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Anticoagulation therapy for stroke prevention
Anticoagulation Therapy for Stroke Prevention

AF treatment

Read time: 60 mins
Last updated:4th May 2023
Published:24th Nov 2021

Individualising atrial fibrillation (AF) treatment helps optimise symptomatic outcomes and reduce stroke risk. Join Professors Robert Story and Renato Lopes to find out more on:

  • The importance of patient consideration in treatment planning
  • The treatment options for atrial fibrillation
  • How the unmet needs in AF are being addressed

Treatment goals in atrial fibrillation

After a patient is diagnosed with atrial fibrillation (AF), the ideal treatment goals include:

  • Restoring the heart to a normal rhythm (called rhythm control)
  • Reducing an overly high heart rate (called rate control)
  • Preventing blood clots (called prevention of thromboembolism such as stroke)
  • Managing risk factors for stroke
  • Preventing additional heart rhythm problems
  • Preventing heart failure

The ESC/EHRA guidelines stress the importance of counselling patients starting AF management to prevent unrealistic expectations and to optimise quality of life1

Broadly, patients and clinicians need to decide between rhythm and rate control. Recent evidence supports early rhythm control for most patients with recently diagnosed AF as well as asymptomatic patients2. Currently, no trial data compares rhythm and rate control as an initial AF treatment. Consensus guidelines suggest restoring sinus rhythm, which may control AF arising from potentially reversible causes or in those patients experiencing an isolated episode3.

If AF recurs, patients who seem especially suitable for rhythm control include3:

  • those who showed a symptomatic improvement during normal sinus rhythm
  • young people
  • those with AF without underlying heart disease
  • patients with substantial symptoms despite control of ventricular rate

Management pathways in atrial fibrillation

Professor Tatjana Potpara, from the School of Medicine, University of Belgrade in Serbia, and co-author of the 2020 ESC guidelines for the diagnosis and management of AF, describes the ABC pathway, a holistic approach to managing patients with AF.

The recent focus of AF treatment has been to streamline patient management pathways and approach AF management in an integrated manner, following the ABC or Atrial fibrillation Better Care Pathway4. This strategy includes: ‘A’ Avoid stroke with anticoagulation; ‘B’ Better symptom care, with patient-centred symptom directed decisions on rate or rhythm control; and ‘C’ Cardiovascular and comorbidity risk management, including attention to risk factors and lifestyle changes (Figure 1).

T3_Stroke_Fig1.png

Figure 1. The ABC pathway for integrated care management in atrial fibrillation (Adapted5). NOAC, non-vitamin K antagonist oral anticoagulants; OAC, oral anticoagulation; TTR, time in therapeutic range; VKA, vitamin K antagonist.

Compliance with the optimised ABC approach optimised care is associated with a significant reduction in mortality and hospitalisations6, and a reduction in healthcare cost associated with cardiovascular events7.

A recent meta-analysis of 285,000 patients treated according to the ABC pathway showed a lower risk of all-cause death (OR, 0.42; 95% CI, 0.31–0.56), cardiovascular death (OR, 0.37; 95% CI, 0.23–0.58), stroke (OR, 0.55; 95% CI, 0.37–0.82) and major bleeding (OR, 0.69; 95% CI, 0.51–0.94). However, in this retrospective study, adherence to the ABC pathway was suboptimal, being adopted only in one in every five patients8. Significant risk reduction was also reported in the GLORIA-AF study9. These results underline the importance of patients’ and healthcare professionals’ education regarding this paradigm shift in treatment management and suggest that a holistic approach is even more needed in those with the highest risk profiles.

‘A’ – Anticoagulation/Avoid stroke

AF increases the risk of stroke five-fold. However, the risk in not homogenous in all patient populations. Decisions about anticoagulation means balancing the benefit of stroke reduction against the risk of haemorrhage using scoring systems.

Before starting anticoagulation, clinicians should use a stratification scheme for stroke and haemorrhage to help balance the risks and benefits3. The ESC/EHRA guidelines recommend the CHA2DS2-VASc (Table 1 and Figure 2) score to predict stroke risk in AF patients.

The C2HEST score (coronary artery disease [CAD] or chronic obstructive pulmonary disease [COPD] - [C2, 1 point each]; hypertension - [H, 1 point]; elderly - [E, age ≥75 years, 2 points]; systolic heart failure - [S, 2 points]; thyroid disease - [T, hyperthyroidism, 1 point]) has a significantly better predictive value than CHA2DS2-VASc score (area under curve [AUC]: 0.881 vs 0.741; P = 0.0017)10.

Table 1. CHA2DS2-VASc scoring system for assessing stroke risk (Adapted3). CHA2DS2-VASc, Congestive heart failure, Hypertension, Age (>65 = 1 point, >75 = 2 points), Diabetes mellitus, Stroke/transient ischemic attack (2 points) Vascular disease (peripheral arterial disease, previous myocardial infarction, aortic atheroma), and Sex category (female gender); CHF, congestive heart failure; TIA, transient ischaemic attack.

Stroke prevention_T3_Table1.png

 

PFI_Stroke_T3_Fig2.png

Figure 2. Risk of stroke and haemorrhage based on the CHA2DS2-VASc (maximum 9 points) and HAS-BLED (maximum 7 points) scoring system (Adapted3). CHA2DS2-VASc, Congestive heart failure, Hypertension, Age (>65 = 1 point, >75 = 2 points), Diabetes mellitus, Stroke/transient ischemic attack (2 points) Vascular disease (peripheral arterial disease, previous myocardial infarction, aortic atheroma), and Sex category (female gender); HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly.

In addition, clinicians should use a bleeding risk stratification scheme, such as HAS-BLED (Figure 2 and Table 2) to assess haemorrhage risk and identify risk factors for major bleeding in people taking anticoagulants (Table 3). Biomarkers, such as high-sensitivity troponin and natriuretic peptide, can help further assess the risk of stroke and bleeding risk in AF1.

