|
INTRODUCTION
Timely referral of patients for heart transplant evaluation requires a keen awareness of when medical management has begun to fail, and the identification of the development of irreversible end-organ damage from chronically reduced cardiac output. Unfortunately, many candidates come to the attention of transplant centers when they are at the end of their life. They are malnourished and typically dependent on inotropic medications and other modes of advanced cardiac support (e.g., intra-aortic balloon pump, mechanical ventilation). Though prior reports describe comparable survival of patients undergoing both elective and urgent transplantation, those patients undergoing urgent transplants have more prolonged recovery periods and more comorbidities including infections and renal failure from their decompensated state. Late referral also precludes the opportunity for patients and families to fully comprehend the short- and long-term care needed for transplantation to be successful.
Because donor organs remain scarce, only the sickest patients with minimal comorbidities are considered for transplantation. This chapter reviews the transplant evaluation process, which conditions are absolute and relative contraindications, and how patients are serially assessed for either delisting or upgrading to a more urgent status. The recent practice of alternate listing (use of less than perfect organs for older patients or patients with substantial comorbidities) will also be discussed.
TRANSPLANT EVALUATION
Patients evaluated for transplant include those patients with New York Heart Association (NYHA) Class III–IV heart failure (HF) with severe left ventricular dysfunction, patients with refractory ischemia, or patients with incessant arrhythmias despite maximal medical or interventional therapies. Upon referral, a reassessment of cardiac function, ischemic burden, and medication tolerance is performed. If the patient is ambulatory, functional status is assessed by measuring peak VO2 (oxygen consumption) during cardiopulmonary exercise testing (CPEX) (Fig. 16-1). CPEX testing has emerged as an important prognostic tool to guide the selection of transplant candidates. The initial study demonstrating the utility of this technique was performed in the late 1980s at the University of Pennsylvania. All ambulatory patients referred for transplant evaluation underwent CPEX testing.1 One hundred and sixteen patients were studied and divided into three groups on the basis of peak VO2:
Group I: peak VO2 <14 mL/kg/min and listed for transplant Group II: peak VO2 >14 mL/kg/min and transplant listing deferred
Group III: peak VO2 <14 mL/kg/min, but not offered transplant listing because of a significant comorbidity One-year survival was 94% in patients with preserved exercise capacity (VO2 >14 mL/kg/min),
70% in patients with reduced VO2 listed for transplant, and 47% in the group with VO2 <14 mL/kg/min, but who were not offered transplantation. The 70% survival in Group II patients was artificially high as all urgent transplants were counted as censored observations. This study demonstrated that patients with VO2 >14 mL/kg/min have a 1-year survival comparable to survival after transplant, indicating that transplant could be safely deferred. Patients with a VO2 <14 mL/kg/min have a significantly worse survival and should be listed. From this, CPEX testing emerged as a key component of the transplant evaluation process.
Since the initial study, many investigators have attempted to improve the predictive value of this test by analyzing the VO2 expressed as a percentage of predicted value and/or by adding ancillary data acquired during testing such as the anaerobic threshold, ventilatory response, and heart rate/blood pressure response. Peak exercise VO2 is affected by age, gender, body weight, pulmonary function, muscle mass, and overall fitness. Patients included in the analysis of VO2 data are those who have achieved maximal exercise testing with identification of ventilatory anaerobic threshold. Whether peak VO2 normalized for predicted values better predicts mortality than absolute VO2 is unclear.2–4 As the majority of transplant candidates continue to be middle-aged men, absolute peak VO2 is probably as effective a predictor as percent-predicted VO2, though at the extremes of age the reverse may occur. Peak VO2 does predict increased mortality in a continuous fashion, without a distinct cut-point, which abruptly increases risk.5,6
In the last 20 years, a few centers have used hemodynamic data measured at peak exercise with an invasive pulmonary catheter to guide triage decisions. Wilson and colleagues evaluated 64 patients referred for cardiac transplant using CPEX testing and simultaneous invasive hemodynamic monitoring.7 Forty-four percent of patients with a normal cardiac response to exercise (as defined by the Higginbotham equation) had a peak VO2 <14 mL/kg/min, while 33% of patients with a peak VO2 >14 mL/kg/min had a severely impaired peak exercise cardiac output.8 Wilson concluded that invasive hemodynamic information should be used in combination with VO2 to determine transplant eligibility, and patients with a low VO2 who demonstrate appropriate cardiac function at peak exercise may not benefit from organ replacement, as the etiology for the low VO2 is a peripheral and not central cardiac mechanism.
