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Comparison of long-term clinical outcomes of percutaneous coronary intervention in vasospastic angina patients associated with significant coronary artery stenosis
International Journal of Cardiology 218 (2016) 75–78
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparison of long-term clinical outcomes of percutaneous coronary intervention in vasospastic angina patients associated with significant coronary artery stenosis Mijoo Kim, Jae-Hyeong Park ⁎, Jae-Hwan Lee, Byung Joo Sun, Seon Ah Jin, Jun Hyung Kim, SiWan Choi, Jin-Ok Jeong, In-Whan Seong Department of Cardiology in Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
a r t i c l e
i n f o
Article history: Received 16 April 2016 Accepted 12 May 2016 Available online 13 May 2016 Keywords: Vasospastic angina Coronary artery stenosis Coronary intervention Percutaneous Symptoms
a b s t r a c t Background: Coronary spasm is the major pathophysiology of vasospastic angina (VA). Medical treatment is usually effective in VA patients without significant stenosis. However, there is little information about the percutaneous coronary intervention (PCI) in VA patients with significant coronary artery stenosis (CAS). Methods: After retrospective screening of all consecutive VA patients from January 2010 to April 2015, we selected significant CAS (N50% of diameter stenosis) after nitrate injection and divided them into two groups according to the presence of PCI. Results: A total of 220 VA patients (41 females, mean age: 58 ± 10 years old) were screened, and 85 were included in this study. Males were predominant in the VA with significant CAS group (89 vs 76%, p = 0.020). PCI was done in 43 patients (51%). The most common culprit coronary artery was the left anterior descending coronary artery (18, 42%), diameter stenosis was significantly higher (66 ± 9 vs 61 ± 10%, p b 0.01), and total number of antianginal medication was significantly lower in the PCI group than in the medical group (1.7 ± 0.9 vs 2.1 ± 0.8, p = 0.039). Moreover, 4 patients underwent PCI to control symptoms in the medical treatment group during the follow-up period (26 ± 13 months). However, additional antiplatelet therapy was necessary in patients with coronary angioplasty, and there were 2 cases with complication associated with angioplasty (1 restenosis and 1 bleeding complication). Conclusion: In VA patients with significant CAS, both treatment modalities showed similar clinical outcomes. Although the PCI can afford symptomatic improvement, it needed additional antiplatelet medications and can be associated with procedural complications. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Vasospastic angina (VA), also known as Prinzmetal's angina, is characterized by ST-segment elevation on electrocardiogram (ECG) and chest pain at rest usually resulted from sudden vasospasm of the epicardial coronary arteries. Vasospasm may occur in angingraphically normal coronary arteries as well as at the level of significantly stenotic coronary arteries [1]. According to the previous reports, spasms can occur in particular coronary stenotic sites in 90% of the cases, when severe organic stenosis is present [2]. Therefore, the treatment of the stenotic coronary lesions by percutaneous coronary intervention (PCI) can prevent future vasospastic occlusion of the coronary lesions and improve symptoms, theoretically. Although there are several case series describing the efficacy of administering calcium channel blockers with PCI for the ⁎ Corresponding author at: Department of Cardiology, Internal Medicine, Chungnam National University, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. E-mail address: [email protected] (J.-H. Park).
http://dx.doi.org/10.1016/j.ijcard.2016.05.056 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
treatment of VA patients with severe coronary stenosis [3–5], the long-term clinical outcomes of PCI have not been studied well in these patients. We compared the long-term clinical outcomes of PCI versus conventional medical treatment in VA patients with significant coronary artery stenosis. 2. Methods 2.1. Patients We retrospectively screened all consecutive patients who underwent coronary angiography with the spasm provocation test at the Chungnam National University Hospital between January 2010 and April 2015. VA was defined as the presence of severe coronary vasospasm (more than 90% occlusion of segment) with transient STsegment elevation and chest pain during the coronary angiography with the provocation test or spontaneously. Also, the spastic coronary lesions were resolved after the injection of nitrate into the causative lesions with an improvement of chest pain and ECG changes associated
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M. Kim et al. / International Journal of Cardiology 218 (2016) 75–78
