Carotid Intima-Media Thickness and Antihypertensive Treatment
A Meta-Analysis of Randomized Controlled Trials
Background and Purpose— Hypertension promotes carotid intima-media thickening. We reviewed the randomized controlled trials that evaluated the effects of an antihypertensive drug versus placebo or another antihypertensive agent of a different class on carotid intima-media thickness.
Methods— We searched the PubMed and the Web of Science databases for randomized clinical trials, published in English before 2005, and included 22 trials.
Results— In 8 trials including 3329 patients with diabetes or coronary heart disease, antihypertensive treatment initiated with an angiotensin-converting enzyme (ACE) inhibitor, a β-blocker, or a calcium-channel blocker (CCB), compared with placebo or no-treatment, reduced the rate of intima-media thickening by 7 μm/year (P=0.01). In 9 trials including 4564 hypertensive patients, CCBs, ACE inhibitors, an angiotensin II receptor blocker or an α-blocker, compared with diuretics or β-blockers, in the presence of similar blood pressure reductions, decreased intima-media thickening by 3 μm/year (P=0.03). The overall beneficial effect of the newer over older drugs was largely attributable to the decrease of intima-media thickening by 5 μm/year (P=0.007) in 4 trials of CCBs involving 3619 patients. In 5 trials including 287 patients with hypertension or diabetes, CCBs compared with ACE inhibitors did not differentially affect blood pressure, but attenuated intima-media thickening by 23 μm/year (P=0.02). The treatment induced changes in carotid intima-media thickness correlated with the changes in lumen diameter (P=0.02), but not with the differences in achieved blood pressure (P>0.53).
Conclusions— CCBs reduce carotid intima-media thickening. This mechanism might contribute to their superior protection against stroke.
Intima-media thickness (IMT) in the carotid arteries can be measured by using high-resolution ultrasonography. Hypertension is a major risk factor for carotid intima-media thickening. Antihypertensive treatment prevents stroke and coronary heart disease. Several recent trials tested the effects of antihypertensive drugs on carotid IMT.1–18 In the present meta-analysis, we investigated whether antihypertensive treatment reduced carotid IMT, whether new antihypertensive drugs were more effective than old agents in the prevention of carotid intima-media thickening, and whether angiotensin-converting enzyme (ACE) inhibitors and calcium-channel blockers (CCB) were equally effective in this regard. We also studied the relevance of using IMT as an intermediate outcome measure for the prevention of mortality and cardiovascular events.
Acquisition and Selection of Trials
We searched the PubMed and the Web of Science citation databases for randomized controlled trials, published in English before August 2005, using as key terms “IMT,” “blood pressure (BP),” and “randomized clinical trial.”
We identified 24 trials,1–24 published between 1996 and 2005. We excluded 1 trial because the follow-up time duration was only 2 months23 and 1 study because out of the 57 patients randomized to quinapril or losartan, 14 crossed over and were not analyzed.24 According to the study design, we classified the remaining 22 trials into 3 groups: 8 trials compared antihypertensive drugs with placebo2,3,5–7,19 or no-treatment,1,4 9 trials compared new with old drug classes,8–14,20,22 and 5 trials compared ACE inhibitors and CCBs.15–18,21
We based our analysis on the summary statistics reported in the literature. For carotid IMT, we extracted for the experimental and control groups separately means and standard deviations at baseline and during follow-up and if available in the published report also changes over time. Within each trial, the control group consisted of patients left untreated1,4 or allocated placebo,2,3,5–7,19 the patients randomized to old drug classes,8–14,20,22 or the patients who received ACE inhibitors in trials comparing these agents with CCBs.15–18,21 The number of patients by randomization group was not reported in the IMT substudy of the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT).7
For each comparison within each trial, we calculated the absolute difference in the mean changes over time in carotid IMT (μm per year) between the experimental and control groups, and computed the standard error (SE) of the difference as described previously.25 The pooled effect for each grouping of trials was derived from the point estimate for each separate trial weighted by the inverse of the variance (1/SE2). Heterogeneity of effect sizes was tested across trials using the χ2 test. If trials were homogeneous (P<0.10), a fixed-effects model was used to calculate pooled effect sizes. Otherwise, a random-effects model was applied. The funnel plot technique was used to evaluate publication bias.25 The effect sizes of carotid IMT were plotted against the sample size of the 22 studies.
