a prospective, randomized trial of single versus dual drug...

A Prospective, Randomized Trial of Single versus Dual Drug Immunosuppression in Heart Transplantation:The Tacrolimus in

Combination,Tacrolimus Alone Compared (TICTAC) Trial

Running Title: Baran et al: The TICTAC Trial

David A. Baran, MD1

Mark J. Zucker, MD, JD1

Luis H. Arroyo, MD1 Margarita Camacho, MD1

Marc E. Goldschmidt, MD1 Stephen J. Nicholls, MBBS, PhD2

Jeanne Prevost-Fernandez1 Candace Carr, RN1

Laura Adams, RN1 Susan Pardi, NP1

Vera Hou, NP1 Maria Binetti, NP1

Jeanine McCahill, NP1 Joanne Chichetti, DNP, APN1

Valerie Viloria, RN1 Mary Gladys SanAgustin, RN1 Jennifer Ebuenga-Smith, RN1

Leslie Mele, RN1

Anthony Martin, APRN1 Donna Blicharz, RN1 Kathy Wolski, MPH2

Ludmilla Olesnicky, MD1 Fang Qian, MD1

Alan L. Gass, MD3 Marc Cohen, MD1

1- Newark Beth Israel Medical Center, Newark, NJ 2- Cleveland Clinic, Cleveland, Ohio

3- Westchester Medical Center, Valhalla, NY Correspondence to David A. Baran, MD, FACC Director, Heart Failure and Transplant Research Newark Beth Israel Medical Center, Newark, NJ Clinical Associate Professor of Medicine, New Jersey Medical School Telephone: (973) 926-7205, Fax: 973-926-2640 Email: [email protected]

Journal Subject Codes: [37] CV surgery: transplantation, ventricular assistance, cardiomyopathy

Jeanine McCahill, NPJeanine McCahill, NPJoanne Chichetti, DNP, APN1

Valerie Viloria, RN1

Mary Gladys SanAgustin, RN1

Jennifer Ebuenga-Smith, RN1

Leslie Mele, RN1

Anthony Martin, APRN1

by guest on June 12, 2018http://circheartfailure.ahajournals.org/

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Abstract

Background Cardiac transplantation, a procedure nearly abandoned in the 1970’s, has evolved

into the standard of care for appropriate patients with end stage heart failure. Much of this

success has been due to improvements in immunosuppression, including the introduction of a

triple-drug regimen. Retrospective reports suggested that single drug immunosuppression with

tacrolimus was feasible. As such, a prospective randomized trial was conducted to test this

approach.

Methods and Results 150 adult de novo heart transplant recipients were enrolled in a

prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy

(MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were

used in the early post-operative period but discontinued in all patients over 8-9 weeks. The

primary endpoint was the composite biopsy score at 6 months post-transplant. Patients were

followed for 1-5 years. The composite biopsy score was similar between groups at 6 and 12

months: 6 month MONO 0.70 ± 0.44 (95 % CI 0.60 - 0.80) vs. COMBO 0.65 ± 0.40 (95 % CI

0.55- 0.74) (p=0.44). Allograft vasculopathy was assessed by angiography and intravascular

ultrasound, with no significant differences noted. Three year survival was also similar (92.4%

MONO vs. 97% COMBO (p=0.58, log-rank).

Conclusions Addition of mycophenolate to single agent immunosuppression did not provide

an advantage over single agent immunosuppression in terms of rejection, allograft vasculopathy,

or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were

successfully discontinued in all patients. These conclusions are tempered by the limited

statistical power associated with a sample size of only 150 patients.

Clinical Trial Registration URL: http://www.clinicaltrials.gov, Unique identifier:

NCT00299221.

Key Words: immunosuppression transplantation; orthotopic heart transplant; randomized

controlled trial; transplantation; intravascular ultrasound

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as the composite biopsy score at 6 months post-transplant. Pa

ars. The composite biopsy score was similar between groups

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significant differences noted Three year survival was also si

as the composite biopsy score at 6 months post-transplant. Pa

ars. The composite biopsy score was similar between groups

ONO 0.70 ± 0.44 (95 % CI 0.60 - 0.80) vs. COMBO 0.65 ± 0

). Allograft vasculopathy was assessed by angiography and in

significant differences noted Three year survival was also si


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Cardiac transplantation, a procedure nearly abandoned in the 1970’s,1, 2 has evolved into the

standard of care for appropriate patients with end stage heart failure. Much of this success can be

attributed to the introduction of cyclosporine A in 1980 which, in combination with

corticosteroids and azathioprine, resulted in one year graft and patient survival of greater than 80

%. 3 There has been little effort over the past 25 years to modify the standard triple-drug

immunosuppression regimen. Efforts have focused on substituting tacrolimus (TAC) for

cyclosporine4, 5, mycophenolate mofetil (MMF) for azathioprine6, or adding a 4th agent to the

regimen7, 8.

