4

Clinical Effectiveness and Need For Long-Term Circulatory Support

IN TERMS OF CLINICAL EFFECTIVENESS, long-term mechanical circulatory support systems (MCSSs) must be compared with alternative forms of treatment for end-stage heart disease. Currently, heart disease in all its forms is the leading cause of death in the United States, but transplantation is the only effective treatment for the substantial portion of all heart disease that results in heart failure. For some types of heart failure, pharmaceuticals can reduce symptom levels, postpone death, or both, but most patients either experience sudden cardiac death or deteriorate to end-stage disease, from which they now die if unable to qualify for and receive a transplant.

This is the clinical context in which long-term MCSS use must be evaluated. As Table 4.1 summarizes, today's expectations are that a fully implantable long-term MCSS will ultimately offer patients approximately the same clinical prospects and quality of life as transplantation. Long-term ventricular assist device (VAD) use during the 1990s will clarify selection criteria; some patients will likely be better served by an MCSS, and transplantation will be more desirable for others. Despite the current lack of long-term MCSS experience, the committee must consider this technology's potential clinical impact.

ESTIMATING THE NEED FOR LONG-TERM SUPPORT

Estimating the number of candidates for long-term, fully implantable circulatory support devices is difficult, because no such device has yet seen human use. The reliability and effectiveness of these devices are unknown. Nonetheless, any consideration of the advisability of continuing with MCSS



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The Artificial Heart: Prototypes, Policies, and Patients 4 Clinical Effectiveness and Need For Long-Term Circulatory Support IN TERMS OF CLINICAL EFFECTIVENESS, long-term mechanical circulatory support systems (MCSSs) must be compared with alternative forms of treatment for end-stage heart disease. Currently, heart disease in all its forms is the leading cause of death in the United States, but transplantation is the only effective treatment for the substantial portion of all heart disease that results in heart failure. For some types of heart failure, pharmaceuticals can reduce symptom levels, postpone death, or both, but most patients either experience sudden cardiac death or deteriorate to end-stage disease, from which they now die if unable to qualify for and receive a transplant. This is the clinical context in which long-term MCSS use must be evaluated. As Table 4.1 summarizes, today's expectations are that a fully implantable long-term MCSS will ultimately offer patients approximately the same clinical prospects and quality of life as transplantation. Long-term ventricular assist device (VAD) use during the 1990s will clarify selection criteria; some patients will likely be better served by an MCSS, and transplantation will be more desirable for others. Despite the current lack of long-term MCSS experience, the committee must consider this technology's potential clinical impact. ESTIMATING THE NEED FOR LONG-TERM SUPPORT Estimating the number of candidates for long-term, fully implantable circulatory support devices is difficult, because no such device has yet seen human use. The reliability and effectiveness of these devices are unknown. Nonetheless, any consideration of the advisability of continuing with MCSS

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The Artificial Heart: Prototypes, Policies, and Patients TABLE 4.1 A Summary Perspective on Treatment Alternatives for End-Stage Heart Disease   Heart Transplantation Long-Term MCSS Advantages and strengths A physiological answer, not involving any device or visible external evidence of transplant No ongoing “upkeep” needed, only medications and periodic tests Current 5-year survival probability is about 70% and may improve A mechanical form of treatment not limited by the supply of donor hearts No periodic testing needed to detect rejection or other problems Survival probability is expected to equal transplantation, once in wide use Risks and limitations Considerable risk of sudden death while on waiting list for a donor heart Substantial risk of diffuse coronary atherosclerosis in donor heart (“chronic rejection”), requiring second transplant or MCSS Some risk of acute rejection, requiring hospitalization Number of procedures is limited (about 2,000 per year) by supply of donor hearts Continuing small but important risk, for TAH recipients, of sudden death as a result of a “hard” device failure Some risk of “soft” device failure, requiring hospitalization for repair or replacement For the foreseeable future, the MCSS will have a finite life; replacement will thus, ultimately, be needed Periodic need to replace implanted battery (may, some day, become a simple outpatient procedure) Inconveniences Rigorous anti-rejection drug is important to survival Need to carry batteries and wear electricity-transmitting belt; 2-to 3-times-per-day substitution of recharged external batteries needed; minimal need for drug therapy Cost (in 1991 $) One-time cost about $90,000; substantial ongoing costs for anti-rejection drugs, catheterization, and other periodic tests Estimated $150,000-200,000 one-time cost; low ongoing cost (primarily for battery replacement) Major complications Rejection of transplanted organ Thromboembolic event; bleeding; infection Most important uncertainties Extent to which long-term outcome will improve over next 10-20 years; whether supply of donor organs will increase Unknown impact of long-term device use on physiology; extent to which device longevity will improve (e.g., from 2 to 5-10 years?)

