Heart Failure Destination Therapy with Left Ventricular Assist Devices in Non-transplant Centres: The Time is Right Antoni Bayes-Genis,1,2 Christian Muñoz-Guijosa,1,2 Evelyn Santiago-Vacas,1,2 Santiago Montero,1,2 Cosme García-García,1,2 Pau Codina,1,2 Julio Núñez3 and Josep Lupón1,2 1. Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 2. Department of Medicine, CIBERCV, Autonomous University of Barcelona, Barcelona, Spain; 3. Servicio de Cardiología, Hospital Clínico Universitario de Valencia, Universidad de Valencia, INCLIVA, Valencia, Spain Abstract For almost half a century, cardiac transplant has been the only long-term treatment for patients with end-stage heart failure. Implantable left ventricular assist devices (LVADs) have emerged as a new treatment option for advanced heart failure as destination therapy for patients either too old or not suitable for transplant. A meta-analysis presenting head-to-head comparisons of cardiac transplant versus LVAD as destination therapy (LVAD-DT) found no difference in 1-year mortality rates between LVAD-DT and cardiac transplant (OR 1.49; 95% CI [0.48– 4.66]; I2=82.8%). Moreover, a recent subanalysis from the Interagency Registry for Mechanically Assisted Circulatory Support found similar outcomes after LVAD-DT implantation in both transplant and non-transplant centres. The time is right for LVAD-DT in non-transplant centres, provided multidisciplinary heart failure teams and expertise are in place. Keywords Cardiac transplant, left ventricular assist device, destination therapy, outcomes Disclosure: AB-G was supported by grants from the Ministerio de Educación y Ciencia (SAF2014-59892), Fundació La MARATÓ de TV3 (201502, 201516), CIBER Cardiovascular (CB16/11/00403 and 16/11/00420) and AdvanceCat 2014-2020. All other authors have no conflicts of interest to declare. Received: 15 April 2019 Accepted: 2 August 2019 Citation: European Cardiology Review 2020;15:e19. DOI: https://doi.org/10.15420/ecr.2019.29.2 Correspondence: Antoni Bayes-Genis, Heart Institute, Hospital Universitari Germans Trias i Pujol, Carretera de Canyet s/n 08916, Barcelona, Spain. E: abayesgenis@gmail.com Open Access: This work is open access under the CC-BY-NC 4.0 License which allows users to copy, redistribute and make derivative works for non- commercial purposes, provided the original work is cited correctly. “The time is always right to do what is right.” Heart Association functional class IIIb to IV, stage D). Cardiac transplant – Martin Luther King Jr (1929–1968) is currently, and has been for the past 50 years, the preferred long-term treatment for eligible patients with end-stage advanced HF. Heart failure (HF) has increased at a fast pace during the 21st century Nevertheless, the availability of donor hearts is limited and not all to become the main cause of morbidity and mortality for patients with patients are eligible for cardiac transplant. cardiovascular disorders in developed nations, leading to increasing healthcare costs and declining quality of life. The expected prevalence In Catalonia, the number of patients with advanced HF is probably of HF was ~25 million in 2011, and was anticipated to rise to >40 million ~500–1000; however, cardiac transplant is only recommended for a worldwide in 2018, according to market research reports and industry limited number of eligible patients aged <70 years. The transplant analysis. Data from the National Heart, Lung and Blood Institute indicate rate in Catalonia has ranged between 55 and 70 hearts per year that HF incidence is ~21 per 1,000 people aged >65 years.1 The total during the past two decades. These numbers illustrate the paucity of costs for HF are projected to reach $69.7 billion by 2030, an increase of donor hearts for transplant, and the fact that most candidates 127% from 2012.2 ultimately do not receive a compatible graft. Implantable left ventricular assist devices (LVADs), which fully or partly support the In Catalonia, the most recent prevalence data indicate that HF affects left ventricle, are an alternative therapy for patients with end-stage 155,883 patients (out of 7.5 million inhabitants).3 Over the past three advanced HF. A long-term LVAD is used as a bridge to transplant (BTT) decades, research has led to better management of HF using drugs, while patients await a suitable heart, or