Sirolimus (Srl) and everolimus (Evl) inhibit the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase, responsible for cell proliferation (eg, T cells) and cytokine receptor-dependent signal transduction (eg, IL-2). The 2 drugs differ in their pharmacokinetic properties with Evl conferring a shorter half life, and therefore allowing faster elimination of Evl exposure compared with Srl. Evl was approved for immunosuppressive therapy in heart transplantation globally since 2004. However, Evl as well as Srl have not been approved for this indication in the United States until now. Nevertheless, per ISHLT registry data, about 10% and 20% of patients worldwide receive mTor inhibitor therapy-based immunosuppression (± calcineurin inhibitor [CNI] therapy) 1 and 5 years after transplantation.1 The role of these drugs is still debated; nevertheless, recent data from trials have shown modalities and patient populations where these drugs might supplement the immunosuppressive armamentarium. In this article, we will review the newest data on clinical use of mTor inhibitors in heart transplantation.
De Novo Data
In recent years, several trials have been conducted with de novo use of Evl or Srl either in combination or without the use of CNIs.
In an open-label, 24-month trial (CRAD 2310), 721 de novo heart transplant recipients were randomized to Evl 1.5 mg or 3.0 mg with reduced-dose cyclosporine A (Csa), or mycophenolate mofetil (MMF) with standard-dose Csa (plus corticosteroids ± induction).2 Whereas the primary efficacy endpoint, consisting of rejection, graft-loss, and death, was achieved in this noninferiority trial (35.1% vs 33.6%), Evl 1.5 mg was inferior to MMF in behalf of renal function (59.5 vs 64.5 mL/min per 1.73 m2, P = 0.02), and there was a higher rate of early death mainly due to infection in both Evl arms, leading to premature termination of the 3-mg Evl arm. Based on this study, the Food and Drug Administration did not approve the drug for use in heart transplantation due to increased mortality risk associated with severe infections in combination with induction therapy during the first 3 months after transplantation. Still, overall 2-year survival was similar between the groups (89.4% vs 90.8%). In a post hoc analysis of several single-center studies, Guethoff et al3 examined an 8-year outcome of de novo Srl + low-dose tacrolimus (tac) versus full-dose tac with MMF. Overall survival was similar between groups (84.7% vs 75%), and there was no benefit concerning the development of angiographically detected graft vasculopathy and renal function. There was a significant difference in freedom from treatment switch at 8-year follow-up (low TAC/SIR 51.7%, TAC/MMF 73.0%, P = 0.038), mainly due to Srl discontinuation. One major limitation of this report was the nature of its analysis (post hoc), and there might have been a significant number of confounding factors influencing the outcome. The latest and most progressive trial in de novo patients was the SCHEDULE trial from Andreassen et al.4,5 In this randomized, open-label trial, 115 de novo heart transplant recipients were randomized to Csa withdrawal or standard-exposure Csa 6 to 11 weeks after transplant. Concomitant immunosuppression consisted of Evl, MMF, and steroids. In the Csa withdrawal group, Evl dose was kept to 6 to 10 ng/mL. One- and 3-year data showed significantly improved renal function in the CNI-free arm (3 years, 77.4 ± 20.2 mL/min vs 59.2 ± 17.4 mL/min; P < 0.001). Intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy (CAV) in the Evl group compared with the Csa group. However, acute rejection incidence was higher in the CNI-free group during the first year (40% vs 18%; P < 0.05).
Besides de novo use of mTOR-based protocols, there have been lots of efforts to minimize or completely wean CNIs in long-term patients after heart transplantation.6 Several smaller, partly prospective trials were undertaken in recent years. Potena et al7 showed stabilization of renal function with conversion to Evl after a reduction of Csa by 70%. However, only a subgroup that did not develop proteinuria (≥150 mg/day) showed a significant improvement of renal function. In a retrospective multicenter cohort of 394 long-term patients with glomerular filtration rate (GFR) of 60 mL/min per 1.73 m2 or less, the authors compared 235 patients after conversion to mTOR (Evl or Srl) with 159 patients after mTOR introduction + CNI minimization.8 Overall, there was no difference in renal function between groups after a median of 2-year follow-up. In multivariate analysis, only early switch to mTOR (<5 years post-TX) showed a significant benefit for renal function. CNI-free patients tended to have a higher acute rejection incidence (P = 0.07). The biggest randomized trial on CNI minimization after introduction of Evl was the Nordic Certican Trial in Heart and Lung Transplantation study. In 282 patients, 1 year or longer after heart or lung transplantation, CNIs were lowered to less than 75 ng/mL Csa or less than 4 ng/mL tac (in combination with MMF or azathioprine and steroids) and compared with a control group without any changes.9 Recently, a 5-year follow-up was published, showing that GFR remained stable in the CNI minimization group (51.3 to 51.4 mL/min) but decreased in controls (from 50.5 to 45.3 mL/min). GFR was significantly higher with CNI minimization at last follow-up (P = 0.004). Rates of rejection, death, and major cardiac events were similar between groups, as was graft function. Pneumonia was more frequent with Evl (18.3% vs 6.4%), potentially due to the nature of a 4-drug regimen in the Evl group. Complete conversion to CNI-free therapy was analyzed in another prospective trial on long-term patients.10,11 One hundred sixteen patients with GFR of 40 to 90 mL/min per 1.73 m2 were randomized to Srl (n = 57) or CNI continuation (n = 59). Intent-to-treat as well as on-therapy analyses showed significant improvement from baseline GFR in the SRL group versus CNI continuation (+3.0 vs −1.4 mL/min per 1.73 m2; P = 0.004 and +4.7 vs –2.1; P < 0.001). Acute rejection rates were numerically higher, and a significant higher discontinuation rate due to adverse events was observed in the Srl group (33.3% vs 0%; P < 0001). Moreover, post hoc multivariate analyses showed low MMF dosage (<1000 mg/d) and nonwhite race to be independent predictors for acute rejection and diabetes to be an independent risk factor for nonimprovement of renal function after conversion to Srl.
