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Pulsed Levosimendan in advanced heart failure due to congenital heart disease: a case series

Pulsed Levosimendan in advanced heart failure due to congenital heart disease: a case series Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 CASE SERIES European Heart Journal - Case Reports (2020) 4, 1–6 doi:10.1093/ehjcr/ytaa080 Congenital heart disease Pulsed Levosimendan in advanced heart failure due to congenital heart disease: a case series 2 2 James Cranley *, Antonia Hardiman , and Leisa J. Freeman , Cardiology Department, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK Received 8 October 2019; first decision 23 October 2019; accepted 17 March 2020; online publish-ahead-of-print 1 May 2020 Background Levosimendan is a non-adrenergic calcium-sensitizing agent with positive inotropic and vasodilatory effects. Its use in acute decompensation of heart failure is established. Good evidence now exists for repetitive infusions of Levosimendan to improve symptoms and reduce hospitalization in advanced heart failure (AdHF) populations. Its use in heart failure resulting from congenital heart disease is not yet commonplace. ................................................................................................................................................................................................... Case summary We present three cases in which pulsed Levosimendan was used in the management of AdHF secondary to under- lying congenital heart disease. There was symptomatic and biomarker evidence of improvement. ................................................................................................................................................................................................... Discussion Intermittent Levosimendan may represent a valuable therapy to reduce hospitalization and improve quality of life in adults with congenital heart conditions. Keywords Advanced heart failure Levosimendan Adult congenital heart disease Case series � � � resistance. The combined effect reduces afterload and increases ino- tropy with consequent improvement in cardiac output and reduction Learning points . • in systemic and pulmonary congestion. It is administered intravenous- Patients with advanced heart failure secondary to congenital ly (IV) through central or peripheral veins but is excreted via the small heart disease are growing in number owing to increasing sur- intestine and has an acetylated active metabolite (OR-1896) with an vival to adulthood in surgically palliated conditions. Levosimendan is a calcium-sensitizing inotropic agent which excretion half-life of approximately 3 days. has shown benefit in other heart failure settings. Its clinical use has been primarily studied in the setting of acute de- The long half-life of Levosimendan lends itself to intermittent compensated heart failure and following cardiac surgery typically in a therapy in the outpatient setting, and in our case series, it critical care environment, where it has been found to be beneficial as 3,4 improved symptoms and avoided hospital admission. sole or adjunctive therapy. Levosimendan has a slow elimination such that it may be administered intravenously at 2- to 4-week inter- . vals. This is a unique property amongst inotropes, permitting repetitive . infusion in the outpatient setting. Levo-Rep, LION-Heart, and LAICA Introduction . 5 . trials have offered evidence of clinical advantage and provide support . for repetitive Levosimendan treatment in the European Society of Levosimendan is an inodilator, improving contractile force without . 6 . Cardiology position statement on advanced heart failure (AdHF). affecting calcium transient magnitude by binding to the cardiac . Advanced heart failure secondary to adult congenital heart disease troponin C subunit. It causes vasodilation by increasing the opening (ACHD) represents a small subgroup posing unique challenges in probability of ATP-sensitive potassium channels on vascular smooth terms of the specifics of its management. At present, Levosimendan muscle cells, leading to reduced systemic and pulmonary vascular *Corresponding author. Tel: þ44 (0)1603 286 286, Email: james.cranley@nhs.net Handling Editor: Domenico D’Amario Peer-reviewers: Christoph Sinning, Esther Cambronero-Cortinas, and Dejan Milasinovic Compliance Editor: Amir Aziz Supplementary Material Editor: Vassilios Parisis Memtsas V The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 2 J. Cranley et al. remains under-studied in ACHD. It has the potential to reduce hospi- Case presentation talization and improve quality of life, making it an enticing prospect in these patients, a growing population who have been identified as Patient 1 causes of ‘high resource use’ admissions. A recent review found that This patient had a history of pulmonary atresia and a large ventricular median charges for an ACHD-related heart failure admission was septal defect (VSD). Pulmonary blood supply was from a single major $59 055; however, the median cost in the most expensive decile of aorto-pulmonary collateral artery dividing into two right-sided the admissions was $1 018 656. branches and single, tortuous left branch. There was no central pul- We present three cases of congenital heart disease complicated monary artery (PA). Initial left Blalock–Taussig (BT) shunt aged 1 with by heart failure treated with pulsed Levosimendan. attempt at unifocalization failed within 1 year. Age 2, a right BT shunt provided some pulmonary blood flow into adolescence. Attempt at balloon dilatation age 21 failed. Further interventional/surgical Timeline Patient 1 Neonatal life Pulmonary atresia with a large ventricular septal defect (VSD), with only a single major aorto-pulmonary collateral artery (MAPCA) and no main pulmonary arteries. Patient underwent neonatal left and right Blalock–Taussig (BT) shunts. Age 1 Left BT shunt blocked Age 2 Right BT shunt blocked Age 21 Right BT shunt angioplasty, subsequent re-occlusion. Age 30—initial evaluation Care transferred to our adult congenital heart disease centre. Advanced heart failure requiring repeated hospital admission for decompensations. 