Retrospective reports of heart transplant patients treated with TAC as monotherapy (following a

short course of corticosteroids) have shown low rates of allograft rejection and excellent

survival. 9, 10 These encouraging data prompted a prospective, randomized trial of de novo heart

transplant recipients treated with TAC monotherapy versus TAC/MMF treatment, following a

very short period of corticosteroid therapy. The interim results have been published previously

11, and now the median 3 year follow-up is described. It was the hypothesis of the study that

heart transplant recipients treated with TAC monotherapy would accrue a similar composite

rejection score as recipients treated with TAC / MMF combination therapy.

Methods

This was a prospective, randomized, controlled, open-label trial with two study groups. All

patients received oral TAC along with MMF and corticosteroids for the first 2 weeks post-

transplantation. Subsequently, study patients were randomized to either the “COMBO” group in

which MMF was maintained (in the absence of limiting side-effects), or the “MONO” group in

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costeroids) have shown low rates of allograft rejection and e

encouraging data prompted a prospective, randomized trial o

treated with TAC monotherapy versus TAC/MMF treatmen


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which MMF was discontinued between 14 and 28 days post-operatively. Randomization for

both study sites was via a sequential series of sealed opaque envelopes each containing a

treatment assignment. Envelopes were prepared in blocks of 25 patients, 13 MONO and 12

COMBO assignments each. This led to a total of 4 extra patients in the MONO group. The study

was approved by the Institutional Review Boards of both study sites and was registered with

ClinicalTrials.gov (NCT00299221).

Eligible study patients were those adults able to provide informed consent who were undergoing

an isolated first heart transplant. Exclusion criteria included ventilator-dependence through 14

days post-transplant (n=10), antibody mediated (humoral) rejection in the first 14 days after

transplant (n=3), intolerance to TAC (n=2), refusal / inability to provide informed consent (n=3).

From April 2004 through September 2008, 150 adult patients at two centers were enrolled, as

detailed on Figure 1.

The primary endpoint of the trial was the mean cumulative International Society for Heart and

Lung Transplantation (ISHLT) biopsy score over the first 6 months post-transplantation. Pre-

specified secondary endpoints were all-cause mortality, incidence of ISHLT grade 2R/3R

rejection over 6 and 12 months, one year mean cumulative ISHLT biopsy score, and the

incidence of allograft vasculopathy.

International Society for Heart and Lung Transplantation Biopsy Score

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olerance to TAC (n=2), refusal / inability to provide informe

rough September 2008, 150 adult patients at two centers were

.


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This scale assigns a numeric value to the grades of allograft rejection according to the older

formulation of the ISHLT. 12, 13 Biopsy grades 0, 1A, 1B, 2, 3A, 3B, and 4 are assigned to

numerical values 0, 1, 2, 3, 4, 5, and 6 respectively. Prior investigators have utilized this scale in

other heart transplant studies. 14, 15 More recently, the ISHLT has revised the grading scheme to

include 0R (former 0), 1R (including former 1A, 1B and 2), 2R (3A), and 3R (3B and 4).16

There were 2 pathologists primarily responsible for interpreting biopsies during the study, and

they were blinded to treatment assignments. A set of biopsies of each pathologic grade were re-

reviewed in a blinded fashion by both pathologists. The agreement between the original reported

biopsy grade and the repeat evaluation was 86.5 % - 92 % for the two pathologists.

Immunosuppressant Dosing

Oral TAC was given to achieve target levels of 8-10 ng/dl within the first 7-10 days post-

transplant. MMF was started at 500-1000 mg twice daily, adjusted according to labs and side

effects. Methylprednisolone 500 mg was given pre-operatively and intra-operatively, followed

by 125 mg intravenously every eight hours times three followed by two doses of 40 mg (every

12 hours). After this, oral prednisone was begun at 0.6 mg/kg daily (or intravenous

methylprednisolone equivalent). Other than a single patient receiving one dose of rabbit anti-

thymocyte globulin, induction therapy was not used.

Long-term TAC trough levels were targeted at 8-10 ng/dl, as a guideline for all patients.

Likewise, the MMF dose target was 2000 mg per day, if tolerated clinically.

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Prednisone was discontinued over 8 weeks post-transplant by means of a weekly weaning

protocol, beginning with a dose of 0.6 mg/kg prednisone during the first post-transplant week.

The dose was decreased by 0.1 mg/kg/day each week and steroids were discontinued by 8 weeks

post-transplant.

During the first 3 post-transplant months only, ISHLT 1R (old grade 2, but not 1A or 1B) and

asymptomatic ISHLT grade 2R rejection was treated with oral prednisone at 1 mg/kg/day for 3

days. Patients with grade 3R or symptomatic lesser grade rejection were hospitalized and were

treated with methylprednisolone 500 mg intravenously on the first day and then 100-250 mg

daily for 2 subsequent days. For all rejection episodes, biopsies were repeated within two weeks.

