Current perioperative management of anticoagulant and antiplatelet use in neuroendovascular therapy: analysis of JR-NET1 and 2.

To evaluate current perioperative antithrombotic management in neuroendovascular therapy in Japan, we analyzed perioperative anticoagulant and antiplatelet use in various procedures and examined their relationships with periprocedural adverse events. Patient's data from nationwide surveys administered by the Japanese Registry of Neuroendovascular Therapy (JR-NET) between January 2005 and December 2007 (JR-NET1) and January 2008 and December 2009 (JR-NET2) were retrospectively analyzed. Compared to JR-NET1, the frequency of perioperative antiplatelet therapy and dual or triple therapy were increased for either aneurysm coiling and percutaneous transluminal angioplasty or stenting in JR-NET2. Although ischemic complications were significantly decreased (4.2% vs. 2.1%, p < 0.001), hemorrhagic complications (2.1% vs. 5.3%, p < 0.001), severe adverse events (1.5% vs. 2.1%, p < 0.001), and total perioperative complications (8.3% vs. 10.3%, p < 0.001) were significantly increased in JR-NET2. The rate of hemorrhagic complications was significantly higher in patients with triple or more perioperative antiplatelet therapy (preoperative: 5.3% vs. 9.2%, p < 0.0001, postoperative: 5.7% vs. 12.7%, p < 0.0001). Perioperative antithrombotic therapy was performed more frequently and intensively in neuroendovascular therapy in Japan. While ischemic complications were decreased, hemorrhagic complications and severe adverse events were increased. These results suggest that intensive antithrombotic therapy has a potential risk of hemorrhagic complications for Japanese patients.

Introduction

Anticoagulants and antiplatelet agents are widely prescribed to lower the rate of perioperative thromboembolic events in neuroendovascular treatments. Endovascular procedures are associated with a risk of immediate or delayed thromboembolic and ischemic complications. At the site of flow stagnation in catheters, a red thrombus consisting of red blood cells and fibrin can form due to activation of coagulation, which is preventable with anticoagulants such as heparin. Thus, use of perioperative anticoagulants represents a critical management strategy in endovascular therapy. However, anticoagulants cannot prevent formation of platelet-rich white thrombi. For example, carotid artery stenting (CAS) can cause intimal injury of the arterial vessel, and implanted thrombogenic foreign devices may trigger activation of platelets and subsequent formation of white thrombi. Antiplatelet agents are essential to prevent thrombotic ischemic event by such mechanism. Dual antiplatelet therapy for at least four days prior to surgery is currently recommended by five academic societies in the United States as perioperative antithrombotic treatment at the time of CAS.[1)] Aneurysm coiling or parent artery occlusion requires thrombosis of the aneurysmal sac for complete obliteration. Immature embolization of the aneurysmal sac, protrusion of coils, or balloon-assisted maneuvers may lead to acute thrombus formation by platelet activation. Antiplatelet therapy prior to procedures has been shown to lower thromboembolic complications in elective coil embolization of cerebral aneurysms.[2)] While perioperative antithrombotic therapy can reduce ischemic complications, there is a potential risk of hemorrhagic complications. Although several antithrombotic therapeutic options are available, optimized management in neuroendovascular therapy is not well defined. Appropriate antiplatelet agents, anticoagulants, dosing, and duration of treatment have not been adequately determined.

To evaluate current perioperative antithromobotic management in neuroendovascular therapy, we retrospectively analyzed patient's data from two Japanese Registry of Neuroendovascular Therapy (JR-NET) studies.

Methods

Study population

JR-NET1 and 2 are retrospective surveys conducted between January 2005 and December 2007 and January 2008 and December 2009, respectively, in Japan regarding neuroendovascular therapy. A total of 23,757 patients registered in JR-NET1 and 2 who received perioperative antithrombotic therapy were retrospectively analyzed for the following parameters: aneurysm coiling (n = 3,902 in JR-NET1, n = 7,723 in JR-NET2), parent artery occlusion for dissecting aneurysm (n = 313 in JR-NET1, n = 818 in JR-NET2), percutaneous transluminal angioplasty (PTA) or stenting of the external carotid artery (n = 2,013 in JR-NET1, n = 5,462 in JR-NET2), extracranial artery (n = 563 in JR-NET1, n = 615 in JR-NET2), or intracranial artery (n = 400 in JR-NET1, n = 647 in JR-NET2), or recanalization therapy for acute stroke (n = 504 in JR-NET1, n = 797 in JR-NET2). Patients with incomplete medical records were excluded from analysis (lack of detailed information: n = 1,304; classification mistake: n = 793, others: n = 8).

