SEARCH

SEARCH BY CITATION

Keywords:

  • Cardiac allograft vasculopathy;
  • cyclosporine;
  • everolimus;
  • heart transplantation;
  • mycophenolate mofetil;
  • randomized

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

In an open-label, 24-month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced-dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard-dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12-month composite incidence of biopsy-proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow-up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: –7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24-month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12-month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced-dose cyclosporine offers similar efficacy to MMF with standard-dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.


Abbreviations
BPAR

biopsy-proven acute rejection

CAV

cardiac allograft vasculopathy

CI

confidence interval

CMV

cytomegalovirus

DMC

Data Monitoring Committe

ISHLT

International Society of Heart and Lung Transplantation

ITT

intention-to-treat

IVUS

intravascular ultrasound

LVAD

left ventricular assist devices

LVEF

left ventricular ejection fraction

MIT

maximum intimal thickness

MMF

mycophenolate mofetil

mTOR

mammalian Target of Rapamycin

NI

noninferiority

rATG

rabbit antithymocyte globulin

RR

risk ratio

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

Modern immunosuppression has improved survival in the first year after heart transplantation by reducing the impact of acute cellular rejection and infection [1]. Increasing survival beyond the first year has proved more difficult. The two major causes of death after year 1, malignancy and cardiac allograft vasculopathy (CAV), appear to be only modestly ameliorated by recent advances in posttransplant management [1].

Inhibition of the mammalian Target of Rapamycin (mTOR) signaling pathway by sirolimus or everolimus reduces the incidence and severity of CAV compared to azathioprine in heart transplant patients [2, 3]. In a randomized trial of 634 de novo heart transplant recipients, everolimus was also associated with a lower incidence of major adverse cardiac events versus azathioprine at 4 years posttransplant [4]. However, use of azathioprine is now outdated due to inferior clinical outcomes compared to mycophenolate mofetil (MMF) [5].

A randomized study was undertaken to compare the efficacy, safety and incidence of CAV in de novo heart transplant patients receiving everolimus at two doses (1.5 mg/day or 3.0 mg/day in divided doses) with reduced-dose cyclosporine versus MMF with full-dose cyclosporine. The primary study objective was to determine the noninferiority (NI) of everolimus to MMF with respect to a composite efficacy endpoint at 12 months posttransplant.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

Study design and conduct

This 24-month, prospective, randomized study (http://www.clinicaltrials.gov, NCT00300274) enrolled patients at 63 transplant centers in Europe, North and South America, Asia and Australasia. An open-label design was used to permit therapeutic drug monitoring of study drugs. The study took place during the period January 2006 to July 2011. All study participants provided written informed consent. The study protocol was approved by the institutional review board of each institution and conducted in accordance with the guidelines of the U.S. Code of Federal Regulations, the European Community Guidance on Good Clinical Practice [6] and the Declaration of Helsinki [7].

Inclusion and exclusion criteria

De novo heart transplant recipients aged 18–70 years were eligible for enrolment. Patients receiving a heart from a donor aged >65 years or with known coronary disease were excluded, as were patients with a donor heart cold ischemia time >6 h or estimated GFR [eGFR] <40 mL/min at screening (MDRD formula, see Ref. 8).

Intervention and concomitant medication

Randomization was performed (blocking size 6) using a centrally generated randomization list (Almac Clinical Technologies, PA, USA). Investigators were informed of the randomization group for each enrolled patient via an interactive voice recognition system. Patients were randomized in a 1:1:1 ratio to receive (1) everolimus 1.5 mg (target trough concentration 3–8 ng/mL) with reduced-dose cyclosporine, (2) everolimus 3.0 mg (target trough concentration 6–12 ng/mL) with reduced-dose cyclosporine or (3) MMF 3 g (1.5 mg b.i.d.) with full-dose cyclosporine. Patients received study medications within 72 h of transplantation. Administration of everolimus (Certican®, Novartis Pharma AG, Basel, Switzerland) and cyclosporine (Neoral®, Novartis Pharma AG) was based on predefined target ranges for trough concentrations (Figure 1). Corticosteroids were administered according to local practice. Centers had to choose between three induction strategies: (1) basiliximab (Simulect®, Novartis Pharma AG) 20 mg on days 0 and 4 posttransplant or (2) rabbit antithymocyte globulin (rATG; Thymoglobulin®, Genzyme, Genzyme Corporation, Cambridge, MA, USA) administered as per local practice, starting on day of transplant and ending ≤5 days posttransplant or (3) no induction. Centers had to apply the chosen induction strategy to all patients enrolled at the center.

image

Figure 1. Study protocol. Study visits took place at baseline, days 1, 4, 6, 15 and 22, and months 1, 2, 3, 4, 5, 6, 9, 12, 18 and 24. CsA = cyclosporine; MMF = mycophenolate mofetil.

Download figure to PowerPoint

Adjunctive medication included statin therapy, which was mandatory for all patients and was started in the early perioperative period. Cytomegalovirus (CMV) prophylaxis was mandatory for a minimum of 30 days for all CMV-negative recipients with a CMV-positive donor.

Efficacy assessment

The primary efficacy endpoint was the composite incidence of biopsy-proven acute rejection (BPAR) of ISHLT grade ≥ 3A (revised nomenclature grade 2R), acute rejection associated with hemodynamic compromise, graft loss/retransplantation, death or loss to follow-up at 12 months posttransplant. Endomyocardial biopsies were obtained at each study visit after day 6 and were graded locally (9,[10]). Central biopsy readings were also performed, and included in a sensitivity analysis. Hemodynamic compromise was defined as one or more of the following: (i) left ventricular ejection fraction (LVEF) ≤30%, (ii) LVEF ≥25% lower than baseline, (iii) fractional shortening ≤20%, (iv) fractional shortening ≥25% lower than baseline or (v) use of inotropic therapy. LVEF and fractional shortening were both defined echocardiographically.

The main secondary efficacy endpoint was the composite incidence of graft loss/retransplantation, death or loss to follow-up. Other secondary efficacy endpoints comprised BPAR of ISHLT grade ≥3A (2R), acute rejection associated with hemodynamic compromise, acute rejection requiring antilymphocyte treatment and death.

Intravascular ultrasound (IVUS) assessment

The primary IVUS efficacy variable was mean change in maximum intimal thickness (MIT) between matched slices from baseline to month 12. Secondary IVUS efficacy variables included the incidence of CAV, defined as an increase of ≥0.5 mm in MIT in ≥1 matched slices of automated pullback sequence from baseline to month 12. The IVUS procedure is described in the Supporting Information.

IVUS was performed within 6 weeks posttransplant (baseline) and at month 12 by predefined centers with IVUS facilities. If an IVUS examination was missed, the reason had to be documented. Additional information is provided in the Supporting Information.

Safety assessment

Safety was assessed on the basis of the occurrence of infections and other adverse events, findings on physical examination and centrally performed laboratory evaluations. The main safety endpoint was renal function at month 12, as assessed by eGFR (MDRD).

