Assessment and Mitigation of Bleeding Risk in Atrial Fibrillation and Venous Thromboembolism: Executive Summary of a European and Asia-Pacific Expert Consensus Paper

Abstract

While there is a clear clinical benefit of oral anticoagulation in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in reducing the risks of thromboembolism, major bleeding events (especially intracranial bleeds) may still occur and be devastating. The decision for initiating and continuing anticoagulation is often based on a careful assessment of both thromboembolism and bleeding risk. The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but thromboembolism and bleeding risk factors often overlap. Also, many factors that increase bleeding risk are transient and modifiable, such as variable international normalized ratio values, surgical procedures, vascular procedures, or drug–drug and food–drug interactions. Bleeding risk is also not a static “one-off” assessment based on baseline factors but is dynamic, being influenced by aging, incident comorbidities, and drug therapies. In this executive summary of a European and Asia-Pacific Expert Consensus Paper, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in patients with AF and VTE, with a view to summarizing “best practice” when approaching antithrombotic therapy in these patients. We address the epidemiology and size of the problem of bleeding risk in AF and VTE, and review established bleeding risk factors and summarize definitions of bleeding. Patient values and preferences, balancing the risk of bleeding against thromboembolism, are reviewed, and the prognostic implications of bleeding are discussed. We propose consensus statements that may help to define evidence gaps and assist in everyday clinical practice.

Keywords

bleeding - oral anticoagulation - atrial fibrillation - venous thromboembolism - risk assessment

Introduction and Scope

While there is a clear clinical benefit of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in preventing future thromboembolic events, major bleeding events may still occur and be devastating.[1]

The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but many of these are also risk factors for thromboembolism. Many factors that increase bleeding are transient and modifiable. Bleeding risk is not static, with a “one-off” assessment based on baseline factors, but dynamic, influenced by aging, incident comorbidities, and drug therapies. Another factor is ethnicity, where East Asians appear more sensitive to antithrombotic therapy-related bleeding.[2]

In this Executive Summary of a European and Asia-Pacific Expert Consensus Paper, we consolidate the contents of the recently published Position Paper on the Assessment and Mitigation of Bleeding risk in Atrial fibrillation and Venous Thromboembolism from the ESC (European Society of Cardiology) Working Group on Thrombosis, in collaboration with the European Heart Rhythm Association (EHRA), Acute Cardiovascular Care Association, and Asia-Pacific Heart Rhythm Society.[3]

Systematic Review

Epidemiology of Bleeding with OAC in AF

Major bleeding occurs in 1.4 to 3.4% of patients with AF treated with vitamin K antagonist (VKA), per annum.[4] Intracranial hemorrhage (ICH) is rare, occurring in 0.1 to 2.5% patients per year,[5] with more recent studies reporting a lower rate of 0.7 to 0.8%([Fig. 2]).[6] Non-vitamin K antagonist oral anticoagulants (NOACs) lower the incidence of major bleeding (−14%) and ICH (−52%) compared with warfarin.[6] [7] Several variables impact on the risk of anticoagulation-related bleeding in patients with AF, including time in the therapeutic range (TTR) and international normalized ratio (INR) variability which also impact the risk of ICH[8] ([Fig. 2]).

Fig. 1 Common bleeding sources with oral anticoagulant therapy.

Fig. 2 Risk factors for anticoagulation-related bleeding.

Epidemiology of Bleeding with OAC in VTE

Anticoagulation is required for the treatment and prevention of VTE, whether deep vein thrombosis or pulmonary embolism, for a minimum of 3 months, with longer term treatment for patients with an unprovoked event or due to a persistent risk factor.[9] [10]

VKA-related major bleeding is approximately 2% during the initial 3 months of anticoagulation, with a fatal bleeding rate of 0.37 to 0.55%.[11] [12] Beyond the first 3 months, major bleeding occurs in 2.74% of patients on VKA.[11] [13]

NOACs are as effective as low-molecular-weight heparin (LMWH)/VKA but associated with less bleeding. In patients with VTE, NOACs were associated with a lower risk of major bleeding (1.08 vs. 1.73%, risk ratio [RR]: 0.63, 95% confidence interval [CI]: 0.51–0.77),[14] as well as fatal bleeding (RR: 0.36%, 95% CI: 0.15–0-87), compared with VKA. During the extended phase, NOAC use was associated with a nonsignificant increase in major bleeding compared with placebo. Major or clinically relevant nonmajor bleeding events were similar with reduced-dose NOACs (apixaban[15] and rivaroxaban[16]) as with aspirin or placebo (RR: 1.19, 95% CI: 0.81–1.77), whereas the there was no significant difference compared with full-dose NOAC, with a trend toward less bleeding with the reduced dose (RR: 0.74; 95% CI: 0.52–1.05).[17]

Definitions of Bleeding

Several definitions are used to define bleeding events in patients on OAC ([Table 1]), including qualitative or quantitative (such as drop in hemoglobin) definitions, or frequently both. The most widely used are the Thrombolysis in Myocardial Infarction (TIMI),[18] Global Use of Strategies To Open occluded arteries (GUSTO),[19] International Society of Thrombosis and Haemostasis (ISTH),[20] [21] and the Bleeding Academic Research Consortium (BARC)[22] classifications, and all have been shown to predict mortality.[23] [24] Heterogeneity in bleeding definitions may in part account for the variability in the reported rate of hemorrhagic complications with OAC.[5]

Table 1 Most frequently used bleeding definitions

TIMI[a]	GUSTO[b]	ISTH[c] [d]	BARC[e]
Major Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on gradient-echo MRI) Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL Fatal bleeding (bleeding that directly results in death within 7 days)	Severe or life-threatening Intracerebral hemorrhage Resulting in substantial hemodynamic compromise requiring treatment	Major Fatal bleeding Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome. Bleeding causing a fall in hemoglobin level of ≥2 g/dL or leading to transfusion of ≥2 units of whole blood or red cells	Type 0 No evidence of bleeding
Minor Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL	Moderate Requiring blood transfusion but not resulting in hemodynamic compromise	Minor All nonmajor bleeds
Requiring medical attention Any overt sign of hemorrhage that meets one of the following criteria and does not meet criteria for a major or minor bleeding event, as defined above Requiring intervention (medical practitioner-guided medical or surgical treatment to stop or treat bleeding, including temporarily or permanently discontinuing or changing the dose of a medication or study drug) Leading to or prolonging hospitalization Prompting evaluation (leading to an unscheduled visit to a health care professional and diagnostic testing, either laboratory or imaging)	Mild Bleeding that does not meet above criteria	Clinically relevant minor Acute or subacute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: • Hospital admission for bleeding, or • A physician-guided medical or surgical treatment for bleeding, or • Change in antithrombotic therapy (including interruption or discontinuation of study drug)	Type 1 Bleeding that is not actionable and does not cause the patient to seek an unscheduled performance of studies, hospitalization, or treatment by a health care professional; it may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a health care professional
Minimal Any overt bleeding event that does not meet the criteria above			Type 2 Any overt, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria for type 3, type 4, or type 5 but does meet at least one of the following criteria: requiring nonsurgical, medical intervention by a health care professional; leading to hospitalization or increased level of care; or prompting evaluation
			Type 3 Clinical, laboratory, and/or imaging evidence of bleeding with specific health care provider responses, as listed below: Type 3a Overt bleeding plus a hemoglobin drop of 3 to 5 g/dL (provided the hemoglobin drop is related to bleed); any transfusion with overt bleeding Type 3b Overt bleeding plus a hemoglobin drop of 5 g/dL (provided the hemoglobin drop is related to bleed); cardiac tamponade; bleeding requiring surgical intervention for control (excluding dental, nasal, skin, and hemorrhoid); bleeding requiring intravenous vasoactive agents Type 3c Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does include intraspinal); subcategories confirmed by autopsy or imaging, or lumbar puncture; intraocular bleed compromising vision
			Type 4 Coronary artery bypass grafting-related bleeding Perioperative intracranial bleeding within 48 hours Reoperation after closure of sternotomy for the purpose of controlling bleeding Transfusion of 5 U of whole blood or packed red blood cells within a 48-hour period Chest tube output 2 L within a 24-hour period
			Type 5 Fatal bleeding Type 5a Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Type 5b Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation

Abbreviation: MRI, magnetic resonance imaging.

^a Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991;115:256–265.

^b GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329:673–682.

^c Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–694.

^d Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010;8:202–204.

^e Mehran R, Rao SV, Bhatt DL et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736–2747.

Clinical Bleeding Risk Factors with OAC for AF or VTE

Risk factors associated with bleeding on OAC are similar in VTE and AF[9] [10] [25] ([Tables 2],[3],[4],[5],[6],[7],[8],[9]), including age ([Table 2]), hypertension ([Table 3]), renal impairment ([Table 4]), abnormal liver function ([Table 5]), prior stroke ([Table 6]), prior bleeding ([Table 7]), anemia ([Table 8]), and malignancy ([Table 9]).

Table 2 Summary of “age” as a risk factor for bleeding in AF patients receiving OACs

Study	Subjects (n)	Type of OACs	Age groups	Main findings	RR/OR/HR (95% CI)	p-Value
SPAF Investigators, 1996	555	VKA	Age >75 vs. ≤75 years	Major bleeding (per year): 4.2 vs. 1.7%	RR: 2.6	0.009
Pengo et al, 2001	433	VKA	Age >75 vs. ≤75 years	Major bleeding (per year): 5.1 vs. 1.0%	RR: 6.6 (1.2–3.7)	0.032
Fang et al, 2004	1,190	VKA	Incremental risk per 5 years	The risk for intracranial hemorrhage increased at ≥85 years of age.	Adjusted OR: 2.5 (1.3–4.7), compared with age 70–74 years	NR
Pisters et al, 2010	5,333	VKA	Age >65 vs. ≤65 years	1-year event rate of major bleeding: 2.3 vs. 0.7%	OR: 2.66 (1.33–5.32)	<0.001
Hankey et al, 2014	14,264	VKA/rivaroxaban	Per decade increase in age	Age is an important risk factor of ICH	HR: 1.35 (1.13–1.63)	0.001
O'Brien et al, 2015	7,411	VKA/dabigatran	Age >75 vs. ≤75 years	Older age had good ability to identify those who bled versus not.	HR: 1.38 (1.17–1.61)	NR
Chao et al, 2020	64,169	VKA/NOACs	Age ≥90, 75–89, and 65–74 years	Major bleeding (per year): 10.53 vs. 6.11 vs. 3.48% ICH (pear year): 1.33 vs 0.99 vs. 0.74%	NR	NR

Abbreviations: AF, atrial fibrillation; HR, hazard ratio; ICH, intracranial hemorrhage; NR, not reported; OACs, oral anticoagulants; OR, odds ratio; NOAC, non-vitamin K antagonist oral anticoagulant; RR, relative risk; SPAF, Stroke Prevention in Atrial Fibrillation; VKA, vitamin K antagonist.

Table 3 Summary of “hypertension” as a risk factor for bleeding in AF patients receiving OACs

Study	Subject (n)	Type of OACs	Definition of hypertension	Main findings	RR/HR (95% CI)	p-Value
SPAF Investigators, 1996	555	VKA	Systolic BP >160 mmHg or diastolic BP >90 mmHg	Increase risk of ICH in patients with poor controlled hypertension	RR: 4.4 for systolic BP >160 mmHg RR: 3.6 for diastolic BP >90 mmHg	0.02 0.04
Fang et al, 2011	9,186	VKA	Diagnosed hypertension as per guideline	Prevalence of hypertension in patients with or without major bleeding: 64.7 vs. 61.9%	HR: 1.5 (1.2–1.9)	0.001
Hankey et al, 2014	14,264	VKA/rivaroxaban	Each 10 mmHg increase of diastolic BP	Increased diastolic BP is independently associated with ICH	HR: 1.17 (1.01–1.36)	0.042
Park et al, 2019	19,679	VKA/edoxaban	≥150 mmHg 140 to <150 mmHg 130 to <140 mmHg (reference)	Major bleeding rate (per year) Edoxaban: 4.37 vs. 2.54 vs 1.88% VKA: 5.65 vs. 4.16 vs. 2.37%	≥150 mmHg: HR = 1.64 (1.26–2.12) 140 to <150 mmHg: HR = 1.36 (1.13–1.62)	<0.001 <0.001
Böhm et al, 2020	18,107	VKA/dabigatran	≥160 mmHg 140 to <160 mmHg 130 to <140 mmHg Systolic BP 120 to <130 mmHg (reference)	Any bleeding rate (per year): 24.99 vs. 17.30 vs. 14.71 vs. 14.61%	≥160 mmHg: HR = 2.01 (1.73–2.32) 140 to <160 mmHg: HR = 1.23 (1.14–1.33)	NR

Abbreviations: AF, atrial fibrillation; BP, blood pressure; HR, hazard ratio; ICH, intracranial hemorrhage; NR, not reported; OACs, oral anticoagulants; RR, relative risk; SPAF, Stroke Prevention in Atrial Fibrillation; VKA, vitamin K antagonist.

Table 4 Summary of “abnormal renal function” as a risk factor for bleeding in AF patients receiving OACs

Study	Subjects (n)	Type of OACs	Definition	Main findings	OR/HR (95% CI)	p-Value
Pisters et al, 2010	5,333	VKA	Presence of chronic dialysis, renal transplantation, or serum creatinine >200 mmol/L	The rate of major hemorrhage was 1.3% in patients without kidney failure versus 5.4% in those with kidney failure.	OR: 2.86 (1.33–6.18)	<0.001
Fang et al, 2011	9,186	VKA	eGFR < 30 mL/min	Prevalence of renal impairment in patients with or without major bleeding: 5.9 vs. 2.7%	HR: 4.3 (3.2–5.8)	<0.001
Fox et al, 2011	14,264	VKA/rivaroxaban	eGFR ≥ 50mL/min eGFR 30–49 mL/min	Major bleeding rate (per year) Rivaroxaban: 3.39 vs. 4.49% VKA: 3.17 vs. 4.70%	NR	NR
Hohnloser et al, 2012	18,122	VKA/apixaban	Divided into 3 groups • eGFR > 80 mL/min • eGFR 50–80 mL/min • eGFR < 50mL/min	Major bleeding rate (per year) Apixaban: 1.46 vs. 2.45 vs. 3.21% VKA: 1.84 vs. 3.21 vs. 6.44%	NR	NR
O'Brien et al, 2015	7,411	VKA/dabigatran	eGFR < 60 mL/min/1.73 m2	Prevalence of renal impairment in patients with or without major bleeding: 48.4 vs. 34.0%	HR: 1.44 (1.21–1.72)	NR

Abbreviations: AF, atrial fibrillation; HR, hazard ratio; eGFR, estimated glomerular filtration rate; NR, not reported; OACs, oral anticoagulants; OR, odds ratio; VKA, vitamin K antagonists.

