Apixaban for Secondary Prevention of Thromboembolism Among Patients With AntiphosPholipid Syndrome

Thrombosis Clinical Trial

— ASTRO-APS  

Official title:

Apixaban for the Secondary Prevention of Thromboembolism: a Prospective Randomized Outcome Pilot Study Among Patients With the AntiphosPholipid Syndrome

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02295475
• Other study ID #: CV185-357
• Secondary ID: 1040354
• Status: Completed
• Phase: Phase 4
• Start date: December 10, 2014
• Est. completion date: March 2022

Study information

• Verified date: September 2023
• Source: Intermountain Health Care, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is designed to compare the safety and effectiveness of two blood thinners, apixaban and warfarin, for the prevention of blood clots in patients who have a higher risk of blood clots than the general population, a condition called "antiphospholipid syndrome".

Description:

This study is a prospective, open-label, blinded event, pilot study that will randomize patients with a history of venous thrombosis and antiphospholipid syndrome (APS) already receiving anticoagulation to either warfarin or apixaban. The study will assess the safety and efficacy of apixaban compared with adjusted dose warfarin for the prevention of recurrent thrombosis (defined as the aggregate of arterial or venous thrombosis) and vascular death. The primary efficacy outcome will be confirmed upon adjudication by a panel blinded to the treatment arm. The primary safety outcome will be major bleeding and clinically relevant non-major bleeding events. Patients who consent to study participation will be randomized to anticoagulation with adjusted dose warfarin sodium or apixaban 5 mg by mouth twice daily. This pilot study will also provide information and experience identifying, recruiting, enrolling and randomizing patients with APS and a history of venous thrombosis to anticoagulation with apixaban or warfarin for the prevention of recurrent thrombosis.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: March 2022
• Est. primary completion date: April 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Be = 18 years of age

2. Have a clinical diagnosis of the antiphospholipid syndrome (APS) and a history of venous thrombosis only (excluding arterial thrombosis as recommended by the Data Safety Monitoring Board (DSMB)) for which the patient is receiving anticoagulation therapy for the prevention of recurrent thrombosis;

1. Anticoagulation is defined as warfarin sodium titrated at the discretion of the clinician to a target INR (International Normalized Ratio) 2.5 (range 2-3), 3.0 (range 2.5-3.5), or 3.5 (range 3-4).

2. Should the patient be receiving some other form of anticoagulation (apixaban, rivaroxaban, edoxaban, dabigatran etexilate, low-molecular weight heparin) and is willing to be randomized to warfarin with a target INR 2.5 or apixaban 5 mg by mouth twice daily and meets all other inclusion criteria.

3. Able to undergo magnetic resonance imaging (MRI) of the brain;

4. Have completed at least 6 months of anticoagulation for the indication of venous thrombosis and be without symptoms or signs consistent with acute thrombosis for a minimum of 6 months;

5. Be willing to provide informed consent to contact the subjects anticoagulation provider for INRs and dosing as well as details regarding any adverse events;

6. A woman of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of hCG (Human Chorionic Gonadotropin) within 24 hours prior to the start of study drug;

7. Women must not be breastfeeding;

8. A WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug apixaban plus 5 half-lives of study drug apixaban (3 days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-treatment completion;

9. Males who are sexually active with any WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug apixaban plus 5 half-lives of the study drug apixaban (3 days) plus 90 days (duration of sperm turnover) for a total of 93 days post-treatment completion;

10. Azoospermic males and women who are continuously not heterosexually active are exempt from contraceptive requirements. However, a WOCBP must still undergo pregnancy testing as described above;

11. If they are actively receiving a strong dual inhibitor of cytochrome P450 3A4 (CYP3A4) and P-gp, such as ketoconazole, itraconazole, ritonavir, and are agreeable to taking apixaban 2.5 mg twice daily.