Discontinuation of everolimus 3.0 mg treatment arm

Enrolment into the everolimus 3.0 mg arm was stopped in March 2008 due to higher early mortality, following a recommendation from the independent Data Monitoring Committee (DMC). There were no a priori stopping rules for the study and the decision was based on expert judgment by the DMC. The protocol was amended to reflect the DMC recommendation that patients already enrolled in the everolimus 3.0 mg arm who had completed more than 3 months in the study with no major problems could continue to receive their current immunosuppression regimen, while patients in this arm who had been in the study for less than 3 months reverted to the standard therapy in use at individual centers.

Statistical analysis

The sample size calculation estimated that 210 patients were needed per treatment group for the study to have a power of 90% to demonstrate NI at a 13% margin for the primary efficacy endpoint (nQuery Advisor 5.0). This calculation was based on a significance level of 2.5% (two-sided) and assumed a primary efficacy failure rate of 41% for everolimus and 45% for MMF, that is, a difference of –4% according to historical trials in heart transplantation. For the IVUS analyses, a sample size of 91 evaluable patients per group was required to provide a power of 80% to detect a between-group difference of 0.06 mm in the primary IVUS efficacy variable. Enrolment of IVUS patients was slower than anticipated, so the enrolment period was extended to reach the sample size required for IVUS analyses.

Due to the premature discontinuation of enrolment into the everolimus 3.0 mg treatment arm, the inferential analyses were performed only for the two remaining arms (everolimus 1.5 mg and MMF). The main statistical analysis was performed to show NI of everolimus 1.5 mg arm to MMF arm at the one-sided 0.0125 level with an NI margin of 13% with respect to the primary endpoint of composite efficacy failure at 12 months. The one-sided 0.0125 level was chosen for the adjustment for multiple comparisons since two comparisons between everolimus 1.5 mg and everolimus 3.0 mg versus MMF were initially planned. With respect to the key safety endpoint of renal function (eGFR [MDRD]) at month 12, the NI analysis of everolimus 1.5 mg arm versus the MMF arm was carried out at the one-sided 0.0125 level with an NI margin of –10 mL/min/1.73 m2.

Efficacy analyses were conducted according to the intention-to-treat (ITT) principle and included all randomized patients. Safety analyses included all randomized patients who received ≥1 dose of study medication. IVUS analyses were performed for the IVUS population, defined as ITT patients with IVUS images for ≥1 matched slices at baseline and month 12. All analyses (12-month and 24-month) were performed when all patients completed 12-month and 24-month study other than IVUS analyses, for which only 12-month data were available.

The mean change in MIT among matched slices from baseline to month 12 was assessed by a t-test in the IVUS population. The incidence of protocol-defined CAV was assessed with Fisher's exact test. Safety data were compared between groups using Wilcoxon rank-sum test for continuous variables and Fisher's exact test for categorical data. Risk ratios (RRs) and confidence intervals (CIs) were provided for adverse events and infections.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

Patient population

In total, 721 patients underwent randomization (ITT population; Figure 2). The proportion of patients discontinuing study medication by month 12 and month 24 in the everolimus 1.5 mg arm was 31.2% (88/282) and 39.0% (110/282), respectively, compared to 24.0% (65/271) and 36.9% (100/271) in the MMF arm. Baseline characteristics were well-balanced between treatment groups (Table 1).

Table 1. Baseline clinical characteristics (ITT population)
 EverolimusMMF
 1.5 mg (N = 282)3 g (N = 271)
  1. BMI = body mass index; CMV = cytomegalovirus; HLA = human leukocyte antigen; MMF = mycophenolate mofetil; rATG = rabbit antithymocyte globulin.

Recipients  
Age (years), mean ± SD51.1 ± 11.050.2 ± 11.9
Male, n (%)225 (79.8)220 (81.2)
Caucasian, n (%)231 (81.9)220 (81.2)
BMI (kg/m2), mean ± SD26.1 (4.4)25.4 (4.5)
Etiology of heart disease, n (%)  
Idiopathic cardiomyopathy121 (42.9)107 (39.5)
Coronary artery disease55 (19.5)58 (21.4)
Congenital heart disease5 (1.8)10 (3.7)
Myocarditis7 (2.5)4 (1.5)
Valvular heart disease7 (2.5)7 (2.6)
Viral cardiomyopathy6 (2.1)5 (1.8)
Other81 (28.7)80 (29.5)
Cold ischemia time  
Mean ± SD (h)3.2 ± 1.13.1 ± 1.1
>4 h, n (%)57 (20.2)52 (19.2)
Mechanical assistance, n (%)  
Hemodialysis3 (1.1)1 (0.4)
Intraaortic balloon pump20 (7.1)13 (4.8)
Ventilation9 (3.2)19 (7.0)
Ventricular assist device53 (18.8)68 (25.1)
Number of HLA mismatches ≥3, n (%)209 (74.1)204 (75.3)
Panel reactive antibodies >20%, n (%)14 (5.0)13 (4.8)
CMV serology status, n (%)  
Donor positive/recipient96 (34.0)85 (31.4)
 positive  
Donor positive/recipient60 (21.3)49 (18.1)
 negative  
Donor negative/recipient51 (18.1)50 (18.5)
 positive  
Donor negative/recipient63 (22.3)68 (25.1)
 negative  
Diabetes at time of transplant, n (%)109 (38.7)107 (39.5)
History of hypertension, n (%)142 (50.4)127 (46.9)
History of hyperlipidemia, n (%)127 (45.0)133 (49.1)
eGFR (MDRD) (mL/min/1.73 m2), mean ± SD66.5 ± 36.367.1 ± 30.3
Induction therapy, n (%)  
Basiliximab101 (35.8)97 (35.8)
rATG86 (30.5)83 (30.6)
No induction92 (32.6)89 (32.8)
Donors  
Age (years ), mean ± SD35.0 ± 13.333.9 ± 12.9
Male, n (%)204 (72.3)181 (66.8)
Caucasian, n (%)174 (61.7)163 (60.1)
image

Figure 2. Patient enrolment and disposition. ITT = intent-to-treat; MMF = mycophenolate mofetil.

Download figure to PowerPoint

In the everolimus 3 mg arm, patient numbers were lower (n = 167), and the incidence of study medication discontinuation was higher (Figure 2), due to premature termination of enrolment following the DMC recommendation and subsequent conversion of patients who had completed less than 3 months in the study to standard immunosuppressive treatment.

Immunosuppression

Mean everolimus concentration in the everolimus 1.5 mg group was within target range throughout the study (Figure 3A). Mean cyclosporine trough levels were at the upper end or slightly above target ranges from month 3 onwards in the everolimus 1.5 mg group, whereas in the MMF group they were mostly at the midpoint of target ranges (Figure 3B). The median (range) daily dose of corticosteroids in the everolimus 1.5 mg and MMF arms, respectively, was 0.10 (0.02–14.11) mg/kg/day and 0.10 (0.02–1.89) mg/kg/day at month 6, 0.07 (0.01–13.72) mg/kg/day and 0.07 (0.01–0.89) mg/kg/day at month 12 and 0.07 (0.02–13.93) mg/kg/day and 0.06 (0.01–16.56) mg/kg/day at month 24. rATG induction was administered to 30.5% (86/282) of everolimus 1.5 mg patients and 30.6% (83/271) of MMF patients, with basiliximab in 35.8% (101/282) and 35.8% (97/271), respectively.

image

Figure 3. Box plots of (A) everolimus trough concentration (B) cyclosporine trough concentration to month 24 posttransplant (safety population). Mean values are joined by a horizontal line. The whiskers represent the 10th and 90th percentiles. The target ranges are displayed as dotted lines. Concentrations measured >2 days after discontinuation of study medication are excluded.