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The Artificial Heart: Prototypes, Policies, and Patients development must project the clinical effectiveness of these devices in order to estimate how many patients can be expected to receive them. At least three reasons exist for estimating clinical effectiveness and device use: to decide whether the number of prospective patients is sufficient to warrant the anticipated R&D costs; to assist those who are responsible for beneficiary populations (e.g., third-party payers) in planning their funding needs; and to ascertain whether the potential patient volumes and thus the aggregate health care costs of using MCSSs are so large that, added to the already high cost of U.S. health care, the burden would be great enough to become a factor in R&D decisions. MCSS, mechanical circulatory support system; TAH, total artificial heart. Any estimate of eventual MCSS use involves judging (1) the magnitude of the population dying of cardiac disease or incapacitated by it and (2) the perceived effectiveness of the particular MCSS in delaying death as well as improving the quality of life by ameliorating symptoms. Such estimates must also consider the impact of the alternative therapies and preventive techniques that may be available in the future, as well as the improvement of existing ones. FROM TEMPORARY TO LONG-TERM USE The use of long-term implantable devices will certainly be tied closely to their effectiveness in supporting patients' circulation and maintaining a satisfactory quality of life. Evidence of physiologic effectiveness has been growing, based upon the experience of temporary device use (Kormos et al., 1990; Portner et al., 1989; Termuhlen et al., 1989). In more than 400 instances, tethered assist devices have been used to support life in conjunction with cardiac transplantation (Miller et al., 1990b); there has been additional experience with these devices during cardiogenic shock following cardiac surgery or acute myocardial infarction (Miller et al., 1990a). Present-day MCSSs can provide blood flows to sustain life, with the device itself outside the body or with an external power source driving the pump by means of a transcutaneous line. These devices can, further, meet the demands of moderate patient activity and also reverse multiple organ dysfunction that has resulted from periods of circulatory insufficiency. Also known are the major complications of these devices, such as bleeding, thromboembolism, and infection, with infection the most likely to be reduced by the use of fully implantable devices. The effects of fully implantable devices on patients' freedom of activity, psychological functioning, and health-related quality of life are not known presently. Reliable, although limited, information as to these factors will not be available until trials of one or more long-term VADs are completed.

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The Artificial Heart: Prototypes, Policies, and Patients PROJECTING DEVICE RELIABILITY AND EFFECTIVENESS An inescapable relationship exists between a circulatory support device's reliability and clinical effectiveness and the number of potential recipients for it. If, either at an early stage of use or after attempts to improve the device have been unsuccessful, a particular type of MCSS results in patient outcomes that are significantly poorer than heart transplantation, most patients and most physicians will wish to use the device only as a last resort. Death during an unsuccessful wait for a donor heart is obviously less desirable, but many patients faced with these two less-than-favorable options might prefer to take their chances on receiving a donor heart. Even if the MCSS's outcome is poor, however, there will remain a group of patients unsuitable for cardiac transplantation who would wish to use, and who could benefit from, a less-than-desirable alternative, that is, a device that offers some probability of life extension for at least a few months. Additionally, some patients who are candidates for heart transplantation, faced with a long waiting period during which their activity and comfort levels are sharply restricted, might choose more immediate relief through the use of a device that will not categorically exclude the possibility of a subsequent transplant. In the upcoming Novacor VAD trial, candidates selected for device use will probably not compete with other transplant candidates, because of the need for the study to make the maximum possible contribution to scientific knowledge, an unlikely outcome if some VAD recipients subsequently received a transplant. (Subjects of long-term VAD clinical trials are likely to be persons over age 65 who would not normally be considered for a heart transplantation.) In the future, however, it is entirely possible that implantation of a long-term device will not preclude subsequent transplantation, although the relative effectiveness of the two approaches at that point would be an important factor in any such decision. At the other extreme, continued research and development may lead to a much improved device that offers a quality of life and a five-year survival probability much better than heart transplantation provides. In that event, more patients will likely become candidates for the implantable device. In order to estimate the extent of long-term MCSS use, the committee has considered both a range of patients' conditions and a range of device safety and effectiveness characteristics. These, collectively, constitute probable circumstances for device use and make possible a preliminary estimate of the extent of that use. For the purpose of exposition, this chapter and the committee's epidemiology study (Appendix D) identify two patient groups based on their medical conditions and prospects for successful MCSS use. The committee designates these as the primary and secondary groups, as discussed further below.

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The Artificial Heart: Prototypes, Policies, and Patients When early trials of long-term VADs are completed and outcome reports published, interested parties will be able to estimate the future use of these devices much more accurately than is now possible. The same will be true of total artificial hearts (TAHs) after their early trials are completed, probably between the years 2005 and 2010. Nevertheless, some conclusions can be drawn, based on the current performance of temporary-use devices. For instance, total or “hard ” failure of a device or component (resulting in a high risk of immediate death), although it may not be easily corrected, is likely to be relatively rare; by contrast, soft failures are not life-threatening. Although they may be more common, they will rarely be fatal and can be corrected. Further, upper bounds for some types of complications can be estimated; for example, patients with a fully implanted MCSS are almost certain to experience lower infection rates than current temporary-MCSS patients with skin-penetrating power lines. A direct relationship thus should exist between device performance and clinical effectiveness, except for two factors. First, because soft failures occur gradually or can be predicted, there is time to correct the failure—for instance, by replacing a prematurely worn-out battery—before the patient suffers permanent harm. Second, the extent of a patient's comorbidities may affect what might otherwise be a predictable outcome, given a device's projected performance. Put another way, some patients with certain comorbidities may react very differently to a particular problem or shortcoming of a device than do patients with other types of comorbidities, or none. RELATING CLINICAL EFFECTIVENESS AND DEVICE USE Given the current uncertainty about MCSS effectiveness, one approach to estimating the potential patient populations for their long-term use is to explicitly relate a range of projected device characteristics and likely patient outcomes to the number of potential patients under each circumstance. Estimates made today in this manner can be used by the National Heart, Lung, and Blood Institute (NHLBI) in deciding about R&D resource allocations, as well as by others interested in the future of mechanical circulatory support. Table 4.2 summarizes characteristics of three types of devices that will affect patient volume. Performance of the devices in the three categories can be summarized in this manner: A device in category A is one whose characteristics make it particularly desirable, comparing favorably with outcomes of heart transplantation in the early 1990s in terms of five-year survival and complication rates. A category B device is somewhat inferior to one in category A, in that survival probability is not as high and complication rates are somewhat

