BTS 2016: Best practice immunosuppression – no more Mr Nice Guy. Interview with Lorna Marson, Lisa Burnapp and Professor Derek Manas from the BTS executive discuss the potential impact on patients if the appeal fails and Professor Nigel Heaton and Dr Varuna Aluvihare (Kings College Hospital) give a surgeon and hepatologist’s view on how NICE renal guidance might affect liver transplantation.

Best practice immunosuppression – no more Mr Nice Guy.  

Nicholas Torpey, Addenbrooke’s Hospital, Cambridge.

Overview by Maria Dalby

The updated recommendations from the National Institute for Health and Care Excellence (NICE) on immunosuppressive therapy for renal transplantation in adults do not reflect current best practice and are marred by numerous inconsistencies and omissions. Dr Nick Torpey, consultant nephrologist and clinical director of transplant services at Addenbrooke’s Hospital in Cambridge, outlined the arguments for appealing against the recommendations on the grounds that it is unreasonable in light of the available evidence.

The first version of NICE technology appraisal (TA) guidance 85 was published in September 2004 and contained a number of open recommendations that allowed for interpretation and adaptation of the therapy according to individual patient needs. At the time most kidney transplant patients were treated with cyclosporine, azathioprine and prednisolone; including induction therapy with basiliximab in the recommendations and accepting tacrolimus as an alternative to cyclosporine represented big steps forward. Since then, the renal transplantation field has undergone dramatic changes: new immunosuppressive agents have been introduced and are widely used, such as thymoglobulin, once-daily tacrolimus, and belatacept; generics have appeared; cyclosporine and azathioprine are no longer used. Immunosuppressive therapy has become more diverse and this reflects the greater diversity seen amongst donors and recipients: compared with 2004 kidneys transplanted today are coming from older donors and to a greater extent from deceased donors, and recipients too tend to be older and more sensitised and have more co-morbidities.

The aim of the updated version of TA 85 was to review all technologies in the field, and whilst the draft guidance does indeed cover a broad range of immunosuppressive regimens, the actual recommendations made in this version are very restrictive. In fact, only one single immunosuppressive protocol is recommended, namely basiliximab induction with immediate-release tacrolimus and mycophenolate mophetil (MMF) as maintenance therapy. Other agents including antithymocyte globulin, prolonged-release tacrolimus, sirolimus, everolimus and belatacept are not recommended – which in reality means these agents should not be used. This wording of the guidance removes any room for interpretation and application of clinical judgment from the nephrologist, for example when treating patients who are intolerant to calcineurin inhibitors.

Of note is that the NICE standing appraisal committee that produced the appraisal determination did not include a single member with a background in nephrology or transplantation. The assessment report that formed the basis of the appraisal was produced by Peninsula Technology Assessment Group (PenTAG) is a voluminous document which comprises a systematic review of randomised clinical trials (RCTs) of immunosuppressive regimens and an economic model to determine the cost-effectiveness of each regimen. The final appraisal determination states upfront that cyclosporine, azathioprine and prednisolone constitute standard therapy in the NHS – Dr Torpey stressed that whilst it may be reasonable to use this regimen as baseline, assuming it as standard therapy is unreasonable. The document also takes an inconsistent approach to licensing and marketing authorisation – neither basiliximab nor MMF is licensed for use with tacrolimus, whilst on the other hand alemtuzumab which is widely used in renal transplantation in the UK and supported by extensive clinical and published experience, is completely dismissed from the recommendations. Any claims made by commentators on the draft document that are not supported by RCTs have also been disregarded – and yet the cost-effectiveness model makes important assumptions regarding key aspects of the therapy (new-onset diabetes after transplantation and biopsy-proven acute rejection) that are based entirely on non-RCT data.

It is widely accepted that as many as 10% of all patients are intolerant to CNI therapy.¹ It is unreasonable to assert, as the appraisal document does, that there are no alternatives to CNI therapy – the alternatives may be more expensive, but not as expensive as having these patients go back to dialysis. Best practice includes prescribing effective immunosuppression to prevent graft loss and minimise adverse effects, and tailoring treatment to the promote health and survival in the individual patient. Imposing a single regimen and assuming that the patient will remain on this is unreasonable. Changing the wording of the recommendations so that tacrolimus BD is positioned as initial therapy and alternatives can be used when deemed clinically appropriate would render this document a better representation of the available evidence and state-of-the-art best practice.

References

1. Ekberg H, Bernasconi C, Tedesco-Silva H, et al. Calcineurin inhibitor minimization in the Symphony study: observational results 3 years after transplantation. Am J Transplant 2009;9:1876-85.