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

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1 Risk Factors for Death After Heart Transplantation: Does a Single-Center Experience Correlate With Multicenter Registries? James F. McCarthy, FRCSI, Patrick M. McCarthy, MD, Malek G. Massad, MD, Daniel J. Cook, PhD, Nicholas G. Smedira, MD, Vigneshwar Kasirajan, MD, Marlene Goormastic, MPH, Kathy Hoercher, MS, and James B. Young, MD Cardiac Transplantation and Mechanical Circulatory Assist Program, Department of Thoracic and Cardiovascular Surgery, The Transplant Center Histocompatibility Laboratory, and Heart Failure and Cardiac Transplant Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio 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. (Ann Thorac Surg 1998;65:1574 9) 1998 by The Society of Thoracic Surgeons 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 Accepted for publication Dec 2, Address reprint requests to Dr McCarthy, Department of Thoracic and Cardiovascular Surgery, Desk F25, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH ( mccartp@cesmtp.ccf.org). 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 by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (98)

2 Ann Thorac Surg McCARTHY ET AL 1998;65: RISK AFTER HEART TRANSPLANTATION 1575 Table 1. Description of Recipient and Donor Characteristics Variable % of Total Transplantation era Transplantation era Previous cardiac operations Male donor Male recipient White recipient CMV-positive recipient HeartMate LVAD bridged Donor hypertensive 27 7 Donor cardiac arrest CMV-positive donor CMV cytomegalovirus; LVAD left ventricular assist device. Material and Methods 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 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 years (range, 18 to 66 years). In comparison, 69% of donors were men. The mean SEM donor age was 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. The decision to implant an LVAD was prompted by a progressive deterioration in the patient s hemodynamics and organ function. The hemodynamic indications for LVAD use included transplantation candidates who had a pulmonary capillary wedge pressure of 20 mm Hg or greater coupled with a cardiac index of 2.0 L min 1 m 2 or less, or a systolic blood pressure of 80 mm Hg or less, despite maximal inotropic agents and IABP support [4]. Details of the device description and implantation technique have been reported [5]. 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 tripledrug combination of cyclosporine, azathioprine, and steroids since the initiation of the program. 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 Table 2. Covariates Analyzed for Risk of Mortality After Heart Transplantation Donor Variables Recipient Variables Other Age Age Transplant era Sex Sex Cold ischemia time Race Race Flow cytometry crossmatch CMV status CMV status Mode of Diagnosis death Hypertension UNOS status Cardiac arrest Pulmonary vascular resistance Previous cardiac operation Mechanical ventilation HeartMate LVAD bridged Intraaortic balloon pump Early rejection episodes CMV cytomegalovirus; LVAD left ventricular assist device; UNOS United Network for Organ Sharing.

3 1576 McCARTHY ET AL Ann Thorac Surg RISK AFTER HEART TRANSPLANTATION 1998;65: Table 3. Early ( 3 months) and Late ( 3 months) Known Causes of Death After Heart Transplantation Identified From a Large Single-Center Experience (Cleveland Clinic Foundation ) Cause of Death 3 Months After Tx 3 Months After Tx Rejection 11 (14%) 25 (32%) a Infection 8 (11%) 5 (7%) Graft failure 4 (5%) 1 (1%) Cerebrovascular 3 (4%) 1 (1%) Hemorrhage 1 (2%) 0 Malignancy 0 7 (9%) Other 4 (5%) 7 (9%) Total 31 (40.3%) 46 (59.7%) a Includes chronic rejection and cardiac allograft vasculopathy. Tx transplantation. 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 Table 4. Risk Factors for Mortality After Heart Transplantation Identified From a Large Single-Center Experience (Cleveland Clinic Foundation ) Variable Risk Ratio p Value Transplantation era Female donor CMV-positive donor PVR 3 Wood units IABP CMV cytomegalovirus; IABP intraaortic balloon pump; PVR pulmonary vascular resistance. Patient demographics are presented in Table 1. Thirtytwo 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 months (longest, 143 months). The mean SEM number of episodes of cellular rejection within the initial 30 days after transplantation was 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. The significant risk factors for death after transplantation identified by multivariate analysis are outlined in Table 4. These included five significant variables: early transplant era (1984 to 1989), female donor, cytomegalovirus seropositive donor, IABP support, and increased pulmonary vascular resistance ( 3 Wood units) in the recipient. Univariate analysis showed positive B-cell flow cytometry crossmatching (data available in 101 patients) and pulmonary hypertension (systolic 50 mm Hg) in the recipient to also significantly affect survival. The actuarial Kaplan-Meier survival estimate for patients with pulmonary vascular resistance less than 3 Wood units was 74% at 5 years compared with only 66% for those with pulmonary vascular resistance of 3 Wood units or more (p 0.04, log-rank test). All other risk factors identified from multicenter registry reports [1, 11] were not significantly associated with death, including reoperation, LVAD support as a bridge to transplantation, increasing donor and recipient age, ischemia times of up to 4.2 hours, and mode of donor death. Tables 5 and 6 depict survival correlated with increasing donor and recipient age. Interestingly, mechanical ventilatory support to transplantation did not impact survival by univariate analysis. The actuarial 5-year survival was 73% in the group with ventilatory support compared with 71% without it (not significant, log-rank test). Comment Heart transplantation continues to be a viable therapeutic option for certain patients with end-stage heart disease, with a reported 1-year survival of 83% worldwide [1]. Previous data clearly demonstrate that the number of transplants performed at a single center affect survival Table 5. Impact of Donor Age on Age (y) 1-Year 5-Year % 85.9% % 70.3% % 71.6% % 70.4% % 60.3% Fig 1. Actuarial patient survival for cardiac transplants in two eras. Total % 73.4%