13 months after evaluation First infusion of Levosimendan (25 mg every 28 days). Marked improvement in symptoms and 6-min walking test for 21 days, followed by return of symptoms. 16 months after evaluation Levosimendan dose reduced (12.5 mg every 28 days). Improvement for initial 14 days post- infusion, followed by return of symptoms. Required (planned) IV diuretics in second half of 28-day cycle. 24 months after evaluation Sudden cardiac death, presumed arrhythmic. Patient 2 Neonatal life Congenital atrial septal defect (ASD) and VSD. Age 3 Pulmonary artery (PA) banding. Age 9 ASD and VSD repair surgery. Age 37 Pause-dependent ventricular tachycardia (VT), pacemaker implanted. Age 43 Right ventricular aneurysm resection. Age 51 Scar-related atrial flutter ablation. Age 52 Cardiac resynchronization therapy-defibrillator implanted. Repeated admissions with de- compensated heart failure. Age 53 Levosimendan commenced (12.5 mg every 28 days). Improved symptoms for 14 days post- infusion then recurrence of symptoms. 12 months after Levosimendan commenced Infusion frequency increased to 12.5 mg every 18 days. 22 months after Levosimendan commenced Sudden cardiac death, presumed arrhythmic. Patient 3 Neonatal life Tetralogy of Fallot with subsequent right BT shunt Age 5 VSD closed, right ventricular outflow tract resected, MAPCA ligated. Age 17 Right ventricle–PA homograft for severe pulmonary regurgitation. Age 26 Xenograft pulmonary valve replacement. Age 36 Atrial flutter ablation. Implantable cardioverter-defibrillator implant. Age 40 VO max 26 mL/kg/min. Age 41 VT ablation. Left ventricular ejection fraction (LVEF) 43%. Age 43 VO max 14 mL/kg/min. Recurrent admissions for decompensated heart failure. LVEF 24%. Age 44—initial Levosimendan therapy Therapy commenced at 12.5 mg every 28 days. Age 47–32 months after Levosimendan commenced First admission with decompensated heart failure since Levosimendan started. Treated with IV diuretics. Age 48–56 months after Levosimendan commenced Remains symptomatically improved. Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 Pulsed Levosimendan in AdHF due to CHD 3 Figure 2 Patient 1: echocardiogram showing dilated right ventricle, with ‘D-ing’ of the interventricular septum towards the Figure 1 Patient 1: chest radiograph showing cardiomegaly. left ventricle in keeping with elevated right-sided pressures. IVS, interventricular septum; LV, left ventricle; RV, right ventricle. options were deemed futile. He was unsuitable for heart–lung trans- plantation due to high antibody burden. Aged 30, he was transferred . symptoms. His 6MWT immediately post-Levosimendan infusion to our centre for palliative care from a tertiary ACHD centre. . doubled (360 m). At the time of initial evaluation, he had cardiomegaly (Figure 1)sec- . He was found dead in bed at home having been well that morn- ondary to severe tricuspid regurgitation and aortic regurgitation, itself . ing—a presumed arrhythmic death. He had survived for 11 months due to marked aortic dilatation. He had also suffered with previous . longer than expected, maintaining a good quality of life. atrial flutter and ventricular tachycardia (VT), both successfully . treated with amiodarone. He had pulmonary hypertension, intolerant . of targeted therapy. He was rejected for heart and lung transplant. . Patient 2 His left ventricular (LV) ejection fraction was 20% and his right . This patient was born with atrial septal defect and VSD, undergoing ventricle was severely dilated and impaired (Figure 2, Supplementary . PA banding aged 3 with subsequent septal defect closure aged 9. material online, File S1). He was not a candidate for cardiac resynch- She had episodic bradycardias with pause-dependent VT, which ronization therapy due to his normal QRS complex duration. responded to pacing. At age 43, she underwent resection of a right Defibrillator implantation had been considered but was deemed in- ventricular (RV) aneurysm (related to previous ventriculotomy for appropriate in view of the palliative nature of his treatment. VSD repair). She had a successful atrial flutter ablation at age 52 Management of his heart failure required frequent admissions for (atriotomy scar). Long-standing impaired ventricular function was intravenous (IV) diuretics, inotrope infusions, and fluid restriction for thought secondary to late repair and lack of myocardial preservation 2–3 weeks at a time. He would manage approximately 1 week and techniques during her childhood surgery. Both right and left ven- then he would require readmission (despite a trial of domiciliary tricles were severely impaired (Figure 3). Coronary assessment was nurse-administered IV diuretics). He had two young children and was unremarkable. Despite cardiac resynchronization therapy with defib- desperately keen to avoid long spells in hospital and was frustrated rillator function (CRT-D), her LV ejection fraction remained poor at not to be able to play with them at all due to poor exercise tolerance, 21% and she had little improvement in symptoms or frequency of his 6-min walking test (6MWT) being <100 m. Furthermore, he had . hospital admissions (Figure 4, Supplementary material online, File S2). AdHF-related cardiorenal syndrome. . Each admission with biventricular heart failure (10–14 days) was man- Approval for repetitive infusions of Levosimendan was obtained. . aged with IV diuretics, fluid restriction, traditional inotropes, and con- Initially, funding was obtained for two 12.5 mg vials of Levosimendan . ventional heart failure management. She would remain at home for each month, each being infused over 24 h. For the first 21 days follow- . 