Apixaban Versus Warfarin in the Evaluation of Progression of Atherosclerotic Calcification and Vulnerable Plaque
| Status: | Completed |
|---|---|
| Conditions: | Atrial Fibrillation, Atrial Fibrillation |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 85 |
| Updated: | 8/9/2018 |
| Start Date: | September 2014 |
| End Date: | April 5, 2017 |
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.
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.
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 death12, 13. 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)14-16. 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 paper27. 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)28. 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
types14-20. 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 calcification21-24 leading to increased
cardiovascular (CV) events25, 26. 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.
composition changes has been acknowledged to be associated with increased plaque rupture,
myocardial infarction and death12, 13. 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)14-16. 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 paper27. 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)28. 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
types14-20. 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 calcification21-24 leading to increased
cardiovascular (CV) events25, 26. 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.
Inclusion Criteria:
- Eligible patients with atrial fibrillation or flutter at enrollment or two or more
episodes of atrial fibrillation, as documented by electrocardiography, at least 2
weeks apart in the 12 months before enrollment; 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, or
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; Any unstable medical, psychiatric, or substance abuse disorder that in
the opinion of the principal investigator is likely to affect the subject's ability to
complete the study; Known allergy to iodinated contrast material; pregnancy, women of
childbearing potential unwilling to use adequate contraception.
We found this trial at
1
site
Torrance, California 90502
Principal Investigator: Matthew Budoff, MD
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