Quantitative Coronary Angiogram Analysis
Nifedipine Retard Versus Angiotensin-Converting Enzyme Inhibitors (JMIC-B Side Arm Study)
This study was performed to compare the effects of nifedipine retard and angiotensin-converting enzyme (ACE) inhibitors on the progression of coronary atherosclerosis by means of quantitative coronary angiogram. Coronary angiogram was performed before the start of the study and during the 3-year treatment period. This study was conducted on the assumption that possible coronary vasodilation, which may be caused by nifedipine, was excluded by administration of sufficient isosorbide dinitrate. The changes from the baseline in the minimum lumen diameter of the coronary artery in all measured segments were negligible in the nifedipine group (+0.02±0.27 mm; P=0.543), whereas they were significantly reduced in the ACE inhibitor group (−0.12±0.27 mm; P<0.001), with a significant difference observed between the groups (P=0.002). The number of progressors in the nifedipine group was significantly lower than that in the ACE inhibitor group (P=0.019), and there was also a significant difference between the groups in the number of patients in whom ≥1 lesion developed after treatment (P=0.040). However, the changes of minimum lumen diameter stratified by baseline percent diameter stenosis demonstrated that progression of coronary atherosclerosis was suppressed in the nifedipine group for lesions with a percent diameter stenosis of ≤40 but was suppressed in both groups for those with a percent diameter stenosis of ≥41. This study suggests that nifedipine retard and ACE inhibitors may be effective in suppression of progression of coronary atherosclerosis, and that nifedipine in particular may be effective for mild to moderate stenosis.
We previously conducted the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) study and reported that the effects of nifedipine retard on cardiovascular events in patients with hypertension complicated by coronary artery disease were similar to those of angiotensin-converting enzyme (ACE) inhibitors.1 In this article, we report the results from the JMIC-B side arm study, in which the effects of nifedipine retard on the progression of coronary atherosclerosis were compared with those of ACE inhibitors using quantitative coronary angiogram (QCA) of the cardiovascular measurement system.
Quantitative Coronary Angiogram
The JMIC-B side arm study was conducted using patients enrolled in the JMIC-B main study. The institutional ethical committee at each participating hospital approved the study, and all patients gave written informed consent to participate. The detailed procedure of patient recruitment is stated in the article on the main study and is omitted here.1 Follow-up films were taken 36 months after the start of treatment. When cardiac events occurring during treatment resulted in percutaneous coronary intervention (PCI), the follow-up was terminated at this time point, and the films taken immediately before PCI were used for evaluation. The routine dose of isosorbide dinitrate administered intracoronarily for coronary angiogram was 5 mg for the right and left coronary arteries (please see the online supplement, available at http://www.hypertension.aha.org). A pair of films for each patient was collected in the core angiographic laboratory at Rakuyo Hospital (Kyoto, Japan) and evaluated by 2 readers of the QCA study in a blind manner. These readers were certified by JMIC-B steering committee, and they were blinded to treatment assignment and temporal sequences of films (see online supplement).
Evaluation of QCA Data
The coprimary end points of the JMIC-B side arm study were changes in the minimum lumen diameter (MLD) and percent diameter stenosis (%DS) for each patient. These end points were compared between the groups. Whereas MLD and %DS were calculated for all segments excluding PCI sites during the treatment period, segments with ≥21% DS on films were defined as lesions. The prespecified secondary end points are the numbers of progressors, stable patients, regressors classified according to the above changes, and the number of new lesions. A list summarizing the categories was prepared (Table 1) based on the work of Jukema et al.2 Furthermore, in reference to the Prospective Randomized Evaluation of the Vascular Effects of the Norvasc Trial (PREVENT) post hoc analysis,3 coronary artery segments were stratified with the baseline %DS (<11%, 11% to 20%, 21% to 30%, 31% to 40%, and ≥41%) to compare changes in MLD before and after treatment for each stratum between the groups.
Statistical analyses can be found in the online supplement available at http://www.hypertension.aha.org.
