Improving outcomes in heart transplantation: The potential of proliferation signal inhibitors

Improving Outcomes in Heart Transplantation: The Potential of Proliferation Signal Inhibitors H. Eisen, J. Kobashigawa, R.C. Starling, H. Valantine, and D. Mancini ABSTRACT Graft failure and mortality among heart transplant recipients remains higher than in populations receiving renal transplants. A major cause of graft loss is cardiac allograft vasculopathy (CAV), a condition characterized by diffuse thickening of coronary blood vessels. CAV often progresses silently, with major cardiac events (eg, ventricular arrhythmia) being the first presentation. Better diagnosis and monitoring of CAV is now possible with intravascular ultrasonography, a sensitive technique for measuring intimal thickness. To date, immunosuppressants have shown little efficacy for preventing CAV. However, a new class of agents, proliferation signal inhibitors (sirolimus and everolimus), have shown considerable efficacy in this regard and for preventing rejection. In an open-label trial, sirolimus therapy was associated with less intimal and medial proliferation than azathioprine. More robust evidence is available from a larger-scale, double-blind trial involving everolimus. At 12-month follow-up the incidence of CAV was significantly lower in patients receiving everolimus (35.7% and 30.4% for everolimus 1.5 and 3.0 mg/d vs 52.8% for azathioprine; P ⬍ .05). Sirolimus and everolimus were also associated with a lower rate of cytomegalovirus infection. As with other immunosuppressants, these agents are associated with adverse events (eg, hyperlipidemia), but they can be managed. Coadministration with calcineurin inhibitors (CNIs) can exacerbate CNI-related nephrotoxicity, but evidence suggests that everolimus administered with reduced-exposure cyclosporine in the maintenance phase preserves renal function without loss of immunosuppressive efficacy. Reduced CNI dosing in de novo patients is also a potential future benefit. Proliferation signal inhibitors have considerable potential for improving outcomes in heart transplantation.

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ardiac transplantation has become the established treatment of choice for eligible patients with endstage congestive heart failure. Despite advances in immunosuppressive medications and combination regimens over the years, there is still scope for improvement in long-term cardiac graft survival rates. Indeed, overall survival outcomes in cardiac transplantation are inferior to those observed in patients receiving kidney transplants (eg, 5-year patient survival in Caucasian patients receiving transplants in the United States between 1996 and 2001 was 84.8% for kidney transplant recipients compared with 73.0% for heart transplants).1 Ensuring graft survival is particularly important in the heart transplant setting, as there is limited availability of donor organs and loss of cardiac grafts generally results in death (unless a rare retransplant can be performed). Cardiac allograft vasculopathy (CAV) is a major cause of

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graft loss in heart transplant recipients and remains a significant obstacle to improving outcomes in this clinical setting.2 This article sets out to provide an overview of the pathogenesis of CAV and factors that contribute to the condition. Importantly, the diagnosis of CAV and monitoring of its progression have been revolutionized by the advent of intravascular ultrasound (IVUS),3 a more practical, sensitive, and flexible technique compared with tradiFrom Drexel University (H.E.), Philadelphia, Pennsylvania, USA; University of California at Los Angeles (J.K.), Los Angeles, California, USA; Cleveland Clinic Foundation (R.C.S.), Cleveland, Ohio, USA; Stanford University (H.V.), Stanford, California, USA; and Columbia University (D.M.), New York, New York, USA. Address reprint requests to Howard Eisen, MD, Chief of Cardiology Division, Drexel University College of Medicine, 245 N 15th Street, Philadelphia, PA. E-mail. [email protected] © 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 37 (Suppl 4S), 4S–17S (2005)

IMPROVING OUTCOMES IN HEART TRANSPLANTATION

tional angiographic methods. The value of IVUS will be realized to an even greater extent as new immunosuppressive agents with efficacy for preventing CAV are introduced. It is to these agents, the proliferation signal inhibitors, that the bulk of this article refers. For the first time, the antiproliferative effects of sirolimus and everolimus on vascular smooth muscle present clinicians with a potential method of controlling CAV. As with other immunosuppressants, however, use of these agents is not without risks. In order to use the reduced-exposure calcineurin inhibitor (CNI) regimens necessary to prevent the pharmacodynamic interaction that leads to nephrotoxicity, proliferation signal inhibitors must be administered with the aid of therapeutic drug monitoring. In addition to reviewing the available data supporting the use of sirolimus and everolimus in heart transplantation, we report in detail on the practical use of everolimus in this setting, as it is this agent that has been most robustly investigated and best characterized in heart transplant recipients, particularly with regard to coadministration with cyclosporine (CsA). CARDIAC ALLOGRAFT VASCULOPATHY: AN UNMET MEDICAL NEED IN CARDIAC TRANSPLANTATION

Coronary artery disease in the transplanted heart, also known as CAV, is the major cause of mortality late after transplantation.4 It affects up to 50% of all heart transplant recipients within 5 years of surgery,2 although intimal thickening may be present in up to 58% of patients at 1 year posttransplant.5 The diffuse nature of vessel involvement limits the potential for successful revascularization, hence the emphasis on agents to prevent progression of vascular remodeling. Unfortunately there is no effective treatment for CAV once it is established. Retransplantation is an option, but it is infrequently performed due to the poor outcomes that are observed following the procedure and because of the limited supply of suitable organs. CAV may develop at any time posttransplantation, but events during the first year after transplantation appear to be important in its pathogenesis. In its early stages, CAV is characterized by diffuse proliferation of smooth muscle cells in cardiac graft blood vessels leading to concentric intimal thickening.6 As CAV progresses, continued thickening of vessel walls leads to luminal stenosis throughout the coronary tree and possibly occlusion of smaller vessels.6 Ultimately, blood supply to the graft is compromised, resulting in graft dysfunction and organ loss. This pathology is quite distinct from the coronary artery disease that is observed in the general population in which atherosclerotic, lipid-filled plaques form at discrete locations in the major coronary arteries.7 Moreover, instead of the chest pain that frequently accompanies development of atherosclerotic disease, myocardial ischemia or infarction associated with CAV tends to be a silent process in which the first symptoms to present can be serious (eg, heart failure or ventricular arrhythmias).8 At present, the mechanisms underlying CAV are not fully

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understood. Multiple factors, however, appear to be involved, all of which contribute to the endothelial injury that triggers smooth muscle cell proliferation. Currently, several different factors are known to be involved:2,9 –13 ●

●

● ● ●

Ischemia of the graft at the time of transplantation. This is one of the more important nonimmune factors, as it leads to endothelial cell injury. Immune factors involving cellular and humoral rejection can further insult the vascular endothelium, leading to a cascade of immunologic responses. Cytomegalovirus (CMV) infection results in anti-endothelial antibodies, and is associated with CAV. Acute rejection with hemodynamic compromise and multiple rejections increase the risk of CAV. Host metabolic factors associated with increased risk for CAV are diabetes and hyperlipidemia.

