Preintrusive thickening of artery walls is detectable in

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1 Differential Effects of Nifedipine and Co-Amilozide on the Progression of Early Carotid Wall Changes Alain Simon, MD; Jérome Gariépy, MD; Dominique Moyse, PhD; Jaime Levenson, MD Background Common carotid artery intima-media thickness (IMT) progression was compared between 4 years of treatment with nifedipine and diuretic. Methods and Results This study, ancillary to the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), involved nifedipine 30 mg or co-amilozide (hydrochlorothiazide 25 mg and amiloride 2.5 mg) with optional subsequent titration. Among 439 randomized hypertensive patients, 324 had 1 year of follow-up (intent-to-treat group), and 242 completed follow-up (until-end-of-study group). Ultrasonography was performed at baseline, 4 months later, and then every year. Central computerized reading provided far-wall IMT, diameter, and cross-sectional area IMT (CSA-IMT). The primary outcome was IMT progression rate (slope of IMT-time regression). Secondary outcomes were changes from baseline ( ) in IMT, diameter, and CSA-IMT. In the until-end-of-study population, between-treatment differences existed in IMT progression rate (P 0.002), IMT (P 0.001), and CSA-IMT (P 0.006), because IMT progressed on co-amilozide but not on nifedipine. In the intent-to-treat population, treatment differences existed in IMT (P 0.004) and CSA-IMT (P 0.04) but not in IMT progression rate (P 0.09). Patients with 2, 3, or 4 years of follow-up showed treatment differences in IMT progression rate (P 0.04, 0.004, 0.007, respectively), IMT (P 0.005, 0.001, 0.005), and CSA-IMT (P 0.025, 0.013, 0.015). Diameter decreased more on co-amilozide than on nifedipine in the intent-to-treat population (P 0.05), whereas blood pressure decreased similarly on both treatments. Conclusions A difference in early carotid wall changes is shown between 2 equally effective antihypertensive treatments. (Circulation. 2001;103: ) Key Words: carotid arteries hypertrophy hypertension drugs Preintrusive thickening of artery walls is detectable in hypertension 1 by ultrasonographic measurement of intima-media thickness (IMT) in the carotid artery. 2 6 It is relevant to assess the influence of antihypertensive treatment on IMT progression, 7 which is faster in the presence of higher blood pressure than lower pressure. 8 Previous trials have compared calcium antagonist and diuretic effects on IMT and shown differences favoring the former. 9,10 This study, 11 ancillary to the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT), 12 compares the effects of nifedipine (long-acting formulation) and co-amilozide on carotid IMT progression in hypertensive patients. Methods Study Population Participants were recruited by French INSIGHT centers with the same criteria as INSIGHT, 12 plus 2 specific criteria: participation in INSIGHT and availability of a good IMT image in the right common carotid artery before randomization. Eligible subjects were men and women 55 to 80 years old with blood pressure of 150/95 mm Hg or systolic values of 160 mm Hg regardless of diastolic and 1 ofthe following risk factors: smoking, hypercholesterolemia, diabetes mellitus, left ventricular hypertrophy, history of cardiovascular disease, family history of myocardial infarction, and proteinuria. Patients with secondary or malignant hypertension, stroke, or myocardial infarction within the previous 12 months were not eligible. Of 469 subjects who met enrollment criteria, 439 fulfilled the blood pressure criteria to be randomized. Randomization was done centrally, including all centers participating, and respecting the randomization criteria of INSIGHT, 12 taking into account age, sex, risk factors, and inclusion in the present study. Among randomized subjects, 324 had 1 year of follow-up and 3 serial IMT measurements, thus allowing IMT progression rate to be estimated (intent-to-treat population, Figure 1). Of these, 242 subjects completed the planned follow-up and had 5 valid IMT measurements (until-end-of-study population, Figure 1). Reasons why not all of the 439 randomized patients completed 1-year follow-up (intent-to-treat) or the planned follow-up (until-end-of-study) are given in Figure 2. Study Treatment After 1 month of treatment with placebo (baseline), patients were randomized in a double-blind fashion to receive nifedipine gastrointestinal-transport-system (GITS) (30 mg) or co-amilozide (amiloride 2.5 mg and hydrochlorothiazide 25 mg) (monotherapy dose 1). Received January 18, 2001; revision received March 28, 2001; accepted March 30, From the Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais, Paris, France. Correspondence to Alain Simon, Centre de Médecine Préventive Cardiovasculaire, Hôpital Broussais, 96 Rue Didot, Paris, France. alain.simon@brs.ap-hop-paris.fr 2001 American Heart Association, Inc. Circulation is available at