4 Ann Thorac Surg McCARTHY ET AL 1998;65: RISK AFTER HEART TRANSPLANTATION 1577 Table 6. Impact of Recipient Age on Age (y) 1-Year 5-Year % 62.9% % 73.0% % 68.5% % 77.1% % 78.7% Total % 73.4% [11, 12]. The risks of death at early and intermediate time points are substantially higher in low-volume transplant centers, which constitute a large proportion of the centers performing transplantation in the United States [12]. Of 7,893 cardiac transplants reviewed in one registry report, as much as 25% of the differences in observed patient mortality were related to center-to-center variability [12]. Multicenter registries have the advantage over singlecenter 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. Not surprisingly, early transplant era is a risk factor for mortality. This has been the case in other reports [18, 19], and probably reflects a combination of a learning curve for the transplantation team, and also a different era when the diagnostic and therapeutic options were not at the present level. The majority of the transplantations (77%) were in the later era and the early learning experience was consolidated here. The improved survival in recent years has the added benefit of allowing expansion of the donor pool [3]. This has been our practice since 1990 and increasing donor and recipient age have not had an adverse impact on survival, as has been reported by some authors [20]. Indeed judicious use of hearts from donors aged more than 50 years, in the presence of a normal coronary angiogram, has allowed us to perform transplantation in older recipients, who are the main beneficiary of this group, with an increasing frequency. Other risk factors identified by multicenter registry reports were not significantly associated with death in our series, including reoperations, ischemia time, and mode of donor death. Previous cardiac operation has been described as a risk factor in single- and multicenter reports [21, 22]. 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 Table 7. Correlation of Early Mortality and Pulmonary Vascular Resistance a PVR (Wood units) Early Mortality ( 3 mo) 2 6/71 (8.5%) /61 (9.8%) /43 (9.3%) /22 (18.2%) 5 4/14 (28.6%) Total 24/211 (11.4%) a 211 patients with complete and verifiable data. PVR pulmonary vascular resistance.

