Linking To The 2024 ESC Guidelines On Atrial Fibrillation “6. [A] Avoid stroke and thromboembolism”

Today, I review, link to, and excerpt from The 2024 ESC Guidelines On Atrial Fibrillation, “6. [A] Avoid stroke and thromboembolism“.

All that follows is from the above resource.

6. [A] Avoid stroke and thromboembolism

6.1. Initiating oral anticoagulation

Atrial fibrillation is a major risk factor for thromboembolism, irrespective of whether it is paroxysmal, persistent, or permanent.^236,237 Left untreated, and dependent on other patient-specific factors, the risk of ischaemic stroke in AF is increased five-fold, and one in every five strokes is associated with AF.²³⁸ The default approach should therefore be to provide OAC to all eligible patients, except those at low risk of incident stroke or thromboembolism. The effectiveness of OAC to prevent ischaemic stroke in patients with AF is well established.^239,240 Antiplatelet drugs alone (aspirin, or aspirin in combination with clopidogrel) are not recommended for stroke prevention in AF.^241,242

6.1.1. Decision support for anticoagulation in AF

Tools have been developed to enable easier implementation of OAC in patients with clinical AF. The majority of OAC clinical trials have used variations of the CHADS₂ score to indicate those at risk (with points for chronic heart failure, hypertension, age, diabetes, and 2 points for prior stroke/transient ischaemic attack [TIA]). Although most available stroke risk scores are simple and practical, the predictive value of scores is generally modest (see Supplementary data online, Table S3).^243–245 Classification and discrimination of adverse events is relatively poor for all scores and hence the benefit of using them to select patients for OAC is unclear. There is also considerable variation in the definition of risk factors across countries,²⁴⁶ and a lack of evidence from clinical trials on the ability of stroke risk scoring to enhance clinical practice.²⁴³ This guideline continues to provide a Class IA recommendation for the use of OAC in patients at risk of thromboembolism. However, in the absence of strong evidence for how to apply risk scores in real-world patients, this has been separated from the use of any particular risk score. This is also in line with regulatory approvals for direct oral anticoagulants (DOACs), which do not stipulate risk scores or numerical thresholds.^25–28,245

Substantive changes have occurred in the decades since these risk scores were developed in regards to population-level risk factor profiles, therapies, and targets.¹⁹⁸ Historical scores do not take into account parameters that have been associated with thromboembolism in contemporary cohorts, such as cancer, chronic kidney disease (CKD), ethnicity, and a range of circulating biomarkers (including troponin and B-type natriuretic peptide [BNP]). As an example, for CKD there is a correlation between decreasing glomerular filtration rate and proteinuria with stroke risk,^247–250 and cohort data suggest a two-fold increased risk of ischaemic stroke and mortality in AF patients with CKD vs. without.²⁵¹ Other factors, such as atrial enlargement, hyperlipidaemia, smoking, and obesity, have been identified in specific cohort studies as additional risk factors for ischaemic stroke in AF.^70,252,253 Biomarkers, such as troponin, natriuretic peptides, growth differentiation factor-15, cystatin C, and interleukin-6, can also indicate residual stroke risk among anticoagulated AF patients.^254,255 Biomarker-guided stroke prevention is currently being evaluated in an ongoing RCT (NCT03753490). Until further validation within RCTs is available, this task force continues to support using simple clinical classification for implementation of OAC. Clinicians should use tools that have been validated in their local population and take an individualized approach to thromboembolic risk stratification that considers the full range of each patient’s specific risk factors. The absolute risk level at which to start OAC in individual patients cannot be estimated from population-level studies. It will vary depending on how those factors interact with other medical issues, and the degree of risk acceptable or tolerated by that person. In general, most of the available risk scores have a threshold of 0.6%–1.0% per annum of thromboembolic events for clinical AF to warrant OAC prescription.

Across Europe, the most popular risk score is CHA₂DS₂–VASc, giving points for congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, prior stroke/TIA/thromboembolism (2 points), vascular disease, age 65–74 years and female sex. However, implementation has varied in terms of gender. Female sex is an age-dependent stroke risk modifier rather than a risk factor per se.^112,256,257 The inclusion of gender complicates clinical practice both for healthcare professionals and patients.²⁵⁸ It also omits individuals who identify as non-binary, transgender, or are undergoing sex hormone therapy. Previous guidelines from the ESC (and globally) have not actually used CHA₂DS₂-VASc; instead providing different score levels for women and men with AF to qualify for OAC. Hence, CHA₂DS₂-VA (excluding gender) has effectively been in place (Table 10).⁷⁸ This task force proposes, in the absence of other locally validated alternatives, that clinicians and patients should use the CHA₂DS₂-VA score to assist in decisions on OAC therapy (i.e. without a criterion for birth sex or gender). Pending further trials in lower risk patients (NCT04700826,²⁵⁹ NCT02387229²⁶⁰), OAC are recommended in those with a CHA₂DS₂-VA score of 2 or more and should be considered in those with a CHA₂DS₂-VA score of 1, following a patient-centred and shared care approach. Healthcare professionals should take care to assess for other thromboembolic risk factors that may also indicate the need for OAC prescription.