2 2950 Circulation June 19, 2001 Figure 1. Distribution of participants by follow-up time in both study populations. Medication titration could subsequently be adapted to obtain blood pressure of 140/90 mm Hg. Three titration levels were performed: (1) monotherapy dose 2, ie, twice monotherapy dose 1; (2) bitherapy, adding atenolol 25 or 50 mg (or enalapril 5 or 10 mg if atenolol was contraindicated); and (3) tritherapy, adding to the bitherapy any other antihypertensive drug exclusive of calcium antagonists and diuretics. Duration of follow-up of the until-end-of-study population was on average 48 months, range 37 to 53 months (Figure 1). Carotid Ultrasonography Investigation was performed in 13 centers with high-resolution imagers, 11 with 5- to 10-MHz probes, by sonographers who were vascular physicians trained in IMT measurement (Appendix). Baseline ultrasound detection of plaque was performed in both carotid arteries. The presence of plaque, defined as a focal echogenic structure encroaching into the lumen with a thickness of 50% of that of the surrounding walls, was positive if 1 plaques were found. 13 Longitudinal scans of the right common carotid artery, 3 cm before the bifurcation (flow divider), were performed at baseline, 4 months after randomization, and every 1 year for the duration of follow-up. This segment, close and parallel to the skin surface, is easy to image, with a lumen-intima interface regular and parallel to the adventitia. The same sonographer performed all scans of each patient throughout the study. Minimum gain was adjusted to visualize the lumenintimal and media-adventitial interfaces defining IMT in the far wall along 1 cm of length. Then, the vessel image was frozen in telediastole by ECG R-triggering and transferred to a computer (Apple Macintosh) with a program of image acquisition (Iôtec, IôDP). This program allowed the image to be digitized and stored. 2,6 The computerized generation of the anatomic situation (mask) of the investigated area at baseline allowed superimposition of the real-time echographic image Figure 2. Reasons why randomized patients did not complete 1-year follow-up (intent-to-treat) or planned follow-up (until-endof-study). n number of patients. under treatment and the mask of the first investigation to improve the repeated identification of the carotid sector. 2,6 Central Reading Images stored on disk were sent to the reading center for off-line analysis by 1 reader blinded to treatment assignment. Far-wall IMT was measured with an automated computerized edge-detection program (Iô, IôDP) on the basis of gray-level density and tissuerecognition algorithms, 2,3,6 locating echoes arising from IMT interfaces and calculating their distance every 100 m along 1 cm length. The program also located the leading edges of far- and near-wall blood-intima interfaces defining lumen diameter (D) and calculated their distance along the same length as IMT. 6 The cross-sectional area of IMT (CSA-IMT) was calculated as follows 14 : IMT (IMT D). Quality Control Program Centers were visited before the study and annually until its termination, with examination of a tissue-equivalent phantom allowing the initial value of the settings to be maintained throughout the study. Because the same phantom was examined, all units and transducers were matched between centers. Images were read after termination of the study, but the reader was not blind to the sequence time of the tracings. Images were read on a field of measure that had the same situation, with regard to the artery and surrounding structure, at baseline and during treatment and was reader-independent thanks to the automated program. Reproducibility of measurement was assessed during the placebo period in 39 random subjects; the mean absolute difference between repeat measures of IMT at 15-day intervals by the same sonographer was mm, in agreement with the precision obtained on the basis of previous studies. 5,6 Study Outcomes Primary outcome was the IMT progression rate estimated in each patient as the slope of the least-squares regression line relating IMT to the time since baseline ultrasonography throughout the follow-up. A minimum of 3 serial IMT assessments (ie, 1 year of follow-up) was required for obtaining a valid estimation of slope. In the until-end-of-study population, the slope was estimated from IMT measurements ( 5) during the entire follow-up period. In the intent-to-treat population, the slope was estimated independently of whether the patient completed the planned follow-up. To analyze how the slope may change as a function of follow-up duration, intention-to-treat analysis was performed in patients who were 2 years, 3 years, or 4 years on treatment. Secondary outcomes consisted of absolute change from baseline (last value under treatment minus baseline value) in IMT, CSA-IMT, and diameter. They were determined in the until-end-of-study population, in the intent-totreat population independently of whether the patient completed the planned follow-up, and in patients with 2, 3, or 4 years on treatment.