We performed a meta-regression analysis to explore whether the effects of antihypertensive drugs on carotid IMT were mediated by effects on BP or lumen diameter. We correlated the differences in carotid IMT between experimental and control treatment with the corresponding differences in BP and lumen diameter. Net treatment effects on BP and lumen diameter were determined by subtracting the mean change in the experimental group from the corresponding mean change in the control group.
We ran statistical analyses using the SAS package, version 8.1 (SAS Institute). For mortality and cardiovascular events, we determined the relative benefit or risk of experimental versus control treatment from the odds ratios in stratified 2×2 contingency tables. We used StatXact for Windows (CYTEL Software Corp), version 4.0, to check the homogeneity of the odds ratios by Zelen test and to compute exact 95% CI.
Characteristics of Trials and Patients
Our analysis included 22 studies1–22 and 9138 subjects, of whom 8449 (92%) had been randomized in 17 double-blind trials and 689 (8%) in 5 studies with an open design (Table 1). In 15 trials,2,3,5–14,16,19,21 the investigators excluded from analysis a proportion of the randomized patients (≈10%) who had incomplete data collection at randomization or during follow-up. Participants in 15 trials1–4,6,7,9–13,17–19,21,22 had a broad range of carotid IMT at baseline, whereas the other studies exclusively recruited patients with5,8,20 or without14–16 plaques according to various definitions. In all8–14,16–18,20–22 but 115 of the actively-controlled studies, the participants had to have systolic or diastolic hypertension. During follow-up, other antihypertensive drugs could be added to the randomized treatment to reach the target of BP.
In all trials, the major characteristics of the patients at baseline were similar between study groups. The mean age of the study subjects ranged from 4917,18 to 6815 years (Table 2). One trial included only patients with hypercholesterolemia.6 The mean BPs at entry ranged from 1297 to 17521 mm Hg systolic and from 763,4,19 to 10417 mm Hg diastolic. Mean follow-up duration was from 0.515–17 to 4.72 years.
In addition to the baseline measurement, carotid IMT was measured during follow-up once in 5 trials,1,15–17,19 twice in 8 trials2–5,12–14,21 and 3 times or more frequently in 9 trials (Table 3).6–11,18,20,22 Carotid IMT was measured at both sides in 16 studies,1–4,7–9,11,14–18,20–22 only at the right5,6,10,12 or left13,19 side in 6 studies, at both the near and far arterial walls in 7 studies,1,3,4,7,8,20,22 or only at far wall in 15 trials.2,5,9–19,21 Mean maximum IMT of multiple carotid segments, the mean of several random measurements, and the mean of the measurements over 1 carotid segment were taken as outcomes in 8,1,3,7–9,11,20,21 9,4,12–19 and 5 trials,2,5,6,10,22 respectively.
Antihypertensive Drugs Versus Placebo or No-Treatment
Altogether, the 8 trials comparing active treatment with placebo or no-treatment included 3329 subjects (Figure 1). Active antihypertensive treatment consisted of an ACE inhibitor in 5 trials (n=2090),1–4,19 a β-blocker in 2 trials (n=862)5,6 and a CCB in 1 trial (n=377; Table 1).7 The weighted mean decrease in systolic pressure across the 8 trials was 6.4 mm Hg (95% CI, 2.2 to 10.5; P=0.003).
Mean IMT at baseline ranged from 6911 to 1259 μm.7 Across the 8 trials, we found significant heterogeneity mainly attributable to the large treatment effect in the Migdalis trial (P=0.001).1 A random-effects model showed that active antihypertensive treatment significantly reduced the yearly increase in carotid IMT by 7 μm (95% CI, −14 to −2; P=0.01). The results of the Migdalis trial1 also produced significant heterogeneity in the 5 ACE inhibitor trials (P=0.003).1–4,19 The pooled effect size based on a random-effects model was similar to that in all trials, but did not reach statistical significance (P=0.07). The combined results of the β-blocker trials5,6 were not statistically significant with borderline significant heterogeneity among individual trials (P=0.05).