as permanent destination new devices and a more holistic approach in multidisciplinary HF therapy (DT) that provides both life prolongation and proper quality clinics. This has led to improvements in survival, yet a percentage of of life. patients with progressive HF continue to require cardiac transplant or mechanical circulatory support to prolong life.4 Cardiac Transplant: Pros and Cons Despite recent advances in mechanical circulatory support, cardiac Approximately 50% of HF patients have reduced ejection fraction, and transplant remains the treatment of choice for patients with 10% of these patients experience refractory HF symptoms (New York advanced HF. The short- and long-term outcomes following cardiac © RADCLIFFE CARDIOLOGY 2020 Access at: www.ECRjournal.com Heart Failure transplant are remarkable, with a median survival of 10.7 years. 5 For and improvements in the operative techniques, as well as better patient transplant patients, there is a marked improvement in survival, selection and complication management have led to a significant quality of life and functional status. 6 During the past decades, there improvement in survival rates. has been continuous improvement in morbidity and mortality, despite older and higher-risk recipients receiving transplants. The 8th Interagency Registry for Mechanically Assisted Circulatory However, graft failure, rejection and infection remain significant Support (INTERMACS) report on >20,000 LVAD implantations from causes of morbidity and mortality, precluding better short- and long- 2006 to 2016 found a 1-year survival rate of 81% and 2-year survival term outcomes. The highest incidence of mortality occurs in the first rate of 70%.9 Nowadays, LVAD therapy constitutes an established 6 months post-transplant, with the perioperative hospitalisation treatment option for well-selected patients with advanced HF. As a period having the highest risk of death. After the first year, the result, the number of transplant and non-transplant centres mortality rate decreases to 3–4% per year.6 integrating LVAD programs in their facilities is rapidly expanding, and a further increase in device implantations is anticipated in the However, mid- to long-term mortality continues to be affected by near future. progressive cardiac allograft vasculopathy, late graft failure, rejection, infectious complications and issues due to chronic Relevant recent literature demonstrates better event-free survival, immunosuppression, including malignancy. The ultimate goals of symptoms and quality of life with LVAD-DT, as compared with optimal preventing rejection and finding alternatives to immunosuppression medical management.10–12 The Risk Assessment and Comparative remain elusive. In addition, chronic kidney disease is common after Effectiveness of Left Ventricular Assist Device and Medical heart transplant and is associated with increased mortality. Management (ROADMAP) study found that 12-month survival was Furthermore, up to 39% of cardiac transplant recipients will develop greater for LVAD-DT versus optimal medical management (80 ± 4% diabetes after transplant. The major factor limiting cardiac transplant versus 63 ± 5%; p=0.022) in patients with New York Heart Association has been the insufficient donor supply, which is currently limited to Class IIIb/IV. Health-related quality of life and depression improved approximately 4,000 hearts annually worldwide. from baseline more significantly with LVADs than with optimal medical management. Destination Therapy with Left Ventricular Assist Devices: Pros and Cons Adverse events were higher in LVAD-DT patients, in the HeartMate LVADs have revolutionised the management of patients with advanced II trial.10 Starling et al. extended these findings up to 2 years of HF, providing an alternative to cardiac transplant. LVADs were initially follow up.11 More recently, the Medical Arm of Mechanically implanted as a BTT to reduce the high mortality rates among patients Assisted Circulatory Support (MedaMACS) Registry reported that who were awaiting donor hearts. However, the paucity of donor survival was similar for medical and LVAD-DT in the overall cohort, organs, along with the substantial increases in the comorbidities and which included the lower severity INTERMACS profiles 6 and 7, but the age of the HF population, have led