Review of Major Clinical Trials with Mycophenolate Mofetil in Cardiac Transplantation

Abstract

Over the past 10 years, the addition of mycophenolate mofetil (MMF) to combination immunosuppressive regimens in cardiac transplant patients has resulted in significant outcomes benefits. Randomized trials and other studies have demonstrated that the use of MMF is associated with a decreased risk of rejection and improved survival. This article will provide an overview of these trials, as well as those evaluating MMF in renal-sparing regimens and in pediatric cardiac transplant recipients. In addition, emerging evidence demonstrating that MMF may provide long-term benefits in reducing cardiac allograft vasculopathy and those evaluating the role of MMF therapeutic drug monitoring in cardiac transplant recipients will be discussed.

During the 10 years since the introduction of mycophenolate mofetil (MMF) there have been important advances in immunosuppressive therapy in cardiac transplantation. Following preclinical and early clinical studies demonstrating the efficacy of MMF in animal models and limited numbers of patients, a large multicenter, randomized trial evaluating the safety and efficacy of MMF in cardiac transplantation was initiated. This trial demonstrated significant improvements in 1-year patient survival and freedom from rejection or allograft loss in patients treated with MMF versus azathioprine (AZA) in combination with cyclosporine (CsA) and corticosteroids (hereafter referred to as steroids). Subsequently, the use of MMF in adult and pediatric cardiac allograft recipients and in renal-sparing protocols has resulted in benefits that include reductions in rejection and cardiac allograft vasculopathy (CAV) progression as well as improvements in renal function and patient survival.

MMF MECHANISM OF IMMUNOSUPPRESSION

MMF, an ester prodrug of mycophenolic acid (MPA), inhibits a key step in the de novo biosynthesis of purines, selectively affecting cells (such as lymphocytes) that are unable to use salvage pathways (¹). Early preclinical studies of MMF demonstrated that MMF (then known as RS-61443) significantly prolonged cardiac transplants in rats and that the combination of MMF with CsA was more effective than either agent alone (¹). Subsequent rat studies demonstrated that recipient rats had significantly diminished proliferative responses to donor cells in mixed lymphocyte reactions and had a very low incidence and severity of graft coronary disease (²).

MMF has novel properties that may contribute to the prevention of cardiac allograft rejection and also provide benefits in reducing the progression of CAV. In a study by Pethig et al. (³), cardiac transplant patients receiving MMF had lower levels of high-sensitive C-reactive protein, a marker of inflammation having a strong association with cardiovascular disease, than did patients receiving AZA (1.0 mg/L versus 1.8 mg/L; P=0.02). Both groups received concurrent CsA and steroids (³). MMF also has been shown to have marked effects on B lymphocytes in heart transplant recipients. Patients receiving MMF had a reduction in circulating B lymphocytes when compared with patients receiving AZA (P<0.01) or with healthy control subjects (P<0.05) (⁴). Additionally, there was a significant decrease in the expression of B-lymphocyte activation markers in patients receiving MMF (⁴).

These findings are reinforced by reports that MMF suppresses antibody levels in heart patients (^{5, 6}). In an evaluation of 263 heart transplant recipients, not only did MMF reduce the risk of high-grade cellular rejection when compared with AZA (P=0.001) but MMF reduced the risk for IgG anticlass II antibody production (P=0.003) during the first year (⁵). In other work, MMF reduced the posttransplant production of antivimentin and anti-human leukocyte antigen antibodies in 86 patients (⁷). Antivimentin titers at 1 year were 104 versus 215 for MMF and AZA, respectively (P=0.01). Studies have shown that patients who achieved antivimentin titers ≥ 120 in the first year posttransplant were significantly more likely to have CAV at 5 years posttransplant (⁸), reinforcing the importance of these findings.

MMF EFFICACY IN REJECTION TREATMENT AND PREVENTION

In 1993, Ensley et al. (⁹) published one of the first clinical reports describing the use of MMF in cardiac transplantation. In an uncontrolled, nonrandomized 8-week, dose-response study, 30 cardiac transplant patients with mild acute rejection (International Society for Heart and Lung Transplantation [ISHLT] rejection grades 1B, 2, and 3A) were converted from AZA to MMF (500 to 3000 mg/day orally) while maintaining baseline doses of CsA and steroids. There was a significant reduction in the mean biopsy score and less myelosuppression in patients receiving MMF versus AZA. This was the first study that found MMF effective and well tolerated in cardiac transplant patients. Other studies in that early time period also demonstrated benefits of MMF in the treatment of recurrent or refractory acute rejection (^10–12).

