Cardiovascular Disease
Conditions
Keywords
Cholesterol, Heart Disease, CT Scan, Crestor, Lipitor
Brief summary
Background: Coronary artery disease causes plaque in arteries. This can cause stroke or heart disease. Drugs called statins might shrink plaque. Researchers want to study how CT scanning can determine if an individuals arterial plaque has decreased while taking statins. Objectives: To measure the change in coronary artery plaque volume in people treated with high-intensity statin therapy using CT and MRI scans. To study the metabolic activity of plaque in arteries. To determine how well plaque measurements from heart CT scans can be replicated. Eligibility: Men ages 40-75 and women ages 40-75 who are good candidates for statin treatment Design: Visit 1: participants will be screened with: * Medical history * Blood tests * Heart MRI and CT scan: An IV inserted into an arm or hand vein removes blood and injects contrast, and medicine if needed. Participants lie on a table that slides into a machine that takes pictures of the body. For the CT scan, if their heart rate is too high, they get medicine to lower it. They breathe in a special way, holding their breath for 5 seconds. Participants will begin high-intensity statin treatment. Participants will have 7 more visits over 3 years. All visits include blood tests and medication review. Some may also include: * Statin treatment adjustment * CT scan * MRI scan * Physical exam Participants may join the PET Substudy. This includes 5 more visits during the study. These include: * Getting an IV in an arm vein * Blood tests * PET scans: They fast 12 hours before. Participants may join the Reproducibility Substudy if they had a slow heart rate during their first CT scan. This includes 1 additional heart CT scan 4 weeks later.
Detailed description
In high risk patients undergoing invasive angiography, intravascular ultrasound (IVUS) has shown reduction of plaque for patients treated with HMG-CoA reductase inhibitors (statins). However, there is no accepted noninvasive method to determine if treatment for atherosclerosis results in reduction of coronary artery plaque. Coronary artery CT angiography (CCTA) is noninvasive and can accurately determine the degree of coronary artery stenosis. In addition, the extent of calcified and noncalcified plaque may be directly measured using this technology at low radiation dose using state-of-the-art CT scanners. Several retrospective studies have previously suggested that CCTA may be able to show plaque regression in the coronary arteries due to statin therapy. The primary aim of this proposal is to determine the change in coronary artery plaque volume in individuals treated with high intensity statin therapy as defined by 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. Men and women who meet the inclusion and exclusion criteria will undergo CCTA examination for the presence or absence of coronary artery plaque. Individuals with evidence of noncalcified coronary plaque by CCTA and who meet criteria for HMG-CoA reductase (statin) therapy will be evaluated for a total of 36 months. The change of coronary artery plaque (progression or no change, or regression) in individuals with noncalcified plaque at baseline will be measured by CCTA at yearly intervals.
Interventions
DRUGRosuvastatin
Participants will receive 20-40 mg once daily
DRUGAtorvastatin
Participants will receive 40-80 mg once daily.
RADIATIONCardiac Computed Tomography (CT)
Cardiac CT angiography (CCTA) provides a non-invasive method of evaluating both calcified and noncalcified plaque volume. Performed at baseline, 12 months 24 months, and 36 months.
RADIATIONCardiac Magnetic Resonance Image (MRI)
Provides a non-invasive method of evaluating both calcified and noncalcified plaque volume. Cardiac MRI may be performed at baseline, and 24 months (optional).
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: A. Men greater than or equal to 40 and less than or equal to 75 years of age; women greater than or equal to 40 and less than or equal to 75 years of age B. Willing to travel to the NIH for follow-up visits. C. Willing to start or modify statin therapy. D. Able to understand and sign informed consent. E. Eligible for primary prevention statin therapy 1. Eligible for at least moderate intensity statin according to 2013 ACC/AHA GRCR (i.e., greater than or equal to 5% 10 year cardiovascular risk, https://my.americanheart.org/professional/StatementsGuidelines/Prevention-Guidelines\_UCM\_457698\_SubHomePage.jsp) OR 2. low (\<5%) 10 year cardiovascular risk per 2013 ACC/ AHA and with coronary artery calcium score greater than or equal to 300 Agatston units or greater than or equal to 75 percentile for age, sex, and ethnicity determined per MESA study (http://www.mesa-nhlbi.org/calcium/input.aspx).