No patient required anti-lymphocyte antibody treatments. CMV and pneumocystis carinii

prophylaxis was given in all patients, regardless of pre-transplant CMV antibody status as

described previously11.

Coronary angiography was routinely performed within 3-6 months post-transplant, and at yearly

intervals thereafter. Starting in 2005, IVUS was utilized at the time of surveillance angiography

when technically feasible. Typically IVUS was performed during the first 2-6 months post-

transplant and at the annual evaluation. The Boston Scientific Galaxy system and Atlantis Pro

SR 40 Mhz IVUS catheter were utilized with motorized automated pullback for all studies.

Typically the left anterior descending coronary artery was imaged, after pre-treatment with

intracoronary nitroglycerin. Studies were archived on digital discs for core lab analysis.

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anti-lymphocyte antibody treatments. CMV and pneumocyst

en in all patients, regardless of pre-transplant CMV antibody


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The core lab was blinded to study group assignments and measured multiple parameters for each

IVUS examination. When possible, individual patient studies were matched based on anatomic

landmarks, allowing precise quantitation of progression of atheroma formation at identical sites

over time. In some cases, the core lab was unable to precisely match baseline and followup

studies based on the presence of anatomic landmarks. Parameters reported include average

plaque area, average lumen area, average maximal intimal thickness, largest intimal thickness,

and percent atheroma volume. In addition, the changes in these parameters from baseline to

follow-up examination were also calculated.

Statistical Analysis

All patient data was examined according to the intention-to-treat principle. The mean ISHLT

biopsy scores were calculated for both groups at 6 and 12 months and compared using t-tests.

Survival or freedom from rejection was quantitated with Kaplan-Meier curves and comparisons

made by log-rank test. Biopsies during the first 14 days post-transplant when all patients

received identical therapy were not analyzed. IVUS parameters were compared by t-tests. In all

cases, two-tailed p<0.05 was considered significant. Analyses were done utilizing JMP 7

software (SAS Institute, Cary, NC).

The power calculations utilized in the design of this trial were based on earlier reports which

described the ISHLT biopsy score. 17 The estimates of average biopsy score and standard

deviation were 1.0 ± 0.4 and 1.5 ± 0.6 in respective reports by Mehra17 and Yamani15 et al.

mexamined according to the intention-to-treat principle. The m


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Using JMP 7 software, Design of Experiments Module, the following parameters were specified

Alpha 0.05, the difference to detect between mean biopsy scores as 0.2, and standard deviation

of error as 0.4. This equated to an 86 % power to detect such a difference with 150 patients.

Results

From April 2004 through September 2008, 150 adult patients were enrolled. The demographics

of this group are detailed in Table 1. There were no significant differences between groups in

regard to age, gender, racial group, pre-transplant diabetes mellitus, incidence of significant

allosensitization, use of a pre-transplant ventricular assist device, or United Network for Organ

Sharing (UNOS) status prior to transplantation.

There were 79 patients in the MONO group and 71 in the COMBO group, and the follow-up is

reported for a median of 3 years (range 1-5 years). The primary endpoint of the trial was the 6

month mean ISHLT biopsy score. The 6 month mean biopsy score was 0.70 ± 0.44 (95 % CI

0.60 - 0.80) in the MONO group and 0.65 ± 0.40 (95 % CI 0.55- 0.74) in the COMBO group

(p=0.44). The 12 month mean biopsy score was 0.67 ± 0.39 (95 % CI 0.59 - 0.76) in the MONO

group and 0.62 ± 0.39 (95 % CI 0.53- 0.71) in the COMBO group (p=0.38). Table 2 lists the

biopsy results for 6 and 12 months post-transplant. The majority of the biopsies were negative or

low-grade (0R-1R).

The observed mean biopsy scores were lower than the average biopsy scores reported by others,

leading to significant alterations in the achieved statistical power. Using StudySize 2.0 software

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nts in the MONO group and 71 in the COMBO group, and h

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(CreoStat HB), the following parameters were entered: Alpha 0.05, standard deviation of error

0.42, sample size 150, equivalence limit 0.1. The achieved power to detect a difference of 0.2 in

biopsy score was 0.15 (15 %) based on these parameters. However, achieving 80 % statistical

power with the same parameters would require a sample size of 1750 patients, which would be

challenging in the arena of cardiac transplantation. This rendered the trial quite underpowered in

terms of the primary endpoint, and justified the long-term surveillance for other hard outcomes

such as allograft vasculopathy and all-cause mortality.

