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Ann Thorac Surg 1999;68:729-733
© 1999 The Society of Thoracic Surgeons

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Alternatives To Transplantation

Permanent ventricular assist device support versus cardiac transplantation

^a Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA

Address reprint requests to Dr Pennington, Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157
e-mail: gpenning{at}wfubmc.edu

Presented at the Fourth International Conference on Circulatory Support Devices for Severe Cardiac Failure, Houston, TX, Oct 3–5, 1997.

Abstract

Background. Although cardiac transplantation provides excellent therapy for some patients with terminal heart failure, the results are limited by the scarcity of donor organs, reduced long-term survival, and comorbid conditions. Current experience with temporary left ventricular assist devices suggest that a permanent, totally, or near totally implantable device may be a viable alternative.

Methods. We analyzed data from the 1997 International Society for Heart and Lung Transplantation (ISHLT) Registry and other literature on heart transplantation and compared survival and complication rates with our experience and that of others with temporary ventricular assist devices. From these data, we attempted to identify those patients who would benefit most from permanent left ventricular assist systems (LVASs).

Results. Among heart transplant candidates, United Network for Organ Sharing (UNOS) status II, O blood type, weight >180 lb, older age, and preformed antibodies are negative factors for receipt of donor hearts. Of patients transplanted, women and nonwhites have poorer outcomes. Success with wearable LVAS’s suggest some of these patients might be better served with an LVAS than with cardiac transplantation.

Conclusions. Because LVAS’s could be made readily available without the need for a waiting list, they might compete well with the strategy of cardiac transplantation.

Since the first cardiac transplantation in the U.S. in 1964 by Hardy and Chavez [1] and subsequent success by Shumway and associates [2], cardiac transplantation has matured as an excellent therapeutic option for patients with severe heart failure. One-year actuarial survival is approximately 80%, 5-year survival is near 65%, and 10-year survival is slightly less than 45% [3]. However, heart transplantation cannot serve the estimated 30,000–60,000 persons who die of heart failure in the US each year and could be candidates for heart transplantation or some form of mechanical circulatory support [4]. In 1995, the mean waiting time for cardiac transplantation was over 200 days, and more than 40% of the patients waited more than 1 year for cardiac transplantation. The strategy of transplantation in which patients may or may not receive a donor heart is inadequate to serve the large number of potential candidates (Fig 1). Because only about 4,000 new patients are listed for cardiac transplantation each year, some 28,000–30,000 are apparently not considered viable candidates to be placed on the list. Of those not placed on the list, it is possible that as many as half of them (13,000) would be candidates for a permanent ventricular assist device (VAD). An important deterrent to listing may be advanced age, because the estimate of 30,000 is made with an upper age limit of 75 years, and the estimate of 60,000 is made with an upper age limit of 85 years. However, these patients may also be considered inappropriate for alternative therapy, such as chronic VAD support. Even if estimates of the large number of "potential" candidates for cardiac transplantation are somewhat skewed by older patients, it seems obvious that a large number of patients may be candidates for permanent VADs.

View larger version (34K): [in this window] [in a new window]   Fig 1. Representation of severe heart failure patients that could benefit from a permanent VAD on an annual basis.

