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Ann Thorac Surg 1998;65:1574-1578
© 1998 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Risk Factors for Death After Heart Transplantation: Does a Single-Center Experience Correlate With Multicenter Registries?

^a Cardiac Transplantation and Mechanical Circulatory Assist Program, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^b The Transplant Center Histocompatibility Laboratory, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^c Heart Failure and Cardiac Transplant Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Accepted for publication December 2, 1997.

Address reprint requests to Dr McCarthy, Department of Thoracic and Cardiovascular Surgery, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195
e-mail: (mccartp{at}cesmtp.ccf.org)

	Abstract

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Background. Risk factors for death after heart transplantation (Tx) are frequently documented from multicenter registries. Although this information is helpful, it reflects a whole range of experiences and results, and may not translate to a particular center. This study was performed to (1) evaluate pre-Tx factors affecting mortality in a single-center experience, and (2) compare these factors with risk factors obtained from multicenter registry reports.

Methods. Review of our transplant database between January 1984 and December 1995 identified 405 adults who received a primary heart Tx. Multiple factors were analyzed, including demographics, Tx era, cytomegalovirus status, United Network for Organ Sharing status of recipient, presence of pulmonary hypertension, previous cardiac operations, mechanical ventilation or circulatory support, ischemia time, number of rejection episodes, and preoperative flow cytometry crossmatching.

Results. One- and 5-year survival rates were 87.8% and 73.4%, respectively (Kaplan-Meier). Contrary to multicenter registry reports, our data indicate that reoperative procedures, left ventricular assist device support, increasing donor and recipient age, and ischemia time up to 4.2 hours are not risk factors for death after Tx. Likewise, mode of donor death is not a risk factor affecting outcome. Significant risk factors for mortality identified by multivariate analysis included early transplant era (1984 to 1989; p = 0.002), female donor (p = 0.042), cytomegalovirus-seropositive donor (p = 0.048), high pulmonary vascular resistance (p = 0.018), and intraaortic balloon pump support (p = 0.03). It also identified a positive B-cell flow cytometry crossmatch (p = 0.015) to be a risk factor with univariate analysis.

Conclusions. Our data identify a group of recipients, reportedly at high risk in multicenter registries, who are not at increased risk of death after Tx. This information supports the growing experience with older donors and recipients and with bridged transplants, and has allowed us to expand our donor pool. These prognostic factors at evaluation allow more liberal selection of patients and donors for transplantation.

	Introduction

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Heart transplantation currently provides the most effective treatment for end-stage heart disease. However, in view of donor shortage, the number of heart transplants performed annually in the United States and worldwide has plateaued [1] and will continue to do so short of attempts to expand the donor pool. Analysis of risk factors is, therefore, important to make informed judgments in any particular potential donor–recipient situation. To date, data analysis from numerous multicenter registries has formed the basis of our risk stratification knowledge. Studies from the Cardiac Transplant Research Database and the Registry of the International Society for Heart and Lung Transplantation continue to list criteria such as increasing donor and recipient age, use of mechanical ventricular assistance, and cold ischemia time as risk factors that affect survival after transplantation [1, 2]. Although data from these multicenter registries are extremely helpful, the information obtained is extrapolated from a number of different centers with different management strategies and ranges of experience, and as a result, may not always represent or translate to a particular center’s experience. It is therefore probable that favorable results of a large center’s experience may be masked in a multicenter study by the inclusion of smaller volume programs with higher mortality [3]. In this study, we sought to analyze the risk factors for mortality after heart transplantation at our center, and to compare these risk factors with data obtained from multicenter registry reports.

	Material and methods

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Patient characteristics
Review of our transplant database between January 1984 and December 1995 identified 405 adult patients (18 years of age or older) who underwent orthotopic heart transplantation at the Cleveland Clinic Foundation. The clinical records of these patients were reviewed retrospectively. The patients were analyzed in two transplant eras: those who received transplants between 1984 and 1989, and those who received transplants between 1990 and 1995. Description of the donor and recipient characteristics are listed in Table 1. There were 315 (78%) male and 90 (22%) female recipients with a mean (± standard error of the mean) age of 48.7 ± 0.5 years (range, 18 to 66 years). In comparison, 69% of donors were men. The mean ± SEM donor age was 30.0 ± 0.6 years (range, 10 to 67 years). All patients had end-stage heart disease that was caused by an ischemic cardiomyopathy in 192 patients (47%) and a nonischemic dilated cardiomyopathy in the remainder (53%). The factors analyzed are listed in Table 2, and include donor and recipient age, gender, race, and cytomegalovirus status; donor mode of death; cause of heart failure; United Network for Organ Sharing status; presence of pulmonary hypertension and previous cardiac operations in the recipient; mechanical ventilatory support or circulatory support to transplantation with the intraaortic balloon pump (IABP) or left ventricular assist device (LVAD; HeartMate, Thermo Cardiosystems Inc, Woburn, MA); organ ischemia time up to 4.2 hours (mean 2.3 hours); flow cytometry crossmatch; number of episodes of cellular rejection; and survival. Myocardial preservation was attained with modified Buckberg solution.

Cellular rejection was graded based on the grading system adopted from the Billingham criteria and the criteria of the International Society for Heart and Lung Transplantation [6, 7], whereby grades I_A, I_B, and II were considered mild rejection, grades III_A and III_B were considered moderate, and grade IV severe rejection. Early rejection referred to all rejection episodes occurring within 30 days of the transplant. Only patients who had moderate and severe rejection were considered in the forthcoming analysis of cellular rejection after transplantation. The technique of flow cytometry crossmatching has been described in previous publications [8–10]. Maintenance immunosuppression consisted of a triple-drug combination of cyclosporine, azathioprine, and steroids since the initiation of the program. Patients with compromised renal function were selectively induced with OKT3 monoclonal antibody after transplantation. This was followed by conversion to cyclosporine-based immunosuppression when their renal function improved. Episodes of acute rejection were initially treated with intravenous methylprednisolone for 3 days. Recurrent or refractory rejection was treated with steroids and OKT3. Other modalities such as plasmapheresis, immunoglobulin, and cytolytic therapy were used in cases of acute rejection when a significant humoral component was suspected.