Exclusion criteria
A. Allergy or prior clinically relevant adverse reaction to Rosuvastatin (does not include minor muscle pain). B. High intensity statin treatment for more than 90 days prior to enrollment C. LDL greater than or equal to 190 mg/ml D. Physician-diagnosed heart attack E. Physician-diagnosed stroke or TIA F. Physician-diagnosed heart failure G. Having undergone procedures related to cardiovascular disease (CABG, angioplasty, valve replacement, pacemaker or defibrillator implantation, any surgery on the heart or arteries) H. Active treatment for cancer I. Prior hypersensitivity reaction to iodinated contrast injection J. Known hyperthyroidism. K. Acute renal failure, renal transplant, dialysis and renal failure clinically diagnosed. L. History of liver transplant or severe liver disease or unexplained elevation of baseline ALT\>3x upper limit of normal M. Pregnancy and nursing N. Mental, neurologic or social condition preventing understanding of the rationale, procedures, risks and potential benefits associated with the trial. O. Any other conditions that precludes safety for MRI and/or CT imaging per the researcher's evaluation. P. Individuals with hemoglobinopathies or severe asthma. Q. Severe renal excretory dysfunction, estimated glomerular filtration (eGFR) rate \< 30 mL/min/1.73m2 body surface area according to the Modification of Diet in Renal Disease criteria Glomerular filtration rate will be estimated using the MDRD 2005 revised study formula: eGFR (mL/min/1.73m2) = 175 x (standardized serum creatinine)-1.154 x (age)-0.203 x 0.742 (if the subject is female) or x 1.212 (if the subject is black)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change of Non-calcified Plaque Volume in Participants Treated With High Intensity Statin Therapy Assessed by Coronary Computed Tomography Angiography | Baseline and 24 months | Mean change of non-calcified plaque volume assessed by Coronary computed tomography angiography in participants treated with high intensity statin therapy (as defined by the 2013 ACC/AHA Guidelines to Reduce Cardiovascular Risk (GRCR). Using anatomical landmarks, a target plaque volume will be defined at baseline and follow up examinations. Software will be used to trace lumen and outer vessel boundaries to determine non-calcified plaque volume. The 2013 ACC/AHA Guidelines to GRCR focuses on the assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk and management of elevated blood cholesterol and body weight in adults. High-intensity statin therapy is defined by: rosuvastatin 20-40 mg or atorvastatin 40-80 mg. The maximum statin dose will be administered that is tolerated by the patient and that maintains LDL-C \> or = 25 mg/dl. High-intensity statin therapy is defined as lowering LDL-C on average by approximately \> or = 50%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change of Non-calcified Plaque Volume in Participants Treated With High Intensity Statin Therapy Assessed by Coronary Computed Tomography Angiography | Baseline and 36 months | Mean change of non-calcified plaque volume assessed by Coronary computed tomography angiography in participants treated with high intensity statin therapy (as defined by the 2013 ACC/AHA Guidelines to Reduce Cardiovascular Risk (GRCR). Using anatomical landmarks, a target plaque volume will be defined at baseline and follow up examinations. Software will be used to trace lumen and outer vessel boundaries to determine non-calcified plaque volume. The 2013 ACC/AHA Guidelines to GRCR focuses on the assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk and management of elevated blood cholesterol and body weight in adults. High-intensity statin therapy is defined by: rosuvastatin 20-40 mg or atorvastatin 40-80 mg. The maximum statin dose will be administered that is tolerated by the patient and that maintains LDL-C \> or = 25 mg/dl. High-intensity statin therapy is defined as lowering LDL-C on average by approximately \> or = 50%. |
| Linear Mixed-effects Regression Coefficient of Age Effect on Plaque Volume | Baseline, 24 months and 36 months | Linear mixed-effects regression coefficient of age effect on plaque volume measured by Coronary artery CT angiography. Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume given one year increase of age. In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware. |
| Linear Mixed-Effects Regression Coefficient of Sex Effect on Plaque Volume (Beta Coefficient) | Baseline, 24 months and 36 months | Linear Mixed-effects Regression Coefficient of sex (female = 0 and male = 1) effect on plaque volume measured by Coronary artery CT angiography (beta coefficient). Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume comparing male verses female (female =0 and male = 1). In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware. |
