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Subgroup analysis of DD-CKD patients across prespecified baseline ESA dose* subgroups1
Subgroup analyses1:
The ESA baseline dose analyses presented within are part of a
subgroup analysis of the pivotal INNO2VATE clinical
trials that has been previously published. The subgroup analyses
were not powered to show differences between treatment arms and
include certain subgroups with small sample sizes.
The subgroup analyses presented here have not been published previously except
in abstract form and are not contained in the Vafseo product
labeling.
Data from the two Phase 3 pivotal trials based on baseline ESA dose:
low dose (less than or equal to 90 U/kg/wk), intermediate dose (greater
than 90 U/kg/wk and less than 300 U/kg/wk), and high dose (greater
than or equal to 300 U/kg/wk). The trials compared Vafseo to darbepoetin
alfa for efficacy (mean change in Hb from baseline to the primary evaluation
period of Weeks 24-36 and secondary evaluation period of Weeks 40-52)
and safety (MACE).*,† Patients were randomized 1:1 to receive Vafseo
with a starting dose of 300 mg once daily or darbepoetin alfa per prescribing
information. Across the two trials, 1770 patients on Vafseo were converted
from an ESA at baseline (low dose, n=916; intermediate dose, n=724;
and high dose, n=102).
There were also 1759 patients on darbepoetin
alfa who were converted from an ESA at baseline (low dose, n=968; intermediate
dose, n=693; and high dose, n=98). Dosing in each treatment arm followed
the protocol-specified dose-adjustment algorithm to achieve and sustain
target Hb levels within 10 to 11 g/dL (US) or 10 to 12 g/dL (outside
the US).
Data limitations1:
- No multiplicity adjustments were applied for MACE or efficacy analyses in the subgroups
- All analyses are presented for descriptive purposes only and should be interpreted with caution
- A higher proportion of patients in the high ESA dose subgroup were Black and had lower hemoglobin concentrations, weights, and BMIs, which could have influenced the results
Prevalent Dialysis Trial (INNO2VATE-2) subgroup analysis: Efficacy stratified by baseline ESA dose
Treatment with Vafseo helped patients maintain baseline Hb levels during the PEP and SEP regardless of baseline ESA dose1
Patients treated with Vafseo in the Prevalent Dialysis Trial (INNO2VATE-2) (N=1777) were categorized into prespecified subgroups based on their baseline ESA dose1:
| Mean change in Hb with Vafseo by baseline ESA dose5 |
Overall (N=1777) |
Low Dose ≤90 U/kg/wk (n=916) |
Intermediate Dose >90 to <300 U/kg/wk (n=724) |
High Dose ≥300 U/kg/wk (n=102) |
|---|---|---|---|---|
| Mean baseline Hb concentration, g/dL mean±SD | 10.25 ± 0.85 | 10.33 ± 0.81 | 10.22 ± 0.87 | 9.72 ± 0.91 |
| Weeks 24-36 (PEP) | ||||
| Mean baseline Hb concentration (observed + imputed), g/dL mean±SD | 10.36 ± 1.01 | 10.53 ± 0.99 | 10.24 ± 0.98 | 9.78 ± 0.95 |
| LS mean change in Hb from baseline (95% CI) | 0.19 (0.12, 0.25) | 0.25 (0.17, 0.33) | 0.12 (0.02, 0.23) | -0.11 (-0.53, 0.30) |
| Weeks 40‐52 (SEP) | ||||
| Mean baseline Hb concentration (observed + imputed), g/dL mean±SD | 10.40 ± 1.04 | 10.60 ± 1.05 | 10.23 ± 0.99 | 9.81 ± 0.91 |
| LS mean change in Hb from baseline (95% CI) | 0.23 (0.16, 0.29) | 0.33 (0.24, 0.41) | 0.10 (-0.01, 0.21) | 0.08 (-0.35, 0.51) |
CI=confidence interval; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; LS=least squares; PEP=primary evaluation period; SD=standard deviation; SEP=secondary evaluation period; wk=week.
Hb concentration in Vafseo and darbepoetin alfa treatment arms over time by ESA dose1,2
- In patients treated with Vafseo, there was a transient decline in mean Hb levels in the high baseline ESA dose subgroup during weeks 2-8, after which levels increased by weeks 24–36. A less pronounced transient decline was observed in the intermediate baseline ESA dose subgroup but not in the low baseline ESA subgroup1
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Data outside the primary (Weeks 24-36) and secondary (Weeks 40-52) evaluation periods are descriptive.
