Vadadustat for Anemia in Dialysis: Safe Oral Option?

randomized-controlled-trial PMID: 33913638

Quick Summary: This study tested vadadustat, an oral pill that helps the body make more red blood cells to fight anemia in kidney disease patients on dialysis. It compared vadadustat to a common injection called darbepoetin alfa. The main finding? Vadadustat worked just as well and was as safe for heart health, offering a needle-free choice for many patients.

What the Research Found

Researchers looked at how well vadadustat treats anemia—a condition where you don't have enough healthy red blood cells—in people with chronic kidney disease (CKD) who need dialysis. Anemia makes you tired and weak, and dialysis patients often deal with it. Vadadustat mimics low-oxygen signals to boost the body's natural production of erythropoietin, a hormone that helps make red blood cells. The study showed it matched the standard treatment in keeping hemoglobin (a key protein in red blood cells) levels steady. It also had similar rates of serious heart issues, proving it's a solid option without added risks.

Key results in simple terms:
- Heart safety: Similar chance of major events like heart attacks or strokes (18.2% for vadadustat vs. 19.3% for the injection).
- Blood health: Hemoglobin levels stayed stable over time, with no big drops compared to the standard drug.
- Side effects: About half of people had serious issues in both groups, but nothing worse with vadadustat.

Study Details

Who was studied: Over 3,900 adults with anemia and CKD on dialysis—some just starting (369 people) and most already on it long-term (3,554 people). They had end-stage kidney issues needing regular dialysis.

How long: Up to 52 weeks (about a year), with key checks at 24-36 weeks and 40-52 weeks.

What they took: Vadadustat as a daily oral pill, adjusted to keep blood levels right. Compared to darbepoetin alfa, given as weekly or monthly shots. Doses were personalized based on blood tests—no fixed amounts listed, but both aimed for hemoglobin between 10-11.5 g/dL.

What This Means for You

If you or a loved one is on dialysis and battles anemia, vadadustat could mean skipping painful injections. It's taken by mouth, which might make sticking to treatment easier and improve daily life. Talk to your doctor—this isn't better than injections, just equally good for most. It won't cure kidney disease but helps manage tiredness and boosts energy. Always check with a healthcare pro before changing meds, especially if you have heart concerns.

Study Limitations

This was an open-label trial, meaning patients and doctors knew who got which treatment, which could bias results. It only included dialysis patients, so it may not apply to earlier-stage kidney disease. The safety checks focused on not being worse (noninferior), but didn't prove it's safer overall. Funded by drug makers, so more independent studies would help confirm findings. Long-term effects beyond a year aren't covered here.

Key Findings

Vadadustat demonstrated noninferiority to darbepoetin alfa for cardiovascular safety and hemoglobin maintenance in dialysis-dependent chronic kidney disease (DD-CKD) patients. The primary safety endpoint—major adverse cardiovascular events (MACE: death, nonfatal myocardial infarction, or nonfatal stroke)—occurred in 18.2% (vadadustat) versus 19.3% (darbepoetin) of patients (hazard ratio [HR] 0.96; 95% CI 0.83–1.11), meeting noninferiority (upper CI <1.25 margin). Efficacy endpoints showed noninferior hemoglobin correction: mean differences ranged from -0.07 to -0.31 g/dL across trials and timepoints, all within the -0.75 g/dL noninferiority margin.

Study Design

This was a pooled analysis of two randomized, open-label, noninferiority phase 3 trials (incident and prevalent DD-CKD cohorts). Total participants: 3,923 (vadadustat: n=1,962; darbepoetin: n=1,961), including 369 incident and 3,554 prevalent dialysis patients. Duration: 52 weeks. Primary safety endpoint was time-to-first MACE; primary efficacy endpoint was mean hemoglobin change from baseline to weeks 24–36.

Dosage & Administration

Vadadustat was administered orally, titrated to maintain hemoglobin levels per protocol. Darbepoetin alfa was given subcutaneously or intravenously per standard care. Specific dose ranges were not detailed in the summary, but both agents were adjusted based on hemoglobin response.

Results & Efficacy

Safety: MACE incidence: 18.2% (vadadustat) vs. 19.3% (darbepoetin); HR 0.96 (95% CI 0.83–1.11; p<0.001 for noninferiority). Key secondary safety endpoint (MACE plus heart failure/thromboembolic hospitalization) showed similar trends.
Efficacy: In prevalent DD-CKD, hemoglobin change at weeks 24–36 was -0.17 g/dL (95% CI -0.23 to -0.10); at weeks 40–52, -0.18 g/dL (95% CI -0.25 to -0.12). All differences were within the -0.75 g/dL noninferiority margin (95% CIs excluded -0.75). Serious adverse events: 55.0% (vadadustat) vs. 58.3% (darbepoetin) in prevalent DD-CKD.

Limitations

Open-label design risked performance bias due to unblinded treatment assignment. Noninferiority margin for safety (1.25) may be considered clinically permissive. Results apply only to dialysis-dependent CKD patients, limiting generalizability to non-dialysis populations. Lack of placebo control and industry funding (Akebia/Otsuka) introduce potential sponsorship bias. Future research should assess long-term outcomes and non-dialysis cohorts.

Clinical Relevance

Vadadustat provides a viable oral alternative to injectable erythropoiesis-stimulating agents (ESAs) like darbepoetin for anemia management in dialysis patients, with comparable cardiovascular safety and hemoglobin control. This may improve treatment adherence by eliminating injections, though real-world monitoring for cardiovascular risks remains essential. Clinicians should consider individual patient factors when selecting ESAs, as vadadustat’s noninferiority does not imply superiority.