Menstruation, Venous Thromboembolism
Conditions
Brief summary
A large proportion of women with menstruating potential with newly diagnosed VTE or atrial fibrillation, treated with apixaban will have less menstrual blood loss than patients randomized to rivaroxaban.
Detailed description
Heavy menstrual bleeding (HMB) complicates the treatment of approximately 9-25% of patients treated with orally administered anti-Xa anticoagulants for venous thromboembolism (VTE, including either pulmonary embolism or deep vein thrombosis). In particular, recent evidence has suggested an increase in length and severity of menstrual bleeding for women treated with rivaroxaban, and this effect may be less severe apixaban treatment.(1;2) Increase in uterine bleeding with rivaroxaban has necessitated hysterectomy in rare cases.(3) Other complications of HMB include reduced drug adherence, decreased perception of wellness (quality of life) and anemia.(4;5) The anti-Xa agents may increase HMB more than vitamin K antagonists.(1) However, in the principal investigators' experience treating over 100 women of menstruating age with rivaroxaban for VTE with varying degree of HMB, no woman has expressed desire to switch to a VKA even when offered this option (unpublished data). We have successfully reduced perception of HMB by switching from rivaroxaban to apixaban in six patients. Comparison of published and supplemental data from AMPLIFY and AMPLIFY Extend to EINSTEIN and EINSTEIN extend trials also support a lower rate of uterine bleeding with apixaban compared with rivaroxaban, although exact comparisons are difficult to make.(6;9) Myers et al recently reported a 9.4% rate of HMB with apixaban, compared with a 25% rate of HMB with rivaroxaban.(2) Accordingly, we hypothesize that women with menstruating potential with newly diagnosed VTE or atrial fibrillation/flutter, treated with apixaban will have less menstrual blood loss than patients randomized to rivaroxaban.
Interventions
DRUGApixaban
10mg BID for 7 days, then 5mg BID for three months
DRUGRivaroxaban
15mg BID for 7 days, then 20mg daily for three months
Sponsors
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Non-pregnant women, age 18-50 * For study purposes, evidence of negative pregnancy is accounted for by the treating physician's initiation of treatment with oral anticoagulants * Objectively diagnosed VTE or atrial fibrillation/flutter * Patient reported active menstruation - does not apply to women who were recently pregnant * Clinical plan and patient agreement to treat with oral anticoagulation for 3 months or longer * Patients must have a working telephone
Exclusion criteria
* Package insert exclusions for Eliquis (Apixban) or Xarelto (Rivaroxaban): \[active pathological bleeding or severe hypersensitivity reaction to XARELTO or ELIQUIS (e.g., anaphylactic reactions)\] * Plan to become pregnant in the next three months. * Concomitant prescribed use of aspirin or thienopyridenes or other platelet inhibiting drugs * Plan for surgical hysterectomy or endometrial ablation * Known uterine cancer * Von Willebrand's disease, or hemophilia * Known coagulopathy from liver disease * Conditions likely to preclude adherence to study procedures: Active intravenous drug use, known alcoholism, homelessness, or uncontrolled psychiatric illness.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PBAC Scores | 3 months | Measure Description: A PBAC Score of \< 100 indicates a normal menstrual cycle. The lowest possible score would be zero. Higher values indicate worse outcomes. The higher theoretical range value cannot be calculated. The scoring mechanism is as follows; Towels * 1 point for each lightly stained towel * 5 points or each moderately soiled towel * 20 points if the towel is completely saturated with blood Tampons * 1 point for each lightly stained tampon * 5 points for each moderately soiled tampon * 10 points if the tampon is completely saturated with blood Clots * 1 point for small clots * 5 points for large clots |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients That Held Drug for Menorrhagia | 1, 2, and 3 months | — |
| Number of Participants With Major Hemorrhage | 3 months | — |
| Number of Participants With Venous Thromboembolism (VTE) | 3 months | — |
| Number of Participants Who Discontinued Planned Drug Administration | 3 months | — |
| Number of Participants With Clinically Relevant Non-major Bleeding | 3 months | — |
| Hemoglobin Concentration | 3 months | Measure Description: Normal hemoglobin range for adult women - 12 - 16 g/dL. Lower levels indicate worse outcomes. |
| Physical Component Summary of Standard From 36 | 3 months | The RAND 36-Item Health Survey (Version 1.0) taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. All items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively. |
| Number of Participants Who Crossed Over to Another Anticoagulant | 3 months | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rivaroxaban Rivaroxaban: 15mg BID for 7 days, then 20mg daily for three months | 8 |
