Elsevier

The Lancet

Volume 364, Issue 9433, 7 August 2004, Pages 503-512
The Lancet

Articles
Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial*

https://doi.org/10.1016/S0140-6736(04)16808-6Get rights and content

Summary

Background

Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin.

Methods

The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat.

Findings

168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13·7% [95% CI –25·7% to 40·7%], p=0·44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR –16·2%, [–157·5% to 47·5%], p=0·71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A €2665 [SD 586] vs €184 [62]; phase B €5095 [2658] vs €322 [170], p<0·0001 for both).

Interpretation

In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney grafts.

Introduction

Mycophenolate mofetil, an ester prodrug of mycophenolic acid that acts by inhibiting the synthesis of purines, has been advocated as a novel drug for acute graft rejection.1 It can specifically suppress proliferation of T and B lymphocytes, theoretically leaving haemopoiesis and polymorphonuclear neutrophil number and activity unchanged; this feature has been presented as a major advantage over azathioprine.1

Mycophenolate mofetil reduced acute rejections of organ transplantation in animals2 and in people in open-label studies that also included ciclosporin.3, 4 Three large registration trials found that mycophenolate mofetil reduced acute rejection by 30 to 50% compared with azathioprine5, 6 or placebo7 at 6 months after transplantation. These findings served to launch mycophenolate mofetil as part of standard treatment for preventing rejection of transplanted kidneys and, more recently, of heart, liver, lung, and bone marrow.8 Nowadays, this drug is used by most transplant centres worldwide as part of maintenance immunosuppression regimens.

However, since the introduction of mycophenolate mofetil, a microemulsion preparation of ciclosporin, Neoral (Novartis, Basel, Switzerland), has become available. Because it is more rapidly, completely, and reproducibly absorbed than Sandimmune (Novartis, Basel, Switzerland), Neoral has become the preferred form of ciclosporin in many centres.9, 10, 11 Whether mycophenolate mofetil retains its better antirejection activity over azathioprine with the present microemulsion preparation of ciclosporin has not been tested. Nor is solid evidence available on whether, in view of current protocols, steroids still have a fundamental role in maintenance immunosuppression regimens. Because of the well recognised adverse effects of long-term steroid use, withdrawal of steroids at some point after transplantation is desirable. Attempts to do so have been made,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 but results have been disappointing so far. The benefits of low-dose or no-steroid protocols included less growth retardation in children,12 and reductions in hypertension,13, 14 dyslipidaemia.15, 16 and glucose intolerance,16 but also more rejections18, 19 so some of the trials had to be prematurely stopped for safety reasons.19

The mycophenolate steroids sparing (MYSS) study—a multicentre, randomised, parallel-group trial—was designed to clarify whether mycophenolate mofetil is better than azathioprine in regimens that include ciclosporin microemulsion, and whether it offers advantages over azathioprine in the opportunity to reduce or stop steroids. Our aim was to compare the risk-benefit profile of mycophenolate mofetil and azathioprine combined with this form of ciclosporin, with or without concomitant steroid therapy.

Section snippets

Patients

Eligible patients were men and women aged 18–70 years who were to receive a first kidney transplant from a cadaver donor. We excluded those with a history of malignant disorders (apart from successfully treated non-metastatic basal or squamous-cell carcinoma of the skin), serological evidence of infection with HIV or hepatitis B virus, systemic infections requiring continued antibiotic therapy, haematological abnormalities (white-blood-cell count <3×109/L, platelet count <1×1011/L, or

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