Anemia, Cardiovascular Disease, Congestive Heart Failure, Heart Failure, Ventricular Dysfunction
Conditions
Keywords
Survival study, morbidity and mortality, heart failure hospitalization, all-cause death, patient-reported outcomes, Kansas City Cardiomyopathy questionnaire, anemia treatment
Brief summary
The purpose of the study is to determine the efficacy of treatment of anemia with darbepoetin alfa compared to placebo on the composite of time to death from any cause or first hospital admission for worsening heart failure in patients with symptomatic left ventricular systolic dysfunction and anemia.
Detailed description
Several epidemiological studies have demonstrated an association between HF and anemia and correlation of increased risk for mortality and hospitalization with low hemoglobin in patients with HF. Earlier single-center interventional studies suggest that meaningful clinical benefits may be achieved by raising hemoglobin concentration in patients with symptomatic HF and anemia. Data from Amgen's completed phase 2 multi-center studies support this hypothesis and show that darbepoetin alfa is well tolerated in patients with symptomatic left ventricular systolic dysfunction and anemia and effectively raises hemoglobin. The pivotal phase 3 Study 20050222 RED-HF Trial is evaluating the effect of treatment with darbepoetin alfa on the composite risk of all-cause mortality or hospitalization for worsening HF in patients with symptomatic left ventricular systolic dysfunction and anemia. This study also evaluates the effect of darbepoetin alfa treatment on all-cause death, on cardiovascular death or hospitalization for worsening HF, and on patient-reported quality-of-life outcomes.
Interventions
DRUGDarbepoetin alfa
Administered by subcutaneous injection
DRUGPlacebo
Placebo subcutaneous injection
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Heart failure of at least 3 months duration and of New York Heart Association (NYHA) class II, III, or IV * hemoglobin between 9.0 g/dL and 12.0 g/dL * left ventricular ejection fraction equal to or less than 40%
Exclusion criteria
* Transferrin saturation (Tsat) \< 15% * Blood pressure \> 160/100 mm Hg * Heart failure primarily due to valvular heart disease or clinically significant valvular heart disease that might lead to surgical correction within 12 months of randomization * Recipient of a major organ transplant or receiving renal replacement therapy * Serum creatinine \> 3.0 mg/dL (\> 265 µmol/L)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to All Cause Death or First Hospitalization for Worsening Heart Failure | From randomization to the end of study; maximum time on study was 73 months | Time to death from any cause or first hospital admission for worsening heart failure (adjudicated by the Clinical Endpoint Committee), whichever occurred first, estimated by Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death From Any Cause | From randomization to the end of study; maximum time on study was 73 months | Time from randomization to death due to any cause, estimated by the Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first. |
| Time to Cardiovascular Death or First Hospital Admission for Worsening Heart Failure | From randomization to the end of study; maximum time on study was 73 months | Time to cardiovascular death or first hospital admission for worsening heart failure, whichever occured first, estimated using the Kaplan Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first. |
| Change From Baseline to Month 6 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | Baseline and Month 6 | The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score. |
| Change From Baseline to Month 6 in KCCQ Symptom Frequency Score | Baseline and Month 6 | The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, Czechia, Denmark, Estonia, Finland, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Latvia, Lithuania, Mexico, Netherlands, Norway, Poland, Portugal, Puerto Rico, Romania, Russia, Slovakia, South Africa, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
First patient enrolled 13 June 2006; Last patient enrolled 4 May 2012
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received dose and administration schedule (every 2 weeks or once a month) changes that simulated the changes for participants receiving darbepoetin alfa. | 1,142 |
| Darbepoetin Alfa Starting dose of 0.75 µg/kg subcutaneously every 2 weeks until hemoglobin concentrations reach 13.0 g/dL on 2 consecutive visits, then monthly dosing, titrated to achieve hemoglobin target of 13.0 g/dL, not to exceed 14.5 g/dL. | 1,136 |
| Total | 2,278 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 83 | 65 |
| Overall Study | Death | 265 | 281 |
| Overall Study | Did not receive investigational product | 2 | 3 |
| Overall Study | Ineligibility determined | 4 | 3 |
| Overall Study | Lost to Follow-up | 16 | 22 |
| Overall Study | Other | 21 | 14 |
| Overall Study | Participant request | 65 | 64 |
| Overall Study | Physician Decision | 47 | 39 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Protocol Violation | 64 | 59 |
| Overall Study | Withdrawal by Subject | 111 | 102 |
Baseline characteristics
| Characteristic | Placebo | Darbepoetin Alfa | Total |
|---|---|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 11.3 | 70.0 years STANDARD_DEVIATION 11.6 | 69.8 years STANDARD_DEVIATION 11.4 |