The efficacy and safety of MMF as a maintenance agent were evaluated in the first large multicenter trial ever performed in the field of cardiac transplantation, with enrollment started in 1994 and results published in 1998 by Kobashigawa et al. (¹³). At the time the trial was initiated, immunosuppressive regimens for heart transplantation relied on a combination of CsA, steroids, and AZA. There was a general sense that new approaches were needed, however. Survival rates at 1 and 5 years were 79% and 63%, respectively, with no improvements having been registered in the preceding decade (¹⁴). Acute rejection was an important cause of heart transplant mortality, not only in the early posttransplant period but in the late transplant period as well (¹⁴), and infections were also a leading cause of death (¹⁵).

The trial was a double-blind, active-controlled trial conducted at 28 centers (¹³). Adult recipients of a first cardiac allograft (n=650) were randomized to receive MMF (3 g/day) or AZA (1.5–3 mg/kg/day), in addition to CsA and steroids. The use of induction therapy was determined by each center according to standard practice. Because the intravenous formulation of MMF was not available at that time, administration of the study drug was delayed until patients were able to receive oral medications; those still unable to take oral medications more than 5 days after transplantation were withdrawn from the study. Because 11% of the patients withdrew before receiving the study drug, separate 12-month analyses were done for enrolled and treated patient groups. Among the 578 treated patients, there was a reduction in the incidence of acute rejection at 6 months (34.3% versus 26.3%; P=0.039) and in mortality at 12 months (6.2% versus 11.4%; P=0.031) for those receiving MMF (n=289) versus AZA (n=289), respectively. There was also a reduction in the requirement for rejection treatment for patients receiving MMF versus AZA (65.7% versus 73.7%, respectively; P=0.026) and a trend for fewer MMF patients to have ≥grade 3A rejection (45.0% versus 52.9%; P=0.055) or require murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF-treated group (53.3% versus 43.6%; P=0.025). There were also fewer patients in the MMF-treated group experiencing rejection with hemodynamic compromise or death/retransplant than patients receiving AZA (11.4% versus 17.3%, respectively; P=0.045) based on post hoc analysis (¹³).

Changes in intravascular ultrasound (IVUS) measurements conducted using the morphometric or nonserial method (including mean intimal thickness, intimal index, and intimal area) from baseline (4 to 6 weeks after transplant) to 12 months were not significantly different between groups, although there was difference in the change in mean luminal area (a post hoc endpoint) between groups (-0.81 versus +0.33 for AZA and MMF, respectively; P=0.007). There was no difference in the use of statins or angiotensin-converting enzyme inhibitors between groups.

The findings of this trial, while notable, were limited in some respects because of the large number of patients who were withdrawn or unable to receive the study drug. This may have been avoided if physicians had been more experienced using the 3 g MMF dose (most centers would have been more accustomed to using 2 g daily, the dose used in renal transplantation) and thus more familiar with managing MMF’s side effects. The use of therapeutic drug monitoring (TDM) might have reduced the number of withdrawals as would the use of intravenous MMF (now available) to allow patients who had been unable to receive oral medication early in the posttransplant period to receive study medication. Additionally, the use of endpoints now commonly used, including CAV and a composite of death/graft loss/acute rejection (AR)/AR with hemodynamic compromise, may have increased the statistical significance of the findings.

Three-year results of the Kobashigawa et al. (¹³) trial recently have been published (¹⁶). In this long-term analysis, fewer patients receiving MMF died or received another transplant than those receiving AZA (11.8% versus 18.3%, respectively; P<0.01), and time to retransplantation or death was also significantly shorter for patients receiving AZA. The change in mean maximal intimal thickness was less for the MMF group compared with the AZA group as well (0.06 mm versus 0.13 mm, respectively; P=0.056).

