Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Four Global Roxadustat Phase3 Trials.

Abstract

Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population. Thromboembolic events with onset before and after week12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset. Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98-4.46) showed a trend towards increased risk of thromboembolic events before week12, and high rate of hemoglobin decline was associated with events after week12 (< - 0.5g/dL/week; OR 3.73; 95%CI 1.68-8.27) as compared to stable hemoglobin levels (≥- 0.1 to < 0.1g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10g/dL: adjusted OR 1.91; 95%CI 1.04-3.50; vs ≥ 12g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95%CI 1.71-8.39; vs ≥ 30%) before event onset were associated with events after week12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%. Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article. NCT02278341, NCT02273726, NCT02052310, NCT02174731.