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MEDICAL FRONTIERS - American Transplant Congress

Philadelphia, Pennsylvania / April 30-May 4, 2011

Incremental Gains in Renal Transplantation

Organ transplantation, made possible by effective strategies to prevent rejection, has been one of the major success stories in medicine over the past several decades. Due to incremental improvements in immunosuppressive regimens, 3-year kidney graft survival rates exceed 90% at high-volume transplant centres. This success has allowed an increased focus on modifying commonly employed immunosuppression regimens to improve quality of life without affecting graft survival. A recent advance is the development of a once-daily prolonged-release formulation of tacrolimus, which is a cornerstone of many immunosuppression regimens; the other is effective steroid-free regimens, which are now yielding graft and patient survival rates commensurate with those achieved with standard regimens. Both approaches are associated with potential improvements in quality of life.

“The goal has always been to provide adequate but avoid excessive immunosuppression, but we are now at a point where we understand this relative balance much better and have some data on which to make better choices,” reported Dr. Diego Cantarovich, Institut de Transplantation et de Recherche en Transplantation (ITERT), CHU Nantes, France, here at the ATC. Making these comments in the context of data he presented on a steroid-free immunosuppressive regimen, he indicated that much of the work with modified or innovative immunosuppression regimens has been performed in renal transplantation.

Among recent incremental advances, the development of a once-daily (q.d.) formulation of tacrolimus is considered modest but highly significant because of its ability to simplify long-term care. The q.d. formulation is now available in several countries in Europe and in Canada, but data confirming efficacy and safety are still accumulating.

OSAKA Results

Newly released data from the phase IIIb OSAKA (Optimizing ImmunoSuppression After Kidney Transplantation with Advagraf) study, a non-inferiority trial conducted at 110 centres in 22 countries, have provided compelling evidence that q.d. tacrolimus is as effective as b.i.d. dosing in the context of a multidrug immunosuppression regimen.

In OSAKA, 1251 adult kidney transplant recipients were randomized in comparable numbers to 1 of 4 immunosuppression protocols. The regimen of the first arm, to which the others were compared, included tacrolimus in the standard b.i.d. dose of 0.2 mg/kg/day with mycophenolate mofetil (MMF) plus corticosteroids. In 2 comparator arms, the q.d. dose of prolonged-release tacrolimus was administered with MMF plus corticosteroids. The q.d. doses in these 2 arms were 0.2 mg/ kg/day and 0.3 mg/kg/day, respectively. In the fourth arm, patients received q.d. tacrolimus in a dose of 0.2 mg/kg/day in combination with MMF, basiliximab and a single bolus of corticosteroids at transplantation. The primary composite end point was efficacy failure rate defined as graft loss, biopsy-confirmed acute rejection (BCAR) or graft dysfunction. Graft dysfunction was defined as an estimated glomerular filtration rate (eGFR) of <40 mL/min/1.73 m2.

There were no significant differences in the primary end point between the 4 arms after 24 weeks of follow-up. The proportion of patients meeting one of the end points fell within a very narrow range of 40.6% to 44.2% among the first 3 arms (Figure 1). In the fourth arm, which received a single dose of steroids, the failure rate was slightly higher at 48.2%. Compared to the b.i.d. arm, the q.d. arms with maintenance steroids were well within the pre-defined non-inferiority margin of 12.5%. The fourth arm did not meet the criterion of non-inferiority.

Figure 1.

The similarity in efficacy was particularly noteworthy because the study was intentionally conducted in a challenging group of renal transplant patients, according to Dr. Laetitia Albano, Transplantation Service, CHU de Nice, France. Approximately 50% of grafts were from extended criteria donors (older than 60 years or at least 50 years old with 2 additional risk factors) and nearly 90% of grafts were from deceased donors. She also noted that the level of eGFR used to define graft dysfunction was higher than that employed in many previous studies.

