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Three Part Question

In patients with [acute heart transplant failure] is [re-transplantation] a valid treatment option in terms of an acceptable [operative and long term mortality]?

Clinical Scenario

You are performing a heart transplant on a 34 year old lady who had a diagnosis of dilated cardiomyopathy. The Donor heart was harvested by another unit. The harvesting surgeon stated that the heart was good quality but in his clinical notes that came with the donor heart he reported a short period of ventricular dilatation prior to explantation.
The transplant is proceeding without complication until you reperfuse the heart and prepare to wean the patient off bypass. No activity returns to the heart and even after 2 hours of reperfusion the donor heart shows no sign of myocardial contraction or electrical activity.
The patient remains on bypass for a further 6 hours, during which time your hospital receives another offer of a heart, which would be entirely suitable for this lady. However there is also a 56-year-old man on your list for which it would also be suitable.
After much discussion with your colleagues it is decided that an acute re-transplantation would be too high risk and the man should get the heart. Your patient has a Left and Right Impella Recover device in order to allow this first donor heart more time to recover.
Unfortunately on the Intensive Care the patient's clinical condition quickly deteriorates and she dies 24 hours later.
You are still unsure as to the success rate of acute re-transplantation and also whether the long-term survival is as good with acute re-transplantation and therefore you resolve to look up the literature on this subject.

Search Strategy

Medline 1966-Jul 2004 and EMBASE 1980-Jul 2004 using the OVID interface
[re-transplant$.mp OR retransplant$.mp] AND [heart.mp or cardiac.mp]

Search Outcome

458 papers were identified by the above search of which 11 papers were deemed to be relevant. In addition the ISHLT registry, 2 relevant case reports and 4 papers identified by cross-checking reference lists were also identified