with the spasm. We included all patients with VA with significant coronary arterial stenosis (diameter stenosis N50%) after the resolution of the spasm into this study. The exclusion criteria were catheter induced spasm during the coronary angiography and patients with previous coronary stenting. We divided our study patients into two groups according to the presence of PCI of the causative lesions. We retrospectively investigated the medical records of the participants in order to observe their long-term clinical features. This study protocol was approved by Chungnam National University Hospital Institutional Review Board. 2.2. Coronary angiography with provocation test Coronary angiography was performed with a radial or femoral artery route. After the subcutaneous injection of lidocaine sufficiently, we inserted an introducing sheath into the arteries by using the Seldinger technique. Left and right coronary angiograms were taken usually with 5-Fr sized Judkins left and right catheters using the standardized technique. After taking baseline coronary angiograms, intravenous ergonovine was used as the spasm introducing agent to provoke coronary vasospasm. The dose of the ergonovine was sequentially increased following the dosing schedule with 50 μg, 100 μg, and 200 μg in every 3-minute intervals. Positive coronary vasospasm was defined as ≥90% decrease in the coronary lumen diameter upon the visual inspection with a transient change of ST segment and/or chest pain. When spasm was induced, sufficient amount of nitrate (up to 1000 μg) was injected intra-coronary in order to identify the resolution of the spasm, improvement of chest pain, and normalization of ST segment change. During the procedure, arterial blood pressure, pulse rate, arterial oxygen saturation and 12-lead ECG were continuously monitored. After the injection of plenty of nitrate, the follow-up coronary angiograms were taken to find any stenotic coronary arterial lesions and evaluate the degree of organic stenosis. The proximal and distal vessel diameters were measured and used as a reference diameter in the quantitative angiographic measurement. According to the algorithm in the dedicated software, lesion length, reference diameter, minimal lumen diameter, and diameter stenosis were measured. Angiographically significant coronary stenosis was defined as N 50% diameter stenosis. If with significant coronary artery stenosis, coronary angioplasty was done with the standard technique by the attending physician's decision. After the predilation with a balloon, the optimal stent was inserted in the stenotic coronary lesions.
3. Results 3.1. Baseline characteristics We initially screened a total of 220 patients with VA. Of them, 85 patients had significant coronary stenosis. Their baseline characteristics were summarized at Table 1. The mean age was significantly higher (61 ± 10 vs 57 ± 10 years old, p = 0.006) and male patients were more predominant (89 vs 76%, p = 0.015) in the stenotic coronary artery group. There were no statistical differences in the presence of hypertension and diabetes mellitus in the two groups. The rate of current smokers was higher in the coronary artery stenosis group (60 vs 44%, p = 0.029). Of total 85 patients with significant coronary stenosis, 43 were treated by the PCI. There was no statistical difference of baseline characteristics in those with and without PCI (Table 2). 3.2. Coronary angiographic findings Results of coronary angiography and quantitative coronary analysis data were summarized in Table 2. There was no statistical difference of reference vessel diameter, minimal luminal diameter and total lesion length between two groups. TIMI flow grade after spasm also did not show significant differences between the two groups (p = 0.742). However, diameter stenosis was higher in the PCI group (66 ± 9 vs 61 ± 10%, p = 0.006). 3.3. Medical treatment and clinical follow up All patients with significant coronary stenosis were treated with various combinations of antianginal medications, such as calcium channel blockers, long acting oral nitrates, nicorandil, and molsidomine. However, the patients with coronary stenting had received dual antiplatelets to prevent stent thrombosis at least 1 year. Patients without coronary stenting were prescribed with more antianginal medications to control their symptoms (1.7 ± 0.9 vs 2.1 ± 0.8, p = 0.039, Table 3).
Table 1 Baseline characteristics of total variant angina patients. Variant angina (n = 220)
2.3. Medical treatment and follow up All VA patients were initially given with a combination of antianginal medications. After the discharge, medications were modified based on their frequency of chest pain. If patients complained chest discomfort despite increasing doses and/or numbers of antianginal medications, they could be treated with the coronary angioplasty by the attending physician's decision. Information on the frequency of chest pain, number and type of antianginal medications, repeated coronary angiography, readmission due to chest pain, and the presence of coronary revascularization during the follow-up period were gathered with the review of the medical records. Also, the data of bleeding, and restenosis were also obtained. All study population was followed at an average of 26 ± 13 months. 2.4. Statistical analysis Data are expressed as mean ± standard deviation (SD) for continuous variables and as frequencies (percentages) for the categorical variables. Statistical analysis was performed using the SPSS 21.0 (SPSS Inc., Chicago, IL, USA) software. A Student's t-test was performed for statistical comparison between the nominal measures, while a chi-square test was performed for the categorical data. Statistical significance level was established as a p-value b 0.05.
Age (year) Male gender Cardiovascular risk factors Hypertension Diabetes mellitus Current smoker Dyslipidemia Blood chemistry BUN (mg/dL) Cr (mg/dL) Total cholesterol (mg/dL) TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Pattern of spasm Single-vessel spasm Multi-vessel spasm Causative spastic vessel LM LAD LCx RCA
p-Value
Coronary artery stenosis (+) (n = 85)
Coronary artery stenosis (−) (n = 135)
61 ± 10 76 (89%)
57 ± 10 103 (76%)
0.006 0.015
36 (42%) 10 (12%) 31 (37%) 45 (53%)
62 (46%) 12 (9%) 60 (44%) 63 (47%)
0.604 0.489 0.029 0.365
15.5 ± 4.7 0.95 ± 0.92 167 ± 36 162 ± 103 49 ± 13 98 ± 31
15.1 ± 4.5 0.82 ± 0.17 169 ± 36 164 ± 99 47 ± 12 102 ± 34
0.484 0.083 0.662 0.859 0.168 0.398
69 (81%) 16 (19%)
108 (80%) 27 (20%)
0.830 0.830
2 (2%) 47 (55%) 27 (32%) 28 (33%)
0 (0%) 63 (47%) 33 (24%) 73 (54%)
0.829 0.213 0.235 0.002
BUN: blood urea nitrogen, Cr: creatinine, TG: triglyceride, HDL-C: high-density lipoproteincholesterol, LDL-C: low-density lipoprotein-cholesterol, LM: left main coronary artery, LAD: left anterior descending coronary artery, LCx: left circumflex coronary artery, RCA: right coronary artery.
M. Kim et al. / International Journal of Cardiology 218 (2016) 75–78 Table 2 Comparison of characteristics according to the presence of percutaneous coronary intervention. VA with coronary artery stenosis (n = 85)
Age (year) Male gender Cardiovascular risk factor Hypertension Diabetes mellitus Current smoker Dyslipidemia Culprit vessel LM LAD LCx RCA TIMI flow after spasm Grade 0 Grade 1 Grade 2 Grade 3 QCA analysis Lesion length (mm) Reference diameter (mm) Minimal luminal diameter (mm) Diameter stenosis (%)
p-Value
PCI (+) (n = 43)
PCI (−) (n = 42)
60 ± 11 39 (91%)
60 ± 10 37 (88%)
0.923 0.738
16 (48%) 6 (14%) 19 (44%) 21 (49%)
20 (37%) 4 (10%) 12 (29%) 24 (57%)
0.332 0.526 0.135 0.443
2 (5%) 16 (37%) 15 (35%) 10 (23%)
0 (0%) 22 (52%) 8 (19%) 12 (29%)
0.157 0.160 0.100 0.576
14 (33%) 10 (23%) 11 (26%) 8 (19%)
13 (31%) 8 (19%) 9 (21%) 12 (29%)
0.874 0.635 0.652 0.279
12.4 ± 5.1 2.9 ± 0.6 1.0 ± 0.3 66.3 ± 9
11.9 ± 4.1 2.7 ± 0.7 1.1 ± 0.4 60.5 ± 10
0.606 0.322 0.068 0.006
VA: vasospastic angina, PCI: percutaneous coronary intervention, LM: left main coronary artery, LAD: left anterior descending coronary artery, LCx: left circumflex coronary artery, RCA: right coronary artery, TIMI: thrombolysis in myocardial infarction, QCA: quantitative coronary analysis.
There were no significant differences of angina symptoms, uptitrations of antianginal medications and taking coronary angiography during the follow-up period. Four patients (10%) in the medical group subsequently underwent PCI to control the recurrent chest pain. One patient (2%) in the coronary stenting group received the target lesion revascularization due to restenosis, and 1 patient had a minor bleeding episode after the PCI (Table 3). 4. Discussion In this study, we found that both treatment modalities showed similar clinical outcomes in VA patients with significant coronary artery stenosis. Although the PCI can be associated with reduced number of antianginal medication, it can be associated with an increased risk of
Table 3 Comparison of clinical outcomes according to the presence of percutaneous coronary intervention. VA with coronary artery stenosis (n = 85)
Antianginal medication Total number (n) No of calcium channel blocker Diltiazem Dihydropyridines Verapamil Nitrates Nicorandil Molsidomine Angina episodes ≥2/month Up-titration of medication Readmission d/t angina Coronary revascularization
PCI (+) (n = 43)
PCI (−) (n = 42)
1.7 ± 0.9 1.1 ± 0.7 25 (58%) 21 (49%) 0 (0%) 15 (35%) 10 (23%) 4 (9%) 20 (47%) 7 (16%) 7 (16%) 1 (2%)a
2.1 ± 0.8 1.3 ± 0.5 32 (76%) 23 (55%) 1 (2%) 23 (55%) 7 (17%) 3 (7%) 20 (48%) 12 (29%) 4 (10%) 4 (10%)b
p-Value
0.039 0.054 0.077 0.585 0.309 0.065 0.448 0.717 0.919 0.174 0.354 0.158
77
complications associated with the procedure and additional antiplatelet medications to prevent stent thrombosis. VA is characterized as a typical angina at rest with transient STsegment elevation on electrocardiogram during the attack of chest pain. Vasospasm is the main mechanism of the disease, which is caused by the contraction of the smooth muscle in the vessel walls rather than directly by atherosclerosis. The prognosis of VA has been known to be favorable compared with other coronary artery disease categories if with sufficient treatment [6]. Calcium channel blockers and nitrates are efficacious for preventing ischemic attack and are main treatment regimens [6,7]. One study showed that calcium channel blockers were effective in 92.5% of Japanese VA patients [8]. Also, long-acting nitrates are available to prevent ischemic attacks. However, when organic coronary