Circulation. 2005;111:113-117
doi: 10.1161/01.CIR.0000151609.60618.3C
(Circulation. 2005;111:113-117.)
© 2005 American Heart Association, Inc.
New Drugs and Technologies |
Drug Therapy in the Heart Transplant Recipient
Part III: Common Medical Problems
JoAnn Lindenfeld, MD;
Robert L. Page, II, PharmD;
Ronald Zolty, MD;
Simon F. Shakar, MD;
Marilyn Levi, MD;
Brian Lowes, MD;
Eugene E. Wolfel, MD;
Geraldine G. Miller, MD
From the Division of Cardiology (J.L., R.Z., S.F.S., B.L., E.E.W.), Center for Womens Health Research (J.L.), Department of Clinical Pharmacy (R.L.P.), and Division of Infectious Diseases (M.L.), University of Colorado Health Sciences Center, Denver; Division of Infectious Diseases, Vanderbilt University, Nashville, Tenn (G.G.M.); and Division of Cardiology, Denver VA Medical Center, Denver, Colo (S.F.S.).
Correspondence to JoAnn Lindenfeld, MD, Division of Cardiology, University of Colorado Health Sciences Center, 4200 E Ninth Ave, B-130, Denver, CO 80262. E-mail joann.lindenfeld{at}UCHSC.edu
Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004.
Key Words: transplantation drugs immunology rejection
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Introduction
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Continued improvement in the long-term survival of heart transplant
recipients has resulted in a population of patients with prolonged
exposure to immunosuppressive drugs.
1 This exposure, coupled
with the increasing age of recipients, has resulted in an impressive
prevalence of comorbidities in these patients. Indeed, by 5
years after transplantation, 95% of recipients have hypertension,
81% have hyperlipidemia, and 32% have diabetes.
1 In addition,
25% to 50% have coronary allograft vasculopathy (CAV), and up
to 33% have chronic renal insufficiency.
25 As more drugs
are developed to both prevent and treat these problems and common
infectious complications after transplantation, it is likely
that the heart transplant recipient will be taking an increasing
number of drugs. Because standard immunosuppressive drugs have
a high potential for drugdrug interactions, the heart
transplant recipient is subject to an enormous risk for drugdrug
interactions. In this article, we briefly review common medical
problems in heart transplant recipients that are routinely addressed
with drug therapy. In Part IV of this series, we provide specific
details of known important and common drugdrug interactions,
along with recommendations for management.
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Coronary Allograft Vasculopathy
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CAV was described in Part I of this series. The mechanism is
incompletely understood but is likely a consequence of both
immunologic and nonimmunologic factors.
3 CAV is present in 42%
of heart transplant recipients at 5 years.
3 After the first
posttransplantation year, CAV is responsible for

20% of all
deaths.
1,6 CAV often involves the coronary arteries in a diffuse
fashion, making percutaneous coronary interventions or bypass
surgery less effective in many cases. Prognosis remains poor
after the development of CAV.
7 No effective prevention for CAV
is available, although statins seem to improve prognosis in
heart transplant recipients, at least in part by ameliorating
CAV.
810
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Hypertension
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Hypertension is common after heart transplantation, occurring
in 50% to 95% of heart recipients.
6,11,12 The excess risk of
hypertension is attributable primarily to the use of calcineurin
inhibitors (CIs) because of both direct effects and the associated
renal insufficiency.
13,14 Although both are CIs, the incidence
of hypertension is lower in patients treated with tacrolimus
than with cyclosporine A (CSA).
15,16 No randomized trials in
heart transplant recipients are large enough to evaluate the
effect of antihypertensive therapy on morbidity, mortality,
and graft survival, but it is likely that antihypertensive therapy
has similar, if not greater, benefits in the heart transplant
recipient than in the general population. One reason is that
blood pressure after cardiac transplantation is characterized
by a disturbed circadian rhythm without the normal nocturnal
blood pressure fall and with a greater 24-hour hypertensive
burden.
11,17,18 Most randomized trials comparing different antihypertensive
drugs have been performed in kidney transplant recipients and
have not demonstrated the superiority of any drug class.
1923 A small, prospective, randomized study in heart transplant recipients
compared lisinopril with diltiazem for 1 year and revealed no
significant difference in blood pressure control, mortality,
creatinine, or side effects between the 2 agents.
24 Among calcium
channel blockers, diltiazem is often used because its inhibition
of cytochrome P450 (CYP450) 3A4 allows a reduction in CI dose
and because of reported favorable effects on VAC.
