Monotherapy and a shorter duration of steroid use is an effective immunosuppressant compared with traditional combination therapy for heart transplant patients, according to the results of the TICTAC trial published online Jan. 7 in Circulation: Heart Failure.
Cardiac transplantation has become the standard of care for certain patients with end-stage heart failure, and this success may partly be due to the introduction of cyclosporine A, which resulted in one-year graft and patient survival of over 80 percent.
However, “there has been little effort over the past 25 years to modify the standard triple-drug immunosuppression regimen," researchers wrote.
“People have assumed since the late '60s when heart transplant was developed that the three-drug approach was adequate, and that there was never any reason to look at less,” David A. Baran, MD, of the Newark Beth Israel Medical Center in Newark, N.J., told Cardiovascular Business News.
To examine that hypothesis, Baran and his colleagues conducted the prospective, randomized TICTAC (the Tacrolimus In Combination, Tacrolimus Alone Compared) trial, to better assess whether a single-drug immunosuppression with tacrolimus was useful during heart transplantation.
The researchers enrolled 150 heart transplant recipients in the open-label trial that compared tacrolimus monotherapy with tacrolimus and mycophenolate mofetil therapy (combo) from April 2004 to September 2008.
The researchers used a composite biopsy score at six months after transplant as the study’s primary endpoint and patients were followed up for one to five years. During the study, corticosteroids were used only during the postoperative period and stopped in all patients after eight to nine weeks.
The researchers randomized 79 patients to the mono group and 71 to the combo group.
They found that six and 12-month composite biopsy scores were similar for groups: 0.70 for mono therapy and 0.65 for combo therapy at six months and 0.67 and 0.62, respectively, at 12 months. Additionally, there were no reported significant differences in allograft vasculopathy when assessed by either angiography or intravascular ultrasound.
The 12-month freedom from allograft rejection was 85.9 percent and 93.1 percent in the mono and combo groups, respectively.
“No rejection occurred in the mono group after 120 days, and a single combo patient had rejection between 180 and 210 days,” the authors wrote.
Similarly, freedom from any treated rejection (use of oral or intravenous steroids) at six months was 74.4 percent and 81.9 percent, respectively, for the mono versus the combo groups, and the rates at 12 months were 70.5 percent and 80.6 percent, respectively.
Nine of the 79 patients in the mono group switched to a combo treatment strategy because of a rejection occurrence.
The rate of three-year survival was 92.4 percent for mono therapy and 97 percent for combo therapy.
“For nearly 30 years, heart transplant patients have been treated with triple therapy consisting of a calcineurin antagonist, a cell-cycle–modulating drug, and corticosteroids,” the authors wrote. The current study outlines that use of mono therapy has similar rates of allograft rejection and that the discontinuation of steroids can occur sooner.
“Most centers will keep patients on lifelong steroids, but that can be avoided, which will eliminate side effects like weight gain and bloating," offered Baran. "In addition, the results show that both groups [mono and combo] did equally well, while the risk of artery blockage in the mono group was extremely low and survival extremely good.
“There was no advantage to using the second drug. We found that relying on three drugs was unnecessary and even two drugs was unnecessary, and we were surprised that the mortality was so low,” Baran noted.
At five years, only 10 percent of patients had died, much less than most studies involving heart transplant patients, he said.
As far as how the results will impact clinical practice, Baran said that physicians now have the option to discontinue steroids after a couple months, which will increase a patient's quality of life.
“The landmark finding here is that in all 150 patients, steroids were stopped,” Baran said. “Now there is randomized data that shows that even if you stop steroids after eight weeks, it’s quite safe for the patients."
In a separate study, researchers found that all patient subsets benefited equally, including females and minorities, who