Chinese expert consensus on antithrombotic management of high‐risk elderly patients with chronic coronary syndrome

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 organizes 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.

Antithrombotic principles in patients with CCS: (1) Ischemic and bleeding risks should be adequately assessed to determine treatment strategies before initiating antithrombotic therapy. (2) Dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) is recommended for patients with high ischemia risk and without high bleeding risk. (3) For CCS patients with low thrombotic risk and/or excessive bleeding risk, intensive antithrombotic therapy is suggested to avoid.

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 burden 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 comprehensive management of CAD, while safer and more suitable antithrombotic strategies are particularly important for elderly patients 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 evidence, 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 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 revascularization; (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 elderly 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 mortality <1%/year. ² Various clinical comorbidities, complex coronary anatomy factors, and interventional device‐related factors can increase 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 artery, cerebral artery, and peripheral artery), and multiple high‐risk factors (such as diabetes mellitus, hypertension, dyslipidemia, renal insufficiency, etc.). ² , ³ , ⁴ The high ischemic risk profile of CCS in the elderly is shown in Table 1.

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.

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, concomitant 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.

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 < 110 g/L); moderate to severe thrombocytopenia (<100 × 109/L); spontaneous bleeding within 6 months (requiring hospitalization and/or transfusion); chronic bleeding diathesis; severe or end‐stage CKD (eGFR < 30 ml·min−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.

2.4. Other characteristics of elderly patients with high‐risk CCS

Elderly patients with CCS may have multiple other clinical conditions, 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 proportion of acute VTE patients with CAD is 10% to 17%. ⁷ , ⁸ Atrial fibrillation or VTE itself may require anticoagulant therapy, so the benefits and risks of antithrombotic therapy should be particularly considered 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 treatment strategies before initiating antithrombotic therapy. ² , ¹⁰ (2) Dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) is recommended for patients with high ischemia risk and without high bleeding risk. (3) For CCS patients with low thrombotic risk and/or excessive bleeding risk, intensive antithrombotic therapy is suggested 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 monitoring is helpful for individual conditions assessment and medication selection, but it is not recommended for routine use. ⁴

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.

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 < 60 kg or
		age > 75 y)
	Ticagrelor	60 mg twice daily

Abbreviations: CCS, chronic coronary syndrome; DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition.

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 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 disease 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 cardiovascular 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 , ¹⁵ , 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

TABLE 4.

Summary of antithrombotic therapy trials of DAPT/DPI ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸

Study	Population	Duration of follow‐up	type of treatment	Population and geriatric subgroups	Primary efficacy endpoint	Bleeding events
					Death, myocardial infarction, stroke	GUSTO moderate/severe bleeding
DAPT	Patients receiving DAPT for 1 year after PCI	18 months	Clopidogrel/prasugrel + aspirin; aspirin + placebo	Overall population (9961)	4.3% versus 5.9%, 0.71 (0.59 ~ 0.85)	2.5% versus 1.6%, 1.61 (1.21 ~ 2.16)
				<75 years (8929)	4.0% versus 5.8%, 0.69 (0.57 ~ 0.83)	2.3% versus 1.3%, 1.78 (1.29 ~ 2.47)
				≥75 years (1032)	6.8% versus 7.1%, 0.95 (0.59 ~ 1.52)	3.7% versus 3.6%, 1.03 (0.54 ~ 1.98)
					Cardiovascular death, myocardial infarction, stroke	TIMI major hemorrhage
PEGASUS‐ TIMI54	Patients with a history of myocardial infarction for 1 to 3 years	33 months	Ticagrelor 60 mg + aspirin; aspirin + placebo	Overall population (21 162)	7.77% versus 9.04%, 0.84 (0.74 ~ 0.95)	2.30% versus 1.06%, 2.32 (1.68 ~ 3.21)
				<75 years (18 079)	7.23% versus 8.27%, 0.86 (10.75 ~ 0.98)	2.05% versus 0.96%, 2.30 (1.60 ~ 3.32)
				≥75 years (3083)	11.0% versus 13.5%, 0.77 (0.59 ~ 1.01)	4.11% versus 1.68%, 2.50 (1.25 ~ 4.97)
					Cardiovascular death, myocardial infarction, stroke	TIMI major hemorrhage
THEMIS	Patients ≥ 50 years of age with type 2 diabetes mellitus and stable CAD	39.9 months	Ticagrelor 60 mg + aspirin; aspirin + placebo	Overall population (19 920)	7.7% versus 8.5%, 0.90 (0.81 ~ 0.99)	2.2% versus 1.0%, 2.32 (1.82 ~ 2.94)
				<65 years (7934)	6.1% versus 7.3%, 0.83 (0.70 ~ 0.98)	2.0% versus 0.9%, 2.33, (1.58 ~ 3.43)
				65–75 years (8890)	7.4% versus 8.4%, 0.89 (0.77 ~ 1.03)	2.3% versus 1.0%, 2.49 (1.75 ~ 3.53)
				≥75 years (2396)	13.6% versus 13.1%, 1.07 (0.86 ~ 1.33)	2.2% versus 1.4%, (1.89, 1.03 ~ 3.49)
					Cardiovascular death, myocardial infarction, stroke	Revised ISTH major hemorrhage
COMPASS	Patients ≥ 65 years with stable CAD, or patients <65 years with ≥ 2 vascular bed diseases or ≥ 2 other risk factors a	23 Month	Rivaroxaban + aspirin; aspirin + placebo	Overall population (16 574)	4% versus 6%, 0.74 (0.65 ~ 0.86)	3% versus 2%, 1.66 (1.37 ~ 2.03)
				Chinese population (1086)	1.5%/yr versus 2.5%/yr, 0.60, (0.27 ~ 1.45)	1.0%/yr versus 1.2%/yr, 0.82 (0.27 ~ 2.44)
				<65 years (n = 3754)	3.7% versus 6.0%, 0.61 (0.45 ~ 0.82)	1.3% versus 1.2%, 1.11 (0.63 ~ 1.96)
				65–75 years (9368)	3.6% versus 4.8%, 0.74 (0.61 ~ 0.91)	3.1% versus 1.9%, 1.62 (1.24 ~ 2.10)
				≥75 years (3452)	6.3% versus 7.1%, HR = 0.87 (0.67 ~ 1.13)	5.3% versus 2.6%, 2.02 (1.41 ~ 2.88)

Abbreviations: DAPT, dual antiplatelet therapy; DPI, dual pathway inhibition; GUSTO, global use of strategies to open occluded coronary arteries; HR, hazard ratio; ISTH, International Society on Thrombosis and Hemostasis; TIMI, thrombolysis in myocardial infarction trial.

^a Current smoking, diabetes mellitus, estimated glomerular filtration rate (eGFR) < 60 ml·min⁻¹·1.73 m⁻², heart failure or non‐lacunar ischemic stroke ≥ 1 month.

Recommendation 1: Elderly CCS patients with multi‐vessel coronary disease are with high ischemia risk. A second antithrombotic drug (P2Y12 receptor antagonist or rivaroxaban 2.5 mg bid) is recommended 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 radial 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 undergoing elective CABG and other antithrombotic drugs discontinued at intervals according to their duration of action and indication (prasugrel stopped ≤7 days before; clopidogrel ≥5 days before; ticagrelor ≥3 days before). Reloading of aspirin after CABG surgery may improve 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 mortality. In the COMPASS study, a subgroup analysis of 1448 patients 4–14 days after CABG suggested that the benefit of DPI in reducing 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 , ²² , ²³ , ²⁴ , 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 thrombosis 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 myocardial 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 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, elective 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 indicated. 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 effect of renal function should also be considered in patients treated with rivaroxaban.

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.

