4?|? Aging Medicine. 2023;6:4–24.wileyonlinelibrary.com/journal/agm2
1?|?INTRODUCTION
The prevalence and mortality of coronary artery disease (CAD) in
China are still at an increasing stage.
1
CAD can be classified as acute
coronary syndrome (ACS) or chronic coronary syndrome (CCS).
2
CCS is the main manifestation type of elderly patients with CAD,
with a large number of patients, long course of disease, and poor
prognosis, leading to decreased quality of life and heavy disease bur-
den and economic burden. Especially in patients with high- risk CCS,
the case fatality rate and total mortality are high. Although current
standard prevention and treatment strategies have prolonged the
survival of patients, the residual cardiovascular risk remains high.
3
Antithrombotic therapy is one of the important strategies for com-
prehensive management of CAD, while safer and more suitable
antithrombotic strategies are particularly important for elderly pa-
tients with high- risk of CCS.
2,3
At present, there are few guidelines
or consensuses for elderly patients with high- risk CCS. In order to
better standardize the antithrombotic treatment of elderly patients
with high- risk CCS, the Geriatrics Branch of the Chinese Medical
Association organizes domestic experts to develop this consensus
for clinicians'' reference based on published clinical research evi-
dence, combined with relevant guidelines, consensus and expert
recommendations in China and abroad.
2?|?DEFINITION OF ELDERLY PATIENTS
WITH HIGH- RISK CCS
2.1? |?Definition of elderly patients with CCS
Elderly patients with CCS are defined as patients 65?years of age and
older with CAD other than ACS,
3
including the following six most
Received: 2 November 2022?
|
?Accepted: 2 December 2022
DOI: 10.1002/agm2.12234
GUIDELINE
Chinese expert consensus on antithrombotic management of
high- risk elderly patients with chronic coronary syndrome
Cuntai Zhang
1
?| Xiaoming Wang
2
?| Cardiovascular Group, Geriatrics Branch of Chinese
Medical Association
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in
any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
? 2023 The Authors. Aging Medicine published by Beijing Hospital and John Wiley & Sons Australia, Ltd.
1
Department of Geriatrics, Tongji
Hospital, Tongji Medical College,
Huazhong University of Science &
Technology, Wuhan, China
2
Department of Geriatrics, Xijing Hospital,
Air Force Medical University, Xi''an, China
Correspondence
Cuntai Zhang, Department of Geriatrics,
Tongji Hospital, Tongji Medical College,
Huazhong University of Science &
Technology, Wuhan 430030, China.
Email: ctzhang0425@163.com
Xiaoming Wang, Department of Geriatrics,
Xijing Hospital, Air Force Medical
University, Xi''an 710032, China.
Email: xmwang@fmmu.edu.cn
Abstract
The prevalence and mortality of coronary artery disease (CAD) in China are still at an
increasing stage. CAD can be classified as acute coronary syndrome (ACS) or chronic
coronary syndrome (CCS). CCS is the main manifestation type of elderly patients with
CAD, with a large number of patients, long course of disease, and poor prognosis,
leading to decreased quality of life and heavy disease burden and economic burden.
Especially in patients with high- risk CCS, the case fatality rate and total mortality are
high. In order to better standardize the antithrombotic treatment of elderly patients
with high- risk CCS, the Geriatrics Branch of the Chinese Medical Association organ-
izes domestic experts to develop this consensus for clinicians'' reference based on
published clinical research evidence, combined with relevant guidelines, consensus,
and expert recommendations in China and abroad.
KEYWORDS
antithrombotic drugs, chronic coronary syndrome, coronary artery disease
24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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?5ZHANG et al.
common clinical conditions
2
: (1) CAD with stable angina symptoms
and/or dyspnea symptoms; (2) new heart failure or left ventricular
dysfunction and suspected of CAD; (3) with or without symptoms
within 1 year after ACS or coronary revascularization; (4) with or
without symptoms more than 1 year after initial diagnosis or revas-
cularization; (5) suspected angina symptoms due to vasospasm or
microangiopathy; and (6) asymptomatic patients found by physical
examination or screening. Elderly high- risk CCS patients include el-
derly CCS patients with high ischemia risk and elderly CCS patients
with high bleeding risk.
2.2? |?Definition of elderly CCS patients with high
ischemia risk
CCS with high ischemia risk is defined as cardiovascular mortality
>3%/year and low ischemia risk is defined as cardiovascular mor-
tality <1%/year.
2
Various clinical comorbidities, complex coronary
anatomy factors, and interventional device- related factors can in-
crease the risk of ischemia- related cardiovascular adverse events.
Elderly CCS patients with high ischemia risk include advanced- age
(≥80?years old) patients with?multi- vessel coronary artery disease,
multi- bed vascular disease (ischemic lesions involving coronary ar-
tery, cerebral artery, and peripheral artery), and multiple high- risk
factors (such as diabetes mellitus, hypertension, dyslipidemia, renal
insufficiency, etc.).
2– 4
The high ischemic risk profile of CCS in the
elderly is shown in Table 1.
2.3? |?Definition of elderly CCS patients with high
bleeding risk
High bleeding risk is strongly associated with long- term mortality.
High bleeding risk with CCS is defined as a risk of major (BARC 3
to 5) bleeding of ≥4% or risk of intracranial hemorrhage of ≥1% at
1 year.
5
Various underlying diseases of important organs, concomi-
tant medications, and surgery- related factors leading to bleeding
diathesis can cause clinical bleeding events (Table 2). The methods
for assessing the high risk of bleeding in elderly patients with CCS
are detailed in Part V.
2.4? |?Other characteristics of elderly patients with
high- risk CCS
Elderly patients with CCS may have multiple other clinical condi-
tions, such as atrial fibrillation (AF) and venous thromboembolism
(VTE). The proportion of elderly CAD patients with AF is 6% to 21%,
and the proportion of AF patients with CAD is 20% to 30%.
6
Despite
the current situation in clinic, there is still lack of CAD combined
with VTE epidemiological data. Only a few have reported that the
proportion of ACS patients with VTE is 4.96% to 14.90% (of which
about 5% are fatal pulmonary thromboembolism), while the propor-
tion of acute VTE patients with CAD is 10% to 17%.
7,8
Atrial fibrilla-
tion or VTE itself may require anticoagulant therapy, so the benefits
and risks of antithrombotic therapy should be particularly consid-
ered when these disorders occurred in the elderly with CCS.
9
3?|?ANTITHROMBOTIC THERAPY IN
ELDERLY CCS PATIENTS WITH HIGH
ISCHEMIA RISK
3.1? |?Principles of antithrombotic therapy in elderly
CCS patients with high ischemia risk
Antithrombotic therapy can significantly benefit patients with CAD,
especially in elderly patients with high- risk CCS.
2,3
Ischemia and
bleeding risk assessment is a key step in antithrombotic therapy.
Antithrombotic principles in patients with CCS: (1) Ischemic and
bleeding risks should be adequately assessed to determine treat-
ment strategies before initiating antithrombotic therapy.
2,10
(2) Dual
antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) is rec-
ommended for patients with high ischemia risk and without high
TABLE 1?High ischemic risk profile
Disease- related factors Lesion- related factors Stent- related factors
? History of recurrent myocardial infarction
? Refractory hypertension
? Diabetes mellitus requiring medication
? ?Polyvascular disease
a
? Left ventricular ejection fraction ≤40%
? Chronic kidney disease with creatinine
clearance rate 15– 60?ml/min
? History of stent thrombosis on antiplatelet
treatment
? Stenting of last remaining patent vessel
? Diffuse multi- vessel disease
b
? Left main disease
? Bifurcation stenting with ≥ two stents implanted
? Interventional therapy for CTO lesions
? Calcified lesions requiring rotational atherectomy
? Interventional treatment with graft vessel
? At least three stents implanted
? At least three lesions treated
? Total stent length?>?60?mm
? First- generation drug- eluting stents
? In- stent restenosis
? Incomplete stent expansion
? Stent vessel diameter?≤?2.5?mm
Abbreviation: CTO, chronic total occlusion.
a
Coronary artery disease combined with at least one of the aortic, cerebral artery, gastrointestinal, lower extremity, upper extremity, and renal
vascular beds.
b
≥2 major epicardial coronary arteries >50% stenosis.
24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
6?
|
??? ZHANG et al.
bleeding risk. (3) For CCS patients with low thrombotic risk and/
or excessive bleeding risk, intensive antithrombotic therapy is sug-
gested to avoid (Figure 1, Table 3).
2,10
(4) Genetic Personality Traits
may affect the reactivity of certain drugs; CYP2C9 and VKORC1
gene polymorphisms are associated with warfarin- related bleeding
adverse reactions, CYP2C19 gene polymorphisms are associated
with clopidogrel response, and selective gene polymorphism moni-
toring is helpful for individual conditions assessment and medication
selection, but it is not recommended for routine use.
4
3.2? |?Antithrombotic therapy in elderly CCS
patients with multi- vessel CAD
3.2.1?|?Long- term antithrombotic therapy for
secondary prevention
Aspirin as a single antiplatelet therapy (SAPT) has a clear benefit in
reducing major adverse cardiovascular events (MACEs) in patients
with CCS.
