JCS 2020 Guideline Focused Update on Antithrombotic Therapy in Patients With Coronary Artery Disease

I. Introduction

In 2019, the Japanese Circulation Society published 2 guidelines in the field of coronary artery disease (CAD): (1) a guideline for acute coronary syndrome (ACS) that integrated guidelines for ST-elevation acute myocardial infarction, non-ST-elevation ACS (NSTE-ACS), and secondary prevention for myocardial infarction, and (2) guideline for revascularization of stable CAD by coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI).^1,2 These guidelines were substantially revised to reflect the latest evidence, but after publication of the revised guidelines, important new evidence was reported and new concepts have been established. In particular, important evidence has accumulated about antithrombotic therapy after PCI that is directly related to daily clinical practice. Therefore, we are providing an update focusing on this area without waiting for the next revision of the entire guideline. Because the risk of bleeding events is higher and the risk of thrombotic events is lower in East Asian patients, the risk/benefit balance between thrombosis and bleeding in East Asian patients is suggested to be different from that in other populations.^3,4 In fact, lower-dose antithrombotic therapy is recommended in East Asia compared with Western countries, and a lower target value for the international standardized ratio of prothrombin time (PT-INR) is also recommended for elderly patients. For these reasons, extrapolation of evidence from the USA and Europe requires careful consideration, and verification by assessment in clinical practice in Japan is always necessary. In this regard, the present update includes clinical trials performed in Japan and the data from these trials played a major role in the preparation of the guideline update. This guideline update also covers patients who are managed conservatively with drug therapy, in addition to those who have undergone reperfusion therapy and coronary revascularization.

The main features of this update are as follows.

1. A consensus document by the Academic Research Consortium (ARC) on high bleeding risk (HBR) for patients who are candidates for treatment with a coronary stent was published simultaneously in Circulation and the European Heart Journal in April 2019.^5,6 We have adopted this consensus document as a guide for treatment strategies.

2. In addition, based on the ARC-HBR definition,^5,6 a “Japanese version of the HBR criteria” has been proposed by consensus for this guideline update.

3. Antithrombotic therapy for CAD in general is considered by combining guidelines for ACS and stable CAD. In addition, in order to provide more practical assistance, the items have been arranged in chronological order to correspond with actual clinical practice.

4. A simple flowchart that covers the essential items has been developed.

5. New directions related to preoperative suspension of antithrombotic therapy, an important issue in this field, have been established.

The previous guidelines adopted the dual antiplatelet therapy (DAPT) score as a method for assessing bleeding risk in both ACS and stable CAD, but there was insufficient evidence to support this in Japan. In East Asia, the risk of bleeding is estimated to be higher and the recently reported HBR concept seems to be more practically important than in the USA and Europe. There are also reports that support the application of the HBR concept in Japanese patients.^7,8 For these reasons, we have adopted the HBR concept^5,6 as a basic strategy. In addition, a Japanese version of the HBR criteria that takes into account risk factors such as low body weight, frailty, heart failure, and dialysis was proposed by consensus among the guideline development team. We concluded that the additional risk factors are characteristics with relevant evidence for Japan and are of great clinical importance because of their high prevalence.

A new clinical concept of chronic coronary syndrome (CCS) in place of stable CAD was presented at the 2019 European Society of Cardiology meeting, and a new guideline for this concept has been issued by the Society.⁹ The new concept emphasizes that ACS and CCS should be viewed as a continuous spectrum rather than as separate diseases. Because it is a rational and practical concept, we have decided to accept it. However, in consideration of possible confusion caused by changing the name of the guideline last year, we decided not to adopt it at this time.

Compared with the previous guideline, the levels of recommendation and descriptions have been partially revised in light of the new evidence. Among the recommended classes, Class III is classified as non-benefit or harm from the clinical viewpoint (Table 1).

Table 1. Classifications and Evidence Levels

Class of Recommendation (COR)
I	There is evidence and/or general agreement that a given procedure or treatment is effective and/or useful.
II	There is conflicting evidence and/or a divergence of opinion about the efficacy/usefulness of a given procedure or treatment.
IIa	There is a high probability of efficacy/usefulness based on evidence and opinion.
IIb	Effectiveness/usefulness is not well established based on evidence and opinion.
III	There is evidence and/or general agreement that the procedure or treatment is not effective and/or useful, or may even be harmful.
III No benefit	There is evidence and/or general agreement that the procedure or treatment is not effective and/or useful.
III Harm	There is evidence and/or general agreement that the procedure or treatment is harmful.
Level of Evidence (LOE)
A	Demonstrated by multiple randomized clinical trials or meta-analysis.
B	Demonstrated by a single randomized clinical trial or large non-randomized studies.
C	Consensus from expert opinion and/or small clinical trials (including retrospective studies and case series).

In order to cover the whole area related to antithrombotic therapy in this update, important statements in the previous guidelines have been partially duplicated in this focused update. However, the information on anticoagulants such as heparin has been omitted, because the content has not been changed.

The contents described cover the data and recommendations for standard patients and do not reflect variations in individual patients in daily clinical practice. In particular, antithrombotic therapy needs to be considered and adapted on the basis of the balance between the risk of bleeding events and thrombotic events. From this point of view, we would like users to read and understand the contents and apply them to clinical practice in an individualized manner instead of following the guidelines blindly. In addition, in areas where evidence is lacking, the broad consensus of experts has been included as appropriate.

II. Risk Assessment (Bleeding and Thrombotic Risks)

1. Clinical Need for Assessing Bleeding and Thrombotic Risks

Oral aspirin plus a thienopyridine antiplatelet agent proved to be effective for the prevention of stent thrombosis in the STARS trial.¹⁰ Since then, DAPT has become the standard of care after stent implantation, but the optimal duration of DAPT remains controversial. The DAPT study showed that long-term use of DAPT reduced the risks of myocardial infarction and stent thrombosis compared with aspirin monotherapy beyond 1 year after PCI.¹¹ On the other hand, long-duration DAPT is associated with increased bleeding and might increase mortality. A meta-analysis including data from this DAPT study also showed that long-duration DAPT significantly increased bleeding risk and mortality compared with short-duration DAPT.^12,13 In view of the fact that continued use of DAPT increases the risk of hemorrhagic complications, the optimal duration of DAPT is a trade-off between thrombosis prophylaxis and hemorrhagic complications. An optimal antithrombotic regimen is sought not only in terms of DAPT duration but also for post-PCI patients needing anticoagulant therapy. In such situations, the rational approach is not to set a uniform duration of DAPT for all patients, but to predict and assess bleeding and thrombotic risks in individual patients in order to select an appropriate tailored antithrombotic therapy, including DAPT duration. Risk-based stratification helps make decisions on antithrombotic regimen (Table 2).

Table 2. Use of Risk Scores as Guide for the Duration of Dual Antiplatelet Therapy (DAPT)

	COR	LOE
The use of risk scores designed to evaluate and stratify the bleeding and thrombosis risks should be considered in the choice of DAPT duration14,15,16	IIa	B

2. Scoring Systems Outside Japan for the Assessment of Bleeding Risk

Scoring systems for making a comprehensive judgment on DAPT duration have been developed outside Japan. The PRECISE-DAPT score seeks to predict the bleeding risk during DAPT, and is calculated before PCI from age, history of bleeding, white blood cell count, hemoglobin, and creatinine clearance (Ccr).⁵ The DAPT score, the classical version prior to PRECISE-DAPT, is intended for use during the chronic phase of therapy at 1 year post-PCI and is increased with smoking, diabetes mellitus, prior myocardial infarction, prior PCI, paclitaxel-eluting stent implantation, stent diameter <3 mm, heart failure or left ventricular ejection fraction (LVEF) <30%, and vein graft stent, whereas higher age decreases the score. The DAPT score simultaneously estimates both bleeding and thrombotic risk. Studies have shown that, in patients with higher DAPT scores, continued use of DAPT reduced death and cardiovascular events, including myocardial infarction and stroke, without increasing bleeding events (Table 3).^11,15,17 The DAPT score has also been reported to be applicable to Japanese patients.¹⁸ Of note, in the DAPT study that serves as the basis for calculating this score, patients who had bleeding events within the first year after PCI were excluded, and therefore this score is applicable only to low-risk patients who tolerated DAPT for 1 year after PCI. Prediction of risks for bleeding and thrombotic events immediately after PCI is more important than at ≥1 year after PCI, but enough evidence has not yet been obtained regarding this period. Therefore, care should be taken in applying those scoring systems developed outside Japan to Japanese clinical practice.

Table 3. PRECISE-DAPT Score and DAPT Score

	PRECISE-DAPT score	DAPT score
Timing of use	At the time of coronary stenting	After 12 months of uneventful DAPT
DAPT duration strategies assessed	Short DAPT (3–6 months) 　vs. Standard/long DAPT (12–24 months)	Standard (12–24 months) 　vs. Long DAPT (30 months)
Score calculation	Hemoglobin, white blood cells, age, creatinine clearance and prior bleeding events.	Age, cigarette smoking, diabetes mellitus, myocardial infarction at presentation, prior PCI or myocardial infarction, paclitaxel-eluting stent, stent diameter <3 mm, history of congestive heart failure or left ventricular ejection fraction <30% and stenting of vein graft.
Score range	0 to 100 points	−2 to 10 points
Decision making cut-off suggested	Score ≥25 → Short DAPT Score <25 → Standard/long DAPT	Score ≥2 → Long DAPT Score <25 → Standard DAPT
Web calculator	www.precisedaptscore.com

(Ref. Costa F, et al. 2017¹⁴ Yeh RW, et al, 2015¹⁷)

In addition to the DAPT and PRECISE-DAPT scores, there are various bleeding risk scoring systems from the PARIS Registry,¹⁹ ADAPT-DES study,²⁰ HORIZON AMI study,²¹ CRUSADE study,²² etc. The PARIS score derived from the PARIS Registry includes scores of not only bleeding risk but also thrombotic risk (Table 4). The common independent predictors of bleeding risk in those studies included chronic kidney disease (CKD), peripheral vascular disease, heart failure, and use of anticoagulants (or atrial fibrillation [AF]).

Table 4. Paris Risk Scores for Bleeding and Thrombotic Events

Risk Score for Major Bleeding Events		Risk Score for Coronary Thrombotic Event
Parameter	Score†	Parameter	Score‡
Age, yrs		Diabetes mellitus
<50	0	None	0
50–59	+1	Non-insulin-dependent	+1
60–69	+2	Insulin-dependent	+3
70–79	+3	Acute coronary syndrome
≥80	+4	No	0
BMI, kg/m2		Yes, Tn-negative	+1
<25	+2	Yes, Tn-positive	+2
25–34.9	0	Current smoking
≥35	+2	Yes	+1
Current smoking		No	0
Yes	+2	CrCl <60 mL/min
No	0	Present	+2
Anemia		Absent	0
Present	+3	Prior PCI
Absent	0	Yes	+2
CrCl <60 mL/min		No	0
Present	+2	Prior CABG
Absent	0	Yes	+2
Triple therapy on discharge		No	0
Yes	+2
No	0

^†Patients categorized as low (0–3), intermediate (4–7) or high (≥8) bleeding risk. ^‡Patients categorized as low (0–2), intermediate (3 or 4) or high (≥5) thrombotic risk. BMI, body mass index; CABG, coronary artery bypass graft; CrCl, creatinine clearance; MI, myocardial infarction; PCI, percutaneous coronary intervention; Tn, troponin. (Ref. Baber U, et al.¹⁹)

3. Scoring Systems Outside Japan for the Assessment of Thrombotic Risk

The scoring systems for short-term thrombotic risk include risk scores or prediction formulas from the CADILLAC study,²³ ACUITY-PCI study,²⁴ NCDR CathPCI,²⁵ and TIMI study.²⁶ The representative methods of evaluating long-term thrombotic risk after PCI are the DAPT score and PARIS score mentioned above. Although calculation of the DAPT score takes into account procedural factors such as stent diameter, the PARIS score uses only patient characteristics as predictors of post-discharge event risks, including ACS, diabetes mellitus, Ccr, prior coronary revascularization by PCI or CABG, and smoking.¹⁹ The predictors of stent thrombosis are also shown in the 2017 European Society of Cardiology (ESC) Guidelines (Table 5). However, the predictive ability of the individual factors is still unknown because the frequency of stent thrombosis has been extremely reduced.

Table 5. Risk Factors for Stent Thrombosis

• History of stent thrombosis with adequate antiplatelet therapy

• First-generation DES

• NSTEMI or STEMI

• Complex PCI (defined as composite of ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion)

• Diffuse lesion in diabetic patients

• CKD

CKD, chronic kidney disease; DES, drug-eluting stent; NSTEMI, Non-ST-elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; PCI, percutaneous coronary intervention. (Ref. Valgimigli M, et al.²⁷, Roffi M, et al.²⁸, Giustino G, et al.²⁹)

4. Scoring Systems From Japan for Risk Evaluation

The CREDO-Kyoto risk scores are proposed to identify patients at high risk of bleeding and thrombotic events using Japanese data (Table 6).¹⁶ These scores are based on data from the CREDO-Kyoto Registry Cohort-2³⁰ and were externally validated using data from the RESET³¹ and NEXT trials.³² CREDO-Kyoto risk scores evaluate thrombotic and bleeding risks separately. Thrombotic risk (0–12 points) is considered to be high when the score is ≥4 points, and bleeding risk (0–11 points) is high when the score is ≥3 points. The discriminatory power (area under the curve [AUC] value) of the CREDO-Kyoto risk scores for thrombotic and bleeding risks is moderate in the range of 0.6–0.75, which is comparable to the scoring systems developed outside Japan described above, but does not represent sufficient predictive ability.³³

Table 6. CREDO-Kyoto Thrombotic and Bleeding Risk Scores

A. Thrombotic Risk Score		B. Bleeding Risk Score
Variable	Points†	Variable	Points‡
Severe CKD	2	Low platelet (<100,000/μL)	2
AF	2	Severe CKD	2
PVD	2	PVD	2
Anemia (Hb <11 g/dL)	2	Heart failure	2
Age ≥75 years	1	Prior MI	1
Heart failure	1	Malignancy	1
Diabetes mellitus	1	AF	1
CTO	1
Total Score Range: 0–12		Total Score Range: 0–11

^†Patients were classified by thrombotic risk score as high ≥4 points, intermediate 2–3 points, or low 0–1 point. ^‡Patients were classified by thrombotic risk score high ≥3 points, intermediate 1–2 points, or low 0 point. Severe CKD indicates those on dialysis or with estimated glomerular filtration rate <30 mL/min/1.73 m². AF, atrial fibrillation; CKD, chronic kidney disease; CREDO-Kyoto, Coronary Revascularization Demonstrating Outcome Study in Kyoto; CTO, chronic total occlusion; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; Hb, hemoglobin; MI, myocardial infarction; PVD, peripheral vascular disease. (Ref. Natsuaki M, et al.¹⁶)

It was also suggested in the CREDO-Kyoto Registry that, in reality, DAPT duration was selected without considering the bleeding and thrombotic risks.¹⁶ By properly utilizing the scores for risk stratification, occurrence of those events might be reduced in the future.

