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(Chest. 2003;123:380-386.)
© 2003 American College of Chest Physicians

Limitations of Medical Therapy in Patients With Pure Coronary Spastic Angina*

Shozo Sueda, MD; Hiroaki Kohno, MD; Hiroshi Fukuda, MD; Kouki Watanabe, MD; Naoto Ochi, MD; Hiroyuki Kawada, MD and Tadao Uraoka, MD

* From the Department of Cardiology (Drs. Sueda, Kohno, Fukuda, and Watanabe), Saiseikai Saijo Hospital, Saijo City, Japan; and the Department of Cardiology (Drs. Ochi, Kawada, and Uraoka), Kita Medical Association Hospital, Ozu, Japan.

Correspondence to: Shozo Sueda, MD, Department of Cardiology, Saiseikai Saijo Hospital, Tsuitachi 269–1, Saijo City, Ehime Prefecture, Japan


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: To assess the efficacy of medication for the treatment of pure coronary spastic angina, 71 consecutive patients with this diagnosis who had undergone coronary arteriography in a hospital with a follow-up of at least 2 years were studied.

Methods and results: All 71 patients without significant organic stenosis were treated with long-acting calcium antagonists. The disappearance of chest pain attacks while receiving medical therapy was observed in 27 patients (38%), whereas the remaining 44 patients (62%) had chest pain attacks. Of special interest, 30 patients had more than one attack per month irrespective of the administration of calcium antagonists or isosorbide dinitrate. Medical treatment showed a good response in female patients (63% vs 31%, respectively; p < 0.05) and those with ST-segment elevation during selective spasm provocation tests (63% vs 30%, respectively; p < 0.05). In contrast, patients with a longer history of chest pain attacks before hospital admission and those with diffuse spasms (77% vs 34%, respectively; p < 0.01) had poor responses to medical treatment. In this study, neither sudden death nor acute myocardial infarction was observed during the follow-up periods.

Conclusion: The limitations of medical therapy, including the administration of long-acting calcium antagonists, were observed in 30 of 71 patients (42%) with pure coronary spastic angina. Medical treatment was effective in only 38% of patients with pure coronary spastic angina in Japan.

Key Words: calcium antagonist • refractory spasm • vasospastic angina


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Spontaneous remission is a frequent outcome in Western people with variant angina.1 2 3 Some authors1 have reported that drug therapy probably can be discontinued at some point in most patients who have a history of variant angina, and, moreover, it is acceptable to begin to taper and discontinue treatment 6 to 12 months after the angina disappears. However, this treatment is controversial in Japanese patients who have coronary spastic angina.

This study sought to determine whether therapy with long-acting calcium antagonists could eliminate chest pain attacks in Japanese patients with pure vasospastic angina, as well as to determine the clinical characteristics of these patients with uncontrollable chest pain attacks irrespective of the administration of long-acting calcium antagonists.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Patients
Between July 1998 and December 1999, pure coronary spastic angina was diagnosed in 71 patients (55 men and 16 women; mean [± SD] age, 63 ± 10 years) using selective spasm provocation tests. In this study, the diagnosis of pure coronary spastic angina was made in patients who met all of the following criteria: (1) burning or squeezing retrosternal chest pain; (2) relief of the pain < 5 min after the administration of sublingual nitroglycerin; (3) a positive selective spasm provocation test; (4) no significant organic stenosis (ie, > 75% narrowing of the coronary luminal diameter); and (5) no subsequent evidence of myocardial necrosis. During this period, coronary angiography was performed in 560 consecutive patients, and selective spasm provocation tests were performed in 238 consecutive patients. All 71 patients without organic stenosis were treated with long-acting calcium antagonists for at least 2 years. After hospital discharge, all patients returned for regular visits (ie, once a month) to a special clinic for coronary spastic angina patients. When angina was not controlled with therapy with one calcium antagonist, long-acting nitrate or nicorandil was added to the regimen. In addition, another calcium antagonist or a ß-blocker was added to treatment when angina was not controlled with this therapy. No patients were lost to follow-up. For hospitalized patients, we checked the residual drugs at each regular visit and confirmed the number of chest pain attacks per month requiring the sublingual administration of nitroglycerin in detail. We excluded chest pain attacks that occurred due to the failure of the patient to take their medication regularly. The dose of calcium antagonists, isosorbide dinitrates, or nicorandil was not gradually tapered in any patients who did not experience angina after undergoing the angiogram. The mean duration of chest pain attacks before hospitalization was 3.6 ± 4.4 years (range, 0 to 12 years). All but three patients had < 50% stenosis and near-normal coronary arteries. Only three patients had moderate atherosclerosis.

