Managing patients with a history of arterial disease and new venous thromboembolism

Visual Abstract

Abstract

Arterial and venous thromboses differ in pathophysiology but share overlapping risk factors such as obesity, metabolic syndrome, and aging. Patients with established arterial disease, such as coronary artery disease, stroke, and peripheral artery disease, may develop venous thromboembolism (VTE) during the acute or chronic phase of their illness. This creates therapeutic tension when anticoagulation for VTE overlaps with antiplatelet therapy. We propose a stepwise clinical approach that first identifies precipitating factors for VTE, then modifies antiplatelet therapy according to the chronicity of the arterial condition and finally estimates thrombosis against bleeding risk aided by scoring systems, available evidence for combination treatment, and interdisciplinary collaboration. Two clinical cases exemplify this stepwise approach.

Learning Objectives

• Understand the incidence and risk factors for VTE in patients with arterial disease

• Select and modify antithrombotic therapy in acute and chronic arterial disease

• Balance thrombosis and bleeding risk using scoring systems and evidence from combination-therapy trials

Introduction

Venous thromboembolism (VTE) is the third most common cause of vascular death after heart attack and stroke and a major contributor to global mortality and morbidity.¹ The mainstay of VTE treatment is therapeutic anticoagulation, most commonly direct oral anticoagulants (DOACs) apixaban, rivaroxaban, edoxaban, or dabigatran. In contrast, ischemic heart disease and stroke are treated predominantly with antiplatelet agents such as aspirin and P2Y12 inhibitors (eg, clopidogrel and ticagrelor). Despite differing pathophysiology, arterial and venous thromboses share overlapping risk factors, such as age, obesity, and cigarette smoking, and evidence suggests a bidirectional relationship between arterial and venous events (Figure 1).²

Figure 1.

Contribution of cardiovascular risk factors to the pathophysiology of venous thromboembolism.

A new VTE in a patient with preexisting arterial disease frequently necessitates combined anticoagulation and antiplatelet therapy.³ However, optimal combination and duration remain uncertain, and practice varies widely depending on the individual's circumstances. We propose 3 focused questions to guide management:

1. Are precipitating factors present for VTE?

2. How is treatment modified by the chronicity of arterial disease?

3. What antithrombotic regimen best balances bleeding and thrombosis risk in the individual patient?

Two clinical vignettes, the first with VTE after a recent arterial event, and the second, VTE in chronic arterial disease, illustrate how this framework supports individualized care.

CLINICAL CASE 1

A 65-year-old man presents with a 3-day history of pleuritic chest pain and shortness of breath. Computed tomography pulmonary angiography shows multiple right segmental and subsegmental pulmonary emboli (PE). He has a background of ischemic heart disease and underwent percutaneous coronary intervention (PCI) with a drug-eluting stent 3 months earlier. He is on aspirin 100 mg daily and clopidogrel 75  mg daily as dual antiplatelet therapy (DAPT).

CLINICAL CASE 2

A 68-year-old woman presents with a 2-day history of pleuritic chest pain and shortness of breath following an 8-hour international flight. She has hypertension, hypercholesterolemia, and type 2 diabetes mellitus and takes aspirin 100  mg daily for intermittent claudication. Computed tomography pulmonary angiography demonstrates a right segmental PE.

Incidence of VTE in patients with preexisting arterial disease

Recent arterial event

VTE after acute myocardial infarction is not uncommon; a Norwegian registry demonstrated a 51% increase in VTE risk following acute myocardial infarction.⁴ VTE also complicates stroke, mainly due to paresis and immobility. In a study of ∼130 000 patients, 0.26% of those with acute ischemic stroke and 0.65% of those with intracranial hemorrhage were readmitted to the hospital for VTE within 90 days.⁵ Including nonhospitalized VTEs, the incidence can be as high as 17%.⁵ Overall, VTE risk triples within 3 months after an arterial event,⁶ or new-onset atrial fibrillation (AF),⁷ and remains modestly elevated (1.29-fold), beyond 3 months (Table 1).⁶

Table 1.