5 1578 McCARTHY ET AL Ann Thorac Surg RISK AFTER HEART TRANSPLANTATION 1998;65: 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 1. Hosenpud JD, Novick RJ, Breen TJ, Keck B, Daily P. The Registry of the International Society for Heart and Lung Transplantation: twelfth official report J Heart Lung Transplant 1995;14: Bourge RC, Stevenson LAW, Naftel DC, et al. Risk factors for death in critically ill patients awaiting cardiac transplantation: a multi-institutional study. Circulation 1995;92(Suppl 1):I Hoercher K, Young JB, Stewart RW, McCarthy PM, Smedira NG, Kendall K. The use of older heart donors may not impact mortality or morbidity: a single center experience [Abstract]. J Heart Lung Transplant 1997;16: Frazier OH, Rose EA, Macmanus Q, et al. Multicenter clinical evaluation of the HeartMate 1000 IP left ventricular assist device. Ann Thorac Surg 1992;53: McCarthy PM, Wang N, Vargo RL. Preperitoneal insertion of the HeartMate 1000 IP implantable left ventricular assist device. Ann Thorac Surg 1994;57: Billingham ME, Cary NRB, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: heart rejection study group. J Heart Transplant 1990;9: Nakhleh RE, Jones J, Goswitz JJ, Anderson EA, Titus J. Correlation of endomyocardial biopsy findings with autopsy findings in human cardiac allografts. J Heart Lung Transplant 1992;11(3 pt 1): Hurley JP, Cook DJ, McCarthy PM, et al. Flow cytometry crossmatching: a method for monitoring antidonor antibodies in heart transplant recipients. Transplant Proc 1995;27: Cook DJ, Klingman LL, Koo AP, Goldfarb D, Dennis VW, Hodge EE. Quantitative flow cytometry cross-matching for precise measurement of donor-specific alloreactivity. Transplant Proc 1994;26: Iwaki Y, Cook DJ, Teresaki PI, et al. Flow cytometry crossmatching in human cadaver kidney transplantation. Transplant Proc 1987;19: Laffel GL, Barnett AI, Finkelstein S, Kaye MP. The relation between experience and outcome in heart transplantation. N Engl J Med 1992;327: Hosenpud JD, Breen TJ, Edwards EB, Daily OP, Hunsicker LG. The effect of transplant center volume on cardiac transplant outcome: a report of the United Nework for Organ Sharing Scientific Registry. JAMA 1994;271: Massad M, McCarthy PM, Cook DJ, et al. Does successful bridging with the implantable left ventricular assist device affect cardiac transplantation outcome? J Thorac Cardiovasc Surg 1996;112: Hosenpud JD, Edwards EB, Lin HM, Daily OP. Influence of HLA matching on thoracic transplant outcomes. Circulation 1996;94: Frazier OH, Rose EA, McCarthy PM, et al. Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system. Ann Surg 1995;222: Griepp RB, Stinson EB, Dong E Jr, Clark DA, Shumway NE. Determinants of operative risk in human heart transplantation. Am J Surg 1971;122: Kirklin JK, Naftel DC, McGriffin DC, McVay RF, Blackstone EH, Karp RB. Analysis of morbid events and risk factors for death after cardiac transplantation. J Am Coll Cardiol 1988; 11: Hauptman PJ, Kartashov AI, Couper GS, et al. Changing patterns in donor and recipient risk: a ten year evolution in one transplant center. J Heart Lung Transplant 1995;14: McGriffin DC, Kirklin JK, Naftel DC, Bourge RC. Competing outcomes after heart transplantation: a comparison of eras and outcomes. J Heart Lung Transplant 1997;16: Drinkwater DC, Laks H, Blitz A, et al. Outcomes of patients undergoing transplantation with older donor hearts. J Heart Lung Transplant 1996;15: De Maria R, Minoli L, Parolini M, et al. Prognostic determinants of six month morbidity and mortality in heart transplant recipients. J Heart Lung Transplant 1996;15: Uthoff K, Wahlers T, Cremer J, Borst HG. Previous open heart operations: a contribution to impaired outcome after cardiac transplantation? Ann Thorac Surg 1997;63: Stewart RW. Cardiac transplantation at the Cleveland Clinic Foundation the first ten years. In: Terasaki PI, Cecka JM, eds. Clinical transplants. Los Angeles: UCLA Tissue Typing Laboratory, 1994: Briganti EM, Bergin PJ, Rosenfeldt FL, Esmore DS, Rabinov M. Successful long-term outcome with prolonged ischemic time cardiac allografts. J Heart Lung Transplant 1995;14: Young JB, Naftel DC, Bourge RC, et al. Matching the heart donor and heart transplant recipient. Clues for successful expansion of the donor pool: a multivariable, multiinstitutional report. J Heart Lung Transplant 1994;13: INVITED COMMENTARY Lies, damned lies and statistics Benjamin Disraeli, British Prime Minister McCarthy and colleagues present the Cleveland Clinic experience in cardiac transplantation and subject their series of patients to univariate and multivariate analysis looking for preoperative risk factors that predict outcome. In their series of 405 patients, they demonstrate excellent 1-year survival and fail to confirm several preoperative risk factors that have been demonstrated to be 1998 by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (98)