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Vascular Access Thrombosis Events in Patients With Dialysis-Dependent CKD Treated With Vadadustat or Darbepoetin
Wolfgang C Winkelmayer1, Steven K Burke2, Glenn M Chertow3
1Section of Nephrology, Baylor College of Medicine, Houston, TX.
Insights
Vadadustat showed similar rates of vascular access thrombosis (VAT) events compared to darbepoetin alfa in patients with dialysis-dependent chronic kidney disease (DD-CKD). This secondary analysis found no significant difference in first or recurrent VAT events between the two treatments.
Area of Science:
- Nephrology
- Cardiovascular Medicine
- Clinical Trials
Background:
- The INNO2VATE program evaluated vadadustat versus darbepoetin alfa in dialysis-dependent chronic kidney disease (DD-CKD) patients with anemia.
- Previous findings demonstrated noninferiority for cardiovascular safety and hemoglobin efficacy of vadadustat.
- Vascular access thrombosis (VAT) is a critical complication in hemodialysis patients.
Purpose of the Study:
- To investigate between-group differences in positively adjudicated vascular access thrombosis (VAT) events.
- To analyze VAT rates as a secondary outcome in the INNO2VATE phase 3 trials.
Main Methods:
- Phase 3, global, open-label, randomized, active-controlled clinical trials involving 3,902 patients with DD-CKD.
- Patients were randomized 1:1 to receive either vadadustat or darbepoetin alfa.
- Vascular access thrombosis (VAT) events were positively adjudicated throughout the study follow-up.
Main Results:
- A total of 426 positively adjudicated VAT events were recorded across 6,468 patient-years.
- First VAT event rates were numerically higher with vadadustat (4.79 per 100 PY) versus darbepoetin alfa (3.86 per 100 PY), but not statistically significant (HR, 1.27; 95% CI, 0.99-1.62).
- Rates of first and recurrent VAT events were similar between the vadadustat and darbepoetin alfa groups (6.58 vs. 6.59 per 100 PY; HR, 1.00; 95% CI, 0.83-1.21).
Conclusions:
- In this secondary analysis, vadadustat treatment was associated with statistically similar rates of first and recurrent VAT events compared to darbepoetin alfa in DD-CKD patients.
- While first VAT events were numerically higher with vadadustat, the difference was not statistically significant.
- The findings suggest comparable safety regarding VAT events between vadadustat and darbepoetin alfa in this population, though trials were not powered for VAT assessment.
Rationale & Objective:
In the global phase 3 INNO2VATE program of patients with dialysis-dependent chronic kidney disease (DD-CKD) and CKD-related anemia (2 trials: patients new to [NCT02865850] and established on maintenance dialysis [NCT02892149]), vadadustat was noninferior to the erythropoiesis-stimulating agent darbepoetin alfa for cardiovascular safety and hemoglobin efficacy. Here, we investigated between-group differences in positively adjudicated vascular access thrombosis (VAT) events.
Study Design:
Phase 3, global, open-label, randomized, active-controlled clinical trials.
Setting & Participants:
A total of 3,902 patients who initiated dialysis within the past 16 weeks (incident DD-CKD trial; N = 365) or who had been treated with dialysis for >12 weeks (prevalent DD-CKD trial; N = 3,537).
Intervention:
Eligible patients randomized 1:1 to vadadustat or darbepoetin alfa.
Outcomes:
Positively adjudicated VAT events.
Results:
In the INNO2VATE program, at baseline, 3,590 (92.0%) randomized patients were receiving hemodialysis: 2,709 (69.4%) via an arteriovenous fistula and 340 (8.7%) via an arteriovenous graft. During 6,468 patient-years (PY) of follow-up, there were 426 positively adjudicated VAT events in 266 individual patients, with 146 randomized to vadadustat and 120 randomized to darbepoetin alfa. Corresponding first VAT rates were 4.79 and 3.86 per 100 PY, respectively (rate difference, 0.94; 95% CI, -0.10 to 1.97; hazard ratio [HR], 1.27; 95% CI, 0.99-1.62). When considering first and recurrent events, VAT rates were 6.58 and 6.59 per 100 PY for the vadadustat and darbepoetin alfa groups, respectively (rate difference, -0.01; 95% CI, -1.26 to 1.24; HR, 1.00; 95% CI, 0.83-1.21).
Limitations:
Trials were not specifically designed to assess VAT rates; uncertain generalizability to nontrial populations.
Conclusions:
In this secondary analysis of the INNO2VATE program in patients with DD-CKD and CKD-related anemia receiving hemodialysis, first VAT rates were numerically higher among patients treated with vadadustat versus darbepoetin alfa but statistically not different. The rates of first and recurrent VAT events were similar between treatment groups.
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