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148 J. Patel and K. Patel
Table 12.3 Overview of common calcineurin inhibitor drug interactions in cardiac transplantation
Drugs that increase cyclosporine/tacrolimus
levels
Calcium channel blockers: diltiazem, verapamil, nifedipine, nicardipine
Antibiotics: erythromycin, clarithromycin,
doxycycline (cyclosporine only)
Antifungal: ketoconazole, voriconazole,
fluconazole
GI agents: metoclopramide, cimetidine,
omeprazole
HIV protease inhibitors Antivirals: aciclovir
Miscellaneous: amiodarone, allopurinol, gra-
pefruit, grapefruit juice, methylprednisolone
Abbreviations GI: gastrointestinal; HIV: human immunodeficiency virus; NSAIDs: non-steroidal anti-inflammatory
drugs
Reprinted from Transplantation Proceedings, 31 (5), J.A. Kobashigawa, Postoperative management following heart
transplantation, 2038–2046, Copyright (1999), with permission from Elsevier
Drugs that decrease cyclosporine/tacrolimus
Levels
Antibiotics: nafcillin and rifampin Antibiotics: aminogly-
Anticonvulsants: phenytoin, phenobarbital,
carbamazepine
Miscellaneous: hypericum perforatum,
ticlopidine (cyclosporine only), cholestyramine
Drugs that enhance
nephrotoxicity
cosides, vancomycin,
trimethoprim-sulfamethoxazole
NSAIDs: all formulations, colchicine
Antifungals: amphotericin B
GI agents: cimetidine,
ranitidine
Antineoplastics:
cisplatin
Care must be taken in specific demographic
groups, such as African-Americans and females,
with regard to high tacrolimus doses and hyperglycemia [25]. In contrast to the side effect
profile seen with cyclosporine, hirsutism, and
gingival hypertrophy do not occur with tacrolimus. But, alopecia may be a side effect of tacrolimus. Tacrolimus is frequently used as a substitute
for cyclosporine when cyclosporine-related toxic
effects occur; the converse is also applicable to
tacrolimus-related toxic effects [25].
Drug Interactions
The calcineurin inhibitors and proliferation signal inhibitors are extensively metabolized by the
cytochrome P-450 3A4 enzyme pathway in the
liver; as a result, their blood levels are affected
by drugs that induce or inhibit this pathway. As
a result, the nephrotoxic effects of CNIs may be
enhanced. The interactions may occur with very
commonly used drugs; as such, constant attention
is required and vigilance as to potential interactions, and utmost care should be taken when
introducing new drugs. Table 12.3 summarizes
the potential interactions of CNIs with common,
everyday medications. It should also be noted
that cyclosporine, but not tacrolimus, inhibits
P-glycoprotein membrane transporters that affect
the metabolism of certain statins [26, 27].
Antiproliferative
An antiproliferative agent is usually used in
current immunosuppressive regimens; azathioprine and mycophenolate mofetil (MMF) are the
most commonly used. Early immunosuppressive protocols in the 1970s used azathioprine
with prednisone, with relatively poor 1-year
survival of 60–65% and 5-year actuarial survival of 35–40% [28, 29]. The introduction of
cyclosporine significantly improved survival and
somewhat relegated the role of azathioprine to
that of an adjunctive agent; with the introduction
of MMF in the 1990s, azathioprine has further
fallen out of favor.
14912 Maintenance Immunosuppression Strategies …
Azathioprine
Mechanism of Action
Azathioprine is a prodrug that is hydrolyzed
rapidly in the blood to 6-mercaptopurine,
which is subsequently converted to thioinosine monophosphate, a purine analog that is its
active metabolite (Fig. 12.1). This purine analog
is incorporated into DNA, thereby inhibiting its
synthesis and the consequent proliferation of
both T and B lymphocytes.