Table 5 Summary of “abnormal liver function” as a risk factor for bleeding in AF patients receiving OACs

Study	Subjects (n)	Type of OACs	Study population	Main findings	HR (95% CI)	p-Value
Fang et al, 2011	9,186	VKA	Diagnosed cirrhosis	Prevalence of liver cirrhosis in patients with or without major bleeding: 1.2 vs. 0.5%	HR: 2.6 (1.1–6.1)	0.03
Efird et al, 2014	103,897	VKA	Patients were defined as having liver disease if there was record ≥1 of the ICD9 codes for chronic liver disease, recorded either in the inpatient or outpatient setting, during the study period.	Patients with liver disease had more hemorrhages when compared with patients without.	HR: 2.02 (1.69–2.42)	<0.001

Abbreviations: AF, atrial fibrillation; HR, hazard ratio; ICD9, International Classification of Diseases-Ninth Revision; OACs, oral anticoagulants; VKA, vitamin K antagonist.

Table 6 Summary of “stroke history” as a risk factor for bleeding in AF patients receiving OACs

Study	Subjects (n)	Type of OACs	Definition	Main findings	RR/HR (95% CI)	p-Value
Pengo et al, 2001	433	VKA	History of thromboembolism	A higher frequency of major primary bleeding in patients who had suffered a previous thromboembolic event	NR	0.03
Fang et al, 2004	1,190	VKA	History of cerebrovascular disease	Prevalence of cerebrovascular disease in patients with or without ICH: 37 vs. 20%	NR	NR
Fang et al, 2011	9,186	VKA	Prior stroke	Prevalence of prior stroke in patients with or without major bleeding: 17.4 vs. 12.4%	HR: 1.4 (1.1–1.9)	0.01
Hankey et al, 2014	14,264	VKA/rivaroxaban	Previous stroke or TIA	Previous stroke or TIA is an independent factor associated with ICH	HR: 1.42 (1.02–1.96)	0.036
O'Brien et al, 2015	7,411	VKA/dabigatran	Prior stroke	Prevalence of prior stroke in patients with or without major bleeding: 13.1 vs. 9.2%	NR	NR

Abbreviations: AF, atrial fibrillation; HR, hazard ratio; ICH, intracranial hemorrhage; NR, not reported; OACs, oral anticoagulants; OR, odds ratio; RR, relative risk; TIA, transient ischemic attack; VKA, vitamin K antagonist.

Table 7 Summary of “bleeding history” as a risk factor for bleeding in AF patients receiving OACs

Study	n	Type of OACs	Definition	Main findings	OR/HR (95% CI)	p-Value
Pisters et al, 2010	5,333	VKA	Prior major bleeding (ICH, hospitalization, hemoglobin decrease >2 g/L, and/or blood transfusion)	The rate of major hemorrhage was 1.3% in patients without prior major bleeding versus 14.8% in those with prior major bleeding	OR: 7.51 (3.00–18.78)	<0.001
Fang et al, 2011	9,186	VKA	Prior GI hemorrhage	Prevalence of prior GI bleeding in patients with or without major bleeding: 12.1 vs 6.8%	HR: 2.1 (1.5–2.9)	<0.001
O'Brien et al, 2015	7,411	VKA/dabigatran	Bleeding history	Bleeding history had good ability to identify those who bled versus not	HR: 1.73 (1.34–2.23)	NR
Šinigoj et al, 2020	2,260	Dabigatran, rivaroxaban, apixaban	Bleeding history	History of bleeding was a significant predictor of major bleeding	HR: 3.32 (1.87–5.90)	<0.001

Abbreviations: AF, atrial fibrillation; GI, gastrointestinal; HR, hazard ratio; ICH, intracranial hemorrhage; NR, not reported; OACs, oral anticoagulants; OR, odds ratio; VKA, vitamin K antagonist.

Table 8 Summary of “anemia” as a risk factor for bleeding in AF patients receiving OACs

Study	Subjects (n)	Type of OACs	Definition	Main findings	HR (95% CI)	p-Value
Fang et al, 2011	9,186	VKA	Hb <13 g/dL in men and <12 g/dL in women	The rate of major hemorrhage was 12.1% in patients without anemia versus 18.8% in those with anemia	HR: 4.2 (3.4–5.3)	<0.001
O'Brien et al, 2015	7,411	VKA Dabigatran	Reduced Hb/hematocrit/history of anemia	Reduced hemoglobin/hematocrit/history of anemia had good ability to identify those who bled versus not	HR: 2.07 (1.74–2.47)	NR
Bonde et al, 2019	18,734	VKA Dabigatran Rivaroxaban	• No anemia  (Hb >7.45 mmol/L for women and >8.07 mmol/L for men) • Mild anemia  (Hb 6.83–7.45 mmol/L for women and 6.83–8.07 mmol/L for men) • Moderate/severe anemia  (Hb <6.83 mmol/L for women and men)	OAC was associated with a 5.3% (95% CI: 2.1–8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anemia	HR: 1.78 (1.30–2.48)	NR
Krittayaphong et al, 2021	1,562	VKA NOACs	Hb <13 g/dL for male and <12 g/dL for female	Anemia was found to be an independent risk factor for major bleeding	HR: 2.96 (1.81–4.84)	NR

Abbreviations: AF, atrial fibrillation; Hb, hemoglobin; HR, hazard ratio; NR, not reported; OACs, oral anticoagulants; NOAC, non-vitamin K antagonist oral anticoagulant; VKA, vitamin K antagonist.

Table 9 Summary of “malignancy” as a risk factor for bleeding in AF patients receiving OACs

Study	Subjects (n)	Type of OACs	Definition	Main findings	HR (95% CI)	p-Value
Fang et al, 2011	9,186	VKA	Any diagnosis of cancer	Prevalence of diagnosed cancer in patients with or without major bleeding: 18.0 vs. 15.1%	HR: 1.7 (1.3–2.2)	<0.001
O'Brien et al, 2015	7,411	VKA/dabigatran	History of cancer	The rate of major bleeding was 23.3% in patients without cancer versus 30.8% in those with cancer	NR	<0.0001
Melloni et al, 2017	9,749	VKA/dabigatran	Any diagnosis of cancer	The rate of major bleeding was 3.45 per 100 patient-years in patients without cancer versus 5.13 per 100 patient-years in those with cancer	HR: 1.21 (1.04–1.40)	0.02
Vedovati et al, 2018	2,288	Dabigatran, rivaroxaban, apixaban	Patients with active cancer, at the time of inclusion in the study, in presence of a diagnosis of cancer or any anticancer treatment within 6 months before the study inclusion, or recurrent locally advanced or metastatic cancer; patients with history of cancer	The higher bleeding risk found in cancer compared with noncancer patients was mainly due to an excess of bleeding at GI and at genitourinary sites	HR: 2.58 (1.08–6.16)	0.033

Abbreviations: AF, atrial fibrillation; GI, gastrointestinal; HR, hazard ratio; NR, not reported; OACs, oral anticoagulants; VKA, vitamin K antagonist.

Dynamic and Modifiable Nature of Bleeding Risk

Some bleeding risk factors are nonmodifiable, such as age, sex, prior bleeding, or stroke, whereas other risks may be correctable, such as uncontrolled blood pressure, transient renal or liver impairment, labile INR, excessive alcohol intake, or concomitant use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) in an anticoagulated patient.

Bleeding risk assessment cannot be a “one-off” and requires regular re-evaluation, due to the dynamic nature of some risk factors, including aging, comorbidities, and concomitant medications.[26] [27] [28]

Advancing age increases the risk of bleeding on OAC ([Table 2]).[29] [30] [31] The risk of ICH is higher with VKAs than with NOACs, and the benefit of NOAC over VKA in reducing ICH is consistent, independent of age.[30] [32] [33]

Most studies show systolic hypertension to be a risk factor for bleeding with OAC, especially ICH,[34] [35] although others did not.[36] [37] Subanalysis of the ENGAGE-AF trial showed that major bleeding was more frequent in patients with a systolic blood pressure >140 mmHg compared with those with lower levels.[35] Importantly, although the efficacy and safety of edoxaban were consistent across the full range of systolic blood pressures, the superior safety profile of edoxaban compared with VKA was most pronounced among patients with elevated diastolic blood pressure.[35] In a nationwide Korean population registry, the risk of ICH was lowest with blood pressure <130/80 mmHg.[38] It would therefore appear prudent to maintain good blood pressure control in patients on OAC.

Acquisition of new risk factors for bleeding over time is well recognized in patients on OAC. In an analysis of 19,566 anticoagulated AF patients, 76.6% of patients who experienced major bleeding had acquired new bleeding risk factors, compared with only 59.0% of those patients without major bleeding (p < 0.001).[26] A Taiwanese registry of 24,990 AF patients showed that by 1 year, around 21% had acquired at least one new bleeding risk factor, including hypertension (5.84%), stroke (5.33%), bleeding (5.06%), concomitant use of antiplatelet agents or NSAIDs (4.34%), and renal (3.08%) or liver (2.22%) impairment.[28] Data from ORBIT AF shows that over a 2-year follow-up, about a quarter of patients had >20% decline in estimated glomerular filtration rate (eGFR) and 3.7% of patients receiving NOACs had eGFR decline sufficient to warrant dose reductions.[39] Real-world data from the PREFER in AF registry suggest that each single point decrease on a modifiable bleeding risk scale was associated with a 30% reduction in major bleeding.[31]

Laboratory-, Biomarker-, and Imaging-Based Risk Factors for Bleeding AF or VTE

Biomarkers can improve the accuracy of bleeding risk stratification based on clinical factors AF[40] [41] [42] but their practical applicability remains limited.

The ABC (Atrial fibrillation Better Care) bleeding risk score, which includes blood biomarkers of bleeding including growth differentiation factor-15 (GDF-15), troponin T, and hemoglobin, has been shown to statistically better predict bleeding than clinical factor-based bleeding risk scores in patients with AF receiving OAC or taking both OAC and antiplatelet therapy (APT), and in different geographic regions,[43] [44] [45] [46] but this was not confirmed in another study.[47] The consecutive addition of different blood-based biomarkers only slightly enhanced the predictive ability of the HAS-BLED score for major bleeding.[48] Blood (e.g., eGFR) and urine (e.g., proteinuria) based biomarkers of renal dysfunction have been used to improve clinical risk stratification for bleeding (as well as stroke) in AF.[49] [50] In patients with VTE on OAC, information on biomarkers and bleeding risk is sparse,[51] and scores including biomarkers such as hemoglobin and/or creatinine (or creatinine clearance) have modest predictive performance.[52] [53]

There are also limitations to using laboratory-based biomarkers at any one time point, to assess bleeding risk, due to the dynamic nature of bleeding risk such that regular re-evaluation of bleeding risk is of utmost importance. In many studies, biomarkers were assessed at baseline, and bleeding events determined many years later; notwithstanding that aging and incident comorbidities, modifiable bleeding risk factors and changes in drug therapies can dynamically influence bleeding. Furthermore, some biomarkers exhibit diurnal variation and inter-/intra-assay variability, may be expensive,[54] and some (e.g., GDF-15) are not routinely available. Although improvement of risk prediction tools, for example, with inclusion of laboratory-based variables, may be desirable, this should not lead to loss of simplicity and practicality, deterring regular or easy bleeding risk estimation.[55]

In patients with AF on OAC, the presence of cerebral microbleed(s) on cerebral magnetic resonance imaging was independently associated with ICH,[56] and addition of cerebral microbleeds to the HAS-BLED score significantly improved the prediction of ICH over the HAS-BLED score alone.[56]

Current Published Bleeding Risk Schema in AF and VTE

Bleeding risk scores are important (1) to identify modifiable risk factors; (2) to identify people who require more regular monitoring; and (3) to estimate an individual's bleeding risk on antithrombotic/OAC therapy.

Several bleeding risk scores ([Table 10]) are available for patients with AF[43] [50] [57] [58] [59] [60] [61] [62] [63] and VTE.[25] [64] [65] [66] [67] [68] [69] [70] [71] [72] These incorporate numerous risk factors, including demographic and clinical information plus biomarkers, ranging from 3[43] [69] to 17[25] factors, with age included in most scores.[49] [53] [61] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] The scores vary in the definitions of common risk factors and in their complexity, which can hinder clinical utility. Most scores stratify patients into low, intermediate, and high risk, demonstrating major bleeding rates ranging from <1[43] to 30%[60] and 0.1[70] to 12.2% per 100-patient years[71] in low- and high-risk groups for AF and VTE bleeding risk scores, respectively ([Table 10]). Bleeding risk assessment only using modifiable bleeding risk factors is inferior to formal bleeding risk score calculation.[73] [79] [80]

Table 10 Bleeding risk scores for atrial fibrillation and venous thromboembolism—risk factors and scoring, risk categories, and bleeding events in the validation cohorts (adapted from Konstantinides et al[9] and Noubiap et al[41])

