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Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials

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European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

We conducted a systematic review of randomized trials to compare the benefits and harms of tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation.

Methods and results

We searched electronic databases and bibliographies up to April 2010. Our review followed the Cochrane and PRISMA guidelines. The meta-analysis included 10 randomized trials with 952 patients. Tacrolimus was significantly superior to cyclosporine (both formula-combined) with regard to hypertension (relative risk [RR] 0.8; 95% confidence interval [CI] 0.69–0.93, p = 0.003), hyperlipidaemia (RR 0.57; 95% CI 0.44–0.74, p < 0.0001), hirsutism (RR 0.17 95% CI 0.04–0.62, p = 0.008), and gingival hyperplasia (RR 0.07 95% CI 0.01–0.37, p = 0.002). No significant differences between the two calcineurin inhibitors were found with regard to acute rejections causing haemodynamic instability, diabetes, renal dysfunction, infection, malignancy, or neurotoxicity. Tacrolimus was significantly superior to microemulsion cyclosporine with regard to mortality (RR 0.64; 95% CI 0.42–0.96, p = 0.03), acute severe biopsy-proven rejection (RR 0.71; 95% CI 0.56–0.90, p = 0.004), hyperlipidaemia (RR 0.57; 95% CI 0.41–0.79, p = 0.0009), hirsutism (RR 0.17 95% CI 0.04–0.62, p = 0.008), and gingival hyperplasia (RR 0.07; 95% CI 0.01–0.37, p = 0.002). Tacrolimus was significantly superior to oil-based cyclosporine with regard to hypertension (RR 0.66; 95% CI 0.54–0.80, p < 0.0001), and hyperlipidaemia (RR 0.57; 95% CI 0.38–0.87, p = 0.009).

Conclusion

Tacrolimus seems to be superior to cyclosporine in heart transplant patients with regard to hypertension, hyperlipidaemia, gingival hyperplasia and hirsutism. In addition, tacrolimus seems to be superior to microemulsion cyclosporine in heart transplant patients with regard to a number of outcomes, including death. More trials with a low risk of bias are needed to determine if the results of the present meta-analysis can be confirmed.

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References

  1. Taylor DO, Stehlik J, Edwards LB et al (2009) Registry of the International Society for Heart and Lung Transplantation: twenty-sixth official adult heart transplant report—2009. J Heart Lung Transplant 28:1007–1022

    Article  PubMed  Google Scholar 

  2. Valantine H (2000) Neoral use in the cardiac transplant recipient. Transplant Proc 32:27S–44S

    Article  CAS  PubMed  Google Scholar 

  3. Kapturczak MH, Meier-Kriesche HU, Kaplan B (2004) Pharmacology of calcineurin antagonists. Transplant Proc 36:25S–32S

    Article  CAS  PubMed  Google Scholar 

  4. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A (1989) FK 506 for liver, kidney, and pancreas transplantation. Lancet 2:1000–1004

    Article  CAS  PubMed  Google Scholar 

  5. McCormack PL, Keating GM (2006) Tacrolimus: in heart transplant recipients. Drugs 66:2269–2279

    Article  CAS  PubMed  Google Scholar 

  6. Banner NR (2006) Tacrolimus: in heart transplant recipients—a viewpoint by Nicholas R. Banner. Drugs 66:2280–2282

    Article  Google Scholar 

  7. Higgins JP, Green S (2009) Cochrane handbook for systematic reviews of interventions version 5.0.2 (updated September 2009). The Cochrane Collaboration. Available from www.cochrane-handbook.org

  8. Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 62:1006–1012

    Article  PubMed  Google Scholar 

  9. Stewart S, Winters GL, Fishbein MC et al (2005) Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 24:1710–1720

    Article  PubMed  Google Scholar 

  10. Royle P, Waugh N (2003) Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system. Health Technol Assess 7(iii):ix-51

    Google Scholar 

  11. Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 273:408–412

    Article  CAS  PubMed  Google Scholar 

  12. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558

    Article  PubMed  Google Scholar 

  13. Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326:219

    Article  PubMed  Google Scholar 

  14. Wetterslev J, Thorlund K, Brok J, Gluud C (2008) Trial sequential analysis may establish when firm evidence is reached in cumulative meta-analysis. J Clin Epidemiol 61:64–75

