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Ann Thorac Surg 1998;65:978-983
© 1998 The Society of Thoracic Surgeons

Heart Retransplantation: A 23-Year Single-Center Clinical Experience

^a Department of Cardiac Surgery, La Pitié Salpétrière Hospital, Paris, France
^b Department of Anatomopathology, La Pitié Salpétrière Hospital, Paris, France
^c Department of Biomathematic and Medical Informatic, La Pitié Salpétrière Hospital, Paris, France

Accepted for publication October 14, 1997.

Address reprint requests to Prof Pavie, 83 Blvd de l’Hôpital, Hôpital de La Pitié-Salpétrière, 75013 Paris, France

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. The main causes of allograft failure after cardiac transplantation are primary graft dysfunction, intractable acute rejection, and coronary graft disease. Despite the important progress in the last several years in graft preservation, surgical techniques, immunosuppression, and treatment of coronary graft disease, retransplantation in selected cases is the only way to achieve long-term recipient survival.

Methods. We compare here in a case-control study 24 retransplantations with 47 first transplants in patients matched for date of transplantation.

Results. Between 1973 and 1996, 1,063 patients underwent cardiac transplantation in our institution. In this cohort, 22 patients had a total of 24 retransplantations (2 second-time retransplantations). The causes of retransplantations were primary graft failure (n = 4), acute rejection (n = 7), coronary graft disease (n = 11), and miscellaneous (n = 2). Survival at 1 and 5 years of patients with retransplantations is 45.5% and 31.2%, and survival of control patients is 59.4% and 38.8% (p = 0.07). An interval between first transplantation and retransplantation shorter (n = 11) or longer (n = 13) than 1 year is associated with a 1-year survival of 27.3% and 61.5% and a 4-year survival of 27.3% and 46%, respectively (not significant). Intervals shorter than 1 year between first transplantation and retransplantation were exclusively secondary to primary graft failure or intractable acute rejection.

Conclusions. In the face of lack of donor grafts, these and other data indicate that retransplantation should be considered cautiously, especially when the interval between the first transplantation and retransplantation is short.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
The main causes of allograft failure after cardiac transplantation are primary graft dysfunction, intractable rejection, and coronary graft disease. Despite the important progress in the last several years in graft preservation, surgical techniques, immunosuppression, and treatment of coronary graft disease, retransplantation in selected cases is the only way to achieve long-term recipient survival. Several studies and data from the International Society for Heart and Lung Transplantation (ISHLT) registry have reported survival and risk factors for retransplantation [1–7]. We report here experience with heart retransplantation during the past 23 years in our institution in both the precyclosporin and cyclosporin eras. Patients receiving retransplantations were compared with patients receiving first transplants, matched for date of transplantation.

	Material and methods

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Patients
Between January 1973 and April 1996, 1,063 patients underwent cardiac transplantation for end-stage cardiac disease in our hospital: 1,001 orthotopic and 62 heterotopic (Fig 1). In this cohort, 24 (2.2%) were retransplanted (22 first time, 2 second time). There were 22 male and 2 female patients, ranging in age from 13 to 56 years (mean age ± standard deviation, 36 ± 14 years). Donors were brain-dead patients who suffered head trauma or cerebrovascular injury. At the beginning of our experience, graft preservation was achieved with a combination of topical hypothermia and cold crystalloid cardioplegia. Since 1980, we have been using cold crystalloid cardioplegia for harvesting on the donor and cold blood cardioplegia for the graft procedure with warm reperfusion at declamping [8]. Orthotopic transplantation was performed according to the technique of Lower and Shumway [9] with some technical variation for retransplantation, which we have described elsewhere [10, 11]. When the first transplantation had been heterotopic, both the native heart and the graft were explanted and the new heart was grafted in the orthotopic position with bicaval anastomoses. In our cohort, ischemic time was 120 ± 60 minutes (mean ± standard deviation).

View larger version (31K): [in this window] [in a new window]   Fig 1. Heart transplantation volumes by year in "La Pitié" between 1973 and 1995. (ReTx = retransplantation; 1° Tx = first transplantation.)

Since May 1982 cyclosporine (1 to 3 mg/kg intravenously beginning between day 1 and 3 depending on renal or liver function, followed by 8 to 10 mg/kg taken orally adjusted to maintain a trough level of 300 to 400 ng/mL using the monoclonal antibody assay) was introduced systematically in our institution as the mainstay of immunosuppressive therapy with a lower dose of prednisolone (methylprednisolone 240 mg intravenously preoperatively and 240 mg intraoperatively followed by prednisone 1 mg/kg per day taken orally and tapered to 0.3 mg/kg per day at day 21), azathioprine (2 mg/kg per day intravenously preoperatively and 2 mg/kg per day taken orally postoperatively adjusted to white blood cell count), and rabbit antithymocyte globulin for rejection prophylaxis in the first postoperative days. Antithymocyte globulin therapy also allows us to delay for a few days the administration of high doses of cyclosporine to preserve renal function.

