The gray areas of oral anticoagulation for prevention of thromboembolic events in atrial fibrillation patients

Abstract

 

Thromboembolic events (TEE) associated with atrial fibrillation (AF) are highly recurrent and usually severe, causing permanent disability or, even, death. Previous data consistently showed significantly lower TEE in anticoagulated patients. While warfarin, a vitamin K antagonist, is still used worldwide, direct-acting oral anticoagulants (DOACs) have shown noninferiority to warfarin in the prevention of TEE, and represent, to date, the preferred treatment. DOACs present favorable pharmacokinetic, safety and efficacy profiles, especially among vulnerable patients including the elderly, those with renal dysfunction or previous TEE. Yet, regarding specific settings of AF patients it is unclear whether oral anticoagulation therapy is beneficial, or otherwise it is the maintenance of sinus rhythm, mostly achieved through a catheter ablation-based rhythm control strategy, that prevents the causal complications linked to AF. While it is known that low-risk patients [CHA₂DS₂-VASc 0 (males), or score of 1 (females)] present low ischemic stroke or mortality rates (<1%/year), it remains unclear whether they need any prophylaxis. Furthermore, the appropriate anticoagulation regimen for those individuals requiring cardioversion, either pharmacologic or electric, as well as peri-procedural anticoagulation in patients undergoing trans-catheter ablation that nowadays encompasses different energies, are still a matter of debate. In addition, AF concomitant with other clinical conditions is discussed and, lastly, the choice of prescribing anticoagulation to asymptomatic patients diagnosed with subclinical AF at either wearable or implanted devices. The aim of this review will be to provide an update on current strategies in the above-mentioned settings, and to suggest possible therapeutic options, finally focusing on AF-related cognitive decline.

Introduction

Atrial fibrillation (AF) is associated with a five-fold increase in the risk of thromboembolic events (stroke/systemic embolism, TEE). When prescribed in individuals with AF at risk of TEE, oral anticoagulation with either a vitamin K antagonist (VKA) or direct-acting oral anticoagulants (DOACs) is highly effective at preventing an ischemic stroke. Recent appraisals in AF management have delineated four major goals, namely cardiovascular risk reduction, symptoms, functional capacity, and quality of life improvements, as well as cardiac and systemic (including TEE) complications prevention;^1–3 of note, such aims have to be pursued independently by using a chosen rhythm or rate control strategy.⁴

Yet, regarding specific settings of AF patients it is unclear whether oral anticoagulation therapy is beneficial, or otherwise it is the maintenance of sinus rhythm, mostly achieved through a catheter ablation-based rhythm control strategy, that prevents the causal complications linked to AF.⁵ Important progress in understanding AF mechanisms and thrombogenicity reconsiders the role of atrial cardiomyopathy (i.e. atrial structural, architectural, contractile, or electrophysiological changes with potentially relevant clinical manifestations, including dementia).⁶

Clinical classification of atrial cardiomyopathy should be based on the atrial structure, morphology, electrical and mechanical function, and the diagnosis could be based on easily accessible parameters (e.g. etiology, the prothrombotic state, and abnormal left atrial volume/function).⁷ By far the most widely used system for estimating stroke risk in AF is the congestive heart failure, hypertension, age (≥75 years), diabetes, stroke/transient ischemic attack (TIA), vascular disease, age (65–74 years), sex category (female) (CHA₂DS₂-VASc) score, which provides points according to the encountered risk factor in a certain patient; it represents the evolution of the previously released CHADS₂ risk score (congestive heart failure, hypertension, diabetes and stroke/TIA/embolism) mainly for age ≥65 years.^1–3

It has been recently proposed to perform AF ablation in the early stages of the disease for obtaining a progressive amelioration in the incidence of persistent forms or recurrent atrial tachyarrhythmia over 3 years of follow-up than initial use of antiarrhythmic drugs (AAD);⁸ such indication does not affect the decision on continuing oral anticoagulation, as for pharmacological/electrical cardioversion (CV) or spontaneous restoration of sinus rhythm, which has been already established by several studies.^1–3 It should be noted that patient decisional regret in taking oral anticoagulants is still remarkable and has pushed the implementation of a new digital decision aid in a multicenter, randomized, comparative effectiveness trial for TEE prevention.⁹ However, disagreements are still present in multiple aspects of anticoagulation prescription. Therefore, the aim of this review will be to focus on the main topics that are as yet unresolved in the thrombo-prophylaxis universe of patients affected by AF.

