Impact of Current Management Practices on Early and Late Death in More Than 500 Consecutive Cardiac Transplant Recipients

Abstract

Objective

To study risk factors for early and late death after heart transplantation in the current era.

Summary Background Data

The current cardiac transplant population differs from earlier periods in that an increasing number of sicker patients, such as those with ventricular assist device (LVAD) support, prior cardiac allotransplantation, and pulmonary hypertension, are undergoing transplantation. In addition, sensitized patients constitute a greater proportion of the transplanted population. Emphasis has been placed on therapies to prevent early graft loss, such as the use of nitric oxide and improved immunosuppression, in addition to newer therapies.

Methods

Five hundred thirty-six patients undergoing heart transplantation between 1993 and 1999 at a single center were evaluated (464 adults and 72 children; 109 had received prior LVAD support and 24 underwent retransplantation). The mean patient age at transplantation was 44.9 years. Logistic regression and Cox proportional hazard models were used to evaluate the following risk factors on survival: donor and recipient demographics, ischemic time, LVAD, retransplantation, pretransplant pulmonary vascular resistance, and immunologic variables (ABO, HLA matching, and pretransplant anti-HLA antibodies).

Results

The rate of early death (less than 30 days) was 8.5% in adults and 8.8% in children. The actuarial survival rate of the 536 patients was 83%, 77%, and 71% at 1, 3, and 5 years, respectively, by Kaplan Meier analysis. Risk factors adversely affecting survival included the year of transplant, donor age, and donor-recipient gender mismatching. Neither early nor late death was influenced by elevated pulmonary vascular resistance, sensitization, prior LVAD support, or prior cardiac allotransplantation.

Conclusions

Previously identified risk factors did not adversely affect short- or long-term survival of heart transplant recipients in the current era. The steady improvement in survival during this period argues that advances in transplantation have offset the increasing acuity of transplant recipients.

Heart transplantation is the treatment of choice for end-stage heart disease. ¹ However, the patient population now undergoing cardiac transplantation is significantly different from that a decade earlier: an increased proportion of patients have mechanical circulatory support devices, have received previous cardiac allografts, or have pulmonary hypertension. Cardiac reoperations and device and retransplant candidates have resulted in a larger number of sensitized patients—that is, patients who are at a higher risk for the development of various adverse immunologic effects both in the pretransplant and the posttransplant period. ² Increasing experience with cardiac transplantation has allowed an expansion in eligibility and a gradual relaxation in conventional exclusion criteria because excellent outcomes have been demonstrated for more medically complex recipients. ³ Improved medical management of patients with end-stage heart disease has also decreased waiting list deaths. In addition, high-risk coronary revascularization and transmyocardial laser revascularization have increased survival and improved quality of life as an alternative to transplantation.

Many risk factors affecting survival after cardiac transplantation have been identified. Although several multicenter, multivariable studies have proposed that specific donor and recipient variables are associated with posttransplant death, interpretation of the data is limited by differing donor and recipient selection criteria and varying pretransplant and posttransplant management strategies at the participating institutions. ^4,5

In view of the considerably different profile of the current cardiac transplant candidate, and given several advances in the perioperative care of transplant recipients, we undertook this current single-center study to examine the impact of demographic, immunologic, and physiologic donor and recipient variables on early and late death (Table 1). Our hypothesis was that the impact of the previously identified risk factors on death may be diminished as a result of recent advances in transplantation that offset the increasing acuity of transplant recipients.

Table 1. VARIABLES STUDIED

METHODS

Patient Selection

Between January 1993 and October 1999, 536 consecutive patients underwent orthotopic cardiac transplantation at the New York Presbyterian Hospital-Columbia Medical Center for the treatment of end-stage heart disease. Selection of recipients was based on ABO compatibility and donor-recipient size matching.

Donor Acceptance Criteria

Donors and recipients are matched for ABO blood type compatibility and size (generally within 20% of body weight). Prospective human leukocyte antigen (HLA) matching is not used; however, recipients with high levels of panel reactive anti-HLA antibodies (more than 20%) are subjected to a prospective crossmatch. Male donors younger than 40 years and female donors less than 45 years of age meet the criteria as suitable donors provided there is no evidence of preexisting heart disease or impaired myocardial function by echocardiography. Older persons may also meet the criteria as suitable donors if coronary atherosclerotic lesions can be excluded, ideally by cardiac catheterization. Our policy on acceptance criteria excludes potential donors with serologies positive for HIV, hepatitis B (hepatitis B sAg) and C, and nonprimary brain cancers.