Table 10: Updated definitions for the CHA₂DS₂-VA score

CHA2DS2-VA component		Definition and comments	Points awardeda
C	Chronic heart failure	Symptoms and signs of heart failure (irrespective of LVEF, thus including HFpEF, HFmrEF, and HFrEF), or the presence of asymptomatic LVEF ≤40%.261–263	1
H	Hypertension	Resting blood pressure >140/90 mmHg on at least two occasions, or current antihypertensive treatment. The optimal BP target associated with lowest risk of major cardiovascular events is 120–129/70–79 mmHg (or keep as low as reasonably achievable).162,264	1
A	Age 75 years or above	Age is an independent determinant of ischaemic stroke risk.265 Age-related risk is a continuum, but for reasons of practicality, two points are given for age ≥75 years.	2
D	Diabetes mellitus	Diabetes mellitus (type 1 or type 2), as defined by currently accepted criteria,266 or treatment with glucose lowering therapy.	1
S	Prior stroke, TIA, or arterial thromboembolism	Previous thromboembolism is associated with highly elevated risk of recurrence and therefore weighted 2 points.	2
In	Vascular disease	Coronary artery disease, including prior myocardial infarction, angina, history of coronary revascularization (surgical or percutaneous), and significant CAD on angiography or cardiac imaging.267ORPeripheral vascular disease, including: intermittent claudication, previous revascularization for PVD, percutaneous or surgical intervention on the abdominal aorta, and complex aortic plaque on imaging (defined as features of mobility, ulceration, pedunculation, or thickness ≥4 mm).268,269	1
A	Age 65–74 years	1 point is given for age between 65 and 74 years.	1

 

BP, blood pressure; CAD, coronary artery disease; CHA₂DS₂-VA, chronic heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, prior stroke/transient ischaemic attack/arterial thromboembolism (2 points), vascular disease, age 65–74 years; HFmrEF, heart failure with mildly reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; PVD, peripheral vascular disease.

 

^aIn addition to these factors, other markers that modify an individual’s risk for stroke and thromboembolism should be considered, including cancer, chronic kidney disease, ethnicity (black, Hispanic, Asian), biomarkers (troponin and BNP), and in specific groups, atrial enlargement, hyperlipidaemia, smoking, and obesity.

© ESC 2024

Recommendation Table 6: Recommendations to assess and manage thromboembolic risk in AF (see also Evidence Table 6)

284 Hart RG, Pearce LA, Rothbart RM, McAnulty JH, Asinger RW, Halperin JL. Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. Stroke prevention in atrial fibrillation investigators. J Am Coll Cardiol 2000;35:183–7. 10.1016/S0735-1097(99)00489-1
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285 Nieuwlaat R, Dinh T, Olsson SB, Camm AJ, Capucci A, Tieleman RG, et al. Should we abandon the common practice of withholding oral anticoagulation in paroxysmal atrial fibrillation? Eur Heart J 2008;29:915–22. 10.1093/eurheartj/ehn101
Google Scholar  Crossref  PubMed  WorldCat

6.2. Oral anticoagulants

Vitamin K antagonists (VKA), predominantly warfarin but also other coumarin and indandione derivatives, have been the principal drugs to prevent thromboembolic events in the context of AF. As with any anticoagulant, a balance must be reached between preventing thromboembolism and preserving physiological haemostasis, with VKA-associated intracranial and other major haemorrhage the most critical limitation for acceptance of OAC. The global switch to DOACs as first-line therapy has changed this risk–benefit balance, allowing more widespread prescription with no need for routine monitoring (see Supplementary data online, Additional Evidence Tables S5–S7). This component of AF management may see substantive changes in the coming years, with a number of factor XI inhibitors in various stages of clinical evaluation. A phase 2 trial of abelacimab in patients with AF has shown lower rates of bleeding compared with rivaroxaban²⁸⁶; however, a phase 3 trial of asundexian was terminated early due to lack of efficacy against apixaban (NCT05643573), despite favourable phase 2 results.²⁸⁷ Regardless of the type of OAC prescribed, healthcare teams should be aware of the potential for interactions with other drugs, foods, and supplements, and incorporate this information into the education provided to patients and their carers. The list of potential interactions with VKA is broad,^288,289 but there are also some common cardiovascular and non-cardiovascular drugs that interact with DOACs.^290,291  Figure 9 highlights common and major interactions to consider for VKAs and DOACs.