25 Posttransplantation
hypertension frequently is difficult to control and often requires
a combination of several antihypertensive agents.
24,26 Blood
pressure after cardiac transplantation is sensitive to a low
sodium diet.
27 In the heart transplant recipient, there are
important pharmacokinetic interactions with the calcium channel
blockers and important pharmacodynamic interactions with ACE
inhibitors. Both are discussed in Part IV of this series.
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Hyperlipidemia
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Lipid abnormalities are present in 60% to 81% of heart transplant
recipients.
2830 Hyperlipidemia is thought to play a role
in the development of CAV, cerebrovascular disease, and peripheral
vascular disease.
30,31 Characteristically, total cholesterol,
LDL cholesterol, apolipoprotein B, and triglycerides increase
by 3 months after transplantation and then generally fall somewhat
after the first posttransplantation year.
8,32,33 Immunosuppressive
drugs, loop diuretics, and renal insufficiency all contribute
to posttransplantation hyperlipidemia.
30,32,33 CIs, prednisone,
and the target of rapamycin inhibitors sirolimus and everolimus
all exacerbate hyperlipidemia.
33,34 One randomized trial and
several nonrandomized studies have demonstrated that tacrolimus
has similar, although less marked, effects on cholesterol, LDL
cholesterol, and triglycerides as CSA.
33,35
The HMG-CoA reductase inhibitors (statins) are as effective in reducing LDL cholesterol in heart transplant recipients as in the nontransplant population.8,9 Two randomized trials comparing pravastatin (20 to 40 mg) or simvastatin (5 to 20 mg) with placebo in heart transplant recipients have demonstrated benefits of statins on mortality, rejection associated with hemodynamic compromise, and CAV.810 The benefits of statins in heart transplant recipients have been suggested to be even greater than in the general population and may be due to both cholesterol lowering and immune modulating effects.8,29 From these data, statins are routinely prescribed to heart transplant recipients according to guidelines provided in Part IV of this series and other reviews.29 However, there is considerable controversy as to which statin and what doses to use in transplant recipients taking CIs, primarily because of the risk of rhabdomyolysis when these drugs are used together. Rhabdomyolysis was not observed in the 2 randomized trials discussed above using pravastatin and simvastatin.810 One observational study that compared simvastatin (20 mg/d) with pravastatin (40 mg/d) demonstrated an increased risk of rhabdomyolysis with simvastatin, but another study did not.36,37 In general, pravastatin is used at doses of 20 to 40 mg, whereas other statins are used at lower than the maximally approved dose for the nontransplant population. Pravastatin may have a lower incidence of rhabdomyolysis because it is not metabolized by cytochrome enzymes like the other statins.38 The incidence of rhabdomyolysis increases substantially when statins are used in high doses in these patients or when fibrates or niacin is added, and these combinations are generally contraindicated in patients taking CIs.29 If statins cannot be used and bile acid sequestrants are prescribed, care must be taken to separate the timing of administration to prevent the bile acid sequestrants from interfering with the absorption of CSA. Ezetimibe is a reasonable alternative in patients who cannot tolerate statins because it does not cause rhabdomyolysis. However, ezetimibe has not been compared with statins to determine whether it results in equivalent efficacy on rejection, graft atherosclerosis, or mortality. Although elevated triglycerides may be important in the development of CAV, no randomized trials have evaluated triglyceride lowering in these patients.29 Fibrates may decrease CSA levels, and the combination of a statin and a fibrate significantly increases the risk for rhabdomyolysis.29 The specific mechanisms and magnitude of drugdrug interactions with the lipid-lowering agents are discussed in Part IV of this series.
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Diabetes
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Diabetes occurs in 32% of heart transplant recipients.
6 A number
of factors, including pretransplantation diabetes, glucocorticoids,
and CIs, contribute to the high prevalence of diabetes.
39 Tacrolimus
is associated with a higher incidence of posttransplantation
diabetes than CSA, especially in blacks and when used in higher
doses.
40 Diabetes is associated with a poorer long-term survival
in both renal and heart transplant recipients.
39,41 There are
remarkably few data about the treatment of diabetes in the heart
transplant recipient and few reports of drugdrug interactions
between hypoglycemic and immunosuppressive drugs. Indeed, even
a recent consensus guideline on diabetes in transplant patients
did not address specific drug therapy.