New Drugs Versus Old Drugs
Among the 9 trials comparing new with old drug classes, the new antihypertensive drug was a CCB in 4 trials (n=3619),8–11 an ACE inhibitor in 3 trials (n=640),12,13,20 an angiotensin II receptor blocker in 1 trial (n=225)14 and an α-blocker in 1 trial (n=80; Table 1).22 Sample sizes varied from 5013 to 2035 patients (Figure 2).11 The weighted mean decrease in systolic pressure across the 9 trials was 1.1 mm Hg (95% CI, −2.5 to 0.3; P=0.11).
Mean IMT at baseline ranged from 59412 to 1410 μm.22 There was no heterogeneity across these trials (P≥0.19). Compared with old drug classes, new hypertensive drugs significantly reduced the yearly increase in carotid IMT by 3 μm (95% CI, −5 to −0.3; P=0.01). This result mainly reflected the effect of CCBs8–11 because overall ACE inhibitors were not different from old drug classes (P=0.19).12,13,20
CCBs Versus ACE Inhibitors
A total of 287 patients were included in 5 trials comparing ACE inhibitors with CCBs (Table 1).15–18,21 The number of patients ranged from 2215 to 126.21 The weighted mean decrease in systolic pressure across the 5 trials was −0.1 mm Hg (95% CI, −3.5 to 3.4; P=0.97).
Mean IMT at baseline ranged from 70216 to 1038 μm (Figure 3).21 No heterogeneity was noticed across the 5 trials (P=0.34). Compared with ACE inhibitors, CCBs significantly reduced the yearly increase in carotid IMT by 23 μm (95% CI, −42 to −4; P=0.02).
The BP difference during follow-up did not predict the treatment-induced difference in the yearly changes of carotid IMT (systolic, n=21; r=0.13; P=0.57 and diastolic, n=22; r=0.16; P=0.49). However, the treatment-induced differences in the yearly changes of carotid IMT correlated weakly and inversely with the differences in lumen diameter of the common carotid artery during follow-up (n=12; r=−0.49; P=0.10; Figure 4). This correlation became significant after further adjustment for mean systolic and diastolic pressures at entry (r=−0.73; P=0.02).
Evaluation of Publication Bias
The funnel plot showed a gap, indicating that few small studies with negative results had been published (Figure 5).
Cardiovascular Morbidity and Mortality
Five placebo-controlled trials2,3,5,7,19,26 and 4 trials evaluating CCBs8,9,11 or an ACE inhibitor20 versus diuretics or a β-blocker reported morbidity and mortality results (Table 4). Because the trials were inadequately powered for hard outcomes, only the odds ratio for all fatal and nonfatal cardiovascular events in trials comparing active treatment with placebo reached statistical significance (P=0.007).
The main finding of our meta-analysis was that treatment with BP-lowering drugs in high-risk patients with diabetes mellitus or coronary heart disease, irrespective of their background treatment, slightly reduced the progression of arterial disease as reflected by carotid intima-media thickening. Furthermore, in the actively-controlled trials CCBs reduced the progression of carotid intima-media thickening more than diuretics, β-blockers or ACE inhibitors. The observed reductions in carotid IMT, though small, approximate to the mean yearly progression of carotid intima-media thickening in middle-aged and older adults.27
Among the trials which compared antihypertensive drug treatment with placebo or no-treatment, the point estimates for all 3 drug classes favored antihypertensive treatment. The Migdalis trial reported large decreases in BP (22/12 mm Hg) and IMT (73 μm/year), but is difficult to interpret because of its open design.1 BP on randomized treatment might also explain the divergent results in 2 double-blind β-blocker trials.5,6 Metoprolol compared with placebo lowered systolic pressure on average by 1 mm Hg in the β-Blockers Cholesterol-lowering Asymptomatic Plaque Study (BCAPS)5 and 3 mm Hg in the Effect of Long-term treatment of metoprolol CR/XL on surrogate Variables for Atherosclerotic disease (ELVA) study.6 A significant effect on the rate of progression of carotid intima-media thickening was only observed in ELVA.6 Patient characteristics, in particular the presence of diabetes mellitus, may account for some of the differences among the trials comparing ACE inhibitors with placebo or no-treatment.1–4,19
In keeping with Fleckenstein’s animal experiments,28 several trials were mounted to test the hypothesis that calcium-channel blockade might be effective in slowing the progression of carotid atherosclerosis. Compared with no-treatment, the effect size tended to be larger in the PREVENT trial7 than that in trials that tested ACE inhibitors1–4,19 or β-blockers.5,6 In the actively controlled trials, CCBs reduced carotid IMT more than diuretics,8–10 a β-blocker11 or ACE inhibitors.15–18,21 In successive quantitative overviews,29 we and other investigators demonstrated that CCBs compared with older drugs, including diuretics, β-blockers and their combination, and compared with ACE inhibitors, provided superior protection against stroke. Furthermore, using meta-regression, we additionally demonstrated that in hypertensive and high-risk patients BP-lowering rather than ancillary drug properties explained most of the cardiovascular protection conferred by antihypertensive drugs, but also that CCBs, independent of their BP-lowering activity, might have a small additional beneficial effect in the prevention of stroke.28 Our current meta-analysis highlights one possible mechanism contributing to the differential effects of antihypertensive drugs on stroke prevention: that is, their influence on the progression of arterial disease at the level of the carotid arteries.
