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Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:462-470

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:462-470.)
© 1996 American Heart Association, Inc.

Articles

Multiple Risk Intervention in High-Risk Hypertensive Patients

A 3-Year Ultrasound Study of Intima-Media Thickness and Plaques in the Carotid Artery

Madis Suurküla; Stefan Agewall; Björn Fagerberg; Inger Wendelhag; John Wikstrand; on behalf of the Risk Intervention Study (RIS) Group1

From the Department of Clinical Physiology, Institute of Heart and Lung Diseases (M.S.) Hypertension Unit, Department of Internal Medicine (S.A., B.F.), and Wallenberg Laboratory for Cardiovascular Research (I.W., J.W.), Sahlgrenska Hospital, Göteborg University, Gothenburg, Sweden.

Correspondence to Prof John Wikstrand, Wallenberg Laboratory, Göteborg University, Sahlgrenska Hospital, S-413 45 Gothenburg, Sweden.


*    Abstract
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 *Abstract
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down arrowResults
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Abstract In spite of optimal blood pressure control, available data indicate that the risk of coronary heart disease remains high in many patients with hypertension. Multifactorial risk intervention programs have therefore been advocated. The aim of the present randomized study was to analyze whether a favorable change in risk factors caused by a comprehensive risk factor modification program (focused mainly on nonpharmacological intervention) might beneficially affect ultrasound-assessed far-wall common carotid intima-media thickness or plaques in the carotid artery in high-risk hypertensive patients (n=81) in comparison with those undergoing usual care (n=83). A further aim was to analyze whether risk factors measured at baseline or follow-up were related to the change recorded in intima-media thickness during follow-up. The results showed in the intervention group a favorable change in LDL cholesterol (-9%), in smoking habits (32% of smokers quit smoking), and in HbA1c (-17% in patients with diabetes mellitus) over the 3.5-year observation period. However, no difference between the two randomization groups could be observed for far-wall common carotid intima-media thickness or plaque status during follow-up. Of all tested potential risk factors, only fasting insulin at baseline (available in nondiabetic patients) was significantly related to the change in mean intima-media thickness during follow-up (r=.25, n=92, P<.01). The relationship (negative) between follow-up serum HDL and change in mean intima-media thickness during the preceding follow-up was of borderline significance. Patients with moderate to large plaques in the carotid artery region at baseline had a significantly larger increase in common carotid artery intima-media thickness during follow-up than patients with no or only small plaques. The results are disappointing and may indicate that either the change in risk factors occurred too late in life or a considerably larger change in concomitant risk factors than we observed is needed to favorably affect intima-media thickness during an observation period of around 3 years in high-risk hypertensive patients.


Key Words: atherosclerosis • hypertension • risk factors • prevention • ultrasound


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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While coronary heart disease is the most common complication of hypertension, epidemiological data demonstrate that the risk of coronary heart disease depends on additional risk factors. The Framingham study indicated that the risk is unevenly distributed at any given blood pressure level; factors such as elevated levels of serum cholesterol, cigarette smoking, glucose intolerance, and evidence of left ventricular hypertrophy each add to increase the risk for coronary heart disease.1 These findings have been corroborated in other studies.2

Various strategies have been advocated for the prevention of coronary heart disease. In spite of optimal blood pressure control, available data indicate that the risk of coronary heart disease remains high in many patients with hypertension.3 4 5 Multifactorial risk intervention programs have therefore been advocated.6 Previous multifactorial intervention trials have included both normotensives and hypertensives. With the exception of a few studies, the outcome has been disappointing, which may be because low-risk populations have been recruited and because favorable changes in risk factors have also occurred in control groups.7 8 9 10 11 12 13 There has not yet been any large controlled trial examining the effect of a multifactorial risk factor modification program in a high-risk hypertensive population.

