JCS 2020 Guideline Focused Update on Antithrombotic Therapy in
Patients With Coronary Artery DiseaseCirculation Journal Circ J
2020; 84: 831 – 865 doi: 10.1253/circj.CJ-19-1109
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 neces- sary. 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
J-STAGE Advance Publication released online March 13, 2020 This
document is an English version of JCS 2020 Guideline Focused Update
on Antithrombotic Therapy in Patients with Coronary
Artery Disease reported at the 84th Annual Scientific Meeting of
Japanese Circulation Society performed in 2020. (Website: http://
www.j-circ.or.jp/guideline/pdf/JCS2020_Kimura_Nakamura.pdf).
Mailing address: Scientific Committee of the Japanese Circulation
Society, 18F Imperial Hotel Tower, 1-1-1 Uchisaiwai-cho,
Chiyoda-ku, Tokyo 100-0011, Japan. E-mail:
[email protected]
Refer to Appendix 1 for the details of members. ISSN-1346-9843 All
rights are reserved to the Japanese Circulation Society. For
permissions, please e-mail:
[email protected]
JCS 2020 Guideline Focused Update on Antithrombotic Therapy in
Patients With Coronary Artery Disease
Masato Nakamura; Kazuo Kimura; Takeshi Kimura; Masaharu Ishihara;
Fumiyuki Otsuka; Ken Kozuma; Masami Kosuge; Toshiro Shinke;
Yoshihisa Nakagawa; Masahiro Natsuaki;
Satoshi Yasuda; Takashi Akasaka; Shun Kohsaka; Kazuo Haze; Atsushi
Hirayama
Table of Contents I. Introduction 831
II. Risk Assessment (Bleeding and Thrombotic Risks) 832
1. Clinical Need for Assessing Bleeding and Thrombotic Risks
832
2. Scoring Systems Outside Japan for the Assessment of Bleeding
Risk 833
3. Scoring Systems Outside Japan for the Assessment of Thrombotic
Risk 833
4. Scoring Systems From Japan for Risk Evaluation 834 5.
Development of ARC-HBR Criteria 836 6. Are the ARC-HBR Criteria
Applicable in Japan? 836 7. Development of “Japanese Version of HBR
Criteria” 836 8. Priority Between Bleeding and Thrombotic
Risk
Scores 839 III. Loading of Antiplatelet Agents 840 1. Aspirin 840
2. P2Y12 Receptor Inhibitors 840
IV. Dual/Single Antiplatelet Therapy 842 1. ACS Patients 842 2.
Stable CAD Patients 845 3. Patients Without PCI 846 V.
Antithrombotic Therapy After PCI in Patients
Requiring Oral Anticoagulation 847 1. Patients With an Indication
for Anticoagulation
Undergoing PCI and ACS Patients 847 2. Japanese Specific Conditions
and Recommendations 849 VI. Perioperative Management of
Antithrombotic
Therapy in Cardiac and Non-Cardiac Surgery 850 1. Cardiac Surgery
850 2. Non-Cardiac Surgery 851
References 857
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 coro- nary 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 pro- posed by consensus for
this guideline update.
3. Antithrombotic therapy for CAD in general is consid- ered 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 concept5,6
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 recom- mended classes, Class III is classified
as non-benefit or harm from the clinical viewpoint (Table 1).
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 recommenda- tions 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
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).
Circulation Journal Vol.84, May 2020
833JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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 hemor- rhagic
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).
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
throm- botic 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.
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]).
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
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
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
Web calculator www.precisedaptscore.com
(Ref. Costa F, et al. 201714 Yeh RW, et al, 201517)
Circulation Journal Vol.84, May 2020
834 NAKAMURA M et al.
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.
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
It was also suggested in the CREDO-Kyoto Registry that, in reality,
DAPT duration was selected without consid- ering 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
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
70–79 +3 Acute coronary syndrome
≥80 +4 No 0
≥35 +2 Yes +1
Current smoking No 0
No 0 Present +2
Present +2 Prior CABG
Absent 0 Yes +2
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)
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
Circulation Journal Vol.84, May 2020
835JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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), hyper- tension, and prior
gastric ulcer (during the period 31 days
Table 6. CREDO-Kyoto Thrombotic and Bleeding Risk Scores
A. Thrombotic Risk Score B. Bleeding Risk Score
Variable Points† Variable Points‡
AF 2 Severe CKD 2
PVD 2 PVD 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)
Risk factors for thrombotic event
Risk factors for ST
Current smoking Prior PCI/CABG PVD Heart failure Elderly Anemia
Atrial fibrillation
First generation DES ≥3 stents implanted ≥3 lesions treated
Bifurcation with 2 stents implanted Total stent length > 60 mm
Stenting of saphenous vein graft Prior ST under DAPT treatment
Stenting of small vessel
ACS Severe CKD
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.
Circulation Journal Vol.84, May 2020
836 NAKAMURA M et al.
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).
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
interpreta- tion of data. The ARC-HBR consists of experts, govern-
ment 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
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
Table 7. Major and Minor Criteria for HBR at the Time of PCI (Ref.
Urban P, et al.5,6)
Major Minor
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
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.
Circulation Journal Vol.84, May 2020
837JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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.