to LVADs being used as a DT for survival was better with LVAD-DT among patients in INTERMACS advanced HF. profiles 4 and 5.12 LVADs can be broadly classified as either pulsatile flow/positive Cardiac Transplant Versus Left Ventricular displacement or continuous flow/rotary systems. Continuous flow Assist Devices for Advanced Heart Failure systems have several advantages over pulsatile flow pumps, including Theochari et al. performed a meta-analysis of the available studies a more compact size and improved surfaces, as well as reduced presenting head-to-head comparisons of cardiac transplant versus surgical trauma and thrombotic complications. Continuous flow LVAD-BTT or LVAD-DT for late (>6 months) all-cause mortality.13 Eight pumps can be further classified into centrifugal and axial flow pumps. studies were included that reported data on 7,957 patients. Seven Centrifugal flow pumps are smaller than the axial pumps available, studies compared cardiac transplant with LVAD-BTT, and five and have a tubular configuration that allows them to be implanted compared cardiac transplant with LVAD-DT, evaluating 1-year faster and even less invasively; therefore, they are probably more mortality. These studies found no difference in 1-year mortality rates cost-effective.7 Third-generation implantable continuous-flow LVADs, between LVAD-BTT and cardiac transplant (OR 0.91; 95% CI [0.62– incorporating improved pump technologies, have improved pump 1.32]; I2=21.2%) or between LVAD-DT and cardiac transplant (OR 1.49; performance and patient healthcare. 95% CI [0.48–4.66]; I2=82.8%; Figure 1). Although complications with LVAD therapy are not uncommon, most are manageable, and current The recent Multicenter Study of MagLev Technology in Patients outcomes clearly support the use of a LVAD in advanced HF. Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 Nevertheless, although there are certainly limitations to cardiac (MOMENTUM 3) trial demonstrated that implantation of a fully transplant, median survival at present is much better with transplant magnetically levitated centrifugal-flow pump (HeartMate 3) was (~12 years) than LVAD (3–4 years).14 associated with better outcomes at 6 months than an axial-flow pump (HeartMate II), primarily because of the lower rate of reoperation for Destination Left Ventricular Assist pump malfunction.8 Devices in Non-transplant Centres Since the US Food and Drug Administration approval of LVAD-DT, the The use of a LVAD as DT (LVAD-DT) was approved by the US Food and number of hospitals offering LVAD therapy has grown rapidly, with a Drug Administration in 2010; since then, LVAD-DT implantations have rising number performed at centres without internal transplant programs. rapidly increased. The proportion of patients allocated to LVAD-DT increased from 19.6% from 2008 to 2010, to 45.7% of all implants in Brinkley et al. sought to determine whether the outcomes after LVAD- 2014. The miniaturisation of devices, the evolution of device technology DT implantation were similar at transplant and non-transplant EUROPEAN CARDIOLOGY REVIEW LVAD-DT in Non-transplant Centres centres.15 The authors analysed all adult recipients of a primary, Figure 1: Forest Plot of the Odds Ratios for 1-year continuous-flow LVAD-DT between 2012 and 2014 from the Mortality Between Cardiac Transplant and Left INTERMACS registry. Subjects were classified according to their Ventricular Assist Device Destination Therapy implanting centre as transplant (n=3,323) or non-transplant (n=260). Outcomes included overall survival, freedom from death or major Study author OR (95% CI) Weight adverse event, rates of individual adverse events, rehospitalisation Ammirati, 2015 1.23 (0.68–2.22) 26.54 and health-related quality of life. The 1-month (94.2%; 95% CI [95.0– Droogne, 2014 1.06 (0.13–8.35) 14.73 93.4] versus 94.2%; 95% CI [97.1–91.4]) and 12-month (76.4%; 95% CI Jakovljevic, 2015 0.17 (0.01–3.29) 9.84 [77.9–74.8] versus 71.3%; 95% CI [77.4–65.2]) survival rates were Sorabella, 2015 1.02 (0.34–3.04) 22.64 similar at transplant versus non-transplant centres (HR 0.88; 95% CI [0.70–1.12]). The risk remained similar after adjustment for baseline Mishra, 2016 6.78 (3.59–12.79) 26.24 characteristics (HR 0.88; 95% CI [0.69–1.12]). The rates for freedom Overall (I2=82.8%; p=0.000) 1.49 (0.48–4.66) 100.00 from