Adverse Eects
The major side effects of azathioprine are hematologic, and hence, complete blood counts should
be regularly monitored. Myelosuppressive
adverse effects, including leukopenia, anemia,
and thrombocytopenia (see Table 12.2), may
occur. Generally dose-dependent, these events
typically resolve after 7–10 days with dose reduction. More rarely, pancreatitis, hepatitis, and
hepatic veno-occlusive disease may also occur.
Mycophenolate Mofetil (MMF)
Mechanism of Action
MMF is a reversible inhibitor of inosine
monophosphate dehydrogenase, a crucial enzyme
in the de novo synthesis of guanine nucleotides.
Proliferating lymphocytes are dependent on this
pathway because it is their only pathway for
purine synthesis and DNA replication. In contrast, other cells use both de novo and salvage
pathways for purine synthesis. Therefore, MMF
is a more selective inhibitor of lymphocyte proliferation than azathioprine. In vivo and in vitro,
mycophenolic acid blocks the proliferation of
T and B cells, inhibits antibody formation, and
inhibits the generation of cytotoxic T cells [30].
Furthermore, MMF down-regulates the expression of adhesion molecules on lymphocytes.
Notes
MMF is largely preferred over azathioprine due
to its reduced adverse effect profile combined
with superior efficacy in maintaining survival
and preventing rejection. In a multi-center,
active-controlled, randomized trial [31], MMF
was compared with azathioprine when used in
conjunction with cyclosporine and corticosteroids in 650 de novo HTx recipients. Because
an intravenous form of the study drug was not
available at the time of the trial, 11% of the
patients withdrew before receiving the drug.
Survival and rejection were similar in both
groups when analyzed in an intention-to-treatment manner. However, among treated patients,
MMF was associated with a significant reduction in both mortality (6 vs. 11%, p = 0.031)
and in the incidence of treatable rejection (66
vs. 74%, p = 0.026) at one year. These find-
ings are supported by retrospective data from
the International Society for Heart and Lung
Transplantation (ISHLT) Thoracic Registry
[32], which find significantly superior actuarial
1 and 3-year survival in MMF patients compared to azathioprine patients. (1 year, 96 vs.
93%; 3 year, 91 vs. 86%; p = 0.0012). MMF has
also been demonstrated to be effective in reversing recurrent rejection when used in place of
azathioprine [33, 34]. In patients with chronic
renal dysfunction, switching from azathioprine
to MMF in combination with cyclosporine
reduction or withdrawal to improve renal function has also been employed as an effective
strategy [33].
Adverse Eects
MMF is considerably less myelosuppressive
than azathioprine and is usually well tolerated (see Table 12.2). The most common side
effects include nausea, vomiting, and diarrhea,
which usually respond to dose adjustment.
Mychophenolate sodium is an alternate formulation of mycophenolate that is enteric coated and
delayed release, thus improving the upper gastroenintestinal tolerability [19]. There is some
data to suggest that the risk of opportunistic
infections may be higher in patients on MMF
compared with azathioprine [31].
150 J. Patel and K. Patel
Proliferation Signal Inhibitors (PSIs): Sirolimus and Everolimus
The proliferation signal inhibitors include
sirolimus and everolimus. Sirolimus is a natural product of the actinomycete Streptomyces
hygroscopicus [35, 36]. Like tacrolimus, sirolimus is a macrolide antibiotic and is structurally
related. Everolimus is an analog of sirolimus,
with a shorter half-life and identical mechanism
of action to sirolimus. The proliferation signal
inhibitors may be considered in select patients
with cardiac allograft vasculopathy, malignancy,
or renal dysfunction.
