Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

Authors


  • Ethical guidelines and hazardous procedures: This study received HIPAA Authorization. The Institutional Review Board at each institution approved the protocol, and all patients gave written, informed consent to participate in the trial.

* Corresponding author: J. A. Kobashigawa, jonk@mednet.ucla.edu

Abstract

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of ≥3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer ≥3A rejections or hemodynamic compromise rejections and an improved side-effect profile.

Introduction

Until the last decade, the standard immunosuppressive regimen for cardiac transplantation patients consisted of cyclosporine (CYA), azathioprine (AZA) and corticosteroids. Because of the significant adverse effects attributed to these anti-rejection medications, and in an effort to further reduce both acute and chronic rejection, newer immunosuppressive agents such as tacrolimus (TAC) have been developed. TAC is also a calcineurin inhibitor like CYA and shares many of its pharmacologic characteristics, but in contrast to CYA, TAC has been associated with lower rates of rejection and fewer adverse effects in liver, kidney and pancreas transplantation (1–5). In cardiac transplantation, two multicenter randomized studies conducted in the United States and in Europe have demonstrated comparable 1-year survival and rejection rates between CYA and TAC, but with some differences in drug-specific adverse effects (6,7). Other recent multicenter randomized trials have compared the newer immunosuppression agents mycophenolate mofetil (MMF), sirolimus (SRL) or everolimus (EVL) with AZA in combination with CYA and corticosteroids and found significant reductions in rejection with MMF, SRL or EVL compared to AZA (8–10). Despite the improvements in immunosuppression therapy, the specific combination of agents associated with the best outcome for adverse effects, rejection and survival in cardiac transplant recipients has not yet been established. This randomized trial was performed to assess the efficacy and safety of three immunosuppressive protocols containing different combinations of agents with clinically demonstrated benefits.

Methods

Study population

Three hundred and forty-three men and women 18 years or older undergoing their first cardiac transplant were enrolled at 28 centers in the United States. Patients were excluded if they had been a recipient of a previous transplant, were a carrier of human immunodeficiency virus or hepatitis B, had a positive prospective B- or T-cell crossmatch, received an IL-2 receptor antibody or received MMF pre-transplantation. Female patients of reproductive capacity were also excluded if they were either pregnant or on an unapproved method of birth control. The Institutional Review Board at each institution approved the protocol, and all patients gave written, informed consent to participate in the trial.

Study design

Patients were randomized within 24 h post-operatively in an open label 1:1:1 frequency to 1 of 3 immunosuppression regimens (Table 1). The intent-to-treat analysis was modeled after FDA regulatory studies and based on those patients who received at least one dose of randomized study drug. Induction therapy with ATGAM, OKT3 or thymoglobulin was allowed according to individual institutional preference. Use of induction therapy was encouraged only for patients with significant renal dysfunction at the time of transplant to avoid the need for early use of calcineurin inhibitors.

Table 1.  Immunosuppression regimens*
 Primary immunosuppression agent
TACCYA
  1. *If the patient had renal dysfunction and induction therapy was used.

  2. †Median drug concentrations determined at weeks 1, 2, 4, and months 3, 6 and 12.

Start dose2–4 mg/day3–5 mg/kg/day
bidbid
Target whole blood trough concentration†
 0–3 months10–20 ng/mL200–400 ng/mL
 > 3 months5–15 ng/mL100–300 ng/mL
 
 Adjunct immunosuppression agent
SRLMMF
Start dose6 mg initially + 2 mg/day in 1 dose3 g/day in 2 or 3 divided doses
Target whole blood trough concentration†4–12 ng/mL3–5 ng/mL

Lipid-lowering therapy with either pravastatin or simvastatin was mandated unless a contraindication was present. Therapy was targeted to achieve LDL-cholesterol 100 mg/dL or less and serum triglycerides 200 mg/dL or less. If a patient was receiving maximum therapeutic dosage levels of these antihypercholesterolemic agents, switching to atorvastatin was allowed.

Cytomegalovirus (CMV) prophylaxis was required for recipients who had positive CMV antibodies or for those who were CMV negative but had received an organ from a positive donor. These patients received ganciclovir 5 to 10 mg/kg intravenously while hospitalized and were then switched at discharge to oral valganciclovir and continued for 3 months. Pneumocystis prophylaxis was administered for at least 1 year per institutional protocol. Fungal prophylaxis was given for a minimum of 6 months, while bacterial prophylaxis was given per institutional protocol.

