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The Cusp of a New Era in Long‐term Mechanical Circulatory Support

2008; Wiley; Volume: 32; Issue: 10 Linguagem: Inglês

10.1111/j.1525-1594.2008.00627.x

1525-1594

John L. Woodard,

Cardiac Arrest and Resuscitation

New rotary mechanical circulatory support (MCS) devices have the potential to finally make long-term MCS a widespread, routine, and cost-effective therapy for the hundreds of thousands of end-stage heart failure (ESHF) patients. The benefits of rotary technology and the opportunity to optimize the associated medical treatments (particularly anticoagulation) should provide significant gains in patient survival and increase the quality of life for these patients, at the same time reducing the incidence and cost of adverse events. However, in order for these potential benefits to make a significant epidemiological impact, we need to commit to bold randomized trials that will provide incontrovertible evidence to the wider cardiology community. Furthermore, as the evidence is gathered, we need to reach the wider medical community with the news that there is a viable and cost-effective alternative therapy available that can halt the inexorable decline in quality of life that most ESHF patients currently endure. The field of MCS has had a history of over 50 years characterized by boundless enthusiasm, determination, and courage on the part of inventors, clinicians, and the patients themselves. Those of us involved in circulatory support have experienced the unrivalled thrill of dramatically saving mortally ill patients and seeing them go on to either transplant or long-term mechanical support. However, these individual successes cannot mask the fact that in terms of epidemiological impact on the thousands of ESHF patients, the benefits of long-term MCS have been trivial. As biomedical engineers we are not alone in this, as the definitive surgical treatment, heart transplantation (HTx), has been similarly characterized in terms of its minimal overall effect 1. In the early history of HTx, initial enthusiasm was followed by disillusionment when initial results were disappointing due to a lack of understanding of the mechanisms of cross-matching and rejection 2. We risk repeating this history if we concentrate only on the technical aspects of MCS and do not give sufficient study to the roles of anticoagulants, infection control, and patient selection on the therapy as a whole. HTx and MCS have been largely utilized as heroic treatments for the very end of end-stage patients, and these treatments have been championed by the technically minded (biomedical engineers and surgeons) rather than our more data-driven colleagues, the cardiologists. Technical advocacy and risk-taking was essential for the early development of MCS technology but we need to move on to where long-term MCS is a widely accepted and routine part of the ESHF treatment armamentarium. This entails a shift in emphasis from technology development to concentrating on optimizing the overall therapy based on an evidence-based approach. In recent times, the advent of more effective drug treatments underpinned by a move away from the traditional “hemodynamic” model of the pathogenesis of heart failure to a “neuroendocrine” model of heart failure has greatly increased the survival of ESHF patients. This has raised the bar for the required survival rates to be achieved by MCS 3 and altered the rationale for surgical treatment of ESHF patients 4 in general. Lately, there has been commensurate success in achieving higher efficacies for MCS, driven from both the medical and technology areas. The most cited randomized trial that attempted to quantitate survival on a left ventricular assist device (LVAD) is the randomized evaluation of mechanical assistance for the treatment of congestive heart failure (REMATCH) study. Although the performance of the LVAD was markedly better than the medical treatment available at the time, the survival at two years was 25% for the LVAD group 5. Even during the same REMATCH trial, Park et al.6 have also shown improved survival and significant reductions in the major adverse events of sepsis (from 0.79 to 0.29/patient-year), renal failure (from 0.4 to 0.08/patient-year), and device infections (from 0.79 to 0.34/patient-year) for patients implanted in the era after 2000. Park et al. ascribed these improved results to both improvements in patient management and device modifications. Reporting only 3.5 years later and using essentially the same device and the same inclusion criteria, Long et al. 7 have achieved survival at 2 years of 77 ± 10% and reported a decrease in adverse events of 38% in a single center study. Perioperative mortality was reduced by a factor of 3.5 (from 31 to 8.7%), and rate of death after discharge decreased by a factor of 2.5 (from 0.48 to 0.19 deaths per patient-year). Long's patient survival results approach those of (approximately) 80% at 2 years for post-HTx survival 8 (for the same era and patient age), despite a sicker cohort who receive long-term MCS. Long et