Spasm Provocation Tests Performed under Medical Therapy: A New Approach for Treating Patients with Refractory Coronary Spastic Angina

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1 ORIGINAL ARTICLE Spasm Provocation Tests Performed under Medical Therapy: A New Approach for Treating Patients with Refractory Coronary Spastic Angina on Emergency Admission Shozo Sueda, Hiroaki Kohno, Toru Miyoshi, Yasuhiro Sasaki, Tomoki Sakaue and Hirokazu Habara Abstract Objective There are no objective methods for evaluating the severity of vasospasms in patients with refractory coronary spastic angina (R-CSA) under adequate medical therapy. We examined whether spasm provocation tests performed under adequate medication are useful for evaluating the severity of disease in R-CSA patients on emergency admission. Methods and Results We performed spasm provocation tests before and after the administration of medical therapy in eight R-CSA patients, including one ventricular fibrillation survivor (VF-S) and seven patients with unstable angina (UAP) on emergency readmission. We also performed these tests only after medical therapy on urgent admission in four R-CSA patients, including two patients with UAP, one patient with VF-S and one patient with acute coronary syndrome. All 12 R-CSA patients had been medicated with 2 vasodilator drugs. Positive coronary spasms were defined as >99% transient narrowing. The coronary artery spasms disappeared in three patients under medication, and mitigation of vasospasticity was observed in three patients. In these six cases we continued the same medications. Meanwhile in two patients, we recommended a consultation for psychosomatic medicine. In contrast, the remaining six R-CSA patients exhibited higher levels of vasospasticity, irrespective of the administration of aggressive medical therapy, in which the doses of vasoactive drugs were increased in order to suppress coronary artery spasms. Conclusion In some R-CSA patients on emergency admission, performing spasm provocation tests under medical therapy is useful for determining the subsequent treatment strategy. Therefore, this test may become a new tool in the treatment of R-CSA. Key words: refractory CSA, spasm provocation test, medication (Intern Med 53: , 2014) () Introduction Acetylcholine (ACh) (1-4) and ergonovine (ER) (5-7) are often employed as a spasm provocation test as a means of invasively diagnosing patients with coronary spastic angina (CSA). After definitively confirming the presence of positive coronary spasms, vasoactive drugs, such as long-acting calcium-channel antagonists, nitrates and nicorandils, are administered. However, despite the administration of these medicines, some CSA patients display resistance to adequate medical therapy. Unstable angina (UAP) or acute coronary syndrome (ACS) patients with coronary artery spasms without fixed narrowing are often encountered on emergency admission. However, there are no useful objective methods for evaluating the effects of medical therapy, except for determining the numbers of chest pain attacks or taking into account sublingual nitroglycerine use (8, 9). In this article, we examined the clinical usefulness of performing spasm provocation tests under medical therapy in Department of Cardiology, Ehime Niihama Prefectural Hospital, Japan Received for publication January 4, 2014; Accepted for publication March 7, 2014 Correspondence to Dr. Shozo Sueda, EZF03146@nifty.com 1739

2 patients with refractory spasms such as those with UAP or ACS. Materials and Methods Study patients and study design We recruited 12 refractory CSA (R-CSA) patients (11 men, mean age: 70.8±8.3 years) with UAP, ACS or a ventricular fibrillation survivor (VF-S) status on urgent admission and performed spasm provocation tests under two vasoactive medications in all 12 patients. R-CSA was defined as angina that could not be controlled, even with the administration of two types of coronary vasodilators according to the JCS guidelines (10). Cardiac scintigrams and 24-hour Holter monitoring were also performed in all patients. The spasm provocation tests were conducted under medications when the patient s chest pain or discomfort continued irrespective