Incidence of venous thromboembolism in patients with acute or chronic arterial disease

Arterial disease	Incidence	Reference
PAD postintervention	4.8% in 90 days after peripheral vascular intervention	Kindell61
Chronic PAD	1.7% in 3 years while on treatment with aspirin 100  mg	Hess62
Acute CAD	1% of admissions for STEMI 0.6% within 30 days of AMI, 0.87% per year 5.6% within 3 months of AMI (PE) 1.1% within 3 months of AMI (DVT)	Al-Ogaili63 Wurtz64 Sorenson65
Stable CAD	∼0.3% per year while on treatment with ≥1 antiplatelet agent 0.7% in 4 years	Cavallari66 Schwartz67
Acute ischemic stroke	8% in 21 days while on aspirin prophylaxis or graded compression stockings 4.8% in patients receiving any type of prophylaxis in 0.5-12 months ∼14.5% within 30 days (radiologically detected DVT) 0.78% (PE) within 30 days	Kelly68 Kamphuisen69 Dennis70 Pongmoragot71
History of ischemic stroke (>3 months)	0.75% per year	Rinde72

AMI, acute myocardial infarction; CAD, coronary artery disease; DVT, deep vein thrombosis; PAD, peripheral artery disease; PE, pulmonary embolism; STEMI, ST-segment elevation myocardial infarction.

Chronic arterial disease

Chronic cardiovascular risk factors also raise VTE risk. Obesity promotes venous stasis, endothelial inflammation, and hypercoagulability, increasing VTE risk 2- to 5-fold.⁸ Metabolic syndrome (a combination of obesity, hyperlipidemia, hypertension, and insulin resistance) raises the risk of VTE recurrence 2.4-fold when at least 3 of the 4 components are present.⁹

These epidemiologic data highlight the importance of identifying precipitating factors for VTE, as they influence treatment duration.

Step 1. Assessment for precipitating factors for VTE

Definitions for major transient (present within 3 months before the VTE), minor transient (present within 2 months before the VTE), and persistent risk factors have been published by the International Society on Thrombosis and Haemostasis and CHEST 2021 guidelines.^10,11 Examples of major transient risk factors include surgery with general anesthesia >30 minutes or bed confinement in the hospital ≥3 days for acute illness. Minor transient risk factors include estrogen exposure and leg injury, whereas persistent risk factors include active cancer and inflammatory conditions. The presence of precipitating factors classifies a VTE as provoked, whereas their absence classifies it as unprovoked.¹⁰

In case 1, it is unclear whether the prior PCI constitutes a provoking factor. If the patient was not hospitalized and remained mobile, the PE is less likely to be attributable to the PCI. In case 2, the proximity of the VTE to the patient's flight is apparent, allowing it to be classified as “provoked.” However, this is not always the case; the acceptable timeframe after a precipitating factor to establish a link with a VTE is sometimes unclear. For example, long-haul flights “precipitate” VTE within 2 weeks.¹² Identification of a transient precipitant generally supports a finite 3- to 6-month course of anticoagulation, whereas the absence of a precipitant favors extended therapy.¹³

Step 2. Modification of antiplatelet treatment based on chronicity of arterial disease

Antiplatelet de-escalation

Management differs between recent and chronic arterial disease. Antiplatelets are usually maintained after a recent acute arterial event, but de-escalation may be appropriate if VTE develops soon after PCI, for example, by switching from ticagrelor to clopidogrel, because therapeutic anticoagulation itself provides some protection against in-stent thrombosis.¹⁴ Assessing pathophysiology and event severity enables an individualized approach. In-stent thrombosis after PCI carries a mortality rate up to 40%,¹⁵ whereas untreated PE historically carries 26% mortality,¹⁶ although modern estimates in ambulatory patients are closer to 5%.¹⁷ Proximal deep vein thrombosis (DVT) left untreated will lead to a PE in roughly half of cases, whereas only one-fourth of distal DVT progresses proximally.¹⁸