These data support the role of a permanent mechanical circulatory support system, which could be an alternative to cardiac transplantation. Such systems have been under development for many years and have had significant support by the National Heart, Lung, and Blood Institute. For this discussion, we will assume that a left ventricular assist system (LVAS) is available that is reliable and safe and can provide prolonged support for periods of 2 to 5 years. The Novacor N-100 wearable LVAS with biological valved conduits (Baxter Healthcare/Novacor, Oakland, CA) and the Heartmate LVAS (Thermocardiosystems Inc, Woburn, MA) are currently in use as electrically powered devices that fulfill all the criteria of completely implantable systems except for their requirement for an externalized drive system. The N-100 LVAS system has the capacity to become a completely implantable system. Likewise, the LVAS developed by Pennsylvania State University and Arrow, Inc (Reading, PA) is approaching a time for clinical trials. Both the Novacor N-100 LVAS and the Pennsylvania State University Arrow LVAS employ an integrated pump and drive unit, a compliance chamber that is to be housed in the pleural space, an internalized battery system that can provide a backup energy source, and a method of transmitting energy across the skin by inductive coupling from a primary to a secondary coil. Although these devices employ different conduits and valve systems, their construction is the prototype upon which assumptions will be made about devices in this treatise. It is presumed that these devices could function without the need for an external drive line and that patients could be relatively free of thromboembolism, infection, and other crippling events that would limit their long-term survival. They would be managed out of the hospital setting, and would be able to incorporate the device into their usual routines, return to work, and contribute to society. They would be relatively independent of support and not require the constant presence of a caregiver.

It is also possible that current VAD technology using externalized drive lines might offer a reasonable alternative to cardiac transplantation. Previous discussions have compared the feasibility and advisability of the use of an externalized drive system in a vented, wearable LVAS [6] as opposed to a totally implantable system [7]. It is not the purpose of this discussion to compare those two systems, but it is feasible that an externalized system might also function well when compared with the overall strategy of cardiac transplantation. The most obvious advantage of these VAD systems over transplantation would be their immediate availability. They could be placed in UNOS status II rather than UNOS status I hospital-bound patients. Such elective implantation protocols might avoid some of the complications of infection and thromboembolism, which currently accompany the use of such devices.

Presuming the availability of a safe and effective, totally implantable, electrically driven, left VAD prompts a comparison with the current strategy of cardiac transplantation as a universal therapy for patients with severe heart failure. A large number of candidates for VADs will come from the nontransplant candidate group, which may include a significant number of patients 65 years or older. However, there is some risk that their complication rate would increase as a result of their advanced age. If one considers the most optimal group for receipt of VADs, prime candidates are those who have been highly selected to receive cardiac transplantation. This asks the question, "Of the 4,000 patients listed for cardiac transplantation per year, how many might profit more by immediate implantation of a permanent VAD rather than remaining on the list or even actually undergoing transplantation?" This question prompts a careful consideration of the differential results of cardiac transplantation. Although results of cardiac transplantation are good (Fig 2), the 5-year survival rate is less than 65%, and the 10-year survival rate is less than 45% [3]. It is also important to examine the comorbidities of cardiac transplantation. Data from the International Society of Heart and Lung Transplantation (Table 1) define the problems during the first 2 years in a series of patients transplanted between April 1994 and December 1996. It is anticipated that hypertension, renal dysfunction, hyperlipidemia, diabetes, and malignancy will not be risk factors related to LVAS. In the 43% of transplant patients requiring rehospitalization in the first year, 35% were related to rejection, infection, or both. The number of hospitalizations required with LVAS patients is not known, but there is some indication from the current out-of-hospital VAD patients that repeated hospitalization is not uncommon, and occurs in as many as 50% of those who have been out of the hospital over a several-month period.

View larger version (16K): [in this window] [in a new window]   Fig 2. Heart transplant actuarial survival 1982–1996. (Reprinted with permission from Hosenpud JD, Bennett LE, Keck BM, Fiol B, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: Fourteenth Official Report—1997. J Heart Lung Transpl 1997;16:691–712.)

In considering the potential complications related to long-term support with totally implantable LVAS, inferences will have to be drawn from the current experience with implantation of devices with externalized drive lines in "bridging" patients to cardiac transplantation [6, 8]. In several series, patients undergoing VAD bridge to cardiac transplantation had a transplantation rate of 65%–70%, and once-transplanted survival rates of 95%–100%. Many of the patients were maintained for periods of several months and some of them as long as 3 years. The primary complications were infection and thromboembolism. The overall incidence of blood-borne infection ranged from 27% to 55% [9–11], but in the experience of Argenziano and associates [9], 13 of 60 (22%) had infections before VAD implantation. Although in their series infection did not statistically influence overall survival rates, 8 of 50 patients undergoing explantation had "VAD endocarditis" and 4 of them died. Two factors may decrease the incidence and severity of infections in long-term totally implantable LVAS patients. One is that the externalized drive line would not be present as a source of infection, and second, patients could be electively scheduled as status II out-of-hospital patients for implantation of the device, thus avoiding problems related to long-term hospitalization.

