Heart Failure
Conditions
Keywords
loop diuretic
Brief summary
TRANSFORM-HF is a large-scale, pragmatic, randomized, unblinded clinical effectiveness study comparing torsemide versus furosemide as treatment for heart failure. Approximately 6,000 patients with heart failure will be enrolled. The primary objective of the TRANSFORM-HF study is to compare the treatment strategy of torsemide versus furosemide on clinical outcomes over 12 months in patients with heart failure who are hospitalized.
Detailed description
* This study will be a randomized, unblinded, two-arm, multi-center clinical trial of patients with heart failure who are hospitalized. Heart failure need not be the reason for hospitalization. Patients will be randomized 1:1 to either oral torsemide OR oral furosemide prior to hospital discharge. Oral dosing of torsemide compared to furosemide will be 1mg:2mg. The specific loop diuretic dose will be at the discretion of the treating physician with the above noted conversion. * Trial enrollment occurs before hospital discharge, at the discretion of the healthcare provider. * As appropriate, adherence to the randomized medication will be encouraged during the remainder of hospitalization and will continue post-discharge. Patients will receive follow-up per standard care without any additional study-specific visits. * Patients will have 30-day, 6-month and 12-month follow-up phone contacts for assessments of vital status, interval hospitalizations, adherence, and quality of life. Central follow-up and collection of hospital discharge summaries via IRB-approved mechanisms. Subsets of patients enrolled early in the study have additional phone contacts beyond 12 months, up to 30 months, at six month intervals, to document vital status.
Interventions
DRUGTorsemide
Loop diuretic
DRUGFurosemide
Loop diuretic
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Yale University
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study will be a randomized, unblinded, two-arm, multi-center clinical trial of patients with heart failure who are hospitalized. Patients will be randomized 1:1 to either oral torsemide OR oral furosemide prior to hospital discharge.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient hospitalized (≥ 24 hours or over a change in calendar date) with worsening of chronic heart failure, or new diagnosis of heart failure AND meets one of the following criteria: 1. Has a left ventricular ejection fraction (EF) ≤40% within 24 months prior to and including index hospitalization by any method (with most recent value used to determine eligibility) 2. Has an elevated natriuretic peptide level (either NT-pro-B-type natriuretic peptide or B-type natriuretic peptide) during index hospitalization as measured by local laboratory (with most recent value used to determine eligibility) 2. Plan for a daily outpatient oral loop diuretic regimen upon hospital discharge with anticipated need for long-term loop diuretic use 3. ≥ 18 years of age 4. Signed informed consent
Exclusion criteria
1. End-stage renal disease requiring renal replacement therapy 2. Inability or unwillingness to comply with the study requirements 3. History of heart transplant or actively listed for heart transplant 4. Implanted left ventricular assist device or implant anticipated \<3 months 5. Pregnant or nursing women 6. Malignancy or other non-cardiac condition limiting life expectancy to \<12 months 7. Known hypersensitivity to furosemide, torsemide, or related agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality, as Measured by Follow-up Phone Call or NDI | up to 30 months | Death information was obtained from the Call Center through 30 months for patients 1-500, through 24 months for patients 501-1000, through 18 months for patients 1001-1500, and through 12 months for the remaining patients (except those who were randomized \< 12 months when the study was stopped by the DSMB). Also death information was obtained through searches of the 2018-2021 National Death Index (NDI) database. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death) | up to 12 months | The time-to-event analysis of all-cause mortality or all-cause primary re-hospitalization was based on the time from randomization through death or the first primary re-hospitalization through 12 months. Patients who died or whose first all-cause re-hospitalization was after month 12 were censored at month 12. Patients who did not have a re-hospitalization and were alive were censored at the minimum of the time of the last re-hospitalization assessment or month 12. |
| Total Re-hospitalizations, as Measured by Follow-up Phone Call | up to 12 months | Total all-cause primary re-hospitalization was defined as a hospitalization after the index hospitalization through month 12 that met one of the following criteria: 1.) at least a 24-hour stay (or a change in calendar date if the time of admission/discharge is not available) or 2.) reported as an in-patient admission by the patient/proxy with an admission date (complete or month and year) and no discharge date (i.e., length of stay could not be derived). Unit of measurement is the total number of re-hospitalizations for each subject (e.g., if a subject had 3 re-hospitalizations, then the outcome is 3 for the subject). |
| Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline, 1 month, 6 months, 12 months | QOL as assessed by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) (range, 0-100 with 100 indicating best health status). The KCCQ was administered prior to randomization (collected by the site) and at Months 1, 6 and 12 (ascertained at the Call Center visits). The outcome is the least square means in Torsemide and Furosemide groups where the difference = Torsemide mean minus Furosemide mean at the monthly assessment. |
| Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 1, month 6, month 12 | Depression was assessed by the Patient Health Questionnaire-2 (PHQ-2) over 12 months. The PHQ-2 inquires about the frequency of depressed mood and anhedonia (inability to feel pleasure) over the past two weeks. The responses to the questions are scored 0 = Not at all, 1 = Several days, 2 = More than half the days, and 3 = Nearly every day. The PHQ-2 total score is obtained by adding the score for each question. The PHQ-2 total score ranges from 0-6. Reported as the number of patients with a total score \<3 versus \>=3. |
Countries
United States
Participant flow
Pre-assignment details
2973 patients consented. 114 not randomized due to patient decision, PI decision, discharge before randomization occurred, died prior to randomization, or did not meet one or more eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Torsemide Oral dosing of torsemide compared to furosemide will be 1mg:2-4mg.