Twelve month freedom from allograft rejection ISHLT grade 2R is presented in Figure 2,

Panel A. The freedom from rejection ISHLT grade 2R at 6 months was 85.9 % and 94.4 % in

the MONO and COMBO groups, respectively (p=0.14 log-rank). At 12 months the freedom

from rejection was 85.9 % and 93.1 % in the MONO and COMBO groups, respectively (p=0.14

log-rank). Several patients experienced more than one rejection of at least ISHLT grade 2R (3

MONO and 3 COMBO patients). No rejection occurred in the MONO group after 120 days, and

a single COMBO patient experienced rejection between 180 and 210 days.

Antibody-mediated rejection occurred in 2 patients (one MONO and one COMBO), both within

the first 90 days post transplant. Both patients responded to a 4 day course of intravenous

immune globulin (total dose 2 grams / kg over 4 days), with no recurrence.

The freedom from any treated rejection (defined as any use of oral or intravenous steroids) is

displayed in Figure 2, Panel B. The freedom from treated rejection was 74.4 % and 81.9 % in the

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MBO groups, respectively (p=0.14 log-rank). At 12 months

85.9 % and 93.1 % in the MONO and COMBO groups, respe

atients experienced more than one rejection of at least ISHLTn


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MONO and COMBO groups, respectively at 6 months and 70.5 % and 80.6% in the MONO and

COMBO groups, respectively at 12 months (p=0.15 log-rank).

Patients were allowed to cross-over treatment assignments at the discretion of the investigators in

this open-label trial. There were 9 / 79 patients who changed from a MONO to a COMBO

treatment strategy due to the occurrence of rejection. The trial protocol allowed clinical judgment

to drive the decision to add MMF to a MONO patient. None of the 9 patients had severe graft

dysfunction or hemodynamic compromise. None of these patients experienced recurrent

rejection after addition of MMF. There were 26 / 71 COMBO patients who were withdrawn from

MMF therapy (usually due to neutropenia unresponsive to MMF dose reduction). Patients who

discontinued MMF remained on TAC monotherapy. Two of these patients experienced a single

episode of grade 2R asymptomatic rejection, which was treated with oral corticosteroids for 3

days. No patient required addition of alternate chronic immunosuppressants, including

maintenance corticosteroids. All analyses are by intention-to-treat.

The effect of MMF discontinuation (group crossover) is explored in Figure 2, Panel C. Depicted

is the freedom from rejection based on the treatment received. The COMBO group is divided

into those patients who receive MMF for at least 6 months, versus those who discontinue the

assigned therapy for intolerance prior to this time post-transplant. While there is no statistically

significant difference, the group with the highest freedom from rejection is those randomized to

COMBO who receive MMF for at least 6 months.

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Freedom from allograft vasculopathy, as assessed by coronary angiography, is shown in Figure

3. Vasculopathy was defined as a 50% or greater luminal stenosis in any vessel (excluding

donor-transmitted disease noted on angiography within 3 months post-transplant). The

angiographic freedom from disease in the MONO group was 100%, 96%, and 96% at 1, 3, and 5

years post-transplantation. In the COMBO group the freedom was 100%, 98.4%, and 98.4%

(p=0.34 MONO vs. COMBO). Diseased segments of at least 70% stenosis were treated with

percutaneous coronary intervention, typically with a drug-eluting stent. Due to small sample size,

and the insensitivity of angiography to detect allograft vasculopathy, it is not possible to rule out

a difference between groups.

IVUS was performed in 138 of 150 patients. Of these, 113 / 138 patients had data which was

technically adequate for core lab analysis. Since IVUS was not available at all points during the

study, not all patients had a baseline examination within 6 months post-transplant as well as a

follow-up study. Baseline (prior to 6 months post-transplant) and follow-up data was available

for 42 patients and this subset was analyzed separately in addition to the overall 113 patient

IVUS data. The analysis of the 113 patient cohort showed no significant differences in any

parameter studied, although there was a consistent trend towards less plaque, less progression of

intimal thickening, and less progression of percent atheroma volume in the MONO group.

Table 3 shows the analysis of the 42 patients with paired baseline (prior to 6 months post-

transplant) and follow-up data. The best studied IVUS parameter in heart transplant recipients is

the average maximal intimal thickness. It has been shown that a change of at least 0.5 mm

between early post-transplant baseline and a 1 year IVUS study is associated with excess risk of

d in 138 of 150 patients. Of these, 113 / 138 patients had da

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death and development of allograft coronary artery disease.18 In the 42 patients with matched

IVUS studies, none of the 22 MONO patients had growth of intimal thickness of 0.5 mm or

more, but 2 of the 20 COMBO patients did (p=0.08). Most of the Core Lab measured indices did

not show statistically significant differences between groups. Only the change in percent

atheroma volume was of borderline statistical significance in favor of the MONO group with

1.78 ± 5.62 % change in MONO and 6.83 ± 10.46 % change in the COMBO group.

