Ten year survival after heart transplantation:
palliative procedure or successful long term
treatment?
S Fraund, K Pethig, U Franke, T Wahlers, W Harringer, J Cremer, H-G Fieguth,
P Oppelt, A Haverich
Abstract
Objective—To investigate the long term
outcome and prognostic factors after
heart transplantation.
Setting—University hospital.
Subjects—120 heart transplant patients
(98 male, 22 female; underlying disease:
dilated cardiomyopathy in 69, coronary
artery disease in 42, miscellaneous in
nine) who had undergone heart transplan-
tation between October 1984 and October
1987. Immunosuppressive treatment was
comparable in all patients and rejection
episodes were treated in a uniform man-
ner.
Methods—Functional status, quality of
life, and potential predictors for long term
survival were investigated.
Results—Actuarial survival rates were
65% at five years and 48% at 10 years; 58
patients survived > 10 years. The major
causes of death were cardiac allograft vas-
culopathy (39%), acute rejection (18%),
infection (11%), and malignancy (11%).
Long term survivors had good exercise
tolerance assessed by the New York Heart
Association classification: 47 (81%) in
grade I/II; 11 (19%) in grade III/IV.
Echocardiography showed good left ven-
tricular function in 48 patients. On angio-
graphy, severe allograft vasculopathy was
present in only 16 patients (28%). Renal
function was only slightly impaired, with
mean (SD) serum creatinine of 148.5
(84.9) µmol/l. Multiple potential predic-
tors of long term survival were analysed
but none was found useful.
Conclusions—Heart transplantation rep-
resents a valuable form of treatment. Sur-
vival for more than 10 years with a good
exercise tolerance and acceptable side
eVects from immunosuppression can be
achieved in about 50% of patients.
(Heart 1999;82:47–51)
Keywords: heart transplantation; long term survival
Despite recent progress in the conservative
treatment of symptomatic heart failure, the
clinical course of this disease remains dismal.
1–3
The introduction of vasodilators and angio-
tensin converting enzyme (ACE) inhibitors has
improved the outcome significantly
4–7
but mor-
tality remains high. A six month mortality of
between 20% and 30%, as shown in the
CONSENSUS (cooperative north Scandina-
vian enalapril survival study), cannot be
regarded acceptable.
6
Heart transplantation provides the most
eVective treatment for patients with end stage
heart failure.
8
Approximately 500 transplanta-
tions are performed in Germany each year.
With the introduction of cyclosporin as an
immunosuppressive agent in the 1980s,
marked improvements in survival were
achieved in heart transplant programmes.
9
However, only limited data are available on the
long term success of this procedure. We there-
fore analysed data from patients surviving
more than 10 years after heart transplantation
and compared them with the results in patients
who died before 10 years.
The aim of the study was to assess the long
term survival after heart transplantation in a
single centre; to characterise quality of life, as
defined by exercise tolerance and end organ
function; and to identify potential predictors of
long term survival.
Methods
STUDY POPULATION
We studied a cohort of 120 patients (98 male,
22 female) who had undergone heart trans-
plantation at our institution between October
1984 and October 1987. They were followed
up closely during the entire period under the
Hannover medical school transplant pro-
gramme until 1997. Baseline demographic
data on the patients are summarised in table 1.
The cause of end stage heart failure and the
indication for heart transplantation was dilated
cardiomyopathy in 69 patients (57.5%), coron-
ary artery disease in 42 (35%), and miscellane-
ous (valve related disease, hypertrophic ob-
structive cardiomyopathy, endocardial fibrosis)
in nine (7.5%). The mean (SD) age of
recipients at the time of transplantation was
42.3 (11.8) years, mean donor age was 25.6
(8.7) years, with 83 male and 27 female donors
(10 with missing data). Eight patients required
retransplantation, five within the first 20 days
owing to acute graft failure and another three
between 3.0 and 9.1 years after transplantation
owing to chronic allograft vascular disease
(CAVD).
IMMUNOSUPPRESSION, DRUG TREATMENT, AND
MONITORING OF REJECTION
All recipients were treated with a similar
immunosuppressive regimen, based on triple
therapy using cyclosporin A, prednisolone, and
azathioprine. The cyclosporin A target levels
Heart 1999;82:47–51 47
Department of
Thoracic and
Cardiovascular
Surgery, Hannover
Medical School, 30623
Hannover, Germany
S Fraund
K Pethig
U Franke
T Wahlers
W Harringer
J Cremer
H-G Fieguth
P Oppelt
A Haverich
Correspondence to:
Dr Pethig.