Download figure to PowerPoint

Efficacy

Everolimus 1.5 mg was noninferior to MMF for the primary efficacy endpoint of composite efficacy failure at month 12 (35.1% vs. 33.6%; difference 1.5%; 97.5% CI for the difference –7.5%, 10.6%; p = 0.002 for NI test with the NI margin of 13%, p = 0.705 for no-difference test). The similarity of the everolimus 1.5 mg and MMF arms was maintained at month 24 (39.4% vs. 41.3%; difference –2.0%; 97.5% CI for the difference –11.3%, 7.4%). Individual components of the composite efficacy failure endpoint also occurred at a similar rate in the two treatment groups at months 12 and 24 (Table 2). A sensitivity analysis based on central reading of biopsy samples showed similar results.

Table 2. Efficacy outcomes (ITT population)
 Month 12Month 24
 EverolimusMMF EverolimusMMF 
 1.5 mg3 g 1.5 mg3 g 
 (N = 282)(N = 271)Difference,(N = 282)(N = 271)Difference,
 n (%)n (%)% (95% CI)n (%)n (%)% (95% CI)
  1. The identification of rejection was based on local laboratory biopsy results.

  2. a

    Composite incidence of ISHLT grade ≥3A (2R) BPAR, acute rejection associated with hemodynamic compromise, death, graft loss/retransplant or loss to follow-up.

  3. b

    A 97.5% CI was applied to the analysis of composite efficacy endpoints.

  4. c

    Including one death, which occurred prior to month 12 in a patient who never received everolimus.

  5. BPAR = biopsy proven acute rejection episodes; CI = confidence interval; MMF = mycophenolate mofetil.

Composite efficacy failurea99 (35.1)91 (33.6)1.5 (−7.5, 10.6)b111 (39.4)112 (41.3)−2.0 (−11.3, 7.4)b
BPAR of ISHLT grade ≥3A(2R)63 (22.3)67 (24.7)−2.4 (−9.5, 4.7)68 (24.1)74 (27.3)−3.2 (−10.5, 4.1)
Acute rejection with11 (3.9)7 (2.6)1.3 (−1.6, 4.3)12 (4.3)14 (5.2)−0.9 (−4.4, 2.6)
hemodynamic compromise      
Death22 (7.8)c13 (4.8)3.0 (−1.0, 7.0)30 (10.6)c25 (9.2)1.4 (−3.6, 6.4)
Graft loss/retransplant4 (1.4)5 (1.8)−0.4 (−2.5, 1.7)7 (2.5)10 (3.7)−1.2 (−4.1, 1.7)
Lost to follow-up9 (3.2)10 (3.7)−0.5 (−3.5, 2.5)10 (3.5)14 (5.2)−1.6 (−5.0, 1.8)
Graft loss/retransplant, death or lost to follow-up33 (11.7)24 (8.9)2.8 (−2.9, 8.6)b43 (15.2)41 (15.1)0.1 (−6.7, 7.0)b
Acute rejection treated with antilymphocyte therapy13 (4.6)9 (3.3)1.3 (−2.0, 4.5)14 (5.0)11 (4.1)0.9 (−2.6, 4.4)

The mortality rate for the everolimus 1.5 mg group was numerically higher at month 12 (7.8% [22/282] vs. 4.8% [13/271] for MMF) but similar at month 24 (10.6% [30/282] vs. 9.2% [25/271], respectively, [ITT population]; Table 2). The timing and causes of death are summarized in Table 3. In the everolimus 3 mg arm, there were 20 deaths among 168 patients in the ITT population (Table 3). At the time of the DMC recommendation to terminate enrolment to the high-dose everolimus arm, 14 patients had died (9.9% vs. 2.8% in the MMF group; log-rank p = 0.0181, Kaplan–Meier analysis), of whom 12 had died within the first 3 months of treatment. In the everolimus 1.5 mg group, the majority of deaths occurred by month 3 (17/30), compared to only 5/25 deaths in the MMF group. This imbalance during the first 3 months was mainly driven by infections in patients receiving rATG induction in the everolimus 1.5 mg group (Table 3). The increased incidence of death in rATG-treated patients in the everolimus 1.5 mg arm was particularly marked in patients with left ventricular assist devices (LVADs) prior to transplantation: 5/12 deaths in rATG/everolimus 1.5 mg were in patients with LVAD. One of the deaths occurred prior to month 12 in a patient who never received study medication. From month 3 onwards more deaths occurred in the MMF group. Other than infection, there were no marked differences in causes of death between the three treatment groups.

Table 3. All deaths to month 24 posttransplant by induction therapy and time of death (days posttransplant) (ITT population)
Everolimus 1.5 mg (N = 282)MMF 3 g (N = 271)Everolimus 3 mg (N = 168)
Cause of deathDayCause of deathDayCause of deathDay
  1. a

    This event was reported after 12-month database lock. It is therefore only included in the 24-month data set.

  2. b

    Patient was randomized to the everolimus 1.5 mg group but did not receive study drug.

  3. rATG = rabbit antithymocyte antiglobulin.

rATG induction
Multiorgan failure, sepsis2Cerebral hemorrhage6Ventricular dysfunction16
Transplant rejection (humoral)6Septic toxic shock70Hypoxic cardiac arrest, right diaphragmatic paralysis53
Sepsis8Ventricular arrhythmia152Multiorgan failure79
Neurological complications23Sepsis164Cerebral hemorrhage195
Multiorgan failure, sepsis24CMV infection, multiorgan failure218Intracerebral bleeding423
Pneumonia44Sudden death246  
Septic shock44Malignant arrhythmias/chronic graft loss630  
Multiorgan failure, sepsis57Small cell carcinoma of lung662  
Multiorgan failure66Respiratory failure748  
Pneumonia, respiratory failure88Cerebrovascular insufficiency751  
Cardiac arrest98    
Septic shock115    
Myocarditis639    
Lung neoplasm, malignant719    
Basiliximab induction
Septic shock17Pleural hemorrhage7Cardiac arrest (hemorrhage)6
Cerebral hemorrhage18Cardiac arrest359aCerebral hemorrhage8
Sepsis38Rejection374Listeriosis21
Presumed acute rejection228Cardiac arrest416Graft failure, right ventricular failure32
Unknown346Sudden death, cause unknown418Pseudomonas pneumonia, bronchopulmonary aspergillosis, anoxic encephalopathy65
Sepsis443Bilateral pneumonia478Rejection318
Acute rejection471  Hyperkalemia (overdose of supplementation)329
Cardiogenic shock507  Respiratory arrest411
No induction
Pulmonary embolism9Basal ganglia hemorrhage16Acute rejection10
Multiorgan failureb11Rejection-induced arrhythmia90Cerebellar hemorrhage20
Septic shock16Sepsis160Sepsis48
Multiorgan failure94Fungal abscess, intracranial sepsis237Anoxic encephalopathy61
Sepsis146Cardiogenic shock255Bone marrow failure/ sepsis65
Transplant coronary artery disease552Brain stem infarction284Septic shock202
Ovarian cancer621Multiorgan failure482Sepsis572
Endocarditis646Pulmonary embolus531  
  Subarachnoid hemorrhage564  