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Radovancevic et al 2003 USA	106 patients undergoing re-transplantation from a database of 7,290 primary heart transplants from 42 USA and Canadian centres. (1990-1999) Reasons for re-transplantation were: Early graft failure (n=34) Acute cardiac rejection (n=15) Coronary allograft vasculopathy (n=39) Miscellaneous (n=17)	Cohort study (level 2b)	1 year Survival of all re-transplantation patients vs primary transplant	Re-transplant 54% 1-year survival	Patients undergoing re-transplantation for coronary allograft failure after 1996 had same survival to primary heart transplant patients. Results poor for patients undergoing re-transplant <6 months after first surgery and for acute graft failure or acute rejection
			Acute rejection	Survival of 32% at 1 yr and 8% at 5 yrs
			Acute re-transplantation <1 month after primary Tx	45% 1 year survival (n=36)
Srivastava 2000 USA	514 adult patients who underwent cardiac retransplantation in the united states between October 1987 and August 1998. data obtained from Joint ISHLT and UNOS registries. Time to re-transplantation 1 day to 15.5 years.	Cohort study (level 2b)	Survival after re-transplantation	65% 1 yr survival. 59% 2 yr survival. 55% 3 yr survival. 1/3rd of deaths within 30 days	One year follow up data available in only 234 patients (45.5%) 90% of patients on inotropes, 27% had a VAD, 31% on a ventilator, 23% IABP
			Primary transplant survival	80% 1 yr survival 70% 3 yr survival
			Re-transplantation within 6 months of first transplant	50% 1 yr survival
Schlechta 2001 Austria	Cohort of 31 heart re-transplantations Performed at a single institution between March 1984 and December 1999.	Cohort study (Level 2b)	Survival for re-transplantation	48% 1 yr survival. 44% 3 yr survival. 37% 5 yr survival	No break down of individual cases or description of time between transplants. Very brief paper.
			Survival for primary transplantation	80% 1 yr survival. 74% 3 yr survival. 67% 5 yr survival
Schnetzler 1998 France	24 re-transplantations from 1973 to 1996, compared to 47 first transplants in patients matched for date of transplantation. Cause 4 primary graft failure, 7 acute rejection, 11 coronary graft disease, 2 misc.	Case control study (level 3b)	Survival at 1 year	Re-transplantation 45.5% 1 yr survival. primary transplant 59.4% 1 yr survival p=0.07	The cohort has 4 patients with primary graft failure who were re-transplanted at day 1, 3, 9 and 30 respectively and only the last patient was alive in 1999 after 9 yrs after the graft while the others died at day 1,3 and 13.
			Survival if re-transplant <1 yr after first operation	27% 1 yr survival
			Survival if re-transplant > 1 yr after first operation	62% 1 yr survival 46% 4 yr survival
Miller et al 1995 USA	63 patients undergoing re-transplantation at a single institution since 1968. Causes 9 primary allograft failure 17 acute rejection 37 graft atherosclerosis 3 constrictive disease	Cohort study (level 3b)	Survival	55% 1 yr survival. 33% 5 yr survival. 22% 10yr survival. (Compared to 81% 1yr and 44% 5 yr survival in primary transplants)
			In hospital mortality post 1981 (cyclosporine era)	24% in hospital mortality
John et al 1999 USA	43 patients undergoing re-transplantation from 1977 to 1999 at a single centre. Cause 33 graft coronary disease 7 acute rejection 2 primary graft failure Interval: 10 hours to 11 yrs	Cohort study (level 2b)	Survival in re-transplantation	Re-transplantation 66% 1yr survival. 51% 5 yr survival	5 patients had re-transplantation within 1 month, all died
			Survival in primary transplantation	Primary transplant 76% 1 yr survival 71% 2 yr survival 60% 5 yr survival. p=0.2 between groups
			Survival after 1993 when primary graft failure or acute rejection<6 months post surgery refused re-transplantation	94% 1yr survival 94% 2yr survival 94% 3 yr survival
Mullins et al 1991 UK	12 patients undergoing acute re-transplantation at Papworth hospital 1 patient re-transplanted day 1, 3 within 11 days and 8 due to coronary occlusive disease	Case series (level 4)	Survival	All 4 patients re-operated within 11 days died.	This is a letter only