Study endpoints

The primary endpoint of this study was the incidence of International Society of Heart and Lung Transplantation (ISHLT) grade 3A or greater rejection or hemodynamic compromise rejection requiring therapy within the first 6 months. Endomyocardial biopsy was performed at all study visits (weeks 1 through 4, 6, 8, 12, 16, 20, 24, months 8 to 9 and months 10 to 12) and when clinically indicated. Biopsies were evaluated according to the ISHLT criteria (11). Hemodynamic compromise was defined as one or more of the following: left ventricular ejection fraction ≤30% or a 20% decrease from baseline and the need for inotropic agents, fractional shortening ≤20% or a 25% decrease from baseline and the need for inotropic agents and/or the need for inotropic agents due to a cardiac index <2.0 L/min/m2 or a 25% decrease from baseline. Treatment of rejection episodes was standardized based on the histologic grade and presence or absence of hemodynamic compromise (Table 2).

Table 2.  Rejection treatment table
ISHLT biopsy gradeNo hemodynamic compromiseHemodynamic compromise
IA, IB, IINo treatmentHigh dose IV 500 to 1000 mg corticosteroids for 3 to 10 days and return to baseline and/or 3 to 14 days of OKT3, ATGAM or thymoglobulin.
IIIA, IIIB2 to 5 mg/kg oral corticosteroids for 3 to 5 days and return to baseline or 500 to 1000 mg IV corticosteroids for 3 days and return to baseline.High dose IV 500 to 1000 mg corticosteroids for 3 to 10 days and return to baseline and/or 3 to 14 days of OKT3, ATGAM or thymoglobulin.
High dose IV 500 to 1000 mg corticosteroids and return to baseline with or without either 3 to 14 days of OKT3, ATGAM or Thymoglobulin.High dose IV 500 to 1000 mg corticosteroids and return to baseline with or without either 3 to 14 days of OKT3, ATGAM or thymoglobulin.

Secondary endpoints of this study included patient and graft survival at 12 months, the incidence of rejection at 12 months, time to the first rejection episode, the number of patients requiring anti-lymphocyte antibody therapy or steroids for rejection at 6 and 12 months, the number of rejections requiring treatment regardless of biopsy grade or presence of hemodynamic compromise and normal serum lipid levels with lipid-lowering therapy at 6 months. The safety assessments for this study included the incidence of bacterial, viral and fungal infections, serum creatinine at 6 and 12 months, incidence and severity of hypertension (systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg), incidence and severity of hyperlipidemia (total cholesterol ≥ 200 mg/dL, triglycerides ≥ 150 mg/dL or LDL ≥ 130 mg/dL), incidence of hyperglycemia, incidence of gastrointestinal tract complications, incidence of hematologic adverse events, incidence of malignancy including lymphoma and lymphoproliferative disease and percentage of patients requiring discontinuation of their medications due to adverse events. Post-transplant diabetes mellitus was defined by the new American Diabetes Association guidelines as two fasting blood glucose samples ≥126 mg/dL or the use of oral antihyperglycemic therapy or insulin. CMV viremia or syndrome was defined as isolation or identification of CMV from any site or by a positive seroconversion in the absence of clinical symptoms. CMV disease was defined as symptomatic CMV infection with histological evidence or a positive CMV culture.

Statistical analysis

Statistical analyses were performed on data from all patients who were randomized, underwent transplantation and received at least one dose of study medications (intent-to- treat population). All statistical analyses were conducted at an α= 0.05 employing two-sided tests using SAS® Version 8.02 software (SAS Institute Inc., Cary, NC). For continuous variables, statistical summaries for normally distributed data were expressed as means, and standard deviations and comparisons among treatment groups were performed using analysis of variance. For data that were not normally distributed, the statistical summaries were expressed as medians, and comparisons among treatment groups were performed using Wilcoxon rank-sum test. For categorical variables, statistical summaries were expressed as counts and percentages with a Pearson chi-square test or Fisher's exact test employed where appropriate. The Kaplan-Meier method using log-rank test was used for survival rate calculations. Statistical analyses were performed by The EMMES Corporation, Rockville, MD.