of the administration of adequate vasodilator drugs during admission. As previously reported (11-13), we carried out the spasm provocation tests by administering ACh or, ER, or adding ACh after conducting an ER test whenever possible. Positive coronary spasms were defined as >99% transient luminal narrowing. When the disappearance or mitigation of provoked spasm was recognized, we judged that these patients could receive continued medication as an outpatient. We subsequently administered or increased the dose of another calcium-channel antagonist, nitrates or nicorandil when a higher level of vasospasticity was observed, irrespective of the use of adequate vasodilator drugs. We also encouraged current smokers to positively quit smoking and recommended that the patient consul the department of psychosomatic medicine if anxiety regarding chest pain/discomfort was a potential cause of their symptoms, irrespective of the disappearance or mitigation of the provoked spasms under medications. We also examined the prognosis and incidence of cardiac events including urgent admission, after the spasm provocation tests carried out under the medications. The procedure was explained in detail to each patient, and informed consent was obtained from all participants. The study protocol was in agreement with the guidelines of the ethics committee at our institution. Sequential spasm provocation tests All drugs except for nitroglycerine were discontinued for at least 24 hours before the start of the study, while nitroglycerine was discontinued at least four hours prior to the start of the study in patients without medications. Cardiac catheterization was performed in the fasting state from 10:00 to 16:00 hours using the brachial artery, as previously reported. After obtaining control coronary arteriograms of the left coronary artery in the right anterior oblique caudal projection and the right coronary artery in the left anterior oblique cranial projection following the injection of 8-10 ml of contrast medium, a temporary pacemaker was inserted into the right ventricle with a pacing rate of 45 beats/ min. Acetylcholine (Neucholin-A, 30 mg/2ml; Zeria Seiyaku, Tokyo, Japan) was injected in incremental doses of 20, 50 and 80 μg into the right coronary artery (RCA) and 20, 50 and 100/(200) μg into the left coronary artery (LCA) over 20 seconds with at least a three-minute interval between each injection. A standard 12-lead electrocardiography (ECG) was recorded every 30 seconds and one minute after each injection of ACh. Coronary arteriograms were obtained when usual chest pain developed or significant ischemic ST changes appeared on ECG. The ER test was started 10 minutes after the last ACh spasm provocation test. ER (Ergometrine injection F, 0.2 mg/ml; Fuji Seiyaku, Tokyo, Japan) was injected at a total doses of 40 μg into the RCA and 64 μg into the LCA, with a duration of each administration of four minutes and at least five-minute intervals between each injection. Two minutes after the completion of each injection, or when any chest pain or ischemic ST changes occurred on ECG, coronary arteriograms were obtained. If no coronary artery spasms were provoked by ER, an additional intracoronary injection of ACh was performed for 20 seconds two minutes after the ER test (50-80 μg ACh into the RCA and μg into the LCA) whenever possible (13). When coronary spasms were induced and did not resolve spontaneously within three minutes after the completion of the ACh and ER injection, or when hemodynamic instability occurred due to the coronary spasm, 2.5 to 5.0 mg of isosorbide dinitrate was injected into the responsible vessel. Spasm provocation tests were also performed under medication in the fasting state from 10:00 to 16:00 hour using the brachial artery while taking adequate vasodilator drugs. Case presentation The data for all 12 R-CSA patients are shown in Tables 1 and 2. Representative cases (Case No. 3, 6, 7, 8, 10 and 11) are described below. Case 3: The patient was a 59-year-old man admitted to our hospital via ambulance due to severe chest pain without ischemic ECG changes (Fig. 1A). Emergency coronary arteriography was performed, and the patient s right coronary artery showed