The 0.2 mg/kg/day dose of prolonged-release tacrolimus was not just non-inferior to the 0.2 mg b.i.d. tacrolimus in otherwise equivalent regimens but “comparable,” Dr. Albano told delegates. Although the 0.3 mg/kg/day dose performed similarly for the primary end point relative to the 0.2 mg doses in either the q.d. or b.i.d. formulations, the BCAR rates were higher (16.1%) on this dose than either the 0.2 mg/kg/day q.d. dose (10.3%) or the 0.2 mg/kg/day b.i.d. dose (13.6%). Overall, there were no signals for either an efficacy or safety advantage for the higher q.d. tacrolimus dose, leading Dr. Albano to suggest that a prolonged-release dose of 0.2 mg/kg/day could be the standard.

Value of Once-daily Immunosupressant Dosing

The inherent value of q.d. vs. b.i.d. therapy is well established. Several studies in a variety of diseases have repeatedly demonstrated that q.d. regimens promote better adherence and are preferred by patients. However, a second study specifically designed to evaluate the impact of q.d. tacrolimus on quality of life provided independent support. In this study, 24 patients were enrolled prospectively; all were receiving b.i.d. tacrolimus. On average, the patients had undergone renal transplantation 4.5 years earlier.

Scores on version II of the validated Treatment Satisfaction Questionnaire for Medication (TSQM II) climbed immediately in several areas after the patients, who took an average of 5.4 drugs/day, were switched from b.i.d. to q.d tacrolimus. This included an 11.6% increase (P<0.01) in the convenience score. Moreover, the number of ingestion time points/day decreased from 2.3 to 1.4 (P<0.001) and the mean number of tablets/day was reduced from 11.3 to 8.1 (P<0.001). There were no significant changes in TSQM scores for effectiveness or side effects, but the self-reported number of missed drug ingestions fell from a mean of 0.4 to 0.1 (P=0.02).

In patients with long-term experience on immunosuppression “using a simplified regimen with tacrolimus q.d. increases therapy satisfaction,” confirmed Dr. Gerben A. J. van Boekel, University of Nijmegen Medical Center, The Netherlands. He predicted that the observed improvement in compliance would have an impact on outcome.

No quality of life or compliance data were presented from the OSAKA trial, but Dr. Albano suggested that convenience and compliance are clearly motivating factors for using a q.d. over a b.i.d. regimen. “In patients who must remain on these drugs indefinitely, any reduction in the burden of therapy is probably important,” she stated.

Steroid-free Immunosuppression: A Practical Approach

In OSAKA, a notable advantage of the fourth study arm, which provided steroid-free immunosuppression after an initial perioperative bolus dose, was a low rate of new-onset type 2 diabetes mellitus (T2DM). Relative to the b.i.d. arm, which had a T2DM rate of 6.4%, and the q.d. 0.2 mg/kg/day arm, which had an intermediate rate (4.9%), T2DM developed in only 2.8% of those receiving steroid-free immunosuppression. Although those in the steroid-free arm had the lowest median eGFR (41.7 mL/min/1.73 m² vs. 48.3, 45.7 and 45.9 in the b.i.d., q.d. 0.2 mg/kg/day and q.d. 0.3 mg/kg/day arms, respectively), these are the types of results that are encouraging several centres to pursue steroid-free regimens, particularly in renal transplantation.

“It has been our orientation that avoidance of steroids is better than withdrawal, and we have been working with steroid-free immunosuppression since 1999,” reported Dr. Cantarovich, who presented long-term follow-up data comparing early steroid withdrawal to a steroid-free regimen at his institution. Offered only to low-risk patients, defined as <25% anti-T-cell antibodies and receipt of a donor graft with <36 hours of cold ischemia time, steroid-free regimens are pursued particularly aggressively in patients with T2DM. The premise of this approach is that “even 3 months of steroids in diabetics is a very bad thing,” he remarked.

In this data set, 597 low-risk, primary renal transplant patients were followed using different corticosteroid treatment strategies. In one, the goal was full steroid avoidance after an initial corticosteroid bolus dose at the time of transplant. In the other, corticosteroids were maintained for 3 months after transplant and then discontinued rapidly. All patients received basiliximab induction, tacrolimus and MMF.