7–10 days and then require readmission. Due to 97% HLA antibod- ing each treatment, he had excellent control of his heart failure; . ies, she was rejected for transplantation. for the latter 6 days, he gradually deteriorated. As a result of . Approval for repetitive Levosimendan infusion was sought and funding issues, Levosimendan was reduced to one vial every month. . approved. During the following 18 months, she was admitted for He continued to have symptomatic improvement for approximately . pulsed Levosimendan therapy every 28 days (1 vial over 24 h). During 14 days following infusion but thereafter required readmission, . this period, she remained free of admissions for decompensated initially at 24 days, then 18 days post-infusion due to heart failure . heart failure (she had one admission with pneumonia and a pre-renal Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 4 J. Cranley et al. Figure 3 Patient 2: echocardiogram showing grossly dilated and impaired left ventricle. LV, left ventricle. Figure 5 Patient 3: gated computed tomography demonstrating non-stenosed xenograft pulmonary valve. PV, pulmonary valve. Patient 3 Patient 3 was born with Tetralogy of Fallot, undergoing a right BT shunt in the first year of life. In childhood, she had repair surgery with . VSD patch closure, RV outflow tract resection, and an aorto- . pulmonary collateral from the descending aorta was ligated. At age . 17, a right ventricle–PA homograft was required for severe pulmon- . ary regurgitation, later this became stenosed and required xenograft . pulmonary valve replacement aged 26. The xenograft pulmonary valve remains without significant stenosis or regurgitation, and no coronary disease on computed tomography (Figure 5). She under- went ablations for atrial flutter and VT and had a dual-chamber implantable cardioverter-defibrillator (ICD) implanted. Severe RV dysfunction is a late consequence of palliative surgery for Fallot’s tetralogy. The RV dysfunction never remodelled following redo Figure 4 Patient 2: chest radiograph showing cardiomegaly and homograft implantation aged 17 nor improved following PVR aged cardiac resynchronization therapy-defibrillator device. 26. In consequence, she has severe functional tricuspid regurgitation due to annular ring dilatation secondary to her markedly dilated right ventricle (Figure 6, Supplementary material online, File S3). acute kidney injury from which she recovered). Following the infu- Cardiopulmonary exercise testing at age 40 showed a VO max of . 2 sion, she was aware of a significant improvement in activities of daily 26 mL/kg/min (normal >24.5 mL/kg/min) however by age 43 this had living for 14 days but then a deterioration with fluid retention and fallen to 14 mL/kg/min and she began to have recurrent admissions increasing breathlessness in the days prior to the next planned infu- for decompensated heart failure. She was not accepted for trans- sion. Infusion frequency was increased to every 18 days with good plantation due to her body mass index of 15.9, 95% HLA antibodies, effect. She suffered from a presumed vasodilatation headache for Group A blood type and significant restrictive lung function. 2–3 days after infusion which responded to 5 days of Triptan with Mechanical ventricular assist devices were not considered since they good effect. 21 months into Levosimendan therapy she suffered 18 . are reserved as a bridge to transplant in our health care system. defibrillator shocks due to VT. Ablation therapy was considered . Approval for Levosimendan infusion was granted when her 6MWT however the patient requested deactivation of her device. She died . was 40 m and her B-type natriuretic peptide (BNP) was 1599 ng/L suddenly the next month aged 55, almost 2 years after commencing . (normal range 0–114 ng/L). She had an excellent response, her monthly Levosimendan. . Levosimendan infusions have permitted her to remain at home. Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 Pulsed Levosimendan in AdHF due to CHD 5 It was 32 months following commencement of Levosimendan . Discussion that she had her first admission with decompensated heart failure. . Adult survival with complex congenital heart disease is now expected This appeared to be pre-terminal with a high BNP (1220 ng/L) and in more than 90% of cases due to improved palliative intervention or reduced 6MWT (224 m). She was referred for palliative care and her surgery, optimal medical therapy and careful clinical surveillance in dedi- ICD was deactivated. However, following IV diuretics and continued cated adult congenital heart clinics.Nearlyhalfofsubsequentdeaths monthly Levosimendan infusions, she has returned home and are due to heart failure at a median age of death of only 48.8 years. As resumed most of her usual activities. 