stenosis is present in VA patients, their prognoses become more unfavorable [9]. The presence of the organic stenosis acts as an important risk factor for the onset of cardiovascular events [10,11]. Moreover, previous studies have reported that coronary spasm occurs in sites with varying degrees of atherosclerosis and can affect the progression of atherosclerosis [12,13]. Therefore, in these patients with VA, eliminating organic stenosis is considered as an effective treatment. Case reports have described that PCI was effective among VA patients with severe organic stenosis whose symptoms were refractory to drug treatment. However, other studies have reported that even if narrowed coronary vessels are widened by the PCI, this is of limited value since spasms can occur in other sites of the vessels along with initially narrowed sites during repeat angiographic spasm provocation tests [14]. In our present study, the VA patients with significant organic stenosis who underwent PCI were taking less antianginal medications (1.7 ± 0.9 vs 2.1 ± 0.8, p = 0.039). Moreover, four patients (10%) who were initially treated medically experienced recurrence of chest pain despite increasing doses of medications and required PCI to control their angina symptoms. However, there were increased complications associated with PCI. One patient (2%) received additional coronary intervention to treat target lesion restenosis. Another patient experienced major bleeding complication associated with the PCI procedure requiring transfusion. Moreover, the patients with PCI needed additional antianginal medications, aspirin plus clopidogrel at least 1 year then aspirin alone indefinitely. 4.1. Limitations Our study has several limitations. First, this study is a retrospective observational study with a relatively small number of patients. Moreover, the favor of PCI and clinic visiting intervals were different according to the physicians. However, all VA patients were treated with similar medications following similar guideline. Second, the coronary spasm was demonstrated in all patients by performing coronary angiography with the ergonovine provocation test, which is known to have a relatively high specificity for VA. Because of the limitations associated with the test method, there were difficulties in accurate evaluation of the frequency of multivessel spasm. 5. Conclusion In conclusion, medical treatment and PCI showed similar clinical outcomes in VA patients with significant coronary stenosis. The PCI might be helpful in improving their symptoms. However, PCI-related complication risks and requirement of additional antiplatelet agents, should be taken into consideration when performing the procedure. Conflict of interest
a
One patient underwent percutaneous coronary intervention to treat the target lesion revascularization. b Four patients had percutaneous coronary intervention for treating refractory angina.
The authors report no relationships that could be construed as a conflict of interest.
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References [1] A. Maseri, S. Severi, M.D. Nes, A. L'Abbate, S. Chierchia, M. Marzilli, A.M. Ballestra, O. Parodi, A. Biagini, A. Distante, “Variant” angina: one aspect of a continuous spectrum of vasospastic myocardial ischemia. Pathogenetic mechanisms, estimated incidence and clinical and coronary arteriographic findings in 138 patients, Am. J. Cardiol. 42 (1978) 1019–1035. [2] R.N. MacAlpin, Relation of coronary arterial spasm to sites of organic stenosis, Am. J. Cardiol. 46 (1980) 143–153. [3] A. Gaspardone, F. Tomai, F. Versaci, A.S. Ghini, P. Polisca, F. Crea, L. Chiariello, P.A. Gioffre, Coronary artery stent placement in patients with variant angina refractory to medical treatment, Am. J. Cardiol. 84 (1999) 96–98. [4] J.A. Lopez, P. Angelini, D.R. Leachman, R. Lufschanowski, Gianturco–Roubin stent placement for variant angina refractory to medical treatment, Catheter. Cardiovasc. Diagn. 33 (1994) 161–165. [5] M.H. Jeong, J.C. Park, J.Y. Rhew, K.T. Kang, S.H. Lee, J.H. Cho, N.H. Kim, K.H. Kim, Y.K. Ahn, Y. Bae, J.G. Cho, J.C. Park, S.H. Kim, J.C. Kang, Successful management of intractable coronary spasm with a coronary stent, Jpn. Circ. J. 64 (2000) 897–900. [6] H. Yasue, A. Takizawa, M. Nagao, S. Nishida, M. Horie, J. Kubota, S. Omote, K. Takaoka, K. Okumura, Long-term prognosis for patients with variant angina and influential factors, Circulation 78 (1988) 1–9. [7] J.C.S.J.W. Group, Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2008): digest version, Circ. J. 74 (2010) 1745–1762. [8] E. Kimura, H. Kishida, Treatment of variant angina with drugs: a survey of 11 cardiology institutes in Japan, Circulation 63 (1981) 844–848.