Figure 9: Common drug interactions with oral anticoagulants.

INR, international normalized ratio of prothrombin time; NSAID, non-steroidal anti-inflammatory drug. This figure depicts only common or major interactions and is not an exhaustive list of all potential interactions. Please see the European Medicines Agency website or your local formulary for more information.

Recommendation Table 7: Recommendations for oral anticoagulation in AF (see also Evidence Table 7)

6.2.1. Direct oral anticoagulants

The DOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) have all demonstrated at least non-inferior efficacy compared with warfarin for the prevention of thromboembolism, but with the added benefit of a 50% reduction in intracranial haemorrhage (ICH).^25–28 Meta-analyses of individual data from 71 683 RCT patients showed that standard, full-dose DOAC treatment compared with warfarin reduces the risk of stroke or systemic embolism (HR, 0.81; 95% CI, 0.73–0.91), all-cause mortality (HR, 0.90; 95% CI, 0.85–0.95), and intracranial bleeding (HR, 0.48; 95% CI, 0.39–0.59), with no significant difference in other major bleeding (HR, 0.86; 95% CI, 0.73–1.00) and little or no between-trial heterogeneity.²⁹² Post-marketing observational data on the effectiveness and safety of dabigatran,^313,314 rivaroxaban,^315,316 apixaban,³¹⁷ and edoxaban³¹⁸ vs. warfarin show general consistency with the respective phase 3 RCTs.

For patients undergoing cardioversion, three underpowered trials showed non-significantly lower rates of cardiovascular events with DOACs compared with warfarin.^319–321 In meta-analysis of these 5203 patients predominantly undergoing electrical cardioversion, the composite of stroke, systemic embolism, myocardial infarction (MI), and cardiovascular death was significantly lower at 0.42% in patients randomized to a DOAC vs. 0.98% in those allocated VKA (risk ratio, 0.42; 95% CI, 0.21–0.86; P = .017), with no heterogeneity between trials and no significant difference in major bleeding.²⁹³

Specific patient subgroups show consistent benefit with DOACs vs. VKAs. For heart failure, major thromboembolic events were lower in DOAC-treated patients vs. warfarin in subgroup analysis of landmark RCTs,³²² confirmed in large-scale real-world data.³²³ In a retrospective cohort of patients aged over 80 years, DOAC use was associated with a lower risk of ischaemic stroke, dementia, mortality, and major bleeding than warfarin,³²⁴ but this may be confounded by prescription bias.

Direct oral anticoagulants retain their efficacy and safety over VKAs in patients with mild-to-moderate CKD (creatinine clearance [CrCl] >30 mL/min),³²⁵ although specific dosing adjustments apply.^25–28,326 In Europe, reduced doses of rivaroxaban, apixaban, and edoxaban are approved in patients with severe CKD (CrCl 15–29 mL/min), although limited numbers of patients were included in the major RCTs against VKA.³²⁷ Dabigatran is more dependent on renal elimination and so is contraindicated with an estimated glomerular filtration rate <30 mL/min/1.73 m². Small trials have been performed in patients on haemodialysis, with two finding no difference between apixaban 2.5 mg twice daily and VKA for efficacy or safety outcomes,^328,329 and one trial showing that rivaroxaban 10 mg led to significantly lower rates of cardiovascular events and major bleeding compared with VKA.³³⁰ Careful institution and regular follow-up are advised when instituting anticoagulants in any patient with impaired renal function (See Supplementary data online, Additional Evidence Table 8).³²⁶

Direct oral anticoagulants as a class should be avoided in specific patient groups, such as those with mechanical heart valves or moderate-to-severe mitral stenosis. In patients with mechanical heart valves, an excess of thromboembolic and major bleeding events among patients on dabigatran therapy vs. VKA was observed, with an RCT terminated prematurely.³³¹ A trial of apixaban vs. VKA after implantation of a mechanical aortic valve was also stopped due to excess thromboembolic events in the apixaban group.³³² The restriction on DOAC use does not apply to bioprosthetic heart valves (including mitral) or after transcatheter aortic valve implantation, where DOACs can be used and trial data show non-inferiority for clinical events compared with VKAs.^304,333,334 With regards to mitral stenosis, the DOAC vs. VKA trials excluded patients with moderate-to-severe disease. In 4531 randomized patients with rheumatic heart disease and AF, VKAs led to a lower rate of composite cardiovascular events and death than rivaroxaban, without a higher rate of bleeding.²⁹⁴ Eighty-two per cent of the patients included had a mitral valve area ≤2 cm, supporting the restriction of DOAC use in patients with moderate-to-severe mitral stenosis. Note that patients with other types of valve disease (mitral regurgitation and others) should preferentially be prescribed a DOAC, and the term ‘valvular’ AF is obsolete and should be avoided.