Additionally, among Japanese patients, anemia is an important risk factor. An analysis of the pooled database of the CREDO-Kyoto Registry Cohort-2, the RESET and NEXT trials indicated that not only severe anemia but even mild anemia, which is defined as a hemoglobin level of 11.0–12.9 g/dL in men and 11.0–11.9 g/dL in women, was associated with bleeding and thrombotic risks.³⁴ Other studies also report an association between anemia and bleeding risk in Japanese patients.³⁵

Other independent risk factors for bleeding that have been identified from post-marketing clinical surveillance data of prasugrel in Japan include oral nonsteroidal anti-inflammatory drugs, oral anticoagulants, anemia, female sex, and prior cerebrovascular disorder (during the 30 days after PCI),³⁶ as well as elderly status (≥80 years old), hypertension, and prior gastric ulcer (during the period 31 days to 1 year after PCI).³⁷ Analyses of the J-PCI Registry, which is a national continuous registry of patients undergoing PCI in Japan, also showed that hemorrhagic complications increased in elderly patients, especially those aged ≥80 years,³⁸ and in women in cases of NSTEMI.³⁹ It has also been reported that PCI through the transradial approach decreases the incidence of hemorrhagic complications.⁴⁰ Another scoring system is the ADAPT score, which was calculated using clinical trial data from South Korea and externally evaluated in a Japanese study.⁴¹ This Asian version score based on the DAPT score is weighted by hemoglobin and age.

For the assessment of thrombotic risk in Japanese patients, such factors as ACS patients and patients at high risk of stent thrombosis should be useful, in addition to thrombotic risk factors from the CREDO-Kyoto risk score,¹⁶ PARIS Registry¹⁹ and DAPT study.¹¹ Figure 1 shows the factors to be considered in assessing thrombotic risk in Japanese patients (risk factors for thrombotic events or stent thrombosis).

Figure 1.

Factors for assessing thrombotic risk in Japanese patients. ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CKD, chronic renal disease; CTO, chronic total occlusion; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; DM, diabetes mellitus; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease; ST, stent thrombosis.

5. Development of ARC-HBR Criteria

Since the use of multiple scoring systems for bleeding risk, differences in the criteria across the various scores have caused difficulties in the interpretation of data when comparing different studies. This led to the initiative to develop a standardized definition of HBR in post-PCI patients by the ARC.^5,6 Use of this standardized ARC-HBR criteria for the patients undergoing PCI is expected to help planning of clinical trials in HBR patients and interpretation of data. The ARC-HBR consists of experts, government agencies, and enterprises in the USA, Europe, Japan, and South Korea. HBR is defined as a BARC 3 or 5 bleeding risk of ≥4% or a risk of an intracranial hemorrhage of ≥1% at 1 year after PCI. As the consensus among the experts, 14 major criteria and 6 minor criteria are presented in Table 7.^5,6 Patients are considered to be HBR if at least 1 major or 2 minor criteria are met, and approximately 20% of post-PCI patients are determined to be HBR. Table 8 shows the scoring systems that were referred to when developing the ARC-HBR criteria, with the addition of the CREDO-Kyoto risk score.¹⁶

Table 7. Major and Minor Criteria for HBR at the Time of PCI (Ref. Urban P, et al.^5,6)

Major	Minor
	Age ≥75 y
Anticipated use of long-term oral anticoagulation*
Severe or end-stage CKD (eGFR <30 mL/min)	Moderate CKD (eGFR 30–59 mL/min)
Hemoglobin <11 g/dL	Hemoglobin 11–12.9 g/dL for men and 11–11.9 g/dL for women
Spontaneous bleeding requiring hospitalization or transfusion in the past 6 mo or at any time, if recurrent	Spontaneous bleeding requiring hospitalization or transfusion within the past 12 mo not meeting the major criterion
Moderate or severe baseline thrombocytopenia† (platelet count <100×109/L)
Chronic bleeding diathesis
Liver cirrhosis with portal hypertension
	Long-term use of oral NSAIDs or steroids
Active malignancy‡ (excluding nonmelanoma skin cancer) within the past 12 mo
Previous spontaneous ICH (at any time) Previous traumatic ICH within the past 12 mo Presence of a bAVM Moderate or severe ischemic stroke§ within the past 6 mo	Any ischemic stroke at any time not meeting the major criterion
Nondeferrable major surgery on DAPT
Recent major surgery or major trauma within 30 d before PCI

A major criterion for ARC-HBR is any criterion that, in isolation, is considered to confer a BARC 3 or 5 bleeding risk of ≥4% at 1 year or any criterion considered to be associated with a risk of ICH of ≥1% at 1 year. A minor criterion for ARC-HBR is defined as any criterion that, in isolation, is considered to confer increased bleeding risk, with a BARC 3 or 5 bleeding rate of <4% at 1 year. *Excludes vascular protection doses.^{42 †}Baseline thrombocytopenia is defined as thrombocytopenia before PCI. ^‡Active malignancy is defined as diagnosis within 12 months and/or ongoing requirement for treatment (including surgery, chemotherapy, or radiotherapy). ^§National Institutes of Health Stroke Scale score ≥5.

bAVM, brain arteriovenous malformation; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; HBR, high bleeding risk; ICH, intracranial hemorrhage; NSAID, nonsteroidal anti-inflammatory drug; PCI, percutaneous coronary intervention.

Table 8. Scores Assessing Long-Term Bleeding Risk in Patients Taking Antiplatelet Therapy

	REACH43	Dutch ASA Score44	DAPT11	PARIS19	PRECISE- DAPT14	BleeMACS45	CREDO-Kyoto Risk Score16
Year of publication	2010	2014	2016	2016	2017	2018	2018
Development data set	REACH registry	Dutch ASA registry	DAPT randomized trial	PARIS registry	Pooled analysis of 8 randomized trials	BleeMACS registry	CREDO-Kyoto registry
Development data set, n	56,616	235,531	11,648	4,190	14,963	15,401	4,778
Patient population	Risk of atherothrombosis†	Low-dose aspirin users	Stable and event-free patients 12 months after PCI	Stable and unstable patients undergoing PCI	Stable and unstable patients undergoing PCI	Patients with ACS undergoing PCI	Stable and unstable patients undergoing PCI
Bleeding outcome	Serious bleeding at 2 years	Upper GI bleeding at a median follow-up of 530 days	Major bleeding between 12 and 30 months after PCI	Major bleeding at 2 years	Out-of-hospital bleeding at a median follow-up of 552 days	Serious spontaneous bleeding at 1 year	Major bleeding at 3 years
Bleeding definition used	Protocol-defined	First episode of upper GI bleeding	GUSTO moderate or severe	BARC 3 or 5	TIMI major or minor	Protocol-defined	GUSTO moderate or severe
Proportion of HBR patients	25% (score >11)	83.1% (score ≥1)	23.4% (score −2 to 0)	8% (score ≥8)	25% (score ≥25)	25% (score ≥26)	13.4% (score ≥3)
Rate of bleeding in the HBR subgroup	2.76% (at 2 years)	1–35% for scores from 2 to 13	2.7% (between 13 and 30 months)	10.7% (at 2 years)	1.8–4.2% (at 1 year)	8.03% (at 1 year)	13.5% (at 3 years)
Also evaluates thrombotic risk	No	No	Yes	Yes	No	No	Yes
Score range	0–23	0–15	−2–10	0–14	0–100	0–80	0–11
Development discrimination	AUC 0.68	AUC 0.64	AUC 0.68	AUC 0.72	AUC 0.73	AUC 0.71 (0.72 in internal validation)	AUC 0.66
Validating data set	CHARISMA	Dutch health insurance database	PROTECT	ADAPT-DES	PLATO and Bern PCI registry	SWEDEHEART	RESET and NEXT
Validating dataset, n	15,603	32,613	8,136	8,130	8,595 and 6,172	96,239 (ACS + PCI); 93,150 (ACS)	4,669
Validation discrimination	AUC 0.64	AUC 0.63	AUC 0.64 (bleeding)	AUC 0.64	AUC 0.70 and 0.66	AUC 0.65 (ACS + PCI); AUC 0.63 (ACS)	AUC 0.66

*The DAPT score is not purely a bleeding risk score; rather, it is a score to predict benefit vs. harm of prolonged DAPT (>1 year) in patients after PCI. Thus, it integrates covariates independently associated with bleeding (but not ischemic) risk and ischemic (but not bleeding) risk.

^†Risk of atherothrombosis in REACH was defined as cardiovascular disease, CAD, peripheral artery disease, or ≥3 cardiovascular risk factors. ACS, acute coronary syndrome; ADAPT-DES, Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents; ASA, aspirin; AUC, area under the curve; BARC, Bleeding Academic Research Consortium; BleeMACS, Bleeding Complications in a Multicenter Registry of Patients Discharged With Diagnosis of Acute Coronary Syndrome; CAD, coronary artery disease; CHARISMA, Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; DAPT, Dual Antiplatelet Therapy Trial; GI, gastrointestinal; GUSTO, Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries; HBR, high bleeding risk; PARIS, Patterns of non-adherence to Anti-platelet regimens In Stented patients; PCI, percutaneous coronary intervention; PLATO, Platelet Inhibition and Patient Outcomes; PRECISE-DAPT, Predicting Bleeding Complications In Patients Undergoing Stent Implantation and Subsequent Dual Anti Platelet Therapy; PROTECT, Patient Related Outcomes With Endeavor Versus Cypher Stenting Trial; REACH, Reduction of Atherothrombosis for Continued Health Registry; TIMI, Thrombolysis in Myocardial Infarction.

6. Are the ARC-HBR Criteria Applicable in Japan?

When the ARC-HBR criteria were applied to the CREDO-Kyoto Registry Cohort-2 in which all post-PCI patients were registered, 43% of the patients were categorized as HBR. The incidence of bleeding (moderate or severe bleeding according to the Global Use of Strategies to Open Occluded Arteries [GUSTO] bleeding criteria) was 10.4% at 1 year, which was extremely high. Patients with multiple risk factors in the ARC-HBR criteria had increased bleeding risk.⁷ Given that the ARC-HBR criteria are based on consensus defining HBR as a predicted annual bleeding rate of ≥4%, the incidence of bleeding was more than double the criterion. The incidence of bleeding events in patients considered to be non-HBR according to the ARC-HBR criteria was 3.4% at 1 year, which was significantly lower. A subanalysis of the STOPDAPT-2 trial⁴⁶ also reported the results of a comparison between HBR and non-HBR patients stratified by the ARC-HBR criteria, suggesting that the benefit of 1 month of DAPT over 12 months of DAPT was greater in HBR patients.⁸ These results indicated, both at the registry level and clinical trial level, that the ARC-HBR criteria can be adequately applied in Japan.

7. Development of “Japanese Version of HBR Criteria”

The patient characteristics that are not included in the ARC-HBR criteria such as low body weight, frailty, CKD involving dialysis, heart failure, and peripheral vascular disease, have been reported to be independently associated with bleeding complications, particularly in Japan. These factors are important not only because they are related to HBR, but also because they are common. For this reason, those bleeding risk factors commonly seen in Japanese patients were added to the ARC-HBR criteria to create the “Japanese version of HBR criteria” as the consensus of the Working Group of the Guidelines (Table 9). These criteria are classified into major and minor criteria according to their degree of risk, and the basis for this classification is shown in Table 9.

Table 9. Major and Minor Criteria for Japanese HBR

Major		Minor
		Age	≥75 years. Biological age and chronological age may differ, and the age is highly individual, so it is not proper to evaluate uniformly. Bleeding risk may be highly increased in patients of age >80 years.37,38,41,48
Low body weight, Frailty	Low body weight (<55 Kg for men, <50 Kg for women) is the bleeding risk factor,49 which is important for Japanese, but not for Westerners. A particular notice is necessary for an elderly woman.36,37,39,48 Traumatic bleeding risk may be increased in the setting of frailty as a result of more frequent falls.
Severe CKD (hemodialysis)	The bleeding risk increases incrementally with worsening CKD,5,16,41,49 especially when eGFR <30 mL/min/1.73 m2,5 or on hemodialysis in both ACS and non-ACS patients47 PCI for hemodialysis patients is more common in Japan.	Moderate CKD	eGFR 30–59 mL/min/1.73 m2.
Moderate to severe anemia	Hemoglobin <11 g/dL. Bleeding risk may be increased according to the degree of anemia.36,37,41	Mild anemia	Hemoglobin 11–12.9 g/dL for men and 11–11.9 g/dL for women.34
Heart failure	Heart failure increases bleeding risk.16,48 A particular notice is necessary, because PCI for an elderly patient with heart failure is more common in Japan.
Anticipated use of long-term oral anticoagulation	Long-term use of oral anticoagulation (in about 10% of PCI patients) may increase the risk of bleeding.5,16,36 It is not rare for elderly patients to have new-onset atrial fibrillation during follow-up after PCI.	Long-term use of oral NSAIDs or steroids	Long-term use of oral NSAIDs or steroids may increase the risk of gastrointestinal bleeding.5,36
Peripheral vascular disease	Peripheral vascular disease is one of the most common clinical presentations of general atherosclerosis, and is related to high bleeding risk.16
History of non-traumatic bleeding events	Gastrointestinal bleeding or urinary tract bleeding requiring hospitalization or transfusion in the past 6 months or at any time, if recurrent.5,36,37		First non-traumatic bleeding event requiring hospitalization or transfusion in the past 6–12 months.
Previous Ischemic Stroke or ICH	Previous spontaneous ICH (at any time), previous traumatic ICH within the past 12 months and presence of a bAVM. Moderate or severe ischemic stroke within the past 6 months.5,36,49 The risk of ICH may be increased in Japanese patients taking aspirin.		Any ischemic stroke at any time not meeting the major criterion.
Thrombocytopenia	Platelet count <100×109/L.5,16,50
Active malignancy	Active malignancy.5,16,51 Active malignancy is defined as diagnosis within 12 months and/or ongoing requirement for treatment (including surgery, chemotherapy, or radiotherapy). Cancer that is considered to be in complete remission or requires only maintenance therapy is not considered active.47
Liver cirrhosis with portal hypertension	Liver dysfunction is a risk factor for bleeding complication in early phase,37 especially in patients with portal hypertension.5
Chronic Bleeding Diatheses	Included in the ARC-HBR criteria.5
Nondeferrable major surgery on DAPT	Included in the ARC-HBR criteria.5
Recent major surgery or major trauma within 30 days before PCI	Consensus is obtained in the ARC-HBR criteria.5

Patients are defined to be at HBR if at least 1 major or 2 minor criteria are met. ACS indicates acute coronary syndrome; ARC-HBR, academic research consortium - high bleeding risk; bAVM, brain arteriovenous malformation; CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; ICH, intracranial hemorrhage; NSAIDs, nonsteroidal anti-inflammatory drugs; and PCI, percutaneous coronary intervention.

In the CREDO-Kyoto Registry Cohort-2, the incidence of bleeding complications (moderate or severe bleeding according to the GUSTO bleeding criteria) was high in patients with peripheral vascular disease, heart failure, or low body weight (10.1–14.2% at 1 year). Even in cases where no other factors (including factors of the ARC-HBR criteria) coexisted, the frequencies were still mostly ≥4%. Considering that the incidence of bleeding complications in non-HBR patients who did not meet any major or minor ARC-HBR criteria was only 2.6%,⁷ the Working Group concluded that it would be reasonable to identify these factors as the major criteria of the “Japanese version of HBR criteria.”

From the analyses of the J-PCI Registry, a national registry of consecutive PCI patients in Japan, it was reported that bleeding risk exponentially increased, especially in elderly patients ≥80 years of age,³⁸ and that elderly patients were often complicated with traumatic intracranial hemorrhage.⁴³ Therefore, ≥80 years of age may need to be classified as major criteria for HBR. However, this population is particularly correlated with low body weight in women. Being female in itself is reported to be a risk factor for bleeding.^36,39 Thus, among patients with low body weight, special attention should be given to elderly women. Bleeding risk is also increased by falls related to frailty. Based on these, low body weight and frailty were combined to be 1 major criterion. Being elderly (≥75 years) was also included in the minor criteria of the “Japanese version of HBR criteria” as in the ARC-HBR criteria. In Japan, PCI is often performed in dialysis patients who are at high bleeding risk,⁴⁷ and therefore dialysis was added to severe CKD.

Figure 2 illustrates the main points of the “Japanese version of HBR criteria” as an aid for understanding and for promoting their utilization.

