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Establishing tacrolimus as the first choice calcineurin inhibitor for liver transplant recipients
12 December 2014
UCL research has established tacrolimus as the first choice calcineurin inhibitor for use in immunosuppressive regimens following liver transplantation, some 550 of which are carried out in the UK alone each year. Compared to the alternative drug, ciclosporin, tacrolimus significantly improves graft survival and reduces patient mortality.
Each year, some 550 people in the UK undergo liver transplants. The vast majority of them must then follow a long-term immunosuppression regimen incorporating the use of a calcineurin inhibitor - a drug that helps prevent organ rejection by ensuring that the immune system does not send T-cells to attack the new liver. The use of calcineurin inhibitors is usually combined with steroid treatment to maximise patients' long-term chances of success.
The two most commonly used calcineurin inhibitors are ciclosporin and a newer drug called tacrolimus. Until relatively recently, though, it was not clear which regimen produced better survival rates. The results of early studies in the US and Europe seemed to suggest that tacrolimus was better, but these findings were not sufficiently robust to provide unambiguous recommendations for clinical practice. However, research conducted by UCL's Professor Andy Burroughs provided much more robust evidence of the advantages that tacrolimus offers over ciclosporin.
A trial conducted in collaboration with colleagues at King's College London showed that the clinical outcome at one year was better with tacrolimus-based immunosuppression than it was with ciclosporin. On the basis of this result, the research team recommended that tacrolimus should be the first choice of calcineurin inhibitor for patients receiving their first liver graft. A subsequent analysis of three-year follow-up data from the same study confirmed the continued advantage of tacrolimus: 62.1% of the patients who had been given tacrolimus were still alive three years after their original liver graft, compared with only 41.6% of those receiving ciclosporin.
Subsequent work by Professor Burroughs and colleagues further revealed that tacrolimus alone provided adequate immunosuppression in 87% of patients, removing the requirement to combine its use with routine or maintenance steroid treatment. Only 64% of ciclosporin patients could be successfully treated in this way. The researchers subsequently showed that lower doses of tacrolimus were equally effective in preventing acute rejection and renal impairment, something of great significance to patients since treatment at lower doses produces fewer side effects than does treatment at standard doses. The results of the trial were later confirmed in a 2006 Cochrane meta-analysis of 16 trials, which showed that treating liver recipients with tacrolimus instead of ciclosporin would avoid acute rejection in 9% of patients, steroid-resistant rejection in 7%, graft loss in 5% and death in 2% of patients.
By demonstrating unambiguously that tacrolimus is superior to ciclosporin, Professor Burroughs' research has changed standard clinical practice in the UK and worldwide, with tacrolimus-based immunosuppression becoming the global 'gold-standard'. Around 90% of the 550 or so patients receiving a liver transplant in the UK each year are now treated with tacrolimus rather than ciclosporin. On the basis of these numbers, tacrolimus-based immunosuppression saved an estimated 165 grafts and 192 lives during the period 2008-2013 alone.