THE STUDY OF THE EARLY NATURAL HISTORY OF ALLOGRAFT VASCULOPATHY HAS BEEN REVOLUTIONIZED BY THE USE OF INTRAVASCULAR ULTRASOUND

In recent years, IVUS has emerged as the new gold standard for atherosclerosis imaging. In contrast to angiographic techniques, IVUS provides cross-sectional images of both the arterial wall and lumen with excellent resolution, revealing the diffuse nature of atherosclerosis and the involvement of reference segments. IVUS also allows visualization of vessel wall remodeling.14 The success of IVUS in monitoring and diagnosing atherosclerotic disease has led to its increased use as an important tool in the evaluation of CAV. Several authors have shown IVUS to be a sensitive technique for the detection of vasculopathy.3,15,16 Furthermore, methods of performing and interpreting IVUS have been standardized,17 and the technique can also be used to assess coronary artery intimal proliferation serially over time.15,17 It should be noted, however, that although IVUS is an effective research tool, it is not widely used in clinical practice. CORONARY ARTERY INTIMAL THICKENING MEASURED BY IVUS STRONGLY CORRELATES WITH LONG-TERM CLINICAL OUTCOMES

Several early studies found an association between intimal thickness posttransplant and the subsequent development of angiographic transplant coronary artery disease and mortality.18,19 More recently, a change in maximal intimal thickness of ⬎0.5 mm between baseline and 1 year posttransplant has become established as the key measure of CAV.20 Figure 1 shows a typical IVUS scan with annotations highlighting the key quantifiable parameters that are useful in the monitoring of vascular remodeling and development of CAV (ie, maximal intimal thickness, minimal intimal thickness, intimal area, and luminal area). A recent study confirmed that a change in intimal thickening of 0.5 mm in the first year after transplant appears to

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Fig 1.

A typical intravascular ultrasound (IVUS) image with arrows depicting key measures of vasculopathy.

be a reliable marker for subsequent development of angiographic evidence of CAV and mortality up to 5 years after heart transplantation.21 This multicenter study utilized blinded technicians at a core laboratory to assess baseline and 1-year IVUS values in 125 patients for whom 5-year follow-up data could be obtained. An increase in maximal intimal thickness of ⬎0.5 mm during the first year posttransplant was associated with a 5-year mortality of 21% compared with 6% for those without this degree of change in intimal thickness. The composite endpoint of major adverse cardiac events, graft loss, or death occurred in 46% of patients who had a change in maximal intimal thickness of ⬎0.5 mm compared with 17% of those with ⬍0.5 mm change in maximal intimal thickness. Overall, the rapid progression in first-year intimal thickening as detected by IVUS appears to represent the cumulative effects of adverse events that ultimately lead to poor clinical outcome.20 PROLIFERATION SIGNAL INHIBITORS: A NEW CLASS OF IMMUNOSUPPRESSIVE AGENT WITH ANTIPROLIFERATIVE PROPERTIES

The diffuse, obliterative nature of CAV means that changes to vascular architecture are nonreversible. Once established, the only effective treatment for the condition is retransplantation; therefore, prevention is the most efficient approach to management. Traditionally used immunosuppressive agents such as calcineurin inhibitors (CNIs), corti-

costeroids, and purine biosynthesis inhibitors have hitherto shown little efficacy for preventing CAV,22,23 although a recent reanalysis of data suggests that mycophenolate mofetil may have some efficacy in this regard.24 Nevertheless, it is clear that better treatment options for prevention of CAV are required. It is here that proliferation signal inhibitors have considerable potential for improving management of heart transplant recipients, as these agents combine effective immunosuppression with antiproliferative effects on smooth muscle cells. In preclinical studies both sirolimus and everolimus have been shown to reduce hyperplasia of vascular smooth muscle. For example, in one study everolimus was given to hyperlipidemic mice that had undergone allogeneic heart or carotid artery transplantation. After administration of everolimus 1.0 mg/kg/d for up to 8 weeks, neointimal formation was significantly reduced compared with animals that had been receiving cyclosporine over the same period.25 Furthermore, intimal thickening was reduced by everolimus (ⱕ2.5 mg/kg/d) in rat models of vascular remodeling and arteriosclerosis, in which segments of aorta were subjected to cold ischemia before transplantation into syngeneic or allogeneic recipients.26,27 The development of graft vascular disease was also examined following administration of sirolimus (mean plasma levels: 14.5 ⫾ 6 ng/mL) to primates with orthotopic aortic allografts. During a follow-up period of 105 days, intimal area and intimal volume in sirolimus-treated animals was significantly lower than in controls.28

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Table 1. Intravascular Ultrasound Measurements at Baseline and 6 Months in an Open-Label Trial of de novo Heart Transplant Recipients Randomized to Receive Sirolimus or Azathioprine

Maximum intima and media thickness (mm) Week 6 (baseline) Month 6 Mean intima and media thickness (mm) Week 6 Month 6 Mean intima and media area (mm2) Week 6 Month 6 Mean lumen diameter (mm) Week 6 Month 6 Mean lumen area (mm2) Week 6 Month 6 Mean vessel area (mm2) Week 6 Month 6 Plaque volume (mm3) Week 6 Month 6 Plaque burden (%) Week 6 Month 6

Azathioprine (n ⫽ 22)

Sirolimus (n ⫽ 38)