All-cause mortality is presented as a Kaplan-Meier plot in Figure 4. Survival in the MONO

group was 97.5%, 92.4% and 87.2% at 1, 3, and 5 years respectively. Survival in the COMBO

patients was 98.6%, 97 %, and 90.6 % at 1, 3, and 5 years respectively (p=0.58, log-rank). The

survival analysis was repeated for the “on-treatment” cohort of patients who did not cross-over

treatment assignment and was similar, with no significant differences noted (p=0.34). It is

important to note that survival between groups was not identical, and given the low sample size

(150 patients), no definitive conclusion may be reached in regards to this severely underpowered

secondary endpoint.

There were 20 episodes of infection requiring treatment noted in the MONO group and 25 in the

COMBO group (p=0.5). Opportunistic infections were rare, with 4 patients treated for

cytomegalovirus disease (2 MONO and 2 COMBO patients), which resolved with therapy. There

were no cases of pneumocystis carinii pneumonia or toxoplasmosis with 1 year of trimethoprim /

sulfamethoxazole prophylaxis.

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Table 4 lists the white blood cell count, blood urea nitrogen, serum creatinine and tacrolimus

levels for the patients in the study at baseline, 6,9 and 12 months post-transplant. While the

values are similar at the time of transplant, the mean white blood cell count is statistically

significantly less at 6 months in COMBO patients (but not in a clinically meaningful degree).

The renal function at 6 months was lower for the MONO grouo, but was no longer significant at

9 months and of borderline significance at 12 months. Long-term follow-up is planned to

monitor renal function over time. Tacrolimus levels were not different between groups at any

time interval.

Discussion

For nearly 30 years, heart transplant patients have been treated with “triple therapy” consisting of

a calcineurin antagonist, a cell-cycle modulating drug and corticosteroids. While several trials

have examined substitutes for one of the components of the combination, TAC monotherapy has

never been prospectively studied before.

The TICTAC trial primarily addresses the safety and comparative efficacy of TAC monotherapy

versus TAC / MMF following a brief course of steroids post-transplant. Patients in both groups

were successfully weaned from steroids, and the 3 year median follow-up results are encouraging

in terms of rejection, vasculopathy and mortality. These three aspects are all linked, as acute

cellular rejection is believed to predispose to the development of allograft vasculopathy15, 18,

which is one of the leading causes of mortality in heart transplant patients. 19

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heart transplant patients have been treated with “triple therap

nist, a cell-cycle modulating drug and corticosteroids. While

titutes for one of the components of the combination, TAC m


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One of the most critical aspects to consider is the patient selection for this trial. 18 patients

transplanted during the trial enrollment period were excluded. The survival of all patient groups

is depicted in Figure 4, Panel B. The excluded patients included 10 whom were ventilator

dependent during the first 14 days post transplant (6 month and 1 year survival of 20 %, and 0 %

respectively), as well as 5 patients who either declined participation in the trial or who had

intolerance to tacrolimus (100 % survival at 1 year post-transplant), and 3 patients with antibody

mediated rejection within 14 days of transplantation (66.7 % survival at 6 and 12 months post-

transplant). It is not likely that any immunosuppressive strategy would improve outcomes in the

10 patients who could not be weaned from the ventilator post-transplant, and therefore their

exclusion does not detract significantly from the utility of the results observed in this trial. None

of these patients experienced allograft rejection (cellular or antibody mediated) during the first

month post-transplant. Patients with early (within the first 14 days only) antibody mediated

rejection also represent a small but high-risk group and it was not felt to be ethical to potentially

randomize such patients to single drug therapy. However, AMR did occur in two patients who

were followed in the trial, both of whom were successfully treated and maintained in the study.

These results compare favorably to prior studies with more traditional immunosuppression. 7, 20,

21 Although some centers do wean “low-risk” patients from corticosteroids typically beginning 6

months post-transplantation, the 2009 ISHLT registry data reveals that 71% of patients still

remain on steroids 1 year post-transplant.22 An alternative approach is therapy with induction

antibody preparations, such as rabbit anti-thymocyte globulin or alemtuzumab to “facilitate”

steroid withdrawal.23, 24 None of these studies report less rejection or improved mortality as

compared to the current study’s findings. While other studies have examined late steroid

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weaning, and not found significant success25, 26, this is the first prospective study to specifically

mandate a rapid weaning schedule based on patient weight. It is important to emphasize that this

trial did not have a group which received chronic steroid therapy, and therefore, did not directly

compare the outcomes of traditional steroid maintenance and rapid steroid weaning. A

prospective, randomized trial comparing traditional steroid weaning by 6-12 months versus 8

week weaning is currently in the planning stages.

The current study integrates IVUS, but not as part of the primary endpoint, since it was not in

routine use at study sites in 2004. Nevertheless, 138 of 150 patients had at least one IVUS study,

and these were analyzed by the Cleveland Clinic IVUS Core Lab, which was not involved in the

conduct of the study. The Core Lab conducted analyses of matched sites by comparing anatomic

landmarks on the studies. Multiple parameters were measured by the Core Lab including percent

atheroma volume (PAV) which has been utilized in a number of recent clinical trials in

atherosclerosis. 27-30 There were 113 patients with studies analyzed by the Core Lab, with the

finding of similar degrees of lumen shrinkage, and plaque growth, over varying periods of time

post-transplant. While the data is most robust when examining paired patient studies, there is

utility to examining the full available dataset, to exclude a signal of harm associated with single

drug therapy.