To determine the relationship between antithrombotic therapy and perioperative complications, the rates of ischemic, hemorrhagic, and groin-site complications for each procedure in patients from the JR-NET2 survey were calculated. Ischemic and hemorrhagic complications were defined as procedure-related intracranial complications within 24 hours following a procedure. Severe adverse events were defined as death or severe disability with a deterioration of ≥ 2 points based on the modified Rankin scale 30 days after a procedure.

Statistics

The chi-square test was used for two-group analyses between JR-NET1 and JR-NET2. The impact of each variable on four perioperative complications (ischemic, hemorrhagic, groin-site hematoma, and severe adverse events) was determined by multivariate logistic regression analysis. All statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, Illinois, USA).

Results

Comparison of perioperative antithrombotic therapy between JR-NET1 and 2

In aneurysm coiling, including ruptured and unruptured coiling and parent artery occlusion with coils, we reviewed perioperative antithrombotic therapy and compared the results of JR-NET1 and JR-NET2 surveys (Table 1). Compared to JR-NET1, preoperative antiplatelet therapy was more frequently performed in JR-NET2 patients (5.9% vs. 13.4% in the ruptured group, p < 0.001; 71.2% vs. 84.5% in the unruptured group, p < 0.001). The frequency of dual therapy was also higher (1.4% vs. 3.4% in the ruptured group, p < 0.001; 23.0% vs. 46.6% in the unruptured group, p < 0.001). Regarding postoperative anticoagulants, use of heparin therapy was decreased and argatroban therapy was increased in both the ruptured and unruptured groups. The most frequently used postoperative antiplatelet therapy for ruptured aneurysm was mono therapy with aspirin, this result was the same also in JR-NET1 and 2. For the unruptured aneurysm, the most frequently used preoperative antiplatelet regimen changed from aspirin mono therapy (40% in JR-NET1) to dual therapy with aspirin-clopidogrel or aspirin-cilostazol (27.5% and 14.7%, respectively, in JR-NET2) (Table 2).

Table 1

Antithrombotic therapy in aneurysm coiling

Variables	Ruptured n (%)		p value	Unruptured n (%)		p value
	JR-NET1	JR-NET2		JR-NET1	JR-NET2
Total number of patients	n = 2,004	n = 3,978		n = 2,211	n = 4,563
Pre-AP
Yes	119 (5.9%)	532 (13.4%)	< 0.001	1,574 (71.2%)	3,857 (84.5%)	< 0.001
Mono	90 (4.5%)	384 (9.7%)	< 0.001	1,033 (46.7%)	1,566 (34.3%)	< 0.001
Dual	27 (1.4%)	137 (3.4%)	< 0.001	509 (23.0%)	2,128 (46.6%)	< 0.001
Triple	0 (0%)	4 (0.1%)	0.373	2 (0.1%)	30 (0.7%)	< 0.01
None	1,624 (81.0%)	3,290 (82.7%)	0.112	523 (23.7%)	536 (11.7%)	< 0.001
Unknown	261 (13.0%)	89 (2.2%)	< 0.001	114 (5.2%)	80 (2.0%)	< 0.001
Post-AP
Yes	–*	2,175 (54.7%)		–*	3,863 (84.7%)
Mono	–*	1,749 (44.0%)		–*	1,837 (40.3%)
Dual	–*	318 (8.0%)		–*	1,650 (36.2%)
Triple	–*	25 (0.6%)		–*	236 (5.2%)
None	–*	1,574 (39.6%)		–*	560 (12.3%)
Unknown	–*	162 (4.1%)		–*	50 (1.1%)
Post-AC
Yes	–*	1,659 (41.7%)		–*	2,997 (65.7%)
Heparin	356 (17.8%)	477 (12.0%)	< 0.001	808 (36.5%)	1,264 (27.7%)	< 0.001
Argatroban	313 (15.6%)	712 (17.9%)	< 0.05	658 (29.8%)	1,868 (40.9%)	< 0.001
Ozagrel	423 (21.1%)	536 (13.5%)	< 0.001	78 (3.5%)	104 (2.3%)	< 0.01
None	–*	2,118 (53.2%)		–*	1,391 (30.4%)
unknown	–*	134 (3.4%)		–*	85 (1.9%)

Indicates postoperative antithrombotic therapy data that were not provided in the JR-NET survey. AC: anticoagulant, AP: anti-platelet, JR-NET: Japanese Registry of Neuroendovascular Therapy.