6MWT improved back to in the cases described here, the recurrent admissions for conventional 426 m and BNP to 770 ng/L (Figure 7). At present, she remains symp- intravenous heart failure therapy have limited short-term benefit but tomatically stable, over 5 years since her first Levosimendan infusion. poor subsequent outcomes. Heart failure medications, validated in acquired heart failure, are not seen to confer the same benefit— particularly in patients with failing systemic right ventricles or severely impaired sub-pulmonary ventricles. Heart transplantation may be pos- sible for some but high HLA antibody burden (often related to prior transfusions) and other comorbidities often prevent listing. A single UK congenital heart transplant centre reported that 56% of referred ACHD cases were not listed. If listed, they spend a long time on the heart transplant list due to more restrictive donor selection, and ven- tricular assist devices have not shown the benefit seen in those with acquired heart conditions awaiting transplantation. . 5 . An excellent review of the literature and evidence base . lends support to the approach adopted for the specific cases described. . In each of our patients, there was a symptomatic improvement . associated with marked reduction in hospitalization (observed in . RELEVANT-HF) and better quality of life for their remaining life span. Levosimendan was well tolerated, without symptomatic hypotension— as found in LIONHEART. Levosimendan infusions were started every 4 weeks with a 24 h infusion (no bolus). Cases 1 and 2 required a reduc- tion in time between infusions (14–21) days, whereas Case 3 continues at almost five years from initiation on 28-day infusions. Individualized funding for Levosimendan infusion is required in the Figure 6 Patient 3: echocardiogram showing severely dilated right ventricle. RV, right ventricle. UK. Approval has been granted in the cases described, having demon- strated that the infusion cost (£920/month) is offset by bed-days saved. The meta-analyses of 345 patients, provides evidence of significant Figure 7 Patient 3: Graph depicting changes in 6-min walking test and N-terminal pro-B-type natriuretic peptide after commencement of Levosimendan. BNP, B-type natriuretic peptide; 6MWT, 6-min walking test. Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 6 J. Cranley et al. benefit for repetitive or pulsed Levosimendan with a significant reduc- . Slide sets: A fully edited slide set detailing this case and suitable for tion in mortality in the AdHF population (with average follow-up . local presentation is available online as Supplementary data. 4 . period of 8 ± 8.3 months) of 10.2% vs. 26.8% in the control group. . With this series, we hope to encourage the formal study of this . Consent: The author/s confirm that written consent for submission therapeutic option in this patient population. A limitation in our ser- . and publication of this case report including image(s) and associated ies is the lack of longitudinal objective data for cases 1 and 2, e.g. text has been obtained from the patient in line with COPE guidance. N-terminal pro-BNP levels. Furthermore, although not undertaken in Conflict of interest: none declared. this series, right heart catheterization data may be useful in determin- ing those patients likely to benefit most from Levosimendan. Although its evidence lies primarily in left heart failure, there is grow- References 1. De Hert SG, Wikstro ¨ m BG, Meyer S, Filippatos G, Yilmaz MB, Grossini E, ing data supporting the benefit of Levosimendan in pulmonary arterial . Jo ¨ rgensen K, Edes I, Guarracino F, Gonza ´lez MJG, Parkhomenko A, Leppikangas hypertension and right heart failure. This may explain the favour- H, Mebazaa A, Pollesello P, Landoni G, Parissis JT, Caimmi P, Fruhwald S, able results seen in our ACHD patients where both ventricles, as Schwinger RHG, Papp Z, Kivikko M, Algotsson L, Follath F, Salmenpera¨M, . Morelli A. Levosimendan: Molecular mechanisms and clinical implications. Int J well as pulmonary vasculature play a role in heart failure. Cardiol 2012;159:82–87. 2. Antila S, Sundberg S, Lehtonen LA. Clinical pharmacology of levosimendan. Clin Pharmacokinet 2007;46:535–552. 3. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Conclusion Gonza ´lez-Juanatey JR, Harjola V-P, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, This case series demonstrates that repetitive Levosimendan infusions Ruschitzka F, Rutten FH, van der Meer P. 2016 ESC Guidelines for the diagno- . sis and treatment of acute and chronic heart failure. Eur Heart J 2016;37: for end-stage heart failure in selected adult survivors of congenital heart 2129–2200. disease is cost-effective with bed-days saved, is well-tolerated, improves 4. Pollesello P, Parissis J, Kivikko M, Harjola VP. Levosimendan meta-analyses: quality of life and reduces admissions. The numbers of ACHD patients Is there a pattern in the effect on mortality? Int J Cardiol 2016;209:77–83. 5. Oliva F, Comin-Colet J, Fedele F, Fruhwald F, Gustafsson F, Kivikko M, Borbe ´ly with end-stage heart failure is increasing and this treatment modality A, Po ¨ lzl G, Tscho ¨ pe C. Repetitive levosimendan treatment in the management of has an important role in the standard of care in that management. advanced heart failure. Eur Hear J Suppl 2018;20:I11–I20. . 6. Crespo-Leiro MG, Metra M, Lund LH, Milicic D, Costanzo MR, Filippatos G, Gustafsson F, Tsui S, Barge-Caballero E, De Jonge N, Frigerio M, Hamdan R, Hasin T, Hu ¨ lsmann M, Nalbantgil S, Potena L, Bauersachs J, Gkouziouta A, Lead author biography Ruhparwar A, Ristic AD, Straburzynska-Migaj E, McDonagh T, Seferovic P, . Ruschitzka F. Advanced heart failure: a position statement of the Heart Failure Dr James Cranley graduated from Association of the European Society of Cardiology. Eur J Heart Fail 2018;20: Oxford medical school with distinc- 1505–1535. . 