    Article  PubMed  Google Scholar 

  15. Grimm M, Rinaldi M, Yonan NA et al (2006) Superior prevention of acute rejection by tacrolimus vs. cyclosporine in heart transplant recipients—a large European trial. Am J Transplant 6:1387–1397

    Article  CAS  PubMed  Google Scholar 

  16. Kobashigawa J, Patel J, Furukawa H et al (2006) Five-year results of a randomized, single-center study of tacrolimus vs microemulsion cyclosporine in heart transplant patients. J Heart Lung Transplant 25:434–439

    Article  PubMed  Google Scholar 

  17. Kobashigawa JA, Miller LW, Russell SD (2004) A randomized, prospective, multicenter comparison of tacrolimus, mycopholate mofetil (mmf) and steroids vs cyclosporine microemulsion, mmf and steroids vs tacrolimus, sirolimus and steroids in de novo cardiac transplantation recipients—6 month report. 3rd International Congress on Immunosuppression, San Diego

  18. Kobashigawa JA, Patel JK, Furukawa H, Marquez A, Oeser BT, Laks H (2004) Five-year results of a randomized single center study of tacrolimus versus microemulsion cyclosporine in heart transplant patients. 3rd International Congress on Immunosuppression, San Diego

  19. Kobashigawa JA, Miller LW, Russell SD et al (2006) Tacrolimus with mycophenolate mofetil (MMF) or sirolimus vs. cyclosporine with MMF in cardiac transplant patients: 1-year report. Am J Transplant 6:1377–1386

    Article  CAS  PubMed  Google Scholar 

  20. Meiser BM, Groetzner J, Kaczmarek I et al (2004) Tacrolimus or cyclosporine: which is the better partner for mycophenolate-mofetil in heart transplant recipients? Transplantation 78:591–598

    Article  CAS  PubMed  Google Scholar 

  21. Meiser BM, Scheersoi T, Pfeiffer M et al (2000) Comparison of trough level adjusted MMF application in combination with either cyclosporine or tacrolimus in a randomized study after heart transplantation. Transplantation 69:695

    Google Scholar 

  22. Meiser BM, Uberfuhr P, Fuchs A et al (1996) Comparison between tacrolimus (FK506) and cyclosporin A (CyA) after heart transplantation: a randomised, controlled clinical study. Zeitschr Kardiol 85 [Suppl 2]:133

    Google Scholar 

  23. Meiser BM, Uberfuhr P, Fuchs A et al (1998) Single-center randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of acute myocardial rejection. J Heart Lung Transplant 17:782–788

    CAS  PubMed  Google Scholar 

  24. Reichart B, Meiser B, Vigano M et al (1998) European multicenter tacrolimus (FK506) heart pilot study: one-year results—European tacrolimus multicenter heart study group. J Heart Lung Transplant 17:1998

    Google Scholar 

  25. Pollock-BarZiv SMD, Dipchand AI, McCrindle BW, Nalli N, West LJ (2005) Randomized clinical trial of tacrolimus- vs cyclosporine-based immunosuppression in pediatric heart transplantation: preliminary results at 15-month follow-up. J Heart Lung Transplant 24:190–194

    Article  Google Scholar 

  26. Rinaldi M, Pellegrini C, Martinelli L et al (1997) FK506 effectiveness in reducing acute rejection after heart transplantation: a prospective randomized study. J Heart Lung Transplant 16:1001–1010

    CAS  PubMed  Google Scholar 

  27. Taylor DO, Barr ML, Radovancevic B et al (1999) A randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus. J Heart Lung Transplant 18:336–345

    Article  CAS  PubMed  Google Scholar 

  28. Wang CH, Ko WJ, Chou N, Wang SS (2004) Efficacy and safety of tacrolimus versus cyclosporine microemulsion in primary cardiac transplant recipients: 6-month results in Taiwan. Transplant Proc 36:2384–2385

