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

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ClinicalTrials.gov Identifier: NCT02090075
Recruitment Status : Completed
First Posted : March 18, 2014
Results First Posted : April 23, 2019
Last Update Posted : April 23, 2019
Sponsor:
Information provided by (Responsible Party):
Matthew J. Budoff, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Tracking Information
First Submitted Date  ICMJE March 16, 2014
First Posted Date  ICMJE March 18, 2014
Results First Submitted Date  ICMJE August 6, 2018
Results First Posted Date  ICMJE April 23, 2019
Last Update Posted Date April 23, 2019
Study Start Date  ICMJE September 2014
Actual Primary Completion Date December 27, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
Coronary Artery Calcium (CAC) Score [ Time Frame: 1 year ]
amount of calcification measured by Agatston Score. The range of values for the Agatston score is 0-10000. Higher score is worse outcome.
Original Primary Outcome Measures  ICMJE
 (submitted: March 17, 2014)
Coronary Artery Calcium (CAC) Score [ Time Frame: 1 year ]
Change History Complete list of historical versions of study NCT02090075 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 29, 2019)
Coronary Plaque on CT Angiography [ Time Frame: 1 year ]
To evaluate if treatment with apixaban therapy, as compared to warfarin therapy, will modify the progression, regression and stabilization of coronary atherosclerosis. Modifications will include differences in plaque volume, composition and arterial remodeling; as well as new atherosclerosis formation. The scale is based upon volume of plaque in the coronary arteries, with zero being no plaque and a higher number being more plaque. There is no scale or maximum measure, this is a linear measure of atherosclerosis volume in the coronary arteries and more is worse. None is best, any plaque is considered worse, and a higher plaque volume represents more atherosclerosis. An individual of average health will have a score of 50.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 17, 2014)
Coronary Plaque on CT Angiography [ Time Frame: 1 year ]
To evaluate if treatment with apixaban therapy, as compared to warfarin therapy, will modify the progression, regression and stabilization of coronary atherosclerosis. Modifications will include differences in plaque volume, composition and arterial remodeling; as well as new atherosclerosis formation
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Apixaban Versus Warfarin in the Evaluation of Progression of Atherosclerotic Calcification and Vulnerable Plaque
Official Title  ICMJE Apixaban Versus Warfarin in the Evaluation of Progression of Atherosclerotic Calcification and Vulnerable Plaque
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Atrial Fibrillation
Intervention  ICMJE
  • Drug: apixaban
    5 po or 2.5 po bid.
    Other Name: eliquis
  • Drug: warfarin
    Other Name: Coumadin
Study Arms  ICMJE
  • Active Comparator: apixaban
    apixaban 5 mg or 2.5 mg po bid
    Intervention: Drug: apixaban
  • Placebo Comparator: warfarin
    warfarin with target INR of 2-3
    Intervention: Drug: warfarin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 17, 2014)
66
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE April 5, 2017
Actual Primary Completion Date December 27, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02090075
Other Study ID Numbers  ICMJE 21183-01
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Matthew J. Budoff, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Study Sponsor  ICMJE Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthew Budoff, MD Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
PRS Account Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP