Study will be published in June 30 New England Journal of Medicine.
A new study shows that a drug, called daclizumab, is effective at reducing organ rejection and risk of infection in heart transplant patients. The multi-center study by cardiologists from the United States, Sweden, Germany and Canada will be published in the June 30 issue of The New England Journal of Medicine.
Oregon Health & Science University cardiologist Ray Hershberger, M.D., was the lead author of the study.
"This is a key study that helps us understand one additional immunosuppressive strategy that can be used. Every patient has different reactions when they receive a new heart, so it's valuable to have several options that allow us to tailor our treatment to their needs," said Hershberger, director of the OHSU Heart Failure and Cardiac Transplantation Program and professor of medicine (cardiology) at the OHSU School of Medicine. His team enrolled more than 30 patients in the study, the largest number from one medical center.
About 2,100 heart transplants are performed every year in the United States, according to the United Network for Organ Sharing.
The first year following a heart transplant is the most dangerous period for patients because the drug therapy they need to prevent their body from rejecting the new organ can increase their risk for life-threatening infections. The challenge has been to find a drug that can prevent rejection, but not increase the risk for infection.
The study focused on whether daclizumab could prevent organ rejection. It compared 434 patients who had received their first heart transplant and were randomly assigned in a double-blind manner to receive five doses of daclizumab or a placebo during a seven-week period. Thirty-one transplantation centers around the world enrolled patients in the study between Aug. 28, 1999, and April 29, 2001.
Following transplantation, all patients in the study received the standard anti-rejection therapy, a combination of cyclosporine, mycophenolate mofetil and corticosteroids, in addition to daclizumab or the placebo.
The study found that the rate of rejection was 25 percent lower in the daclizumab group of patients than in the placebo group. Within six months of their heart transplants, 77 of the 216 patients in the daclizumab group reached the primary end point (rejection, heart dysfunction, death or loss to follow up), compared with 104 of the 218 patients in the placebo group (36 percent versus 48 percent). There was no survival difference between patients who received placebo and daclizumab.
In addition, researchers noted that it took three times longer for the patients in the daclizumab group to reach the primary end point than it did for those in the placebo group (61 versus 21 days). The one-year follow-up indicated the same advantage.
These results confirmed what scientists discovered in an earlier study conducted on only 55 heart transplant patients at one medical center and another study of organ rejection in kidney transplant patients.
"We're always trying to improve transplantation results. Prior to the approval of cyclosporine in 1983, the death rate in the first year after transplant was 70 percent to 80 percent. With cyclosporine it fell to 20 percent to 30 percent. Today, a good heart transplant program should have no more than a 15 percent death rate. But this number is still too high," said Hershberger. "The results of this study are an incremental step in a long road to improving outcomes for heart transplant patients."
Patients in both study groups had infections that commonly occur in transplant patients when anti-rejection medication weakens their immune systems. These opportunistic infections are caused by viruses or fungus that live in the body and take advantage of weakened immune systems following transplantation.
However, six patients in the daclizumab group versus none in the placebo group died during the first year after transplantation from bacterial rather than opportunistic infections. A careful review found that the patients who received daclizumab also received an additional immunosuppressive drug called cytolytic therapy to treat complications soon after surgery.
Because the study was double-blinded, clinical investigators didn't know which patients were receiving daclizumab and which were not. Patients who received cytolytic therapy continued to receive five doses of daclizumab during a seven-week period. As a result, some patients were treated with up to five different drugs - standard triple-drug therapy, daclizumab and cytolytic drug therapy - that may have predisposed them to bacterial infection.
"The investigators thought that this was a concerning and clinically relevant signal that the prolonged use of daclizumab following cytolytic therapy, can cause increased bacterial infection," said Hershberger. "In real practice, after cytolytic therapy becomes a necessary treatment in the first few days post-transplant, physicians would not continue giving additional doses of daclizumab and I think it's unlikely that we'd see this level of infection in those cases. The study results indicate that daclizumab should not be used following cytolytic therapy."
The study was sponsored by the maker of daclizumab, Roche Laboratories.
"Most heart transplant physicians use what they know works. Even though I'm the first author, analyzed the data and wrote the paper, I have been waiting for this study to be published and to receive critical review by the transplant community before recommending we adopt it in our program, said Hershberger.
Since it started in 1985, OHSU's Heart Transplant Program has transplanted more than 460 hearts.