Effect of sarpogrelate and high‐dose statin on the reduction of coronary spasm in vasospastic angina: A two by two factorial, pilot randomized study

Abstract Background Vasospastic angina (VSA) is characterized by coronary spasm, which can be aggravated by vasoactive substances such as serotonin. Hypothesis Sarpogrelate, a selective serotonin receptor antagonist, and high‐dose statin have some effects on the reduction of coronary spasm in patients with VSA. Methods We recruited 100 patients with angiographically confirmed VSA, and randomly assigned them into four groups: sarpogrelate with high‐dose statin (Group A, n = 25), sarpogrelate with low‐dose or no statin (Group B, n = 25), placebo with high‐dose statin (Group C, n = 25), and placebo with low‐dose or no statin (Group D, n = 25). The primary endpoint was the remission of coronary spasm on 1‐year follow‐up provocation test. Results The most common site of coronary spasm was left anterior descending artery (42%). Most patients (96%) took calcium channel blockers, and 46% were treated with vasodilators. Overall, 40% of patients reported no chest pain at 1 year, and 23% showed complete remission of coronary spasm on 1‐year follow‐up provocation test. No difference was observed in symptomatic and angiographically complete remission rate between the sarpogrelate and the placebo group. Although the apolipoprotein B level at the 1‐year follow‐up was significantly lower in the high‐dose statin group, symptomatic and angiographic outcomes were not different according to statin intensity. Distal thrombolysis in myocardial infarction (TIMI) flow on initial provocation test was independently associated with angiographically complete remission. Conclusions Sarpogrelate or high‐dose statin did not significantly improve the angiographic remission rate in patients with VSA. Distal TIMI flow on initial provocation test could predict the complete remission of coronary spasm at follow‐up.

provocation test was independently associated with angiographically complete remission.
Conclusions: Sarpogrelate or high-dose statin did not significantly improve the angiographic remission rate in patients with VSA. Distal TIMI flow on initial provocation test could predict the complete remission of coronary spasm at follow-up. ischemia. 1,2 Ischemic episodes of VSA are aggravated by physical or psychological stress, exposure to the cold, or hyperventilation. [3][4][5] Furthermore, several pharmacologic agents such as catecholamines, parasympathomimetic agents, anticholinesterase agents, beta-adrenergic blocking agents, ergonovine, serotonin, and histamine can induce coronary spasm. [6][7][8][9] Serotonin (5-hydroxytryptamine or 5-HT) mediates vasoconstriction and platelet aggregation by 5-HT 2A receptors on vascular smooth muscle cells and platelets. Sarpogrelate is a selective 5-HT 2A antagonist, which inhibits vasoconstriction and platelet aggregation, and is theoretically beneficial in the treatment of VSA. 10 However, there are no data on treating patients with VSA, even though sarpogrelate has been widely used as an antiplatelet agent in peripheral artery disease.
Although the pathogenesis of VSA is not yet fully understood, vascular endothelial dysfunction, coronary microvascular dysfunction, and Ca 2+ -mediated vascular smooth muscle cell hyperplasia have been suggested to be the main contributors. [11][12][13][14] Moreover, some investigators have proposed that coronary spasm is an early form of atherosclerosis, based on the results of several animal studies and intravascular imaging studies for assessment of spastic artery. [15][16][17][18] However, there has been debate regarding the beneficial effects of statin, a well-known coronary artery plaque stabilizer, for patients with VSA. 19,20 To address this debate, we conducted a 2 × 2 factorial randomized controlled trial to evaluate the efficacy of sarpogrelate and high-dose statin for reduction of coronary spasm in patients with VSA.