Risk score	Number of risk factors	Risk factors (score for each factor)	Risk categories (bleeding events in the validation cohort per 100 patient-years)
			Low	Intermediate	High
Atrial fibrillation
HAS-BLED	9	↑SBP (1); severe renal/hepatic disease (1 each); stroke (1); bleeding (1); labile INR (1); age >65 (1); APT/NSAIDs (1); alcohol excess (1)	0–1 (1.02–1.13)	2 (1.88)	≥3 (≥3.74)
ORBIT	5	Age ≥75 (1); ↓Hb/Hct/anemia (2); bleeding history (2); ↓renal function (1); APT (1)	0–2 (2.4[a])	3 (4.7)	≥4 (8.1)
ABC	3	Age[b]; biomarkers[b] (GDF-15 or cystatin C/CKD-EPI, cTnT-hs, and Hb); previous bleed[b]	<1% (0.62)	1–2% (1.67)	>3% (4.87)
ATRIA	5	Anemia (3); severe renal disease (3); age ≥75 (2); prior bleed (1); hypertension (1)	0–3 (0.83)	4 (2.41)	5–10 (5.32)
HEMORR2HAGES	12	Hepatic/renal disease (1); ethanol abuse (1); malignancy; age >75 (1); ↓Plt (1); re-bleeding risk (2); ↑BP (1); anemia (1); genetic factors (1); ↑falls risk (1); stroke (1)	0–1 (1.9–2.5)	2–3 (5.3–8.4)	≥4 (10.4–12.3)
Shireman et al	8	Age ≥70 (0.49); female (0.31); previous bleed (0.58); recent bleed (0.62); alcohol/drug abuse (0.71); DM (0.27); anemia (0.86); APT (0.32)	≤1.07 (0.9%[b])	>1.07 to <2.19 (2.0%[b])	≥2.19 (5.4%[b])
OBRI	4	Age ≥65 (1); previous stroke (1); previous GI bleed (1); recent MI/ anemia/DM/↑creatinine (1)	0 (3%c)	1–2 (8%c)	3–4 (30%c)
Venous thromboembolism
ACCP	17	Age 66–75 (1), >75 (1); previous major bleed (1); active cancer (1); metastatic cancer (1); renal failure (1); liver failure (1); thrombocytopenia (1); previous stroke (1); diabetes mellitus (1); anemia (1); APT (1); TTR <60% (1); comorbidity (1); recent surgery (1); frequent falls (1); alcohol abuse (1); NSAIDs (1)	No risk factors (0.8%[d])	1 risk factor (1.6%[d])	≥2 risk factors (≥6.5%[d])
VTE-BLEED	6	Active cancer (2); male with uncontrolled arterial hypertension (1); anemia (1.5); previous bleeding (1.5); age ≥60 (1.5), renal dysfunction (1.5)	<2 (0.2%[e]) (0.4%[f])	–	≥2 (1.4%[e]) (2.8%[f])
EINSTEIN score	6	Rivaroxaban (vs. VKA); age; Hb; male sex[a]; Black (vs. Caucasian); Asian (vs. Caucasian); history of CVD	NR	NR	NR
Hokusai score	5	Female sex (1); APT (1); ↓Hb (1); history of hypertension (1); SBP >160 mmHg (1)	0 (1.4%[g]) (1.1%[f])	1 (1.0%[g]) (1.45[f])	2 (2.1%[g]) (2.1%[f])
Seiler et al	7	Previous major bleeding (1); active cancer (1); low physical activity (2); anemia (1); thrombocytopenia (1); APT/NSAIDs (1); poor INR control (1)	0–1 (1.4)	2–3 (5.0)	>3 (12.2)
IMPROVE	10	Active GI ulcer (4.5); recent bleed (4); ↓Plt (4); age ≥75 (3.5); hepatic/renal failure (2.5 each); ICU/CCU admission (2.5); CV catheter (2); rheumatic disease (2); current cancer (2); male (1)	<7 (2.7%)	–	≥7 (6.5%)
RIETE	6	Recent major bleed (2); ↑creatinine (1.5); anemia (1.5); cancer (1); pulmonary embolism (1); age >75 (1)	0 (0.1%)	1–4 (2.8%)	>4 (6.2%)
Kuijer et al	3	Age ≥60 (1.6); female (1.3); malignancy (2.2)	0 (0.6%)	1–3 (1.7%)	>3 (6.7%)

Abbreviations: ↓ reduced/decreased; ↑ elevated/increased; ABC, age, biomarkers, clinical history; ACCP, American College of Chest Physicians; APT, antiplatelet therapy; ATRIA, Anticoagulation and Risk Factors in Atrial fibrillation; BP, blood pressure; CCU, coronary care unit; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; cTnT-hs, high-sensitivity cardiac troponin T; CV, central venous; CVD, cardiovascular; GDF-15, growth differentiation factor-15; GI, gastrointestinal; HAS-BLED, (uncontrolled) hypertension, abnormal renal or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs/drink (alcohol); Hb, hemoglobin; HEMORR₂HAGES, hepatic/renal disease, ethanol abuse, malignancy, age, reduced platelet function, re-bleeding risk [2 points], (uncontrolled) hypertension, anemia, genetic factors, falls risk, stroke; Hct, hematocrit; ICU, intensive care unit; IMPROVE, International Medical Prevention Registry on Venous Thromboembolism; INR, international normalized ratio; NR, not reported; NSAIDs, nonsteroidal anti-inflammatory drugs; ORBIT-AF, Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; Plt, platelet count or function; RIETE, Registro Informatizado de la Enfermedad ThromboEmbolica; SBP, systolic blood pressure; TTR, time in the therapeutic range; VKA, vitamin K antagonist.

Note: Definitions for risk factors included in scores (where specified).

HAS-BLED: SBP >160 mmHg; dialysis, renal transplant, or serum creatinine >200 µmol/L; cirrhosis, bilirubin >2 times upper limit of normal (ULN), AST/ALT/ALP >3 times ULN; previous stroke (ischemic or hemorrhagic); previous major bleed or bleeding predisposition (anemia and/or severe thrombocytopenia); TTR < 60%; age > 65; APT/NSAIDs; >8 units/week of alcohol.

ORBIT: Age ≥75; Hb <13 g/dL in men or <12 g/dL in women, or hematocrit (<40% in men or 36% in women), or history of anemia; any previous GI, intracranial or hemorrhagic stroke; eGFR < 60 mg/dL/1.73 m²; APT.

ABC: As defined in the table.

ATRIA: Hb <13 g/dL in men or <12 g/dL in women; eGFR < 30 mL/min or dialysis dependent; age ≥ 75; any previous bleed; hypertension.

HEMORR₂HAGES: no further detail on specific definitions given in derivation paper.

Shireman: Age ≥ 70; female; history of bleeding; recent bleed; alcohol or drug abuse; diabetes mellitus; hematocrit <30% during hospitalization; APT.

OBRI: Age ≥ 65; previous stroke; previous GI bleed; recent MI or anemia (hematocrit < 30%) or diabetes mellitus or serum creatinine >1.5 mg/dL.

ACCP: Age 66–75 and >75; previous major bleed; active cancer; metastatic cancer, renal failure (CrCL < 30–60 mL/min), history of liver failure, thrombocytopenia (<100,000), previous stroke/TIA, diabetes, anemia (Hb < 10 g/dL), APT, TTR < 60%, comorbidity, recent surgery (<3 months), frequent falls (≥2 in last year), history of alcohol abuse, NSAIDs.

VTE-BLEED: Active cancer (≤6 months of VTE, excluding basal cell or squamous cell carcinoma of skin; recently recurrent or progressive cancer or any cancer that required anticancer treatment within 6 months before the VTE was diagnosed), male with uncontrolled arterial hypertension (SBP ≥ 140 mmHg at baseline); anemia (Hb < 13 g/dL⁻¹ in men; <12 g/dL⁻¹ in women); history of major or nonmajor clinically relevant bleeding, rectal bleeding, frequent nose bleeding or hematuria, age ≥ 60, eGFR < 60mL/min⁻¹.

EINSTEIN: Only criterion further specified was male sex if Hb <12 g/dL.

Hokusai: Female; APT, Hb ≤ 10 g/dL, history of hypertension; SBP > 160 mmHg.

Seiler: Previous major bleed; active cancer; low physical activity; anemia; thrombocytopenia; APT or NSAIDs; poor INR control.

IMPROVE: Active GI ulcer; recent bleed (≤3 months); Plt (<50 × 10⁹/L); age ≥75; hepatic failure (INR > 1.5) or renal failure (moderate GFR 30–59 mL/min/m² or severe <30 mL/min/m²); ICU/CCU admission; central venous catheter; rheumatic disease; current cancer; male.

RIETE: Recent major bleeding; creatinine >1.2 mg/dL; anemia (Hb < 13 g/dL⁻¹ in men; <12 g/dL⁻¹ in women); cancer; clinically overt pulmonary embolism.

Kuijer: Age ≥ 60; male; malignancy.

^a Bleeding event in original derivation cohort.

^b At 3 months; ↓ reduced/decreased; ↑ elevated/increased.

^c Score for each variable in ABC score is based on a nomogram (see reference[3])

^d Annualised risk.

^e Dabigatran arm.

^g Edoxaban arm.

^f Warfarin arm.

Among the bleeding risk scores for AF,[43] [50] [57] [58] [59] [60] [61] [62] the HAS-BLED score[59] has been most widely validated across the spectrum of the AF patient pathway, from OAC/antithrombotic-naïve patients to those established on OAC,[77] [78] [84] and is predictive of ICH.[81] In a contemporary cohort of AF patients treated with NOACs, the ORBIT was inferior to the HAS-BLED score.[82]

The HAS-BLED score has also been validated in non-AF populations, including those with VTE, or those undergoing bridging therapy.[74] [75] [76] [85] A systematic review[83] evaluating the HAS-BLED,[59] HEMORR₂HAGES,[57] ATRIA,[50] and ABC-Bleeding[43] scores concluded that HAS-BLED was the best for predicting major bleeding, albeit with modest evidence base.[83] A prospective App-based intervention in a cluster-randomized trial, which included the HAS-BLED score, reduced major bleeding events, addressed modifiable risk factors, and increased OAC uptake, compared with usual care.[86]

Eight clinical risk scores for predicting major bleeding in patients with VTE ([Table 10]) have been developed,[25] [64] [65] [66] [67] [68] [69] [70] [71] some focusing on the acute phase,[64] [67] [70] long-term treatment,[68] [69] specific subgroups of VTE, for example, cancer-associated thromboembolism,[87] [88] and the elderly,[71] with three[65] [66] [68] derived from cohorts treated with NOACs. Several prediction rules attempting to quantify the bleeding risk of an individual by adding weighted[68] [69] [70] or unweighted[25] [59] [61] [75] risk factors have been derived from and/or tested in VTE patient cohorts ([Table 10]).

Bleeding risk scores for VTE have been less extensively validated than those for AF.[72] Critical appraisal[72] of seven bleeding risk scores developed for VTE (ACCP,[25] EINSTEIN,[65] Hokusai,[66] Kuijer,[69] RIETE,[70] Seiler,[71] VTE-BLEED[68]) and seven validated in VTE cohorts but derived in AF or mixed-indication cohorts (ATRIA,[50] HAS-BLED,[59] HEMORR₂HAGES,[57] mOBRI,[61] OBRI,[62] ORBIT,[58] Shireman[60]) concluded that existing bleeding risk scores are not useful in assisting treatment decisions to cease or extend OAC after the initial 3-month period, with modest ability to predict bleeding (c-statistic: 0.68 [0.65–0.75]) and even lower in external validation studies (0.59 [0.52–0.71]).[72] Bleeding risk scores derived in non-VTE populations have poor predictive ability (0.57 [0.52–0.71]); the only exception was the recalibrated HAS-BLED score (c-statistic: 0.69).[72] [75] External validation of the VTE-BLEED score,[68] derived from a population treated with dabigatran or warfarin, demonstrated predictive ability across patient groups[89] [90] [91] and for ICH and/or fatal bleeding.[92] External validation of the EINSTEIN or Hokusai scores has not been undertaken.

In patients with VTE on NOAC, the prognostic precision of six bleeding risk scores (HAS-BLED,[59] ORBIT,[58] ATRIA-Bleeding,[50] Kuijer,[69] RIETE,[70] VTE-BLEED[68]) was found to be modest and similar, with c-statistics for VTE-BLEED of 0.674 (95% CI: 0.593–0.755), ORBIT of 0.645 (95% CI: 0.523–0.767), and RIETE of 0.604 (95% CI: 0.510–0.697).[52] Another study of patients with VTE ≥65 years receiving VKA[53] evaluating 10 clinical bleeding risk scores (VTE-BLEED,[68] RIETE,[70] ACCP,[25] Seiler,[71] Kuijer,[69] Kearon, OBRI,[61] [62] ATRIA,[50] HAS-BLED,[59] HEMORR₂HAGES[57]) showed c-statistics ranging from 0.47 (OBRI[61] [62]) to 0.70 (Seiler[71]) for major bleeding and 0.52 (OBRI[61] [62]) to 0.67 (HEMORR₂HAGES[57]) for clinically relevant bleeding. A recent review of bleeding risk assessment in patients with VTE[93] concluded that the HAS-BLED or RIETE scores are beneficial in identifying patients at high bleeding risk (HBR) during early-phase OAC treatment, with VTE-BLEED advantageous in identifying low-risk patients who could benefit from extended OAC for secondary prophylaxis.

In summary, simple bleeding risk scores based on clinical factors generally have modest predictive ability (c-indexes approximately 0.6). More complicated clinical bleeding risk scores modestly improve prediction (perhaps to 0.65) and the addition of biomarkers will always improve on clinical factor-based scores (with c-indexes around 0.7). Ultimately, bleeding risk scores need to balance statistical prediction against simplicity and practicality (incorporating both modifiable and nonmodifiable bleeding risks), for use in everyday busy clinical scenarios.

A limitation of current bleeding prediction tools is an unclear immediate actionability for treatment decisions; although in light of the importance of bleeding on prognosis, bleeding risk assessment should inform decision making in clinical practice, especially for mitigation of modifiable bleeding risks and scheduling HBR patients for early review and follow-up as part of the holistic or integrated care approach to AF management.[86]

Patient Values and Preferences

Shared decision making[94] is important to enable health care professionals to inform patients about treatment options, risks, benefits, and length of treatment, and to allow open dialogue to increase the uptake of OAC and long-term adherence.[95] [96] [97] [98] [99] [100] [101] [102] Patients with AF would generally accept a higher risk of bleeding for a corresponding reduction in stroke risk but there is considerable variability in the number of bleeds which would be accepted.[103] [104] [105] [106] [107] [108] In contrast, physicians generally worry more about the harm from bleeding.[106] [109] [110] A reduction in major bleeding was second to stroke prevention as the most valued attribute of OAC.[111] [112] Similarly, patients with VTE[96] appear to value reduction in VTE risk over potential bleeding risk.[96] [113] [114] [115] [116] [117] Among cancer patients, risk of bleeding was less important than ensuring that VTE prophylaxis did not interfere with cancer treatment and OAC efficacy.[118] [119]

Studies assessing patient preferences toward VKAs versus NOACs[105] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] indicate that when efficacy and safety are similar, patients with AF and VTE commonly favored simpler, more convenient treatment regimens, less frequent dosing, fixed-dose medication, without need for regular monitoring or bridging, or drug–food interactions.[103] [111] [112] [117] [121] [130] [131] [132] [133] [134] [135]

Approach to Assessment and Bleeding Risk Mitigation

General AF Population

After the evaluation of thromboembolic risk, bleeding risk should also be evaluated. Quality indicators for the care and outcomes of adults with AF published by EHRA include the proportion of patients with bleeding risk assessment using a validated method, such as the HAS-BLED score.[136]

The appropriate use of a validated score is essential. All clinical guidelines for the management of AF recommend bleeding risk assessment prior to or on OAC, with the HAS-BLED score recommended by the ESC,[97] American College of Chest Physicians,[101] and Asia-Pacific Heart Rhythm Society,[137] given its simplicity and evidence base.[86] The ACC/AHA/HRS AF guidelines did not propose any specific bleeding risk scheme.[138]

The 2021 NICE guideline acknowledged low to very low quality evidence for its recommended use of the ORBIT score based on better calibration in NOAC users,[139] but also emphasized attention to modifiable risk factors for bleeding, including uncontrolled hypertension, poor INR control, concurrent medication, excessive alcohol consumption, and addressing reversible causes of anemia. Of note, all these modifiable risk factors listed are already included in the HAS-BLED score.