41 With the increased
prevalence of renal insufficiency in heart transplant recipients,
one would expect relative contraindications to metformin and
fluid retention and weight gain with the thiazolinediones.
42 Shorter-acting sulfonylureas are preferred over longer-acting
sulfonylureas in patients with renal insufficiency.
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Chronic Renal Insufficiency
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Renal insufficiency is a common adverse effect of CIs, and no
effective therapy has been developed to prevent this problem.
Creatinine levels >2 mg/dL occur in 24% to 33% of heart transplant
recipients at 4 to 5 years after transplantation, and 3% to
8% ultimately develop end-stage renal disease.
4,5,43,44 It is
not known whether ACE inhibitors or angiotensin receptor blockers
are effective in decreasing the progression of CI-induced renal
disease. The decrease in glomular filtration rate after transplantation
results in an increased potential for drugdrug interactions
with drugs secreted or eliminated by the kidney.
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Antiplatelet Therapy
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CAV causes as many deaths in years 1 to 3 after transplantation
as do infections or rejection and is responsible for 17% of
all deaths occurring after the third posttransplantation year.
6 Routine use of antiplatelet agents, especially aspirin, in cardiac
transplant recipients is based on their utility in nontransplant
patients with ischemic heart disease, along with data suggesting
that enhanced platelet activity may be important in the pathogenesis
of CAV.
45
There are no randomized trials evaluating the benefits of antiplatelet therapy in heart transplant recipients. Animal studies using antiplatelet agents and studies in human heart transplant recipients using warfarin and dipyridamole have shown conflicting results for CAV.4648 Studies suggest that heart transplant recipients appear to be aspirin resistant compared with a nontransplant population even at aspirin doses as high as 500 mg/d.49 Evaluation of ticlopidine at a dose of 250 mg BID in 12 patients showed profound suppression of platelet aggregation.50 Ticlopidine, however, decreases CSA levels, which can lead to rejection.50 Rhabdomyolysis has been reported with clopidogrel.51 Currently, it remains uncertain whether heart transplant recipients should continue to use standard doses of aspirin, use higher doses of aspirin, switch to thienopyridines, or abandon the use of antiplatelet agents altogether. Additional interactions between CIs and thienopyridines are discussed in Part IV of this series.
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Infection Prophylaxis
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Infections cause

20% of deaths in the first year after transplantation
and remain a common cause of morbidity and mortality after the
first year.
6 With the advent of routine prophylaxis, the predominant
infections seen in the first month after transplantation are
nosocomial bacterial and fungal infections related to mechanical
ventilation, catheters, and the surgical site. Before routine
use of prophylaxis during periods of increased immunosuppression,
reactivation of herpes simplex and infections with opportunistic
infections such as
Pneumocystis jiroveci (carinii) (PCP), cytomegalovirus
(CMV),
Aspergillus species, and
Nocardia species were common.
52,53 Prophylaxis against CMV, PCP, herpes simplex virus, and oral
candidiasis now is used routinely during the first 6 to 12 months
after transplantation when the risk of these infections is high.
After the initial 6 posttransplantation months, the most common
infections are community acquired, and prophylactic antibiotics
can generally be discontinued.
Pneumocystis jiroveci (carinii)
Before the institution of prophylaxis, PCP was seen in 9% to 11% of all heart transplant recipients, with a mortality rate of 11% to 38%.53 The prophylactic use of trimethoprim-sulfamethoxazole (1 double-strength tablet 3 to 7 times per week) has eliminated PCP.52,53 This prophylactic regimen is also highly effective for preventing Nocardia infection and toxoplasmosis. Trimethoprim-sulfamethoxazole prophylaxis is generally reinstituted during episodes of increased risk for PCP such as enhanced immunosuppression with antilymphocyte agents or acute and chronic rejection.54 Potential side effects include rash, renal insufficiency, hyperkalemia, and bone marrow suppression.55
Fungal Infections
Aspergillosis and Candida species are the most common fungal infections after heart transplantation. Nystatin oral solution or clotrimazole troches are routinely used in the first 6 to 12 posttransplantation months or with enhanced immunosuppression to prevent oral candidiasis. In patients who present a higher risk for systemic fungal infections, fluconazole, itraconazole, or occasionally amphotericin-B may be prescribed prophylactically. Voriconazole, fluconazole, and itraconazole have a high potential for drugdrug interactions with CIs and sirolimus and are discussed in detail in Part IV of this series. Caspofungin has not yet been evaluated as prophylactic therapy.