Among Asian patients with non-valvular AF, new-model– COOL-AF predictive models for all-cause mortality, ischaemic stroke/systemic embolism and major bleeding has shown a good predictive ability. The COOL-AF model for all-cause mortality was found superior to the GARFIELD Refitted and CHA2DS2-VASc model11.

Table 2. HAS-BLED scoring system for assessing haemorrhage risk (Adapted1). HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol concomitantly.

Stroke prevention_T3_Table2.png

Table 3. Risk factors for haemorrhage in patients taking anticoagulants (Adapted1,12). AF, atrial fibrillation; CHF, congestive heart failure.

Stroke prevention_T3_Table3.png

‘B’ – Better symptom control

Rate control is an integral part of AF management, and pharmacological control is often sufficient to improve AF-related symptoms.

Beta-blockers, diltiazem, or verapamil are recommended as first-choice drugs to control heart rate in AF patients with left ventricular ejection fraction (LVEF) ≥ 40%1,13, while beta-blockers and/or digoxin are recommended to control heart rate in AF patients with LVEF < 40%1.

‘C’ – Cardiovascular risk factors and concomitant diseases

The ‘C’ component of the ABC pathway includes identification and management of concomitant diseases, cardiometabolic risk factors, and unhealthy lifestyle factors. Management of risk factors and cardiovascular disease complements stroke prevention and reduces AF burden and symptom severity.

The latest recommendations from the ESC regarding lifestyle interventions and management of risk factors in patients with AF are1:

  • Identification and management of risk factors and concomitant diseases is recommended as an integral part of AF treatment
  • Modification of unhealthy lifestyle and targeted therapy of intercurrent conditions is recommended to reduce AF burden and symptom severity
  • Opportunistic screening for AF is recommended in hypertensive patients
  • Attention to good blood pressure control is recommended in AF patients with hypertension to reduce AF recurring and risk of stroke and bleeding

Integrated management of patients with atrial fibrillation

The new approach to an integrated management of AF patients put the patients at the centre and requires a coordinated and agreed patient-individualised care pathway to deliver optimised treatment by an interdisciplinary team (Figure 3).

T3_Stroke_FigX.png

Figure 3. Example of an integrated atrial fibrillation management interdisciplinary team (Adapted1). The figure gives an example on the potential composition of AF teams showing a variety of different specialists supporting individual patients as needed. AF, atrial fibrillation.

The 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS) introduced changes in the recommendations about integrated AF management1. Specifically, they recommend that, to optimise shared decision making about specific AF treatment options physicians should inform the patient about advantages/limitations and benefit/risks associated with considered treatment options and discuss the potential burden of the treatment with the patient, including the patient’s perception of treatment burden in the treatment decision.

Preventing blood clots using anticoagulants

In this video, Professor Tatjana Potpara from the School of Medicine, University of Belgrade in Serbia, and co-author of the 2020 ESC guidelines for the diagnosis and management of AF, elaborates on the recommendations for oral anticoagulant therapy for stroke prevention in patients with atrial fibrillation (AF).

The ‘A’ in the ABC approach to patient management for atrial fibrillation (AF) refers to ‘avoiding stroke with anticoagulation’. Most AF patients, other than those at very low stroke risk, should receive anticoagulants.

Anticoagulation is an important aspect of management to reduce the risk of ischaemic stroke in all AF patients1,14

The coagulation cascade (Figure 4) refers to a series of enzymatic reactions that begins when damage to the endothelium of a blood vessel exposes circulating platelets to collagen in the wall, and plasma factor VII/VIIa to extravascular tissue factor. Other proteins (including von Willebrand factor) help platelets bind to the damaged vessel wall. The complex between tissue factor VIIa – the ‘extrinsic pathway’ – activates the coagulation cascade15.

PFI_Stroke_T3_Fig4.png

Figure 4. The coagulation cascade showing the intrinsic and extrinsic pathways (Adapted16).

Thrombus development depends on additional platelets and amplification of the coagulation cascade by the intrinsic pathway, which includes factors VIII and IX. Platelets amplify the coagulation cascade by providing a surface that stimulates thrombosis15. Thrombin (factor II) promotes platelet activation. In turn, platelet activation facilitates further thrombin generation. Thrombin also activates multiple factors in the coagulation cascade, including production of fibrinogen from fibrin, which stabilises the thrombus15,16.

Anticoagulants act on critical steps in the cascade to prevent thrombus formation. This Learning Zone introduces the two classes of anticoagulants used in AF management: vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs). The ESC/EHRA guidelines recommend that most AF patients, other than those at very low stroke risk, should receive anticoagulants1.

Warfarin

Warfarin’s clinical use as an anticoagulant dates back to 195417. Warfarin, acenocoumarol and dicoumarol interfere with all the coagulation factors that depend on vitamin K16,18. So, vitamin K antagonists reduce levels of several coagulation factors (II [prothrombin], VII, IV and X) and thrombotic factors (protein C, S and Z)16,18. This diversity of action, combined with marked variations in warfarin metabolism, makes predicting the articulatory effect of a dose of warfarin difficult16,18.

Using warfarin to maintain an international normalised ratio (INR) target range of two to three reduces the risk of recurrent stroke by 64% in AF patients (from 23% to 9%)19. In a study that followed patients for five years after experiencing an AF-related stroke, warfarin reduced mortality by 60%20. Warfarin remains the anticoagulant of choice for AF related to metallic prosthetic heart valves and mitral stenosis, and for patients with non-valvular AF and severe renal dysfunction21

Warfarin can, however, prove difficult to use clinically. For instance, the INR needs to remain within the target range. An INR more than three is associated with an increased risk of haemorrhage. An INR less than two is associated with an increased risk of thrombotic events. Maintaining patients in the target INR range of two to three is often difficult: AF patients taking warfarin may be outside the target range for almost 50–65% of the time16,17. Two-thirds of the remainder have INRs below two predisposing to thromboembolism. A third are above three, increasing the risk of haemorrhage16.

