3-Year Follow-Up of Patients With Coronary Artery Spasm as Cause of Acute Coronary Syndrome

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1 Journal of the American College of Cardiology Vol. 57, No. 2, by the American College of Cardiology Foundation ISSN /$36.00 Published by Elsevier Inc. doi: /j.jacc Year Follow-Up of Patients With Coronary Artery Spasm as Cause of Acute Coronary Syndrome The CASPAR (Coronary Artery Spasm in Patients With Acute Coronary Syndrome) Study Follow-Up Peter Ong, MD,* Anastasios Athanasiadis, MD,* Gabor Borgulya, MD, MSC, Matthias Voehringer, MD,* Udo Sechtem, MD* Stuttgart, Germany; and London, United Kingdom Objectives Background Methods Results Conclusions We sought to determine the prognosis of patients with acute coronary syndrome without culprit lesion and proof of coronary spasm during 3 years of follow-up. Coronary artery spasm has been identified as an alternative cause for acute coronary syndrome (ACS) in patients without culprit lesion. In the CASPAR (Coronary Artery Spasm as a Frequent Cause for Acute Coronary Syndrome) study, we recently showed that 50% of ACS patients without culprit lesion, in whom intracoronary acetylcholine provocation was performed, had coronary spasm. However, data on prognosis in these patients are sparse. After 3 years of follow-up, data regarding the following end points were obtained: death (cardiac and noncardiac), nonfatal myocardial infarction, and recurrent angina leading to repeated coronary angiography. The analysis focused on patients with a culprit lesion (n 270) and patients without a culprit lesion (n 76) but with acetylcholine provocation (total n 346). In patients without culprit lesion, there was no cardiac death or nonfatal myocardial infarction during follow-up; 1 patient died due to a noncardiac cause. However, 38 of 76 patients reported persistent angina requiring repeated angiography in 3 cases (3.9%). Thirty of 270 patients with culprit lesion died due to a cardiac cause (11.1%) and 13 due to a noncardiac cause (4.8%). Eleven patients had nonfatal myocardial infarction (4.1%) and 27 repeated angiography due to persistent or recurrent angina (10%). Patients with a culprit lesion had a higher mortality and more coronary events compared with those without (p , log-rank test). ACS patients without culprit lesion and proof of coronary spasm have an excellent prognosis for survival and coronary events after 3 years compared with patients with obstructive ACS. However, persistent angina represents a challenging problem in these patients, leading in some cases to repeated coronary angiography. (J Am Coll Cardiol 2011;57:147 52) 2011 by the American College of Cardiology Foundation Despite improvements in diagnosis and therapy over the last years, mortality among patients with acute coronary syndrome (ACS) is still high (1,2). Among others, we could recently show that ACS patients frequently have no culprit lesion and that these patients often suffer from coronary artery spasm as an explanation for their acute chest pain (3,4). The CASPAR (Coronary Artery Spasm as a Frequent Cause for Acute Coronary Syndrome) study (4) revealed no culprit lesion in 138 out of 488 ACS patients undergoing From the *Department of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany; and the Clinical Trials Unit, St. George s University of London, London, United Kingdom. The authors have reported that they have no relationships to disclose. Manuscript received March 8, 2010; revised manuscript received August 3, 2010, accepted August 10, emergency coronary angiography, and 86 underwent intracoronary acetylcholine (ACH) provocation for the detection of coronary spasm, which was positive in 42 patients (49%). Regarding outcome, however, there are only a few studies in a similar cohort of patients. Wang et al. (3) reported 93 Japanese ACS patients with insignificant coronary artery disease who underwent intracoronary ergonovine testing for the detection of coronary spasm. Thirty-eight patients had a positive test (41%). After a median follow-up of 25 months, there were no cardiac deaths, but there were 3 nonfatal myocardial infarctions, 2 of them in the spasm group. However, it is unclear whether these results can be extrapolated to Caucasian patients, as racial differences have been described between Asian and Caucasian patients with coronary spasm (5). Consequently, we determined the