As shown in Table 1 , 24 patients had essential hypertension, 54 patients demonstrated habitual smoking, 29 patients had hyperlipidemia, and 15 patients had overt diabetes mellitus. The mean values for the levels of serum cholesterol, triglycerides, and high-density lipoprotein cholesterol were 195 ± 30, 126 ± 67, and 51 ± 15 mg/dL, respectively. Calcium antagonists, isosorbide dinitrates, nicorandil, and ß-blockers were administered in 100%, 39%, 41%, and 7% of all patients, respectively. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers were administered in 24% of patients, while antiplatelet agents were given to 35% of patients.


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  		Table 1.. Clinical Characteristics of Patients*

 
Written informed consent was obtained from all patients before they entered the study, and the protocol was in agreement with the guidelines of the institutional ethics committee.

Spasm Provocation Test
All drugs except for nitroglycerin were discontinued for > 24 h before the start of the study, and nitroglycerin also was discontinued > 4 h before the start of the study. Cardiac catheterization was performed from 10:00 AM to 4:00 PM using the brachial artery in the fasting state, as previously reported.4 5 6 7 After patients underwent control coronary arteriograms of the left coronary artery (LCA) in the right anterior oblique with caudal projection and of the right coronary artery (RCA) in the left anterior oblique with cranial projection, which were obtained by the injection of 8 to 10 mL contrast medium, a temporary pacemaker was inserted into the right ventricle of each patient, and the pacing rate was set at 45 beats/min. First, an acetylcholine test was performed in principle. Then, if no spasm was provoked, the intracoronary administration of ergonovine was performed.

Acetylcholine chloride (Neucholin-A, 30 mg/2 mL) [Zeria Shinyaku; Tokyo, Japan] was injected into the RCA in incremental doses of 20, 50, and 80 µg in 10 mL 0.9% saline solution, and into the LCA in incremental doses of 20, 50, and 100 µg over > 20 s. Patients were asked to report any chest pain and to grade it on a scale of 1 to 10. A standard 12-lead ECG was recorded every 30 s. One minute after each intracoronary injection of acetylcholine, or when the usual chest pain or significant ischemic ST changes on the ECG appeared, coronary arteriograms were obtained. The time interval between each injection was at least 3 min. The ergonovine test was started 10 min after the last acetylcholine provocation test. Ergonovine (Ergometrine Maleate, 0.2 mg/mL) [Fuji Seiyaku; Tokyo, Japan] in 0.9% saline solution was injected into the RCA in total doses of 40 µg/40 mL and into the LCA in total doses of 64 µg/64 mL over > 4 min each. The time interval between each injection was 5 min. Two minutes after the completion of each injection, or when any chest pain or ischemic ST changes on the ECG occurred, coronary arteriograms were obtained.

The degree of ST-segment depression was measured 80 ms after the J point. We considered positive at least one of the following ischemic ECG changes demonstrated during and/or after the pharmacologic tests: (1) ST-segment elevation of > 0.2 MV in at least two related leads; and (2) ST-segment depression of 0.1 MV of a horizontal or downsloping type or > 0.2 MV of a junctional type.

Angiographic Analysis
During the study, arterial BP and ECG leads (II) were continuously monitored on an oscilloscope with polygraphy. In this study, coronary arteriograms were analyzed separately by two independent observers. Coronary spasm was defined as total or subtotal obstruction (ie, > 99%) associated with an attack of chest pain, ischemic ST-segment changes on the ECG, or both. Focal spasm was defined as a discrete transient vessel narrowing of >= 99% that was localized in the major coronary artery, whereas diffuse spasm was diagnosed when transient vessel narrowing of >= 99%, compared with baseline coronary angiography, was observed from the proximal to distal segment in the three major coronary arteries. Proximal spasm was defined according to the American Heart Association (AHA) classification8 of segments 1, 2, 5, 6, and 11, and distal spasm also was defined according to AHA classification of segments 3, 4, 7, 8, 9, 12, 13, and 14. Patients with catheter-induced spasms were excluded from this study. Significant organic stenosis was defined as a >= 75% luminal narrowing. Coronary arteries were measured after the intracoronary administration of isosorbide dinitrate (2.5 to 5.0 mg) to evaluate coronary atherosclerosis according to the AHA classification system.