Intravascular ultrasonography

The IVUS and non-IVUS subpopulations were comparable in terms of demographic and baseline characteristics except for ethnicity, etiology of heart disease and use of induction therapy (Table S1). Evaluable IVUS data were available at baseline and 12 months from 189 patients, with similar characteristics in the everolimus and MMF cohorts (Table S1). The mean increase in average MIT from baseline to month 12 was smaller with everolimus 1.5 mg versus MMF (0.03 ± 0.05 mm vs. 0.07 ± 0.11 mm, p < 0.001). The mean changes in other IVUS variables from baseline to month 12, including intimal area, index and volume, were also significantly smaller with everolimus 1.5 mg than in the MMF group (Table 4).

Table 4. Results of the IVUS analysis of the evaluable patients in the IVUS substudy
Change from baselineEverolimus 1.5 mgMMF 3 g 
to month 12(N = 88)(N = 101)p-Valuea
  1. a

    A t-test was performed for the change in average MIT, Wilcoxon rank-sum tests for other continuous variables and Fisher's exact tests for categorical variables.

  2. b

    CAV was defined as a 0.5 mm increase in maximum intimal thickness in at least one matched slice of an automated pullback sequence from baseline to month 12.

  3. c

    De novo disease was defined as those sites in the vessel with a maximum intimal thickness <0.5 mm at baseline and an increase >0.5 mm at month 12.

  4. CAV = cardiac allograft disease; IVUS = intravascular ultrasonography; MIT = maximum intimal thickness; MMF = mycophenolate mofetil.

Average MIT (mm)  <0.001
Mean ± SD0.03 ± 0.050.07 ± 0.11 
Median (min, max)00.02 (–0.12, 0.19)0.03 (–0.15, 0.56) 
Patients with CAV, n (%)b11 (12.5)27 (26.7)0.018
Patients with de novo disease, n (%)c8 (9.1)20 (19.8)0.042
Average intimal area (mm2)  0.012
Mean ± SD0.14 ± 0.360.48 ± 0.81 
Median (min, max)0.11 (–1.45, 0.96)0.27 (–0.98, 3.71) 
Average intimal index  <0.001
Mean ± SD0.01 ± 0.020.03 ± 0.06 
Median (min, max)0.01 (–0.06, 0.09)0.02 (–0.12, 0.33) 
Normalized total intimal volume (mm3)   
Mean ± SD3.40 ± 8.7511.44 ± 8.070.012
Median (min, max)2.58 (–34.69, 23.14)6.39 (–23.60, 89.09) 

The incidence of protocol-defined CAV was also lower with everolimus 1.5 mg (12.5% [11/88]) vs. MMF (26.7% [27/101], p = 0.018).

Renal function

Baseline eGFR was similar between groups (Table 1). Mean eGFR showed a lower posttransplant peak in the everolimus 1.5 mg arm than the MMF group, then stabilized from month 4 onwards (Figure 4). From month 12 to month 24, eGFR remained stable in both groups: mean (SD) change was –0.67 (15.6) mL/min/1.73 m2 for everolimus 1.5 mg, and 1.6 (16.8) mL/min/1.73 m2 for MMF (Figure 4). Mean (SD) values for eGFR were 59.4 (22.8) mL/min/1.73 m2 in the everolimus 1.5 mg arm and 64.7 (28.1) mL/min/1.73 m2 with MMF at month 12 (p = 0.009), and 59.5 (22.4) mL/min/1.73 m2 and 64.5 (23.8) mL/min/1.73 m2 at month 24 (p = 0.020).

image

Figure 4. Estimated GFR (eGFR) to month 24 in the everolimus 1.5 mg and MMF study group (intent-to-treat [ITT] population). Data are shown as mean values with 95% confidence intervals (CIs).

Download figure to PowerPoint

At month 12 posttransplant, the main safety objective of NI of renal function for everolimus 1.5 mg versus MMF was not met since the lower limit of the CI was lower than the NI margin of –10 mL/min/1.73 m2 (difference in mean eGFR –5.55 mL/min/1.73 m2, 97.5% CI [–10.9, –0.2]). At month 24, the difference in mean eGFR was –6.5 mL/min/1.73 m2, 97.5% CI –11.9, –1.0 mL/min/1.73 m2. Everolimus 1.5 mg was associated with a mean (SD) decrease in eGFR from baseline to month 12 of –9.2 (38.2) versus –4.1 (31.1) mL/min/1.73 m2 with MMF (p = 0.223). The mean (SD) decrease in eGFR from month 1 to month 12, however, was significantly less with everolimus 1.5 mg versus MMF (–8.6 [24.6] vs. –14.6 [30.0] mL/min/1.73 m2, p = 0.009), suggesting that the loss in renal function in the everolimus group occurred mainly during the first postoperative month when cyclosporine exposure was the same in both treatment arms.

Post hoc, eGFR was analyzed for 53 centers, which achieved target cyclosporine exposure levels (10 centers were excluded that did not achieve the separation in cyclosporine exposure between everolimus and MMF groups). In this analysis, the mean (SD) eGFR decrease from baseline to month 12 was comparable (everolimus 1.5 mg [n = 229] –6.65 (40.6) mL/min/1.73 m2 vs. MMF [n = 222] –4.4 (28.7) mL/min/1.73 m2, p = 0.486). At month 12, the difference in mean eGFR between everolimus 1.5 mg and MMF was –3.6 mL/min/1.73 m2; 97.5% CI –8.9, 1.8 mL/min/1.73 m2.

Adverse events

Almost all patients in each arm reported at least one adverse event during the study (Table 5). Pericardial effusion reported as an adverse event was more common with everolimus 1.5 mg at month 12 (43.4% [121/279] vs. MMF 28.4% [76/268]; RR 1.53 [95% CI 1.21, 1.93]; p < 0.001) and month 24 (44.1% [123/279] vs. 29.5% [79/268], RR 1.50 [95% CI 1.19, 1.88]; p < 0.001), but the frequency of pericardial tamponade did not differ significantly at month 12 and no patient died due to this condition. The incidence of pleural effusions, peripheral edema, sternal and nonsternal wound healing events was similar between groups (Table 5).

Table 5. Adverse events and laboratory parameters (safety population)
 Month 12Month 24
 EverolimusMMFRR (95% CI)EverolimusMMFRR (95% CI)
 1.5 mg3 geverolimus1.5 mg3 geverolimus
 (N = 279)(N = 268)1.5 mg vs. MMF(N = 279)(N = 268)1.5 mg vs. MMF
  1. a

    One additional death occurred in a patient who never received everolimus and was therefore excluded from the safety population.

  2. CI = confidence interval; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MMF = mycophenolate mofetil; RR = risk ratio.

Any adverse event, n (%)279 (100.0)265 (98.9)1.01 (1.00, 1.02)279 (100.0)266 (99.3)1.01 (1.00, 1.02)
Adverse event leading to premature discontinuation of study drug, n (%)83 (29.7)51 (19.0)1.56 (1.15, 2.12)93 (33.3)69 (25.7)1.29 (1.00, 1.68)
Any serious adverse event, n (%)198 (71.0)154 (57.5)1.24 (1.09, 1.40)209 (74.9)168 (62.7)1.19 (1.07, 1.34)
Death21 (7.5)a13 (4.9)1.55 (0.79, 3.04)29 (10.4)25 (9.3)1.11 (0.67, 1.85)
Nonfatal196 (70.3)149 (55.6)1.26 (1.11, 1.44)207 (74.2)164 (61.2)1.21 (1.08, 1.36)
Most frequent adverse events (≥20% in any treatment group), n (%)
Anemia97 (34.8)69 (25.7)1.35 (1.04, 1.75)108 (38.7)76 (28.4)1.37 (1.07, 1.74)
Constipation69 (24.7)58 (21.6)1.14 (0.84, 1.56)70 (25.1)63 (23.5)1.07 (0.79, 1.44)
Cough57 (20.4)42 (15.7)1.30 (0.91, 1.87)68 (24.4)51 (19.0)1.28 (0.93, 1.77)
Diarrhea51 (18.3)63 (23.5)0.78 (0.56, 1.08)65 (23.3)72 (26.9)0.87 (0.65, 1.16)
Dyspnea47 (16.8)43 (16.0)1.05 (0.72, 1.53)63 (22.6)53 (19.8)1.14 (0.83, 1.58)
Headache78 (28.0)63 (23.5)1.19 (0.89, 1.58)87 (31.2)70 (26.1)1.19 (0.91, 1.56)
Hypertension122 (43.7)120 (44.8)0.977 (0.81, 1.18)134 (48.0)125 (46.6)1.03 (0.86, 1.23)
Insomnia75 (26.9)54 (20.1)1.33 (0.98, 1.81)77 (27.6)60 (22.4)1.23 (0.92, 1.65)
Leukopenia34 (12.2)62 (23.1)0.53 (0.36, 0.77)37 (13.3)69 (25.7)0.52 (0.36, 0.74)
Nausea58 (20.8)71 (26.5)0.79 (0.58, 1.06)65 (23.3)77 (28.7)0.81 (0.61, 1.08)
Pericardial effusion121 (43.4)76 (28.4)1.53 (1.21, 1.93)123 (44.1)79 (29.5)1.50 (1.19, 1.88)
Peripheral edema151 (54.1)133 (49.6)1.09 (0.93, 1.28)161 (57.7)153 (57.1)1.01 (0.87, 1.17)
Pleural effusion78 (28.0)62 (23.1)1.21 (0.91, 1.61)79 (28.3)63 (23.5)1.20 (0.91, 1.60)
Pyrexia46 (16.5)40 (14.9)1.10 (0.75, 1.63)56 (20.1)47 (17.5)1.14 (0.81, 1.62)
Tremor55 (19.7)54 (20.1)0.98 (0.70, 1.37)59 (21.1)61 (22.8)0.93 (0.68, 1.27)
Other events of clinical interest, n (%)
Hyperlipidemia83 (29.7)60 (22.4)1.33 (1.00, 1.77)104 (37.3)72 (26.9)1.39 (1.08, 1.78)
Sternal wound healing event68 (24.4)52 (19.4)1.26 (0.91, 1.73)68 (24.4)50 (18.7)1.31 (0.94, 1.81)
Nonsternal wound healing event37 (13.3)35 (13.1)1.02 (0.66, 1.56)45 (16.1)40 (14.9)1.08 (0.73, 1.60)
Stomatitis/mouth ulceration23 (8.2)13 (4.9)1.70 (0.88, 3.29)27 (9.7)16 (6.0)1.62 (0.89, 2.94)
Neutropenia44 (15.8)94 (35.1)0.45 (0.33, 0.62)50 (17.9)108 (40.3)0.44 (0.33, 0.59)
Thrombocytopenia33 (11.8)29 (10.8)1.09 (0.68, 1.75)31 (11.1)30 (11.2)0.99 (0.62, 1.59)
Thrombotic and thromboembolic events43 (15.4)25 (9.3)1.65 (1.04, 2.63)64 (22.9)45 (16.8)1.37 (0.97, 1.92)
Thrombotic microangiopathy3 (1.1)0 (0.0)NA3 (1.1)0 (0.0)NA
Proteinuria9 (3.2)5 (1.9)1.73 (0.59, 5.09)9 (3.2)4 (1.5)2.16 (0.67, 6.93)
New-onset diabetes mellitus27 (9.7)16 (6.0)1.62 ( 0.89, 2.94)26 (9.3)16 (6.0)1.56 (0.86, 2.84)
Interstitial lung disease1 (0.4)0 (0.0)NA1 (0.4)0 (0.0)NA
Infections181 (64.9)169 (63.1)1.03 (0.91, 1.17)194 (69.5)180 (67.2)1.04 (0.92, 1.16)
Bacterial84 (30.1)59 (22.0)1.37 (1.03, 1.82)86 (30.8)68 (25.4)1.21 (0.93, 1.59)
Viral38 (13.6)76 (28.4)0.48 (0.34, 0.68)41 (14.7)85 (31.7)0.46 (0.33, 0.65)
CMV20 (7.2)52 (19.4)0.37 (0.23, 0.60)20 (7.2)58 (21.6)0.33 (0.21, 0.54)
Fungal23 (8.2)21 (7.8)1.05 (0.60, 1.86)25 (9.0)22 (8.2)1.09 (0.63, 1.89)
Unknown60 (21.5)40 (14.9)1.44 (1.00, 2.07)75 (26.9)46 (17.2)1.57 (1.13, 2.17)
Other87 (31.2)80 (29.9)1.04 (0.81, 1.35)101 (36.2)97 (36.2)1.00 (0.80, 1.25)
Neoplasms21 (7.5)11 (4.1)1.83 (0.90, 3.73)35 (12.5)30 (11.2)1.12 (0.71, 1.77)
Benign11 (3.9)3 (1.1)3.52 (0.99, 12.49)15(5.4)20 (7.5)0.72 (0.38, 1.38)
Malignant10 (3.6)9 (3.3)1.07 (0.44, 2.59)23 (8.2)21 (7.8)1.05 (0.60, 1.86)
Laboratory values of interest
Hemoglobin (g/dL)      
Mean ± SD11.7 ± 1.912.3 ± 1.8<0.00111.7 ± 2.012.3 ± 1.8<0.001
Median (min, max)11.6 (6.7, 7.0)12.4 (6.3, 6.4) 11.6 (6.5, 16.6)12.4 (6.3,16.6) 
White blood cells (cells ×103/mm3      
Mean ± SD7.3 ± 3.56.4 ± 2.8<0.0017.5 ± 3.66.6 ± 2.9<0.001
Median (min, max)6.5 (2.0, 28.7)5.8 (1.8, 19.1) 6.6 (1.9, 28.7)6.1 (1.4, 4.4) 
Platelets (109/L)      
Mean ± SD244 ± 98244 ± 860.760240 ± 97239 ± 830.976
Median (min, max)237 (43, 928)230 (74, 612) 233 (43, 928)227 (74, 612) 
Total cholesterol (mmol/L)      
Mean ± SD5.3 ± 1.44.7 ± 1.2<0.0015.0 ± 1.24.6 ± 1.2<0.001
Median (min, max)5.2 (1.6,13.0)4.6 (1.4, 7.9) 4.9 (1.6, 9.7)4.5 (1.4, 8.5) 
HDL-cholesterol (mmol/L)      
Mean ± SD1.5 ± 0.51.3 ± 0.4<0.0011.4 ± 0.51.3 ± 0.5<0.001
Median (min, max)1.4 (0.3, 3.1)1.3 (0.2, 3.1) 1.3 (0.3, 2.9)1.2 (0.2, 3.2) 
LDL-cholesterol (mmol/L)      
Mean ± SD2.9 ± 1.22.6 ± 0.90.0082.7 ± 0.92.6 ± 0.90.054
Median (min, max)2.8 (0.1, 9.4)2.5 (0.6, 5.0) 2.6 (0.1, 6.4)2.5 (0.6, 5.3) 
Ratio of total cholesterol to HDL-cholesterol     0.443
Mean ± SD4.0 ± 1.74.2 ± 2.20.3334.0 ± 1.74.2 ± 2.3 
Median (min, max)3.6 (1.7, 17.3)3.7 (1.6, 26.3) 3.7 (1.7, 17.3)3.7 (1.8, 26.3) 
Triglycerides (mmol/L)      
Mean ± SD2.3 ± 1.32.1 ± 1.30.0062.3 ± 1.52.0 ± 1.30.065
Median (min, max)2.0 (0.6, 8.2)1.7 (0.4, 8.3) 1.9 (0.6, 13.1)1.7 (0.4, 9.8) 