Exclusion Criteria

Exclusion criteria for cardiac transplantation have historically consisted of factors that determine long-term survival (e.g., cancer), increase perioperative risk (e.g., pulmonary hypertension, recent pulmonary embolus, active infection), or affect the patient’s ability to take care of himself or herself (e.g., untreated major psychiatric illness, recent substance abuse). However, many of these comorbidities are being reevaluated because our experience has demonstrated improved outcomes in patients thought to be conventionally at risk (e.g., those with diabetes mellitus). Pretransplant pulmonary hypertension, defined as more than 6 Woods units, has been considered a relative contraindication to cardiac transplantation.

Surgical Techniques

Donor hearts were harvested from beating-heart brain-dead persons. Graft procurement and preservation involved cold cardioplegic arrest using University of Wisconsin solution and topical hypothermia. From 1993 to 1996, orthotopic cardiac transplantation was performed using the biatrial technique described by Lower and Shumway. ⁶ Since 1996, we have performed almost all transplants using the bicaval anastomosis technique.

Immunosuppressive Regimen

Triple therapy was administered to all patients undergoing cardiac transplantation (i.e., steroids, cyclosporine, azathioprine). Since 1983, all patients undergoing transplantation at the New York Presbyterian Hospital-Columbia Medical Center have received cyclosporine-based immunosuppression. Current dosing for standard triple-therapy immunosuppression consists of the following:

• Cyclosporine: preoperative dose of 3 to 6 mg/kg followed by intravenous doses (1–2 mg/kg/24 hours) until oral intake is tolerated. Daily oral doses (3–6 mg/kg) are adjusted so that serum levels are maintained at 300 to 350 ng/mL. After 6 to 12 months, cyclosporine dosing is reduced to maintain serum levels between 100 and 150 ng/mL.

• Azathioprine: preoperative oral dose (4 mg/kg) followed by daily intravenous doses of 2 mg/kg until the patient can tolerate oral medications, when azathioprine is changed to mycophenolate mofetil starting at a dose of 1,000 mg twice daily (since 1996).

• Methylprednisolone: intravenous dose of 500 mg administered during the operation and followed in the postoperative period by 125 mg every 8 hours for three doses. Prednisone is then instituted at a daily oral dose of 1 mg/kg and gradually tapered during 4 months to 0.1 mg/kg/day.

Twenty-eight patients in this study received daclizumab, an interleukin (IL)-2 inhibitor, in addition to triple-therapy immunosuppression as part of a randomized trial.

We have developed a protocol for sensitized patients that incorporates repeated cycles every 3 weeks of intravenous cyclophosphamide pulses (0.5–1.0 g/m²) together with intravenous immune globulin (IVIg, 2 g/kg in four divided daily doses). This was administered in the pretransplant period until the potential recipient underwent cardiac transplantation after a negative donor-specific crossmatch.

Management of Rejection

Rejection was diagnosed by routine endomyocardial biopsy, performed weekly for the first 6 weeks, every 2 weeks for the next 6 months, and then monthly for the next year. Routine treatment of grade 3A or greater rejection consisted of an increase in oral prednisone to 100 mg/day for 3 days followed by a taper for 1 week to the baseline dose. If rejection persisted, as seen on endomyocardial biopsy, after a course of oral prednisone therapy, or if rejection was accompanied by altered hemodynamics, intravenous methylprednisolone (1 g daily for 3 days) was used to reverse rejection. OKT3 was used in two conditions: grade 3A/B rejection that persists despite the use of a second intravenous steroid pulse, or rejection with severely compromised hemodynamics. Four weeks after completion of the OKT3 course, antibodies against murine OKT3 were measured. Patients with titers of anti-OKT3 antibodies greater than 1:100 and persistent cellular rejection in the setting of compromised hemodynamics were treated with antithymocyte globulin (ATGAM). Hemodynamically stable patients with either persistent grade 3A/B or 4 rejection despite multiple courses of steroids, OKT3, and ATGAM, or recurrence of grade 3A/B rejection within 2 weeks of having completed therapy with OKT3 or ATGAM were candidates for photopheresis therapy.