Mechanism of Action
Sirolimus and everolimus bind to the same family of immunophilins as tacrolimus, the FKBPs,
but instead of blocking calcineurin-dependent
T-cell activation, the resultant complex inhibits a key regulatory kinase; mammalian target of rapamycin (mTOR) (Fig. 12.1). mTOR
phosphorylates proteins that play a vital role in
cell cycle regulation. In turn, connecting signals from the growth factor receptors to the cell
nucleus stimulate growth and proliferation of T
and B lymphocytes [37, 38]. In this way, sirolimus/everolimus is able to specifically inhibit
cell division. Notably, sirolimus has also been
noted to inhibit arterial smooth muscle and
endothelial cell growth via inhibition of mTOR;
this has translated to reduced allograft atherosclerosis in animal models [39, 40].
Notes
Sirolimus, which was discovered before everolimus, has been shown to effectively inhibit
acute graft rejection and treat refractory acute
graft rejection in HTx recipients [39]. In randomized, open-label clinical trials, sirolimus
has demonstrated reduced rejection compared
to azathioprine, though with similar mortality
[41]. Furthermore, sirolimus has been shown to
decrease the development of cardiac allograft
vasculopathy (CAV), as assessed by intravascular ultrasound (IVUS) at 6 months; the benefit was maintained at 2 years [41]. In existing
patients with CAV, sirolimus was also demonstrated to slow the progression of CAV as per
angiography [42]. Interestingly, sirolimus has
also been noted for its antitumor effects; a useful quality in a field where a major cause of
death after transplant is malignancy. In a recent
study, the switch from cyclosporine to sirolimus
in renal transplant recipients who subsequently
developed Kaposi’s sarcoma was shown to
reduce tumor burden significantly [43].
Clinical trials involving everolimus have
also demonstrated largely positive results. In
a randomized double-blind prospective 634
patient three-arm trial that compared everolimus (1.5 or 3 mg) to azathioprine [44], significantly less patients on everolimus reached the
6-month composite endpoint of death, graft loss
or retransplantation, loss to follow-up, biopsyproven severe acute rejection, or rejection with
hemodynamic compromise (36.4 and 27.0%,
compared to 46.0%). Furthermore, a decrease
in the development of CAV, as assessed by
IVUS at 12 months, was observed in the
everolimus groups compared to those on azathioprine. These study results are further supported by a clinical trial of 721 patients [45]
which found no difference between everolimus
and MMF in 2-year survival and rejection, and
actually found a favorable effect of everolimus in reducing CAV compared to MMF [46].
Interestingly, the rates of cytomegalovirus
(CMV) infection have been noted to be significantly lower in everolimus patients compared to
azathioprine.
Adverse Eects
When administered alone, sirolimus/everolimus
are not noted to adversely affect renal function.
Data from clinical trials shows that everolimus
with low-dose cyclosporine has been shown
not to worsen [47] and may even improve renal
function when compared to standard-dose cyclosporine with MMF—a finding supported in
multiple prospective studies [45, 47–50], including the NOCTET study by Gullestad et al. and
the SCHEDULE trial, which showed regular
everolimus with no cyclosporine (with MMF)
15112 Maintenance Immunosuppression Strategies …
to be superior to cyclosporine with MMF for
renal function. In the MANDELA study, both
everolimus with reduced CNI and everolimus as
part of a CNI-free regimen improved and stabilized renal function by estimated GFR (moreso
in the CNI-free group) [51]. However, in both
the SCHEDULE and MANDELA studies (both
CNI-free studies), there were more asymptomatic rejection episodes but no impact on survival. While potent effective immunosuppressive
drugs, use of proliferation signal inhibitors following HTx has remained limited because of
evidence from clinical trials regarding worsening CNI nephrotoxicity, delayed wound healing
and dehiscence, and increased infection [52, 53].
Furthermore, data from the everolimus versus
MMF trial showed an increased mortality from
infection in the patient group with high-dose
everolimus (3.0 mg) [45]. Other major adverse
effects of the proliferation signal inhibitors
include hyperlipidemia, hypertriglyceridemia
with increased LDL cholesterol, mouth ulceration, deep venous thrombosis, proteinuria, and
more rarely, thrombocytopenia, neutropenia, and
anemia (see Table 12.2) [54–58]. Rarely, cases
of noninfectious pneumonitis have been reported
with sirolimus [54].
