This meeting was the third in a series of conferences on each major solid organ transplanted. The goal of the meetings was to draft guidelines for criteria for including patients on the United Network for Organ Sharing (UNOS) heart transplant waiting list. A total of 84 physicians and surgeons representing 73 transplant programs attended the 1-day meeting held at the Natcher Center at the National Institutes of Health. A survey was sent to the medical and surgical directors of all UNOS-approved heart transplant centers prior to the conference that sought their opinions on several topics relevant to listing criteria which were collated and reviewed during the conference. There were areas of near 100% consensus, other areas in which there was only a majority opinion, and still others in which there was no agreement.
The initial presentation of the conference was a review of current UNOS data showing nearly 7000 patient registrations in 1996 and currently nearly 4000 people on the active NOS heart transplant waiting list. This represents a 200% increase over the last 5 years as there were only 2000 patients on the list in 1992. Unfortunately, there have been only an average of 2300 available donor hearts each of the last 3 years. Thus, we add approximately 200 more patients to the waiting list each month than there are donor hearts available. This growing disparity between the number of patients listed and the number who have received transplants has led to several serious problems, including longer waiting times, which have increased from 120 days in 1993 to the current average of 312 days; an increasing percentage of patients receiving transplants as status I patients, which now averages over 60% and ranges as high as 75-80% in some regions; and a persistent 10-20% mortality rate for patients on the list. Allocation is based on time on the list, and these data emphasize the need to establish uniform criteria to limit the number of waiting list patients to those who have refractory heart failure and have the greatest survival advantage (1-7).
It is noteworthy that the current 1-year survival rate for heart transplantation reported by UNOS and the International Society for Heart and Lung Transplantation is 83%, and this rate has not changed for the past 5 years. On the other hand, the increasing percentage of patients receiving transplants as status I patients has resulted in a much sicker group of patients undergoing this procedure, and the preserved survival rate is quite an accomplishment. Awareness of the increased time on the waiting list has led some centers to list patients early, i.e., before they have severe heart failure that is truly refractory to all medical therapies. There was consensus at the conference and with the survey that (1) patients should not be listed early in order to accrue time on the list and (2) the patient should meet accepted criteria for transplantation and be ready to undergo the procedure from the day of listing.
Heart transplants are unique from most other solid organs transplanted in that there are an increasing number of therapies that may improve ventricular function and functional status to such a degree as to preclude the need for transplantation. Therefore, the initial portion of the conference dealt with the use of exercise testing, which has been shown to be the best prognosticator of survival with which to screen potential candidates among patients with advanced heart failure. There was consensus that all patients should be on maximal medical therapy for at least 2 weeks before they undergo functional evaluation.
The following are the specific recommendations for all ambulatory candidates. These recommendations are not applicable to the 10% of patients with cardiogenic shock, patients whose heart failure requires intravenous inotropic or mechanical support, and patients who have unstable angina, refractory ventricular arrhythmias, or unusual hypertrophic or restrictive myopathies refractory to medical management who are unable to perform exercise testing. These patients may not meet these criteria, but their short- and long-term outcomes are much better with transplantation.
INITIAL SCREENING TEST
All ambulatory patients (with the exception of those described above) should undergo an oxygen consumption treadmill exercise test as the initial screen of transplant candidacy. The test is not considered reliable unless the patient has reached the anaerobic threshold or has a respiratory exchange ratio >1.1. Data were cited from Mancini (8) and others (9) showing that (1) patients with a peak oxygen consumption (V˙O2) of <12 ml/kg/min had a very poor 1-year survival rate and warranted listing for transplantation in nearly all cases if free of contraindications; (2) those with a V˙O2 between 12 and 14 ml/kg/min will often have sufficiently severe clinical limitations to warrant listing; but (3) patients with a V˙O2 of >14 ml/kg/min alone, especially if >18, in the absence of significant comorbid conditions, such as refractory angina or arrhythmias, have a survival rate that would likely equal or exceed that expected with transplantation and in general do not merit listing by V˙O2 criteria alone. However, these criteria use specific cut points. The data have not been analyzed as a continuous variable, and therefore, the final recommendation for listing a patient for transplantation is a peak V˙O2 >15 ml/kg/min).