findings of severe spasms (Fig. 2a, b). Following the administration of abundant nitrates into the responsible vessels, both coronary arteries gradually dilated, and no fixed stenosis was detected as shown in Fig. 2 (c, d). He was diagnosed with CSA and discharged after receiving two calcium-channel antagonists (diltiazem R: 100 mg/day before sleep & amlodipine: 5 mg/day in the morning). Six months later, he was again readmitted to our hospital via ambulance due to severe chest pain. His ECG demonstrated ST elevation in the inferior and anterior leads, as shown in Fig. 1B. After several administrations of nitroglycerine, the ST elevation gradually decreased. However, ventricular fibrillation occurred, and the patient recovered to a sinus rhythm under a direct current. After placing the direct current, emergency coronary angiography was performed, 1740

3 Table 1. Patients Characteristics and Medication/Strategy before and after Spasm Provocation Test under the Medication No Age/ Sex Risk factor Medication statin Another therapy Before After (add and dose up) Chest pain Acute admission Prognosis 1 91/M NC smoker, HT Nif-R (40mg) Dil-R (200mg) ISMN (40mg) Nico (15mg) 2 77/M NC smoker, HT Beni (20mg) Dil-R (200mg) ISMN (40mg) Nico (15mg) 3 59/M C smoker, HT, DL Dil-R (200mg) Beni (8mg) ISMN (40mg) 4 62/M C NC smoker, DL Beni (8mg) Dil-R (200mg) ISMN(40mg) Nico (15mg) 5 71/M NC smoker, HT Nif-R (80mg) Dil-R (200 mg) ISMN (40 mg) Nit-tape (40mg) 6 73/F Beni (8mg) Dil-R (200mg) ISMN (40mg), Nico (15mg) 7 72/M C NC smoker, DM, Amlo (5mg) Di-R (200mg) DL ISMN (40mg) Nico (15mg) 8 71/M C NC smoker, DM, Nif-R (60mg) Dil-R (200mg) DL ISMN (40mg) Nico (20mg) 9 73/M NC smoker, HT Nif-R (40mg), Dil-R (200mg) ISMN (40mg) 10 71/M C NC smoker, DM, Nif-R (40mg) HT, DL ISMN (40mg) Nico (15mg) 11 64/M C NC smoker, HT Beni (8mg) Nif-R (60mg) ISMN (40mg) Nico (20mg) 12 65/M C NC smoker, DM, DL Dil-R (200mg) ISMN (40mg) Beni (8mg) Nit-tape (40mg) (Amlo off) Nif-R (60mg 80mg) Nit-tape (40mg) Beni (16mg) Nico (15mg) Dil-R (200mg) Nico (15mg 20mg) Beni (8mg 12mg) Nif-R (60mg 80mg) Beni (8mg) Nico (15mg) (12 mo) yes good no Alive (4 mo) yes fair yes Alive (61 mo) (100 mo) no Psychosomatic no yes Alive medicine (27 mo) no Psychosomatic no no Alive medicine (17 mo) (58 mo) no PCI for LAD no no Alive (44 mo) yes fair no Alive (52 mo) (34 mo) (31 mo) (24 mo) (C: current, NC smoker: non-current smoker, HT: hypertension, DM: diabetes mellitus, DL: dyslipidemia, Nif-R: nifedipine-r, Dil-R: diltiazem-r, Beni: benidipine, Amlo: amlodipine, ISMN: isosobide mononitrate, Nico: nicolandil, Nit-tape: nitrate tape, M: male, F: female, good: chest pain attack < 1/month, fair: 1/month < chest pain attack < 4/month, mo: month) Table 2. Sequential Spasm Provocation Test Data in Patients with Resistant CSA No Age/Sex (duration) diagnosis ACh (μg) (RCA/LCA) ACh provoked spasm ER (μg) (RCA/LCA) ER provoked spasm ER + ACh (μg) (RCA/LCA) ER + ACh provoked spasm 1 91/M Rest 50/100 3 vessel (d) (med) (220 mo) UAP 50/100 no spasm 40/64 no spasm 40+75/ no spasm 2 77/M Rest 50/100 #1(f), #7(d) 40/64 no spasm 40+50/ #1(d), #7(d) 2 (med) (48 mo) UAP 80/200 no spasm 40/64 no spasm 40+80/ no spasm 3 (med) 59/M VF-S,Variant 50/100 no spasm /M Rest 20/50 3 vessel (d) (med) (10 mo) UAP 80/100 #8 (d) 40/64 no spasm 40+80/ #8 (d) 5 71/M UAP 50/100 #4(d), #8(d) 40/64 no spasm 40+50/ #4(d), #7(d),#11(d) 5 (med) (1 mo) UAP 50/100 #6(d) 40/64 no spasm 40+80/ #8(d) 6 73/F Rest /64 3 vessel (d) (med) (17 mo) UAP 75/200 #8(d) 40/64 no spasm 40+75/ #8(d), #11(f) 7 72/M VF-S 20/20 #2(t), #7(d), #11(d) (med) (4 mo) UAP 20/100 #2(t), #8(d), #11(d) /M Variant 20/ #2(d), #7 spontaneous (med) (0.5 mo) UAP 20/20 #4(d), #7(d) /M Rest #1(d) (med) (12 mo) UAP 50/100 #1(f), #7(f) 40/64 no spasm 40+50/ #1(d), #7(d) 10 (med) 71/M UAP /64 #2(f), #7(f) (med) 64/M UAP 80/100 #2(f), #7,8(d), #13(d) (med) 65/M ACS 50/50 #2(d), #7,8(d), #11(d) (med: under the medication, M: male, F: female, mo: month, Rest: rest angina, UAP: unstable angina, VF-S: ventricular fibrillation survivor, d: diffuse spasm, t: total spasm, f: focal spasm, ruled line portions: under the medical therapy) which showed normal coronary angiograms (Fig. 2e, f). Prior to discharge