Results

Patient accounting

Of the 343 patients randomized into the study, 9 were excluded from all analyses, leaving 334 in the intent-to-treat population (ITT) (Figure 1). In the TAC/SRL group, 2 patients did not receive study drug: 1 died, and 1 withdrew from the study. In the TAC/MMF group, 5 patients did not receive study drug: 2 patients did not undergo transplantation, 1 died 1 day post-transplant prior to receiving study drug, 1 did not meet the eligibility criteria and 1 withdrew prior to study drug administration. In the CYA/MMF group, 1 patient died and 1 withdrew, both prior to study drug being given.

Figure 1.

Patient accounting.

Baseline characteristics

Demographic and other baseline characteristics of patients included in the ITT analyses were similar across all three treatment groups (Table 3).

Table 3.  Patient demographics and baseline characteristics*
 TAC/SRL n = 111TAC/MMF n = 108CYA/MMF n = 115
  1. *Values are medians unless otherwise indicated.

  2. †Hypertension is defined as a systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg or receiving treatment.

  3. ‡Hyperlipidemia is defined as total cholesterol ≥ 200 mg/dL or triglycerides ≥ 150 mg/dL or LDL ≥ 130 mg/dL or receiving treatment.

Age, mean, yr54.354.551.9
Gender, % male828173
Race/ethnicity, %
 White808979
 Black14817
 Asian211
 Hispanic422
Indication for cardiac transplant, %
 Idiopathic39.634.336.5
 Ischemic50.554.649.6
 Valvular5.43.76.1
 Congenital1.82.80.9
 Other2.74.67.0
Cholesterol, mg/dL (n)151 (100)157 (94)151 (101)
LDL, mg/dL (n)88 (92)93 (92)85 (89)
HDL, mg/dL (n)38 (96)37 (87)38 (91)
Triglycerides, mg/dL| (n)107 (99)106 (94)106 (100)
Systolic blood pressure, mm Hg (n)110 (105)112 (104)112 (114)
Diastolic blood pressure, mm Hg (n)66 (105)64 (104)66 (114)
Serum creatinine, mg/dL1.30 (110)1.10 (108)1.10 (115)
Diabetes mellitus, %21.628.727.8
Hypertension†, %34.236.137.4
Hyperlipidemia‡, %53.260.250.4
CMV mismatch
 Donor +, Recipient −, %20.725.020.9
Induction therapy, total (%)
 OKT3162016
 ATGAM012
 Thymoglobulin182219
 Daclizumab110
Donor age, yr, mean30.734.333.3
Ischemic time, h, mean (SD)3.23.23.3

Immunosuppression therapy

At 1 year, median blood drug levels of TAC, CYA and SRL were within the respective target ranges of 5 to 15 ng/mL, 100 to 300 ng/mL and 4 to 12 ng/mL (Table 4). Median levels of mycophenolic acid (MPA) were below the target of 3 to 5 ng/mL for groups treated with MMF. Levels were slightly higher for patients also treated with TAC (2.1 ng/mL) compared with those treated with CYA (1.6 ng/mL).

Table 4.  Drug dosages and blood concentrations at 1 year*
 TAC/SRLTAC/MMFCYA/MMF
  1. *Values are medians (numbers).

  2. †1-year values.

  3. ‡Mycophenolic acid.

Dose, mg/day (n)
 TAC5 (82)4 (91)
 CYA225 (76)
 SRL†2 (75)
 MMF2000 (84)2000 (84)
 Corticosteroids5 (80)5 (83)5 (89)
Blood concentration, ng/mL
 TAC8.1 (77)8.8 (85)
 CYA170 (73)
 SRL5.1 (61)
 MPA‡2.1 (70)1.6 (70)

Efficacy outcomes

There was no statistically significant difference in the primary endpoint of 6-month incidence of ≥3A rejection or hemodynamic compromise rejection requiring treatment among the three groups (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271). Results of secondary endpoints at 1 year included no significant difference in rejection ≥3A or hemodynamic compromise rejection requiring treatment (p = 0.056) among the three treatment groups; however, this endpoint was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group (23.4% vs. 36.8%, p = 0.029) (Table 5). There was no significant difference in the overall Kaplan-Meier probabilities of grade 3A or greater biopsy among treatment groups (Table 5). Yet, differences in incidence of any treated rejection were statistically significant across the three groups, with lower values seen in the TAC groups (p < 0.001) (Figure 2). The incidence of hemodynamic compromise or use of antilymphocyte therapy was low and not significantly different among treatment groups. Overall 1-year survival was 91% in the TAC/SRL group, 95% in the TAC/MMF group and 90% in the CYA/MMF group, but the differences were not statistically significant.