Numerous factors potentially influence warfarin metabolism, including drug- and food-interactions, alcohol intake and genetic polymorphisms. As a result, individual warfarin doses vary widely between patients and within the same person, ranging from 0.5 mg/day to more than 20 mg/day17. So, people taking warfarin require frequent monitoring and adherence can be poor22.

Warfarin’s side effects

Warfarin commonly causes bleeding: the rates of major and fatal bleeding are 7.2 and 1.3 per 100 patient years respectively17

The absolute risk of developing warfarin-related intracranial haemorrhage is small compared with the benefits arising from avoiding strokes. Nevertheless, the risk of major bleeding complications are more than double in patients with poor INR control, especially those older than 75 years23. Warfarin’s other side-effects include skin necrosis, hair loss and even venous limb gangrene17.

Warfarin’s pharmacokinetics can also make the drug difficult to use in clinical practice. Warfarin, for example, has a slow onset of action21. Furthermore, the biologically inactive clotting factors need to degrade before normal coagulation returns, which can take several days. As a result, warfarin’s half-life is approximately 40 hours16.

Direct oral anticoagulants (DOACs)

Nomenclature

Direct oral anticoagulants (DOACs) are also known as non-vitamin K antagonist oral anticoagulants or novel oral anticoagulants (NOACs) and include apixaban, dabigatran, edoxaban and rivaroxaban

We will refer to DOACs, as there is a possibility that a healthcare professional might mistake NOAC for ‘no anticoagulants’ with potentially serious or even life-threatening consequences24

For eligible AF patients, the ESC/EHRA guidelines recommend a DOAC in preference to warfarin or another vitamin K antagonist. The guidelines also recommend DOACs rather than a vitamin K antagonist or aspirin in AF patients who experienced a previous stroke. However, the guidelines do not recommend DOACs for patients with mechanical heart valves or moderate-to-severe mitral stenosis, where warfarin is the preferred oral anticoagulant1.

In contrast to warfarin, DOACs are highly specific and show a relatively high affinity for a single enzyme in the coagulation cascade18. Apixaban, edoxaban and rivaroxaban directly inhibit factor Xa, thereby disrupting the intrinsic and the extrinsic pathways and preventing thrombin formation15,19. Dabigatran etexilate directly inhibits thrombin16.

DOACs bind to the active site of the enzymes involved in the coagulation cascade and so compete with the normal substrates. Importantly, DOACs do not completely inhibit the enzyme, which means a strong procoagulant stimulus can overcome the anticoagulant effect18. This property might explain why the risk of intracranial haemorrhage seems to be lower with some DOACs than with warfarin. The brain is rich in tissue factor, a potent stimulus for coagulation. Exposure of blood to brain tissues could, therefore, overcome DOAC inhibition18.

Pharmacokinetics and pharmacodynamics of DOACs

The relationship between DOAC levels and standard measures of anticoagulation, such as the INR and activated partial thromboplastin time and drug levels is non-linear. Therefore, these measures do not help determine anticoagulation efficacy and routine monitoring is not required21

The pharmacokinetics of DOACs differ markedly from those of warfarin. DOACs have more consistent and predictable dose-response and time to reach steady state than warfarin, for example. The actions of DOACs depend on the plasma concentration rather than the synthesis of clotting factors. Therefore, the onset of action with DOACs is more rapid than with warfarin, achieving full anticoagulation within 1–2 hours of dosing16,21.

The half-lives of apixaban (9–14 hours), dabigatran (12–17 hours), edoxaban (10–14 hours) and rivaroxaban (7–11 hours) are shorter than that of warfarin16,25. Also, the offset of action is more rapid than with warfarin: most of the anticoagulation effect has disappeared within 24 hours of the last dose21. Moreover, DOACs show minimal interactions with diet. However, clinicians should recommend that patients take rivaroxaban and dabigatran with food to ensure optimal uptake and reduce the risk of dyspepsia respectively21.

A better understanding of the PK/PD of DOACs in older adults, who account for nearly half of all DOAC users, is required to ensure appropriate treatment. DOAC exposure in older adults may have high interindividual variability because of the distinctive characteristics of the elderly. Although there appears to be no effect of age on edoxaban, rivaroxaban, or dabigatran exposure, peak concentrations of apixaban were 40% higher in older adults than in young volunteers. Evidence indicate dabigatran had the highest interindividual variability of any DOAC, and because its dose adjustment criterion is only age, it is not a preferred option. Furthermore, DOAC exposure outside of on-therapy ranges was significantly associated with stroke and bleeding events26.

Obesity may have a minor impact on the PK/PD of dabigatran, apixaban, or rivaroxaban, according to a recent literature review. Although dabigatran may raise the risk of gastrointestinal bleeding, it proved beneficial in AF patients with morbid obesity. Apixaban or rivaroxaban standard dosage is efficient and secure for VTE and AF patients with morbid obesity27.

Efficacy of DOACs

As mentioned above, using warfarin to maintain an INR target range of 2–3 reduces the risk of recurrent stroke by 64% in AF patients19. DOACs further reduce recurrent stroke and systemic embolism by 14% compared with warfarin in non-valvular AF (from 6% to 5%), without increasing the risk of major bleeding19. When evaluating these results, it is important to bear in mind that most of the original clinical trials comparing warfarin with DOACs were non-inferiority, rather than superiority, studies28.

While the studies investigated the risk of haemorrhage extensively, the definition of bleeding differed. Therefore, comparing the haemorrhage risk with the different DOACs is difficult. Nevertheless, the risk of haemorrhage was consistently comparable to or less than with warfarin21. Moreover, 30-day mortality after a major bleeding episode was 13% with warfarin and 9% with a DOAC (dabigatran)29.

A meta-analysis included 13 randomised controlled trials (RCT) and 27 observational studies, 32 involving AF patients and 8 people with venous thromboembolism. Overall, the results from the RCTs were consistent with the observational studies and showed that DOAC showed similar or superior efficacy and effectiveness to warfarin22

Some differences emerged between the DOACs. For example, in AF patients, apixaban, dabigatran and edoxaban – but not rivaroxaban – were associated with a 10% to 71% decreased risk of major bleeding, myocardial infarction, haemorrhagic stroke, all-cause mortality, and intracerebral haemorrhage compared with warfarin (Figure 5)21. A recent prospective observational study revealed that clinical events in patients with AF treated with rivaroxaban were comparable with PIONEER-AF trial30.