Follow-up of patients receiving retransplantations was similar to that of patients with first-transplant procedures. In addition to biopsies or echocardiographies driven by clinical suspicion of acute rejection, we applied a policy of frequent systematic echocardiographies and biopsies early after the graft. According to our previously published results, acute rejection on echocardiography was suspected on the basis of a decrease in left ventricular function, an increase in left ventricular mass or posterior wall thickness, and a decrease of more than 20% in isovolumetric relaxation time or mitral pressure half-time taking the patient as his own control [12, 13]. Rejection was then confirmed and graded according to endomyocardial biopsy [14]. Currently, ISHLT grade Ia or Ib rejection is treated with prednisolone 1.5 mg/kg per day taken orally for 5 days, ISHLT grade II or IIIa rejection with methylprednisolone 15 mg/kg per day intravenously for 3 days, and ISHLT grade IIIb or IV rejection with methylprednisolone 15 mg/kg per day intravenously for 3 days and antithymocyte globulin (2.5 mg/kg per day for 3 to 5 days) or OKT3 (5 mg · kg^-1 · day^-1 for 14 days).

We report follow-up of all patients receiving retransplantation up to October 21, 1996. We compared these patients with patients receiving first-time transplants in a case-control study. We chose as control patients (2 controls for each retransplantation) patients receiving first-time transplants who were grafted immediately before or after each patient receiving retransplantation (excluding heterotopic first-time or heart-lung transplantation). Actuarial rate of survival was calculated for each patient group.

Statistical analysis
Survival curves in the case-control study and in subgroup analysis were performed according to Kaplan-Meier analysis. Differences between groups were calculated with the log-rank test. We also used the Breslow-Gehan-Wilcoxon test, which places more weight on early survival times. Finally, to take into account the possible differences between the retransplantation and control groups, we performed an analysis using the Cox model controlling for donor, recipient age, or ischemic time. Differences between groups for percentages were calculated with the Fisher’s exact test and differences for other variables with the nonparametric Wilcoxon test. The level retained for statistical significance was p less than 0.05.

	Results

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The original diagnoses of end-stage cardiac disease (Table 1) in the 22 patients (20 male and 2 female patients for a total of 24 retransplantations) who underwent retransplantation were idiopathic cardiomyopathy in 9 (41%), ischemic heart disease in 8 (36%), valvular disease in 2 (9%), and other diagnoses in 3 (14%). The indications for retransplantation (Table 2) were primary graft failure in 4 (17%), refractory acute rejection in 7 (29%), coronary graft disease in 11 (46%), and others in 2 (8%). One of the patients receiving retransplantation for refractory acute rejection also had a restrictive cardiomyopathy in the context of multiple episodes of acute rejection.

The typical picture of hyperacute rejection on histology was found on none of the hearts that had primary graft dysfunction. Nevertheless, the patient put on Jarvik assistance had an infiltrate with a few clustered polymorphonuclear leukocytes and lymphocytes, sometimes arranged around blood vessels.

Refractory acute rejection
The 7 patients who underwent retransplantation for acute rejection were operated on before 1987. All the patients had hemodynamic instability before the graft. Three died in the early postoperative period (1 primary graft dysfunction, 1 postanoxic encephalopathy, and 1 aspergillosis bronchopneumonia with septicemia and myocarditis). Two died of acute refractory rejection more than 7 months and 4.5 years after the second graft. Two had prolonged survival and again underwent retransplantation 3.5 and 8.3 years after the first retransplantation for coronary graft disease.

Coronary graft disease
Eleven patients underwent retransplantation for coronary graft disease. Most of them had some degree of congestive heart failure, but none had to be hospitalized before retransplantation. The coronary angiograms performed before retransplantation showed for all the patients a severe diffuse three-vessel disease. Histopathologic examination of the grafts after explantation confirmed the diffuse form of the disease with its characteristic concentric fibrointimal hyperplasia. Three patients died in the early postoperative period and 1 died after 8.5 years. Seven patients are still alive after a mean follow-up of 2.2 years (range, 2.5 months to 4.2 years).

Miscellaneous
Patient 11, who received a transplant in a heterotopic position, underwent retransplantation 26 days after the primary transplant for refractory heart failure. In the meantime, he received treatment for suspicion of acute rejection despite a negative endomyocardial biopsy. Histopathologic examination at explantation retrieved in the donor heart an old posterior myocardial infarction and no sign of acute rejection. It is therefore likely that the cause of heart failure was multifactorial including some degree of primary graft dysfunction.

Patient 10, who also received a transplant in a heterotopic position, had a refractory heart failure that appeared after an acute myocardial infarction on the native heart and finally led to retransplantation.

