Atherosclerosis, Carotid Artery Diseases
Conditions
Keywords
Angiotensin receptor blockade, Oxidative stress, Endothelial dysfunction
Brief summary
The EFFERVESCENT trial is designed to evaluate the effects of a specific ARB, called valsartan, on atherosclerosis. The investigators want to know if treatment with valsartan will increase the blood levels of markers responsible for repair of the vessel wall, reduce oxidation and inflammation, improve the function of the blood vessels, and arrest or slow down the progression of atherosclerosis over time.
Detailed description
Atherosclerosis or 'hardening of the arteries' is a process that ultimately leads to the development of heart attacks, strokes, poor circulation, and death. Millions of Americans are affected by this progressive disease of the arteries. Researchers have tried to understand the very complex processes that lead to hardening of the arteries. Part of this research has taught the investigators that there are specific molecules that can cause damage or injury to the vessel wall by increasing oxidation and inflammation which, in turn, leads to atherosclerosis. Other molecules and cells have been found that can actually repair the vessel wall. Currently, the best treatment the investigators have for preventing or slowing atherosclerosis is to control the patients' risk factors such as high blood pressure, diabetes, or cholesterol levels using prevention and specific drugs. Angiotensin receptor blockers (ARBs) are a class of drugs that have been shown in clinical trials to have many beneficial effects in patients with high blood pressure, advanced heart diseases (such as after heart attack and heart failure), and diabetes. However, whether these drugs will also be useful in people with early signs of hardening of the arteries, measured as a thickening of the carotid (neck) arteries is unknown, and is the purpose of this study. The EFFERVESCENT trial is designed to evaluate the effects of a specific ARB, called valsartan, on atherosclerosis. The investigators want to know if treatment with valsartan will increase the blood levels of markers responsible for repair of the vessel wall, reduce oxidation and inflammation, improve the function of the blood vessels, and arrest or slow down the progression of atherosclerosis over time. In this study, the investigators will recruit subjects who have a hardening or thickening of their carotid arteries, one of the main blood vessels in the neck. People will be screened with ultrasound or sonar examination for this. Two-thirds of those eligible for participation will receive valsartan while the remaining one-third will receive a placebo pill. The investigators and subjects will be unaware of which drug is being given until the end of the study. The study will last for 2 years. Half of the individuals will also be treated with a statin drug (used for cholesterol reduction) and the remaining individuals will not be on a statin. The investigators will measure carotid artery thickening with magnetic resonance imaging (MRI); forearm blood vessel function using ultrasound; and they will perform blood tests to measure oxidation and inflammation in the blood stream and circulation stem cells that are responsible for healing. These tests will be repeated at 3 months, 1 year and 2 years after starting treatment. The investigators will also collect blood for genotyping where the DNA will be stored for future analysis to study whether subjects' genotype alters their susceptibility to treatments. The investigators' hypothesis is that ARB treated individuals will have less oxidation and inflammation, higher levels of stem cells, and a slower progression of arterial thickening. Finding an early treatment for atherosclerosis would hopefully prevent future strokes, heart attacks, and deaths leading to improved longevity and reduced medical expenditure.
Interventions
DRUGValsartan
Valsartan was titrated to a target dose of 320 mg orally daily
DRUGPlacebo
A matched placebo pill will be given orally daily.
Sponsors
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* \> 0.65 mm intima-media thickness of the carotid artery measured by ultrasound * Males aged 21-80 years or women without child bearing potential up to age 80 * Can be on concomitant therapy with aspirin, thiazide diuretics, calcium antagonists (for treatment of hypertension), or beta-receptor antagonists. * May be on statin if on stable dose for at least 2 months before recruitment
Exclusion criteria
* Angiotensin-converting enzyme (ACE) inhibitor or ARB therapy in the previous 3 months. * Initiation or change in dose of statin therapy within 2 months before the study * Inability to return to Emory for follow-up blood drawing and MR imaging * Age \< 21 or \> 80 years * Premenopausal females with potential for pregnancy * Current neoplasm * Chronic renal failure \[creatinine \> 2.5 mg/dL\] * Diabetes with hemoglobin (Hb) A1c \> 8.5 * Anticipated change in lipid lowering therapy * Inability to give informed consent * MR
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Mean Vessel Wall Area (VMA) of the Carotid Bulb From Baseline to 2 Years | Baseline, 2 years | The PI will measure carotid artery thickening with magnetic resonance imaging. |
Countries
United States
Participant flow
Recruitment details
Emory Healthcare sites or by advertisement between March 2005 and October 2008.
Pre-assignment details
60 of the enrolled subjects were already on long-term statin therapy and were stratified for statin use before randomization. Subjects on statin therapy were switched to simvastatin 40 mg daily unless they were already on high dose statin therapy and thus were placed on 80 mg daily of simvastatin for the duration of the study.
Participants by arm
| Arm | Count |
|---|---|
| Valsartan Valsartan titrated up to 320 mg orally daily
Valsartan: Valsartan was titrated to a target dose of 320 mg orally daily | 80 |
| Placebo Patients received a placebo instead of Valsartan | 40 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 9 | 1 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Withdrawal by Subject | 14 | 3 |
Baseline characteristics
| Characteristic | Valsartan | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 80 Participants | 40 Participants | 120 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 9 | 62 years STANDARD_DEVIATION 9 | 60 years STANDARD_DEVIATION 9 |
| Region of Enrollment United States | 80 participants | 40 participants | 120 participants |
| Sex: Female, Male Female | 38 Participants | 21 Participants | 59 Participants |
| Sex: Female, Male Male | 42 Participants | 19 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 80 | 0 / 40 |
| serious Total, serious adverse events | 3 / 80 | 0 / 40 |
Outcome results
Primary
Change in the Mean Vessel Wall Area (VMA) of the Carotid Bulb From Baseline to 2 Years
The PI will measure carotid artery thickening with magnetic resonance imaging.
Time frame: Baseline, 2 years
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valsartan | Change in the Mean Vessel Wall Area (VMA) of the Carotid Bulb From Baseline to 2 Years | -6.7 mm2 | Standard Deviation 2.4 |
| Placebo | Change in the Mean Vessel Wall Area (VMA) of the Carotid Bulb From Baseline to 2 Years | 3.4 mm2 | Standard Deviation 3.1 |