Three factors are known to influence peak V˙O2: age, gender, and body surface area (10). Use of absolute peak V˙O2 may result in over- or underestimation of the severity of disease in some patients, especially at the extremes of age and weight. Examples include young patients who may be expected to have a peak V˙O2 of >35 ml/kg/min who may be quite compromised and at high risk of death with a V˙O2 of 20 ml/kg/min and yet would not qualify if peak V˙O2 alone were used. Similarly, a 61-year-old woman who weighs 115 pounds and who has a peak V˙O2 of 15 ml/kg/min may be 60% of predicted V˙O2 for her age, gender, and body surface area and not warrant transplantation. Data were presented demonstrating that using published nomograms of the predicted peak V˙O2 and calculating the percentage of predicted V˙O2 may be equally as sensitive and specific as absolute V˙O2 in predicting survival.
Therefore, patients with either a peak V˙O2 of >15 ml/kg/min or <55% of predicted V˙O2 should be considered as having clear documentation of severe cardiac dysfunction and warrant further evaluation for listing for transplantation. Both tests are of greater prognostic value if done serially to identify patients with significant deterioration or improvement. There was near consensus that the results of V˙O2 testing may be the most discriminating predictor of mortality or need for urgent transplantation but should be taken in context with other important prognostic indicators.
Patients who demonstrate severe end-stage heart failure by V˙O2 testing merit a formal evaluation that is an assessment of comorbidities that either alone or in combination may represent relative or absolute contraindication to transplantation. The following is a list of areas to be included in the assessment and some specific, absolute, and relative contraindications for each parameter.
There was consensus that all patients considered for transplantation should be screened and evaluated for reversible pulmonary hypertension by invasive hemodynamic monitoring, given the data from several large databases that indicate that pulmonary hypertension is one of the leading causes of death early after transplantation. While several criteria that employ specific cut points have been shown to correlate with outcome (11), it is clear that pulmonary hypertension is a continuous variable with increasing risk with higher pressures and resistance values. The following variables, either alone or especially in combination, were considered relative contraindications to transplantation. These are after an aggressive challenge with one or more vasodilator or inotropic agents either alone or in combination while maintaining a systolic blood pressure of >90 mmHg: pulmonary vascular resistance >5 Wood units; transpulmonary gradient >15; and pulmonary vascular resistance index >6 Wood units.
Repeat hemodynamic testing is recommended at variable intervals. Most conference attendees considered the minimal time between measurements of pulmonary artery pressure to be 6 months in those patients who require more than several hours of drug therapy to reach acceptable resistance levels, to a maximum of 12 months between measurements of ensure that previously stable patients do not progress to unacceptable levels of pulmonary hypertension while on the list.
Establishing an age limit for transplantation is not a policy or practice in any other organ discipline, but it remains a controversial issue in heart transplantation. One common difficulty in the use of absolute age is the frequent disparity between chronologic and physiologic age. Results from a number of centers have demonstrated that satisfactory results can be obtained in patients over 50 years of age, although increasing age over 50 years is potentially a significant comorbid condition that may be associated with a negative impact on transplant outcome. There was consensus that comorbidities such as renal insufficiency were accentuated in the older patient groups, and there was unanimous agreement that patients over the age of 50 years may warrant additional screening tests for comorbid conditions. However, there was a consensus that age alone should not be considered a contraindication and should be used only as an exclusion factor when considered with other comorbid risk factors.
Numerous studies have demonstrated that psychosocial issues relating to adaptability, compliance, cognitive function, social support, and financial support have an important influence on posttransplant outcomes (12-19). There was unanimous opinion that screening for psychosocial issues was mandatory for all potential heart transplant recipients. Such screening should include a structured interview that can be performed by a social worker with experience working with heart transplant recipients or by a qualified mental health professional, such as a psychologist, a psychiatrist, or psychiatric social worker. If significant concerns are identified on screening, then a formal evaluation by a qualified mental health professional is indicated.
Appendix A contains recommendations for psychosocial criteria for transplant listing that include some recommended relative and absolute contraindications that were unanimously accepted.
There were several specific psychosocial issues addressed, including:
- Substance abuse. Substance abuse has been associated with noncompliance, a high rate of recidivism, and poor outcome after transplantation. The difference between abuse and use is somewhat difficult to define; however, there was consensus that current abuse of tobacco, alcohol, or illicit drugs was an absolute contraindication to transplantation. There was also near consensus that all patients should have a documented period of abstinence from substance use before being listed for transplantation. This period ranged from a minimum of 3 months to up to 6 months, with random testing performed in many programs to confirm abstinence. Patients who acutely develop refractory heart failure and require placement on the waiting list as status I may require variation from the policy. There was near consensus that patients with a long history of substance abuse that has caused documented functional impairment (e.g., loss of work or law violations) should be seen by a trained substance abuse mental health professional and accepted as a candidate only after satisfactory report of stability and prognosis and possible completion of a detoxification program.