Mancini and colleagues repeated Wilson’s protocol to validate his conclusions, but found that peak VO2 did correlate with peak cardiac output in their patients.9 Although peak VO2 and peak cardiac output were positively correlated, in multivariate analysis only left ventricular stroke work and stroke work index were shown to predict survival (stroke work is derived from measurements of mean arterial blood pressure, heart rate, pulmonary capillary wedge pressure, and cardiac output). The inability to predict survival using either VO2 or cardiac output may have been due to small sample size (65 patients). Nevertheless, the addition of hemodynamic monitoring to CPEX adds a level of complexity that is difficult to routinely perform. At this time routine use of hemodynamic monitoring during exercise is not advocated.
More recently, ventilatory data during CPEX testing have emerged as a significant predictor of mortality in patients with HF. The ventilatory response to exercise, measured as the ratio of VE to VCO2, is increased in patients with HF. VE/VCO2, also called the ventilatory equivalent for carbon dioxide, expresses the amount of ventilation required to eliminate a given amount of CO2 produced by metabolizing tissues. Because it is measured at the mouthpiece during expiration, it is strongly influenced by dead-space breathing. For some patients, an elevated VE/VCO2 ratio (normal VE/VCO2 = 25) reflects an increased stimulus to breathe off accumulating CO2, whereas in others it may reflect abnormal breathing patterns secondary to overstimulation of peripheral ergoreceptors and/or pulmonary congestion. VE/VCO2 has emerged as a powerful prognostic indicator of survival in patients with HF. In one study, a VE/VCO2 slope >34 was associated with a higher NYHA functional class, a lower ejection fraction, lower peak VO2, and lower survival rate at 18 months.10 VE/VCO2 has not yet been evaluated in a large prospective cohort to more precisely define the sickest transplant candidates.
Although data derived from CPEX testing can yield powerful information, there are other, more routine clinical markers that have prognostic value. Aaronson and colleagues developed a statistical model to predict survival in ambulatory HF patients referred for transplant evaluation.11 This model, called the Heart Failure Survival Score (HFSS), is a multivariable predictive index that was derived from data on 80 clinical characteristics of 268 ambulatory patients with advanced HF. The final model included the smallest number of noninvasive variables that could predict survival. The HFSS was later validated in a cohort of 223 patients with advanced HF. The final seven variables included different aspects of HF physiology: myocardial ischemia, resting heart rate, mean arterial blood pressure, ejection fraction, intraventricular conduction delay, peak VO2, and serum sodium. The total HFSS was calculated by summing the individual variables, with each variable weighted slightly differently. A HFSS >8.09 correlated with a 1-year event-free survival of 93%, whereas a HFSS ≤8 was associated with a 1-year event-free survival significantly worse than that expected after transplant. Accordingly, patients without contraindications to transplant are listed if the HFSS is <8.
Current practice utilizes the VO2 >14 mL/kg/ min cutoff for deferring listing, with serial assessment every 6–18 months to monitor for deterioration. Some, but not all, centers also incorporate the HFSS into the evaluation. As for invasive hemodynamic data obtained at peak exercise, the debate continues over whether an invasive procedure provides prognostic information that is not already evident from noninvasive assessment. In cases where there is a marked dissociation of peak VO2 and peak cardiac output (as obtained through invasive hemodynamic measurements, or at peak exercise with dobutamine stress-echo), there is a genuine concern that heart transplant may not markedly improve functional capacity. Thus, there is continued interest in developing noninvasive strategies to assess cardiac output at peak exercise and correlate it with peak VO2.
Finally, data regarding evaluation for heart transplant candidacy using peak VO2 and the HFSS were derived in cohorts of patients before the “b-blocker era.” Because b-blockers decrease heart rate, peak exercise capacity is generally not improved despite their positive impact on survival. The value of peak VO2 in predicting survival in the b-blocker era has been examined. Most studies confirm the continued value of this variable, although with the improved survival with b-blockers, the cut-point for VO2 is probably lower in the range of 10–12 mL/kg/min. For patients on b-blockers, the HFSS rather than peak VO2 seems to predict more accurately who should be listed.12,13
CANDIDATE SELECTION CRITERIA
Once it has been determined that a patient is ill enough for transplant listing and that all conventional strategies have been exhausted, the next part of the evaluation focuses on absolute and relative contraindications to successful transplantation. In the early years of transplant, a set of empirically derived contraindications were generated from experienced transplant programs.14 These traditional exclusion criteria are listed in Table 16-1. The exclusion criteria list was formulated as a consensus among heart transplant experts who either through clinical experience or outcome analysis determined that the listed factors were significant obstacles to short- and/or long-term survival. Selection criteria continue to evolve as new therapies emerge for comorbidities, newer immunosuppressive therapies simplify posttransplant care, and more experience is gained.
Age
The age guideline for transplant varies between transplant centers. Age >65 years as an upper limit of transplantability has been examined carefully, because of the increased incidence of HF as well as comorbidities in this age group.15,16 An analysis of patients >65 years who underwent cardiac transplantation between 1992 and 2002 demonstrated similar 1- and 10-year actuarial survival rates when compared to a younger cohort matched for sex, HF etiology, United Network of Organ Sharing (UNOS) status at time of transplant, immunosuppressive regimen, and other pretransplant comorbidities, for example, hypertension and diabetes.17 There were no differences in postoperative ICU or total length of stay, but there was an increase in posttransplant coronary artery disease in the older population. Survival posttransplantation of older patients in other single-center studies has been variable, with some investigators reporting an improved survival in older patients and other centers a comparable or worse survival (Fig. 16-2).
Pulmonary Hypertension
Severe, fixed pulmonary hypertension (>6 Wood units) remains a contraindication as the newly transplanted normal right ventricle (RV) cannot generate the pressure to overcome the resistance across the pulmonary bed with resultant RV dilatation and failure. Some degree of pulmonary hypertension is acceptable and can be managed perioperatively with vasodilation or with inhaled nitric oxide. The risk for worsening survival increases in a continuous fashion as the pulmonary vascular resistance increases.18,19 Preoperatively patients with moderate-to-severe pulmonary hypertension are often placed on home milrinone infusion to allow some relaxation of pulmonary vascular resistance. Another strategy is to offer implantable mechanical assistance as a bridge to transplantation, for the purpose of unloading the left heart and thereby allowing some recovery/relaxation of the pulmonary circuit.
Recent Pulmonary Embolism
Pulmonary embolism often results in pulmonary infarct. In the setting of immunosuppressive therapy, this can develop into a pulmonary abscess, which can be very difficult to eradicate posttransplant.20 For this reason, most centers require a 3-month waiting period after a pulmonary embolism. Monitoring the resolution of lung damage by serial chest computerized tomography (CT) scans can sometimes shorten this delay to transplant.
Severe Chronic Obstructive Pulmonary Disease
Severe chronic obstructive pulmonary disease (COPD) remains a contraindication to transplant due to the high risk of ventilator dependence postoperatively. Also, patients are at risk for more frequent decompensation requiring mechanical ventilation during seasonal influenza and/or from pneumonia/bronchitis. Lastly, quality of life and functional status often remain limited secondary to chronic respiratory disease. Thus, transplantation of the heart makes no major impact on quality of life, although it may improve quantity.
Recent Peptic Ulcer Disease
Recent peptic ulcer disease is a temporary contraindication because gastric lesions can be colonized with cytomegalovirus (CMV) or candida, which can later cause systemic disease. Most centers wait 3 months after the occurrence of gastric ulcer before offering transplant.