Accepted for publication
18 February 1999
were 250 to 300 µg/l for the first year, 150–200
µg/l for the second, and then 100–150 µg/l
(monoclonal assay). Dose adjustments were
determined according to serum creatinine
concentrations, maximum values of 120 to 150
µmol/l being considered acceptable. In 99
patients, inductive cytolytic treatment with
antithymocyte globulin (ATG) was given. All
patients were monitored with routine en-
domyocardial biopsies and echocardiography.
Episodes of rejection were treated with a three
day course of methylprednisolone (500–1000
mg/day). Standard drugs were used for the
treatment of hypertension, with ACE inhibitors
as first choice and calcium channel blockers of
the nifedipine type and clonidine used in addi-
tion as required. Almost every patient received
diuretic treatment with low dose frusemide
(furosemide) (20 mg/day).
FOLLOW UP DATA
Patients were seen regularly at the outpatient
department at least every three months beyond
the first year after transplantation. Quality of
life of the surviving patients was assessed, using
a standardised questionnaire. Coronary angio-
graphies were performed at one to two year
intervals. Cardiac catherisation results were
available in the 58 long term survivors and the
31 deceased patients who lived for more than
one year after their transplants. Classification
of CAVD was as follows: grade 0, normal
angiogram; 1, luminal obstruction < 30%; 2,
31–50%; 3, > 50%; 4, complete closure of the
vessel.
ANALYSIS OF PREDICTIVE FACTORS
Analysis of predictive factors was performed
comparing characteristics of long term survi-
vors with deceased patients. The following
variables were analysed: recipient age, donor
age, sex, cytomegalovirus (CMV) status, HLA
mismatch (available in 73 cases), lipid levels at
year 1, ischaemic time, ATG induction treat-
ment, mean dose/day of cyclosporin A, azathio-
prine, and prednisolone at year 1, and the
number of antihypertensive drugs at year 1.
DATA ANALYSIS
Data analysis was performed using a computer
assisted software package (SPSS, version
6.0.1). Continuous variables are presented as
mean (SD). Univariate comparison between
surviving and deceased patients for diVerent
risk factors was performed by ÷
2
test for
non-continuous variables and by unpaired two
tailed t test for continuous values. For multi-
variate analysis, a logistic regression was
chosen (backward, LR). Probability (p) values
< 0.05 were considered significant. Actuarial
survival rates were computed according to the
Kaplan–Meier estimate using the log rank test.
Results
SURVIVAL
Of the total cohort, 58 patients survived more
than 10 years, with an actuarial survival rate of
78.3% at 1 year, 65% at 5 years, and 48% at 10
years (fig 1).
There were 62 deaths among the study
population during the follow up period. Causes
of death in the entire study group are given in
fig 2A. The most common causes of death were
chronic graft failure owing to CAVD (n = 24;
39%), early right heart failure (n = 11; 18%),
infections (n = 7; 11.2%), and malignancies
(n = 7; 11.2%). Forty per cent of the deaths
occurred within the first year of transplanta-
tion, mainly from acute graft rejection. Causes
of death in year 1 are shown in fig 2B.