The aim of the present study was to analyze whether a favorable change in risk factors caused by a comprehensive risk factor modification program might beneficially affect ultrasound-assessed far-wall common carotid intima-media thickness or plaques in the carotid artery in high-risk hypertensive patients. A further aim was to analyze whether risk factors measured at baseline or follow-up were related to the change recorded in intima-media thickness during the 3-year follow-up. Results from the baseline ultrasound investigation have been published earlier.14


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Study Groups
At the Hypertension Unit, Sahlgrenska Hospital, Göteborg University, Sweden, a group of hypertensive men (N=508) at high risk for coronary heart disease was recruited to an open, randomized, parallel-group study of the feasibility and effects of a comprehensive multiple risk factor modification program; for details see below.15 From this group one third of the patients were randomly selected to take part in an ultrasound study of the carotid artery. The sample size calculation was based on the following assumptions: that the ultrasound measurements of carotid artery mean intima-media thickness were associated with a method error of 12% (coefficient of variation, see below); that the variability of the measured difference in intima-media thickness was 40%; and that a specific intervention effect of 20% reduction in intima-media thickness was judged as clinically important. With {alpha}=0.05 and ß=0.20, this calculation showed that 150 patients were required in the study, taking into account a certain fraction of patients lost from the follow-up examination. Of 169 patients randomized to the ultrasound study, 164 agreed to take part; 81 men were randomized to multiple risk intervention and 83 to usual care. The treatment goal was diastolic blood pressure <90 mm Hg in both groups, and antihypertensive treatment (ie, selection of drugs) was purposely kept similar in the two hypertensive subgroups.15 In 140 men, ultrasound recordings were achieved both at baseline and after a mean follow-up time of 3.4 years. Reasons for patients lost to follow-up regarding the ultrasound investigation are given in Table 1Down. Mean heart rate was somewhat higher and diastolic blood pressure somewhat lower in patients lost to follow-up than in those followed (70 versus 63 beats per minute, P<.01, and 88 versus 91 mm Hg, P<.05, respectively).


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  		Table 1. Reasons for Patients Lost Regarding Paired Observations From the Ultrasound Study (Intention-to-Treat)

All patients had long-standing treated hypertension diagnosed according to previously reported criteria and examination routines.15 These men are representative of high-risk hypertensive patients in Gothenburg, since the majority (>90%) were recruited earlier by screening a random third of all men in their respective age groups in the Göteborg Primary Preventive Trial.8 The inclusion criteria were male sex, age 50 to 72 years (at randomization), and one or more of the following: serum cholesterol level >=6.5 mmol/L, tobacco smoking corresponding to one cigarette or more per day, or diabetes mellitus defined according to World Health Organization criteria.16 The exclusion criteria were unwillingness to participate or serious chronic disease that might interfere with compliance or the interpretation of results.

All patients gave informed consent after written and oral information, and the study was approved by the Ethical Committee of Göteborg University. At entry, the history of prior or present cardiovascular disease as well as of diabetes mellitus was documented in all patients. All end points during follow-up were collected on specially designed case record forms and evaluated according to predefined standardized criteria blindly without knowledge of group to which the patients belonged.17

Blood Pressure
Resting blood pressure was measured phonographically (Korotkoff sounds recorded on electrocardiographic paper) in the right arm after supine rest in connection with the ultrasound examination as earlier described.18 Blood pressure was calculated to the nearest 1 mm Hg and was the mean of two recordings. In addition, casual blood pressure was measured in the hypertension group at the Hypertension Unit after 5 minutes of recumbent rest with conventional auscultatory technique, and the mean of two measurements was used.

Smoking
Information on smoking habits was obtained by a self-administered questionnaire and subsequently checked in an interview. The total number of years of smoking was multiplied by the average number of cigarettes smoked daily. The product was called "cigarette-years."

Definition of Clinical End Points
Manifest cardiovascular disease was defined according to standardized criteria as earlier described in detail.14 17 In summary, cardiovascular disease at baseline was defined as either history of myocardial infarction, coronary bypass surgery, angina pectoris, stroke, transient ischemic attack, aortic aneurysm, or intermittent claudication; an angiographic study indicating atherosclerotic disease; surgery related to peripheral vascular disease; or a major electrocardiographic finding according to the Minnesota code,19 ie, definite Q or QS item (1:1 or 1:2), definite ST- or T-wave item (4:1-2, 5:1-2), left bundle-branch block (7:1), or an increased width of the QRS-complex above 0.12 second (7:4). Hard end points during follow-up were defined as death, acute myocardial infarction, definite silent myocardial infarction, or stroke. A definite silent myocardial infarction was defined as a new Minnesota code 1:1 or 1:2 without clinical signs of acute myocardial infarction during follow-up. Soft end points during follow-up were defined as the occurrence of new cases of any of the other end points referred to above.