3 Simon et al IMT and Antihypertensive Treatment 2951 TABLE 1. Baseline Data by Treatment Assignment in Until-End-of-Study and s Nifedipine GITS Co-Amilozide Until End of Until End of Parameter Study Intent to Treat Study Intent to Treat Number, n Age, y 65.1 (0.6) 65.2 (0.5) 65.9 (0.5) 65.7 (0.5) Male sex, n (%) 59 (51) 80 (50) 58 (46) 84 (51) Body mass index, kg/m (0.4) 27.7 (0.3) 28.2 (0.4) 28.2 (0.3) Blood pressure, mm Hg Systolic 160 (2) 162 (2) 160 (1) 161 (1) Diastolic 93 (1) 94 (1) 93 (1) 94 (1) Associated risk factors, n (%) Smoking 29 (25) 44 (28) 31 (24) 42 (26) Hypercholesterolemia 61 (53) 89 (56) 60 (47) 76 (46) Diabetes mellitus 28 (24) 35 (22) 32 (25) 38 (23) ECG left ventricular hypertrophy 5 (4) 6 (4) 8 (6) 8 (5) Personal cardiovascular disease 17 (15) 28 (18) 21 (17) 27 (17) Family history of myocardial infarction 17 (15) 24 (15) 21 (17) 26 (16) Ultrasound carotid plaque 35 (30) 52 (33) 44 (35) 55 (34) Carotid IMT, mm (0.012) (0.012) (0.011) (0.009) Carotid lumen diameter, mm 6.56 (0.08) 6.52 (0.07) 6.58 (0.07) 6.54 (0.06) Carotid CSA-IMT, mm (0.43) (0.36) (0.34) (0.31) Data are mean (SEM) or number (n) of subjects with percentage (%). Between treatment group differences were all nonsignificant. TABLE 2. Percentage of Participants on Monotherapy, Bitherapy, or Other Combination by Treatment Group in the Monotherapy Bitherapy Dose 1 Dose 2 Atenolol Enalapril Other Nifedipine GITS 1-year year year year Co-amilozide 1-year year year year Between-group differences were all nonsignificant. Statistical Issues Sample size was chosen to provide 90% power (with 2P 0.05) to detect a mm difference in change from baseline in IMT after 3 years between treatment groups, with an expected SD of the change of mm. 11 Accordingly, 165 patients were required per group, ie, a total of 330, which was increased by 30% (430 patients) to take the withdrawals into account. It was decided before unblinding that the primary analysis would be done in the until-endof-study population because the precision of the primary outcome was greater than in the intent-to-treat population. All patients of the until-end-of-study population had 5 valid IMT assessments, whereas some patients in the intent-to-treat population had only 3 IMT assessments. Between treatment group differences in parameters were tested with Student s t test for independent groups. Within treatment group differences in parameters from zero were tested with a paired t test. Multivariate analysis was used to test between treatment group differences after adjustment for (1) ultrasound center; (2) baseline covariates including age, sex, body mass index, associated risk factors, ultrasound plaque, and diastolic pressure; and (3) absolute change in diastolic pressure (last value under treatment minus baseline value). Statistical analysis was performed with an SAS software package (V12) for Windows operating system. Results The intent-to-treat, until-end-of-study, and randomized populations did not differ at baseline. Treatment groups did not differ in baseline parameters in either study population (Table 1). The percentages of participants on monotherapy (dose 1 or 2) or bitherapy (atenolol or enalapril) did not differ between treatment groups (Table 2). Decreases in pressure were similar in the until-end-of-study and intent-to-treat populations at different durations of follow-up (Figure 3). IMT Progression Rate Until-End-of-Study Population The IMT progression rate differed between treatment groups before (P 0.002) and after (P 0.003) adjustment for center, baseline covariates, and diastolic pressure change. Withingroup comparison to zero showed that IMT progressed significantly on co-amilozide (P 0.001) but not on nifedipine (Table 3). In the whole intent-to treat population, the difference in IMT progression rate between treatments did not reach statistical