Exclusion Criteria:

1. A history of arterial thromboembolism (e.g., stroke, myocardial infarction, or other arterial thrombosis);

2. Another indication for long-term anticoagulation for which no FDA (Food & Drug Administration) approval of apixaban exists (e.g., mechanical heart valve);

3. A life expectancy of less than 1 year;

4. Is unable to attend follow-up appointments;

5. Is participating in a clinical trial or has participated in a trial within the last 30 days;

6. Is receiving concomitant dual antiplatelet therapy;

7. Requires aspirin dose of greater than 165 mg daily;

8. Requires clopidogrel, ticagrelor, prasugrel, or another P2Y12 inhibitor;

9. A hemoglobin level of less than 8 mg per deciliter;

10. A platelet count of less than 50,000 per cubic millimeter;

11. Serum creatinine level of more than 2.5 mg per deciliter or a calculated creatinine clearance of less than 25 ml per minute;

12. Alanine aminotransferase or aspartate aminotransferase level greater than 2 times the upper limit of the normal range;

13. A total bilirubin more than 1.5 times the upper limit of the normal range;

14. Have active cancer for which treatment (chemotherapy/radiation therapy) is being delivered or has been delivered within the last 3 months;

15. Are actively taking a strong dual inducer of CYP3A4 and P-gp, such as:

• rifampin

• carbamazepine

• phenytoin

• St.John's wort

16. Intend pregnancy or breastfeeding within the next year;

17. Have a known allergy to apixaban, rivaroxaban, or edoxaban;

18. Have experienced thrombosis while receiving warfarin at a target INR of 2 to 3 and have been assigned a higher target INR at the discretion of the treating clinician;

19. Have active pathological bleeding;

20. Have a history of catastrophic APS (CAPS) as defined by clinical routine;

21. At the discretion of the investigator, are not considered to be good candidates secondary to a safety concern.

Patients who meet the above inclusion & exclusion criteria will be offered participation in the study. After informed consent is obtained, the patient will be consented for Magnetic Resonance Imaging (MRI). A brain MRI without contrast including weighted imaging and fluid-attenuated inversion recovery (FLAIR) will be performed as a study procedure to rule out prior stroke. If the patient has radiographic evidence of prior stroke on this MRI, then the patient will not be randomized, and will not be included in future study procedures or study analyses.

Related Conditions & MeSH terms

• Antiphospholipid Syndrome
• Syndrome
• Thromboembolism
• Thrombosis

Intervention

Drug:
• Apixaban

• Warfarin

Locations

Country	Name	City	State
United States	The James Comprehensive Cancer Center	Columbus	Ohio
United States	Intermountain Medical Center	Murray	Utah

Sponsors (3)

Lead Sponsor	Collaborator
Scott C. Woller, MD	Bristol-Myers Squibb, University of Utah

Country where clinical trial is conducted

United States, 

References & Publications (38)

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

Alarcon-Segovia D, Perez-Vazquez ME, Villa AR, Drenkard C, Cabiedes J. Preliminary classification criteria for the antiphospholipid syndrome within systemic lupus erythematosus. Semin Arthritis Rheum. 1992 Apr;21(5):275-86. doi: 10.1016/0049-0172(92)90021-5. — View Citation

Asherson RA, Khamashta MA, Ordi-Ros J, Derksen RH, Machin SJ, Barquinero J, Outt HH, Harris EN, Vilardell-Torres M, Hughes GR. The "primary" antiphospholipid syndrome: major clinical and serological features. Medicine (Baltimore). 1989 Nov;68(6):366-74. — View Citation

Bamber L, Wang MY, Prins MH, Ciniglio C, Bauersachs R, Lensing AW, Cano SJ. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep-vein thrombosis. Thromb Haemost. 2013 Oct;110(4):732-41. doi: 10.1160/TH13-03-0243. Epub 2013 Jul 11. — View Citation

Bates SM, Jaeschke R, Stevens SM, Goodacre S, Wells PS, Stevenson MD, Kearon C, Schunemann HJ, Crowther M, Pauker SG, Makdissi R, Guyatt GH. Diagnosis of DVT: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e351S-e418S. doi: 10.1378/chest.11-2299. — View Citation

Cano SJ, Lamping DL, Bamber L, Smith S. The Anti-Clot Treatment Scale (ACTS) in clinical trials: cross-cultural validation in venous thromboembolism patients. Health Qual Life Outcomes. 2012 Sep 26;10:120. doi: 10.1186/1477-7525-10-120. — View Citation

Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de Ramon E, Buonaiuto V, Jacobsen S, Zeher MM, Tarr T, Tincani A, Taglietti M, Theodossiades G, Nomikou E, Galeazzi M, Bellisai F, Meroni PL, Derksen RH, de Groot PG, Baleva M, Mosca M, Bombardieri S, Houssiau F, Gris JC, Quere I, Hachulla E, Vasconcelos C, Fernandez-Nebro A, Haro M, Amoura Z, Miyara M, Tektonidou M, Espinosa G, Bertolaccini ML, Khamashta MA; Euro-Phospholipid Project Group (European Forum on Antiphospholipid Antibodies). Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis. 2015 Jun;74(6):1011-8. doi: 10.1136/annrheumdis-2013-204838. Epub 2014 Jan 24. — View Citation

Cohen AT, Spiro TE, Buller HR, Haskell L, Hu D, Hull R, Mebazaa A, Merli G, Schellong S, Spyropoulos A, Tapson V. Extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study protocol. J Thromb Thrombolysis. 2011 May;31(4):407-16. doi: 10.1007/s11239-011-0549-x. — View Citation

Cohen H, Machin SJ. Antithrombotic treatment failures in antiphospholipid syndrome: the new anticoagulants? Lupus. 2010 Apr;19(4):486-91. doi: 10.1177/0961203310361355. — View Citation

Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser SH, Diaz R, Talajic M, Zhu J, Pais P, Budaj A, Parkhomenko A, Jansky P, Commerford P, Tan RS, Sim KH, Lewis BS, Van Mieghem W, Lip GY, Kim JH, Lanas-Zanetti F, Gonzalez-Hermosillo A, Dans AL, Munawar M, O'Donnell M, Lawrence J, Lewis G, Afzal R, Yusuf S; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011 Mar 3;364(9):806-17. doi: 10.1056/NEJMoa1007432. Epub 2011 Feb 10. — View Citation

Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139-51. doi: 10.1056/NEJMoa0905561. Epub 2009 Aug 30. Erratum In: N Engl J Med. 2010 Nov 4;363(19):1877. — View Citation

Cronan JJ. Venous thromboembolic disease: the role of US. Radiology. 1993 Mar;186(3):619-30. doi: 10.1148/radiology.186.3.8430164. — View Citation

Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003 Sep 18;349(12):1133-8. doi: 10.1056/NEJMoa035241. Erratum In: N Engl J Med. 2003 Dec 25;349(26):2577. N Engl J Med. 2004 Jul 8;351(2):200. — 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

Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibodies, and the risk of thrombosis in the antiphospholipid syndrome. Blood. 2003 Oct 15;102(8):2717-23. doi: 10.1182/blood-2002-11-3334. Epub 2003 Jun 19. No abstract available. — View Citation

Giannakopoulos B, Krilis SA. How I treat the antiphospholipid syndrome. Blood. 2009 Sep 3;114(10):2020-30. doi: 10.1182/blood-2009-05-220756. Epub 2009 Jul 8. — View Citation

Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FW, Zhu J, Wallentin L; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27. — View Citation

Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press. 1992 Aug;1(2):113-9. doi: 10.3109/08037059209077502. — View Citation

Keeling D, Mackie I, Moore GW, Greer IA, Greaves M; British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012 Apr;157(1):47-58. doi: 10.1111/j.1365-2141.2012.09037.x. Epub 2012 Feb 8. No abstract available. — View Citation

Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995 Apr 13;332(15):993-7. doi: 10.1056/NEJM199504133321504. — View Citation

Lassen MR, Ageno W, Borris LC, Lieberman JR, Rosencher N, Bandel TJ, Misselwitz F, Turpie AG; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008 Jun 26;358(26):2776-86. doi: 10.1056/NEJMoa076016. — View Citation

Les I, Ruiz-Irastorza G, Khamashta MA. Intensity and duration of anticoagulation therapy in antiphospholipid syndrome. Semin Thromb Hemost. 2012 Jun;38(4):339-47. doi: 10.1055/s-0032-1304720. Epub 2012 Mar 30. — View Citation

Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, Derksen RH, DE Groot PG, Koike T, Meroni PL, Reber G, Shoenfeld Y, Tincani A, Vlachoyiannopoulos PG, Krilis SA. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x. — View Citation

Nayer A, Ortega LM. Catastrophic antiphospholipid syndrome: a clinical review. J Nephropathol. 2014 Jan;3(1):9-17. doi: 10.12860/jnp.2014.03. Epub 2014 Jan 1. — View Citation

Petri M. Thrombosis and systemic lupus erythematosus: the Hopkins Lupus Cohort perspective. Scand J Rheumatol. 1996;25(4):191-3. doi: 10.3109/03009749609069986. — 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. doi: 10.1001/jama.1990.03440200057023. — View Citation