7. Chan J, Collins RT, Hall M, John A. Resource utilization among adult congenital tion before working at Royal heart failure admissions in pediatric hospitals. Am J Cardiol 2019;123:839–846. Brompton, Addenbrooke s, and 8. Verheugt CL, Uiterwaal C, Van Der Velde ET, Meijboom FJ, Pieper PG, Van Dijk Royal Papworth hospitals as an aca- APJ, Vliegen HW, Grobbee DE, Mulder B. Mortality in adult congenital heart dis- . ease. Eur Heart J 2010;31:1220–1229. demic clinical fellow. He is currently 9. Cao J, Cordina R, Jackson D, Kotchetkova I, Lal S, Celermajer DS. Heart failure a cardiology registrar in the East of . admissions and poor subsequent outcomes in adults with congenital heart dis- England with a subspecialty interest . ease. Eur J Heart Fail 2018;20:812–815. 10. Irving C, Parry G, O’Sullivan J, Dark JH, Kirk R, Crossland DS, Chaudhari M, in cardiac electrophysiology. . Griselli M, Hamilton JRL, Hasan A. Cardiac transplantation in adults with con- genital heart disease. Heart 2010;96:1217–1222. . 11. Comı´n-Colet J, Manito N, Segovia-Cubero J, Delgado J, Garcı´a Pinilla JM, Almenar L, Crespo-Leiro MG, Sionis A, Blasco T, Pascual-Figal D, Gonzalez- Vilchez F, Lambert-Rodrı´guez JL, Grau M, Bruguera J; on behalf of the LION-HEART Study Investigators. Efficacy and safety of intermittent intravenous . outpatient administration of levosimendan in patients with advanced heart failure: Supplementary material . the LION-HEART multicentre randomised trial. Eur J Heart Fail 2018;20: 1128–1136. Supplementary material is available at European Heart Journal - Case 12. Hansen MS, Andersen A, Nielsen-Kudsk JE. Levosimendan in pulmonary hyper- . tension and right heart failure. Pulm Circ 2018;8:2045894018790905. Reports online. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal - Case Reports Oxford University Press

Pulsed Levosimendan in advanced heart failure due to congenital heart disease: a case series

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© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
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Abstract

Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 CASE SERIES European Heart Journal - Case Reports (2020) 4, 1–6 doi:10.1093/ehjcr/ytaa080 Congenital heart disease Pulsed Levosimendan in advanced heart failure due to congenital heart disease: a case series 2 2 James Cranley *, Antonia Hardiman , and Leisa J. Freeman , Cardiology Department, Norfolk and Norwich University Hospital, Colney Lane, Norwich NR4 7UY, UK Received 8 October 2019; first decision 23 October 2019; accepted 17 March 2020; online publish-ahead-of-print 1 May 2020 Background Levosimendan is a non-adrenergic calcium-sensitizing agent with positive inotropic and vasodilatory effects. Its use in acute decompensation of heart failure is established. Good evidence now exists for repetitive infusions of Levosimendan to improve symptoms and reduce hospitalization in advanced heart failure (AdHF) populations. Its use in heart failure resulting from congenital heart disease is not yet commonplace. ................................................................................................................................................................................................... Case summary We present three cases in which pulsed Levosimendan was used in the management of AdHF secondary to under- lying congenital heart disease. There was symptomatic and biomarker evidence of improvement. ................................................................................................................................................................................................... Discussion Intermittent Levosimendan may represent a valuable therapy to reduce hospitalization and improve quality of life in adults with congenital heart conditions. Keywords Advanced heart failure Levosimendan Adult congenital heart disease Case series � � � resistance. The combined effect reduces afterload and increases ino- tropy with consequent improvement in cardiac output and reduction Learning points . • in systemic and pulmonary congestion. It is administered intravenous- Patients with advanced heart failure secondary to congenital ly (IV) through central or peripheral veins but is excreted via the small heart disease are growing in number owing to increasing sur- intestine and has an acetylated active metabolite (OR-1896) with an vival to adulthood in surgically palliated conditions. Levosimendan is a calcium-sensitizing inotropic agent which excretion half-life of approximately 3 days. has shown benefit in other heart failure settings. Its clinical use has been primarily studied in the setting of acute de- The long half-life of Levosimendan lends itself to intermittent compensated heart failure and following cardiac surgery typically in a therapy in the outpatient setting, and in our case series, it critical care environment, where it has been found to be beneficial as 3,4 improved symptoms and avoided hospital admission. sole or adjunctive therapy. Levosimendan has a slow elimination such that it may be administered intravenously at 2- to 4-week inter- . vals. This is a unique property amongst inotropes, permitting repetitive . infusion in the outpatient setting. Levo-Rep, LION-Heart, and LAICA Introduction . 