae, Sacubitril/valsartan in adult congenital heart disease patients with chronic heart failure - a single centre case series and call for an international registry, Heart Lung Circ. (2019)https://doi.org/10.1016/j. hlc.2018.12.003. [8] G. Lluri, J. Lin, L. Reardon, P. Miner, K. Whalen, J. Aboulhosn, Early experience with sacubitril/valsartan in adult patients with congenital heart disease, World J. Pediatr. Congenit Heart Surg. 10 (2019) 292–295. [9] C.A. Warnes, R. Liberthson, G.K. Danielson, A. Dore, L. Harris, J.I. Hoffman, et al., Task force 1: the changing profile of congenital heart disease in adult life, J. Am. Coll. Cardiol. 37 (2001) 1170–1175. [10] A.P. Bolger, R. Sharma, W. Li, M. Leenarts, P.R. Kalra, M. Kemp, et al., Neurohormonal activation and the chronic heart failure syndrome in adults with congenital heart disease, Circulation. 106 (2002) 92–99. [11] O. Tutarel, S. Dangwal, J. Bretthauer, M. Westhoff-Bleck, P. Roentgen, S.D. Anker, et al., Circulating miR-423_5p fails as a biomarker for systemic ventricular function in adults after atrial repair for transposition of the great arteries, Int. J. Cardiol. 167 (2013) 63–66. [12] T. van der Bom, M.M. Winter, B.J. Bouma, M. Groenink, H.W. Vliegen, P.G. Pieper, et al., Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot trial, Circulation. 127 (2013) 322–330. [13] R.E. Shaddy, M.M. Boucek, D.T. Hsu, R.J. Boucek, C.E. Canter, L. Mahony, et al., Carvedilol for children and adolescents with heart failure: a randomized controlled trial, JAMA. 298 (2007) 1171–1179. [14] L. Lopez, M.S. Cohen, R.H. Anderson, A.N. Redington, D.G. Nykanen, D.J. Penny, et al., Unnatural history of the right ventricle in patients with congenitally malformed hearts, Cardiol. Young 20 (Suppl. 3) (2010) 107–112. [15] M.M. Winter, B.J. Bouma, M. Groenink, T.C. Konings, J.G. Tijssen, D.J. van Veldhuisen, et al., Latest insights in therapeutic options for systemic right ventricular failure: a comparison with left ventricular failure, Heart. 95 (2009) 960–963.
Please cite this article as: S.J. Maurer, C. Pujol Salvador, S. Schiele, et al., Sacubitril/valsartan for heart failure in adults with complex congenital heart disease, International Journal of Cardiology, https://doi.org/10.1016/j.ijcard.2019.06.031