Apixaban Versus Warfarin in the Evaluation of Progression of Atherosclerotic Calcification and Vulnerable Plaque

NCT ID: NCT02090075

Last Updated: 2019-04-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 66 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2017-04-05

Brief Summary

Vitamin K-antagonists (VKA) such as warfarin are the most widely used blood thinners for irregular heart beats like atrial fibrillation. Several lines of evidence indicate, however, that these agents also cause calcification of vessels (hardening of the vessels). Vascular calcification is one of the recently revealed side-effects of warfarin therapy. We will be randomizing 66 patients to either take warfarin or a new blood thinner that works without affecting vitamin k (apixaban). Patients will undergo blood testing and a CT angiogram (non-invasive angiogram) at the beginning of the study, and then be followed for one year with quarterly visits including blood tests and given either warfarin or vitamin K. After one year, they will undergo another CT angiogram and examination and blood tests and the effect of apixaban and warfarin are tested to look at plaque and changes over time. Patients will be consented in a private room and the risks and benefits will be explained. The risks include the CT angiogram and the possibility of either remaining on warfarin therapy for another year (standard of care) or taking a medicine that doesn't require monitoring (apixaban) for one year. The CT angiograms will require some contrast and some radiation dose, which will be minimized as much as possible. A cardiologist will be present during each CT angiogram to minimize risk and ensure patient safety.

Detailed Description

The progression of atherosclerotic plaques characterized by various anatomic plaque composition changes has been acknowledged to be associated with increased plaque rupture, myocardial infarction and death. Coronary computed tomography angiography (CCTA) has emerged as a novel non-invasive modality with high diagnostic performance for detection and assessment of atheroma compared to invasive coronary angiography (ICA) and intravascular ultrasound (IVUS). Beyond stenosis severity, CCTA also permits anatomic quantification of numerous atheroscleroticStudy design This is a prospective, single-centered, randomized, open-label trial with blinded adjudication of results (plaque composition) designed to compare apixaban (2.5 mg or 5 mg BID per the current guideline) with warfarin (target international normalized ratio, 2.0 to 3.0) for 52 weeks on calcified plaque, coronary plaque composition and volume in patients with non-valvular AF.

Study population The targeted population included patients aged 18-84 years with non-valvular AF or flutter at enrollment or two more episodes of AF (as documented by electrocardiography) at least 2 weeks apart in the 12 months before enrollment. The inclusion and exclusion criteria were shown in detail in a recent paper. Subjects were enrolled from May 2014 to December 2015 and randomized into warfarin group (VKA_group) or apixaban group (Api_group). Of the 66 originally enrolled patients, 56 had complete data at final follow-up, including interpretable CCTA scans at baseline and follow-up. All subjects were followed up for a total 52 weeks.

Coronary CTA scan protocol All CT scans were performed with a 64-slice CT scanner (Lightspeed VCT; General Electric Healthcare Technologies, Milwaukee, WI, USA), or 256-slice CT scanner (Revolution CT; General Electric Healthcare Technologies, Milwaukee, WI, USA). Before CCTA, a prospective non-enhanced coronary calcium (CAC) scan was performed. For quantitative assessment of CAC, the Agatston score was calculated, using a 3 mm CT slice thickness and a detection threshold of ≥130 HU involving ≥1 mm2 area/lesion (3 pixels). CCTA was performed using a collimation of 64 × 0.625 mm or 256 × 0.625 mm and a rotation time of 0.4 s or 0.28 s. The tube current was 400-770 mA (depending on body weight), at 100-120 kV. Contrast material at a flow rate of 5.0 mL/s was administered in the antecubital vein, with volumes depending on the total scan time (60-80 mL). In the absence of contraindications, patients with a heart rate ≥60 bpm were administered 50-100 mg metoprolol oral and up to 40 mg metoprolol intravenous if needed. Interpretation was performed by expert reading by an experienced cardiologist (M.J.B) blinded to all clinical data.

plaque phenotypes, plaque burden and ability to differentiate between various plaque types. Also, recent technology providing low radiation dose for CCTA with approximately < 1-3mSv allows us to investigate the effects of different therapies using serial CCTA.

Warfarin, a vitamin K antagonist (VKA) and one of the most commonly used oral anti-coagulants, has been showed to increase vascular calcification leading to increased cardiovascular (CV) events. However, apixaban, a direct Factor Xa inhibitor, has no interaction with vitamin K and its effect on the progression of atherosclerotic plaques is still unknown. The potential benefit of avoiding VKA therapy and the favorable effects of factor Xa inhibitors may contribute to a reduction in CV events. We aimed to compare apixaban with warfarin on progression of coronary plaque composition and volume in non-valvular AF patients using CCTA.

Conditions

Atrial Fibrillation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

apixaban

apixaban 5 mg or 2.5 mg po bid

Group Type: ACTIVE_COMPARATOR

apixaban

Intervention Type: DRUG

5 po or 2.5 po bid.

warfarin

warfarin with target INR of 2-3

Group Type: PLACEBO_COMPARATOR

warfarin

Intervention Type: DRUG

Interventions

apixaban

5 po or 2.5 po bid.

Intervention Type: DRUG

warfarin

Intervention Type: DRUG

Other Intervention Names

eliquis; Coumadin

Eligibility Criteria

Inclusion Criteria

• Eligible patients with atrial fibrillation or flutter
• Age 18-84 years
• Willingness to participate in the study and ability to sign informed consent.

Exclusion Criteria

• Atrial fibrillation due to a reversible cause
• moderate or severe mitral stenosis
• conditions other than atrial fibrillation that require anticoagulation (e.g., a prosthetic heart valve)
• A need for aspirin at a dose of >165 mg a day or for both aspirin and P2Y-inhibitor
• Serious bleeding event in the previous 6 months or a high risk of bleeding (eg, active peptic ulcer disease)
• a platelet count of <100,000/mm3 or hemoglobin level of <10 g/dL
• stroke within the previous 10 days
• documented hemorrhagic tendencies, or blood dyscrasias
• Renal insufficiency (serum creatinine level of 12.5 mg per deciliter or calculated creatinine clearance of <50 ml per minute)
• Weight in excess of 325 pounds
• Resting hypotension (systolic blood pressure of <90mmHg) or resting hypertension (systolic blood pressure of >170mmHg or diastolic blood pressure of >110 mmHg)
• History of active malignancy requiring concurrent chemotherapy
• Known allergy to iodinated contrast material
• pregnancy, women of childbearing potential unwilling to use adequate contraception.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Matthew J. Budoff

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Matthew Budoff, MD

Role: PRINCIPAL_INVESTIGATOR

Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Locations

Los Angeles Biomedical Research Institute

Torrance, California, United States

Countries

United States

References

Win TT, Nakanishi R, Osawa K, Li D, Susaria SS, Jayawardena E, Hamal S, Kim M, Broersen A, Kitslaar PH, Dailing C, Budoff MJ. Apixaban versus warfarin in evaluation of progression of atherosclerotic and calcified plaques (prospective randomized trial). Am Heart J. 2019 Jun;212:129-133. doi: 10.1016/j.ahj.2019.02.014. Epub 2019 Mar 13.

Reference Type: DERIVED

PMID: 31002997 (View on PubMed)

Other Identifiers

21183-01

Identifier Type: -

Identifier Source: org_study_id