Diabetes Mellitus
Over time there has been a liberalization of accepting patients with diabetes. Patients with “brittle” diabetes typically remain ineligible for transplantation. Many of these patients were diagnosed with juvenile diabetes and have been on insulin for many years. They often have multiorgan damage related to diabetes, including the etiology of their heart disease. The high doses of steroids initially required at the time of transplantation can cause severe hyperglycemia and ensuing metabolic disarray that can recur during episodes of rejection, which is largely treated with pulse steroids.
However, many patients with insulin-dependent diabetes have undergone successful cardiac transplantation even with evidence of mild-to-moderate end-organ damage. These patients must be very motivated to manage their own care in a meticulous fashion in order for transplant to be safe and successful. For patients with diabetes, similar posttransplant outcomes when compared to patients without diabetes have been described in some studies, but not in others.21,22
Human Immunodeficiency Virus Seropositivity
A limited number of patients with human immunodeficiency virus (HIV) disease have undergone cardiac transplantation in the United States. Individual cases suggest that outcomes are maximized when patients enter transplantation with a high CD4 count and undetectable viral load. As highly active antiretroviral therapy (HAART) markedly prolongs the lives of patients with HIV, referral of these patients for cardiac transplantation may become more common.
Amyloidosis
For most transplant centers, amyloidosis remains a contraindication to transplant. To be considered for transplant, amyloid deposition must be limited to the heart. However, recurrence of amyloid in the transplanted heart has been described as early as 4 months postoperatively, though some recipients have survived more than 4 years.23–25 Thus transplant is possible, but low-term survival is unacceptably low particularly when using a scarce resource. Recently, a few centers have combined heart transplantation with autologous stem cell transplant in patients with isolated cardiac amyloidosis and have demonstrated improved survival.26 In our center, we have offered combined heart stem cell transplant to 11 patients. None of the patients thus far have had recurrence of amyloidosis, with our longest follow-up being 3 years.
Psychosocial Instability
Psychosocial evaluation is an important aspect of the transplant evaluation. Active or recent alcohol and drug addiction continue to be a contraindication to transplantation. Additionally, patients must have a history of medical compliance as well as a family member or significant other who can assist with their health needs. For some patients, the rigors of transplantation may simply be too overwhelming to manage. Patients must also have a stable living situation. Patients who are noncompliant prior to transplant are unlikely to be successful recipients. The result is organ rejection and a lost opportunity for another listed candidate.
WAITING LIST DEMOGRAPHICS
After the cardiac transplant evaluation is completed, the case is presented before a multidisciplinary transplant committee and a decision is made regarding listing. If the decision is made to proceed to transplant, the patient is then listed for transplant with the UNOS. The priority status of the patient is also determined and registered, along with the patient’s blood type, age, weight, height, and need for crossmatch. When a donor is identified, regional procurement agencies match the organ to the recipient, based not only on the priority status, but also by time on the list and geographic location.
While each transplant candidate is considered individually for potential listing, candidacy algorithms are somewhat influenced by the number and summed characteristics of the patients already waiting. For example, patients with blood type O have prolonged wait times due to competition for organs while the wait for type AB patients can be just a few months. Body weight is a key variable in wait time, particularly for patients who do not resemble their “geographic” body type. Similarly, sensitized patients (frequently multiparous women or patients who have required multiple transfusions) will also have a more prolonged wait due to need to prospectively identify a negative crossmatch.
From 1992 to 2001, the mean waiting time on the list significantly increased with 46% of registrants now waiting >2 years. Patients are designated as Status 1A, 1B, or 2. Status 1A patients are considered to have <30 days to live, and by definition must be in an ICU, on one or two high-dose inotropic agents with an indwelling pulmonary catheter, or those patients requiring mechanical support (intra-aortic balloon pump, mechanical ventilator, or an assist device). Status 1B patients are stable on low-dose inotropic support or have a normal functioning ventricular assist device, either in the hospital or at home. Prior to 1998, Status 1 patients had not yet been divided into 1A and 1B categories.