Biochemical Analysis
Blood Lipids
Blood samples for total serum cholesterol, serum triglycerides, and lipoprotein fractions were drawn after a fasting period of 10 to 12 hours. Cholesterol and triglyceride levels were determined by fully enzymatic techniques.20 21 HDL cholesterol was determined after precipitation of apolipoprotein B-containing lipoproteins with manganese chloride and heparin.22 LDL cholesterol was calculated as described by Friedewald et al.23

HbA1c, Glucose, and Insulin
In diabetic patients, the fraction of HbA1c was determined with an automatic high-performance liquid chromatographic technique at the department of Clinical Chemistry, Sahlgrenska University Hospital. Venous blood was drawn after an overnight fast and after 5 minutes of supine rest for determination of fasting glucose and fasting insulin, using the glucose oxidase technique and a radioimmunoassay (Pharmacia Insulin RIA; Pharmacia Diagnostics), respectively.

Ultrasonography
Examination Procedure
Subjects were examined in a supine position with an ultrasound scanner (Acuson 128), as earlier described in detail.14 At the start of this study, a 7-MHz transducer was not available; therefore, some of the patients were examined with a 5-MHz transducer in the beginning of the study (no difference between the two randomization groups). In a methodological substudy, a comparison of the 5- and 7-MHz transducers showed similar mean values for intima-media thickness (0.92±0.38 and 0.91±0.40 mm, respectively; r=.98, n=32). The distal part of the right common carotid artery was scanned by modifying the ultrasound beam to pass perpendicularly to the vessel wall to achieve the typical two-line image of the vessel wall structures from both the anterior and posterior wall in the same image. At the position of the thickest part of the far-wall intima-media complex (visually judged), an image was captured by electrocardiographic triggering on top of the R wave. If the image was judged to be of good quality, it was recorded on videotape. This procedure was repeated three times to obtain three separate images available for analysis. To achieve the same part of the far wall imaged at the follow-up investigation as at baseline, the transducer position and image topography were noted on a special protocol, which also included a drawing of vessel topography. This protocol, which was used as a guidance at the follow-up investigation, did not give any information on intima-media thickness or the occurrence of plaques at baseline.

Measurement of Intima-Media Thickness and Lumen Diameter in the Common Carotid Artery
The videorecorded frozen images were analyzed offline in a computerized analyzing system along a 10-mm-long section of the common carotid artery by manually tracing interfaces of interest on the video screen with the assistance of a digitizing table and a mouse.14 24 25 Analyses of all images from the baseline and follow-up investigations were performed after the last follow-up examination and in a blinded manner with regard to results from the baseline examination when the 3-year follow-up images were analyzed. About 10 boundary points were marked along each echo interface. Between these marked points, the echo interfaces were interpolated by the computer, so that 100 boundary points were analyzed for each 10-mm section. Intima-media thickness was defined as the distance from the leading edge of the lumen-intima interface of the far wall to the leading edge of the media-adventitia interface of the far wall and lumen diameter by the distance between the leading edges of the intima-lumen interface of the near wall and the lumen-intima interface of the far wall. Average intima-media thickness and lumen diameter were calculated along the 10-mm-long section (100 pairs of boundary points); maximum intima-media thickness and minimum lumen diameter in each section were also given by the computer. An estimate of the mean cross-sectional area of the intima-media complex was calculated as the difference between the total area inside the adventitia and the lumen area: {pi}(LDmean/2+IMTmean)2-{pi}(LDmean/2)2, where LDmean is mean lumen diameter and IMTmean is mean intima-media thickness. For all variables, the mean of three separate images was calculated. Cross-sectional intima-media area was not calculated in patients with plaques present in the common carotid artery (n=4) and in another five patients in whom paired observations of both intima-media thickness and lumen diameter were not achieved. Interobserver variability studied in our laboratory with repeated recordings by two independent observers has shown a coefficient of variation for mean intima-media thickness of 10.2%, for maximum intima-media thickness 8.9%, and for mean cross-sectional intima-media area 11.5%. For mean and minimum lumen diameter, the coefficients of variation were 2.8% and 3%, respectively.

