Management of Vasculitis-associated Alveolar Hemorrhage: A Bayesian Reanalysis of PEXIVAS

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Abstract RATIONALE: Diffuse alveolar hemorrhage (DAH) is a rare and life-threatening manifestation of antineutrophil-cytoplasmic antibody (ANCA)-associated vasculitis (AAV). PEXIVAS was a randomized-controlled trial that showed that plasma exchange (PLEX) did not improve outcomes in patients with AAV, and that a reduced-dose glucocorticoid taper was non-inferior to standard-dose taper. However, a minority of patients in PEXIVAS had DAH, which may limit the generalizability of these findings. We used a Bayesian approach to reanalyze PEXIVAS to evaluate the effect of these interventions on patients with DAH. METHODS: PEXIVAS enrolled adults with granulomatosis and polyangiitis or microscopic polyangiitis with either DAH or reduced kidney function. Individuals were randomized in 2x2 design to PLEX or no PLEX and standard-dose or reduced-dose glucocorticoid taper, the latter of which was designed as a non-inferiority trial. Our primary outcome was the hazard ratio (HR) of overall survival. Published means and standard deviations of HR were used in the Bayesian framework as the likelihood, modelled as a log-normal distribution using a non-informative prior (i.e., implying no prior belief). We obtained the posterior mean HR and 95% credible interval (CrI), as well as the probability that PLEX reduced mortality (HR <1) or that reduced-dose glucocorticoids led to greater mortality (HR >1) by calculating the area under the curve (AUC) of the posterior distribution beyond each threshold. RESULTS: 704 individuals were recruited in PEXIVAS, of which 191 had DAH. Using a non-informative prior, we found that mean HR with PLEX was 0.45 (95% CrI 0.14-1.42) for those with DAH and 0.86 (95% CrI 0.43-1.71) without DAH. By evaluating AUC, we found that PLEX led to a 67% probability of increased survival (HR <1) in those without DAH, but a 93% probability of increased survival in those with DAH. With a reduced-dose glucocorticoid taper, individuals without DAH had a mean HR 0.46 (95% CrI 0.22-0.95), whereas those with DAH had a mean HR 1.33 (95% CrI 0.57-3.11). Reduced-dose glucocorticoid taper corresponded to a 2% probability of increased mortality (HR >1) in individuals without DAH, but a 74% probability of increased mortality in those with DAH. CONCLUSION: Using a Bayesian approach, we show that individuals with AAV with DAH may benefit from PLEX, although appear to derive greater harm from a reduced-dose glucocorticoid taper. These results suggest the need for further review of treatment strategies in this subpopulation.

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