Table 2

Antiplatelet agent use in aneurysm coiling

	Ruptured		p value	Unruptured		p value
	JR-NET1	JR-NET2		JR-NET1	JR-NET2
Preoperative
Mono therapy
Aspirin	78 (3.9%)	327 (8.2%)	< 0.001	885 (40.0%)	1,013 (22.2%)	< 0.001
Ticlopidine	5 (0.3%)	5 (0.1%)	0.269	107 (4.8%)	31 (0.68%)	< 0.001
Cilostazol	1 (0.1%)	19 (0.5%)	< 0.05	35 (1.6%)	61 (1.3%)	0.422
Clopidogrel	0	31 (0.8%)	< 0.001	5 (0.2%)	460 (10.1%)	< 0.001
Others	6 (0.3%)	2 (0.1%)	< 0.05	1 (0.1%)	1 (0.0%)	0.818
Dual therapy
ASA-TCL	14 (0.7%)	9 (0.2%)	< 0.01	274 (12.4%)	113 (2.5%)	< 0.001
ASA-CLP	4 (0.20%)	85 (2.1%)	0.054	51 (2.3%)	1,253 (27.5%)	< 0.001
ASA-CSZ	9 (0.45%)	36 (0.9%)	< 0.001	180 (8.1%)	672 (14.7%)	< 0.001
CSZ-CLP	0 (0%)	7 (0.2%)	0.139	0 (0%)	81 (1.8%)	< 0.001
Others	0	0		4 (0.2%)	9 (1.7%)	0.879
Postoperative
Mono therapy
Aspirin	201 (10.0%)	1,259 (31.6%)	< 0.001	229 (10.4%)	1,319 (28.9%)	< 0.001
Ticlopidine	16 (0.8%)	16 (0.4%)	< 0.05	57 (2.6%)	35 (0.8%)	< 0.001
Cilostazol	34 (1.7%)	298 (7.5%)	< 0.001	12 (0.5%)	157 (3.4%)	< 0.001
Clopidogrel	1 (0.1%)	172 (4.3%)	< 0.001	2 (0.1%)	323 (7.1%)	< 0.001
Others	–*	4 (0.1%)		–*	3 (0.1%)
Dual therapy
ASA-TCL	28 (1.4%)	26 (0.7%)	< 0.001	250 (11.3%)	105 (2.3%)	< 0.001
ASA-CLP	32 (1.60%)	126 (3.2%)	< 0.001	253 (11.4%)	535 (11.7%)	0.734
ASA-CSZ	2 (0.10%)	147 (3.7%)	< 0.001	29 (1.3%)	928 (20.3%)	< 0.001
CSZ-CLP	0 (0%)	12 (0.3%)	< 0.05	1 (0.1%)	68 (1.5%)	< 0.001
Others	–*	7 (1.31%)		–*	14 (2.6%)

Indicates postoperative antiplatelet therapies that were not mentioned in the JR-NET1 survey. ASA: aspirin, CSZ: cilostazol, JR-NET: Japanese Registry of Neuroendovascular Therapy, TCL: ticlopidine.

Next, we reviewed perioperative antithrombotic therapy in PTA or stenting, including PTA or stenting of the external carotid artery (CAS), extracranial artery, or intracranial artery, and compared the results of JR-NET1 and JR-NET2 surveys (Table 3). The frequency of preoperative antiplatelet therapy was not significantly different between JR-NET1 and JR-NET2 (96.6% and 96.3%, respectively, p = 0.474). However, compared to JR-NET1, the mono therapy frequency was significantly decreased (17.2% vs. 6.6%, p < 0.001) and dual or triple therapy was significantly increased (74.8% vs. 84.5%, p < 0.001) in JR-NET2. Regarding postoperative anticoagulants, use of heparin therapy was decreased (37.8% vs. 21.8%, p < 0.001) in JR-NET2 compared to JR-NET1.