Hypercholesterolemia, hypertriglyceridemia,
thrombocytopenia and mouth ulcers are generally at least partially responsive to dose reduction [54]. PSI-induced hyperlipidemia also
responds to conventional treatment with HMGCoA reductase inhibitors (statins) and fibric acid
derivatives (fibrates) [59].
Drug Interactions
It must be noted that interactions with sirolimus/
everolimus and statins or fibrates may occur as
a result of competitive metabolism via CYP3A
[60]. Thus, heightened awareness is necessary
for potential hepatic and muscular toxicity when
combining statins or fibrates with sirolimus/
everolimus. In a microcosm of immunosuppression, the risk of hyperlipidemia must be balanced
against the powerful anti-atherogenic effects.
Statins
The use of statins post-cardiac transplant is now
widespread and will be discussed in Chap. 13.
They are typically initiated a week or two after
transplant.
Major Clinical Trials of Maintenance Immunosuppression Regimens— Which Agent to Use?
Part of the reason that there remains no standardized protocol for immunosuppression is a
lack of available evidence. Indeed, relatively few
HTx procedures occur per year, thus limiting the
number of randomized clinical trials available
to inform treatment decisions. Consequently,
the majority of ISHLT guideline recommendations are class IIa or IIb and based on level B or
C evidence [61]. The most commonly used regimen consists of a triple therapy regimen, consisting of a corticosteroid, calcineurin inhibitor,
and antiproliferative agent.
Typical major study endpoints of clinical trials of immunosuppression in HTx have included
the following, either alone or in combination:
survival, rejection, CAV, and adverse events.
While survival is the most important endpoint,
the low population typical of HTx studies means
that most studies are not powered to demonstrate a mortality benefit. However, the clinical
endpoints of rejection, CAV, and adverse events,
which studies are often powered to detect differences in, are noted to either indirectly or directly
affect mortality, morbidity, and quality of life
and thus are considered clinically reasonable
endpoints for the purposes of comparison.
Survival appears to be largely comparable in
all the randomized clinical trials of immunosuppressants in HTx, and in any case, these studies
were not powered to demonstrate survival difference. The other clinical endpoints of rejection,
CAV, and adverse events have revealed differences between immunosuppressive regimens
152 J. Patel and K. Patel
across several trials. The major randomized
clinical trials of immunosuppressive therapy in
HTx are summarized in Table 12.4 [19–22, 31,
41, 44, 45, 47, 50, 62–65].
Comparison by Survival
Clinical trials have not demonstrated differences
in survival among the various immunosuppressive regimens, primarily due to inadequate statistical power. There is, however, one notable
exception; in a multicenter clinical trial of MMF
compared to azathioprine, a treated-patient
analysis demonstrated significant 1-year survival benefit for patients on MMF [31]. In this
case, the intent-to-treat analysis was severely
skewed by unusually high rates of perioperative
mortality in the MMF group that occurred by
chance, with patients having been randomized
before transplant. Since this trial, and other subsequent trials confirming a benefit to MMF in
not just survival but also CAV [66], MMF has
become the antiproliferative of choice over azathioprine. Nevertheless, the randomized clinical trials comparing cyclosporine to tacrolimus
[17, 18, 22], everolimus to MMF [45], sirolimus
to MMF, sirolimus to azathioprine [41], and
everolimus to azathioprine [44] have not shown
a survival benefit.
Comparison by Incidence of Rejection
Several immunosuppressive agents have been
shown to decrease the incidence of rejection
(Table 12.4). However, it must be noted that
many of these trials assessing the efficacy of
MMF [31], everolimus [44] and sirolimus [41]
used azathioprine as the comparator, which itself
has fallen out of favor—thus making the comparison less clinically useful. Nevertheless, more
recent clinical trials for everolimus have used
MMF as a comparator, including the large multicenter everolimus versus MMF trial [45].