    Article  CAS  PubMed  Google Scholar 

  29. Wang CH, Ko WJ, Chou N, Wang SS (2004) Therapeutic drug monitoring of tacrolimus in cardiac transplant recipients: a comparison with cyclosporine neoral. Transplant Proc 36:2386–2387

    Article  CAS  PubMed  Google Scholar 

  30. Wang SS, Chou NK, Chi NH et al (2008) Heart transplantation under cyclosporine or tacrolimus combined with mycophenolate mofetil or everolimus. Transplant Proc 40:2607–2608

    Article  CAS  PubMed  Google Scholar 

  31. Groetzner J, Meiser BM, Schirmer J et al (2001) Tacrolimus or cyclosporine for immunosuppression after cardiac transplantation: which treatment reveals more side effects during long-term follow-up? Transplant Proc 33:1461–1464

    Article  PubMed  Google Scholar 

  32. Groetzner J, Meiser B, Schirmer J et al (2001) Tacrolimus/mycophenolate mofetil vs cyclosporine/mycophenolate mofetil: comparison of mycophenolate mofetil acid trough levels and coronary vasomotor function. J Heart Lung Transplant 20:191

    Article  Google Scholar 

  33. Groetzner J, Meiser B, Schirmer J et al (2002) Tacrolimus/mycophenolate mofetil vs cyclosporine/mycophenolate mofetil: impact on infections following cardiac transplantation. J Heart Lung Transplant 21:120

    Article  Google Scholar 

  34. Schirmer J, Meiser B, Kadner A et al (2001) Tacrolimus versus cyclosporine after HTX: comparison of long-term effects. J Heart Lung Transplant 20:191

    Article  Google Scholar 

  35. Grimm M, Rinaldi M, Yonan NA (2003) Efficacy and safety of tacrolimus (TAC) vs. cyclosporine microemulsion (CME) in de novo cardiac transplant recipients: 6-month results. J Heart Lung Transplant 22:S92

    Article  Google Scholar 

  36. Taylor DO, Barr ML, Radovancevic B et al (1997) A comparison of tacrolimus- and cyclosporine-based immunosuppression in cardiac transplantation. J Heart Lung Transplant 16:72

    Google Scholar 

  37. Petrakopoulou P, Anthopoulou L, Muscholl M et al (2006) Coronary endothelial vasomotor function and vascular remodeling in heart transplant recipients randomized for tacrolimus or cyclosporine immunosuppression. J Am Coll Cardiol 47:1622–1629

    Article  CAS  PubMed  Google Scholar 

  38. von Steinbüchel N, Limm H, Leopold C, Carr D (2000) Assessment of health-related quality-of-life in patients after heart transplantation under therapy with tacrolimus or cyclosporine. Transpl Int 13 [Suppl 1]:S609–S614

    PubMed  Google Scholar 

  39. Reichart B, Meiser B, Vigano M et al (2001) European multicenter tacrolimus heart pilot study: three year follow-up. J Heart Lung Transplant 20:249–250

    Article  PubMed  Google Scholar 

  40. Gluud LL (2006) Bias in clinical intervention research. Am J Epidemiol 163:493–501

    Article  PubMed  Google Scholar 

  41. Eisen HJ, Hobbs RE, Davis SF et al (2001) Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine—results at 24 months after transplantation. Transplantation 71:70–78

    Article  CAS  PubMed  Google Scholar 

  42. Podesser BK, Rinaldi M, Yona NA et al (2005) Comparison of low and high initial tacrolimus dosing in primary heart transplant recipients: a prospective European multicenter study. Transplantation 79:65–71

    Article  CAS  PubMed  Google Scholar 

  43. Cantarovich M, Barkun J, Giannetti N, Cecere R, Besner JG, Tchervenkov J (2004) History of C2 monitoring in heart and liver transplant patients treated with cyclosporine microemulsion. Transplant Proc 36:442S–447S

    Article  CAS  PubMed  Google Scholar 

  44. Iversen M, Nilsson F, Sipponen J et al (2009) Cyclosporine C2 levels have impact on incidence of rejection in de novo lung but not heart transplant recipients: the NOCTURNE study. J Heart Lung Transplant 28:919–926