Besides immunosuppressive efficacy and potential benefit for renal function, mTORs have been shown to have protective effects against the development of CAV. In 3 of the abovementioned de novo and conversion trials, intravascular ultrasound was used as a surrogate marker for development of CAV. In the 2310 trials, the Evl group showed significant lower intimal proliferation after 1 year. These findings remained lower, irrespective of sex, age, diabetic status, donor disease, and across lipid categories.2 Data from the SCHEDULE trial, in de novo CNI-free patients, showed reduced progression of CAV 36 months after transplantation.5 Moreover, Masetti et al12 demonstrated a protective effect of Evl after early implementation (during the first year), whereas there was no impact after late conversion. Similar data from the Nordic Certican Trial in Heart and Lung Transplantation trial showed no difference in CAV progression between Evl-treated patients and the control group after late conversion.9 It still remains a question if mTOR will have an impact on protection against clinically relevant CAV, defined by significant coronary lesions.
There exists growing evidence that mTOR inhibitors have a beneficial influence on 2 transplantation-associated complications: cytomeglovirus (CMV) infection and malignancy. All de novo trials using mTOR inhibitors have shown a reduced incidence of CMV infection after heart transplantation.2–4 Even in the setting of valgancicolovir prophylaxis or CMV high-risk combinations (D+/R−), there seems to be a benefit when compared with azathioprine or MMF.
mTor inhibitors have been successfully used in cancer therapy including renal cell carcinoma and breast cancer. There has been a long-lasting debate within the community if mTor inhibitors will have a protective effect against the development of posttransplant malignancy. However, there exist only small reports on the beneficial effect of de novo Evl therapy in overall cancer development and conversion to an Evl-based immunosuppressive regimen in skin cancer.13,14
Unfortunately, a big problem in using mTOR inhibitors is the low tolerability of the drug. In most heart transplant trials, the dropout rate due to adverse events was between 20% and 30%.2-11 Nevertheless, there exist no clear data on which of the patients will tolerate the drug.
SUMMARY AND DISCUSSION
Almost 20 years after the first mTOR inhibitor trials started, there is still a raging debate where they will find a place in immunosuppression after heart transplantation. Reviewing the newest data cannot supply enough evidence to use these drugs in all patients. However, there is an ongoing change of paradigms in posttransplant care. General protocols that fit all patients cannot exist and experts slowly accept the fact that individualized immunosuppression will provide a better alternative for de novo as well as long-term patients. The discrepancy of global approval status of the drugs clearly show the problems associated with generalized protocols, because overimmunosuppression lead to higher death rates in patient subpopulations.
A drug is only as good as the experts who know how to use it. Today, there exist patient populations who will benefit from using mTOR inhibitors:
- patients with a high risk for acute rejection;
- patients with a high risk for CMV infection;
- patients with renal insufficiency, where a CNI-free de novo protocol will be useful;
- patients with a high risk for developing early graft vasculopathy.
- patients with renal insufficiency, where a CNI-free protocol will be useful;
- patients with skin cancer development (although the evidence is still small);
Future research should focus on the impact of mTOR-based protocols on long-term complications (cancer, CAV, renal failure) that impair survival and personalized de novo protocols for patients with special needs (sensitized patients, chronic renal insufficiency).
1. Lund LH, Edwards LB, Dipchand AI, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-third adult heart transplantation report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant
2. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart transplantation: a randomized, multicenter trial. Am J Transplant
3. Guethoff J, Stroeh K, Grinninger C, et al. De novo sirolimus with low-dose tacrolimus versus full-dose tacrolimus with mycophenolate mofetil after heart transplantation—8-year results. J Heart Lung Transplant
4. Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant
5. Andreassen AK, Andersson B, Gustafsson F, et al. Everolimus initiation with early calcineurin-inhibitor withdrawal in de novo heart transplant recipients: three-year results from the randomized SCHEDULE study. Am J Transplant
6. Zuckermann AO, Aliabadi AZ. Calcineurin-inhibitor minimization protocols in heart transplantation. Transpl Int
7. Potena L, Prestinenzi P, Bianchi IG, et al. Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study. J Heart Lung Transplant
8. Gonzalez-Vilchez F, Vazquez de Prada JA, Paniagua MJ, et al. Use of mTOR inhibitors in chronic heart transplant recipients with renal failure: calcineurin-inhibitors conversion or minimization? Int J Cardiol
9. Gullestad L, Eiskjaer H, Gustafsson F, et al. Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial. Transpl Int
10. Zuckermann A, Keogh A, Crespo-Leiro MG, et al. Randomized controlled trial of sirolimus conversion in cardiac transplant recipients with renal insufficiency. Am J Transplant
11. Zuckermann A, Eisen H, Tai SS, et al. Sirolimus conversion after heart transplant: risk factors for acute rejection and predictors of renal function response. Am J Transplant
12. Masetti M, Potena L, Nardozza M, et al. Differential effect of everolimus on progression of early and late cardiac allograft vasculopathy in current clinical practice. Am J Transplant
13. Euvrard S, Boissonnat P, Roussoulières A, et al. Effect of everolimus on skin cancers in calcineurin inhibitor-treated heart transplant recipients. Transpl Int
14. Rivinius R, Helmschrott M, Ruhparwar A, et al. Analysis of malignancies in patients after heart transplantation with subsequent immunosuppressive therapy. Drug Des Devel Ther