[9] M. Ishii, K. Kaikita, K. Sato, T. Tanaka, K. Sugamura, K. Sakamoto, Y. Izumiya, E. Yamamoto, K. Tsujita, M. Yamamuro, S. Kojima, H. Soejima, S. Hokimoto, K. Matsui, H. Ogawa, Acetylcholine-provoked coronary spasm at site of significant organic stenosis predicts poor prognosis in patients with coronary vasospastic angina, J. Am. Coll. Cardiol. 66 (2015) 1105–1115. [10] Y. Takagi, S. Yasuda, R. Tsunoda, Y. Ogata, A. Seki, T. Sumiyoshi, M. Matsui, T. Goto, Y. Tanabe, S. Sueda, T. Sato, S. Ogawa, N. Kubo, S. Momomura, H. Ogawa, H. Shimokawa, Japanese coronary spasm A. Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association, Circ. Arrhythm. Electrophysiol. 4 (2011) 295–302. [11] Y. Schachinger, M.B. Britten, A.M. Zeiher, Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease, Circulation 101 (2000) 1899–1906. [12] T. Kuga, H. Tagawa, H. Tomoike, W. Mitsuoka, S. Egashira, Y. Ohara, A. Takeshita, M. Nakamura, Role of coronary artery spasm in progression of organic coronary stenosis and acute myocardial infarction in a swine model. Importance of mode of onset and duration of coronary artery spasm, Circulation 87 (1993) 573–582. [13] H. Suzuki, S. Kawai, T. Aizawa, K. Kato, S. Sunayama, R. Okada, H. Yamaguchi, Histological evaluation of coronary plaque in patients with variant angina: relationship between vasospasm and neointimal hyperplasia in primary coronary lesions, J. Am. Coll. Cardiol. 33 (1999) 198–205. [14] Y. Tanabe, E. Itoh, K. Suzuki, M. Ito, Y. Hosaka, I. Nakagawa, M. Kumakura, Limited role of coronary angioplasty and stenting in coronary spastic angina with organic stenosis, J. Am. Coll. Cardiol. 39 (2002) 1120–1126.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Comparison of long-term clinical outcomes of percutaneous coronary intervention in vasospastic angina patients associated with significant coronary artery stenosis Mijoo Kim, Jae-Hyeong Park ⁎, Jae-Hwan Lee, Byung Joo Sun, Seon Ah Jin, Jun Hyung Kim, SiWan Choi, Jin-Ok Jeong, In-Whan Seong Department of Cardiology in Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, Korea
a r t i c l e
i n f o
Article history: Received 16 April 2016 Accepted 12 May 2016 Available online 13 May 2016 Keywords: Vasospastic angina Coronary artery stenosis Coronary intervention Percutaneous Symptoms
a b s t r a c t Background: Coronary spasm is the major pathophysiology of vasospastic angina (VA). Medical treatment is usually effective in VA patients without significant stenosis. However, there is little information about the percutaneous coronary intervention (PCI) in VA patients with significant coronary artery stenosis (CAS). Methods: After retrospective screening of all consecutive VA patients from January 2010 to April 2015, we selected significant CAS (N50% of diameter stenosis) after nitrate injection and divided them into two groups according to the presence of PCI. Results: A total of 220 VA patients (41 females, mean age: 58 ± 10 years old) were screened, and 85 were included in this study. Males were predominant in the VA with significant CAS group (89 vs 76%, p = 0.020). PCI was done in 43 patients (51%). The most common culprit coronary artery was the left anterior descending coronary artery (18, 42%), diameter stenosis was significantly higher (66 ± 9 vs 61 ± 10%, p b 0.01), and total number of antianginal medication was significantly lower in the PCI group than in the medical group (1.7 ± 0.9 vs 2.1 ± 0.8, p = 0.039). Moreover, 4 patients underwent PCI to control symptoms in the medical treatment group during the follow-up period (26 ± 13 months). However, additional antiplatelet therapy was necessary in patients with coronary angioplasty, and there were 2 cases with complication associated with angioplasty (1 restenosis and 1 bleeding complication). Conclusion: In VA patients with significant CAS, both treatment modalities showed similar clinical outcomes. Although the PCI can afford symptomatic improvement, it needed additional antiplatelet medications and can be associated with procedural complications. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Vasospastic angina (VA), also known as Prinzmetal's angina, is characterized by ST-segment elevation on electrocardiogram (ECG) and chest pain at rest usually resulted from sudden vasospasm of the epicardial coronary arteries. Vasospasm may occur in angingraphically normal coronary arteries as well as at the level of significantly stenotic coronary arteries [1]. According to the previous reports, spasms can occur in particular coronary stenotic sites in 90% of the cases, when severe organic stenosis is present [2]. Therefore, the treatment of the stenotic coronary lesions by percutaneous coronary intervention (PCI) can prevent future vasospastic occlusion of the coronary lesions and improve symptoms, theoretically. Although there are several case series describing the efficacy of administering calcium channel blockers with PCI for the ⁎ Corresponding author at: Department of Cardiology, Internal Medicine, Chungnam National University, Chungnam National University Hospital, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Korea. E-mail address: [email protected] (J.-H. Park).