Table 5.  Rejection at 1 year*
Type of rejectionTAC/SRL n = 111TAC/MMF n = 107**CYA/MMF n = 114**p-value
  1. *Values are numbers (percentages).

  2. **One patient in each of these treatment groups died prior to first biopsy.

  3. ***p-value = 0.009 Tac/MMF vs. CsA/MMF group only.

  4. ****p-value = 0.029 Tac/MMF vs. CsA/MMF group only.

  5. †p < 0.001, Fisher's exact test.

≥ grade 3A biopsy or hemodynamic compromise requiring treatment, n (%)28 (25.2)25 (23.4)****42 (36.8)0.056
≥ grade 3A biopsy requiring treatment, n (%)27 (24.3)24 (22.4)38 (33.3)0.151
Any treated rejection, n (%)39 (35.1)45 (42.1)***68 (59.6) †<0.001
Hemodynamic compromise, n (%)6 (5.4)4 (3.7)9 (7.9)0.425
Antilymphocyte therapy + steroids, n (%)6 (5.4)9 (8.4)10 (8.8)0.591
Figure 2.

Probability of any treated rejection through 12 months; Kaplan-Meier curves.

Adverse effects

At 1 year, the incidence of individual adverse events was generally comparable among the three treatment groups. However, there were statistically significant differences in median serum creatinine (SCr) (p = 0.032) and triglycerides (p = 0.028), with the lowest values observed in the TAC/MMF group (Table 6). Among patients whose baseline serum creatinine level was >1.5 mg/dL, the highest median serum creatinine was observed in the TAC/SRL group (p = 0.045), while values were comparable between TAC/MMF and CYA/MMF groups.

Table 6.  Secondary endpoints at 1 year*
 TAC/SRL n = 111TAC/MMF N = 108CYA/MMF n = 115
  1. *Values are medians unless otherwise noted.

  2. †p = 0.028, Wilcoxon rank-sum test.

  3. ‡p = 0.032, Wilcoxon rank-sum test.

  4. §p = 0.045, Fisher's exact test.

  5. p = 0.005, Chi-square test.

Total cholesterol, mg/dL (n)174 (93)170 (96)183 (95)
LDL, mg/dL (n)96 (77)97 (79)98 (77)
Triglycerides, mg/dL (n)162 (93)126 (96)154† (95)
Received anti-hypertensive therapy, % (n)76 (109)79 (108)82 (114)
Serum creatinine, mg/dL (n)1.5 (98)1.3 (100)1.5‡ (101)
 Baseline > 1.5, mg/dL (n)2.0 (28)1.5 (15)1.6§ (22)
Fasting blood glucose, nondiabetic patients
 1 sample ≥126 mg/dL, % (n)68.6 (87)55.8 (77)57.8 (83)
 2 samples ≥126 mg/dL, % (n)38.8 (87)31.6 (77)25.3 (83)
Anti-hyperglycemic therapy, % (n)
 Nondiabetic at baseline49.4 (75)59.7 (72)45.8 (75)
 All patients60.6 (109)70.4 (108)59.6 (114)
Insulin therapy >30 days at 0–12 months, % (n)
 Nondiabetic at baseline24.7 (85)13.0 (77)7.2∥ (83)
 All patients37.6 (109)32.4 (108)27.2 (114)

Median systolic blood pressure increased from baseline levels in all treatment groups. There were no statistically significant differences among the groups with respect to the percentage of patients who required antihypertensive treatment during the study (Table 6). However, a numerically larger percentage of patients from the CYA/MMF group (97%) experienced hypertension (systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg) during the 12 months compared with either the TAC/SRL (93%) or the TAC/MMF (88%) groups, and more CYA/MMF patients required two or more medications for hypertension than in both TAC groups, although this difference was not statistically different (p = 0.054).

There were no statistically significant differences in the incidence of new onset diabetes diagnosed using the American Diabetic Association guidelines or in the incidence of one or two fasting blood glucose ≥126 mg/dL in non-diabetic patients among the three groups, although this incidence was numerically highest for the TAC/SRL group (Table 6). The largest number of patients who required antihyperglycemic therapy was observed in the TAC/MMF arm, but the differences among treatment groups were not statistically significant. Significantly, more patients in the TAC/SRL group required insulin therapy.

