medwireNews: ScanCLAD study findings support the use of once-per-day tacrolimus over twice daily ciclosporin for immunosuppression after lung transplantation.
“Our study supports the use of tacrolimus as the first choice of calcineurin inhibitor after lung transplantation,” say the researchers.
The cumulative incidence of chronic lung allograft dysfunction (CLAD) at 3 years following bilateral lung transplantation was significantly lower among 124 patients randomly assigned to receive tacrolimus than 125 assigned to receive ciclosporin treatment, at 13% versus 39%, corresponding to a hazard ratio (HR) in favor of tacrolimus of 0.28, report Göran Dellgren (Sahlgrenska University Hospital, Gothenburg, Sweden) and colleagues in The Lancet Respiratory Medicine.
The findings were based on the current definition of CLAD, say the researchers, which is “an irreversible decrease in FEV1 [forced expiratory volume in 1 second] to less than 80% of baseline FEV1 after lung transplantation, and encompasses the older description [of] bronchiolitis obliterans syndrome (characterised by small airway fibrosis and obstructive lung physiology) as well as restrictive allograft syndrome (characterised by parenchymal or pleural fibrosis and restrictive physiology).”
The trial participants (mean age 55 years; 55% men) were selected from five different centers across Scandinavia between 2016 and 2019.
Patients in the tacrolimus treatment group received a 0.05–0.10 mg/kg dose immediately before transplantation and 0.1–0.2 mg/kg per day after transplantation, while the ciclosporin group received a 2.0–3.0 mg/kg dose before transplantation and a total of 3.0 mg/kg over two doses per day afterwards. Both groups also received mycophenolate mofetil and corticosteroids postoperatively.
Dellgren et al report that in addition to significantly reducing the risk for CLAD, tacrolimus treatment was associated with significantly improved event-free survival – a composite of any treated acute rejection, CLAD, graft loss, or patient death, compared with ciclosporin – which occurred in 29% of patients versus 53% of those treated with ciclosporin.
Overall survival rates were similar between the two groups, at 79% with tacrolimus and 74% with ciclosporin. And among patients who had results available for at least one lung function test post-transplantation, the chances of allograft survival were significantly better with tacrolimus than ciclosporin, at an HR of 0.49.
With regard to safety, there was a significantly lower rate of acute reactions requiring treatment in the tacrolimus than the ciclosporin group, at 40% versus 57%. All of the patients had at least one adverse event, and the serious adverse event rates were 87% and 90%, respectively, but the number of events did not differ significantly between the two groups in either case. The most frequent adverse events were infection, acute reaction, and anemia.
“On the basis of these results, tacrolimus should be used as the standard comparison in future studies of new immunosuppressive drugs after lung transplantation,” the investigators conclude.
In a comment accompanying the study, Michael Combs, from the University of Michigan in Ann Arbor, USA, notes that previous research has shown improved medication adherence when tacrolimus is taken once a day rather than twice, and suggest that this level of dosing may result in “more efficacious immunosuppression and, thus, lower rates of CLAD and rejection.”
Combs also points out that the 13% CLAD rate with tacrolimus in the current study is “considerably lower” than the approximate 33% rate in the International Society for Heart and Lung Transplantation registry, despite tacrolimus being the most commonly used calcineurin inhibitor.
He therefore observes that “the decreased incidence of CLAD in the ScanCLAD study might not be attributable to tacrolimus alone,” and says it remains to be seen “why CLAD incidence has not meaningfully declined over time despite the increasingly widespread use of tacrolimus.”
These findings were simultaneously presented at the ERS International Congress 2023, held in Milan, Italy.
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Lancet Respir Med 2023; doi:10.1016/S2213-2600(23)00293-X
Lancet Respir Med 2023; doi:10.1016/S2213-2600(23)00307-7
Dellgren G, Kromann Lund T, Raivio P, et al. ScanCLAD: a Scandinavian multicenter randomized study evaluating if once-daily tacrolimus versus twice-daily cyclosporine reduces the 3-year incidence of chronic lung allograft dysfunction after lung transplantation. ERS 2023. Clinical trials session, abstract RCT802.