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The Artificial Heart: Prototypes, Policies, and Patients TABLE 4.2 MCSS Device Performance Characteristics Groups Characteristic Device A Device B Device C Minimum device survival ratea >70% at 5 years (same as transplantation now) >80% at 2 years <50% at 2 years Rate of surgery to repair or replace soft device failure 10% per year 20% per year 30% per year Annual rate of thromboembolic events About 2% (perhaps higher) 2-4% (same as 2 artificial heart valves) 14-20% Annual rate of infection requiring intensive antibiotic therapyb 1% 5% 10% Other Compares favorably to 1990 transplantation outcomes Works well enough to improve patient to NYHA Class I or II Poor energy transmission; transcutaneous power cable often needed aMay be skill-dependent, based on the experience of the personnel at the particular institution, as is the case with heart transplantation. bComplication rates may vary, depending on the severity of the patient 's illness. NYHA, New York Heart Association. SOURCE: Committee projections based on workshop discussions withexperts. greater. Such a device nonetheless has the potential to improve a heart failure patient's condition from moribund or partially disabled to a reasonable level of functioning, notwithstanding a long-term mortality risk. A category C device is one that would likely be used only by patients whose survival is in doubt and for whom transplantation is not available or carries a risk of death during the waiting period that is too great. Although it could be called a “problem” device, a category C device would still offer a reasonable prospect of survival at a moderate functional level for a period of up to two years. The Role of Comorbidities The comorbidities suffered by end-stage heart disease patients complicate the task of projecting patient populations for MCSS use. For instance, a psychosocial comorbidity such as alcoholism or cognitive impairment may hinder a patient's ability to adhere to the regimen needed to care for the MCSS, so the patient may require support from a relative or friend

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The Artificial Heart: Prototypes, Policies, and Patients either constantly or periodically. Medical comorbidity (e.g., metastatic cancer, brittle diabetes) may be so serious as to shorten the patient 's life expectancy unduly, even if the device works well. Theoretically, one could use both anticipated device performance and the epidemiology of expected comorbidities to make estimates of potential patient populations for MCSS use; doing so has the potential to be more refined than the two-dimensional approach used here. Unfortunately, the data currently available about coexisting conditions are inadequate to allow such projections with a reasonable degree of certainty. Data are scarce about the natural history of particular forms of heart disease; considering the impact of comorbidities would make the estimates even less certain. The presence of serious comorbidities has been used in reaching the committee's epidemiological estimates that are discussed below. Less serious comorbidities are not considered, pending additional evidence about their impact on MCSS clinical effectiveness to be derived from forthcoming long-term VAD trials. OTHER INFLUENCES ON THE USE OF CIRCULATORY SUPPORT DEVICES Other factors besides anticipated device performance affect the number of potential patients for MCSS use. The Impact of Other Heart Disease Treatment Technologies In the United States and some other industrialized countries, both the incidence (the rate at which new cases appear) and the mortality rates of coronary heart disease (CHD) are decreasing, attributable in part to reduced smoking, dietary alterations, and other lifestyle changes. The absolute numbers of individuals who develop heart disease and die of it, however, are projected to increase (Weinstein et al., 1987), largely because of the steadily increasing size of the older population, for whom heart disease is the leading cause of death. In the near future, CHD prevalence, i.e., the number of persons with this disease, is also likely to increase, due both to the increasing population and to extended survival of persons after they are diagnosed as having CHD. Additionally, neither new measures to prevent CHD nor other forms of treatment appear likely soon to reduce the number of patients who progress to end-stage disease. The volume of surgery to bypass stenosed coronary arteries appears to have reached a plateau, and direct treatment of stenosed coronary arteries by such techniques as angioplasty and atherectomy has been effective for only limited periods. Progression of the disease process has been the rule.

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The Artificial Heart: Prototypes, Policies, and Patients Thus, in spite of therapies that ameliorate symptoms and improve function, the basic disease continues to progress, and the number of individuals eventually coming to an end stage has not been strikingly reduced by these strategies. Continuing MCSS research should not, however, be considered a substitute for encouraging the diffusion of less dramatic and less costly therapies that have the potential to intervene successfully in the course of heart failure at an earlier stage. Even heart transplantation does not completely free patients from the possibility of heart failure. Indeed, the anticipated fate of 20 to 30 percent of all transplant patients is failure of the transplanted organ. Hence, even using all current strategies, the number of patients who are potential candidates for long-term mechanical support will not decrease in the near future, although they will seek treatment at a more advanced age. Further, there are promising gains in understanding mechanisms of the progression of the ventricular dysfunction that occurs in heart failure (Francis and Cohn, 1990). This research may eventually lead to new forms of treatment that slow or even halt the progression of disease and thus reduce the volume of new end-stage patients or, more likely, increase the average age at which the devices may be primarily needed. It is not possible to predict how these new treatments will influence the demand for MCSSs in the next 20 years. Quality-of-Life Determinants The clinical effectiveness of all technologies is influenced by the humanness of the patient. The health-related quality of life of patients with end-stage heart disease is a major factor in assessing the outcomes of MCSS use (see Chapter 5). Patients' quality of life and health status, however, should not be equated with the much broader set of determinants that define the context in which patients seek health care. These determinants include (1) personal health habits, health knowledge, and attitudes; (2) social resources and networks of personal contacts; and (3) various economic, educational, and psychologic resources (Patrick and Erickson, 1988; Patrick et al., 1988; see also Bergner, 1985). Several of these determinants are reported to influence significantly the prognosis and outcomes of patients receiving treatments somewhat similar to MCSS (Lubeck and Bunker, 1982; Evans et al., 1984; Christopherson, 1986; Pycha et al., 1986; NIH, 1987; Kalbfleisch et al., 1989; Vlay et al., 1989). Many patients, health care providers, and third-party payers have an intuitive sense of the importance of these factors and, through various mechanisms, such as patient counseling and case management, attempt to direct or reinforce the influencing factors in a positive direction. Clinical trials, registries, and focused research can add to the understanding of the degree and