A large 2006 European multicenter trial comparing tacrolimus to cyclosporine reported by
Grimm et al. [22] revealed a significantly lower
rejection rate at 6 months for tacrolimus compared to cyclosporine (both in combination with
azathioprine). More recently, a three-arm trial
compared regimens of tacrolimus/MMF, tacrolimus/sirolimus, and cyclosporine/MMF [19] (all
in combination with corticosteroids) and found
that both the tacrolimus regimens had significantly less treated rejection at 6 months than the
regimen with cyclosporine/MMF. Furthermore,
tacrolimus/MMF when compared only to cyclosporine/MMF had significantly lower incidences
of cellular rejection (ISHLT grade > 3A/2R) and
any treated rejections.
Therefore, the overall rejection data from
the clinical trials suggest that tacrolimus-based
regimens may have benefit over cyclosporinebased regimens (class IIb/level B of evidence)
[19, 21]. Regarding specific combinations, comparisons of the contemporary immunosuppressive combination regimens of tacrolimus/MMF
and cyclosporine/MMF suggest that tacrolimus/
MMF may have benefit over cyclosporine/MMF
for preventing rejection (class IIb/level B of evidence). Everolimus with reduced-dose cyclosporine has not been compared to tacrolimus/
MMF in a randomized trial.
However, the relative advantage of tacrolimus-based therapy for rejection is balanced by
an increased incidence of diabetes. Furthermore,
the tacrolimus/sirolimus-treated patients in this
three-arm trial had lower rejection but increased
nephrotoxic events and impaired wound healing,
rendering this regimen less desirable compared
with tacrolimus/MMF [19].
A 721-patient multicenter clinical trial in
2013 compared everolimus to MMF; specifically, reduced dose everolimus 1.5 mg with
reduced-dose cyclosporine was found to be no
different to MMF with standard-dose cyclosporine in terms of 1 and 2-year biopsy-proven
acute rejection, although 3-month mortality
was found to be higher in everolimus patients
who had undergone induction [45]. Other studies comparing everolimus with low-dose cyclosporine to MMF (with or without low-dose
cyclosporine) also demonstrated no difference
in rates of rejection compared to MMF [48,
49]. However, a Scandinavian trial investigating
12 Maintenance Immunosuppression Strategies …
153
Other
NS for hypergly-
MMF = more
AZA = more
Hypertension Hematologic GI disorders
triglycerides
MMF = more
cemia treatment
diarrhea and
leukopenia
any opportunistic
NS for glucose
esophagitis
CSA = more
infection
intolerance
hypertension
NS
CSA = more
hypertension
CSA = higher
chol and tri
NS NS NS NS for wound
EVR
EVR
infection
groups = higher
chol and tri
groups = lower
viral/CMV but
AZA = more
arrhythmia and
AZA = more
nausea
groups = more
NS SIR
groups = higher
NS for chol; SIR
SIR
more bacterial
infections
groups = lower
atrial fibrillation;
SIR groups = more
mouth ulcers and
SIR
groups = more
diarrhea
anemia and
throm-
bocytopenia
trig
CMV but more
pneumonia
abnormal healing
TAC = more
diabetes mellitus
and tremor;
CSA = more gum
CYA = more
cholelithiasis
TAC = more
anemia
CSA = more
hypertension
CSA = higher
chol and trigly-
cerides
hyperplasia and
hirsutism
(continued)
44, 45, 47, 50, 62–65]
Table 12.4 Overview of results from major randomized multicenter clinical trials comparing efficacy of immunosuppressive drugs in cardiac transplantation [19–22, 31, 41,
NS;
**MMF = less
MMF = less
rejection
*MMF = higher
survival
650 3 yrs
Kobashigawa
Study n Follow-up Survival Rejection CAV by IVUS Renal function Infections Cholesterol and
et al. 1998
CAV at 1 year
82 1 yr NS NS NS NS
MMF versus
AZA [31]
Reichart et al.
1998
TAC versus
EVR
groups = worse
renal function
EVR
groups = less
CAV
groups = less
rejection
85 1 yr NS NS NS NS
CSA [21]
Taylor et al.
1999
TAC versus
634 1 yr NS EVR
CSA [20]
Eisen et al.
2003
EVR versus
SIR
groups = worse
renal function
SIR
groups = less
CAV
groups = less
rejection at 6
months
136 2 yrs NS SIR
AZA [44]
Keogh et al.
2004
SIR versus
AZA [41]
NS NS
TAC = less
rejection at 6
months
314 1.5 yr NS
Grimm et al.
(2006)
TAC versus
CSA [22]
154 J. Patel and K. Patel
Other
TAC/SIR = more
Hypertension Hematologic GI disorders
NS NS
triglycerides
NS for chol
TAC/SIR = lower
insulin therapy
and impaired
wound healing;
MMF = lower
trig
TAC /
viral but more
fungal infections
NS for diabetes
mellitus
NS NS for malignancy
MMF = more
hospitalized
infections
MMF = more
leukopenia
EVR = Less
CMV infections
TAC
TAC /
alone = higher
MMF = more
mean white
blood cell
count, but
not clinically
hospitalized
infections
dose = higher
meaningful
NS NS NS EVR 3.0mg high
groups = higher
EVR
EVR = Less
CMV infections
overall rate of
discontinuation
due to increased
mortality
chol and trigly-
cerides
(continued)
Study n Follow-up Survival Rejection CAV by IVUS Renal function Infections Cholesterol and
Table 12.4 (continued)
TAC/MMF = best
renal function
groups = lower
any treated
343 1 yr NS NS; TAC
Kobashigawa
et al. (2006)
TAC/MMF
rejection
versus TAC/
SIR versus
58 1 yr NS NS NS NS TAC /
CSA/MMF
[19]
Baran et al.
group = numeri-
cally better renal
function
176 1 yr NS NS NS
2007 TAC/
MMF versus
TAC [63]
et al. 2008
EVR/rd-CSA
versus
Lehmkuhl
150 5 yrs NS NS NS NS; TAC alone
MMFsd-CSA
[47]
Baran et al.
2011 TAC/
MMF versus
TAC alone
[64]
EVR
EVR
721 2yrs NS EVR
Eisen et al.
groups = worse
groups = less
groups = nume-
2013
renal function
CAV
rically more
rejection
EVR-CSA
versus MMF-
CSA [45]
12 Maintenance Immunosuppression Strategies …
Other
roids = more
diarrhea
MMF-ste-
NS EVR-rd-CNI-
Hypertension Hematologic GI disorders
NS NS
triglycerides
EVR
groups = higher
chol and trigly-
cerides
MMF-ste-
roids—more
hypertension
NS EVR-rd-CNI-
155
EVR-numerically
more infections
EVR group-better
renal function
EVR group-
less CAV
rejection in
EVR only
group, but no
difference after
115 3yrs*** NS More mild
1 year
CNI-free—less
infections, inclu-
ding CMV
CNI-free—better
renal function
MMF-ste-
roids = less
rejection
162 1 yr NS EVR-rd-CNI-
Study n Follow-up Survival Rejection CAV by IVUS Renal function Infections Cholesterol and
Table 12.4 (continued)
Andreassen
et al. 2014
EVR-rd-CSA
followed by
EVR only
(early CSA
withdrawal)
versus MMF-
CSA [50, 65]
Barten et al.
