MADRID — Less immunosuppression was better than more for heart transplant patients, according to a report at the annual meeting of the International Society for Heart and Lung Transplantation.
Monotherapy with oral tacrolimus led to significantly better outcomes than did a combination of tacrolimus plus mycophenolate mofetil (MMF) in a randomized, controlled study of 58 heart transplant patients, said Dr. David A. Baran.
“Paradoxically, we showed a significant reduction in the total rejection burden with monotherapy,” said Dr. Baran, research director of the heart failure treatment and heart transplant program at Newark (N.J.) Beth Israel Medical Center. The finding, from the first prospective, controlled trial of tacrolimus monotherapy, “may herald the end of 'one size fits all' immunosuppression.”
Dr. Baran acknowledged that the findings raise a fundamental question: Why should patients have less organ rejection with reduced immunosuppression? The answer is not yet clear, but he speculated that it may be linked to why transplant recipients generally have fewer rejection episodes the further out they progress from surgery. “It's possible that monotherapy allows more rapid 'aging' of the transplant,” he said. The development of clinical tolerance might involve various immune mechanisms, such as clonal deletion or T-suppressor cells.
The study involved patients who received a first-time heart transplant at either Beth Israel or Mount Sinai Medical Center in New York during April 2004 through August 2005. Following surgery, all patients were treated with oral tacrolimus and MMF, along with the steroid therapy that would continue for 2–5 months after surgery. Two weeks after surgery, the patients were randomized to either continue both tacrolimus and MMF or to tacrolimus alone. Drug discontinuation was nonblinded. During the next 6 months, eight of the patients randomized to receive combination therapy had to withdraw from their MMF regimen because of severe intolerance.
The study's primary end point was the average biopsy score at 6 months after transplantation. The average score was 0.60 in the combination-therapy group and 0.44 in the monotherapy group, a statistically significant difference that showed less organ rejection in the monotherapy group.
Follow-up also showed fewer rejection episodes with monotherapy, especially during the first 90 days after surgery. Serum creatinine levels were similar in both groups.
One patient in the monotherapy group developed an asymptomatic episode of significant (class 3A) rejection, and was switched to combination therapy with MMF. Two patients in the combination therapy group also developed class 3A rejection, one of whom had hemodynamic compromise. Two other patients in the combination-treatment group became infected with cytomegalovirus.
The study was partially funded by Astellas Pharma Inc., which markets oral tacrolimus (Prograf). Dr. Baran does not have any financial relationship with Astellas.