The incidence of nonfatal serious adverse events was greater in the everolimus 1.5 mg group compared to the MMF group (month 12: 70.3% [196/279] vs. 55.6% [149/268], RR 1.26 [95% CI 1.11, 1.44]; month 24: 74.2% [207/279] vs. 61.2% [164/268], RR 1.21 [95% CI 1.08, 1.36]; Table S2). This was partly due to a higher rate of pericardial effusions reported as serious adverse events (month 12: 13.3% [37/279] with everolimus 1.5 mg, 4.1% [11/268] with MMF; month 24: 13.6 [38/279] with everolimus vs. 4.5% [12/268] with MMF). Discontinuation of study medication due to an adverse event was more frequent in the everolimus 1.5 mg group versus the MMF group at month 12 (29.7% [83/279] vs. 19.0% [51/268], RR 1.56 [95% CI 1.15, 2.12]), but the difference was smaller at month 24 (33.3% [93/279] vs. 25.7% [69/268], RR 1.29 [95% CI 1.00, 1.68]; Table S3).

CMV infections (defined as antigenemia-positive or PCR positive) were less frequent with everolimus 1.5 mg than MMF at month 12 (7.2% [20/279] vs. 19.4% [52/268], p < 0.001) and at month 24 (7.2% [20/279] vs. 21.6% [58/268], p < 0.001). Bacterial infections occurred less frequently in the MMF group compared to the everolimus 1.5 mg arm at month 12 and month 24 (Table 5). The incidence of neoplasms was similar between groups (Table 5).

Laboratory values

Mean hemoglobin level was lower in the everolimus 1.5 mg group versus the MMF arm, while mean white blood cell count was higher in the everolimus 1.5 mg group (Table 5). Statin therapy was administered to 94% of patients, at a similar rate in the everolimus 1.5 mg group and the MMF group (94.6% and 94.0%, respectively) and with a similar mean duration (368 and 342 days, respectively). Mean total cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride levels were significantly higher in the everolimus 1.5 mg arm versus MMF at month 12 with the difference persisting for total cholesterol and HDL-cholesterol at month 24 (Table 5). The ratio of total cholesterol to HDL was similar between groups at months 12 and 24 (Table 5).

Everolimus 3.0 mg treatment arm

Data relating to the discontinued everolimus 3.0 mg treatment arm are presented in Tables S4–S7.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

The main findings of this large, prospective, randomized, multicenter study were as follows: (i) Everolimus 1.5 mg (target 3–8 ng/mL) was noninferior to MMF in preventing the composite efficacy failure at months 12 and this similarity was maintained at month 24. (ii) Everolimus 1.5 mg significantly reduced intimal proliferation on blinded IVUS assessment during the first year posttransplant. (iii) The early improvement in renal function after transplantation diminished over time with everolimus 1.5 mg such that NI versus MMF was not shown, but renal function stabilized from month 4 onwards. The absence of NI may have been related to nonadherence to cyclosporine reduction targets at some centers. (iv) Everolimus 1.5 mg was associated with significantly fewer CMV infections than MMF, consistent with the known increased rate of CMV infection with MMF. (v) Nonfatal serious adverse events and study drug discontinuations due to adverse events were more frequent with everolimus 1.5 mg than MMF. (vi) There was a higher mortality rate in patients receiving everolimus 3.0 mg (target 6–12 ng/mL), leading to discontinuation of recruitment to this treatment arm, although the 12-month mortality (10.1%) in this group could be considered acceptable [11].

Despite lower cyclosporine trough levels, patients in the everolimus 1.5 mg group experienced a similar rate of rejection with or without hemodynamic compromise compared to MMF-treated patients. Indeed, there are preliminary data to suggest that even lower everolimus exposure with reduced calcineurin inhibitor may maintain efficacy following heart transplantation [12]. Mortality was numerically higher in the everolimus 1.5 mg arm versus the MMF group at month 12 but became similar by month 24. The numerical difference in the first year was due to excess early (≤3 months) mortality from infections in everolimus-treated patients receiving rATG. High rates of infection have been reported previously in rATG-treated heart transplant patients [13] and increased mortality from infection has been observed in overimmunosuppressed heart transplant recipients given induction therapy [14].