PFI_Stroke_T3_Fig5.png

Figure 5. Results of a meta-analysis showing the effectiveness of DOAC in atrial fibrillation and venous thromboembolism (Adapted22). bid, twice a day.

The choice of DOAC depends on several factors, including hepatic and renal function, potential for drug interactions, patient preference, cost and tolerability21

The choice of DOAC should be well considered21. For example, 15–20% of patients with CKD have AF1. Renal function might influence the choice of DOAC: 85% of a dose of dabigatran is excreted unchanged in urine, compared with 27% and 33% of a dose of apixaban and rivaroxaban, respectively. Indeed, warfarin remains the anticoagulant of choice for patients with non-valvular AF and severe renal dysfunction21. In addition, the risk of gastrointestinal bleeding may be higher with rivaroxaban, edoxaban and dabigatran compared with warfarin29.

In a large multinational population-based study (France, Germany, the United Kingdom, and the United States) of 527 226 new DOAC users, when compared to dabigatran, edoxaban, and rivaroxaban, apixaban use was associated with a lower risk of GIB and comparable rates of ischemic stroke or systemic embolism, ICH, and all-cause mortality in patients with AF. This finding held true for patients aged ≥80, as well as those with CKD, who are frequently underrepresented in clinical trials31. Further, when compared to warfarin/LMWH, DOACs greatly decrease the likelihood of bleeding in patients with different severity of liver disease. In comparison to warfarin, DOACs were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding. However, the incidence of clinical outcomes in patients with AF and chronic liver disease varied between individual DOACs and warfarin, as well as between DOACs in head-to-head comparisons32. Moderate/severe anaemia is a risk factor for serious GI bleeding in AF patients receiving DOACs, whereas stroke risk is the same whether or not anaemia was present at baseline33.

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DOACs in valvular atrial fibrillation 

AF worsens the prognosis of people with severe valvular disease1. However, DOACs are generally indicated for non-valvular AF, which denotes patients without rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves1. These patients were excluded from the RCTs28,34. Nevertheless, in most studies of DOACs, about 20% of enrolled patients had valvular defects, including mild mitral stenosis, mitral regurgitation, aortic stenosis, aortic regurgitation and tricuspid regurgitation14. DOACs are effective in people with native valvular AF, producing similar reductions in stroke, systemic embolism and intracranial haemorrhage compared with warfarin in people with and without valvular AF14. Also, DOACs  may be an effective and safe alternative to VKA in patients with AF after surgically implanted bioprosthetic heart valves or repair with AF35.

DOACs in non-valvular atrial fibrillation

A recent systematic review and meta-analysis of real-world evidence compared warfarin and DOACs for non-valvular atrial fibrillation (NVAF) patients, including more than 2 million patients36. NOACs effectively reduced the stroke risk compared to warfarin (HR 0.77; 95% CI, 0.69–0.87; P<0.01). Moreover, NOACs effectively lowered all-cause mortality risk (HR 0.71; 95% CI, 0.63–0.81; P<0.01). From the safety aspect, compared to warfarin, NOACs significantly reduced major bleeding risk (HR 0.68; 95% CI, 0.54–0.86; P<0.01) and intracranial bleeding risk (HR 0.54; 95% CI, 0.42–0.70; P<0.01). These results demonstrated that NOACs had more efficacy than warfarin in preventing stroke in NVAF patients. NOACs were also related to a lower risk of all-cause mortality, intracranial bleeding, and major bleeding and lower medical costs than warfarin. Among NOACs, apixaban and edoxaban might have a better safety and efficacy profile compared to warfarin. According to updated meta-analysis of 37 RCTs, apixaban had the lowest degree of major GI risk among standard-dose DOACs. Among low-dose DOACs, edoxaban was associated with a lower risk of major GI bleeding than rivaroxaban37. A recent systematic review and meta-analysis of real-world studies (46 studies) sows that apixaban is associated with a lower risk of GIH when compared to dabigatran, rivaroxaban, and VKA, whereas rivaroxaban is associated with a higher risk of GIH when compared to both dabigatran and VKA38. Dabigatran appears to be associated with GI bleedings more frequently than other DOACs as per analysis of spontaneous pharmacovigilance reports from EudraVigilance between 2012-201739. Similarly, rivaroxaban and apixaban were found to have better safety profiles than dabigatran in an five year (2017-2021) analysis of the Italian National Pharmacovigilance Network, with rivaroxaban causing statistical significant fewer overall ICH events than apixaban40. However, review of large-scaled post-marketing surveillance studies in Japan indicated increased major bleeding incidence in AF patients with apixaban, more likely due to dose reduction criteria41.

DOACs in valvular heart disease

A meta-analysis of four RCTs encompassed 71,526 AF patients, including 13,574 with valvular heart disease.

Compared with warfarin, DOACs reduced the risk of stroke or systemic embolism by 30% and 16% in those with and without valvular heart disease respectively28

No significant difference in mortality emerged in patients with valvular heart disease but declined by 18% in those without valvular disease. Neither group showed a significant difference in the rate of major bleeds. However, the risk of intracranial haemorrhage was 53% and 51% lower compared with warfarin in those with and without valvular disease respectively28.

DOACs in atrial fibrillation with ACS and/or PCI

There has been debate about the optimal anticoagulation therapy in patients with AF in the setting of ACS or PCI, a population known to have increased risk of bleeding and ischaemic complications42,43.

Professor Robert Storey from the University of Sheffield (UK) highlights the unmet needs and evolving treatment landscape for patients with AF and ACS.

Current ESC guidelines on myocardial revascularisation recommend either triple therapy with aspirin, antiplatelet medication clopidogrel (a platelet P2Y12 inhibitor) and an oral anticoagulant for at least one month (and up to six months in patients with greater ischaemic vs. bleeding risk) or dual therapy with antiplatelet and oral anticoagulant medications (in patients with greater bleeding vs. ischaemic risk)1,44. Updated guidelines and expert consensus documents in Europe and the United States are relatively consistent in terms of antithrombotic therapy recommendations in patients with AF undergoing PCI (Figure 6).

T3_Stroke_Fig6.png

Figure 6: Antithrombotic therapy duration varies according to guidelines (Adapted)45. CS, acute coronary syndrome; AF, atrial fibrillation; CCS, chronic coronary syndrome; DAT, dual-antithrombotic therapy; OAC, oral anticoagulant; TAT, triple-antithrombotic therapy.

There is agreement that in the absence of contraindications, a DOAC is preferred over a vitamin K antagonist46. Indeed, the RE-DUAL PCI trial recently showed that in patients with and without ACS, dual therapy with 110 mg and 150 mg dabigatran reduced bleeding risks compared with warfarin therapy in patients with AF after PCI7. The ENTRUST-AF PCI trial is also ongoing to compare the risk of bleeding complications after PCI treatment with the DOAC edoxaban vs. vitamin K antagonists plus dual antiplatelet therapy47.

Professor Renato Lopes from Duke University Medical Centre (USA) introduces the ENTRUST study.

While the strategy of dropping aspirin to reduce risk of bleeding complications in the presence of other anticoagulant drugs has recently emerged, it wasn’t known whether this would also be preferable in patients with AF and ACS and/or PCI until the recent AUGUSTUS study48. AUGUSTUS was an open-label, randomised controlled trial to evaluate the safety of the DOAC apixaban vs. vitamin K antagonist and aspirin vs. aspirin placebo in this patient population49.

AUGUSTUS included 4,614 patients from 33 countries with AF who had a recent ACS and/or underwent PCI, all of them on an antiplatelet medication with a six month follow up. The primary (safety) outcome was major bleeding and secondary outcomes included death or hospitalisation and a composite of ischaemic events. The protocol allowed two hypotheses to be investigated49:

  • Whether the DOAC apixaban (5 mg or 2.5 mg twice daily) was non-inferior or superior to vitamin K antagonist at reducing bleeding events
  • Whether aspirin was inferior to placebo for reducing bleeding in patients on DOAC treatment

Primary outcomes49:

  • In the anticoagulant-regimen comparison, a bleeding event was observed in 10.5% of patients treated with apixaban, compared with 14.7% of patients receiving a vitamin K antagonist, resulting in an event rate per 100 patient-years significantly lower among patients receiving apixaban (HR 0.69; 95% CI, 0.58–0.81). This met the criteria for both non-inferiority and superiority (P<0.001)
  • In the antiplatelet-regimen comparison, a bleeding event was observed in 16.1% of patients receiving aspirin, compared with 9.0% of patients receiving placebo (HR 1.89; 95% CI, 1.59–2.24; P<0.001)

Secondary outcomes49:

  • Patients in the apixaban group had a lower incidence of death or hospitalisation than those in the vitamin K antagonist group: 23.5% vs. 27.4% (HR 0.83; 95% CI, 0.74–0.93; P=0.002), but no difference in death or hospitalisation at 6 months was noted between patients receiving aspirin and those receiving placebo
  • At 6 months, there were no differences with regards to death or ischaemic events (myocardial infarction, definite or probable stent thrombosis, stroke, or urgent revascularisation) in the apixaban or vitamin K antagonist groups (154 vs. 163 events, respectively) or in the aspirin or placebo groups (149 vs. 168 events, respectively)

The authors concluded that in this patient population, an antithrombotic treatment regime that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalisations49.

Further, a meta-analysis of four trials of antithrombotic treatment in patients with AF, ACS and/or PCI (including AUGUSTUS) confirmed that a regimen of a DOAC plus antiplatelet medication was associated with less bleeding compared with vitamin K antagonists plus dual antiplatelet therapy and that omitting aspirin caused less bleeding50.

DOACs in atrial fibrillation with CKD

Chronic kidney disease (CKD) and AF often coexist. CKD is a prothrombotic and prohaemorrhagic condition regardless of AF and, in this context, AF might accelerate CKD progression.

In patients with CKD, the risk of stroke, systemic thromboembolism (TE) and myocardial infarction (MI) is higher than in AF patients with no renal disease. A Danish study found that AF patients with non-end-stage CKD or end-stage CKD had an increased risk of stroke/TE of 50% and 83%, respectively, compared to patients without renal disease51.

Since all DOACs are dependent on renal clearance while VKAs such as warfarin are cleared mainly by the liver52, there have been concerns regarding DOAC efficacy and safety in CKD patients. However, several clinical trials and real-world studies have now shown that DOACs are as effective and safe as VKA in AF patients with CKD51. In a meta-analysis of 19 studies (RCTs and non-RCTs) of AF patients with CKD, DOACs, especially apixaban and edoxaban, demonstrated improved efficacy and safety than warfarin. For patients with advanced CKD, apixaban was associated with the lowest risk of major bleeding among OACs53. The AXADIA-AFNET 8 randomized trial has shown similar safety profile and composite and individual rates of all-cause mortality; major bleeding; and myocardial infarction between apixaban and VKA in patients with AF on haemodialysis54. Recently findings from CODE-AF registry have shown DOAC was associated with a lower risk of major or CRNM bleeding compared to warfarin and a lower risk of composite adverse clinical outcomes compared to no OAC in AF patients with advanced CKD or ESRD on dialysis55.  Furthermore, indirect comparisons showed that high-dose apixaban and edoxaban might be more likely associated with a better net clinical profile in AF patients with moderate CKD56.

DOACs in atrial fibrillation with cancer 

Atrial fibrillation (AF) is an increasingly common codiagnosis in cancer patients. A recent nationwide analysis from the Austrian patients found that patients with hematologic malignancies had the highest risk of AF, with a relative risk of 9.15. A recent meta-analysis of 23 studies (non-RCTs) has shown that AF is not uncommon in patients with breast cancer and vice versa57. Patients with AF have more complicated clinical histories due to cancer, which mostly raises the risk of bleeding58. Clinical guidelines recommend DOAC over warfarin to treat isolated nonvalvular atrial fibrillation; however, there are no guidance on nonvalvular atrial fibrillation treatment in cancer patients59. In a large retrospective study, DOACs were associated with similar risks of stroke, systemic embolism, and major bleeding in older adults with cancer and AF as warfarin. DOAC use was associated with a similar risk of cardiovascular death and a lower risk of all-cause death when compared to warfarin60.

DOACs in atrial fibrillation in the elderly

The prevalence of AF increases with age and age is an independent risk factor for adverse outcome in AF. Oral anticoagulation is associated with a net clinical benefit in elderly patients despite their elevated bleeding risk, and the 2020 European Society of Cardiology (ESC) guidelines for the management of AF recommend DOACs for stroke prevention over vitamin K antagonists, without age restrictions1. A study conducted in Norway showed that, in patients ≥75 years initiating oral anticoagulation for AF, standard and reduced dose DOACs were associated with similar risks of stroke/TE as warfarin and lower or similar risks of bleeding. Therefore, the DOACs appear to be a safe option also in elderly patients61.

Switching antithrombotic medications is common in the elderly AF population. Importantly, switching to treatment recommended by guidelines improves both effectiveness and safety62. Furthermore, systemic embolism, major bleeding, intracranial haemorrhage, and cardiovascular death appear to be lower with DOACs than with warfarin63.

More on US and European guidelines for managing atrial fibrillation

Heart rate control in atrial fibrillation

Heart rate control is only suitable for some atrial fibrillation (AF) patients; this section suggests when heart rate control may be appropriate.

Antiarrhythmic drugs (AADs) are not routinely used for asymptomatic AF or by people with permanent AF who did not undergo rhythm control1,3. AADs also have important contraindications and cause dose-limiting adverse events. Nevertheless, AADs can re-establish normal heart rate and left ventricular function in AF patients with cardiomyopathy and may increase the likelihood of successful electrical cardioversion if initial attempts were unsuccessful3.

The choice of AAD for ventricular rate control depends on the patient’s lifestyle and comorbidities64. The ESC/EHRA guidelines recommend beta-blockers, digoxin or the calcium channel blockers diltiazem or verapamil to control heart rate in AF patients with left ventricular ejection fraction (LVEF) of at least 40%; with combination therapy if a single dose drug does not achieve target heart rate (Table 4). The guidelines recommend beta-blockers with or without digoxin in AF patients with LVEF less than 40%. Amiodarone may be appropriate for acute rate control in patients with haemodynamic instability or severely depressed LVEF1.

Table 4. ESC/EHRA 2020 recommendations for long-term ventricular rate control in atrial fibrillation patients (Adapted1). AF, atrial fibrillation; BPM, beats per minute; ECG, electrocardiogram; ESC, European Society of Cardiology; LVEF, left ventricular ejection fraction.

aCombining beta-blocker with verapamil or dilitiazem should be performed with careful monitoring of heart rate by 24-h ECG to check for bradycardia.
Recommendations Class Level
Beta-blockers, diltiazem, or verapamil are recommended as first-choice drugs to control heart rate in AF patients with LVEF ≥40%. I B
Beta-blockers and/or digoxin are recommended to control heart rate in AF patients with LVEF <40%. I B
Combination therapy comprising different rate controlling drugsa should be considered if a single drug does not achieve the target heart rate. IIa B
A resting heart rate of <110 bpm (i.e. lenient rate control) should be considered as the initial heart rate target for rate control therapy. IIa B

Figure 7 depicts a proposed algorithm for rate and rhythm control in patients who are acutely, critically ill, or postoperatively developing a new episode of AF. 

T3_Stroke_Fig8.png

Figure 7: An  algorithm for controlling rate and rhythm in acute, critically ill, or postoperative patients is proposed. Electrical cardioversion should be attempted if acute rate control is ineffective (dotted line) (Adapted)65. Ad: amiodarone; BB: beta-blockers; Dx: Digoxin/Digitoxin. *Anticoagulation following guideline recommendation. **ABC: Atrial Fibrillation Better Care algorithm.

Heart rate targets

The ESC/EHRA 2020 guidelines suggest a resting heart rate of less than 110 beats per minute as the initial heart rate target for rate control therapy. If a single AAD does not adequately reduce heart rate, the guidelines suggest combination therapy1

More on US and European guidelines for managing atrial fibrillation

Electrical cardioversion in atrial fibrillation

Electrical cardioversion is a cornerstone of atrial fibrillation (AF) care, but patients still need effective anticoagulation and pretreatment. 

Initially, many AF patients require ventricular rate control to reduce the risk that tachycardia will cause cardiomyopathy and CHF, even if the patient does not show left ventricular systolic dysfunction3. Nevertheless, 20–30% of AF patients show left ventricular dysfunction1. Patients with emergent AF and haemodynamic instability because of very rapid ventricular rates or structural heart disease may need urgent cardioversion with one or more shocks with direct electrical current producing 200 to 300 joules to restore sinus rhythm64,66. The electric shock synchronises with the QRS complex, which avoid triggering ventricular fibrillation66.

Elective electrical cardioversion (defibrillation) is the treatment of choice for AF associated with haemodynamic instability. In other cases of symptomatic persistent or long-standing persistent AF, patient and physician influence the choice between pharmacological and electrical cardioversion1.

External cardioversions were also found to be safe and clinically important changes in device function were rare in patients with contemporary pacemakers and implantable cardioverter-defibrillators67.  

The ESC/EHRA guidelines advocate pre-treatment with amiodarone, flecainide, ibutilide or propafenone before electrical cardioversion.