In the JMIC-B side arm study, 77 institutions specializing in cardiovascular diseases agreed to submit coronary angiogram films of patients to the core angiographic laboratory before and 36 months after the start of treatment. Of 210 patients in the JMIC-B side arm study, 12 patients withdrew from the study, and 15 were judged to be ineligible by the QCA analysis committee because their initial coronary angiogram films were poor in quality and did not permit them to be read in the correct angiographic views. The remaining 183 consisted of 95 in the nifedipine group and 88 in the ACE inhibitor group. In the nifedipine group, 5 patients discontinued the study because of adverse drug reactions in the follow-up period, and 7 were excluded from analyses because their follow-up coronary angiogram films were taken in angiographic views that were inconsistent with those of the initial films. In the ACE inhibitor group, 6 patients discontinued the study because of adverse drug reactions, and 3 were excluded from analyses because of inconsistent film angiographic views. Study analyses were performed on the data from the remaining 83 and 79 patients in the nifedipine and ACE inhibitor groups, respectively. There was no significant difference in the number of patients excluded from analysis between the groups (P=0.561). Furthermore, when baseline patient characteristics in patients included in analysis were compared with those in patients lost from the study, no difference was found in any item.
The mean duration to follow-up coronary angiogram was 31.2±14.4 and 28.8±14.4 months in the nifedipine and ACE inhibitor groups, respectively. The proportion of patients who completed the 3-year coronary angiogram follow-up was 72% and 61% in the nifedipine and ACE inhibitor groups, respectively. The baseline characteristics were not different between the 2 groups (Table 2). For a history of myocardial infarction among patient characteristics, no statistically significant differences were found between the groups in the percentage of patients with previous Q-wave myocardial infarction (QMI) or non-QMI (P=0.528 for QMI; P=0.542 for non-QMI). With regard to the severity of baseline coronary artery disease, we compared the groups in terms of the distribution of the number of coronary artery branches with a lesion as well as the %DS and MLD for all segments. The comparison revealed no differences (Table 3); specifically, no biases were evident in the severity of coronary artery disease. The average dose in the nifedipine group during the treatment period was 33.9±9.7 mg per day. In the ACE inhibitor group, although the brand of ACE inhibitors was not specified, commonly used drugs included enalapril (55 patients), imidapril (11 patients), and lisinopril (13 patients). The overall mean dose of the ACE inhibitor group was 5.8±1.8 mg per day, and the average dose for those drugs was 5.1±1.6, 6.1±2.1, and 8.4±2.3 mg per day, respectively. There was no difference in the proportion of patients on aspirin products, nitrates, 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors, or β-blockers between the groups (Table 2). Similarly, no differences were seen between the groups in the number of smokers or patients with concurrent diabetes mellitus.
Table 3 shows the changes in the mean MLD (ΔMLD) and in the %DS (Δ%DS) on a by-patient basis. For all the measurement segments, ΔMLD was negligible in the nifedipine group, but ΔMLD was significantly reduced after treatment in the ACE inhibitor group (P<0.001), with a significant difference observed between the groups (P=0.002). Δ%DS was significantly decreased in the nifedipine group (P<0.001) but negligibly changed in the ACE inhibitor group, showing a significant difference between the 2 treatment groups (P=0.002).
ΔMLD for lesions (%DS ≥21) increased significantly in the nifedipine group (P<0.001) and was very small in the ACE inhibitor group, showing a significant difference between the groups (P=0.016). Δ%DS was significantly reduced in the nifedipine and ACE inhibitor groups (P<0.001 and P=0.001, respectively), and no differences were found between the groups. ΔMLD for no lesions (%DS <21) negligibly changed in the nifedipine group but significantly decreased in the ACE inhibitor group, showing a significant difference between the 2 groups (P=0.014). Furthermore, the Figure illustrates results of a comparison of ΔMLD on a by-patient basis stratified by the degree of baseline %DS. In the nifedipine group, ΔMLD was significantly increased for baseline %DS of 21% to 30% and ≥41% (P=0.01 and P<0.001, respectively). In the ACE inhibitor group, ΔMLD was significantly decreased for baseline %DS of <11% and 11% to 20% (P<0.001 and P=0.015, respectively) but was significantly increased for lesions with baseline %DS of ≥41% (P=0.004). A comparison of ΔMLD between the groups revealed that nifedipine was superior to ACE inhibitors in the suppression of progression for baseline %DS of 11% to 20% and 21% to 30% (P=0.017 and P=0.005, respectively), whereas no differences were found between the groups for baseline %DS of ≥41%. There was a large difference in the proportion of patients who completed the 3-year coronary angiogram follow-up between the 2 groups. The absolute ΔMLD data for all segments were adjusted by the percentage of the actual follow-up duration based on the 3-year follow-up period. The adjusted ΔMLD was 0.03±0.57 and −0.21±0.60 mm per 3 years for the nifedipine and ACE inhibitor groups, respectively, with a significant difference observed between the groups (P=0.014). The results were similar to those before adjustment.