Differences in the progression of carotid IMT might be attributable to either functional or structural changes in the vessel wall, or both. However, it is difficult to differentiate these 2 mechanisms. Our current meta-regression analysis suggests that the treatment-induced differences in carotid IMT might at least in part be attributed to the corresponding differences in changes of lumen diameter. IMT is inversely related to lumen diameter. The reduction in carotid IMT in the patients treated with a CCB might therefore be attributable to a functional decrease by its vasodilatory effect and not necessarily to a structural decrease in intima-media cross-sectional area. This hypothesis is also supported by the observation of a larger effect in short-term studies15–18 than in long-term trials.7–11 Therefore, the clinical relevance of changes in carotid IMT as an intermediate outcome measure has to be further studied in trials with mortality and morbidity as end points.
In conclusion, compared with no-treatment, diuretics/β-blockers or ACE inhibitors, CCBs attenuate the rate of progression of carotid intima-media thickening. Whether these findings are attributable to functional changes through vasodilation without a structural decrease in cross-sectional area and whether these findings have implications for the long-term prevention of cardiovascular complications such as stroke, remain to be proven. In the prevention of carotid intima-media thickening, CCBs are more effective than ACE inhibitors, which in turn are more effective than placebo or no-treatment, but not more active than diuretics/β-blockers.
Sources of Funding
During his stay in Leuven (Belgium), Dr Wang was supported by the bilateral scientific and technical collaboration between China and Flanders (contract number BIL02/10). This research was also supported by a grant from the Shanghai Commission of Science and Technology (03JC14058).
Dr Messerli received a research grant from Novartis and is in the Speakers Bureau/Honoraria of Pfizer, GSK, Novartis, Abbott. Dr. Safar is a consultant and on the Advisory Board for Servier. All other authors have no conflicts-of-interest to report.
- Received January 6, 2006.
- Revision received April 18, 2006.
- Accepted April 28, 2006.
MacMahon S, Sharpe N, Gamble G, Clague A, Ni Mhurchu C, Clark T, Hart H, Scott J, White H. for the PART-2 Collaborative Research Group. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. J Am Coll Cardiol. 2000; 36: 438–443.
Lonn EM, Yusuf S, Dzavik V, Doris CI, Yi Q, Smith S, Moore-Cox A, Bosch J, Riley WA, Teo KK; for the SECURE Investigators. Effects of ramipril and Vitamin E on atherosclerosis: the Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and Vitamin E (SECURE). Circulation. 2001; 103: 919–925.
Hosomi N, Mizushige K, Ohyama H, Takahashi T, Kitadai M, Hatanaka Y, Matsuo H, Kohno M, Koziol JA. Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non-insulin-dependent diabetes mellitus. Stroke. 2001; 32: 1539–1545.
Hedblad B, Wikstrand J, Janzon L, Wedel H, Berglund G. Low-dose metoprolol CR/XL and fluvastatin slow progression of carotid intima-media thickness: main results from the β-Blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS). Circulation. 2001; 103: 1721–1726.
Wiklund O, Hulthe J, Wikstrand J, Schmidt C, Olofsson SO, Bondjers G. Effect of controlled release/extended release metoprolol on carotid intima-media thickness in patients with hypercholesterolemia: a 3-year randomized study. Stroke. 2002; 33: 572–577.
Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini J, Miller ME, Riley W; for the PREVENT Investigators. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation. 2000; 102: 1503–1510.
Zanchetti A, Agabiti Rosei E, Dal Palù C, Leonetti G, Magnani B, Pessina A; for the Verapamil in Hypertension and Atherosclerosis Study (VHAS) Investigators. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens. 1998; 16: 1667–1676.
Simon A, Gariépy J, Moyse D, Levenson J. Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changes. Circulation. 2001; 103: 2949–2954.
Zanchetti A, Bond G, Hennig M, Neiss A, Mancia G, Dal Palù C, Hansson L, Magnani B, Rahn KH, Reid JL, Rodicio J, Safar M, Eckes L, Rizzini P; on behalf of the ELSA investigators. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis. Principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. Circulation. 2002; 106: 2422–2427.
Boutouyrie P, Bussy C, Hayoz D, Hengstler J, Dartois N, Laloux B, Brunner H, Laurent S. Local pulse pressure and regression of arterial wall hypertrophy during long-term antihypertensive treatment. Circulation. 2000; 101: 2601–2606.
Roman MJ, Alderman MH, Pickering TG, Pini R, Keating JO, Sealey JE, Devereux RB. Different effects of angiotensin-converting enzyme inhibition and diuretic therapy on reductions in ambulatory blood pressure, left ventricular mass, and vascular hypertrophy. Am J Hypertens. 1998; 11: 387–396.
Ludwig M, Stapff M, Ribeiro A, Fritschka E, Tholl U, Smith RD, Stumpe KO. Combination of the effects of losartan and atenolol on common carotid artery intima-media thickness in patients with hypertension: results of a 2-year, double-blind, randomized, controlled study. Clin Ther. 2002; 24: 1175–1193.
Topouchian J, Asmar R, Sayegh F, Rudnicki A, Benetos A, Bacri AM, Safar ME. Changes in arterial structure and function under trandolapril-verapamil combination in hypertension. Stroke. 1999; 30: 1056–1064.
Asselbergs FW, van Roon AM, Hillege HL, de Jong PE, Gans RO, Smit AJ, Van Gilst WH. Effects of fosinopril and pravastatin on carotid intima-media thickness in subjects with increased albuminuria. Stroke. 2005; 36: 649–653.
Zanchetti A, Crepaldi G, Bond MG, Gallus G, Veglia F, Mancia G, Ventura A, Baggio G, Sampieri L, Rubba P, Sperti G, Magni A. Different effects of antihypertensive regimens based on fosinopril or hydrochlorothiazide with or without lipid lowering by pravastatin on progression of asymptomatic carotid atherosclerosis: principal results of PHYLLIS–a randomized double-blind trial. Stroke. 2004; 35: 2807–2812.
Hoogerbrugge N, de Groot E, de Heide LH, de Ridder MA, Birkenhageri JC, Stijnen T, Jansen H. Doxazosin and hydrochlorothiazide equally affect arterial wall thickness in hypertensive males with hypercholesterolaemia (the DAPHNE study). Doxazosin Atherosclerosis Progression Study in Hypertensives in the Netherlands. Neth J Med. 2002; 60: 354–361.
Uchiyama-Tanaka Y, Mori Y, Kishimoto N, Fukui M, Nose A, Kijima Y, Yamahara H, Hasegawa T, Kosaki A, Matsubara H, Iwasaka T. Comparison of the effects of quinapril and losartan on carotid artery intima-media thickness in patients with mild-to-moderate arterial hypertension. Kidney Blood Press Res. 2005; 28: 111–116.
Dickersin K, Berlin JA. Meta-analysis: state-of-the-art science. Epidemiol Rev. 1992; 14: 154–176.
Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA, de Zeeuw D, de Jong PE, van Veldhuisen DJ, Van Gilst WH. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria. Circulation. 2004; 110: 2809–2816.
Cheng KS, Mikhailidis DP, Hamilton G, Seifalian AM. A review of the carotid and femoral intima-media thickness as an indicator of the presence of peripheral vascular disease and cardiovascular risk factors. Cardiov Res. 2002; 54: 528–538.