Safety outcomes

As presented in Table 7, the number of patients withdrawn from the calcineurin inhibitor that they were randomized to was lowest for the TAC/MMF group (9/108; 8.3%) when compared to the TAC/SRL group (24/111; 21.6%) and CYA/MMF group (25/115; 21.7%). The principal reason for withdrawal of TAC in the TAC/SRL group was renal dysfunction while refractory rejection was the primary reason for withdrawal of CYA in the CYA/MMF group. No patients were withdrawn from either TAC group due to refractory rejection. Of the 9 patients withdrawn from TAC in the TAC/MMF group, 7 were placed on CYA, and 2 were completely withdrawn from calcineurin inhibitors (1 of these patients placed on SRL). Of the 24 patients withdrawn from TAC in the TAC/MMF group, 13 were placed on CYA, and 11 were withdrawn completely from calcineurin inhibitors (6 of these patients were placed on MMF and 1 of these patients were placed on AZA). Of the 25 patients withdrawn from CYA in the CYA/MMF group, 23 were placed on TAC while 2 were withdrawn completely from calcineurin inhibitors (no other drugs added).

Table 7.  Adverse events*
 TAC/SRL n = 111TAC/MMF n = 108CYA/MMF n = 115
  1. *Values are n (%).

  2. †p = 0.015, Fisher's exact test.

Discontinuation of TAC or CYA24 (21.6)9 (8.3)25 (21.7)
 Renal dysfunction9 (8.1)1 (0.9)5 (4.3)
 Refractory rejection0013 (11.3)
 Neurotoxicity2 (1.8)4 (3.7)2 (1.7)
Discontinuation of MMF or SRL39 (35.1)18 (16.7)17 (14.8)
 Leukopenia5 (4.5)8 (7.4)7 (6.1)
 Renal dysfunction9 (8.1)01 (0.9)
 Diarrhea5 (4.5)5 (4.6)0
Infectionn = 109n = 108n = 114
 Viral9 (8.3)22 (20.4)23 (20.2)
 CMV infection/syndrome3 (2.8)14 (13.0)14 (12.3)
 Fungal18 (16.5)8 (7.4)13 (11.4)
 Candida14 (12.8)7 (6.5)12 (10.5)
 Bacterial39 (35.8)37 (34.3)42 (36.8)
Malignancyn = 109n = 108n = 114
 All2 (1.8)5 (4.6)9 (7.9)
 Skin0 (0)4 (3.7)5 (4.4)
 Other2 (1.8)1 (0.9)4 (3.5)
Death10 (9.0)5 (4.6)12 (10.4)
Othern = 111n = 108n = 114
 WBC < 3000 mcg/L33 (29.7)38 (35.2)45 (39.5)
 Platelets < 75 000/ microL35 (31.5)24 (22.2)31 (27.2)
 Hemoglobin < 10 mg/dL92 (82.9)89 (82.4)101 (88.6)
 Magnesium < 1.2 mEq/L18 (16.2)26 (24.1)19 (16.7)
 Impaired wound healing26 (23.4)11 (10.2)14 (12.3)†
 Interstitial pneumonia3 (2.7)01 (0.9)
 Hirsutism4 (3.6)2 (1.9)10 (8.8)
 Gingival hypertrophy007 (6.1)
 Cushingoid features10 (9.0)14 (13.0)22 (19.3)

More patients were withdrawn from SRL than from MMF. Renal dysfunction was the primary reason for withdrawal of SRL. All other side effects were similar among the three groups, although diarrhea was the primary reason for withdrawal of SRL and MMF in patients treated with TAC. Leukopenia was the primary reason for MMF withdrawal in both the TAC and CYA groups. Leukopenia was most frequent in the TAC/MMF group, but differences among treatment groups were not statistically significant.

There were fewer viral infections, including CMV, but more fungal infections, in the TAC/SRL group compared with the other two groups (Table 7). The incidence of impaired wound healing was significantly higher (p = 0.015) for the TAC/SRL arm while the percentages of patients with gingival hypertrophy were significantly (p = 0.001) higher in the CYA/MMF group. The incidence of hirsutism was also higher in the CYA/MMF group, but the difference was not statistically significant. Despite comparable treatment with lipid lowering medications, significantly more (p = 0.001) CYA/MMF patients experienced hypercholesterolemia ≥240 mg/dL than patients in either TAC group. Malignancy was documented for 9 patients in the CYA/MMF group compared with 5 in the TAC/MMF group and 2 in the TAC/SRL group. Skin cancer was the most common (9 of 16) among all of the malignancies reported (Table 7).