0.62 ⫾ 0.4 0.70 ⫾ 0.41*

0.49 ⫾ 0.26 0.50 ⫾ 0.28

.034 .0032

0.24 ⫾ 0.17 0.35 ⫾ 0.26

0.19 ⫾ 0.13 0.19 ⫾ 0.12

.051 ⬍.0001

3.0 ⫾ 1.9 4.0 ⫾ 2.7†

2.5 ⫾ 1.6 2.4 ⫾ 1.6

.14 .0001

3.8 ⫾ 0.8 3.5 ⫾ 0.9

4.0 ⫾ 0.6 3.9 ⫾ 0.6

.22 .0032

12.0 ⫾ 5.4 10.3 ⫾ 4.7

12.8 ⫾ 4.0 12.4 ⫾ 3.8

.36 .01

15.0 ⫾ 5.4 14.3 ⫾ 4.4

15.3 ⫾ 4.1 14.8 ⫾ 4.2

.74 .50

5.9 ⫾ 3.9 7.9 ⫾ 5.4†

4.9 ⫾ 3.4 4.9 ⫾ 3.2

21.1 ⫾ 13.7 29.4 ⫾ 19.1†

16.4 ⫾ 10.1 16.2 ⫾ 9.6

P (sirolimus vs AZA)

.16 .0004 .036 ⬍.0001

Reproduced with permission from American Heart Association, Inc.30 AZA, azathioprine. *P ⬍ .01, †P ⬍ .001, paired t test within group comparisons at baseline vs 6 months.

The potential shown by proliferation signal inhibitors for reducing intimal hyperplasia in coronary arteries in animal models of immune and nonimmune injury is now being realized in the clinical setting. Recent years have seen the publication of encouraging data from a number of studies conducted in heart transplant patients. PROLIFERATION SIGNAL INHIBITORS IN THE PREVENTION OF VASCULAR REMODELING Sirolimus for the Prevention of Cardiac Allograft Vasculopathy

The beneficial effects of sirolimus with regard to CAV have been demonstrated in two small-scale, open-label, clinical trials.29,30 The first trial involved 46 patients who were undergoing maintenance immunosuppression at a mean of 4.3 ⫾ 2.3 years posttransplantation. All patients were classified as having serious coronary artery disease (ie, epicardial stenosis ⬎ 50%, IVUS-measured intimal thickening ⬎ 0.5 mm, and/or severe diffuse vessel tapering). Twenty-four patients were randomized to receive standard care, while 22 received sirolimus. Progression of CAV was graded by semiquantitative catheterization scores checked by two blinded, independent observers. Baseline catheterization scores were comparable in the two treatment groups. At 1-year follow-up, catheterization score had not changed significantly from baseline values in patients receiving sirolimus (16.5 ⫾ 7.3 at baseline vs 16.6 ⫾ 8.3 at 1 year; P ⫽ .41), whereas it had increased significantly in

those patients who were assigned to standard care (19.0 ⫾ 10.3 at baseline vs 23.4 ⫾ 10.9 at 1 year; P ⬍ .01). These data suggest that sirolimus is effective for slowing the progression of established CAV, although confirmation is required in a larger population using less subjective methods of quantification. The second study was conducted in a larger population of de novo heart transplant recipients treated at five centers in Australia and New Zealand.30 A total of 136 patients were recruited, of whom 92 received sirolimus 3 mg/d or 5 mg/d and 44 received azathioprine, in addition to CsA, corticosteroids, and pravastatin. In this study, CAV was measured using IVUS at 6 weeks (baseline), 6 months, and 24 months posttransplant. Paired data for 12 matched slices were available for 60 patients at 6-month follow-up and for 58 patients at 24-month follow-up; data from patients receiving different doses of sirolimus were grouped together. At baseline, parameters of vascular disease were similar in both patient groups, except maximal intimal thickness and plaque burden, which were less severe in the sirolimus group. After 6 months of treatment, maximal intimal thickness, mean intimal area, plaque volume, and plaque burden had all increased significantly from baseline values in patients receiving azathioprine but not in those assigned to sirolimus (Table 1). In those patients who were available for 24-month follow-up, mean intimal area, mean lumen diameter, plaque volume, and plaque burden had worsened significantly from baseline in both sirolimus- and azathio-

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Table 2. Intravascular Ultrasound Measurements at Baseline and 24 Months in an Open-Label Trial of de novo Heart Transplant Recipients Randomized to Receive Sirolimus or Azathioprine

Maximum intima and media thickness (mm) Week 6 (baseline) Month 24 Mean intima and media thickness (mm) Week 6 Month 24 Mean intima and media area (mm2) Week 6 Month 24 Mean lumen diameter (mm) Week 6 Month 24 Mean lumen area (mm2) Week 6 Month 24 Mean vessel area (mm2) Week 6 Month 24 Plaque volume (mm3) Week 6 Month 24 Plaque burden (%) Week 6 Month 24

Azathioprine (n ⫽ 20)

Sirolimus (n ⫽ 38)

P (sirolimus vs AZA)

0.6 ⫾ 0.4 0.9 ⫾ 0.4

0.5 ⫾ 0.3 0.5 ⫾ 0.3

.1619 .0865

0.19 ⫾ 0.12 0.32 ⫾ 0.19

0.15 ⫾ 0.12 0.22 ⫾ 0.16

.3496 .0048

2.7 ⫾ 1.7 3.8 ⫾ 2.2*

2.4 ⫾ 1.6 2.8 ⫾ 2.0†

.3853 .0397

3.7 ⫾ 0.7 3.4 ⫾ 0.7†

3.8 ⫾ 0.7 3.8 ⫾ 0.6*

.4705 .0042

12.0 ⫾ 5.3 9.4 ⫾ 3.8

12.9 ⫾ 4.1 11.7 ⫾ 3.7

.2887 .0047

14.8 ⫾ 5.4 13.3 ⫾ 4.4

15.3 ⫾ 4.4 14.6 ⫾ 4.5

.5853 .1600

5.6 ⫾ 3.5 7.1 ⫾ 4.7*

4.7 ⫾ 3.4 5.7 ⫾ 4.1†

.1866 .1105

19.1 ⫾ 12.7 28.7 ⫾ 15.3*

15.8 ⫾ 9.7 18.3 ⫾ 11.3*

.1313 .0002

Reproduced with permission from American Heart Association, Inc.30 AZA, azathioprine. *P ⬍ .001, †P ⬍ .01, paired t test within group comparisons at baseline vs 24 months.

