(Chest. 2003;124:2074-2078.)
© 2003
American College of Chest Physicians
Did the Widespread Use of Long-Acting Calcium Antagonists Decrease the Occurrence of Variant Angina?*
Shozo Sueda, MD;
Hiroaki Kohno, MD;
Hiroshi Fukuda, MD and
Tadao Uraoka, MD
* From the Department of Cardiology (Drs. Sueda, Kohno, and Fukuda), Saiseikai Saijo Hospital, Saijo City, Japan; and the Department of Cardiology (Dr. Uraoka), Kita Medical Association Hospital, Ozu City, Japan.
Correspondence to: Shozo Sueda, MD, Department of Cardiology, Saiseikai Saijo Hospital, Tsuitachi 269-1, Saijo City, Ehime Prefecture, Japan 793-0027; e-mail: EZF03146{at}nifty.or.jp
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Abstract
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Background: We have not often encountered variant angina (VA) since the use of long-acting calcium antagonists (L-CAs) became widespread.
Objectives: This study examined the frequency of VA retrospectively.
Methods and results: We diagnosed angiographically confirmed coronary spastic angina (CSA) in 349 consecutive patients using selective spasm provocation tests from January 1991 to December 2002. During this period, 3,148 diagnostic cardiac catheterizations and 1,515 selective spasm provocation tests were performed. Seventy-four of these 349 patients (21.2%) had VA. Coronary spasms were defined as transient luminal narrowings of > 99%, and VA was defined as an ST elevation during spontaneous attacks or noninvasive stress tests. We classified the 12 years of the study into four periods of 3 years each. No tendency to decrease for the ratio of the number of patients with CSA and the number of selective spasm provocation tests was observed among the four time periods (18%, 24%, 32%, and 23%, respectively). However, the number of patients with VA (28, 33, 9, and 4) and the VA/CSA ratio (32%, 28%, 14%, and 5%, respectively) in the four group significantly decreased. The frequency of administration of calcium antagonists (CAs) before hospital admission (49% vs 33%, respectively; p < 0.05) was significantly higher in the last time period (from 2000 to 2002) than in the first period (from 1991 to 1993). L-CAs were administered in > 90% of CSA patients who had been medicated with CAs before hospital admission in the last period (from 2000 to 2002), while L-CAs were administered in only 20% in the former period (from 1991 to 1993). The administration of statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers before hospital admission gradually increased according to the period passed, but not significantly.
Conclusion: The frequency of VA has decreased in Japan, possibly due to the widespread use of therapy with L-CAs.
Key Words: long-acting calcium antagonist • variant angina
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Introduction
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More than 40 years ago, Prinzmetal et al1
reported on variant angina (VA), a new cardiac disease. Racial differences between white and Japanese patients have been reported by Beltrame et al2
and Pristipino et al.3
Spontaneous remission was a frequent outcome in Western patients with VA.4
However, it was a rare phenomenon in Japanese patients with coronary spastic angina (CSA), regardless of therapy with a full spectrum of medications, including calcium antagonists (CAs).5
Long-acting CAs (L-CAs), as well as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers often have been administered to patients with hypertension in Japan. Because the number of coronary spasms was three times higher in Japanese people than in Western people,6
an L-CA was sometimes first administered in patients with ischemic heart disease instead of ß-blockers.
In this study, we examined the frequency of VA retrospectively. We also examined whether or not the administration of L-CAs before hospital admission in patients with CSA had increased over the past 12 years in a single center.
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Materials and Methods
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Study Subjects
From January 1991 to December 2002, we performed 3,148 consecutive diagnostic cardiac catheterizations and 1,515 consecutive selective spasm provocation tests. As noninvasive tests, we performed 8,456 treadmill exercise tests and 10,475 24-h Holter monitoring sessions. During this period, CSA was diagnosed in 349 patients using selective spasm provocation tests, and 74 of these 349 patients had VA. Spontaneous ST elevation was observed in 49 patients (anterior ST elevation, 25 patients; inferior ST elevation, 24 patients), and the remaining 25 patients (anterior ST elevation, 10 patients; inferior ST elevation, 15 patients) had ST elevation during or after undergoing treadmill exercise tests. Only three patients experienced ST elevations during 24-h Holter monitoring sessions. Percutaneous coronary intervention was performed in 40 CSA patients with organic stenosis (non-VA, 19 patients; and VA, 21 patients). Two patients underwent emergent coronary bypass surgery after hospital admission.
VA was defined as angina pectoris occurring in association with a transient ECG elevation of 
2 mm, either during spontaneous angina attacks or during noninvasive spasm provocation procedures. Non-VA was defined as angina pectoris without ST-segment elevation due to any noninvasive spasm provocation procedures or spontaneous attacks. Pure VA was defined as < 75% organic stenosis, and nonpure VA was defined as 75% organic stenosis.