Figure 2.

Factors for HBR to be considered when performing PCI. Note: This figure is not intended to show the major and minor criteria of the “Japanese version of HBR criteria” (Table 9), but to promote understanding of HBR factors in Japan. HBR, high bleeding risk; CKD, chronic kidney disease; ICH, intracranial hemorrhage; and NSAIDs indicate nonsteroidal anti-inflammatory drugs; PCI, percutaneous coronary intervention; PVD, peripheral vascular disease.

In actual clinical practice, it is desirable to properly assess the bleeding risk of individual patients to choose the appropriate antithrombotic therapy regimen, including the optimal DAPT duration. On the other hand, we need to keep in mind that there is no such clinical study that prospectively evaluated whether or not clinical results would be improved by choosing antithrombotic regimen based on the risk scores.

8. Priority Between Bleeding and Thrombotic Risk Scores

There are many common factors between the bleeding and thrombotic risk factors, and generally, if bleeding risk is high, then thrombotic risk is also high. In the Japanese CREDO-Kyoto risk score, CKD, AF, peripheral vascular disease, and heart failure are common factors for both thrombotic and bleeding risk. Finding that the predictors of thrombotic and bleeding risks overlap has been reported not only in Japan, but also in Western countries, indicating that patients at high thrombotic risk are also at high bleeding risk. Accordingly, Costa et al.⁵² investigated the benefit from long-term DAPT in terms of the PRECISE-DAPT bleeding score and complexity of the PCI procedure (complex PCI: stent implantation shown in Table 5). In their study, long-term DAPT was effective only in patients at low bleeding risk who underwent complex PCI, and short-term DAPT was more effective in patients at low bleeding risk who underwent non-complex PCI and even in patients who underwent complex PCI if they were at high bleeding risk. A similar outcome was reported from the PARIS Registry.¹⁹

Moreover, the 2017 ESC Guidelines recommended that, when considering appropriate antithrombotic therapy, it is practical to evaluate DAPT duration by considering bleeding risk first, and thrombotic risk should not be the priority.²⁷ As the term “East Asian paradox” indicates, bleeding risk might be higher and ischemic risk is lower among East Asians including Japanese compared with Caucasians.^3,53–55 Consequently, bleeding risk should be the priority in determining the use of antithrombotic drugs, and thus the present guideline recommends that the antithrombotic regimen should be determined based on Japanese version of HBR (Figure 3).

Figure 3.

Antithrombotic regimen based on Japanese version of HBR criteria. When switching from short-term DAPT to monotherapy, P2Y₁₂ receptor inhibitor is considered as a single drug rather than aspirin. Direct oral anticoagulant (DOAC) is considered as OAC monotherapy, if possible. C/P, clopidogrel/prasugrel; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; OAC, oral anticoagulant; SAPT, single antiplatelet therapy.

III. Loading of Antiplatelet Agents (Table 10–13)

Table 10. Class of Recommendation (COR) and Level of Evidence (LOE) for Loading of Antiplatelet Agents for Patients With STEMI

	COR	LOE
Chewable aspirin 162–324 mg loading dose should be given to aspirin-naïve patients in whom STEMI is strongly suspected56,57	I	A
Prasugrel 20 mg loading dose should be given to P2Y12 receptor inhibitor-naïve patients before primary PCI58–60	I	A
Clopidogrel 300 mg loading dose should be given to P2Y12 receptor inhibitor-naïve patients before primary PCI, when prasugrel is not available or is contraindicated61	I	A
Ticagrelor 180 mg loading dose may be considered in P2Y12 receptor inhibitor-naïve patients before primary PCI, when prasugrel or clopidogrel are not available or are contraindicated62–64	IIb	B

PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

Table 11. Class of Recommendation (COR) and Level of Evidence (LOE) for Loading of Antiplatelet Agents for Patients With NSTE-ACS

	COR	LOE
Chewable aspirin 162–324 mg loading dose should be given to aspirin-naïve patients in whom NSTE-ACS is strongly suspected56,57	I	A
Prasugrel 20 mg loading dose should be given to P2Y12 receptor inhibitor-naïve patients in whom coronary anatomy is known and who are proceeding to PCI58,59,65	I	A
Clopidogrel 300 mg loading dose should be given to P2Y12 receptor inhibitor-naïve patients before PCI, when prasugrel is not available or is contraindicated61	I	A
Ticagrelor 180 mg loading dose may be considered in P2Y12 receptor inhibitor-naïve patients before PCI, when prasugrel or clopidogrel are not available or are contraindicated63–65	IIb	B

NSTE-ACS, non-ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention.

Table 12. Class of Recommendation (COR) and Level of Evidence (LOE) for Loading of Antiplatelet Agents for Patients With Stable CAD

	COR	LOE
Chewable aspirin 162–324 mg loading dose should be given to aspirin-naïve patients before PCI56,57	I	A
Prasugrel 20 mg or clopidogrel 300 mg loading dose should be given to P2Y12 receptor inhibitor-naïve patients before PCI66,67	I	C

CAD, coronary artery disease; PCI, percutaneous coronary intervention.

Table 13. Class of Recommendation (COR) and Level of Evidence (LOE) of Loading for Antiplatelet Agents for Patients With ACS in Whom PCI Is Not Planned

	COR	LOE
Chewable aspirin 162–324 mg loading dose should be given to aspirin-naïve patients in whom ACS is strongly suspected56,57	I	A

ACS, acute coronary syndrome; PCI, percutaneous coronary intervention.

1. Aspirin

Many trials have demonstrated that aspirin is useful for improving the prognosis of ACS, and that the sooner aspirin administration, the greater the improvement in mortality rate.^56,57 Therefore, aspirin should be given as soon as possible, except for those patients with severe blood disorders, aspirin-induced asthma, or hypersensitivity to aspirin. Patients should chew 2–4 tablets of aspirin 81 mg or 2–3 tablets of aspirin 100 mg to obtain rapid onset of antiplatelet activity. In Japan, a tablet of aspirin 330 mg is also available, although it is not officially approved for CAD.

2. P2Y₁₂ Receptor Inhibitors

2.1 Selection of P2Y₁₂ Receptor Inhibitor

Because DAPT, a combination of aspirin and P2Y₁₂ receptor inhibitor, is mandatory to prevent stent thrombosis,¹⁰ a loading dose should be given before PCI to patients who are naïve of these drugs. The importance of loading of antiplatelet agents before PCI should be emphasized for patients with ACS, because of the increased risk of stent thrombosis caused by the thrombotic nature of the culprit lesion. In the PCI-CURE study, patients with NSTE-ACS were randomly assigned with a clopidogrel 300-mg loading dose or placebo in addition to aspirin. Patients were pretreated with aspirin and study drug for a median of 10 days before PCI.⁶¹ Before PCI, significantly fewer patients on clopidogrel than on placebo had cardiovascular events. After PCI, stented patients received an open-label P2Y₁₂ receptor inhibitor (either clopidogrel or ticlopidine) in combination with aspirin. The incidence of cardiovascular events was significantly lower in the clopidogrel pretreatment group. The CREDO study randomly assigned patients to receive a 300-mg clopidogrel loading dose or placebo 3–24 h before elective PCI.⁶⁶ Contrary to the PCI-CURE study, there was no significant difference in the 28-day incidence of cardiovascular events between the 2 groups. However, among patients who received clopidogrel at least 6 h before PCI, there was a trend towards fewer cardiovascular events in the clopidogrel group. These findings indicated the importance of prompt platelet inhibition, and led to subsequent research for novel drugs or for appropriate timing of drug loading.

Because thienopyridine is a prodrug that requires conversion to active metabolite before irreversibly binding to the platelet P2Y₁₂ receptor, it takes much time to confer antiplatelet activity. Prasugrel is a third-generation thienopyridine that has simpler metabolic pathway and more prompt antiplatelet effect as compared with clopidogrel. The TRITON-TIMI 38 study compared prasugrel (60-mg loading dose and 10-mg daily maintenance dose) with clopidogrel (300-mg loading dose and 75-mg daily maintenance dose) in ACS patients scheduled for PCI.⁵⁸ The cardiovascular events rate was significantly reduced in the prasugrel group. A significant reduction was observed by the first prespecified time point, 3 days. Major bleeding, including fatal bleeding, occurred more frequently in the prasugrel group. CABG-related major bleeding was approximately 4-fold more frequent in patients receiving prasugrel.

Thienopyridines must be metabolized to the active form via the cytochrome P450 system, especially CYP2C19. Polymorphism of CYP2C19, which blunts CYP2C19 and reduces drug activity, is common in the Japanese population. Because the drug activity of clopidogrel is susceptible to CYP2C19 polymorphism, the doses used for Japanese patients are the same as used abroad; that is,, a clopidogrel 300-mg loading dose and 75-mg daily maintenance dose. In contrast, because prasugrel is less susceptible to CYP2C19 polymorphism, reduced doses (20-mg loading dose and 3.75-mg daily maintenance dose) are administered to Japanese patients, whereas a 60-mg loading dose and 10-mg daily maintenance dose are used abroad. The PRASFIT-ACS study⁵⁹ compared reduced-dose prasugrel (20-mg loading dose and 3.75-mg daily maintenance dose) with clopidogrel (300-mg loading dose and 75-mg daily maintenance dose) in Japanese patients with ACS undergoing PCI. Patients assigned to the reduced dose of prasugrel had a lower incidence of cardiovascular events, although the difference was not statistically significant because of the small sample size. The incidence of bleeding was similar in both groups.

Ticagrelor is a direct, reversibly binding P2Y₁₂ receptor inhibitor that can be used in patients for whom clopidogrel and prasugrel are not available. The PLATO study⁶² randomized patients with ACS to either ticagrelor (180-mg loading dose and 90-mg twice daily maintenance dose) or clopidogrel (300–600-mg loading dose and 75-mg daily maintenance dose). Treatment with ticagrelor as compared with clopidogrel significantly reduced the cardiovascular events rate without an increase in the major bleeding rate. The PHILO study,⁶³ which consisted of Asian patients with ACS, mainly Japanese patients, compared ticagrelor with clopidogrel. The dose of ticagrelor was the same as in the PLATO study. Contrary to PLATO, the cardiovascular events rate and the bleeding rate were numerically higher in the ticagrelor group, although the differences were not statistically significant. The ISAR-REACT 5 study⁶⁴ compared ticagrelor with prasugrel in European patients with ACS. The incidence of cardiovascular events was significantly lower in the prasugrel group than in the ticagrelor group, but the incidence of major bleeding was not significantly different between the groups.

Cangrelor is an intravenous, reversibly binding P2Y₁₂ receptor inhibitor that has a short plasma half-life (<10 min). Although cangrelor is used abroad, it is not approved for clinical use in Japan.

2.2 Timing of P2Y₁₂ Receptor Inhibitor Loading

The TRITON-TIMI 38 study⁵⁸ assigned ACS patients scheduled for PCI either to a prasugrel group or clopidogrel group. Patients with NSTE-ACS were randomized after their coronary anatomy was found to be suitable for PCI, while patients with STEMI were randomized without knowledge of coronary anatomy and the study drug was given promptly. The ACCOAST study⁶⁵ investigated the effect of the timing of P2Y₁₂ receptor inhibitor loading in patients with NSTE-ACS who were scheduled to undergo coronary angiography and PCI, if indicated. Patients were assigned to receive prasugrel 30-mg loading dose before angiography (pretreatment group) or placebo (control group). When PCI was indicated, an additional 30 mg of prasugrel was given in the pretreatment group at the time of PCI and 60 mg of prasugrel was given in the control group. Pretreatment with prasugrel did not reduce the incidence of cardiac events up to 30 days, but increased the incidence of major bleeding complications. The ATLANTIC study⁶⁸ compared prehospital (in the ambulance) vs. in-hospital (in the catheterization laboratory) treatment with ticagrelor in patients with STEMI, diagnosed by ambulance personnel. The median time difference between the 2 treatment strategies was 31 min. The 2 co-primary endpoints, ≥70% resolution of ST-segment elevation before PCI and a TIMI flow grade 3 in the infarct-related artery on initial angiography, did not differ significantly between the 2 groups. However, the incidence of definite stent thrombosis was lower in the prehospital group than in the in-hospital group and the incidence of bleeding was similar. TRITON-TIMI 38⁶⁰ reported a prespecified study that focused on patients with STEMI, in whom the study drug was given without knowledge of coronary anatomy. Pretreatment with prasugrel as compared with clopidogrel reduced the cardiovascular events rate without increasing bleeding.

Prompt antiplatelet effect is crucial for loading. The CRUSH study⁶⁹ assigned patients with STEMI who were treated with a prasugrel 60-mg loading dose to either whole or crushed tablets. Compared with whole tablets, crushed prasugrel led to reduced P2Y₁₂ reaction units by 30 min after loading, which persisted at 4 h. Pharmacokinetics analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel tablets. In Japan, an orally disintegrating (OD) tablet of prasugrel 20 mg is available and is expected to show prompt antiplatelet activity comparable to that with a crushed tablet. It has been reported that morphine use delays the onset of action of oral P2Y₁₂ receptor inhibitor in patients with STEMI.⁷⁰ In the CRUSH study, morphine administration was associated with modestly reduced exposure to the active metabolite of prasugrel, but with similar T_max and C_max.

Based on the evidence described above, we recommend administration of P2Y₁₂ receptor inhibitor loading as soon as possible for patients with STEMI and before PCI for patients with NSTE-ACS. For P2Y₁₂ receptor inhibitor-naïve patients with stable CAD, P2Y₁₂ receptor inhibitor loading is recommended before stenting, while starting with the maintenance dose without loading may be applied if there is enough time before elective PCI.⁶⁷ Less susceptibility to CYP2C19 and prompt onset of antiplatelet activity are key points for loading of a P2Y₁₂ receptor inhibitor. Furthermore, factors that accelerate or delay drug absorption should be considered. Even today, the risk of stent thrombosis is highest on the day of PCI. Prompt onset of antiplatelet activity by loading contributes to improvement in early outcomes of PCI. On the other hand, early efficacy and risk of bleeding are like two sides of a coin. PCI practice that pays much attention to the risk of bleeding complication is advocated.

IV. Dual/Single Antiplatelet Therapy (Table 14)

Table 14. Class of Recommendation (COR) and Level of Evidence (LOE) of Dual/Single Antiplatelet Therapy for Patients With ACS Undergoing PCI

	COR	LOE
Prasugrel 3.75 mg daily or clopidogrel 75 mg daily in addition to aspirin 81–162 mg daily is recommended for 3–12 months following coronary stent deployment59,71–73	I	A
Ticagrelor may be considered if administration of both clopidogrel and prasugrel on top of aspirin is contraindicated in patients with indication of DAPT62,63	IIb	B
Prolonged DAPT should be considered for patients with low bleeding risk and high thrombotic risk including stent thrombosis11	IIa	B
Shortening of DAPT duration to 1–3 months is recommended following stent deployment in patients with high bleeding risk74,75	I	A
Life-long aspirin 81–162 mg daily is recommended unless contraindicated76–78	I	A
Monotherapy with P2Y12 receptor inhibitor should be considered when aspirin is contraindicated79	IIa	C
Monotherapy with P2Y12 receptor inhibitor should be considered in patients with high thrombotic and high bleeding risk following short-term DAPT46,75,80	IIa	A
Concomitant use of warfarin is recommended in patients with post-myocardial infarction with left ventricular and left atrial thrombus, severe heart failure, left ventricular aneurysm, and preceding artificial valve replacement81	I	B
In atrial fibrillation patients with high bleeding risk who undergo PCI, concomitant use of 3 drugs including anticoagulants, and DAPT should not be continued more than 1 month27,82–84	III Harm	B

DAPT, dual antiplatelet therapy; PCI, percutaneous coronary intervention.