The 2020 ESC AF guideline emphasizes that, irrespective of the score used, the main aim is to identify modifiable bleeding risk factors,[97] including controlling blood pressure, cessation of nonessential APT or NSAIDs, improving TTR, and reduction/cessation of alcohol ([Fig. 3]). Most modifiable bleeding risk factors in the ESC AF guideline are incorporated into the HAS-BLED score. Since an individual's bleeding risk is composed of both nonmodifiable and modifiable risk factors, simply focusing on modifiable risk factors alone is inferior to formal assessment with a bleeding risk score.[73] [79] [80]

Fig. 3 A in the Atrial fibrillation Better Care pathway. ABC, Atrial fibrillation Better Care; APT, antiplatelet therapy; BP, blood pressure; CHA₂DS₂-VASc, congestive heart failure, hypertension, age 75 years (2 points), diabetes, stroke/TIA/thromboembolism (2 points), vascular disease, age 65–74 years, sex category (female); DM, diabetes mellitus; HAS-BLED, (uncontrolled) hypertension, abnormal renal, or liver function, stroke, bleeding, labile international normalized ratio, elderly, drugs/drink (alcohol); HF, heart failure; NOAC, non-vitamin K antagonist oral anticoagulant; NSAIDs, nonsteroidal anti-inflammatory drugs; OAC, oral anticoagulation; OSA, obstructive sleep apnea; TTR, time in the therapeutic range; VKA, vitamin K antagonist. (Adapted from Lother et al[1].)

Generally, HBR should not be a reason to withhold OAC, except for situations in which the risk/benefit ratio excessively favors no antithrombotic treatment.[97] [138] [140] [141] [142] Instead, efforts should be made to identify and address all modifiable bleeding risks and provide more frequent risk assessment.[26] [97] [101] [143]

General VTE Population

Notwithstanding the limitations of bleeding risk scores for VTE discussed earlier, bleeding risk assessment is recommended both upon initiation of anticoagulation and at follow-up, with more frequent re-assessment when bleeding risk is high.[144]

Most current VTE guidelines leave the choice of bleeding risk score to the clinician,[10] [144] although the 2020 NICE VTE guideline[145] recommends the HAS-BLED score and advises stopping anticoagulation if the score is ≥4 and cannot be modified. In case of persistent HBR, the patient's personalized risk:benefit ratio for OAC should be assessed and if judged to favor extended anticoagulation, a reduced dose of the NOACs apixaban (2.5 mg twice daily) or rivaroxaban (10 mg once daily) should be considered after 6 months of therapeutic anticoagulation.

Surgery and Endoscopic and Endovascular Procedures

• Peri-ablation of atrial arrhythmias: Catheter ablation, especially left-sided ablation, is associated with a small but relevant approximately 0.5% risk of severe bleeding,[146] including cardiac tamponade and 1 to 2% access-site bleeds,[147] [148] related to vascular access and peri-interventional anticoagulation.[148] Ablation also carries a risk of thrombotic events, with left-sided procedures carrying an approximately 1% risk of thrombosis and stroke.[147] [148] Continuation of OAC for AF ablation is safe with a trend toward fewer bleeding events and may also help in preventing periprocedural stroke ([Table 11]).[149] Most guidelines agree on three main points[97] [101] [141] [142] [150]: (1) uninterrupted OAC is recommended for patients undergoing ablation; (2) after the procedure, OAC is essential for at least 8 weeks in all patients; and (3) long-term OAC beyond the first 8 weeks should be considered on the basis of risk profile (CHA₂DS₂-VASc). Regarding the type of OAC, both NOACs and VKAs are options, although meta-analyses report a trend favoring NOACs with respect to major bleeding.[151]

• Cardiovascular implantable electronic device (CIED): In patients without mechanical valves, anticoagulation may briefly be interrupted for CIED implantation, without bridging. In patients with mechanical valves, uninterrupted VKA is preferable to interruption of VKA with heparin bridging (see the section on bridging).

Table 11 Randomized controlled trial of uninterrupted oral anticoagulation in atrial fibrillation catheter ablation

	COMPARE[4]	VENTURE-AF[10]	RE-CIRCUIT-AF[11]	AXAFA-AFNET 5[12]	ELIMINATE-AF[13]
OAC treatment	Heparin bridging vs. warfarin (1:1)	Rivaroxaban vs. warfarin (1:1)	Dabigatran vs. warfarin (1:1)	Apixaban vs. warfarin (1:1)	Edoxaban vs. warfarin (2:1)
Number of patient (n)	790/793	124/124	317/318	318/315	411/203
Age (y), mean or median	61/24	58.6/60.5	59.1/59.3	64.0/64.0	60.0/61.0
Male gender (%)	76/74	68.4/72.6	72.6/77	69/65	70.6/73.4
BMI, kg/m2, mean or median	NA	29.8/28.9	28.5/28.8	28.4/28.2	28.1/27.8
CHA2DS2-VASc score	1: 29/26 2: 34/36 ≥3: 37/38	1.5/1.7	2/2.2	2.4/2.2	0: 23.4/21.7 1: 26.5/28.1 ≥2: 50.1/50.2
Prior stroke or TIA (%)	7/8	0/2.4	3.2/2.8	7.5/7.3	5.4/3.9
Congestive heart failure (%)	15/17	9.7/7.3	9.8/10.7	24.5/22.9	17.3/19.2
Hypertension (%)	81/83	47.6/46	52.4/55.7	89/91.4	60.8/59.6
Diabetes (%)	38/40	6.5/11.3	9.5/10.7	12.9/11.1	13.4/15.8
Types of AF (%) •  Paroxysmal AF •  Persistent AF	29/25 71/75	76.6/70.2 23.4/29.8	67.2/68.9 32.8/31.2	59.4/56.5 40.6/43.6	69.1/64.5 25.5/30
TEE prior to ablation (%)	NA	NA	100	84.6	74.6
Duration of OAC before ablation	3–4 wk	3 wk	4–8 wk	30 d	21–28 d
Estimated NOAC compliance (%)	NA	99.9	97.6	97	97
INR, time in therapeutic range (%)	NA	79.8	85.7	84	84
ACT (s), mean or median	NA	302/332	330/340	310/348	3,014/322.6
Primary outcome	Thromboembolic events (stroke/TIA/systemic thromboembolism)	Major bleeding events (ISTH)	Major bleeding events (ISTH)	All-cause mortality, stroke, or major bleeding (BARC≥2)	All-cause mortality, stroke, or major bleeding event (ISTH)
Follow-up	48 h	30 d	8 wk	3 mo	90 d
Primary outcome event (%)	4.9/0.25[a]	0/0.8	1.6/6.9[a]	6.9/7.3	2.7/1.7
Death (%)	0/0	0/0.8	0/0	0.3/0.3	0/0
Ischemic stroke (%)	3.7/0.25	0/0.8	0/0.3	0.6/0	0.3/0
Major bleeding (%)	0.76/0.38	0/0.8	1.6/6.9	3.1/4.4	2.4/1.7
Death/ischemic stroke/major bleeding (%)	5.7/0.63	0/2.4	1.6/7.2	4.0/4.7	2.7/1.7

Abbreviations: AF, atrial fibrillation; ACT, activated clotted time; BARC, Bleeding Academic Research Consortium; BMI, body mass index; INR, international Normalized ratio; ISTH, International society on Thrombosis and Hemostasis; NOAC, non-vitamin K antagonist oral anticoagulant; NA, not available; OAC, oral anticoagulant; TIA, transient ischemic attack.

^a Significant with p < 0.01.

A study comparing patients undergoing CIED implantation with interrupted (for 2 days) versus uninterrupted NOAC was prematurely stopped for futility, with far fewer bleeding events than anticipated.[152] Therefore, both stopping and continuing NOAC are possible options ([Table 12]).[153] [154] [155] [156] [157] For patients on a NOAC undergoing low bleeding risk interventions (i.e., infrequent bleeding or with nonsevere clinical impact), last dose intake the day before the procedure is appropriate in most cases,[142] with resumption of NOAC on the first postoperative day. Procedures with uninterrupted OAC should be performed by an experienced operator, paying close attention to achieving good hemostasis.

Table 12 Prospective and retrospective cohort studies (sample size ≥100) of periprocedural oral anticoagulation in atrial fibrillation patients undergoing cardiac rhythm device procedures

Study	Design	Subjects (n)	Age (y), mean	Continued OAC (%)	Interrupted OAC (%)	Timing of OAC interruption (h), mean or median	Timing of OAC resumption	Antiplatelet therapy (%)	Clinically significant hematoma (%)	Other device-related bleeding (%)	Thromboembolic and other complications (%)
Birnie et al	BRUISE CONTROL 1 prospective randomized control trial	Warfarin 681	72 y	50.3%	Heparin bridging 49.7%	NA	NA	Warfarin Aspirin: 38.2% P2Y12: 6.2% Heparin bridging aspirin: 40.5% P2Y12: 6.1%	Warfarin: 3.5% Heparin bridging: 16.0%	Pericardial effusion Warfarin: 0% Heparin bridging: 0.3%	Stroke/TIA Warfarin: 0.6% Heparin bridging: 0% MI Warfarin: 0% Heparin bridging: 0.3%
Black-Maier et al [7]	Retrospective analysis of ORBIT-AF	Warfarin 284 NOAC 60	Warfarin 77 y NOAC 70.5 y	Warfarin 36% NOAC 35%	Warfarin 64% NOAC 65%	NA	NA	Warfarin Aspirin: 35% P2Y12: 7.4% NOAC Aspirin: 51.7% P2Y12: 8.3%		Major bleeding −ve warfarin: 1% +ve warfarin: 3% −ve NOAC: 0% +ve NOAC: 0%	Stroke/TIA −ve warfarin: 1% +ve warfarin: 1% −ve NOAC: 0% +ve NOAC: 0%
Essebag et al	Post-hoc analysis of RE-LY trial	VKA 201 Dabigatran 410	73 y	0%	100%	VKA: 144 h (total pre- + post-) NOAC: 53 h	NOAC: 34 h	Aspirin: 44% P2Y12: 8%	VKA, bridging: 10.8% VKA, no bridging: 2.4% NOAC: 2.2%	Major bleeding VKA, bridging: 2.7% VKA, no bridging: 0.6% NOAC: 1.0%	Stroke VKA, bridging: 0% VKA, no bridging: 0.6% NOAC: 0.2%
Leef et al	Post-hoc analysis of ROCKET-AF trial	VKA 211 Rivaroxaban 242	75 y	25%	75%	VKA: 5 d NOAC: 3 d	VKA: 3 d NOAC: 2 d	–	NOAC: 0.4% VKA: 2.9% −ve OAC: 1.2% +ve OAC: 2.7%	Major bleeding NOAC: 1.2% VKA: 1.0% −ve OAC: 1.2% +ve OAC: 0.9%	Stroke/SE NOAC: 1.3% VKA: 0.5% −ve OAC: 0.6% +ve OAC: 1.8%
Ricciardi et al	Prospective randomized pilot trial	NOAC 101 (dabigatran = 37, rivaroxaban = 33, apixaban = 31)	76 y	49.5%	50.5%	Dabigatran: 24–48 h Rivaroxaban/ apixaban: 24 h	≥24 h	Aspirin: 15.8% P2Y12: 5.9% Both: 3%	−ve NOAC: 0% +ve NOAC: 2%	Any hematoma −ve NOAC: 4% +ve NOAC: 3.9% Loss of Hb >2 g/dL −ve NOAC: 6% +ve NOAC: 9.8%	Pocket infection +ve NOAC: 1%
Birnie et al	BRUISE CONTROL 2 prospective randomized control trial	NOAC 647 (dabigatran = 96, rivaroxaban = 106, apixaban = 125)	74	49.3%	50.5%	Dabigatran: 24–48 h Rivaroxaban/apixaban: 48 h	≥24 h	Aspirin 17.4% P2Y12: 3.6%	−ve NOAC: 2.1% +ve NOAC: 2.1%	Any hematoma −ve NOAC: 4.8% +ve NOAC: 5.5% Pericardial effusion −ve NOAC: 0.3% +ve NOAC: 0.3%	Stroke −ve NOAC: 0.3% +ve NOAC: 0.3%
Tsai et al	Retrospective analysis	NOAC 100 (dabigatran = 28, rivaroxaban = 61, apixaban = 10, edoxaban = 1)	78 y	100%	0%	NA	NA	Aspirin: 6% P2Y12: 2%	+ve NOAC: 1%	Pericardial effusion +ve NOAC: 1%	0%
Steffel et al	Post-hoc analysis of ENGAGE AF trial	VKA 324 Edoxaban 549	74 y	26%	74%	Median 7 days (pre- + post-)	NA	Aspirin: 32% P2Y12: 2.5%	NA	Major bleeding −ve VKA: 0% +ve VKA: 0% −ve NOAC: 0% +ve NOAC: 0.5%	Stroke +ve VKA: 1.1% −ve VKA: 0.9% +ve NOAC: 0.5% −ve NOAC: 0.4%

Abbreviations: MI, myocardial infarction; NOAC, non-vitamin K antagonist oral anticoagulant; NA, not available; OAC, oral anticoagulant; SE, systemic embolism; TIA, transient ischemic attack; VKA, vitamin K antagonist; −ve, interrupted; +ve, continued.

• Surgical procedures: The periprocedural management of patients with AF or VTE with a clinical indication for OAC who require elective surgery or an endoscopic or endovascular procedure represents a frequent clinical challenge, with most recommendations based on expert consensus.[5] [158] [159] [160] [161] An individualized approach by local physicians is mandatory. Management needs to balance the procedural bleeding risk and the thromboembolic risk associated with the underlying condition.

The procedural bleeding risk classification must consider both the prevalence of hemorrhagic complications and its consequences, with several attempts to categorize the risk of bleeding related to different interventional procedures.[159] [160] [161] Procedures with low rates of bleeding but relevant associated sequelae (e.g., intracranial or spinal surgery) should be classified as high risk. In addition, comorbid conditions (e.g., older age, kidney or liver dysfunction) that can increase the risk of periprocedural bleeding should be considered.

The thromboembolic risk associated with the indication for OAC is classified according to the annual risk of arterial thromboembolism or VTE: high if the risk is >10%, moderate between 5 and 10%, and low when <5% ([Table 13]).[158] [159] [161]

Table 13 Stratification of thromboembolic risk according to clinical indication for oral anticoagulation

Risk	Indication for OAC
	AF	VTE
High	• CHA2DS2-VASc ≥7   • Recent (within 3 months) stroke/TIA   • Rheumatic mitral valve disease	• Recent (within 3 months) VTE   • Severe thrombophilia (e.g., homozygous factor V Leiden or prothrombin 20210 mutation, protein C, protein S, or antithrombin deficiency, antiphospholipid syndrome, multiple defects)
Moderate	• CHA2DS2-VASc 5–6   • Stroke/TIA >3 months	• VTE within the past 3–12 months   • Nonsevere thrombophilia (e.g., heterozygous factor V Leiden or prothrombin gene mutation)   • Recurrent VTE   • Active cancer + VTE
Low	• CHA2DS2-VASc 1–4   • No history of stroke/TIA	• VTE >12 months and no other risk factors

Abbreviations: AF, atrial fibrillation; OAC, oral anticoagulation; TIA, transient ischemic attack; VTE, venous thromboembolism.

