Early withdrawal of corticosteroids after kidney transplantation was associated with a lower rate of cardiovascular (CV) events compared with long-term corticosteroid administration, according to a study presented at the American Transplant Congress, held in Philadelphia from April 30 to May 4. Lead author Nicole Schmidt, PharmD, of the University of Cincinnati in Ohio, said that the decrease in CV events became apparent 3–4 years after transplant in the group of patients with early withdrawal, even though these patients had more coronary artery disease before transplant. There were no differences in overall patient survival or in CV-related deaths between the early corticosteroid withdrawal group and the long-term corticosteroid immunosuppression maintenance group, Schmidt said.
In general, CV disease accounts for about 30 percent of deaths among kidney transplant recipients. Schmidt said that clinical trials and a recent meta-analysis showed that corticosteroid avoidance or withdrawal has been associated with a decrease in CV risk factors, including new-onset diabetes, hypertension, hyperlipidemia, and weight gain. But, she said, “We still have limited long-term studies that have actually translated this cardiovascular risk reduction into actual [reduction in] cardiovascular events and ultimately, patient survival.”
The investigators therefore evaluated 1004 patients who received renal transplants between 1998 and 2010, 714 of whom underwent early withdrawal and 290 of whom were receiving long-term corticosteroid maintenance. Early withdrawal was defined as steroid withdrawal within 7 days after transplantation. This group tended to be older, had more men, had fewer African Americans, and had more coronary artery disease before transplant.
The early withdrawal group had fewer repeat transplants (9.5 percent) than did the long-term steroid group (14.5 percent), less delayed graft function (7.7 percent versus 15.2 percent, respectively), more HLA mismatches (mean 3.3 versus 2.1), but lower mean class II peak and current cytotoxic panel reactive antibodies.
In terms of immunosuppressive therapy, more of the early withdrawal patients were given tacrolimus (89.9 percent versus 51.7 percent) and sirolimus (22.1 percent versus 0.3 percent) and had less use of cyclosporin (9.1 percent versus 48.3 percent). More than 97 percent of each group was receiving mycophenolate mofetil. The long-term steroid maintenance group received mean steroid doses of 8.6 mg/day at 6 months and was still receiving a mean of 5.3 mg/day at 7 years.
The mean pre- and posttransplant total cholesterol was lower in the early withdrawal group compared with the long-term steroid group (168.6 versus 178.2 mg/dL and 172.9 versus 189.1 mg/dL, respectively. All other pre- and posttransplant cholesterol values, including LDL cholesterol, did not differ significantly between the groups. Other CV risk factors were largely the same except that after transplant, patients in the long-term steroid group had a mean diastolic blood pressure that was 1.9 mm Hg higher, and they were taking more antihypertensive medications. The median follow-up times were 4.2 years for the early withdrawal group and 5.9 years for the patients receiving long-term steroid administration.
“Patients that received chronic steroid regimens experienced definitely more cardiovascular events than those that were withdrawn from steroids within 7 days after transplantation,” Schmidt reported. CV events occurred in 14 percent of the early withdrawal group and in 24.5 percent of the long-term steroid administration group. Kaplan-Meier analysis predicted 10-year CV event rates of 24 percent and 35 percent, respectively. The most common CV event experienced in both groups was angina.
The two groups did not show any significant difference in terms of patient survival. “When we looked at just the … cardiovascular-related deaths, we found, again, that there was no significant difference between the two groups,” Schmidt said.
Session co-chair Ram Peddi, MD, a transplant nephrologist at California Pacific Medical Center in San Francisco, raised the question whether longer follow-up might change the outcomes. Because there were some differences in demographic characteristics between the two groups at baseline, he suggested that a multivariate analysis should be performed to adjust for the differences.
In fact, Schmidt did present such an analysis in a later session during the conference. It showed that early steroid withdrawal was associated with a reduction of 54 percent in the risk of CV events (odds ratio [OR] = 0.459). Risk factors for the development of CV events were pretransplant diabetes mellitus (OR = 2.69) and smoking (OR = 1.88). The investigators concluded that when adjustment was made for multiple risk factors, their 12-year experience provides strong evidence for a protective effect of early corticosteroid withdrawal on CV events.
A third analysis from the same group of investigators showed that at 10 years, patient survival was 76 percent in both groups, and CV-related events accounted for 15 percent of the deaths for both.
Peddi said that it has long been known that patients can benefit in terms of CV disease if corticosteroids are withdrawn early. “I think we all are aware of the cardiovascular risks associated with corticosteroids, but [early withdrawal] is now possible with the newer immunosuppressive drugs that are available because especially the tacrolimus and mycophenolate and also the induction therapy offer better immunosuppression that is enabling us to take the patients off steroids,” he said.