Aggressive Risk-Factor Modification in Patients With Subclinical Atherosclerosis Reduces Plaque Burden and Regresses Carotid Artery Wall Thickness

Linda Brookes, MSc

Disclosures

July 28, 2006

Editorial Collaboration

Medscape &

Presenter: Bradley F. Bale, MD (Heart Attack Prevention Clinic, Spokane, Washington)

Aggressive global risk-factor management can stop -- or even regress -- atherosclerosis in patients without necessarily reducing low-density lipoprotein (LDL) cholesterol to levels as low as the current guidelines suggest, according to the results of an observational study carried out in a private, nonuniversity clinic in the northwestern United States.[1] The study used measurements of carotid artery intima-media thickness (CIMT) obtained by ultrasound screening as a marker of atherosclerosis at the start of the study and 1 year after treatment to evaluate the effect of global risk-factor assessment and treatment on the process of atherosclerosis. Dr. Bale and colleagues found not only a significant improvement in CIMT but also in plaque burden. This latter finding was unexpected and an exciting new observation in clinical medicine, Dr. Bale declared.

Dr. Bale is active in promoting the prevention of heart disease and heart attack risk assessment, and he began with a description of how the study was carried out at the Heart Attack Prevention Clinic in Spokane, Washington, a clinical center that he started in 2003. The clinic concentrates on identifying a patient's risk factors for heart disease by a combination of physical examination, radiologic imaging, ultrasound, and blood and urine testing, followed by development of an individual preventive treatment regimen for each patient.

Patients

All patients seen at Dr. Bale's clinic after November 2003 who were screened for cardiovascular risk factors and underwent initial and follow-up CIMT testing after 1 year of aggressive management were eligible for the case series review study. The study involved 209 patients who had a mean age of 55.7 years; 38% were women, all of whom were white. About 95% of the patients were being screened for primary prevention. The majority of patients were overweight (mean body mass index [BMI], 28.8 kg/m2), hyperlipidemic, and hypertensive; almost 50% had metabolic syndrome; and at least 74% had atherosclerosis, as defined by B-mode ultrasound (Table 1).

Table 1. Risk Factors in Study Patients
Risk Factor Patients (%)
Current smoker 6
Family history of CHD 7
Diabetes 12
Hyperlipidemia 98
Hypertension 68
CHD/CHD equivalent 22
Metabolic syndrome 49
CIMT > 1.2 mm 74
CHD = coronary heart disease; CIMT = carotid intima-media thickness
Treatment

Patients were offered appropriate lifestyle counseling, including dietary advice and discussion of psychosocial issues. Very aggressive pharmacologic treatment was prescribed to control or reduce known cardiovascular risk factors (Table 2). Most patients were prescribed antiplatelet agents, statins, angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs); 65% were put on extended-release niacin; and > 50% were on a thiazolidinedione (glitazone). At the start of the study the average number of cardiovascular medications per patient was 3 ± 2, whereas by the end of the 1-year study patients were taking an average of 5 ± 2 medications (P < .001), including combination lipid-lowering therapy in 76%.

Table 2. Medications Prescribed
Drug Class Patients (%)
Statins 89
Antiplatelet agents 88
ACE inhibitors or ARBs 78
Niacin extended-release 65.4
Thiazolidinediones 53.4
Fibrates 27
Ezetimibe 14
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker
Results

Over 1 year, significant improvements were seen in all lipid parameters (Table 3). Dr. Bale noted that although after 1 year the median LDL cholesterol was 89 mg/dL (2.3 mmol/L), this was not as low as some of the recent clinical trial results and guidelines recommend.