Loire R, Boissonnat P 1996 France	38 patients undergoing 42 re-transplants 26 cases of graft coronary disease 12 patients with acute graft failure and rejection (50% re-operated within 12 days)	Cohort study	Survival	Re-transplantation for graft coronary disease similar to primary transplantation. In Acute re-transplantation group 9 out of 12 patients died
Michler et al 1993 USA	14 patients undergoing re-transplantation Causes 8 graft coronary disease 5 rejection 1 intra-operative graft failure	Cohort study (level 2b)	Survival	Re-transplantation 71% 1 yr survival. 60% 2 yr survival. Primary transplant 75% 1 yr survival 71% 2 yr survival. P =N/S
Kanter et al 2004 USA	17 children undergoing 20 re-transplantations mean interval was 5.5 years	Cohort study (level 3b)	Survival at 1 and 3 yrs	Re-transplantation 94% 1 yr survival, 78% 3 yr survival. Primary transplant 81% 1 yr survival 73% 3 yr survival.	Only 2 children had re-transplantation due to acute graft failure, one died.
Dearani et al 2001 USA	22 children undergoing re-transplantation from 1985-1999 Causes 5 primary graft failure 1 acute rejection 16 allograft vasculopathy 2 patients had re-transplantation within 24 hrs while on ECMO, and one child required iv inotropes and haemodialysis Transplant interval 1 day to 9.4 years	Cohort study (level 2b)	Survival	Re-transplantation 82% 3 year survival. Primary transplant 77% 3 year survival. Re-transplantation 1 of 19 intra-operative deaths	Both children who required ECMO and the child who required iv inotropes died within 30 days.
Taylor et al 2004	ISHLT registry from 1982-2003, of which 2% are re-transplantations. 19% of patients transplanted in 2003 are on LVAD support 13,523 patients from 1995-98 7,067patients from 1999-Jun 2002 (Roughly 140 re-transplants)	Cohort study (level 2b )	Survival of re-transplantation when >12 months after first transplant	Re-transplantation 82% 1 yr survival. Primary transplant 83% 1yr survival.	LVAD implantation is no longer a risk factor for mortality.
			Risk of re-transplantation on mortality	1995-1998 re-transplant Odd ratio for increased risk 1.76 P<0.0001. 1999-Jun 2002 re-transplant odds ratio for increased risk 1.08 p=0.7
de Boer et al 1991 USA	46 patients in the Eurotransplant programme undergoing re-transplant after acute graft failure and high urgent listing. 13 patients had an LVAD and 5 patients had an IABP	Cohort study (level 2b)	Survival	1 year survival was 36% compared to 81% for primary transplant Patients on LVAD support had a 21% 1 year survival	23 cases re=transplanted within 30 days 28/46 re=transplants failed at a median of 5 days (range 1-213 days), 17 within 1 week
Marelli et al 2000 USA	56 patients undergoing re-transplantation at UCLA, California, from 1988. 9 patients had re-transplantation for acute graft failure.	Cohort study (level 2b)	Survival	Re-transplantation 43% 5-year survival. Primary transplantation 75% 5-year survival	Report on 47 re-transplantations is a short report of their full experience of 1,000 transplants in this paper
			Survival in acute graft failure group	6/9 patients having re-transplantation for acute graft failure died within 60 days
Ensley et al 1992 USA	449 patients undergoing re-transplantation, reported to the registry of The International Society for Heart and Lung Transplantation from 1968 to 1991, and a matched group of 421 primary heart transplants. Groups matched for centre, gender, age, and date of transplant.	Cohort study (level 2b)	1 year survival	Re-transplantation 48% 1-year survival Primary Transplant 79% 1-year survival. 'Ideal' patients undergoing re-transplation. 68% 1-year survival.	Re-transplantation patients had a 15% 24 hour mortality. This is data from a very old database.
			Risk Factors for decreased survival for re-transplantation	Re-transplantation less than 6 months from first. (61%vs36%). Acute rejection. Mechanical assistance. Date of operation.