2 148 Ong et al. JACC Vol. 57, No. 2, 2011 ACS Patients With Coronary Spasm: 3-Year Follow-Up January 11, 2011: Abbreviations and Acronyms ACH acetylcholine ACS acute coronary syndrome ECG electrocardiogram LCA left coronary artery NSTEMI non ST-segment elevation myocardial infarction STEMI ST-segment elevation myocardial infarction TIMI Thrombolysis In Myocardial Infarction UAP unstable angina pectoris prognosis of the German patients of the CASPAR study during 3 years of follow-up. Methods The design of the CASPAR study has been reported previously (4). Epicardial coronary spasm was defined as 75% coronary diameter reduction during ACH infusion in comparison to the relaxed state after intracoronary nitroglycerin administration together with a reproduction of the patient s initial symptoms. The degree of vasoconstriction was quantitatively analyzed with QCA-CMS version 7.0 (Medis- Software, Leiden, the Netherlands). Follow-up. Patient follow-up data were obtained using a written questionnaire. Additional information was obtained from medical records of outpatient visits or of hospital readmissions. In patients for whom none of these data were available, information was obtained by calling the patient or the patient s general practitioner. All information was obtained between June and December 2009, 3 years after study entry. The end points were defined as death, nonfatal myocardial infarction, and recurrent angina pectoris leading to repeated coronary angiography. The cause of death was further classified as cardiac or noncardiac according to the patient medical records, death certificates, or information by the general practitioner. Coronary events were defined as a combination of cardiac death and nonfatal myocardial infarction. Of all 488 patients from the initial study, follow-up focused on patients with culprit lesion (n 350) and patients without culprit lesion (n 86) but with an ACH test. Follow-up data were available in 346 patients (79.4%) of whom 270 patients belonged to the group with culprit lesion (77% follow-up) and 76 patients to the group without culprit lesion (88% follow-up) (Fig. 1). Predictors for outcome in patients without culprit lesion. In patients without culprit lesion who underwent ACH testing, the following binary parameters were obtained for later outcome analysis: reproduction of angina during ACH testing, presence of ischemic electrocardiogram (ECG) shifts during ACH testing (ST-segment depression or ST-segment elevation of 1 mm in at least 2 contiguous leads), and presence of the slow coronary flow phenomenon defined as a Thrombolysis In Myocardial Infarction (TIMI) frame count of 27 frames in at least 1 coronary artery according to Gibson et al. (6). Statistical analysis. Data analysis was performed utilizing SPSS version 16.0 (SPSS Inc., Chicago, Illinois). Results are expressed as mean SD. The Fisher exact test was used for categorical variables. The t test was used to compare Figure 1 Study Flow Chart ACH acetylcholine; CASPAR Coronary Artery Spasm in Patients With Acute Coronary Syndrome.

3 JACC Vol. 57, No. 2, 2011 January 11, 2011: Ong et al. ACS Patients With Coronary Spasm: 3-Year Follow-Up 149 Patient Table 1MainPatient Clinical Main Characteristics Clinical Characteristics Culprit Lesion Present Culprit Lesion Absent Total p Value n Male 191 (71%) 34 (45%) 225 (65%) Age (yrs) 69 (61 77) 65 (54 71) 68 (59 76) LVEF 57 (44 70) 70 (62 78) 61 (48 72) Troponin I (normal 0.16 /l)* 6.15 ( ) 0.02 ( ) 1.92 ( ) Death 51 (19%) 1 (1%) 52 (15%) Cardiac death 30 (11%) 0 30 (8.7%) Nonfatal myocardial infarction 11 (4.1%) 0 11 (3.2%) Persistent angina 78 (28.9%) 38 (50%) 116 (33.5%) Repeated coronary angiography 27 (10%) 3 (3.9%) 30 (8.7%) Values are n, n (%), or median (interquartile range). *Normal troponin I 0.16 g/l. LVEF left ventricular ejection fraction. continuous variables. For values without normal distribution, median and interquartile ranges are stated, and Mann- Whitney U test was used. Kaplan-Meier curves were calculated for visualizing overall survival as well as freedom from coronary events of patients compared with those without culprit lesion. A log-rank test was performed to compare both curves. After univariate analysis, multivariate Cox regression analysis was carried out for the identification of independent predictors of outcome. A 2-tailed p value 