Torsemide: Loop diuretic | 1,431 |
| Furosemide Oral dosing of torsemide compared to furosemide will be 1mg:2-4mg.
For patients receiving loop diuretics other than furosemide, conversion to furosemide equivalents will be as follows:
1 mg oral torsemide = 2-4 mg oral furosemide
1 mg oral or intravenous bumetanide = 40 mg oral furosemide
Furosemide: Loop diuretic | 1,428 |
| Total | 2,859 |
Baseline characteristics
| Characteristic | Torsemide | Total | Furosemide |
|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 14 | 64.5 years STANDARD_DEVIATION 14 | 65 years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 75 Participants | 155 Participants | 80 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1355 Participants | 2700 Participants | 1345 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 12 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 37 Participants | 63 Participants | 26 Participants |
| Race (NIH/OMB) Black or African American | 474 Participants | 968 Participants | 494 Participants |
| Race (NIH/OMB) More than one race | 65 Participants | 123 Participants | 58 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 13 Participants | 20 Participants | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) White | 831 Participants | 1668 Participants | 837 Participants |
| Region of Enrollment United States | 1431 Participants | 2859 Participants | 1428 Participants |
| Sex: Female, Male Female | 498 Participants | 1055 Participants | 557 Participants |
| Sex: Female, Male Male | 933 Participants | 1804 Participants | 871 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 373 / 1,431 | 374 / 1,428 |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
All-cause Mortality, as Measured by Follow-up Phone Call or NDI
Death information was obtained from the Call Center through 30 months for patients 1-500, through 24 months for patients 501-1000, through 18 months for patients 1001-1500, and through 12 months for the remaining patients (except those who were randomized \< 12 months when the study was stopped by the DSMB). Also death information was obtained through searches of the 2018-2021 National Death Index (NDI) database.
Time frame: up to 30 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Torsemide | All-cause Mortality, as Measured by Follow-up Phone Call or NDI | 373 Participants |
| Furosemide | All-cause Mortality, as Measured by Follow-up Phone Call or NDI | 374 Participants |
Comparison: To determine whether torsemide is superior to furosemide with respect to all-cause mortality among patients hospitalized for heart failure.p-value: 0.76595% CI: [0.885, 1.18]Regression, Cox
Secondary
All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death)
The time-to-event analysis of all-cause mortality or all-cause primary re-hospitalization was based on the time from randomization through death or the first primary re-hospitalization through 12 months. Patients who died or whose first all-cause re-hospitalization was after month 12 were censored at month 12. Patients who did not have a re-hospitalization and were alive were censored at the minimum of the time of the last re-hospitalization assessment or month 12.
Time frame: up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Torsemide | All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death) | 677 Participants |
| Furosemide | All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death) | 704 Participants |
Comparison: To determine whether torsemide is superior to furosemide with respect to all-cause mortality or first all-cause hospitalization through month 12 among patients hospitalized for heart failure.p-value: 0.11395% CI: [0.826, 1.02]Regression, Cox
Secondary
All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death)
All-cause mortality or all-cause hospitalization over 30 days
Time frame: 30 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Torsemide | All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death) | 149 Participants |
| Furosemide | All-cause Mortality or All-cause Hospitalization, as Measured by Follow-up Phone Call or NDI (for Death) | 157 Participants |
Comparison: To determine whether torsemide is superior to furosemide with respect to all-cause mortality or first all-cause hospitalization through day 30 among patients hospitalized for heart failure.p-value: 0.6195% CI: [0.753, 1.181]Regression, Cox
Secondary
Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call
QOL as assessed by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) (range, 0-100 with 100 indicating best health status). The KCCQ was administered prior to randomization (collected by the site) and at Months 1, 6 and 12 (ascertained at the Call Center visits). The outcome is the least square means in Torsemide and Furosemide groups where the difference = Torsemide mean minus Furosemide mean at the monthly assessment.
Time frame: Baseline, 1 month, 6 months, 12 months
Population: Participants with both baseline and monthly KCCQ-CSS scores available (i.e., change from baseline at the month assessment could be analyzed).