For PCI, the American College of Cardiology and European Society of Cardiology guidelines recommend minimizing triple therapy for 1 week to 30 days based on thrombotic risk.^19,20 Dual therapy (oral anticoagulant, preferably DOAC, plus P2Y12 inhibitor, preferably clopidogrel) is advised for months 1 to 12, followed by oral anticoagulant monotherapy thereafter. For high thrombotic risk/low bleeding risk, triple therapy is continued for 1 month, then dual therapy for 12 months. For low thrombotic/high bleeding risk, dual therapy is given for 6 months, followed by oral anticoagulant monotherapy. While these guidelines have been developed for AF rather than VTE, the data are relevant for VTE and are based on best available practice.²¹ When selecting an antiplatelet agent to continue with anticoagulant therapy, clopidogrel is generally favored over aspirin, given the stronger antiplatelet effect of clopidogrel.^19-22

A similar approach applies to VTE after acute ischemic stroke. Anticoagulation is usually withheld for at least 24 hours and timed to avoid hemorrhagic transformation.^23,24 While infarct size and stroke severity guide the timing of initiation of oral anticoagulation, robust data are lacking.²⁵ Patients with minor to moderate ischemic stroke may start DOAC 48 hours later, with antiplatelet discontinuation, whereas oral anticoagulation is withheld for 1 to 2 weeks in patients with large infarctions, symptomatic hemorrhagic transformation, or poorly controlled hypertension, although recent data support starting DOAC as early as day 4.²⁴ For patients with significant VTE who cannot receive anticoagulation, an inferior vena cava filter should be considered (Figure 2).

Figure 2.

Algorithm for the antithrombotic management of patients requiring anticoagulant after an acute arterial event. Triple therapy is given in percutaneous coronary intervention with stenting, whereas patients with a medically treated acute coronary syndrome can receive oral anticoagulation therapy with antiplatelet (clopidogrel) for 6 months.²² Recent studies favor early direct oral anticoagulant (DOAC) initiation (within 4 days) in patients with atrial fibrillation and ischemic stroke.²⁵ VTE, venous thromboembolism.

Antiplatelet discontinuation

In chronic arterial disease, antiplatelet therapy can often be discontinued once therapeutic anticoagulation is started to reduce bleeding. Peripheral artery disease (PAD) (intermittent claudication) has a 6% annual mortality and typically requires an antiplatelet agent.²⁶ Guidelines recommend that patients with AF and stable PAD (no new vascular event in the past 12 months) receive oral anticoagulant alone, as concomitant antiplatelet therapy does not reduce stroke or other cardiovascular events but increases bleeding. Disease-modifying treatments (statins, calcium-channel blockers) may further reduce arterial risk (Figure 3).^25,27

Figure 3.

Algorithm for the antithrombotic management of patients with venous thromboembolism and chronic arterial disease.

Efficacy of oral anticoagulants in the prevention of arterial disease

Low-dose anticoagulation is emerging for the prevention of arterial thrombosis. In symptomatic PAD, rivaroxaban 2.5  mg twice a day plus aspirin 100  mg daily reduced arterial events vs aspirin alone but increased major bleeding (International Society on Thrombosis and Haemostasis definition).²⁸ Although DOACs are not indicated for other arterial diseases, rivaroxaban may delay coronary atherosclerosis progression.²⁹ In AF with stable coronary artery disease, rivaroxaban monotherapy (10-15 mg once daily) was noninferior to rivaroxaban plus antiplatelet in preventing arterial events and had less bleeding.³⁰