Angiography/Diagnosis of Coronary Disease

Patients underwent annual coronary angiography. The diagnosis of transplant-related coronary artery disease was based on either discrete lesions resulting in more than 50% obstruction of the proximal or middle portions of major graft vessels, or diffuse, concentric narrowing of the whole vessels, including their branches. If transplant-related coronary artery disease was identified, the frequency of angiography was increased to twice yearly. Patients were not given routine vasodilators before coronary injections. All angiograms were reviewed by a cardiologist and compared with the previous year’s films to detect the presence of luminal irregularities, discrete stenoses, loss of third-order branches, or pruning of vessels. Explanted hearts and autopsy specimens were examined for evidence of vessel occlusion and irregularities, ischemic damage, and acute cardiac rejection.

HLA Typing

Serologic typing of HLA-A and HLA-B loci was performed using standard microcytotoxicity techniques. HLA-DR typing was performed by serologic analysis.

Detection of Anti-HLA Antibodies

Sera were obtained from all patients and screened for the presence of lymphocytotoxic antibodies against separated T lymphocytes and B lymphocytes obtained from a panel of 70 persons representative of all HLA class I and class II antigens found in the North American population. Sera were screened for complement-mediated lytic activity in the presence or absence of dithioerythritol. Total T-cell panel reactive antibodies (PRA) was considered positive if serum, in the absence of dithioerythritol, reacted against greater than 20% of the T-cell reference panel.

A prospective panel reactive antibody screen was performed on all patients who underwent transplantation. A negative prospective donor-specific lymphocyte crossmatch was required before transplantation when the panel reactive antibody titer exceeded 20%.

Statistical Analysis

Actuarial survival of patients was estimated by Kaplan-Meier analysis, ⁷ with P values calculated by log-rank statistics. Cox proportional hazard and logistic regression models ⁸ were used to evaluate the following risk factors on survival: donor and recipient demographics, ischemic time, ventricular assist device (LVAD) support, retransplantation, pretransplant pulmonary vascular resistance (PVR), and immunologic variables (ABO, HLA matching, and pretransplant anti-HLA antibodies). For the multivariable survival analysis after transplantation, variables with a univariate P < .25 were entered into a Cox proportional hazards model. This model is a multiple regression analysis for examining the time to a dichotomous outcome and the potential associated risk factors by modeling a linearized function of a set of covariates. The interpretation of a risk factor allowed into the final model with a P < .05 is that it is an independent risk factor associated with the event, over and above other potential risk factors included in the equation. The risk ratio is the ratio of the estimated hazard for those with the characteristic variable in question to the estimated hazard for those without, controlling for other variables (or covariates). For all statistical analysis, data were analyzed using SAS System software (SAS Institute, Inc., Cary, NC).

RESULTS

Demographic Data

Recipient Data

Five hundred thirty-six patients undergoing heart transplantation between 1993 to 1999 at New York Presbyterian Hospital-Columbia Medical Center were evaluated. The cause of end-stage heart disease in this population of 536 patients consisted of ischemic cardiomyopathy (n = 189, 35.4%), idiopathic cardiomyopathy (n = 184, 34.4%), congenital heart disease (n = 41, 7.6%), dilated cardiomyopathy (n = 72, 13.4%), and other (n = 50, 9.3%). The mean age of patients at transplantation was 44.9 ± 19 years (range younger than 1 year to 73 years); the median was 51 years. Among adult recipients, the mean age at transplantation was 50.8 ± 12.5 years (range 18–73); the mean age of pediatric patients at transplantation was 7.2 ± 5.7 years (range younger than 1 year to 17 years). There were 394 male and 142 female patients (male:female ratio 3:1). The mean follow-up period was 2.5 years.

One hundred nine patients (20.3%) underwent insertion of an LVAD before transplantation, and 24 (4.5%) had received previous cardiac allografts. The mean duration of LVAD use before transplantation was 107.6 ± 85.5 days (range 1–541). Seventy-two patients (13.6%) undergoing cardiac transplantation had diabetes mellitus.

Donor Data

The mean donor age was 29.1 ± 14 years (range younger than 1 year to 63 years). The mean donor age during each year in the study period ranged from 27.4 to 30.3 years and did not differ significantly from year to year (P = .6). The mean donor age for adult recipients was 31.8 ± 13 years (range 7–63) compared with 11.6 ± 12.2 years (range younger than 1 year to 54 years) for pediatric recipients. The mean donor ischemic time was 178.7 ± 65.2 minutes.

