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Anticoagulation Therapy for Stroke Prevention

AF treatment

Read time: 60 mins
Last updated:16th Jun 2022
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 QoL1.

Broadly, patients and clinicians need to decide between rhythm and rate control. Currently, no trial data compares rhythm and rate control as an initial AF treatment. However, consensus guidelines suggest restoring sinus rhythm, which may control AF arising from potentially reversible causes or in those patients experiencing an isolated episode2.

If AF recurs, patients who seem especially suitable for rhythm control include2:

  • 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

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 Pathway3. 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 (Adapted4). 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 hospitalisations5, and a reduction in healthcare cost associated with cardiovascular events6.

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 patients7. 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 benefits2. The ESC/EHRA guidelines recommend the CHA2DS2-VASc (Table 1 and Figure 2) score to predict stroke risk in AF patients.

Table 1. CHA2DS2-VASc scoring system for assessing stroke risk (Adapted2). 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 (Adapted2). 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.

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Preventing blood clots using anticoagulants

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 patients1,10

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 cascade11.

PFI_Stroke_T3_Fig4.png

Figure 4. The coagulation cascade showing the intrinsic and extrinsic pathways (Adapted12).

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 thrombosis11. 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 thrombus11,12.

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 195413. Warfarin, acenocoumarol and dicoumarol interfere with all the coagulation factors that depend on vitamin K12,14. So, vitamin K antagonists reduce levels of several coagulation factors (II [prothrombin], VII, IV and X) and thrombotic factors (protein C, S and Z)12,14. This diversity of action, combined with marked variations in warfarin metabolism, makes predicting the articulatory effect of a dose of warfarin difficult12,14.

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%)15. In a study that followed patients for five years after experiencing an AF-related stroke, warfarin reduced mortality by 60%16. 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 dysfunction17

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 time12,13. Two-thirds of the remainder have INRs below two predisposing to thromboembolism. A third are above three, increasing the risk of haemorrhage12.

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/day13. So, people taking warfarin require frequent monitoring and adherence can be poor18.

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 respectively13

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 years19. Warfarin’s other side-effects include skin necrosis, hair loss and even venous limb gangrene13.

Warfarin’s pharmacokinetics can also make the drug difficult to use in clinical practice. Warfarin, for example, has a slow onset of action17. 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 hours12.

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 consequences20

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 cascade14. Apixaban, edoxaban and rivaroxaban directly inhibit factor Xa, thereby disrupting the intrinsic and the extrinsic pathways and preventing thrombin formation12,15. Dabigatran etexilate directly inhibits thrombin12.

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 effect14. 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 inhibition14.

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 required17

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 dosing12,17.

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 warfarin12,21. Also, the offset of action is more rapid than with warfarin: most of the anticoagulation effect has disappeared within 24 hours of the last dose17. 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 respectively17.

Efficacy of DOACs

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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 control1,2. 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 unsuccessful2.

The choice of AAD for ventricular rate control depends on the patient’s lifestyle and comorbidities38. 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.

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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 dysfunction2. 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 rhythm38,39. The electric shock synchronises with the QRS complex, which avoid triggering ventricular fibrillation39.

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

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

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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 6), 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 during pregnancy. Clinicians should also manage cardiovascular risk factors and help patients avoid AF triggers to facilitate sinus rhythm control1.

PFI_Stroke_Fig15.png

Figure 6. 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.

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.

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 AAD, 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 7)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
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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)40. 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 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)15. 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 atrium1,2. 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 disease2. A single catheter ablation shows a long-term success rate of 54% and 42% in paroxysmal and non-paroxysmal AF respectively40. Some patients with paroxysmal AF require repeated catheter ablations1.

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

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References

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