Patient Classification (Table 4)
The number of progressors in the nifedipine group was significantly lower than that in the ACE inhibitor group (P=0.019), and there was also a significant difference between the groups in the number of patients in whom ≥1 lesion developed after treatment (P=0.040). When the number of new lesions per patient was compared between the groups, it was lower in the nifedipine group than in the ACE inhibitor group (P=0.072).
Other Factors Affecting the Progression of Coronary Atherosclerosis (Table 5)
Systolic and diastolic blood pressure levels during the follow-up period were significantly lower than those during the observation period at month 6 and thereafter in both groups (paired t test; P<0.05), and no significant differences were found in the degree of blood pressure reduction between the groups. Similarly, no significant differences in heart rate changes were observed between the groups. There were no significant differences between the groups in total cholesterol levels during the follow-up period. Regarding HDL cholesterol levels, no significant differences were seen between the groups during the follow-up period. No significant differences were found in the incidence of cardiac events between the groups (nifedipine group 25 patients; ACE inhibitor group 22 patients). Angina pectoris requiring hospitalization occurred in 16 and 13 patients in the nifedipine and ACE inhibitor groups, respectively. Nonfatal myocardial infarction occurred in 2 and 6 patients in the nifedipine and ACE inhibitor groups, respectively. Nonscheduled percutaneous transluminal coronary angioplasty/coronary artery bypass grafting was performed after the start of treatment in 17 and 18 patients in the nifedipine and ACE inhibitor groups, respectively.
This study verified that nifedipine was superior to ACE inhibitors in the suppression of progression of coronary atherosclerosis and in the reduction of development of new lesions. However, an intergroup comparison of changes in the MLD by the degree of baseline %DS revealed a significant increase in the MLD in both groups for lesions with a ≥41% baseline %DS. This result suggests that ACE inhibitors and calcium channel blockers can also suppress the progression of atherosclerosis in coronary lesions with advanced stenosis. The regression effect of the calcium channel blocker for more significant lesions is consistent with the post hoc analysis of the PREVENT trial.3 However, previous studies (eg, Simvastatin/Enalapril Coronary Atherosclerosis Trial [SCAT]4 and Quinapril Ischemic Event Trial [QUIET]5) assessing the suppression of coronary atherosclerosis progression via QCA analysis showed negative results for ACE inhibitors. For carotid intima-media thickness (IMT), the INSIGHT side arm study6 showed that nifedipine decreased the IMT, the PREVENT study7 demonstrated that amlodipine decreased IMT, and the ELSA study8 suggested that lacidipine slowed down progression of carotid IMT. For ACE inhibitors, the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE)9 and the Plague Hypertension Lipid Lowering Italian Study (PHYLLIS)10 showed that ACE inhibitors decreased IMT of the carotid bifurcation and internal carotid artery, whereas the PART-2 Collaborative Research Study11 demonstrated no suppressive effects of the same drug on IMT of the common carotid artery. The results of the ELVERA trial,12 in which a calcium channel blocker was compared with an ACE inhibitor for their effects on atherosclerosis, have been published recently. Whereas the calcium channel blocker was superior to the ACE inhibitor in the decrease of IMT of the carotid artery, the effect on IMT of the femoral artery was similar for both drugs, and no differences were found between the drugs in the average value for all regions analyzed. Investigators in the trial focused attention on the fact that the carotid and femoral arteries mainly consist of elastic and muscular fibers, respectively, and suggested that the effects of calcium channel blockers and ACE inhibitors could be dependent on differences in the vessel wall and vascular endothelial function of the regions analyzed. Calcium channel blockers have been reported to have antiatherosclerotic effects in animal studies and in experiments using human cultured cells. This is thought to be mediated by a number of factors, including antioxidant activity and enhancement of NO production.13 Although most of these effects require a much higher dose than usual clinical doses, it has been reported recently that some calcium channel blockers can suppress atherosclerosis even at clinical doses.3,6,7,8⇓⇓⇓ ACE inhibitors, on the other hand, have been reported to suppress atherosclerosis progression in various processes by inhibiting angiotensin II formation and bradykinin degradation.14
In the present study, no significant differences were found in the achieved blood pressure levels and the degree of their reduction between the 2 groups. The proven intergroup difference in suppression of coronary arthrosclerosis progression cannot be attributed to the difference in blood pressure reduction level but possibly to that of the class of agents used.