11
The CAPRIE study showed a minor benefit of clopidogrel
TABLE 2?High bleeding risk profile
Disease- related factors Lesion- related factors Surgery- related factors
Uncontrolled hypertension
(≥180/120?mm?Hg,
1?mm?Hg = 0.133?kPa); anemia
(Hb?
thrombocytopenia (<100?null?10
9
/L);
spontaneous bleeding within
6 months (requiring hospitalization
and/or transfusion); chronic bleeding
diathesis; severe or end- stage
CKD (eGFR
?1
·1.73?m
?2
);
previous history of intracranial
hemorrhage; traumatic intracranial
hemorrhage within 12?months; known
cerebral arteriovenous malformations;
ischemic stroke within 6 months;
major gastrointestinal hemorrhage
within 6 months; cirrhosis with portal
hypertension; active malignancy
within 12?months
Clinically significant bleeding during antiplatelet
or anticoagulation treatment, Concomitant
OAC, Long- term use of NSAIDs and steroids
Planned major surgery during DAPT treatment,
Major surgery/trauma within 30?days
Abbreviations: CKD, chronic kidney disease; DAPT, dual antiplatelet therapy; Hb, hemoglobin; NSAID, nonsteroidal antiinflammatory drug; OAC, oral
anticoagulant.
FIGURE 1?Antithrombotic treatment process in elderly high- risk CCS patients.
2,10
bid, twice daily; CAD, coronary artery disease; CCS,
chronic coronary syndrome; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition.
Recommend antithrombotic therapy Antiplatelet therapy may be considered
Prior history of
myocardial infarction
or revascularization
Radiographic evidence
of definite CAD
Aspirin 75-100 mg/day
(If intolerable, clopidogrel 75 mg/day)
Without high ischemia risk, with high bleeding risk
With high ischemia risk, without high bleeding risk
Assess the risk of bleeding/ischemia
Consider addition of the second antithrombotic agent
Yes
Yes
No
No
Do not recommend
antithrombotic therapy
No additional antithrombotic
drugs are recommended
DPI DAPT
Aspirin 75-100 mg/day + clopidogrel
75 mg/day
Aspirin 75-100 mg/d + prasugrel 10
mg/d
Aspirin 75-100 mg/day + ticagrelor 60
mg bid
Aspirin 75-100 mg/d + rivaroxaban 2.5
mg bid
24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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?7ZHANG et al.
monotherapy compared with aspirin in the secondary prevention of
cardiovascular disease, driven mainly by the benefit in the subgroup
of patients with peripheral arterial disease (PAD), while the safety
was similar.
12
The most recent HOST- EXAM study showed that
clopidogrel was superior to aspirin in clinical adverse events after
change into long- term SAPT in stable patients who underwent DAPT
for 6– 18?months after drug- eluting stent (DES) implantation (mean
age 63?years, diabetes 34%, hypertension 61%, chronic kidney dis-
ease 13%, previous myocardial infarction 16%, previous stroke 5%,
and two- or three- vessel CAD 50%), but there was a trend towards
an increase in all- cause mortality.
13
For CCS patients with high ischemia risk, residual cardiovascu-
lar risk remains high under current standard secondary prevention,
and annual cardiovascular mortality may still be as high as 3%.
2
An
increasing number of studies have shown that DAPT with long- term
aspirin and P2Y12 receptor antagonists has a clear benefit compared
with aspirin alone in elderly CCS patients with high ischemia risk
(Table 4).
14– 16
DPI consisting of aspirin and rivaroxaban 2.5 mg twice
daily significantly reduced MACEs in patients with CCS and has a
clear net clinical benefit.
17,18
Recommendation 1: Elderly CCS patients with multi- vessel cor-
onary disease are with high ischemia risk. A second antithrombotic
drug (P2Y12 receptor antagonist or rivaroxaban 2.5 mg bid) is rec-
ommended on top of aspirin 75– 100?mg/day for elderly CCS patients
without high bleeding risk and who also have multi- vessel coronary
disease, while single antiplatelet therapy is recommended for those
elderly CCS patients with high bleeding risk.
3.2.2?|?Perioperative and secondary prophylactic
antithrombotic therapy for elective PCI
When selecting invasive strategies, it is recommended to use the ra-
dial artery approach whenever possible to reduce the complications
of the approach.
19,20
Compared with bare- metal stents (BMS), the
use of drug- eluting stents (DES) in elderly patients combined with
shorter DAPT courses has been proved with more benefits in terms
of safety and efficacy.
19,20
Recommendation 2: In view of the increasing use of drug- coated
balloons (DCB), it is recommended to consider the use of DCB in
patients with vessel diameter?<3.0?mm or stent thrombosis, and the
duration of DAPT may be considered reducing to 4?weeks in patients
with DCB. However, the risk of bleeding and thrombosis should be
monitored and evaluated continuously, and the duration of DAPT
should be adjusted at any time accordingly.
Recommendation 3: The duration of DAPT is recommended to
be at least 4?weeks for patients after BMS implantation.
Recommendation 4: In patients after DES implantation, the
duration of DAPT is recommended to be 6 months. Patients with
high bleeding risk may consider shortening the duration of DAPT
to?<6 months, and DAPT can be maintained for more than 6 months
in patients with high ischemia risk and low bleeding risk.
Recommendation 5: In patients treated with DCB therapy, the
duration of DAPT is recommended to be at least 4?weeks.
3.2.3?|?Perioperative and secondary prophylactic
antithrombotic therapy for elective coronary artery
bypass grafting (CABG)
Aspirin should normally be continued in patients with CCS undergo-
ing elective CABG and other antithrombotic drugs discontinued at
intervals according to their duration of action and indication (prasu-
grel stopped ≤7?days before; clopidogrel ≥5?days before; ticagrelor
≥3?days before). Reloading of aspirin after CABG surgery may im-
prove graft patency. Small sample randomized controlled trials (RCT)
results have suggested a slightly superior graft patency rates with
DAPT compared with aspirin monotherapy, but not in terms of mor-
tality. In the COMPASS study, a subgroup analysis of 1448 patients
4– 14?days after CABG suggested that the benefit of DPI in reduc-
ing MACEs was consistent with that of the overall population, and
the results need to be further explored and validated for the CABG
population.
2,21– 25
Recommendation 6: Antiplatelet therapy should be given 6 to
24?h after CABG in patients with CCS.
Recommendation 7: In case of concurrent high risk of throm-
bosis and low risk of bleeding, long- term lowest effective dose of
DAPT is recommended, and DPI may also be considered; in case of
concurrent low risk of thrombosis or high risk of bleeding, long- term
SAPT is recommended.
3.2.4?|?Perioperative and secondary prophylactic
antithrombotic therapy for noncardiac surgery
Non- cardiac surgery is associated with an increased risk of myo-
cardial infarction (MI), and it is recommended to postpone elective
non- cardiac surgery until the recommended course of DAPT has
been completed following PCI.
2
After coronary stent placement,
regardless of stent type, elective surgery requiring discontinuation
of P2Y12 receptor antagonists may be considered 1 month after
TABLE 3?Treatment options for a second antithrombotic agent
on top of aspirin 75– 100?mg/day in CCS patients with high ischemia
risk and without high bleeding risk
2,10
Regimen Drug selection Dose
DPI Rivaroxaban 2.5 mg twice daily
DAPT Clopidogrel 75?mg once daily
Prasugrel 10 mg once daily
(5 mg/day, if body
weight?
age?>?75?y)
Ticagrelor 60?mg twice daily
Abbreviations: CCS, chronic coronary syndrome; DAPT, dual
antiplatelet therapy; DPI, dual pathway inhibition.
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8?
|
??? ZHANG et al.
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24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
???
|
?9ZHANG et al.
stent placement if aspirin therapy can be maintained throughout
the perioperative period 26. For patients with recent MI or other
high ischemia risk requiring intensive antithrombotic therapy, elec-
tive surgery can be delayed until a maximum of 6 months.
26
Surgery
between 3– 6 months may also be considered by a multidisciplinary
team including a cardiac interventional specialist, if clinically indi-
cated.
2,26
Bleeding risk classification (Table 5) should be performed
prior to noncardiac surgery. Preoperative discontinuation or not
and duration of discontinuation should be determined based on the
bleeding risk and the currently used antithrombotic drugs. The ef-
fect of renal function should also be considered in patients treated
with rivaroxaban.
Recommendation 8: Aspirin should be continued in most types
of surgery, with the benefit outweighing the risk of bleeding, but
for surgeries with very high bleeding risk (intracranial surgery,
transurethral prostatectomy, posterior chamber surgery, etc.), as-
pirin is recommended to be discontinued for at least 5?days before
surgery.
Recommendation 9: In patients who receive P2Y12 receptor in-
hibitors before surgery, it is recommended to discontinue ticagrelor
for at least 3?days and clopidogrel for at least 5?days prior to most
types of surgery, except for surgeries with minimal bleeding risk
(Table 5, Figure 2); for patients with high ischemia risk, it is reason-
able to choose intravenous platelet membrane glycoprotein IIb/IIIa
receptor antagonist (GPI) as bridging therapy until 4 h before surgery
after discontinuing P2Y12 receptor antagonist.
Recommendation 10: Antiplatelet therapy should be resumed as
soon as possible (preferably within 24?h) after surgery.
Recommendation 11: In patients who planned for elec-
tive noncardiac surgery and treated with DPI, the strategies for
whether aspirin is discontinued or not and the duration of dis-
continuation are the same as DAPT treatment (Figure 2). The
preoperative discontinuation duration of rivaroxaban should be
adjusted according to the surgical bleeding risk and creatinine
clearance (Tables 5 and 6).