death or major adverse event at 12 months (29.0%; 95% CI [30.6– Note: Weights are from random 27.3] versus 29.8%; 95% CI [36.0–23.6]) were similar at transplant and effects analysis non-transplant centres (adjusted HR 1.01; 95% CI [0.87–1.18]; Figure Favours LVAD-DT Favours HTx There was no difference in 1-year mortality rates between left ventricular assist device as 2). The individual adverse event rates, rehospitalisation and post- destination therapy (LVAD-DT) and cardiac transplant (HTx) among the five studies. Source: implant health-related quality of life were also similar. The authors Theochari et al. 2018.13 Reproduced with permission from AME Publishing Company. concluded that in a large, modern cohort of LVAD-DT recipients, outcomes after implantation were similar at transplant and non- Figure 2: Kaplan–Meier Analysis of Freedom transplant centres.15 from Death or Major Adverse Events at Transplant and Non-transplant Centres Assuming the appropriate infrastructure is in place (described below), the findings of these studies should mitigate concerns regarding a 1 broader extension of LVAD-DT, as the expanded access to this Major event-free survival restorative and life-saving therapy at non-transplant centres has 0.75 maintained good patient outcomes. 0.50 Characteristics of a Left Ventricular Assist Device Destination Therapy Program 0.25 In general, an LVAD-DT program is considered a challenging endeavour, p=0.473 yet it does not require the co-existence of a parallel in-hospital transplant program. The Essen Experience, recently reported by 0 0 6 12 18 24 Papathanasiou and Luedike, provided the following advice.16 Months Number at risk A LVAD-DT program should be part of a multidisciplinary HF clinic Non-transplant 232 91 44 23 10 Transplant 2,989 1,140 656 383 220 consisting (at least) of a cardiology and a cardiac surgery department with an adequate number of potential LVAD-DT candidates. Non-transplant Transplant Considering the multi-organ manifestations of advanced HF and the Follow-up Non-transplant Transplant broad spectrum of non-surgical interventions indicated in this patient 1 month 66.1% (71.9–60.4) 60.6% (62.3–58.9) cohort, the candidate centre should perform interventional and 3 months 53.6% (59.7–47.4) 48.8% (50.5–47.1) surgical cardiac procedures, cardiac electronic device implantation, 42.0% (48.1–35.8) 40.0% (41.7–38.3) 6 months and intensive cardiovascular care. A dedicated outpatient clinic is part 12 months 29.8% (36.0–23.6) 17.2% (30.6–27.3) of the required infrastructure to provide high-quality, long-term care 24 months 20.0% (27.0–13.0) 17.2% (18.8–15.6) of ambulatory patients. Major adverse events included death, stroke, major bleeding, pump exchange, device infection, device malfunction and right heart failure. Source: Brinkley et al. 2018.15 Reproduced with permission from Wolters Kluwer Health. The physician leadership team is the core of the LVAD-DT program. An experienced HF cardiologist and a cardiac surgeon with expertise in mechanical circulatory support should supervise all aspects of device site consulting service should be available for the end-of-life care of implementation, including patient selection, staff training, quality LVAD patients. controls and cost-effectiveness. Conclusion A qualified team of surgeons, HF cardiologists and nurses familiar with LVADs have transformed the treatment landscape of HF and are now the complexity of LVAD-DT should be organised. Staff training in special adopted for long-term ambulatory support of patients with advanced skills, and familiarity with the psychosocial, technical and disease. As the number of LVAD-DT implants is anticipated to rise, pharmaceutical issues is of paramount importance for all parties. clinicians will need to integrate dedicated programs in their HF clinics Rehabilitation physicians should be part of the caring team. and be actively involved in the care of patients on LVAD support. Indeed, all LVAD centres, regardless of their transplant capabilities, are A transplant centre affiliation is necessary for patients who are or may required to have multidisciplinary HF teams to guide patient selection become eligible for LVAD-BTT and should be offered transplant and assist in the long-term care of this unique population. The time is candidacy. Participation in a palliative care network or at least an on- right for LVAD-DT in non-transplant centres. EUROPEAN CARDIOLOGY REVIEW Heart Failure 1. Huffman MD, Berry JD, Ning H, et al. Lifetime risk for heart healun.2011.08.003; PMID: 21962016. 