Comparison of Clopidogrel-based Antiplatelet Therapy Versus Warfarin as Secondary Prevention Strategy for AntiPhospholipid Syndrome-related STROKE

Cardiovascular Diseases Clinical Trial

— APS-STROKE  

Official title:

Comparison of Clopidogrel-based Antiplatelet Therapy Versus Warfarin as Secondary Prevention Strategy for AntiPhospholipid Syndrome-related STROKE (APS-STROKE)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05995600
• Other study ID #: H-2304-096-1425
• Status: Recruiting
• Phase: Phase 4
• Start date: February 20, 2024
• Est. completion date: October 2028

Study information

• Verified date: April 2024
• Source: Seoul National University Hospital
• Contact: Wookjin Yang, MD
• Phone: +82-2-2072-2114
• Email: ywj_2002[@]naver.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Antiphospholipid syndrome (APS) has a close association with ischemic stroke; however, the optimal treatment strategy for APS-related stroke has yet to be established. The clinical guidelines suggest using warfarin for APS-related stroke, but these suggestions are largely based on retrospective studies from the 1990s and expert opinion, rather than high-quality clinical trials. Moreover, the evidence on the role of antiplatelet drugs other than aspirin (e.g., clopidogrel) in APS-related stroke is particularly limited. Considering the relatively young age of patients with APS and the high clinical burden of using warfarin, it is necessary to verify whether warfarin is essential. Thus, the investigators aim to compare clopidogrel-based antiplatelet therapy and warfarin as a secondary preventive medication for patients with APS-related stroke. APS-STROKE is an exploratory, multicenter, prospective, randomized, open, blinded-endpoint clinical trial. Adult patients with definite APS who have a history of ischemic stroke will be included. Patients with high-risk APS (triple positivity or persistently high titers of anti-cardiolipin or anti-β2-glycoprotein I antibodies), systemic lupus erythematous, or indications for continued antiplatelet or anticoagulant therapy will be excluded. Eligible patients will be 1:1 randomized to receive clopidogrel-based antiplatelet therapy or warfarin. Patients assigned to the clopidogrel-based antiplatelet therapy group will be permitted to use additional antiplatelet drugs other than clopidogrel at the investigator's discretion. The primary outcome is a composite of any death, major adverse cardiovascular events, systemic thromboembolic events, and major bleeding during a follow-up period of at least 2 years. This study would provide valuable information for determining the optimal secondary prevention strategy for APS-related stroke.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 400
• Est. completion date: October 2028
• Est. primary completion date: July 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

Inclusion Criteria:

• Age 19 years or older
• History of ischemic stroke (cerebral infarction, transient ischemic attack, or retinal arterial ischemic event)
• Patients who meet the laboratory diagnostic criteria for antiphospholipid syndrome (APS)
• Patients or guardians who agree to the study protocol and sign with informed consent

Exclusion Criteria:

• Patients with high-risk antiphospholipid antibody profile (triple positivity; persistent high-titers exceeding 80 U/mL of anti-cardiolipin or anti-ß2 glycoprotein I antibodies)
• Systemic lupus erythematous
• Patients unable to discontinue previously taken anticoagulants or antiplatelet agents (e.g., atrial fibrillation, valvular heart disease, or a history of percutaneous coronary intervention)
• Women who are pregnant, breastfeeding, or intending to become pregnant during the study period
• Deemed unsuitable for participation in the study for more than two years, as per the investigators' discretion

Related Conditions & MeSH terms

• Antiphospholipid Syndrome
• Cardiovascular Diseases
• Cerebrovascular Disease
• Cerebrovascular Disorders
• Ischemia
• Ischemic Attack, Transient
• Ischemic Stroke
• Major Bleed
• Stroke
• Syndrome
• Transient Ischemic Attack

Intervention

Drug:
• Antiplatelet Drug
Clopidogrel ± other antiplatelet drug
• Warfarin
Warfarin (target prothrombin time-international normalized ratio 2.0-3.0)