1. ACS Patients

1.1 ST-Elevation Myocardial Infarction (STEMI) Patients

Since demonstrated in STARS (Stent Anti-thrombotic Regimen Study) trial, DAPT with aspirin (81–162 mg/day) and P2Y₁₂ receptor inhibitor has become the standard of care after coronary artery stent deployment,^10,71,72 and indication of stent has expanded. In Japan, the rate of stent deployment in primary PCI is over 90%.⁸⁵ Accurate estimations of thrombotic risk and bleeding risk are required when deciding DAPT duration. However, East Asians, including Japanese, are considered to have high bleeding risk and low thrombotic risk compared with Westerners, so Western guidelines might not be directly applied to Asian patients, as suggested in recent studies reported from various Asian countries.^4,16,55,86

Prasugrel and ticagrelor as P2Y₁₂ receptor inhibitors with potent antiplatelet effects that are less affected by CYP2C9 genetic polymorphism have significantly reduced thrombotic events compared with clopidogrel.^62,63,74 However, the incidence of bleeding events is higher with both drugs compared with clopidogrel. In Europe and the USA, the use of prasugrel has been limited to ACS patients who are scheduled for PCI, because prasugrel has shown increased lethal bleeding episodes.⁵⁸ In contrast, the approved dose of prasugrel in Japan is approximately one-third of the globally approved dose. The following points have been given as reasons. Pharmacokinetic study of healthy patients has revealed that East Asian patients, including Japanese, Korean, and Chinese, have blood concentrations of prasugrel active metabolites ≥40% higher than patients in Europe and the USA, which led to significant suppression of platelet aggregation.⁸⁷ In addition, a phase 2 study showed more potent antiplatelet effects with low-dose prasugrel than with clopidogrel.⁸⁸ Based on these results, the PRASFIT-ACS (Prasugrel compared with Clopidogrel for Japanese Patients with ACS Undergoing PCI) trial was performed to compare prasugrel and clopidogrel in ACS patients. The prasugrel group, which received an initial loading dose of prasugrel (20 mg) in combination with aspirin followed by administration of a maintenance dose of 3.75 mg/day from the next day, had lower rate of cardiovascular events compared with the clopidogrel group without an increase in major bleeding events, which differed from the TRITON (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel–Thrombolysis In Myocardial Infarction) TIMI-38 trial in Europe and the USA.⁵⁹ Efficacy and tolerability of Japanese dose of prasugrel are reported to be favorable in Japan according to post-marketing surveillance.³⁷

Ticagrelor was approved in Japan at the same dose as approved in Europe and the USA. The PHILO (Phase the international study of ticagrelor and clinical outcomes in Asian ACS patients) trial targeting ACS patients in East Asia, mainly from Japan, showed that the ticagrelor group had insignificantly, but numerically higher thrombotic and bleeding event rates.⁶³ Moreover, a Korean cohort study, in which approximately 70,000 ACS patients were registered, showed that the ticagrelor group had a lower mortality rate, but higher incidence of bleeding events compared with the clopidogrel group. Additionally, it has been reported that compared with the administration of clopidogrel, administration of prasugrel (in the same dose as in Europe and the USA) had a higher incidence of bleeding events, but did not show a decrease in thrombotic events.⁸⁶ Similarly, a Korean randomized study that enrolled 800 ACS patients compared regular doses of ticagrelor and of clopidogrel demonstrated a significant increase in bleeding events in the ticagrelor group (11.7% vs. 5.3%, P=0.002). The ticagrelor group also had a high ischemic event rate, but it was not statistically significant (9.2% vs. 5.8%, P=0.07).⁵⁵ These results suggest the difficulties of directly applying results from clinical trials in Europe and the USA to patients in East Asia including Japan.

Recently, the ISAR-REACT5 (Intracoronary Stenting And Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5) trial directly compared administration of ticagrelor and prasugrel (global doses) in ACS patients. This study reported that less thrombotic events occurred in the prasugrel group; however, bleeding events were equivalent.⁶⁴ In the prasugrel group, it was allowed to administer an initial loading dose to non STEMI (NSTEMI) patients after confirming coronary artery lesions on coronary angiography and to decrease the doses tailored to the patients’ risk. Thus, the prasugrel group with an individual approach rather than a single treatment strategy showed favorable results, which differed from the hypothesis.

It is important to firstly identify HBR patients among ACS patients and to select an appropriate antithrombotic therapy.⁶ STEMI patients are at especially high risk of recurrence of thrombotic events, and thus DAPT duration is normally prolonged (Figure 3). In this 2020 JCS guideline focused update, HBR is to be assessed according to the “Japanese version of HBR criteria”.

ACS patients, including STEMI patients, are classified as high risk for thrombotic events. Although the standard duration of DAPT is 1 year according to guidelines in Europe and the USA, shortening the DAPT duration has been recently tested. The DAPT-STEMI trial targeting STEMI patients undergoing drug-eluting stent (DES) deployment revealed that 6-month DAPT was non-inferior to 12-month DAPT for the prevention of cardiovascular events.⁸⁹ The SMART-DATE (Safety of 6-month duration of dual antiplatelet therapy after acute coronary syndromes) trial demonstrated that in ACS patients who underwent placement of DES, 6-month DAPT was non-inferior to 12-month DAPT for major cardiovascular events. However, the incidence of myocardial infarction as a secondary endpoint was significantly higher in the 6-month DAPT group than in the 12-month group.⁷³ Moreover, subgroup analysis of ACS patients in the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial demonstrated that ticagrelor monotherapy after 3-month DAPT as compared with prolonged DAPT with aspirin and ticagrelor was associated with s significant reduction of BARC (bleeding academic research consortium) type 2, 3, or 5 bleeding without an increase in ischemic events. Therefore, in this guideline, 3–12 months has been set as the standard duration of DAPT in ACS patients who are considered to have high thrombotic risk. Further, when switching from DAPT to monotherapy within 6 months, P2Y₁₂ receptor inhibitor rather than aspirin is recommended as the single drug.

1.2 NSTE-ACS Patients

The main objective of treatment for NSTE-ACS patients is improvement in both the short- and long-term prognosis. Therefore, it is important to estimate the risk of adverse events when planning treatment strategies. Usually, an early invasive strategy (within 24 h) is chosen when meeting high-risk criteria and a late invasive strategy (within 72 h) in the case of moderate risk criteria. On the basis of coronary angiography results, the heart team should discuss and decide which treatment strategy to be taken, including PCI, CABG, or conservative treatment, because we sometimes face multivessel disease with unclear ischemic culprit lesions or multiple lesions that are all supposed to be culprit lesions. Because emergency coronary angiography is not always followed by coronary revascularization via PCI in NSTE-ACS patients, there remain uncertainties regarding the optimal potency and timing of antiplatelet therapy.

NSTEMI patients are also high risk for thrombotic events. Nevertheless, we should first evaluate NSTEMI patients as being or not being HBR as for STEMI patients, and then, we should choose appropriate antiplatelet therapy considering the balance between thrombotic risk and bleeding risk.

1.3 Antithrombotic Therapy to Reduce Bleeding Risk

1.3.1 Aspirin Monotherapy

Most previous studies evaluating shortened DAPT duration adopted the protocol of continuing low-dose aspirin after completion of DAPT (Table 15). Few studies have been performed in ACS patients alone, and fairly low-risk patients were enrolled in those studies because of the nature of randomized study of DAPT duration. Thus, it is considered that these results might not be applicable to a wide spectrum of patients.

Table 15. Clinical Studies of Chiefly Maintaining Aspirin After Completion of DAPT

Trial (n)	DAPT period (months)	Target patients	Trial design	Primary endpoint	Result
RESET (2,217)90	3 vs. 12	PCI	Non-inferiority	NACE	〇
OPTIMIZE (2,199)91	3 vs. 12	PCI	Non-inferiority	NACE	〇
REDUCE ACS (1,496)92	3 vs. 12	ACS-PCI	Non-inferiority	NACE	〇
EXCELLENT (1,443)93	6 vs. 12	PCI	Non-inferiority	TVF	〇
SECURITY (1,399)94	6 vs. 12	PCI	Non-inferiority (discontinued)	NACE	〇
ISAR-SAFE (4,000)95	6 vs. 12	PCI	Non-inferiority (discontinued)	NACE	〇
I-LOVE-IT-2 (1,829)96	6 vs. 12	PCI	Non-inferiority	TLF	〇
IVUS-XPL (1,400)97	6 vs. 12	PCI	Non-inferiority	NACE	〇
OPTIMA-C (1,368)98	6 vs. 12	PCI	Non-inferiority	MACE	〇
DAPT-STEMI (870)89	6 vs. 12	ACS-PCI	Non-inferiority	NACE	〇
SMART-DATE (2,172)73	6 vs. 12	ACS-PCI	Non-inferiority	MACE	〇
NIPPON (2,772)99	6 vs. 18	PCI	Non-inferiority (discontinued)	NACE	〇
ITALIC (1,822)100	6 vs. 24	PCI	Non-inferiority	NACE	〇

DAPT, dual antiplatelet therapy; MACE, major adverse cardiac event; NACE, net adverse clinical event; PCI, percutaneous coronary intervention; TLF, target lesion failure; TVF, target vessel failure.

1.3.2 Monotherapy With P2Y₁₂ Receptor Inhibitor

The treatment strategy that continues P2Y₁₂ receptor inhibitor instead of aspirin after completion of DAPT has been evaluated with the aim of reducing the risk of gastrointestinal tract hemorrhage and intracranial hemorrhage associated with low-dose aspirin and simultaneously maintaining preventive effects against thrombotic events (Table 16). The SMART-CHOICE (Smart Angioplasty Research Team: Comparison Between P2Y12 Antagonist Monotherapy vs Dual Antiplatelet Therapy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents) trial including 58% ACS patients, which compared a group that continued P2Y₁₂ receptor inhibitor after completion of 3-month DAPT and a group that received DAPT for 12 months, showed non-inferiority in the incidence of cardiovascular events in the 3-month DAPT group.⁸⁰ The GLOBAL LEADERS (Long-term ticagrelor monotherapy vs. standard dual antiplatelet therapy followed by aspirin monotherapy in patients undergoing biolimus-eluting stent implantation) trial compared ticagrelor monotherapy after 1-month DAPT with ticagrelor plus aspirin and aspirin monotherapy after 12-month DAPT with ticagrelor plus aspirin in ACS patients and clopidogrel plus aspirin in stable patients. There was no significant difference in the primary endpoint (composite of Q-wave myocardial infarction or all-cause death) at 2 years between 2 groups. In a post hoc subgroup analysis of ACS patients (47% of the total population), ticagrelor monotherapy after 1-month DAPT with ticagrelor plus aspirin was associated with significant reduction of major bleeding at 1 year without an increase in the primary endpoint as compared with 12-month DAPT with ticagrelor plus aspirin.¹⁰¹ The TWILIGHT trial was performed in PCI patients who have anatomically and clinical features associating with high risk of thrombotic or bleeding events. It included 65% ACS patients. Patients were randomly assigned into a group that discontinued aspirin after 3-month DAPT with ticagrelor (90 mg twice daily) plus low-dose aspirin and a group that continued DAPT with ticagrelor (90 mg twice daily) plus low-dose aspirin. The 3-month DAPT group that discontinued aspirin showed a significantly lower incidence of bleeding events according to BARC type 2, 3, or 5 and had a comparable incidence of ischemic events.⁷⁵ Based on these observations, monotherapy with P2Y₁₂ receptor antagonist with a more potent antiplatelet effect rather than low-dose aspirin monotherapy might be appropriate following short-term DAPT in patients with high thrombotic and high bleeding risk.

Table 16. Clinical Studies of Maintaining P2Y₁₂ Receptor Inhibitor After Completion of DAPT

Trial (n)	DAPT duration (months)	Target patients	Trial design	Primary endpoint	Result
GLOBAL LEADERS (15,968)102	1 vs. 12	PCI	Superiority	Death/ Myocardial infarction	×
STOP-DAPT 2 (3,045)46	1 vs. 12	PCI	Non-inferiority	NACE	〇
SMART-CHOICE (3,000)80	3 vs. 12	PCI	Non-inferiority	MACE	〇
TWILIGHT (9,000)75	3 vs. 12	PCI	Superiority	Hemorrhage	〇
TICO (3,000)103	3 vs. 12	ACS-PCI	Superiority	NACE	Ongoing
STOPDAPT-2 ACS (4,100)	1 vs. 12	ACS-PCI	Non-inferiority	NACE	Ongoing

ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; MACE, major adverse cardiac event; NACE, net adverse clinical event; PCI, percutaneous coronary intervention.

As previously mentioned, the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy After Everolimus-Eluting Cobalt-Chromium Stent 2) trial included a large proportion of stable CAD patients. The STOPDAPT-2 ACS trial is currently in progress in Japan for evaluation of the incidence of thrombotic and bleeding events at 12 months after stent placement, in which ACS patients undergoing PCI with cobalt–chromium everolimus-eluting stents were randomly assigned to a 1-month DAPT group and 12-month DAPT group.

1.3.3 De-Escalation

The switch strategy has been studied as a method to decrease the risk of bleeding. In this strategy, DAPT with prasugrel or ticagrelor plus low-dose aspirin is administered only in the early phase after the onset of ACS, followed by switching to DAPT with clopidogrel plus low-dose aspirin. The small-scale TOPIC (Timing of Platelet Inhibition after ACS) trial showed that bleeding events decreased with no increase in ischemic events at 1 year through the strategy of switching to clopidogrel at 1 month after onset of ACS.¹⁰⁴

1.3.4 Other Approaches

Another approach is where enhancement or attenuation of DAPT for individual patients is based on genetic polymorphism or platelet function measurement. Recently, 1 treatment strategy has been reported to be beneficial, in which potent P2Y₁₂ receptor inhibitor is switched to clopidogrel in patients who are identified as non carrying the loss-of-function genetic polymorphism of the CYP2C19 enzyme that decreases clopidogrel’s effect.¹⁰⁵ However, as of today, no study has clearly revealed the benefit of stopping DAPT based on the results from platelet aggregation test.¹⁰⁶

Times have shifted to the era of a more individualized approach. Standard duration for DAPT is 6–12 months for ACS patients with high thrombotic risk; however, in cases of shortening DAPT to 1–3 months taking into considerationbleeding risk, monotherapy with P2Y₁₂ receptor antagonist might be an effective treatment option.

2. Stable CAD Patients (Table 17)

Table 17. Class of Recommendation (COR) and Level of Evidence (LOE) of Dual/Single Antiplatelet Therapy for Patients With Stable CAD Undergoing PCI

	COR	LOE
Prasugrel 3.75 mg daily or clopidogrel 75 mg daily in addition to aspirin 81–162 mg daily is recommended for 1–3 months following coronary stent deployment46,74	I	A
Life-long aspirin is recommended unless contraindicated76–78	I	A
Monotherapy with P2Y12 receptor inhibitor should be considered when aspirin is contraindicated79	IIa	C
Continuation of DAPT up to 30 months may be considered in patients with a high thrombotic risk and low bleeding risk who experience no bleeding events during 12-month DAPT11	IIb	B
Shortening of DAPT to 1–3 months should be considered for patients with high bleeding risk8,46	IIa	B
Monotherapy with P2Y12 receptor inhibitor should be considered in patients with high thrombotic and high bleeding risk following 1–3 months of DAPT8,46,75,80	IIa	A
1–3 months of DAPT should be considered for patients who undergo PCI with DCB alone107,108	IIa	B

DAPT, dual antiplatelet therapy; DCB, drug-coated balloon; PCI, percutaneous coronary intervention.