Inappropriate dose reductions for DOACs are frequent in clinical practice,³¹¹ but need to be avoided as they increase the risk of stroke without decreasing bleeding risk.³¹⁰ Hence, DOAC therapy should be instituted according to the standard full dose as tested in phase 3 RCTs and approved by regulators (Table 11). The prescribed dosage should consider the individual patient’s profile.³³⁵ Drug interactions need to be considered in all patients taking or planned for DOACs (see Figure 9 for common drug interactions).³³⁶ There is insufficient evidence currently to advise on routine laboratory testing for DOAC levels. However, in certain situations, measurement of DOAC levels (where available) may be helpful, such as severe bleeding, the need for urgent surgery, or thromboembolic events despite apparent DOAC compliance.^337,338 Patients should always be involved in decision-making on anticoagulation,³³⁹ leading to better alignment with personal preferences that can help to increase understanding and adherence.

Table 11: Recommended doses for direct oral anticoagulant therapy

DOAC	Standard full dose	Criteria for dose reduction	Reduced dose only if criteria met
Apixaban	5 mg twice daily	Two out of three needed for dose reduction: (i) age ≥80 years (ii) body weight ≤60 kg (iii) serum creatinine ≥133 µmol/L.	2.5 mg twice daily
Dabigatran	150 mg twice daily	Dose reduction recommended if any apply: (i) age ≥80 years (ii) receiving concomitant verapamil. Dose reduction considered on an individual basis if any apply: (i) age 75–80 (ii) moderate renal impairment (creatinine clearance 30–50 mL/min) (iii) patients with gastritis, oesophagitis, or gastro-oesophageal reflux (iv) others at increased risk of bleeding.	110 mg twice daily
Edoxaban	60 mg once daily	Dose reduction if any apply: (i) moderate or severe renal impairment (creatinine clearance 15–50 mL/min) (ii) body weight ≤60 kg (iii) concomitant use of ciclosporin, dronedarone, erythromycin, or ketoconazole.	30 mg once daily
Rivaroxaban	20 mg once daily	Creatinine clearance 15–49 mL/min.	15 mg once daily

 

DOAC, direct oral anticoagulant.

 

Dose and dose adjustments are taken from the European Medicines Association Summary of Product Characteristics for each DOAC. There may be other patient-specific reasons for providing a reduced dose, but, in general, the standard full dose should be used to provide optimal prevention of thromboembolism related to AF. Note that antiplatelet agents should be stopped in most patients when commencing a DOAC (see Section 6.3). A number of drug interactions exist with each DOAC and should be taken into consideration (see Figure 9).

© ESC 2024

6.2.2. Vitamin K antagonists

Vitamin K antagonist therapy reduces stroke risk by 64% and mortality by 26% in patients with AF at elevated thromboembolic risk (mostly warfarin in trials, compared with placebo or no treatment).²³⁹ Vitamin K antagonists are still used in many patients worldwide, but prescriptions have declined sharply since the introduction of DOACs.^340,341 Vitamin K antagonists are currently the only treatment option in AF patients with mechanical heart valves or moderate-to-severe mitral valve stenosis.^294,331 The use of VKAs is not only limited by numerous drug and food interactions (Figure 9), but also a narrow therapeutic range. This requires frequent monitoring and dose adjustment according to the prothrombin time expressed as the international normalized ratio (INR).³⁴² If the time in therapeutic range (TTR) is maintained for long periods (e.g. >70% with INR 2.0–3.0), then VKA can be effective for thromboembolic protection with an acceptable safety profile.^{295–297,343} However, VKAs are associated with higher rates of intracranial bleeding,^299,300 and also higher rates of other types of bleeding compared with DOACs.⁸³

In view of the potential safety benefits, switching from VKAs to a DOAC is justified where there are concerns about intracranial bleeding or for patient-choice reasons, and a switch is recommended where patients have failed to maintain an adequate TTR (<70%). This depends on patients fulfilling eligibility criteria for DOACs and should take into account other correctable reasons for poor INR control. There is limited data on switching OAC in older patients (≥75 years) with polypharmacy or other markers of frailty. A recent trial in this patient group prematurely stopped for futility showed that switching from VKAs to DOACs led to a higher primary outcome rate of major or clinically relevant non-major bleeding events compared with continuing with INR-guided VKA (17.8 vs. 10.5 per 100 patient-years, driven by non-major bleeds).³⁰⁹ Hence, in such patients who are clinically stable with good TTR, VKAs may be continued rather than switching to a DOAC after an open discussion with the patient and shared decision-making.