al. emphasized that although technical device improvements had some influence on the improved results, the importance of patient management and patient selection were the key factors. With the advent of rotary devices for MCS, there is another opportunity for a substantial improvement in outcomes based on the triad of new technical features, medical management optimized for rotary devices, and a broader base of patients to select from. The most obvious technical improvements that rotary devices offer are long service life and high reliability compared with their pulsatile forbears. By not having the requirement to make either urgent or emergent replacements of the MCS device, the morbidity and mortality associated with multiyear MCS can be greatly reduced. In the earlier era, failure of the pulsatile LVAD was the second most frequent cause of death in the REMATCH study 5 and device replacement was still a major factor reported by Long et al. (seven times, in five patients, 0.26 per patient-year). This has been significantly improved in rotary MCS systems such the VentrAssist, which had two postoperative replacements in 33 patients (0.11/patient-year), and no mortality associated with device failure in the 33 patients studied 9. Similarly in another rotary MCS BTT cohort there were five device replacements representing 0.08/patient-year in 133 cases (of which only two were strictly device failures) and only one death associated with (a non-wear-out) device malfunction for HeartMate II 10. In a recent editorial in this journal, Mussivand 11 advocated shifting the emphasis from designing more advanced pumps to reducing the adverse events common to all MCS. He has presented a strong case that infection is one of the most significant challenges. Rotary devices should provide an advantage in this respect as they provide a much less venerable substrate for chronic infection. This is due to the vastly smaller biomaterial area exposed to the tissues and blood, a reduction in the portal for bacterial entry via the very small/flexible drivelines, and in some cases, the lack of an abdominal pump “pocket.” Bleeding is another issue that may benefit from widespread adoption of rotary devices in combination with better patient selection/implant timing and pharmacologic agents. As indicated in the International Society for Heart & Lung Transplantation MCS registry by Deng et al. 12 and the Interagency Registry for Mechanically Assisted Circulatory Support registry 13, bleeding is the second most common adverse event reported with ventricular assist device implantation. In MCS, bleeding has many potential contributory causes including dyscrasia associated with high CVP/liver dysfunction, the extensive implant surgery, and chronic anticoagulation/anti-platelet therapies. Better patient selection probably has a contribution to make in terms of limiting the progression of liver dysfunction and the less extensive surgery for rotary devices limits sites for surgical bleeding. However, the greatest gains may be in optimizing the anticoagulation/antiplatelet regime used for rotary devices. In contrast to pulsatile MCS that can produce red clots in areas of low flow, rotary MCS devices subject the blood to elevated shear stresses. In devices like the VentrAssist or Heartware that have no flow obstructions (such as bearing supports), there is elevated shear stress in all areas and no areas in which stasis occurs. Its seems plausible that, unless the patients have issues of ventricular mural thrombus resulting from stasis, we should shift the emphasis away from high levels of anticoagulants (some of which have a very small therapeutic range) and concentrate on addressing the issue of shear-activated platelets for rotary MCS. Anecdotally, there have been a number of cases of the VentrAssist and HeartMate II being utilized with only antiplatelet medication resulting in no thrombotic sequelae and a reduced incidence of previously intractable bleeding. In such cases, the antiplatelet drugs of choice are probably those that target the platelet's shear-activated ADP receptor such as clopidogrel rather than the more commonly used aspirin that inhibits the thromboxane receptor. Although long-term MCS has been around for decades, the number of implants has been small and therefore the opportunity to systematically evaluate lower anticoagulant use or implement multicenter trials of new anticoagulants in long-term MCS patients has been rare. This is in contrast to other devices and common medical conditions where new anticoagulant/antiplatelet therapies have been extensively studied and shown considerable benefit. As an example, fondaparinux (a selective factor Xa inhibitor) has shown considerable benefits during percutaneous coronary intervention for acute coronary syndrome, a situation of abnormally high shear stresses somewhat analogous to that seen in rotary pumps. As reported in the OASIS-5 14 trial, fondaparinux substantially reduced bleeding at the same time maintaining a low level of thrombotic events. Another useful line of investigation into adverse bleeding