| Linear Mixed-effects Regression Coefficient of Race Effect on Plaque Volume (Beta Coefficient) | Baseline, 24 months and 36 months | Linear Mixed-effects Regression Coefficient of Effects race (white = 1 and non-white = 0) effect on plaque volume measured by Coronary artery CT angiography. Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume comparing race (white = 1 and non-white = 0). In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware. |
| Linear Mixed-effects Regression Coefficient of Body Mass Index Effect on Plaque Volume | Baseline, 24 months and 36 months | Linear Mixed-effects Regression Coefficient of Body Mass Index Effect on Plaque Volume measured by Coronary artery CT angiography. Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume given one kg/m\^2 increase of BMI. In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque Participants with coronary artery plaque will receive moderate to high statin treatment at either 20-40 mg once daily Rosuvastatin or 40-80 mg once daily of Atorvastatin. | 79 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Physician Decision | 5 |
| Overall Study | Withdrawal by Subject | 14 |
Baseline characteristics
| Characteristic | Moderate to High Statin Treatment in Participants With Coronary Artery Plaque |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 49 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age, Continuous | 65.4 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 72 Participants |
| Region of Enrollment United States | 79 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 79 |
| other Total, other adverse events | 56 / 79 |
| serious Total, serious adverse events | 8 / 79 |
Outcome results
Primary
Mean Change of Non-calcified Plaque Volume in Participants Treated With High Intensity Statin Therapy Assessed by Coronary Computed Tomography Angiography
Mean change of non-calcified plaque volume assessed by Coronary computed tomography angiography in participants treated with high intensity statin therapy (as defined by the 2013 ACC/AHA Guidelines to Reduce Cardiovascular Risk (GRCR). Using anatomical landmarks, a target plaque volume will be defined at baseline and follow up examinations. Software will be used to trace lumen and outer vessel boundaries to determine non-calcified plaque volume. The 2013 ACC/AHA Guidelines to GRCR focuses on the assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk and management of elevated blood cholesterol and body weight in adults. High-intensity statin therapy is defined by: rosuvastatin 20-40 mg or atorvastatin 40-80 mg. The maximum statin dose will be administered that is tolerated by the patient and that maintains LDL-C \> or = 25 mg/dl. High-intensity statin therapy is defined as lowering LDL-C on average by approximately \> or = 50%.
Time frame: Baseline and 24 months
Population: Intention to treat analysis for those participants with observed plaque volumes by Coronary artery CT angiography at baseline and 24 months will be included in the primary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque | Mean Change of Non-calcified Plaque Volume in Participants Treated With High Intensity Statin Therapy Assessed by Coronary Computed Tomography Angiography | 23.3 mm^3 | Standard Deviation 76.6 |
p-value: 0.0256Wilcoxon Signed Rank Tests
Secondary
Linear Mixed-effects Regression Coefficient of Age Effect on Plaque Volume
Linear mixed-effects regression coefficient of age effect on plaque volume measured by Coronary artery CT angiography. Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume given one year increase of age. In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware.
Time frame: Baseline, 24 months and 36 months
Population: Intention to treat for those participants with observed plaque volumes by Coronary artery CT angiography at baseline, 24 months and 36 months will be included in the secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque | Linear Mixed-effects Regression Coefficient of Age Effect on Plaque Volume | 1.48 mm^3/year | Standard Deviation 2.65 |
p-value: 0.58Regression, Linear
Secondary
Linear Mixed-effects Regression Coefficient of Body Mass Index Effect on Plaque Volume
Linear Mixed-effects Regression Coefficient of Body Mass Index Effect on Plaque Volume measured by Coronary artery CT angiography. Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume given one kg/m\^2 increase of BMI. In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware.