two weeks after admission, a spasm provocation test of ACh was performed under medical therapy, including two calcium-channel antagonists (diltiazem R: 200 mg/day & benidipine: 8 mg/day) and a nitrate (isosorbide mononitrate: 40 mg/day). As shown in Table 2, no spasms were provoked under the medical therapy (Fig. 2g-j), and we believed that this therapy would be effective in suppressing the patient s chest pain in daily life. For 61 months after the spasm provocation test, the patient sometimes complained of chest pain and experienced one urgent admission without a hospital stay. Although he quit smoking for two years, he subsequently restarted this habit. Case 6: The patient was a 73-year-old woman who was readmitted to our hospital due to recurrent rest and effort angina. Sixteen months earlier, the intracoronary injection of ER had provoked diffuse three vessel spasms, and she was diagnosed with multiple CSA. Following the administration of two calcium-channel blockers (benidipine: 8 mg/day & diltiazem R: 200 mg/day) and a nitrate (isosorbide mononi- 1741

4 Intern Med 53: , 2014 Figure 1. ECG findings (Case No. 3). A: first admission, B: second admission a c e g b d f h i j Figure 2. CAG findings (Case No. 3). a, b: before ISDN on first admission, c, d: after ISDN on first admission, e, f: after DC for ventricular fibrillation on second admission, g: after 50 μg ACh under the medication, h: after 100 μg ACh under the medication, i. j: after ISDN trate: 40 mg/day), she experienced resistant chest discomfort at rest and effort during daily life, possibly due to mental stress about her family. Treatment with sublingual nitroglycerine several times a day was necessary to treat her chest symptoms. She was urgently readmitted to our hospital due to frequent chest symptoms. A spasm provocation test was performed under medication. As shown in Table 2, the intracoronary injection of 200 μg of ACh provoked spasms in the distal left anterior descending (LAD) (#8), whereas ER did not provoke spasms in either coronary artery. Meanwhile, intracoronary injection of ACh after the ER test caused spasms in the distal LAD (#8) with a diffuse type pattern and the proximal left circumflex (LCX) (#11) with a focal type pattern. We judged that the above medical therapy was able to decrease the patient s vasospasticity, thus allowing her to be discharged. We recommended that such patients should consult the department of psychosomatic medicine, which helped to gradually decrease and resolve her chest symptoms. For 17 months after the spasm provocation test performed under medications, she experienced no episodes of urgent admission to the hospital. Case 7: The patient was a 72-year-old man who was transferred to our hospital via ambulance for VF-S, as shown in Fig. 3A. On the emergency coronary arteriograms, no fixed stenosis (Fig. 4a, b) was detected, irrespective of the presence of abnormal ST-T changes (Fig. 3B). Following the administration of a calcium channel blocker (amlodipine: 5 mg/day) and nitrate (isosorbide mononitrate: 40 mg/day), he complained of no further chest pain. Prior to discharge under no medications, the intracoronary administration of 20 μg of ACh provoked three-vessel spasms consisting of proximal RCA total (#2) spasms, mid LAD diffuse spasms (#7), and proximal LCX diffuse spasms (#11), as shown in Fig. 4c and 4d. Approximately four months later, he was readmitted to our hospital via ambulance due to recurrent chest pain attacks. We administered another calcium channel blocker (diltiazem R: 200 mg/day) and nicorandil (15 mg/ day) after the readmission. Under full medication, a spasm provocation test was performed. In the RCA, the injection of 20 μg of ACh provoked a total spasm at #2 (Fig. 4e). Meanwhile, in the LCA, the injection of 100 μg of ACh provoked diffuse spasms in both the distal LAD (#8) and 1742