4 2952 Circulation June 19, 2001 significance (P 0.09) (Table 3), but in the subgroup of individuals who received only the randomization medications (monotherapy dose 1 or 2), the difference between nifedipine and co-amilozide was significant ( versus mm/y, P 0.05). In patients with 2, 3, or 4 years of follow-up, the difference in IMT progression rate was significant between treatments before adjustment (P 0.04, 0.004, 0.007, respectively) and after adjustment (P 0.04, 0.003, 0.010) (Table 3). In the subgroup of patients receiving the randomization medications (monotherapy), the difference between nifedipine and co-amilozide was also significant in subjects with 2 years of follow-up ( versus mm/y, P 0.05), 3 years of follow-up ( versus mm/y, P 0.01), or 4 years of follow-up ( versus mm/y, P 0.01). Within-group comparison to zero showed that IMT progressed significantly on co-amilozide in the whole intent-totreat population (P 0.05) and in patients with 2, 3, or 4 years of follow-up (P 0.01, P 0.001, P 0.001) but did not on nifedipine (Table 3). Changes From Baseline in IMT and CSA-IMT Until-End-of-Study Population Changes in IMT and CSA-IMT differed between treatments before adjustment (P 0.001, P 0.006) and after adjustment (P 0.002, P 0.005) (Table 4). Within-group comparison to zero showed that IMT and CSA-IMT increased on coamilozide (P 0.001) but not on nifedipine (Table 4). Figure 3. Changes from baseline in blood pressure by treatment group in until-end-of-study and intent-to-treat populations. Data are mean (SEM). Between treatment group differences are all not significant. Within-group differences from zero are all P In the whole intent-to-treat population, changes in IMT and CSA-IMT differed between treatments before adjustment (P 0.004, P 0.037) and after adjustment (P 0.008, P 0.036) (Table 4). Changes in IMT and CSA-IMT differed between treatments in patients with 2 years (P 0.005, P 0.025), 3 years (P 0.001, P 0.013), or 4 years (P 0.005, P 0.015) of follow-up, and such differences persisted after adjustment (Table 4). Within-group comparisons showed that IMT increased from baseline on coamilozide in the whole intent-to-treat population and in patients with 2, 3, or 4 years of follow-up (P 0.001) but did not on nifedipine (Table 4); CSA-IMT increased from baseline on co-amilozide only in patients with 3 or 4 years of follow-up (P 0.05) but did not on nifedipine (Table 4). Change in Diameter From Baseline Until-End-of-Study Population Diameter decreased on nifedipine (P 0.05) and co-amilozide (P 0.001), and diameter changes did not differ between the 2 treatments (Figure 4). Diameter decreased on co-amilozide in the whole intent-totreat population (P 0.001) and in patients with different duration of follow-up (P 0.001) but did not change on nifedipine except in patients with 4 years of follow-up (P 0.05) (Figure 4). Diameter changes were different between drugs in the whole intent-to-treat population (P 0.05) and in patients with 3 years of follow-up (P 0.05) but not in patients with 1 or 4 years of follow-up (Figure 4). TABLE 3. Between Treatment Group Differences in Progression Rate of Carotid IMT in Until-End-of-Study and s Annualized Progression Rate of IMT, mm/y Nifedipine GITS Co-Amilozide P Population No. Mean (SEM) No. Mean (SEM) Unadjusted Adjusted Until end of study (0.0020) (0.0018) Intent to treat All patients (0.0026) (0.0022)* y follow-up (0.0019) (0.0019) y follow-up (0.0019) (0.0018) y follow-up (0.0021) (0.0018) Adjustment was done on ultrasound center, baseline covariates, and change in diastolic pressure. *P 0.05, P 0.01, P progression rate vs zero within treatment group.