5 . trials have offered evidence of clinical advantage and provide support . for repetitive Levosimendan treatment in the European Society of Levosimendan is an inodilator, improving contractile force without . 6 . Cardiology position statement on advanced heart failure (AdHF). affecting calcium transient magnitude by binding to the cardiac . Advanced heart failure secondary to adult congenital heart disease troponin C subunit. It causes vasodilation by increasing the opening (ACHD) represents a small subgroup posing unique challenges in probability of ATP-sensitive potassium channels on vascular smooth terms of the specifics of its management. At present, Levosimendan muscle cells, leading to reduced systemic and pulmonary vascular *Corresponding author. Tel: þ44 (0)1603 286 286, Email: james.cranley@nhs.net Handling Editor: Domenico D’Amario Peer-reviewers: Christoph Sinning, Esther Cambronero-Cortinas, and Dejan Milasinovic Compliance Editor: Amir Aziz Supplementary Material Editor: Vassilios Parisis Memtsas V The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 2 J. Cranley et al. remains under-studied in ACHD. It has the potential to reduce hospi- Case presentation talization and improve quality of life, making it an enticing prospect in these patients, a growing population who have been identified as Patient 1 causes of ‘high resource use’ admissions. A recent review found that This patient had a history of pulmonary atresia and a large ventricular median charges for an ACHD-related heart failure admission was septal defect (VSD). Pulmonary blood supply was from a single major $59 055; however, the median cost in the most expensive decile of aorto-pulmonary collateral artery dividing into two right-sided the admissions was $1 018 656. branches and single, tortuous left branch. There was no central pul- We present three cases of congenital heart disease complicated monary artery (PA). Initial left Blalock–Taussig (BT) shunt aged 1 with by heart failure treated with pulsed Levosimendan. attempt at unifocalization failed within 1 year. Age 2, a right BT shunt provided some pulmonary blood flow into adolescence. Attempt at balloon dilatation age 21 failed. Further interventional/surgical Timeline Patient 1 Neonatal life Pulmonary atresia with a large ventricular septal defect (VSD), with only a single major aorto-pulmonary collateral artery (MAPCA) and no main pulmonary arteries. Patient underwent neonatal left and right Blalock–Taussig (BT) shunts. Age 1 Left BT shunt blocked Age 2 Right BT shunt blocked Age 21 Right BT shunt angioplasty, subsequent re-occlusion. Age 30—initial evaluation Care transferred to our adult congenital heart disease centre. Advanced heart failure requiring repeated hospital admission for decompensations. 13 months after evaluation First infusion of Levosimendan (25 mg every 28 days). Marked improvement in symptoms and 6-min walking test for 21 days, followed by return of symptoms. 16 months after evaluation Levosimendan dose reduced (12.5 mg every 28 days). Improvement for initial 14 days post- infusion, followed by return of symptoms. Required (planned) IV diuretics in second half of 28-day cycle. 24 months after evaluation Sudden cardiac death, presumed arrhythmic. Patient 2 Neonatal life Congenital atrial septal defect (ASD) and VSD. Age 3 Pulmonary artery (PA) banding. Age 9 ASD and VSD repair surgery. Age 37 Pause-dependent ventricular tachycardia (VT), pacemaker implanted. Age 43 Right ventricular aneurysm resection. Age 51 Scar-related atrial flutter ablation. Age 52 Cardiac resynchronization therapy-defibrillator implanted. Repeated admissions with de- compensated heart failure. Age 53 Levosimendan commenced (12.5 mg every 28 days). Improved symptoms for 14 days post- infusion then recurrence of symptoms. 12 months after Levosimendan commenced Infusion frequency increased to 12.5 mg every 18 days. 22 months after Levosimendan commenced Sudden cardiac death, presumed arrhythmic. Patient 3 Neonatal life Tetralogy of Fallot with subsequent right BT shunt Age 5 VSD closed, right ventricular outflow tract resected, MAPCA ligated. Age 17 Right ventricle–PA homograft for severe pulmonary regurgitation. Age 26 Xenograft pulmonary valve replacement. Age 36 Atrial flutter ablation. Implantable cardioverter-defibrillator implant. Age 40 VO max 26 mL/kg/min. Age 41 VT ablation. Left ventricular ejection fraction (LVEF) 43%. Age 43 VO max 14 mL/kg/min. Recurrent admissions for decompensated heart failure. LVEF 24%. Age 44—initial Levosimendan therapy Therapy commenced at 12.5 mg every 28 days. Age 47–32 months after Levosimendan commenced First admission with decompensated heart failure since Levosimendan started. Treated with IV diuretics. Age 48–56 months after Levosimendan commenced Remains symptomatically improved. Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 Pulsed Levosimendan in AdHF due to CHD 3 Figure 2 Patient 1: echocardiogram showing dilated right ventricle, with ‘D-ing’ of the interventricular septum towards the Figure 1 Patient 1: chest radiograph showing cardiomegaly. left ventricle in keeping with elevated right-sided pressures. IVS, interventricular septum; LV, left ventricle; RV, right ventricle. options were deemed futile. He was unsuitable for heart–lung trans- plantation due to high antibody burden. Aged 30, he was transferred . symptoms. His 6MWT immediately post-Levosimendan infusion to our centre for palliative care from a tertiary ACHD centre. . doubled (360 m). At the time of initial evaluation, he had cardiomegaly (Figure 1)sec- . He was found dead in bed at home having been well that morn- ondary to severe tricuspid