Daprodustat Should Be Avoided in CKD Patients Not on Dialysis Due to Lack of FDA Approval and Increased Heart Failure Risk
Daprodustat is FDA-approved only for patients already receiving dialysis for at least 4 months and is specifically NOT approved for non-dialysis CKD patients. 1 This regulatory restriction reflects significant safety concerns that emerged during clinical trials.
Key Safety Concerns in Non-Dialysis Patients
Cardiovascular Risk Signal
The ASCEND-ND trial demonstrated a concerning trend toward increased heart failure hospitalizations in non-dialysis patients treated with daprodustat compared to conventional ESAs:
- First heart failure hospitalization: HR 1.22 (95% CI 0.95-1.56), though not statistically significant 2
- Total (first and recurrent) heart failure hospitalizations: Rate ratio 1.46 (95% CI 1.11-1.92, p=0.007) - this WAS statistically significant 2
- The risk was particularly elevated in patients with pre-existing heart failure history: HR 1.37 (95% CI 0.89-2.11) 2
In contrast, dialysis patients showed no such increase (rate ratio 1.01,95% CI 0.74-1.39) 2, which likely contributed to the FDA's decision to approve daprodustat only for dialysis patients.
Regulatory Decision
The FDA specifically excluded non-dialysis patients from approval despite daprodustat demonstrating non-inferiority to ESAs for hemoglobin correction 1. This decision was based on the unfavorable risk-benefit profile in this population, particularly the heart failure signal.
Clinical Implications
For non-dialysis CKD patients with anemia, use conventional ESAs or other HIF-PHIs that have demonstrated better safety profiles in this population (such as roxadustat, which has different regulatory status in some jurisdictions).
Additional Safety Considerations for All HIF-PHIs
Even if considering other HIF-PHIs in non-dialysis patients, be aware of class-wide concerns 3:
- Potential tumor growth enhancement
- Worsening retinopathy risk
- Cyst growth in autosomal dominant polycystic kidney disease (absolute contraindication) 3
- Thrombotic events
- Drug-drug interactions with oral medications
When Patients Progress to Dialysis
Once a patient has been on dialysis for at least 4 months, daprodustat becomes an appropriate option, particularly for:
- Patients hyporesponsive to ESAs 4
- Those who prefer oral therapy over injections
- Patients with chronic inflammation (though evidence is limited) 3
The bottom line: Daprodustat lacks regulatory approval and demonstrated increased heart failure hospitalizations in non-dialysis CKD patients, making it inappropriate for this population regardless of theoretical advantages of oral administration.