6.2.3. Clinical vs. device-detected subclinical AF

The known benefit of anticoagulation applies to clinical AF. Two RCTs have been published assessing the value of DOAC therapy in device-detected subclinical AF. The ARTESiA trial (Apixaban for the Reduction of Thromboembolism in Patients With Device-Detected Sub-Clinical Atrial Fibrillation) was completed with 4012 patients with device-detected subclinical AF and a mean follow-up of 3.5 years.²⁸² The primary efficacy outcome of stroke or systemic embolism was significantly less in those randomized to apixaban compared with aspirin (HR, 0.63; 95% CI, 0.45–0.88; P = .007). In the intention-to-treat analysis, the primary safety outcome of major bleeding was higher with apixaban (HR, 1.36; 95% CI, 1.01–1.82; P = .04). The NOAH trial (Non-vitamin K Antagonist Oral Anticoagulants in Patients With Atrial High Rate Episodes) was stopped prematurely due to safety concerns and futility for the efficacy of edoxaban, and hence provides limited information.²⁸¹ The analysis of 2536 patients with device-detected atrial high-rate episodes and a median follow-up of 21 months identified no difference in a composite of cardiovascular death, stroke, or embolism comparing edoxaban and placebo (HR, 0.81; 95% CI, 0.60–1.08; P = .15). Those randomized to edoxaban had a higher rate of the composite of death or major bleeding than placebo (HR, 1.31; 95% CI, 1.02–1.67; P = .03). Patients had a low burden of device-detected subclinical AF in both trials (median duration 1.5 h and 2.8 h, respectively), with lower rates of thromboembolism (around 1% per patient-year) than would be expected for an equivalent cohort of patients with clinical AF and a CHA₂DS₂-VASc score of 4.

281 Kirchhof P, Toennis T, Goette A, Camm AJ, Diener HC, Becher N, et al. Anticoagulation with edoxaban in patients with atrial high-rate episodes. N Engl J Med 2023;389:1167–79. 10.1056/NEJMoa2303062
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Considering the trade-off between potential benefit and the risk of major bleeding, this task force concludes that DOAC therapy may be considered in subgroups of patients with asymptomatic device-detected subclinical AF who have high estimated stroke risk and an absence of major bleeding risk factors (see Section 6.7). The duration and burden of subclinical AF that could indicate potential benefit from OAC remains uncertain.³⁴⁴ Regardless of the initial decision on OAC, patients with subclinical AF should receive management and follow-up for all aspects of AF-CARE as the risk of developing clinical AF is high (6%–9% per year).

6.3. Antiplatelet drugs and combinations with anticoagulants

Antiplatelet drugs, such as aspirin and clopidogrel, are not an alternative to OAC. They should not be used for stroke prevention, and can lead to potential harm (especially among elderly patients with AF).^345–347 In ACTIVE W (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events), dual antiplatelet therapy (DAPT) with aspirin and clopidogrel was less effective than warfarin for the prevention of stroke, systemic embolism, MI, or vascular death (annual risk of events 5.6% vs. 3.9%, respectively; P = .0003), with similar rates of major bleeding.³⁴⁸ The AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial demonstrated a lower rate of stroke or systemic embolism with apixaban compared with aspirin (HR, 0.45; 95% CI, 0.32–0.62; P < .001), with no significant difference in major bleeding (there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin).²⁴²

The combination of OAC with antiplatelet agents (especially aspirin) without an adequate indication occurs frequently in clinical practice (see Supplementary data online, Additional Evidence Table S9).^349,350 Bleeding events are more common when antithrombotic agents are combined, and no clear benefit has been observed in terms of prevention of stroke or death.³⁴⁹ In general, combining antiplatelet drugs with anticoagulants (DOACs or VKAs) should only occur in selected patients with acute vascular disease (e.g. acute coronary syndromes; see Section 9.2). The combination of low-dose rivaroxaban (2.5 mg) with aspirin reduced the risk of stroke in patients with chronic vascular disease in a subanalysis of the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial,^351,352 but this cannot be generalized to AF patients because those with an indication for full-dose anticoagulants were excluded.

Recommendation Table 8: Recommendations for combining antiplatelet drugs with anticoagulants for stroke prevention (see also Evidence Table 8)