Recommendation 12: The continuation/administration of
rivaroxaban is suggested to be several hours after surgeries
with low bleeding risk and 24 to 72?h after surgery with high bleed-
ing risk.
3.3? |?Elderly CCS patients with multi- bed
vascular disease
Multi- bed vascular disease is defined as CAD combined with at least
one of the vascular bed lesions of aorta, cerebral arteries, gastro-
intestinal tract, lower extremities, upper extremities, and kidneys.
Patients with 2 or more vascular bed lesions are at high risk of
thromboembolism and should be treated with intensive antithrom-
botic therapy. Current studies have shown that DAPT or DPI can
reduce MACEs in patients with multi- bed vascular disease, and as-
pirin in combination with P2Y
12
receptor antagonist or rivaroxaban
2.5 mg bid is recommended for secondary prevention in elderly CCS
patients with multi- bed vascular disease and low bleeding risk.
16,17,28
3.3.1?|?CCS patients with PAD
Clopidogrel monotherapy reduced MACEs compared with aspirin in
patients with previous myocardial infarction and complicated with
PAD or stroke.
12
In patients with previous PCI complicated with PAD,
ticagrelor monotherapy had similar efficacy to aspirin.
29
Clopidogrel
combined with aspirin benefited patients with multi- bed vascular
disease.
30
Ticagrelor combined with aspirin reduced MACEs but
increased the risk of major bleeding in patients with multi- bed vas-
cular disease and a 1- 3- year history of previous myocardial infarc-
tion.
16
Ticagrelor combined with aspirin reduced the risk of ischemic
events but increased the risk of major and intracranial bleeding in
CCS patients with type 2 diabetes mellitus.
14
Ticagrelor combined
with aspirin had a higher incidence of ischemic events than aspirin
alone in CCS patients with type 2 diabetes mellitus and multi- bed
vascular disease.
14
In the COMPASS study, compared with aspirin alone, DPI re-
duced the risk of MACEs and limb ischemic events, increased the
risk of major bleeding, but did not increase the risk of fatal bleeding
in patients with concomitant PAD (Table 7).
31
In the VOYAGER study, DPI decreased the composite endpoint
of MACE and limb ischemia, increased ISTH major bleeding, but did
not increase TIMI major bleeding in patients with PAD who had un-
dergone lower extremity revascularization.
32
TABLE 5?Bleeding risk classification in elective noncardiac surgery/procedures
6,27
Bleeding risk classification Name of surgery or procedure
Minor bleeding risk Tooth extraction (1– 3 teeth), periodontal surgery, dental implant, subgingival scaling/cleaning; cataract
or glaucoma surgery; endoscopy without biopsy or excision; superficial surgery (e.g. abscess incision,
small area skin excision, skin biopsy, etc.)
Low bleeding risk Complex dental surgery; simple endoscopic biopsy; minor orthopedic surgery (foot or hand surgery, or
arthroscopy, etc.)
High bleeding risk Peripheral arterial revascularization (e.g. aortic aneurysm repair, vascular bypass); neurosurgery;
posterior chamber surgery; spinal or epidural anesthesia; lumbar diagnostic puncture; complex
endoscopic procedures (e.g. multiple/bulky polypectomy, sphincterotomy under ERCP); abdominal
surgery (including liver biopsy); thoracic surgery; major urological surgery; extracorporeal shock
wave lithotripsy; major orthopedic surgery
Abbreviation: ERCP, endoscopic retrograde cholangiopancreatography.
24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
10?
|
??? ZHANG et al.
Recommendation 13: Dual pathway inhibition (aspirin?+?rivarox-
aban 2.5 mg bid) is recommended for secondary prevention in el-
derly CCS patients with PAD and low bleeding risk.
3.3.2?|?CCS patients with stroke
Analysis of the previous stroke subgroups of MATCH, SPS3, and
CHARISMA showed that aspirin + clopidogrel had no efficacy ben-
efit in the secondary prevention of stroke and increased the risk of
major bleeding.
33– 35
In the CHANCE study, in patients with acute
mild ischemic stroke or transient ischemic attack (TIA) (within 24?h
of onset), DAPT for 21?days followed by clopidogrel 75?mg/day
alone to 90?days reduced 90- day MACEs without increasing the risk
of major bleeding
36
; in the POINT study, DAPT for 90?days reduced
90- day MACEs but increased the risk of major bleeding.
37
In the
SOCRATES study, there was no significant difference in MACEs and
major bleeding between ticagrelor monotherapy and aspirin mono-
therapy within 90?days in patients with acute non- severe stroke.
38
The THALES study confirmed that aspirin + ticagrelor reduced the
30- day risk of stroke or death in patients with mild to moderate
noncardiogenic ischemic stroke or TIA (within 24?h of onset), but
there was increased risk of major bleeding and no difference in
disability.
39
COMPASS subgroup analysis showed (Table 8) that low- dose
rivaroxaban + aspirin reduced MACEs, ischemic stroke, or embolic
stroke of undetermined source (ESUS) without increasing minor
bleeding but increased major bleeding in CCS/PAD patients with
concomitant stroke (at least 1 month after onset of non- lacunar
stroke), and low- dose rivaroxaban + aspirin also reduced MACEs,
ischemic stroke, or ESUS without increasing hemorrhagic stroke, but
increased major and minor bleeding in CCS/PAD patients without a
history of stroke (primary prevention of stroke).
40
Recommendation 14: In CCS patients with acute stroke, long-
term aspirin 75– 100?mg/day is recommended, and clopidogrel
75?mg/day is recommended for patients who are intolerant to
aspirin.
Recommendation 15: In patients with mild stroke, initiation of
dual antiplatelet (aspirin?+?clopidogrel) therapy for 21?days within
24?h of onset is beneficial for the secondary prevention of early
stroke (from the onset of symptoms to 90?days).
FIGURE 2?Perioperative DAPT management in elderly CCS patients undergoing noncardiac surgery.
6,26
GPI, intravenous platelet
membrane glycoprotein IIb/IIIa receptor antagonist.
a
Surgeries with very high bleeding risk such as intracranial surgery, transurethral
prostatectomy, posterior chamber surgery, etc.
Perioperative DAPT Management in Elderly CCS Patients
Undergoing Noncardiac Surgery
Surgeries with
Minor bleeding risk
Surgeries with
Very high bleeding risk
a
Most types of Surgeries
Continue aspirin
Continue P2Y12 receptor antagonist
Continue aspirin
Discontinue P2Y12 receptor antagonist before
procedure
Ticagrelor: discontinue at least 3 days
Clopidogrel: discontinue at least 5
days
Prasugrel: discontinue at least 7 days
Consider GPI as bridging therapy until
4 h before procedure for high ischemic
risk patients
Discontinue aspirin at least 5 days before
procedure
Discontinue P2Y12 receptor antagonist before
procedure
Ticagrelor: discontinue at least 3
days
Clopidogrel: discontinue at least 5
days
Prasugrel: discontinue at least 7 days
Consider GPI as bridging therapy
until 4 h before procedure for high
ischemic risk patients
Antiplatelet therapy should be resumed as soon as possible after surgery (preferably within 24 h)
TABLE 6?Preoperative discontinuation duration of rivaroxaban
in patients undergoing elective noncardiac surgery and treated with
DPI
6
Creatinine
clearance (ml/
min)
Risk of procedural bleeding
Low
bleeding
risk Minor bleeding risk
High
bleeding
risk
≥80
50?~?79 ≥24?h No discontinuation
required
≥48?h
30?~?49
15?~?29 ≥36?h
<15 No indication
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???
|
?11ZHANG et al.
Recommendation 16: In CCS patients with stroke and low bleed-
ing risk (at least 1 month after onset of non- lacunar stroke), rivarox-
aban 2.5 mg bid?+?aspirin 75– 100 mg qd is recommended.
3.4? |?Elderly CCS patients with other high-
risk factors
In elderly CCS patients with other high- risk factors, such as diabe-
tes mellitus, hypertension, chronic kidney disease, heart failure, and
advanced age, antithrombotic therapy should be determined by the
risk of ischemia and bleeding.
4?|?ANTITHROMBOTIC THERAPY IN
ELDERLY CCS PATIENTS WITH AF
4.1? |?Principles of antithrombotic therapy in elderly
CCS patients with atrial fibrillation
CCS patients require antiplatelet therapy to reduce myocardial is-
chemic events, whereas AF patients with high risk of thromboembo-
lism require oral anticoagulants (OACs) to reduce stroke and other
thromboembolic events. Combination anticoagulant and antiplatelet
therapy in CCS patients with AF have demonstrated superiority in
reducing ischemic and thromboembolic events but increased the
risk of bleeding.
6
The ischemia/thromboembolism and bleeding risk
need to be assessed when considering choosing an OAC monother-
apy or OAC?+?SAPT for elderly CCS patients with AF. Advanced- age
patients are often associated with hepatic and renal dysfunction and
concomitant medication, which may increase the risk of drug– drug
interactions and adverse reactions. It is recommended to strengthen
the comprehensive management of advanced- age patients and ad-
just the dose of OAC appropriately.
