Evolving Disruption in Left Ventricular Assist Systems: Forgiving but not Yet Forgettable

This article refers to ‘Long-term evaluation of a fully magnetically levitated circulatory support device for advanced heart failure—2-year results from the HeartMate 3 CE Mark Study’ by J.D. Schmitto et al., published in this issue on pages xxx. Early enthusiasm in artificial heart replacement took root in earnest in 1964 when the National Institute of Health in the United States ignited efforts with a goal to achieve a fully implantable artificial heart by 1970.1 This was a period of great ebullience; the space programme had been launched, and by 1969 man had stepped foot on the moon. That same year, Cooley implanted a total artificial heart, developed by Domingo Liotta, that supported the circulation effectively for 64 h, till a donor heart became available, although the patient died of overwhelming infection within a few days after transplantation.2 Even as space seemed exceedingly conquerable, the sophistication of intricate human bio-engineering became unambiguously apparent when artificial technology to develop a mechanical long-term support heart was unable to reliably match perfections of the biological heart. A durable total artificial heart seemed a blurry dream as challenges of stressful blood flow, thromboembolism and infection appeared insurmountable. It was then that attention shifted towards a lesser, more feasible goal to support but not replace the function of the left side of the heart, a target that could be accomplished with a mechanical pump implanted in tandem with the native heart. This ushered in the era of left ventricular assist systems. By 2001 evidence began to accumulate that mechanical unloading with a left ventricular assist device (HeartMate XVE, Thoratec Corp, Pleasanton, CA, USA), then a bulky contraption placed within the abdomen and connected to the native left ventricle and systemic aorta, outperformed therapy with continuous inotropic support and improved survival in patients otherwise ineligible for transplantation.3 This pivoted our interest towards durable pulsatile mechanical circulatory support, however device-related morbidity led by frequent complications of infection, stroke and malfunctioning pump parts reduced zeal for broad acceptance of these mimics of left ventricular physiology. The lack of widespread use ushered in a major thought disruption, which led to the next clinical innovation in 2009 when an axial continuous-flow pump with a mechanical bearing (HeartMate II, Thoratec Corp) was demonstrated to be superior to the bulky pulsatile pumps.4 This advance was based on the fundamental recognition that pulsatile flow may not be absolutely necessary to provide circulatory support and led to the development of smaller, more durable pumps, with no valves, fewer moving parts and characteristics capable of providing a sufficient range of cardiac output to allow for normal ambulation. These pumps permitted independent support with a median survival reaching 2 years or longer. Clinical adoption began to increase worldwide and survival improved beyond what was observed in the trials since clinicians learnt to select patients with an enhanced benefit to risk profile and more diligent surveillance and monitoring was undertaken in the ambulatory setting.5 Even smaller centrifugal continuous-flow pumps, implanted within the thorax in continuity with the left ventricle, that utilized a combination of hydrodynamic and partial magnetic levitation were introduced (HeartWare HVAD, Medtronic, Framingham, MA, USA), and these served to broaden the treated population permitting use by smaller adults and children.6 By 2010, use of such non-pulsatile pumps began to accelerate steadily but challenges of haemocompatibility remained. The unnatural physiology conferred by invoking continuous flow renders the patient peripherally pulseless and a unique constellation of adverse effects become evident. A sentinel example was the finding of gastrointestinal bleeding linked to the development of an acquired von Willebrand syndrome characteristically similar to observations in situations of critical aortic stenosis, also known as the Heydes syndrome.7 Other troubling issues have included the development of aortic valve fusion, aortic regurgitation and a high incidence of neurological injury and stroke.8, 9 Right heart failure and infection related to the driveline (that exits out of the body to provide a connection to the power source) have continued to be a staple problem. Oddly, right heart failure late in the course of support is emerging as a particularly bothersome issue.10, 11 The axial continuous flow pump (HeartMate II) has been associated with a high incidence of de-novo pump thrombosis; a complication also observed with the hydrodynamic centrifugal flow pump (HeartWare HVAD) but at a lower rate. On the contrary, comparative effectiveness trials have demonstrated that this smaller profile pump (HeartWare HVAD) is associated with a considerably higher rate of neurological injury and stroke compared with the HeartMate II pump.12 These two principal impediments of de-novo pump thrombosis