Hypertension. 2005;45:1153-1158
Published online before print April 25, 2005,
doi: 10.1161/01.HYP.0000165677.71421.8c
(Hypertension. 2005;45:1153.)
© 2005 American Heart Association, Inc.
Quantitative Coronary Angiogram Analysis
Nifedipine Retard Versus Angiotensin-Converting Enzyme Inhibitors (JMIC-B Side Arm Study)
Eiji Shinoda;
Yoshiki Yui;
Kazuhisa Kodama;
Atsushi Hirayama;
Hiroshi Nonogi;
Kazuo Haze;
Tetsuya Sumiyoshi;
Saichi Hosoda;
Chuichi Kawai for the Japan Multicenter Investigation for Cardiovascular Diseases-B Study Group
From the Rakuyo Hospital (E.S.), Kyoto, Japan; Kyoto University Hospital (Y.Y.), Japan; Osaka Police Hospital (K.K., A.H.), Japan; National Cardiovascular Center (H.N.), Suita, Japan; Osaka City General Hospital (K.H.), Japan; The Sakakibara Heart Institute (T.S., S.H.), Tokyo, Japan; and Takeda General Hospital (C.K.), Kyoto, Japan.
Correspondence to Yoshiki Yui, MD, Department of Cardiovascular Medicine, Kyoto University Hospital, 54 Kawara-cho, Shogoin, Sakyo-Ku, Kyoto 606--8507, Japan. E-mail yoshiki{at}kuhp.kyoto-u.ac.jp
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Abstract
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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.
Key Words: nifedipine • angiotensin-converting enzyme • atherosclerosis
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Introduction
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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.
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Methods
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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
Statistical analyses can be found in the online supplement available at http://www.hypertension.aha.org.
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Results
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Patient Characterization
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 ß-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.
QCA Measurements
Table 3 shows the changes in the mean MLD (
MLD) and in the %DS (%DS) on a by-patient basis. For all the measurement segments, MLD was negligible in the nifedipine group, but MLD was significantly reduced after treatment in the ACE inhibitor group (P<0.001), with a significant difference observed between the groups (P=0.002). %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).
MLD 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). %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. MLD 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 MLD on a by-patient basis stratified by the degree of baseline %DS. In the nifedipine group, MLD 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, MLD 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 MLD 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 MLD 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 MLD 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.
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Discussion
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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 study
6 showed that nifedipine decreased the IMT, the PREVENT study
7 demonstrated that amlodipine decreased IMT, and the ELSA study
8 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 Study
11 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.
Perspectives
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.
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Acknowledgments
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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;
first decision January 13, 2005;
accepted March 30, 2005.
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Abstract
Introduction
P<0.05;