Rivaroxaban vs Apixaban on Menstrual Blood Loss

Venous Thromboembolism Clinical Trial

— RAMBLE  

Official title:

Randomized Trial to Test Effect of Rivaroxaban or Apixaban on Menstrual Blood Loss in Women (RAMBLE)

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02761044
• Other study ID #: 1604457633
• Status: Not yet recruiting
• Phase: Phase 3
• First received: April 29, 2016
• Last updated: May 20, 2016
• Start date: May 2016
• Est. completion date: May 2019

Study information

• Verified date: May 2016
• Source: Indiana University
• Contact: Jeffrey A Kline, MD
• Phone: 317-287-3007
• Email: jefkline[@]iu.edu
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate women with heavy menstrual bleeding that have venous thromboembolism or atrial fibrillation. There will be a comparison of the anti-coagulants; drugs rivaroxaban or apixaban to see if one of the drugs works better to control bleeding during the women's menses.

Description:

Heavy menstrual bleeding complicates the treatment of approximately nine to twenty five percent of patients treated with orally administered anti-Xa anticoagulants for venous thromboembolism, 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 with apixaban treatment. Increase in uterine bleeding with rivaroxaban has necessitated hysterectomy in rare cases. Other complications of heavy menstrual bleeding include reduced drug adherence, decreased perception of wellness (quality of life) and anemia. The anti-Xa agents may increase heavy menstrual bleeding more than vitamin K antagonists. However, in the principal investigators' experience treating over one hundred women of menstruating age with rivaroxaban for venous thromboembolism with varying degree of heavy menstrual bleeding, no woman has expressed desire to switch to a vitamin K antagonists even when offered this option (unpublished data). The investigators have successfully reduced perception of heavy menstrual bleeding by switching from rivaroxaban to apixaban in six patients. Comparison of published and supplemental data from large trials of apixaban versus rivaroxaban to treat venous thromboembolism reveals a lower rate of uterine bleeding with apixaban compared with rivaroxaban, although exact comparisons are difficult to make. Myers et al recently reported a 9.4 percent rate of heavy menstrual bleeding with apixaban, compared with a 25 percent rate of heavy menstrual bleeding with rivaroxaban. Accordingly, the investigators hypothesize that a larger proportion of women with menstruating potential with newly diagnosed venous thromboembolism or atrial fibrillation, treated with apixaban will have less menstrual blood loss than patients randomized to rivaroxaban.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 308
• Est. completion date: May 2019
• Est. primary completion date: December 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 49 Years

Eligibility

Inclusion Criteria:

• Non-pregnant women, age <50,

• Objectively diagnosed VTE or atrial fibrillation within the previous 30 days, and no menstrual cycle since diagnosis

• Patient reported active menstruation, requiring >3 menstrual periods in the previous 6 months

• Clinical plan and patient agreement to treat with oral anticoagulation for 3 months or longer

• Patients must have a working mobile phone

Exclusion Criteria:

• Package insert exclusions for Eliquis or Xarelto: [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 thienopyridines 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.

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• apixaban
In the primary (intent to treat) analysis, the proportions of patient achieving clinical success will be compared based upon their initial randomization (apixaban or rivaroxaban). In the secondary per-protocol analysis, the proportions will be compared between patients who completed 3 months of their primary drug assignment.
• rivaroxaban
In the primary (intent to treat) analysis, the proportions of patient achieving clinical success will be compared based upon their initial randomization (apixaban or rivaroxaban). In the secondary per-protocol analysis, the proportions will be compared between patients who completed 3 months of their primary drug assignment.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Indiana University	Indiana University Health

References & Publications (21)

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; PLIFY-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, Büller 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

Elmouchi DA, VanOosterhout S, Muthusamy P, Khan M, Puetz C, Davis AT, Brown MD. Impact of an emergency department-initiated clinical protocol for the evaluation and treatment of atrial fibrillation. Crit Pathw Cardiol. 2014 Jun;13(2):43-8. doi: 10.1097/HPC.0000000000000008. — View Citation

Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990 Aug;97(8):734-9. — View Citation

Kaatz S, Ahmad D, Spyropoulos AC, Schulman S; Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015 Nov;13(11):2119-26. — View Citation

Kahn SR, Shbaklo H, Lamping DL, Holcroft CA, Shrier I, Miron MJ, Roussin A, Desmarais S, Joyal F, Kassis J, Solymoss S, Desjardins L, Johri M, Ginsberg JS. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008 Jul;6(7):1105-12. doi: 10.1111/j.1538-7836.2008.03002.x. Epub 2008 Jun 1. — View Citation

Kline JA, Jimenez D, Courtney DM, Ianus J, Cao L, Lensing AW, Prins MH, Wells PS. Comparison of Four Bleeding Risk Scores to Identify Rivaroxaban-treated Patients With Venous Thromboembolism at Low Risk for Major Bleeding. Acad Emerg Med. 2016 Feb;23(2):144-50. doi: 10.1111/acem.12865. Epub 2016 Jan 14. — 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. IN PRESS.

Kline JA, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, Diercks DB, Klinger JR, Hernandez J. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014 Apr;12(4):459-68. doi: 10.1111/jth.12521. — View Citation

Klok FA, van Kralingen KW, van Dijk AP, Heyning FH, Vliegen HW, Kaptein AA, Huisman MV. Quality of life in long-term survivors of acute pulmonary embolism. Chest. 2010 Dec;138(6):1432-40. doi: 10.1378/chest.09-2482. Epub 2010 May 21. — 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. Review. — View Citation

Matteson KA, Boardman LA, Munro MG, Clark MA. Abnormal uterine bleeding: a review of patient-based outcome measures. Fertil Steril. 2009 Jul;92(1):205-16. doi: 10.1016/j.fertnstert.2008.04.023. Epub 2008 Jul 16. Review. — View Citation

Myers B, Webster A. Heavy menstrual bleeding on Rivaroxaban - Comparison with Apixaban. Br J Haematol. 2016 Mar 11. doi: 10.1111/bjh.14003. [Epub ahead of print] — View Citation

PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990 May 23-30;263(20):2753-9. — View Citation

Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. — View Citation

Sesti F, Ruggeri V, Pietropolli A, Piancatelli R, Piccione E. Thermal balloon ablation versus laparoscopic supracervical hysterectomy for the surgical treatment of heavy menstrual bleeding: a randomized study. J Obstet Gynaecol Res. 2011 Nov;37(11):1650-7. doi: 10.1111/j.1447-0756.2011.01596.x. Epub 2011 Jul 25. — View Citation

Stewart LK, Peitz GW, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, Diercks DB, Klinger JR, Kline JA. Contribution of fibrinolysis to the physical component summary of the SF-36 after acute submassive pulmonary embolism. J Thromb Thrombolysis. 2015 Aug;40(2):161-6. doi: 10.1007/s11239-014-1155-5. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Patient reported menstrual bleeding	Normal patient reported menstrual bleeding volume assessed as <100 arbitrary unit score on the Pictorial Blood Loss Assessment Chart (PBAC) on all menstrual periods.	3 months	Yes
Secondary	rate of discontinuation	Number of patients who discontinue assigned anticoagulant treatment	3 months	Yes
Secondary	how many patients held drug	Number of patients who hold dosing	3 months	No
Secondary	rate of recurrent venous thrombus embolism	Number of patients with recurrent venous thromboembolism	3 months	Yes
Secondary	rate of major hemorrhage	Number of patients with clinically relevant non-major bleeding	3 months	Yes
Secondary	Stable hemoglobin concentration	Hemoglobin concentration not lower than 2.0 g/dL below the hemoglobin concentration measured at enrollment	3 months	Yes
Secondary	SF36	Normalized physical component score =45 from the Standard Form 36 quality of life instrument (SF-36) measured at three months	3 months	No
Secondary	PCS value	Physical componet score is at least equal to PCS at enrollment	3 months	No