American Heart Journal
Volume 144, Issue 2 , Page E1, August 2002

Effectiveness of a novel serotonin blocker, sarpogrelate, for patients with angina pectoris☆☆☆★

Tottori, Kyoto, Fukui, Tokyo, and Hirosaki, Japan

From the aDivision of Cardiology, First Department of Internal Medicine, Tottori University, Tottori, the bCollege of Medical Technology, Kyoto University, Kyoto, the cFirst Department of Internal Medicine, Fukui Medical University, Fukui, the dSecond Department of Internal Medicine, Tokyo Medical University, Tokyo, the eSecond Department of Internal Medicine, Hirosaki University, Hirosaki, and the fDivision of Cardiology, Takeda Hospital, Kyoto, Japan

Received 12 December 2001; accepted 12 February 2002.

Article Outline

Abstract 

Background We have recently demonstrated that a single oral administration of sarpogrelate, a 5-HT2A receptor antagonist, may improve exercise capacity in anginal patients with well-developed collaterals. The aim of the current study was to investigate the effectiveness of 2-week treatment with sarpogrelate on anginal symptoms and exercise capacity in anginal patients. Methods A treadmill exercise test was repeated after a 2-week period with or without sarpogrelate (100 mg 3 times a day) in 20 patients with angiographically proven stable angina. Anginal symptoms and daily physical activity by the specific activity scale (SAS) were also evaluated. Results Treatment with sarpogrelate significantly increased the SAS score and prolonged exercise time to the onset of 0.1-mV ST depression. When data were analyzed in a subgroup of patients (n = 8) with well-developed collaterals, the treatment with sarpogrelate decreased the number of anginal attacks (control vs sarpogrelate, 3.0 ± 2.8 vs 0.9 ± 1.1/2 weeks, P < .05), increased the SAS score (5.2 ± 1.6 vs 6.2 ± 1.3 METS, P < .05), and increased the time to the onset of 0.1-mV ST depression (235 ± 84 vs 295 ± 127 seconds, P < .05). In addition, the double product at the onset of 0.1-mV ST depression increased by 15% (P < .05) after sarpogrelate. In contrast, all parameters were not significantly changed after sarpogrelate treatment in patients (n = 12) without well-developed collaterals. Conclusions These findings indicate the therapeutic effectiveness of sarpogrelate for anginal patients, especially for patients with well-developed collaterals. (Am Heart J 2002;144:e1.)

 

Sarpogrelate is a novel serotonin blocker, which specifically antagonizes 5-HT2A receptors.1, 2 Antiplatelet action of this agent is well documented,3, 4 and this drug is currently used for the treatment of atherosclerosis obliterans in several countries including China, Korea, and Japan. Coronary and collateral circulation is regulated by various vasoactive substances including serotonin. Serotonin is reported to reduce blood flow to the collateral-dependent myocardium in a canine model.5 In patients with angina pectoris with well-developed collaterals, we have demonstrated that a single oral administration of sarpogrelate improves exercise capacity and attenuates myocardial ischemia during exercise.6

The findings of our previous study suggest that sarpogrelate has potential as an antianginal drug. In addition, sarpogrelate may be related to pain modulation in anginal patients. Indeed, sarpogrelate has been tested successfully for the neuropathic pain in patients with postherpetic neuralgia and reflex sympathetic dystrophy.7, 8 Thus it remains to be elucidated whether continuous treatment with sarpogrelate is efficacious in patients with stable angina pectoris. Therefore, the current study was undertaken to investigate the efficacy of sarpogrelate on anginal symptoms and exercise capacity in patients with chronic stable angina pectoris.

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Methods 

Patient selection 

We investigated 20 patients (14 males, 6 females) aged between 57 and 79 years (mean 67 ± 6 y) with chronic stable effort angina in Canadian Cardiovascular Society Functional Class I to III. All had angiographically proven significant coronary stenosis (≥70%) involving one or more major coronary arteries and developed ≥0.1-mV ST-segment depression during treadmill exercise testing. None had acute exacerbation of symptoms in the preceding 6 months nor had any ever had a Q-wave myocardial infarction. None had undergone percutaneous transluminal coronary angioplasty or coronary artery bypass grafting surgery. Patients with bundle-branch block, valvular heart disease, and cardiomyopathy were excluded. The protocol was approved by the ethics committee of the each institution, and all subjects gave written informed consent for this study.