Efficacy of aspirin in the prevention of VTE

Low-dose aspirin, widely used for arterial prophylaxis, may also provide modest protection against venous thrombosis.³¹ After standard anticoagulation for a first VTE, aspirin has been evaluated as secondary prophylaxis. In EINSTEIN-CHOICE, patients with proximal DVT or PE who completed 6 to 12 months of anticoagulation and were in equipoise for continuation experienced a 4.4% VTE recurrence rate on low-dose aspirin compared with a historical 10% in untreated patients.³² INSPIRE showed aspirin reduced recurrent VTE by over one-third in first unprovoked events,³³ but ASPIRE found no significant reduction vs placebo.³⁴ WAFASA reported that aspirin 100 mg led to a ∼40% decrease in VTE recurrence without increased major bleeding (0.3% per year).³⁵ A meta-analysis confirmed aspirin (100-160  mg) significantly reduced VTE, DVT, PE, and VTE-related mortality (especially in primary prevention and provoked VTE) but showed no benefit in secondary prevention when given at 100  mg daily and was accompanied by increased bleeding.³¹

Step 3. Assessment of thrombotic vs bleeding balance in patients with VTE after an arterial event

Risk scores

In the assessment of a new VTE, clinicians must weigh thrombotic and bleeding risks, especially when combined therapy is required. Various specialty-specific scores exist: cardiology,^22,36 hematology/respiratory,^37,38 neurology,³⁹ and vascular surgery.⁴⁰ Combined scoring systems, including risk factors for arterial thrombosis, venous thrombosis, and bleeding in the same model, are still under development or require validation. One example of a “combined” prediction score is the VTE-PREDICT model; it uses 14 variables, including blood pressure and antiplatelet use.⁴¹ Arterial scores include DAPT for PCI (a score of ≥2 equates high risk with 1.4% thrombosis at 30 months, supporting dual antiplatelet therapy >12 months)²² and CHA₂DS₂-VASc risk assessment scores for AF-related stroke.²⁰

For VTE, the Vienna Prediction Model estimates recurrence risk after unprovoked VTE,⁴² whereas the VTE-BLEED score predicts bleeding during or after anticoagulation.^43,44 Bleeding tools include HAS-BLED (a score ≥3 means high risk with 3.7%-5.8% major bleeding in 1 year).⁴⁵ The National Institute for Health and Care Excellence guidelines recommend cessation of anticoagulation for secondary prevention in AF if the HAS-BLED score is ≥4 and cannot be modified.⁴⁶ CHAP⁴⁷ and VTE-PREDICT⁴¹ are also used but lack external validation.

Despite limitations, risk calculators often influence management. For example, the application of VTE-PREDICT in case scenarios altered the proposed therapy.⁴⁸ Clinicians should therefore consider available prediction platforms when discussing management with other medical or surgical specialties. A summary of scoring systems relevant to VTE and arterial disease (including PCI and PAD) is provided in Table 2 for reference. Although informative, the direct comparison of numerical values derived from different risk prediction scores extends beyond the evidence. In many cases, the decision is more nuanced, as there is a lack of data to support a clear answer for the individual's presentation.

Table 2.

Examples of integrated risk assessment scores for arterial thrombosis, VTE, and bleeding