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The Artificial Heart: Prototypes, Policies, and Patients direction of specific determinants or combinations for condition-specific populations such as end-stage heart disease patients. Such information will be helpful to all parties involved in discussing prognoses with patients and in making decisions about alternative treatments. Additionally, information on determinants may be useful in the future for determining coverage eligibility for specific high-risk technologies. Patient Preferences for Life-Sustaining Treatment The demand for MCSS will also be influenced by patient and family preferences for life-sustaining treatment. Findings of a recent study indicate that only 33 percent of elderly adults facing imminent death, preventable through the use of technology, will opt for life-sustaining treatment; patients indicate that they prefer such treatment only while critically ill but do not desire it after they become permanently unconscious (Danis et al., 1991). The majority prefer not to be kept alive. Evidence is inconclusive as to what percentage of patients in need of and eligible for heart transplantation or an MCSS will opt for death rather than undergo such a procedure. Several factors have been identified as relevant to the patient's decision making about life-sustaining treatment: degree of independence the patient will retain; presence and severity of comorbidities; perceived quality of life following treatment; clinical prognosis; attitudes and preferences of family and close friends; risk tolerance; prior experiences with death and disease of others; finances; and attitudes and values of the patient about illness, meaning of life, religion, death, and dying (OTA, 1987; Rabinovich and Cohen-Mansfield, 1989; Walden et al., 1989). Other Factors Other considerations will also affect individual patients' decisions about a technology such as MCSS. Perhaps the most important is reimbursement, that is, the coverage and payment policies of third-party payers. Chapter 9 examines more fully the effect of third-party payers on MCSS utilization. EPIDEMIOLOGICAL PROJECTIONS Previous Studies Several previous studies have attempted to determine the number of end-stage heart disease patients whose lives might be prolonged by an effective cardiac support or replacement device. Estimates based on mortality statistics, disease incidence, and life expectancy have ranged from 6,000 to 66,000 annually in the United States alone (NHI, 1969; NHLI, 1973; NHLBI, 1980;

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The Artificial Heart: Prototypes, Policies, and Patients Lubeck and Bunker, 1982). The size of the population currently receiving heart transplantations or waiting for them, when adjusted to include those not eligible for transplantation because of age and contraindications, suggests a need for long-term MCSSs of at least 15,000 per year, but other considerations suggest an even greater need. Researchers at the Mayo Clinic performed a population study in which they reviewed all deaths in Olmsted County, Minnesota, using restrictive criteria for age, associated disease, and time limitations between the onset of life-limiting illness and potential MCSS use. Based on key assumptions that the devices would be offered only to patients under age 70 who are free of major comorbidities and who survive the initial cardiac episode by at least two hours, they projected 11,000 to 23,000 potential users of an effective MCSS device per year nationwide (Kottke et al., 1990). However, major differences between the health and socioeconomic characteristics of Olmsted County residents and of the total U.S. population require careful interpretation of these figures, because many epidemiological markers of heart disease (e.g., incidence and mortality rates) from Olmsted County are substantially lower than those for the nation as a whole. The Committee's Projection To update the epidemiological studies just mentioned and form a basis for its own consideration of the need for these devices, the committee commissioned an epidemiological study (Funk, 1991), included in this report as Appendix D. The main focus of the epidemiological study is what we have denominated the primary group of patients who are potential candidates for implantation of a long-term MCSS. This group comprises those in the final phase of end-stage heart disease, functionally either moribund (in Class IV of the New York Heart Association [NYHA] functional classifications) or partially disabled, being maintained on intensive medical therapy (those in the lower portion of NYHA Class III). The primary group thus encompasses patients now eligible for heart transplantation and numerous others who are not eligible for reason of age, transplant-related contraindications that do not apply to an MCSS, or lack of access to a transplant center. The committee's study found that the primary population of candidates for both forms of long-term MCSS totaled between 30,000 and 60,000 persons in 1990, depending on the age that is considered to be the typical upper limit for device implantation, respectively 75 and 85. The committee notes, however, that these upper age limits are being used exclusively to estimate probable MCSS need; once MCSSs are approved for general use, only clinical factors should be used to select patients to receive an implant. As discussed in Chapter 8, MCSS use should never be denied solely on the basis of chronological age.