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.), aspirin is recommended to be discontinued for at least 5 days before surgery.

Recommendation 9: In patients who receive P2Y12 receptor inhibitors 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 reasonable to choose intravenous platelet membrane glycoprotein IIb/IIIa receptor antagonist (GPI) as bridging therapy until 4 h before surgery after discontinuing P2Y12 receptor antagonist.

FIGURE 2.

Perioperative DAPT management in elderly CCS patients undergoing noncardiac surgery. ⁶ , ²⁶ GPI, intravenous platelet membrane glycoprotein IIb/IIIa receptor antagonist. ^aSurgeries with very high bleeding risk such as intracranial surgery, transurethral prostatectomy, posterior chamber surgery, etc.

Recommendation 10: Antiplatelet therapy should be resumed as soon as possible (preferably within 24 h) after surgery.

Recommendation 11: In patients who planned for elective noncardiac surgery and treated with DPI, the strategies for whether aspirin is discontinued or not and the duration of discontinuation 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).

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

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 bleeding 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, gastrointestinal 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 antithrombotic therapy. Current studies have shown that DAPT or DPI can reduce MACEs in patients with multi‐bed vascular disease, and aspirin in combination with P2Y₁₂ 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 vascular disease and a 1‐3‐year history of previous myocardial infarction. 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 reduced 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

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 < 0.05.

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 undergone lower extremity revascularization. ³²

Recommendation 13: Dual pathway inhibition (aspirin + rivaroxaban 2.5 mg bid) is recommended for secondary prevention in elderly 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 benefit in the secondary prevention of stroke and increased the risk of major bleeding. ³³ , ³⁴ , 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 monotherapy 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

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 < 0.05.

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).

Recommendation 16: In CCS patients with stroke and low bleeding risk (at least 1 month after onset of non‐lacunar stroke), rivaroxaban 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 diabetes 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 ischemic events, whereas AF patients with high risk of thromboembolism 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 monotherapy 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 adjust the dose of OAC appropriately. ⁶

4.2. Evaluation before antithrombotic treatment

4.2.1. Thromboembolic risk assessment

CHAD₂S₂‐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 CHAD₂S₂‐VASC score ≥ 2 points (male)/≥3 points (female); (2) AF patients with CHAD₂S₂‐VASC score of 1 (male)/2 (female) should consider the use of OAC, balancing the individualized characteristics of net clinical benefit and patient preference; (3) patients with CHAD₂S₂‐VASC score of 0 (male)/1 (female) should avoid anticoagulant therapy to prevent thromboembolism. In the CHAD₂S₂‐VASC scoring items, age 65–74 years is 1 point, 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 assess 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 mandatory 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 receiving 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 bleeding in CCS patients with NVAF ⁴² ; a meta‐analysis of the OAC‐ALONE study and AFIRE study have shown that the efficacy of OAC monotherapy is similar to that of OAC + SAPT, with a lower bleeding risk. ⁴³

Recommendation 17: Based on the CHAD₂S₂‐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 anticoagulation (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 continuation 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/thrombosis is low or bleeding risk is high, followed by an OAC long‐term monotherapy.

Recommendation 22: It is recommended to use a NOAC in preference 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 CHAD₂S₂‐VASC score ≥ 2 (male)/≥3 (female) and with the following conditions ⁴⁸ , ⁴⁹ , ⁵⁰ : (1) not suitable for long‐term standard anticoagulant 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/noncompliance with long‐term anticoagulant therapy.

Recommendation 24: Oral anticoagulant therapy should be given for 45 days after successful left atrial appendage closure followed 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 anticoagulation, 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 lacking for antithrombotic therapy in elderly CCS patients with VTE. Recommendations are made based on relevant studies and treatment guidelines. The commonly used anticoagulant treatment regimens for VTE are shown in Table 9. ⁹ , ⁵¹ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵ , ⁵⁶ , ⁵⁷

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.