Model/score	Primary risk assessment	VTE score predictive parameters	Score and estimated risk	Reference
VIENNA and Updated VIENNA	Risk of recurrent VTE after an unprovoked VTE	Sex, site of VTE, D-dimer (µg/mL) 3 weeks after discontinuation of OAC	Nomogram-based score Updated Vienna score 0-220: 7% recurrence in 5 years Score >220: 41% recurrence in 5 years	37 73
VTE-PREDICT	Risk of recurrent VTE and bleeding from continuing OAC for VTE	Sex, age, OAC >3 months, antiplatelet agent, NSAIDs, PE, estrogen therapy, surgery, trauma or immobilization, history of VTE, cancer, bleeding, stroke, BMI, systolic blood pressure, Hb	Formula calculates 1- and 5-year estimated risk of recurrent VTE and bleeding with continuing OAC or discontinuation	41 74
HERDOO2	VTE recurrence after 5-7 months of OAC for VTE	Hyperpigmentation, edema, redness, D-dimer, obesity, older age	Score 0-4 0-1: no indication for long-term OAC in women 2-4: indication for long-term OAC	Rodger, BMJ, 2017
VTE-BLEED	Major bleeding in patients receiving OAC for VTE	Cancer, sex, hypertension, Hb, history of bleeding, age, renal function	Low bleeding risk <2 High bleeding risk >2	44
CHAP	Major bleeding in patients receiving OAC for VTE	Creatinine, Hb, age, antiplatelet agent	High risk: 3.9% major bleeding events per year No high risk: 1.1%	47
DAPT score	Arterial thrombotic event or bleed in patients continuing thienopyridine beyond 12 months after PCI	Age, diabetes mellitus, prior MI or PCI, hypertension, PAD, heart failure, renal insufficiency, MI at presentation, vein-graft PCI	Score −2 to 9 Score ≥2: favorable benefit/risk ratio for prolonged DAPT (ie, incidence of MI or stent thrombosis ∼6% with discontinuation of DAPT) Score <2: unfavorable benefit/risk ratio	22 75
PRECISE-DAPT	Risk of bleeding in patients continuing DAPT after PCI	Age, creatinine clearance, Hb, white blood cell count, prior bleeding	Score ≥25: TIMI major or minor bleeding ∼4% over ∼12 months of DAPT Score <25: ∼1.8% over ∼12 months	76
OACC3-PAD	5-year risk of amputation or death and risk of bleeding following hospitalization for PAD			40 https://score.germanvasc.de/
SMART and SMART2	10-year risk for MI, stroke, or vascular death in atherosclerotic vascular disease	Age, sex, smoking, blood pressure, diabetes mellitus, CAD, cerebrovascular disease, abdominal aortic aneurysm, PAD, time since first diagnosis of CVD, HLD, total cholesterol, eGFR, hsCRP	Mathematical formula calculating the 10-year risk of CVD <10%, 10%-20%, 20%-30%, >30%	77 78 https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Risk-assessment/SMART-Risk-Score#
SCORE2	10-year risk for MACE in individuals with type 2 diabetes	Risk of geographic region, sex, age, age of diabetes diagnosis, current smoking, Mediterranean diet, step count (optional), systolic blood pressure, HbA1c, eGFR, total cholesterol, HDL-cholesterol, LDL-cholesterol, statin, ezetimibe, bempedoic acid, PCSK9 inhibitor, antithrombotic treatment, GLP1 receptor agonist, SGLT2 inhibitor	Mathematical formula calculating the 10-year risk of CVD 0-30%	79 https://u-prevent.com/calculators/results/score2Diabetes
CHA₂DS₂-VASc	Risk of stroke in AF	Congestive heart failure, hypertension, age 75  y or older, diabetes mellitus, previous stroke or thromboembolism, vascular disease, ages 65-74, female sex	Score 0-9 Score 0 annual stroke risk 0% 1: 1.3% 2: 2.2% 3: 3.2% 4: 4.2% 5: 6.7% 6: 9.8% 8: 12.5% 9: 15.2%	80
ATRIA	Risk of stroke in AF	Previous stroke, age, sex, diabetes mellitus, chronic heart failure, hypertension, proteinuria, eGFR	Score 0-15 Score 0-5: low risk, 0.63% recurrence in 1 year Score 6: moderate risk, 1.91% Score 7-15: high risk, 3.89%	81
HEMORR2HAGES	Risk of bleeding in AF	H Hepatic or renal disease E Ethanol M Malignancy O Older age R Reduced platelet count or function R Rebleeding risk (ie, prior bleed) H Hypertension (uncontrolled) A Anemia G Genetic factors (CYP2C9 variant) E Excessive fall risk S Stroke	Score 0 to >5 Score 0: 1.9% bleeds in 1 year 1: 2.5% 2: 5.3% 3: 8.4% 4: 10.4% ≥5: 12.3%	82
ORBIT	Risk of bleeding in patients with AF on OAC	Age, anemia, bleeding history, eGFR, antiplatelet agents	Score 0-7 Score 0: 1.7% bleeds in 1 year 1 point: 2.3% 2 points: 2.9% 3 points: 4.7% 4 points: 6.8% 5 points: 9.0% 6 points: 12.3% 7 points: 14.9%	83
HASBLED score	Risk of major bleeding in patients with AF	Hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, elderly, drugs or alcohol	High risk score ≥3 Major bleed 3.7-5.8% in 1 year	45