- Obesity. The available literature suggests that obesity is an important comorbid condition that adversely affects outcome in heart transplantation. Adverse affects included increased risk of coronary disease in the graft, hypertension, and wound infection. While several specific cut points of weight or body mass index have been associated with increased risk or morbidity, it seems clear that obesity is a continuous variable. There was general agreement that the risk of comorbidities begins to increase when the patient is >120% of ideal body weight and that >140% of ideal body weight would be a relative contraindication to transplantation. Other measures of obesity, such as body mass index, may also identify patients at high risk for complications.
- Osteoporosis. One of the highest morbidity-producing complications of prednisone use following transplantation is spontaneous fracture due to osteoporosis. There are new therapies that can increase bone density and decrease the risk of fracture. There was consensus that all patients over 60 years of age, those with known osteoporosis, and those at high risk (immobility or obesity) should have a bone density study performed as part of the initial evaluation. There is an increased risk of fracture with bone density more than one standard deviation below normal. Patients with density of >2 standard deviations below normal are at high risk. Monitoring of vitamin D and calcium levels and x-rays of the hips and spine may be warranted in all patients.
- Malignancy. The risk of most malignancies increases with age, and the addition of immunosuppressive therapy may accelerate the progression of early occult malignancy and limit the survival benefit after transplantation. Broad screening in all patients is not cost-effective, but other age- or symptom-driven screening tests should be performed in every patient seriously considered for transplant candidacy. All patients should have several stool guaiacs, mammograms and PAP smears or prostate-specific antigen tests, and chest x-rays as a minimum. Patients with preexisting non-skin malignancy should have an oncologist consult regarding grade, duration of remission, and prognosis.
- Alternative surgery. Recent reports have demonstrated the improved outcome of conventional cardiac surgical procedures, such as coronary bypass and valve replacement, in high-risk patients with a very depressed ejection fraction. There was consensus that all patients with ischemic etiology should undergo evaluation for reversible ischemia and viable or hibernating myocardium that would be amenable to surgical or catheter interventional techniques as an alternative to transplantation. Such an evaluation may consist of a history and review of coronary angiograms, nuclear stress testing, or myocardial viability studies. Similar standards were uniformly endorsed for a valvular heart disease to include an adequate echocardiogram. There was broad agreement that these high-risk alternative surgeries should be performed only in transplant centers with mechanical assist devices available should a suboptimal response to surgery occur. Other procedures, such as partial left ventriculectomy and cardiomyoplasty, are still under investigation and should not be considered legitimate alternatives to transplantation at this time, but they may be palliative in some patients.
- Care while on the list. There was consensus that once a patients is accepted for heart transplantation, he or she should be examined at least every 3-4 months by a heart failure specialist at the transplant center. In addition, the patient should be enrolled in a cardiac rehabilitation program to maximize physical function. The prescription for exercise should be done in conjunction with a heart failure specialist and usually should be based on the results of the oxygen consumption treadmill test and determination of anaerobic threshold.
- Reevaluation while on the list. Given that a percentage of patients placed on most transplant lists with the above criteria will benefit significantly from cardiac rehabilitation and the care of a heart failure specialist, there was consensus that all patients listed for heart transplant should undergo reevaluation with V˙O2 testing at least every 6 months. In addition, other tests, such as hemodynamic assessment of pulmonary hypertension or ventricular function by echo or nuclear scan, may be warranted. Patients whose V˙O2 results rise above the guidelines described above should be placed on an "inactive" status, and the test should be repeated again 3 months later. If the peak V˙O2 is still >15 ml/kg/min or >55% of predicted V˙O2, the patient may warrant removal from the transplant waiting list given the excellent survival reported in several series. However, issues of persistence of other comorbidities and quality of life may warrant keeping the patient on the list. This recommendation has been greatly aided by the new UNOS policy that all time accumulated on the active waiting list will be held forever for a patient who is removed from the list and subsequently deteriorates, so that the patient may be relisted with the previously accrued time added.
- Renal function. There was brief discussion about what level of renal function (serum creatinine or creatinine clearance) should be a relative or absolute contraindication to transplantation. Many medications that candidates may be taking (e.g., angiotensin-converting enzyme inhibitors and diuretics) may be associated with impaired renal function but may not represent intrinsic kidney disease. Similarly, low cardiac output may worsen mild impairment. Some data suggest that a normal urinalysis coupled with renal ultrasound showing two kidneys with normal cortices may be adequate demonstration of reversibility. There was a majority opinion that a serum creatinine level of >3.0 mg/dl was a relative contraindication to transplantation.