Source: Modified from Vivas et al[161].

Generally, temporary interruption without bridging is recommended for low or moderate thromboembolic risk patients, with bridging only for high-risk patients. Bridging is rarely needed with NOACs, given their short half-life. When temporary interruption is required, the duration for withholding OAC is mostly based on the procedural bleeding risk and the INR values 5 to 7 days before the procedure in case of VKAs, or renal function with NOACs ([Table 14]). For some procedures with low hemorrhagic risk (e.g., diagnostic endoscopy without biopsy), uninterrupted OAC is safe both in patients on VKA (INR ≤ 3) or NOACs.[152] [162] When treatment on uninterrupted OAC is not feasible, the periprocedural strategy will depend on the patient's risk of thromboembolism ([Fig. 4]) and is discussed in more detail in the section on “Bridging” later.

Fig. 4 Simplified algorithm for selecting the periprocedural management strategy of OAC in patients undergoing an elective surgery or invasive procedure. *Bridging with parenteral heparin is generally not necessary with DOACs. DOAC, direct oral anticoagulant; OAC, oral anticoagulation.

Table 14 Recommended duration for withholding OAC prior to a procedure when temporary interruption is needed

NOAC
	Procedural bleed risk
CrCl (mL/min)		<15	15–29	30–49	50–79	≥80
Dabigatran	Low	≥96 h[a]	≥72 h	≥48 h	≥36 h	≥24 h
	Intermediate, high, or uncertain	No data[a]	≥120 h	≥96 h	≥72 h	≥48 h
CrCl (mL/min)		<15	15–29	≥30
Apixaban, rivaroxaban, or edoxaban	Low	≥48 h	≥36 h	≥24 h
	Intermediate, high, or uncertain	≥72 h[b]	≥72 h[b]	≥48 h
VKA
INR 5–7 days prior to the procedure [c]		<2	2–3	>3
Warfarin[d]		3–4 d	5 d	>5 d

Abbreviations: CrCl, creatinine clearance; DOAC, direct acting oral anticoagulant; dTT, dilute thrombin time; INR, international normalized ratio; VKA, vitamin K antagonist.

^a Consider measuring dTT.

^b Consider measuring agent-specific anti-Xa level.

^c INR must be measured again 24 hours before the procedure.

^d If other VKA than warfarin is used, the durations may be adjusted according to the drug half-life.

Postprocedure, OAC may be re-initiated once hemostasis is achieved in the absence of bleeding. In most situations with low postprocedural bleeding risk, OAC can be resumed within 24 hours (generally on the day following the procedure), whereas it is reasonable to wait 48 to 72 hours if the risk of postprocedural bleeding is high.[159] [161] [163]

Measures to mitigate bleeding in patients on OAC requiring emergency procedures is beyond the scope of this manuscript and can be found elsewhere,[142] [161] [164] including possible use of a reversal agent, such as intravenous vitamin K, idarucizumab[165] for dabigatran or andexanet alfa for factor Xa inhibitors,[166] [167] or 4-factor prothrombin complex concentrate (PCC) and PCC as first options for VKAs and NOACs, respectively.[164] [168]

Presentation with ACS and/or Requiring PCI

In patients requiring combined OAC and APT, such as those with AF or VTE presenting with acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI), the risk of bleeding is increased.[169] In this setting, the predictive value of scores is generally poor, with the HAS-BLED score performing best[170] [171] and shown to predict significant bleeding in AF patients undergoing PCI.[172] The Academic Research Consortium has defined HBR (BARC 3 or 5 bleeding) for patients undergoing PCI as the presence of one major or two minor characteristics[173] ([Table 15]), which can be found in up to 40% of patients.

Table 15 ARC major and minor criteria for HBR at time of PCI; high bleeding risk defined as at least one major or two minor criteria

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

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

^a This excludes dual pathway inhibition doses.

^b Baseline thrombocytopenia defined as thrombocytopenia prior to PCI.

^c Active malignancy defined as diagnosis within 12 months and/or ongoing requirement for treatment (including surgery, chemotherapy, or radiotherapy).

^d National Institutes of Health Stroke Scale [NIHSS] score ≥5.

An increased risk of bleeding is apparent in both the peri-PCI and postdischarge periods and strategies to minimize such risk should therefore be applied before, during, and after PCI.[174] Pre-PCI approaches include avoidance of routine pretreatment with APT, with P2Y₁₂ inhibitor generally given only after coronary angiography has confirmed the decision to proceed to PCI.[174] [175] Peri-PCI strategies include the preferential use of the radial approach and avoidance of glycoprotein IIb/IIIa inhibitors.

For elective procedures, European guidelines recommend uninterrupted VKA if the INR <2.5,[175] whereas North American guidelines recommend uninterrupted VKA if INR <2,[176] with interruption of VKA considered when INR is above these thresholds. Intra-PCI administration of reduced-dose unfractionated heparin (UFH) is recommended.[175] [176]

In patients on NOAC, timely interruption in elective patients may be considered, as indicated in the European guidelines[175] and is clearly recommended by North American guidelines.[176] Both guidelines recommend administration of weight-adjusted dose UFH for patients on NOAC undergoing both elective and emergency PCI,[175] [177] [178] owing to the uncertain protection of NOAC against PCI-related ischemic events.

Following PCI, the type and duration of APT should be carefully considered to minimize bleeding.[174] An initial short course of triple antithrombotic therapy (TAT) with OAC and dual APT (DAPT) of aspirin and clopidogrel is warranted to early ischemic events ([Fig. 5]).[97] To mitigate the increased risk of bleeding with TAT, the more potent P2Y₁₂ inhibitors prasugrel and ticagrelor should be avoided, with European guidelines indicating that ticagrelor or prasugrel be used as part of TAT only in exceptional circumstances such as stent thrombosis,[175] and North American guidelines suggesting that ticagrelor can be considered in patients at high stent thrombosis risk although prasugrel should be avoided.[176]

Fig. 5 Management of antithrombotics in patients presenting with ACS and/or requiring PCI or stents. ACS, acute coronary syndrome; PCI, percutaneous coronary intervention.

The duration of TAT should be minimized to 1 to 4 weeks ([Fig. 5]). Subsequent antithrombotic management is determined by whether long-term OAC is indicated. In most AF and VTE patients for whom indefinite OAC is warranted, double antithrombotic therapy (DAT) with OAC and single APT (SAPT), preferably clopidogrel, should follow initial TAT and be maintained up to 6 to 12 months, based on the patient's bleeding and ischemic risks[175] [176] ([Fig. 5]), followed by OAC alone indefinitely.[175] [176] [179] [180] Prolongation of DAT beyond 1 year may be considered in selected patients with both clinical and/or anatomical features for increased ischemic cardiac events[175] [176] ([Fig. 5]). In contrast, in patients with a first episode of VTE, in whom OAC is discontinued after 3 months, DAPT comprising aspirin and clopidogrel should be resumed upon OAC cessation with duration tailored to type of event and procedural characteristics.[176]

In addition to limiting the duration of TAT, as well as of DAT, strategies to minimize the risk of bleeding should also aim to reduce the intensity of OAC. A target INR at the lower end of the therapeutic range (2.0–2.5) is recommended with VKA,[175] aiming for TTR >65–70%.[181] NOACs are preferable to VKA as part of combination therapy and switching from warfarin should be routinely considered.[175] To date, no specific NOAC appears preferable since no head-to-head comparisons have been performed and all of them, given as part of DAT, have shown a favorable safety and efficacy profile compared with TAT including warfarin.[182] [183] [184] [185] In the AUGUSTUS trial, among patients with AF and either ACS or PCI treated with a P2Y₁₂ inhibitor, treatment with apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations than regimens that included a VKA, aspirin, or both.[184] Subanalysis of data from the RE-DUAL PCI trial, which compared DAT (dabigatran 110 or 150 mg twice daily, clopidogrel, or ticagrelor) with TAT (warfarin, clopidogrel or ticagrelor, and aspirin), showed that DAT with dabigatran reduced bleeding both in non-HBR and HBR patients, with a greater magnitude of benefit among non-HBR patients.[186] NOACs should be given at the recommended doses, with the possible exceptions of dabigatran and rivaroxaban for which the lower doses of 110 mg twice daily and 15 mg once daily, respectively, are preferable when used as part of TAT.[175]

In patients at HBR not on OAC when presenting for PCI, but developing an indication for OAC later, several bleeding-avoidance strategies should be considered: (1) in the setting of NSTEMI, avoidance of DAPT pretreatment in patients at HBR reduces bleeding risk[187] [188]; (2) radial is preferred over femoral access to reduce bleeding complications[188] [189]; (3) in patients not pretreated with oral APT, during urgent/emergency PCI, intravenous antiplatelet agents may be used, and the intravenous P2Y₁₂ inhibitor cangrelor may be preferred over glycoprotein IIb/IIIa inhibitors[190]; (4) newer generation drug-eluting stents have displaced bare metal stents also in HBR patients as their quick re-endothelialization allows a shorter duration of DAPT after PCI,[191] and finally (5) administration of proton-pump inhibitors and avoidance of NSAIDs.[192]

Patients with Cancer

Patients with cancer, particularly gastric or urothelial tumors, have an increased risk of bleeding on OAC compared with patients without cancer,[193] [194] [195] and proton-pump inhibitors should be routinely considered to mitigate this risk.

Patients with AF and cancer experience similar or lower bleeding with NOAC compared with VKA,[195] [196] [197] [198] with the exception of patients with gastrointestinal cancers or active gastrointestinal mucosal abnormalities.[199]

In cancer patients with VTE, NOACs significantly reduce bleeding compared with VKA.[200] Apixaban and edoxaban have similar safety profile to LMWH,[15] [201] with excess bleeding mainly observed in patients with gastrointestinal cancer.[201] [202] A meta-analysis showed no difference in major bleeding between LMWH and VKA treatment, whereas NOACs significantly lowered bleeding risk compared with VKA (2.5 vs. 4.2%, RR: 0.58, 95% CI: 0.35–0.99). Pooled data from the only two RCTs comparing NOACs against LMWH showed significantly higher incidence of major bleeding with NOACs (6.5 vs. 3.7%, RR: 1.75, 95% CI: 1.10–2.77).[203]

Bridging Therapy

Patients Treated with OAC Undergoing Interventional or Surgical Procedures

While bridging with either UFH or LMWH may theoretically reduce the periprocedural thrombotic risk, it substantially increases periprocedural bleeding.[163] Irrespective of the perioperative anticoagulation strategy used, the incidence of thromboembolic events is 0 to 1% ([Table 12]). In patients undergoing CIED implantation, uninterrupted VKA without bridging is associated with lower thromboembolic and bleeding rates[162] and reduced length of stay.[162] [204] Heparin-bridging results in a 4.5-fold increase in postoperative hematoma compared with a continued warfarin strategy,[162] and a sizeable hematoma is an independent risk factor for subsequent device infection.[205] [206]

In AF patients, bridging significantly increased bleeding, with no ischemic benefit.[163] [207]

Postoperatively, bridging with parenteral agents is not required with NOACs, but could be considered in selected high thromboembolic risk patients when resuming VKA.

A routine bridging strategy is not recommended in the current 2020 ESC AF Guideline[97] and an ESC/EHRA document on the use of NOACs[208] emphasized that bridging should be avoided.

Patients Treated with OAC with Prior Stent Requiring Surgery

In patients with prior coronary stenting, antithrombotic therapy is required to reduce the risk of stent thrombosis. The decision on APT bridging requires careful evaluation of bleeding and ischemic (stent thrombosis) risk. The thrombotic risk falls with time from PCI, being relatively high in the first 3 to 6 months, intermediate at 6 to 12 months, and low beyond 12 months.[209] While OAC may be discontinued for elective or urgent surgery, there is concern that patients with prior stenting on single or no APT may be left with insufficient antithrombotic protection to prevent stent thrombosis such that the bridging APT strategy may be required. There are specific clinical and angiographic risk factors which increase ischemic risk.[209] [210]

The risk of perioperative hemorrhage is very high with hepatic resection, and with many other surgical procedures including splenectomy, gastrectomy, thyroid surgery, nephrectomy, prostatectomy, and aortic or redo cardiac surgery.[209] Additionally, the site of potential bleeding is critical, for example, even relatively minor bleeding with neurosurgery or ophthalmic surgery can be catastrophic. Bridging of APT usually involves starting (or continuing with) aspirin, and consideration should be given to temporary transition with an intravenous antiplatelet agent in patients who would otherwise require DAPT (if they were not on OAC).

For patients with high ischemic and HBR, consideration should be given to postponing elective surgery beyond 6 months post-PCI, when SAPT with aspirin may be considered, or if this is not possible, every effort should be made to employ bridging strategies that mitigate risk, with the use of DAPT with clopidogrel rather than more potent P2Y₁₂ inhibitors, or preferably using intravenous cangrelor, which has a short half-life in case of major bleeding.[161] [209]

Consensus Statements

• Bleeding risk reflects the interaction of nonmodifiable and modifiable bleeding risks. Simply focusing on modifiable bleeding risk factors is an inferior strategy to the use of formal bleeding risk scores.

• Bleeding risk is not a static “one-off” assessment but is dynamic, being influenced by aging, incident comorbidities, surgical/interventional procedures, and use of modifiers (such as proton-pump inhibitors) or drug therapies.

• Simple bleeding risk scores based on clinical factors have modest predictive value and calibration for bleeding events, and addition of biomarkers improves the performance of clinical factor-based bleeding risk scores. Ultimately, the use of bleeding risk scores needs to balance statistical prediction against simplicity and practicality for use in everyday busy clinical scenarios.

• In patients with AF, a formal structured risk-score-based bleeding risk assessment is recommended to help identify nonmodifiable risk factors and address modifiable bleeding risk factors, and to identify patients potentially at high risk of bleeding who should be scheduled for more frequent clinical review. The HAS-BLED score should be used.

• Treatment of patients with AF according to an integrated care or holistic approach, based on the ABC (Atrial fibrillation Better Care) pathway, is associated with a lower risk of major bleeding and this should be applied.

• In VTE patients, the choice of the bleeding risk score is at the discretion of the clinician. The 2020 NICE VTE guideline recommends use of the HAS-BLED score.

Conflict of Interest

None declared.

^* These are co-chairs of the document and joint senior authors.

Note: The review process for this paper was fully handled by Christian Weber, Editor in Chief.