MANAGEMENT OF LISTED PATIENTS
It is sometimes the case that referral to a transplant center allows a “fresh look” at an individual patient. Medication regimens are altered, dietary teaching is reviewed, and often high-risk revascularization with ventricular assist device “backup” results in improvement in functional status. Patients may initially be listed, but if they demonstrate sustained, objective improvement in peak VO2, they may be well enough to be delisted. This is appropriate, although not very common. In one study evaluating the outcomes of patients listed for ≥6 months on the waiting list demonstrated that <5% of patients become well enough to be delisted.27 More often, Status 2 patients undergo serial reevaluation for subacute decompensation and development of new or worsening comorbidities, for example, progressive pulmonary hypertension. Patients who demonstrate poor compliance, that is, inability to keep appointments or follow recommendations, are often placed on probation and occasionally removed from the list.
We recently analyzed long-term follow-up data for sequential measurement of peak VO2 and HFSS in 227 transplant candidates.28 Survival to reevaluation, free from UNOS 1 transplant or left ventricular assist device (LVAD), was determined by the Kaplan-Meier method with censoring at UNOS 2 transplant. Survival differed by HFSS stratum (P <0.001) and by peak VO2 stratum (P <0.001). Patients who deteriorated from low-to medium- or high-risk HFSS or peak VO2 had worse survival than those who remained low risk (P <0.01 and P <0.001 respectively). Medium- or high-risk patients who improved to low risk tended to have higher survival than those who remained medium or high risk (P = 0.06 and P <0.16 respectively). Patients who improved to low risk had a 1-year survival of 72% for both HFSS and peak VO2. However, patients who improved to low risk and were treated with b-blockers had a 1-year survival (89% for HFSS and 83% for peak VO2) comparable to that post-transplant (84%). Both peak VO2 and the HFSS can be successfully used for serial evaluation of HF mortality risk in ambulatory patients with advanced HF. Patients on the heart transplant waiting list should undergo serial evaluation to assess their continued need for transplantation. Patients who have been judged too well for transplantation should also be periodically reevaluated to determine if their HF has become severe enough to warrant placement on the transplant waiting list.
ALTERNATE LISTING
Criteria for identifying a donor heart have been developed to maximize transplant outcome. The ideal donor organ comes from a patient <30 years old, who has suffered no chest wall contusion, with no prior medical conditions, no current infections, no history of substance abuse, and an anticipated ischemic time <2 hours (cross-clamp to implantation). Ideal donors are scarce, and for this reason, there has been a relaxation of criteria, particularly regarding age, with a more focused view on coronary artery disease, left ventricular hypertrophy, and risk factors for coronary artery disease. In these situations, angiogram or even dobutamine stress echo are performed prior to accepting the organ. Donor age was the first criteria to be relaxed in response to the donor shortage. Numerous studies have been done demonstrating that an aging heart without coronary artery disease does not appear to translate into worsened outcome for the recipient.29–31
The practice of alternate listing began when it was observed that many potential organs are refused. Some programs have created a “second list” whereby patients with high-risk situations (e.g., age >65 years, HIV+, amyloidosis), who would have been turned down for transplant in the past, can now be offered an alternate heart. These cases are more difficult to manage, because of the additional comorbidities, and pose novel questions related to how far a program should reach to consider either a high-risk donor or a high-risk recipient. Alternative listing first began in 1996 at UCLA, mostly expanding the age of the donor organ to patients who had minor exclusion criteria (e.g., diabetes mellitus).32 The algorithm established was that a donor offer would be made to the targeted Status 1 patients, if declined then the organ would be offered to appropriate Status 2 patients. If still available, it would then be offered to a patient on the alternate list. These patients have the right to refuse the organ and can state their preferences in advance (e.g., some patients will refuse an organ from a donor with hepatitis C). It is important for referring cardiologists to recognize that aging patients or patients with comorbidities may still be eligible for transplantation, but that they may need to accept an alternate listing status.