In an effort to clarify the impact of MMF in cardiac transplantation despite the confounding issues surrounding the randomized trial (¹³), an analysis of data from the Joint ISHLT/United Network for Organ Sharing Thoracic Registry was conducted in 2001 by Hosenpud and Bennett (¹⁷). A total of 5599 patients (4942 CsA/AZA and 657 CsA/MMF) having been on either AZA or MMF (but not both) from the time of discharge were evaluated (patients enrolled in the previous randomized trial were excluded from analysis). Transplants had to take place between April 1, 1994, and December 31, 1997, to allow a minimum of 18 months of follow-up at the time of the analysis. Baseline characteristics were similar between groups except that recipient age was slightly higher in the MMF group, more MMF patients were undergoing retransplantation, and more MMF patients were on ventricular-assist devices. In contrast, more AZA patients were on intraaortic balloon counterpulsation and more AZA patients were in an intensive care unit immediately pretransplant. Total ischemic time was slightly longer in the MMF group.

Results of the analysis found no significant differences in morbidities between the groups posttransplantation, including infection, rejection, or CAV at 1 year (¹⁷). However, there was a highly significant (P=0.0012) improvement in Kaplan-Meier survival curve in the MMF versus AZA treatment group (94.5% versus 92.5% at 1 year, 92.3% versus 88.9% at 2 years, and 87.1% versus 84.5% at 3 years, respectively). This difference was confirmed in a logistic regression analysis of 3-year mortality. MMF at discharge was associated with an odds ratio of 0.62 (P=0.0106), indicating that MMF reduced the risk of mortality at 3 years by approximately 50%, accounting for all other known important risk factors. Furthermore, differences in demographics between the groups were predicted to disadvantage the MMF group (¹⁷). These data provided independent support, based on a large patient population, for the improved long-term survival benefits demonstrated in the randomized MMF/AZA clinical trial, suggesting that these findings are broadly applicable within the cardiac transplant population.

OTHER MMF EFFICACY TRIALS

In addition to the randomized, multicenter trials (^13–16) other trials and studies evaluated MMF in cardiac transplant recipients in combination with either CsA (^{3, 4, 18–21}) or tacrolimus (TAC) (¹⁸) and in calcineurin inhibitor (CNI)-sparing regimens (^22–25). Table 1 (^{3, 4, 13, 16, 18–25}) provides a summary of published findings from these studies.

TABLE 1: Major trials of mycophenolate mofetil in cardiac transplantation

In the late 1990s, the use of TAC in place of CsA became more widespread in transplantation. Studies evaluating the combination of MMF with TAC were published by Meiser et al. (²⁶) in 1999, by Teebken et al. (²⁰) in 2002, and by Meiser et al. (¹⁸) in 2004 (Table 1). Meiser et al. (¹⁸) conducted a trial aimed at determining whether trough level-adjusted MMF was more effective in combination with TAC or CsA. A second objective was to evaluate the impact of these drugs on MMF dosage. Sixty cardiac allograft recipients were randomized to receive either TAC (n=30) or CsA (n=30) in combination with MMF and steroids. Target blood trough levels of TAC, CsA, and MPA were in the range of 10–15 ng/mL, 100– 300 ng/mL, and 1.5–4.0 μg/mL, respectively. Baseline characteristics were well balanced between groups. All patients were successfully withdrawn from steroids within 6 months of transplant. After a mean follow-up period of 683 days for the MMF/TAC group and 586 days for the MMF/CsA group, patients in the TAC group were more likely to be free from rejection than patients in the CsA group (P=0.0001) (¹⁸). Although there was no difference in patient survival between groups, the incidence of acute rejections per 100 patient-days was lower in patients receiving TAC versus the CsA group (0.03 versus 0.15, respectively; P<0.00007). Furthermore, lower doses of MMF were required to achieve the targeted MPA blood levels in the TAC- versus CsA-treated patients. Mean angiographically defined CAV scores were 1.85±3.18 in the TAC/MMF group and 3.95±4.8 in the CsA/MMF group (P=0.08). There were no significant differences in safety between the two groups except that patients in the TAC/MMF group had a significantly lower mean diastolic blood pressure at 2 years after transplantation than patients treated with CsA/MMF.

Several smaller clinical trials showed MMF to be effective and safe in cardiac transplant patients (Table 1) (^{3, 4, 19, 21}). In a study by Taylor et al. (²¹), 43 patients who had been stable while participating in an earlier MMF efficacy trial were either maintained on MMF or were converted to AZA. Patients converting to AZA had a higher incidence of treated allograft rejection than those remaining on MMF (10/20 [50%] versus 1/23 [4%], respectively; P=0.002). The mean biopsy score also was higher in patients converted to AZA (1.2 versus 1.7; P=0.02) (²¹).

