RAMBLE - Rivaroxaban vs. Apixaban for Heavy Menstrual Bleeding

Venous Thromboembolism Clinical Trial

— (RAMBLE)  

Official title:

Randomized Trial to Test the Effect of Rivaroxaban or Apixaban on Menstrual Blood Loss in Women

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02829957
• Other study ID #: RAMBLE
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: September 2016
• Est. completion date: February 13, 2020

Study information

• Verified date: October 2023
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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for VTE with varying degree of HMB, no woman has expressed desire to switch to a VKA even when offered this option (unpublished data).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.

Other known NCT identifiers

• NCT02761044

Recruitment information / eligibility

• Status: Completed
• Enrollment: 19
• Est. completion date: February 13, 2020
• Est. primary completion date: February 13, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Menstruation
• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• Apixaban
10mg BID for 7 days, then 5mg BID for three months
• Rivaroxaban
15mg BID for 7 days, then 20mg daily for three months

Locations

Country	Name	City	State
United States	Eskenazi Health System	Indianapolis	Indiana
United States	Indiana University Health Methodist Hospital	Indianapolis	Indiana

Sponsors (1)

Lead Sponsor	Collaborator
Indiana University

Country where clinical trial is conducted

United States, 

References & Publications (9)

Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10.1056/NEJMoa1302507. Epub 2013 Jul 1. — View Citation

Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013 Feb 21;368(8):699-708. doi: 10.1056/NEJMoa1207541. Epub 2012 Dec 8. — View Citation

Beam DM, Kahler ZP, Kline JA. Immediate Discharge and Home Treatment With Rivaroxaban of Low-risk Venous Thromboembolism Diagnosed in Two U.S. Emergency Departments: A One-year Preplanned Analysis. Acad Emerg Med. 2015 Jul;22(7):788-95. doi: 10.1111/acem.12711. Epub 2015 Jun 25. — View Citation

De Crem N, Peerlinck K, Vanassche T, Vanheule K, Debaveye B, Middeldorp S, Verhamme P, Peetermans M. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists. Thromb Res. 2015 Oct;136(4):749-53. doi: 10.1016/j.thromres.2015.07.030. Epub 2015 Aug 4. — View Citation

EINSTEIN Investigators; Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. doi: 10.1056/NEJMoa1007903. Epub 2010 Dec 3. — View Citation

EINSTEIN-PE Investigators; Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. doi: 10.1056/NEJMoa1113572. Epub 2012 Mar 26. — View Citation

Kline JA, Kahler ZP, Beam DM. Outpatient treatment of low-risk venous thromboembolism with monotherapy oral anticoagulation: patient quality of life outcomes and clinician acceptance. Patient Prefer Adherence. 2016 Apr 15;10:561-9. doi: 10.2147/PPA.S104446. eCollection 2016. — View Citation

Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health. 2007 May-Jun;10(3):183-94. doi: 10.1111/j.1524-4733.2007.00168.x. — View Citation

Myers B, Webster A. Heavy menstrual bleeding on Rivaroxaban - Comparison with Apixaban. Br J Haematol. 2017 Mar;176(5):833-835. doi: 10.1111/bjh.14003. Epub 2016 Mar 11. No abstract available. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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	3 months
Secondary	Number of Participants Who Discontinued Planned Drug Administration		3 months
Secondary	Number of Patients That Held Drug for Menorrhagia		1, 2, and 3 months
Secondary	Number of Participants With Major Hemorrhage		3 months
Secondary	Number of Participants With Venous Thromboembolism (VTE)		3 months
Secondary	Number of Participants Who Crossed Over to Another Anticoagulant		3 months
Secondary	Number of Participants With Clinically Relevant Non-major Bleeding		3 months
Secondary	Hemoglobin Concentration	Measure Description: Normal hemoglobin range for adult women - 12 - 16 g/dL. Lower levels indicate worse outcomes.	3 months
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.	3 months