6
4.2? |?Evaluation before antithrombotic treatment
4.2.1?|?Thromboembolic risk assessment
CHAD
2
S
2
- VASC scoring is recommended for thromboembolic
risk assessment in patients with nonvalvular atrial fibrillation
(NVAF)
6,41
: (1) long- term anticoagulant therapy is recommended in
AF patients with a CHAD
2
S
2
- VASC score?≥?2 points (male)/≥3 points
(female); (2) AF patients with CHAD
2
S
2
- VASC score of 1 (male)/2
(female) should consider the use of OAC, balancing the individu-
alized characteristics of net clinical benefit and patient prefer-
ence; (3) patients with CHAD
2
S
2
- VASC score of 0 (male)/1 (female)
should avoid anticoagulant therapy to prevent thromboembolism.
In the CHAD
2
S
2
- VASC scoring items, age 65– 74?years is 1 point,
TABLE 7?Comparison of efficacy and safety endpoints between low- dose rivaroxaban + aspirin and aspirin in the PAD subgroup of
COMPASS study
18,31
Population
HR (95% CI) for rivaroxaban 2.5 mg twice daily + aspirin versus aspirin
Primary efficacy
endpoint All- cause mortality Major bleed
Net clinical
benefit
Overall (n = 18 278) 0.76 (0.66?~?0.86) 0.82 (0.71?~?0.96) 1.70 (1.40?~?2.05) 0.80
(0.70?~?0.91)
PAD subgroup (n = 4996)
a
0.72 (0.57?~?0.90) 0.91 (0.72?~?1.16) 1.61 (1.12?~?2.31) 0.75 (0.60?~?0.94)
Lower extremity arterial disease (n = 3699) 0.74 (0.57?~?0.96) NA 1.75 (1.16?~?2.65) NA
Carotid artery disease (n = 1297) 0.63 (0.38?~?1.05) NA 1.18 (0.55?~?2.51) NA
Abbreviations: bid, twice daily; HR, hazard ratio; NA, not available; PAD, peripheral artery disease.
a
PAD subgroup includes peripheral artery bypass surgery, peripheral angioplasty, amputation due to arterial vascular disease, intermittent
claudication with ankle brachial index <0.90 and/or peripheral vascular stenosis >50% confirmed by angiography or ultrasound, prior carotid
revascularization, and carotid atherosclerosis with asymptomatic carotid stenosis >50% confirmed by angiography or ultrasound.
P?
TABLE 8?Comparison of efficacy and safety endpoints in the previous stroke subgroup of COMPASS study
18,40
Population
HR (95% CI) for rivaroxaban 2.5 mg bid + aspirin versus aspirin
Primary efficacy
endpoint Stroke Major bleed
Hemorrhagic
stroke
Overall (n = 18 278) 0.76 (0.66?~?0.86) 0.58 (0.44?~?0.76) 1.70 (1.40?~?2.05) 1.49 (0.67?~?3.31)
With previous stroke (n = 686) 0.57 (0.34?~?0.96) 0.42 (0.19?~?0.92) 3.79 (1.07?~?13.4) NA
Without history of stroke (n = 17 592) 0.77 (0.67?~?0.88) 0.60 (0.45?~?0.80) 1.66 (1.37?~?2.01) 1.29 (0.57?~?2.94)
Abbreviations: bid, twice daily; HR, hazard ratio; NA, not available.
P?
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12?
|
??? ZHANG et al.
and age?≥?75?years is 2 points. Therefore, elderly CCS patients with
AF should consider whether and how to apply OAC based on the
results of (1) and (2) above.
4.2.2?|?Bleeding risk assessment
At present, the HAS- BLED scoring system is mainly developed to as-
sess the bleeding risk in patients with NVAF,
6,41
in which a score?≤?2
points is considered to be an indicator of low- risk bleeding and a
score?≥?3 points indicates high- risk bleeding, it does not mean man-
datory discontinuation of anticoagulation therapy, but attention
should be paid to screening and correction of reversible factors that
increase the bleeding risk, as well as enhanced monitoring after re-
ceiving anticoagulant therapy, such as strict control of hypertension
within the target range and monitoring INR to ensure its stability in
the therapeutic window.
4.3? |?Antithrombotic therapy in elderly CCS
patients with AF
AFIRE study demonstrated that rivaroxaban monotherapy was non-
inferior to rivaroxaban + SAPT, with a lower incidence of major bleed-
ing in CCS patients with NVAF
42
; a meta- analysis of the OAC- ALONE
study and AFIRE study have shown that the efficacy of OAC mono-
therapy is similar to that of OAC?+?SAPT, with a lower bleeding risk.
43
Recommendation 17: Based on the CHAD
2
S
2
- VASC score, OAC
monotherapy at prophylactic dose for stroke is recommended for
CCS patients with atrial fibrillation if anticoagulation is indicated.
Recommendation 18: Aspirin 75– 100?mg/day (or clopidogrel
75?mg/day) may be considered in addition to long- term OAC in CCS
patients with AF who also have high ischemic risk and without high
bleeding risk.
Recommendation 19: When oral anticoagulation is initiated in a
patient with AF who is eligible for a NOAC, a NOAC is recommended
in preference to a vitamin K antagonist.
4.4? |?Antithrombotic therapy after PCI in CCS
patients with AF
A meta- analysis showed that PCI (OAC?+?SAPT) was more effective
than triple antithrombotic therapy (OAC?+?DAPT) in reducing the
risk of bleeding and had a similar effect on the incidence of major
adverse cardiovascular events in patients after PCI.
44,45
The risk
of bleeding may be inversely related to the quality of anticoagula-
tion (stability of INR)
46
; among the factors influencing the risk of
major bleeding, the risk factors for bleeding may be greater than the
combined antithrombotic regimen itself.
47
Considering the need for
long- term OAC treatment in CCS patients with atrial fibrillation, it
is recommended to select a new generation of DES during PCI to
reduce bleeding complications.
6
Recommendation 20: Triple therapy with DAPT and an OAC for
1 month after PCI should be considered for patients with high risk
of ischemia/thrombosis and without high bleeding risk and continu-
ation of dual therapy with OAC for up to 12?months, followed by an
OAC long- term monotherapy.
Recommendation 21: Early cessation (until discharge) of
OAC?+?DAPT and continuation of dual therapy with OAC?+?SAPT for
up to 6 months should be considered if the risk of ischemia/throm-
bosis is low or bleeding risk is high, followed by an OAC long- term
monotherapy.
Recommendation 22: It is recommended to use a NOAC in pref-
erence to a VKA in combination with antiplatelet therapy.
Recommendation 23: Major hemorrhage has been reported to
be relevant with many factors, such as advanced age, hypertension,
liver or renal dysfunction, and history of stroke, so decision making
should balance ischemic and bleeding risks when considering the
treatment regime after PCI in elderly patients with AF. Concomitant
use of a proton pump inhibitor is considered in patients who are at
high risk of gastrointestinal bleeding.
4.5? |?Percutaneous left atrial appendage closure
(LAAC)
LAAC is one of the strategies to prevent thromboembolic events in
patients with atrial fibrillation. LAAC may be considered for patients
with CHAD
2
S
2
- VASC score?≥?2 (male)/≥3 (female) and with the fol-
lowing conditions
48– 50
: (1) not suitable for long- term standard an-
ticoagulant therapy; (2) continue to suffer thromboembolic events
despite long- term use of standard anticoagulant therapy; (3) HAS-
BLED score?≥?3, or subjective and objective factors that limit the use
of anticoagulation therapy such as patient preference/noncompli-
ance with long- term anticoagulant therapy.
Recommendation 24: Oral anticoagulant therapy should be
given for 45?days after successful left atrial appendage closure fol-
lowed by DAPT therapy for 6 months, and a SAPT monotherapy
could be switched after reaffirmed by the examination results until
the 6- month course of treatment is complete.
48
Recommendation 25: In patients with contraindications to an-
ticoagulation, DAPT within 3 to 6 months after procedure could be
regarded as a feasible regime n, followed by long- term use of aspirin
alone.
5?|?ANTITHROMBOTIC THERAPY IN
ELDERLY CCS PATIENTS WITH VTE
5.1? |?The principle of antithrombotic therapy in
elderly CCS patients with VTE
At present, the firm evidence from large- scale RCTs is still lack-
ing for antithrombotic therapy in elderly CCS patients with
VTE. Recommendations are made based on relevant studies and
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?13ZHANG et al.
treatment guidelines. The commonly used anticoagulant treatment
regimens for VTE are shown in Table 9.
9,51– 57
Recommendation 26: Anticoagulation is the foundation treat-
ment for VTE, and anticoagulants mainly include low molecular
weight heparin (LMWH), VKAs, and NOACs.
Recommendation 27: A NOAC is preferred over a VKA for non-
cancer- associated VTE, whereas LMWH or a NOAC are recom-
mended for cancer- associated VTE.
Recommendation 28: The course of anticoagulation for VTE is
determined by whether provoked by a temporary risk factor or a
chronic risk factor. If VTE is caused by a transient risk factor such
as surgery, it suggests using a shorter course of anticoagulation
(3 months) for primary treatment; if it is caused by tumors, various
chronic conditions, or prolonged immobilization, anticoagulant ther-
apy may be continued for a longer course.
Recommendation 29: In advanced- age patients with VTE who
are treated with NOACs, the dose should be adjusted according to
the patient''s renal function.