0.05 was considered significant. Results Of the 86 patients who underwent ACH testing in the initial study, 42 showed epicardial coronary spasm with reproduction of the initial symptoms. Patients with a negative ACH test reported reproduction of symptoms in 17 of 44 patients (39%), and an intermediate vasoconstriction without reproduction of symptoms was observed in 15 of 44 patients (34%) during initial ACH infusion. Eight patients had significant epicardial vasoconstriction without reproduction of symptoms, and 4 patients had no symptoms and no relevant vasoconstriction on ACH testing. Follow-up. The results regarding the end points are shown in Tables 1 and 2. Fifty-two patients died during follow-up (15%), 14 due to a noncardiac cause (4%) (septic shock following pneumonia [n 2], multiorgan failure after gastrointestinal operation [n 4], pulmonary sarcoma [n 1], pulmonary embolism [n 1], cancer [n 6]). The cause of death could not be ascertained in 8 patients, all of whom belonged to the culprit lesion group. Thirty patients died due to a cardiac cause (11.1% cardiovascular mortality). They were all part of the culprit lesion group. Patients died due to acute fatal myocardial infarction in 15 cases and due to heart failure in the other 15. Overall, 41 patients suffered from a coronary event (30 cardiac deaths and 11 nonfatal myocardial infarcts); none of them belonged to the group without culprit lesion. Statistical analysis revealed significant differences between patients with and without culprit lesion for sex, age, left ventricular ejection fraction, and troponin I levels (p 0.05) (Table 1). There were no differences when comparing patients with and without coronary spasm (Table 2). Predictive factors. Univariate Cox regression analysis revealed the presence of a culprit lesion, age, left ventricular ejection fraction, and troponin I levels as predictors for all-cause death and coronary events. After multivariate Cox regression analysis, age and left ventricular ejection fraction remained as independent predictors (Table 3). Clinical Table 2Characteristics Clinical Characteristics of Patients Without of Patients Culprit Without Lesion Culprit Lesion Epicardial Coronary Spasm on ACH Testing Present Absent p Value n Male 18 (49%) 16 (41%) Age (yrs) 61 (53 70) 62 (54 73) LVEF 70 (62 79) 70 (62 77) Troponin I* 0.02 ( ) 0.02 ( ) Death 0 1 (2.6%) Cardiac death Nonfatal myocardial infarction Persistent angina 17 (46%) 21 (54%) Repeated coronary angiography 1 (2.7%) 2 (5.1%) Values are n, n (%), or median (interquartile range). *Normal troponin I 0.16 g/l. ACH acetylcholine; other abbreviations as in Table 1.

4 150 Ong et al. JACC Vol. 57, No. 2, 2011 ACS Patients With Coronary Spasm: 3-Year Follow-Up January 11, 2011: Univariate for All-Cause and Univariate Death Multivariate and and Coronary Multivariate Cox Regression EventsCoxAnalysis Regression Table 3 Analysis for All-Cause Death and Coronary Events All-cause death Univariate Multivariate Culprit lesion ( ), ( ), Sex ( ), ( ), Age ( ), ( ), LVEF ( ), ( ), Troponin I* ( ), ( ), Coronary events Culprit lesion ( ), ( ), Sex ( ), ( ), Age ( ), ( ), LVEF ( ), ( ), Troponin I* ( ), ( ), Values are hazard ratio (95% confidence interval), p value. *Normal troponin I 0.16 g/l. LVEF left ventricular ejection fraction. In patients without culprit lesion, 59 (69%) of the initial 86 who underwent ACH testing had reproduction of angina during ACH infusion. Among the 76 patients in whom follow-up data were available, 53 (70%) had angina during initial ACH testing, 38 (50%) had recurrent angina at follow-up, and 25 (33%) had both. Comparison of patients with angina at the initial ACH test and those with recurrent angina at follow-up revealed no statistically significant association (p 0.448). Ischemic ECG shifts during initial ACH testing were observed in 35 out of 86 patients (41%), of whom 14 had recurrent angina at follow-up. There was no statistically significant association between patients who showed ischemic ECG shifts at initial ACH testing and those with recurrent angina at follow-up (p 0.999). The TIMI frame count analysis revealed a slow coronary flow phenomenon in at least 1 coronary artery in 10 out of 86 patients (12%), of whom 2 (2%) showed slow flow in all 3 vessels. Although 6 of the latter 10 patients reported recurrent angina at follow-up (60%), comparison of