GRAFT FUNCTION AND SIDE EFFECTS OF
IMMUNOSUPPRESSION
In the study population, 58 patients (48.3%)
survived the 10 year period, with a mean
observation period of 11.1 (0.7) years. Assess-
ment of the quality of life by the self assessment
questionnaire was optimistic in about 75% of
the patients. Only two patients were seriously
dissatisfied. To the question “Would you
decide to have a heart transplant again?” only
five gave a negative response. Exercise toler-
Table 1 Patient characteristics and evaluation of potential predictors for long term
survival
All patients
(n = 120)
Long term
survivors
(n =58)
Deceased
patients
(n = 62) p Value
Recipient related factors
Age at transplant (years) 42.3 (11.8) 42.1 (11.5) 42.5 (11.6) 0.8
Sex
Male 98 (81.7%) 49 (84.5%) 49 (79%) 0.4
Female 22 (18.3%) 9 (15.5%) 13 (21%)
Cause of heart failure
DCM 69 (57.5%) 36 (62.1%) 33 (53.2%) 0.2
CAD 42 (35%) 16 (27.6%) 26 (41.9%)
Others 9 (7%) 6 (10.3%) 3 (4.8%)
Cholesterol at year 1 (mmol/l) 6.7 (2.0) 7.0 (2.3) 6.4 (1.6) 0.1
Triglycerides at year 1 (mmol/l) 2.6 (1.8) 2.6 (1.9) 2.5 (1.4) 0.8
Donor related factors
Donor age 25.6 (8.7) 23.9 (8.8) 26.9 (8.4) 0.08
Donor sex
Male 83 (69.2%) 38 (65.5%) 45 (72.6%) 0.9
Female 27 (22.5%) 12 (20.7%) 15 (24.2%)
CMV mismatch (mismatch/non-
mismatch) 25/40 9/17 16/23 0.4
Ischaemic time (min) 137.6 (43.1) 137.2 (42.8) 138 (43) 0.9
HLA mismatch (47 missing) 4.6 (0.9) 4.6 (1.0) 4.6 (0.9) 0.8
Drug treatment
ATG treatment 99 46 53 0.7
Mean dose of cyclosporin (mg/day) 327.8 (83.0) 318.7 (81.8) 338.1 (84.0) 0.2
Mean dose of azathioprine (mg/day) 99.8 (30.4) 102 (25.5) 97 (35.2) 0.4
Mean dose of prednisolone at year 1
(mg/day) 10.9 (3.4) 10.7 (3.7) 10.9 (3.0) 0.8
Number of antihypertensive drugs at
year 1 1.2 (0.9) 1.0 (0.9) 0.7
Data are expressed as mean value (SD) and n (%). Groups were compared by unpaired two tailed
t test for independent values. Non-continuous variables were assessed by ÷
2
analysis. p Values
< 0.05 were considered statistically significant.
ATG, antithymocyte globulin; CAD, coronary artery disease; DCM, dilated cardiomyopathy.
Figure 1 10 year actuarial survival rates computed by
Kaplan–Meier estimate:
*
—
*
, dilated cardiomyopathy as
the underlying disease;
v
—
v
, coronary artery disease as the
underlying disease.
1.0
0.9
0.7
0.8
0.6
0.4
0.5
0.3
10864
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
20
48 Fraund, Pethig, Franke, et al
ance in long term survivors could be shown to
be excellent, with 14 patients (24.1%) being in
New York Heart Association (NYHA) func-
tional class I, 33 (56.9%) in class II, nine
(15.5%) in class III, and two (3.4%) in class IV,
as assessed by routine visits to the outpatient
department. Normal graft function was dem-
onstrated by echocardiographic quantification
of left ventricular contractility, with a mean
(SD) ejection fraction of 61 (5)%.
As an index of end organ impairment we
assessed renal function, defined by serum cre-
atinine. The mean serum creatinine was 148.5
(84.9) µmol/l, showing an acceptable func-
tional status, with only one patient requiring
chronic haemodialysis. Table 2 gives the data
for this group.
ALLOGRAFT VASCULOPATHY
The most recent coronary angiography in the
survivors showed no signs of graft vasculopathy
in 27 patients (46.6%), 15 (25.8%) had a
luminal obstruction of grade 1 or 2, and only
16 (27.6%) had high grade vasculopathy. Cor-
onary angiograms were available in 31 de-
ceased patients; in 13 cases (41.9%) a luminal
obstruction of 50% and more was detectable,
as compared with 16/58 (27.6%) in long term
survivors. In addition, the latency until the first
sign of graft vasculopathy (< 30% luminal
obstruction) diagnosed in this group was 40.9
(31.6) months, whereas the latency in the long
term surviving group was 76.4 (28.5) months.
MALIGNANCY
There was a high incidence of malignant
tumours in both the deceased patients and the
long term survivors. In the overall cohort, 17
patients (14.1%) developed non-cutaneous
malignant tumours, with lymphoma being the
commonest (nine cases, 52.9% of all tumours).