Recent systematic review and network meta-analysis of RCTs (n=28) comparing the anti-arrhythmic drugs (AADs) in patients with AF undergoing electrical cardioversion demonstrated improved restoration of sinus rhythm with Class III AADs (OR, 2.41; 95% credible interval (CrI): 1.37 to 4.62, high certainty) and amiodarone (OR: 2.58; 95% CrI: 1.54 to 4.37, high certainty) compared to no treatment or rate control68. 

Another review (45 RCTs and 16 observational studies) suggests applying biphasic waveforms, high-energy (≥200 J ) shocks, and manual pressure increase the likelihood of sinus rhythm conversion following AF69. 

Meta-analysis of data from 10 RCTs shows that there was no difference in the rate of cardioversion between the anterior-posterior versus anterior-lateral electrode positioning during cardioversion in patients with AF at low energy, or the number of delivered shocks or mean energy of the delivered shocks70.

Pharmacological cardioversion in atrial fibrillation

Find out which patients may be more suitable for pharmacological than electrical cardioversion.

In recent onset atrial fibrillation (AF) (Figure 8), the ESC/EHRA 2020 guidelines recommend rhythm control to improve symptoms and quality of life in symptomatic patients with AF. Rhythm control is the preferred strategy in elderly aged <65 years and during pregnancy2 (Figure 9). Clinicians should also manage cardiovascular risk factors and help patients avoid AF triggers to facilitate sinus rhythm control1.

PFI_Stroke_Fig15.png

Figure 8. Rhythm control of recent onset atrial fibrillation (Adapted1). AF, atrial fibrillation; HFmrEF, heart failure with mid-range ejection fraction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LVH, left ventricular hypertrophy.

T3_Stroke_Fig10.png

Figure 9.  Recommendations for rhythm management in patients with nonpermanent AF (Adapted)2. AF, atrial fibrillation; LA, left atrium. 

Among patients with hemodynamically stable new onset AF, there was no difference of the electrical cardioversion only approach over the pharmacological cardioversion method with or without electrical cardioversion regarding the success rate of conversion to the sinus rhythm71. 

For patients with new onset AF, a paradigm shift towards rhythm control rather than rate control is taking place2.

For patients with new onset AF who do not have a history of ischaemic or structural heart disease, flecainide, propafenone or vernakalant are options for pharmacological cardioversion. Some patients with infrequent symptomatic paroxysmal AF can self-administer a single bolus of oral flecainide or propafenone at home to restore sinus rhythm, once the treatment’s safety is established in hospital1.

Ibutilide is another option for pharmacological cardioversion in AF, provided patients do not have a history of ischaemic or structural heart disease. The ESC/EHRA 2020 guidelines recommend amiodarone in patients with ischaemic or structural heart disease or both. Vernakalant offers an alternative to amiodarone, provided patients do not have hypotension, severe heart failure or severe structural heart disease, in particular aortic stenosis1.

For new onset AF in critically unwell patients, Amiodarone seems more effective than diltiazem at cardioversion. Short-acting -antagonists esmolol and landiolol were more likely effective for cardioversion than diltiazem72.

Sub analyses of the EAST-AFNET4 study has shown that systematic early rhythm control (ERC- AAD, catheter ablation, or cardioversion) therapy reduces cardiovascular complications in patients with a high comorbidity burden, as defined by a CHA2DS2-VASc score 4 compared to usual therapy. ERC also improves these patients' quality of life. However, the risk/benefit of ERC may be unfavourable in patients with fewer comorbidities. Future ERC safety may be increased by avoiding bradycardia and medication toxicity73.

Long-term antiarrhythmic drugs (AADs)

The choice of AAD for long-term maintenance of sinus rhythm and to prevent recurrent AF needs to account for comorbidities, cardiovascular risk factors, the potential for serious pro-arrhythmia and extra-cardiac toxic effects, patient preferences and symptom burden. For instance, amiodarone is more effective in preventing AF recurrences than other AAD74, but extra-cardiac toxic effects are common and increase with the duration of treatment. As a result, the guidelines suggest considering other AADs before using amiodarone1.

The ESC/EHRA 2020 guidelines suggest (Figure 10)1:

  • dronedarone, flecainide, propafenone or sotalol to prevent recurrent symptomatic AF in patients with normal left ventricular function and without pathological left ventricular hypertrophy
  • dronedarone to prevent recurrent symptomatic AF in patients with stable coronary artery disease and without congestive heart failure (CHF)
  • amiodarone to prevent recurrent symptomatic AF in CHF patients
  • clinicians should periodically evaluate the AAD to confirm patients’ eligibility

PFI_Stroke_T3_Fig7.png

Figure 10. Initiation of long-term rhythm control in symptomatic atrial fibrillation patients (Adapted1). AF, atrial fibrillation; LVH, left ventricular hypertrophy.

ECG recording during the initiation of an AAD should be considered to monitor heart rate, detect QRS and QT interval prolongation and AV block. The guidelines do not recommend AADs in people with a QT interval of more than 0.5 seconds or those with significant node disease or atrioventricular node dysfunction who do not have a functioning permanent pacemaker. If the patient does not want to undergo ablation or the approach is not indicated, clinicians could consider adding atrial-based bradycardia pacing to drug treatment that induces or exacerbates sinus node dysfunction to allow AAD treatment to continue. If recurrences seem likely, AAD could be considered following AF ablation to maintain sinus rhythm1.

Some non-AAD drugs have antiarrhythmic effects1. As previously mentioned, the renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of some cases of AF3. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), both of which modulate this system, as well as beta-blockers may prevent new-onset AF in patients with CHF and reduced ejection fraction. ACE inhibitors and ARBs may also prevent of new-onset AF in patients with hypertension, particularly when associated with left ventricular hypertrophy. ACE inhibitors and ARBs are not recommended for the secondary prevention of paroxysmal AF in patients with little or no underlying heart disease1.

Electrical cardioversion is indicated if an AF episode is poorly tolerated from a hemodynamic standpoint. Otherwise, sinus rhythm can be restored with intravenous pharmacological cardioversion, and an antiarrhythmic of class I or class III is taken orally to prevent recurrences75.