Table 3

Antithrombotic therapy in PTA or stenting

Variables	PTA or stenting		p value
	JR-NET1	JR-NET2
Total number of patients	n = 2,976	n = 6,724
Pre-AP
Yes	2,834 (96.6%)	6,473 (96.3%)	0.474
Mono	514 (17.2%)	446 (6.6%)	< 0.001
Dual	2,090 (70.2%)	5,080 (75.6%)	< 0.001
Triple	137 (4.6%)	598 (8.9%)	< 0.001
None	116 (3.9%)	62 (0.9%)	< 0.001
Unknown	26 (0.9%)	189 (2.8%)	< 0.001
Post-AP
Yes	–*	6,519 (97.0%)
Mono	–*	382 (5.7%)
Dual	–*	5,229 (78.9%)
Triple	–*	567 (8.4%)
None	–*	27 (0.4%)
Unknown	–*	178 (2.6%)
Post-AC
Yes	–*	4,051 (60.2%)
Heparin	1,125 (37.8%)	1,468 (21.8%)	< 0.001
Argatroban	1,086 (36.5%)	2,570 (38.2%)	0.105
Ozagrel	97 (3.3%)	192 (2.9%)	0.281
None	–*	2,399 (35.7%)
Unknown	–*	274 (4.1%)

Indicates postoperative antithrombotic therapy data that were not described in the JR-NET1 survey. AP: antiplatelet, AC: anticoagulant, JR-NET: Japanese Registry of Neuroendovascular Therapy, PTA: percutaneous transluminal angioplasty.

The most frequently used preoperative antiplatelet regimen changed from aspirin-ticlopidine (44% in JR-NET1) to aspirin-clopidogrel dual therapy (36.6% in JR-NET2) (Table 4).

Table 4

Antiplatelet agents used in PTA or stenting

	PTA or stenting		p value
	JR-NET1	JR-NET2
	n = 2,976	n = 6,724
Preoperative
Mono therapy
Aspirin	281 (9.4%)	169 (2.5%)	< 0.001
Ticlopidine	133 (4.5%)	34 (0.5%)	< 0.001
Cilostazol	71 (2.4%)	65 (1.0%)	< 0.001
Clopidogrel	11 (0.4%)	130 (1.9%)	< 0.001
Others	21 (0.7%)	7 (0.1%)	< 0.001
Dual therapy
ASA-TCL	1,308 (44.0%)	697 (10.4%)	< 0.001
ASA-CLP	128 (4.3%)	2,462 (36.6%)	< 0.001
ASA-CSZ	590 (19.8%)	1,352 (20.1%)	0.749
CSZ-CLP	6 (0.2%)	505 (7.5%)	< 0.001
Others	58 (1.9%)	83 (1.2%)	< 0.01
Postoperative
Mono therapy
Aspirin	48 (1.6%)	170 (2.5%)	< 0.01
Ticlopidine	33 (1.1%)	19 (0.3%)	< 0.001
Cilostazol	11 (0.4%)	71 (1.1%)	< 0.001
Clopidogrel	5 (0.2%)	121 (1.8%)	< 0.001
Others	–*	14 (0.2%)
Dual therapy
ASA-TCL	1,217 (40.9%)	1,022 (15.2%)	< 0.001
ASA-CLP	120 (4.0%)	2,608 (38.8%)	< 0.001
ASA-CSZ	590 (19.8%)	1,354 (20.1%)	< 0.001
CSZ-CLP	10 (0.3%)	472 (7.0%)	< 0.05
Others	–*	281 (4.2%)

Indicates postoperative antiplatelet therapies that were not mentioned in the JR-NET1 survey. ASA: aspirin, CSZ: cilostazol, JR-NET: Japanese Registry of Neuroendovascular Therapy, PTA: percutaneous transluminal angioplasty, TCL: ticlopidine.

Relationship between perioperative antithrombotic therapy and complications

Perioperative complication rates were compared between 7,695 JR-NET1 patients and 16,062 JR-NET2 patients. Ischemic complications were significantly decreased (4.2% vs. 2.1%, p < 0.001), whereas hemorrhagic complications (2.1% vs. 5.3%, p < 0.001) and severe adverse events (1.5% vs. 2.1%, p < 0.001) were significantly increased. The rate of groin-site complications was similar between the two groups (0.6% vs. 0.7% p = 0.219). The incidence of all perioperative complications was significantly higher in JR-NET2 patients compared to JR-NET1 (8.3% vs. 10.3%, p < 0.001).

