A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus.

BACKGROUND: Cytomegalovirus (CMV) infection in recipients of cardiac transplants is associated with higher rates of morbidity. A recent phase III trial showed highly significantly (P<0.001) lower CMV rates with the proliferation signal inhibitor everolimus compared to azathioprine (AZA). To better define this association, data on CMV risk factors were collected retrospectively and analyzed. METHODS: Data on CMV risk factors from a multicenter phase III trial on de novo heart transplant recipients (n=634) receiving a triple immunosuppressive regimen randomized to everolimus 1.5 mg/day (group 1), everolimus 3 mg/day (group 2), or AZA (group 3) were merged with prospectively collected CMV-related outcome data and analyzed. RESULTS: CMV-positive donors (D+) and CMV-negative recipients (R-) were evenly distributed across groups 1-3 at 36/209 (17.2%), 48/211 (22.7%), and 38/214 (17.8%), respectively. CMV prophylaxis had been given for a mean (SD) of 175 (127.8), 183 (137.1), and 177 (132.9) days, respectively. In the high-risk D+/R- subgroup with prophylaxis, the proportions of patients with CMV infection compared with group 3 (12/29 [41.4%]) were 3/25 (12.0%) in group 1 (P=0.031) and 6/36 (16.7%) in group 2 (P=0.049). In D+/R+ subgroups either with or without prophylaxis, the everolimus groups had less CMV disease (P<0.001). The incidence of CMV syndrome, organ involvement, and laboratory evidence was lower with everolimus use compared to AZA. CONCLUSIONS: Everolimus is associated with lower rates of CMV infection, syndrome, or organ involvement, suggesting an additional advantage from the use of everolimus in cardiac transplant recipients.

Prevention of acute rejection and allograft vasculopathy by everolimus in cardiac transplants recipients: a 24-month analysis.

BACKGROUND: Everolimus is an immunosuppressive agent that reduces cardiac allograft vasculopathy. This report presents the 24-month results of a multicenter trial of everolimus vs azathioprine in heart transplantation. METHODS: A total of 634 patients were randomized to receive 1.5 mg everolimus, 3 mg everolimus or azathioprine, with cyclosporine and steroids. A 12-month, double-blind, double-dummy period was followed by a 12-month open-label period. RESULTS: At 24 months, the percentage of patients reaching the composite efficacy end-points was significantly lower with everolimus (1.5 mg: 45.9%, p = 0.016; 3 mg: 36.0%, p < 0.001) than with azathioprine (57.5%). The change in maximal intimal thickness from baseline to 24 months was significantly smaller with everolimus 1.5 mg (0.07 mm, p = 0.014) and 3 mg (0.06 mm, p = 0.004) compared with azathioprine (0.15 mm). The 24-month incidence of vasculopathy was 33.3% with everolimus 1.5 mg, 45.5% with everolimus 3 mg and 58.3% with azathioprine (p = 0.017 vs everolimus 1.5 mg). Incidence of cytomegalovirus infection was 3-fold lower in patients receiving everolimus compared with azathioprine (7.2% and 7.1% in the 1.5-mg and 3-mg everolimus cohorts, respectively, and 21% in the azathioprine group; p < 0.0001). Median serum creatinine levels at 24 months were higher with everolimus than with azathioprine, but decreased when cyclosporine exposure was reduced (everolimus 1.5 mg: baseline 167 micromol, after 6 months 157.5 micromol; everolimus 3 mg: baseline 185.6 micromol, after 6 months 160 micromol; azathioprine: baseline 123.3 micromol, after 6 months 127 micromol). CONCLUSIONS: Everolimus significantly reduced acute rejection and limited the progression of allograft vasculopathy at 24 months compared with azathioprine. Although graft and patient survival was comparable at 24 months, everolimus therapy may improve longer-term outcomes after heart transplantation.

Multicenter intravascular ultrasound validation study among heart transplant recipients: outcomes after five years.

OBJECTIVES: We sought to assess the validity of first-year intravascular ultrasound (IVUS) data as a surrogate marker for long-term outcome after heart transplantation. BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival. Intravascular ultrasound is more sensitive than coronary angiography and detects intimal thickening (early CAV) in the coronary arteries of the donor heart. Single-center studies have suggested first-year IVUS results might be a surrogate marker for long-term outcome. METHODS: First-year IVUS results and subsequent five-year clinical follow-up data were reviewed in 125 heart transplant recipients from five institutions. The IVUS tapes (at baseline and one year) were re-analyzed at a core IVUS laboratory. The change in maximal intimal thickness (MIT) from baseline to one year was recorded for several matched sites in the same coronary artery. Patients were classified into two groups: those with >/=0.5 mm in the MIT in any matched site (group 1) and those with MIT <0.5 mm (group 2). RESULTS: Group 1 patients compared with group 2 patients had a higher incidence of death or graft loss (D/GL, 20.8% vs. 5.9%; p = 0.007), had more nonfatal major adverse cardiac events and/or D/GL (45.8% vs. 16.8%; p = 0.003), and had more findings of newly occurring angiographic luminal irregularities (65.2% vs. 32.6%, p = 0.004). CONCLUSIONS: This multicenter study suggests that progression of intimal thickening >/=0.5 mm in the first year after transplantation appears to be a reliable surrogate marker for subsequent mortality, nonfatal major adverse cardiac events, and development of angiographic CAV through five years after heart transplantation.

Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients.

BACKGROUND: Everolimus, a novel proliferation inhibitor and immunosuppressive agent, may suppress cardiac-allograft vasculopathy. We conducted a randomized, double-blind, clinical trial comparing everolimus with azathioprine in recipients of a first heart transplant. METHODS: A total of 634 patients were randomly assigned to receive 1.5 mg of everolimus per day (209 patients), 3.0 mg of everolimus per day (211 patients), or 1.0 to 3.0 mg of azathioprine per kilogram of body weight per day (214 patients), in combination with cyclosporine, corticosteroids, and statins. The primary efficacy end point was a composite of death, graft loss or retransplantation, loss to follow-up, biopsy-proved acute rejection of grade 3A, or rejection with hemodynamic compromise. RESULTS: At six months, the percentage of patients who had reached the primary efficacy end point was significantly smaller in the group given 3.0 mg of everolimus (27.0 percent, P<0.001) and the group given 1.5 mg of everolimus (36.4 percent, P=0.03) than in the azathioprine group (46.7 percent). Intravascular ultrasonography showed that the average increase in maximal intimal thickness 12 months after transplantation was significantly smaller in the two everolimus groups than in the azathioprine group. The incidence of vasculopathy was also significantly lower in the 1.5-mg group (35.7 percent, P=0.045) and the 3.0-mg group (30.4 percent, P=0.01) than in the azathioprine group (52.8 percent). The rates of cytomegalovirus infection were significantly lower in the 1.5-mg group (7.7 percent, P<0.001) and the 3.0-mg group (7.6 percent, P<0.001) than in the azathioprine group (21.5 percent). Rates of bacterial infection were significantly higher in the 3.0-mg group than in the azathioprine group. Serum creatinine levels were also significantly higher in the two everolimus groups than in the azathioprine group. CONCLUSIONS: Everolimus was more efficacious than azathioprine in reducing the severity and incidence of cardiac-allograft vasculopathy, suggesting that everolimus therapy may alleviate this serious problem.

Improved treatment response with basiliximab immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-controlled trial.

Basiliximab, a high-affinity chimeric monoclonal antibody, is effective in reducing acute rejection episodes in renal allograft recipients. We assessed the ability of this antibody to similarly improve the outcome in liver transplant recipients. Adult recipients of a primary cadaveric liver transplant were randomized to treatment, stratified by hepatitis C virus (HCV) seropositivity. Patients were administered 40 mg of basiliximab (n = 188) or placebo (n = 193) as two 20-mg bolus injections days 0 and 4, plus cyclosporine and steroids. Primary efficacy variables were biopsy-confirmed acute rejection and its composite end point, including death or graft loss, and were assessed at 6 and 12 months and by HCV cohort. Because of differential efficacy responses between HCV-positive and HCV-negative cohorts, an additional analysis incorporating HCV recurrence as a component of treatment failure, termed problem-free transplant, was introduced. Safety and tolerability were monitored over the 12 months of the study. All 381 patients were assessable, and no meaningful differences in background characteristics were apparent between treatment groups. Biopsy-confirmed acute rejection rates 6 months after transplantation were 35.1% in the basiliximab group versus 43.5% in the placebo group. For death, graft loss, or first biopsy-confirmed acute rejection, rates were 44.1% versus 52.8%, respectively. The reduction in rejection episodes was concentrated in the HCV-negative cohort (14.5% relative to placebo; P =.034), with a much smaller difference (2.9%) in the HCV-positive cohort. For HCV-positive patients, problem-free transplant was shown at 12 months in 26.6% of the basiliximab group versus 11.6% in the placebo group (P =.020) and for all patients at 12 months in 39.7% of the basiliximab group versus 30.1% in the placebo group (P =.035). The incidence of infection and other adverse events was similar across the two treatment groups. There were 56 deaths (25 deaths, basiliximab group; 31 deaths, placebo group) over the 12-month study. The intravenous bolus injection was well tolerated. Immunoprophylaxis with 40 mg of basiliximab, in combination with cyclosporine and steroids, reduces the incidence of acute rejection episodes with no clinically relevant safety or tolerability concerns. The influence of HCV recurrence on efficacy results can be accounted for in future trials by using the concept of problem-free transplant, incorporating recurrence as a component of treatment failure.