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In survival data analysis, a competing risk is an event whose occurrence precludes or alters the chance of the occurrence of the primary event of interest. In large cohort studies with long-term follow-up, there are often competing risks. Further, if the event of interest is rare in such large studies, the case-cohort study design is widely used to reduce the cost and achieve the same efficiency as a cohort study. The conventional additive hazards modeling for competing risks data in case-cohort studies involves the cause-specific hazard function, under which direct assessment of covariate effects on the cumulative incidence function, or the subdistribution, is not possible. In this paper, we consider an additive hazard model for the subdistribution of a competing risk in case-cohort studies. We propose estimating equations based on inverse probability weighting methods for the estimation of the model parameters. Consistency and asymptotic normality of the proposed estimators are established. The performance of the proposed methods in finite samples is examined through simulation studies and the proposed approach is applied to a case-cohort dataset from the Sister Study. This article is protected by copyright. All rights reserved.

INTRODUCTION The contribution of coagulation activation to the pathogenesis of sickle cell disease (SCD) remains incompletely defined. We evaluated the efficacy and safety of rivaroxaban, an oral direct factor Xa inhibitor, in subjects with sickle cell anemia. MATERIALS AND METHODS In this pilot, single-center, randomized, double-blind, placebo-controlled, crossover study, eligible subjects with sickle cell anemia received rivaroxaban or placebo. The effect of rivaroxaban on coagulation activation, endothelial activation, inflammation, and microvascular blood flow was evaluated. RESULTS Fourteen patients (HbSS - 14; females - 9) with mean age of 38 ± 10.6 years were randomized to receive rivaroxaban 20 mg daily or placebo for 4 weeks and, following a 2-week washout phase, were "crossed-over" to the treatment arm opposite to which they were initially assigned. Mean adherence to treatment with rivaroxaban, assessed by pill counts, was 85.6% in the first treatment period and 93.6% in the second period. Treatment with rivaroxaban resulted in a decrease from baseline of thrombin-antithrombin complex versus placebo (-34.4 ug/L [95% CI: -69.4, 0.53] vs. 0.35 ug/L [95% CI: -3.8, 4.5], p = .08), but the difference was not statistically significant. No significant differences were observed in changes from baseline of D-dimer, inflammatory, and endothelial activation markers or measures of microvascular blood flow. Rivaroxaban was well tolerated. CONCLUSIONS Rivaroxaban was safe but did not significantly decrease coagulation activation, endothelial activation, or inflammation. Rivaroxaban did not improve microvascular blood flow. Adequately powered studies are required to further evaluate the efficacy of rivaroxaban in SCD. Clinicaltrials.gov Identifier: NCT02072668.