After PCI using first-generation DES, DAPT duration tends to be prolonged because of concerns about delayed healing and stabilization of the stented segments. As the vascular healing response has been improved with second- or later generation DES, several clinical trials have been performed to verify the efficacy and safety of shortened DAPT. Trials such as ISAR-SAFE (Intracoronary Stenting and Antithrombotic Regimen: Safety and Efficacy of 6 Months Dual Antiplatelet Therapy After Drug-Eluting Stenting),⁹⁵ ITALIC (Is There A Life For DES After Discontinuation Of Clopidogrel) trial,¹⁰⁹ SECURITY (Second Generation Drug-Eluting Stent Implantation Followed by Six-Versus Twelve-MonthDual Antiplatelet Therapy),⁹⁴ or NIPPON (Nippon ICD Plus Pharmacologic Option Necessity)⁹⁹ performed in Japan have consistently shown no clinical benefit of prolonged DAPT. Moreover, it has become evident that second-generation DES have a clearly lower risk of stent thrombosis compared with first-generation DES,¹¹⁰ which supports the practice change towards shortening the DAPT duration.

The American College of Cardiology (ACC) and the American Heart Association (AHA) guidelines as well as those of European Society of Cardiology (ESC) recommend, for prevention of stent thrombosis after stent deployment, aspirin plus minimum of 6 months of clopidogrel for stable CAD patients with low bleeding risk and aspirin plus 1–3 months of clopidogrel for those with high bleeding risk.^27,111 Clinical trials such as NIPPON or STOPDAPT in Japan⁷⁴ showed no association between shortening of DAPT with an increase in stent thrombosis or cardiovascular events. In the STOPDAPT 2 trial, a group that continued clopidogrel after 1-month DAPT and a group that continued DAPT with clopidogrel plus aspirin for 1 year were compared to assess the incidence of death, myocardial infarction, stroke, stent thrombosis, and bleeding (minor and major bleeding according to TIMI criteria); there was a favorable net clinical benefit (comprehensive efficacy with consideration for risk) in the 1-month DAPT group.⁴⁶ As shown in section 2.6, tolerability of shortened DAPT followed by P2Y₁₂ receptor inhibitor monotherapy has been shown in clinical trials such as GLOBAL LEADERS, SMART-CHOICE, TWILIGHT, and STOPDAPT2. Moreover, among the patients enrolled in the STOPDAPT2 trial, the clinical benefit of 1-month DAPT was more prominent in patients with HBR according to the ARC-HBR criteria.⁸ Based on those results, it is recommended that patients with HBR should avoid prolonged DAPT and have a shortened duration of DAPT to less than 3 months considering bleeding risks. Additionally, it is also recommended that switching to monotherapy with P2Y₁₂ receptor inhibitor should be considered when DAPT is shortened to less than 3 months. On the other hand, continuing low-dose aspirin alone following >6-month duration of DAPT is appropriate in low-risk patients. Additionally, the optimal duration of antiplatelet therapy may differ by race and may be changed with upcoming new devices.

As an alternative strategy, PCI with drug-coated balloon (DCB) alone without stent deployment may be considered to shorten the duration of DAPT.¹⁰⁷ Currently, in Japan, lesions suitable for DCB treatment are small vessels of <3.0 mm in angiographic vessel diameter and in-stent restenosis. BASKET-SMALL2 (The Basel Stent Kosten-Effektivitäts Trial: Drug-Coated Balloons vs. Drug-Eluting Stents in Small Vessel Interventions) trial was carried out to study treatment of small blood vessels of <3.0 mm diameter, in which patients were randomized to either DCB therapy or second-generation DES. Incidence of major adverse cardiovascular events (MACE) at 12 months was 7.5% in the DCB group and 7.3% in the DES group, which revealed non-inferiority in the DCB group.¹⁰⁸ In this study, durations of DAPT after DCB therapy were stipulated as 4 weeks for stable CAD patients and 12 months for ACS patients, which is possibly 1 strategy for shortening DAPT duration for stable CAD patients.

3. Patients Without PCI (Table 18)

Table 18. Class of Recommendation (COR) and Level of Evidence (LOE) of Antiplatelet Therapy for Patients With ACS and Stable CAD in Whom PCI Is Not Planned

	COR	LOE
Life-long aspirin is recommended unless contraindicated76–78	I	A
DAPT with aspirin 81–100 mg daily plus clopidogrel 75 mg daily should be administered for minimum of 6–12 months in ACS patients112	I	B
Monotherapy with P2Y12 receptor inhibitor may be considered when aspirin is contraindicated108	IIa	C
Monotherapy with aspirin or P2Y12 receptor inhibitor may be considered in patients with HBR6	IIb	C

ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; HBR, high bleeding risk; PCI, percutaneous coronary intervention.

Even after a diagnosis of ACS, occasionally invasive examinations or coronary revascularization cannot be performed because of various patient factors and backgrounds. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial compared a group receiving aspirin monotherapy and a group receiving DAPT with aspirin plus clopidogrel and revealed that fewer cardiovascular events were observed in the DAPT group and an incremental increase in bleeding events was noted according to aspirin dosage in the aspirin monotherapy group.¹¹² The PEGASUS-TIMI54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin Thrombolysis In Myocardial Infarction 54) trial and THEMIS (Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) trial targeting patients with a history of myocardial infarction and diabetic patients without a history of myocardial infarction compared a DAPT group with aspirin plus clopidogrel and a group with aspirin monotherapy. A decrease in cardiovascular events and an increase in bleeding events were noted in the DAPT group.^113,114 However, the TRILOGY (Targeted Platelet Inhibition to Clarify the Optimal Strategy) trial, in which ACS patients under 75 years of age without coronary revascularization were randomized into a DAPT group with aspirin plus prasugrel and a DAPT group with aspirin plus clopidogrel, showed no differences in cardiovascular and bleeding events between the 2 groups.¹¹⁵ It is still unclear whether the results of these clinical trials can be applied to Japanese patients, because the balance of ischemic and bleeding risk in Japanese patients is different from that in Caucasian patients. In Japan, patients who cannot undergo invasive examinations or coronary revascularization are often the oldest-old or likely to have severe concomitant disorders. Thus, prevention of bleeding events might often be more important than trying to maximally decrease cardiovascular events. Anyhow, when conservative medical treatment for either ACS or stable CAD patients without coronary revascularization is planned, assessing HBR should come first and optimal antiplatelet therapy should be pursued under consideration of the individual patient’s condition and comorbidities.

V. Antithrombotic Therapy After PCI in Patients Requiring Oral Anticoagulation (Table 19)

Table 19. Class of Recommendation (COR) and Level of Evidence (LOE) for Patients With CAD Requiring Oral Anticoagulation

	COR	LOE
Triple therapy (Dual therapy with a P2Y12 receptor inhibitor and an OAC) should be considered in patients undergoing coronary stent deployment during the periprocedural period (within 2 weeks)82–84,116–118	I	C
P2Y12 receptor inhibitor and OAC is recommended after periprocedural period for patients undergoing coronary stent deployment83,84,116,117	I	A
In patients with non-valvular AF requiring anticoagulation and antiplatelet treatment, DOACs should be preferred over VKAs83,84,116–118	I	A
VKAs with antiplatelet drug should be chosen after revascularization and acute coronary syndrome in patients with thrombus in the left ventricle or left atrium, due to old myocardial infarction, severe heart failure, left ventricle aneurysm, and patients with mechanical prosthetic valves81,119–123	I	B
Patients with mechanical prosthetic valves may take aspirin together with VKAs beyond 1 year after coronary stent placement124–127	IIa	C
In patients with an indication for a VKA in combination with aspirin and/or a P2Y12 receptor inhibitor, the dose intensity of the VKA should be carefully controlled with a target INR in the lower part of the recommended target range$ and time in the therapeutic range >65%27	IIb	C
OAC without antiplatelet agents is recommended in patients beyond 1 year after coronary stent placement, patients after CABG, and patients with CAD without coronary revascularization*128–130	I	B
Use approved dose of DOACs for prevention of stroke in patients treated with antiplatelet therapy	IIa	A
Triple therapy with aspirin, a P2Y12 receptor inhibitor, and an OAC should not be continued beyond 1 month after PCI in patients with particularly high bleeding risk82–84,116–118,128–130	III Harm	B

*Evidence shown with rivaroxaban. ^$PT-INR 1.6–2.5 (≥70 years), 2.0–2.5 (<70 years). CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; DOAC, direct oral anticoagulant; VKA, Vitamin K antagonist.

Patients with AF,¹³¹ mechanical prosthetic valve,¹¹⁹ thrombus in the left ventricle or atrium,¹²⁰ left ventricular aneurysm,^121,122 deep vein thrombosis/pulmonary thromboembolism, and thrombotic diathesis require OAC therapy to avoid thromboembolic events. In the above, patients with AF are particularly increasing with the aging population, and approximately 10% of PCI patients have concomitant AF.^132,133 The use of long-term OAC (with a vitamin K antagonist [VKA] or DOAC) after PCI is considered as a major ARC-HBR criterion published in 2019 (Table 7).^5,6 For AF patients who do not need OACs (i.e. CHADS₂ score=0), DAPT using aspirin and a P2Y₁₂ receptor inhibitor should be prescribed after stent implantation. When OAC is required in addition to DAPT, discontinuation of aspirin at the time of discharge or for no longer than 1 month has been recommended to decrease bleeding complications in the previous JCS guideline on revascularization of stable CAD (2018 edition).² In the chronic phase of CAD, OAC monotherapy is encouraged based on 2 Japanese randomized studies: the OAC-Alone (Oral Anticoagulation Alone) trial that demonstrated non-inferiority of OAC alone relative to combination therapy with an antiplatelet agent for a composite of cardiovascular and bleeding events, and the AFIRE (Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease) trial that demonstrated superiority of rivaroxaban monotherapy over combination therapy with rivaroxaban and an antiplatelet agent for both bleeding events and cardiovascular events.^129,130 In general, the combination of antithrombotic regimens greatly increases bleeding risks. As the thrombotic risk decreases, the number of antithrombotic agents should be reduced. In this focus update, some recommendations are updated according to several AF-PCI trials published in 2019.

1. Patients With an Indication for Anticoagulation Undergoing PCI and ACS Patients

1.1 Clinical Trials of AF-PCI

Ceasing aspirin and maintaining clopidogrel after PCI was first evaluated in the WOEST (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing) trial comparing dual therapy with an OAC and clopidogrel to triple therapy with an OAC plus DAPT.⁸² The dual therapy demonstrated significantly lower incidence of both bleeding and ischemic events than the triple therapy. This regimen, an OAC plus a P2Y₁₂ receptor inhibitor without aspirin, is to be called the “WOEST-like regimen” and had a large impact on antithrombotic therapy afterwards. However, this trial had several limitations, including a relatively small sample size and only warfarin as the OAC. In the DOAC era, the 4 AF-PCI trials using DOACs have been published comparing the WOEST-like regimen with triple therapy as follows.

• PIONEER AF-PCI trial demonstrated that bleeding events in the dual therapy group with rivaroxaban 15 mg plus clopidogrel 75 mg were significantly fewer than in the triple therapy group, and ischemic events were similar between the 2 groups.⁸⁴ It is of note that rivaroxaban 15 mg is a reduced dose outside Japan, although it is standard dose in Japan.

• RE-DUAL PCI trial compared 2 dabigatran doses and VKA after PCI.⁸³ Although aspirin prescription was limited up to 3 months in the VKA group, both groups of dabigatran doses (220 mg and 300 mg) demonstrated superiority to the VKA group in bleeding events. RE-DUAL PCI included Japanese and East Asian populations. East Asia and Japanese substudy showed results consistent with those in the entire population. Therefore, the results of this study may be applicable to patients in Japan.

• AUGUSTUS study was presented in 2019, comparing aspirin with placebo as well as warfarin with apixaban in a 2×2 factorial design. Rates of ISTH major or clinically relevant bleeding were significantly lower in the apixaban group than in the warfarin group. The aspirin group had major and clinically relevant bleeding twice as high as the placebo group.¹¹⁶ All-cause death and hospitalization were set as efficacy endpoints in this study. The apixaban group demonstrated better efficacy than warfarin for this endpoint, but there was no efficacy with adding aspirin as compared with placebo. However, careful attention should be paid to patients with particularly high risk of stent thrombosis, because a numerically higher incidence of stent thrombosis was observed in the placebo group than in the aspirin group.¹³⁴

• ENTRUST-AF demonstrated that dual therapy using edoxaban and clopidogrel was non-inferior to warfarin triple therapy and tended to have a lower rate of bleeding endpoints.¹¹⁷ This trial was published in 2019.

Four randomized trials and meta-analyses using a DOAC consistently showed 20–40% reduction in bleeding events in the DOAC dual therapy groups as compared with the triple therapy groups without increasing ischemic events (Table 20). According to these clinical trials, long-term use of aspirin should be avoided during anticoagulation, and early termination of aspirin, the so-called “WOEST-like regimen”, is proven to be reasonable. Therefore, it is recommended that triple therapy (OAC plus DAPT) should be given only for the periprocedural period within 2 weeks, followed by dual therapy with a DOAC and clopidogrel. Although there is no evidence regarding the timing of aspirin discontinuation, aspirin should be stopped within 14 days after PCI in order to decrease bleeding¹¹⁸ (Figure 2). On the other hand, aspirin should be given at the time of PCI, because there are no data to date on performing PCI without aspirin. Appropriate duration of dual therapy using a DOAC and P2Y₁₂ receptor inhibitor is thought to be 12 months according to the clinical trials. As an expert opinion, dual therapy may be shortened up to 6 months in patients with very high bleeding risk in line with the recommendation in the European guidelines.^2,135

Table 20. Clinical Trials of AF-PCI Comparing DOAC to Warfarin

	RE-DUAL PCI6	PIONEER AF-PCI133	AUGUSTUS5	ENTRUST AF-PCI82
DOAC	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Study type	Open-label, randomized	Open-label, randomized	Open-label, randomized (ASA vs. placebo blinded)	Open-label, randomized
Patients	2,725	2,124	4,614	1,506
Follow-up	30 months	12 months	6 months	12 months
Japanese patients’ enrollment	Yes	No	No	No
Treatment groups	· D110 mg bid + P2Y12I · D150 mg bid + P2Y12I · WF + ASA + P2Y12I	· R15 mg qd + P2Y12I · R2.5 mg bid + ASA + P2Y12I · WF + ASA + P2Y12I	· A5 mg bid + P2Y12I · A5 mg bid + ASA + P2Y12I · WF + P2Y12I · WF + ASA + P2Y12I	· E60 mg qd + P2Y12I · WF + ASA + P2Y12I
Reduction in bleeding events’ as compared with WF triple therapy group (ISTH major/clinically relevant)	· D110 mg arm 48% · D150 mg arm 28%	· R15 mg arm 41% · R2.5 mg arm 37%	· A5 mg + P2Y12I arm 44%	· E60 mg 17%

A, apixaban; ASA, aspirin; E, edoxaban; D, dabigatran; P2Y₁₂I, P2Y₁₂ receptor inhibitor (clopidogrel, prasugrel, ticagrelor); R, rivaroxaban; WF: warfarin.

1.2 ACS Patients Requiring Anticoagulation

ACS is one of the major conditions with high thrombotic risk. Triple therapy (OAC plus DAPT) was allowed for up to 6 months in the previous JCS guidelines for this subset of patients. However, results of all AF-PCI studies may be applicable for ACS patients, because those trials included ACS patients in more than half of the entire population. Dual therapy with a DOAC and a thienopyridine is superior to triple therapy in ACS patients as well as in stable CAD patients.^136,137 If the patients have some thrombotic risks such as a history of stent thrombosis and a thrombotic diathesis, triple therapy may be considered for 1–3 months.