Prandoni P, Cogo A, Bernardi E, Villalta S, Polistena P, Simioni P, Noventa F, Benedetti L, Girolami A. A simple ultrasound approach for detection of recurrent proximal-vein thrombosis. Circulation. 1993 Oct;88(4 Pt 1):1730-5. doi: 10.1161/01.cir.88.4.1730. — View Citation

Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, Hailpern SM, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O'Donnell C, Roger V, Sorlie P, Steinberger J, Thom T, Wilson M, Hong Y; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008 Jan 29;117(4):e25-146. doi: 10.1161/CIRCULATIONAHA.107.187998. Epub 2007 Dec 17. No abstract available. Erratum In: Circulation. 2010 Jul 6;122(1):e10. Kissela, Bret [corrected to Kissela, Brett]. — View Citation

Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993 Mar 1;69(3):236-9. — View Citation

Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med. 1992 Aug 15;117(4):303-8. doi: 10.7326/0003-4819-117-4-303. — View Citation

Ruiz-Irastorza G, Khamashta MA, Hunt BJ, Escudero A, Cuadrado MJ, Hughes GR. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med. 2002 May 27;162(10):1164-9. doi: 10.1001/archinte.162.10.1164. — 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. doi: 10.1111/j.1538-7836.2005.01204.x. — View Citation

Stein PD, Gottschalk A, Sostman HD, Chenevert TL, Fowler SE, Goodman LR, Hales CA, Hull RD, Kanal E, Leeper KV Jr, Nadich DP, Sak DJ, Tapson VF, Wakefield TW, Weg JG, Woodard PK. Methods of Prospective Investigation of Pulmonary Embolism Diagnosis III (PIOPED III). Semin Nucl Med. 2008 Nov;38(6):462-70. doi: 10.1053/j.semnuclmed.2008.06.003. — View Citation

van Belle A, Buller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW, Kramer MH, Kruip MJ, Kwakkel-van Erp JM, Leebeek FW, Nijkeuter M, Prins MH, Sohne M, Tick LW; Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006 Jan 11;295(2):172-9. doi: 10.1001/jama.295.2.172. — View Citation

van Walraven C, Jennings A, Oake N, Fergusson D, Forster AJ. Effect of study setting on anticoagulation control: a systematic review and metaregression. Chest. 2006 May;129(5):1155-66. doi: 10.1378/chest.129.5.1155. — View Citation

Vianna JL, Khamashta MA, Ordi-Ros J, Font J, Cervera R, Lopez-Soto A, Tolosa C, Franz J, Selva A, Ingelmo M, et al. Comparison of the primary and secondary antiphospholipid syndrome: a European Multicenter Study of 114 patients. Am J Med. 1994 Jan;96(1):3-9. doi: 10.1016/0002-9343(94)90108-2. — View Citation

Witt DM, Sadler MA, Shanahan RL, Mazzoli G, Tillman DJ. Effect of a centralized clinical pharmacy anticoagulation service on the outcomes of anticoagulation therapy. Chest. 2005 May;127(5):1515-22. doi: 10.1378/chest.127.5.1515. — View Citation

* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate (number divided by duration) of clinically overt thromboses (arterial and/or venous) or vascular death		From time of first dose of study drug through 2 days after receiving the last dose of study drug at the end of 12 months of treatment
Primary	Rate (number divided by duration) of occurrence of major (including fatal) and clinically relevant non-major bleeding	Major bleeding is clinically overt bleeding accompanied by one or more of the following: a decrease in the hemoglobin level of 2 g per deciliter or more, transfusion of 2 or more units of packed red cells, bleeding at a critical site (intracranial, intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment syndrome, or retroperitoneal), or fatal bleeding. Clinically relevant non-major bleeding is defined as clinically overt bleeding that does not satisfy the criteria for major bleeding and that led to hospital admission, physician-guided medical or surgical treatment, or a change in antithrombotic therapy.	From time of first dose of study drug through 2 days after receiving the last dose of study drug at the end of 12 months of treatment
Secondary	Net clinical benefit (combination of occurrence of thrombosis and bleeding rates)	Sum of number of thrombosis and bleeding events divided by duration	From time of first dose of study drug through 2 days after receiving the last dose of study drug at the end of 12 months of treatment