Cumulative survival for all patients having first transplants in our institution (Fig 2) at 1 and 5 years during the period between 1991 and 1996 is 71.6% and 63.4%. In the case-control study (Fig 3) comparing retransplantations with first transplantations matched for the date of transplantation, survival of control patients at 1 and 5 years is 59.4% and 38.8%. Survival of patients undergoing retransplantations is 45.5% and 31.2%. This trend toward a better survival in control patients just fails to reach statistical significance (p = 0.063 according to the Cox model controlling for donor age; recipient age, ischemic time, and sex were also tested but did not change the results). To identify risk factors we then performed a subgroup analysis of patients who underwent retransplantation according to the interval between first transplant and retransplantation (Fig 4). An interval shorter (n = 11) or longer (n = 13) than 1 year is associated with a 1-year survival of 27.3% and 61.5% and a 4-year survival of 27.3% and 46%, respectively. This result does not achieve statistical significance (p = 0.21) in our study, in which the number of patients in each group is small. Indication for retransplantation in cases of short intervals between first transplant and retransplantation were exclusively primary graft failure and graft rejection resistant to steroids and antithymocyte globulins, whereas long intervals (>1 year) were associated mainly with diagnosis of coronary graft disease (and in 2 cases of refractory acute rejection).

View larger version (8K): [in this window] [in a new window]   Fig 2. Actuarial survival of primary heart transplant recipients between 1991 and 1996.

View larger version (13K): [in this window] [in a new window]   Fig 3. Actuarial survival of primary transplant and retransplant recipients in the case-control study.

View larger version (10K): [in this window] [in a new window]   Fig 4. Actuarial survival of patients with intervals between transplantation of greater than or less than 1 year.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

Our study shows a trend toward worse survival associated with retransplantation as compared with primary transplantation, albeit the increased risk profile of the control group and the low power of the study do not allow our results to achieve statistical significance (p = 0.063). It should be noted that the two curves diverge in the early postoperative period and then stay parallel, indicating that the worse prognosis of retransplantation is mainly in relationship with an increased perioperative mortality. In our study, patients undergoing retransplantation who survive this period seem to have the same long-term prognosis as control patients. In the ISHLT registry, in which patients surviving more than 6 months after first transplantation or retransplantation were compared, those receiving retransplantations had a trend (p = 0.08) toward worse survival [7].

In the literature, perioperative mortality has been attributed to an increased incidence of "mediastinitis, intrathoracic bleeding requiring reintervention and acute renal failure requiring dialysis," as well as an increased incidence of primary graft failure [7]. Incidence of infection, incidence of rejection, and time to first treated rejection seem to be the same in patients receiving first transplants and retransplants [2, 4, 6]. The increased mortality associated with positive donor-specific crossmatch may be in relationship with an increased severity of acute rejection. Moreover, it is tempting to relate this increased mortality to the observed increase in the so-called nonspecific primary graft failure, which could indeed be a form of hyperacute rejection. In our cases of primary graft dysfunction, the patients did not have a positive crossmatch.

We also find, in keeping with the literature [1, 7], a worse survival when the interval between first transplantation and retransplantation is less than 1 year. Again, the insufficient size of our population did not permit our results to achieve statistical significance. It seems, however, that the prognosis is particularly poor in our cohort when the indication to retransplantation is primary graft failure (3 of 4 patients died within 13 days of transplantation and only 1 achieved long-term survival). The prognosis seems somewhat better when the indication to retransplantation is refractory acute rejection (3 patients of 7 died in the postoperative period and 1 died of acute rejection 7 months after retransplantation).

According to these results, we continue to perform retransplantation procedures in selected good-risk patients with long-term intervals since the first graft. This policy may be affected in the near future by the good long-term survival obtained in recipients of first heart transplants, which results in a dramatic increase in the number of patients presenting with coronary graft disease and thus in the number of potential candidates for retransplantation.

On the contrary, facing the severe lack of donor grafts and the poor prognosis of patients undergoing retransplantation after short intervals, our policy is to discuss indication for retransplantation in these patients on a case-by-case basis [19]. In fact (see Table 2) we have not performed a single retransplantation for acute refractory rejection or primary graft failure since 1990. The 10 most recent indications for retransplantation were coronary graft disease.

One could theoretically discuss the indication for ventricular assist devices as a bridge to retransplantation in these patients when direct retransplantation carries an unacceptably high risk and therefore raises an ethical issue in the context of lack of donors. In our experience however, the results of ventricular assist device support in these situations are very poor; because of the high cost of these devices, and therefore their limited availability, our policy has evolved over the last several years.