Recommendation 30: In elderly CCS patients with VTE, the an-
tithrombotic treatment strategy should be determined by the onset
time of VTE and the time of PCI.
5.2? |?Elderly CCS patients with acute VTE
In elderly CCS patients who developed with acute VTE, different
antithrombotic strategies depend on the indication for antiplatelet
therapy.
Recommendation 31: In CCS patients with acute VTE, who have
undergone PCI and treatment with antiplatelet therapy but without
a history of ACS, different antithrombotic regimens could be con-
sidered according to the time after PCI (see Figure 3), and 3 sce-
narios could be set and recommended accordingly as follows: (1) In
the patients who have undergone PCI no more than 6 months, it
is recommended to discontinue aspirin, continue clopidogrel, and
start anticoagulant drugs (preferred NOACs) for most patients; (2)
In the patients who have undergone PCI between 6– 12?months, it is
recommended to continue SAPT (aspirin or clopidogrel) until 1 year
after PCI, with concomitant use of OACs; (3) In the patients who
have undergone PCI over 12 months, it is recommended to use anti-
coagulant therapy alone.
Recommendation 32: In CCS patients with acute VTE, who have
undergone CABG and treatment with antiplatelet therapy but with-
out a history of ACS, it is recommended to continue aspirin and start
the anticoagulant therapy within 1 year after CABG; for the patient
who has undergone CABG over 1 year, it is recommended to use
anticoagulant therapy alone.
Recommendation 33: In patients with acute VTE and a history
of ACS, the antithrombotic regimens are selected based on the time
since the onset of ACS (see Figure 4), and four different scenarios
set and recommended accordingly as follows: (1) In patients with a
history of ACS?≤?12?months, it is recommended to discontinue as-
pirin, continue P2Y
12
inhibitors (clopidogrel preferred), and initiate
anticoagulant therapy (NOACs preferred) for most patients; (2) In
patients with a history of ACS?>?12?months, antiplatelet drugs may be
discontinued and most patients may use the anticoagulation therapy
alone; (3) In patients with high bleeding risk and low ischemic risk,
the course of antiplatelet therapy may be considered to be short-
ened; and (4) In patients with high thrombotic risk and low bleed-
ing risk, single antiplatelet therapy (aspirin or clopidogrel) combined
with anticoagulation therapy may be continued after 12?months at
the discretion of the clinician.
5.3? |?Elderly CCS patients with previous VTE
Recommendation 34: Based on the considerable risk of recurrent
VTE after an unprovoked event or an event provoked by active can-
cer, indefinite anticoagulant therapy is recommended in most such
patients if they are at average bleeding risk, and time- limited anti-
coagulant therapy is recommended if they are at increased bleeding
risk.
Recommendation 35: For women and patients with normal D-
dimer levels who have a lower risk of recurrent VTE after a first un-
provoked event, anticoagulant therapy may be discontinued. Some
validated clinical decision tools such as the HERDOO2 scoring sys-
tem may be helpful to identify patients at high recurrent risk to de-
termine the need for extended anticoagulant therapy.
TABLE 9?Common clinical anticoagulation regimens for VTE
Anticoagulation regimen Specific dosing regimen
Heparin + warfarin bridging regimen Warfarin 2.5 to 6.0 mg/day bridging with parenteral heparin (unfractionated heparin
or LMWH) initially. Measure the INR 2 to 3?days later, discontinue the heparin, and
continue warfarin until the INR is in the therapeutic range (2.0– 3.0) and maintain for
24?h.
Rivaroxaban monotherapy regimen 15?mg bid for the first 3?weeks, 20?mg qd
a
after 3?weeks to 6 months, and 10 mg qd after
6 months (20?mg qd is considered for patients with high VTE recurrence risk
b
)
Heparin + edoxaban sequential regimen Initial heparin injection for 5– 10?days, followed by edoxaban 60?mg qd
a
Heparin + dabigatran sequential regimen Initial heparin injection for 5– 10?days, followed by dabigatran 150?mg bid
a
Abbreviations: bid, twice daily; INR, international normalized ratio; LMWH, low molecular weight heparin; qd, once daily.
a
Dose adjustment is required according to the degree of renal insufficiency, as detailed in the individual product labeling.
b
Patients with complex complications, or patients suffer recurrent VTE when receiving rivaroxaban 10 mg qd.
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Recommendation 36: In all patients on indefinite therapy, the
risks and benefits of continuing anticoagulant therapy should be re-
assessed at least annually. For patients requiring indefinite anticoag-
ulant therapy, the principles for concurrent use of antiplatelet agents
are provided in Section 4.2.
5.4? |?Elderly CCS patients with VTE undergoing
elective PCI
Different antithrombotic strategies should be determined according
to whether the anticoagulant course is completed and the type of
anticoagulant agent in VTE patients who require PCI.
Recommendation 37: In a patient has completed the course of
OAC therapy for VTE, it could switch to aspirin?+?P2Y
12
receptor an-
tagonists based on perioperative antithrombotic principles of PCI.
Recommendation 38: If a patient within a time- limited course of
OAC therapy for VTE requires elective PCI, it is suggested to defer
the PCI until the patient has completed their OAC therapy, at which
time the OAC can be discontinued.
Recommendation 39: If PCI cannot be delayed until the end of
anticoagulation, or urgent/emergency PCI is required, drug manage-
ment should be performed according to perioperative antithrom-
botic principles of PCI, and NOAC?+?P2Y
12
receptor antagonists or
warfarin?+?P2Y
12
receptor antagonists is preferred as the replace-
ment therapy after the perioperative period. and proton pump in-
hibitors; if PPIs are intolerable, switch to H2- receptor antagonists.
In patients on indefinite anticoagulant therapy and in those
within a time- limited course of anticoagulant therapy who require
urgent or emergent PCI, perioperative antithrombotic principle of
PCI is suggested to be followed. NOAC?+?P2Y
12
receptor antago-
nists or warfarin?+?P2Y
12
receptor antagonists are preferred as the
FIGURE 3?Antithrombotic strategies
for CCS patients with acute VTE without
history of ACS but with history of PCI.
9
ACS, acute coronary syndrome; BMS,
bare metal stent; DES, drug- eluting stent;
PCI, percutaneous coronary intervention;
VTE, venous thromboembolism; Aspirin
75– 100?mg/day (triple therapy) may be
continued for up to 30?days if the risk of
thrombosis is high and the risk of bleeding
is low;
#
A small proportion of patients
with high thrombotic risk and low bleeding
risk may consider to continue single
antiplatelet therapy + oral anticoagulant
(OAC) therapy after completing standard
course of antiplatelet therapy.
FIGURE 4?Antithrombotic strategies
for patients with acute VTE and history
of ACS.
9
ACS, acute coronary syndrome; PCI,
percutaneous coronary intervention;
VTE, venous thromboembolism; Aspirin
75– 100?mg/day (triple therapy) may be
continued for up to 30?days if the risk of
thrombosis is high and the risk of bleeding
is low;
#
A small proportion of patients
with high thrombotic risk and low bleeding
risk may be considered to continue single
antiplatelet therapy + oral anticoagulant
(OAC) therapy after completing standard
course of antiplatelet therapy.
Patients with acute VTE and a history of ACS
Time since onset of ACS and/or time since PCI
> 12 Months ≤ 12 months
Initiate
anticoagulation
Initiate
anticoagulation
Discontinue antiplatelet drug
#
Discontinue aspirin
Continue P2Y12 receptor antagonist
(clopidogrel preferred)
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?15ZHANG et al.
replacement therapy after the perioperative period. For the patients
with high risk of gastrointestinal bleeding, we recommend starting
or continuing a gastrointestinal mucosal protective agent, and pro-
ton pump inhibitors (PPIs) are preferred (or histamine H
2
- receptor
antagonist if intolerable); if patients are at high risk of thrombosis
and low risk of bleeding, aspirin 75– 100?mg/day may be added for
short- term triple therapy within 30?days after PCI.
6?|?BLEEDING RISK ASSESSMENT IN
ELDERLY CCS PATIENTS TREATED WITH
ANTITHROMBOTIC THERAPY
6.1? |?Introduction of bleeding risk assessment tools
Elderly CCS patients have both high thrombosis risk and high bleed-
ing risk. Antithrombotic therapy is faced with a dilemma. This is
mainly due to the clinical characteristics of elderly patients, including
coexistence of multiple diseases, complex coronary lesions, debili-
tation, falls, malnutrition, impaired renal function, etc. Bleeding risk
assessment in elderly CCS patients treated with antithrombotic ther-
apy should include two parts: bleeding risk assessment of antiplate-
let therapy and bleeding risk assessment of anticoagulant therapy.
At present, commonly used bleeding risk assessment tools in-
clude PRECISE- DAPT score, HAS- BLED score, etc. The ARC- HBR
criteria includes multiple characteristics of the elderly patients and
is also used in clinical practice as a necessary supplement to the
PRECISE- DAPT score and the HAS- BLED score.
58,59
ARC- HBR crite-
ria are recommended to be used in clinical studies to further validate
its predictive value of bleeding risk in elderly CCS patients treated
with antithrombotic therapy.