Survival

Actuarial Survival

The actuarial survival rate of the 536 patients undergoing cardiac transplantation between 1993 to 1999 was 83% at 1 year (95% confidence interval [CI] 80–86), 77% at 3 years (95% CI 73–81), and 71% at 5 years (95% CI 66–76) by Kaplan-Meier analysis (Fig. 1). The actuarial survival rate of adult patients was 83%, 76%, and 70% at 1, 3, and 5 years, respectively, by Kaplan-Meier analysis; the corresponding rates for pediatric patients were 83%, 83%, and 76% (P = .3).

Figure 1. Actuarial survival of patients undergoing primary cardiac transplantation from 1993 to 1999. The squares represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis.

Early and Late Death

The rate of early death (less than 30 days) was 8.5% in adults and 8.8% in children (P = .9). The actuarial survival rate in patients surviving more than 30 days was 90%, 83%, and 77% at 1, 3, and 5 years, respectively. There was no difference in actuarial survival between adult and pediatric recipients surviving more than 30 days (P = .15).

Univariate Analysis

Univariate analysis revealed donor age, recipient gender, donor gender, and donor-recipient gender mismatching as significant risk factors adversely affecting survival after cardiac transplantation (Table 2).

Table 2. UNIVARIATE ANALYSIS

*P < .05.

Multivariate Analysis

Risk Factors for Early Death

Multivariate analysis revealed that a pretransplant diagnosis of congenital heart disease, donor age, and donor-recipient gender mismatching significantly reduced the 30-day survival rate (Table 3). Neither elevated PVR nor prior sensitization affected the risk of early death.

Table 3. MULTIVARIATE ANALYSIS: EARLY DEATH

CI, confidence interval.

* Any donor–recipient gender combination other than male–male.

Risk Factors for Late Death

Year of transplant, donor age, and donor-recipient gender mismatching significantly reduced the long-term survival rate (Table 4). The risk of late death was not increased in sensitized patients, patients with pulmonary hypertension, patients with prior LVAD support, or patients undergoing retransplantation. No other demographic or immunologic variables evaluated were found to reduce the survival rate.

Table 4. MULTIVARIATE ANALYSIS: LONG-TERM SURVIVAL

CI, confidence interval.

* For every 3-year period, odds of survival after transplant increased by 1.6 times.

† Any donor–recipient gender combination other than male–male.

Significant Risk Factors

Donor Age

A donor 56 years or older had the worst influence on survival; a donor age of 56 years was identified as a threshold for poor survival. There was no significant difference in actuarial survival between patients who received allografts from donors 45 to 55 years and those from donors younger than 45 (Fig. 2). Donor age also had a significant effect on the early death rate after cardiac transplantation. The early death rate in patients receiving hearts from donors younger than 45 (n = 433), 45 to 55 (n = 74), and 56 or older (n = 18) was 6.3%, 11.0%, and 22.2%, respectively (P = .02 for 56 years or older vs. all the others).

Figure 2. Actuarial survival of patients undergoing primary cardiac transplantation using hearts from donors <45 years, 45–55 years, and ≥56 years. The squares, triangles, and circles represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis.

Recipient Gender

Female recipients had a significant risk for poor survival; the variable of female gender as a risk factor was significant when only patients surviving more than 30 days were analyzed. A donor-recipient gender match other than a male recipient to a male donor had a poorer survival rate (Fig. 3).

Figure 3. Actuarial survival of patients undergoing primary cardiac transplantation comparing male recipient to male donor gender matching vs. all other donor-recipient gender matches. The squares and triangles represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis.

Year of Transplant

The survival rate increased during every year during the study period. For every 2-year period during this era, the odds of survival after cardiac transplantation increased by 1.2 times; for every 3-year period, the odds improved by 1.6 times (Fig. 4).

Figure 4. Actuarial survival of patients undergoing primary cardiac transplantation during each year of the study period (1993–1999). The symbols represent actual events, positioned along the horizontal axis at the time of the event and by the Kaplan-Meier method along the vertical axis.