Invasive treatment for atrial fibrillation

Invasive treatments offer an option when drugs are contraindicated, poorly tolerated or not fully effective. The ESC/EHRA 2020 guidelines, for instance, suggest considering atrioventricular node ablation to control heart rate in patients unresponsive or intolerant to intensive rate and rhythm control therapy. These patients will, however, become pacemaker dependent1

Excision of the left atrial appendage

As discussed, at least 90% of the emboli that cause atrial fibrillation (AF)-related strokes arise in the left atrial appendage (LAA)76. So, surgical excision or occlusion of the LAA may be an option for some patients, especially those undergoing cardiac surgery for another indication2. Recent technological advances, such as percutaneous and intracardiac devices, make closing the LAA easier and are, therefore, more effective than conventional surgery2.

LAA thrombi were associated with a significantly lower 10-year survival probability (31% versus 69%). Advanced structural heart disease, inflammation, diabetes, and impaired renal function all contribute to LAA thrombus formation. Younger age, non-permanent AF, and faster LAA flow velocities were all associated with thrombus resolution77. So, surgical excision or occlusion of the LAA may be an option for some patients, especially those undergoing cardiac surgery for another indication3. Recent technological advances, such as percutaneous and intracardiac devices, make closing the LAA easier and are, therefore, more effective than conventional surgery3.

LAA excision had no significant effect on the risk of stroke or systemic embolism during a 2.7 year follow up compared to the control group (1.75% and 1.87% per year respectively)18. So, the ESC/EHRA 2020 guidelines suggest that patients at risk of stroke should continue anticoagulation following LAA occlusion or exclusion1. The guidelines recommend considering LAA occlusion for stroke prevention in AF patients with contra-indications for long-term anticoagulants, such as those with a history of life-threatening bleeds without a reversible cause and those undergoing cardiac surgery or thoracoscopic AF surgery1.

Catheter ablation

Pulmonary veins are the most common ectopic site that triggers paroxysmal AF. Catheter ablation uses radiofrequency ablation or cryothermy balloon catheters to create lesions that encircle the pulmonary vein, producing a non-conducting scar. As a result, aberrant electrical activity cannot spread to the atrium1,3. Catheter ablation is a first-line alternative to AAD to prevent recurrent AF and to improve symptoms in some patients with symptomatic paroxysmal AF based on patient preference and the balance of risks and benefits1.

Catheter ablation is generally more effective in patients with paroxysmal AF than in those with more advanced disease, which is usually associated with significant structural heart disease3. A single catheter ablation shows a long-term success rate of 54% and 42% in paroxysmal and non-paroxysmal AF respectively78. Some patients with paroxysmal AF require repeated catheter ablations1. Also, patients with heart failure with preserved ejection fraction and mildly reduced ejection fraction (may benefit from cryoballoon ablation with significant heart failure improvement and high sinus rhythm maintenance79.

Complications of catheter ablation

Catheter ablation is associated with complications, some of which may be life-threatening, including periprocedural death (less than 0.2% of catheter ablations), oesophageal perforation or fistula (less than 0.5%) and periprocedural stroke, TIA or air embolism (less than 1%)1

Other possible complications of catheter ablation include cardiac tamponade (1–2%), pulmonary vein stenosis (less than 1%), persistent phrenic nerve palsy (1–2%), vascular complications (2–4%) and asymptomatic cerebral embolism (5–20%)1. The clinical significance of asymptomatic cerebral embolism is unknown1.

When to consider catheter ablation

The ESC/EHRA 2020 guidelines suggest catheter ablation of paroxysmal AF in patients who have symptomatic recurrences while taking AADs and who need further rhythm control. Catheter or surgical ablation is also an option to improve symptoms in persistent or long-standing persistent AF that is refractory to AADs1.

Professor John Camm of the University of London (UK) describes when catheter ablation is an appropriate option for patients.

Catheter ablation (Figure 11) is an option for people with symptomatic AF, CHF and suspected tachycardiomyopathy with reduced ejection fraction to improve symptoms and cardiac function. Catheter ablation can also prevent recurrence of common (typical) atrial flutter if documented or observed during the procedure and may avoid pacemaker implantation in patients with AF-related bradycardia1.

PFI_Stroke_T3_Fig 8.png

Figure 11. Catheter ablation offers a potential treatment for some symptomatic atrial fibrillation patients (Adapted1).

Oral anticoagulation should continue for at least 8 weeks after catheter or surgical ablation and indefinitely in high-risk patients, even if the procedure appears to have restored sinus rhythm. Patients can continue warfarin or direct oral anticoagulants (DOAC) during catheter ablation to maintain effective anticoagulation1.

Surgical ablation

Surgical ablation may be appropriate for patients undergoing open chest cardiac surgery for other indications, such as valve repair or replacement, or coronary artery bypass grafting3. During the Maze procedure, for example, the surgeon makes numerous incisions in the atrium, forming lines of scar tissue. This blocks electrical conduction and so attenuates the abnormal activity underlining AF22. The success of the Maze procedure varies between centres. Typically, however, 80–90% of patients are free from AF for a year following the Maze procedure. The minimally invasive Cox-Maze technique uses cryotherapy, radiofrequency or high-intensity focused ultrasound to create linear scars in the atrium22.

When to consider surgery for atrial fibrillation

The ESC/EHRA 2020 guidelines suggest considering minimally invasive surgery with epicardial pulmonary vein isolation in patients with symptomatic AF after catheter ablation fails. Maze surgery, possibly using a minimally invasive technique, is an option for symptomatic and refractory persistent AF or AF that persists after ablation to improve symptoms1.

The guidelines also suggest considering maze surgery, preferably on both atria, for patients undergoing cardiac surgery to improve AF symptoms. Clinicians should balance the added risk of the procedure against the benefit of rhythm control therapy. Surgeons could also consider maze surgery on both atria or pulmonary vein isolation in asymptomatic AF patients who are undergoing cardiac surgery for another indication1.

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