regurgitation and aortic regurgitation, itself . ing—a presumed arrhythmic death. He had survived for 11 months due to marked aortic dilatation. He had also suffered with previous . longer than expected, maintaining a good quality of life. atrial flutter and ventricular tachycardia (VT), both successfully . treated with amiodarone. He had pulmonary hypertension, intolerant . of targeted therapy. He was rejected for heart and lung transplant. . Patient 2 His left ventricular (LV) ejection fraction was 20% and his right . This patient was born with atrial septal defect and VSD, undergoing ventricle was severely dilated and impaired (Figure 2, Supplementary . PA banding aged 3 with subsequent septal defect closure aged 9. material online, File S1). He was not a candidate for cardiac resynch- She had episodic bradycardias with pause-dependent VT, which ronization therapy due to his normal QRS complex duration. responded to pacing. At age 43, she underwent resection of a right Defibrillator implantation had been considered but was deemed in- ventricular (RV) aneurysm (related to previous ventriculotomy for appropriate in view of the palliative nature of his treatment. VSD repair). She had a successful atrial flutter ablation at age 52 Management of his heart failure required frequent admissions for (atriotomy scar). Long-standing impaired ventricular function was intravenous (IV) diuretics, inotrope infusions, and fluid restriction for thought secondary to late repair and lack of myocardial preservation 2–3 weeks at a time. He would manage approximately 1 week and techniques during her childhood surgery. Both right and left ven- then he would require readmission (despite a trial of domiciliary tricles were severely impaired (Figure 3). Coronary assessment was nurse-administered IV diuretics). He had two young children and was unremarkable. Despite cardiac resynchronization therapy with defib- desperately keen to avoid long spells in hospital and was frustrated rillator function (CRT-D), her LV ejection fraction remained poor at not to be able to play with them at all due to poor exercise tolerance, 21% and she had little improvement in symptoms or frequency of his 6-min walking test (6MWT) being <100 m. Furthermore, he had . hospital admissions (Figure 4, Supplementary material online, File S2). AdHF-related cardiorenal syndrome. . Each admission with biventricular heart failure (10–14 days) was man- Approval for repetitive infusions of Levosimendan was obtained. . aged with IV diuretics, fluid restriction, traditional inotropes, and con- Initially, funding was obtained for two 12.5 mg vials of Levosimendan . ventional heart failure management. She would remain at home for each month, each being infused over 24 h. For the first 21 days follow- . 7–10 days and then require readmission. Due to 97% HLA antibod- ing each treatment, he had excellent control of his heart failure; . ies, she was rejected for transplantation. for the latter 6 days, he gradually deteriorated. As a result of . Approval for repetitive Levosimendan infusion was sought and funding issues, Levosimendan was reduced to one vial every month. . approved. During the following 18 months, she was admitted for He continued to have symptomatic improvement for approximately . pulsed Levosimendan therapy every 28 days (1 vial over 24 h). During 14 days following infusion but thereafter required readmission, . this period, she remained free of admissions for decompensated initially at 24 days, then 18 days post-infusion due to heart failure . heart failure (she had one admission with pneumonia and a pre-renal Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 4 J. Cranley et al. Figure 3 Patient 2: echocardiogram showing grossly dilated and impaired left ventricle. LV, left ventricle. Figure 5 Patient 3: gated computed tomography demonstrating non-stenosed xenograft pulmonary valve. PV, pulmonary valve. Patient 3 Patient 3 was born with Tetralogy of Fallot, undergoing a right BT shunt in the first year of life. In childhood, she had repair surgery with . VSD patch closure, RV outflow tract resection, and an aorto- . pulmonary collateral from the descending aorta was ligated. At age . 17, a right ventricle–PA homograft was required for severe pulmon- . ary regurgitation, later this became stenosed and required xenograft . pulmonary valve replacement aged 26. The xenograft pulmonary valve remains without significant stenosis or regurgitation, and no coronary disease on computed tomography (Figure 5). She under- went ablations for atrial flutter and VT and had a dual-chamber implantable cardioverter-defibrillator (ICD) implanted. Severe RV dysfunction is a late consequence of palliative surgery for Fallot’s tetralogy. The RV dysfunction never remodelled following redo Figure 4 Patient 2: chest radiograph showing cardiomegaly and homograft implantation aged 17 nor improved following PVR aged cardiac resynchronization therapy-defibrillator device. 26. In consequence, she has severe functional tricuspid regurgitation due to annular ring dilatation secondary to her markedly dilated right ventricle (Figure 6, Supplementary material online, File S3). acute kidney injury from which she recovered). Following the infu- Cardiopulmonary exercise testing at age 40 showed a VO max of . 