Scenario #1: while it is known that low-risk patients [CHA₂DS₂-VASc 0 (males), or score of 1 (females)] present low ischemic stroke or mortality rates (<1%/year), it remains unclear whether they need any prophylaxis.

Because oral anticoagulants increase bleeding risk, their use is generally not recommended for patients at the lowest risk for stroke, with the logical (but not really proven) assumption that the potential risks outweigh the gains in this setting of patients. For patients with one CHA₂DS₂-VASc factor (besides sex category, which is now accepted to constitute a risk modifier, rather than a risk factor per se), the European Society of Cardiology (ESC) and the 2019 focused update of the American Heart Association (AHA), American College of Cardiology (ACC), Heart Rhythm Society (HRS) 2019 guidelines recommend that oral anticoagulation may be considered. The Canadian Cardiovascular Society (CCS) recommends anticoagulation for age ≥65 years and any of the CHADS₂ factors, but not for vascular disease or female sex alone (CHADS-65; essentially the CHA₂DS₂-VASc without vascular disease or female sex). A recent systematic analysis of prothrombotic indices (namely plasma clot permeability, clot lysis time, endogenous thrombin potential, von Willebrand factor, and plasminogen-activator inhibitor-1) has been conducted on 52 patients with a CHA₂DS₂-VASc score of 0 in men or 1 in women and compared with 118 individuals with a CHA₂DS₂-VASc score of 1 in men or 2 in women;¹⁰ the results emphasize the important thrombotic risk associated with age 65–74 years, while they do not suggest a significant prothrombotic predisposition in patients with vascular disease or female sex.

It seems that oral anticoagulation conferred a lower risk of TEE in AF patients who had a single nonsex-based risk factor for stroke,¹¹ but such results have not been confirmed by a Korean registry that found higher TEE in a large low-risk cohort.¹²

The default position is to offer stroke prevention through anticoagulant drugs unless patients are at minimal risk (Table 1).^10–12 These patients with relatively lower risk of stroke are not well represented in pivotal AF trials, and future studies considering potential hypercoagulability states are warranted (Table 2).

Table 1 - Evidence that OAC is beneficial, useful and effective for TEE prevention in AF

General agreement on TEE prevention	LOE
DOACs are recommended in preference to VKAs (excluding patients with mechanical heart valves or moderate-to-severe mitral stenosis)	A
Patient with ‘minimal risk’ (CHA2DS2-VASc score = 0 in men, or 1 in women) should not be offered antithrombotic therapy	A
OAC is recommended in patients with CHA2DS2-VASc score ≥2 in men or ≥3 in women	A
If a VKA is used, a target INR of 2.0–3.0 is recommended, with individual TTR ≥ 70%	B
General agreement on peri-cardioversion management
In patients with AF undergoing cardioversion, DOACs are recommended with similar efficacy and safety as warfarin	A
For cardioversion of AF/AFL, anticoagulation is recommended for a minimum of 3 weeks before cardioversion	B
Transesophageal echocardiography is recommended to exclude cardiac thrombus as an alternative to 3-week preprocedural anticoagulation	B
When thrombus is identified on transesophageal echocardiography, effective anticoagulation is recommended for at least 3 weeks before cardioversion of AF	B
In patients at risk of stroke, it is recommended that OAC therapy is continued long term after cardioversion	B
Recommendations for stroke risk management peri-catheter ablation
Preprocedural management of stroke risk includes initiation of OAC for at least 3 weeks before ablation	C
For patients undergoing AFib catheter ablation who have been therapeutically anticoagulated, performance of the ablation procedure without OAC interruption is recommended	A
Recommendations for stroke risk management after catheter ablation
Systemic anticoagulation with VKA or DOACs is continued for at least 2 months	C
Long-term anticoagulation (>2 months) depends on the patient's stroke risk profile and not on successful/unfavorable procedure ablation	C