5 Figure 3. ECG findings (Case No. 7). A: during AED, B: on admission proximal LCX artery (#11), as shown in Fig. 4f. We judged that this medication would not be sufficient to suppress the next attack and switched from amlodipine (5 mg) to another calcium-channel blocker (benidipine 8 mg/day) and increased the dose of the nitrates (nitrate tape: 40 mg/day). No ventricular tachycardia or fibrillation was induced by the stimulated electrophysiological study. The patient did not agree to implantation of an implantable cardioverter defibrillator (ICD) device. After receiving these medications, his chest symptoms gradually improved and ultimately disappeared. Furthermore, under the above medications, including a statin, the patient complained of no chest pain for 58 months, with no urgent admissions to the hospital. He has also since quit smoking. Case 8: The patient was a 71-year-old man admitted to our hospital due to recurrent rest and effort angina who was diagnosed with UAP. Coronary angiography was performed in the morning at least session of vasodilative drugs for 12 hours. As shown in Fig. 5b, i, moderate fixed stenosis (75%) was observed in the mid LAD. Before undergoing a spasm provocation test, the patient complained of his usual chest pain accompanied with ST elevation in the V1-5 leads. The LAD exhibited total obstruction at #7 (Fig. 5a, c). After providing spontaneous spasm relief, a diffuse coronary spasm was provoked in the RCA by the injection of 20 μg of ACh (Fig. 5d). We diagnosed the patient with variant angina with a very high disease activity and multiple spasms. Two calcium channel antagonists (nifedipine R: 60 mg/day & diltiazem R: 200 mg/day) and nitrates (isosorbide mononitrate: 40 mg/day)/nicorandil (20 mg/day) were administered. Two weeks after discharge, the patient was readmitted via ambulance to our hospital due to frequent chest pain attacks. We performed a second spasm provocation test under these medications. The injection of 20 μg of ACh provoked spasms in the distal RCA (#4) with a diffuse type pattern (Fig. 5f) and in the mid LAD with total obstruction at fixed stenosis (Fig. 5e). We therefore selected the treatment strategy of percutaneous coronary intervention with a bare metal stent in the mid LAD lesion (Fig. 5j) and increased the dose of the calcium channel blocker (nifedipine R: mg/day), after which the patient s chest discomfort gradually disappeared. For 44 months under the above medications, he did not experience any acute admissions to the hospital and complained of no episodes of chest pain. He has since quit smoking. Case 10: The patient was a 71-year-old man with diabetes mellitus, hypertension and dyslipidemia. Approximately three months earlier, he had developed chest pain and discomfort in the early morning while walking. Although nitrate (isosorbide mononitrate: 40 mg/day) and nicorandil (15 mg/day) were administered under treatment with a calciumchannel blocker (nifedipine R: 40 mg/day), inferior ischemia was suspected on thallium cardiac scintigrams. He was subsequently admitted to our hospital via ambulance due to frequent severe chest pain attacks. The day after admission, we performed cardiac catheterization, which showed no fixed stenosis (Fig. 6c, d). The intracoronary administration of ER provoked focal spasms in both the mid left anterior descending artery and mid right coronary artery accompanied by usual chest pain and significant ischemic ECG changes (Fig. 6a, b). Another calcium-channel blocker (diltiazem R: 200 mg/day) was administered and the dose of nicorandil was increased (15 20 mg/day). For 34 months after the spasm provocation test, the patient did not complain of chest pain and experienced no episodes of urgent admission. He also quit smoking for approximately three years. Case 11: The patient was a 64-year-old man who had been diagnosed with CSA at 48 years of age. Under treatment with one calcium-channel blocker (benidipine: 8 mg/ day) and nitrate (isosorbide mononitrate: 40 mg/day) he complained of no chest pain. However, three months prior to admission, he often complained of chest pain attacks at rest and on effort. While another calcium-channel blocker (nifedipine: 60 mg/day) and nicorandil (20 mg/day) were administered, he was admitted to our hospital via ambulance. Neither elevation of cardiac enzymes nor ischemic ECG changes were noted. However, anterior and inferior ischemic findings were observed on thallium cardiac scintigrams, and coronary arteriography was performed under full medication. Although, no significant coronary stenosis was found (Fig. 7a, b), three-vessel diffuse spasms were provoked on an ACh spasm provocation test performed under medication (Fig. 7c, d). We therefore increased the dose of the calcium channel blocker (benidipine: 8 12 mg/day & nifedipine: mg/day). For 31 months after the spasm provocation test, the patient experienced no urgent admission, and his chest pain was controlled with these above 1743