1.3 Patients With Mechanical Prosthetic Valves

Mechanical heart valves carry a higher risk of thromboembolism than bioprosthetic valves. In this population, aspirin is conventionally prescribed in addition to warfarin without established evidence.¹²⁴ Meta-analysis demonstrated that the addition of antiplatelet therapy was associated with reduced risk of thromboembolic events with an associated increase in major bleeding.^125,126 Low-dose aspirin in addition to an OAC may be justified in patients with mechanical heart valves. Therefore, dual therapy with an OAC and aspirin may be allowed for those patients with mechanical heart valves complicated by chronic phase of CAD. However, studies on this subject are very old and small, which makes it difficult to apply them to the recent guidelines. ESC/EACTS guidelines recommended initiating aspirin only if there is additional risk, such as previous thromboembolism or concurrent CAD, despite adequate warfarin control.¹²⁷

1.4 Antithrombotic Therapy for AF Patients With Stable CAD in the Chronic Phase

There were limited data on antithrombotic therapy for patients with AF and stable CAD, except for registries overseas, when the previous JCS guidelines were issued.¹²⁸ Now, 2 Japanese randomized trials have been published within the past 1 year. The OAC-ALONE study in 2018 failed to show non-inferiority of OAC monotherapy to OAC plus antiplatelet therapy for cardiovascular events because of insufficient power, but demonstrated non-inferiority of OAC monotherapy to OAC plus antiplatelet therapy for the composite of cardiovascular and bleeding events, and a trend towards superiority for bleeding events.¹²⁹ The AFIRE study, published in 2019, enrolled 2,236 Japanese patients with AF and chronic CAD at least 1 year remote from the last coronary revascularization or no prior revascularization. It demonstrated that rivaroxaban monotherapy reduced ischemic events such as death, stroke, thromboembolic events, myocardial infarction, and urgent revascularization by 28%, which was not only non-inferior but also superior to dual therapy, although the superiority analysis was not prespecified. Bleeding events and all-cause death were also significantly decreased by 41% and 45%, respectively.¹³⁰ Because the bleeding risk in Japanese patients is higher than for Caucasians, the prognostic impact of the increase in bleeding complications using both an OAC and an antiplatelet agent as compared with OAC monotherapy would be greater in Japan than in Western countries. Therefore, in this guideline, OAC monotherapy is recommended as the standard antithrombotic regimen for AF patients in the chronic phase of CAD (Figure 2), which may be defined as follows: (1) >1 year remote from the last revascularization, either PCI or CABG; (2) >1 year from recent myocardial infarction; and (3) known CAD, but without coronary revascularization.

2. Japanese Specific Conditions and Recommendations

Considering the high bleeding risk in this patient subset, as well as the accumulated evidence and progress in treatment devices, triple therapy (OAC plus DAPT) should be discontinued at the time of hospital discharge, or for 2 weeks at the longest. The previous JCS guidelines recommended 1-month triple therapy, but in this guideline a very short duration of triple therapy is considered to be preferable, because aspirin was discontinued at the timing of randomization in all 4 AF-PCI studies using DOAC and the longest duration of triple therapy was 2 weeks in the AUGUSTUS trial. If the patient has a particularly high thrombotic risks, 1–3 months’ triple therapy may be considered. If the patient has extremely high bleeding risk, dual therapy with an OAC and an antiplatelet may be shortened to 6 months, while the standard duration of dual therapy is still 12 months. These recommendations may be consistent with the previous JCS guidelines. OAC monotherapy should be the standard antithrombotic regimen after 12 months (Figure 2).

Table 5 demonstrates the high thrombotic risk for stent thrombosis caused by complex PCI procedures as suggested by the ESC guideline. This may be helpful for deciding on the duration of triple therapy in Japan.^29,138 It is nevertheless important to avoid unnecessarily complex procedures, which mandate prolongation of triple therapy with increased risk of bleeding (Table 21).

Table 21. Strategies to Avoid Bleeding Complications in Patients Treated With Oral Anticoagulant

Keep triple therapy (OAC plus DAPT) as short as possible; use dual therapy after PCI (OAC + P2Y12 receptor inhibitor)

Consider the use of DOAC instead of VKA when DOACs are not contraindicated

Consider a target INR in the lower part of recommended target range (20–25 for patients <70 years old, 16–25 for ≥70 years old) and maximize time in therapeutic range (>65%) when VKA is used

Routine use of PPIs

Transradial approach as much as possible

Avoid complex PCI not to increase thrombotic risks if possible

DOAC, direct oral anticoagulant; INR, international normalized ratio; PCI, percutaneous coronary intervention; PPI, proton-pump inhibitor; VKA, vitamin K antagonist.

In cases of severe bleeding or emergency surgery, reversal agents are available for OACs. Idarucizumab is a humanized monoclonal antibody fragment, and completely reverses the anticoagulant effect of dabigatran within minutes by intravenous injection or drip infusion.

Andexanet alfa is a recombinant, modified human Factor Xa that serves as a Factor Xa decoy to sequester direct and indirect Factor Xa inhibitors. Andexanet alfa is currently in phase 3 clinical trial. Prothrombin complex concentrate (PCC) is rapidly effective in reducing antithrombotic activity and is available in Japan. PCC should be considered for management of major bleeding in warfarin-treated patients, because it acts more rapidly than vitamin K administration.

The approved dose of prasugrel (3.75 mg/day) in Japan is much lower than in other countries (10 mg/day). Although the combination of prasugrel and an OAC is contraindicated in Europe and the USA, low-dose prasugrel may be used as part of dual therapy in Japan, because its administration for PCI in ACS patients did not increase bleeding complications in Japanese clinical studies. However, it is important to note that data on prasugrel use in this AF-PCI setting are insufficient so far.¹³⁹

VI. Perioperative Management of Antithrombotic Therapy in Cardiac and Non-Cardiac Surgery

1. Cardiac Surgery

1.1 Preoperative Management of Antithrombotic Therapy in CABG

In patients on aspirin who are scheduled for CABG, continuation of aspirin during the perioperative period has been shown to be associated with a moderately increased risk of bleeding, but with a significant reduction in the risk of perioperative myocardial infarction and death.^143,150 Therefore, it is recommended to continue aspirin (81–162 mg/day) throughout the perioperative period in patients undergoing CABG (Table 22).

Table 22. Class of Recommendation (COR) and Level of Evidence (LOE) for Antithrombotic Therapy in Patients Scheduled for CABG

	COR	LOE
The heart team should estimate the balance between bleeding and thrombotic risks, and guide the timing of CABG as well as the perioperative management of antithrombotic therapy	I	C
In patients undergoing CABG, continue aspirin (81–162 mg/day) throughout the perioperative period	I	C
In patients treated with DAPT after coronary stent deployment who subsequently undergo CABG, resume P2Y12 receptor inhibitor therapy with loading postoperatively as soon as is deemed safe, so that DAPT can be continued for the recommended duration	I	C
In patients with ACS treated with DAPT who undergo CABG and do not require long-term OAC therapy, resume P2Y12 receptor inhibitor therapy with loading postoperatively as soon as is deemed safe, and it should be continued for up to 12 months	I	C
In patients on P2Y12 receptor inhibitors who need to undergo non-emergency CABG, postponing surgery should be considered for at least 3, 5, and 7 days after discontinuation of ticagrelor, clopidogrel, and prasugrel, respectively140–142	IIa	B
In patients with stable CAD who undergo OPCAB, DAPT after surgery is considered to improve the patency of the vein graft143,144	IIa	B
In patients without an indication for anticoagulants, it is not recommended to use anticoagulants to improve the patency of the graft after CABG145,146	III No benefit	A
P2Y12 receptor inhibitors should not be used preoperatively for the purpose of improving the patency of the graft after CABG147–149	III Harm	B

ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, coronary artery disease; DAPT, dual antiplatelet therapy; OAC, oral anticoagulant; OPCAB, off-pump CABG.

It has been demonstrated that DAPT is beneficial in reducing ischemic events compared with aspirin monotherapy in patients with ACS; however, the preoperative continuation of DAPT until CABG in ACS patients increases the risk of perioperative bleeding.^151–153 It has also been shown that continuation of DAPT until surgery does not reduce ischemic events or improve graft patency in stable CAD patients undergoing CABG.^147–149

Therefore, discontinuation of P2Y₁₂ receptor inhibitors prior to CABG is recommended. The timing of CABG in patients treated with DAPT after the onset of ACS needs to be determined based on the balance between thrombotic and bleeding risks. Heart team discussion is recommended for decision making on the timing of CABG as well as the perioperative management of antithrombotic therapy (Table 22).

The time frame for the preoperative discontinuation of P2Y₁₂ receptor inhibitors varies because of the different pharmacological properties of these agents (Table 23).^154,155 The CABG substudy of the CURE trial showed that discontinuation of clopidogrel for ≥5 days before CABG did not increase the risk of bleeding complications.¹⁵¹ In the CABG substudy of the TRITON-TIMI 38 trial, there was a higher incidence of CABG-related bleeding complications with prasugrel than with clopidogrel.¹⁵³ Prasugrel has a longer offset time of action than clopidogrel, and the preoperative discontinuation interval for prasugrel should be longer (i.e. at least 7 days before the surgery) than that for clopidogrel.^154,155 Several large observational studies in patients undergoing CABG demonstrated that preoperative discontinuation of ticagrelor for ≥3 days was not associated with an increased risk of bleeding-related complications.^140–142 Based on these findings, it is recommended that ticagrelor, clopidogrel, and prasugrel be discontinued before non-emergency CABG for at least 3, 5, and 7 days, respectively (Tables 22,23). Some observational studies have shown that platelet function testing may be useful to guide decisions on the timing of CABG in patients who have recently received P2Y₁₂ receptor inhibitors.^156–159

Table 23. Pharmacological Properties of P2Y₁₂ Receptor Inhibitors

	Clopidogrel	Prasugrel	Ticagrelor
Receptor blockade	Irreversible	Irreversible	Reversible
Prodrug	Yes	Yes	No
Half-life	~6 h	~7 h	8–12 h
Type of binding	Competitive	Competitive	Noncompetitive
Frequency	Once daily	Once daily	Twice daily
Onset of action	2–8 h	30 min to 4 h	30 min to 4 h
Offset of action	5–7 days	7–10 days	3–5 days
Drug interaction with CYP enzymes	CYP2C19	No	CYP3A

CYP, cytochrome P450 (modified from reference¹⁵⁵).

1.2 Postoperative Antithrombotic Therapy After CABG

In patients treated with DAPT after coronary stent deployment who subsequently undergo CABG, it is recommended to resume P2Y₁₂ receptor inhibitor therapy with loading postoperatively as soon as is deemed safe, and DAPT should be continued until the recommended duration of therapy is completed. The effect of postoperative DAPT on clinical outcomes in ACS patients who undergo CABG has been investigated in several studies. In the CABG substudy of the CURE trial, DAPT using clopidogrel showed fewer cardiovascular events (cardiovascular death, myocardial infarction and stroke) and greater bleeding complications at 1 year than aspirin monotherapy, although the differences were not statistically significant.¹⁵¹ The CABG substudies of the TRITON-TIMI 38 and PLATO trials along with a meta-analysis showed that DAPT using potent P2Y₁₂ receptor inhibitors such as prasugrel or ticagrelor following CABG in ACS patients resulted in lower mortality than DAPT using clopidogrel; however, an increase in bleeding was observed in the prasugrel, but not in the ticagrelor group compared with the clopidogrel group.^152,153,160 Therefore, in ACS patients treated with DAPT and CABG, it is recommended to resume P2Y₁₂ receptor inhibitor therapy with loading postoperatively as soon as is deemed safe, and it should be continued for up to 12 months (Table 22). In contrast, postoperative DAPT in stable CAD patients who undergo CABG has not been shown to reduce mortality. Nevertheless, several randomized controlled trials and meta-analyses have shown that postoperative DAPT improves the patency of the vein graft compared with aspirin monotherapy in patients with stable CAD who undergo CABG (especially off-pump CABG).^{27,143,144,161–163}

There is limited evidence on the clinical impact of triple therapy (OAC+DAPT) after CABG in patients who require OAC. Considering that triple therapy substantially increases bleeding complications compared with double therapy (OAC and single antiplatelet therapy) without reducing thrombotic events after PCI, triple therapy should be avoided after CABG. A meta-analysis showed that the postoperative use of warfarin did not exhibit improved efficacy in terms of graft patency after CABG compared with aspirin monotherapy.¹⁴⁵ Because bleeding complications are less with aspirin than with warfarin, aspirin monotherapy is preferable to warfarin for improving graft patency after CABG. In addition, the Post CABG trial revealed that the additional use of low-dose warfarin combined with aspirin did not improve graft patency.¹⁴⁶ Based on these findings, it is not recommended to use anticoagulants to improve graft patency after CABG in patients without a formal indication for anticoagulants (Table 22).^145,146 Nevertheless, the clinical effectiveness of a DOAC after CABG has not been investigated in randomized controlled trials, and should be evaluated in future trials.

1.3 Cardiac Surgeries Other Than CABG

Perioperative management in cardiac surgery in previous guidelines generally refers to CABG, and the clinical evidence on perioperative management in cardiac surgeries other than CABG (e.g. valve replacement or valve repair) is limited. In patients with CAD, perioperative management of antithrombotic therapy in cardiac surgeries other than CABG should generally conform to that in CABG.¹⁶⁴ However, postoperative antithrombotic therapy for improving graft patency does not need to be taken into account unless CABG is simultaneously performed. Perioperative management of anticoagulant therapy, which is generally required in patients who undergo valve replacement, will be described later (see Chapter VI 2.4 and 2.5).

2. Non-Cardiac Surgery (Table 24)

Table 24. Class of Recommendation (COR) and Level of Evidence (LOE) for Perioperative Antithrombotic Therapy in Patients Undergoing Elective Non-Cardiac Surgery

	COR	LOE
It is recommended to evaluate the perioperative risk of bleeding for the management of perioperative antithrombotic therapy	I	C
It is recommended to continue aspirin perioperatively if the bleeding risk allows, and to resume the recommended antiplatelet therapy (with loading in case of a resumption of P2Y12 receptor inhibitor therapy) as soon as possible postoperatively (within 24–72 h)164–169	I	B
In patients treated with DAPT after DES deployment undergoing elective non-cardiac surgery, it is recommended to postpone surgery to 6 months or later after DES deployment if possible170	I	B
In patients with low thrombotic risk who are on DAPT after DES deployment and undergoing elective non-cardiac surgery, postponing surgery for 3 months or more after DES deployment should be considered170–172	IIa	B
Discontinuation of P2Y12 receptor inhibitors should be considered at least 3, 5, and 7 days before surgery for ticagrelor, clopidogrel, and prasugrel, respectively140–142	IIa	B
A multidisciplinary expert team should be considered for preoperative evaluation of patients with an indication for DAPT before elective surgery	IIa	C
In patients treated with DAPT after DES deployment, elective non-cardiac surgery may be postponed for up to 3 months (in low thrombotic risk) or for up to 6 months (in high thrombotic risk*), if aspirin is continued perioperatively.167,170–172	IIb	C
It is not recommended to use perioperative heparin as bridging therapy for antiplatelet therapy165	III No benefit	B
In patients with atrial fibrillation, the preoperative use of heparin as bridging therapy for warfarin is not recommended173	III No benefit	B
Elective non-cardiac surgery should not be performed within 1 month after coronary stent deployment174	III Harm	B

*High thrombotic risk includes patients who undergo PCI for ACS or complex PCI (see Chapter II). ACS, acute coronary syndrome; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; PCI, percutaneous coronary intervention.