DISCUSSION

Several previous studies have identified multiple risk factors for poor cardiac transplant survival rates, including the need for pretransplant mechanical circulatory support, elevated PVR, prior cardiac transplantation, immunologic sensitization, and prolonged donor ischemic times. ^4,5,9 The current cardiac transplant population differs from that of earlier periods in that an increasing number of patients are being considered for transplantation who have one or more of these risk factors. Our findings suggest that survival outcome has been unaffected by the increased severity of such comorbid conditions. Our data are notable for six important findings.

First, pretransplant pulmonary hypertension, defined as more than 6 Woods units, has traditionally been considered a relative contraindication to cardiac transplantation. We previously demonstrated a correlative risk for 30-day death in patients with both fixed and reversible pulmonary hypertension in a cohort of patients between 1983 and 1994. ¹⁰ However, as seen in this study, recent advances in the preoperative and perioperative management of recipients have reduced posttransplant deaths in patients with pulmonary hypertension. These findings probably reflect several programmatic changes at our institution since 1994, including perioperative use of phosphodiesterase inhibitors, early LVAD implantation, and liberal use of perioperative inhaled nitric oxide, all of which have been shown to reduce PVR in the perioperative period. ^11,12 Although pulmonary hypertension is still an important clinical parameter of transplant candidacy, in the current era it no longer has a marked impact on the 30-day death rate.

Second, the International Registry of Heart and Lung Transplantation has identified prior LVAD support as a risk factor for poor survival after cardiac transplantation. ⁴ In contrast, we believe that early implantation of LVADs, before the development of end-organ dysfunction, helps reduce the rate of periimplantation death. We have previously shown that a longer duration of LVAD support before transplantation also improves hemodynamics and the chance of long-term survival as a result of improved end-organ function and physiologic status. ¹³ An aggressive physical rehabilitation program further improves the overall medical condition of these patients. We have previously shown that patients with LVAD support for an adequate duration (approximately 3 months) demonstrate better exercise performance than patients with severe congestive heart failure (ambulatory transplant candidates) and comparable exercise performance to that of patients with mild congestive heart failure. In addition, a higher VO₂ anerobic threshold was noted in the patients with LVAD support. ¹⁴ Also, despite an increased risk of infections with prolonged LVAD support, infections have not been shown to reduce the survival rate. ^15,16 In the current study, despite the critical condition of these patients, survival rates after cardiac transplantation were comparable in patients with and without LVADs.

Third, patients with high PRA levels (more than 20%) are considered to be sensitized to various alloantigens and require a donor-specific T-cell crossmatch before transplantation to exclude the presence of lymphocytotoxic IgG antibodies against donor HLA class I antigens, which can cause early graft failure as a result of complement-mediated humoral rejection. ¹⁷ Because a donor-specific T-cell crossmatch is a contraindication to transplantation, sensitized candidates have longer waiting times before they receive a cardiac allograft and higher death rates while waiting for an organ. In addition, the presence of preformed anti-HLA class II antibodies predicts increased frequency of and earlier time to acute cellular rejection and earlier onset of accelerated coronary artery disease. ¹⁸ Cyclophosphamide is a cytotoxic agent with the potential to inhibit both preactivated B and T cells, and intravenous immune globulin (IVIg) neutralizes preformed anti-HLA antibodies through a variety of immunologic mechanisms. ^19,20 The strategy we have used to reduce these negative effects of preformed antibodies includes a combination of cyclophosphamide and IVIg. We have previously demonstrated that this regimen, when given before the transplant, reduces the waiting time to the level in nonsensitized patients. ²¹ The posttransplant use of cyclophosphamide has also prevented induction of anti-HLA class II antibodies, prolonged the rejection-free interval, and reduced cumulative rejections to levels in nonsensitized patients. ²² The results of this study imply that taken together, these therapeutic strategies have reduced the adverse outcomes conferred by sensitization.

Fourth, pediatric patients have been identified as a group that has a poorer outcome in some multicenter studies, especially infants and younger children with congenital heart disease. ^23,24 As in an earlier report from this institution, ²⁵ results in the pediatric population were comparable to those in the adult population in this study. However, a pretransplant diagnosis of congenital heart disease remains a risk factor for early death after cardiac transplantation. Two possible explanations of this finding are that children with inoperable or previously attempted correction of congenital heart defects have an increased postoperative death rate as a result of irreversible changes in their pulmonary vasculature or an increased risk of bleeding secondary to multiple previous operations.