patients with slow coronary flow (n 10) and those with recurrent angina at follow-up (n 38) did not reveal the slow coronary flow phenomenon as a predictor of recurrent angina (p 0.480). Survival curves. Kaplan-Meier analysis showed a significantly higher all-cause mortality in patients with culprit lesion compared with those without (p , log-rank test) (Fig. 2). Comparison of coronary events between the 2 latter groups equally disclosed a significant difference (p , log-rank test) (Fig. 3). Discussion This is the first study, to our knowledge, reporting an excellent prognosis regarding survival and coronary events in Caucasian patients with documented coronary spasm as cause for ACS. Figure 2 Kaplan-Meier Survival Curves: All-Cause Mortality Kaplan-Meier survival curves (cumulative survival) for all-cause mortality showing significantly more deaths in the group with culprit lesion (cl, green) than in the group without (cl, blue) (p , log-rank test) during follow-up (1,095 days). The number of patients alive during follow-up is given below the graph. Cum cumulative. Figure 3 Kaplan-Meier Survival Curves: Coronary Events Kaplan-Meier curves (cumulative survival) comparing coronary events in patients with and without culprit lesion. The culprit lesion group (cl, green) had significantly more events than the group without culprit lesion (cl, blue) (p , log-rank test) during follow-up (1,095 days). The number of patients without coronary events during follow-up is given below the graph. Cum cumulative.

5 JACC Vol. 57, No. 2, 2011 January 11, 2011: Ong et al. ACS Patients With Coronary Spasm: 3-Year Follow-Up 151 Patients with culprit lesion. The unfavorable outcome regarding survival and coronary events in patients with culprit lesion is in line with other studies (7). It can be explained by the fact that these patients were more often male and had higher biomarker levels of troponin at study entry, corresponding to a larger amount of myocardial damage. Consequently, patients with culprit lesion had a lower left ventricular ejection fraction and a higher risk for cardiac events (8). Patients without culprit lesion. Patients without culprit lesion showed no cardiac death or nonfatal myocardial infarction during follow-up. This is compatible with previous reports (9,10). The favorable outcome of our patients without culprit lesion could be related to the fact that they most often presented with unstable angina (n 70) rather than non ST-segment elevation myocardial infarction (NSTEMI) (n 5) or ST-segment elevation myocardial infarction (STEMI) (n 1), supporting the hypothesis that prolonged coronary spasm can mimic true obstructive ACS but usually with only little myocardial damage (11). Other studies, though, have described a higher incidence of cardiac death and nonfatal myocardial infarction in subsets of patients with coronary artery spasm (12,13). Hannebicque et al. (14) reported that 10.6% of 210 coronary spasm patients suffered a myocardial infarct during a mean follow-up of 55 months. However, infarcts only occurred in patients who had spasm in the setting of obstructive coronary artery disease at baseline angiography. Bory et al. (15) described long-term follow-up of 277 French, mainly non-acs patients with coronary spasm and unobstructed coronary arteries. In this group, 3.6% suffered from cardiac death and 6.5% from myocardial infarction after a median follow-up of 89 months. This difference might be due to the different inclusion criteria. Of importance, 71.5% of the Bory et al. (15) patients were smokers, compared with only 23.8% in our study. Smoking can lead to constant and severe endothelial damage and likely contributes to a higher susceptibility for spasm-related myocardial infarction (16,17). The better outcome in our patients may also be related to stringent treatment of all patients with angiotensin-converting enzyme inhibitors, statins, and individually titrated combinations of calcium antagonist and nitrates. Data on prognosis in Asian ACS patients with coronary spasm and insignificant coronary artery disease are sparse. Wang et al. (3) showed a good outcome regarding cardiac death in their 93 Japanese ACS patients with unobstructed coronary arteries. However, there were 2 nonfatal myocardial infarctions among the patients with proof of coronary spasm (5.3%) at a median follow-up of 25 months. The higher incidence