Discussion

Significant improvements in outcome following cardiac transplantation have been made over the past two decades, largely as a result of advances in immunosuppressive therapy. Despite these improvements, the combination of immunosuppressive agents most advantageous to cardiac transplant patients has yet to be established. Although there was no significant difference among the three groups in the primary endpoint of 6-month incidence of ≥3A rejection or hemodynamic compromise rejection requiring treatment, the 1-year results (secondary endpoints) of this study found a significant difference in the incidence of any treated rejection, with a lower incidence observed in the two TAC groups. Median serum triglycerides and median serum creatinine were significantly lower in the TAC/MMF treatment group than in the other groups. In addition, there were no significant differences in hypertension and new onset diabetes mellitus among the groups.

Rejection and complications of rejection therapy remain the primary causes of death in the first year after heart transplantation (12). Advances in immunosuppression using CYA- and TAC-based regimens have reduced the frequency of these problems. Two randomized, prospective, multicenter, open-label, clinical studies (one in the United States and one in Europe) comparing CYA with TAC have been conducted in heart transplant patients (6,7). These two studies have suggested comparability in outcomes between TAC and CYA in combination with AZA and corticosteroids, particularly in rejection outcome. However, these studies used the earlier formulation of CYA, which has erratic absorption compared to the newer microemulsion formulation. In addition, MMF (8), SRL (9) and EVL (10), three newer anti-proliferative agents, have been found to have greater benefits in outcomes than AZA when administered in combination with CYA and corticosteroids. Therefore, the microemulsion formulation of CYA, TAC, MMF and SRL were the immunosuppressive agents tested in the current study.

The current randomized study compared the three combinations of TAC/MMF, CYA/MMF and TAC/SRL taken with corticosteroids in heart transplant patients and found that the incidences of ISHLT grade ≥ 3A rejection, hemodynamic compromise rejection or rejection treated with antilymphocyte antibody therapy were not significantly different among the three groups. These findings corroborate the results of previous studies comparing CYA and TAC in combination with AZA (6,7). Moreover, in the current study, the benefit of a lower incidence of any treated rejection observed for patients in the TAC groups might have reflected lower treatment of noncellular or, possibly, humoral rejection. It has been shown in a rat aorta-graft study (13) and a single center study (14) that TAC reduced the development of circulating antibodies by a greater amount than CYA. In further support of the clinical rejection benefit of TAC, refractory rejection requiring discontinuation of either calcineurin inhibitor occurred only in the CYA/MMF group. Support for this finding has been consistent in the literature (15–18).

Development of cardiac allograft vasculopathy is one of the major problems limiting long-term survival in cardiac transplant patients. The evidence that hyperlipidemia is associated with poorer outcome in transplant recipients is somewhat equivocal; however, most studies suggest such an association for both cholesterol and triglycerides (19). In a previously conducted randomized trial, the TAC group had a lower 6-month cholesterol level than the CYA group, and all lipid fractions including triglycerides were significantly higher in CYA-treated patients (6). In the current study, serum triglyceride levels were significantly different among treatment groups while no significant differences were found for serum cholesterol. Approximately 90% of the patients in this study were receiving statin therapy for hyperlipidemia. Nevertheless, patients treated with TAC/MMF had the lowest median blood triglyceride levels, indicating an advantage of TAC with respect to lipids, particularly when given in combination with MMF. The comparable use of statins among treatment groups in this study is important to differentiating an effect specific to TAC, as statin therapy not only inhibits cholesterol production, but can also reduce the incidence of cardiac allograft vasculopathy and hemodynamic compromise rejection and improve survival (20).

Calcineurin inhibitor nephrotoxicity after cardiac transplantation is well known, with a similar incidence reported between CYA and TAC when given in combination with AZA (6,21). In the current study, median serum creatinine was significantly different among treatment groups, with the lowest level found in the TAC/MMF group, despite slightly higher blood TAC levels compared with the TAC/SRL group.