Fifth, prior cardiac allotransplantation has also been identified as a risk factor for poorer survival after repeat cardiac transplantation. Since 1993, we restricted our indication for retransplantation only to patients with transplant coronary artery disease or graft rejection occurring later than 6 months after the transplant, avoiding retransplantation for patients with primary graft failure and early graft rejection (based on previous experience). ²⁶ As demonstrated in the current study, with these revised criteria, results of cardiac retransplantation have been extremely satisfactory and comparable to those of patients undergoing primary transplantation.

Finally, the influence of donor variables on outcome is reflected in our findings demonstrating the impact of donor gender and age on the posttransplant death rate. The improved survival exhibited by male recipients who received male donor hearts, compared with other donor-recipient combinations, adds credibility to the previously reported role of donor-recipient gender matching in determining outcomes after cardiac transplantation. ^27,28 However, the influence of gender is complex, and results have not always been consistent in the literature. ²⁹ Until this issue is more clearly defined, we do not believe that gender should be a criterion in the allocation of donor hearts, especially in view of the present shortage of organs. However, there may be a role for closer immunologic monitoring and stronger immunosuppression in situations of donor-recipient gender mismatch.

We identified increased donor age to be a strong predictor of poor survival after cardiac transplantation, especially on early and late death. The effect of increased donor age on survival, especially 56 years or older, is in agreement with the results of the International Registry. ⁴ However, the increased risk of death conferred by using hearts from older donors may be secondary to our practice of using older donors in sicker recipients, so this finding may not represent an intrinsic effect of older donor age. Hearts from older donors should be evaluated on an individual basis using current acceptance criteria as a guideline, depending on the urgency of the clinical situation and the distance required for organ procurement.

In summary, the improvement in survival during each year of the study demonstrates steady progress in pretransplant and posttransplant care. Although exact factors that contributed to this steady improvement in survival are hard to pinpoint, several changes that have contributed are improved immunosuppression, earlier use of LVAD devices, improved management of sensitized patients, revisions in the criteria for retransplantation, and the liberal use of pulmonary vasodilator therapy in the peritransplant period.

Limitations

We did not attempt to correlate individual specific interventions and changes on survival; rather, we evaluated the influence of current overall management strategies on early and late death at a single center. It is consistently difficult to evaluate outcome results in the field of transplantation because of constant improvements in pretransplant care, better techniques of posttransplant surveillance and detection of infection and rejection, as well as an increasing armamentarium of immunosuppressive and antimicrobial agents. The influence of posttransplant complications such as rejection, infection, and transplant coronary artery disease on survival was not assessed.

CONCLUSIONS

Our current recipient cohort includes patients who would have been refused transplantation in an earlier era. We have demonstrated not only that cardiac transplantation provides satisfactory long-term survival for patients with end-stage heart disease, but also that previously identified risk factors no longer significantly reduce posttransplant survival. Gender matching and donor age need to be studied to characterize their influence on outcome. Consistent annual improvement in survival justifies our current overall management and provides an incentive to develop innovative therapeutic strategies.

Discussion

Dr. R. Morton Bolman (Minneapolis, Minnesota): The group at Columbia has made many landmark contributions to the field of heart transplantation over the years. Under the leadership of surgical giant Keith Reemtsma, and his ongoing brilliant inspiration, this program began in the 1970s. Under Eric Rose and Craig Smith, it has grown to international prominence and unquestioned leadership in this field.

Along the way, Columbia has made many contributions to our understanding of heart transplantation. They have taught us much about increased pulmonary vascular resistance, how to measure it, how to index it to the body size, and how to minimize its impact on posttransplant outcomes. Careful and critical analysis has always characterized their approach.

More recently, Columbia has become the world leader in the application of left ventricular assist devices to patients with end-stage heart failure as a bridge to transplant. They have demonstrated, along with others, that transplant outcomes after LVAD are equivalent to those where LVAD is not necessary. This is quite remarkable, given the fact that patients needing LVAD are at death’s door and are not transplant candidates when these devices are placed, and yet these individuals can be rehabilitated and successfully transplanted.