prine-treated patients; however, there were significant between-group differences favoring sirolimus with respect to mean intimal thickness, mean intimal area, mean lumen diameter, mean lumen area, and plaque burden (Table 2). Overall, patients receiving sirolimus exhibited less coronary disease than those receiving azathioprine with significantly better preservation of coronary artery lumen. Everolimus in the Prevention of Cardiac Allograft Vasculopathy

Like sirolimus, everolimus has also demonstrated efficacy for preventing CAV and its progression. Importantly, the evidence of everolimus’ benefits in the heart transplant setting has the advantage of being derived from a largescale, double-blind, randomized clinical trial.31 The everolimus phase III study in heart transplantation included a total of 634 de novo heart transplant recipients who were randomly assigned to receive 1.5 mg of everolimus per day, 3.0 mg of everolimus per day, or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day, in combination with cyclosporine, corticosteroids, and statins.31 Per protocol, IVUS examinations were to be performed both at baseline and 12 months in patients who were still receiving study medication. Ultimately, 70 of the 209 patients (33%) in the 1.5 mg everolimus arm, 69 of the 211 patients (33%) in the 3 mg everolimus arm, and 72 of the 214 patients (34%) in the azathioprine arm had paired baseline and 1-year IVUS tapes that were techni-

cally adequate for interpretation (ie, including at least 11 site-matched slices). The 211 patients with technically adequate baseline and 1-year IVUS examinations met the prospectively defined sample size definition. Physicians performing IVUS and interpreters of IVUS were blinded as to treatment assignment. Although not all patients were able to undergo both baseline and 1-year IVUS examinations, the study population represents a very large cohort of patients, with patient numbers and demographic features being similar across treatment groups. Moreover, many patients who did not have matching IVUS studies were excluded for technical reasons not subject to bias. Efficacy failure and creatinine clearance were similar for those everolimus-treated patients with paired IVUS results and those without, suggesting that these factors did not influence IVUS outcomes. It is interesting to note that similar numbers of patients in each group had IVUS performed, despite differences in renal function. Consistent with prior studies,32 creatinine clearance (demonstrated by logistic regression analysis) was not associated with the development of intimal thickening or CAV measured by IVUS (data on file at Novartis). Thus, the everolimus study IVUS population can be considered to be typical of, and relevant to, the larger population of heart transplant patients. At 12-month follow-up the incidence of vasculopathy (predefined as an increase in maximal intimal thickness of

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Fig 2. Mean (⫾SD) change from baseline to 12 months in IVUS-measured parameters of cardiac allograft vasculopathy for patients randomized to everolimus or azathioprine in a phase III clinical trial of everolimus in heart transplantation: (a) maximal intimal thickness, (b) intimal area, (c) intimal volume, and (d) intimal index. Reproduced with permission from Massachusetts Medical Society.31

0.5 mm from baseline) was significantly lower in the everolimus 1.5 mg group (35.7%; P ⫽ .045) and the everolimus 3.0 mg group (30.4%; P ⫽ .01) than in the azathioprine group (52.8%). Moreover, the mean changes from baseline in maximal intimal thickness, intimal area, intimal volume, and intimal index (a measure of the area of stenosis) were significantly lower among patients treated with either dose of everolimus than they were for patients in the azathioprine group (Fig 2). Changes in the different IVUS parameters did not differ significantly between the everolimus dosing groups. Figure 3 shows typical intravascular ultrasonograms from a patient in the azathioprine arm of the study; at baseline, maximal intimal thickness was 0.3 mm but by 12-month follow-up it had increased to 1.1 mm as a result of neointimal hyperplasia. At 24-month follow-up, the incidence of CAV was 33.3% and 45.5% in everolimus 1.5 mg and 3.0 mg groups, respectively.33 In the azathioprine group, however, 58.3%

of patients had CAV at this timepoint (P ⬍ .05 vs everolimus 1.5 mg group). The mean change in maximal intimal thickness from baseline was 0.07, 0.06, and 0.15 mm for each treatment group, respectively (P ⬍ .05 everolimus vs azathioprine). Data from the everolimus phase III study in heart transplantation were therefore concordant in demonstrating the benefit of everolimus in reducing all measures of blood vessel remodeling, and with respect to the size of treatment effect. Moreover, follow-up at 2 years posttransplant demonstrated that everolimus-associated clinical benefits were sustained in the longer term. Reductions in vascular remodeling were therefore a consistent feature of everolimus and sirolimus trials in heart transplant patients. Furthermore, these positive effects in reducing intimal thickening and CAV are consistent with the mechanism of action of proliferation signal inhibitors and earlier preclinical studies.

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Fig 3. Intravascular ultrasonograms showing maximal intimal thickness at (A) baseline and (B) 12-month follow-up in a patient randomized to azathioprine during a phase III study of everolimus in heart transplantation. At baseline, most of the vessel appears to be monolayer; the intima is so thin it is not detectable by intravascular ultrasonography. At 12 months, there is considerable intimal thickening, indicating the occurrence of cardiac allograft vasculopathy. Reproduced with permission from Massachusetts Medical Society.31

Sirolimus- and Everolimus-Eluting Stents in Coronary Artery Disease

Data supporting the efficacy of everolimus and sirolimus for preventing or slowing pathological vascular remodeling are also available from outside the transplant context. When implanted in the form of drug-eluting stents, both agents have shown significant efficacy for reducing intimal thickening in patients with coronary artery disease.34 –36 For example, in a randomized, double-blind trial involving 1058 patients in the United States, sirolimus-eluting stents were compared with standard devices.35 Minimal luminal diameter and extent of stenosis were similar in both treatment groups prior to, and immediately after, stent implantation. After 240 days, minimal lumen diameter in stent and 5 mm either side of the device was significantly greater in patients implanted with a sirolimus stent rather than a standard stent (2.15 ⫾ 0.61 vs 1.60 ⫾ 0.72 mm; P ⬍ .001). Furthermore, the percentage of lumen diameter affected by stenosis was smaller in the sirolimus group (23.6% ⫾ 16.4% vs 43.2% ⫾ 22.4%; P ⬍ .001). Overall, 3.2% of patients with sirolimus stents had in-stent restenosis compared with 35.4% of those with a standard stent (P ⬍ .001). In a study by Grube et al, 27 patients with de novo coronary lesions were given an everolimus-eluting stent, while 15 were given a bare metal stent.36 The 6-month rate of angiographically determined in-stent restenosis was 0% for patients with everolimus stents compared with 9.1% for those with standard stents (P ⫽ NS). However, associated

lumen loss was 0.11 mm in the everolimus group compared with 0.85 mm in the standard care group (P ⬍ .001). These findings were mirrored by IVUS measurements that identified a significantly smaller increase in neointimal volume for patients with everolimus-eluting stents (2.9 ⫾ 1.9 mm3/mm vs 22.4 ⫾ 9.4 mm3/mm in the bare metal stent group; P ⬍ .001).