We classified the 12 years of the study into four periods of 3 years each, as follows: first period, 1991 to 1993; second period, 1994 to 1996; third period, 1997 to 1999; and fourth period, 2000 to 2002.
Informed consent was obtained from each patient for cardiac catheterization, for the provocation test for the induction of coronary artery spasms, and for percutaneous coronary intervention. The protocol of this study was in agreement with the guidelines of the ethics committee at our institution.
Coronary Angiography With a Spasm Provocation Test
Coronary arteriography was performed by the injection of 6 to 8 mL contrast medium with the Sones technique from 10:00 AM to 4:00 PM after patients had gone without any medication for at least 24 h. A bipolar electrode catheter was inserted into the right ventricular apex through the femoral or antecubital vein and was connected to a temporary pacemaker set at a rate of 45 beats/min.
As previously reported,7
8
9
10
11
the provocation of coronary vasospasm was performed with an intracoronary injection of acetylcholine or ergonovine. Acetylcholine was injected in incremental doses of 20, 50, and 80 µg into the right coronary artery, and in doses of 20, 50, and 100 µg into the left coronary artery over > 20 s, with at least a 3-min interval between each injection. Ergonovine was administered at a rate of 10 µg/min over 4 min for a maximum dose of 40 µg in the right coronary artery, and at a rate of 16 µg/min over > 4 min for a total dose of 64 µg in the left coronary artery, with at least a 5-min interval between each injection. When a coronary spasm was induced and did not resolve spontaneously within 3 min after completion of the acetylcholine or ergonovine injection, or when hemodynamic instability due to a coronary spasm occurred, 2.5 to 5.0 mg isosorbide dinitrate was injected into the responsible vessel. During the study, arterial BP and a 12-lead ECG were continuously monitored on an oscilloscope with a polygraph (Nihon Kohden; Tokyo, Japan). A standard 12-lead ECG was recorded every 30 s.
The diameter of the lumen and the percentage of luminal diameter narrowing of coronary arteries were measured by an automatic edge-counter detection computer analysis system. The size of the coronary catheter was used to calibrate the image in millimeters, and the measurement was performed in the same projection as for coronary angiography. Significant organic stenosis was defined as 75% luminal narrowing. The arterial segments of coronary arteries were determined according to the American Heart Association classification system12
after intracoronary administration of 5.0 mg isosorbide dinitrate.
Medications Before Hospital Admission
We examined the medications used, including isosorbide dinitrate and nicorandil, short-acting CAs (S-CAs), L-CAs, statins, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, before hospital admission in patients with CSA. S-CAs were defined as diltiazem, nifedipine, or verapamil, and L-CAs were defined as diltiazem R, nifedipine L, nifedipine CR, amlodipine, cilnidipine, benidipine, barnidipine hydrochloride, nitrendipine, nisoldipine, nilvadipine, nicardipine hydrochloride, and manidipine hydrochloride. We also examined coronary interventions, including stents, in patients with CSA.
Statistical Analysis
Values are expressed as the mean ± SD. Differences among proportions were analyzed by the 
2 test with correction or the analysis of variance test. A p value of < 0.05 was considered to be statistically significant.
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Results
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The Frequency of CSA and VA
As shown in Table 1
, the ratio of the number of patients with CSA and the number of selective spasm provocation tests was variable but did not decrease over the four time periods. However, the number of patients with VA, the ratio of the number of patients with CSA and the diagnostic cardiac catheterization number, and the ratio of patients with VA and CSA were significantly decreased, according to the time periods passed.
Noninvasive Stress Tests and VA
As shown in Table 2
, 25 patients of all VA patients (33.8%) had ST elevation induced by a noninvasive stress test. Nine of 25 patients had significant organic stenosis. ST elevation occurring on 24-h Holter monitoring was observed in only three patients, with one patient each in the first three time periods. Twenty-five patients experienced ST elevation during or after undergoing treadmill exercise tests. The ratio of ST elevation and 24-h Holter monitoring was not different among the four time periods. Moreover, the incidence of ST elevation on treadmill exercise tests was not different among the four time periods. In the fourth time period, only one patient had ST elevation on noninavasive stress tests.
