A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus After Liver Transplantation—PROTECT

Fischer, Lutz; Klempnauer, J.; Beckebaum, Susanne; Metselaar, Herold J.; Neuhaus, P.; Schemmer, Peter; Settmacher, Utz; Heyne, Nils; Clavien, Pierre Alain; Muehlbacher, Ferdinand; Morard, Isabelle; Wolters, Heiner; Vogel, Wolfgang; Becker, Tim; Sterneck, Martina; Lehner, Frank; Klein, Christoph; Kazemier, Geert; Pascher, Andreas; Schmidt, Jan; Rauchfuß, F.; Schnitzbauer, Andreas A.; Nadalin, Silvio; Hack, M.; Ladenburger, S.; Schlitt, Hans J.

doi:10.1111/j.1600-6143.2012.04049.x

Cited by 177 publications

(221 citation statements)

References 19 publications

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“…In the H2304 study, patients did not receive induction therapy and MPA was not permitted after randomization. In contrast, the PROTECT study showed that patients given basiliximab induction with gradual early withdrawal of CNI (tacrolimus or cyclosporine [CsA]) over an eight-week period did not experience increased BPAR (10,11).…”

Section: Accepted Articlementioning

confidence: 89%

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

Saliba

Duvoux

Gugenheim

et al. 2017

American Journal of Transplantation

101

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International audienceSIMCER was a 6-mo, multicenter, open-label trial. Selected de novo liver transplant recipients were randomized (week 4) to everolimus with low-exposure tacrolimus discontinued by month 4 (n = 93) or to tacrolimus-based therapy (n = 95), both with basiliximab induction and enteric-coated mycophenolate sodium with or without steroids. The primary end point, change in estimated GFR (eGFR; MDRD formula) from randomization to week 24 after transplant, was superior with everolimus (mean eGFR change +1.1 vs. −13.3 mL/min per 1.73 m2 for everolimus vs. tacrolimus, respectively; difference 14.3 [95% confidence interval 7.3–21.3]; p < 0.001). Mean eGFR at week 24 was 95.8 versus 76.0 mL/min per 1.73 m2 for everolimus versus tacrolimus (p < 0.001). Treatment failure (treated biopsy-proven acute rejection [BPAR; rejection activity index score >3], graft loss, or death) from randomization to week 24 was similar (everolimus 10.0%, tacrolimus 4.3%; p = 0.134). BPAR was more frequent between randomization and month 6 with everolimus (10.0% vs. 2.2%; p = 0.026); the rate of treated BPAR was 8.9% versus 2.2% (p = 0.055). Sixteen everolimus-treated patients (17.8%) and three tacrolimus-treated patients (3.2%) discontinued the study drug because of adverse events. In conclusion, early introduction of everolimus at an adequate exposure level with gradual calcineurin inhibitor (CNI) withdrawal after liver transplantation, supported by induction therapy and mycophenolic acid, is associated with a significant renal benefit versus CNI-based immunosuppression but more frequent BPAR

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Section: Accepted Articlementioning

confidence: 89%

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

Saliba

Duvoux

Gugenheim

et al. 2017

American Journal of Transplantation

101

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“…In the PROTECT study, subjects were randomized to either conversion to everolimus-based immunosuppression or continuation of CNI-based therapy at 4 weeks after LTx (26).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, subsequent single-center observational studies (not clinical trials) comparing de novo sirolimus initiation at time of LTx have not shown an increased risk of graft failure or HAT as compared to other strategies, which underscore the importance of making the data of this multicenter study available to clinicians (15,20). Second, given emerging literature on the role of another mTOR inhibitor, everolimus, it is important to gauge whether similarities exist in the risk and benefit profile for these two medications (21)(22)(23)(24)(25)(26)(27). Above all, transparency in the full presentation of the results of the study are important given that it may impact our current approach to management of immunosuppression after LTx.…”

Section: Introductionmentioning

confidence: 99%

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

Asrani

Wiesner

Trotter

et al. 2014

American Journal of Transplantation

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We studied whether the use of sirolimus with reduceddose tacrolimus, as compared to standard-dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international multicenter, open-label, active-controlled randomized trial (2000)(2001)(2002)(2003), adult primary liver transplant recipients (n ¼ 222) were randomly assigned immediately after transplantation to conventional-dose tacrolimus (trough: 7-15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4-11 ng/mL) and reduced-dose tacrolimus (trough: 3-7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24-month cumulative incidence of graft loss (26.4% vs. 12.5%, p ¼ 0.009) and patient death (20% vs. 8%, p ¼ 0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p ¼ 0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p ¼ 0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced-dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional-dose tacrolimus alone.

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“…56,57,60 Two recently published studies have shown a better glomerular filtration rate in Everolimus group as compared to CNIs. 61,62 Metabolic Syndrome (MS)…”

Section: Kidney Injury and Immunosuppressionmentioning

confidence: 99%

Current Status of Immunosuppression in Liver Transplantation

Choudhary

Saigal

Shukla

et al. 2013

Journal of Clinical and Experimental Hepatology

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With advancements in immunosuppressive strategies and availability of better immunosuppressive agents, survival rate following liver transplantation has improved significantly in the recent times. Besides improvements in surgical techniques, the most important factor that has contributed to this better outcome is the progress made in the field of immunosuppression. Over the last several years, the trend has changed to tailored immunosuppression with the aim of achieving optimal graft function while avoiding its undesirable side effects. Induction agents are no longer used routinely and the aim is to provide minimal immunosuppression in the maintenance phase. The present review discusses the various types of immunosuppressive agents, their mechanism of action, clinical utility, advantages and disadvantages, and their side effects in short and long-term. It also discusses about tailoring immunosuppression in presence of various situations such as renal dysfunction, metabolic syndrome, hepatitis C recurrence, cytomegalovirus infections and so on. The issue of chronic kidney disease and the available renal sparing immunosuppressive strategies has been particularly stressed upon. Finally, it discusses about the practical aspects of various immunosuppression regimens including drug monitoring. ( J CLIN EXP HEPATOL 2013;3:150-158)

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A Randomized, Controlled Study to Assess the Conversion From Calcineurin-Inhibitors to Everolimus After Liver Transplantation—PROTECT

Cited by 177 publications

References 19 publications

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

Efficacy and Safety of Everolimus and Mycophenolic Acid With Early Tacrolimus Withdrawal After Liver Transplantation: A Multicenter Randomized Trial

De Novo Sirolimus and Reduced-Dose Tacrolimus Versus Standard-Dose Tacrolimus After Liver Transplantation: The 2000–2003 Phase II Prospective Randomized Trial

Current Status of Immunosuppression in Liver Transplantation

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