2017;5:518–27. https://doi.org/10.1016/j.jchf.2017.02.016; failure among white and black Americans. J Am Coll Cardiol 6. McCartney SL, Patel C, Del Rio JM. Long-term outcomes and PMID: 28396040. 2013;61:1510–7. https://doi.org/10.1016/j.jacc.2013.01.022; management of the heart transplant recipient. Best Pract Res 12. Ambardekar AV, Kittleson MM, Palardy M, et al. Outcomes with PMID: 23500287. Clin Anaesthesiol 2017;31:237–48. https://doi.org/10.1016/j. ambulatory advanced heart failure from the Medical Arm of 2. Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and bpa.2017.06.003; PMID: 29110796. Mechanically Assisted Circulatory Support (MedaMACS) stroke statistics – 2018 update: a report from the American 7. Olsen DB. The history of continuous-flow blood pumps. Artif Registry. J Heart Lung Transplant 2019;38:408–17. https://doi. Heart Association. Circulation 2018,137:e67–492. https://doi: Organs 2000;24:401–4. https://doi. org/10.1016/j.healun.2018.09.021; PMID: 30948210. 10.1161/CIR.0000000000000558; PMID: 29386200. org/10.1046/j.1525-1594.2000.06652.x; PMID: 10886055. 13. Theochari CA, Michalopoulos G, Oikonomou EK, et al. Heart 3. Cainzos-Achirica M, Capdevila C, Vela E, et al. Individual 8. Mehra MR, Naka Y, Uriel N, et al. A fully magnetically levitated transplant versus left ventricular assist devices as destination income, mortality and healthcare resource use in patients with circulatory pump for advanced heart failure. N Engl J Med therapy or bridge to transplant for 1-year mortality: a chronic heart failure living in a universal healthcare system: a 2017;376:440–50. https://doi.org/10.1056/NEJMoa1610426; systematic review and meta-analysis. Ann Cardiothorac Surg population-based study in Catalonia, Spain. Int J Cardiol PMID: 27959709. 2018;7:3. https://doi.org/10.21037/acs.2017.09.18; 2019;277:250–7. https://doi.org/10.1016/j.ijcard.2018.10.099; 9. Kirklin JK, Pagani FD, Kormos RL, et al. Eighth annual PMID: 29492379. PMID: 30413306. INTERMACS report: special focus on framing the impact of 14. Goldstein DJ, Meyns B, Xie R, et al. Third annual report from 4. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guidelines adverse events. J Heart Lung Transplant 2017;36;1080–6. https:// the ISHLT Mechanically Assisted Circulatory Support Registry: for the diagnosis and treatment of acute and chronic heart doi.org/10.1016/j.healun.2017.07.005; PMID: 28942782. a comparison of centrifugal and axial continuous-flow left failure: The Task Force for the diagnosis and treatment of 10. Estep JD, Starling RC, Horstmanshof DA, et al. Risk assessment ventricular assist devices. J Heart Lung Transplant 2019;38:352– acute and chronic heart failure of the European Society of and comparative effectiveness of left ventricular assist device 63. https://doi.org/10.1016/j.healun.2019.02.004; Cardiology (ESC). Developed with the special contribution of and medical management in ambulatory heart failure patients: PMID: 30945637. the Heart Failure Association (HFA) of the ESC. Eur Heart J results from the ROADMAP Study. J Am Coll Cardiol 15. Brinkley DM, DeNofrio D, Ruthazer R, et al. Outcomes after 2016;37:2129–200. https://doi.org/10.1093/eurheartj/ehw128; 2015;66:1747–61. https://doi:10.1016/j.jacc.2015.07.075; continuous-flow left ventricular assist device implantation as PMID: 27206819. PMID: 26483097. destination therapy at transplant versus nontransplant 5. Stehlik J, Edwards LB, Kucheryavaya AY, et al. The Registry of 11. Starling RC, Estep JD, Horstmanshof DA, et al. Risk assessment centers. Circ Heart Fail 2018;11:e004384. https://doi. the International Society for Heart and Lung Transplant: and comparative effectiveness of left ventricular assist org/10.1161/CIRCHEARTFAILURE.117.004384; PMID: 29540471. Twenty-eighth Adult Heart Transplant Report – 2011. J Heart device and medical management in ambulatory heart failure 16. Papathanasiou M, Luedike P. The evolution of left ventricular Lung Transplant 2011;30:1078–94. https://doi.org/10.1016/j. patients: the ROADMAP study 2-year results. JACC Heart Fail assist devices. HeathManagement 2019;19:70–2. EUROPEAN CARDIOLOGY REVIEW