and stroke have stalled efforts at expanded application of these pumps into less sicker patients suffering a poor quality of life. Indeed, a trial to address this population was halted due to the lack of sufficient enrolment and of equipoise.13 The fully magnetically levitated centrifugal flow pump, the HeartMate 3 (Abbott, Abbott Park, IL, USA) maintains an intrathoracic implant profile, is frictionless due to absence of mechanical bearings, possesses wider flow pathways (as much as 20-fold greater than other devices) and is even designed with an intrinsic pulse (the speed is programmed to go up and down in an asynchronous mode). These properties have been clinically validated by the demonstration of an absence of haemolysis and reduction in shearing of circulating high molecular weight multimers of von Willebrand antigen.7, 14, 15 In this issue of the Journal, Schmitto and colleagues16 provide support for preserved haemocompatibility of the HeartMate 3 pump in the long term by demonstrating the absence of haemolysis and pump thrombosis at 2 years. These investigators courageously embarked on the first steps of feasibility for this device and we consequently conducted the pivotal MOMENTUM 3 study, which has now reported its 2-year outcome and demonstrated superiority in comparison to the HeartMate II axial flow pump.17 Importantly, in addition to absence of pump exchange for de-novo thrombosis, the MOMENTUM 3 study demonstrated a marked reduction in overall stroke rates in favour of the HeartMate 3 pump. In a comprehensive analysis of stroke events within this trial experience, we have also demonstrated that while a disabling stroke event is associated with a poor prognosis in the short term, an initially non-disabling stroke event confers an equally poor late prognosis at 2 years.18 Thus, the advantage provided by the HeartMate 3 on a reduction in stroke events is likely to be associated with life years gained as the outlook continues to improve into the longer term period. In the elegant editorial by Lund,19 he discusses the continuing challenges ahead including the need to develop a fully implantable device with an internal power source, however one area deserves more closer scrutiny and this relates to the economic ramifications of this therapy. Adoption of any novel technology requires close consideration of accepted thresholds that constitute a society's willingness to pay for a new therapy. These tolerances vary from country to country and within the United States, most experts argue that an incremental cost-effectiveness ratio (ICER; the cost in USD to gain one quality-adjusted life year) of USD $100 000 is deemed to be acceptable. Investigations using projected economic modelling into the long term for older pumps such as HeartMate II pump have suggested that the ICER for such therapy compared with standard medical therapy in advanced heart failure is at USD $198 000, and thus not optimally cost-effective.20 Other studies have shown that this amount is highly sensitive to rehospitalizations and ambulatory care in the post-discharge phase of management. We investigated the comparative use of healthcare resources between the HeartMate II and the HeartMate 3 device from cost data accrued within the MOMENTUM 3 trial and demonstrated that post-discharge costs were 51% lower in the HeartMate 3 than with the HeartMate II pump ($37 685 ± 4251 vs. $76 599 ± 11 889, P < 0.001) and of equal magnitude in either bridge to transplant or destination therapy intent.20 These cost reductions were due to a reduction in rehospitalization-related economy of hospital days, resulting mostly from decreased rates of pump thrombosis and stroke. These cost reductions move us closer to the acceptable ICER, and continued efforts to decrease post-implant care costs will be critical in achieving cost containment that allows for this therapy to be adopted in most regions of the world. As an example, further reduction in morbidity such as gastrointestinal bleeding could accrue from minimizing anticoagulation with the HeartMate 3 pump, which has proven resilient to the challenge of pump thrombosis. In this regard, a pilot experience of low intensity anticoagulation has shown safety of such an approach up to 1 year of follow up.21 This provides rationale to conduct a powered clinical trial to assess lower exposure to anticoagulation in an effort to decrease bleeding-related morbidity and its associated costs. We now have a much more forgiving pump in the HeartMate 3 that reduces the morbidity of pump malfunction, is associated with lower stroke rates, and translates into reduced overall cost of care. We now await the next advance once the technologically forgiving benefits of the HeartMate 3 pump are coupled with a truly internalized powered system that can confer forgettability of the device for our patients. Conflict of interest: M.R.M reports consulting income from Abbott, Medtronic, Janssen, Mesoblast, NupulseCV, Bayer and Portola. In addition, he serves as Editor in Chief of the Journal of Heart and Lung Transplantation. These views do not represent the official stance of the journal nor the Society that it represents.