Time frame: Baseline, 24 months and 36 months
Population: Intention to treat for those participants with observed plaque volumes by Coronary artery CT angiography at baseline, 24 months and 36 months will be included in the secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque | Linear Mixed-effects Regression Coefficient of Body Mass Index Effect on Plaque Volume | 7.65 mm^3/[kg/m^2] | Standard Deviation 2.68 |
p-value: 0.006Regression, Linear
Secondary
Linear Mixed-effects Regression Coefficient of Race Effect on Plaque Volume (Beta Coefficient)
Linear Mixed-effects Regression Coefficient of Effects race (white = 1 and non-white = 0) effect on plaque volume measured by Coronary artery CT angiography. Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume comparing race (white = 1 and non-white = 0). In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware.
Time frame: Baseline, 24 months and 36 months
Population: Intention to treat for those participants with observed plaque volumes by Coronary artery CT angiography at baseline, 24 months and 36 months will be included in the secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque | Linear Mixed-effects Regression Coefficient of Race Effect on Plaque Volume (Beta Coefficient) | 35.66 Beta coefficient [mm^3] | Standard Deviation 859.39 |
p-value: 0.69Regression, Linear
Secondary
Linear Mixed-Effects Regression Coefficient of Sex Effect on Plaque Volume (Beta Coefficient)
Linear Mixed-effects Regression Coefficient of sex (female = 0 and male = 1) effect on plaque volume measured by Coronary artery CT angiography (beta coefficient). Plaque volumes (mm3) were quantified from coronary CTA exams using a validated automated method developed by Cleerly. Regression coefficient is the mean change of plaque volume comparing male verses female (female =0 and male = 1). In the mixed-effects model the outcomes are plaque volumes measured at Baseline, 24 months and 36 months as described in 2011 Applied Longitudinal Analysis Wiley Series in Probability and Statistics by Fitzmaurice, Laird, and Ware.
Time frame: Baseline, 24 months and 36 months
Population: Intention to treat for those participants with observed plaque volumes by Coronary artery CT angiography at baseline, 24 months and 36 months will be included in the secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque | Linear Mixed-Effects Regression Coefficient of Sex Effect on Plaque Volume (Beta Coefficient) | 100.58 beta coefficient [mm^3] | Standard Deviation 51.99 |
p-value: 0.06Regression, Linear
Secondary
Mean Change of Non-calcified Plaque Volume in Participants Treated With High Intensity Statin Therapy Assessed by Coronary Computed Tomography Angiography
Mean change of non-calcified plaque volume assessed by Coronary computed tomography angiography in participants treated with high intensity statin therapy (as defined by the 2013 ACC/AHA Guidelines to Reduce Cardiovascular Risk (GRCR). Using anatomical landmarks, a target plaque volume will be defined at baseline and follow up examinations. Software will be used to trace lumen and outer vessel boundaries to determine non-calcified plaque volume. The 2013 ACC/AHA Guidelines to GRCR focuses on the assessment of cardiovascular risk, lifestyle modifications to reduce cardiovascular risk and management of elevated blood cholesterol and body weight in adults. High-intensity statin therapy is defined by: rosuvastatin 20-40 mg or atorvastatin 40-80 mg. The maximum statin dose will be administered that is tolerated by the patient and that maintains LDL-C \> or = 25 mg/dl. High-intensity statin therapy is defined as lowering LDL-C on average by approximately \> or = 50%.
Time frame: Baseline and 36 months
Population: Intention to treat for those participants with observed plaque volumes by Coronary artery CT angiography at baseline and 36 months will be included in the secondary analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Moderate to High Statin Treatment in Participants With Coronary Artery Plaque | Mean Change of Non-calcified Plaque Volume in Participants Treated With High Intensity Statin Therapy Assessed by Coronary Computed Tomography Angiography | 8.86 mm^3 | Standard Deviation 75.3 |
p-value: 0.0254Wilcoxon Signed Rank Tests