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Torsemide | Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline to Month 6 | 70.61 score on a scale |
| Torsemide | Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline to Month 1 | 69.52 score on a scale |
| Torsemide | Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline to Month 12 | 70.00 score on a scale |
| Furosemide | Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline to Month 1 | 68.22 score on a scale |
| Furosemide | Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline to Month 6 | 71.01 score on a scale |
| Furosemide | Change in Health-related Quality of Life (QOL), as Measured by Follow-up Phone Call | Baseline to Month 12 | 69.98 score on a scale |
Comparison: To determine whether torsemide improves the QOL at 1 month compared to Furosemide as assessed by the KCCQ among patients hospitalized for heart failure.p-value: 0.19495% CI: [-0.66, 3.26]Mixed Models Analysis
Comparison: To determine whether torsemide improves the QOL at 6 months compared to Furosemide as assessed by the KCCQ among patients hospitalized for heart failure.p-value: 0.71895% CI: [-2.53, 1.74]Mixed Models Analysis
Comparison: To determine whether torsemide improves the QOL at 12 months compared to Furosemide as assessed by the KCCQ among patients hospitalized for heart failure.p-value: 0.98795% CI: [-2.26, 2.3]Mixed Models Analysis
Secondary
Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2)
Depression was assessed by the Patient Health Questionnaire-2 (PHQ-2) over 12 months. The PHQ-2 inquires about the frequency of depressed mood and anhedonia (inability to feel pleasure) over the past two weeks. The responses to the questions are scored 0 = Not at all, 1 = Several days, 2 = More than half the days, and 3 = Nearly every day. The PHQ-2 total score is obtained by adding the score for each question. The PHQ-2 total score ranges from 0-6. Reported as the number of patients with a total score \<3 versus \>=3.
Time frame: Month 1, month 6, month 12
Population: Participants with data available at each time point.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Torsemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 12 | PHQ-2 score > = 3 | 95 Participants |
| Torsemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 1 | PHQ-2 score > = 3 | 148 Participants |
| Torsemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 6 | PHQ-2 score < 3 | 658 Participants |
| Torsemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 6 | PHQ-2 score > = 3 | 113 Participants |
| Torsemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 12 | PHQ-2 score < 3 | 533 Participants |
| Torsemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 1 | PHQ-2 score < 3 | 790 Participants |
| Furosemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 12 | PHQ-2 score < 3 | 537 Participants |
| Furosemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 1 | PHQ-2 score < 3 | 813 Participants |
| Furosemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 6 | PHQ-2 score > = 3 | 119 Participants |
| Furosemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 1 | PHQ-2 score > = 3 | 150 Participants |
| Furosemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 12 | PHQ-2 score > = 3 | 82 Participants |
| Furosemide | Symptoms of Depression as Measured by the Patient Health Questionnaire-2 (PHQ-2) | Month 6 | PHQ-2 score < 3 | 672 Participants |
Comparison: To determine whether torsemide reduces symptoms of depression at 1 month compared to Furosemide as assessed by the PHQ-2 among patients hospitalized for heart failure.p-value: 0.904Wilcoxon (Mann-Whitney)
Comparison: To determine whether torsemide reduces symptoms of depression at 6 months compared to Furosemide as assessed by the PHQ-2 among patients hospitalized for heart failure.p-value: 0.829Wilcoxon (Mann-Whitney)
Comparison: To determine whether torsemide reduces symptoms of depression at 12 months compared to Furosemide as assessed by the PHQ-2 among patients hospitalized for heart failure.p-value: 0.342Wilcoxon (Mann-Whitney)
Secondary
Total Re-hospitalizations, as Measured by Follow-up Phone Call
Total all-cause primary re-hospitalization was defined as a hospitalization after the index hospitalization through month 12 that met one of the following criteria: 1.) at least a 24-hour stay (or a change in calendar date if the time of admission/discharge is not available) or 2.) reported as an in-patient admission by the patient/proxy with an admission date (complete or month and year) and no discharge date (i.e., length of stay could not be derived). Unit of measurement is the total number of re-hospitalizations for each subject (e.g., if a subject had 3 re-hospitalizations, then the outcome is 3 for the subject).
Time frame: up to 12 months
Population: Participants who had at least one re-hospitalization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Torsemide | Total Re-hospitalizations, as Measured by Follow-up Phone Call | 940 re-hospitalizations |
| Furosemide | Total Re-hospitalizations, as Measured by Follow-up Phone Call | 987 re-hospitalizations |
Comparison: To determine whether torsemide is superior to furosemide with respect to total all-cause hospitalizations through month 12 among patients hospitalized for heart failure.p-value: 0.36695% CI: [0.836, 1.068]Regression, Linear