Rationale and design of "Can Very Low Dose Rivaroxaban (VLDR) in addition to dual antiplatelet therapy improve thrombotic status in acute coronary syndrome (VaLiDate-R)" study : A randomised trial modulating endogenous fibrinolysis in patients with acute coronary syndrome

Ying X Gue, Rahim Kanji, David M Wellsted, Manivannan Srinivasan, Solange Wyatt, Diana A Gorog, Ying X Gue, Rahim Kanji, David M Wellsted, Manivannan Srinivasan, Solange Wyatt, Diana A Gorog

Abstract

Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

Keywords: Acute coronary syndrome; Endogenous fibrinolysis; NOAC; Rivaroxaban; Thrombosis.

Conflict of interest statement

The study is funded by Bayer PLC (Grant No. IIR-GB-2017-4575). Bayer Plc have had no input into the trial design or the writing of this manuscript. DAG has received travel grants from Bayer Plc, and institutional research grants from Bayer PLC and Bristol Myer Squibb. DAG is related to a company director in Thromboquest Ltd. which manufactures the GTT, but neither she, nor her spouse or children have financial involvement or equity interest in, or received financial assistance, support or grants from the aforementioned company and the aforementioned company will have no involvement in the design, conduct or the finance of this research study. Consumables will be purchased as normal commercial transactions without the manufacturer giving any financial support. There are no other contracts, benefits or personal relationships to disclose.

Figures

Fig. 1
Fig. 1
Outline of study and follow-up procedure

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