Cardiac catheterization 

All patients were referred for conventional diagnostic right and left heart catheterization, together with left ventriculography and selective coronary angiography, to evaluate coronary atherosclerotic lesions and left ventricular function. Selective coronary arteriography was performed by means of the femoral approach. A contrast medium was injected with enough force and in sufficient quantity to provide good visualization of the coronary arteries. Multiple projections of right and left coronary arteries were routinely obtained. After the left ventricular pressure had returned to baseline levels, left ventricular cineangiography was performed at a 30 degrees right anterior oblique projection. The diameter of the coronary arteries was measured with a caliper on suitably magnified 35-mm cineframes at end-diastole. A significant coronary stenosis was defined as ≥70% narrowing of a major coronary artery branch.

Grading of coronary perfusion 

The degree of perfusion of the ischemia-related coronary artery was graded on a scale of 0 to 3 as follows. (0) There is no anterograde flow beyond the point of occlusion. (1) The contrast material passes beyond the area of obstruction but “hangs up” and fails to opacify the entire coronary bed distal to the obstruction for the duration of the cineangiographic filming sequence. (2) The contrast material passes across the obstruction. However, the rate of entry of the contrast material into the vessel distal to the obstruction or its rate of clearance from the distal bed (or both) is perceptibly slower than its entry into or clearance from comparable areas (for example, the opposite coronary artery of the coronary bed proximal to the obstruction). (3) Anterograde flow into the bed distal to the obstruction occurs as quickly as anterograde flows into the bed proximal to the obstruction and clearance of the contrast material from the involved bed is as rapid as clearance from an uninvolved bed in the same vessel or the opposite artery.9

Grading of coronary collateral circulation 

Collateral circulation was graded on a scale of 0 to 3, depending on the degree of opacification of the occluded vessel. The score (collateral index) was based on the injection that best opacified the occluded vessel: 0, none; 1, filling of side branches of the artery to be perfused with collateral vessels and no visualization of the epicardial segment; 2, partial filling of the epicardial segment with collateral vessels; 3, complete filling of the epicardial segment with collateral vessels.10 Three observers assessed the coronary cineangiograms in blinded fashion and reached a consensus regarding the Thrombolysis In Myocardial Infarction (TIMI) flow grade and collateral filling.

Protocol 

Before entering into the study, all subjects performed several preliminary exercise tests to habituate to the treadmill test. All antianginal medication including nitrates, calcium-channel antagonists, β-blockades, and antiplatelet agents were withdrawn at least 7 days before the study. Sublingual nitroglycerin was allowed for the anginal symptom relief. Each patient kept a diary and was instructed to record each anginal attack and the use of sublingual nitroglycerin. The change in daily physical activities was evaluated with the use of questionnaires for specific physical activities.11 To minimize the effects of habituation to the treadmill test, the order of tests with and without sarpogrelate was randomized. Therefore, half of the patients were given 100 mg sarpogrelate 3 times a day for 14 days, and a posttreatment treadmill exercise test was performed 1 to 2 hours after the morning dose of sarpogrelate. Sarpogrelate was then stopped, and an additional treadmill test was performed at the end of 2-week period of no therapy. A washout period was not set before the 2-week of no therapy because sarpogrelate has a short biological half-life of 0.7 hours. The other half of the patients performed a treadmill test after a 2-week period of no therapy, and the treadmill test was repeated at the end of 2 weeks of sarpogrelate treatment. Dietary and smoking habits were not changed during the study.

Treadmill exercise testing 

Symptom-limited graded treadmill exercise testing was performed with the use of standard Bruce protocol.12 A 12-lead electrocardiogram was recorded at rest and at 1-minute intervals until the onset of limiting chest pain, leg fatigue, or ≥0.2 mV ST-segment depression. Blood pressure was measured with a sphygmomanometer during each minute of exercise and recovery. Time to 0.1-mV ST-segment depression was defined as the elapsed time from initiation of exercise to the occurrence of horizontal or downsloping 0.1-mV ST-segment depression measured at 80 ms after the J point. In this study, the heart rate and blood pressure at the onset of 0.1-mV ST-segment depression were measured to determine the ischemic threshold. All exercise tests and ST-segment evaluations were performed by investigators blinded to the results of coronary angiograms and treatment status.

Statistical analysis 

Data are expressed as mean ± SD. A 2-way analysis of variance by means of the Bonferroni method was carried out to investigate differences in treadmill test parameters, anginal attacks, specific activity scale score, and nitroglycerin usage between control and sarpogrelate treatment. Significance was designated at a P value of <.05.