5,58,59
Geriatric comprehensive assessment should be performed be-
fore bleeding risk assessment for elderly CCS patients treated with
antithrombotic therapy, with emphasis on falls, polydrug use, debil-
itation, dementia, etc. Based on the assessment results, appropriate
measures should be taken to further reduce the risk of bleeding,
60– 69
e.g. take active measures to correct orthostatic hypotension, im-
prove cerebral blood supply, and conduct gait training to reduce the
risk of falls; reduce the increased drug side effects and drug interac-
tions, pay attention to co- administered antiplatelet drugs or antico-
agulants, correct hypoproteinemia, and reduce the bleeding risk of
polydrug use; improve the surrounding environment, educate care-
givers, select single- dose drugs without monitoring, and increase the
treatment safety and compliance of elderly patients with cognitive
impairment.
70
Bleeding risk assessment in elderly CCS patients treated with an-
tithrombotic therapy also requires attention to dynamic assessment.
Various clinical and physiological parameters of elderly patients are
constantly changing (e.g. renal function, blood pressure control,
anemia, etc.). Various factors fluctuated affect geriatric assessment,
which will further affect the assessment of grade of bleeding risk.
Clinicians should closely observe the clinical situation of elderly pa-
tients and make plans for dynamic monitoring and evaluation, know
the change in bleeding risk of patients at any time, and timely opti-
mize the antithrombotic treatment regimen.
71– 75
Recommendation 40: The PRECISE- DAPT score is recommended
for bleeding risk assessment in patients on antiplatelet therapy.
Recommendation 41: The HAS- BLED score is recommended for
bleeding risk assessment in patients on anticoagulant therapy, with
high predictive accuracy and good predictive value for intracranial
hemorrhage.
6.2? |?Bleeding risk assessment in elderly CCS
patients treated with antithrombotic therapy
Bleeding risk assessment in elderly CCS patients with antithrom-
botic therapy should fully consider the bleeding risk of antiplatelet
therapy and anticoagulant therapy, and individualized risk assess-
ment should be performed based on comprehensive assessment of
the elderly.
Recommendation 42: In elderly CCS patients without AF or VTE,
it is recommended to use the PRECISE- DAPT score to assess the
bleeding risk of antithrombotic therapy and develop a long- term an-
tithrombotic treatment strategy based on the complexity of coro-
nary artery lesions (Table 10, Figure 1).
Recommendation 43: In elderly CCS patients with NVAF or
VTE, it is recommended to use the HAS- BLED score for bleeding
risk assessment of antithrombotic therapy and develop a long- term
antithrombotic treatment strategy based on the thrombosis risk as-
sessment and the complexity of coronary artery lesions (Table 11).
7?|?MANAGEMENT OF BLEEDING IN
ELDERLY HIGH- RISK CCS PATIENTS WITH
ANTITHROMBOTIC THERAPY
7.1? |?Recognition of bleeding degree of
antithrombotic therapy and management principles
7.1.1?|?Judgment of bleeding degree
There have been many criteria for the definition or grading of
bleeding. For standardization and comparison, a unified BARC
bleeding classification criteria (Table 12) was developed in 2011
to identify clinically variable degrees of bleeding and to intervene
accordingly. ISTH criteria are often used to define major bleeding
events when anticoagulants are used.
76
In 2020, the determina-
tion of the bleeding degree related to antithrombotic therapy in
CAD patients with AF was updated again in China and abroad.
The ACC guidelines recommend that the next intervention should
be determined based on the site of bleeding, time of occurrence,
severity, time of the last dose of anticoagulant drug, and other
factors affecting bleeding (e.g. liver and kidney function, alcohol
abuse, concomitant medications, previous bleeding history).
77
The
degree of bleeding is categorized into minor, moderate, and major
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bleeding by Chinese expert consensus (Table 13). Recognition of
the degree of bleeding plays an important role in subsequent cor-
responding treatment measures.
7.1.2?|?General bleeding management principles of
antithrombotic treatment
1. Management of bleeding associated with antiplatelet drug
therapy: there is no specific reversal agent for antiplatelet drugs
at present, and special attention should be paid to the moni-
toring and management of bleeding (Figure 5).
78
2. Management of bleeding associated with anticoagulant therapy
(Figure 6).
6,27,77,79– 81
7.2? |?Common types and management of
bleeding of antithrombotic therapy
7.2.1?|?Intracerebral hemorrhage
Intracerebral hemorrhage (ICH) is the most serious type of hem-
orrhage of antithrombotic therapy, and attention should be paid
to blood pressure management and etiological treatment.
82
In pa-
tients without high risk of thrombosis, restarting anticoagulation
may be postponed to 4?weeks later; in patients with new ICH who
have little prognostic impact and high risk of ischemia, resumption
of antiplatelet therapy may be considered on Day 7 to 10 after
discontinuation; the type or dose of antiplatelet drugs may also
be reduced as appropriate, and ticagrelor is recommended to be
avoided.
77
Recommendation 44: In patients with systolic blood pressure of
150 to 220?mm Hg, blood pressure can be lowered to 130 to 140?mm
Hg within hours if there is no contraindication for acute antihyper-
tensive treatment; for those with systolic blood pressure?>?220?mm
Hg, close monitoring of blood pressure and continuous intravenous
infusion of drugs to control blood pressure should be performed,
with target systolic blood pressure of 160?mm?Hg.
Recommendation 45: Discontinue antithrombotic therapy im-
mediately in the event of intracerebral hemorrhage.
Recommendation 46: Warfarin- related ICH: intravenous infu-
sion of vitamin K; prothrombin complex (PCC) can be considered
as an alternative; platelet transfusion therapy can be considered if
needed.
Recommendation 47: NOAC- related ICH: corresponding antag-
onists (e.g. idarucizumab for dabigatran) can be used if available;
PCC or activated prothrombin complex (aPCC) can be considered if
there is no specific reversal agent; platelet transfusion can be con-
sidered if needed.
Recommendation 48: Unfractionated heparin- related ICH:
treatment with protamine sulfate is recommended.
Recommendation 49: Antiplatelet drug- related ICH: platelet
transfusion therapy is not routinely recommended.
7.2.2?|?Gastrointestinal bleeding
Gastrointestinal injury caused by aging increases the risk of bleed-
ing of antithrombotic therapy in advanced- age patients, and the gas-
trointestinal tract is the most common site of bleeding complicated
by antithrombotic treatment in patients with CCS.
83,84
Proton pump
inhibitors (PPIs) reduce the risk of gastrointestinal bleeding, espe-
cially in patients with a history of gastrointestinal bleeding or ulcers
and concomitant antiplatelet therapy or OAC therapy.
6,26,85– 88
Long-
term use of PPIs may increase the risk of hypomagnesemia, but the
role of monitoring serum magnesium levels is unclear.
2,6
For patients
with well- defined indications requiring long- term PPI treatment, the
use of minimum effective dose is relatively safe and the benefits far
outweigh the risks.
Recommendation 50: Helicobacter pylori (HP)- positive patients
should be treated with HP eradication.
Recommendation 51: In patients treated with aspirin, DAPT, or
OAC, concomitant PPIs are recommended if there is a high risk of
gastrointestinal bleeding.
Recommendation 52: Some PPIs competitively inhibit the anti-
platelet effect of clopidogrel through CYP2C19 and may affect its
clinical efficacy. Therefore, PPIs less affected by CYP2C19 (e.g. pan-
toprazole, rabeprazole, etc.) are recommended when combined with
clopidogrel, and concomitant use of clopidogrel with omeprazole or
esomeprazole are not recommended.
TABLE 10?Antithrombotic regimens in elderly CCS patients without atrial fibrillation or VTE
PRECISE- DAPT score Complexity of coronary artery lesions
a
Antithrombotic regimen
≥25 points Whether complicated with complex coronary artery lesions
or not
SAPT
<25 points Complicated with complex coronary artery lesions
No complicated with complex coronary artery lesions
DPI or DAPT
Select DPI, DAPT, or SAPT based on ischemic risk
Abbreviations: CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; SAPT, single antiplatelet therapy;
VTE, venous thromboembolism.
a
Complex coronary artery lesions include multivessel disease, more than three stents, left main stem stent implantation, double stent implantation,
and total stent length greater than 60?mm.
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?17ZHANG et al.
Recommendation 53: Once gastrointestinal bleeding occurs,
endoscopy should be completed within 24?h of initial diagnosis; pa-
tients at high risk of rebleeding should be treated with high- dose PPI
(80?mg bolus followed by 8 mg/h for 72?h) as soon as possible, and
adjusted accordingly to endoscopic typing and hemostasis results.
Recommendation 54: Transcatheter arterial embolization (TAE)
should be considered first in advanced- age patients who have un-
successful endoscopic hemostasis or who have complex comorbidi-
ties/are ineligible for surgery.
Recommendation 55: Colonoscopy is considered to be the most
important approach to determine the cause and location of colorec-
tal bleeding and endoscopy hemostasis is recommended.
Recommendation 56: Capsule endoscopy should be consid-
ered a first- line diagnostic tool for patients with negative findings
on upper and lower gastrointestinal endoscopy and suspected small
bowel bleeding, and it should be done 72?h after the cessation of
bleeding but within 14?days.
7.2.3?|?Anemia caused by bleeding
Hemorrhage complicated by antithrombotic therapy may cause ane-
mia, and anemia is an independent risk factor for the hemorrhagic
and ischemic events in elderly patients with chronic CAD.
89,90
Recommendation 57: In the elderly patients, more attention
should be paid to volume resuscitation, and a restrictive volume re-
suscitation strategy is recommended to achieve target blood pres-
sure until bleeding is controlled.