According to the control state of the patient during the 2 years after starting the medication, we classified these 71 patients into the four following groups: (1) disappearance of chest pain attacks for at least 1 year, 27 patients; (2) less than one attack per month, 14 patients; (3) less than four attacks per month but more than one attack per month, 15 patients; and (4) four or more attacks per month, 15 patients.

Statistical Analysis
All data were presented as the mean ± SD. Categoric variables were compared using the Fisher exact test and {chi}2 test. Intergroup differences were assessed using an analysis of variance, a {chi}2 test, or an unpaired t test when appropriate. A p value of < 0.05 was considered to be significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Characteristics
As shown in Table 2 , the duration of angina before diagnosis was significantly longer in patients who experienced four or more attacks per month than in those in the other three groups (mean duration, 8.1 ± 5.3 vs 2.4 ± 3.3 years, respectively; p < 0.01). No differences regarding coronary risk factors were observed among the four groups. The disappearance rate of chest pain attacks in female patients was significantly higher than that in male patients (62.5% [10 of 16 patients] vs 30.9% [17 of 55 patients]; p < 0.01). No difference regarding the mode of chest symptoms before hospital admission was observed among the four groups. Medical treatment significantly decreased the number of chest pain attacks compared to the number of attacks experienced before hospital admission (2.7 ± 4.9 vs 5.7 ± 8.0 attacks per month, respectively; p < 0.01).


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  		Table 2.. Comparison of Clinical Characteristics Among Four Groups*

 
Medical Treatment
Long-acting calcium antagonists were administered to all 71 patients, and a quarter of the patients who were experiencing four or more attacks per month received two calcium antagonists. The standard maximal dose of a long-acting calcium antagonist was administered to all 30 patients who were experiencing more than one attack per month. As shown in Table 3 , patients were treated with amlodipine (19 patients; mean dose, 5 mg), benidipine (23 patients; mean dose, 6.6 ± 1.9 mg; range, 4 to 8 mg), diltiazem R (19 patients; mean dose, 158 ± 50 mg; range, 100 to 200 mg), nifedipine CR (6 patients; mean dose, 40 mg), cilnidipine (6 patients; mean dose, 16.7 ± 5.2 mg; range, 10 to 20 mg), or nitrendipine (4 patients; mean dose, 10 mg). More than half the patients (63% [45 of 71 patients]) were treated with a combination of a calcium antagonists and isosorbide dinitrate/nicorandil, whereas the remaining 26 patients (37%) were treated with a calcium antagonist alone. ß-blockers were administered to 13 to 27% of patients who had frequent chest pain attacks, while no patients with fewer chest pain attacks were treated with ß-blockers.


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  		Table 3.. Comparison of Medical Treatment Among Four Groups*

 
Angiographic Characteristics
As shown in Table 4 , diffuse spasms were significantly more often observed in patients with chest pain attacks than in those without chest pain attacks (76.6% [59 of 77 patients] vs 32.6% [15 of 46 patients], respectively; p < 0.01). No difference regarding proximal spasms was observed between patients who experienced a disappearance of chest pain attacks and those who had chest pain attacks (29 of 46 patients [63.0%] vs 45 of 77 patients [58.4%]; difference not significant). Medication suppressed more chest pain attacks in patients who experienced ST-segment elevation during spasm provocation tests than those who did not experience ST-segment elevation (18 of 27 patients [67%] vs 13 of 44 patients [30%]; p < 0.05). Focal spasms were observed in 20 of 31 patients (64.5%) with ST-segment elevation during spasm provocation tests.


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  		Table 4.. Comparison of Angiographic Characteristics Among Four Groups*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Comparisons With Western People
Spontaneous remission is a frequent outcome in Western people with variant angina. Waters et al9 also reported that many patients with variant angina who are asymptomatic during long periods of treatment with calcium antagonists may not require further therapy, and ergonovine testing appears to be an objective method of evaluating the clinical status of patients with variant angina.10 However, in Japanese patients who experience coronary vasospasms, remission is unclear. According to previous reports,11 12 Japanese patients with variant angina have shown more favorable outcomes than those in Western patients. The natural history of medically treated patients with pure coronary artery spasms is good, except in the acute phase within 1 month from onset in either Western or Japanese patients.13 14 15 The disappearance of chest pain attacks after patients receive medical therapy may lead to spontaneous remission. However, in this study, spontaneous remission was unknown because all patients were treated with calcium antagonists or isosorbide dinitrates. Thus, it may not be safe to stop medication, including the administration of calcium antagonists, in Japanese patients with coronary vasospasms, as has been the case for Western patients.