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Results 

Analysis in all anginal patients 

Changes in anginal episode, the specific activity scale score, the time to the onset of 0.1-mV ST depression, and the double product at 0.1-mV ST depression are shown in Figure 1.

  • View full-size image.
  • Fig. 1. 

    Effects of 2-week treatment with sarpogrelate on number of anginal attacks (left top), specific activity scale score (right top), time to onset of 0.1-mV ST depression (left bottom), and double product at 0.1-mV ST depression (right bottom) in all 20 patients. Treatment with sarpogrelate increased the specific activity scale score and prolonged time to onset of 0.1-mV ST depression.

The number of anginal attacks was not significantly different during sarpogrelate treatment, but the specific activity scale score significantly increased during treatment with sarpogrelate. In treadmill tests, the exercise time to the onset of 0.1-mV ST depression was significantly prolonged by the treatment with sarpogrelate. The total exercise time (control vs sarpogrelate, 374 ± 116 vs 418 ± 133 seconds, P < .01) was also significantly increased by the sarpogrelate treatment. The double product at the onset of 0.1-mV ST depression was not significantly altered with the sarpogrelate treatment.

Subgroup analysis based on collateral circulation 

To evaluate the impact of collateral circulation on the efficacy of sarpogrelate treatment, data were analyzed in the 2 subgroups divided by the nature of collaterals. Specifically, the patients were divided into 2 groups according to the degree of perfusion of the ischemia-related coronary artery: Group A (n = 8) patients had TIMI grade 0 or 1 flow and Rentrop collateral index 2 or 3; group B (n = 12) had TIMI grade 2 or 3 flow and Rentrop collateral index 0 or 1. The clinical and angiographic characteristics of the patients are listed in Table I.

Table I. Clinical and angiographic data of the patients with angina pectoris
Subgroups
TotalGroup AGroup B
No.20812
Male/female14/65/39/3
Age (y)67 ± 666 ± 768 ± 6
Ischemia-related artery (n)
RCA844
LAD835
LCx413
Multivessel disease (%)555058
Ejection fraction (%)72 ± 769 ± 674 ± 7

Data are presented as mean ± SD. Group A, Patients with well-developed collateral circulation; Group B, patients with severely stenosed ischemia-related coronary arteries; RCA, right coronary artery, LAD, left anterior descending coronary artery, LCx, left circumflex coronary artery.

There were no significant differences in age or male-to-female distribution between groups A and B. Approximately half of the patients in each group had multivessel disease. The left ventricular ejection fraction was not significantly different between the 2 groups.

The number of anginal attacks and specific activity scale score during the 2-week control and 2-week sarpogrelate treatment periods are summarized in Figure 2.

  • View full-size image.
  • Fig. 2. 

    Effects of 2-week treatment with sarpogrelate on number of anginal attacks (left panel) and on specific activity scale score (right panel). Group A, Patients with well-developed collateral circulation; Group B, patients with severely stenosed, ischemia-related coronary arteries.

In group A, which included patients with well-developed collaterals, anginal attacks significantly decreased (control vs sarpogrelate, 3.0 ± 2.8 vs 0.9 ± 1.1/2 weeks, P < .05) and the specific activity scale score significantly increased (5.2 ± 1.6 vs 6.2 ± 1.3 METS, P < .05) after the treatment with sarpogrelate. However, in group B, which included patients with severely stenosed ischemia-related coronary arteries, the sarpogrelate treatment did not significantly change the number of anginal attacks (4.2 ± 5.1 vs 4.3 ± 5.3/2 weeks, not significant [NS]) or the specific activity scale score (6.3 ± 1.3 vs 6.4 ± 1.2 METS, NS). Nitroglycerin usage tended to be decreased after sarpogrelate treatment in group A (1.6 ± 1.9 vs 0.3 ± 0.5/2 weeks, P = .09), but it was not significantly changed in group B (0.3 ± 0.7 vs 0.5 ± 1.0/2 weeks, NS).

Treadmill exercise data in subgroups of patients are shown in Figure 3.

  • View full-size image.
  • Fig. 3. 

    Effects of 2-week treatment with sarpogrelate on time to onset of 0.1-mV ST depression (left panel) and on double product at 0.1-mV ST depression (right panel). Group A, Patients with well-developed collateral circulation; Group B, patients with severely stenosed ischemia-related coronary arteries.