AF, atrial fibrillation; BMI, body mass index; CAD, coronary artery disease; CVD, cerebrovascular disease; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HLD, hyperlipidemia; hsCRP, high-sensitivity C-reactive protein; INR, international normalized ratio; LDL, low-density lipoprotein; MACE, major adverse cardiovascular events; MI, myocardial infarction; NSAIDs, nonsteroidal anti-inflammatory drugs; OAC, oral anticoagulant (warfarin or DOAC); PAD, peripheral artery disease; PCI, percutaneous coronary intervention; PE, pulmonary embolism; TIMI, Thrombolysis in Myocardial Infarction; VTE, venous thromboembolism.

Patient comorbidities

Patient comorbidities further guide anticoagulant choice and dosing.⁴⁹ For example, in chronic kidney disease stage 4/5 with AF, apixaban 5  mg twice a day carries a higher bleeding risk than 2.5  mg twice a day (4.9 vs 2.9 events/100 person-years) with similar stroke/systemic embolism rates (3.3 vs 3.0 events/100 person-years).⁵⁰ Apixaban may have a more favorable profile in cirrhosis.⁵¹ Apixaban has recently been shown to have a lower bleeding risk compared with rivaroxaban for the treatment of VTE (COBRRA trial).⁵² Warfarin is preferred in antiphospholipid syndrome and severe kidney insufficiency, whereas low-molecular-weight heparin is indicated in pregnancy and patients requiring parenteral treatment. Table 3 summarizes bleeding risks with antithrombotics for various cardiovascular indications and combinations,⁵³ whereas Table 4 provides the definitions for bleeding used in some of these trials. Gastroprotection with proton-pump inhibitors is recommended in patients on antithrombotic therapy with prior upper-gastrointestinal lesions or high bleeding risk and for patients on dual therapy (anticoagulation and antiplatelet).⁵⁴

Table 3.