Comment(s)

Radovancevic et al searched the Cardiac Transplant Research Database from the USA and Canada from 1990-1999, specifically looking at the results of 106 patients undergoing re-transplantation. They found that patients who had suffered early graft failure or acute rejection performed particularly poorly as did any patients re-operated within 6 months of the first transplant with a 1 year survival of less than 50%. They did report that in the last 4 years of the database figures were improving and that coronary allograft vasculopathy patients were now surviving as successfully as primary heart transplant patients. It is not clear from this paper how acutely the 36 patients who had re-transplantation less than 1 month post-op had their second operation. Shrivastava in 2000 reported results from 514 patients who had undergone re-transplantation. They found only a 50% 1yr survival in patients having re-transplantation within 6 months of their first operation, and only a 65% 1 yr survival overall. This was a very ill cohort of patients with 90% on iv inotropes, 27% on a ventricular assist device and 32% ventilated, although there was no subset analysis of patients having a re-transplantation within days of first operation. Of note this study had 1 year follow up data on only 45% of their patients. Schlechter briefly reported the Vienna experience of 31 cases. They had a 48% 1-year survival and a 37% 5-year survival although they did not report any breakdowns of the clinical status of the patients or the time to re-transplantation. Schnetzler reported 24 cases of re-transplantation. 4 patients had early re-operation, at days 1, 3, 9 and 30 and only the patient having the re-operation at 30 days survived. Overall results showed a 46% 1-year survival Smith et al reported the results of 63 patients who underwent re-transplantation. They achieved an overall 55% 1 year survival and a 33% 5 year survival which was significantly poorer than their 81% 1 year survival in primary heart transplant patients. John et al reported a dismal survival in patients with acute graft failure with death occurring in all 5 patients being re-transplanted within 1 month of primary transplant. However after they instituted new guidelines for re-transplantation, namely excluding patients with acute graft failure, acute rejection within 6 months, end-organ dysfunction or pulmonary hypertension, their 4-year survival was 94%. Also the overall results of the 43 patients undergoing re-transplantation were not significantly different to their cohort of primary transplants. In 1988 the Eurotransplant organ exchange programme initiated a 'high urgency' priority for patients undergoing re-transplantation for acute graft failure. 46 patients underwent re-transplantation, 13 of whom had a Left ventricular assist device (LVAD) and 5 with an IABP. The survival was poor with only a 36% 1-year survival. In addition, patients on an LVAD had a 21% 1-year survival and 17 of all 28 deaths occurred within 1 week of retransplantation. These results were disappointing and the High urgency system for re-transplant was stopped. Papworth surgeons replied in a letter to these reports stating that in 4 patients re-transplanted by themselves within 11 days of acute failure all died, and only 8 patients with coronary occlusive disease have so far survived in their experience. Loire et al in France performed 42 re-transplantations in 38 patients. While survival was comparable to primary surgery in patients that suffered graft coronary disease, 9 out of 12 patients who suffered acute graft failure died after re-transplantation. Michler reported 13 patients who underwent re-transplantation. Their 71% 1-year survival was similar to primary transplantation, although all but one were performed more than 30 days after first transplant. They conclude that except for acute graft failure, re-transplantation has a good survival. 2 case reports were found that were similar to our own case scenario (not included in the table). Jurmann reported the case of a patient who had immediate graft failure. An IABP was placed and an RVAD to assist the right ventricle and allow weaning from bypass. This patient was then quickly re-transplanted and is NYHA class I, 13 months after re-transplantation. In a second patient reported by Wahlers, the donor heart suffered left ventricular distension on harvesting. Immediate graft failure occurred complicated by aortic valve insufficiency. The Aortic valve was replaced, and an IABP inserted, but CPB could not be weaned. After 11 hours on CPB another donor heart became available and was successfully re-transplanted, and the patient was well 3 months post-operatively. Marelli et al reported their experience with 47 re-transplantations. 6 of the 9 patients with acute graft failure died and overall the 5-year survival was 43%, which was significantly poorer than their 75% survival in 1,000 primary transplantations. Ensley performed a risk analysis of 449 patients who underwent re-transplantation from the ISHLT database from 1968-1991. They found that patients undergoing re-transplantation had a significantly lower survival with a 48% 1-year survival, compared to 79% for primary transplant. Predictive risk factors for mortality were: re-transplant within 6 months of the first operation; presence of a mechanical assist device and acute graft failure. In contrast to adults, children seem to do better with re-transplantation, although acute graft failure is still associated with a high mortality. Kanter reported a 95% 1-year survival in 17 children, although 1 of the 2 children with acute graft failure died. Dearani reported re-transplantation in 22 patients. They report an 81% 3-year survival, which is the same as for their primary transplants, although 2 patients on ECMO and one patient on iv inotropes died. The ISHLT is the largest registry of Heart transplants and has provided a yearly report for many years now, including reports on re-transplantation in the past. Here only the 2004 paper is included. This report provides some very interesting data on re-transplantation. In contrast to previous years, re-transplantation is no longer a risk factor for increased mortality, with the odds ratio for increased risk having dropped from 1.76 in 1995-98 to 1.08 in 1999-2002. This is thought to be due to more stringent guidelines for re-transplantation, and alternative strategies for acute graft failure including mechanical assist devices. It is also interesting to note that the presence of a mechanical assist device no longer contributes to decreased survival. The registry reports that the incidence of re-transplantation remains at around 2% with around 140 being performed between 1999-2002. Thus in summary, acute re-transplantation due to graft failure has been a much-tested strategy but is associated with a high mortality. Far more successful is re-transplantation for graft coronary disease many months or years after primary surgery. In view of the decreasing availability of donor hearts and the improving success of mechanical assist devices, the management of acute graft failure or acute rejection should now consist entirely of placement of a mechanical assist device. The ISHLT reports that this strategy allows safe re-transplantation in patients with graft coronary disease or stable patients with mechanical assist devices.

Clinical Bottom Line

While re-transplantation for graft coronary disease has a similar survival to patients undergoing primary transplantation, acute graft failure or rejection should be treated with a mechanical assist device, as acute re-transplantation is associated with an unacceptably high mortality.