Malignancy was the cause of death in 11% of
the deceased patients. However, malignant dis-
ease was found in the long term survivors as
well (eight cases (13.7%): lymphoma in three,
lung cancer in two, colon cancer in one, and
haematological neoplasia in one), five of these
being in complete remission after successful
treatment at the time of writing.
ANALYSIS OF PREDICTIVE FACTORS
Analysis of predictive factors was performed
comparing characteristics of the long term sur-
vivors and the deceased patients. Using both a
univariate analysis and a multivariate logistic
regression, no independent predictors of long
term survival for more than 10 years could be
identified. The data on factors relating to
recipient, donor, procedure, and treatment are
summarised in table 1. There was no signifi-
cant diVerence between the two groups. There
was a trend for a higher proportion of patients
with dilated cardiomyopathy to survive more
than 10 years after heart transplantation; this
resulted in a 10 year survival rate of 38% for
coronary artery disease versus 55% for dilated
cardiomyopathy (NS, log rank test).
Discussion
During the past 25 years considerable progress
has been made in understanding the pathogen-
esis of the heart failure syndrome. On the basis
of this knowledge several advances have been
made in the conservative management in this
patient group.
5610
However, despite the intro-
duction of vasodilators and ACE inhibitors,
one year mortality still ranges from 15% among
unselected patients to 50% among those in
NYHA functional class IV.
67
In contrast, heart transplantation allows one
year and five year survival rates of about 80%
and 60% to 70%, respectively.
11
However, with
more than 30 years of clinical experience with
replacement of the heart, only limited data are
Figure 2 (A) Causes of death in group as a whole; (B) causes of death in year 1.
A
11%
11%
18%
39%
Allograft vasculopathy
21%
Early right heart failure
Infection
Malignancy
Other
B
28%
12%
48%
12%
Acute rejection
Non-specific graft failure
Infection
Other
Table 2 NYHA classification and organ function of long
term survivors
n(%)
Exercise tolerance
NYHA class I
class II
class III
class IV
14 (24.1)
33 (56.9)
9 (15.5)
2 (3.5)
Allograft vasculopathy
CAVD 0
1
2
3
4
27 (46.6)
9 (15.5)
6 (10.3)
15 (25.9)
1 (1.7)
Graft/organ function
Ejection fraction (%) 61 (5)
Mean creatinine (µmol/l) 148.5 (84.9)
Non-cutaneous malignancy 8 (13.7)
Classification of CAVD: grade 0, normal angiogram; 1, luminal
obstruction < 30%; 2, 31–50%; 3, > 50%; 4, complete closure
of the vessel.
NYHA, New York Heart Association.
Long term results after heart transplantation 49
available in allograft recipients surviving 10
years and more. We therefore analysed a
patient population undergoing heart transplan-
tation more than 10 years earlier to character-
ise survival, graft function, and side eVects of
immunosuppression in the hope of identifying
potential predictors of long term survival.
Our study represents a single centre ap-
proach with a 10 year survival rate of 48%,
compared with 45% reported by the multicen-
tre International Society for Heart and Lung
Transplantation registry. These results are far
superior to medical treatment alone. Before the
introduction of vasodilators and ACE inhibi-
tors, a one year mortality of approximately
50% was the norm with conservative
management.
12
In the CONSENSUS trial, in
which patients with severe heart failure were
randomised to receive placebo or enalapril in
addition to conventional treatment, the mor-
tality at 12 months was 36% in the enalapril
group and 52% in the placebo group.
6
In the
V-Heft I (vasodilator in heart failure) study,
which included patients with mild to moderate
clinical heart failure, the cumulative mortality
over four years was 53.6%.
7
However, quality of life is also a major issue
after heart transplantation. In the CONSEN-
SUS study, 42% of the enalapril treated
patients had improvement in their NYHA
functional class, but three quarters of the
surviving patients remained in NYHA func-
tional class III and IV. In our transplant popu-
lation the majority of patients (81%) were in
NYHA functional class I and II as long as 10
years after the procedure. Exercise tolerance
proved to be remarkably improved compared
with optimum medical treatment. Further-
more, invasive and non-invasive evaluation of
graft function by cardiac catherisation and
echocardiography revealed normal cardiac
function with a mean ejection fraction of 61
(5)%. These results are in agreement with the
findings of previous investigations.
