BIOLOGIC AND THERAPEUTIC ADVANCES IN HEART TRANSPLANTATION I

L. Gullestad¹, H. Eiskjaer², G.C. Riise³, V. Sigurdardottir³, S. Mortensen⁴, L. Mared⁵, B. Ekmehag⁵, S. Simonsen⁶, . Bjørtuft⁶, B. Rundqvist³, K. Jansson⁷, E. Gude⁶, D. Solbu⁸, M. Iversen^4
1Cardiology, Oslo University Hospital Rikshospitalet, 0027/NORWAY, ², Arhus University Hospital, Aarhus/DENMARK, ³, Sahlgrenska University Hospital, Gothenburg/SWEDEN, ⁴, Copenhagen University Hospital Rigshospitalet, Copenhagen/DENMARK, ⁵, Lund University Hospital, Lund/SWEDEN, ⁶, Oslo University Hospital Rikshospitalet, Oslo/NORWAY, ⁷, Linköping University Hospital, Linköping/SWEDEN, ⁸, Novartis Norge AS Pharma, Oslo/NORWAY

Body: Introduction: The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. This was confirmed by the 12 months results of this study in heart or lung transplanted (HTx or LTx) patients which demonstrated a mean difference in measured GFR between the control (CNI) and everolimus (with reduced CNI) groups of 5.1 mL/min/1.73m2, p<0.0001 (in press (Transplantation)) Methods: Patients who completed the main 12 months study were invited to be included in an extension study of 12 months continuing in the same treatment groups. The main study was a 12-month, open-labeled, multicenter study, in which maintenance thoracic transplant patients (GFR 20-90 mL/min/1.73m2) > 1 year post transplant who were randomized to continue standard CNI-based immunosuppression or to start everolimus with predefined CNI exposure minimization. All patients were receiving steroids and mycophenolate or azathioprine. Results: 292 patients were randomized (140 everolimus, 142 controls; 190 HTx, 92 LTx) in the main 12 months study. 236 patients (109 everolimus, 127 controls; 155 HTx, 81 LTx) were included in the extension study. These results are based on the 24 months follow-up of this extension study population. CNI reduction (cyclosporine or tacrolimus) was about 60% in the everolimus cohort at 12 and 24 months compared to baseline. The primary endpoint, mean difference in mGFR was 6.0 and 6.2 mL/min/1.73m2 at month 12 and 24 (p<0.0001). For the HTx and LTx subgroups the mean difference after 24 months were 6.1 (p=0.006) and 7.1 (p=0.012) respectively. There was an interaction with time, with a greater increase in GFR among everolimus treated patients with a shorter time post-transplant. Everolimus-treated HTx and LTx patients in the lowest tertile for time post-transplant (12-36 months) exhibited mean increases of 8.5 mL/min/1.73m2 compared with 6.9 and 2.2 mL/min/1.73m2 for those in the two upper tertiles (36-72 months and above 72 months). The incidence of biopsy proven acute rejections (BPAR) was low and comparable between the groups (For HTx 2 BPAR in each group, for LTx 0 and 3 BPARs in the control vs everolimus group). In the main 12 months study we observed a higher incidence of serious adverse events (SAE) and a higher number of treatment withdrawals caused by side effects in the everolimus cohort. However, in this extension study, no differences between the groups were seen with regard to incidence or type of serious adverse events (Incidence of SAE 42.5% vs 41.3% in control vs everlimus group). Conclusion: Initiation of everolimus with CNI minimization offers a significant improvement in renal function in maintenance HTx and LTx patients without a negative impact on efficacy or safety. The initial benefit in renal functions seen after 12 months is sustained after 24 months. The greatest benefit was observed in patients with a shorter time since transplantation.

Disclosure: All authors have declared no conflicts of interest.