Bleeding risk from anticoagulants and antiplatelets

Antithrombotic	Bleeding incidence	Risk ratio or hazard ratio	Reference
Low-dose aspirin (most studies 100  mg once daily)	GI bleeding 0.04%-0.3% per year Severe bleeding (GUSTO criteria) 1.3% in 28 months Major bleeding 0.23% per year	RR 1.4 compared with no aspirin HR 1.43 compared with no aspirin	84 85 86
Clopidogrel 75  mg once daily	Major bleeding (according to International Classification of Diseases, Ninth Revision) 3.6% in 1.1 years Major bleeding: 0.70% per year	HR 1.12 compared with aspirin	87 88
Ticagrelor 90  mg twice a day	Major bleeding (BARC 3-5) 0.8% in 9 months	HR 0.37 compared with ticagrelor + aspirin	89
Clopidogrel + aspirin	All bleeding 7.4% per year Severe bleeding (GUSTO) 2.3% in 28 months	RR 1.91 compared with warfarin	90 85
Ticagrelor + aspirin	Major bleeding (BARC 3-5) 2.1% in 9 months Major bleeding (TIMI) 1.7% and minor bleeding (TIMI) 3.1% in 10-day hospitalization	Major bleeding OR 1.48 compared with clopidogrel + aspirin	89 91
Apixaban therapy dose 10  mg twice a day for 1 week, then 5  mg twice a day	Major bleeding (ISTH) 0.1% per year (after completion of 6- to 12-month anticoagulation for VTE) CRNMB 4.2% per year Major bleeding (ISTH) 2.1% per year in AF Clinically relevant bleed 3% in 3 months	Major bleeding RR 0.25 compared with placebo HR 0.69 compared with warfarin	92 93 52
Apixaban prophylaxis 2.5  mg twice a day	Major bleeding (ISTH) 0.2% per year CRNMB 3% per year		94
Rivaroxaban therapy dose 15  mg twice a day for 3 weeks, then 20  mg once daily	During first 6-12 months of anticoagulation: Major bleeding (ISTH) 0.8% CRNMB 7.3% After completion of 6-12 months anticoagulation for VTE: Major bleeding (ISTH) 0.7% per year CRNMB 5.4% per year Clinically relevant bleed 6% in 3 months Major bleeding (ISTH) 3.6% per year CRNMB 11.8% per year (in AF)	Major bleeding HR 1.0 compared with warfarin	95 52 96
Rivaroxaban prophylaxis 10  mg once daily	Major bleeding (ISTH) 0.4% per 1 year CRNMB 2.0% per 1 year	Major bleeding HR 1.64 compared with aspirin	97
Dabigatran therapy dose 110  mg twice a day 150  mg twice a day started 5 days after parenteral anticoagulant	Major bleeding 2.71% per year (110 mg twice a day) and 3.11% per year (150  mg of dabigatran) (in AF)		98
Edoxaban therapy dose 60  mg once daily, or 30  mg once daily (if creatinine clearance 30-50  mL/min or a body weight <60  kg) started 5 days after parenteral anticoagulant	Major bleeding (ISTH) 1.4% per year CRNMB 7.2% per year	Major bleeding HR 0.84 compared with warfarin	99
Warfarin dose adjusted for INR 2-3	All bleeding: 3.9% per year Major bleeding (ISTH) 3.4% per year CRNMB 11.4% (in AF)		90 96
OAC (edoxaban, rivaroxaban, warfarin) + single antiplatelet	Major bleeding (ISTH) 5.7% in 21 months	HR 1.69 compared with OAC monotherapy	100
Rivaroxaban 2.5  mg twice a day or 5  mg twice a day + aspirin	Major bleeding events 3.1% in 23 months in the rivaroxaban + aspirin group	RR 1.7 (compared with aspirin alone)	101
Rivaroxaban 2.5  mg + aspirin 100  mg	Fatal bleeding 0.09% in 1 year Symptomatic bleeding in critical organ 0.8% per year	Fatal bleeding HR 1.49 compared with aspirin alone	28
Triple therapy	All bleeding: 15.7% per year BARC grade 3 bleeding: 12.7% per year Major bleeding 2.2% at 30 days	RR 3.7 compared with warfarin alone HR 3.9 compared with warfarin alone	90 102 103

AF, atrial fibrillation; BARC, Bleeding Academic Research Consortium; CRNMB, clinically relevant nonmajor bleeding; GI, gastrointestinal; GUSTO, Global Use of Streptokinase and t-PA for Occluded Coronary Arteries bleeding classification; HR, hazard ratio; INR, international normalized ratio; ISTH, International Society on Thrombosis and Haemostasis; OAC, oral anticoagulant; OR, odds ratio; RR, risk ratio; TIMI, Thrombolysis in Myocardial Infarction.

Table 4.