Viral Infections
Viral infections, especially CMV, are a major cause of morbidity and mortality, with an incidence of CMV as high as 24% in CMV IgG-negative recipients of CMV IgG-positive donor hearts (D+/R).56 CMV infection has been associated with CAV, rejection, and enhanced immunosuppression, resulting in additional opportunistic infections such as fungal disease and end-organ disease (eg, pneumonitis, retinitis, and bone marrow involvement).54,5661 Use of prophylactic intravenous ganciclovir or oral valganciclovir in the CMV-seronegative recipient of a CMV-positive donor has been shown to effectively prevent CMV infection in this high-risk population.59,6264 In addition, preemptive use of oral valganciclovir or intravenous ganciclovir in all transplant recipients with evidence of active CMV viremia on routine monitoring has been shown to prevent symptomatic disease.59,63 Ganciclovir may result in bone marrow suppression, and routine complete blood count monitoring is required. Reactivation of herpes simplex virus 1 and 2 and herpes zoster occurs commonly after transplantation, so patients who are seropositive routinely receive prophylaxis with acyclovir, famciclovir, or valacyclovir. In patients taking ganciclovir or valganciclovir for CMV, no additional prophylaxis for herpes simplex virus is necessary.
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Gout
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The high risk of drugdrug interactions makes gout a particularly
vexing therapeutic problem.
65 Causes of gout after heart transplantation
include pretransplantation gout, use of CI, frequent use of
loop diuretics, and renal insufficiency.
66 Because there are
significant pharmacokinetic and pharmacodynamic drugdrug
interactions with nonsteroidal anti-inflammatory drugs and colchicine,
glucocorticoids are often used to treat episodes of acute gout.
Colchicine may be used to treat acute gout, but there appears
to be an increased risk of colchicine myoneuropathy, which is
discussed in more detail in the drugdrug interaction
section.
66 Nonsteroidal anti-inflammatory drugs often result
in worsening renal insufficiency and hyperkalemia, especially
in patients taking CIs. Prophylaxis of recurrent gout with allopurinol
is effective, but doses of allopurinol and azathioprine must
be reduced significantly when used together, and this combination
usually is avoided because of the potential for life-threatening
neutropenia.
67 There is no interaction between mycophenolate
mofetil and allopurinol. Uricosuric agents may be effective
in some patients.
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Osteoporosis
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Osteoporosis resulting in vertebral fractures is a common and
debilitating problem after heart transplantation. The cause
is multifactorial, compounded by the nearly 50% pretransplantation
prevalence of osteopenia and osteoporosis in patients with advanced
heart failure.
68,69 Glucocorticoids are the major factor in
additional bone loss after transplantation, with contributions
from renal insufficiency and CIs. Two years after heart transplantation,
as many as 28% of recipients have osteoporosis in the lumbar
spine, with vertebral fractures reported in up to 30%.
7072 The risk for fractures is highest in those with osteoporosis,
but fractures may develop even in those with normal bone density
before transplantation.
71,72 Most bone loss occurs in the first
6 to 12 months after transplantation when steroid doses are
highest.
73 Bisphosphonates have been shown to prevent bone loss
and fractures in nontransplant patients receiving glucocorticoids.
74,75 Several, but not all, studies suggest that bisphosphonates can
prevent bone loss and fractures after cardiac and liver transplantation.
69,76,77 Bisphosphonates have a lower risk of hypercalciuria than calcitriol.
77 Recommendations for patients receiving >5 mg/d prednisone
for 3 months include calcium (1500 mg/d) and vitamin D (800
IU/d), regular weight-bearing exercise, and a bisphosphonate.
78,79
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Depression
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Depression has been reported in up to 25% of cardiac transplant
recipients at 1 to 3 years after transplantation, with most
episodes seen in the first year.
80 There is an 18% prevalence
of depression even at 5 and 10 years after transplantation.
81 Thus, a large number of heart transplant recipients are likely
to be taking antidepressant drugs. There are substantial differences
in the effect of various selective serotonin reuptake inhibitors
on CSA levels, as discussed in Part IV of this series.
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Acknowledgments
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This work was supported by the Paul and Elisabeth Merage Family
Fund in Cardiology.
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Footnotes
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This is Part III of a 4-part series. Part I appeared in the
December 14, 2004, issue of the journal (
Circulation. 2004;110:37343740);
Part II appeared in the December 21/28, 2004, issue (
Circulation.
2004;110:38583865); and Part IV will appear in the January
18, 2005, issue.
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