Nearly a third of the patients in the trial had an early baseline IVUS and a matching follow-up

study, with results presented in Table 3. Previous studies such as Eisen et. al.20 have also

obtained IVUS studies in approximately a third of patients (211 of 634 patients, 33 %).There

were no statistically significant differences, except for a strong trend towards a smaller change in

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PAV in the MONO vs. COMBO group (p=0.055). There were non-significant trends towards

less lumen shrinkage, less intimal thickening, and less atheroma in the MONO group.

Despite the advantages of IVUS, angiography remains the most commonly utilized modality to

assess allograft vasculopathy. ISHLT Registry data report that 20 % of patients will have

angiographically apparent disease by 3 years, rising to 30 % at 5 years.22 While the numbers of

patients in this study was relatively small, the incidence of allograft vasculopathy was less than 5

% in both groups with a median 3 year follow-up period. Taken together, these results indicate

that there is no significant disadvantage to TAC monotherapy and there may be a benefit of less

medication.

It is notable that survival was similar between groups with less than 3% mortality during the first

year post-transplant, although the trial was underpowered to assess this endpoint, and excluded

the patients who remained ventilator dependent post-transplant. Registry data consistently show

that the largest declines in post-transplant survival occur during the first year. These findings

suggest a new direction for future trials in cardiac transplantation. Perhaps efforts should be

directed towards reducing immunosuppression, and identification of surrogate markers which

would allow safe and effective minimization of these toxic but life-saving drugs.

The fact that less immunosuppression is associated with a very low risk of rejection is counter-

intuitive and unexpected. One theory is that the low TAC levels during the first week post-

transplant may provide a Window of Opportunity for Immunologic Engagement (WOFIE) which

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vival was similar between groups with less than 3% mortality

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may enhance the production of T-regulatory cells.31 This is speculative at best and the current

study provides no mechanistic insight into the clinical outcomes observed.

Limitations

The most important limitation of this work is that it is underpowered. The event rates garnered

from the literature which were used in the power calculations were much higher than those

observed in this study. Therefore, no concrete assessment may be made as to the equivalence of

the two study groups. Similarly, the trial is not appropriately powered to assess mortality and the

IVUS analyses are limited by the lack of consistent baseline and follow-up studies. In addition,

this study is not applicable to those patients with AMR in the first 14 days post-transplant, or

patients remaining ventilator-dependent during the same period. These limitations are partially

counter-balanced by a median 3 year follow-up, along with independent core lab analysis of the

IVUS data using the latest and most sensitive IVUS analysis techniques.

The questions of whether, when, and in whom single immunosuppression might be considered

clearly warrant re-examination and further investigation. Clearly, patient compliance and the

ability of the transplant team to closely monitor these patients and coordinate their care is critical

to successful outcomes. Nevertheless, these findings may be most reassuring to clinicians who

are faced with the need to rapidly reduce immunosuppression due to not infrequent problems

such as intolerance to MMF or severe infections in the early months post-transplant when these

data may be applicable.

Conclusion

follow up stuudididdddd e

st 14444444 d d d d d ddayayayayayayays s s s s s s popopopopopopoststststststst-t-t

v n

y b

e

ventilator-dependent during the same period. These limitation

y a median 3 year follow-up, along with independent core lab

e latest and most sensitive IVUS analysis techniques.


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The TICTAC trial is the first prospective test of single versus dual drug maintenance

immunosuppression in heart transplantation. Steroid weaning was successful in all study

patients, and should be considered a potential option for heart transplant patients who can be

monitored closely during the weaning process. The excellent 3-year survival and low rates of

allograft rejection and vasculopathy observed in both arms of this study support the efficacy of

either TAC monotherapy or TAC / MMF along with a brief course of corticosteroids post-

transplantation.


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Sources of Funding

This trial was partially supported by two investigator-initiated grants from Astellas

Pharmaceuticals which covered enrollment of the first 50 patients, and the core lab analysis of

intravascular ultrasound data. The database was designed and maintained by the authors who had

full access to the data. There was no involvement of Astellas in the design, writing, or decision to

submit the paper.