In patients implanted with VADs in order to bridge them to cardiac transplantation, the incidence of thromboembolism ranges from 3% to 35%. There is considerable difficulty in defining how many of these thromboembolic events are actually related to the device. In a series of patients from St. Louis University, the thromboembolism rate was 14%, whereas the stroke rate was only 9% [12]. In a multiinstitutional study of the Thermocardiosystems LVAS (Woburn, MA), the clinical thromboembolic rate was 6% and the stroke rate was about 3%. At autopsy, another 3% or 4% incidence of thromboembolic events was identified that had not been apparent clinically [13].

Depending upon the device, anticoagulation may not be required for long-term implantation, but it is likely that most permanent LVAS patients will receive platelet deaggregating drugs if not anticoagulants. However, many patients today with mechanical heart valves do very well with chronic anticoagulation. It is likely that if infection can be avoided, the incidence of thromboembolism in permanent LVAS patients would be small and that over time this incidence would decrease as the surfaces of the devices become more biolized and less reactive.

The risk of device failure is a long-term concern. However, current performance of temporary devices suggest that total or "hard" failure of a device or component resulting in high risk of immediate death is rare. "Soft" failures may be more common but will be rarely fatal and usually correctable. For example, failure of a valve in the conduit of a LVAS might be gradual and allow implantation of a new valve without significant risk to the patient. A prematurely worn-out battery might be replaced before the patient suffered harm. The total implantability of the device may be useful in respect to decreasing the rate of infection and in terms of patient convenience. The concept of being machine dependent may have some adverse effect on the patient’s quality of life in that recipients might be perceived as "different" or "handicapped" when compared with a "well" person. A positive psychological feature is the fact that LVAS insertion does not necessitate removal of the natural heart, which might be able to temporarily support the circulation, or recover sufficiently to allow for device removal.

One of the most important considerations of cardiac transplantation versus LVAS support is the question of the quality of life. From recent experiences with the Novacor Baxter LVAS and the Thermocardiosystems Heartmate in the bridge-to-transplant population, one could surmise that quality of life may be reasonably satisfactory. By January 1997, 25% of patients who received the Novacor LVAS as a bridge to transplantation were managed out of the hospital. A significant number of them have returned to work and enjoyed active, productive lives. These patients have become quite accustomed to using their externalized battery sources and seem to manage their daily activities without undue stress. They are able to camouflage their externalized battery packs so that it is not obvious that they are being mechanically supported. These devices with externalized drive lines are not as "forgettable" as the totally implantable devices will be.

The exercise capacity in cardiac transplant recipients and LVAS recipients is an important determinant of quality of life. Studies in cardiac transplant recipients [14, 15] demonstrate that, at rest, they have an increased heart rate, increased blood pressure, and low normal cardiac output. During exercise, peak heart rate, stroke volume, cardiac output, peak power output, pulse pressure, heart rate reserve, total VO₂, and absolute VO₂ at ventilatory threshold are all less than normal. Left ventricular function is impaired when compared with postoperative coronary artery bypass patients [16]. This decrease has been attributed to cardiac denervation, diastolic dysfunction, some abnormality in oxygen transport or utilization, deconditioning, cardiac rejection, and coronary artery disease. Their exercise capacity may increase with time up to 5 years and may improve with increase in muscle mass and lean body weight. Autonomic reenervation may actually increase peak heart rate during exercise [17], although this is quite controversial. Finally, recent studies suggest that cavo-caval anastomosis may increase atrial emptying and result in better functional capacity [18]. While some individual patients with cardiac transplantation function well, most patients have important physiological limitations.

