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Ann Thorac Surg 1996;61:399-402
© 1996 The Society of Thoracic Surgeons
Division of Cardiothoracic Surgery, Department of Surgery, College of Physicians & Surgeons, New York, New York
Abstract
Increasing in frequency, and claiming more than 250,000 lives per year, heart failure represents a major public health problem. In spite of newer medical therapies, a significant proportion of patients progress to irreversible end-stage heart disease, for which cardiac transplantation remains the only long term hope. The inability to meet the demand for donor organs has led to the development of left ventricular assist devices as a temporizing measure while awaiting a transplantation. The ``bridging to transplantation'' experience has firmly established the efficacy of these devices as short-term and medium-term mechanical assistance and has provided valuable lessons applicable to long-term support. Mechanical cardiac assistance technology has dramatically improved and can provide reliable univentricular support with minimal thromboembolic and infectious complications. Although major obstacles remain, the potential benefits are great enough and the morbidity and mortality of end-stage heart disease high enough to warrant the evaluation of wearable left ventricular assist devices for long-term mechanical assistance.
With a prevalence of 3 million cases [1], an incidence of more than 400,000 cases per year [2], a fatality rate of 250,000 cases per year [2], and escalating direct costs (currently estimated at $35 billion/year [3]), heart failure represents a public health problem of tremendous proportions. In fact, heart failure is the only form of heart disease that is increasing in frequency, with annual mortality rates far exceeding those due to human immunodeficiency virus infection and breast cancer. Although emerging medical therapies like angiotensin converting enzyme inhibitors have provided substantial improvement in survival and quality of life for patients with mild-to-moderate congestive heart failure [4], approximately 60,000 patients go on to have development of end-stage congestive heart failure unresponsive to maximal medical therapy [5].
Orthotopic cardiac transplantation remains the most effective therapy for the treatment of end-stage cardiac failure. Despite its undeniable potential to provide superior long-term survival and excellent quality of life, widespread applicability of transplantation is limited by a shortage of donor organs and by an ever-increasing number of suitable transplant candidates. In fact, cardiac transplantation is an effective treatment for only 2,000 patients per year [6, 7]; as a result, the epidemiologic impact of heart transplantation is trivial.
Fully Implantable and Wearable Assist Devices: Lessons Learned
The failure to meet the increasing demand for donor organs has resulted in an explosive search for alternatives to cardiac transplantation. Leading the way has been the development of fully implantable systems and wearable ventricular assist devices. Although much research and political attention have been focused on the development of aesthetically appealing, fully implantable mechanical devices, a number of obstacles currently restrict their clinical use. Of particular concern have been the obligatory compliance chambers, which require intermittent percutaneous instrumentation to add or remove air, and are therefore subject to potential infection and fluid accumulation. In addition, failure of the electronic controller, the transcutaneous energy transfer system, or the electric motor of the fully implanted system would require nothing less than a reoperation. Finally, recipients of such devices would still need to wear an external power supply and likely require lifelong anticoagulation. At present, fully implantable systems, although ultimately more desirable, require refinement and clinical testing before long-term trials are undertaken.
The realistic present alternative to fully implantable mechanical support is the wearable ventricular assist device. Whereas early designs of the left ventricular assist device (LVAD) required patients to be tethered to bulky external consoles, control and power systems for these devices have been miniaturized, making these units ``wearable,'' thus providing unrestricted ambulation and independent patient function despite the necessity for extracorporeal connections (Fig 1
). The bridge-to-transplantation experience with both the early and wearable designs has established the efficacy of these devices for short- and medium-term mechanical support and has provided, in addition, valuable lessons directly applicable to long-term cardiac assistance.
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Second, the development of textured blood-contacting surfaces and use of porcine inflow and outflow valves, as exemplified by the Thermo Cardiosystems HeartMate device, have minimized the risk of thromboembolism even in the absence of anticoagulant agents. The sintered-titanium microspheres on the pump housing and the integrally textured polyurethane on the flexing pusher-plate diaphragm allow formation of a tenacious thrombus, which evolves into a stable pseudointimal layer that does not embolize (Fig 2). This salutary effect may be partly related to the presence of pluripotent stem cells in the neointima of these textured biosurfaces [12].
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Wearable Left Ventricular Assist Devices: Current State of the Art
Use of any presently available wearable left ventricular assist system for long-term therapy will be associated with appreciable morbidity and mortality. Nevertheless, in light of the extremely poor prognosis and quality of life of patients with end-stage heart disease, we strongly believe that devices are likely to meaningfully prolong survival and improve quality of life in this group of patients. Before attempting to validate this hypothesis, we must first consider whether the current wearable LVAD can overcome important obstacles to long-term mechanical circulatory support, namely, device reliability, device morbidity, and quality of life.
With regard to device reliability, it would be preposterous to proclaim that a perfectly reliable device, with no failure rate, can be designed. Rather, the ideal device should, much like airplane systems, be designed to provide redundancy or back-up mechanisms. With the currently available HeartMate 1205 wearable electric device, three levels of fail-safe rescue exist. First, of course, is the native heart. Second, the extracorporeal nature of the electronic control unit allows for easy access; should software, chip or electronic failure supervene, the damaged portion of the device can be easily replaced. Finally, with pusher-plate technology, the device can be pneumatically actuated if the electric motor of the device fails. A handheld portable pneumatic pump (Fig 3) has been recently designed that can be used to pump an LVAD for hours, if not days, with an awake pumper. Although hardly perfect, this system provides three potential back-up mechanisms for device failure without need for reoperation.
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With regard to infections, recent review of the Thermo Cardiosystems experience with 200 patients revealed an incidence of 10% in driveline infections, and positive blood cultures in almost 10% of LVAD recipients. Undoubtedly, a serious infectious mortality rate can be expected for patients undergoing LVAD placement. On the other hand, patients with congestive heart failure are at high risk for systemic infection even without external drive lines. Among a control group of patients eligible but not receiving LVAD support, infections developed in 33% [10], demonstrating that the potential for infection is increased in this critically ill group of patients.
Ideally, a surgical intervention must not only restore normal physiology but also must provide the patient with substantial improvement in quality of life. In this context, wearable LVADs not only improve cardiac, neurohormonal, and end-organ function but in addition, they allow the patient to engage in rehabilitation, unrestricted ambulation, and discharge to home. The newly gained autonomy unquestionably enhances the emotional and psychological well-being of these patients [16, 17]. In fact, only activities that would result in submersion of percutaneous pneumatic vents (ie, swimming, bathing) are proscribed, although showering is possible with special vent precautions.
In our opinion, the accumulating experience with wearable systems as bridges to transplantation justifies evaluation of such systems for long-term treatment of end-stage heart disease at this time.
Long-Term Trial Design
To maximize the likelihood of demonstrating a device benefit for patients with end-stage heart failure, the target population must have a high expected mortality. To this effect, we believe the ideal target group should comprise complicated New York Heart Association class IV patients treated with state-of-the-art medical therapy. Furthermore, these patients must not meet transplant eligibility criteria; cross-overs to transplantation would certainly confound the results of an intention-to-treat randomized trial. Such exclusionary guidelines will, in addition, not deny transplantation to any potential candidate who might benefit from it.
To ensure adequate numbers and generalizable results, a randomized multicenter design with a minimum observation period of 2 years is desirable. Based on retrospective data derived from review of the heart failure population at three large institutions (Columbia-Presbyterian, The Cleveland Clinic Foundation, and The Texas Heart Institute), the expected 2-year survival in a medically treated control group would be about 25%.
The primary trial hypothesis is that a wearable LVAD can prolong survival in a target population compared with a medically treated control group. Our estimate of the survival in the device population is perhaps disappointing. Assuming a realistic operative mortality rate of 10%, a combined 2-year mortality rate of 30% due to infection and thromboembolism, and a 10% 2-year mortality rate due to device failure, a 50% 2-year survival rate in device patients is projected. Thus, even in a plausible worst-case scenario, this trial anticipates a 33% reduction in the overall mortality rate over a 2-year period, approximately double the survival benefit of angiotensin-converting enzyme inhibitors in heart failure patients [5]. If this can be achieved, we believe it would represent a highly meaningful improvement in survival for patients with end-stage heart disease. Again, a concomitant improvement in quality of life must be documented.