2.1 Preoperative Evaluation in Non-Cardiac Surgery

It is estimated that 5–25% of patients who have received coronary stents will need to undergo non-cardiac surgery within 5 years after stent deployment.¹⁷⁵ A higher risk of cardiovascular events has been reported, especially in the early postoperative period after non-cardiac surgery, in patients with coronary stents.^174,176,177 Perioperative discontinuation of antiplatelet therapy increases the risk of coronary thrombosis, particularly in stented segments. Surgery per se is associated with pro-inflammatory and pro-thrombotic effects, which also increases the risk of thrombosis in the entire coronary arterial tree, including stented segments.^178,179 The timing of the surgery and perioperative management of antithrombotic therapy in patients on DAPT undergoing surgical procedures need to be determined with consideration of the following: (1) the surgical bleeding risk, (2) the individual bleeding risk, (3) the thrombotic risk particularly if DAPT needs to be interrupted, and (4) the consequences of delaying surgery.^147,180,181 Given the complexity of these considerations, a multidisciplinary expert team involving cardiologists, anesthesiologists, and surgeons should be considered for preoperative evaluation in elective surgery (Table 24). If antithrombotic therapy needs to be interrupted perioperatively, the surgical bleeding risk and perioperative thrombotic risk should be explained to the patient before the surgery to obtain consent for the perioperative discontinuation of antithrombotic therapy.

2.2 Timing of Non-Cardiac Surgery

In elective non-cardiac surgery after PCI, it is recommended to postpone the surgery until completion of the recommended duration of DAPT to reduce the risk of perioperative thrombosis and bleeding. Previous recommendations for the duration of DAPT and the timing of non-cardiac surgery in patients treated with DES were generally based on observations in those who received first-generation DES.^181–184 It is recommended that elective non-cardiac surgery be postponed for 6 months or more after DES deployment if the risk of delaying surgery is acceptable (Figure 4, Table 24).¹⁷⁰ However, newer-generation DES have exhibited a lower risk of stent thrombosis and appear to require a shorter minimum duration of DAPT than first-generation DES.^{46,93,185,186} Many registries have shown that the perioperative thrombotic risk in non-cardiac surgery in patients who received DES deployment reaches a stable level at 3–6 months after PCI.^170–172 Therefore, in patients with low thrombotic risk who require elective non-cardiac surgery soon after DES deployment, postponing surgery for 3 months or more after PCI should be considered (Figure 4, Table 24). In patients at high thrombotic risk because of ACS or complex PCI procedure, postponing surgery for 6 months or more after DES deployment may be reasonable to minimize the risk of perioperative thrombotic complications. Two large cohort studies investigating patients who received coronary stents and underwent surgery have demonstrated that the risk of postoperative adverse cardiac events including myocardial infarction was high within the first month after PCI.^187,188 DAPT should not be discontinued within 1 month after stent deployment, and considering the high surgical bleeding risk when surgery is performed during continuation of DAPT, elective non-cardiac surgery should not be performed within 1 month after coronary stent deployment (Figure 4, Table 24).^174,189 When non-cardiac surgery cannot be delayed for a longer period (>3–6 months), postponing surgery for 1–3 (in low thrombotic risk) or 1–6 months (in high thrombotic risk) after DES deployment may be considered if aspirin is continued perioperatively (Figure 4, Table 24).^{167,170–172} In those cases, however, non-cardiac surgery should be performed in a hospital where catheterization laboratories are available on a 24-hour basis so that perioperative thrombotic events can be treated immediately. In the case of emergency or urgent surgery within 1 month after stent deployment, surgical procedures during continuation of DAPT are inevitable, and careful management of perioperative bleeding is required.

Figure 4.

Timing of elective non-cardiac surgery following PCI. *“High thrombotic risk” includes patients who underwent PCI for ACS or complex PCI (see Chapter II). In the case of emergency or urgent surgery within 1 month after PCI (except for POBA), procedures during continuation of DAPT are inevitable and careful management of perioperative bleeding is required.

It has been reported that plain old balloon angioplasty (POBA) alone was not associated with perioperative cardiac events after non-cardiac surgery performed soon after PCI.^190,191 In patients treated by POBA alone who need to undergo non-cardiac surgery, postponing surgery for 2 weeks or more (≥1 month if possible) after PCI should be considered (Figure 4).^175,190,191 In patients undergoing non-cardiac surgery who received bare metal stents (BMS), postponing surgery for 1 month or more (≥3 months if possible) after PCI should be considered to avoid perioperative thrombotic complications (Figure 4).^175,188 There is little evidence for the management of antithrombotic therapy in patients treated by drug-coated balloon (DCB) undergoing non-cardiac surgery. In the ESC guidelines (2017 focused update), the recommended duration of DAPT after DCB treatment is the same as that after DES or BMS deployment: 6 months in ACS patients with high bleeding risk (Class IIa, evidence level B), and 3 months (Class IIa, evidence level B) or 1 month (Class IIb, evidence level C) in stable CAD patients with high bleeding risk.²⁷ The BASKET-SMALL 2 trial showed that DCB was not inferior to DES with respect to major adverse cardiac events (MACE) in patients with a small native CAD (<3.0 mm in diameter), in which stable CAD patients treated by DCB received DAPT for 1 month.¹⁰⁸ The current guideline recommends that non-cardiac surgery be postponed for 3 months or more after DCB treatment, but postponing surgery for 1–3 months after DCB treatment may be considered when surgery cannot be delayed (Figure 4).

2.3 Classification of the Risks of Non-Cardiac Surgery

Patients who require non-cardiac surgical interventions can be divided into low-, intermediate-, and high-risk groups based on the prediction model for 30-day mortality (Surgical Mortality Probability Model [S-MPM]). With this model, 30-day mortality has been reported to be <0.5% in low-, 1.5-4.0% in intermediate-, and >10% in high-risk groups.^175,192 Classification of the bleeding risk in non-cardiac surgery has been proposed in a consensus document from Italian societies of cardiology, surgery, and anesthesiology,¹⁶⁴ and the 2018 European Heart Rhythm Association Practical Guide.¹³⁵ In the current guideline, patients who require non-cardiac surgery are first classified into low-, intermediate-, and high-risk groups based on their surgical bleeding risk, followed by assessment of the individual risk of perioperative thrombosis and bleeding to determine the perioperative management of antithrombotic therapy (Figure 5, Table 25).^{135,164,193–195} With a low surgical bleeding risk, it is recommended to continue aspirin perioperatively, and P2Y₁₂ receptor inhibitor therapy is discontinued in patients with low perioperative thrombotic risk, although continuation of P2Y₁₂ receptor inhibitor therapy is considered in patients with high perioperative thrombotic risk, which includes those who are within the recommended period of DAPT. With an intermediate surgical bleeding risk, it is recommended to continue aspirin and discontinue P2Y₁₂ receptor inhibitor therapy, irrespective of the perioperative thrombotic risk, although both aspirin and P2Y₁₂ receptor inhibitors should be discontinued in thoracic surgery. With a high surgical bleeding risk, DAPT should be discontinued in patients with low perioperative thrombotic risk, although the continuation of aspirin is considered in those with high thrombotic risk. However, in cases when bleeding becomes a critical complication, such as surgeries in an enclosed space (e.g. spinal, intracranial, and eye posterior chamber surgeries) or thoracic surgery, DAPT should be discontinued even in patients with high thrombotic risk (Figure 5, Table 25).^{135,164,193–195}

Figure 5.

Perioperative management of antiplatelet therapy in patients with coronary artery disease (CAD) who undergo non-cardiac surgery. DAPT, dual antiplatelet therapy. P2Y₁₂I: P2Y₁₂ receptor inhibitor. In addition to surgical bleeding risk, individual bleeding risk needs to be taken into account. *High perioperative thrombotic risk includes patients on DAPT during the recommended period. For other thrombotic risks, see Chapter II.

Table 25. Surgical Bleeding Risks With Non-Cardiac Surgery

	Low surgical bleeding risk	Intermediate surgical bleeding risk	High surgical bleeding risk
General surgery	Hernioplasty, plastic surgery of incisional hernias, cholecystectomy, appendectomy, colectomy, gastric resection, intestinal resection, breast surgery, superficial surgery (e.g. abscess incision, small dermatologic excisions)	Hemorrhoidectomy, splenectomy, gastrectomy, obesity surgery, rectal resection, thyroidectomy	Hepatic resection, duodenocefalopancreasectomy
Vascular surgery	Carotid endarterectomy, bypass or endarterectomy of the lower extremity, thoracic endovascular aortic repair (TEVAR), endovascular aortic repair (EVAR), limb amputations	Open abdominal aorta surgery	Open thoracic and thoracoabdominal surgery
Orthopedic surgery	Hand surgery, shoulder and knee arthroscopy, minor spine surgery	Prosthetic shoulder surgery, major spine surgery, knee surgery (anterior cruciate ligament, osteotomies), foot surgery	Major prosthetic surgery (hip or knee), major traumatology (pelvis, long bones), fractures of the proximal femur in the elderly
Urology surgery	Flexible cystoscopy, ureteral catheterization, ureteroscopy	Prostate biopsy, orchiectomy, circumcision	Radical and partial nephrectomy, percutaneous nephrostomy, percutaneous lithotripsy, cystectomy, radical prostatectomy, transurethral resection of prostate (TURP), transurethral resection of bladder tumor (TURBT), penectomy, partial orchiectomy
Thoracic surgery	Wedge resection, diagnostic videothoracoscopy, chest wall resection	Lobectomy, pneumonectomy, mediastinoscopy, sternotomy, mediastinal mass excision	Esophagectomy, pleuropneumonectomy, decortication of lung
Digestive endoscopy	Upper gastrointestinal endoscopy or colonoscopy with or without biopsy, echoendoscopy without biopsy, capsule endoscopy, endoscopic retrograde cholangiopancreatography (ERCP), balloon endoscopy, endoscopic marking, stent placement (pancreatic, biliary, etc.), dilated papilla without sphincterotomy	Polypectomy, endoscopy with fine needle aspiration biopsy for solid lesions, stenosis dilatation (esophageal, colorectal), argon plasma coagulation treatment, percutaneous endoscopic gastrostomy (PEG), endoscopic treatment of gastroesophageal varices	Dilatation in achalasia, mucosectomy, submucosal resection, ampullectomy of the ampulla of Vater, echography with fine needle aspiration biopsy of pancreatic cystic lesions
Others	Dental interventions (teeth extraction, periodontal surgery, incision of abscess, implant positioning), cataract surgery, bronchoscopy, etc.	Bronchial biopsy, transbronchial needle aspiration, etc.	Spinal or epidural anesthesia, lumbar diagnostic puncture, spinal and cranial neurosurgery, eye posterior chamber surgery, etc.

Ref. EuroIntervention 2014; 10: 38¹⁶⁴ and Eur Heart J 2018; 39: 1330.¹³⁵

2.4 Discontinuation of Antithrombotic Therapy Before Non-Cardiac Surgery

a. Antiplatelet Therapy

Perioperative continuation of aspirin in non-cardiac surgery has been shown to increase the frequency of bleeding complications 1.5-fold more than the withdrawal of aspirin, although it did not lead to an increased severity of bleeding complications.¹⁷¹ On the other hand, a meta-analysis showed that non-adherence or withdrawal of aspirin was associated with a 3-fold higher risk of MACE, suggesting that aspirin discontinuation should be considered only when the bleeding risk clearly overwhelms that of the thrombotic risk.¹⁹⁶ In the majority of non-cardiac surgeries, aspirin provides benefit that outweighs the bleeding risk; therefore, it should be continued perioperatively if the bleeding risk allows (Figures 5,6A, Table 24). However, in cases of high surgical bleeding risk with low perioperative thrombotic risk, or in cases when bleeding becomes a critical complication such as in thoracic, spinal, intracranial, or eye posterior chamber surgeries, discontinuation of aspirin should be considered at least 7 days before surgery (Figures 5,6B).^{9,27,171,172,197}

Figure 6.

Time frames for discontinuation and reimplementation of antiplatelet therapy in patients undergoing elective surgery. It is recommended to continue aspirin perioperatively if the bleeding risk allows. However, in case of high surgical bleeding risk with low perioperative thrombotic risk, or if bleeding becomes a critical complication, discontinuation of aspirin should be considered at least 7 days before surgery.

In contrast, most non-cardiac surgeries require discontinuation of P2Y₁₂ receptor inhibitors (Figure 5). Discontinuation of ticagrelor, clopidogrel, and prasugrel should be considered at least 3, 5, and 7 days before surgery, respectively (Figure 6, Tables 23,24).^140–142 In cases where the consequences of even minor bleeding would be unacceptable (e.g. spinal surgeries or other neurosurgical procedures) or the bleeding risk largely outweighs the ischemic risk (e.g. high surgical bleeding risk in stable CAD patients who received a single stent more than 6 months earlier), P2Y₁₂ receptor inhibitors may be discontinued for a longer duration to ensure no residual platelet inhibition at the time of planned surgery.

In Western countries, bridging therapy with intravenous, reversible glycoprotein IIb/IIIa receptor inhibitors such as eptifibatide or tirofiban may be considered in patients with a very high risk of stent thrombosis.¹⁹⁸ However, these agents are not approved in Japan. Cangrelor, a reversible intravenous P2Y₁₂ receptor inhibitor, has been shown to effectively inhibit platelet aggregation¹⁹⁹ and exhibit a quicker offset of action than eptifibatide or tirofiban.²⁰⁰ Considering the well-known role of P2Y₁₂ receptor inhibition in preventing stent thrombosis in addition to the aforementioned characteristics, cangrelor is a more attractive alternative to glycoprotein IIb/IIIa receptor inhibitors; however, this agent is not approved in Japan. It is not recommended to use perioperative heparin as bridging therapy for antiplatelet therapy, because the effectiveness of bridging therapy with heparin in preventing stent thrombosis has not been proven (Table 24).¹⁶⁵

The PARIS registry is a prospective observational study that investigated the relationship between DAPT cessation and cardiac events during a 2-year period after PCI with stent deployment. The study showed that DAPT cessation because of disruption (non-compliance or because of bleeding) was associated with an increased risk of MACE at an early time point after cessation, whereas interruption of DAPT based on physician judgement in patients undergoing surgery at any time point after PCI was not associated with an increased risk of MACE.¹⁷⁰ When patients on P2Y₁₂ receptor inhibitor monotherapy undergo non-cardiac surgery, preoperative switching to aspirin monotherapy and the perioperative continuation of aspirin may be considered; however, because there is little evidence on this point, this needs to be investigated in future trials.

b. Anticoagulant Therapy

In patients on OAC therapy who undergo minor bleeding-risk surgery or procedures where bleeding is easily controlled (e.g. teeth extraction or superficial surgery), it is recommended not to interrupt OAC therapy perioperatively (Table 26). In patients on a DOAC who undergo low bleeding-risk surgery, it is recommended that they take the last DOAC dose at least 24 h before surgery if kidney function is normal.¹³⁵ For patients on dabigatran, the timing of last intake should be at least 36 h before surgery if Ccr is 50–79 mL/min and at least 48 h if Ccr is 30–49 mL/min. For patients on rivaroxaban, apixaban, or edoxaban, with a CCr of 15–29 mL/min, the timing of last intake should be at least 36 h before surgery (Table 26). In patients on a DOAC undergoing intermediate or high bleeding-risk surgery, it is recommended to take the last DOAC dose at least 48 h before surgery when kidney function is normal.¹³⁵ For patients on dabigatran, the timing of last intake should be at least 72 h before surgery if creatinine clearance (Ccr) is 50–79 mL/min and at least 96 h if Ccr is 30–49 mL/min (Table 26). In patients on warfarin who undergo low, intermediate, or high bleeding-risk surgery, discontinuation of warfarin from 3 to 5 days before surgery should be considered (Table 26).