5 Simon et al IMT and Antihypertensive Treatment 2953 TABLE 4. Between Treatment Group Differences in Absolute Change ( ) From Baseline in Carotid IMT and CSA-IMT in Until-End-of-Study and s Nifedipine GITS Co-Amilozide P Population No. Mean (SEM) No. Mean (SEM) Unadjusted Adjusted Until end of study IMT, mm (0.009) (0.007) CSA-IMT, mm (0.240) (0.196) Intent to treat All patients IMT, mm (0.007) (0.006) CSA-IMT, mm (0.189) (0.168) years follow-up IMT, mm (0.008) (0.007) CSA-IMT, mm (0.204) (0.178) years follow-up IMT, mm (0.008) (0.007) CSA-IMT, mm (0.221) (0.193)* years follow-up IMT, mm (0.009) (0.007) CSA-IMT, mm (0.244) (0.198)* Adjustment was done on ultrasound center, baseline covariates, and change in diastolic pressure. *P 0.05, P change vs zero within treatment group. Discussion In the until-end-of-study population, IMT progression rate and changes from baseline in IMT and CSA-IMT (an estimate of arterial wall mass) were different between treatments. In the intent-to-treat population, treatment difference in IMT rate did not reach statistical significance, whereas changes in IMT and CSA-IMT were significantly different between treatments; but in patients with 2, 3, or 4 years of follow-up, significant treatment differences existed in IMT progression rate as well as in changes in IMT and CSA-IMT. Thus, the nonsignificant treatment difference in IMT progression rate of the intent-to-treat population was due to patients who were Figure 4. Changes from baseline in diameter by treatment group in until-end-of-study and intent-to-treat populations. Data are mean (SEM). *P 0.05, P change vs zero within group. only 1 year on treatment. This follow-up is not sufficiently long to determine IMT progression rate with good precision, especially because measurement at 4 months was taken too early. Different treatment effects on IMT result because IMT progressed on co-amilozide, whereas it did not on nifedipine. The possibility that atenolol and hydrochlorothiazide both have negative effects on IMT progression (ie, by increasing insulin resistance) has been excluded by the analysis of those individuals who received only the randomization medications (monotherapy) and who exhibited the same different drug effects on IMT progression rate as the whole population. Several points of these findings have to be considered. First, previous trials (especially MIDAS and VHAS 9,10 ) have shown beneficial effects of calcium antagonists on carotid IMT compared with diuretic agents. The MIDAS study concluded that there was no difference in IMT effects of isradipine and hydrochlorothiazide, because there was no divergence in the IMT progression slope between treatments, 9 but when data were analyzed as IMT change from baseline, differences existed favoring isradipine. 9 The VHAS study found a greater effect of verapamil than chlorthalidone on IMT progression when the slope of IMT change was corrected by the initial IMT value. 10 The VHAS analysis, however, took into account thicker lesions in the bifurcation and internal carotid artery; this may explain why we found progression with diuretics and no change with nifedipine but VHAS found regression with both drugs and greater regression with verapamil. 10 Another point is the physiological meaning of the treatment effects on IMT change. This latter may be a result of medial hypertrophy or intimal thickening reflecting early atherosclerosis. 15 We cannot distinguish between these mechanisms, because ultrasonography does not