2019
EVR-MMF-
steroids
(CNI-free)
versus
EVR-rd-CNI-
Treated-patient population (see text)
MMF-ste-
roids [51]
*
** Reanalysis of MMF IVUS data
*** Subsequent 3-year follow up study, published 2016
CAV, cardiac allograft vasculopathy; CYA, cyclosporine; EVL, everolimus; EVL/rd, everolimus/reduced exposure; IVUS, intravascular ultrasound; MMF, mycophenolate
mofetil; MMFsd, mycophenolate mofetil/standard exposure; NS, not statistically significant; SRL, sirolimus; TAC, tacrolimus.
156 J. Patel and K. Patel
low-dose everolimus with early cyclosporine
withdrawal followed by regular everolimus dosing compared to standard cyclosporine therapy
(both groups with MMF and steroids) showed
higher asymptomatic rejection in the everolimus
group, further supporting the notion that caution
is required in the early initiation of everolimus
[50]. The EVERHEART study demonstrated
that delayed everolimus initiation avoided
adverse events (via a primary composite safety
endpoint) without compromising efficacy [67].
Comparison by Eect on Cardiac
Allograft Vasculopathy (CAV)
In many of the randomized trials of immunosuppression, CAV as an endpoint has been assessed
through the use of IVUS assessment at 1-year
post-transplant compared to baseline. Prior studies have established that an increase of 0.5 mm
or more in maximal intimal thickness on coronary IVUS within the first year after HTx, is
associated with a significantly increased risk
of 5-year all-cause death, myocardial infarction, and the subsequent development of angiographic severe CAV. Thus, IVUS has served
as a surrogate endpoint for CAV in subsequent
immunosuppression trials. Furthermore, IVUS is
increasingly used to identify patients at high risk
for future cardiovascular events, and may aid in
allowing therapeutic adjustment of immunosuppression [68]. Several of the recent randomized
immunosuppressive trials including the MMF
versus azathioprine [31], everolimus versus azathioprine [44] and sirolimus versus azathioprine
[41] trials demonstrated benefit compared to
azathioprine in the first-year IVUS results, with
a lower incidence of patients developing CAV
as defined by an increase of 0.5 mm or more in
maximal intimal thickness on coronary IVUS
within the first year after HTx.
The MMF versus azathioprine study showed
benefit in CAV retardation using a threshold for
first-year change in maximum intimal thickness
greater than 0.3 mm, but at 0.5 mm significant
benefit was no longer seen. The sirolimus versus azathioprine study [41] showed benefit for
sirolimus therapy using the usual 0.5 mm threshold; however, patients were studied at baseline
and at 6 months, not 12, after HTx, making
IVUS less useful for predictions of subsequent
CAV. Nevertheless, in a randomized study of
cardiac transplant patients with established CAV,
sirolimus has been demonstrated to slow disease
progression as determined by angiography (not
IVUS) [42].
In particular, the everolimus studies have
been the clearest in demonstrating a benefit in
CAV retardation over azathioprine and MMF. In
the everolimus versus azathioprine trial, this was
demonstrated using several IVUS parameters
(intimal volume, intimal area, intimal index in
addition to maximal intimal thickness > 0.5 mm)
[44]. Additionally, in the multicenter trial comparing 1.5 mg everolimus as compared to
standard MMF, there was significantly reduced
proportion of patients on everolimus with CAV
as defined by IVUS [45]. Furthermore, while
not a direct comparison against MMF, the CAV
benefits of everolimus are further supported by
IVUS data from a Scandinavian trial investigating low-dose everolimus with early cyclosporine
withdrawal followed by regular everolimus dosing compared to standard cyclosporine therapy
(both groups with MMF and steroids), which
show a lower incidence of 12-month > 0.5 mm
increase in maximal intimal thickness in the
everolimus group [65].