- Primary systemic diseases. In general, patients with coexisting systemic diseases that may limit short- or long-term survival (e.g., amyloidosis, sarcoidosis, or some types of muscular dystrophy) were considered by the vast majority of attendees to have a contraindication to transplantation.
Appendix A: Psychosocial Assessment
Successful predictors Absence of:
- Substance abuse
- Active psychosis
- Suicidal behavior
- Personality disorder
- Demonstrated medical compliance
- Adequate neurocognitive function
- Adequate social support system
- Adequate financial support system
Characteristics of noncompliant patients Studies have shown an association between noncompliance and increased mortality. There is a higher incidence with:
- Unmarried/less family support
- Antisocial personality disorder
- Current substance abuse
- Less education
- Less income
- Longer time posttransplant
- No axis I or axis II diagnosis or axis I diagnosis only
- Both axis I and axis II diagnosis present
*Caution is needed with an axis II diagnosis. The legal definition of the term "individuals with handicaps" includes a patient with a low IQ. By law, "handicapped" individuals cannot be discriminated against or excluded from programs that receive federal funds.
- Medical compliance
- Adequate neurocognitive ability
- Adequate social support
- Ongoing substance abuse
- Refractory psychiatric condition
- Suicidal behavior
- Severe personality disorder
- Combined axes I and II diagnosis
- Previous chronic substance abuse
- Limited social support
- Limited adaptive ability
A structured interview by a mental health professional is recommended.
1. Miller LW, Kubo SH, Young JB, Stevenson LW, Loh E, Costanzo MR. Report of the consensus conference on candidate selection for heart transplantation-1993. J Heart Lung Transplant 1995; 14(3): 562.
2. Miller LW, Stevenson LW. Candidate selection for heart transplantation. Cardiol Clin 1995; 13: 1.
3. Costanzo MR, Augustine S, Bourge R, et al. Selection and treatment of candidates for heart transplantation: a statement for health professionals from the Committee on Heart Failure and Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1995; 92(12): 3593.
4. O'Connell JB, Bourge RC, Costanzo-Nordin MR, et al. Cardiac transplantation-recipient selection, donor procurement, and medical follow-up: a statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation 1992; 86(3): 1061.
5. Mudge GH, Stevenson LW, Bourge R, et al. Task force 3: recipient guidelines/prioritization. J Am Coll Cardiol 1993; 22(1): 1.
6. Vagelos R, Fowler MB. Selection of patients for cardiac transplantation. Cardiol Clin 1990; 8(1): 23.
7. Bocchi EA, Bellotti G, Moreira LF, et al. Mid-term results of heart transplantation, cardiomyoplasty, and medical treatment of refractory heart failure caused by idiopathic dilated cardiomyopathy. J Heart Lung Transplant 1996; 15(7): 736.
8. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH Jr, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure. Circulation 1991; 83(3): 778.
9. Kao W, Jessup M. Exercise testing and exercise training in patients with congestive heart failure. J Heart Lung Transplant 1993; 13(4): S117.
10. Stelken AM, Younis LT, Jennsion 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.
11. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992; 19(1): 48.
12. Paris W, Muchmore J, Pribil A, Zuhdi N, Cooper DK. Study of the relative incidences of psychosocial factors before and after transplantation and the influence of posttransplantation psychosocial factors on heart transplantation outcome. J Heart Lung Transplant 1994; 13: 424.
13. Chacko RC, Harper RG, Kunik M, Young J. Relationship of psychiatric mordibity and psychosocial factors in organ transplant candidates. Psychosomatics 1996; 37: 100.
14. Frazier P, et al. Correlates of non-compliance among renal transplant recipients. Clin Transplant 1994; 8: 550.
15. Chacko RC, Harper RG, Gotto J, Young J. Psychiatric interview and psychometric predictors of cardiac transplant survival. Am J Psychiatry 1996; 153: 1607.
16. Twillmann RK, Manetto C, Wellisch DK, Wolcott DL. The transplant evaluation rating scale: a revision of the psychosocial levels system for evaluating organ transplant candidates. Psychosomatics 1993; 34: 144.
17. Olbrisch ME, Levenson JL, Hamer R. The PACT: a rating scale for the study of clinical decision-making in psychosocial screening of organ transplant candidates. Clin Transplant 1989; 3: 164.
18. Hecker J, Norvell N, Hills H. Psychologic assessment of candidates for heart transplantation: toward a normative data base. J Heart Transplant 1989; 8(2): 171.
19. Levenson JL, Olbrisch ME. Psychosocial evaluation of organ transplant candidates: a comparative survey of process, criteria, and outcomes in heart, liver, and kidney transplantation. Psychosomatics 1993; 34(4): 314.