    Article  PubMed  Google Scholar 

  45. Fan Y, Xiao YB, Weng YG, Hetzer R (2009) Tacrolimus versus cyclosporine microemulsion for heart transplant recipients: a meta-analysis. J Heart Lung Transplant 28:58–66

    Article  Google Scholar 

  46. Mehra MR, Uber PA, Park MH, Prasad AK, Scott RL (2001) A randomized comparison of an immunosuppressive strategy using tacrolimus and cyclosporine in black heart transplant recipients. Transplant Proc 33:1606–1607

    Article  CAS  PubMed  Google Scholar 

  47. McAlister VC, Haddad E, Renouf E, Malthaner RA, Kjaer MS, Gluud LL (2006) Cyclosporin versus tacrolimus as primary immunosuppressant after liver transplantation: a meta-analysis. Am J Transplant 6:1578–1585

    Article  CAS  PubMed  Google Scholar 

  48. Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC (2005) Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 331:810–821

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

This work was supported by a grant from the Rigshospitalet Research Council to LP.

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Authors and Affiliations

  1. Copenhagen Trial Unit, Centre for Clinical Intervention Research, Cochrane Hepato-biliary Group, Department 3344, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Luit Penninga, Christian H. Møller & Christian Gluud

  2. Department of Surgery and Transplantation C2122, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Luit Penninga

  3. Department of Cardiothoracic Surgery RT 2152, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Christian H. Møller & Daniel A. Steinbrüchel

  4. Department of Cardiology, B2142, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Finn Gustafsson

Authors
  1. Luit Penninga
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  2. Christian H. Møller
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  3. Finn Gustafsson
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  4. Daniel A. Steinbrüchel
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  5. Christian Gluud
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Corresponding author

Correspondence to Luit Penninga.

Electronic supplementary material

Supplementary material (forrest plots of all meta-analyses and an additional table on immunosuppressive treatment strategies and drug target levels of the included studies) is available at European Journal of Clinical Pharmacology online.

Figure 7

Intervention effect of tacrolimus vs. cyclosporine on rejection causing hemodynamic instability (GIF 9 kb)

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Figure 8

Intervention effect of tacrolimus vs. cyclosporine on infection rate (GIF 8 kb)

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Figure 9

Intervention effect of tacrolimus vs. cyclosporine on CMV-infection rate (GIF 6 kb)

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Figure 10

Intervention effect of tacrolimus vs. cyclosporine on malignancy (GIF 9 kb)

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Figure 11

Intervention effect of tacrolimus vs. cyclosporine on basocellular skin cancer (GIF 6 kb)

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Figure 12

Intervention effect of tacrolimus vs. cyclosporine on renalfailure requiring haemodialysis (GIF 8 kb)

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Figure 13

Intervention effect of tacrolimus vs. cyclosporine on serum creatinine (μmol/L) (GIF 10 kb)

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Figure 14

Intervention effect of tacrolimus vs. cyclosporine on chronic allograft vasculopathy (GIF 7 kb)

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Figure 15

Intervention effect of tacrolimus vs. cyclosporine on hirsutism (GIF 6 kb)

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Figure 16

Intervention effect of tacrolimus vs. cyclosporine on gingival hyperplasia (GIF 6 kb)

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Figure 17

Intervention effect of tacrolimus vs. cyclosporine on neurotoxicity (GIF 8 kb)

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Figure 18

Intervention effect of tacrolimus vs. cyclosporine on total blood cholesterol (mmol/L) (GIF 9 kb)

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Table 3

Immunosuppressive treatment strategies of included trials (DOC 64 kb)

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Penninga, L., Møller, C.H., Gustafsson, F. et al. Tacrolimus versus cyclosporine as primary immunosuppression after heart transplantation: systematic review with meta-analyses and trial sequential analyses of randomised trials. Eur J Clin Pharmacol 66, 1177–1187 (2010). https://doi.org/10.1007/s00228-010-0902-6

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  • DOI: https://doi.org/10.1007/s00228-010-0902-6

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