At 3 months, 87.5% of the steroid avoidance group, which included 159 patients, were steroid-free, rising to 97% by 36 months and to 100% at 48 months. In the corticosteroid withdrawal group (n=438), 50% were steroid-free at 3 months, rising to 82% at month 36 and to 83% at 48 months. Patient survival (95%) and graft survival (84%) were found to be identical at 5 years. Although the number of patients treated for acute rejection was similar (8.6%), the rates of hypertension, thromboembolism events and microangiopathic events were higher among those who received steroid withdrawal rather than avoidance. Although serum creatinine measures and eGFR were similar in the 2 groups overall, a multivariate analysis indicated that the hazard ratio for developing T2DM was increased 8.18-fold in the steroid withdrawal group relative to the steroid avoidance group. In addition, the greater rate of cytomegalovirus (CMV) infection in the steroid withdrawal arm, despite valganciclovir prophylaxis in both arms, approached statistical significan
=0.09).

Table 1.

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Regarding major outcomes, “the data demonstrate that steroid avoidance is non-inferior, but non-inferior for me is superior because of the well-known problems with steroids,” Dr. Cantarovich told delegates. He added that the steroid avoidance protocol is now being used in all low-risk patients at his institution. In higher-risk patients, corticosteroids remain standard in the maintenance regimen but the goal is to stop after 3 months.

Other strategies to simplify regimens toward the goal of sustaining current rates of graft survival while reducing the burden of adverse events or the demands of therapy are encouraged by the evidence that modifications in treatment regimens, such as q.d. rather than b.i.d. tacrolimus and steroid avoidance rather than withdrawal, can be performed successfully. In some cases, such as steroid avoidance, the success of treatment is likely to be highly dependent on patient selection. In others, a better understanding of the optimal degree of immune suppression appears to be generating more universally applicable innovations.

Summary

The development of q.d. prolonged-release tacrolimus and strategies to reduce steroid exposure are emblematic of current efforts to preserve the high rates of graft survival now being achieved even among patients receiving donor organs of suboptimal quality. In patients who will require indefinite immunosuppression with often complex or challenging regimens, incremental improvements in convenience and tolerability are extremely meaningful. Although it is likely that immunosuppression will be increasingly individualized with more information about relative risks, the trial data outlining relative rates of efficacy and safety are facilitating rational choices.

Questions and Answers

The following section is based on discussions during the ATC scientific sessions with Dr. Laetitia Albano, Transplantation Service, CHU de Nice, France.

Q: OSAKA study results show that q.d. prolonged-release tacrolimus met the criteria for non-inferiority, but is there any subgroup of patients who might be better treated with the b.i.d. formulation?

A: No, not that I am aware of. The data show that prolonged-release tacrolimus is as effective as the b.i.d. formulation and, of course, it is much easier for the patient, so we would expect an improvement in compliance. There are no obvious circumstances in which there would be any advantage in going to a b.i.d. therapy when a q.d. regimen is available.

Q: Could you tell us more about the dose-ranging result? You concluded that 0.2 mg/kg is the dose of choice but again, are there circumstances in which a higher dose might make sense?

A: We did not see any evidence of an advantage for the 0.3 mg/kg dose in regard to outcomes such as a reduced acute rejection rate, but it was slightly less well tolerated. In evaluating a q.d. dose in this study, we wanted to make certain that we were not overlooking any advantages in regard to a higher dose, but the 0.2 mg/kg dose provided the best balance of efficacy and safety in the study overall, and there are no data to suggest a higher dose might be beneficial in any subgroup.

Q: The non-inferior boundary of 12.5% seems relatively wide. How did you select this criterion for equivalence?

A: This was not selected by us. This is now a standard that is being used in Europe, but in any case, results from the q.d. and b.i.d. 0.2 mg/kg doses were very similar for the primary outcome and did not approach this boundary.

Q: With the availability of the q.d. formulation, are you now switching all or most patients?

A: I think the q.d. tacrolimus will be the standard. We now have controlled data to demonstrate that it is easier to use and just as effective, so I am not sure why this would not be preferred for general use.