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The Artificial Heart: Prototypes, Policies, and Patients The size of the pool of potential MCSS recipients gradually increases (e.g., to an annual range between 35,000 and 70,000 in 2010) as a result of general population growth during this period, in particular as the “baby boom” generation born in the 1940s and 1950s moves into the age range of high heart-disease incidence.1 This study took into account sudden deaths and serious comorbidities, but it did not consider the nature of the device to be implanted. This range of sizes for the primary group of potential MCSS candidates encompasses the upper limit of the findings from previous studies of the artificial heart program. The most recent of those, however, was performed seven years ago, at a time when the nature of the devices to be implanted was somewhat less clear than at present. The committee believes that between 35,000 and 70,000 potential candidates for an MCSS—either VAD or TAH—is a reasonable projection of need as of the year 2010 for the primary patient group. This conclusion assumes that a VAD meeting the characteristics described above as Device B—or, perhaps, Device A—will have completed clinical trials and received approvals from the Food and Drug Administration (FDA) and at least some third-party payers by the turn of the century. Between 1997 (the earliest a VAD is likely to receive FDA approval) and 2010, the annual number of VADs implanted each year will probably increase gradually—from near zero to a number potentially in the 35,000-70,000 range. Because of the short life expectancy of medically treated patients, there is very little year-to-year backlog of patients. The growth of VAD use will be constrained by several factors: delays in third-party approvals; inadequate payment rates that adversely affect some hospitals' interest in the technology; and the time required for surgical teams, beyond those now experienced in using temporary VADs, to be trained in implanting them. The volume of heart transplant procedures increased gradually during the early 1980s, constrained by similar factors, but plateaued at a much smaller number because of the limited availability of donor hearts. MCSS use in an annual range of 35,000 to 75,000 may seem high, especially in relation to the 2,085 heart transplants performed in 1990. The projected use range reflects, however, an approximate growth rate between 25 and 35 percent per year, using as starting points a volume of 1,600 (the 1988-1989 number of transplant cases) and 1997 as the earliest possible full 1   The committee's projections of potential MCSS candidates are for first-time implantations. Particularly in the early years of use, a substantial number of either complete or partial (e.g., the internal battery) MCSS replacements will be needed. Projecting the number of replacements is not possible at this time, other than by using estimates such as the probabilities used in the committee's cost-effectiveness analysis.

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The Artificial Heart: Prototypes, Policies, and Patients year of MCSS use. Neither a potential annual volume between 35,000 and 70,000 nor a 25 to 35 percent growth rate differs greatly from the diffusion rates of other cardiovascular technologies such as pacemakers and coronary angioplasty. Effect of a Less-than-Ideal Device As previously discussed, the use of long-term MCSSs will depend heavily on the characteristics of the devices available. This estimate of the size of the potential candidate population assumes a device that has at least the performance characteristics described above as Device B. If a device that meets those characteristics is not developed and approved until early in the next century, this projection should be moved an equal period of time into the future. Conversely, if forthcoming long-term VAD trials find that the devices perform extremely well—approaching the Device A description in Table 4.2 —then the range of potential use projected for 2010 is possibly too low. As soon as a high-performance device becomes available, considerable patient demand can be anticipated, expressed through such routes as legislators, labor negotiations, and patient advocates. The extent of such pressures to make the device available will have a considerable impact on the annual growth in use, as hospitals, third-party payers, and the physicians who care for cardiac patients can be expected to respond to those demands by encouraging coverage approvals. Currently, the limit placed on heart transplantation by the supply of donor hearts is so stringent that no consideration can be given to transplants for patients other than those seriously disabled by their end-stage disease. Pressure to perform transplants at an early stage in the course of patients' illness would thus have been to no avail. Less Disabled Patients The foregoing discussion has focused on a primary group of patients who are disabled by end-stage heart disease and who, with few exceptions, will be the individuals receiving long-term MCSSs in the early years of their use. These devices could, however, be used eventually with at least some patients in a much larger group (designated by us and in Appendix D as the secondary group), those whose end-stage disease is now being managed at least temporarily by medication. These patients are able to function within the severe limitations of their disease; some of them may require hospitalization one or more times each year. The committee's review indicates that as many as 400,000 individuals may be included in this secondary group, based on numbers of patients hospitalized for congestive heart failure. (In contrast, those hospitalized for coronary [atherosclerotic] heart disease

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The Artificial Heart: Prototypes, Policies, and Patients are, on average, much less likely to require an MCSS than patients with a primary diagnosis of congestive heart failure.) The limitations of the data are so great, however, that this number may be in error by 100,000 or more persons in either direction. It is not realistic to consider relaxing the indications for MCSS use to include this much larger group of patients unless the health care system reallocates substantial resources from other areas of health care to pay for these procedures, and develops the resources (e.g., trained surgical teams, facilities) to handle the recurring annual demand from the very seriously ill patients in the primary group. This “break-even” point appears likely to occur in approximately 2010. After 2010, based on the clinical evidence developed in the intervening 15 years of use, clinicians and epidemiologists should be able to define more clearly than is now possible how many of these individuals, somewhat less disabled by their cardiac disease than those in the primary group, can benefit from an MCSS. At this time, the committee 's best estimate is that MCSSs of high-performance (category A) characteristics could potentially, at some point in the period between 2010 and 2030, be used in as many as 200,000 patients from the secondary group annually unless, by then, other preventive and therapeutic advances have made substantial inroads into the volume of heart failure patients. Additional Potential Patients At some point, probably not before the 2020s, MCSSs likely will be used in limited numbers with two additional patient groups. One group is persons less disabled by their heart failure than those in our secondary group. These individuals are at some risk for sudden death and may have symptoms of their heart disease, particularly if they overexert in relation to their limitations. They are, however, able to function and thus would be interested in an MCSS only if it provided a level of functioning that is considerably improved over their present state, as well as an improved prospect of avoiding sudden death. Some may also wish to become candidates for a long-term MCSS to prevent their condition from worsening. They might be willing to undergo surgery if the MCSS then available offered a very high probability of improving their quality of life and, more important, preventing future decline in their functional capacity. Second, such a device when developed would also likely be used with some patients suffering from other forms of unbeatable heart disease, such as intractable angina or an arrhythmic disorder so severe that it cannot be controlled by an automatic implantable cardioverter defibrillator. Although not heart-failure patients, these individuals would be able to benefit from a high-performance MCSS in much the same manner as those with heart failure.