Recommendation 26: Anticoagulation is the foundation treatment 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 recommended 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 therapy 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 antithrombotic 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 considered according to the time after PCI (see Figure 3), and 3 scenarios 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 anticoagulant therapy alone.

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.

Recommendation 32: In CCS patients with acute VTE, who have undergone CABG and treatment with antiplatelet therapy but without 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 aspirin, continue P2Y₁₂ 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 shortened; and (4) In patients with high thrombotic risk and low bleeding risk, single antiplatelet therapy (aspirin or clopidogrel) combined with anticoagulation therapy may be continued after 12 months at the discretion of the clinician.

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.

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 cancer, indefinite anticoagulant therapy is recommended in most such patients if they are at average bleeding risk, and time‐limited anticoagulant 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 unprovoked event, anticoagulant therapy may be discontinued. Some validated clinical decision tools such as the HERDOO2 scoring system may be helpful to identify patients at high recurrent risk to determine the need for extended anticoagulant therapy.

Recommendation 36: In all patients on indefinite therapy, the risks and benefits of continuing anticoagulant therapy should be reassessed at least annually. For patients requiring indefinite anticoagulant 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 + P2Y₁₂ receptor antagonists 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 management should be performed according to perioperative antithrombotic principles of PCI, and NOAC + P2Y₁₂ receptor antagonists or warfarin + P2Y₁₂ receptor antagonists is preferred as the replacement therapy after the perioperative period. and proton pump inhibitors; 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 + P2Y₁₂ receptor antagonists or warfarin + P2Y₁₂ receptor antagonists are preferred as the 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 proton pump inhibitors (PPIs) are preferred (or histamine H₂‐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 bleeding 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, debilitation, falls, malnutrition, impaired renal function, etc. Bleeding risk assessment in elderly CCS patients treated with antithrombotic therapy should include two parts: bleeding risk assessment of antiplatelet therapy and bleeding risk assessment of anticoagulant therapy.

At present, commonly used bleeding risk assessment tools include 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 criteria 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 before bleeding risk assessment for elderly CCS patients treated with antithrombotic therapy, with emphasis on falls, polydrug use, debilitation, dementia, etc. Based on the assessment results, appropriate measures should be taken to further reduce the risk of bleeding60, 61, 62, 63, 64, 65, 66, 67, 68, 69 e.g. take active measures to correct orthostatic hypotension, improve cerebral blood supply, and conduct gait training to reduce the risk of falls; reduce the increased drug side effects and drug interactions, pay attention to co‐administered antiplatelet drugs or anticoagulants, correct hypoproteinemia, and reduce the bleeding risk of polydrug use; improve the surrounding environment, educate caregivers, 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 antithrombotic 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 patients and make plans for dynamic monitoring and evaluation, know the change in bleeding risk of patients at any time, and timely optimize the antithrombotic treatment regimen. ⁷¹ , ⁷² , ⁷³ , ⁷⁴ , 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 antithrombotic therapy should fully consider the bleeding risk of antiplatelet therapy and anticoagulant therapy, and individualized risk assessment 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 antithrombotic treatment strategy based on the complexity of coronary artery lesions (Table 10, Figure 1).

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.

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 assessment and the complexity of coronary artery lesions (Table 11).

TABLE 11.

Antithrombotic regimens in elderly CCS patients with NVAF or VTE

HAS‐BLED score	CHA2DS2‐VASC 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.

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 determination 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 bleeding by Chinese expert consensus (Table 13). Recognition of the degree of bleeding plays an important role in subsequent corresponding treatment measures.

TABLE 12.

BARC bleeding classification criteria ⁷⁷

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 13.

Bleeding classification criteria ⁶ , ⁷⁶

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

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 monitoring and management of bleeding (Figure 5). ⁷⁸

FIGURE 5.

Management of bleeding associated with antiplatelet therapy. ⁷⁸ DAPT is dual antiplatelet therapy; SAPT is single antiplatelet therapy.