Results from the most recent multicenter, randomized trial involving MMF in cardiac transplant recipients were presented by Kobashigawa and colleagues at the ISHLT annual meeting in 2005 (²⁷). Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either TAC/sirolimus (SRL), TAC/MMF, or CsA/MMF. At 12 months, the differences between treatment groups in survival, incidence of treated ISHLT rejection grade ≥3A, or incidence of hemodynamic compromise rejection were not statistically significant. There were, though, significant differences in the incidence of any treated rejection (TAC/SRL=35%, TAC/MMF=42%, CsA/MMF=60%; P<0.001 for each MMF combination versus TAC/SRL). Median serum creatinine (SCr) levels were lower in patients receiving TAC/MMF (1.3 mg/dL) than in either of the other groups (1.5 mg/dL for both TAC/SRL and CsA/MMF; P=0.032). Fewer viral infections, including cytomegalovirus, were reported in the TAC/SRL group. The authors concluded that in cardiac transplant patients, TAC/MMF appears to offer advantages over TAC/SRL or CsA/MMF when considering both any treated rejection and side-effect profiles.

MMF in Renal-Sparing Protocols

In patients with chronic renal dysfunction, the reduction of CNI exposure, either through dose reduction or complete withdrawal, has been studied as a means of minimizing further deterioration of renal function. MMF-based CNI-sparing strategies were evaluated in three trials (Table 1) (^22–24).

In 2004, Angermann et al. (²²) reported the results of a large multicenter study demonstrating that CsA dose reduction can improve chronic renal dysfunction in cardiac transplant patients. This comparative, prospective study evaluated an intervention arm (n=109; recruited from nine centers) in which MMF was introduced de novo (89% of participants) or substituted for AZA (11% of participants) followed by CsA reduction. All patients in the study arm received steroids, irrespective of whether or not they were receiving steroids at enrollment. In the control arm (n=52; recruited from one center), patients remained on their existing regimen (standard-dose CsA, with or without AZA; steroid use was not specified). Serum creatinine levels at the end of the 8-month study period decreased by 23.3±50.7 μmol/L (P<0.0001) in the intervention arm but increased by 7.3±46.9 μmol/L (P=0.992) in the control group (P=0.0001 for the comparison between groups). In the intervention arm, the CsA levels were 57±24 ng/mL versus 116±36 ng/mL for the intervention versus control groups, respectively. Renal function improved regardless of entry SCr values (from 150 to 310 μmol/L; there was no improvement at ≥ 310 μmol/L) or the presence of diabetes. Myocardial biopsies (available only for the intervention arm) diagnosed three reversible subclinical rejection episodes (²²).

Other single-center studies have also demonstrated that CNI dose reduction with the addition of MMF or substitution of MMF for AZA resulted in improvement in renal function without increased risk of rejection (Table 1) (^{23, 25}). An unpublished prospective, nonrandomized, multicenter study by Rabago et al. (²⁸) evaluated 83 patients with chronic renal insufficiency following MMF substitution for AZA and progressive CsA dose reduction. Patients had significant improvements in renal function (SCr, urea, and creatinine clearance) and total serum cholesterol. There were five acute rejection episodes greater than grade 2.

Complete CsA withdrawal also has been investigated as a means of curtailing worsening renal function in cardiac transplant patients. Dureau et al. (²⁹) used this strategy in a small study of eight cardiac transplant patients (5-11 years after transplant) with SCr levels of 263–409 μmol/L while receiving CsA, AZA, and steroids. AZA was converted to a progressively increasing MMF dose (1 to 3 g/day) and titrated according to hematologic and gastrointestinal tolerance. There were no episodes of acute rejection during the 4- to 12-month follow-up period. Following CsA withdrawal, renal function improved in 7/8, or 88%, of patients. One patient underwent dialysis, and CsA was reintroduced.