2 sion, she was aware of a significant improvement in activities of daily 26 mL/kg/min (normal >24.5 mL/kg/min) however by age 43 this had living for 14 days but then a deterioration with fluid retention and fallen to 14 mL/kg/min and she began to have recurrent admissions increasing breathlessness in the days prior to the next planned infu- for decompensated heart failure. She was not accepted for trans- sion. Infusion frequency was increased to every 18 days with good plantation due to her body mass index of 15.9, 95% HLA antibodies, effect. She suffered from a presumed vasodilatation headache for Group A blood type and significant restrictive lung function. 2–3 days after infusion which responded to 5 days of Triptan with Mechanical ventricular assist devices were not considered since they good effect. 21 months into Levosimendan therapy she suffered 18 . are reserved as a bridge to transplant in our health care system. defibrillator shocks due to VT. Ablation therapy was considered . Approval for Levosimendan infusion was granted when her 6MWT however the patient requested deactivation of her device. She died . was 40 m and her B-type natriuretic peptide (BNP) was 1599 ng/L suddenly the next month aged 55, almost 2 years after commencing . (normal range 0–114 ng/L). She had an excellent response, her monthly Levosimendan. . Levosimendan infusions have permitted her to remain at home. Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 Pulsed Levosimendan in AdHF due to CHD 5 It was 32 months following commencement of Levosimendan . Discussion that she had her first admission with decompensated heart failure. . Adult survival with complex congenital heart disease is now expected This appeared to be pre-terminal with a high BNP (1220 ng/L) and in more than 90% of cases due to improved palliative intervention or reduced 6MWT (224 m). She was referred for palliative care and her surgery, optimal medical therapy and careful clinical surveillance in dedi- ICD was deactivated. However, following IV diuretics and continued cated adult congenital heart clinics.Nearlyhalfofsubsequentdeaths monthly Levosimendan infusions, she has returned home and are due to heart failure at a median age of death of only 48.8 years. As resumed most of her usual activities. 6MWT improved back to in the cases described here, the recurrent admissions for conventional 426 m and BNP to 770 ng/L (Figure 7). At present, she remains symp- intravenous heart failure therapy have limited short-term benefit but tomatically stable, over 5 years since her first Levosimendan infusion. poor subsequent outcomes. Heart failure medications, validated in acquired heart failure, are not seen to confer the same benefit— particularly in patients with failing systemic right ventricles or severely impaired sub-pulmonary ventricles. Heart transplantation may be pos- sible for some but high HLA antibody burden (often related to prior transfusions) and other comorbidities often prevent listing. A single UK congenital heart transplant centre reported that 56% of referred ACHD cases were not listed. If listed, they spend a long time on the heart transplant list due to more restrictive donor selection, and ven- tricular assist devices have not shown the benefit seen in those with acquired heart conditions awaiting transplantation. . 5 . An excellent review of the literature and evidence base . lends support to the approach adopted for the specific cases described. . In each of our patients, there was a symptomatic improvement . associated with marked reduction in hospitalization (observed in . RELEVANT-HF) and better quality of life for their remaining life span. Levosimendan was well tolerated, without symptomatic hypotension— as found in LIONHEART. Levosimendan infusions were started every 4 weeks with a 24 h infusion (no bolus). Cases 1 and 2 required a reduc- tion in time between infusions (14–21) days, whereas Case 3 continues at almost five years from initiation on 28-day infusions. Individualized funding for Levosimendan infusion is required in the Figure 6 Patient 3: echocardiogram showing severely dilated right ventricle. RV, right ventricle. UK. Approval has been granted in the cases described, having demon- strated that the infusion cost (£920/month) is offset by bed-days saved. The meta-analyses of 345 patients, provides evidence of significant Figure 7 Patient 3: Graph depicting changes in 6-min walking test and N-terminal pro-B-type natriuretic peptide after commencement of Levosimendan. BNP, B-type natriuretic peptide; 6MWT, 6-min walking test. Downloaded from https://academic.oup.com/ehjcr/article/4/3/1/5827826 by guest on 26 August 2020 6 J. Cranley et al. benefit for repetitive or pulsed Levosimendan with a significant reduc- . Slide sets: A fully edited slide set detailing this case and suitable for tion in mortality in the AdHF population (with average follow-up . local presentation is available online as Supplementary data. 4 . period of 8 ± 8.3 months) of 10.2% vs. 26.8% in the control group. . With this series, we hope to encourage the formal study of this . Consent: The author/s confirm that written consent for submission therapeutic option in this patient population. A limitation in our ser- . and publication of this case report including image(s) and associated ies is the lack of longitudinal objective data for cases 1 and 2, e.g. text has been obtained from the patient in line with COPE guidance. N-terminal pro-BNP levels. Furthermore, although not undertaken in Conflict of interest: none declared. this series, right heart catheterization data may be useful in determin- ing those patients likely to benefit most from Levosimendan. 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Journal

European Heart Journal - Case ReportsOxford University Press

Published: Jun 1, 2020

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