Next, we evaluated the relationship between perioperative antithrombotic therapy and complications from the JR-NET2 survey. For postoperative anticoagulant therapy, ischemic complications in patients treated with postoperative anticoagulant therapy were significantly higher [6.3% vs. 3.5%, odds ratio (OR) 2.23, (95% confidence interval, CI 2.48–7.02), p < 0.001], particularly with argatroban or ozagrel, and hemorrhagic complications were significantly lower (1.2% vs. 3.6%, OR 0.675 [95% CI 0.42–1.07], p < 0.001 in univariate and p = 0.098 in multivariate analyses) (Table 5). The rate of groin-site complications was similar between the patients treated with and without postoperative anticoagulant therapy (0.7% vs. 0.6%, p = 0.483). The rate of severe adverse events was significantly higher in patients who were not treated with post-operative anticoagulant therapy (2.7% vs. 1.8%, OR 4.172 [95% CI 2.478–7.023], p < 0.01).

Table 5

Relationship between postoperative anticoagulants and complications

Variables	Anticoagulant		p value	Heparin		p value	Argatroban		p value	Ozagrel		p value
	Used	Not used		Used	Not used		Used	Not used		Used	Not used
Total number of patients	9,312	6,060		3,609	11,741		5,353	9,997		885	14,465
Ischemic complications	587 (6.3%)	212 (3.5%)	< 0.001	191 (5.3%)	604 (5.2%)	0.762	416 (7.8%)	383 (3.8%)	< 0.001	71 (8.0%)	728 (5.0%)	< 0.001
Hemorrhagic complications	109 (1.2%)	216 (3.6%)	< 0.001	39 (1.1%)	286 (2.4%)	< 0.001	54 (1.0%)	271 (2.7%)	< 0.001	20 (2.3%)	305 (2.1%)	0.754
Groin-site complications	69 (0.7%)	39 (0.6%)	0.482	27 (0.7%)	81 (0.7%)	0.705	48 (0.9%)	60 (0.6%)	< 0.05	4 (0.5%)	104 (0.7%)	0.477
Severe adverse events	172 (1.8%)	162 (2.7%)	< 0.01	67 (1.9%)	267 (2.3%)	0.138	101 (1.9%)	233 (2.3%)	0.077	30 (3.4%)	304 (2.1%)	< 0.05

For preoperative antiplatelet therapy, ischemic complications (4.0% vs. 1.2%, p < 0.0001) and severe adverse events (3.8% vs. 1.4%, p < 0.0001) were significantly higher in patients who were not treated with antiplatelet therapy compared to patients with antiplatelet therapy. Hemorrhagic (9.2% vs. 5.3%, p < 0.0001) and groin-site complications (2.4% vs. 0.6%, p < 0.0001) were significantly higher in patients treated with three or more antiplatelet agents compared to other patients. The rate of ischemic complications decreased based on the number of preoperative antiplatelet agents used (4.0%, 1.9%, 1.0%, and 0.6% for no treatment and mono, dual, and triple therapy, respectively), and the rate of hemorrhagic complications increased based on the number of postoperative antiplatelet agents (3.6%, 4.7%, 5.4%, and 12.7% for no treatment and mono, dual, and triple therapy, respectively). Same results were obtained for postoperative antiplatelet therapy (Table 6).

Table 6

Relationship between perioperative complications and antiplatelet therapy

Preoperative antiplatelet therapy	None	Mono	Dual	≥ Triple
Number of patients	3,888	2,396	7,345	632
Ischemic	156 (4.0%)*	46 (1.9%)	75 (1.0%)	4 (0.6%)
Hemorrhagic	221 (5.7%)	132 (5.5%)	375 (5.1%)	58 (9.2%)*
Groin-site	8 (0.2%)	20 (0.8%)	57 (%0.8)	15 (2.4%)*
Severe adverse event	148 (13.8%)*	42 (1.8%)	95 (1.3%)	8 (1.3%)
Postoperative antiplatelet therapy	None	Mono	Dual	≥ Triple
Number of patients	606	4,124	7,340	844
Ischemic	179 (6.9%)*	88 (2.1%)	46 (0.6%)	6 (0.7%)
Hemorrhagic	93 (3.6%)	195 (4.7%)	395 (5.4%)	107 (12.7%)*
Groin-site	8 (0.3%)	22 (0.5%)	60 (0.8%)	20 (2.4%)*
Severe adverse event	146 (5.6%)*	71 (1.7%)	100 (1.4%)	10 (1.2%)

Significant differences (p < 0.01) between variables with asterisks and the other three groups.

