Five-year Outcome of an Early Everolimus-based Quadruple Immunosuppression in Lung Transplant Recipients: Follow-up of the 4EVERLUNG Study
Everolimus-based quadruple low calcineurin inhibitor (CNI) maintenance immunosuppression has been shown to be effective in preserving short-term renal function without compromising efficacy or safety after lung transplantation; however, long-term benefit remains unknown.
METHODS:An investigator-initiated 5-y follow-up analysis of the 4EVERLUNG study (NCT01404325), comparing everolimus-based quadruple low CNI with standard triple regimen, was performed. Patients who remained on the randomized drug regimen until the end of the 5-y observation were analyzed as the per protocol (PP) population. Patients in whom the assigned regimen was switched were analyzed as the intention-to-treat (ITT) population.
RESULTS:In total, 123 patients (95%) from the core study were analyzed. During the observation period in 11 patients (19%) of the standard triple regimen and in 30 patients (46%) of the quadruple low CNI regimen, the assigned immunosuppressive regimen was switched ( P = 0.002). Estimated glomerular filtration rate at 5-y follow-up did not differ between the groups in both the ITT (56 [48-73] versus 58 [48-69] mL/min; P =0.951) and PP (59 [50-73] versus 59 [48-69] mL/min; P = 0.946) populations. Thromboembolic events occurred more frequently in the quadruple low CNI regimen (ITT: 11% versus 24%, P = 0.048; PP: 11% versus 22%, P = 0.162). There was a trend for a higher chronic lung allograft dysfunction-free survival for the quadruple low CNI regimen in the PP population ( P = 0.082). No difference in the graft survival was found.
CONCLUSIONS:Initiation of an early everolimus-based quadruple low CNI regimen may have no long-term benefit on renal function. The immunosuppressive efficacy and safety profile seems comparable with the standard triple regimen.
CET Conclusion
| Reviewer: | Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford |
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| Conclusion: | This paper reports the 5-year follow up of a previously published study in lung transplantation. The first publication showed that the addition of everolimus to standard immune suppression regimen allowed the minimisation of CNI exposure. Despite being underpowered, the original publication of the study demonstrated improved eGFR at 12 months, with no change in rejection rates or infectious complications. Over the total 5-year follow-up a substantial proportion (46%) had to switch away from the everolimus arm. There was a significantly increased risk of thromboembolic events in the everolimus arm of the study (24% versus 11%). At 5 years there was no significant difference in GFR between the 2 study arms (in both intention-to-treat and per protocol analysis). There was also no difference in graft survival. It seems that any short-term benefit in renal function is lost over time, whether switching back off everolimus or not. With such a susbtantial proportion changing immune suppression, crossing over and long term follow up with other potential medication changes, it does become difficult to separate effects. |
Study Details
| Aims: | This study aimed to report the five-year outcomes of the 4EVERLUNG study, which compared everolimus-based quadruple low calcineurin inhibitor (CNI) versus standard triple regimen in lung transplant recipients. |
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| Interventions: | Patients were randomised to receive either the everolimus-based quadruple low CNI regimen or the standard triple regimen. |
| Participants: | Data from 123 out of 130 lung transplant recipients randomised in the 4EVERLUNG study were analysed. |
| Outcomes: | Renal function, biopsy-proven acute cellular rejection, chronic lung allograft dysfunction [CLAD], death and safety endpoints. |
| Follow Up: | 5 years |
Metadata
| Funding: | Industry funding |
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| Publication type: | Randomized Controlled Trial, Randomised Controlled Trial |
| Trial registration: | ClinicalTrials.gov - NCT01404325 |
| Organ: | Lung |
| Language: | English |
| Author email: | nikolaus.kneidinger@med.uni-muenchen.de |
| MeSH terms: | Everolimus; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Transplant Recipients; 0 (Immunosuppressive Agents); 9HW64Q8G6G (Everolimus) |