| Study design and population
The present study was a 2 × 2 randomized prospective single-center trial. The study protocol was approved by the Institutional Review Board of Samsung Medical Center, and all patients provided written informed consent. From 2012 to 2016, 20-to 70-year-old patients with VSA were recruited. At the initial evaluation, coronary spasm was angiographically proven, which was defined as thrombolysis in myocardial infarction (TIMI) flow of less than 3 with chest pain or significant ST-T wave change by spontaneous coronary spasm or intracoronary ergonovine spasm provocation test. The main exclusion criteria were cardiac arrest due to coronary spasm, left main spasm, significant fixed coronary artery stenosis of more than 70%, severe left ventricular dysfunction (ejection fraction <30%), bleeding tendency, and significant liver and kidney disease. Patients with coagulation disorders, platelet count less than 50 000/μL, or prothrombin time more than 2.0 (international normalized ratio) were considered to indicate bleeding tendency.
Significant liver disease was defined as aspartate aminotransferase or alanine aminotransferase of more than 100 U/mL, and renal failure was defined as serum creatinine of more than 2.0 mg/dL. Pregnant or breastfeeding patients were also excluded. Clinical Trial Registration Information: ClinicalTrials.gov, NCT01674686.
A total of 100 VSA patients were included. They were randomly assigned to a sarpogrelate or a placebo group at a one-to-one ratio.
Each group was also randomly divided into a high-dose statin and a low-dose or no statin group. Randomization was done via a webbased system by computer-generated block randomization. The dose of sarpogrelate was 100 mg twice a day. The high-dose statin group was prescribed atorvastatin 80 mg once a day, while the low-dose or no statin group was prescribed simvastatin 20 mg once a day or no statin medication. Group A took sarpogrelate and high-dose statin, group B took sarpogrelate and low-dose or no statin, group C took placebo and high-dose statin, and group D took placebo and low-dose or no statin. Each group had 25 patients (Supporting Information, Figure S1). After randomization, to control symptoms, use of calcium channel blockers (CCBs) or nitrates was based on physician discretion.

| Study procedures and follow-up
Before the spasm provocation test, routine right and left coronary angiography (CAG) was performed. If any significant stenosis (angiographic luminal stenosis >70%) was observed, the spasm provocation test was canceled. After performing routine CAG, the intracoronary ergonovine spasm provocation test was started using the left coronary artery first. Two bolus doses of ergonovine maleate were injected into each coronary artery at an interval of 2 minutes: 10 μg followed by 20 μg for the left coronary artery and 10 μg followed by another 10 μg for the right. Before injection of the second dose, CAG was performed and 12-lead ECG was taken. The test was stopped immediately after a positive result was obtained, and intracoronary nitroglycerin 200 to 600 mg was administered until the spasm had been relieved angiographically.
Vital signs, height, body weight, and blood tests including complete blood count, lipid profile, liver function test, blood urea nitrogen, creatinine, and C-reactive protein were checked at baseline, 1, 3, 6, and 12 months of follow-up. Echocardiography was performed at baseline. Prothrombin time level was checked at baseline, and creatine kinase level was checked at 1 and 12 months of follow-up.
Apolipoprotein B, apolipoprotein A1, and lipoprotein (a) levels were checked at baseline and 12 months of follow-up.

| Statistical analysis
Continuous variables were compared using the Student's t-test or Mann-Whitney test where applicable. Categorical data were assessed using the chi-square test or Fisher's exact test, as appropriate. To identify independent predictors of complete remission, the odds ratio (OR) and 95% confidence interval (CI) were calculated using a multivariate logistic regression model that included sex, hypertension, diabetes mellitus, alcohol abstinence, sarpogrelate, high-dose statin, and distal TIMI flow 0 at the initial provocation test. Statistical analyses were performed with SPSS software version 18 (IBM Corp, Armonk, New York). All tests were two-tailed and P < .05 was considered statistically significant.

| Baseline clinical and angiographic characteristics according to sarpogrelate
Baseline clinical and angiographic characteristics in the sarpogrelate group vs the placebo group are shown in Table 1. Overall, the mean age was 57.4 years, 92% were men, and 78% drank alcohol. Most patients (96.0%) had been prescribed CCBs, and 46% had been prescribed vasodilators after angiographically proven vasospasm. There were no significant differences in general cardiovascular risk factors, alcohol intake, results of laboratory tests, and medication at discharge between the sarpogrelate and placebo groups (Table 1).
Forty-seven patients showed no fixed stenosis on initial CAG. No patient was diagnosed with microvascular spasm, which was defined as angina symptom with ischemic ECG changes without significant epicardial coronary artery spasm (>75%). 21 There were two patients with multivessel spasm involving the LAD and the LCX at the same time. Spontaneous spasm was observed in three patients. Fortytwo percent of the coronary spasms were located at LAD, which was followed by the right coronary artery at 35% and LCX at 21%. Fiftyseven percent of the patients showed distal TIMI 0 flow after intracoronary ergonovine injection. There were no differences in spasm location and grade of distal TIMI flow between the sarpogrelate and placebo groups (Table 1).