In group A, sarpogrelate increased the time to the onset of 0.1-mV ST depression during the treadmill exercise from 235 ± 84 to 295 ± 127 seconds (P < .05). The total treadmill exercise time was also significantly increased from 346 ± 145 to 407 ± 165 seconds (P < .01) in patients in group A. In contrast, in group B, both the time to the onset of 0.1-mV ST depression (260 ± 82 vs 275 ± 101 seconds, NS) and the total exercise time (393 ± 94 vs 425 ± 114 seconds, NS) remained unchanged despite the 2-week treatment with sarpogrelate. The double product at 0.1-mV ST depression during exercise increased significantly after the treatment with sarpogrelate in group A (19.0 ± 5.6 vs 21.9 ± 7.4 × 103 mm Hg beats/min, P < .05); however, in group B the double product at 0.1-mV ST depression was not significantly changed after sarpogrelate (24.4 ± 5.2 vs 23.8 ± 6.7 × 103 mm Hg beats/min, NS).

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Discussion 

This study confirms our previous investigation6 that treadmill exercise capacity is improved by sarpogrelate in patients having chronic stable angina and a well-developed collateral circulation. In addition, the current study indicates the therapeutic efficacy of sarpogrelate treatment for these patients. Sarpogrelate administered 3 times a day achieves symptomatic amelioration of myocardial ischemic episodes, especially in anginal patients with well-developed collaterals.

Serotonin blocker and coronary collateral circulation 

In the previous study,6 we have demonstrated that a serotonin blocker, sarpogrelate, alleviates exercise-induced myocardial ischemia possibly by attenuating the effects of serotonin on coronary collateral vessels. Recently, Kyriakides et al13 reported that another intravenously injected serotonin blocker, ketanserin, also augments coronary collateral blood flow during acute coronary occlusion by an angioplasty balloon in patients with effort angina. From these observations that serotonin blockers attenuate the effects of serotonin on coronary collateral vessels, it is likely that platelet activation, and the resultant serotonin production and release in a coronary artery proximal to the origin of collateral vessels, has the potential to decrease blood flow to the collateral dependent myocardium by causing collateral vasoconstriction.5

Effects of sarpogrelate on patients with collaterals 

It is interesting to note that the beneficial effects of sarpogrelate on anginal symptoms and daily physical activities were apparent in patients with a well-developed collateral circulation. Both the time to the onset of ischemia during exercise and total exercise time were significantly prolonged after sarpogrelate in these patients. These findings lead us to speculate that a serotonin blocker, sarpogrelate, augments collateral circulation in patients with well-developed collateral vessels and improved ischemic threshold during physical activity. In the current study, the double product at the onset of 0.1-mV ST depression was used as a reliable index of coronary blood flow reserve to the potentially ischemic myocardium. This was based on the observation by Waters et al14 that in patients with chronic effort angina the double product at the onset of ischemia remains relatively constant in repeated exercise testing despite a considerable variability in exercise time to the onset of ischemia. In our patients with well-developed collateral vessels, sarpogrelate increased the double product at 0.1-mV ST depression by 15%. These findings suggest an increase in blood flow supply to the potentially ischemic collateral-dependent area, which resulted in the improved exercise capacity in our patients with a well-developed collateral circulation.

Effects of sarpogrelate on patients without collaterals 

The effects of the 2-week treatment with sarpogrelate were minimal, if any, in patients with no or poor collaterals. These findings imply that sarpogrelate did not dilate the highly stenotic ischemia-related coronary artery. There is a discrepancy between our findings and the recent report by Miyata et al,15 which documents the inhibition of serotonin-induced coronary artery spasm by sarpogrelate in a porcine model. The difference may be explained by the absence of intact vascular smooth muscle cells responsible for dealing with both serotonin and sarpogrelate at the site of the high grade stenosis in our patients.

Limitations 

We acknowledge that the major limitation of this study is the small number of patients. This may have contributed to the lack of statistical significance of some of the results. Second, we did not obtain direct evidence of the augmented flow reserve of the collateral circulation. Our previous study6 demonstrated that a single oral administration of sarpogrelate decreased the severity score of tetrofosmin myocardial scintigraphy in patients with a well-developed collateral circulation. Further studies are needed to determine whether chronic treatment with sarpogrelate improves exercise perfusion images. Third, the design of this study was not double-blind and placebo-controlled. The number of self-reporting anginal episodes may have been influenced by this study design. However, the order of treatment with and without sarpogrelate was randomized, and the exercise test and its analysis were performed by investigators who were blinded to the results of coronary angiograms and medication. Furthermore, the fact that significant changes in clinical and exercise variables were apparent in patients with well-developed collaterals suggests that the effects of sarpogrelate were not totally explained by the placebo effects. Finally, the safety issue could not be addressed in our small number of subjects. Studies with larger numbers of anginal patients are necessary to address the safety issue.