IVUS is considered the most sensitive method of detecting and monitoring CAV. An increase in MIT ≥ 0.5 mm in the first year posttransplant is predictive for subsequent CAV-related mortality and nonfatal major adverse cardiac events [15-17]. Here, patients in the everolimus 1.5 mg group exhibited a smaller increase in MIT compared to MMF at month 12, coupled with a reduced incidence of protocol-defined CAV, a difference that was statistically significant despite the higher rate of discontinuation in the everolimus 1.5 mg arm. This finding is consistent with results of the Phase III trial of everolimus versus azathioprine [2]. While CAV is not in itself a clinical endpoint, it is the most frequent cause of late (>5 years) graft loss and death after heart transplantation [18, 19], and as such any reduction in risk of CAV is of potential long-term benefit.

Everolimus 1.5 mg was associated with lower eGFR than MMF. The findings of a post hoc analysis indicate that suboptimal adherence of a few centers to the reduction of cyclosporine exposure in the everolimus group contributed to inferior renal function. Renal function in the everolimus 1.5 mg arm stabilized from month 4 to the end of the study at month 24. Cyclosporine target exposure ranges were comparable during the first month posttransplant in all treatment groups, and it could be speculated that reduced cyclosporine exposure in the everolimus 1.5 mg group from time of transplant may have been advisable, as has been achieved in recent studies of everolimus versus mycophenolic acid in de novo kidney [20] and liver [21] transplant recipients. The peak in eGFR that occurred shortly after transplantation was unexpected, and it is possible that this may reflect a cyclosporine-induced increase in tubular creatinine secretion [22], giving rise to artificially higher eGFR values according to the MDRD formula in the immediate posttransplant period. This would be consistent with the observation that the rise in eGFR was greater in the MMF arm, in which patients received higher cyclosporine exposure.

Everolimus 1.5 mg was associated with more pericardial effusions, but with similar rates of pericardial tamponade, pleural effusions and edema, compared to the MMF arm. In contrast to findings from a retrospective study of sirolimus with reduced-exposure cyclosporine [23], sternal and other wound healing was not impaired compared to the MMF cohort. There were more serious nonfatal adverse events with everolimus 1.5 mg compared to MMF, partly due to more frequent pericardial effusions. Consistent with this, there was a higher overall rate of study drug discontinuation due to adverse events in the everolimus 1.5 mg group, largely accounted for by effusions and by hematological and lipid abnormalities.

CMV infection was significantly less frequent with everolimus 1.5 mg versus MMF, as reported previously [24-26], and consistent with the lower rate of CMV infection reported for everolimus versus azathioprine [2]. Since CMV infection is associated with increased risk for CAV [27], this may have contributed to the lower rate of protocol-defined CAV at month 12 in the everolimus 1.5 mg cohort.

Certain limitations of the study should be taken into account. First, the trial could not be blinded to investigators due to the need for therapeutic drug monitoring of everolimus and cyclosporine. Second, the study design required centers to apply a selected induction strategy for all enrolled patients. Third, evaluable IVUS data were only available in approximately 31% of patients and IVUS was not performed after month 12, and so any longer-term difference in intimal proliferation and cardiac events could not be assessed as was done for an earlier study versus azathioprine [4]. Fourth, tacrolimus is now more frequently employed in heart transplant recipients than cyclosporine, and while both agents are calcineurin inhibitors the current findings cannot necessarily be extrapolated to tacrolimus-treated patients.

In conclusion, everolimus at a target concentration of 3–8 ng/mL with reduced-dose cyclosporine achieved similar efficacy to MMF with standard-dose cyclosporine following heart transplantation, although discontinuation due to adverse events was more frequent with everolimus. rATG induction with concurrent administration of everolimus with cyclosporine appears inadvisable due to a high rate of early infection-related deaths and should be avoided. Everolimus at higher levels of exposure (6–12 ng/mL) is not advised within the current regimen due to an increased mortality rate. Cyclosporine exposure reduction is essential with concomitant everolimus to avoid nephrotoxicity. The reduction in renal function recovery early posttransplant in the everolimus 1.5 mg group may merit exploration of lower calcineurin inhibitor exposure in the first month posttransplant. Everolimus was more efficacious than MMF in preventing intimal proliferation at 12 months posttransplant and CMV infection, both of which are major causes of graft failure and death.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

The authors are grateful to Stephen J. Nicholls who undertook the analysis of IVUS data at the Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA.

Funding source: The study was funded by Novartis Pharma AG. The study protocol was developed by Novartis in collaboration with a Scientific Steering Committee. Novartis undertook monitoring of study conduct, study management, data quality control and statistical analysis. When the 24-month data became available, a medical writer (Caroline Dunstall) inserted these data to a version of the manuscript that had been developed by the authors, and incorporated author changes, with funding from Novartis Pharma AG.

Author contributions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

H.J.E., J.K., R.C.S., H.L. and A.Z. contributed to the study protocol. All external authors contributed to data collection. H.J.E., J.K., R.C.S., A. Kfoury, H.R., S.S.W., B.C., A.V.B., G.E., S.H., H.L., A. Keogh, M.R., L.P., A.Z. and S.J.N. collected study data. D.F.P. participated in study design, collected study data and interpreted data. G.D. performed the statistical analysis. C.C.A. and P.L. contributed to the interpretation of data. H.J.E., J.K. and R.C.S. wrote the initial manuscript. All authors reviewed and critically revised the manuscript for content and approved the final version of the manuscript for submission.

Disclosure

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. H.J.E. has acted as a medical advisor to Novartis. J.K. has received research support from Novartis and Roche, acted as a medical advisor to Novartis and is a member of Novartis speaker's bureau. R.C.S. has received research support from Novartis and is a member of a Novartis steering committee. D.F.P. has no conflicts of interest to declare. A. Kfoury has received research support from Novartis and XDx. H.R. is a Novartis principal investigator and member of a Wyeth Data Monitoring Committee. S.S.W. has no conflicts of interest to declare. B.C. has received research support from Novartis, Bayer and Pfizer, acts as a consultant to Novartis and is a member of the speaker's bureau for AstraZeneca and Merck. A.V.B. has received research support from Novartis, Amgen, Cardioxyl, Medtronic and Daxor and acts as a consultant for St. Jude Medical. G.E. has received research support from Novartis. S.H. has received research support from Novartis. H.L. has received research support from Novartis and Roche. A. Keogh is a member of advisory boards for Actelion, Pfizer and GlaxoSmithKline, and has participated in clinical studies for Pfizer, Actelion, Bayer, Lilly, Novartis, Wyeth and Gilead. M.R. has received research support from Novartis. L.P. has acted as a consultant to Novartis and has been a medical advisor to Genzyme. A.Z. has received grant supports from Novartis and Roche. G.D., C.C.A. and P.L. are employees of Novartis.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information

The RAD A2310 Study Principal Investigators and Co-Principal Investigators:

Argentina: Fundacion Favaloro, Buenos Aires—R. Favaloro, M. P. Lastra, L. Favaloro; Sanatorio Parque, Santa Fe—J. Sgrosso, F. Diez; Australia: St Vincents Hospital, Darlinghurst—E. Kotlyar, P. Macdonald, C. Hayward, C. Coveman, J. Suttie, S. Faddy, A. Keogh; Royal Perth Hospital, Perth—G. O'Driscoll, L. Dembo, M. Best; Prince Charles Hospital, Chermside—G. Javorsky, D. Meyers; Austria: Universitaetsklinikum Wien—A. Aliabadi, S. Mahr, M. Groemmer, D. Zimpfer, A. Zuckermann; Belgium: Cliniques Universitaires Saint-Luc, Bruxelles—A. Poncelet, O. Vancaeneghem, O. Gurné; Canada: Toronto General Hospital, Toronto—M. McDonald, D. Delgado, V. Rao, H. Ross; Institut Univ. de cardiologie et pneumologie de Québec, Sainte-Foy—M-H. Leblanc, M. Senechal, B. Cantin; University of Alberta Hospital, Edmonton—J. Burton, W. Tymchak, L. Lalonde, D. Kim; New Halifax Infirmary, Halifax—M. Rajda; France: CHU De Strasbourg Hôpital Civil Medicale B, Strasbourg—E. Epailly; Hôpital Cardiologique de Lyon—P. Boissonnat; CHU Hôpital de Brabois, Nancy—M.-F. Mattei, Hôpital Pitie Salpetriere, Paris—I. Gandjbakhch, S. Varnous, J.-P. Villemot; Hôpital Georges Pompidou, Paris—R. Guillemain, P. Chevalier, C. Amrein; Germany: Universitaetsklinik Regensburg—T. Pühler, A. Haneya, L. Ruppecht, S. Hirt; Deutsches Herzzentrum Berlin—M. Bettmann, U. Busch, B. Debus, S. Hornig, D. Van der Spek, H. Lehmkuhl; Herz-u. Diabeteszentrum NRW/Ruhr-Universität Bochum—G. Tenderich, U. Schultz, S. Eckert; Kliniken der Medizinischen Hochschule Hannover—C. Bara, M. Avsar, C. Kuhn, A. Meyers, I. Tudorache; Universitaetsklinikum Hamburg- Eppendorf—A. Costardt-Jackle, D. Koschyk, L. Baholli, S. Meyer, D. Knappe; Universitaetsklinikum Kiel—M. von Tschirschnitz; Italy: Az.Ospedaliero-Universitaria S.Giovanni Battista di Torino— M. Rinaldi, M. Ribezzo, F. Savia, M. La Torre, C. Barbero; Az.Osp.di Bologna Policl.S.Orsola-Malpighi Univ.degli Studi, Bologna—A. Branzi, L. Potena, M. Masetti, F. Grigioni; Fondazione IRCCS Policlinico S.Matteo, Pavia—M. Viganò, C. Pellegrini, F. Testa; Azienda Ospedaliera S. Camillo-Forlanini, Roma—F. Musumeci, P. Lilla Della Monica, F. Sbaraglia; Azienda Ospedaliera G. Brotzu, Cagliari—M. Porcu, M. Corda; A.O.-Università di Padova-Università degli Studi, Padova—G. Gerosa, G. Feltrin, C. D'Agostino; New Zealand: Auckland Hospital—P. Ruygrok, A. Coverdale, C. Wasywick, P. Alison; Norway: Rikshospitalet, Hjertemedisinsk avdeling, Oslo—A. Andreassen, E. Gude; Spain: Hospital Universitario Reina Sofia, Córdoba—J. Arizon, J. Castillo, A. Lopez-Granados; Hospital Puerta De Hierro Majadahonda, Madrid—J. Segovia, L. Pulpon, M. Gómez, L. Silva; United Kingdom: Wythenshawe Hospital, Manchester—N. Yonan; Papworth Hospital, Cambridge—J. Parameshwar; Queen Elizabeth Hospital, Birmingham—I. Wilson, M. Mukadam; United States: University of Florida College of Medicine, Gainesville—J. Aranda, J. Hill, R. Schofield, E. Handberg, D. Leach, D. F. Pauly; Cedars-Sinai Heart Institute, Los Angeles—J. Kobashigawa; UCLA Medical Center, Los Angeles—G. Fonarow; Intermountain Medical Center, Murray—D. Renlund, R. Alhareti, D. Budge, A. Kfoury; Medical University of South Carolina, Charleston—A. Van Bakel, N. Pereira; Kaufman Center for Heart Failure, Heart and Vascular Institute, Cleveland Clinic Foundation, Cleveland—J. Young, R. C. Starling; Cleveland Clinic—S. J. Nicholls; Washington University School of Medicine, St. Louis—G. Ewald; Drexel University College of Medicine/Hahnemann University Hospital, Philadelphia—S. Hankins, A. Berger, H.J. Eisen; Cardiovascular Center of Puerto Rico and the Caribbean, San Juan—H. Banchs-Pieretti; Methodist Hospital / DeBakey Heart Failure Research Center, Houston—G. Torre; Tufts-Medical Center, Boston—D. Denofrio, A. A. Weintraub, A. Ehsan; Loyola University Medical School, Maywood—A. Heroux; University of Michigan Health System, Ann Arbor—K. Aaronson; Duke University Heart Failure Research, Durham—S. Dev, G. Felker, J. Rogers; Stanford University School of Medicine, Falk Cardiovascular Research Center, Stanford—H. V-V. Kaeppler, W. Fearon; University of Texas Medical Branch, Division of Cardiothoracic, Galveston—S. Lick; University of Wisconsin Hospital and Clinics—N. M. Edwards; Columbia University Medical Center—D. Mancini; Penn State College of Medicine, Hershey—J. Boehmer; Massachusetts General Hospital—M. Semigran; Temple University Hospital, Philadelphia—J. Fitzpatrick, J. Wald; Recanati Miller Transplant Institute, New York—S. Pinney; St Luke's Medical Center Cardiac Services, Milwaukee—T. Hastings, B. Pisani; Texas Cardiovascular Consultants, Austin—M.B. Cishek; Thomas Jefferson University Hospital, Philadelphia—P. Mather; Emory University Hospital—W. Book; UNC Division of Cardiology, Chapel Hill—P. Chang; California Pacific Medical Center, San Francisco—E. Haeusslein; Taiwan: National Taiwan University Hospital, Taipei— S-S. Wang, R-B. Hsu, N-K. Chou.

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. Author contributions
  9. Disclosure
  10. References
  11. Appendix
  12. Supporting Information
FilenameFormatSizeDescription
ajt12181-sup-0001-TableS1.doc266K

Supplementary Methods

IVUS procedure

Table S1: Demographic and transplant characteristics of the patients within the IVUS subpopulation and compared to the non-IVUS population

Table S2: Most frequent nonfatal serious adverse events (≥2% of any treatment group; safety population)

Table S3: Adverse events leading to study drug discontinuation (≥1% of any treatment group; safety population)

Table S4: Baseline clinical characteristics in the everolimus 3.0 mg cohort (ITT population)

Table S5: Efficacy outcomes in the everolimus 3.0 mg cohort (n = 168) (ITT population)

Table S6: Relevant safety parameters in the everolimus 3.0 mg cohort (n = 167) (safety population)

Table S7: Laboratory values in the everolimus 3.0 mg cohort (n = 167) (safety population, on-treatment patients; last observation carried forward [LOCF] method)

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.