Plaques in the Carotid Artery Region
Scanning procedure. With the aim to identify and record the occurrence of atherosclerotic plaque, the carotid artery was scanned from the distal part of the common carotid artery and further {approx}10 mm up in the external and internal carotid arteries.14

At the position of the best visibility of a plaque, ie, the biggest cross-sectional area in a longitudinal transaxial view (visually judged) sometimes attained by guidance of successive cross-sectional views along the plaque extension, three separate images were captured (R-wave–triggered) and recorded on videotape.

Plaque assessment. A semiquantitative subjective scale (visual scoring) was used to grade the size of plaques in the four locations in the carotid artery region: external and internal carotid arteries, carotid bulb, and distal part of the common carotid artery. This analysis included plaques in the near and far walls of the vessel. A plaque was defined as a distinct area with an intima-media thickness more than 50% thicker than neighboring sites judged visually.14 Plaques were graded as grade 0, no plaque; grade 1, one or more small plaques (each less than {approx}10 mm2); grade 2, moderate-sized plaques (the differentiation between grades 1 and 2 was made subjectively in most cases, and quantitative measurement of the area was made in the computerized analyzing system24 only when the size of the plaque was not obvious to the observer); and grade 3, large plaques that cause a change in blood flow defined by the pulsed-Doppler curve: peak systolic velocity >1.2 m/s at 60° Doppler angle.26

Global assessment of change in plaque status during follow-up. For each patient, the videotaped recordings from baseline and the follow-up investigation were displayed on two TV monitors next to each other. Plaques were judged and compared both from the video recorded scanning procedure and from frozen images. The examiner made a global visual assessment and classified the plaque status at the 3-year examination in the following categories: unchanged, progression, or regression compared with baseline. This assessment was done without the examiner's knowing to which group the paired images belonged.

Risk Factor Modification Program
A randomized half of the patients participated in a comprehensive risk factor modification program directed toward established cardiovascular risk factors, and the other half continued with usual care. A special intervention team consisting of a physician and a dietitian implemented lifestyle changes in a program that included an information meeting followed by five weekly group meetings. Spouses were also invited to participate. The treatment was based on nutritional advice and a behavioristic approach aiming at a change in dietary habits. The goal was to lower total serum cholesterol to <6.0 mmol/L, to improve metabolic control in diabetic patients (reduce HbA1c to <6%), and to reduce the degree of overweight.15 17 Simultaneously, smokers were invited to a smoking cessation program with five weekly meetings, starting with a similar information meeting with the spouse as mentioned above. The patients were offered nicotine chewing gum to reduce symptoms of nicotine abstinence. After implementation of this program, the responsible doctor and the nurses at the Hypertension Unit continued to reinforce the changes in diet and smoking habits. Lipid-lowering drugs were recommended if the treatment goals were not achieved. During the first year, this risk factor modification program focused mainly on nonpharmacological intervention. The details of this intervention program and the effects of intervention in the total study group (N=508) have been reported elsewhere.15 17

Statistical Analysis
All statistics were analyzed using SPSS for Windows 6.0. Student's t test, paired or unpaired as appropriate, was used to compare means, and 95% confidence intervals for the differences studied were also calculated. "Net difference" was defined as the difference between the intragroup change observed in the intervention group and the intragroup change observed in the usual-care group; the intragroup change was calculated as the difference between the follow-up and the baseline values. Net difference in cigarette-years during follow-up was tested with the Mann-Whitney U test and also illustrated with the 95% confidence interval.

Nonparametric Spearman's rank correlation test was used in the correlation analyses, with the relationship illustrated with Pearson's correlation coefficient (r). A test for trend (Mantel-Haenszel {chi}2) was used to analyze the relationship between a discrete variable (ie, plaque status at baseline) and a continuous variable (ie, change in intima-media thickness during follow-up). Fisher's exact test was used to analyze two proportions. In a number of univariate tests, the relationship between the value for some risk factors at baseline or follow-up (see "Results" section) and the observed change in the studied ultrasound variables during follow-up (intima-media thickness mean and maximum, cross-sectional intima-media area, lumen diameter) was analyzed. Because of the large number of tests performed in these univariate analyses, the level of significance was set to P<.01 (two-sided). For all other situations, P<.05 (two-sided) was regarded as statistically significant.