6.4. Residual ischaemic stroke risk despite anticoagulation

Although OAC significantly reduces the risk of ischaemic stroke in patients with AF, there remains a residual risk.^252,354 One-third of patients with AF presenting with an ischaemic stroke are already on anticoagulation,³⁵⁵ with heterogeneous aetiology.³⁵⁶ This may include non-AF-related competing stroke mechanisms (such as large artery and small vessel diseases), non-adherence to therapy, an inappropriately low dose of anticoagulant, or thromboembolism despite sufficient anticoagulation.³⁵⁷ Laboratory measurement of INR or DOAC levels may contribute to revealing an amenable cause of the stroke. Regardless of anticoagulation status, patients with ischaemic stroke are more likely to have cardiovascular risk factors.³⁵⁸ Many clinicians managing patients with an incident stroke despite taking anticoagulation will be tempted to switch their anticoagulant regimen. While there may be some advantage in switching from VKAs to DOACs for protection against future recurrent ischaemic or haemorrhagic stroke, this task force does not recommend routinely switching from one DOAC to another, or from a DOAC to a VKA, since this has no proven efficacy.^252,356,359 There may be individual reasons for switching, including potential interactions with new drugs; however, there is no consistent data across countries that adherence or efficacy differs between once- and twice-daily approaches.^360,361 Emerging, but observational evidence suggests that switching provides limited reduction in the risk of recurrent ischaemic stroke.^252,356,359 The alternative strategy of adding antiplatelet therapy to OAC may lead to an increased risk of bleeding.^356,359 Aside from thorough attention to underlying risk factors and comorbidities, the approach to management of patients with a stroke despite OAC remains a distinct challenge.

Recommendation Table 9: Recommendations for thromboembolism despite anticoagulation (see also Evidence Table 9)

6.5. Percutaneous left atrial appendage occlusion

Percutaneous left atrial appendage occlusion (LAAO) is a device-based therapy that aims to prevent ischaemic stroke in patients with AF.^362,363 In the VKA era, two RCTs compared warfarin with LAAO using the Watchman device. The 5-year pooled outcomes demonstrated a similar rate of the composite endpoint (cardiovascular or unexplained death, systemic embolism, and stroke) between the LAAO and warfarin arms. Those randomized to LAAO had significantly lower rates of haemorrhagic stroke and all-cause death, but also a 71% non-significant increase in ischaemic stroke and systemic embolism.³⁶⁴ With DOACs demonstrating similar rates of major bleeding to aspirin,²⁴² warfarin in the control arms in these trials is no longer standard of care and hence the place of LAAO in current practice is unclear. The Amulet occluder is an alternative LAAO device which was non-inferior in an RCT to the Watchman device for safety events (procedure-related complications, death, or major bleeding) and thromboembolism.³⁶⁵ In the PRAGUE-17 trial, 402 AF patients were randomized to DOAC or LAAO (Watchman or Amulet), with non-inferiority reported for a broad composite primary endpoint of stroke, TIA, systemic embolism, cardiovascular death, major or non-major clinically relevant bleeding, and procedure/device-related complications.^366,367 Larger trials^368,369 are expected to provide more comprehensive data that can add to the current evidence base (see Supplementary data online, Additional Evidence Table S10).

Pending further RCTs (see Supplementary data online, Table S4), patients with a contraindication to all of the OAC options (the four DOACs and VKAs) have the most appropriate rationale for LAAO implantation, despite the paradox that the need for post-procedure antithrombotic treatment exposes the patient to a bleeding risk that may be equivalent to that of DOACs. Regulatory approvals based on RCT protocols suggest the need for 45 days of VKA plus aspirin after implantation, followed by 6 months of DAPT in patients with no major peri-device leaks, and then ongoing aspirin (see Supplementary data online, Figure S2).^370–372 However, real-world practice is markedly different and also varied. Direct oral anticoagulant administration at full or reduced dose has been proposed as a treatment alternative to warfarin.³⁷³ Observational studies have also supported the use of antiplatelet therapy without associated increases in device-related thrombosis or stroke.^374–376 In a propensity-matched comparison of patients receiving limited early OAC vs. antiplatelet treatment post-Watchman implantation, thromboembolic event rates and bleeding complications were similar.³⁷⁷ While waiting for solid RCT data (NCT03445949, NCT03568890),³⁷⁸ pertinent decisions on antithrombotic treatment are usually made on an individualized basis.^379–381 Prevention of recurrent stroke, in addition to OAC, is another potential indication for LAAO. Only limited data are so far available from registries,³⁸² with ongoing trials expected to provide more insight (NCT03642509, NCT05963698).

Left atrial appendage occlusion device implantation is associated with procedural risk including stroke, major bleeding, device-related thrombus, pericardial effusion, vascular complications, and death.^{362,383–385} Voluntary registries enrolling patients considered ineligible for OAC have reported low peri-procedural risk,^{372,376,386,387} although national registries report in-hospital major adverse event rates of 9.5% in centres performing 5–15 LAAO cases per year, and 5.6% performing 32–211 cases per year (P < .001).³⁸⁸ Registries with new-generation devices report a lower complication rate compared with RCT data.^389,390 Device-related thrombi occur with an incidence of 1.7%–7.2% and are associated with a higher risk of ischaemic stroke.^{386,391–397} Their detection can be documented as late as 1 year post-implantation in one-fifth of patients, thus mandating a late ‘rule-out’ imaging approach.³⁹¹ Likewise, follow-up screening for peri-device leaks is relevant, as small leaks (0–5 mm) are present in ∼25% and have been associated with higher thromboembolic and bleeding events during 1 year follow-up in a large observational registry of one particular device.³⁹⁸