H A S - B L E D
score
CHA
2
DS
2
- VA S C
score
Complexity of
coronary artery
lesions
a
Antithrombotic regimen
≥3 points ≥3 points (M)/4
points (F)
Complicated with
complex coronary
artery lesions
Aspirin + OAC (prophylactic
doses for stroke prevention
from AF or therapeutic
doses for VTE
b
) can be used
No complicated with
complex coronary
artery lesions
2 points (M)/3
points (F)
Complicated with
complex coronary
artery lesions
Aspirin + OAC (prophylactic
doses for stroke prevention
from AF or therapeutic
doses for VTE
b
) can be used
with caution
No complicated with
complex coronary
artery lesions
OAC can be used with caution
<2 points (M)/3
points (F)
Complicated with
complex coronary
artery lesions
Aspirin + OAC (prophylactic
doses for stroke prevention
from AF or therapeutic
doses for VTE
b
) can be used
with caution
No complicated with
complex coronary
artery lesions
SAPT can be considered
<3 points ≥2 points (M)/3
points (F)
– Aspirin + OAC (prophylactic
doses for stroke prevention
from AF or therapeutic
doses for VTE
b
) can be used
– Complicated with
complex coronary
artery lesions
<2 points (M)/3
points (F)
No complicated with
complex coronary
artery lesions
OAC can be used
Abbreviations: CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; NVAF, non-
valvular atrial fibrillation; OAC, oral anticoagulant; SAPT, single antiplatelet therapy; VTE, venous
thromboembolism.
a
Complex coronary artery lesions include multivessel disease, more than three stents, left main
stem stent implantation, double stent implantation, and total stent length greater than 60?mm.
b
If rivaroxaban is selected, the prophylactic doses for stroke prevention from AF are 20 or 15?mg,
while the therapeutic doses for VTE are 15?mg bid for the first 3?weeks, 20?mg qd after 3?weeks to
6 months, and 20 or 10 mg after 6 months.
TABLE 11?Antithrombotic regimens in
elderly CCS patients with NVAF or VTE
24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
18?
|
??? ZHANG et al.
Recommendation 58: It is recommended that a low initial Hb be
considered an indicator for severe bleeding associated with coagu-
lopathy; the use of repeated Hb measurements is also considered.
It is recommended that serum lactate and/or base deficit measure-
ments be used as a sensitive test to estimate and monitor the extent
of bleeding and shock.
Recommendation 59: In patients with symptomatic anemia or
active bleeding, the recommended indication for transfusion therapy
is Hb?
to be no more than 90?g/L. Improper indication of transfusion may
increase mortality.
Recommendation 60: Monitor the ionized calcium levels within
normal range during massive transfusion. Calcium chloride is recom-
mended for correcting hypocalcemia.
7.3? |?Prevention and treatment of bleeding risk in
special populations
7.3.1?|?Prevention and treatment of bleeding risk in
patients with renal dysfunction
There is a progressive, independent, inverse linear relationship be-
tween decreased glomerular filtration rate (eGFR) and the risk of
hemorrhagic stroke. Patients with chronic kidney disease (CKD) and
those with end- stage renal disease (ESRD) undergoing dialysis are
more prone to severe gastrointestinal bleeding. For patients with
renal insufficiency, the 2019 US guidelines for the management of
AF suggest that renal function should be assessed prior to adminis-
tration of NOACs, and different types of NOACs should be selected
Category Criteria
Type 0 No bleeding
Type 1 Bleeding that is not actionable
Type 2 Significant bleeding, but not reaching type 3– 5, requiring medical intervention
Type 3 3a: hemoglobin drops of 30– 50?g/L, requiring blood transfusion
3b: cardiac tamponade, hemoglobin drops of ≥50?g/L, bleeding requiring
intravenous vasoactive agents
3c: intracranial hemorrhage, spinal cord hemorrhage, intraocular bleed
compromising vision.
Type 4 CABG- related bleeding within 48?h
Type 5 Probable (5a) or definite (5b) fatal bleeding
TABLE 12?BARC bleeding classification
criteria
77
Category Criteria
Minor bleeding Epistaxis, small ecchymosis of skin, bleeding after minor trauma
Moderate bleeding Gross hematuria, large spontaneous ecchymosis, no hemodynamic
disturbance but requiring transfusion
Major bleeding Life- threatening bleeding, including bleeding at critical sites, such as
intracranial and retroperitoneal bleeding, and bleeding leading
to hemodynamic instability
TABLE 13?Bleeding classification
criteria
6,76
FIGURE 5?Management of bleeding
associated with antiplatelet therapy.
78
DAPT is dual antiplatelet therapy; SAPT is
single antiplatelet therapy.
Bleeding during antiplatelet therapy
Mild or minor bleeding
Major bleeding Moderate bleeding
Continue DAPT (dual ●
●
antiplatelet therapy)
Consider reduction of
DAPT duration or
de-escalation therapy
(ticagrelor replaced by
clopidogrel)
Consider DAPT change
into SAPT (single
antiplatelet therapy)
Prefer to retain P2Y12
receptor antagonists
Restart DAPT after
bleeding correction
Immediately discontinue
all antithrombotic
medications
Re-evaluate the need for
antiplatelet regimen of
DAPT or SAPT after
stopping bleeding
●●
●●
●
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???
|
?19ZHANG et al.
based on serum creatinine concentration levels in NVAF patients
with moderate to severe CKD and CHAD
2
S
2
- VASC score?≥?2 points
(male)/≥3 points (female).
91
Retrospective studies have shown that
rivaroxaban is similar in efficacy to warfarin in NVAF patients with
stage 4– 5 chronic kidney disease or undergoing hemodialysis, and it
significantly reduces the risk of major bleeding.
92,93
Recommendation 61: Aspirin can be used without dose adjust-
ment in patients with stage 1– 5 CKD. Clopidogrel and ticagrelor can
be used without dose adjustment in patients with stage 1– 4 CKD
(eGFR?≥?15?ml·min
?1
·1.73?m
?2
). In patients with stage 5 CKD, clopido-
grel is only used for patients with selective indications (e.g. stent
thrombosis prophylaxis), and ticagrelor is not recommended.
Recommendation 62: Warfarin is recommended as the first- line
anticoagulation in patients on dialysis or with creatinine clearance
(CrCl)?
Recommendation 63: Dabigatran etexilate is contraindicated in
patients with severe renal insufficiency (CrCl 15 to 29?ml/min). It is
recommended that the dosage of oral factor Xa inhibitors should be
reduced and used with caution.
Recommendation 64: The dosage of DOACs should be reduced in
patients with moderate renal insufficiency (CrCl 30– 49?ml/min), such
as rivaroxaban 15?mg qd, edoxaban 30?mg qd, or dabigatran etexilate
110?mg bid. When apixaban is given in patients with mild to moderate
renal insufficiency (CrCl 30– 95?ml/min) or normal renal function, a low-
dose regimen (2.5 mg twice daily) is recommended for patients?≥?2 of
the following: age?≥?80?years, weight?≤?60?kg, creatinine?≥?133?μmol/L.
7.3.2?|?Prevention and treatment of bleeding risk in
patients with hepatic insufficiency
Antithrombotic therapy is more difficult in patients with chronic
liver disease due to increased risk of thrombosis and bleeding.
94,95
There are no available guideline recommendations for anticoagu-
lant therapy in patients with liver disease. Due to impaired hepatic
function, decreased plasma albumin levels (plasma protein binding
rate: rivaroxaban 95%?>?apixaban 85%?>?edoxaban 55%?>?dabigatran
35%), and decreased cytochrome P450 enzyme activities (apixaban
FIGURE 6?Management of
bleeding associated with anticoagulant
drug
6,27,77,79– 81
Bleeding during anticoagulant therapy
Minor bleeding Major bleeding
Moderate bleeding or non-major
bleeding requiring management
Symptomatic supportive care, ?
?
dosing delay or interruption
Continuation of oral
anticoagulants may be
considered for nonserious
patients who do not require
hospitalization, surgery, or
intervention, but
comorbidities leading to
bleeding are needed to be
assessed to determine the dose
of oral anticoagulants
Discontinue oral
anticoagulants
Symptomatic fluid
replacement and blood
transfusion
Vitamin K1 IV (1 to 10 mg)
can be given to patients taking
warfarin
Oral charcoal and/or gastric
lavage can be given to reduce
drug absorption within 2 to 4 h
of NOAC administration
Ensure airway patency and
large-caliber venous access
OAC reversal agents such as
vitamin K, PCC, or aPCC,
factor Xa inhibitor reversal
agent andexanet alfa, and
factor IIa inhibitor, can be used
if available
Resuscitation and local
hemostasis should not be
delayed when obtaining and
using reversal agents, and
volume resuscitation may be
performed with isotonic
crystalloid solution (e.g., 0.9%
NaCl or lactated Ringer''s
solution).
Dabigatran etexilate can be
cleared by hemodialysis and
other NOACs are not suitable
for dialysis
Immediately consider
restarting anticoagulation once
the patient''s condition is stable
??
?
?
?
?
?
?
?
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20?
|
??? ZHANG et al.
and rivaroxaban are mainly metabolized by CYP3A4, a small amount
of edoxaban is metabolized by CYP3A4, and dabigatran is not me-
tabolized by P450 enzymes), the anticoagulant effect of OACs is en-
hanced in such patients.