AF, atrial fibrillation; AFL, atrial flutter; CHA₂DS₂- VASc, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, sex category (female); DOACs, direct oral anticoagulants; INR, international normalized ratio; LOE, level of evidence; OAC, oral anticoagulation; TEE, thromboembolic events; TTR, time in therapeutic range; VKA, vitamin K antagonists.Adapted from the European Society of Cardiology guideline document – doi: 10.1093/europace/euab065 – ‘2021 European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation’.¹³

Table 2 - Present and future of gray areas in oral anticoagulation

Scenario	Acronym/clinical setting	Current appraisals	Future areas of investigation/possible approach to therapy
#1	♂ CHA2DS2VASc = 0 ♀ CHA2DS2VASc = 1	Overall low stroke risk Benefit of OAC likely outweighed by bleeding	Very low-risk patients with paroxysmal AF and elevated biomarkers of coagulation activity (e.g. factor IXa-antithrombin) might be anticoagulated due to their prethrombotic state
#2	CV	If AF <12 h; AF 12–48 h in low-risk pts = no OAC required If AF >48 h or unknown; AF 12–48 h in high-risk pts = 3 weeks OAC	RCTs designed to address anticoagulation vs. no anticoagulation in AF patients undergoing CV with a definite duration of AF <48 h are lacking
#3	AF ablation	For patients undergoing AF catheter ablation who have been therapeutically anticoagulated with warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban, performance of the ablation procedure without OAC interruption is recommended	RCT-based evidence comparing ‘truly’- and ‘minimally’ interrupted DOACs strategies is unavailable at present Monoclonal antibodies (e.g. abelacimab) and small molecules (e.g. milvexian and asundexian) might provide safer anticoagulation and reduced bleeding by targeting FXI
#4	SCAF/AHREs	Data on optimal management of AHREs and subclinical AF are lacking; asymptomatic episodes >24 h in high TEE risk patients would recommend starting OAC	Close monitoring of the rhythm for early identification of AF, pending the publication of the NOAH-AFNET, and ARTESiA studies
#5	Secondary/reversible AF	Patients who present with adverse features – such as hemodynamic compromise, syncope, myocardial ischemia, or acute pulmonary edema – that are believed to be because of, or exacerbated by AF, the patient should receive urgent CV regardless of the duration of AF or anticoagulation status; all patients who receive emergency CV should be anticoagulated for a minimum of 4 weeks afterwards if no contraindications	Future studies may determine whether increased arrhythmia surveillance or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity
#6	Cognitive decline	Multiple observational trials have shown that catheter ablation is also associated with a lower risk of cognitive decline, dementia and improved cognitive testing that can be explained through a variety of pathways	Long-term, adequately powered randomized trials are required to define the role of catheter ablation in the management of AF to reduce risk of cognitive decline, stroke, and dementia

AF, atrial fibrillation; AHREs, atrial high-rate episodes; CHA₂DS₂-VASc, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, sex category (female); CV, cardioversion; OAC, oral anticoagulation; pts, patients; RCTs, randomized clinical trials; SCAF, subclinical atrial fibrillation; TEE, thromboembolic events.

Scenario #2: the appropriate anticoagulation regimen for those individuals requiring cardioversion, either pharmacologic or electric, is still a matter of debate, as well as its duration.