of myocardial infarcts compared to our study might be due to the different inclusion criteria because the Wang et al. (3) study comprised more NSTEMI patients. Furthermore, a different genetic background in Asian compared with Caucasian patients leading to a higher prevalence of coronary spasm could explain these differences (5). Nakayama et al. (18) showed that mutations in the endothelial nitric oxide synthase gene in Japanese patients can predispose to coronary spasm. A sizeable proportion of patients without coronary spasm had persistent angina and repeated coronary angiography during follow-up (Table 2). However, importantly, in patients with a negative ACH test, only 4 had no relevant vasoconstriction and no symptoms during ACH testing. The other patients had either reproduction of symptoms and/or an intermediate vasoconstriction during ACH infusion. Furthermore, TIMI frame count analysis revealed a slow coronary flow phenomenon in 10 patients of the initial 86 who underwent ACH testing in at least 1 coronary artery (12%), of whom 4 patients had no coronary spasm during ACH infusion. These findings could possibly be explained by an abnormal coronary vasoreactivity of the coronary microcirculation. In this group of patients, abnormalities of the coronary microcirculation resulting in a reduced coronary reserve or microvascular spasm (19) could have caused repetitive angina during exercise or at rest (20). In fact, it has been reported that coronary microvascular dysfunction can be the reason for acute chest pain at rest and ACS (21,22). These results suggest that microvascular abnormalities during ACH testing should be pursued as these patients might require medical treatment and follow-up in a similar way to those with epicardial coronary spasm. The fact that our patients without culprit lesion required repeated coronary angiography in only 4% of cases is different from previously reported studies. Johnson et al. (23) reported about 21% of patients requiring repeated angiography during 3-year follow-up in women with chest pain, normal coronary arteries, and evidence of myocardial ischemia. The fact that coronary vasospasm was established in our patients as the true cause of the patients symptoms followed by initiation of medical treatment (i.e., calciumchannel blocker and nitrates) might have avoided the frequent reassessment as described in the other less wellcharacterized cohorts. Clinical implications. Patients with ACS without culprit lesion seem to have an excellent prognosis regarding overall survival and coronary events. Intracoronary acetylcholine provocation is suggested for the identification of epicardial coronary spasm. Despite antispastic treatment, recurrent chest pain continues to be a challenging problem in these patients. Therefore, management plans should not only integrate institution of appropriate therapy at the time of diagnosis (i.e., angiotensin-converting enzyme inhibitors, statins, calcium-channel blockers, and nitrates) but also include follow-up with adjustment of antianginal therapy. Study limitations. Although, after establishing the diagnosis of coronary spasm, a standardized treatment including a calcium-channel blocker and nitrates was initiated, the medication during follow-up was not systematically modified with regard to the patients symptoms. The numbers for

6 152 Ong et al. JACC Vol. 57, No. 2, 2011 ACS Patients With Coronary Spasm: 3-Year Follow-Up January 11, 2011: persistent angina might have been different if treatment had been adjusted during follow-up. Furthermore, it cannot be excluded that patients lost to follow-up may have suffered from an adverse event. However, in our opinion, the likelihood of patients without culprit lesion and missing follow-up data having suffered from events is very low. This is supported by the small number of patients lost to follow-up in this group (n 10) compared with 80 in the group with culprit lesion and the fact that all of the latter 10 patients had a normal left ventricular ejection fraction ( 60%) and also no elevation of troponin I concentrations ( 0.02 g/l). Conclusions Caucasian patients with ACS, no culprit lesion, and coronary spasm have an excellent and significantly better prognosis for survival and coronary events after 3 years compared with patients with culprit lesion. 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