References

1. Radovancevic B, McGiffin DC, Kobashigawa JA, Cintron GB, Mullen GM, Pitts DE, O'Donnell J, Thomas C, Bourge RC, Naftel DC. Retransplantation in 7,290 primary transplant patients: a 10-year multi-institutional study. J Heart Lung Transplant 2003;22:862-868.
2. Srivastava R, Keck BM, Bennett LE, Hosenpud JD. The results of cardiac retransplantation: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Sharing Thoracic Registry. Transplantation 2000;70:606-612.
3. Schlechta B, Kocher AA, Ehrlich M, Ankersmit J, Ploner M, Walch K, Nourani F, Czerny M, Wolner E, Grimm M. Heart retransplantation: institutional results of a series of 31 cases. Transplant Proc. 2001;33:2759-2761.
4. Schnetzler B, Pavie A, Dorent R, Camproux AC, Leger P, Delcourt A, Gandjbakhch I. Heart retransplantation: a 23-year single-center clinical experience. Ann Thorac Surg 1998;65:978-983.
5. Smith JA, Ribakove GH, Hunt SA, Miller J, Stinson EB, Oyer PE, Robbins RC, Shumway NE, Reitz BA. Heart retransplantation: the 25-year experience at a single institution. J Heart Lung Transplant 1995;14:832-839.
6. John R, Chen JM, Weinberg A, Oz MC, Mancini D, Itescu S, Galantowicz ME, Smith CR, Rose EA, Edwards NM. NM Long-term survival after cardiac retransplantation: a twenty-year single-center experience. J Thorac Cardiovasc Surg 1999;117:543-555.
7. Mullins P, Scott J, Chauhan A, Graham T, Aravot D, Large S, Schofield P, Wallwork J. Acute heart retransplantation.[comment]. Lancet 1991;337:1552-1553.
8. Loire R, Boissonnat P. [Cardiac retransplantation (42 cases in 38 patients). Indications and outcome]. [French]. Arch Mal Coeur Vaiss. 1996;89:229-234.
9. Michler RE, McLaughlin MJ, Chen JM, Geimen R, Schenkel F, Smith CR, Barr ML, Rose EA Clinical experience with cardiac retransplantation. J Thorac Cardiovasc Surg 1993;106:622-629.
10. Jurmann MJ, Wahlers T, Coppola R, Fieguth HG, Haverich A. Early graft failure after heart transplantation: management by extracorporeal circulatory assist and retransplantation. J Heart Transplant 1989;8:474-478.
11. Wahlers T, Frimpong-Boateng K, Haverich A, Schafers HJ, Fieguth HG, Coppola R, Jurmann M, Borst HG. Management of immediate graft failure after cardiac transplantation using cardiopulmonary bypass and intraaortic balloon-pumping followed by cardiac retransplantation. Thorac Cardiovasc Surg 1986;34:389-390.
12. Kanter KR, Vincent RN, Berg AM, Mahle WT, Forbess JM, Kirshbom PM. Cardiac retransplantation in children. Ann Thorac Surg 2004;78:644-649.
13. Dearani JA, Razzouk AJ, Gundry SR, Chinnock RE, Larsen RL, del Rio MJ, Johnston JK, Bailey LL. Pediatric cardiac retransplantation: intermediate-term results. Ann Thorac Surg 2001;71:66-70.
14. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Keck BM, Hertz MI. The registry of the international Society for Heart and Lung Transplantation: Twenty-first Official Adult Heart Transplant Report-2004. J Heart Lung Transplant 2004;23:796-803.
15. de Boer J, Cohen B, Thorogood J, Zantvoort FA, D'Amaro J, Persijn GG. GG Results of acute heart retransplantation. Lancet 1991;337:1158.
16. de Boer J, Cohen B, Thorogood J, D'Amaro J, Persijn GG. Results of acute heart retransplantation in Eurotransplant. Transpl. Int. 1992;5 Suppl 1:S219-S220.
17. Marelli D. Laks H. Bresson J. Houston E. Fazio D. Tsai FC. Hamilton M. Moriguchi J. Fonarow GC. Ardehali A. Camara R. Burch C. Alejos JC. George B. Kawata N. Kobashigawa J. Sixteen-year Experience with 1,000 Heart transplants at UCLA. Clinical Transplants 2000:297-310.
18. Ensley RD, Hunt S, Taylor DO, Renlund DG, Menlove RL, Karwande SV, O'Connell JB, Barr ML, Michler RE, Copeland JG, Miller LW. Predictors of survival after repeat Heart Transplantation. J Heart Lung Transplant 1992:11:S142-58.