Usefulness of Calcium Antagonists and Isosorbide Dinitrates
Kimura and Kishida16 reported that various calcium antagonists were effective for suppressing the number of spontaneous attacks in Japanese patients with variant angina, while medical treatment such as verapamil, nifedipine, diltiazem, and nitrates are effective for suppressing chest pain attacks in Western people with coronary spastic angina.17 18 19 20 Waters et al1 reported that 82% of patients with variant angina became asymptomatic under medication during 1 to 2 years of follow-up, and that spontaneous remission was obtained in 45% of the patients. However, in our study, only 38% of patients with vasospastic angina became asymptomatic, irrespective of the optimal medical therapy. The medical treatment that is available now, including the use of calcium antagonists, may have some limitations in terms of spontaneous remission in Japanese patients with coronary artery spasms.

Clinical Characteristics of Patients With Good Response to Medical Therapy
Medical treatment eliminated chest pain attacks in female patients, patients with focal spasms, and patients with ST-segment elevation during spasm provocation tests in this study. According to previous reports,1 spontaneous remission was more common in patients with organic stenosis in Western people. Japanese patients with coronary artery spasms had significantly less organic stenosis than did Western patients.21 22 This may be related to the relatively low rate of disappearance of chest pain attacks found in this study. In fact, our study subjects had pure coronary spastic angina. Waters et al1 also reported that the rate of spontaneous remission in women was higher than that in men (59% vs 38%, respectively). Medical treatment may decrease the spasmogenicity in vessels undergoing focal spasms, compared to those undergoing diffuse spasms, because focal spasms have smaller areas of dysfunction compared to those in vessels undergoing diffuse spasms.23 24 In our study, two thirds of patients with ST-segment elevations had focal spasms. This may be why medical therapy was effective in patients with ST-segment elevation during selective spasm provocation tests.

Clinical Characteristics of Patients With Persistent Angina Irrespective of Medical Therapy
Waters et al1 reported that patients with persistent angina were more likely to have had normal or near-normal coronary arteriograms, while persistent angina patients were characterized by a longer duration of rest angina before hospital admission. In our study, medical treatment also had little effect on reducing coronary artery tone in patients with a longer history of chest pain attacks before hospital admission, as has been shown by data from previous studies.1 Moreover, patients with diffuse spasms had poor responses to medical therapy, and the mode of angina was not different between patients with good responses and those with poor responses. Because diffuse spasms produced more extensive areas of dysfunction compared to focal spasms,25 26 the same dose of medical therapy may have clinical limitations in suppressing chest pain attacks in patients with pure coronary artery spasms in Japan.

The Continuation of Spasmodicity
More than half of Western people with variant angina showed spontaneous remission after receiving the optimal therapy with calcium antagonists for at least 1 year. However, persistent symptoms have been observed27 over many years in Japanese patients with vasospastic angina and without significant atherosclerosis. Moreover, fluctuations in spastic location often have been observed in Japanese patients with coronary artery spasms.28 This difference between Japanese and Western patients with coronary spastic angina may involve a difference in gene expression.29 Because coronary spasms may recur even after a remission of >= 1 year, therapy should not be discontinued, especially in patients with a history of myocardial infarction, syncope, or severe life-threatening arrhythmias due to spasms.30

Medication in Patients With Poor Responses to Medical Therapy
In patients who are resistant to a reduction or elimination of chest pain attacks, more calcium antagonists, isosorbide dinitrate, or nicorandil should be administered until chest pain attacks disappear. However, adverse effects due to higher doses of or different combinations of agents may lead to therapy being discontinued. Supplementation of therapy with vitamins C and E may be another therapy to decrease the chest pain attacks.31 32 33 Moreover, the ß1-selective denopamine also may have the potential to reduce coronary artery tones.34 In patients with refractory spasms, we should employ new approaches to stabilize coronary tone. Because no direct comparison has been carried out, although comparisons were made in previously published work > 20 years ago with different historical backgrounds and study designs, further studies are needed to clarify the relationship between spontaneous remission and medical treatment in patients with pure coronary spastic angina.


   Acknowledgements
 
We acknowledge the helpful comments of Yuji Shigematsu, MD, Associate Professor Mareomi Hamada, MD, and Professor Kunio Hiwada, MD.


   Footnotes
 
Abbreviations: AHA = American Heart Association; LCA = left coronary artery; RCA = right coronary artery

Received for publication January 25, 2002. Accepted for publication June 26, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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