OTHER EFFICACY BENEFITS OF PROLIFERATION SIGNAL INHIBITORS Acute Rejection

Uncomplicated acute rejection may engender little immediate risk to patients, yet its treatment is not without complications (eg, infection, malignancy, and steroid side effects). Even when rejection episodes are controlled, they have longer-term consequences and can ultimately limit graft and patient survival. The prognostic significance of acute rejection is illustrated by a recent analysis from the Cardiac Transplantation Research Database (CTRD) (personal communication from Dr James Kirklin, University of Alabama, USA) in which the desirability of remaining rejection-free becomes clear. As Fig 4 shows, the risk of mortality increases markedly with the number of rejection episodes a patient experiences. Only around 30% of patients with six rejection episodes survived to 9 years posttransplant, while around 55% of rejection-free patients were alive 11 years posttransplant.

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Fig 4. Transplant patient survival decreases depending on the number of acute rejection episodes that occur. Data from the Cardiac Transplantation Research Database (personal communication from Dr James Kirklin, University of Alabama, USA).

Fig 5. Incidence of biopsy-proven acute rejection (International Society for Heart and Lung Transplantation grade ⱖ 3A) in an open-label study of sirolimus and azathioprine in de novo heart transplant recipients. From Keogh, et al.30

Efficacy of Sirolimus for Preventing Acute Rejection

First occurrence of biopsy-proven acute rejection (International Society for Heart and Lung Transplantation [ISHLT] grade ⱖ 3A) was the primary end point in the previously described, open-label clinical trial of sirolimus in heart transplantation.30 After 6 months of treatment, patients randomized to sirolimus 3 or 5 mg/d had a significant lower rate of acute rejection than those receiving azathioprine (Fig 5). Survival rates at 12 months did not differ significantly between patients receiving sirolimus or azathioprine

(85.3%, 86.2%, and 90.9%, respectively, in the sirolimus 3 mg, sirolimus 5 mg, and azathioprine groups; P ⫽ .746). The trial, however, was not powered to detect differences in mortality. Efficacy of Everolimus for Preventing Acute Rejection

In the phase III study of everolimus in de novo heart transplant patients, the primary efficacy endpoint, “efficacy failure,” was a composite of death, graft loss or a second transplantation, loss to follow-up or biopsy-proven rejection

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Table 3. Incidence of the Primary Endpoint, Efficacy Failure, in a Phase III Study Comparing Everolimus and Azathioprine in de novo Heart Transplant Recipients31,33 Everolimus, 1.5 mg (n ⫽ 209)

Everolimus, 3 mg (n ⫽ 211)

Azathioprine, (n ⫽ 214)

P value

Month 6

76 (36.4%)

57 (27.0%)

100 (46.7%)

Month 12

87 (41.6%)

68 (32.2%)

113 (52.8%)

Month 24

96 (45.9%)

76 (36%)

123 (57.5%)

.031* ⬍.001† .037‡ .020* ⬍.001† .045‡ .016* ⬍.001†

Rate of Efficacy Failure at

Efficacy failure defined as acute rejection of ISHLT grade ⱖ 3A, acute rejection associated with HDC, graft loss, death, or loss to follow-up. *Everolimus 1.5 mg vs azathioprine; †everolimus 3 mg vs azathioprine; ‡everolimus 1.5 mg vs everolimus 3 mg (pairwise Z-test, P ⱕ .05).

Fig 6. Kaplan-Meier curves showing the incidence of biopsy-proven acute rejection (ISHLT grade ⱖ 3A) in heart transplant patients receiving everolimus or azathioprine in a phase III clinical trial. Acute rejection represented the majority of efficacy events and was markedly reduced by everolimus. From Mancini, et al.33

of ISHLT ⱖ grade 3A, or any episode of rejection associated with hemodynamic compromise in the first 6 months after transplantation, or both.31 A difference in this endpoint was achieved when, at 12-month follow-up, significantly lower proportions of patients receiving everolimus had experienced efficacy failure than had those in the azathioprine group (Table 3). Furthermore, clinically meaningful and statistically significant benefits of everolimus treatment were sustained up to 24 months (Table 3). The main driver of this result was the marked decrease in acute rejection of ISHLT grade ⱖ 3A among everolimustreated patients compared with those receiving azathioprine (Fig 6). In summary, both proliferation signal inhibitors demonstrated efficacy for reducing the rate of biopsy-proven acute rejection in heart transplant patients when compared with azathioprine. Everolimus and sirolimus therefore combine immunosuppressive efficacy with antiproliferative effects on smooth muscle.

Cytomegalovirus Infections

Considerable evidence suggests a role for viruses in the development of CAV. For example, observational data, experimental models, and therapeutic trials implicate human CMV in the initiation or progression of CAV.13,37 The development of anti-endothelial antibodies as a result of CMV infection is one of several mechanisms by which this disease might cause donor vascular endothelial cell injury.38 CMV infection may also contribute to endothelial dysfunction and CAV by dysregulation of the endothelial nitric oxide synthase pathway.39 Immunosuppressant therapies prescribed for patients following transplantation can unfortunately predispose patients to infection, including CMV. There is, however, good evidence from clinical trials in heart transplant patients that proliferation signal inhibitors, such as everolimus, are associated with lower rates of CMV infection than for other immunosuppressant agents. Within the everolimus heart transplantation study, CMV infection was categorized as either CMV syndrome (fever

IMPROVING OUTCOMES IN HEART TRANSPLANTATION Table 4. Incidence of Cytomegalovirus (CMV) Infection at 12Month Follow-up in a Randomized Clinical Trial of Everolimus Versus Azathioprine in Heart Transplant Patients

Overall CMV infection (%) CMV disease (%) CMV syndrome (%)

Everolimus, 1.5 mg (n ⫽ 209)