*    Results
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 up arrowMethods
*Results
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Clinical Cardiovascular Disease During Follow-up
Eleven patients died during follow-up; 4 in the intervention group and 7 in the usual-care group. Another 11 patients suffered nonfatal hard end points; 5 in the intervention group and 6 in the usual-care group. In addition, another 13 patients free of hard and soft end points at baseline were diagnosed with soft end points during follow-up; 8 in the intervention group and 5 in the usual-care group.

Cardiovascular Risk Factors During Follow-up in Patients With Available Paired Ultrasound Recordings
Table 2Down gives baseline and follow-up data on anthropometric variables, blood pressure, and some cardiovascular risk factors. At baseline, there were no differences in these characteristics between the two groups studied. Mean changes from baseline to follow-up were calculated in each group and "net" intergroup changes calculated (Table 2Down). Significantly larger reductions in the intervention group compared with the usual-care group were seen for casual heart rate, total and LDL cholesterol, and HbA1c (in patients with diabetes mellitus). Furthermore, 8 of 25 smokers (32%) in the intervention group quit smoking, which none of the smokers in the usual-care group did (P<.01). Smoking consumption during follow-up (cigarette-years) was significantly lower in patients classified as smokers at baseline in the intervention group than in patients classified as smokers at baseline in the usual-care group (P<.01, Table 2Down). Resting diastolic blood pressure decreased slightly more in the usual-care group, which might be a chance finding since no such change was observed for casual diastolic blood pressure (Table 2Down). Other variables remained essentially unchanged from baseline to follow-up in the two randomization groups. At the 3-year investigation, 35 patients (49%) in the intervention group had reached the treatment goal of serum cholesterol <6.0 mmol/L, and 5 of the patients with diabetes mellitus (33%) had achieved HbA1c<6%; the corresponding figures in the usual-care group were 38% and 6%, respectively. At the follow-up investigation, 44% of the patients in the intervention group were prescribed cholesterol-lowering drugs compared with 3% of the patients in the usual-care group.


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  		Table 2. Anthropometric Data, Blood Pressure, Heart Rate, and Some Other Cardiovascular Risk Factors at Baseline and at the Ultrasound Follow-up Investigation in All Patients With Paired Observations for Intima-Media Thickness or Plaque Occurrence in the Two Study Groups

Intima-Media Thickness and Lumen Diameter in the Two Study Groups at Baseline and at Follow-up
There was a close relationship between ultrasound variables recorded at baseline and at follow-up, with similar r values in the two study groups (intervention group and usual-care group), respectively: for intima-media thickness mean, r=.79 and r=.70 (Fig 1Down); for intima-media maximum, r=.79 and r=.66; for cross-sectional intima-media area, r=.67 and r=.76. For lumen diameter mean, r=.93 and r=.90 (Fig 1Down); and lumen diameter minimum, r=.91 and r=.88, respectively. The results also showed that far-wall mean intima-media thickness, and cross-sectional intima-media area of the common carotid artery increased significantly and to a similar degree in the two groups (Table 3Down). Lumen diameter increased significantly in the intervention group (P<.05) but not in the usual-care group (P=.08), with no significant difference between groups.



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  		Figure 1. Top, Illustration of the relationship between the value recorded for mean intima-media thickness in each patient at the baseline investigation and at the 3-year follow-up investigation. Solid circles refer to patients randomized to the intervention group (r=.79, n=61) and open circles to the control group (r=.70, n=59). The dotted line indicates the line of identity. Bottom, Illustration of the relationship between the value recorded for mean lumen diameter in each patient at the baseline investigation and the 3-year follow-up investigation. Solid circles refer to patients randomized to the intervention group (r=.93, n=56) and open circles to the control group (r=.90, n=57). The dotted line indicates the line of identity.


