Atherosclerosis, Cardiovascular Disease
Conditions
Keywords
atherosclerotic plaque, MRI, inflammatory markers, statins
Brief summary
The purpose of this study is to investigate the added benefits of increased high-density lipoprotein (HDL) cholesterol serum levels over and above those achieved by lipid lowering therapy guided by current guidelines, in older individuals with cardiovascular disease.
Detailed description
The hypothesis being tested is that the current standard lipid lowering therapy, combined with a 20 percent or greater increase in serum HDL induced by long-acting niacin, reduces plaque size in older individuals with cardiovascular disease. The specific aims of testing this hypothesis are: 1. to determine the effects of statin plus placebo vs. statin plus niacin therapy on plaque size and composition, 2. to determine whether alterations of inflammatory markers of atherosclerosis induced by lipid lowering therapy parallel alterations of plaque architecture and composition in older patients with cardiovascular disease, 3. to determine the effects of these interventions on the incidence of cardiovascular and cerebrovascular events. The results of the trial will be directly applicable to developing strategies for plaque stabilization in the elderly who suffer the most from the severe complications of advanced cardiovascular atherosclerosis. A total of 144 participants aged 65 and older with cardiovascular or cerebrovascular disease will be recruited. Participants will be randomized to receive either statin plus niacin or statin plus a placebo for 18 months. Participants will be provided a prescription for fluvastatin 80 mg to be taken on a daily basis, or they may continue their ongoing or any other cholesterol-lowering drugs such as pravastatin 80 mg daily, simvastatin 20 mg daily, atorvastatin up to 20 mg daily or rosuvastatin up to 20 mg daily. Ten visits are expected, initially every 4 weeks for dose adjustment. Then visits will be every 6 months; MRI, Inflammatory Markers tests, and other lab tests will be done at baseline and the visits at months 6, 12, and 18.
Interventions
DRUGany statin
Participants will be provided a prescription for fluvastatin 80 mg to be taken on a daily basis, or they may continue their ongoing or any other cholesterol-lowering drugs such as pravastatin 80 mg daily, simvastatin 20 mg daily, atorvastatin up to 20 mg daily or rosuvastatin up to 20 mg daily for 18 months
DRUGniacin
long-acting niacin daily for 18 months
DRUGPlacebo
matching placebo pill daily for 18 months
Sponsors
National Institute on Aging (NIA)
Johns Hopkins University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged 65 or older * Documented clinical cardiovascular or cerebrovascular disease due to atherosclerosis * Candidate for lipid lowering therapy; no contraindication to fluvastatin, niacin or aspirin therapy * Low-density lipoprotein (LDL) cholesterol below 150 mg/dl if untreated or below 125 mg/dl on statin monotherapy * Willing to discontinue present therapy if private physician agrees with enrollment * Eligible to undergo trans-esophageal magnetic resonance imaging (MRI); no contraindications to Gadolinium-DTPA, the contrast agent used * Willing to sign Informed Consent
Exclusion criteria
* Ineligibility for MRI procedure due to pacemaker, metal implants, or other ferromagnetic devices * Claustrophobia * Previously documented esophageal disease which would preclude trans-esophageal MRI * LDL-C greater than 150 mg/dl off lipid lowering therapy or daily statin therapy requiring doses greater than 20 mg of atorvastatin, 20 mg of simvastatin, 80 mg of lovastatin, 80 mg of pravastatin, 80 mg of extended release fluvastatin, or 20 mg of rosuvastatin * Contraindication or allergy to statins or aspirin * Current use of or known intolerance or allergy to Niaspan (a long-acting niacin) * Allergy or intolerance to Gadolinium-DTPA (MRI contrast agent) * Liver or kidney failure defined clinically and by laboratory data * Mental, neurologic or social condition preventing understanding of the rationale, procedures, risks and potential benefits associated with the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Plaque Architecture and Composition Directly Measured by Magnetic Resonance Imaging (MRI) in the Aorta and Carotid Arteries | 18 months | The primary endpoint is Changes in plaque architecture and composition directly measured by magnetic resonance imaging (MRI) in the aorta and carotid arteries. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Multiple Combined Events ( Cardiovascular and Cerebrovascular Events as Well as Myocardial Revascularization) | 18 months | Cerebrovascular events (newly diagnosed) such as Stroke and Myocardial revascularization (specifically coronary artery bypass grafting, percutaneous coronary interventions, carotid endarterectomy) were recorded |
Countries
United States
Participant flow
Recruitment details
Participants were randomized in a 1:1 ratio to receive niacin or placebo, using a random number schema stratified to ensure equal numbers between age 65-74 years and 75 years and above. Study took place in a university outpatient center.
Pre-assignment details
Participants were over age 65 years with a history of cardiovascular events or evidence of atherosclerosis at angiography (\>50% stenosis) or non-invasive imaging, with baseline LDL\<3.24 mmol/L if already on statin therapy and \<3.89 mmol/L if untreated. There were no restrictions on HDL level.
Participants by arm
| Arm | Count |
|---|---|
| Niacin Plus Statin Extended release niacin (1500 mg daily) plus statin therapy to reach their National Cholesterol Education Program-defined low density lipoprotein (LDL)cholesterol target | 72 |
| Placebo Plus Statin placebo plus statin therapy to reach their National Cholesterol Education Program-defined low density lipoprotein (LDL)cholesterol target | 73 |
| Total | 145 |
Baseline characteristics
| Characteristic | Niacin Plus Statin | Placebo Plus Statin | Total |
|---|---|---|---|
| Age, Continuous | 73 years | 72 years | 73 years |
| Region of Enrollment United States | 72 participants | 73 participants | 145 participants |
| Sex: Female, Male Female | 14 Participants | 13 Participants | 27 Participants |
| Sex: Female, Male Male | 58 Participants | 60 Participants | 118 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 72 | 2 / 73 |
| serious Total, serious adverse events | 1 / 72 | 1 / 73 |
Outcome results
Primary
Changes in Plaque Architecture and Composition Directly Measured by Magnetic Resonance Imaging (MRI) in the Aorta and Carotid Arteries
The primary endpoint is Changes in plaque architecture and composition directly measured by magnetic resonance imaging (MRI) in the aorta and carotid arteries.
Time frame: 18 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Niacin Plus Statin | Changes in Plaque Architecture and Composition Directly Measured by Magnetic Resonance Imaging (MRI) in the Aorta and Carotid Arteries | 7 percentage of internal carotid artery | Standard Error 0.2 |
| Placebo Plus Statin | Changes in Plaque Architecture and Composition Directly Measured by Magnetic Resonance Imaging (MRI) in the Aorta and Carotid Arteries | 5 percentage of internal carotid artery | Standard Error 0.2 |
Secondary
Multiple Combined Events ( Cardiovascular and Cerebrovascular Events as Well as Myocardial Revascularization)
Cerebrovascular events (newly diagnosed) such as Stroke and Myocardial revascularization (specifically coronary artery bypass grafting, percutaneous coronary interventions, carotid endarterectomy) were recorded
Time frame: 18 months
Population: Cardiovascular event (stroke) was seen in only 1 patient and 5 patients needed myocardial revascularization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Niacin Plus Statin | Multiple Combined Events ( Cardiovascular and Cerebrovascular Events as Well as Myocardial Revascularization) | 6 Participants |
| Placebo Plus Statin | Multiple Combined Events ( Cardiovascular and Cerebrovascular Events as Well as Myocardial Revascularization) | 2 Participants |