Everolimus, 3 mg (n ⫽ 211)

Azathioprine (n ⫽ 214)

7.7* 1.9 1.9

7.6* 3.7 2.8

21.5 6.5 4.2

*P ⫽ .001 everolimus vs azathioprine. From Dorent, et al.40

for at least 2 days, plus one of the following symptoms: neutropenia, leukopenia, viral syndrome) or CMV disease (systemic disease with CMV organ involvement).31 At 12-month follow-up, overall CMV infection (CMV syndrome, disease, or organ involvement) occurred at a reduced rate relative to azathioprine, despite comparable use of CMV prophylaxis in each group (Table 4).40 In the sirolimus study in heart transplant recipients, one patient in the sirolimus 3 mg group (2.9%) and one patient in the sirolimus 5 mg group (1.7%) had systemic CMV infection at 12-month follow-up.30 This compared favorably with the azathioprine group, in which six patients (13.6%) had systemic CMV infection (P ⬍ .05 vs sirolimus 5 mg). Tissue-invasive CMV infection was present in three patients in the sirolimus 3 mg group (8.8%), none of those receiving sirolimus 5 mg, and three patients receiving azathioprine (6.8%). Thus, reduced levels of CMV infection appear to be a class-related effect that is observed with both everolimus and sirolimus treatment. SAFETY ISSUES ASSOCIATED WITH PROLIFERATION SIGNAL INHIBITORS

No immunosuppressant agent currently used in cardiac transplantation is fully safe. All drugs in this indication have safety concerns but must be considered sufficiently effective, given those concerns, to be of value in patient management. For example, the frequently used CNIs, CsA, and tacrolimus are associated, to differing degrees, with a range of toxic effects including hypertension (particularly in heart transplant patients), blood lipid disturbances, and newonset diabetes after transplantation.41 Both agents are also known to cause nephrotoxicity with long-term use,41 and CsA causes cosmetic adverse events such as gum hypertrophy and hirsuitism. These problems are, however, well documented and well known by clinicians. Experience with these agents is sufficient that many adverse events can be avoided through intelligent dosing strategies or effectively managed if they do occur. Despite their associated safety problems, the risk– benefit ratio of CNIs is such that they continue to form the cornerstone of post– heart transplant immunosuppression. Safety concerns in clinical trials of proliferation signal inhibitors include an increase in certain types of infection (eg, bacterial infections including pneumonia) and an increase in blood lipid levels.30,31 These events are becoming well understood by transplant clinicians and specific coun-

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termeasure therapy is available to address them (eg, statin therapy in the case of hyperlipidemia). A specific problem that arises during proliferation signal inhibitor therapy, and one that requires careful consideration by the clinician, is the interaction between these agents and CNIs (eg, CsA). Preclinical studies have suggested a synergistic relationship between everolimus and CsA with regard to immunosuppressive efficacy42; however, there is also evidence that coadministration of these two classes of agents can exacerbate CNI-related nephrotoxicity. For example, in the trial by Keogh et al in which heart transplant patients were randomized to receive sirolimus or azathioprine in addition to standard-dose CsA and corticosteroids, serum creatinine levels were higher in patients treated with sirolimus than in those receiving azathioprine.30 At 12-month follow-up, mean serum creatinine was 137.7, 165.1, and 125.4 ␮mol/L in the sirolimus 3 mg, sirolimus 5 mg, and azathioprine groups, respectively. Similarly, in the phase III everolimus study in heart transplantation, in which patients also received standard-dose CsA and corticosteroids, mean serum creatinine levels at 12 months posttransplant were 181 ␮mol/L in the everolimus 1.5 mg group, 189 ␮mol/L in the everolimus 3.0 mg group, and 147 ␮mol/L in the azathioprine group.31 Randomized, blinded, pivotal studies, including largescale everolimus trials in heart and kidney transplantation, were undertaken before the impact of everolimus–CsA interactions was well understood, particularly in relation to how CsA dosing and blood trough levels must be managed in patients receiving combined immunosuppressant regimens of this type. Although some data on therapeutic drug monitoring in patients receiving sirolimus have been published (eg, in relation to target blood levels),43 there is a much larger body of data relating to coadministration of CsA and everolimus in both heart and kidney transplantation.44 – 46 Indeed, pharmacokinetic and pharmacodynamic (PK/PD) analyses have demonstrated the significant contribution of CsA to the nephrotoxicity of the combined regimen, thereby highlighting the need to employ reducedexposure CsA regimens in conjunction with everolimus. EXPOSURE-EFFECT RELATIONSHIPS FOR EVEROLIMUS AND CYCLOSPORINE IN HEART TRANSPLANTATION

Exposure– effect relationships for everolimus and CsA in heart transplantation are similar to those seen in renal transplantation44,45 and demonstrate that (1) increased CsA exposure increases the risk for renal function impairment (decreased creatinine clearance) and (2) in the context of adequate exposure to everolimus, reduced CsA exposure does not increase the risk of rejection. The PK/PD analyses therefore support a recommendation to reduce CsA dosing when used in conjunction with everolimus. Figure 7 shows response-surface analysis in heart transplant recipients receiving everolimus and CsA in the phase III study from 2 weeks after transplantation (Novartis, data on file). Clearly, increased exposure to everolimus (shown by

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Fig 7. Everolimus plus reduced-dose cyclosporine is effective for preventing acute rejection. Response-surface analysis for days 15 to 225 in a phase III study, showing reduced risk for acute rejection (y-axis) as a function of increased everolimus exposure (x-axis). Cyclosporine exposure (average trough blood level; z-axis) had no effect on rejection within the concentration range tested (Novartis, data on file).