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Table 2.. Correlation Between 24-h Holter ECG Monitoring and Noninvasive Exercise Tests Results in Patients With VA*
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Medication Before Hospital Admission and Coronary Intervention in CSA
As shown in Table 3
, CAs were administered in a third of all CSA patients before hospital admission. Moreover, 30.4% of all patients with CSA had received isosorbide dinitrate/nicorandil, and both a CA and isosorbide dinitrate/nicorandil were administered in 23.8% of patients with CSA. L-CAs were administered in > 90% of patients who had been medicated with CAs before hospital admission in the third time period (from 1997 to 1999) and the fourth time period (from 2000 to 2002), while in the first time period (from 1991 to 1993), only six patients (20.7%) had received L-CAs. Table 4
shows that the administration of statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers before hospital admission gradually increased according to the period passed, but not significantly. Plain old balloon angioplasty was performed in 26 patients, and coronary stents were implanted in 14 patients with CSA. The number of coronary interventions in patients with CSA was gradually decreased, according to the decrease in VA occurrence.
Pure VA vs Nonpure VA
As shown in Table 5
, the frequency of pure VA decreased, while in contrast, nonpure VA increased. In the first two time periods (from 1991 to 1996), pure VA was observed in 47 of 61 VA patients (77%), while pure VA accounted for only 6 of 13 VA patients (46.1%) in the latter two time periods (from 1997 to 2002). The incidence of pure VA significantly decreased (77% vs 46.1%, respectively; p < 0.05).
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Discussion
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Prinzmetal et al1
reported VA as a new type of angina occurring at rest > 40 years ago. Because coronary spasms were observed in Asia more often than in the West, many studies on coronary spasms were performed in Asia. However, the frequency of VA has not been reported until now. In this article, we clarified the incidence of VA in Japan in a single center over the last 12 years.
Two Types of VA
VA was classified into the following two types: ST elevation without significant organic stenosis (ie, pure VA); and ST elevation complicated with severe atherosclerotic lesions leading to an acute coronary syndrome, such as acute myocardial infarction or unstable angina. L-CAs should be administered first in all VA patients, while coronary bypass surgery or percutaneous coronary intervention should be selected for patients with lesions having severe atherosclerotic changes showing flow limitation. In previous reports,13
14
15
prognosis after hospital admission was good in patients with pure VA, but the mortality rate was high in patients with VA complicated with severe atherosclerosis requiring intervention, such as in those patients with acute coronary syndrome. In this study, the incidence of pure VA significantly decreased according to the time period passed.
Clinical Implications
More than 12 years ago, only S-CAs like diltiazem, nifedipine, and verapamil were available clinically. In the latter half of 1990, various L-CAs, including diltiazem R, nifedipine L, nifedipine CR, amlodipine, cilnidipine, and benidipine, were made available to patients with hypertension or ischemic heart disease. Both CAs and isosorbide dinitrate were effective in suppressing anginal attacks due to coronary artery spasms in Western people.16
17
18
Moreover, spontaneous remission was a frequent outcome in Western patients with VA.4
In contrast, this is controversial in Japan. We recently reported5
the limitations of medical therapy, including L-CAs, in patients with pure CSA. However, the administration of L-CAs decreased the number of anginal attacks. The widespread use of therapy with L-CAs might suppress the frequency of ST elevation in pure CSA patients with high disease activity.
L-CAs suppressed the increased coronary tone in patients with VA and non-VA. In the near future, pure VA may be a rare cardiac disease, even in Japan. However, the frequency of CSA was not diminished among the four time periods. CAs did not act as fundamental drugs to repair the impaired endothelium or damaged smooth muscle, and only decreased coronary artery tone. Thus, cardiac catheterization, including spasm provocation tests, is ultimately necessary for diagnosing moderate or low disease activity in CSA patients.
Study Limitations
This study was a retrospective and single-center trial. However, we performed selective spasm provocation tests on about half of the patients who underwent diagnostic cardiac catheterizations. CSA was observed in 1 of 10 patients who underwent diagnostic cardiac catheterizations. We did not compare the absolute contribution of therapy with L-CAs regarding the occurrence of VA. Multiple factors, such as the widespread use of CAs, statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and coronary interventions, including stents, are involved in the occurrence of VA clinically. In this study, we failed to show a correlation between the occurrence of VA and the widespread use of statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and coronary interventions. A further prospective multicenter trial is necessary to investigate VA occurrence worldwide.
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Acknowledgements
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We acknowledge the helpful comments of Yuji Shigematsu, MD, Mareomi Hamada, MD, Jitsuo Higaki, MD, and Kunio Hiwada, MD.
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Footnotes
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Abbreviations: CA = calcium antagonist; CSA = coronary spastic angina; L-CA = long-acting calcium antagonist; S-CA = short-acting calcium antagonist; VA = variant angina;
Received for publication November 15, 2002.
Accepted for publication April 28, 2003.
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References
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- Ginsburg, R, Lamb, IH, Schroeder, JS, et al Randomized double-blind comparison of nifedipine and isosorbide dinitrate therapy in variant angina pectoris due to coronary artery spasm. Am Heart J 1982;103,44-48[CrossRef][ISI][Medline]
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Abstract
Introduction