These graphs display mean Hb levels over time. Means ±SD (denoted by I bars) are presented here to show the extent of variability, which might have been less apparent if means ±SE were presented, given the large sample size.
Prevalent Dialysis Trial (INNO2VATE-2) subgroup analysis: Safety
Cardiovascular outcomes in the prespecified subgroup analysis1,3,§
The incidence of MACE|| among patients treated with Vafseo was similar across baseline ESA doses.1,3
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Treatment-emergent serious adverse events of special interest (≥10%)
by baseline ESA dose subgroups3
| ≤90 U/kg/wk | >90 to <300 U/kg/wk | ≥300 U/kg/wk | ||||
|---|---|---|---|---|---|---|
| Event, n (%) | Vafseo (n=949) | Darbepoetin Alfa (n=992) | Vafseo (n=764) | Darbepoetin Alfa (n=738) | Vafseo (n=111) | Darbepoetin Alfa (n=103) |
| Any TE SAESI | 337 (35.5) | 396 (39.9) | 312 (40.8) | 338 (45.8) | 48 (43.2) | 57 (55.3) |
| Hypertension | 122 (12.9) | 165 (16.6) | 144 (18.8) | 159 (21.5) | 25 (22.5) | 35 (34.0) |
| Congestive Heart Failure | 77 (8.1) | 97 (9.8) | 85 (11.1) | 92 (12.5) | 14 (12.6) | 17 (16.5) |
| Hyperkalemia | 70 (7.4) | 98 (9.9) | 75 (9.8) | 84 (11.4) | 15 (13.5) | 21 (20.4) |
| Hepatotoxicity | 60 (6.3) | 59 (5.9) | 53 (6.9) | 64 (8.7) | 14 (12.6) | 10 (9.7) |
ESA=erythropoiesis-stimulating agent; TE SAESI=treatment-emergent serious adverse events of special interest; wk=week.
Dosing in the Prevalent Dialysis Trial (INNO2VATE-2)
Vafseo doses over time across subgroups by baseline ESA dose††
- All patients started on Vafseo 300 mg at study entry regardless of baseline ESA dose1
- In the Vafseo treatment arm, the protocol allowed dose increases of 150 mg every 4 weeks. Dose decreases could occur more frequently. Doses may range from 150 mg to 600 mg1
- By week 12, 52.3%, 64%, and 71.8% of patients were increased to 450 mg or 600 mg in the low, intermediate, and high baseline ESA dose subgroups, respectively1
-In the high baseline group, 50% of patients were receiving 600 mg
- During PEP and SEP, these percentages increased further, especially in the high baseline ESA dose subgroup1
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This analysis includes only those patients who were on Vafseo and not those whose dosages were interrupted due to elevated hemoglobin levels, ESA rescue, or adverse events. Data presented are the most common administered dose received during that study week. Data are observational and doses may have been increased or decreased per protocol.1
††Omits percentage of patients on 0 mg.1
ESA=erythropoiesis-stimulating agent; PEP=primary evaluation period; SEP=secondary evaluation period; wk=week.
Learn more about Vafseo PI dosing and dosing data in the overall study populationMeet Vince, a 57-year-old patient with anemia due to CKD who has been undergoing in-center hemodialysis for 8 months and receiving high-dose ESA for anemia management
“I pour my heart into serving my community, but balancing that with managing my condition can be difficult.”
obese (80 kg; BMI 30)
9.0 g/dL
Transferrin saturation=35%
Serum ferritin=831 ng/mL
Hypothetical patient profile. Not an actual patient.
BMl=body mass index; CKD=chronic kidney disease; COPD=chronic obstructive pulmonary disease; ESA=erythropoiesis-stimulating agent; Hb=hemoglobin; IV=intravenous.
WARNING: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS
THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS.
VAFSEO increases the risk of thrombotic vascular events, including major adverse cardiovascular events (MACE).
Targeting a hemoglobin level greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events, as occurs with erythropoietin stimulating agents (ESAs), which also increase erythropoietin levels.
No trial has identified a hemoglobin target level, dose of VAFSEO, or dosing strategy that does not increase these risks.
Use the lowest dose of VAFSEO sufficient to reduce the need for red blood cell transfusions.
CONTRAINDICATIONS
- Known hypersensitivity to VAFSEO or any of its components
- Uncontrolled hypertension
WARNINGS AND PRECAUTIONS
- Increased Risk of Death, Myocardial Infarction (MI), Stroke, Venous Thromboembolism, and Thrombosis of Vascular AccessA rise in hemoglobin (Hb) levels greater than 1 g/dL over 2 weeks can increase these risks. Avoid in patients with a history of MI, cerebrovascular event, or acute coronary syndrome within the 3 months prior to starting VAFSEO. Targeting a Hb level of greater than 11 g/dL is expected to further increase the risk of death and arterial and venous thrombotic events. Use the lowest effective dose to reduce the need for red blood cell (RBC) transfusions. Adhere to dosing and Hb monitoring recommendations to avoid excessive erythropoiesis.
- HepatotoxicityHepatocellular injury attributed to VAFSEO was reported in less than 1% of patients, including one severe case with jaundice. Elevated serum ALT, AST, and bilirubin levels were observed in 1.8%, 1.8%, and 0.3% of CKD patients treated with VAFSEO, respectively. Measure ALT, AST, and bilirubin before treatment and monthly for the first 6 months, then as clinically indicated. Discontinue VAFSEO if ALT or AST is persistently elevated or accompanied by elevated bilirubin. Not recommended in patients with cirrhosis or active, acute liver disease.
- HypertensionWorsening of hypertension was reported in 14% of VAFSEO and 17% of darbepoetin alfa patients. Serious worsening of hypertension was reported in 2.7% of VAFSEO and 3% of darbepoetin alfa patients. Cases of hypertensive crisis, including hypertensive encephalopathy and seizures, have also been reported in patients receiving VAFSEO. Monitor blood pressure. Adjust anti-hypertensive therapy as needed.
- SeizuresSeizures occurred in 1.6% of VAFSEO and 1.6% of darbepoetin alfa patients. Monitor for new-onset seizures, premonitory symptoms, or change in seizure frequency.
- Gastrointestinal (GI) ErosionGastric or esophageal erosions occurred in 6.4% of VAFSEO and 5.3% of darbepoetin alfa patients. Serious GI erosions, including GI bleeding and the need for RBC transfusions, were reported in 3.4% of VAFSEO and 3.3% of darbepoetin alfa patients. Consider this risk in patients at increased risk of GI erosion. Advise patients about signs of erosions and GI bleeding and urge them to seek prompt medical care if present.
- Serious Adverse Reactions in Patients with Anemia Due to CKD and Not on DialysisThe safety of VAFSEO has not been established for the treatment of anemia due to CKD in adults not on dialysis and its use is not recommended in this setting. In large clinical trials in adults with anemia of CKD who were not on dialysis, an increased risk of mortality, stroke, MI, serious acute kidney injury, serious hepatic injury, and serious GI erosions was observed in patients treated with VAFSEO compared to darbepoetin alfa.
- MalignancyVAFSEO has not been studied and is not recommended in patients with active malignancies. Malignancies were observed in 2.2% of VAFSEO and 3.0% of darbepoetin alfa patients. No evidence of increased carcinogenicity was observed in animal studies.
ADVERSE REACTIONS
- The most common adverse reactions (occurring at ≥ 10%) were hypertension and diarrhea.
DRUG INTERACTIONS
- Iron supplements and iron-containing phosphate binders: Administer VAFSEO at least 1 hour before products containing iron.
- Non-iron-containing phosphate binders: Administer VAFSEO at least 1 hour before or 2 hours after non-iron-containing phosphate binders.
- BCRP substrates: Monitor for signs of substrate adverse reactions and consider dose reduction.
- Statins: Monitor for statin-related adverse reactions. Limit the daily dose of simvastatin to 20 mg and rosuvastatin to 5 mg.
USE IN SPECIFIC POPULATIONS
- Pregnancy: May cause fetal harm.
- Lactation: Breastfeeding not recommended until two days after the final dose.
- Hepatic Impairment: Not recommended in patients with cirrhosis or active, acute liver disease
VAFSEO is indicated for the treatment of anemia due to chronic kidney disease (CKD) in adults who have been receiving dialysis for at least three months.
Limitations of Use
- VAFSEO has not been shown to improve quality of life, fatigue, or patient well-being.
- VAFSEO is not indicated for use:
- As a substitute for red blood cell transfusions in patients who require immediate correction of anemia.
- In patients with anemia due to CKD not on dialysis.
Please note that this information is not comprehensive. Please click here for the Full Prescribing Information, including BOXED WARNING and Medication Guide.