Discussion

Thromboembolic events appeared to be the most common adverse events in neuroendovascular therapy. Antithrombotic therapy is prescribed to lower the rate of thromboembolic complications. For aneurysm coiling, Yamada et al. reported that the rate of symptomatic thromboembolic complications was significantly lower in patients who received antiplatelet therapy (2% with and 16% without antiplatelet agents.[2)] For CAS, McKevitt et al.[3)] reported that dual antiplatelet therapy showed lower incidences of both ischemic complications (0% vs. 25%, respectively) and hemorrhagic complications (9% vs. 17%, respectively) compared to aspirin mono therapy plus anticoagulant therapy. Dalainas et al.[4)] also reported similar results. From the results of reported studies, it is convinced that dual (or more) antiplatelet therapy was more effective to prevent perioperative complications.

Although intensive antithrombotic therapy reduces the risk of ischemic complications, there are concerns that it may increase the risk of hemorrhagic complications. A prospective study on antiplatelet therapy for preventing thrombotic events in cerebrovascular patients showed that the rate of bleeding events was higher with dual than with single antiplatelet therapy.[5,6)] The bleeding with antithrombotic therapy (BAT) study in Japanese patients showed that the incidence of bleeding events was 2.0% in the dual antiplatelet therapy group compared to 1.21% in the single therapy group.[7)]

In the present study, we found that perioperative antithrombotic therapy has changed to be more frequently performed preoperatively with multiple agents in JR-NET2 compared to JR-NET1. In aneurysm coiling, preoperative antiplatelet therapy for coiling of unruptured aneurysm was shifted to dual antiplatelet therapy. We can speculate that this result may be influenced by introduction of new techniques, such as balloon assist techniques or stent assist techniques. Such complicated procedures increase the risk of thromboembolic complications or severe adverse events and require intensive antithrombotic therapy as preventative measures.[8)] In PTA and stenting, dual antiplatelet therapy had been widely recognized as the “gold standard.”[1)] The percentage of dual antiplatelet therapy was high enough in JR-NET1.

However, while ischemic complications significantly decreased, hemorrhagic complications, severe adverse events, and total perioperative complications significantly increased in JR-NET2. The present study demonstrated several relationships between perioperative antithrombotic therapy and complications. For postoperative anticoagulant therapy, ischemic complication was significantly higher but hemorrhagic complication was significantly lower in patients treated with postoperative anticoagulant therapy. This inconsistency may be because treatment with postoperative anticoagulant therapy depends on the onset of intraoperative ischemic or hemorrhagic complications. The rate of severe adverse events was significantly higher in patients who were not treated with postoperative anticoagulant therapy. For perioperative antiplatelet therapy, although ischemic complications and severe adverse events were significantly higher in patients who were not treated with antiplatelet therapy, hemorrhagic and groin-site complications were significantly higher in patients treated with three or more antiplatelet agents. Japanese individuals tend to have a smaller physique than Westerners. We speculate that conventional antithrombotic therapy protocols may lead to overdose in Japanese patients. In particular, it was reported that there is a higher incidence of intracerebral hemorrhage in Asian patients compared to patients of other ethnicities.[9)]

This study has several limitations. It was conducted retrospectively and courses of treatment were decided independently at each facility. These two factors may have influenced complication rates. Because postoperative use of anticoagulants depends on the occurrence of intraoperative adverse events, the rate of ischemic complications in patients with postoperative anticoagulant therapy was higher, but the rate of hemorrhagic complications was lower. A prospective study should be performed to identify the actual effects of perioperative antithrombotic therapy on perioperative complications.

Conclusion

In the present study, perioperative antithrombotic therapy was shown to be more frequently performed using multiple agents in neuroendovascular therapy in Japan. Although the rate of ischemic complications was decreased, the rate of hemorrhagic complications or severe adverse events was increased. Caution should be taken when prescribing three or more antiplatelet agents due to an increased risk of hemorrhagic complications. Additional considerations regarding suitable antithrombotic agents, doses, and duration of perioperative antithrombotic therapy are necessary in Japanese patients.