Table 3. Lipid Parameters (Median) at Baseline and at 1 Year*
Parameter Baseline 1 Year
Total cholesterol -- mg/dL (mmol/L) 196 (5.07) 160 (4.15)
Triglycerides -- mg/dL (mmol/L) 109 (1.23) 80 (0.90)
HDL cholesterol -- mg/dL (mmol/L) 55 (1.42) 59 (1.53)
LDL cholesterol -- mg/dL (mmol/L) 113 (2.92) 89 (2.30)
Total/HDL cholesterol 3.6 2.8
Triglycerides/HDL cholesterol 2.2 1.5
Non-HDL cholesterol -- mg/dL (mmol/L) 143 (3.70) 101 (2.61)
Apo B (g/L) 90 77
Apo = apolipoprotein; HDL = high-density lipoprotein; LDL = low-density lipoprotein

*P < .001 for all comparisons between baseline and 1 year

It should be noted that with this aggressive treatment approach, significant improvements were also seen in several nonlipid parameters, including blood pressure and inflammatory markers (Table 4).

Table 4. Nonlipid Parameters (Median) at Baseline and at 1 Year*
Parameter Baseline 1 Year
Systolic blood pressure 127 116
Diastolic blood pressure 82 75
High-sensitivity CRP (mg/L) 1.0 0.8
Fibrinogen (mg/dL) 371 299
CRP = C-reactive protein

*P < .05 for all comparisons between baseline and 1 year

No patient showed deterioration in hepatic or renal function or significant changes in glycemic parameters. There were also no changes in BMI (median 27.9 kg/m2 vs 27.8 kg/m2 at baseline vs 1 year, respectively), despite > 50% of patients being on thiazolidinediones, which are associated with weight gain.

CIMT

CIMT testing and evaluation of the results for Dr. Bale's clinic were done by an outside organization (CardioRisk Ultrasound Inc., Salt Lake City, Utah) with standardized protocols. CIMT is defined as the mean of six 10-mm measurements taken from the right and left anterior, posterior, and lateral views of the common carotid artery. Plaque is defined as an IMT measurement of ≥ 1.2 mm from the common bifurcation and/or internal carotid artery. Plaque burden is defined as the sum of IMTs of plaques in an individual patient.

The CIMT tests revealed significant improvement in the atherosclerotic process, as shown by a significant reduction in IMT, a reduction in plaque number (extent of disease), and a reduction in plaque burden (extent and severity of disease) (Table 5).

Table 5. CIMT at Baseline and at 1 Year*
Parameter Baseline 1 Year
Common CIMT (mm) 0.771 ± 0.118 0.736 ± 0.110
Number of plaques 2.0 ± 1.5 1.8 ± 2.0
Sum of plaques (plaque burden) 4.2 ± 3.8 3.7 ± 3.4
CIMT = carotid intima-media thickness

*P < .001 for all comparisons between baseline and 1 year

Especially important, in light of a decrease to "only" a mean LDL level at the end of treatment of 90 mg/dL, 87% of patients showed regression CIMT and 52% regression of plaque burden (Table 6).

Table 6. CIMT and Plaque Burden (Percentage of Patients)
Regression No Change Progression
CIMT 87.1 0.5 12.4
Plaque burden 51.7 33.9 14.4
CIMT = carotid intima-media thickness
Safety

Adverse events reported during the study were few and minor. There were no cardiovascular events, no serious adverse drug events, and only 20% of patients reported minor adverse drug events (Table 7).

Table 7. Minor Adverse Events
Adverse Event Patients (%)
Muscle complaints 9.1
Flushing/itching 2.1
Glucose 1.9
Swelling 1.4
Other 4.8
Implications

Dr. Bale believes that this study shows that "silent vascular disease" (ie, atherosclerosis) can be identified by B-mode ultrasound prior to the occurrence of any events. Effective global risk-factor assessment and aggressive treatment can be delivered in a private practice setting with only minor risk for adverse events. Most importantly, this observational study has also shown that lowering LDL cholesterol to < 75 mg/dL (1.94 mmol/L) is not necessary if there is a global approach to treatment, Dr. Bale added. "These are very exciting results," he said, calling for a double-blind, randomized study utilizing the same approach.

Reference
  1. Bale BF, Doneen AL, Drueding R, et al. Aggressive risk factor modification in patients with subclinical atherosclerosis reduces plaque burden and regresses carotid artery wall thickness. Atherosclerosis. 2006;7(suppl):161. Abstract Tu-W20:5.

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