Another strategy of CsA withdrawal that has been evaluated is replacement of CNIs with SRL in patients receiving MMF. Groetzner et al. (²³) introduced a CNI-free immunosuppressive regimen to 31 cardiac transplant recipients with late (0.2 to 14.2 years posttransplant) renal impairment (SCr levels >1.9 mg/dL). Patients were first converted to SRL starting with 6 mg/day and then 2 mg/day, with dose adjustments made to achieve target trough levels of 8 to 14 ng/mL. MMF was continued, with MPA trough levels adjusted to 1.5 to 4 μg/mL. Subsequently, CNI inhibitors were reduced by 20% then progressively reduced until they were completely withdrawn (mean time to withdrawal was 2.8 weeks). Survival was 90% after a mean follow-up of 13±95 months. No acute rejection episodes were detected during the study period, and renal function improved following CNI withdrawal (SCr levels of 3.14±0.76 mg/dL and 2.14±0.83 mg/dL, preintervention and postintervention, respectively; P=0.001). In three patients, hemodialysis therapy was stopped completely after conversion (²³).

Meiser et al. (³⁰) recently reported the results of a small pilot study investigating whether a de novo CNI-free immunosuppressive regimen based on trough level adjusted MMF and SRL after cardiac transplantation is effective and can prevent renal impairment. Cardiac transplant patients (n=8) received SRL 6 mg on the day of transplant followed by 2 mg/day with subsequent dose adjustments to maintain target trough levels of 10-15 ng/mL. MMF 2 g/day was administered intravenously for the first 2 to 3 days posttransplant followed by oral MMF (minimum dose 1 g/day) adjusted to achieve MPA plasma trough concentrations of 2.5 to 4.0 μg/mL. Patients also received steroids, tapered over a period of 4 weeks, and antithymocyte globulin induction for 4 days (³⁰).

During a mean follow-up period of 241±80 days (range: 115-352), patient survival was 100% and freedom from rejection was 75% (6/8 patients) (³⁰). Two patients had one rejection episode each (grades 1B-3A and 3A-3B). Following treatment with steroids and (in the case of one patient) a switch from SRL/MMF to SRL/TAC, both of these patients remained free from rejection. Two patients required initial hemodialysis for 3 to 5 days for preexisting renal impairment. Mean SCr levels declined within the first 2 weeks posttransplant, remaining stable thereafter. The most frequent adverse events were moderate myelosuppression, intermittent elevations of cholesterol and triglyceride levels, pericardial effusions, and peripheral edema (³⁰). Although a small, uncontrolled study of a limited duration, these preliminary findings indicate that de novo CNI-free immunosuppressive regimens using MMF and SRL can be safe and effective in preserving renal function.

Despite the apparent success of these MMF-based renal-sparing protocols in cardiac transplantation, there is little information on how to implement such regimens. In the case of CNI dose-reduction and CNI-withdrawal regimens, the optimal timing and circumstances (i.e., at what SCr levels) under which CNI dose reduction should be initiated in cardiac transplant patients have not been established. The specific strategies of low-dose CNI or complete CNI withdrawal with substitution of MMF and/or SRL may need to be individualized, with larger studies needed to confirm efficacy and safety. In the case of de novo CNI-free protocols the promising pilot studies will require substantiation in larger trials with long-term follow-up.

MMF in Pediatric Cardiac Transplantation

Because there have been no multicenter, controlled trials of immunosuppressive maintenance regimens in pediatric cardiac transplant patients, the choice of therapy has been guided primarily by institutional practice and the experiences of individual centers (³¹). In addition to the usual issues of rejection and CAV, there is also serious concern about the risks of steroid use in pediatric patients. With the increased availability of new immunosuppressive agents such as MMF over the past several years, steroid-sparing regimens likely will become standard (³¹).

Very few immunosuppressive regimens have been evaluated in pediatric heart transplant recipients, and most studies have involved very few patients. In a 1997 study, Boucek et al. (³²) studied 17 pediatric patients receiving CsA, AZA, and steroids with antithymocyte induction followed by 6 weeks of MMF therapy. There was a decrease in the number of episodes of rejection per patient with this protocol when compared with a historical control group (P<0.05) (³²).

A retrospective study evaluated 21 pediatric cardiac transplant patients receiving TAC (n=20) or CsA (n=1) with AZA (³²). AZA was switched to MMF for a variety of reasons, including rejection, inability to wean from steroids, donor-recipient mismatches, CAV, and side effects of immunosuppression. Following introduction of MMF, rejections improved in 93% of those switched for rejection. Steroids were successfully withdrawn in 28%, and steroid dose reduction was achieved in 20% (³³).