Fig 8. Everolimus plus reduced-dose cyclosporine (CsA) is effective for preventing acute rejection. Quartile analysis from a phase III study in heart transplantation based on CsA exposure over days 1 to 28. Efficacy failure rates in the everolimus arms did increase in patients in the lower quartiles for CsA exposure (Novartis, data on file).

increasing trough blood levels) was associated with reduced risk of rejection. The response surface graph is, however, horizontal with respect to CsA blood levels, indicating that across CsA exposures, everolimus was similarly effective. Indeed, this observation is confirmed in an analysis of different patient cohorts from within the study. Here, in contrast to the azathioprine group, efficacy failure did not

increase in everolimus-treated patients who were in the lowest quartiles for CsA exposure (Fig 8; Novartis, data on file). Response-surface plots from the everolimus phase III study also demonstrate the benefits that reducing CsA dose have on renal function in heart transplant patients. Combining everolimus with CsA may lead to potentiation of

IMPROVING OUTCOMES IN HEART TRANSPLANTATION

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Fig 9. Cyclosporine (CsA) but not everolimus exposure is associated with reduced renal function. Probability of a 30% decrease in creatinine clearance after month 1 in a phase III study (y-axis) is a function of CsA exposure (average trough blood levels; z-axis). Everolimus (x-axis) demonstrated no effect on the probability of poorer renal function. (Novartis, data on file).

CNI-related nephrotoxicity, but as Fig 9 shows, reduced renal function is still dependent on CsA exposure rather than everolimus exposure (Novartis, data on file). Increased CsA trough blood levels were associated with an increased probability of a 30% reduction in creatinine clearance rate, while increasing everolimus trough blood level did not affect renal function. Prospective trials in kidney transplantation provide results consistent with those predicted by the exposureresponse models and indicate that prospective lowering of CsA combined with concentration-controlled everolimus is associated with a better overall clinical safety profile and maintained efficacy.46 In one study, after 12 months of treatment with concentration-controlled everolimus (blood trough level 3 to 8 ng/mL) and reduced-exposure CsA, the incidence of biopsy-proven acute rejection among patients initially assigned to everolimus 1.5 or 3.0 mg/d was 26% and 19%, respectively.47 Moreover, mean serum creatinine levels were 126 and 134 ␮mol/L, while mean creatinine clearance was 65 mL/min and 64 mL/min, respectively. These findings within another transplant setting provide assurance that reduced CsA exposure in patients treated with everolimus is accompanied by good renal function but not at the expense of efficacy failure. A recent case series of seven patients shows how everolimus can be used with reduced-dose CsA in the heart transplant setting.48 Everolimus trough blood levels were maintained at 3 to 8 ng/mL, while mean CsA trough blood levels were reduced from 224 ng/mL at 2 weeks posttrans-

plant to 205 ng/mL at 4 weeks (8.2% reduction) and to 188 ng/mL at 8 to 14 weeks (further 8.6% reduction). Two of the seven patients experienced mild rejection (ISHLT grade 1A). In this limited practical clinical experience, therefore, combining everolimus with reduced-dose CsA did not lead to an increase in acute rejection. EVEROLIMUS DATA ARE SUFFICIENT TO GUIDE CLINICAL PRACTICE IN HEART TRANSPLANTATION

Medical need in cardiac transplantation is such that newer agents, such as sirolimus and tacrolimus, are used out of label, without specific guidance, in this indication. As of 2003, however, everolimus has been approved in Europe for prevention of rejection of renal and heart transplants in combination with CsA and corticosteroids. Heart transplant clinicians experienced in dosing everolimus, or sirolimus, understand the importance of modifying the CsA dose to prevent renal toxicity. Based upon quartile analysis and PK/PD analysis of everolimus and CsA exposure within the phase III trial regimen, one can conclude it is possible to reduce the overall exposure to CsA and improve renal function without compromising efficacy: ●

●

Initial everolimus dosing at 1.5 mg/d with adjustment to maintain trough levels ⬎3 ng/mL is associated with low rates of rejection.44 Exposure-response analyses do not support an influence of CsA on efficacy failure beyond a critical 2-week period

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●

●

(see Fig 7). Therefore, CsA dosing to achieve trough levels of 250 to 400 ng/mL during the first month posttransplant is prudent. Maintenance of CsA trough blood levels is particularly important during this early period as one may need to adjust everolimus dosing through therapeutic drug monitoring to maintain optimal everolimus trough levels above 3 ng/mL. Achievement of optimal everolimus blood trough levels assures effective immunosuppression that allows subsequent reduction in CsA dose. It is important to remember that endomyocardial biopsy at regular intervals is standard procedure at virtually all transplant centers, thus underexposure to CsA in patients in the midst of active rejection is avoided. Conversely, CsA dose reduction can be confidently pursued in patients without evidence of rejection on biopsy. Evidence from the everolimus phase III trial in heart transplantation suggests that after 1 month CsA trough blood levels of 200 ng/mL are sufficiently high to maintain immunosuppressive efficacy; after 6 months CsA trough blood levels as low as 100 ng/mL are likely to be adequate. These levels represent substantial reduction from the mean and median exposure to CsA during the trial; however, the data are sufficient to predict maintenance of effective immunosuppression and improvement in renal outcomes when lower doses are used. Case study data suggest that CsA blood trough levels in the region of 135 to 150 ng/mL are sufficient to maintain efficacy in patients receiving everolimus.48

SUMMARY

As discussed, there remain substantial unmet medical needs in cardiac transplantation, specifically in relation to the prevention of chronic allograft vasculopathy. A new class of immunosuppressive agents, the proliferation signal inhibitors sirolimus and everolimus, hold significant potential for improving long-term outcomes in heart transplant patients through their inhibition of vascular remodeling processes. Both agents, but particularly everolimus, have demonstrated efficacy for reducing CAV parameters for at least 2 years following transplantation. Proliferation signal inhibitors have also been shown to be associated with lower rates of biopsy-proven acute rejection than azathioprine and a lower incidence of CMV infection, both of which are risk factors for development of CAV. Proliferation signal inhibitors are associated with certain safety issues, notably effects on blood lipids and enhancement of CNI-related nephrotoxicity. However, as explained, no immunosuppressant agent currently used in cardiac transplantation is truly safe, but the safety profile of these agents is now understood and manageable by clinicians. Currently available data relating to heart transplantation are adequate to guide safe and effective dosing of everolimus and CsA such that efficacy is maintained without risk to renal function. In summary, the totality of benefits including reduced incidence of CAV, lower rates of acute rejec-