http://dx.doi.org/10.1016/j.ijcard.2016.05.056 0167-5273/© 2016 Elsevier Ireland Ltd. All rights reserved.
treatment of VA patients with severe coronary stenosis [3–5], the long-term clinical outcomes of PCI have not been studied well in these patients. We compared the long-term clinical outcomes of PCI versus conventional medical treatment in VA patients with significant coronary artery stenosis. 2. Methods 2.1. Patients We retrospectively screened all consecutive patients who underwent coronary angiography with the spasm provocation test at the Chungnam National University Hospital between January 2010 and April 2015. VA was defined as the presence of severe coronary vasospasm (more than 90% occlusion of segment) with transient STsegment elevation and chest pain during the coronary angiography with the provocation test or spontaneously. Also, the spastic coronary lesions were resolved after the injection of nitrate into the causative lesions with an improvement of chest pain and ECG changes associated
76
M. Kim et al. / International Journal of Cardiology 218 (2016) 75–78
with the spasm. We included all patients with VA with significant coronary arterial stenosis (diameter stenosis N50%) after the resolution of the spasm into this study. The exclusion criteria were catheter induced spasm during the coronary angiography and patients with previous coronary stenting. We divided our study patients into two groups according to the presence of PCI of the causative lesions. We retrospectively investigated the medical records of the participants in order to observe their long-term clinical features. This study protocol was approved by Chungnam National University Hospital Institutional Review Board. 2.2. Coronary angiography with provocation test Coronary angiography was performed with a radial or femoral artery route. After the subcutaneous injection of lidocaine sufficiently, we inserted an introducing sheath into the arteries by using the Seldinger technique. Left and right coronary angiograms were taken usually with 5-Fr sized Judkins left and right catheters using the standardized technique. After taking baseline coronary angiograms, intravenous ergonovine was used as the spasm introducing agent to provoke coronary vasospasm. The dose of the ergonovine was sequentially increased following the dosing schedule with 50 μg, 100 μg, and 200 μg in every 3-minute intervals. Positive coronary vasospasm was defined as ≥90% decrease in the coronary lumen diameter upon the visual inspection with a transient change of ST segment and/or chest pain. When spasm was induced, sufficient amount of nitrate (up to 1000 μg) was injected intra-coronary in order to identify the resolution of the spasm, improvement of chest pain, and normalization of ST segment change. During the procedure, arterial blood pressure, pulse rate, arterial oxygen saturation and 12-lead ECG were continuously monitored. After the injection of plenty of nitrate, the follow-up coronary angiograms were taken to find any stenotic coronary arterial lesions and evaluate the degree of organic stenosis. The proximal and distal vessel diameters were measured and used as a reference diameter in the quantitative angiographic measurement. According to the algorithm in the dedicated software, lesion length, reference diameter, minimal lumen diameter, and diameter stenosis were measured. Angiographically significant coronary stenosis was defined as N 50% diameter stenosis. If with significant coronary artery stenosis, coronary angioplasty was done with the standard technique by the attending physician's decision. After the predilation with a balloon, the optimal stent was inserted in the stenotic coronary lesions.
3. Results 3.1. Baseline characteristics We initially screened a total of 220 patients with VA. Of them, 85 patients had significant coronary stenosis. Their baseline characteristics were summarized at Table 1. The mean age was significantly higher (61 ± 10 vs 57 ± 10 years old, p = 0.006) and male patients were more predominant (89 vs 76%, p = 0.015) in the stenotic coronary artery group. There were no statistical differences in the presence of hypertension and diabetes mellitus in the two groups. The rate of current smokers was higher in the coronary artery stenosis group (60 vs 44%, p = 0.029). Of total 85 patients with significant coronary stenosis, 43 were treated by the PCI. There was no statistical difference of baseline characteristics in those with and without PCI (Table 2). 3.2. Coronary angiographic findings Results of coronary angiography and quantitative coronary analysis data were summarized in Table 2. There was no statistical difference of reference vessel diameter, minimal luminal diameter and total lesion length between two groups. TIMI flow grade after spasm also did not show significant differences between the two groups (p = 0.742). However, diameter stenosis was higher in the PCI group (66 ± 9 vs 61 ± 10%, p = 0.006). 3.3. Medical treatment and clinical follow up All patients with significant coronary stenosis were treated with various combinations of antianginal medications, such as calcium channel blockers, long acting oral nitrates, nicorandil, and molsidomine. However, the patients with coronary stenting had received dual antiplatelets to prevent stent thrombosis at least 1 year. Patients without coronary stenting were prescribed with more antianginal medications to control their symptoms (1.7 ± 0.9 vs 2.1 ± 0.8, p = 0.039, Table 3).