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The Artificial Heart: Prototypes, Policies, and Patients VENTRICULAR ASSISTANCE VERSUS A TOTAL ARTIFICIAL HEART The total number of patients likely to benefit from either type of long-term MCSS, and thus potential candidates to receive one, is useful for many purposes. NHLBI is interested specifically in the potential volume of TAH use, however, as one factor in deciding whether to continue that aspect of its artificial heart program. Current information does not allow a precise estimate of the proportion of patients suitable for an MCSS that will benefit from biventricular support and, therefore, a total artificial heart. It is only a presumption that those suffering from cardiomyopathy—currently half of those receiving heart transplants (Kriett and Kaye, 1990)—have uniform myocardial disease and will require biventricular support. The information from the international registry of temporary MCSS use as a bridge to transplantation does not include etiology. It does identify that biventricular support has been employed in 78 percent of those acutely ill patients (Miller et al., 1990b). An unidentified number of these patients were in acute myocardial failure immediately subsequent to extracorporeal circulation during surgery and procedure-related cardiac ischemia. At present, it is generally accepted that patients are more likely to require biventricular support if they are unable to survive without an MCSS and have as the precipitating factor acute ischemia induced by operation and/or acute myocardial infarction. In contrast, others who are less likely to require biventricular support include individuals with advancing chronic illness manifest by left ventricular failure and characteristically suffering from ischemic heart disease. The international registry prevalence of 78 percent biventricular support does not indicate whether use of this type of support resulted from an evaluation of need, a general policy at the institution, or availability of particular devices, all factors that might have influenced treatment decisions. Other reports of the need for biventricular support in bridging operations are as low as 36 percent (Kanter et al., 1988). Improvement in right ventricular function in patients receiving a left ventricular assist device (LVAD) as a bridge to transplantation has also been reported (Kormos et al., 1990). An extensive literature on the effects of left ventricular assist on right ventricular function has not been definitive, but it does suggest that the reconfiguration of the ventricles as a result of left ventricular unloading by the LVAD is either neutral or advantageous to right ventricular performance (Farrar et al., 1984; Farrar et al., 1985; Elbeery et al., 1990). Other factors also affect the choice of a TAH or ventricular support. On the one hand, using a TAH requires removing the patient's natural heart, which eliminates the possibility of even very limited support of the circulation by a badly damaged natural heart if the device fails completely. Thus,

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The Artificial Heart: Prototypes, Policies, and Patients a TAH will be used only when a single long-term VAD will not meet the patient's needs. (No current R&D activity has a goal of two fully implantable VADs.) On the other hand, operative risks increase each time open-heart surgery is performed, so any doubt as to the patient's need for biventricular support is likely to be resolved in favor of using a TAH. Experience with early VAD clinical trials will provide considerable additional information to assist in determining the need for long-term biventricular support. Especially in the early years of long-term VAD use when the volume of implant procedures is limited, patients who are acutely ill and thus may have already suffered damage to other organs will typically be accorded the highest priority to receive a VAD, and these are the patients most likely, from present data, to need biventricular support. As MCSS availability increases, however, surgeons will be able to implant the devices at an earlier point in the patient's deteriorating course of illness. This will probably reduce the proportion of TAHs needed but, because of the increased total volume, the overall need for TAHs will remain approximately stable. Another factor in the need for TAHs is their present stage of development, on a time line approximately 10 years later than the first model of VAD. Thus, although routine VAD use may begin in the late 1990s, the first FDA approval of a TAH is not likely before 2003 or 2004 at the earliest. By that time, it is probable that third-party payers ' experience with long-term VADs will make them more receptive to approving TAH use without lengthy delays. A final factor in the need for TAHs is that transplantation will remain, for the foreseeable future, the treatment of choice for patients clearly needing long-term biventricular support, such as patients with some forms of cardiomyopathy. The volume of donor hearts probably will not meet the total need from this patient group. Moreover, the need for TAHs is also likely to continue for patients who have rejected a transplanted heart and for clinical reasons cannot receive a second one, as well as for patients for whom transplantation is contraindicated for immunologic or other medical reasons. Therefore, just as the committee has estimated the potential need for VADs to begin in 1997 and build gradually, it believes there could be a continuing and substantial potential need for biventricular support, much greater than the current annual 1,600-2,000 transplant volume. This need will begin to be satisfied as soon as the TAH development process allows. The ultimate TAH need cannot be estimated precisely but will probably lie in the range of 15 to 25 percent of the total number of MCSSs needed, or a potential of approximately 10,000 to 20,000 as of 2010, depending on the upper age limit of the typical patient. As noted above, once devices are widely available, physicians will be very reluctant to use a TAH when a