Thus, there is considerable evidence for CAV
benefit with MMF, everolimus and sirolimus
over azathioprine, and thus these drugs should
be considered for inclusion (class IIb, level B)
[41, 44, 66]. There is also strong evidence to
suggest that everolimus is superior to MMF for
CAV retardation [45]. However, there remain
concerns with safety, regarding renal dysfunction for everolimus/sirolimus when combined
with standard-dose cyclosporine, and thus caution should be exercised; with low-dose cyclosporine, everolimus appears safer in this regard
]. Furthermore, the use of 0.5 mm change
[48–50
in maximal intimal thickness on 12-month IVUS
as a surrogate for subsequent CAV and poor outcomes is only strictly applicable to the everolimus versus azathioprine and everolimus versus
15712 Maintenance Immunosuppression Strategies …
MMF studies. Overall, the value of everolimus
in retarding allograft vasculopathy appears superior to the competition, but this must be balanced against its negative aspects.
Comparison by Adverse Eect Prole
While survival, rejection data and CAV data are
comparable amongst the newer agents of MMF,
everolimus and sirolimus, adverse events are
often the deciding factor regarding the choice to
use a specific drug regimen for a certain patient.
Regarding everolimus/sirolimus, the inferior renal function seen when in combination
with standard-dose cyclosporine, along with
other side effects of hyperlipidemia, edema
and impaired wound healing and greater risk
of infection, must be considered when seeking
to use this combination. Sirolimus is also noted
to cause significantly higher rates of anemia,
thrombocytopenia, diarrhea and mouth ulceration. There appears to be a general trend for
significantly increased serious adverse events in
trials comparing everolimus, without affecting
the primary endpoint [49, 50, 65]. Nevertheless,
from a renal standpoint, the use of everolimus
in more recent trials with reduced or even withdrawn cyclosporine has demonstrated either
comparable or improved renal function, compared to MMF with standard-dose cyclosporine
[45, 49, 50, 69].
Evidence from other, nonrandomized studies has also demonstrated that conversion from
CNI-based immunosuppression to sirolimusbased immunosuppression results in improved
renal function [70, 71]. A recent multicenter
randomized trial demonstrated that conversion
to CNI-free immunosuppression (MMF, sirolimus) was superior to CNI-reduced immunosuppression in improving renal failure in late HTx
recipients (average 5 years post-transplant) with
renal insufficiency [72].
Other side effects must also be considered:
Patients on cyclosporine had higher cholesterol
and triglyceride levels, and more hypertension,
cholelithiasis, hirsutism, and gum hyperplasia than tacrolimus-treated patients [19–21].
However, tacrolimus-treated patients had more
diabetes mellitus, tremor, and anemia than
cyclosporine-treated patients. When comparing the regimen of tacrolimus/MMF compared
to tacrolimus/sirolimus and cyclosporine/MMF
had the best renal function and lowest triglyceride levels [19]. However, the tacrolimus/
sirolimus group had a higher incidence of poor
wound healing and the most patients on insulin
therapy.
Overall, sirolimus/everolimus is often preferred in patients with CAV, but are generally
not used in the first few months due to the drug
leading to poor wound healing, increased infection risk, potentiating the calcineurin inhibitor
nephrotoxic effects, and propensity for other
adverse events and side effects.
Individualizing Immunosuppression
Caution should be exercised in the interpretation of the aforementioned trials. The most
appropriate dose of the medications is unknown,
so outcomes in clinical trials may be affected
by different doses. Adverse effects may result
from a drug interaction within a combination
(e.g. tacrolimus with sirolimus) rather than a
drug by itself. Additionally, randomized clinical trials tend to include a lower risk population
with many exclusion criteria (to exclude high
risk patients) including renal dysfunction, older
age, and pre-sensitized patients. Nevertheless,
even taking these concerns into account, there
are important findings that can be taken from
the results of the randomized clinical trials and
applied to our practice.
The adverse events observed for specific
drugs and combinations in the randomized
clinical trials further support need for individualization of immunosuppression. For example, patients with high risk for CMV infection
might benefit from everolimus- or sirolimusbased immunosuppression; patients with gingival hyperplasia from a tacrolimus-based
regimen; patients with pre-existing diabetes or
excess tremors/peripheral neuropathy from a