Data from the PREVENT study demonstrated that amlodipine did not retard the reduction of MLD of mild lesions compared with placebo.7 As a potential reason for a discrepancy between our results and this finding of amlodipine, Japanese patients with atherosclerosis often have coronary spasm,15 which could aggravate coronary atherosclerosis.16
Total coronary occlusion is a thrombotic condition induced by plaque rupture or erosion, and it causes acute coronary syndrome. Calcium channel blockers and ACE inhibitors may “pacify” plaques through disparate mechanisms, even if antiatherosclerotic effects are more prominent with another class of drugs. Data from a trial by Mancini et al suggested that amlodipine could stabilize vulnerable plaques.17 In the present study, total coronary occlusion during the follow-up period was observed at 5 segments in the nifedipine group and at 9 segments in the ACE inhibitor group. The small numbers of totally occluded segments and patients with acute events precluded an evaluation of the effects of the study drugs on plaque stabilization. Although potentially contributory effects of nifedipine and ACE inhibitors have been assessed based on the results of basic research,18,19⇓ these need to be verified in clinical studies that include intravascular echography.
We did not consider the coronary dilatating action of nifedipine in measuring MLD because we considered that administration of isosorbide dinitrate at the time of coronary angiogram had resulted in sufficient vasodilatation. This study was conducted on the assumption that possible coronary vasodilation, which may be caused by nifedipine, was excluded by administration of sufficient isosorbide dinitrate. However, the present study has a limitation that it is problematic whether the effect of nifedipine to dilate coronary artery was completely excluded by isosorbide dinitrate. Glagov et al reported compensatory remodeling in response to arterial wall thickening in the initial stages of atherosclerosis progression.20 This change in the arterial wall can be evaluated quantitatively by means of intravascular ultrasound (IVUS). However, when the study started in 1994, IVUS was not widely used in clinical settings in Japan. In recently published results of the CAMELOT study21 evaluating the suppression of progression of coronary atherosclerosis by means of IVUS, compared with baseline, IVUS showed progression in the placebo group, a trend toward progression in the enalapril group, and no progression in the amlodipine group.
The results of this study suggest that nifedipine retard and ACE inhibitors may be effective in the suppression of progression of coronary atherosclerosis, and that nifedipine in particular may be an effective treatment for a wide range of lesions with mild to moderate stenosis. However, for all future studies, the suppression of coronary atherosclerosis progression should be evaluated not only on the basis of changes in the coronary stenosis represented by MLD, but also via IVUS.
This study was supported by a grant from the Preventive Arteriosclerosis Research Association (1-24-4), Ebisu Shibuya-ku, Tokyo, Japan.
- Received January 6, 2005.
- Revision received January 13, 2005.
- Accepted March 30, 2005.
- ↵Yui Y, Sumiyoshi T, Kodama K, Hirayama A, Nonogi H, Kanmatsuse K, Origasa H, Iimura O, Ishii M, Saruta T, Arakawa K, Hosoda A, Kawai C. Comparison of nifedipine retard with angiotensin-converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) Randomized Trial. Hypertens Res. 2004; 27: 181–191.
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- ↵Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, 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, Bond MG, Hening M, Neiss A, Mancia G, Palu CD, 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. Circulation. 2002; 106: 2422–2427.
- ↵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. Effect 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.
- ↵Zanchetti A, Crepaldi G, Bond G, Gallus G, Veglia M, Mancia G. Effects of fosinopril and pravastatin on progression of asymptomatic carotid atherosclerosis in hypertension: results of Plague Hypertension Lipid Lowering Italian Study (PHYLLIS). J Hypertens. 2003; 21 (suppl 4): S346.
- ↵MacMahon S, Sharpe N, Gamble G, Clague A, Mhurchu CN, Clark T, Hart H, Scott J, White H. Randomized, placebo-controlled trial of the angiotensin-converting enzyme inhibitor, ramipril, in patients with coronary or other occlusive arterial disease. Part-2 Collaborative Research Group. Prevention of Atherosclerosis with Ramipril. J Am Coll Cardiol. 2000; 36: 438–443.
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- ↵Candido R, Jandeleit-Dahm KA, Cao Z, Nesteroff SP, Burns WC, Twigg SM. Dilley RJ, Cooper ME, Allen TJ. Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice. Circulation. 2002; 106: 246–253.
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