Statistical analysis
When indicated, data are presented as mean ± standard error of the mean. In all, 22 covariates were analyzed as potential risk factors for death after transplantation (Table 2). This analysis included all deaths, both early and late. Actuarial survival curves were generated by the Kaplan-Meier method, and differences were analyzed by the log-rank test. Significant risk factors for mortality were identified using the Cox proportional-hazards model. Three Cox models were run for the patients with complete data for each set of variables. A p value less than 0.05 indicated significance.

	Results

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Patient demographics are presented in Table 1. Thirty-two patients (7.9%) were on mechanical ventilatory support at the time of transplantation, 29 (7.2%) were on IABP support, and 21 (5.2%) were on both, whereas 47 (12%) were on an LVAD. The patients were followed up for a mean ± SEM duration of 41.2 ± 1.6 months (longest, 143 months). The mean ± SEM number of episodes of cellular rejection within the initial 30 days after transplantation was 0.78 ± 0.04 episodes. There were 99 deaths among the 405 patients (24%). The causes of early (<3 months after transplantation) and late deaths (>3 months) are listed in Table 3. Figure 1 demonstrates the Kaplan-Meier survival curves for those patients transplanted in the early (1984 to 1989) and late (1990 to 1995) eras. The overall 1-, 3-, and 5-year actuarial survival rates were 87.8%, 80.1%, and 73.4%, respectively.

View larger version (15K): [in this window] [in a new window]   Fig 1. Actuarial patient survival for cardiac transplants in two eras.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Multicenter registries have the advantage over single-center studies of evaluating a large number of patients in a relatively short period of time. Therefore there is an increased ability to detect risk factors and differences among patient groups. However, because of the large variability in each center’s institutional protocols and results, risk stratification may not translate to a particular center’s experience. Previous reports from our institution have clearly demonstrated that presence of an implantable LVAD in bridged patients was not a risk factor for death after transplantation [13] in contrast to multicenter registry data [1, 14]. Not infrequently, other organ failure develops in patients with heart failure who are waiting for a donor. These patients have demonstrated improvement in the state of their multiorgan dysfunction and in their physical condition after bridging [13, 15]. It seems logical then to assume that if early results after LVAD implantation are optimal these patients should be in a reasonably good condition at the time of transplantation [13]. Interestingly although the presence of an LVAD has not been demonstrated to be a risk factor for death after transplantation at our center, presence of an IABP before transplantation does constitute a significant risk, probably because of the hemodynamic instability of the patient requiring acute support. Pulmonary vascular resistance was also identified as a risk factor as demonstrated in Table 7 and as previously shown by other groups [16, 17]. This remains so despite our practice of implanting oversized high-quality hearts in these recipients. However we have just begun to use nitric oxide in some of these patients and this may affect early survival.

Risk factors for death after transplantation identified by multivariate analysis of data from the registry of the International Society for Heart and Lung Transplantation [1] identified recipient risk factors that were not found to affect survival at our center. These included need for left ventricular assistance or ventilatory support preoperatively, progressive age, and race. Likewise, the donor age and race, and organ ischemia time, which were included as risk factors in the registry report, were not found to affect survival in our study.

It should be emphasized that risk stratification is a dynamic process that may change among transplant eras. Certain risk factors identified at our center have been neutralized over time, whereas some persist and yet others emerge. Severe rejection was a risk factor in our early experience [23]. Now it apparently is not, perhaps reflecting a more aggressive approach to this problem with earlier diagnosis, improved immunosuppressive therapy, and increasing use of plasma exchange. Likewise the duration of organ ischemia, although still less than 4.2 hours, was previously a risk factor but now appears not to be [23]. This finding is supported by some authors [24] and refuted by others [1, 25]. Intraaortic balloon pump counterpulsation has recently emerged as a risk factor that may reflect the debilitated condition of this subgroup of patients. Therefore in the era of worsening donor shortages and longer waits, transfer of IABP-dependent patients to LVAD support may be advantageous.

This study has a number of limitations. The number of patients analyzed is relatively small when compared with large registries [1, 25]. It concentrates only on mortality as an end point, and is retrospective. However, it shows that multicenter registry results do not always translate to a single center, and thus it is of significance. This is particularly important when considering the relatively few large-volume centers and the relatively larger number of low-volume centers.

In conclusion, data from our center identified a group of recipients, reportedly at high risk in multicenter registries, who were not found to be at increased risk of death after transplantation. This information supports the growing experience with older donors and recipients and with bridged transplants, and has allowed us to expand our donor pool to include older donors and long-distance procurement. Our data also suggest that the experience level of the center, the presence of high pulmonary vascular resistance in the recipient, and positive B-cell reactions on prospective flow cytometry crossmatching may be significant factors affecting outcome. These prognostic factors may allow more liberal selection of patients and donors for transplantation.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): James F. McCarthy Patrick M. McCarthy Malek G. Massad Nicholas G. Smedira Vigneshwar Kasirajan James B. Young Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by McCarthy, J. F. Articles by Young, J. B. Search for Related Content PubMed PubMed Citation Articles by McCarthy, J. F. Articles by Young, J. B.