The exercise capacity of patients with implantable LVAS cannot be accurately predicted but, from the bridge to transplantation experience, it is apparent that improvement in exercise tolerance occurs. Maximum VO₂ is a well-characterized indicator of functional status and prognosis in patients with advanced heart failure. Peak oxygen consumption with upright treadmill exercise increased from 10 to 14 mL O₂/kg/min in a group of patients supported for a mean of 50 days after left VAD implantation [19]. Other postoperative studies suggest that the native left ventricle may contribute to function during exercise by actively filling the left VAD, which reduces filling time and overcomes inflow cannula impedance. It may also augment total cardiac output with parallel ejection out of the native aortic valve and reduce ventricular interaction-related changes in functional right ventricular diastolic compliance [20]. It is clear that exercise capacity increases during the first several months after VAD insertion because patients have improved organ function, resolution of pulmonary edema, and a decrease in pulmonary artery pressure and resistance. These changes significantly augment right ventricular function, which also usually improves with time [21]. It is anticipated that patients with long-term LVAS will achieve reasonably high levels of exercise capacity and not be limited by activities of daily living. Whether they will be able to participate in athletic events and vigorous work is not entirely clear, but seems feasible.

The economic considerations of long-term LVAS support are an extremely important consideration in the modern era of restricted resources. The use of these devices on a broad scale will necessitate some indication that they are economically feasible. Although our current health care environment is dominated by economic efficiency, it is hoped that technology, which clearly improves patient welfare, may still be welcome if it is at least economically neutral. Although the actual cost of these devices cannot be accurately assessed at this time, some data are helpful in determining cost effectiveness. In a study of total artificial hearts by the Institute of Medicine, cost effectiveness was measured by the relationship of costs to quality-adjusted life years (QALYs) [4]. It was estimated that the cost per QALY in 1991 dollars for hemodialysis was $50,000, for two-vessel coronary artery bypass grafting, $34,000, and for a total artificial heart for 2 years, approximately $105,000. The cost calculation of QALYs for LVAS was not calculated, but it was estimated that it would be significantly less than for a total artificial heart [1]. Furthermore, in a probing review of the question, "Can our society afford mechanical hearts?" Poirier [22] suggested that an investment of $100,000 in an individual for the device and implantation costs coupled with an ongoing maintenance cost of $4,000 per year could within 4 years return to society an income greater in value than the investment if the individual could earn an annual salary of $40,000 per year. If the same individual had complications resulting in intermittent loss of salary, the payback period might be extended by an additional 2 years. However, by Poirier’s estimation, circulatory support systems represented a potential to increase our gross national product, leading to a higher standard of living. Although many assumptions were made in order to reach that conclusion, it does seem feasible that LVAS could be economically acceptable. When one surveys the large number of patients with congestive heart failure entering our hospitals and intensive care units every year, some of them repeatedly during the period of time that implantation of a device might be considered, there may be considerably more savings than have been predicted. Expensive readmissions to Coronary Care Units could be avoided by the out-of-hospital maintenance of patients on chronic LVAS. If the devices can be relatively problem free and not require multiple readmissions for replacement of parts or devices, employers may be receptive to these patients returning to work. It is not known whether the relatively low reemployment percentage for cardiac transplant patients is related to their need to continue to take expensive medications or their other medical problems. If LVAS patients are spared these costly medications and comorbidities, they may actually be better risks for long-term employment. Most importantly, current treatment, which engenders enormous annual costs to treat patients with congestive heart failure in the last 6 months of life, often does not cure their underlying disease or give them improved quality of life. Long-term LVAS may offer the opportunity to improve all of the above in these patients who face a high mortality during their last 6 months of life. Although transplantation will be important to maintain a small core of congestive heart failure patients, it is apparent that unless some major changes occur in immunosuppressive therapy or organ donor supply, LVAS’s hold the best promise for the future in making any real impact on this huge public health problem.

References

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