It is well established clinical practice that patients who present with nonvalvular AF of <48 h in duration should be considered for CV, even in the absence of preexisting anticoagulation.¹³ The risk with more prolonged periods of AF is that restoration of sinus rhythm may precipitate embolism of intra-atrial thrombus causing stroke. After the recommended 3 weeks of therapeutic anticoagulation (Table 2), the stroke risk in elective CV of AF ranges from 0.3% to 0.8%. In the FinCV study,¹⁴ the risk of TEE was 0.7% when CV was performed without anticoagulation within 48 h of AF onset. However, a delay to CV of 12 h or longer from symptom onset was associated with a greater risk of TEE (1.1%). When the duration of AF was less than 12 h, the risk of TEE was low (0.3%) without anticoagulation. Another study from Cleveland Clinic¹⁵ demonstrated the incidence of TEE in parallel groups with and without oral anticoagulation. Among 567 CVs in 484 patients without therapeutic anticoagulation (mean CHA₂DS₂-VASc score, 2.3 ± 1.7), 6 had neurological events (1.06%), all in patients on acetylsalicylic acid (ASA) alone.

Among 898 CVs in 709 patients on therapeutic anticoagulation (mean CHA₂DS₂-VASc score, 2.6 ± 1.7; P = 0.017), 2 neurological events occurred [0.22%; odds ratio (OR): 4.8; P = 0.03], both off anticoagulation at the time of stroke.

No TEE occurred in patients with CHA₂DS₂-VASc score <2 (P = 0.06) or in patients with postoperative AF. Finally, it has been addressed that for determining a true risk–benefit assessment of routine short-term anticoagulation in low-risk patients, the following parameters, which are the low incidence of TEE, the number of patients to be treated to avoid an event, and the side effects of a potential overuse of anticoagulants should be taken into account.¹⁶

In this regard, postprocedural administration of anticoagulants in low-risk patients should be considered as overtreatment. All guidelines have specific recommendations for anticoagulation surrounding CV. For AF >48 h, the three guidelines recommend all patients be anticoagulated for 3 weeks before and 4 weeks after CV. The recommendations vary for patients with AF ≤48 h (Table 3).

Table 3 - List of debated indications about usefulness of oral anticoagulation in AF patients, according to recent ESC guidelines

Recommendations for the prevention of thromboembolic events in AF	LOE
HAS-BLED score should be considered to help address modifiable bleeding risk factors, and to identify patients at high risk of bleeding (HAS-BLED score ≥ 3)	IIa, B
OAC should be considered in patients with a CHA2DS2-VASc score of 1 in men or 2 in women	IIa, B
Long-term OAC therapy to prevent thromboembolic events should be considered in patients at risk for stroke with postoperative AF after noncardiac surgery	IIa, A
Long-term OAC therapy to prevent thromboembolic events may be considered in patients at risk for stroke with postoperative AF after cardiac surgery	IIb, B
Recommendations for stroke risk management peri-cardioversion
Effective anticoagulation should be initiated as soon as possible before every cardioversion of AF or AFL	IIa, B
In patients with AF duration of >24 h undergoing cardioversion, therapeutic anticoagulation should be continued for at least 4 weeks	IIa, B
In patient with a definite duration of AF <24 h and low stroke risk (CHA2DS2-VASc 0 for men and 1 for women) postcardioversion anticoagulation for 4 weeks may be omitted	IIb, C
Recommendations for stroke risk management peri-catheter ablation
In AF patients with stroke risk factors not taking OAC before ablation, it is recommended that preprocedural management of stroke risk includes initiation of anticoagulation and the use of TOE to exclude LA thrombus before ablation	IIa, C

AFib, atrial fibrillation; AFL, atrial flutter; CHA₂DS₂-VASc, congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65–74 years, sex category (female); ESC, European Society of Cardiology; HAS-BLED, hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly (>65 years), drugs/alcohol concomitantly; LA, left atrial; LOE, level of evidence; OAC, oral anticoagulation; TOE, transoesophageal echocardiography.Adapted from the European Society of Cardiology guideline document – doi: 10.1093/europace/euab065 – ‘2021 European Heart Rhythm association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation’.¹³