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  		Table 3. Far-Wall Intima-Media Thickness, Lumen Diameter, and Mean Cross-Sectional Area of the Intima-Media Complex in the Common Carotid Artery at Baseline and at the Ultrasound Follow-up Investigation in All Patients With Paired Observations in the Two Study Groups

Global Visual Assessment of Changes in Plaque Status
Compared with baseline, plaque status remained unchanged in 48 patients (77%) in the intervention group and 41 patients (71%) in the usual-care group. According to the visual assessment, progress was at hand in 14 patients (23%) in the intervention group and 15 patients (26%) in the usual-care group. Two patients in the usual-care group were judged to demonstrate regression, which none of the patients in the intervention group did. There was no significant difference between the groups regarding change in plaque status during follow-up as judged from this visual scoring.

Change in Intima-Media Thickness in Relation to Some Studied Risk Factors and Plaque Status in the Two Study Groups Combined
Since the change in intima-media thickness was very similar in the two groups during follow-up, the patients have been handled as one group in the following analyses, relating some risk factors at baseline or follow-up to change in ultrasound variables during follow-up.

Risk Factors at Baseline and at Follow-up
Of all tested potential risk factors (body mass index, systolic, diastolic, and pulse pressure, heart rate, serum total cholesterol, LDL cholesterol, HDL cholesterol, LDL/HDL ratio, triglycerides, HbA1c, fasting insulin, fasting glucose, and cigarette-years), only fasting insulin at baseline (available in nondiabetic patients) was significantly related to the change in ultrasound variables during follow-up, but only for the change in mean intima-media thickness (r=.25, n=92, P<.01, Fig 2Down) and the change in cross-sectional intima-media area (r=.29, n=86, P<.01), and not for the change in maximum intima-media thickness (r=.17, n=92, P=.11). The relationship between follow-up serum HDL and change in mean (and also maximum) intima-media thickness during the preceding follow-up was of borderline significance (r=-.26 and r=-.23; P=.016 and P=.012, respectively; n=116). None of the other above-mentioned risk factors from the 3-year follow-up investigation was related to the change in ultrasound variables during the preceding follow-up.



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  		Figure 2. Illustration of the relationship between fasting insulin at the baseline investigation and the change in mean intima-media thickness recorded during follow-up (r=.25, n=92, P<.01, nondiabetic patients only). In this analysis, all patients have been handled as one group, but for illustrative purposes, solid circles refer to patients randomized to the intervention group (n=46) and open circles to the control group (n=46). Fasting insulin was missing in two nondiabetic patients at the baseline investigation.

Smoking Habits During Follow-up
There was no significant relationship between cigarette-years during follow-up and change in ultrasound variables during follow-up. Within the intervention group, there was no difference in change in intima-media thickness during follow-up between patients who continued to smoke (n=17) and those who quit smoking (n=8).

Plaque Status at Baseline
The increase in mean far-wall common carotid intima-media thickness was significantly correlated with plaque status at baseline (P<.001, Fig 3Down). The increase in mean intima-media thickness was 0.13±0.24 mm in the group with moderate to large plaques (n=43) compared with 0.02±0.13 mm in the group without plaques (n=46), P<.05, 95% confidence interval for difference, 0.03 to 0.19 mm.



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  		Figure 3. Change in intima-media thickness between the baseline and 3-year follow-up investigations (expressed as mm/year) in relation to plaque status at baseline. Since no difference was observed between the intervention and usual-care group, the figure illustrates the whole study group.

Change in Intima-Media Thickness in Relation to Manifest Clinical Cardiovascular Disease
Patients with manifest clinical cardiovascular disease (n=58) at the 3-year follow-up investigation had changes in intima-media thickness during follow-up similar to the group of patients who were still without signs or symptoms of manifest clinical cardiovascular disease (n=62) (data not shown). However, both at baseline and at follow-up, lumen diameter and cross-sectional intima-media area (but not intima-media thickness) were significantly larger in the former group compared with the latter (data not shown).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The results of the present randomized multiple risk intervention study in high-risk hypertensive patients demonstrated a favorable change in several concomitant risk factors in the intervention group over the 3.5-year observation period. The net reduction in LDL cholesterol was 9%, 32% of the smokers quit smoking, HbA1c was reduced by 17% in patients with diabetes mellitus, and there was a trend for a reduction in fasting insulin in nondiabetic patients. However, no difference between the two randomization groups could be observed in the progression rate for the ultrasound variables studied. Far-wall intima-media thickness and cross-sectional intima-media area increased in both groups to a similar degree. The high correlation between the baseline and follow-up values indicates that the ultrasound data are reliable. However, we cannot exclude the possibility that beneficial qualitative changes occurred in atherosclerotic lesions that were not detected by our quantitative measurements.

This ultrasound study, performed in a random third of patients from a randomized study in 508 high-risk hypertensive males, was designed to investigate the feasibility and effects of a multifactorial intervention program on some predefined risk factors.15 17 To our knowledge, this is the first large controlled trial that examines the effects of such a multifactorial risk-factor modification program in a population of patients with hypertension. The intervention program in the total group (N=508) resulted in significant net reductions in body weight, total and LDL cholesterol, blood glucose, and smoking habits.17 During follow-up, there were no significant differences between randomization groups in cardiovascular mortality or morbidity, with the exception of a significantly lower stroke incidence in the intervention group. Inferences are at present, however, not justified because of limited numbers.17

The absence of a difference in ultrasound intima-media thickness during follow-up between the intervention group and the usual-care group may be reviewed in the light of the results from some other ultrasound studies.

The Cholesterol Lowering Atherosclerosis Study (CLAS), a small, randomized 4-year study in 78 patients, showed a significant reduction of far-wall common carotid intima-media thickness after treatment with colestipol-niacin therapy plus dietary advice.27 28 In the Asymptomatic Carotid Artery Plaque Study (ACAPS), a large, double-blind, randomized clinical trial in asymptomatic subjects with early carotid atherosclerosis and moderately elevated LDL cholesterol levels, lovastatin treatment demonstrated regression of mean maximum intima-media thickness (including measurements in the common carotid artery as well as in the carotid bulb and the internal carotid artery).29 The results of this study also indicated a reduced risk of hard end points in the actively treated group. In the Pravastatin, Lipids, and Atherosclerosis in the Carotids (PLAC-2) study, 151 patients with coronary heart disease were randomized to placebo or pravastatin. After 3 years of follow-up, a significant net reduction in common carotid intima-media thickness was observed in the actively treated group.30 Also in this study, the results indicated an improvement in clinical outcome along with the reduction in intima-media thickness in the common carotid artery, although no significant reduction was recorded in intima-media thickness in the internal carotid artery or the carotid bulb. Several other papers are under way; positive results for far-wall common carotid intima-media thickness have been reported and published in abstract form.31 32 33 In our own laboratory, a group of 49 patients with familial hypercholesterolemia was studied during 3 years of follow-up. The majority of patients were given pravastatin in monotherapy or in combination with cholestyramine. A 32% net reduction in LDL cholesterol was observed, and concomitantly, a significant reduction in far-wall common carotid intima-media thickness was recorded in comparison with a low-risk control group followed over 3 years.33 34

The cholesterol lowering in all the studies referred to above27 28 29 30 31 32 33 was much more pronounced (more than 25% reduction in LDL cholesterol) than in the present study, which during the first year used only nonpharmacological means to try to reduce cholesterol levels in the intervention group. In addition, the mean age of the patients in all the other studies was lower than in the present study, although in two of the studies, the mean age was >60 years.29 30 Our risk-factor modification program focused mainly on nonpharmacological intervention, and after 3 years, less than half of the patients in the intervention group were prescribed cholesterol-lowering drugs. The results are disappointing and may indicate that either the change in risk factors occurred too late in life or a considerably larger change in concomitant risk factors than we observed is needed to affect intima-media thickness favorably during an observation period of {approx}3 years in high-risk hypertensive patients. The data further indicate that even a very ambitious and well-organized nonpharmacological intervention program with a high participation rate can lead only to modest changes in LDL cholesterol levels compared with pharmacological intervention with modern lipid-lowering drugs. There is a series of consistent data showing that pharmacological intervention leading to a more pronounced reduction in LDL cholesterol is associated with a significant decrease in intima-media thickness and also to improvements in clinical outcome.27 28 29 30 31 32 33 Several of these other positive studies have had a sample size similar to the one in the present study.27 28 30 33

One might speculate that the improvement in clinical outcome seen in several recently published studies after cholesterol-lowering therapy with the statins29 30 35 36 may be secondary to qualitative changes in atherosclerotic lesions or in factors involved in the thrombogenesis-fibrinolysis balance, and not just secondary to a decrease in intima-media thickness.37 38 39 In one study comparing two antihypertensive drugs, opposite trends were seen for clinical outcome and short-term change in intima-media thickness during follow-up.40 41 However, in this study, the increase in intima-media thickness seen in the group randomized to thiazide diuretic treatment might have been secondary to a decrease in lumen diameter, which underlines the importance of also measuring lumen diameter in ultrasound studies of early atherosclerotic changes in the vessel wall.25 Furthermore, it underlines the importance of also closely monitoring clinical outcome in ultrasound studies of atherosclerosis progression and regression. Death and myocardial infarction are definitely of greater importance for the patient than a moderate progression or regression of an atherosclerotic plaque.42

In the combined groups in the present study, the relationship between several potential risk factors and the 3-year change in intima-media thickness was analyzed. In nondiabetic patients, there was a positive correlation between fasting insulin at baseline and change in intima-media thickness during follow-up, although there was no significant relationship between fasting insulin at the 3-year follow-up and the preceding change in intima-media thickness during follow-up. A substudy to the present study performed at the 3-year follow-up showed a significant relationship between reduced insulin sensitivity and common carotid intima-media thickness in patients without signs of clinical cardiovascular disease.43 Insulin has been suggested as a trophic factor of importance in atherogenesis.44 The relationship (negative) between follow-up HDL and change in intima-media thickness during follow-up was only of borderline significance (P=.01 to .02) but is still interesting. Results from other studies have also indicated a possible significant relationship (negative) between serum HDL and progression rate of common carotid intima-media thickness27 45 and also between serum HDL and progression of carotid stenosis.46

Change in plaque status during follow-up did not differ between groups. However, plaque status at baseline proved to be a powerful predictor of intima-media thickness progression during follow-up. Patients with moderate to large plaques had a much larger progression rate than patients with no or only small plaques. These findings corroborate earlier reports.45 46 47 Apparently, plaque occurrence in the carotid region may indicate a more rapidly progressing atherosclerotic disease, at least regionally. This view is supported by the observation at baseline that plaque size and intima-media thickness were positively interrelated, as well as plaque status and presence of clinical cardiovascular disease.14 Atherosclerosis is a disease affecting the intima, leading to intimal thickening, but there is no method available at present that can measure only intima thickness in vivo. However, intima-media thickness may be measured accurately with ultrasound, and an increase in intima-media thickness in atherosclerotic-prone areas is used as an indicator of intimal thickening.25 26 27 28 29 30 31 32 33 34 More studies, however, are needed to clarify the correlation between the thickness of the intima-media complex in large arteries and coronary atherosclerosis and coronary heart disease.

In conclusion, no beneficial effect on the ultrasound progression rate of carotid intima-media thickness could be detected from the multifactorial risk intervention program, not even in the group with the most rapidly increasing intima-media thickness (those with moderate to large plaques at baseline). On the other hand, net reductions in LDL cholesterol levels after our mainly nonpharmacologically based intervention tended to be relatively modest compared with what has been achieved with pharmacological intervention in recently reported studies. Available data may thus indicate either that the change in concomitant risk factors occurred too late in life or that pharmacological intervention is needed to achieve a more pronounced decrease in LDL cholesterol and a concomitant favorable decrease in carotid intima-media thickness.27 28 29 30 31 32 33 34 The groups will be prospectively followed, and ultrasound variables and clinical outcome studied again after 6 years of follow-up.


*    Acknowledgments
 
This study was supported by grants from the Swedish Medical Research Council (project No. B94-19X-09937-02B and B95-19X-09937-04B), the King Gustaf V and Queen Viktoria foundation, the Swedish Heart Lung Foundation, and Astra Hässle Cardiovascular Research Laboratories, Mölndal, Sweden. The authors acknowledge the excellent technical assistance of Caroline Schmidt. Additional participants in the RIS group include Ove K. Andersson, Marianne Hartford, Thomas Hedner, Hans Herlitz, Susanne Ljungman, Bengt Persson, Ola Samuelsson, Bengt Widgren, and Marian Wysocki.


*    Footnotes
 
1 A list of additional participants in this research study appears in the "Acknowledgments." Back

Received March 10, 1995; accepted October 20, 1995.


*    References
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*References
 

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