EISEN, KOBASHIGAWA, STARLING ET AL

tion, and reduction of CMV infection outweigh the risks associated with proliferation signal inhibitor use. As such, these agents offer an overall positive benefit-risk profile in the heart transplant setting. Licensing of these agents for prevention of rejection and CAV in heart transplant recipients will provide clinicians with clear guidance on their use. It should, however, be recognized that the optimal use of all drugs in transplantation evolves over time. Thus, there is also a requirement for educational materials for prescribing clinicians, careful tracking of patient outcomes, and studies to further optimize treatment regimens. Future studies should investigate the long-term efficacy of proliferation signal inhibitors for controlling CAV and characterize regimens involving reduced-exposure CNIs and/or corticosteroids. REFERENCES 1. Organ Procurement and Transplantation Network reports 1996 –2001. Available at: www.optn.org. Accessed February 2005 2. Kobashigawa J: Review what is the optimal prophylaxis for treatment of cardiac allograft vasculopathy? Curr Control Trials Cardiovasc Med 1:166, 2000 3. Jimenez J, Kapadia SR, Yamani MH, et al: Cellular rejection and rate of progression of transplant vasculopathy: a 3-year serial intravascular ultrasound study. J Heart Lung Transplant 20:393, 2001 4. Taylor DO, Edwards LB, Mohacsi PJ, et al: The registry of the international society for heart and lung transplantation: twentieth official adult heart transplant report—2003. J Heart Lung Transplant 222:616, 2003 5. Kapadia SR, Ziada KM, L’Allier PL, et al: Intravascular ultrasound imaging after cardiac transplantation: advantage of multi-vessel imaging. J Heart Lung Transplant 19:167, 2000 6. Billingham ME: Histopathology of graft coronary disease. J Heart Lung Transplant 11(suppl):S38, 1992 7. Kirklin JK, Young JB, McGiffin DC, et al: Cardiac allograft vasculopathy (chronic rejection). In Kirklin JK, Young JB, McGiffin DC (eds): Heart Transplantation. New York: Churchill Livingstone; 2002, p 615 8. Moien-Ashfari F, McManus BM, Laher I: Immunosuppression and transplant vascular disease: benefits and adverse effects. Pharmacol Ther 100:141, 2003 9. Pinney SP, Mancini D. Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention and treatment. Curr Opin Cardiol 19:170, 2004 10. Caforio ALP, Tona F, Belloni Fortina A, et al: Immune and non-immune predictors of cardiac allograft vasculopathy onset and severity: multivariate risk factor analysis and role of immunosuppression. Am J Transplant 4:962, 2004 11. Valantine HA: Cardiac allograft vasculopathy after heart transplantation: risk factors and management. J Heart Lung Transplant 23:S187, 2004 12. Kirklin JK, Naftel DC, Parker J, et al: Evolving trends in risk profiles and causes of death after heart transplantation: a ten-year multi-institutional study. J Thorac Cardiovasc Surg 125:881, 2003 13. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE: Cytomegalovirus infection is associated with cardiac allograft rejection and atherosclerosis JAMA 261: 3561, 1989 14. Guedes A, Tardif JC: Intravascular ultrasound assessment of atherosclerosis. Current Atherosclerosis Reports 6:219, 2004 15. Kapadia SR, Nissen SE, Ziada KM, et al: Development of transplantation vasculopathy and progression of donor-transmitted atherosclerosis comparison by serial intravascular ultrasound imaging. Circulation 98:2672, 1998

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17S 32. Kobashigawa J, Starling RC, Mehra MR, Bhat G, Kormos RL, Barr ML: Impact of ongoing post cardiac transplant risk factors on outcomes: a multi-center study. Am J Transplant 3(suppl):457, 2003 33. Mancini D, Viganò M, Pulpon LA, et al: 24-month results of a multicenter study of Certican for the prevention of allograft rejection and vasculopathy in de novo cardiac transplant recipients. Am J Transplant 3(suppl 5):550, 2003 34. Sharma S, Bhambi B, Nyitray W: Sirolimus eluting coronary stents. N Engl J Med 347:1285, 2002 35. Moses JW, Leon MB, Popma JJ, et al: Sirolimus eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 349:1315, 2003 36. Grube E, Sonoda S, Ikeno F, et al: Six and twelve month results from first human experience using everolimus eluting stents with bio-absorbable polymer. Circulation 109:2168, 2004 37. Weill D: Role of cytomegalovirus in cardiac allograft vasculopathy. Transpl Infect Dis 3(suppl 2):44, 2001 38. Toyoda M, Galfayan K, Galera OA, Petrosian A, Czer LS, Jordan SC: Cytomegalovirus infection induces anti-endothelial cell antibodies in cardiac and renal allograft recipients. Transplant Immunology 5:104, 1997 39. Valantine HA: The role of viruses in cardiac allograft vasculopathy. Am J Transplant 4:169, 2003 40. Dorent R, Valantine H, Parameshwar J, et al: Everolimus is associated with a reduced incidence of CMV infection in heart transplantation. J Heart Lung Transplant 22:S141, 2003 41. Keogh A: Calcineurin inhibitors in heart transplantation. J Heart Lung Transplant 23(suppl 5s):S202, 2004 42. Schuurman HJ, Cottens S, Fuchs S, et al: SDZ, a new rapamycin derivative: synergism with cyclosporine. Transplantation 64:32, 1997 43. MacDonald A, Scarola J, Burke JT, Zimmerman JJ: Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther 22(suppl B):B101, 2000 44. Starling RC, Hare JM, Hauptman P, et al: Therapeutic drug monitoring for everolimus in heart transplant recipients based on exposure– effect modeling. Am J Transplant 4:2126, 2004 45. Lorber M, Ponticelli C, Whelchel J, et al: Therapeutic drug monitoring for everolimus in kidney transplantation using 12month exposure, efficacy, and safety data. Clin Transplant 19:145, 2005 46. Vitko S, Tedesco H, Eris J, et al: Everolimus with optimized cyclosporine dosing in renal transplant recipients: 6-month safety and efficacy results of two randomized studies. Am J Transplant 4:626, 2004 47. Magee J, Tedesco H, Pascual J, et al: Efficacy and safety of 2 doses of everolimus combined with reduced-dose Neoral in de novo kidney transplant recipients: 12 month analysis. Abstract presented at the American Transplant Congress May 14 –19, Boston, Mass, USA 48. Lehmkuhl H, Hummel M, Dandel M, Grauhan C, Knossalla C, Hetzer R: Everolimus (Certican) in heart transplantation— early experience. Abstract accepted for presentation at ISHLT congress, Philadelphia, Pa, USA, April 5–9, 2005