In 2018, the CCS recommended that the decision to cardiovert be based on the risk of TEE (CHADS₂ <2 vs. ≥2) as well as the duration of AF (episode onset <1–2 h vs. ≥12–48 h).¹

In 2020, the ESC adopted similar recommendations but recommended that risk stratification be based on CHA₂DS₂-VASc.² In contrast, the AHA/ACC/HRS guidelines permit the immediate CV for AF or atrial flutter < 48 h in the absence of oral anticoagulation or transesophageal echocardiography.³ The choice of rhythm control through CV (Fig. 1) should be discussed with patients considering the risks, as well as the benefits deriving from this approach as recently underlined by the EAST-AFNET 4 trial.⁵ When pharmacological CV fails, the physician can then switch to electrical CV. This drug–shock treatment is more effective than electrical CV alone (successful conversion: 96% vs. 92%, respectively).¹⁷ Following CV, the CCS, AHA/ACC/HRS, and the ESC all recommend anticoagulation for at least 4 weeks, although anticoagulation may be optional if the patient is at low risk for stroke (Table 3) with onset of AF <24 h (ESC) or < 48 h (AHA/ACC/HRS), respectively. In this regard, it was suggested that considering the bleeding risk unavoidably conferred by oral anticoagulation, especially in the first month after treatment onset, short-term anticoagulation of early-onset (<48 h) AF in patients with low risk of stroke (CHA₂DS₂-VASc = 0–1) may be omitted.¹⁸

Fig. 1: Rhythm control management and anticoagulation. Cardioversion (either pharmacological or electrical) requirements according to onset of atrial fibrillation, previous thromboembolic events (TEE), and CHA₂DS₂VASc risk score. Black rectangles with continuous line indicate steps toward choice of cardioversion. Red rectangle with dashed line indicates exclusion criteria. Yellow rectangle with dashed line indicates undesired procedure if criteria are present. Green rectangle with dashed line indicates approved procedure if criteria are present. BP, blood pressure; DC, direct current; DOACs, direct-acting oral anticoagulants; LA, left atrium; MV, mitral valve; RVR, rapid ventricular rate.

All guidelines recognize that the quality of evidence regarding post-CV anticoagulation for AF or atrial flutter <48 h is low, thus – despite the relative consensus – the strength of recommendations remains weak. A recent European survey further investigated this gray area of clinical AF management for TEE prevention, reporting heterogeneity in the anticoagulation management both before and post-CV in low stroke risk patients with AF <48 h, mainly due to: a) residual utilization of low-molecular-weight heparin instead of DOACs; b) preferred requirement of transoesophageal echocardiography for electrical CV but not for pharmacological CV; c) high adherence to anticoagulation for 4 weeks after electrical more than after pharmacological CV; d) scarce recommendation of long-term anticoagulation after CV for the early recognized episodes (<24 h) of AF.¹⁹

Scenario #3: peri-procedural anticoagulation in patients undergoing trans-catheter ablation, might require selective adjustments according to the different energy delivered.

Anticoagulation during the peri-procedural period of AF ablation is important given the high inherent risk of stroke under this time window. The major debate in this field focuses on several points, namely uninterrupted anticoagulation use, bridging with heparin, anticoagulation interruption/resumption, and drug switching schemes. Indeed, bridging has been associated with a 4.5-fold increased risk of complications, including major pericardial effusion and major vascular events.