To provide an 80% likelihood (power) of observing the anticipated difference between the device and medically treated groups, an enrollment of 150 patients would be required if our assumptions regarding mortality are correct. With this in mind, 1 to 1 randomization to devices, and considering the cost of the devices, a trial of this nature would cost about $25 million.
In addition to testing our primary hypothesis-a survival benefit-a number of secondary end points would be addressed: in particular, whether device recipients benefit from improved exercise capacity, a reduction in hospitalizations for heart failure control, and a decline in cardiac-related deaths.
From a pragmatic standpoint, several advantages are foreseeable. Such a trial would serve to establish a methodology for device evaluation for patients with congestive heart failure; it would define device morbidity for future device improvements; and finally, it would allow us to carry out hard estimates of device cost-effectiveness vis-à-vis the largely futile expensive medical therapies that are currently used.
A trial, which in response to the acronyms generated by our medical colleagues we have titled REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure), has been designed based on the above principles using the Thermo Cardiosystems electric LVAD (submitted to National Heart, Lung and Blood Institute). At present, practical application of long-term mechanical circulatory assistance can be reasonably approached with a device that is minimally thrombogenic, reasonably reliable, wearable, and repairable. If successful, the trial will firmly establish an important role for mechanical circulatory assistance for the long-term treatment of end-stage heart disease.
Footnotes
Presented at The Third International Conference on Circulatory Support Devices for Severe Cardiac Failure, Pittsburgh, PA, Oct 28-30, 1994.
Address reprint requests to Dr Rose, Department of Surgery, Milstein Hospital, 177 Fort Washington Ave, 7th Fl, 7GN-435, New York, NY 10032.
References
This article has been cited by other articles:
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  M. N. Kavarana, M. S. Pessin-Minsley, J. Urtecho, K. A. Catanese, M. Flannery, M. C. Oz, and Y. Naka Right ventricular dysfunction and organ failure in left ventricular assist device recipients: a continuing problem Ann. Thorac. Surg., March 1, 2002; 73(3): 745 - 750. [Abstract] [Full Text] [PDF]
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 M. Murtra The adventure of cardiac surgery Eur J Cardiothorac Surg, February 1, 2002; 21(2): 167 - 180. [Full Text] [PDF]
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A. G. Rose, S. J. Park, A. J. Bank, and L. W. Miller Partial aortic valve fusion induced by left ventricular assist device Ann. Thorac. Surg., October 1, 2000; 70(4): 1270 - 1274. [Abstract] [Full Text] [PDF]
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 A K Mahmood, J M Courtney, S Westaby, M Akdis, and H Reul Critical review of current left ventricular assist devices Perfusion, September 1, 2000; 15(5): 399 - 420. [PDF]
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 M. C. Deng, T. D.T. Tjan, B. Asfour, and H. H. Scheld Left ventricular assist devices -- reasons to be enthusiastic Eur J Heart Fail, August 31, 1999; 1(3): 289 - 291. [Full Text] [PDF]
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E. A. Rose, A. J. Moskowitz, M. Packer, J. A. Sollano, D. L. Williams, A. R. Tierney, D. F. Heitjan, P. Meier, D. D. Ascheim, R. G. Levitan, et al. The REMATCH trial: rationale, design, and end points Ann. Thorac. Surg., March 1, 1999; 67(3): 723 - 730. [Abstract] [Full Text] [PDF]
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 S. A. Hunt and O.H. Frazier Mechanical Circulatory Support and Cardiac Transplantation Circulation, May 26, 1998; 97(20): 2079 - 2090. [Full Text] [PDF]
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J. J. DeRose Jr, J. P. Umana, M. Argenziano, K. A. Catanese, H. R. Levin, B. C. Sun, E. A. Rose, and M. C. Oz Improved Results for Postcardiotomy Cardiogenic Shock With the Use of Implantable Left Ventricular Assist Devices Ann. Thorac. Surg., December 1, 1997; 64(6): 1757 - 1762. [Abstract] [Full Text]
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