New onset diabetes is observed in 24% of patients at 1 year and in 32% at 5 years after cardiac transplantation according to data from a large international registry (12). The precise impact of new onset diabetes on the outcome of cardiac transplant patients is difficult to assess, as few studies have described the condition in this population. Two reports have indicated that patients with diabetes at the time of cardiac transplantation have a poorer outcome than those without the condition (22,23). Conversely, another study has reported no difference in morbidity and mortality between cardiac transplant patients with diabetes at the time of transplantation compared with non-diabetic transplant recipients (24). In general, a trend toward a slightly higher diabetogenic effect has been observed for TAC, although it has generally failed to reach statistical significance (5–7,21,25). In the current study, post-transplant diabetic rates, defined by the new American Diabetes Association guidelines as two fasting blood glucose samples ≥126 mg/dL or the use of oral antihyperglycemic therapy or insulin, were not significantly different among the three treatment groups for all criteria except use of insulin. A significantly lower percentage of patients in the CYA/MMF group who were nondiabetic at baseline required use of insulin therapy at 1 year.

Consistent with findings from other US and European trials (6,7), 1-year incidence of infection was similar among groups in this study. However, there were fewer viral infections, but more fungal infections, in the TAC/SRL group compared with the other two groups. The lower incidence of CMV infection observed with SRL or EVL immunosuppression is consistent with data reported from other clinical trials (10,26). Death due to infection was not significantly different among the three groups and overall 1-year mortality rate was also similar.

The rate of new malignancies ranged from 1.8% (2/109) in the TAC/SRL group to 4.6% (5/108) and 7.9% (9/114) in the TAC/MMF and CYA/MMF groups, respectively, and the majority of the malignancies reported were skin cancer (9 of 16 reported). A recent analysis of the United Network for Organ Sharing (UNOS) database found a rate of 1–1.5% for new malignancies among renal transplant patients treated concomitantly with calcineurin inhibitors and TOR (target of rapamycin) inhibitors such as SRL (27). The lowest malignancy rate in the present study was found among patients in the TAC/SRL group, which is consistent with what has been reported.

A larger number of patients discontinued either TAC or SRL in the TAC/SRL group compared to the other two groups, predominantly due to renal dysfunction. Despite this finding, the TAC/SRL group had similar rejection incidence and patient survival. In all three groups, there were a significant number of patients that discontinued their study medications and switched their drug regimen from the initial randomized group. Therefore, the observations made in this article should be interpreted with some caution in light of the discrepancies that might be seen between an intent-to-treat and a drug-combination-received analysis. Although TAC doses were similar for both the TAC/MMF group and the TAC/SRL group, TAC trough blood levels were higher in the TAC/MMF group. Of interest, despite a significantly higher TAC blood level in the TAC/MMF group, serum creatinine was significantly lower in this group compared to the other two groups. In addition, despite a similar dose of MMF administered in the TAC/MMF group compared with the CYA/MMF group, trough blood levels of MPA, a metabolite of MMF, were slightly higher in the TAC/MMF group as had been reported previously (28).

Although there was no difference in the primary endpoint of this study, secondary endpoints suggest that the combination of TAC/MMF appears to offer more advantages than either TAC/SRL or CYA/MMF in cardiac transplant patients, including a lower incidence of any treated rejection and an improved side-effect profile.

Appendix

1. University of California, Los Angeles – J. Kobashigawa
2. University of Minnesota – L. Miller
3. Duke University – S. Russell
4. Barnes Hospital – G. Ewald
5. Beth Israel – M. Zucker
6. University of Pennsylvania – L. Goldberg
7. Temple University – H. Eisen
8. University of Alabama – B. Rayburn
9. University of Cincinnati – L. Wagoner
10. Albany Medical College – L. Zisman
11. Medical University of South Carolina – N. Pereira
12. Henry Ford Hospital – B. Czerska
13. University of Pittsburgh – R. Kormos
14. Tampa General Hospital – M. Weston
15. Johns Hopkins – J. Conte
16. St. Luke's, Milwaukee – J. Hosenpud
17. University of Michigan – K. Aaronson
18. University of Florida – J. Hill
19. University of Arizona – J. Copeland
20. Cedars Sinai – L. Czer
21. University of Chicago – A. Anderson
22. Massachusetts General – G. W. Dec
23. Methodist Houston – G. Torre-Amione
24. Baylor University, Dallas – C. Yancy
25. Emory University – J. D. Vega
26. Brigham and Women's – J. Jarcho
27. Columbia University – D. Mancini
28. Jewish Hospital, Louisville – G. Bhat
29. Fujisawa Health Care, Inc. – M. R. First, W. E. Fitzsimmons, D. Tolzman, K. Salm, R. Washington
30. Emmes Corporation – P. Van Veldhuizen, J. Gao

Acknowledgment

This study was supported by a grant from Fujisawa Healthcare Inc., Deerfield, IL.

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