Recommendation Table 10: Recommendations for percutaneous left atrial appendage occlusion (see also Evidence Table 10)

6.6. Surgical left atrial appendage occlusion

Surgical occlusion or exclusion of the left atrial appendage (LAA) can contribute to stroke prevention in patients with AF undergoing cardiac surgery.^399,400 The Left Atrial Appendage Occlusion Study (LAAOS III) randomized 4811 patients with AF to undergo or not undergo LAAO at the time of cardiac surgery for another indication. During a mean of 3.8 years follow-up, ischaemic stroke or systemic embolism occurred in 114 patients (4.8%) in the occlusion group and 168 (7.0%) in the control arm (HR, 0.67; 95% CI, 0.53–0.85; P = .001).⁴⁰¹ The LAAOS III trial did not compare appendage occlusion with anticoagulation (77% of participants continued to receive OAC), and therefore, surgical LAA closure should be considered as an adjunct therapy to prevent thromboembolism in addition to anticoagulation in patients with AF.

There are no RCT data showing a beneficial effect on ischaemic stroke or systemic embolism in patients with AF undergoing LAAO during endoscopic or hybrid AF ablation. A meta-analysis of RCT and observational data showed no differences in stroke prevention or all-cause mortality when comparing LAA clipping during thoracoscopic AF ablation with percutaneous LAAO and catheter ablation.⁴⁰² While the percutaneous LAAO/catheter ablation group showed a higher acute success rate, it was also associated with a higher risk of haemorrhage during the peri-operative period. In an observational study evaluating 222 AF patients undergoing LAA closure using a clipping device as a part of endoscopic or hybrid AF ablation, complete closure was achieved in 95% of patients.⁴⁰³ There were no intra-operative complications, and freedom from a combined endpoint of ischaemic stroke, haemorrhagic stroke, or TIA was 99.1% over 369 patient-years of follow-up. Trials evaluating the beneficial effect of surgical LAA closure in patients undergoing cardiac surgery but without a known history of AF are ongoing (NCT03724318, NCT02701062).⁴⁰⁴

There is a potential advantage for stand-alone epicardial over percutaneous LAA closure in patients with a contraindication for OAC, as there is no need for post-procedure anticoagulation after epicardial closure. Observational data show that stand-alone LAA closure using an epicardial clip is feasible and safe.⁴⁰⁵ A multidisciplinary team approach can facilitate the choice between epicardial or percutaneous LAA closure in such patients.⁴⁰⁶ The majority of safety data and experience in epicardial LAA closure originate from a single clipping device (AtriClip)^403,407,408 (see Supplementary data online, Additional Evidence Table S11).

Recommendation Table 11: Recommendations for surgical left atrial appendage occlusion (see also Evidence Table 11)

6.7. Bleeding risk

6.7.1. Assessment of bleeding risk

When initiating antithrombotic therapy, modifiable bleeding risk factors should be managed to improve safety (Figure 10).^414–418 This includes strict control of hypertension, advice to reduce excess alcohol intake, avoidance of unnecessary antiplatelet or anti-inflammatory agents, and attention to OAC therapy (adherence, control of TTR if on VKAs, and review of interacting medications). Clinicians should consider the balance between stroke and bleeding risk—as factors for both are dynamic and overlapping, they should be re-assessed at each review depending on the individual patient.^419–421 Bleeding risk factors are rarely a reason to withdraw or withhold OAC in eligible patients, as the risk of stroke without anticoagulation often outweighs the risk of major bleeding.^422,423 Patients with non-modifiable risk factors should be reviewed more often, and where appropriate, a multidisciplinary team approach should be instituted to guide management.

Figure 10: Modifying the risk of bleeding associated with OAC.

DOAC, direct oral anticoagulant; GI, gastrointestinal; INR, international normalized ratio of prothrombin time; NSAID, non-steroidal anti-inflammatory drug; OAC, oral anticoagulant; TTR, time in therapeutic range; VKA, vitamin K antagonist. ^aAbsolute contraindications for OAC therapy are rare, and include primary intracranial tumours and intracerebral bleeds related to amyloid angiopathy. In most cases, contraindications may be relative or temporary. Left atrial appendage occlusion can be performed through a percutaneous or endoscopic approach.