Bleeding scores

Bleeding score				Reference
ISTH	Major Fatal bleeds, bleeds in critical organs (intracranial, spinal), or symptomatic bleeds causing a hemoglobin drop of ≥2  g/dL with a transfusion of ≥2 units of red blood cells	Clinically relevant nonmajor Overt bleed that does not meet major criteria but requires medical intervention, hospitalization, or discontinuation of antithrombotic therapy	Nonclinically relevant minor Minor bleeds that do not meet the criteria for clinically relevant	104 105
TIMI	Major Intracranial hemorrhage, a hemoglobin drop of ≥5  g/dL, or a hematocrit drop of ≥15%	Minor Involves a hemoglobin drop of ≥3  g/dL (or ≥4  g/dL without an overt site), or a hematocrit drop of ≥10% (or ≥12% without an overt site)	Minimal A clinically overt event not meeting the criteria of major or minor	106
BARC	1, Minimal bleeding: Minimal bleeding that does not meet the criteria for other types and does not require medical attention 2, Clinically evident but minor bleeding: Overt, actionable bleeding that requires intervention by a health care professional, leads to hospitalization or increased care, or prompts an evaluation, but does not meet the criteria for major bleeding	3, Major bleeding 3a: Significant bleeding where there is a hemoglobin drop of 3 to less than 5  g/dL 3b: Significant bleeding where there is a hemoglobin drop of 5  g/dL or more 3c: Includes intracranial hemorrhage or fatal bleeding	4, CABG-related bleeding 5, Fatal bleeding	107

BARC, Bleeding Academic Research Consortium; CABG, coronary artery bypass graft; ISTH, International Society on Thrombosis and Haemostasis; TIMI, Thrombolysis in Myocardial Infarction.

Duration of treatment

After completing the finite course of therapeutic dose oral anticoagulation, the risk of recurrent VTE must be reassessed. Provoked VTE recurs at ∼3% per year (0.7% with surgical factors, 4.2% with nonsurgical factors), whereas unprovoked VTE recurs at 7.4% per year.⁵⁵

A practical strategy is to transition to a prophylaxis dose of DOAC (eg, rivaroxaban 10  mg once daily) plus aspirin 100  mg daily if the bleeding risk is not high. The RENOVE trial compared apixaban 2.5  mg twice a day or rivaroxaban 10  mg daily with therapy doses of the same and found a similarly low recurrence but substantially less clinically relevant bleeding, supporting prophylaxis doses for extended prevention of VTE.⁵⁶ Additional data show dual-pathway inhibition, with very low-dose rivaroxaban 2.5  mg twice a day plus aspirin 100  mg daily, further reducing VTE risk in chronic atherosclerosis.⁵⁷

Applying these principles to the vignettes:

In case 1, anticoagulation is started for VTE (eg, apixaban 10  mg twice a day for 1 week, then 5  mg twice a day). DAPT is reduced to a single antiplatelet (clopidogrel) due to the high bleeding risk of triple therapy and minimal additional arterial benefit.^58,59

In case 2, aspirin is stopped because therapeutic DOAC (eg, rivaroxaban 15  mg twice a day for 3 weeks, then 20  mg daily for 6 months) increases bleeding when combined with aspirin without a clear arterial benefit in stable arterial disease. Aspirin is resumed after the completion of anticoagulation.

Knowledge gaps and future directions

There are knowledge gaps in the management of VTE in patients with preexisting arterial disease. Optimal maintenance regimens after the VTE treatment phase in patients with coexisting arterial disease are not defined. Questions remain about the management of VTE in less common arterial territories and about prediction models that integrate arterial and venous thrombosis and bleeding risk within a single framework. Studies are underway to employ artificial intelligence and machine learning capabilities to improve the prediction of thrombotic and bleeding events in thrombosis and hemostasis, which will find applications in complex patient populations with venous and arterial risk factors.⁶⁰

Conclusions

VTE is a common occurrence in the general population, with an increased incidence in people with cardiovascular risk factors. Although guidance exists for specific scenarios such as post-PCI, many cases require individualized therapy. Management demands assessment of precipitating factors, chronicity of arterial disease, and careful evaluation of thrombotic vs bleeding risk with the aid of risk scores. However, in many instances, a multifaceted approach is required to amalgamate patient comorbidities, comedications, preferences, and practicalities into an individualized management plan. Interdisciplinary collaboration, regular monitoring, dose adjustment, and patient education remain essential for achieving the best balance between treating thrombosis and avoiding bleeding (Visual Abstract).

Conflict-of-interest disclosure

Echo Deng: none to disclose.

Freda H. Passam: none to disclose.

Off-label drug use

Echo Deng: not applicable.

Freda H. Passam: not applicable.