Table 1 Baseline characteristics of total variant angina patients. Variant angina (n = 220)
2.3. Medical treatment and follow up All VA patients were initially given with a combination of antianginal medications. After the discharge, medications were modified based on their frequency of chest pain. If patients complained chest discomfort despite increasing doses and/or numbers of antianginal medications, they could be treated with the coronary angioplasty by the attending physician's decision. Information on the frequency of chest pain, number and type of antianginal medications, repeated coronary angiography, readmission due to chest pain, and the presence of coronary revascularization during the follow-up period were gathered with the review of the medical records. Also, the data of bleeding, and restenosis were also obtained. All study population was followed at an average of 26 ± 13 months. 2.4. Statistical analysis Data are expressed as mean ± standard deviation (SD) for continuous variables and as frequencies (percentages) for the categorical variables. Statistical analysis was performed using the SPSS 21.0 (SPSS Inc., Chicago, IL, USA) software. A Student's t-test was performed for statistical comparison between the nominal measures, while a chi-square test was performed for the categorical data. Statistical significance level was established as a p-value b 0.05.
Age (year) Male gender Cardiovascular risk factors Hypertension Diabetes mellitus Current smoker Dyslipidemia Blood chemistry BUN (mg/dL) Cr (mg/dL) Total cholesterol (mg/dL) TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) Pattern of spasm Single-vessel spasm Multi-vessel spasm Causative spastic vessel LM LAD LCx RCA
p-Value
Coronary artery stenosis (+) (n = 85)
Coronary artery stenosis (−) (n = 135)
61 ± 10 76 (89%)
57 ± 10 103 (76%)
0.006 0.015
36 (42%) 10 (12%) 31 (37%) 45 (53%)
62 (46%) 12 (9%) 60 (44%) 63 (47%)
0.604 0.489 0.029 0.365
15.5 ± 4.7 0.95 ± 0.92 167 ± 36 162 ± 103 49 ± 13 98 ± 31
15.1 ± 4.5 0.82 ± 0.17 169 ± 36 164 ± 99 47 ± 12 102 ± 34
0.484 0.083 0.662 0.859 0.168 0.398
69 (81%) 16 (19%)
108 (80%) 27 (20%)
0.830 0.830
2 (2%) 47 (55%) 27 (32%) 28 (33%)
0 (0%) 63 (47%) 33 (24%) 73 (54%)
0.829 0.213 0.235 0.002
BUN: blood urea nitrogen, Cr: creatinine, TG: triglyceride, HDL-C: high-density lipoproteincholesterol, LDL-C: low-density lipoprotein-cholesterol, LM: left main coronary artery, LAD: left anterior descending coronary artery, LCx: left circumflex coronary artery, RCA: right coronary artery.
M. Kim et al. / International Journal of Cardiology 218 (2016) 75–78 Table 2 Comparison of characteristics according to the presence of percutaneous coronary intervention. VA with coronary artery stenosis (n = 85)
Age (year) Male gender Cardiovascular risk factor Hypertension Diabetes mellitus Current smoker Dyslipidemia Culprit vessel LM LAD LCx RCA TIMI flow after spasm Grade 0 Grade 1 Grade 2 Grade 3 QCA analysis Lesion length (mm) Reference diameter (mm) Minimal luminal diameter (mm) Diameter stenosis (%)
p-Value
PCI (+) (n = 43)
PCI (−) (n = 42)
60 ± 11 39 (91%)
60 ± 10 37 (88%)
0.923 0.738
16 (48%) 6 (14%) 19 (44%) 21 (49%)
20 (37%) 4 (10%) 12 (29%) 24 (57%)
0.332 0.526 0.135 0.443
2 (5%) 16 (37%) 15 (35%) 10 (23%)
0 (0%) 22 (52%) 8 (19%) 12 (29%)
0.157 0.160 0.100 0.576
14 (33%) 10 (23%) 11 (26%) 8 (19%)
13 (31%) 8 (19%) 9 (21%) 12 (29%)
0.874 0.635 0.652 0.279
12.4 ± 5.1 2.9 ± 0.6 1.0 ± 0.3 66.3 ± 9
11.9 ± 4.1 2.7 ± 0.7 1.1 ± 0.4 60.5 ± 10
0.606 0.322 0.068 0.006
VA: vasospastic angina, PCI: percutaneous coronary intervention, LM: left main coronary artery, LAD: left anterior descending coronary artery, LCx: left circumflex coronary artery, RCA: right coronary artery, TIMI: thrombolysis in myocardial infarction, QCA: quantitative coronary analysis.