In the COMPARE trial of 1584 cases, interrupted anticoagulation significantly increased TEE risk (4.94% vs. 0.25%, P < 0.001) compared with uninterrupted anticoagulation, while major bleeding complications were nonsignificantly different (0.76% vs. 0.38%), and minor bleeding events were more frequent in the interrupted group (22.0% vs. 4.1%, P < 0.001).²⁰ These results were confirmed by a meta-analysis including 12 studies and 17,434 patients, demonstrating that uninterrupted anticoagulation was associated with lower TEE risk (0.25% vs. 1.21%, P = 0.003), major bleeding (1.44% vs. 2.03%, P = 0.02) and minor bleeding (5.35% vs. 19.6%; P < 0.001) events.²¹ Of note, DOACs have better safety and similar efficacy among patients receiving AF ablation, compared with the uninterrupted warfarin. The management of anticoagulation surrounding AF catheter ablation is important, as trans-septal puncture (TSP) can substantially increase the TEE risk. The CCS guidelines suggested uninterrupted anticoagulation in 2018.¹ The 2020 ESC guidelines were updated to recommend a similar approach.² The 2019 AHA/ACC/HRS guidelines did not specifically discuss anticoagulation surrounding catheter ablation but suggest that bridging decisions should balance the risk of stroke and bleeding.³ These discrepancies may reflect practice differences across healthcare systems and relative risk.

Left atrial catheter ablation is an intervention with a risk of major groin bleedings as well as serious bleeding secondary to TSP and manipulation/ablation in the left atrium (although the incidence of these complications has been decreasing, particularly in experienced centers). On the contrary, the intervention directly increases TEE risk. Recent international consensus statements and guidelines recommend performing left atrial catheter ablation under uninterrupted anticoagulant treatment with VKAs (target international normalized ratio 2.0–2.5), since such a strategy was associated with less TEE and bleedings as compared with bridging with heparin.

The efficacy and safety of uninterrupted DOACs vs. VKA therapy for AF ablation have been examined in dedicated randomized clinical trials (RCTs) for all DOACs (Table 1, bottom lines).

The last dose of once-daily based DOACs were recommended (rivaroxaban) or mandated (edoxaban) to be administered in the evening before the procedure, whereas twice-daily dosed drugs (apixaban, dabigatran) were administered in the morning of the procedure.¹³

Although substantial variations in the event rate in the VKA arm of these trials were observed, major bleedings were overall lower with DOACs without an increase in TEE.

A recent meta-analysis of 25 studies²² confirmed a lower rate of bleeding events with DOACs vs. VKA at a similar TEE rate.

It has been proposed to switch intake to the evening well in advance (e.g. 1 week) of the intervention for the once-daily based DOACs edoxaban and rivaroxaban.

Whether opting to administer the last DOACs dose shortly before the procedure (i.e. ‘truly uninterrupted’) for BID dosed DOACs or to go for a short cessation period (last DOACs dose on the evening before the procedure) may depend on a number of factors including renal function, routine practice is represented by heparin administration prior to TSP, and administration of protamine prior to sheath removal.

Indeed, particularly in the latter case, patients may be exposed to low anticoagulant levels following the procedure if the morning dose is withheld. RCT-based evidence comparing ‘truly’ and ‘minimally’ interrupted DOACs strategies, however, is not available (Table 2).²³

Post procedural re-introduction of DOACs follows current guideline recommendations.^1–3

However, some clinical features might require lifelong anticoagulation; among them, left atrial size was associated with late AF recurrence and TEE.²⁴

To lessen such risk, and to rule out the possibility of nonadherence to anticoagulation from patients at higher risk of complications, individualized interventions such as left atrial appendage occlusion,²⁵ even in conjunction with catheter ablation²⁶ would be somehow beneficial.

Finally, there are emerging energy delivery techniques that probably would require new RCTs for assessing if the timepoints so far elucidated are still the road to be followed. For instance, cryo-balloon ablation (CBA) has been associated with intact tissue ultrastructure and endothelial cell preservation after pulmonary vein isolation (PVI);²⁷ however, PVI (with either CBA or contact force-sensing radiofrequency catheter) has been associated with endothelial damage per se.²⁸ On the other hand, an early study of surgical electroporation devices noted occasional endothelial denudation in veins and arteries located within myocardial lesions, but these vessels remained patent.²⁹

Scenario #4: the choice of prescribing anticoagulation to asymptomatic patients diagnosed with subclinical AF at either wearable or implanted devices requires patient-targeted considerations.