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The Artificial Heart: Prototypes, Policies, and Patients VAD appears likely to suffice, so it is improbable that the number of TAHs required could increase to as much as half of the overall need for long-term MCSSs among the primary patient group. Very few TAHs will be needed by the secondary group of patients, however— perhaps 5 percent of the 200,000 potential maximum volume—because intervention is occurring much earlier in the disease process. Considerable clinical uncertainty also remains. Until VADs have been implanted for two years or longer in a substantial number of patients, clinicians will not be able to know whether VADs represent a solution to the needs of the majority of end-stage heart disease patients. Some unanticipated problem may be revealed, making the VAD less useful than the TAH for defined groups of patients. This constitutes an argument for not suspending the TAH development process, at least until results of long-term VAD use are reported for more than the initial 20 trial patients. THE NEED FOR MORE RESEARCH Basic and Clinical Research Concerning Heart Failure Little is known about the underlying mechanisms of heart failure. The committee is concerned that, whatever action NHLBI takes concerning the artificial heart program, its support of research on mechanisms of heart failure should continue. Additional knowledge about the causes and course of heart failure may soon make possible forms of prevention or treatment that will obviate some patients' need for either heart transplantation or an MCSS, if research that is deemed scientifically meritorious can continue. Epidemiological Research Heart disease is the leading cause of death in the United States and many other countries, but there still are deficiencies in knowledge of its epidemiology. In particular, age-, sex-, and race-specific data concerning the natural course of heart failure and other forms of end-stage heart disease in representative populations apparently do not exist. Additional limitations on the ability to estimate numbers of potential MCSS recipients include these: There is very little knowledge of comorbidity in end-stage heart disease. Hospitalization information is based on discharge data instead of using unique patient identifiers in order to track multiple hospitalizations. Hospital discharge diagnostic codes and death certificate entries lack clarity in such respects as the mutual exclusiveness of terms such as coronary heart disease, congestive heart failure, and atherosclerotic heart disease.

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The Artificial Heart: Prototypes, Policies, and Patients NHLBI deserves commendation for its sponsorship of a four-site longitudinal study of heart disease in older patients that is now under way. The committee hopes that additional research on such issues can be initiated, possibly involving patients under age 65 and perhaps drawing on the comprehensive Framingham Heart Study data base. Further, the level of understanding of study results will be improved if the data from major epidemiological studies are made available on “public use” data tapes for analysis by other investigators. SUMMARY AND CONCLUSIONS At this point in the development of long-term MCSSs, it is difficult to estimate the precise need for them, were they to be approved for general use. The committee's epidemiological review supports the previous studies that found the ultimate potential total use of both long-term VADs and TAHs to lie at some point in the range of 6,000 to 66,000 per year and probably nearer the high side. More than a decade will have to pass before a substantial volume of MCSS implantations can occur. The principal limit on growth in use will be uncertainty about the clinical benefits achievable by the devices available at any particular time; technological effectiveness will be the major determinant of these benefits. The committee concludes that a total volume of initial MCSS use of between 35,000 and 70,000 devices per year could be achieved by the year 2010, based on the projected range of need in the primary group of patients. The committee recognizes the considerable uncertainty inherent in these estimates, which cannot be resolved until many long-term VADs have been implanted for several years and the patients ' outcomes reported. If resources are made available to meet the demand from the primary group, indications for MCSS use may gradually broaden into a larger secondary group of patients, those not yet disabled by their heart failure. The committee estimates that about 200,000 persons in this secondary group could potentially be candidates for MCSS annually, if the devices then available have high-performance characteristics. There is, however, little likelihood that this volume of MCSS use could occur much before 2020. Until some point in the 2005-2010 period, virtually all the long-term devices implanted will be VADs. Assuming that the first TAH is approved for general use at roughly the mid-point of the 2000-2010 decade, TAH use will increase but probably level off in the 2010s, at a potential maximum volume in the range of 10,000 to 20,000 per year. With the high end of the potential volume and a total implantation cost (in 1991 dollars) of about $200,000, the nation's annual health care bill will increase about $4 billion for TAH use alone, which translates to 0.7 percent of the annual total

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The Artificial Heart: Prototypes, Policies, and Patients health care spending in the United States. With inclusion of 50,000 VADs, the total cost rises to almost $12 billion, or 2 percent of total spending. The committee concludes that NHLBI should undertake, possibly with the involvement of the Centers for Disease Control, the development of additional epidemiological data about the natural history of end-stage heart disease. REFERENCES Bergner, M. 1985. Measurement of health status. Medical Care 23:696-704. Christopherson, L. K. 1986. Organ transplantation and artificial organs. International Journal of Technology Assessment in Health Care 2:553-562. Danis, M., L. I. Southerland, J. M. Garrett, J. L. Smith, F. Hielema, C. G. Pickard, et al. 1991. A prospective study of advance directives for life-sustaining care . New England Journal of Medicine 324:882-888. Elbeery, J. R., C. H. Owen, M. A. Savitt, J. W. Davis, M. P. Feneley, J. S. Rankin, et al. 1990. Effects of the left ventricular assist device on right ventricular function. Journal of Thoracic and Cardiovascular Surgery 99:809-816. Evans, R. W., D. L. Manninen, T. D. Overcast, L. P. Garrison, Jr., J. Yagi, K. Merrikin, et al. 1984. The National Heart Transplantation Study: Final Report. Vol. 3: Survival, Quality of Life, Cost. Seattle, Wash.: Battelle Human Affairs Research Center. Farrar, D. J., P. G. Compton, H. Dajee, J. D. Fonger, and J. D. Hill. 1984. Right heart function during left heart assist and the effects of volume loading in a canine preparation. Circulation 70:708-716. Farrar, D. J., P. G. Compton, J. J. Hershon, and J. D. Hill. 1985. Right ventricular function in an operating room model of mechanical left ventricular assistance and its effects in patients with depressed left ventricular function . Circulation 72:1279-1285. Francis, J. M., and J. N. Cohn. 1990. Heart failure: Mechanisms of cardiac and vascular dysfunction and the rationale for pharmacologic intervention. Federation of American Societies of Experimental Biology Journal 4:3068-3075. Funk, M. 1991. Epidemiology of End-Stage Heart Disease. Paper prepared for the Institute of Medicine study (see Appendix D). Kalbfleisch, K. R., M. H. Lehmann, R. T. Steinman, K. Jackson, K. Axtell, C. D. Schuger, et al. 1989. Reemployment following implantation of the automatic cardioverter defibrillator. American Journal of Cardiology 64:199-202. Kanter, K. R., L. R. McBride, D. G. Pennington, M. T. Swartz, S. A. Ruzevich, L. W. Miller, et al. 1988. Bridging to cardiac transplantation with pulsatile assist devices . Annals of Thoracic Surgery 46:134-140. Kormos, R. L., H. S. Borovetz, T. Gasior, J. F. Antaki, J. M. Armitage, J. M. Pristas, et al. 1990. Experience with univentricular support in mortally ill cardiac transplant candidates. Annals of Thoracic Surgery 49:261-272. Kottke, T. E., D. T. Pesch, R. L. Frye, D. C. McGoon, C. A. Warnes, and L. T. Kurland. 1990. The potential contribution of cardiac replacement to the control of cardiovascular diseases: A population-based estimate. Archives of Surgery 125:1148-1151.