events is to study the effect of the MCS devices themselves on the coagulation system. A recent article by Geisen et al. 15 suggests that both pulsatile and rotary devices may result in acquired von Willebrand disease (AvWD), which may explain the incidence of intractable mucocutaneous/gastrointestinal bleeding seen in MCS patients. Established AvWD treatments such as antifibrinolytics may be indicated for such cases. With the numbers of rotary devices now being implanted, it is probably time we started evaluating such new therapies in multicenter trials to reduce the considerable morbidity associated with bleeding. REMATCH was a bold step forward in MCS clinical investigations that generated Level 1 evidence about the benefits of MCS in a very sick patient population. Since this study, the technology and reliability of ventricular assist devices has improved substantially as have the options of medical therapy. So much so, that the clinical evidence provided in the REMATCH study is no longer applicable to current heart failure drug or device therapy. New randomized trials are urgently needed to generate contemporary Level 1 data for both new devices and improved management of MCS patients. The VentrAssist EVERLAST destination therapy trial is such a study 16. EVERLAST is a multicenter, prospective, randomized, controlled clinical trial currently enrolling in the USA, with a novel two-armed design that takes into account the perspectives of patients and heart failure clinicians with regard to treatment preferences. It potentially allows for MCS to be applied earlier in the disease process but also permits urgent MCS when indicated. Its primary outcomes are based on stroke-free, device failure-free survival with a 2-year follow-up. Because of the limited numbers of MCS patients available, the ability to achieve sufficient statistical power in randomized trials using traditional endpoints such as all-cause mortality has been problematic, and is the subject of intense debate among the heart failure community 17. One attractive solution, recently proposed, is to employ composite endpoints that are used to rank the outcomes for all patients in an MCS trial 18. This could potentially give adequate statistical power (comparable with all-cause mortality) at the same time addressing all aspects of the patient experience according to the authors. Perhaps because heart failure is primarily a disease of old age and has a worse prognosis than most cancers 19, there appears to be a certain sense of inevitability about the diagnosis. According to Copeland (quoting US statistics), only 17% of the heart failure population see a cardiologist 20. The historical low levels of MCS use are therefore not so much a problem of the lack of MCS awareness among cardiologists, primary caregivers, and gerontologists, but a problem of the “Cinderella” status 19 of heart failure itself. When HTx was the only definitive treatment, limited donor numbers meant that the fortunate few who received an HTx at tertiary centers represented an acceptable outcome. Now that virtually unlimited numbers of highly satisfactory long-term MCS devices are available with good reimbursement (particularly in the USA), it is a tragedy that more patients are not referred to those who can help them. We must do all in our power to get the word out. We are on the cusp of a new era of long-term MCS. The degree to which we succeed will be determined not by further leaps in pump technology, but rather by improving the management of patients, by producing incontrovertible evidence of the benefits of the therapy, and by spreading the word to the general medical community that a diagnosis of heart failure no longer means inexorable deterioration and death. Dr. John Woodard is a biomedical engineer who has international experience in invention, design, testing, regulatory affairs, and clinical use of cardiovascular devices over a period of more than 20 years. He is currently employed as Chief Scientific Officer of Ventracor Limited, an Australian public company developing the VentrAssist left ventricular assist system that has now been implanted in over 320 patients. As one of the three original inventors of this device and the founder, he has been closely involved in the development of the device into the main product of a company that now employs 150 people. He previously worked for 5 years at Baxter Healthcare Corporation, Novacor Division (Oakland, CA, USA) where he was Corporate Scientist worked on the design, in vivo testing (Stanford Medical School), and initial European clinical trials of the Novacor heart assist system. Dr. Woodard has a Company Director's Diploma (Order of Merit), BE in Electrical Engineering (Honors), an MSc in Biophysics, and a PhD in Biomedical Engineering from the University of New South Wales, Australia, and did postdoctoral studies at the Heart Research Institute, San Francisco, CA, USA. John is a member of the ISO Technical Committee for Cardiac Circulatory Support Systems and a member of the Board of Trustees of the International Society for Rotary Blood Pumps.