Higher AF-related medical costs justify strategies to identify and treat undiagnosed AF. Opportunistic AF screening is associated with lower costs than systematic screening. Appropriate choice of the screening tool and setting is important, and a favorable cost-effectiveness profile has been estimated for screening programs based on pulse palpation, hand-held ECG devices, and smartphones with pulse photo-plethysmography algorithms.² Both systematic and opportunistic screening are more cost-effective than routine practice for patients aged ≥65 years, with opportunistic screening more likely to be cost-effective than systematic population screening. However, before posing a definite diagnosis of AF that mandates a rhythm/rate therapy as well as TEE prevention, a standard 12-lead ECG recording³⁰ or a single-lead ECG tracing of ≥30 s showing heart rhythm with no discernible repeating P waves and irregular RR intervals (when atrioventricular conduction is not impaired) are the only exams to be considered diagnostic of clinical AF.³¹ Recent guidelines provide a strong recommendation to interrogate dual chamber pacemakers and defibrillators, as well as cardiac resynchronization therapy devices with atrial leads for detecting the occurrence of atrial high-rate episodes (AHREs). From this perspective, two ongoing clinical trials will assess the feasibility of continuous OAC in patients with subclinical AF or AHREs recorded by implanted devices.

The randomized, double-blind, multicenter NOAH-AFNET 6 study evaluates the efficacy of edoxaban compared to ASA or no antithrombotic therapy in preventing stroke, cardiovascular death and TEE after AHREs detection by implanted devices’ recordings in patients >65 years of age and at least one additional risk factor.³² The ARTESiA trial, a prospective, multicenter, double-blind, randomized controlled trial, focuses, instead, on individuals with risk factors for stroke and subclinical AF detected by implanted devices. Randomization is to either apixaban or ASA, with a primary composite end point of stroke, TIA, and TEE during an estimated follow-up of 3 years.³³

On the other hand, a post hoc randomized clinical trial of implantable loop recorder (ILR) screening for AF vs. usual care in individuals aged ≥70 years with risk factors did not find a significant reduction in disabling or lethal stroke; while cardioembolism was relatively rare, observed strokes were ischemic, mostly due to small-vessel disease, and AF detection by ILR was associated with more severe events compared with the undetected ones.³⁴ Current recommendations on AHREs detected by implanted devices are to consider them as innocent bystanders when they are of short duration and occur in patients with low/intermediate TEE risk. On the other hand, AHREs longer than 24 h in high TEE risk patients would recommend starting anticoagulation; in any event, closer follow-up visits for AF development are mandatory. This point has been analyzed in 2133 patients with paroxysmal AF who underwent 14-day-long electrocardiographic assessment, strikingly showing that, when the burden of AF increases, even those low-risk patients may display a considerable stroke risk while the net clinical benefit of anticoagulation is favorable.³⁵

Scenario #5: management of patients with secondary/reversible causes of AF

A Danish nationwide cohort study demonstrated comparative TEE risk in AF with and without a secondary precipitant, such as alcohol intoxication, thyrotoxicosis, myocardial infarction, surgery, and infection in conjunction with AF.³⁶ Other concomitant clinical conditions surrounding the heart including acute pericardial disease, pulmonary embolism, or other acute pulmonary disease have been addressed independently.³⁷ In general, AF with a secondary precipitant was associated with the same risk of TEE as AF without a secondary precipitant, and long-term AF-related stroke and mortality were similar between individuals with and without secondary AF. Future studies may determine whether increased arrhythmia surveillance³⁸ or adherence to general AF management principles in patients with reversible AF precipitants will reduce morbidity (Table 2).

