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Is the conclusion valid?
- G Morris-Stiff (24 May 1999)
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Meta-analysis of tacrolimus vs cyclosporin
- Peter A Andrews (17 June 1999)
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G Morris-Stiff
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EDITOR - We read with interest the recent meta-analysis of randomised trials
comparing cyclosporin (Sandimmun) and tacrolimus (BMJ 24th April 1999 318;
1104-7). There are a couple of interesting points that have arisen from
this analysis which may have a bearing on its conclusions.
Unfortunately, the first study cited Shapiro et al. does not have a minimum of one year follow-up, rather the "median follow-up is 1.12 years, with a range of 0.17 to 2.25 years". This paper should also be excluded on the grounds that it is not a randomised trial but rather compares a group of tacrolimus-treated patients with "a nearly concurrent group of patients treated with cyclosporine.." It is also difficult to draw conclusions, particularly from a United Kingdom point of view, because two of the studies routinely used antibody induction therapy and in a third study this was not detailed. This is a practice not commonly adopted in the British Isles. Furthermore, the drug doses, routes of administration, drug monitoring and treatment of rejection episodes differed markedly between studies. The fact that three of the four studies were multicentre trials with allowances for local protocols leads to a further tier of potential variation. In addition, all 4 studies evaluated the old cyclosporine preparation Sandimmun which is no longer available in the United Kingdom. This is alluded to in the text however, its successor Neoral has improved absorption and a lower acute rejection rate than Sandimmun thus making any direct comparisons between the formulations impossible. In an attempt to compare Neoral and Prograf we are currently conducting a single centre randomised control trial for patients undergoing cadaveric renal transplantation. We have so far recruited 200 patients, 179 (Prograf n=90, Neoral n=89) of whom have a minimum of 6 months follow-up (median follow-up 25 months). The acute rejection rate for Prograf-treated patients was 32% and for the Neoral was group 39% (p=n.s.). Serum creatinines were better in the Prograf group at 1 year (129 Tmol/l versus 153 Tmol/l; p<0.05) and 2 years (129 Tmol/l versus 157 Tmol/l; p<0.05). The use of OKT3 or ALG was lower in the Prograf group as was the need for conversion to MMF. The incidence of post- transplant glucose intolerance was greater in the Prograf group (p<0.05) whilst hypercholesterolaemia was more prevalent in the Neoral group (p<0.05). The antihypertensive medication requirements were also greater in the Neoral group (p<0.05). Whilst Prograf is undoubtedly more expensive than Neoral, the additional costs of OKT3 and MMF therapy means that in the short-term the overall total packages of care closely balance2. Our study is continuing so as to evaluate the long-term effects of these two calcineurin inhibitors. 1 Shapiro R, Jordan V, Scantlebury V., et al. FK 506 in clinical kidney transplantation 2 Morris Stiff G, Richards T, Singh J, et al. Pharmaco-economic study of FK 506 (Prograf) and cyclosporine A Neoral in cadaveric renal transplantation. Transplant Proc, 1998; 30: 1285-6. G Morris-Stiff A Khan I Quiroga R Baboo W A Jurewicz Department of Transplant Surgery Competing interests: The study is in part funded by a research grant from Fujisawa pharmaceuticals (Prograf). However, we are in charge of the data and its analysis, and the company have no right to veto any of our findings. We also receive financial support from Novartis (Neoral) and from Roche pharmaceuticals for other aspects of this ongoing study. |
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Peter A Andrews
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EDITOR - The meta-analysis by Knoll and Bell1 is an interesting piece of detective work that, if nothing else, demonstrates the paucity of high quality comparative research in this field. It is, however, of little relevance to current practice. Since the early 1990's, the introduction of an improved, microemulsion version of cyclosporin (Neoral®) has substantially improved the results of transplantation using cyclosporin as induction and maintenance therapy. Although first demonstrated in liver transplantation,2,3 such an effect is increasingly clear in renal transplantation. For example, a recent study in which the two versions of cyclosporin were directly compared showed a 13% reduction in the incidence of acute rejection in the group taking Neoral® when compared to the original preparation (Sandimmun®).4 This compares to reductions of 1%, 15.7%, and 19.8% in the three trials in the meta-analysis for which data are available. Clearly, correction for this would substantially alter the interpretation when extrapolating from this meta-analysis to current clinical practice. Interpretation of the data is not helped by the increasing view that the relationship between early acute rejection and graft survival is not straightforward. Indeed, the absolute number of rejection episodes, particularly those which resolve completely following steroid therapy, may not be good surrogates for long-term outcome.4,5 In contrast, most would accept that the severity of rejection is strongly correlated with outcome. While the authors note an increased use of 'rescue' therapy in the cyclosporin group, consistent with a higher incidence of severe rejection, interpretation is subject to the same criticism when extrapolating to the microemulsion formulation of cyclosporin. Over-riding the above is the fact that these indices are, in any case, of little true relevance. The critical information required by the transplant community - and the patient - relates to graft and patient survival. Only long-term follow-up of the large cohorts transplanted with tacrolimus and microemulsion versions of cyclosporin will resolve the issue of where the advantage, if any, lays. Other, new immunosuppressives will also impact upon this equation. In the meantime, clinicians have a delicate task in balancing the higher incidence of diabetes and glucose intolerance with tacrolimus against the worse lipid profile and the cosmetic side effects of cyclosporin. Peter A Andrews Consultant Nephrologist SW Thames Renal Unit St Helier Hospital Carshalton Surrey SM5 1AA I wish to declare the following competing interest. I have received expenses and travel costs in connection with conference attendance from both Novartis and Fujisawa, manufacturers of cyclosporin and tacrolimus respectively. I have used both drugs as part of immunosuppressive protocols in a number of transplant units. I have received no direct payment from either company and have no formal connection with either. 1 Knoll GA, Bell RC. Tacrolimus versus cyclosporin for immunosuppression in renal transplantation: meta-analysis of randomised trials. BMJ 1999;318:1104-7. (24 April). 2 Mirza DF, Gunson BK, Soonawalla Z, et al. Reduced acute rejection after liver transplantation with Neoral-based triple immunosuppression. Lancet 1997;349: 701-2. 3 Otto M-G, Mayer AD, Clavien P-A, Cavallari A, Gunawardena KA, Mueller EA. Randomized trial of cyclosporine microemulsion (Neoral) versus conventional cyclosporine in liver transplantation. Transplantation 1998; 66:1632-1640. 4 Pollard SG, Lear PA, Ready AR, Moore RH, Johnson RWG. Comparison of microemulsion and conventional formulations of cyclosporin A in preventing acute rejection in de novo kidney transplant patients. Transplantation. In Press. 5 Pelletier RP, Cosio FG, Henry ML, et al. Acute rejection following renal transplantation. Evidence that severity is the best predictor of subsequent graft survival time. Clin Transplant 1998;13:543-52. |
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