CHICAGO – Results of the landmark PEXIVAS study – far and away the largest randomized trial ever done in ANCA-associated vasculitis – will likely change treatment in a couple of major ways.
“I think this trial will have an impact on care. Based on these findings, physicians should strongly reconsider the utility of plasma exchange as a treatment for AAV [antineutrophil cytoplasmic antibody–associated vasculitis] patients and should now consider using lower cumulative doses of glucocorticoids for the treatment of severe AAV,” PEXIVAS coprincipal investigator, said at the annual meeting of the American College of Rheumatology.
That’s because the trial demonstrated that plasma exchange neither saved lives nor avoided end-stage renal disease, while utilization of oral glucocorticoids in doses substantially lower than the high-dose current standard significantly reduced the serious infection rate without causing less effective disease control, according to Dr. Merkel, chief of rheumatology and professor of medicine and epidemiology at the University of Pennsylvania in Philadelphia.
comprised 704 patients with severe granulomatosis with polyangiitis or microscopic polyangiitis, making it more than twice as large as any other trial in AAV. This was a multicenter, international, open-label, randomized trial with a 2-by-2 factorial design. To qualify as having severe AAV, participants had to have an estimated glomerular filtration rate below 50 mL/min per 1.73 m2 and/or lung hemorrhage.
“This was in essence two trials embedded within one protocol in the factorial design,” he explained.
The impetus for this major clinical trial was a recognition that mortality due to AAV remains high, especially in the first year, with a clear unmet need for better, less toxic therapies. Indeed, it’s estimated that only 29% of deaths in the first year after diagnosis are due to the vasculitis disease itself, while over 50% of the mortality is caused by infection, much of it collateral damage from immunosuppressive therapies.
Dr. Merkel, who heads the National Institutes of Health–supported, said the time was right for a clinical trial aimed at improving patient management: “Clinical equipoise exists for the efficacy of both plasma exchange and reduced-dose glucocorticoids in ANCA-associated vasculitis.”
The patients underwent induction therapy with cyclophosphamide or rituximab (Rituxan) plus IV methylprednisolone. Then they were randomized to seven plasma exchange sessions in 14 days or no plasma exchange, and further randomized to conventional weight-based, high-dose oral glucocorticoids or a lower-dose regimen. Those on the reduced-dose regimen received 54% of the cumulative amount of glucocorticoids used in the standard-dose group through the first 3 months, and 61% over the course of 6 months. By week 4, those on the reduced-dose regimen were on an average of 25 mg/day, while those on standard therapy were on 50 mg/day. Adherence to assigned study arms exceeded 90%. Patients were followed prospectively for 1-7 years.
The primary endpoint, a composite of all-cause mortality or development of end-stage renal disease, occurred in 28% of patients on plasma exchange and 31% of those who did not undergo plasma exchange, a nonsignificant difference indicative of a lack of benefit for the intervention. No differential effect was seen in prespecified subgroups based on age, creatinine clearance, ANCA type, form of immunosuppression, or presence or absence of lung hemorrhage.
Further, the primary endpoint occurred in 28% of patients on reduced-dose glucocorticoids, compared with 26% on full-dose therapy; again, a nonsignificant difference, meaning lower-dose therapy didn’t result in less effective disease control. But it did result in a significant reduction in the prespecified endpoint of serious infections in the first year: 27% versus 33% with full-dose therapy, representing a 30% relative risk reduction.
Audience members wanted to know if there are any circumstances at all in which Dr. Merkel would now consider resorting to plasma exchange, such as maybe in AAV patients at the most extreme end of the severity spectrum.
“I’m not sure I should be the one dictating that; I think the world needs to see the data,” he replied.
That being said, he added, “I think these data are incredibly helpful to physicians and patients as they face this decision. I think plasma exchange is an expensive therapy and somewhat invasive. I think our results indicate that the benefit that we may have thought was there is not there.”
The study was sponsored by the National Institutes of Health, the Food and Drug Administration, the U.K. Medical Research Council and the National Institute for Health Research, the Canadian Institutes of Health Research, and the governments of France, Australia, and New Zealand. The presenter reported receiving research funding from the ACR, EULAR, FDA, NIH, Patient-Centered Outcomes Research Institute, and the Vasculitis Foundation. He also receives research funding from and/or serves as a consultant to more than a dozen pharmaceutical companies.