Clinical trial NCT02829957: RAMBLE - Rivaroxaban vs. Apixaban for Heavy Menstrual Bleeding
Official title: Randomized Trial to Test the Effect of Rivaroxaban or Apixaban on Menstrual Blood Loss in Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Venous Thromboembolism
Menstruation
Lead sponsor: Indiana University
Sponsor class: OTHER
First posted: 2016-07-12
Enrollment: 19
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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for VTE with varying degree of HMB, no woman has expressed desire to switch to a VKA even when offered this option (unpublished data).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

Eligibility criteria: 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.

Primary outcomes:
measure: PBAC Scores
timeFrame: 3 months
Secondary outcomes:
measure: Number of Participants Who Discontinued Planned Drug Administration
timeFrame: 3 months
measure: Number of Patients That Held Drug for Menorrhagia
timeFrame: 1, 2, and 3 months
measure: Number of Participants With Major Hemorrhage
timeFrame: 3 months
measure: Number of Participants With Venous Thromboembolism (VTE)
timeFrame: 3 months
measure: Number of Participants Who Crossed Over to Another Anticoagulant
timeFrame: 3 months
measure: Number of Participants With Clinically Relevant Non-major Bleeding
timeFrame: 3 months
measure: Hemoglobin Concentration
timeFrame: 3 months
measure: Physical Component Summary of Standard From 36
timeFrame: 3 months
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Eskenazi Health System
state: Indiana
city: Indianapolis
country: United States
facility: Indiana University Health Methodist Hospital
state: Indiana
Study officials:
affiliation: Indiana University
name: Jeffrey A Kline, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
citation: 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.
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.
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.
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.