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Disclosures

David A Baran:

Research Grant: Astellas Pharma, Amount: >= $10,000

Honoraria: Astellas, Amount: < $10,000

Expert Witness: Unpaid voluntary trstimony at Medicaid of New Jersey Generic Substitution

committee

Mark Jay Zucker:

Research Grant: Astellas, Amount: >= $10,000

Luis H Arroyo: No disclosures

Margarita Camacho:


Marc E Goldschmidt:


Stephen James Nicholls:

Research Grant: Astellas Pharma grant for IVUS Core Lab Analysis, Amount: >= $10,000

Jeanne Prevost-Fernandez: No disclosures

Candace Carr: No disclosures

Laura Adams: No disclosures

Susan Pardi: No disclosures

Vera Hou: No disclosures

Maria Binetti: No disclosures

Jeanine McCahill: No disclosures

h

t

i

ho:

tellas, Amount: >= $10,000

idt:


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JoAnne Chichetti: No disclosures

Valerie Viloria: No disclosures

Mary Gladys SanAgustin: No disclosures

Jennifer Ebuenga-Smith: No disclosures

Leslie Mele: No disclosures

Anthony Martin: No disclosures

Donna Blicharz: No disclosures

Kathy Wolski:

Research Grant: Astellas Pharma grant to support statistical review of trial data, Amount: >=

$10,000

Ludmilla Olesnicky: No disclosures

Fang Qian: No disclosures

Alan L Gass:

Research Grant: Astellas Pharma- Support for TICTAC trial enrollment, Amount: < $10,000

Honoraria: Astellas Pharma- CME lectures, Amount: < $10,000

Marc Cohen: No disclosures

ew of trial datta,a,a,a,a,aa f

y

c

y: No disclosures

closures


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Table 1. Group Characteristics

Factor MONO Group (n=79)

COMBO Group (n=71)

p-value

Age 55 ± 10.7 55 ± 11.6 0.51

Male Gender 62 60 0.40

Black Race 17 11 0.40

Pre-Tx DM 28 22 0.40

PRA 10 % 23 22 0.86

Pre-Tx VAD 21 19 0.98

High-Risk CMV 23 (29 %) 13 (18 %) 0.13

Donor Age 31.3 ± 12.8 31.7 ± 12.4 0.87

Female Donor 37 (46.8 %) 24 (33.8 %) 0.13

Cold Ischemic Time 198 ± 51 194 ± 47 0.59

UNOS Status 1A 45 31

UNOS Status 1B 30 38

UNOS Status 2 4 2

0.15

m

37 (46.8 %) 24 (33.8 %) 0.13

me 198 ± 51 194 ± 47 0.59

45 31

30 38 0.15


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Table 2. Biopsy Data

MONO Group # Biopsies / %

COMBO Group # Biopsies / %

6 Months 12 Months 6 Months 12 Months Grade 0R 330 / 45% 425 / 47 % 315 / 47 % 416 / 50 % Grade 1R (1A) 314 / 43 % 381/ 42 % 275 / 41 % 330 / 40 % Grade 1R (1B) 48 / 6 % 53 / 6 % 39 / 6 % 45 / 5 % Grade 1R (2) 31 / 4 % 37 / 4 % 32 / 5 % 37 / 4 % Grade 2R 13 / 2 % 13 / 1 % 7 / 1.0 % 8 / 1.0 % Grade 3R 2 / 0.3 % 2 / 0.2 % 0 0 Total 738 / 100 % 911 / 100 % 668 / 100 % 836 / 100 %


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Table 3. Intravascular Ultrasound Data- Cohort with Baseline and Follow-up Exam (N=42)

Baseline Examination ( 180 days)

Follow-up Examination

Change- Baseline to Follow-up

IVUS Parameter MONO group (N= 22)

COMBO group (N=20)

p-value (comparison Baselines)

MONO group (N= 22)

COMBO group (N= 20)

p-value (comparison Follow-ups)

MONO group (N= 22) Mean ± SE

COMBO group (N=20)

p-value (Paired T-test baseline to follow-up)

Average Plaque Area 2.44 ± 0.64

2.73 ± 1.13

0.31 2.66 ± 0.91

3.42 ± 2.06

0.12 0.22 ± 0.69

0.69 ± 1.33

0.15

Average Lumen Area 9.71 ± 2.91

10.26 ± 2.87

0.54 9.26 ± 2.55

8.64 ± 2.92

0.46 -0.45 ± 2.4

-1.62 ± 2.75

0.15

Average Maximal Intimal Thickness

0.36 ± 0.09

0.39 ± 0.16

0.51 0.40 ± 0.11

0.51 ± 0.28

0.10 0.035 ± 0.099

0.12 ± 0.22

0.12

Largest Intimal Thickness

0.68 ± 0.30

0.71 ± 0.35

0.78 0.76 ± 0.31

0.88 ± 0.50

0.35 0.075 ± 0.22

0.166 ± 0.44

0.39

Percent Atheroma Volume

20.72 ± 5.41

21.02 ± 6.94

0.87 22.49 ± 6.15

27.68 ± 12.54

0.09 1.78 ± 5.62

6.83 ± 10.46

0.055

Average Maximal Intimal Thickness 0.5mm (# patients, % of patients)