6 2954 Circulation June 19, 2001 measure medial and intimal thickness separately. Thus, our interpretation is dependent on indirect arguments. Those for medial hypertrophy are that IMT has been measured in distal common carotid artery free of atherosclerotic plaque and that medial hypertrophy is specifically related to hypertension. 1 Conversely, the implication of atherogenesis is supported (1) by the fact that IMT, even measured locally, may reflect a widespread atherosclerosis-related phenomenon (in particular in elderly high-risk patients) 16 and (2) by previously demonstrated antiatherogenic properties of calcium antagonists. 17 Arguments in favor of an atherogenic nature of IMT change would have been strengthened if investigation had been extended to plaques. Although the presence of plaque was analyzed at baseline as a part of risk stratification, the thickness of plaque and its change throughout the study were not assessed because our computerized measurement was inappropriate. Thus, our work does not permit us to assess whether the effects of treatments on IMT may reflect different effects on vascular hypertrophy rather than on atherosclerosis. A third point to discuss is the meaning of different effects on carotid IMT when the effects of 2 treatments on mortalitymorbidity are equal in INSIGHT, 12 as well as in our patients, with limitations due to the smallness of the sample. An explanation may be that early wall change, such as IMT, cannot predict relatively short-term occurrence of complications. In consideration of the well-recognized predictive value of IMT, 16 the beneficial effects of nifedipine on IMT may announce a smaller incidence of complications in the longer term. The last findings are diameter changes that may influence wall thickness. They occur at the beginning of treatment (when pressure is reduced) and remain relatively stable without progression as the IMT changes, suggesting that they did not confound IMT progression over time. Furthermore, the decrease in diameter is more pronounced on co-amilozide than on nifedipine, probably because the latter vasodilates the carotid artery 18 and counteracts the passive diameter decrease due to pressure lowering. Such a difference, however, disappears in patients with the longest follow-up. In summary, we report clear-cut differences in early carotid wall changes between 2 equally effective antihypertensive strategies. The general applicability of the findings may be limited by the facts that our population was small and that the sample (until-end-of-study population) from which our main conclusions were drawn was smaller than the one estimated to give a 90% power to detect. Therefore, our findings would need to be confirmed by larger studies. Appendix Sonographers: Angers, M. Davinroy; Blois, H. Ducoux; Bordeaux, V. Dehant, J.C. Saby; Cavaillon, P. Giraud, J.Y. Brunet; La Rochelle, J.P. Chantereau, G. Desprairie; Nantes, G. Fauvel; Nimes, M. Dauzat; Paris Nord, F. Luizy; Paris Sud, J. Gariépy; Roanne, P. Drevon; Thionville, S. Kownator; Toulouse, B. Chamontin, J. Amar; Toulon, N. Dagorn. Reader: J. Gariépy. Technical assistance: M. Massonneau. Bayer project leaders: J.C. Provost, A. Deverly. Statistician: D. Moyse. Management Committee: A. Simon, J. Levenson, J. Gariepy, J.L. Megnien, D. Moyse, A. Deverly, M. Massonneau. Acknowledgments This study was supported by Bayer Pharma. We thank the INSIGHT investigators for recruiting participants, M. Crichi for secretarial assistance, and J. Menard for advice in the writing of the manuscript. References 1. Chobanian AV Corcoran lecture: Adaptive and maladaptive response of the arterial wall to hypertension. 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