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The Artificial Heart: Prototypes, Policies, and Patients Kriett, J. M., and M. P. Kaye. 1990. The Registry of the International Society for Heart Transplantation: Seventh official report—1990. Journal of Heart Transplantation 9:323-330. Lubeck, D. P., and J. P. Bunker. 1982. Case Study #9: The Artificial Heart: Cost, Risks, and Benefits. In: Office of Technology Assessment. The Implications ofCost-Effectiveness Analysis of Medical Technology: Background Paper #2: Case Studies of Medical Technologies. Washington, D.C.: U.S. Government Printing Office. Miller, C. A., W. E. Pae, Jr., and W. S. Pierce. 1990a. Combined Registry for the Clinical Use of Mechanical Ventricular Assist Devices: Postcardiotomy cardiogenic shock . Transactions of the American Society for Artificial Internal Organs 36:43-46. Miller, C. A., W. E. Pae, Jr., and W. S. Pierce. 1990b. Combined Registry for the Clinical Use of Mechanical Ventricular Assist Pumps and the Total Artificial Heart in conjunction with heart transplantation: Fourth official report—1989 . Journal of Heart Transplantation 9:453-458. NHLI (National Heart and Lung Institute). 1973. The Totally Implantable ArtificialHeart: Legal, Social, Ethical, Medical, Economic, and Psychological Implications. Report by the Artificial Heart Assessment Panel. DHEW Publication No. (NIH) 74-191. NHI (National Heart Institute). 1969. Cardiac Replacement: Medical, Ethical, Psychological, and Economic Implications. Report by the Ad Hoc Task Force on Cardiac Replacement. DHEW Publication No. (NIH) 77-1240. NHLBI (National Heart, Lung, and Blood Institute). 1980. Mechanically AssistedCirculation. Report of the NHLBI Advisory Council Working Group on Circulatory Assistance and the Artificial Heart. Bethesda, Md.: NHLBI. NIH (National Institutes of Health). 1987. Infantile Apnea and Home Monitoring. NIH Publication No. 87-2905. National Institutes of Health, Public Health Service, U.S. Department of Health and Human Services. OTA (Office of Technology Assessment). 1987. Life-Sustaining Technologies and the Elderly. OTA-BA-306. U.S. Congress. Washington, D.C.: U.S. Government Printing Office. Patrick, D. L., and P. Erickson. 1988. What constitutes quality of life? Concepts and dimensions. Clinical Nutrition 7(2):53-63. Patrick, D. L., J. Stein, M. Porta, C. W. Porter, and T. C. Ricketts. 1988. Poverty, health services, and health status: Lessons from rural America . Milbank Quarterly 66:105-136. Portner, P. M., P. E. Oyer, D. G. Pennington, W. A. Baumgartner, B. P. Griffith, W. R. Frist, et al. 1989. Implantable electrical left ventricular assist system: Bridge to transplantation and the future. Annals of Thoracic Surgery 47:142-150. Pycha, C., A. D. Gulledge, J. Hutzler, N. Kadri, and J. Maloney. 1986. Psychological responses to the implantable defibrillator: Preliminary observations. Psychosomatics 27:841-845. Rabinovich, B. A., and J. Cohen-Mansfield. 1989. Nursing home residents' preferences regarding life-sustaining interventions. In: R. Cornman et al., eds. Proceedings of the Maryland Gerontological AssociationSeventh Annual Meeting, May 12, 1989. Baltimore, Md.: Maryland Gerontological Association, pp. 85-86.

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The Artificial Heart: Prototypes, Policies, and Patients Termuhlen, D. F., M. T. Swartz, D. G. Pennington, L. R. McBride, E. A. Szukalski, J. E. Reedy, et al. 1989. Thromboembolic complications with the Pierce-Donachy ventricular assist device. Transactions of the American Society for Artificial Internal Organs 35:616-618. Vlay, S. C., L. C. Olson, G. L. Fricchione, and R. Friedman. 1989. Anxiety and anger in patients with ventricular tachyarrhythmias. Responses after automatic internal cardioverter defibrillator implantation . PACE 12:366-373. Walden, J. A., L. W. Stevenson, K. Dracup, J. Wilmarth, J. Kobashigawa, and J. Moriguchi. 1989. Heart transplantation may not improve quality of life for patients with stable heart failure. Heart & Lung 18:497-506. Weinstein, M. C., P. G. Coxson, L. W. Williams, T. M. Pass, W. B. Stason, and L. Goldman. 1987. Forecasting coronary heart disease incidence, mortality, and cost: The Coronary Heart Disease Model. American Journal of Public Health 77:1417-1426.