There were no significant differences of angina symptoms, uptitrations of antianginal medications and taking coronary angiography during the follow-up period. Four patients (10%) in the medical group subsequently underwent PCI to control the recurrent chest pain. One patient (2%) in the coronary stenting group received the target lesion revascularization due to restenosis, and 1 patient had a minor bleeding episode after the PCI (Table 3). 4. Discussion In this study, we found that both treatment modalities showed similar clinical outcomes in VA patients with significant coronary artery stenosis. Although the PCI can be associated with reduced number of antianginal medication, it can be associated with an increased risk of
Table 3 Comparison of clinical outcomes according to the presence of percutaneous coronary intervention. VA with coronary artery stenosis (n = 85)
Antianginal medication Total number (n) No of calcium channel blocker Diltiazem Dihydropyridines Verapamil Nitrates Nicorandil Molsidomine Angina episodes ≥2/month Up-titration of medication Readmission d/t angina Coronary revascularization
PCI (+) (n = 43)
PCI (−) (n = 42)
1.7 ± 0.9 1.1 ± 0.7 25 (58%) 21 (49%) 0 (0%) 15 (35%) 10 (23%) 4 (9%) 20 (47%) 7 (16%) 7 (16%) 1 (2%)a
2.1 ± 0.8 1.3 ± 0.5 32 (76%) 23 (55%) 1 (2%) 23 (55%) 7 (17%) 3 (7%) 20 (48%) 12 (29%) 4 (10%) 4 (10%)b
p-Value
0.039 0.054 0.077 0.585 0.309 0.065 0.448 0.717 0.919 0.174 0.354 0.158
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complications associated with the procedure and additional antiplatelet medications to prevent stent thrombosis. VA is characterized as a typical angina at rest with transient STsegment elevation on electrocardiogram during the attack of chest pain. Vasospasm is the main mechanism of the disease, which is caused by the contraction of the smooth muscle in the vessel walls rather than directly by atherosclerosis. The prognosis of VA has been known to be favorable compared with other coronary artery disease categories if with sufficient treatment [6]. Calcium channel blockers and nitrates are efficacious for preventing ischemic attack and are main treatment regimens [6,7]. One study showed that calcium channel blockers were effective in 92.5% of Japanese VA patients [8]. Also, long-acting nitrates are available to prevent ischemic attacks. However, when organic coronary stenosis is present in VA patients, their prognoses become more unfavorable [9]. The presence of the organic stenosis acts as an important risk factor for the onset of cardiovascular events [10,11]. Moreover, previous studies have reported that coronary spasm occurs in sites with varying degrees of atherosclerosis and can affect the progression of atherosclerosis [12,13]. Therefore, in these patients with VA, eliminating organic stenosis is considered as an effective treatment. Case reports have described that PCI was effective among VA patients with severe organic stenosis whose symptoms were refractory to drug treatment. However, other studies have reported that even if narrowed coronary vessels are widened by the PCI, this is of limited value since spasms can occur in other sites of the vessels along with initially narrowed sites during repeat angiographic spasm provocation tests [14]. In our present study, the VA patients with significant organic stenosis who underwent PCI were taking less antianginal medications (1.7 ± 0.9 vs 2.1 ± 0.8, p = 0.039). Moreover, four patients (10%) who were initially treated medically experienced recurrence of chest pain despite increasing doses of medications and required PCI to control their angina symptoms. However, there were increased complications associated with PCI. One patient (2%) received additional coronary intervention to treat target lesion restenosis. Another patient experienced major bleeding complication associated with the PCI procedure requiring transfusion. Moreover, the patients with PCI needed additional antianginal medications, aspirin plus clopidogrel at least 1 year then aspirin alone indefinitely. 4.1. Limitations Our study has several limitations. First, this study is a retrospective observational study with a relatively small number of patients. Moreover, the favor of PCI and clinic visiting intervals were different according to the physicians. However, all VA patients were treated with similar medications following similar guideline. Second, the coronary spasm was demonstrated in all patients by performing coronary angiography with the ergonovine provocation test, which is known to have a relatively high specificity for VA. Because of the limitations associated with the test method, there were difficulties in accurate evaluation of the frequency of multivessel spasm. 5. Conclusion In conclusion, medical treatment and PCI showed similar clinical outcomes in VA patients with significant coronary stenosis. The PCI might be helpful in improving their symptoms. However, PCI-related complication risks and requirement of additional antiplatelet agents, should be taken into consideration when performing the procedure. Conflict of interest
a
One patient underwent percutaneous coronary intervention to treat the target lesion revascularization. b Four patients had percutaneous coronary intervention for treating refractory angina.
The authors report no relationships that could be construed as a conflict of interest.
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