In a 2005 retrospective analysis of 50 pediatric cardiac transplantations performed over a period of 15 years at a single center, Groetzner et al. (³⁴) reported that freedom from rejection after 5 years was 40% with primary CsA immunosuppression and 56% with TAC; since the introduction of MMF, this increased to 62%. Actuarial freedom from acute rejection for patients receiving MMF with TAC or CsA was 59% versus only 17% for those receiving AZA or steroids with TAC or CsA (P=0.0013). There was a very low incidence (4.3%) of neoplastic disease in this study. The authors now use the combination of MMF and TAC as their standard immunosuppressive regimen in pediatric cardiac transplant recipients (³⁴).

MMF also has been suggested as a component of immunosuppressive regimens for the prevention and treatment of severe hemodynamic compromise in pediatric cardiac patients (³⁵) and for pediatric patients with declining renal function (³⁶). In a 2005 study by Boyer et al. (³⁶), 14 pediatric patients with a progressive decline in renal function were converted from AZA to MMF, with a 50% decrease in CsA dosage. Prior to the intervention, the glomerular filtration rate (assessed by inulin clearance) had decreased from 84 mL/min/1.73 m² at 1 year posttransplant to 50 mL/min/1.73 m² at 5 years. At 1 year after the therapy change, inulin clearance increased by 67% (from 47 mL/min/1.73 m² to 78 mL/min/1.73 m²; P=0.02). There were three episodes of acute rejection, with 79% of patients remaining rejection-free after the conversion.

Together, these limited studies of MMF in pediatric cardiac transplant recipients support a role for MMF in reducing acute rejection. MMF appears to have a useful role in both steroid-sparing and CNI-sparing regimens in pediatric patients.

MMF EFFECTS ON CAV

The immunosuppressive and anti-inflammatory properties of MMF may provide long-term benefits in reducing the risk of CAV in cardiac transplant recipients. These include the previously discussed reductions in levels of C-reactive protein (³) and antivimentin antibodies (⁷) in patients receiving MMF versus AZA. Weis et al. (³⁷) reported that in cardiac transplant patients the combination of TAC/MMF appeared to be superior to TAC/AZA in preserving early coronary vasomotor function, endothelial nitric oxide synthase expression, and inducible nitric oxide synthase suppression as well as cardiac interleukin-6 release. Since these factors, in addition to the risks posed by rejection, are believed to be predictors of CAV, MMF may have a beneficial impact on the subsequent development of CAV.

IVUS is one of the important tools used to study CAV. One of the earlier studies demonstrating the prognostic value intimal thickness as measured by IVUS has in predicting CAV was performed by Rickenbacher et al. in 1995 (³⁸). Based on an evaluation of 145 cardiac transplant recipients by IVUS (48-month follow-up), a mean intimal thickness of >0.3 mm was associated with a significantly worse 4-year overall survival (73% versus 96%, respectively; P=0.005) and cardiac survival (79% versus 96%, respectively; P=0.005) when compared with a mean intimal thickness ≪0.3 mm at a mean of 3.1±2.2 years (³⁸).

Due to the improved immunosuppression with MMF in the first year, Pethig et al. (³) postulated that beneficial effects of MMF on intimal hyperplasia and systemic inflammation might be found late after cardiac transplant as well. They evaluated 30 cardiac transplant patients (2.0±1.1 years posttransplant) randomized to receive MMF (2 g/day) or to continue with AZA, both in combination with CsA and steroids. In addition to the previously mentioned lower values for high-sensitive C-reactive protein in the MMF group, IVUS analysis showed a weak trend toward a larger increase in plaque volume in the AZA group whereas MMF-treated patients tended to show a small increase in vessel dimensions (³).

The 1998 MMF trial by Kobashigawa et al. (¹³) found no difference between the MMF and AZA groups in first-year IVUS results as analyzed by morphometric analysis (average of 10 evenly spaced sites without matching sites between studies). An alternate method of analysis is based on site-to-site comparisons of IVUS data. Site-to-site comparison of maximal intimal thickness has been reported to be a clinically relevant surrogate marker for outcome in a recent IVUS study (³⁹). This IVUS measurement of maximal intimal thickness most likely reflects a heightened immune response by the recipient to the donor heart, which can lead to CAV and subsequent poor outcome. Therefore, in 2004 Kobashigawa et al. (⁴⁰) reanalyzed the IVUS data from the 1998 trial using a site-to-site method. The original IVUS images were reviewed and found to be interpretable in 190 patients (99 MMF and 91 AZA). When compared to the MMF group, the AZA group had a greater number of patients with first-year maximal intimal thickness ≥0.3 mm (43% versus 23%; P=0.005), a decrease in the mean lumen area (P=0.02), and a decrease in the mean vessel area (P=0.03). The MMF group actually experienced an increase in mean vessel area during the first year. Thus, patients receiving MMF appeared to have significantly less progression of first-year intimal thickening with the potential for improved long-term outcome.