We have supported 9 patients with primary graft dysfunction, 6 with ventricular assist devices and 3 with total artificial hearts [20]. None of them were weaned and only 2 could undergo retransplantation. One of these patients achieved long-term survival. In the case of refractory acute rejection, only a few successes have been reported in the literature [21]. In our series, we have supported 5 patients and none of them could undergo retransplantation [22]. We therefore think that primary graft failure and refractory acute rejection are contraindications to ventricular assist device support.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We are indebted to Aileen Caufield and Thierry Berney for their dedication in preparing the manuscript and to Monique Thallier, who helped us in collecting the data.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Ensley R.D., Hunt S., Taylor D.O., et al. Predictors of survival after repeat heart transplantation. J Heart Lung Transplant 1992;11:S142-S158.[Medline]
2. Michler R.E., McLaughlin M.J., Chen J.M., et al. Clinical experience with cardiac retransplantation. J Thorac Cardiovasc Surg 1993;106:622-631.[Abstract]
3. Martinelli L., Rinaldi M., Goggi C., et al. Emergency and elective cardiac transplantation. Eur J Cardiothorac Surg 1993;7:587-590.[Abstract]
4. Dein J.R., Oyer P.E., Stinson E.B., Starnes V.A., Shumway N.E. Cardiac retransplantation in the cyclosporin era. Ann Thorac Surg 1989;48:350-355.[Abstract]
5. Smith J.A., Ribakove G.H., Hunt S.A., et al. Heart retransplantation: the 25-year experience at a single institution. J Heart Lung Transplant 1995;14:832-839.[Medline]
6. Loire R., Boissonnat P. Cardiac retransplantation. Indications and outcome. Arch Mal Coeur 1996;89:229-234.
7. Hosenpud J.D., Novick R.J., Bennett L.E., Keck B.M., Fiol B., Daily O.P. The Registry of the International Society for Heart and Lung Transplantation: thirteenth official report—1996. J Heart Lung Transplant 1996;15:655-674.[Medline]
8. Nataf P., Pavie A., Bramaconte L., Bors V., Cabrol C., Gandjbakhch I. Myocardial protection by blood cardioplegia and warm reperfusion in heart transplantation. Ann Thorac Surg 1992;53:525-526.[Abstract]
9. Lower R.R., Shumway N.E. Studies on orthotopic transplantation of the canine heart. Surg Forum 1960;11:18-20.[Medline]
10. Cabrol C., Gandjbakhch I., Pavie A., et al. Heart and heart-lung transplantation: technique and safeguards. Heart Transplant 1984;3:110-114.
11. Cabrol C., Gandjbakhch I., Pavie A., et al. Modification in orthotopic heart transplantation: surgical technique. Clin Transplant 1987;1:95-98.
12. Desruennes M., Corcos T., Cabrol A., et al. Doppler echocardiography for the diagnosis of acute cardiac allograft rejection. J Am Coll Cardiol 1988;12:63-70.[Abstract]
13. Desruennes M., Solis E., Cabrol A., et al. Doppler echocardiography: an excellent noninvasive method for the detection of acute cardiac allograft rejection. Transplant Proc 1989;21:3634-3645.[Medline]
14. Billingham M.E., Cary N.R., Hammond E., 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;9:587-593.[Medline]
15. Stratta J.R., Choong-San O., Sollinger H.W., et al. Kidney retransplantation in the cyclosporine era. Transplantation 1988;45:40-45.[Medline]
16. Almond S.P., Matas A.J., Gillingham K., et al. Risk factors for second renal allografts immunosuppressed with cyclosporine. Transplantation 1991;52:253-258.[Medline]
17. D’Allesandro A.M., Ploeg R.J., Knechtle S.J., et al. Retransplantation of the liver: a seven-year experience. Transplantation 1993;55:1083-1087.[Medline]
18. Stratta R.J., Taylor R.J., Sudan D., Sindhi R., Castaldo P. Experience with pancreas retransplantation. Transplant Proc 1995;27:3020-3021.[Medline]
19. Cabrol C., Pavie A., Gandjbakhch I. Retransplantation cardiaque: expérience de la Pitié. In: Cabrol C., ed. Greffes cardiaques. Paris: Flammarion, 1996:214-217.
20. Kawaguchi A.T., Cabrol C., Gandjbakhch I., Pavie A., Bors V., Muneretto C. Preoperative risk analysis in patients receiving Jarvik-7 artificial heart as bridge to transplantation. Eur J Cardiothoracic Surg 1991;5:509-514.[Abstract]
21. Oaks T.E., Pae W.E., Miller M.A., Pierce W.S. Combined registry for the clinical use of mechanical ventricular assist pump and the total artificial heart in conjunction with heart transplantation: fifth official report. J Heart Transplant 1990;10:621-625.
22. Pavie A., Leger P., Rabago G., et al. Clinical use of mechanical cardiac assist devices. In: Akutsu T., Koyanagi H., eds. Heart replacement artificial heart 4. New York: Springer-Verlag, 1993:185-191.

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