| Device Usage CRT with or without ICD | 143 participants | 143 participants | 286 participants |
| Device Usage ICD without CRT | 124 participants | 122 participants | 246 participants |
| Device Usage None | 875 participants | 871 participants | 1746 participants |
| Kansas City Cardiomyopathy Questionnaire: Overall Summary Score | 56.5 units on a scale STANDARD_DEVIATION 22.5 | 55.8 units on a scale STANDARD_DEVIATION 22.6 | 56.2 units on a scale STANDARD_DEVIATION 22.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 162 participants | 162 participants | 324 participants |
| Race/Ethnicity, Customized Black or African American | 113 participants | 89 participants | 202 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 84 participants | 98 participants | 182 participants |
| Race/Ethnicity, Customized Japanese | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 12 participants | 3 participants | 15 participants |
| Race/Ethnicity, Customized White or Caucasian | 768 participants | 781 participants | 1549 participants |
| Region Eastern Europe and Russia | 227 participants | 227 participants | 454 participants |
| Region Latin America and Asia | 286 participants | 285 participants | 571 participants |
| Region North America | 323 participants | 321 participants | 644 participants |
| Region Western Europe, Israel, South Africa, Australia | 306 participants | 303 participants | 609 participants |
| Sex: Female, Male Female | 486 Participants | 458 Participants | 944 Participants |
| Sex: Female, Male Male | 656 Participants | 678 Participants | 1334 Participants |
| Study Specific Characteristic [Kansas City Cardiomyopathy Questionnaire: Symptom Frequency Scale | 63.3 units on a scale STANDARD_DEVIATION 25.2 | 63.1 units on a scale STANDARD_DEVIATION 25.6 | 63.2 units on a scale STANDARD_DEVIATION 25.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 741 / 1,140 | 710 / 1,133 |
| serious Total, serious adverse events | 741 / 1,140 | 781 / 1,133 |
Outcome results
Primary
Time to All Cause Death or First Hospitalization for Worsening Heart Failure
Time to death from any cause or first hospital admission for worsening heart failure (adjudicated by the Clinical Endpoint Committee), whichever occurred first, estimated by Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.
Time frame: From randomization to the end of study; maximum time on study was 73 months
Population: Intent-to-treat (ITT) analysis set, defined as all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to All Cause Death or First Hospitalization for Worsening Heart Failure | 1260.0 days |
| Darbepoetin Alfa | Time to All Cause Death or First Hospitalization for Worsening Heart Failure | 1184.0 days |
p-value: 0.87195% CI: [0.9, 1.13]Stratified Log Rank
Secondary
Change From Baseline to Month 6 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score
The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.
Time frame: Baseline and Month 6
Population: Intent-to-treat participants with non-missing change from Baseline to Month 6 in KCCQ score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Month 6 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | 4.48 units on a scale | Standard Error 0.68 |
| Darbepoetin Alfa | Change From Baseline to Month 6 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score | 6.68 units on a scale | Standard Error 0.68 |
p-value: 0.00595% CI: [0.65, 3.75]Mixed Models Analysis
Secondary
Change From Baseline to Month 6 in KCCQ Symptom Frequency Score
The KCCQ is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Least squares means were calculated from a mixed effects model estimating treatment effect adjusted for region, type of device, and Baseline KCCQ score.
Time frame: Baseline and Month 6
Population: Intent-to-treat participants with non-missing change from Baseline to Month 6 in KCCQ score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Month 6 in KCCQ Symptom Frequency Score | 3.91 units on a scale | Standard Error 0.76 |
| Darbepoetin Alfa | Change From Baseline to Month 6 in KCCQ Symptom Frequency Score | 6.20 units on a scale | Standard Error 0.76 |
p-value: 0.01195% CI: [0.53, 4.05]Mixed Models Analysis
Secondary
Time to Cardiovascular Death or First Hospital Admission for Worsening Heart Failure
Time to cardiovascular death or first hospital admission for worsening heart failure, whichever occured first, estimated using the Kaplan Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.
Time frame: From randomization to the end of study; maximum time on study was 73 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Cardiovascular Death or First Hospital Admission for Worsening Heart Failure | 1414.0 days |
| Darbepoetin Alfa | Time to Cardiovascular Death or First Hospital Admission for Worsening Heart Failure | 1395.0 days |
p-value: 0.92295% CI: [0.89, 1.14]Stratified Log Rank
Secondary
Time to Death From Any Cause
Time from randomization to death due to any cause, estimated by the Kaplan-Meier method. Participants not experiencing a qualifying event during the study were censored at their last contact time or the study termination date, whichever occurred first.
Time frame: From randomization to the end of study; maximum time on study was 73 months
Population: Intent-to-treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to Death From Any Cause | 1637.0 days |
| Darbepoetin Alfa | Time to Death From Any Cause | 1629.0 days |
p-value: 0.51295% CI: [0.92, 1.19]Stratified Log Rank