1, 4.6 % 4, 20 % 0.11 5, 22.7 %

7, 35 % 0.38 0, 0% 2, 10 % 0.08 (Likelihood ratio)

Time to IVUS Exam Post-transplant

106.7 ± 32.6

113.9 ± 33.7

0.49 564.5 ± 204.5

567.0 ± 235

0.97

0.0.0.0.0.0.0.10101010101010 0 11 0 28

8

7

0.11 0.28 8 0.76 ±

0.31 0.88 ± 0.50

0.35

7 22.49 ± 6.15

27.68 ± 12.54

0.09


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Table 4. Selected Laboratory Values Post-transplant

Baseline at Transplant 6 Months Post-transplant 9 Months Post-transplant 12 Months Post-transplant Factor MONO COMBO p-

value MONO COMBO p-

value MONO COMBO p-

value MONO COMBO p-

value White Blood Cell Count

9.3 ± 5.7 9.5 ± 5.1 0.81 5.63 ± 3.0

4.6 ± 1.7 0.01 5.75 ± 2.2

5.1 ± 1.9 0.07 6.37 ± 2.6

5.74 ± 2.4 0.13

Blood Urea Nitrogen

24 ± 13.3 24 ± 11.8 0.80 33 ± 11.4 29 ± 9.4 0.01 31 ± 10.8 29 ± 11.3 0.34 30 ± 11.2

29 ± 11.1 0.53

Serum Creatinine 1.24 ± 0.43

1.26 ± 0.5

0.80 1.63 ± 0.51

1.43 ± 0.42

0.007 1.56 ± 0.46

1.58 ± 1.33

0.87 1.64 ± 0.7

1.44 ± 0.49

0.05

Tacrolimus Level - - - 10.8 ± 2.7

10.8 ± 4.0 0.98 9.9 ± 3.1 9.8 ± 3.2 0.95 9.8 ± 3.1 9.8 ± 3.8 0.95 9.9.9.9.9.9.9.9 9 99999 ± ± ±±±±± 3.3.3.3.3.3.3.1 1111 11 9999999


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Figure Legends

Figure 1. Study Flow Diagram. This diagram illustrates flow from recruitment to study group assignment. Figure 2, Panel A. Freedom from Allograft Rejection: 2R / 3R Rejection. This is a Kaplan-Meier

plot of freedom from significant cardiac allograft rejection (ISHLT grades 2R or 3R)

Figure 2, Panel B. Freedom from Any Treated Allograft Rejection. This is a Kaplan-Meier plot

of freedom from any cardiac allograft rejection which was treated. (Symptomatic or clinically

suspicious rejection, even if the tissue diagnosis was negative and treatment was discontinued.)

Figure 2, Panel C. Freedom from Allograft Rejection 2R/3R This graph examines the patients

who were intolerant to MMF and their rejection outcome. Patients who did not discontinue MMF

(maintained the treatment they were randomized to for at least 6 months) are compared to those

who discontinue MMF within the first 6 months post-transplant, as well as all patients

randomized to the MONO group.

Figure 3. Freedom from Angiographically Detected Allograft Vasculopathy. This is a Kaplan-

Meier plot of the freedom from angiographically detected allograft vasculopathy. This was

defined as a 50% or greater luminal stenosis in any vessel (excluding donor-transmitted disease

noted on angiography within 3 months post-transplant).

d. (Symptommatatatatatatati

d treaeaeaeaeaeae tttttttmemememememementntntntntntnt w wwwwwwasaaaaa

d

reedom from Allograft Rejection 2R/3R This graph examin

to MMF and their rejection outcome. Patients who did not d


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Figure 4, Panel A. Survival post-transplant. This is a Kaplan Meier plot of survival post-

transplant for the 150 subjects in the trial.

Figure 4, Panel B. This is a Kaplan Meier plot of survival comparing patients entered into the

TICTAC trial with those excluded (based on inclusion criteria).


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Fang Qian, Alan L. Gass and Marc CohenEbuenga-Smith, Leslie Mele, Anthony Martin, Donna Blicharz, Kathy Wolski, Ludmilla Olesnicky,

Binetti, Jeanine McCahill, Joanne Chichetti, Valerie Viloria, Mary Gladys SanAgustin, JenniferJ. Nicholls, Jeanne Prevost-Fernandez, Candace Carr, Laura Adams, Susan Pardi, Vera Hou, Maria

David A. Baran, Mark J. Zucker, Luis H. Arroyo, Margarita Camacho, Marc E. Goldschmidt, StephenTrial

Transplantation: The Tacrolimus in Combination, Tacrolimus Alone Compared (TICTAC) A Prospective, Randomized Trial of Single versus Dual Drug Immunosuppression in Heart

Print ISSN: 1941-3289. Online ISSN: 1941-3297 Copyright © 2011 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation: Heart Failure published online January 7, 2011;Circ Heart Fail.

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