13 14
In 1993,
von Scheidt evaluated the long term haemody-
namic profile of heart transplant recipients up
to seven years after the procedure and reported
essentially normal systolic function with no
evidence of the development of a dilated or
restrictive post-transplantation cardiomyopa-
thy over time.
14
Apart from good functional graft status,
accelerated graft vasculopathy was identified as
one of the most critical issues in the long term
follow up of heart transplant recipients.
15–18
This unique form of an accelerated coronary
syndrome is characterised by endothelial dys-
function and a multifocal intimal hyperplasia
modified by coronary artery remodelling.
19–21
The prevalence of this complication—as as-
sessed by angiography—is approximately 10%
to 15% at one year and 35% to 50% five years
after transplantation.
22 23
Recent reports were
also able to show positive eVects on the devel-
opment of CAVD by lipid lowering treatment
with statins as well as by diltiazem
administration.
24 25
Because of the retrospective
design of our study, comprising patients trans-
planted between 1984 and 1987, only a small
minority received these agents. Future pro-
spective studies will have to evaluate whether
the introduction of these drugs (in 1994/95)
has resulted in clinical benefit.
The clinical impact of CAVD on heart trans-
plantation was confirmed in our patient cohort.
CAVD was the major cause of death in 39% of
the patients. In deceased patients the first signs
of CAVD (30% luminal obstruction) were
diagnosed significantly earlier than in long
term survivors (after 40.9 (31.6) months v 76.4
(28.5) months, p < 0.05). Peak incidence of
death from CAVD was between five and 10
years after heart transplantation. Most interest-
ingly, the majority of long term survivors
presented with only low grade vasculopathy
(72.4% less than grade 2), suggesting a positive
selection in this subgroup and raising hopes for
a stable subsequent course.
Renal function in our cohort showed only
moderate impairment, with a mean serum cre-
atinine of 148.5 (84.9) µmol/l and only one
patient requiring chronic haemodialysis. This
important finding suggests that chronic dam-
age to the kidneys caused by long term
treatment with cyclosporin A can be minimised
by optimal adjustment of the dose, using toxic-
ity adjusted drug level monitoring. As shown
by Hausen et al, the concept of cyclosporin A
dose adjustment governed primarily by renal
function does not aVect the incidence of
rejection.
26
Finally, the development of malignancy
remains a point of major concern as an impor-
tant cause of death in long term survivors after
any type of solid organ transplantation, as well
as in heart transplantation.
27 28
Nearly 25% of
our patients suVered from malignant disease
during the 10 year period (13.7% of long term
survivors and 11.2% dying from malignancy).
This represents one of the most challenging
problems for future attempts to optimise the
immunosuppressive protocols. Induction treat-
ment with OKT 3, a major determinant of
lymphoma incidence, was not used in our
cohort during the study period. ATG was used
as cytolotytic induction treatment in 99
patients, with no significant diVerence between
survivors and non-survivors.
Searching for predictive factors for survival,
Bourge et al reviewed the data from the cardiac
transplant research database established in
1990.
29
Analysing short term periods, they
identified diVerent recipient (younger and
older age), donor (older age, smaller body sur-
face area), and clinical (longer ischaemic time)
risk factors for death after transplantation.
However, evaluation of diVerent recipient,
donor, and treatment related factors in our
cohort showed no significant influence on long
term outcome. The incidence of HLA mis-
match, which was shown to correlate with early
allograft rejection incidence and graft survival
by De Mattos et al and Smith et al,
30 31
was not
diVerent in our survivor and non-survivor
groups, though complete data were only avail-
able in 73 patients. We only found a positive
trend in patients with dilated cardiomyopathy
as the underlying disease, which might reflect
the younger age of the recipients (39.1 (12.2) v
50 Fraund, Pethig, Franke, et al
48.2 (5.8) years), less concomitant disease, and
better general physical condition in this sub-
group.
In summary, the results of cardiac transplan-
tation have improved significantly over the last
two decades, with an increasing number of
patients surviving between 10 and 20 years
after transplantation. As we were able to show
in our population, nearly 50% of patients will
survive a 10 year period with acceptable
exercise tolerance and quality of life. Thus
heart transplantation should be regarded as a
valuable treatment option. The major obstacle
for the future of these patients will be to over-
come chronic graft vasculopathy and the devel-
opment of malignancies.
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Long term results after heart transplantation 51