Conclusions 

Although our study was not placebo-controlled and double-blinded, the results suggest that treatment with sarpogrelate improves the daily physical activity and exercise capacity, with the amelioration of ischemic changes during exercise in patients with stable angina pectoris. In patients with a well-developed collateral circulation, the beneficial effects of sarpogrelate were even more apparent, with a possible augmentation of flow reserve of the collateral circulation. These data suggest that sarpogrelate may have a role in the treatment of angina in patients with extensive disease and extensively developed collaterals. Because other antianginal medications were withdrawn from the patients, the additional benefit of sarpogrelate with conventional antianginal therapy remains undetermined. Further study will be necessary to clarify the efficacy of additive sarpogrelate treatment in anginal patients treated with conventional antianginal medications.

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References 

  1. Takeda Y, Takeda A, Urano T. MCI-9042, the new selective antagonist of serotonergic (5-HT2A) receptors. Cardiovasc Drug Rev. 1997;15:101–121
  2. Maruyama K, Kinami J, Sugita Y, et al.  MCI-9042: high affinity for serotonergic receptors as assessed by radioligand binding assay. J Pharmacobiodyn. 1991;14:177–181
  3. Nishio H, Inoue A, Nakata Y. Binding affinity of sarpogrelate: a new antiplatelet agent, and its metabolite for serononin receptor subtype. Arch Intern Pharmacodyn Ther. 1996;331:189–202
  4. Kikumoto R, Hara H, Ninomiya K, et al.  Syntheses and platelet aggregation inhibitory and antithrombotic properties of [2-[(omega-aminoalkoxy)phenyl]ethyl]benzenes. J Med Chem. 1990;33:1818–1823
  5. Wright L, Homans DC, Laxson DD, et al.  Effect of serotonin and thromboxane A2 on blood flow through moderately well developed coronary collateral vessels. J Am Coll Cardiol. 1992;19:687–693
  6. Tanaka T, Fujita M, Nakae I, et al.  Improvement of exercise capacity by sarpogrelate as a result of augmented collateral circulation in patients with effort angina. J Am Coll Cardiol. 1998;32:1982–1986
  7. Ogawa S, Suzuki H, Shiotani M, et al.  A randomized clinical trial of sarpogrelate hydrochloride for neuropathic pain in patients with post-herpetic neuralgia and reflex sympathetic dystrophy. Pain Clinic. 1998;11:125–132
  8. Otake T, Ieshima H, Ishida H, et al.  Bone atrophy in complex regional pain syndrome patients measured by microdensitometry. Can J Anaesth. 1998;45:831–838
  9. TIMI Study Group . The thrombolysis in myocardial infarction (TIMI) trial: phase I findings. N Engl J Med. 1985;312:932–936
  10. Rentrop KP, Cohen M, Blanke H, et al.  Changes in collateral filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. J Am Coll Cardiol. 1985;5:587–592
  11. Miyagi K, Asanoi H, Ishizaka S, et al.  Importance of total leg muscle mass for exercise intolerance in chronic heart failure. Jpn Heart J. 1994;35:15–26
  12. Bruce RA, Hornsten TR. Exercise stress testing in evaluation of patients with ischemic heart disease. Prog Cardiovasc Dis. 1969;11:371–390
  13. Kyriakides ZS, Sbarouni E, Nikolaou N, et al.  Intracoronary ketanserin augments coronary collateral blood flow and decreases myocardial ischemia during balloon angioplasty. Cardiovasc Drug Ther. 1999;3:415–422
  14. Waters DD, McCans JL, Crean PA. Serial exercise testing in patients with effort angina. Variable tolerance, fixed threshold. J Am Coll Cardiol. 1985;6:1011–1015
  15. Miyata K, Shimokawa H, Higo T, et al.  Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model. J Cardiovasc Pharmacol. 2000;35:294–301

☆ Supported by “Research for the Future” Program (JSPS-RFTF 99 I 00201) from the Japan Society for the Promotion of Science and a Grant-in-Aid for Scientific Research, 10557067, from the Ministry of Education, Science, and Culture, Tokyo, Japan.

☆☆ Reprint requests: Masatoshi Fujita, MD, College of Medical Technology, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

★ E-mail: mfujita@kuhp.kyoto-u.ac.jp

PII: S0002-8703(02)00076-5

doi:10.1067/mhj.2002.124056

American Heart Journal
Volume 144, Issue 2 , Page E1, August 2002

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