Cognitive decline/vascular dementia as atrial fibrillation-related outcome

AF is associated with an increased risk of dementia, though the mechanisms are not fully elucidated. In addition, AF can lead to silent cerebral ischemias, twice as common in AF compared with sinus rhythm patients.³⁹ These lesions can be found at magnetic resonance imaging and are directly associated with cognitive impairment. AF can also cause microbleeds (Fig. 2), possibly facilitated by anticoagulation treatment, whose presence and number are correlated with a reduced cognitive function.⁴⁰ Some evidence suggests that risk can be blunted with different therapies and approaches.

Fig. 2: Cardiovascular determinants of dementia. The main factors associated with cardioembolic brain damage are reported on the left side. Overall, persistent brain injury can progressively determine critical alterations in both white and gray matters of the brain, which can be hypothesized when patients and/or care givers report some specific symptoms (central square). Oral anticoagulation (OAC), and ablative strategies that prevent thromboembolic events and reduce the impact of atrial fibrillation (AF) on brain perfusion, respectively, can limit the cerebral degeneration depicted from the left to the right side of the figure. BP, blood pressure; Chol, cholesterol; CVD, cardiovascular diseases.

In a large population-based database from the United Kingdom,⁴¹ the increased risk of dementia associated with AF has been recently quantified, demonstrating that anticoagulation produces a trend toward less dementia in patients with AF, but a significant reduction in dementia was only found in those without a history of stroke and TIA.

More recently, it has been supposed that AF catheter ablation might be more effective than pharmacologic rhythm control alone at cutting the risk for dementia. A meta-analysis of five prospective observational studies, comprising more than 60 000 patients, having a median follow-up of 12.5 years indicates a nearly 30% increased risk of dementia, independently from cerebrovascular accidents/TIAs in AF;⁴² similarly, an observational ongoing study⁴³ comprising 20 years of data is probably approaching a 41% reduction (P < 0.0001) in risk for dementia among those who underwent catheter ablation after attempted rhythm control with AAD, compared with those managed with pharmacologic rhythm control therapy alone.

Further studies are warranted to establish whether the invasive arrhythmia management could have an impact on cognitive decline and vascular dementia.⁴⁴

Conclusion

Thromboembolic risk stratification for AF is rapidly evolving, and new data continue to emerge; while clinical CHADS₂ and CHA₂DS₂VASc risk scores are likely to remain a cornerstone of practice due to their ease of calculation, the contemporary cardiovascular professional should be aware of additional risk factors that increase TEE. In the real-world setting, the stroke risk of patients with AF is not static. Increasing age, different blood pressure controls, cardiovascular status, and diabetes would all predispose to TEE (Fig. 2). Thus, a patient without an identified stroke risk factor at baseline may need anticoagulation during follow-up. Baseline risk assessment, even using the CHA₂DS₂-VASc score, may not necessarily relate to stroke risk 5 or 10 years later, and more importantly it has been suggested that overall AF burden may expose more patients to TEE than just the longest episode.

In summary, according to the gray areas above elucidated the diagnostic accuracy of the CHADS₂ and CHA₂DS₂VASc risk scores may not fully resemble the propensity of developing TEE by all patients. One word of caveat about the discussed scenarios is indeed that they do not reflect the global utilization of DOACs; in fact, low penetrance of these drugs has been registered mainly in the Asiatic continent where platelet inhibition is preferred, as opposed to western countries in which DOACs prescription ranges from 52.4% to 79.2%.^45,46 Therefore, while the scientific community is involved in early recognition, perhaps through newer technologies implemented with artificial intelligence,³⁸ and is offering ablative techniques for better rhythm management more quickly and to a broader spectrum of patients, antiplatelet monotherapy is mistakenly considered the antithrombotic choice for several patients: achieving equal access to affordable, high-quality medications should be pursued worldwide and is essential for reducing health disparities, in TEE prevention as well.

Conflicts of interest

There are no conflicts of interest.