MMF TDM IN CARDIAC TRANSPLANTATION

TDM in cardiac transplant patients receiving MMF has not been extensively investigated, although preclinical studies demonstrated a correlation between MPA levels and histologic severity of graft rejection (⁴¹). Findings from eight studies that attempted to correlate pharmacokinetic parameters in cardiac transplant patients receiving MMF with outcomes are summarized in Table 2 (^{25, 26, 42–47}). The role of TDM in optimizing the efficacy of MMF when used in combination with TAC and steroids was evaluated in a two-phase study by Meiser et al. (²⁶) in 1999. In both phases 1 and 2, TAC doses were adjusted to achieve target levels of 10 to 15 ng/mL.

TABLE 2: Pharmacokinetic studies in cardiac transplantation

In phase 1, 15 patients received a fixed dose of MMF (2 g/day) in combination with TAC and steroids. Rejection was diagnosed in 33.3% (5/15) of patients (1.33±1.18 episodes/patient) during a mean follow-up period of 436±88 days. Retrospective analyses of this group indicated that rejection episodes did not occur in patients with mean MPA plasma levels >3 μg/mL. No association was seen between TAC whole blood concentrations and the incidence of rejection.

During phase 2, 30 patients had MMF dosage adjusted to maintain target MPA plasma levels of 2.5 to 4.5 μg/mL (²⁶). Mean MMF dose and MPA plasma levels were 3.2±1.1 and 2.5±0.7, respectively, at 1 month and 2.7±1.2 and 3.4±1.2, respectively, at 6 months. All patients who completed 6 months of the study were successfully weaned from steroids. During follow-up (mean: 696±62 days), only 10% (3/30) of patients experienced rejection (0.1±0.31 episodes/patient). Mean plasma levels in the three patients with rejection were 0.7, 1.3, and 0.9. This study demonstrated that with the use of TDM, a very low incidence of rejection was achieved.

While the preceding study lends support to the use of TDM in cardiac transplantation, other studies investigating MMF/TDM in cardiac transplantation have reported mixed results. Some studies (Table 2) (^{25, 42–47}) reported no correlation between MPA trough or minimal levels and rejection (^{25, 42, 43}) while others reported that higher MPA levels were associated with decreased incidence or severity of rejection (^{44, 45}). The sole study using area under the curve (AUC) measurement to assess MPA levels reported that preliminary findings indicated lower MPA AUC and free MPA AUC values (⁴⁶). An interesting finding of these studies is the high proportion of patients who did not achieve therapeutic levels with either MPA (^{27, 46}) or CNIs (^{43, 44}). A study by Cantarovich et al. (⁴⁸) highlighted the importance of maintaining a balance between agents; the risk of rejection was similar between groups with either a higher CsA level and a lower MMF dose or a lower CsA level and a higher MMF dose.

Despite the relative lack of evidence on which to draw conclusions in cardiac transplant recipients, recommendations for the application of TDM as a guide to MMF therapy were formulated during a roundtable discussion among laboratory scientists and clinicians with expertise in MPA TDM (⁴⁹). The authors recommended a MPA predose concentration of 1 to 3.5 μg/mL to minimize the risk of rejection after heart transplantation. In addition, because appreciable within-patient fluctuations may occur, the dose should not be changed on the basis of a single predose measurement. In patients with severe renal impairment or hypoalbuminemia or to monitor for the risk of severe leukopenia, measuring free MPA AUC may be more appropriate.

SUMMARY

Over the past 10 years, the addition of MMF to the immunosuppressive regimen in cardiac transplant patients has resulted in significant outcomes benefits. The randomized trials have demonstrated a reduction in rejection with subsequent improvement in survival. Utilizing MMF TDM may improve outcomes, particularly when using CNI-sparing or CNI-free protocols. The reanalysis of the IVUS data from the multicenter, randomized MMF trial has suggested that MMF not only decreases the risk of rejection and improves survival but reduces the development of CAV as well.