| Apixaban Apixaban: 10mg BID for 7 days, then 5mg BID for three months | 11 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | Rivaroxaban | Total | Apixaban |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 19 Participants | 11 Participants |
| d-dimer | 661 ng/ml | 840.5 ng/ml | 1031 ng/ml |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 18 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| hgb | 12.6 g/dl | 12.7 g/dl | 13.0 g/dl |
| pbac-pictoral bloodloss assessment chart | 173.5 score | 148 score | 142 score |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 14 Participants | 8 Participants |
| Region of Enrollment United States | 8 participants | 19 participants | 11 participants |
| Sex: Female, Male Female | 8 Participants | 19 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Short Form Health Survey (SF-36) | 57.9 Score | 55.4 Score | 55.4 Score |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 11 |
| other Total, other adverse events | 4 / 8 | 5 / 11 |
| serious Total, serious adverse events | 0 / 8 | 0 / 11 |
Outcome results
Primary
PBAC Scores
Measure Description: A PBAC Score of \< 100 indicates a normal menstrual cycle. The lowest possible score would be zero. Higher values indicate worse outcomes. The higher theoretical range value cannot be calculated. The scoring mechanism is as follows; Towels * 1 point for each lightly stained towel * 5 points or each moderately soiled towel * 20 points if the towel is completely saturated with blood Tampons * 1 point for each lightly stained tampon * 5 points for each moderately soiled tampon * 10 points if the tampon is completely saturated with blood Clots * 1 point for small clots * 5 points for large clots
Time frame: 3 months
Population: The number of participants at baseline differ from those of the outcome measurements because some participants were lost to followup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban | PBAC Scores | 292 score on a scale |
| Apixaban | PBAC Scores | 146 score on a scale |
Secondary
Hemoglobin Concentration
Measure Description: Normal hemoglobin range for adult women - 12 - 16 g/dL. Lower levels indicate worse outcomes.
Time frame: 3 months
Population: The number of participants at baseline differ from those of the outcome measurements because some participants were lost to followup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban | Hemoglobin Concentration | 12.8 g/dl |
| Apixaban | Hemoglobin Concentration | 13.25 g/dl |
Secondary
Number of Participants Who Crossed Over to Another Anticoagulant
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Number of Participants Who Crossed Over to Another Anticoagulant | 3 Participants |
| Apixaban | Number of Participants Who Crossed Over to Another Anticoagulant | 1 Participants |
Secondary
Number of Participants Who Discontinued Planned Drug Administration
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Number of Participants Who Discontinued Planned Drug Administration | 4 Participants |
| Apixaban | Number of Participants Who Discontinued Planned Drug Administration | 2 Participants |
Secondary
Number of Participants With Clinically Relevant Non-major Bleeding
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Number of Participants With Clinically Relevant Non-major Bleeding | 3 Participants |
| Apixaban | Number of Participants With Clinically Relevant Non-major Bleeding | 0 Participants |
Secondary
Number of Participants With Major Hemorrhage
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Number of Participants With Major Hemorrhage | 0 Participants |
| Apixaban | Number of Participants With Major Hemorrhage | 0 Participants |
Secondary
Number of Participants With Venous Thromboembolism (VTE)
Time frame: 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Number of Participants With Venous Thromboembolism (VTE) | 0 Participants |
| Apixaban | Number of Participants With Venous Thromboembolism (VTE) | 0 Participants |
Secondary
Number of Patients That Held Drug for Menorrhagia
Time frame: 1, 2, and 3 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rivaroxaban | Number of Patients That Held Drug for Menorrhagia | 0 Participants |
| Apixaban | Number of Patients That Held Drug for Menorrhagia | 0 Participants |
Secondary
Physical Component Summary of Standard From 36
The RAND 36-Item Health Survey (Version 1.0) taps eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. All items are scored so that a high score defines a more favorable health state. In addition, each item is scored on a 0 to 100 range so that the lowest and highest possible scores are 0 and 100, respectively.
Time frame: 3 months
Population: The number of participants at baseline differ from those of the outcome measurements because some participants were lost to followup.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rivaroxaban | Physical Component Summary of Standard From 36 | 55.5 Score |
| Apixaban | Physical Component Summary of Standard From 36 | 45.6 Score |