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
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
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
months after PCI
Major bleeding between 12 and 30 months after
PCI
Out-of-hospital bleeding
Serious spontaneous bleeding at
Bleeding definition used Protocol-defined
GUSTO moderate or
minor Protocol-defined GUSTO
moderate or severe
8% (score ≥8)
25% (score ≥25)
25% (score ≥26)
13.4% (score ≥3)
2.76% (at 2 years)
2 to 13
2.7% (between 13
and 30 months)
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
6,172
(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.
Circulation Journal Vol.84, May 2020
838 NAKAMURA M et al.
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.
Circulation Journal Vol.84, May 2020
839JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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 hemor- rhage.43 Therefore,
≥80 years of age may need to be classi- fied 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.
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
AnticoagulantNSAIDs steroids
Severe CKD
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.
Factors in red circle need attention in Japanese
Circulation Journal Vol.84, May 2020
840 NAKAMURA M et al.
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).
III. Loading of Antiplatelet Agents (Table 10–13)
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 disor- ders, 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
3 months
6 months
12 months
SAPT
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.
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841JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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 pretreat- ment 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 cardio- vascular 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 thieno- pyridine 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 mainte- nance
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 approx- imately 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 popula- tion. 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
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 consid- ered in P2Y12
receptor inhibitor-naïve patients before primary PCI, when
prasugrel or clopido- grel 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 consid- ered 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
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842 NAKAMURA M et al.
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 mainte- nance 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 treat- ment 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 Tmax and Cmax.
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 suscepti-
bility 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 absorp- tion 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
complica- tion is advocated.
IV. Dual/Single Antiplatelet Therapy (Table 14)
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 esti- mations of thrombotic risk and bleeding
risk are required when deciding DAPT duration. However, East
Asians,
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843JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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 How- ever, 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 signifi-
cant 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 clopido- grel 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
surveil- lance.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 regis-
tered, 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 administra- tion 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 coro-
nary 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)
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
Circulation Journal Vol.84, May 2020
844 NAKAMURA M et al.
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. How- ever, 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 coro- nary angiography results, the
heart team should discuss and decide which treatment strategy to be
taken, including PCI, CABG, or conservative treatment, because we
some- times 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
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 OPTIMIZE
(2,199)91 3 vs. 12 PCI Non-inferiority NACE REDUCE ACS (1,496)92 3
vs. 12 ACS-PCI Non-inferiority NACE EXCELLENT (1,443)93 6 vs. 12
PCI Non-inferiority TVF SECURITY (1,399)94 6 vs. 12 PCI
Non-inferiority (discontinued) NACE ISAR-SAFE (4,000)95 6 vs. 12
PCI Non-inferiority (discontinued) NACE I-LOVE-IT-2 (1,829)96 6 vs.
12 PCI Non-inferiority TLF IVUS-XPL (1,400)97 6 vs. 12 PCI
Non-inferiority NACE OPTIMA-C (1,368)98 6 vs. 12 PCI
Non-inferiority MACE DAPT-STEMI (870)89 6 vs. 12 ACS-PCI
Non-inferiority NACE SMART-DATE (2,172)73 6 vs. 12 ACS-PCI
Non-inferiority MACE NIPPON (2,772)99 6 vs. 18 PCI Non-inferiority
(discontinued) NACE ITALIC (1,822)100 6 vs. 24 PCI Non-inferiority
NACE 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.
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
SMART-CHOICE (3,000)80 3 vs. 12 PCI Non-inferiority MACE TWILIGHT
(9,000)75 3 vs. 12 PCI Superiority Hemorrhage 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.
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845JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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.
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 gastro- intestinal 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 inci- dence of
cardiovascular events in the 3-month DAPT group.80 The GLOBAL
LEADERS (Long-term ticagrelor monotherapy vs. standard dual
antiplatelet therapy fol- lowed 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, mono- therapy 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.
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
poly- morphism or platelet function measurement. Recently, 1
treatment strategy has been reported to be beneficial, in which
potent P2Y12 receptor inhibitor is switched to clopi- dogrel 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 stop- ping 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 consider- ationbleeding risk, monotherapy with
P2Y12 receptor antagonist might be an effective treatment
option.
2. Stable CAD Patients (Table 17)
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) recom- mend, for prevention of stent thrombosis
after stent deployment, aspirin plus minimum of 6 months of clopi-
dogrel 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
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846 NAKAMURA M et al.
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 (compre- hensive 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 pro- longed 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)
Even after a diagnosis of ACS, occasionally invasive examinations
or coronary revascularization cannot be performed because of
various patient factors and back- grounds. 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 cardiovas- cular
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 Throm-
bolysis 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
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.
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.
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847JCS 2020 Guideline Focused Update on Antithrombotic Therapy for
CAD
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)
Patients with AF,131 mechanical prosthetic valve,119 thrombus in
the left ventricle or atrium,120 left ventricular aneu-
rysm,121,122 deep vein thrombosis/pulmonary thromboem- bolism, 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 inhib- itor 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 revascular- ization
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 Anti- coagulation 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 superi-
ority 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
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
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.
Circulation Journal Vol.84, May 2020
848 NAKAMURA M et al.
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 popu- lations. 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 throm- bosis 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 recommenda- tion in the European
guidelines.2,135
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 thromboem- bolism 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
addi- tion 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. How- ever, studies on this
subject are very old and small, which
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
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.
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849JCS 2020 Guideline Focused Update on Antithrombotic Therapy for