Several bleeding risk scores have been developed to account for a wide range of clinical factors (see Supplementary data online, Table S5 and Additional Evidence Tables S12 and S13).⁴²⁴ Systematic reviews and validation studies in external cohorts have shown contrasting results and only modest predictive ability.^{244,425–434} This task force does not recommend a specific bleeding risk score given the uncertainty in accuracy and potential adverse implications of not providing appropriate OAC to those at thromboembolic risk. There are very few absolute contraindications to OAC (especially DOAC therapy). Whereas primary intracranial tumours⁴³⁵ or an intracerebral bleed related to cerebral amyloid angiopathy⁴³⁶ are examples where OAC should be avoided, many other contraindications are relative or temporary. For example, a DOAC can often be safely initiated or re-initiated after acute bleeding has stopped, as long as the source has been fully investigated and managed. Co-prescription of proton pump inhibitors is common in clinical practice for patients receiving OAC that are at high risk of gastrointestinal bleeding. However, the evidence base is limited and not specifically in patients with AF. Whereas observational studies have shown potential benefit from proton pump inhibitors,⁴³⁷ a large RCT in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease found that pantoprazole had no significant impact on upper gastrointestinal bleeding events compared with placebo (HR, 0.88; 95% CI, 0.67–1.15).⁴³⁸ Hence, the use of gastric protection should be individualized for each patient according to the totality of their perceived bleeding risk.

Recommendation Table 12: Recommendations for assessment of bleeding risk (see also Evidence Table 12)

6.7.2. Management of bleeding on anticoagulant therapy

General management of bleeding in patients receiving OAC is outlined in Figure 11. Cause-specific management is beyond the scope of these guidelines, and will depend on the individual circumstances of the patient and the healthcare environment.⁴⁴⁷ Assessment of patients with active bleeding should include confirmation of the bleeding site, bleeding severity, type/dose/timepoint of last anticoagulant intake, concomitant use of other antithrombotic agents, and other factors influencing bleeding risk (renal function, platelet count, and medications such as non-steroidal anti-inflammatories). INR testing and information on recent results are invaluable for patients taking VKAs. Specific coagulation tests for DOACs include diluted thrombin time, ecarin clotting time, ecarin chromogenic assay for dabigatran, and chromogenic anti-factor Xa assay for rivaroxaban, apixaban, and edoxaban.^447–449 Diagnostic and treatment interventions to identify and manage the cause of bleeding (e.g. gastroscopy) should be performed promptly.

Figure 11: Management of oral anticoagulant-related bleeding in patients with AF.

DOAC, direct oral anticoagulant; FFP, fresh frozen plasma; INR, international normalized ratio of prothrombin time; OAC, oral anticoagulant; PCC, prothrombin complex concentrate; VKA, vitamin K antagonist.

In cases of minor bleeding, temporary withdrawal of OAC while the cause is managed is usually sufficient, noting that the reduction in anticoagulant effect is dependent on the INR level for VKAs or the half-life of the particular DOAC.

For major bleeding events in patients taking VKAs, administration of fresh frozen plasma restores coagulation more rapidly than vitamin K, but prothrombin complex concentrates achieve even faster blood coagulation with fewer complications, and so are preferrable to achieve haemostasis.⁴⁵⁰ In DOAC-treated patients where the last DOAC dose was taken within 2–4 h, charcoal administration and/or gastric lavage may reduce further exposure. If the patient is taking dabigatran, idarucizumab can fully reverse its anticoagulant effect and help to achieve haemostasis within 2–4 h in uncontrolled bleeding.⁴⁵¹ Dialysis can also be effective in reducing dabigatran concentration. Andexanet alfa rapidly reverses the activity of factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) (see Supplementary data online, Additional evidence Table S14). An open-label RCT comparing andexanet alfa to usual care in patients presenting with acute ICH within 6 h of symptom onset was stopped early due to improved control of bleeding after 450 patients had been randomized.⁴⁵² As DOAC-specific antidotes are not yet available in all institutions, prothrombin complex concentrates are often used in cases of serious bleeding on factor Xa inhibitors, with evidence limited to observational studies.⁴⁵³

Due to the complexities of managing bleeding in patients taking OAC, it is advisable that each institution develop specific policies involving a multidisciplinary team that includes cardiologists, haematologists, emergency physicians/intensive care specialists, surgeons, and others. It is also important to educate patients taking anticoagulants on the signs and symptoms of bleeding events and to alert their healthcare provider when such events occur.³³⁵

The decision to reinstate OAC will be determined by the severity, cause, and subsequent management of bleeding, preferably by a multidisciplinary team and with close monitoring. Failure to reinstitute OAC after a bleed significantly increases the risk of MI, stroke, and death.⁴⁵⁴ However, if the cause of severe or life-threatening bleeds cannot be treated or reversed, the risk of ongoing bleeding may outweigh the benefit of thromboembolic protection.³³⁵

Recommendation Table 13: Recommendations for management of bleeding in anticoagulated patients (see also Evidence Table 13)