• 2Management of bleeding associated with anticoagulant therapy (Figure 6). ⁶ , ²⁷ , ⁷⁷ , ⁷⁹ , ⁸⁰ , ⁸¹

FIGURE 6.

Management of bleeding associated with anticoagulant drug ⁶ , ²⁷ , ⁷⁷ , ⁷⁹ , ⁸⁰ , 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 hemorrhage of antithrombotic therapy, and attention should be paid to blood pressure management and etiological treatment. ⁸² In patients 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 antihypertensive 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 immediately in the event of intracerebral hemorrhage.

Recommendation 46: Warfarin‐related ICH: intravenous infusion 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 antagonists (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 considered 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 bleeding of antithrombotic therapy in advanced‐age patients, and the gastrointestinal 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, especially in patients with a history of gastrointestinal bleeding or ulcers and concomitant antiplatelet therapy or OAC therapy. ⁶ , ²⁶ , ⁸⁵ , ⁸⁶ , ⁸⁷ , 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 antiplatelet effect of clopidogrel through CYP2C19 and may affect its clinical efficacy. Therefore, PPIs less affected by CYP2C19 (e.g. pantoprazole, rabeprazole, etc.) are recommended when combined with clopidogrel, and concomitant use of clopidogrel with omeprazole or esomeprazole are not recommended.

Recommendation 53: Once gastrointestinal bleeding occurs, endoscopy should be completed within 24 h of initial diagnosis; patients 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 unsuccessful endoscopic hemostasis or who have complex comorbidities/are ineligible for surgery.

Recommendation 55: Colonoscopy is considered to be the most important approach to determine the cause and location of colorectal bleeding and endoscopy hemostasis is recommended.

Recommendation 56: Capsule endoscopy should be considered 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 anemia, 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 resuscitation strategy is recommended to achieve target blood pressure until bleeding is controlled.

Recommendation 58: It is recommended that a low initial Hb be considered an indicator for severe bleeding associated with coagulopathy; the use of repeated Hb measurements is also considered. It is recommended that serum lactate and/or base deficit measurements 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 < 70 g/L, and the maximum target value of Hb is recommended 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 recommended 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 between 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 administration of NOACs, and different types of NOACs should be selected based on serum creatinine concentration levels in NVAF patients with moderate to severe CKD and CHAD₂S₂‐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 adjustment 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, clopidogrel 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) < 15 ml/min.

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 anticoagulant 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 and rivaroxaban are mainly metabolized by CYP3A4, a small amount of edoxaban is metabolized by CYP3A4, and dabigatran is not metabolized by P450 enzymes), the anticoagulant effect of OACs is enhanced in such patients. ²⁷

Recommendation 65: Child‐Pugh classification of hepatic impairment 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 severe 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 antiplatelet study populations are patients with a median age < 65 years, while data are still lacking in patients older than 65 years of age. Particularly, advanced‐age patients are often excluded from randomized controlled studies, so caution should be exercised in the use of antiplatelet therapy in advanced‐age patients. ⁹⁶ , ⁹⁷ , ⁹⁸ , ⁹⁹

The phenomenon of comorbidities and polydrug use is common in advanced‐age patients, who are vulnerable to drug–drug interactions 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 anticoagulant therapy. ⁴¹

Recommendation 70: Bleeding risks should guide the optimization of antithrombotic drugs in advanced‐age patients and avoiding PCI and surgical treatment if possible.

Recommendation 71: Combination of antiplatelet and anticoagulant 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 reduced, and the risk of bleeding should be adequately assessed before the procedure.

Recommendation 72: In advanced‐age patients with suspected platelet disorders, bedside platelet function testing is recommended. Mean platelet count < 50 × 10⁹/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 × 10⁹/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 accurately 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 bleeding should be accurately determined and treated promptly; all attributes 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 antithrombotic 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.

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)

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