• References

• 1 Lother A, Kaier K, Ahrens I. et al. Bleeding complications drive in-hospital mortality of patients with atrial fibrillation after transcatheter aortic valve replacement. Thromb Haemost 2020; 120 (11) 1580-1586
• 2 Kim HK, Tantry US, Smith Jr SC. et al. The East Asian Paradox: an updated position statement on the challenges to the current antithrombotic strategy in patients with cardiovascular disease. Thromb Haemost 2021; 121 (04) 422-432
• 3 Gorog DA, Gue YX, Chao T-F. et al. Assessment and mitigation of bleeding risk in atrial fibrillation and venous thromboembolism: a position paper from the ESC Working Group on Thrombosis, in collaboration with the European Heart Rhythm Association, the Association for Acute CardioVascular Care and the Asia-Pacific Heart Rhythm Society. Europace. 2022 DOI: 10.1093/europace/euac020
• 4 Agarwal S, Hachamovitch R, Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis. Arch Intern Med 2012; 172 (08) 623-631
• 5 Lip GYH, Andreotti F, Fauchier L. et al; Document reviewers. Bleeding risk assessment and management in atrial fibrillation patients: a position document from the European Heart Rhythm Association, endorsed by the European Society of Cardiology Working Group on Thrombosis. Europace 2011; 13 (05) 723-746
• 6 Ruff CT, Giugliano RP, Braunwald E. et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014; 383 (9921): 955-962
• 7 López-López JA, Sterne JAC, Thom HHZ. et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ 2017; 359: j5058
• 8 Björck F, Renlund H, Lip GY, Wester P, Svensson PJ, Själander A. Outcomes in a warfarin-treated population with atrial fibrillation. JAMA Cardiol 2016; 1 (02) 172-180
• 9 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
• 10 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
• 11 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139 (11) 893-900
• 12 Nieto JA, Solano R, Ruiz-Ribó MD. et al; Riete Investigators. Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 2010; 8 (06) 1216-1222
• 13 Lecumberri R, Alfonso A, Jiménez D. et al; RIETE investigators. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110 (04) 834-843
• 14 Kakkos SK, Kirkilesis GI, Tsolakis IA. Editor's Choice - efficacy and safety of the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban in the treatment and secondary prevention of venous thromboembolism: a systematic review and meta-analysis of phase III trials. Eur J Vasc Endovasc Surg 2014; 48 (05) 565-575
• 15 Agnelli G, Buller HR, Cohen A. et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (08) 699-708
• 16 Weitz JI, Lensing AWA, Prins MH. et al; EINSTEIN CHOICE Investigators. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med 2017; 376 (13) 1211-1222
• 17 Vasanthamohan L, Boonyawat K, Chai-Adisaksopha C, Crowther M. Reduced-dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2018; 16 (07) 1288-1295
• 18 Bovill EG, Terrin ML, Stump DC. et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991; 115 (04) 256-265
• 19 GUSTO investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329 (10) 673-682
• 20 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
• 21 Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 (01) 202-204
• 22 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
• 23 Kikkert WJ, van Geloven N, van der Laan MH. et al. The prognostic value of bleeding academic research consortium (BARC)-defined bleeding complications in ST-segment elevation myocardial infarction: a comparison with the TIMI (Thrombolysis In Myocardial Infarction), GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), and ISTH (International Society on Thrombosis and Haemostasis) bleeding classifications. J Am Coll Cardiol 2014; 63 (18) 1866-1875
• 24 Franco L, Becattini C, Beyer-Westendorf J. et al. Definition of major bleeding: prognostic classification. J Thromb Haemost 2020; 18 (11) 2852-2860
• 25 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
• 26 Chao TF, Lip GYH, Lin YJ. et al. Incident risk factors and major bleeding in patients with atrial fibrillation treated with oral anticoagulants: a comparison of baseline, follow-up and delta HAS-BLED scores with an approach focused on modifiable bleeding risk factors. Thromb Haemost 2018; 118 (04) 768-777
• 27 Chang TY, Lip GYH, Chen SA, Chao TF. Importance of risk reassessment in patients with atrial fibrillation in guidelines: assessing risk as a dynamic process. Can J Cardiol 2019; 35 (05) 611-618
• 28 Chao TF, Chan YH, Chiang CE. et al. Continuation or discontinuation of oral anticoagulants after HAS-BLED scores increase in patients with atrial fibrillation. Clin Res Cardiol 2021; 111 (01) 23-33
• 29 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
• 30 Kato ET, Giugliano RP, Ruff CT. et al. Efficacy and safety of edoxaban in elderly patients with atrial fibrillation in the ENGAGE AF-TIMI 48 trial. J Am Heart Assoc 2016; 5 (05) e003432
• 31 Rohla M, Weiss TW, Pecen L. et al. Risk factors for thromboembolic and bleeding events in anticoagulated patients with atrial fibrillation: the prospective, multicentre observational PREvention oF thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF). BMJ Open 2019; 9 (03) e022478
• 32 Chao TF, Chiang CE, Liao JN, Chen TJ, Lip GYH, Chen SA. Comparing the effectiveness and safety of nonvitamin K antagonist oral anticoagulants and warfarin in elderly asian patients with atrial fibrillation: a nationwide cohort study. Chest 2020; 157 (05) 1266-1277
• 33 Eikelboom JW, Wallentin L, Connolly SJ. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123 (21) 2363-2372
• 34 Goodman SG, Wojdyla DM, Piccini JP. et al; ROCKET AF Investigators. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol 2014; 63 (09) 891-900
• 35 Park S, Bergmark BA, Shi M. et al. Edoxaban versus warfarin stratified by average blood pressure in 19 679 patients with atrial fibrillation and a history of hypertension in the ENGAGE AF-TIMI 48 trial. Hypertension 2019; 74 (03) 597-605
• 36 Rao MP, Halvorsen S, Wojdyla D. et al; Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Steering Committee and Investigators. Blood pressure control and risk of stroke or systemic embolism in patients with atrial fibrillation: results from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. J Am Heart Assoc 2015; 4 (12) e002015
• 37 Vemulapalli S, Hellkamp AS, Jones WS. et al. Blood pressure control and stroke or bleeding risk in anticoagulated patients with atrial fibrillation: results from the ROCKET AF Trial. Am Heart J 2016; 178: 74-84
• 38 Kim D, Yang PS, Kim TH. et al. Ideal blood pressure in patients with atrial fibrillation. J Am Coll Cardiol 2018; 72 (11) 1233-1245
• 39 Inohara T, Holmes DN, Pieper K. et al; ORBIT AF Patients and Investigators. Decline in renal function and oral anticoagulation dose reduction among patients with atrial fibrillation. Heart 2020; 106 (05) 358-364
• 40 Vílchez JA, Roldán V, Hernández-Romero D, Valdés M, Lip GY, Marín F. Biomarkers in atrial fibrillation: an overview. Int J Clin Pract 2014; 68 (04) 434-443
• 41 Noubiap JJ, Sanders P, Nattel S, Lau DH. Biomarkers in atrial fibrillation: pathogenesis and clinical implications. Card Electrophysiol Clin 2021; 13 (01) 221-233
• 42 Berg DD, Ruff CT, Morrow DA. Biomarkers for risk assessment in atrial fibrillation. Clin Chem 2021; 67 (01) 87-95
• 43 Hijazi Z, Oldgren J, Lindbäck J. et al; ARISTOTLE and RE-LY Investigators. The novel biomarker-based ABC (age, biomarkers, clinical history)-bleeding risk score for patients with atrial fibrillation: a derivation and validation study. Lancet 2016; 387 (10035): 2302-2311
• 44 Berg DD, Ruff CT, Jarolim P. et al. Performance of the ABC scores for assessing the risk of stroke or systemic embolism and bleeding in patients with atrial fibrillation in ENGAGE AF-TIMI 48. Circulation 2019; 139 (06) 760-771
• 45 Pol T, Hijazi Z, Lindbäck J. et al. Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas. Open Heart 2021; 8 (01) e001471
• 46 Hijazi Z, Oldgren J, Lindbäck J. et al. Evaluation of the age, biomarkers, and clinical history-bleeding risk score in patients with atrial fibrillation with combined aspirin and anticoagulation therapy enrolled in the ARISTOTLE and RE-LY trials. JAMA Netw Open 2020; 3 (09) e2015943
• 47 Esteve-Pastor MA, Rivera-Caravaca JM, Roldan V. et al. Long-term bleeding risk prediction in 'real world' patients with atrial fibrillation: comparison of the HAS-BLED and ABC-Bleeding risk scores. The Murcia Atrial Fibrillation Project. Thromb Haemost 2017; 117 (10) 1848-1858
• 48 Rivera-Caravaca JM, Marín F, Vilchez JA. et al. Refining stroke and bleeding prediction in atrial fibrillation by adding consecutive biomarkers to clinical risk scores. Stroke 2019; 50 (06) 1372-1379
• 49 Singer DE, Chang Y, Borowsky LH. et al. A new risk scheme to predict ischemic stroke and other thromboembolism in atrial fibrillation: the ATRIA study stroke risk score. J Am Heart Assoc 2013; 2 (03) e000250
• 50 Fang MC, Go AS, Chang Y. et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study. J Am Coll Cardiol 2011; 58 (04) 395-401
• 51 Galeano-Valle F, Ordieres-Ortega L, Oblitas CM, Del-Toro-Cervera J, Alvarez-Sala-Walther L, Demelo-Rodríguez P. inflammatory biomarkers in the short-term prognosis of venous thromboembolism: a narrative review. Int J Mol Sci 2021; 22 (05) 2627
• 52 Vedovati MC, Mancuso A, Pierpaoli L. et al. Prediction of major bleeding in patients receiving DOACs for venous thromboembolism: a prospective cohort study. Int J Cardiol 2020; 301: 167-172
• 53 Frei AN, Stalder O, Limacher A. et al. Comparison of bleeding risk scores in elderly patients receiving extended anticoagulation with vitamin K antagonists for venous thromboembolism. Thromb Haemost 2021; 121 (11) 1512-1522
• 54 Esteve-Pastor MA, Roldán V, Rivera-Caravaca JM, Ramírez-Macías I, Lip GYH, Marín F. The use of biomarkers in clinical management guidelines: a critical appraisal. Thromb Haemost 2019; 119 (12) 1901-1919
• 55 Proietti M, Mujovic N, Potpara TS. Optimizing stroke and bleeding risk assessment in patients with atrial fibrillation: a balance of evidence, practicality and precision. Thromb Haemost 2018; 118 (12) 2014-2017
• 56 Wilson D, Ambler G, Shakeshaft C. et al; CROMIS-2 collaborators. Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study. Lancet Neurol 2018; 17 (06) 539-547
• 57 Gage BF, Yan Y, Milligan PE. et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J 2006; 151 (03) 713-719
• 58 O'Brien EC, Simon DN, Thomas LE. et al. The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 2015; 36 (46) 3258-3264
• 59 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138 (05) 1093-1100
• 60 Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest 2006; 130 (05) 1390-1396
• 61 Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med 1998; 105 (02) 91-99
• 62 Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. Am J Med 1989; 87 (02) 144-152
• 63 Lane DA, Lip GYH. Stroke and bleeding risk stratification in atrial fibrillation: a critical appraisal. Eur Heart J Suppl 2020; 22 (Suppl O): O14-O27
• 64 Decousus H, Tapson VF, Bergmann JF. et al; IMPROVE Investigators. Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators. Chest 2011; 139 (01) 69-79
• 65 Di Nisio M, Ageno W, Rutjes AW, Pap AF, Büller HR. Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists. Thromb Haemost 2016; 115 (02) 424-432
• 66 Di Nisio M, Raskob G, Büller HR. et al. Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists. Thromb Haemost 2017; 117 (04) 784-793
• 67 Hostler DC, Marx ES, Moores LK. et al. Validation of the International Medical Prevention Registry on venous thromboembolism bleeding risk score. Chest 2016; 149 (02) 372-379
• 68 Klok FA, Hösel V, Clemens A. et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J 2016; 48 (05) 1369-1376
• 69 Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159 (05) 457-460
• 70 Ruíz-Giménez N, Suárez C, González R. et al; RIETE Investigators. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100 (01) 26-31
• 71 Seiler E, Limacher A, Mean M. et al. Derivation and validation of a novel bleeding risk score for elderly patients with venous thromboembolism on extended anticoagulation. Thromb Haemost 2017; 117 (10) 1930-1936
• 72 de Winter MA, van Es N, Büller HR, Visseren FLJ, Nijkeuter M. Prediction models for recurrence and bleeding in patients with venous thromboembolism: a systematic review and critical appraisal. Thromb Res 2021; 199: 85-96
• 73 Esteve-Pastor MA, Rivera-Caravaca JM, Shantsila A, Roldán V, Lip GYH, Marín F. Assessing bleeding risk in atrial fibrillation patients: comparing a bleeding risk score based only on modifiable bleeding risk factors against the HAS-BLED score. The AMADEUS trial. Thromb Haemost 2017; 117 (12) 2261-2266
• 74 Costa F, Tijssen JG, Ariotti S. et al. Incremental value of the CRUSADE, ACUITY, and HAS-BLED risk scores for the prediction of hemorrhagic events after coronary stent implantation in patients undergoing long or short duration of dual antiplatelet therapy. J Am Heart Assoc 2015; 4 (12) e002524
• 75 Brown JD, Goodin AJ, Lip GYH, Adams VR. Risk stratification for bleeding complications in patients with venous thromboembolism: application of the HAS-BLED bleeding score during the first 6 months of anticoagulant treatment. J Am Heart Assoc 2018; 7 (06) e007901
• 76 Kooiman J, van Hagen N, Iglesias Del Sol A. et al. The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment. PLoS One 2015; 10 (04) e0122520
• 77 Gorman EW, Perkel D, Dennis D, Yates J, Heidel RE, Wortham D. Validation of the HAS-BLED tool in atrial fibrillation patients receiving rivaroxaban. J Atr Fibrillation 2016; 9 (02) 1461
• 78 Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED bleeding risk-prediction scores in patients with atrial fibrillation undergoing anticoagulation: the AMADEUS (evaluating the use of SR34006 compared to warfarin or acenocoumarol in patients with atrial fibrillation) study. J Am Coll Cardiol 2012; 60 (09) 861-867
• 79 Guo Y, Zhu H, Chen Y, Lip GYH. Comparing bleeding risk assessment focused on modifiable risk factors only versus validated bleeding risk scores in atrial fibrillation. Am J Med 2018; 131 (02) 185-192
• 80 Chao TF, Lip GYH, Lin YJ. et al. Major bleeding and intracranial hemorrhage risk prediction in patients with atrial fibrillation: attention to modifiable bleeding risk factors or use of a bleeding risk stratification score? A nationwide cohort study. Int J Cardiol 2018; 254: 157-161