| Baseline clinical and angiographic characteristics according to statin intensity
Baseline clinical and angiographic characteristics according to statin therapy are shown in Table S1. The proportion of cardiovascular risk factors, alcohol intake, blood tests including lipid profiles, medication at discharge, location and grade of fixed stenosis, spasm location, and grade of distal TIMI flow were similar between the high-dose statin group and the low-dose or no statin group, with the exception of age.
Patients in the high-dose statin group were older than those in the low-dose or no statin group.   Outcomes according to statin therapy are presented in Table 3.

| Outcomes
More patients showed improvement of fixed stenosis in the high dose statin group than in the low-dose or no statin group without statistical significance (4 vs 1, P = .366). The alcohol abstinence rate was not different between the two groups. Neither the symptomatic remission nor the angiographically complete remission rates were different between the high-dose statin and the low-dose or no statin groups.
Triglyceride, apolipoprotein A1, and lipoprotein (a) levels were not different according to statin therapy. On the other hand, the total cholesterol, low-density lipoprotein (LDL), and apolipoprotein B levels were significantly lower in the high-dose statin group than in the lowdose or no statin group (Figure 1).

| Independent predictors of angiographically complete remission at the 1-year follow-up visit
According to the baseline characteristics of coronary vasospasm, patients were divided into three groups; spontaneous spasm (n = 3),  based on these mechanisms, [24][25][26] and are recommended in current guidelines to manage VSA. 27,28 However, some patients have recurrent angina symptoms even while taking sufficient medication including CCB and nitrates. Furthermore, one study also suggested that angina symptoms could occur more frequently during the CCB withdrawal period. 24 In regard to these limitations, several medications that were perceived to be relevant to coronary spasm were evaluated for managing VSA. Serotonin (5-hydroxytryptamine, 5-HT) is one of the most important vasoconstrictor triggers with a possible role in coronary spasm. It mediates vasoconstriction by 5-HT 2A receptors on vascular smooth muscle cells, and also promotes platelet aggregation. 10 However, the role of serotonin in VSA is controversial. 29-31 Sarpogrelate hydrochloride, a selective 5-HT 2A antagonist, suppresses platelet aggregation and inhibits thrombus formation and vascular smooth muscle cell proliferation, and is widely used to improve vascular function in peripheral arterial disease. 10 It has been also reported to inhibit serotonin-induced coronary vasospasm in an animal study 32  This study has several limitations. First, the sample size and followup rate were low. Based on the results of this pilot study (complete remission rate 20% in the sarpogrelate group and 25% in the placebo group), a total of 2432 patients will be needed to prove the difference between serotonin antagonist and placebo with consideration of 10% withdrawal rates. Due to the invasiveness of the provocation test, the rate of consent withdrawal was high, and only 62% of patients underwent the 1-year follow-up spasm test. Second, the selection of treatment strategies other than sarpogrelate and statin was based on the doctor's preference. Third, because most of the enrolled patients were men in this study, evaluation of coronary microvascular spasm, which is known to be more prevalent in women, could not be performed. Finally, we determined the extent of stenosis via visual estimation instead of intravascular ultrasound or optical coherence tomography, and thus stenosis in fixed disease could have been under-or overestimated.

| CONCLUSIONS
Sarpogrelate and high-dose statin did not appear to affect the symptomatic or angiographic outcomes of VSA. With proper medical therapies such as CCB, 23% of followed patients with VSA showed complete remission of coronary spasm at the 1-year follow-up. If coronary spasm was severe enough to show distal TIMI 0 flow at the initial spasm test, the chance of complete remission of coronary spasm was lower at the 1-year follow-up.

ACKNOWLEDGMENTS
This work was supported by the Yuhan Corporation.