27
Recommendation 65: Child- Pugh classification of hepatic im-
pairment is recommended.
Recommendation 66: In patients with mild hepatic impairment,
no dose adjustment is required for antiplatelet drugs such as aspirin,
clopidogrel, and ticagrelor.
Recommendation 67: Clopidogrel should be used with caution
and ticagrelor is contraindicated in patients with moderate to severe
liver disease who may have a bleeding tendency.
Recommendation 68: Warfarin can be used in most patients with
liver disease and is currently the only OAC used in patients with se-
vere hepatic insufficiency. INR monitoring should be within 2.0 to
3.0, but the safety of warfarin in patients with hepatic insufficiency
remains to be further confirmed, given the instability of warfarin
plasma concentrations and the undistinguished reason for increased
INR values that may be the use of warfarin or underlying disease
progression.
Recommendation 69: No dose adjustment of NOACs is required
for patients with mild hepatic impairment; conventional doses of
dabigatran, apixaban, or edoxaban should be used with caution in
patients with moderate hepatic impairment, and rivaroxaban is not
recommended.
7.3.3?|?Prevention and treatment of bleeding risk in
advanced- age or frail patients
Advanced age (≥75?years) or frailty is one of the main risk factors for
bleeding. Based on the clinical study evidence, the majority of the an-
tiplatelet study populations are patients with a median age?
while data are still lacking in patients older than 65?years of age.
Particularly, advanced- age patients are often excluded from rand-
omized controlled studies, so caution should be exercised in the use
of antiplatelet therapy in advanced- age patients.
96– 99
The phenomenon of comorbidities and polydrug use is common
in advanced- age patients, who are vulnerable to drug– drug interac-
tions especially in patients taking warfarin, which interacts with a
wide range of drugs. NOACs also have definitive interactions with
some specific drugs such as antifungals, immunosuppressants, and
dronedarone, which increases the risk of bleeding, and extra caution
is required.
27
HAS- BLED score can be used to identify patients at
high risk of bleeding (score?≥?3 points as high risk), correct controlled
bleeding risk factors, and follow up regularly throughout anticoagu-
lant therapy.
41
Recommendation 70: Bleeding risks should guide the optimiza-
tion of antithrombotic drugs in advanced- age patients and avoiding
PCI and surgical treatment if possible.
Recommendation 71: Combination of antiplatelet and anti-
coagulant therapy should be avoided in advanced- age patients
undergoing surgery. Such surgery should be postponed until the
antithrombotic course is terminated or the dosage could be re-
duced, and the risk of bleeding should be adequately assessed be-
fore the procedure.
Recommendation 72: In advanced- age patients with suspected
platelet disorders, bedside platelet function testing is recom-
mended. Mean platelet count?
9
/L is a critical point for the
use of antiplatelet agents and anticoagulant agents. If necessary,
apheresis platelets transfusion could be considered to maintain
platelet count?≥?50 null?10
9
/L (cryoprecipitate transfusion may also be
considered to maintain fibrinogen?>?100?mg/dl if coagulation factors
are insufficient).
In the treatment of elderly high- risk CCS patients, the efficacy
and safety of antithrombotic agents should be carefully evaluated.
For those patients, the risk of bleeding and ischemia should be ac-
curately assessed. and the indications for extensive antithrombotic
therapy with DPI or DAPT should be well specified, regular follow
up and correcting the risk factors of ischemia or bleeding in a timely
manner should also be considered, and the extent and site of bleed-
ing should be accurately determined and treated promptly; all attri-
butes above are aimed to maximize the antithrombotic benefit and
minimize the risk of bleeding.
FUNDING INFORMATION
Not applicable.
ACKNOWLEDGMENTS
Not applicable.
AUTHOR CONTRIBUTIONS
Initiate and organization of this consensus: Cuntai Zhang and
Xiaoming Wang. Writing the initial draft (including substantive
translation): Editing group of the on Chinese expert consensus on an-
tithrombotic management of high-risk elderly patients with chronic
coronary syndrome. Preparation and presentation of the published
work: Xiang Gao, Jinli Wang. Critical review and revision: Cuntai
Zhang, Xiaoming Wang Cardiovascular Group, Geriatrics Branch of
Chinese Medical Association.
CONFLICT OF INTEREST
Zhang Cuntai is the Editorial Board members of Aging Medicine and
co-authors of this paper. To minimize bias, they were excluded from
all editorial decision making related to the acceptance of this paper
for publication. Other authors have nothing to disclose.
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How to cite this article: Zhang C, Wang X, Cardiovascular
Group, Geriatrics Branch of Chinese Medical Association..
Chinese expert consensus on antithrombotic management of
high- risk elderly patients with chronic coronary syndrome.
Aging Med. 2023;6:4-24. doi:10.1002/agm2.12234
APPENDIX 1
Academic Consultants (in the order of last name in Pinyin): Li Xiaoying
(General Hospital of the People''s Liberation Army of China); Wang
Jianye (Beijing Hospital); Yu Pulin (Beijing Institute of Geriatrics,
National Health Commission).
Academic Secretary: Gao Xiang (General Department, Tongji
Hospital, Tongji Medical College, Huazhong University of Science
and Technology).
Authoring Experts (in the order of the written sections): Liu
Hongbin (Department of Geriatric Cardiology, General Hospital
of the People''s Liberation Army of China), Zhang Cuntai (General
Department, Tongji Hospital, Tongji Medical College, Huazhong
University of Science and Technology); Hong Huashan (Department
of Geriatrics, Fujian Medical University Union Hospital); Li Yan
(Department of Geriatrics, First People''s Hospital of Yunnan
Province); Wang Xiaoming (Department of Geriatrics, Xijing
Hospital of Air Force Medical University); Gao Haiqing (Department
of Geriatrics, Qilu Hospital of Shandong University); Lin Zhanyi
(Department of Geriatrics, Guangdong Provincial People''s Hospital);
Bai Xiaojuan (Department of Geriatrics, Shengjing Hospital
Affiliated to China Medical University); Li Shan (Department of
Geriatric Cardiovascular Diseases, General Hospital of the People''s
Liberation Army of China); Gao Xiang (General Department, Tongji
Hospital, Tongji Medical College, Huazhong University of Science
and Technology); Fang Meiqin (Department of Geriatrics Hospital,
Fujian Medical University Union Hospital); He Xu (Department of
Geriatrics, Yunnan First People''s Hospital); Li Rong (Department
of Geriatrics, Xijing Hospital of Air Force Medical University); Xiao
Yunling (Department of Geriatrics, Qilu Hospital of Shandong
University); Yu Wan (Department of Geriatrics, Shengjing Hospital
Affiliated to China Medical University).
Discussion Experts (in the order of last name in Pinyin): Cheng
Biao (Department of Geriatrics, Sichuan Provincial People''s
Hospital); Chen Long (Department of Geriatrics, Shenzhen Hospital
of Southern Medical University); Fang Ningyuan (Department of
Geriatrics, Renji Hospital Affiliated to Shanghai Jiaotong University
School of Medicine); Gao Xuewen (Department of Geriatrics, Inner
Mongolia Autonomous Region People''s Hospital); Guo Yifang
(Department of Geriatrics, Hebei People''s Hospital); Huang Gairong
(Department of Geriatrics, Henan Provincial People''s Hospital); Han
Lulu (Department of Geriatrics, Shengjing Hospital Affiliated to
China Medical University); Liu Deping (Department of Cardiology,
Beijing Hospital); Liang Jiangjiu (Department of Geriatrics, The
First Affiliated Hospital of Shandong First Medical University);
Liu Ze (Department of Geriatrics, General Hospital of Southern
Theatre Command);Mao Yongjun (Department of Geriatrics,
Affiliated Hospital of Qingdao University); Ou Baiqing (Department
of Geriatrics, Hunan Provincial People''s Hospital); Shen Lin
(Department of Geriatrics, Qilu Hospital of Shandong University);
Tian Tao (Department of Geriatrics, Linyi People''s Hospital,
Shandong Province); Tu Ling (General Department, Tongji Hospital,
Tongji Medical College, Huazhong University of Science and
Technology); Tian Wen (Department of Geriatrics, First Affiliated
Hospital of China Medical University); Wen Hong (Department of
Geriatrics, First Affiliated Hospital of Guangxi Medical University);
Wang Jianchun (Department of Geriatrics, Shandong Provincial
Hospital); Wang Zhaohui (Department of Geriatrics, Tongji Hospital,
Tongji Medical College, Huazhong University of Science and
Technology);Wu Zhenli (Department of Geriatrics, Inner Mongolia
Autonomous Region People''s Hospital); Xing Kun (Department
of Geriatrics, Shaanxi Provincial People''s Hospital); Yang Ruiying
(Department of Cardiovascular Diseases, General Hospital
of Ningxia Medical University); Yang Yunmei (Department of
Geriatrics, The First Affiliated Hospital of Zhejiang University); Yang
Li (Department of Geriatrics, Yan''an Hospital, Kunming); Zeng Min
(Health Center, Hainan Province People''s Hospital); Zhou Xiaohui
(Department of Geriatrics, The First Affiliated Hospital of Xinjiang
Medical University)
24750360, 2023, 1, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/agm2.12234 by CochraneChina, Wiley Online Library on [14/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
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