Can a high-risk candidate who is transplanted with a high-risk organ have an optimal outcome? At UCLA, a recent study demonstrated worsened 90-day survival among transplant patient from the alternate list, compared to the standard list.33 In our center, data on alternate list outcomes over the last 4 years indicate that there is no survival advantage to receiving a standard organ over an alternate organ.34 There was no difference in 30- and 90-day survival, length of ICU stay, overall hospital stay, posttransplant circulatory support, or posttransplant continuous venovenous hemofiltration (CVVH). There was, however, a significant difference in intubation time and rate of sternal wound infection. Importantly, mortality postalternate heart transplantation was primarily the result of infection and in no case was the result of primary graft failure. Interestingly, 22% of hearts used for the alternate list were acceptable for the standard list, but unmatchable. Thirty-two percent of alternate heart donors were categorized as such because of donor hepatitis B/C seropositivity. If outcome data from alternate listing continue to demonstrate that survival is comparable to standard listing, this may generate more interest in expanding the donor pool, as well as raise additional ethical questions regarding the definition of an “alternate” recipient.
SUMMARY AND CONCLUSIONS
Cardiac transplantation has evolved into a highly successful strategy to offer a second chance to patients with end-stage HF. It is also a highly complex process of evaluation, monitoring, and ultimately matching the right organ with the right patient. It is important for referring cardiologists to clearly understand the process of transplant evaluation to identify more precisely which of their patients should be evaluated, and what their patients should expect when they come to a transplant center.
REFERENCES
1. Mancini DM, Eisen H, Kussmaul W, et al. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation. 1991;83:778–786.
2. Aaronson K, Chen T, Mancini D. Demonstration of the continuous nature of peak VO2 for predicting survival in ambulatory patients evaluated for transplant. J Heart Lung Transplant. 1996;15:S66S.
3. Osada N, Chaitman BR, Miller LW, et al. Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation. J Am Coll Cardiol. 1998;31: 577–582.
1. Stelken AM, Younis LT, Jennison SH, et al. Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy. J Am Coll Cardiol. 1996;27:345–352.
2. Aaronson K. Cardiopulmonary exercise testing identifies low risk patients with heart failure and severely impaired exercise capacity considered for heart transplantation. J Am Coll Cardiol. 1998;31:577–582.
3. Aaronson KD, Mancini DM. Is percentage of predicted maximal exercise oxygen consumption a better predictor of survival than peak exercise oxygen consumption for patients with severe heart failure? J Heart Lung Transplant. 1995;14:981–989.
4. Wilson J, Schwartz J, Sutton M, et al. Prognosis in severe heart failure: relation to hemodynamic measurements and ventricular ectopic activity. J Am Coll Cardiol. 1983;2:403–410.
5. Higginbotham MB, Morris KG, Williams RS, et al. Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ Res. 1986;58:281–291.
6. Mancini D, Katz S, Donchez L, et al. Coupling of hemodynamic measurements with oxygen consumption during exercise does not improve risk stratification in patients with heart failure. Circulation. 1996;94:2492–2496.
7. Chua TP, Ponikowski P, Harrington D, et al. Clinical correlates and prognostic significance of the ventilatory response to exercise in chronic heart failure. J Am Coll Cardiol. 1997;29:1585–1590.
8. Aaronson K, Schwartz JS, Chen T, et al. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation. 1997;95:2660–2667.
9. Powhani A, Murali S, Mathier M, et al. Impact of beta-blocker therapy on functional capacity criteria for heart transplant listing. J Heart Lung Transplant. 2003;22:70–77.
10. Lund LH, Aaronson KD, Mancini DM. Predicting survival in ambulatory patients with severe heart failure on beta-blocker therapy. Am J Cardiol. 2003;92:1350–1354.
11. Mudge GH, Goldstein S, Addonizio LJ, et al. The 24th Bethesda Conference: cardiac transplantation. Task Force 3: recipient guidelines/prioritization. J Am Coll Cardiol. 1993;22:21–31.
1. Aronow WS. Epidemiology, pathophysiology, prognosis, and treatment of systolic and diastolic heart failure in elderly patients. Heart Disease. 5(4):279–294.
2. Bacchetta MD, Ko W, Gerardi LN, et al. Outcomes of cardiac surgery in nonagenarians: a 10-year experience. Ann Thorac Surg. 2003;75(4):1215–1220.
3. Morgan JA, John R, Weinberg AD, et al. Long-term results of cardiac transplantation in patients 65 years of age and older: a comparative analysis. Ann Thorac Surg. 2003;76:1982–1987. |