Table 26. Time Frames for Discontinuation and Reimplementation of Anticoagulant Therapy in Patients Undergoing Elective Surgery

A. Minor surgical bleeding risk or procedures where bleeding is easily controlled (e.g. teeth extractions, superficial surgery)
		Day −5	Day −4	Day −3	Day −2	Day −1	Day of surgery	Day +1	Day +2	Day +3
DOAC		〇	〇	〇	〇	△ (≥12 h)	△ Resume ≥6~8 h post surgery	〇	〇	〇
Warfarin		〇	〇	〇	〇	〇	△ Resume within 24 h post surgery	〇	〇	〇
B. Low surgical bleeding risk
		Day −5	Day −4	Day −3	Day −2	Day −1	Day of surgery	Day +1	Day +2	Day +3
Dabigatran	Ccr ≥80 mL/min	〇	〇	〇	〇	△ (≥24 h)	△ Resume ≥6~8 h post surgery	〇	〇	〇
	Ccr 50~79 mL/min	〇	〇	〇	△ (≥36 h)	X*		〇	〇	〇
	Ccr 30~49 mL/min	〇	〇	〇	△ (≥48 h)	X*		〇	〇	〇
Rivaroxaban Apixaban Edoxaban	Ccr ≥30 mL/min	〇	〇	〇	〇	△ (≥24 h)		〇	〇	〇
	Ccr 15~29 mL/min	〇	〇	〇	△ (≥36 h)	X*		〇	〇	〇
Warfarin		△ (>3~5d)	△ (>3~5d)	X*	X*	X*	△* Resume within 24 h post surgery	〇*	〇*	〇*
C. Intermediate or high surgical bleeding risk
		Day −5	Day −4	Day −3	Day −2	Day −1	Day of surgery	Day +1	Day +2	Day +3
Dabigatran	Ccr ≥80 mL/min	〇	〇	〇	△ (≥48 h)	X*	△* Resume ≥6~8 h post surgery (as soon as possible) with consideration of bleeding status		△* Resume ≥48~72 h post surgery in case of uncontrolled bleeding
	Ccr 50~79 mL/min	〇	〇	△ (≥72 h)	X*	X*
	Ccr 30~49 mL/min	〇	△ (≥96 h)	X*	X*	X*
Rivaroxaban, Apixaban, Edoxaban		〇	〇	〇	△ (≥48 h)	X*
Warfarin		△ (>3~5d)	△ (>3~5d)	X*	X*	X*	△* Resume within 24 h post surgery	〇*	〇*	〇*

〇: Intake. △: Decision to take or not take medicine based on the time schedule of the surgery and the patient’s condition. The time within the parenthesis denotes the recommended timing of last intake before surgery. X: Stop therapy. *Bridging with heparin is not recommended in principle. However, if the strict control of anticoagulation is required (e.g. patients who have an artificial valve, etc.), bridging with heparin may be considered. In addition, in case of uncontrolled bleeding after surgery, bridging with heparin may be considered, which potentially allows the prevention of thromboembolism as well as easier management of bleeding. DOAC, direct oral anticoagulant. Ref, Eur Heart J 2018; 39: 1330.¹³⁵

In patients taking warfarin who undergo surgery, perioperative bridging therapy with heparin has been conventionally conducted. In the BRIDGE trial, patients with atrial fibrillation on warfarin undergoing elective surgeries or invasive procedures were randomly assigned to receive bridging therapy with low-molecular-weight heparin or placebo. The incidence of arterial thromboembolism during the 30 days after the procedure did not differ between the groups, although the incidence of major bleeding was significantly higher in the bridging group.¹⁷³ Based on these findings, the preoperative use of heparin as bridging therapy for warfarin is not recommended in patients with atrial fibrillation (Tables 24,26). However, if strict control of anticoagulation is required (e.g. patients who have an artificial valve, etc.), perioperative bridging with heparin may be considered. In patients taking a DOAC, the predictable waning of the anticoagulation effect allows properly timed short-term cessation of DOAC therapy before surgery; therefore, bridging therapy with heparin may not be required.¹³⁵

For dabigatran, a specific reversal agent, idarucizumab, is available in Japan. Idarucizumab is a humanized monoclonal antibody fragment that binds dabigatran with high affinity and specificity, and rapidly reverses its anticoagulation activity. The anticoagulation reversal by idarucizumab can be used in patients taking dabigatran who present with life-threatening bleeding or have to undergo urgent high bleeding-risk surgery or intervention. The RE-VERSE AD trial showed that the intravenous administration of idarucizumab completely reversed the anticoagulant effect of dabigatran within minutes, which was maintained for 24 h in most patients.²⁰¹ In the full cohort analysis of the RE-VERSE AD trial, the median time to the cessation of bleeding was 2.5 h among patients with overt bleeding (except for intracranial hemorrhage) who could be assessed, and the median time to the initiation of the intended procedure was 1.6 h among patients who required an urgent procedure.²⁰²

2.5 Reimplementation of Antithrombotic Therapy After Non-Cardiac Surgery

In the case of preoperative discontinuation of P2Y₁₂ receptor inhibitors, it is recommended to resume P2Y₁₂ receptor inhibitor therapy with loading as soon as possible postoperatively (within 24–72 h), and continue DAPT until the recommended duration of therapy is completed (Figure 6, Table 24).^164–166 DOAC therapy can be generally resumed at 6–8 h after the end of surgery if bleeding is well controlled. In the case of uncontrolled postoperative bleeding, the resumption of a DOAC should be considered at 48–72 h after surgery (Table 26). In patients receiving idarucizumab preoperatively, dabigatran can be restarted as early as 24 h after surgery because of its short half-life (initial half-life: ∼45 min),²⁰³ and other DOACs can be started at any time postoperatively (≥6–8 h after surgery), even after idarucizumab administration. Warfarin should be restarted postoperatively as soon after surgery as is deemed safe (whenever the bleeding is well controlled). In the BRIDGE trial, warfarin was restarted within 24 h after surgery in patients without bridging therapy, which resulted in reduced bleeding without increasing thromboembolism compared with those who received bridging therapy with heparin. Based on these findings, postoperative bridging therapy with heparin should not be required in patients with atrial fibrillation who undergo elective surgery (Table 26).¹⁷³ Nevertheless, given that only 10% of the patients had major surgeries in the BRIDGE trial, there is the possibility that the postoperative use of heparin may be useful in some cases for the prevention of thromboembolism and easier management of bleeding, especially in high bleeding-risk surgeries.

Appendix 1 Details of Members

Chair

• Kazuo Kimura, MD, PhD, Division of Cardiology, Yokohama City University Medical Center

• Masato Nakamura, MD, PhD, Division of Cardiovascular Medicine, Toho University Ohashi Medical Center

Members

• Masaharu Ishihara, MD, PhD, Department of Cardiovascular and Renal Medicine, Hyogo College of Medicine

• Takeshi Kimura, MD, PhD, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine

• Masami Kosuge, MD, PhD, Division of Cardiology, Yokohama City University Medical Center

• Ken Kozuma, MD, PhD, Division of Cardiology, Department of Internal Medicine, Teikyo University School of Medicine

• Yoshihisa Nakagawa, MD, PhD, Division of Cardiovascular Medicine, Department of Internal Medicine, Shiga University of Medical Science

• Masahiro Natsuaki, MD, PhD, Department of Cardiovascular Medicine, Saga University

• Fumiyuki Otsuka, MD, PhD, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center

• Toshiro Shinke, MD, PhD, Division of Cardiology, Department of Medicine, Showa University School of Medicine

• Satoshi Yasuda, MD, PhD, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center

External Evaluation Committee Members

• Takashi Akasaka, MD, PhD, Department of Cardiovascular Medicine, Wakayama Medical University

• Kazuo Haze, MD, PhD, Department of Cardiology, Kashiwara Municipal Hospital

• Atsushi Hirayama, MD, PhD, Cardiovascular Division, Osaka Police Hospital

• Shun Kohsaka, MD, PhD, Department of Cardiology, Keio University School of Medicine

Appendix 2 Disclosure of Potential Conflicts of Interest (COI): JCS 2020 Guideline Focused Update on Antithrombotic Therapy in Patients With Coronary Artery Disease

Author	Employer/ leadership position (private company)	Shareholder	Patent royalty	Honorarium	Payment for manuscripts	Research grant	Scholarship (educational) grant	Endowed chair	Other rewards	Potential COI of the marital partner, first-degree family members, or those who share income and property	Research grant	Scholarship (educational) grant
Chair: Kazuo Kimura				Daiichi Sankyo Company, Limited Sanofi K.K. Bristol-Myers Squibb Boehringer Ingelheim Japan, Inc.		Otsuka Pharmaceutical Co., Ltd. Bayer Yakuhin, Ltd. Research Institute for Production Development Japan Agency for Medical Research and Development Sanofi K.K. Bristol-Myers Squibb	Takeda Pharmaceutical Company Limited Ono Pharmaceutical Co., Ltd. Bayer Yakuhin, Ltd.
Chair: Masato Nakamura				Sanofi K.K. TERUMO CORPORATION Daiichi Sankyo Company, Limited Bayer Yakuhin, Ltd.	Daiichi Sankyo Company, Limited	Daiichi Sankyo Company, Limited Sanofi K.K.
Members: Masaharu Ishihara				Amgen Astellas BioPharma K.K. MSD K.K. Sanofi K.K. Bayer Yakuhin, Ltd. Daiichi Sankyo Company, Limited		Amgen Astellas BioPharma K.K.	MSD K.K. Astellas Pharma Inc. Abbott Vascular Japan Co., Ltd. MID,Inc. Goodman Co.,LTD. Sanofi K.K. Sumitomo Dainippon Pharma Co., Ltd. Takeda Pharmaceutical Company Limited TERUMO CORPORATION Nipro Corporation Nippon Shinyaku Co., Ltd. Bayer Yakuhin, Ltd. Pfizer Japan Inc. Fukuda Life Tech Co. Ltd. Fukuda Denshi Co., Ltd Boston Scientific Corporation Shionogi & Co., Ltd. Kowa Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Teijin Pharma Limited Mitsubishi Tanabe Pharma Corporation Japan Lifeline Co.,Ltd.	Abbott Medical Japan L.L.C Medtronic Japan Co., Ltd. Boehringer Ingelheim Japan, Inc.			Amgen Astellas BioPharma K.K.	Abbott Vascular Japan Co., Ltd. Otsuka Pharmaceutical Co., Ltd. Takeda Pharmaceutical Company Limited
Members: Fumiyuki Otsuka				Abbott Vascular Japan Co., Ltd. Boston Scientific Corporation
Members: Takeshi Kimura				Amgen Astellas BioPharma K.K. Abbott Vascular Japan Co., Ltd. Kowa Pharmaceutical Co., Ltd. Sanofi K.K. Daiichi Sankyo Company, Limited Boehringer Ingelheim Japan, Inc. Bristol-Myers Squibb Boston Scientific Corporation		Nipro Corporation EP-CRSU Co., Ltd. Edwards Lifesciences Corporation Daiichi Sankyo Company, Limited Pfizer Japan Inc.	Daiichi Sankyo Company, Limited Mitsubishi Tanabe Pharma Corporation Takeda Pharmaceutical Company Limited Boehringer Ingelheim Japan, Inc. Otsuka Pharmaceutical Co., Ltd. Astellas Pharma Inc.
Members: Ken Kozuma				Sanofi K.K. TERUMO CORPORATION Abbott Vascular Japan Co., Ltd. Daiichi Sankyo Company, Limited Bayer Yakuhin, Ltd. Edwards Lifesciences Corporation Boehringer Ingelheim Japan, Inc. Boston Scientific Corporation Bristol-Myers Squibb Takeda Pharmaceutical Company Limited ZEON MEDICAL INC Life Science Institute, Inc.		Edwards Lifesciences Corporation MEDICO’S HIRATA INC. Abbott Vascular Japan Co., Ltd.	Astellas Pharma Inc. Abbott Vascular Japan Co., Ltd. Daiichi Sankyo Company, Limited
Members: Masami Kosuge				Daiichi Sankyo Company, Limited
Members: Toshiro Shinke				Daiichi Sankyo Company, Limited Abbott Vascular Japan Co., Ltd. Sanofi K.K. Bayer Yakuhin, Ltd. Daiichi Sankyo Company, Limited Goodman Co.,LTD.		Daiichi Sankyo Company, Limited Abbott Vascular Japan Co., Ltd.	Otsuka Pharmaceutical Co., Ltd. Daiichi Sankyo Company, Limited Boehringer Ingelheim Japan, Inc. Medtronic Japan Co., Ltd. Nihon Kohden Corp. Fukuda Life Tech Co. Ltd. Fukuda Denshi Co., Ltd Philips Respironics GK. TEIJIN LIMITED Boston Scientific Corporation Abbott Medical Japan L.L.C Japan Lifeline Co.,Ltd.					Boston Scientific Corporation Japan Lifeline Co.,Ltd. Philips Respironics GK. Fukuda Denshi Co., Ltd
Members: Yoshihisa Nakagawa				Daiichi Sankyo Company, Limited Bayer Yakuhin, Ltd. Abbott Vascular Japan Co., Ltd. Bristol-Myers Squibb Kowa Pharmaceutical Co., Ltd. Boston Scientific Corporation Sanofi K.K. MSD K.K.			Bayer Yakuhin, Ltd.
Members: Masahiro Natsuaki				AstraZeneca K.K. Abbott Vascular Japan Co., Ltd. Daiichi Sankyo Company, Limited Amgen Astellas BioPharma K.K.
Members: Satoshi Yasuda				Daiichi Sankyo Company, Limited Abbott Vascular Japan Co., Ltd. Bristol-Myers Squibb Takeda Pharmaceutical Company Limited Sanofi K.K. Bayer Yakuhin, Ltd. AstraZeneca K.K.		TERUMO CORPORATION Abbott Vascular Japan Co., Ltd. Bayer Yakuhin, Ltd. Quintiles Transnational Japan k.k. JSR Corporation Takeda Pharmaceutical Company Limited IQVIA Services Japan K.K. Actelion Pharmaceuticals Japan Ltd.	Bayer Yakuhin, Ltd. Takeda Pharmaceutical Company Limited
External Evaluation Committee Members: Takashi Akasaka				St. Jude Medical Japan Co., Ltd. Daiichi Sankyo Company, Limited Boehringer Ingelheim Japan, Inc. Amgen Astellas BioPharma K.K. Abbott Vascular Japan Co., Ltd.		Infraredx, Inc.	St. Jude Medical Japan Co., Ltd. ACIST Medical Systems HeartFlow Japan G.K. Bayer Yakuhin, Ltd. Astellas Pharma Inc. Pfizer Japan Inc. Daiichi Sankyo Company, Limited	St. Jude Medical Japan Co., Ltd. Abbott Vascular Japan Co., Ltd. Goodman Co.,LTD. TERUMO CORPORATION Boston Scientific Corporation Nipro Corporation			The Japan Research Foundation for Healthy Aging Japan Heart Foundation
External Evaluation Committee Members: Shun Kohsaka				Bayer Yakuhin, Ltd. Bristol-Myers Squibb		Bayer Yakuhin, Ltd. Daiichi Sankyo Company, Limited
External Evaluation Committee Members: Kazuo Haze				Eisai Co., Ltd.
External Evaluation Committee Members: Atsushi Hirayama				Sanofi K.K. Astellas Pharma Inc. Sumitomo Dainippon Pharma Co., Ltd. Bristol-Myers Squibb AstraZeneca K.K. TOA EIYO LTD. Boehringer Ingelheim Japan, Inc. Amgen Astellas BioPharma K.K. Daiichi Sankyo Company, Limited Bayer Yakuhin, Ltd.				Active Medical Co.,Ltd. Abbott Medical Japan L.L.C Fukuda Denshi Co., Ltd Hokushin Medical Co.,Ltd. Boston Scientific Corporation KURIBARA MEDICAL INSTRUMENTS Otsuka Pharmaceutical Co., Ltd. Medtronic Japan Co., Ltd. Japan Lifeline Co.,Ltd.			Daiichi Sankyo Company, Limited Bristol-Myers Squibb Bayer Yakuhin, Ltd.

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