Locations

Country	Name	City	State
Korea, Republic of	Hallym University Sacred Heart Hospital	Anyang
Korea, Republic of	Busan Paik Hospital	Busan
Korea, Republic of	Pusan National University Hospital	Busan
Korea, Republic of	Chungbuk National University Hospital	Cheongju-si
Korea, Republic of	Hallym University Chuncheon Sacred Heart Hospital	Chuncheon
Korea, Republic of	Kangwon National University Hospital	Chuncheon
Korea, Republic of	Keimyung University Dongsan Medical Center	Daegu
Korea, Republic of	Yeungnam University Medical Center	Daegu
Korea, Republic of	Chungnam National University Hospital	Daejeon
Korea, Republic of	Hanyang University Guri Hospital	Guri-si
Korea, Republic of	Chonnam National University Hospital	Gwangju
Korea, Republic of	Chosun University Hospital	Gwangju
Korea, Republic of	Gachon University Gil Medical Center	Incheon
Korea, Republic of	Inha University Hospital	Incheon
Korea, Republic of	Jeju National University Hospital	Jeju
Korea, Republic of	Jeonbuk National University Hospital	Jeonju
Korea, Republic of	Chungnam National University Sejong Hospital	Sejong
Korea, Republic of	Seoul National University Bundang Hospital	Seongnam
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Ewha Woman University Seoul Hospital	Seoul
Korea, Republic of	Ewha Womans University Mokdong Hospital	Seoul
Korea, Republic of	Hallym University Kangdong Sacred Heart Hospital	Seoul
Korea, Republic of	Hanyang University Seoul Hospital	Seoul
Korea, Republic of	Konkuk University Medical Center	Seoul
Korea, Republic of	Korea University Anam Hospital	Seoul
Korea, Republic of	Kyung Hee University Medical Center	Seoul
Korea, Republic of	Seoul Metropolitan Government-Seoul National University Boramae Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital	Seoul
Korea, Republic of	Uijeongbu Eulji Medical Center	Uijeongbu
Korea, Republic of	Yongin Severance Hospital	Yongin

Sponsors (2)

Lead Sponsor	Collaborator
Seoul National University Hospital	Samjin Pharmaceutical Co., Ltd.

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (19)

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Kleindorfer DO, Towfighi A, Chaturvedi S, Cockroft KM, Gutierrez J, Lombardi-Hill D, Kamel H, Kernan WN, Kittner SJ, Leira EC, Lennon O, Meschia JF, Nguyen TN, Pollak PM, Santangeli P, Sharrief AZ, Smith SC Jr, Turan TN, Williams LS. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021 Jul;52(7):e364-e467. doi: 10.1161/STR.0000000000000375. Epub 2021 May 24. No abstract available. Erratum In: Stroke. 2021 Jul;52(7):e483-e484. — View Citation

Krnic-Barrie S, O'Connor CR, Looney SW, Pierangeli SS, Harris EN. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors influencing recurrent thrombosis. Arch Intern Med. 1997 Oct 13;157(18):2101-8. — 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

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Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12. — View Citation

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Udry S, Latino JO, Belizna C, Peres Wingeyer S, Fernandez Romero DS, de Larranaga G. A high-risk laboratory profile of antiphospholipid antibodies and thrombosis is associated with a large number of extra-criteria manifestations in obstetric antiphospholipid syndrome. Immunol Res. 2019 Dec;67(6):478-485. doi: 10.1007/s12026-019-09110-x. — View Citation

Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Wang C, Li H, Meng X, Cui L, Jia J, Dong Q, Xu A, Zeng J, Li Y, Wang Z, Xia H, Johnston SC; CHANCE Investigators. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013 Jul 4;369(1):11-9. doi: 10.1056/NEJMoa1215340. Epub 2013 Jun 26. — View Citation

Woller SC, Stevens SM, Kaplan D, Wang TF, Branch DW, Groat D, Wilson EL, Armbruster B, Aston VT, Lloyd JF, Rondina MT, Elliott CG. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv. 2022 Mar 22;6(6):1661-1670. doi: 10.1182/bloodadvances.2021005808. — View Citation

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* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite endpoint	Composite endpoint of any death, major adverse cardiovascular events (MACEs), systemic thromboembolic events, and major bleeding. MACE includes any stroke, transient ischemic attack, and acute coronary syndrome (i.e., ST-elevation myocardial infarction, non-ST elevation myocardial infarction, and hospitalization with unstable angina) in this study. Major bleeding refers to bleeding events meeting the criteria for Bleeding Academic Research Consortium (BARC) type 3 or 5.	2 years
Secondary	MACE	MACE includes any stroke, transient ischemic attack, and acute coronary syndrome (i.e., ST-elevation myocardial infarction, non-ST elevation myocardial infarction, and hospitalization with unstable angina) in this study.	2 years
Secondary	Ischemic stroke	Ischemic stroke or transient ischemic attack	2 years
Secondary	Any bleeding	Major or minor bleeding according to definitions from BARC	2 years
Secondary	Major bleeding	BARC bleeding type 3 or 5	2 years
Secondary	Intracranial bleeding	Intracranial bleeding that is objectively confirmed by brain imaging	2 years
Secondary	Clinically relevant non-major bleeding	Any bleeding that does not fit the criteria for major bleeding but does meet at least one of the following criteria: requiring nonsurgical, medical intervention by a healthcare professional; leading to hospitalization or increased level of care; prompting evaluation.	2 years
Secondary	Any death	Death from any cause	2 years
Secondary	Thrombosis-related death	Death from arterial, venous, or capillary thrombotic events	2 years