6 Intern Med 53: , 2014 Figure 4. CAG findings (Case No. 7). a,b: after first admission, c, d: after 20 μg ACh under 24 hour no medication, e: after 20 μg ACh under the medication, f: after 100 μg ACh under the medication, g, h: after ISDN a c e g i b d f h j Figure 5. CAG findings (Case No. 8). a, c: spontaneous spasm, b: after spontaneous spasm relief, d: after ACh 20 μg, e: after ACh 20 μg under the medication, f: after ACh 20 μg under the medication, g, h: after ISDN, i: before PCI, j: after PCI medicines. In addition, he quit smoking. Results Spasm provocation tests were performed under medical therapy in 12 R-CSA patients, including those with UAP or ACS. As shown in Table 2, the coronary artery spasms disappeared in only three patients (Case No. 1-3) following the ACh test performed under medication, whereas the remaining nine patients experienced provoked spasms on the ACh, ER and addition of ACh after ER tests. A decrease in vasospasticity was obtained in three (Case No. 4-6) of the nine patients with spasms provoked under medications, while six patients (Case No. 7-12) exhibited higher levels of vasospasticity, irrespective of the administration of aggressive medi- cal therapy. We therefore decided that all three patients with decreased spasticity could be treated as outpatients with these medications. In contrast, we chose to administer/increase the dose of another calcium channel blocker and nitrate or nicorandil in six patients with higher level of vasospasticity. Moreover, percutaneous coronary intervention therapy was selected for moderate stenosis in the mid LAD due to provoked spasms in one patient (Case No.8). Based on the results of the spasm provocation tests performed under adequate medical therapy, we were able to obtain proof that these medications suppress coronary artery spasms during daily life in less than half of the R-CSA patients. Moreover, we decided to administer another calcium channel blocker/nitrate/nicorandil and increased the dose of these medicines to suppress coronary artery spasms during daily 1744

7 Intern Med 53: , 2014 Figure 6. CAG findings (Case No.10). a: after 64 μg ER into LCA under the medication, b: after 40 μg into RCA under the medication, c, d: after ISDN Figure 7. CAG findings (Case No. 11). a, b: after ISDN, c: after 100 μg ACh into LCA under the medication, d: after 80 μg ACh into RCA under the medication 1745

8 life. In this series, we recommended consultation with the department of psychosomatic medicine in two cases. We also encouraged all patients to quit smoking; however, one patient was unable to do so. After undergoing spasm provocation tests, two patients were urgently readmitted to our hospital, although they were subsequently discharged to home without a hospital stay. No major cardiac events or hospital stays were observed, and we were able to manage all 12 patients as outpatients for 38.7±26.4 months (4-100 months). Prior to the administration of the spasm provocation tests performed under medications, the number of vasodilator drugs administered was 3.5±0.7, which increased to 3.8±0.4 after the spasm provocation tests. Discussion In this article, we reported the findings of spasm provocation tests performed under adequate medical therapy in 12 R-CSA patients on urgent admission. In principle, ACh and ER spasm provocation tests are a diagnostic tool for inducing of coronary artery spasms. However, in clinical practice, physicians encounter R-CSA patients, regardless of the use of adequate medical therapy, including two or three calciumchannel blockers and optimal nitrates/nicorandil. In such situations, there are no useful tools for evaluating the effects of medical therapy, except for assessing the number of nitroglycerine administration or results of ECG monitoring. We performed spasm