• 81 Lip GY, Lin HJ, Hsu HC. et al. Comparative assessment of the HAS-BLED score with other published bleeding risk scoring schemes, for intracranial haemorrhage risk in a non-atrial fibrillation population: the Chin-Shan Community Cohort Study. Int J Cardiol 2013; 168 (03) 1832-1836
• 82 Proietti M, Romiti GF, Vitolo M, Potpara TS, Boriani G, Lip GYH. Comparison of HAS-BLED and ORBIT bleeding risk scores in AF patients treated with NOACs: a report from the ESC-EHRA EORP-AF general long-term registry. Eur Heart J Qual Care Clin Outcomes 2021; DOI: 10.1093/ehjqcco/qcab069.
• 83 Borre ED, Goode A, Raitz G. et al. Predicting thromboembolic and bleeding event risk in patients with non-valvular atrial fibrillation: a systematic review. Thromb Haemost 2018; 118 (12) 2171-2187
• 84 Senoo K, Lip GY. Predictive abilities of the HAS-BLED and ORBIT bleeding risk scores in non-warfarin anticoagulated atrial fibrillation patients: an ancillary analysis from the AMADEUS trial. Int J Cardiol 2016; 221: 379-382
• 85 Lip GY, Lane DA. Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. J Thromb Haemost 2016; 14 (09) 1711-1714
• 86 Guo Y, Lane DA, Chen Y, Lip GYH. mAF-App II Trial investigators. Regular bleeding risk assessment associated with reduction in bleeding outcomes: the mAFA-II randomized trial. Am J Med 2020; 133 (10) 1195-1202.e2
• 87 Alatri A, Mazzolai L, Kucher N. et al. The Modified Ottawa Score and clinical events in hospitalized patients with cancer-associated thrombosis from the Swiss VTE Registry. Semin Thromb Hemost 2017; 43 (08) 871-876
• 88 Fuentes HE, Tafur AJ, Caprini JA. et al; RIETE Investigators. Prediction of early mortality in patients with cancer-associated thrombosis in the RIETE database. Int Angiol 2019; 38 (03) 173-184
• 89 Klok FA, Barco S, Konstantinides SV. External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism. Thromb Haemost 2017; 117 (06) 1164-1170
• 90 Klok FA, Barco S, Turpie AGG. et al. Predictive value of venous thromboembolism (VTE)-BLEED to predict major bleeding and other adverse events in a practice-based cohort of patients with VTE: results of the XALIA study. Br J Haematol 2018; 183 (03) 457-465
• 91 Klok FA, Presles E, Tromeur C. et al; PADIS-PE Investigators. Evaluation of the predictive value of the bleeding prediction score VTE-BLEED for recurrent venous thromboembolism. Res Pract Thromb Haemost 2019; 3 (03) 364-371
• 92 Klok FA, Barco S, Konstantinides SV. Evaluation of VTE-BLEED for predicting intracranial or fatal bleeding in stable anticoagulated patients with venous thromboembolism. Eur Respir J 2018; 51 (04) 1800077
• 93 Nopp S, Ay C. Bleeding risk assessment in patients with venous thromboembolism. Hamostaseologie 2021; 41 (04) 267-274
• 94 Ali-Ahmed F, Pieper K, North R. et al. Shared decision-making in atrial fibrillation: patient-reported involvement in treatment decisions. Eur Heart J Qual Care Clin Outcomes 2020; 6 (04) 263-272
• 95 Escobar C, Borrás X, Bover Freire R. et al. A Delphi consensus on the management of oral anticoagulation in patients with non-valvular atrial fibrillation in Spain: ACOPREFERENCE study. PLoS One 2020; 15 (06) e0231565
• 96 Etxeandia-Ikobaltzeta I, Zhang Y, Brundisini F. et al. Patient values and preferences regarding VTE disease: a systematic review to inform American Society of Hematology guidelines. Blood Adv 2020; 4 (05) 953-968
• 97 Hindricks G, Potpara T, Dagres N. et al; ESC Scientific Document Group. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42 (05) 373-498
• 98 Lane DA, Aguinaga L, Blomström-Lundqvist C. et al. Cardiac tachyarrhythmias and patient values and preferences for their management: the European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulación Cardíaca y Electrofisiología (SOLEACE). Europace 2015; 17 (12) 1747-1769
• 99 Lane DA, Lip GY. Patient's values and preferences for stroke prevention in atrial fibrillation: balancing stroke and bleeding risk with oral anticoagulation. Thromb Haemost 2014; 111 (03) 381-383
• 100 Joseph-Williams N, Elwyn G, Edwards A. Knowledge is not power for patients: a systematic review and thematic synthesis of patient-reported barriers and facilitators to shared decision making. Patient Educ Couns 2014; 94 (03) 291-309
• 101 Lip GYH, Banerjee A, Boriani G. et al. Antithrombotic Therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest 2018; 154 (05) 1121-1201
• 102 Witt DM, Nieuwlaat R, Clark NP. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018; 2 (22) 3257-3291
• 103 Wilke T, Bauer S, Mueller S, Kohlmann T, Bauersachs R. Patient preferences for oral anticoagulation therapy in atrial fibrillation: a systematic literature review. Patient 2017; 10 (01) 17-37
• 104 Alonso-Coello P, Montori VM, Díaz MG. et al. Values and preferences for oral antithrombotic therapy in patients with atrial fibrillation: physician and patient perspectives. Health Expect 2015; 18 (06) 2318-2327
• 105 Böttger B, Thate-Waschke IM, Bauersachs R, Kohlmann T, Wilke T. Preferences for anticoagulation therapy in atrial fibrillation: the patients' view. J Thromb Thrombolysis 2015; 40 (04) 406-415
• 106 Devereaux PJ, Anderson DR, Gardner MJ. et al. Differences between perspectives of physicians and patients on anticoagulation in patients with atrial fibrillation: observational study. BMJ 2001; 323 (7323): 1218-1222
• 107 Man-Son-Hing M, Laupacis A, O'Connor A. et al. Warfarin for atrial fibrillation. The patient's perspective. Arch Intern Med 1996; 156 (16) 1841-1848
• 108 Najafzadeh M, Gagne JJ, Choudhry NK, Polinski JM, Avorn J, Schneeweiss SS. Patients' preferences in anticoagulant therapy: discrete choice experiment. Circ Cardiovasc Qual Outcomes 2014; 7 (06) 912-919
• 109 Levitan BYZ, Gonzalez JM, Hauber AB. et al. Patient and physician preferences in the United States for benefits and risks of anticoagulant use in atrial fibrillation: results from a conjoint-analysis study. Value Health 2013; 16 (03) PA11
• 110 Okumura KIH, Yasaka M, Gonzalez JM. et al. Japanese patients and physicians preferences for anticoagulants use in atrial fibrillation: results from a conjoint-analysis study. Value Health 2012; 15 (07) A380
• 111 Lane DA, Meyerhoff J, Rohner U, Lip GYH. Atrial fibrillation patient preferences for oral anticoagulation and stroke knowledge: results of a conjoint analysis. Clin Cardiol 2018; 41 (06) 855-861
• 112 Lane DA, Meyerhoff J, Rohner U, Lip GYH. Patients' perceptions of atrial fibrillation, stroke risk, and oral anticoagulation treatment: an international survey. TH Open 2018; 2 (03) e233-e241
• 113 Haac BE, O'Hara NN, Mullins CD. et al. Patient preferences for venous thromboembolism prophylaxis after injury: a discrete choice experiment. BMJ Open 2017; 7 (08) e016676
• 114 Quante M, Thate-Waschke I, Schofer M. [What are the reasons for patient preference? A comparison between oral and subcutaneous administration]. Z Orthop Unfall 2012; 150 (04) 397-403
• 115 Barcellona D, Contu P, Sorano GG, Pengo V, Marongiu F. The management of oral anticoagulant therapy: the patient's point of view. Thromb Haemost 2000; 83 (01) 49-53
• 116 Keita I, Aubin-Auger I, Lalanne C. et al. Assessment of quality of life, satisfaction with anticoagulation therapy, and adherence to treatment in patients receiving long-course vitamin K antagonists or direct oral anticoagulants for venous thromboembolism. Patient Prefer Adherence 2017; 11: 1625-1634
• 117 Lutsey PL, Horvath KJ, Fullam L. et al. Anticoagulant preferences and concerns among venous thromboembolism patients. Thromb Haemost 2018; 118 (03) 553-561
• 118 Cajfinger F, Debourdeau P, Lamblin A. et al; TROPIQUE investigators. Low-molecular-weight heparins for cancer-associated thrombosis: adherence to clinical practice guidelines and patient perception in TROPIQUE, a 409-patient prospective observational study. Thromb Res 2016; 144: 85-92
• 119 Noble S, Matzdorff A, Maraveyas A, Holm MV, Pisa G. Assessing patients' anticoagulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology. Haematologica 2015; 100 (11) 1486-1492
• 120 Andrade JG, Krahn AD, Skanes AC, Purdham D, Ciaccia A, Connors S. Values and preferences of physicians and patients with nonvalvular atrial fibrillation who receive oral anticoagulation therapy for stroke prevention. Can J Cardiol 2016; 32 (06) 747-753
• 121 Attaya S, Bornstein T, Ronquillo N. et al. Study of warfarin patients investigating attitudes toward therapy change (SWITCH Survey). Am J Ther 2012; 19 (06) 432-435
• 122 Barcellona D, Luzza M, Battino N, Fenu L, Marongiu F. The criteria of the Italian Federation of Thrombosis Centres on DOACs: a “real world” application in nonvalvular atrial fibrillation patients already on vitamin K antagonist. Intern Emerg Med 2015; 10 (02) 157-163
• 123 Boom MS, Berghuis EM, Nieuwkerk PT, Pinedo S, Büller HR. When do patients prefer a direct oral anticoagulant over a vitamin K antagonist?. Neth J Med 2015; 73 (08) 368-372
• 124 Gebler-Hughes ES, Kemp L, Bond MJ. Patients' perspectives regarding long-term warfarin therapy and the potential transition to new oral anticoagulant therapy. Ther Adv Drug Saf 2014; 5 (06) 220-228
• 125 Ghijben P, Lancsar E, Zavarsek S. Preferences for oral anticoagulants in atrial fibrillation: a best-best discrete choice experiment. PharmacoEconomics 2014; 32 (11) 1115-1127
• 126 Cottrell SLC, Tilden D, Robinson P. Preference and willingness to pay study to assess the value of an anticoagulation therapy modelled on dabigatran etexilate using discrete choice analysis: a UK pilot study of warfarin-naive atrial fibrillation patients. Value Health 2009; 12: A339
• 127 Wang Y, Xie F, Kong MC, Lee LH, Ng HJ, Ko Y. Patient-reported health preferences of anticoagulant-related outcomes. J Thromb Thrombolysis 2015; 40 (03) 268-273
• 128 Wang YKM, Ko Y. Utility evaluation of health states related to stroke and stroke prophylaxis. Value Health 2013; 16: A292
• 129 Zamorano JLGW, Sandberg A, Oberdiek AMS, Bakhai A. Patient preferences fro chronic treatment for stroke prevention: results from the European Patient Survey in Atrial Fibrillation (EUPS-AF) [poster]. Presented at: European Society of Cardiology Congress, August 25–29, 2012. Munich, Germany:
• 130 MacLean S, Mulla S, Akl EA. et al. Patient values and preferences in decision making for antithrombotic therapy: a systematic review: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e1S-e23S
• 131 Man-Son-Hing M, Gage BF, Montgomery AA. et al. Preference-based antithrombotic therapy in atrial fibrillation: implications for clinical decision making. Med Decis Making 2005; 25 (05) 548-559
• 132 Weernink MGM, Vaanholt MCW, Groothuis-Oudshoorn CGM, von Birgelen C, IJzerman MJ, van Til JA. Patients' priorities for oral anticoagulation therapy in non-valvular atrial fibrillation: a multi-criteria decision analysis. Am J Cardiovasc Drugs 2018; 18 (06) 493-502
• 133 Brekelmans MP, Kappelhof M, Nieuwkerk PT, Nierman M, Buller HR, Coppens M. Preference for direct oral anticoagulants in patients treated with vitamin K antagonists for venous thromboembolism. Neth J Med 2017; 75 (02) 50-55
• 134 Elewa HF, DeRemer CE, Keller K, Gujral J, Joshua TV. Patients satisfaction with warfarin and willingness to switch to dabigatran: a patient survey. J Thromb Thrombolysis 2014; 38 (01) 115-120
• 135 Zolfaghari S, Harenberg J, Frölich L. et al. Development of recommendations to continue anticoagulation with one of the two types of oral anticoagulants based on the identification of patients' preference. Semin Thromb Hemost 2015; 41 (02) 166-177
• 136 Arbelo E, Aktaa S, Bollmann A. et al; Chair, Co-chair, Reviewers, review coordinator. Quality indicators for the care and outcomes of adults with atrial fibrillation. Europace 2021; 23 (04) 494-495
• 137 Chao TF, Joung B, Takahashi Y. et al. 2021 focused update consensus guidelines of the Asia Pacific Heart Rhythm Society on Stroke Prevention in Atrial Fibrillation: executive summary. Thromb Haemost 2022; 122 (01) 20-47
• 138 January CT, Wann LS, Calkins H. et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2019; 74 (01) 104-132
• 139 Perry M, Kemmis Betty S, Downes N, Andrews N, Mackenzie S. Guideline Committee. Atrial fibrillation: diagnosis and management-summary of NICE guidance. BMJ 2021; 373 (1150): n1150
• 140 Chiang CE, Okumura K, Zhang S. et al. 2017 consensus of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation. J Arrhythm 2017; 33 (04) 345-367
• 141 Andrade JG, Verma A, Mitchell LB. et al; CCS Atrial Fibrillation Guidelines Committee. 2018 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. Can J Cardiol 2018; 34 (11) 1371-1392
• 142 Steffel J, Collins R, Antz M. et al. 2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace 2021; 23 (10) 1612-1676
• 143 Joung B, Lee JM, Lee KH. et al; KHRS Atrial Fibrillation Guideline Working Group. 2018 Korean guideline of atrial fibrillation management. Korean Circ J 2018; 48 (12) 1033-1080
• 144 Konstantinides SV, Meyer G, Becattini C. et al. 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J 2019; 54 (03) 1901647
• 145 McCormack T, Harrisingh MC, Horner D, Bewley S. Guideline Committee. Venous thromboembolism in adults: summary of updated NICE guidance on diagnosis, management, and thrombophilia testing. BMJ 2020; 369: m1565
• 146 Calkins H, Yong P, Miller JM. et al; The Atakr Multicenter Investigators Group. Catheter ablation of accessory pathways, atrioventricular nodal reentrant tachycardia, and the atrioventricular junction: final results of a prospective, multicenter clinical trial. Circulation 1999; 99 (02) 262-270
• 147 Friedman DJ, Pokorney SD, Ghanem A. et al. Predictors of cardiac perforation with catheter ablation of atrial fibrillation. JACC Clin Electrophysiol 2020; 6 (06) 636-645
• 148 Cappato R, Calkins H, Chen SA. et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3 (01) 32-38
• 149 Di Biase L, Burkhardt JD, Santangeli P. et al. Periprocedural stroke and bleeding complications in patients undergoing catheter ablation of atrial fibrillation with different anticoagulation management: results from the Role of Coumadin in Preventing Thromboembolism in Atrial Fibrillation (AF) Patients Undergoing Catheter Ablation (COMPARE) randomized trial. Circulation 2014; 129 (25) 2638-2644
