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Allograft Vasculopathy With Rituximab After Cardiac Transplantation
Study Questions:
Does the use of rituximab in primary heart transplant recipients without allosensitization attenuate coronary artery vasculopathy (CAV)?
Methods:
The study is a placebo-controlled trial of which 163 adult participants were randomized to either 1000 mg of rituximab (n = 89) or placebo (n = 74) on day 0 and day 12 post-transplant. Eligible patients had to have a <10% panel of reactive antibodies (PRA), and estimated glomerular filtration rate (eGFR) of ≥40 ml/min/1.73 m2. The primary outcome was change in percent atheroma volume (PAV) measured using intravascular ultrasound (IVUS) at 1 year. The sample size required was 300 subjects, but due to conclusion of the study funding period, the enrollment goal could not be achieved.
Results:
Data for the primary outcome were available for 49 (55%) patients in the rituximab arm and 37 (50%) in the placebo arm. Following rituximab treatment, there was effective depletion of circulating CD20+ cells compared to placebo. At 1 year, the mean change in PAV was +6.8% (8.2%) with rituximab versus +1.9 (4.4%) with placebo (p = 0.0019). While there were between-group differences in clinical characteristics and secondary outcomes, they were not statistically significant. For example, there were 6.8% deaths in the placebo arm and 3.4% in the rituximab arm (p = 0.28), acute graft rejection in 24.7% in the rituximab group, and 32.4% in the placebo group (p = 0.35).
Conclusions:
Rituximab administration at the time of transplant was associated with an increase in CAV, as measured by PAV at 1 year after transplant in patients with PRA <10% pretransplant.
Perspective:
The findings are alarming, showing unexpectedly that rituximab administration led to accelerated CAV; counter to results in experiments in nonhuman primates. The study was severely hampered by low enrollment and inadequate imaging data, with only 86 out of a goal of 300 patients having analyzable data points. Whether the study limitations confound the main findings cannot be ascertained, but the differences in atheroma volume between the rituximab and placebo group are staggering enough that they cannot be ignored. The implications go beyond cardiac transplant; as anti-inflammatory therapies are being considered for treatment of atherosclerotic diseases. Inflammation is a small word referring to an extremely complex process that straddles healing and injury, and further study is needed to better understand how best to target that process we know is intimately involved in driving atherosclerosis.
Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Cardiac Surgery and Heart Failure, Acute Heart Failure, Heart Transplant, Interventions and Imaging, Echocardiography/Ultrasound
Keywords: Allografts, Atherosclerosis, Composite Tissue Allografts, Glomerular Filtration Rate, Graft Rejection, Heart Failure, Heart Transplantation, Immunosuppression, Inflammation, Plaque, Atherosclerotic, Transplantation, Homologous, Ultrasonography
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