Today we heard the careful analysis of 536 patients transplanted between 1993 and 1999. The authors tell us that elevated pulmonary vascular resistance, immunologic sensitization, left ventricular assist device support, and prior heart transplantation are no longer risk factors for mortality in the modern era under their management guidelines. Thirty-day mortality has dropped from 12% to 6% during this time frame. I would like to ask the authors four questions.

First, what is the current waiting time for hearts in New York City? Second, given these outstanding results and the relatively large number of available donors in New York City, how are patients triaged to heart transplant with or without a VAD, or to other high-risk conventional procedures—revascularization, valve repair, et cetera?

Thirdly, can you describe the approach to pulmonary hypertension screening and preoperative decision-making that has allowed this factor to be removed from the list of risk factors for mortality?

Finally, what is your policy on the older donor, given your data showing that there is poor survival with donor age over 56?

Presenter Dr. Niloo Edwards (New York, New York): I will start with the fourth question first, which was the donor age greater than 56. We really have restricted the use of those organs to patients who are extremely sick, even before we knew that this impacted on poorer long-term survival. So it is quite possible that the poorer outcome is more a reflection of the acuity of the recipient than the acuity of the donor.

In terms of our preoperative screening for pulmonary hypertension, we still use a routine nipride test to see if the pulmonary vascular resistance decreases. If the pulmonary resistance did not drop below 6 Wood units, we tended to reject those patients for primary heart transplant and would either refer them for heart-lung transplant or reject them altogether for transplantation.

However, with this new data we are much more relaxed in our willingness to take these patients with a slightly higher pulmonary vascular resistance. And we attribute the advantage of being able to transplant these patients primarily to three things. One is the use of milrinone, a phosphodiesterases inhibitor which helps the right ventricle. The second is nitric oxide, which lowers the pulmonary pressures without a drop in systemic pressure. And probably the third is using a bicaval anastomotic technique as opposed to a biatrial where there is less tricuspid regurgitation and therefore the right ventricle can tolerate the strain of pulmonary hypertension better.

All patients who are referred for transplantation are first considered for some kind of repairative procedure. We currently use PET scans for patients with ischemic disease, and any patient basically with aortic stenosis will wind up with some kind of repair procedure.

Dr. Thorall J. Sundt (St. Louis, Missouri): Remarkable advances have been made in the last 5 to 7 years in the medical management of heart failure. In our institution, this has certainly led to later and later referral of patients for consideration of heart transplantation, and, it is my impression, higher and higher serum creatinines at the time of evaluation with an increase in postoperative renal dysfunction. Recipients, therefore, tend to be more “marginal.”

I have two questions: Have you seen a similar phenomenon in terms of more and more renal dysfunction at the time of evaluation for transplantation? Do you believe that there is more late renal failure requiring kidney transplantation? And is this medical strategy helpful or harmful? Secondly, as you have demonstrated, we are increasingly faced with transplanting what I call “marginal recipients.” With the limitation of donors, we are increasingly asked to use “marginal donors.” How do you match these two? Do you use marginal donors for marginal recipients?

Dr. Edwards: We have tried to avoid using high-risk recipients to match with high-risk donors. The reason is primarily that the high-risk recipient usually needs a good heart and putting in a high-risk donor is sort of tantamount to condemning them not to survive the operation, so whenever possible we avoid doing that combination. With the advent of the left ventricular assist device and our ability to implant those successfully, those patients would wind up with a left ventricular assist device.

It is true that we do see patients who are often referred with early signs of other end-organ dysfunction, such as rising creatinines and signs that they are chronically poorly perfused. In fact, it turns out that our status 1s who are waiting in-house, our current event rate is about 60% at 90 days. In other words, 60% of patients either die or wind up on a ventricular assist device if they are not transplanted within 90 days, which is staggeringly high. But that is the reality of this generation of transplant recipients.

Dr. Nancy L. Ascher (San Francisco, California): Certainly these short-term results are outstanding. But one of the major limitations in cardiac and renal transplants has been the issue of chronic rejection. I wonder if you have had an opportunity to evaluate your patients at 5 years out to determine whether your triple therapy has effected less chronic rejection in these patients, less graft atherosclerosis.

Dr. Edwards: We have not been able to look at that. There have been a number of programmatic changes over the 7-year study period that we have looked at. We have looked at long-term survivors, 10-year-and-greater survivors, to look at what factors in them have made them long-term survivors, and that study is still in process.