• 150 Sticherling C, Marin F, Birnie D. et al. Antithrombotic management in patients undergoing electrophysiological procedures: a European Heart Rhythm Association (EHRA) position document endorsed by the ESC Working Group Thrombosis, Heart Rhythm Society (HRS), and Asia Pacific Heart Rhythm Society (APHRS). Europace 2015; 17 (08) 1197-1214
• 151 Romero J, Cerrud-Rodriguez RC, Alviz I. et al. Significant benefit of uninterrupted DOACs versus VKA during catheter ablation of atrial fibrillation. JACC Clin Electrophysiol 2019; 5 (12) 1396-1405
• 152 Birnie DH, Healey JS, Wells GA. et al. Continued vs. interrupted direct oral anticoagulants at the time of device surgery, in patients with moderate to high risk of arterial thrombo-embolic events (BRUISE CONTROL-2). Eur Heart J 2018; 39 (44) 3973-3979
• 153 Essebag V, Proietti R, Birnie DH. et al. Short-term dabigatran interruption before cardiac rhythm device implantation: multi-centre experience from the RE-LY trial. Europace 2017; 19 (10) 1630-1636
• 154 Leef GC, Hellkamp AS, Patel MR. et al. Safety and efficacy of rivaroxaban in patients with cardiac implantable electronic devices: observations from the ROCKET AF trial. J Am Heart Assoc 2017; 6 (06) e004663
• 155 Steffel J, Ruff CT, Braunwald E. et al. Edoxaban and implantable cardiac device interventions: insights from the ENGAGE AF-TIMI 48 trial. Europace 2019; 21 (02) 306-312
• 156 Tsai CT, Liao JN, Chao TF. et al. Uninterrupted non-vitamin K antagonist oral anticoagulants during implantation of cardiac implantable electronic devices in patients with atrial fibrillation. J Chin Med Assoc 2019; 82 (04) 256-259
• 157 Black-Maier E, Kim S, Steinberg BA. et al; Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators. Oral anticoagulation management in patients with atrial fibrillation undergoing cardiac implantable electronic device implantation. Clin Cardiol 2017; 40 (09) 746-751
• 158 Douketis JD, Spyropoulos AC, Spencer FA. et al. Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): e326S-e350S
• 159 Doherty JU, Gluckman TJ, Hucker WJ. et al. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: a report of the American College of Cardiology Clinical Expert Consensus Document Task Force. J Am Coll Cardiol 2017; 69 (07) 871-898
• 160 Raval AN, Cigarroa JE, Chung MK. et al; American Heart Association Clinical Pharmacology Subcommittee of the Acute Cardiac Care and General Cardiology Committee of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; and Council on Quality of Care and Outcomes Research. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation 2017; 135 (10) e604-e633
• 161 Vivas D, Roldán I, Ferrandis R. et al; Expert reviewers. Perioperative and periprocedural management of antithrombotic therapy: consensus document of SEC, SEDAR, SEACV, SECTCV, AEC, SECPRE, SEPD, SEGO, SEHH, SETH, SEMERGEN, SEMFYC, SEMG, SEMICYUC, SEMI, SEMES, SEPAR, SENEC, SEO, SEPA, SERVEI, SECOT and AEU. Rev Esp Cardiol (Engl Ed) 2018; 71 (07) 553-564
• 162 Birnie DH, Healey JS, Wells GA. et al; BRUISE CONTROL Investigators. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med 2013; 368 (22) 2084-2093
• 163 Douketis JD, Spyropoulos AC, Kaatz S. et al; BRIDGE Investigators. Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015; 373 (09) 823-833
• 164 Tomaselli GF, Mahaffey KW, Cuker A. et al. 2020 ACC expert consensus decision pathway on management of bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2020; 76 (05) 594-622
• 165 Levy JH, van Ryn J, Sellke FW. et al. Dabigatran reversal with idarucizumab in patients requiring urgent surgery: a subanalysis of the RE-VERSE AD study. Ann Surg 2021; 274 (03) e204-e211
• 166 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
• 167 Connolly SJ, Crowther M, Eikelboom JW. et al; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380 (14) 1326-1335
• 168 Niessner A, Tamargo J, Morais J. et al. Reversal strategies for non-vitamin K antagonist oral anticoagulants: a critical appraisal of available evidence and recommendations for clinical management-a joint position paper of the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy and European Society of Cardiology Working Group on Thrombosis. Eur Heart J 2017; 38 (22) 1710-1716
• 169 Hansen ML, Sørensen R, Clausen MT. et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010; 170 (16) 1433-1441
• 170 Roldán V, Marín F, Fernández H. et al. Predictive value of the HAS-BLED and ATRIA bleeding scores for the risk of serious bleeding in a “real-world” population with atrial fibrillation receiving anticoagulant therapy. Chest 2013; 143 (01) 179-184
• 171 Riva N, Bellesini M, Di Minno MN. et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study. Thromb Haemost 2014; 112 (03) 511-521
• 172 Yoshida R, Ishii H, Morishima I. et al. Impact of nutritional and inflammation status on long-term bleeding in patients undergoing percutaneous coronary intervention with an oral anticoagulant. J Atheroscler Thromb 2019; 26 (08) 728-737
• 173 Urban P, Mehran R, Colleran R. et al. Defining high bleeding risk in patients undergoing percutaneous coronary intervention. Circulation 2019; 140 (03) 240-261
• 174 Capodanno D, Bhatt DL, Gibson CM. et al. Bleeding avoidance strategies in percutaneous coronary intervention. Nat Rev Cardiol 2021; 19 (02) 117-132
• 175 Lip GYH, Collet JP, Haude M. et al; ESC Scientific Document Group. 2018 Joint European consensus document on the management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous cardiovascular interventions: a joint consensus document of the European Heart Rhythm Association (EHRA), European Society of Cardiology Working Group on Thrombosis, European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Association of Acute Cardiac Care (ACCA) endorsed by the Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA). Europace 2019; 21 (02) 192-193
• 176 Kumbhani DJ, Cannon CP, Beavers CJ. et al. 2020 ACC expert consensus decision pathway for anticoagulant and antiplatelet therapy in patients with atrial fibrillation or venous thromboembolism undergoing percutaneous coronary intervention or with atherosclerotic cardiovascular disease: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2021; 77 (05) 629-658
• 177 Vranckx P, Verheugt FWA, de Maat MP. et al. A randomised study of dabigatran in elective percutaneous coronary intervention in stable coronary artery disease patients. EuroIntervention 2013; 8 (09) 1052-1060
• 178 Vranckx P, Leebeek FWG, Tijssen JGP. et al. Peri-procedural use of rivaroxaban in elective percutaneous coronary intervention to treat stable coronary artery disease. The X-PLORER trial. Thromb Haemost 2015; 114 (02) 258-267
• 179 Yasuda S, Kaikita K, Akao M. et al; AFIRE Investigators. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N Engl J Med 2019; 381 (12) 1103-1113
• 180 Matsumura-Nakano Y, Shizuta S, Komasa A. et al; OAC-ALONE Study Investigators. Open-label randomized trial comparing oral anticoagulation with and without single antiplatelet therapy in patients with atrial fibrillation and stable coronary artery disease beyond 1 year after coronary stent implantation. Circulation 2019; 139 (05) 604-616
• 181 Proietti M, Airaksinen KEJ, Rubboli A. et al; AFCAS Study Group. Time in therapeutic range and major adverse outcomes in atrial fibrillation patients undergoing percutaneous coronary intervention: the Atrial Fibrillation Undergoing Coronary Artery Stenting (AFCAS) registry. Am Heart J 2017; 190: 86-93
• 182 Gibson CM, Mehran R, Bode C. et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016; 375 (25) 2423-2434
• 183 Cannon CP, Bhatt DL, Oldgren J. et al; RE-DUAL PCI Steering Committee and Investigators. Dual antithrombotic therapy with dabigatran after PCI in atrial fibrillation. N Engl J Med 2017; 377 (16) 1513-1524
• 184 Lopes RD, Heizer G, Aronson R. et al; AUGUSTUS Investigators. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. N Engl J Med 2019; 380 (16) 1509-1524
• 185 Vranckx P, Valgimigli M, Eckardt L. et al. Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or chronic coronary syndrome presentation: a pre-specified analysis of the ENTRUST-AF PCI trial. Eur Heart J 2020; 41 (47) 4497-4504
• 186 Costa F, Valgimigli M, Steg PG. et al. Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI. Eur Heart J Cardiovasc Pharmacother 2020; 8 (03) 216-226
• 187 Ibanez B, James S, Agewall S. et al; ESC Scientific Document Group. 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39 (02) 119-177
• 188 Collet J-P, Thiele H, Barbato E. et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2021; 42 (14) 1289-1367
• 189 Neumann FJ, Sousa-Uva M, Ahlsson A. et al. 2018 ESC/EACTS guidelines on myocardial revascularization. EuroIntervention 2019; 14 (14) 1435-1534
• 190 Capodanno D, Milluzzo RP, Angiolillo DJ. Intravenous antiplatelet therapies (glycoprotein IIb/IIIa receptor inhibitors and cangrelor) in percutaneous coronary intervention: from pharmacology to indications for clinical use. Ther Adv Cardiovasc Dis 2019; 13: 1753944719893274
• 191 Krucoff MW, Urban P, Tanguay J-F. et al. Global approach to high bleeding risk patients with polymer-free drug-coated coronary stents: the LF II study. Circ Cardiovasc Interv 2020; 13 (04) e008603
• 192 Olsen AS, McGettigan P, Gerds TA. et al. Risk of gastrointestinal bleeding associated with oral anticoagulation and non-steroidal anti-inflammatory drugs in patients with atrial fibrillation: a nationwide study. Eur Heart J Cardiovasc Pharmacother 2020; 6 (05) 292-300
• 193 Al-Samkari H, Connors JM. Managing the competing risks of thrombosis, bleeding, and anticoagulation in patients with malignancy. Blood Adv 2019; 3 (22) 3770-3779
• 194 Angelini DE, Radivoyevitch T, McCrae KR, Khorana AA. Bleeding incidence and risk factors among cancer patients treated with anticoagulation. Am J Hematol 2019; 94 (07) 780-785
• 195 Melloni C, Shrader P, Carver J. et al; ORBIT-AF Steering Committee. Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry. Eur Heart J Qual Care Clin Outcomes 2017; 3 (03) 192-197
• 196 Shah S, Norby FL, Datta YH. et al. Comparative effectiveness of direct oral anticoagulants and warfarin in patients with cancer and atrial fibrillation. Blood Adv 2018; 2 (03) 200-209
• 197 Fanola CL, Ruff CT, Murphy SA. et al. Efficacy and safety of edoxaban in patients with active malignancy and atrial fibrillation: analysis of the ENGAGE AF - TIMI 48 trial. J Am Heart Assoc 2018; 7 (16) e008987
• 198 Chen ST, Hellkamp AS, Becker RC. et al. Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKET AF. Eur Heart J Qual Care Clin Outcomes 2019; 5 (02) 145-152
• 199 Delluc A, Wang TF, Yap ES. et al. Anticoagulation of cancer patients with non-valvular atrial fibrillation receiving chemotherapy: guidance from the SSC of the ISTH. J Thromb Haemost 2019; 17 (08) 1247-1252
• 200 Sidahmed S, Abdalla A, Kheiri B. et al. Anticoagulants for the treatment of venous thromboembolism in patients with cancer: a comprehensive systematic review, pairwise and network meta-analysis. Crit Rev Oncol Hematol 2020; 152: 103005
• 201 Raskob GE, van Es N, Verhamme P. et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
• 202 Young AM, Marshall A, Thirlwall J. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36 (20) 2017-2023
• 203 Kirkilesis GI, Kakkos SK, Tsolakis IA. Editor's Choice - a systematic review and meta-analysis of the efficacy and safety of anticoagulation in the treatment of venous thromboembolism in patients with cancer. Eur J Vasc Endovasc Surg 2019; 57 (05) 685-701
• 204 Tolosana JM, Berne P, Mont L. et al. Preparation for pacemaker or implantable cardiac defibrillator implants in patients with high risk of thrombo-embolic events: oral anticoagulation or bridging with intravenous heparin? A prospective randomized trial. Eur Heart J 2009; 30 (15) 1880-1884
• 205 Polyzos KA, Konstantelias AA, Falagas ME. Risk factors for cardiac implantable electronic device infection: a systematic review and meta-analysis. Europace 2015; 17 (05) 767-777
• 206 Essebag V, Verma A, Healey JS. et al; BRUISE CONTROL Investigators. Clinically significant pocket hematoma increases long-term risk of device infection: BRUISE CONTROL INFECTION study. J Am Coll Cardiol 2016; 67 (11) 1300-1308
• 207 Kuo HC, Liu FL, Chen JT, Cherng YG, Tam KW, Tai YH. Thromboembolic and bleeding risk of periprocedural bridging anticoagulation: a systematic review and meta-analysis. Clin Cardiol 2020; 43 (05) 441-449
• 208 Steffel J, Verhamme P, Potpara TS. et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
• 209 Rossini R, Tarantini G, Musumeci G. et al; Italian Society of Interventional Cardiology (SICI-GISE), Italian Society for the Study of Haemostasis and Thrombosis (SISET), Italian Society of Anesthesia and Intensive Care Medicine (SIAARTI), Italian Society of Surgery (SIC), Italian Society for Cardiac Surgery (SICCH), Italian Society of Vascular and Endovascular Surgery (SICVE), Italian Society of Urology (SIU), Italian Orthopaedic Society (SIOT), Italian Society of Thoracic Surgeons (SICT), Italian Federation of Scientific Societies of Digestive System Diseases (FISMAD), Italian Society of Digestive Endoscopy (SIED), Italian Association of Hospital Gastroenterology and Digestive Endoscopy (AIGO), Italian Association of Gastroenterology and Digestive Endoscopy (SIGE), Italian Society of Maxillofacial Surgery (SICMF), Italian Society of Reconstructive Plastic Surgery and Aesthetics (SICPRE), Italian Society of Gynecology and Obstetrics (SIGO), Italian Society of Neurosurgery (SINch), Italian Association of Hospital Pulmonologist (AIPO), Italian Society of Periodontology (SIdP), Italian Society of Ophthalmology (SOI), Italian Association of Hospital Otorhinolaryngologist (AOOI), Italian Association of Hospital Surgeons (ACOI), Association of Obstetricians Gynecologists Italian Hospital (AOGOI). A multidisciplinary approach on the perioperative antithrombotic management of patients with coronary stents undergoing surgery: surgery after stenting 2. JACC Cardiovasc Interv 2018; 11 (05) 417-434
• 210 Cao D, Chandiramani R, Capodanno D. et al. Non-cardiac surgery in patients with coronary artery disease: risk evaluation and periprocedural management. Nat Rev Cardiol 2021; 18 (01) 37-57

Publication History

Received: 17 May 2022

Accepted: 19 May 2022

Article published online:
06 July 2022