provocation tests under adequate medical therapy in patients with R-CSA, such as that involving UAP or ACS. If such tests do not provoke spasms or mitigate vasospasticity, these medical therapies may be effective in suppressing coronary artery spasms in daily life. If severe spasms are provoked even under adequate medical therapy, this finding may prove that few medicines effectively suppress coronary artery spasms. The provoked spasms documented on pharmacological tests may not be the same as coronary artery spasms experienced during daily life. However, we were able to obtain only the number of chest pain attacks or sublingual nitroglycerine administrations per day or week as measurements of the disease activity. The threshold for chest pain is different in each CSA patient. A third of ischemic ST segment changes showed symptoms, while the remaining attacks are associated with episodes of silent ischemia, as reported by Yasue (14). Non-invasive methods, such as hyperventilation, cold stress, exercise and mental stress tests are useful for the diagnosing disease and evaluating the effects of medical therapy (15-18). However, the positive rate on these tests is not very high, with the exception of the hyperventilation test. Even in CSA patients with a high disease activity, it is not possible to identify all ischemic ECG changes and/or chest symptoms by performing a hyperventilation test. Due to the potential for serious complications during the hyperventilation test (19), we cannot recommend the use of this test to evaluate the efficacy of medical therapy as a bed side examination. Although serious complications of invasive spasm provocation tests, such as ventricular fibrillation, ventricular tachycardia, shock, hypotension and bradycardia, have been reported (20-22), invasive spasm provocation tests are safer than non-invasive spasm provocation tests. In the cardiac catheterization laboratory, it is possible to manage refractory spasms via the intracoronary injection of nitrates in addition to various interventions. Therefore, we recommend performing spasm provocation tests under medical therapy, especially in R-CSA patients, such as those with UAP/ACS or VF-S. In addition, in the future, it may be possible to recognize the real degree of vasospasticity in each CSA patient and select the individual treatment strategy for R-CSA. In this study, we selected treatment strategies other than those vasodilator drugs. After consulting with the department of psychosomatic medicine, the patient s chest discomfort and pain disappeared in two cases. Therefore, it may be possible to decrease the administration of large dose of medications. Some CSA patients experience significant mental stress, which can lead to a refractory CSA-like state. When obtaining negative findings for provoked spasms on spasm provocation tests performed under medication, physicians should select another approach in order to prevent a refractory spasm state. It is also necessary to not perform spasm provocation tests under medication in patients with well-controlled CSA treated with optimal medicines. Moreover, this method may be useful for decreasing the dose of medications in VF-S patients with coronary artery spasms. Further studies are needed to objectively evaluate the degree of vasospasticity among CSA patients in the real world. The authors state that they have no Conflict of Interest (COI). Acknowledgement We acknowledge the helpful comments of Professor Yuji Shigematsu, MD and Professor Kunio Hiwada, MD. References 1. Yasue H, Horio Y, Nakamura N, et al. Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm. Circulation 74: , Okumura K, Yasue H, Matsuyama K, et al. Sensitivity and specificity of intracoronary injection of acetylcholine for the induction of coronary artery spasm. J Am Coll Cardiol 12: , Okumura K, Yasue H, Horio Y, et al. Multivessel coronary spasm in patients with variant angina: a study with intracoronary injection of acetylcholine. Circulation 77: , Sueda S, Ochi N, Kawada H, et al. Frequency of provoked coronary vasospasm in patients undergoing coronary arteriography with spasm provocation test of acetylcholine. 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