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New trial data prompt update of the ESC guideline on AF

Dr Irene Savelieva (left) and Professor John Camm discuss the European Society of Cardiology guideline on atrial fibrillation and risk stratification and management strategies

Atrial fibrillation (AF) is the most commonly sustained arrhythmia, with an incidence of 3.1 cases in men and 1.9 cases in women per 1000 person-years in individuals aged under 64 years of age, rising to 19.2 cases per 1000 person-years in those aged 65–74 years, and as high as 31.4–38.0 cases in octogenarians.1 A rise in the proportion of the older population with improved survival from previously fatal cardiovascular conditions, and a recently observed trend towards a continuous increase in the incidence of AF at younger ages, are likely to result in a considerable increase in the number of patients with AF over the next four decades. This prediction is based on less recent and conservative estimates from the Framingham Study in the US and the Rotterdam Study in Europe, which put the lifetime risk for development of AF at one in four for individuals aged 40 years and older.2,3

A recent report from Scotland published in the British Journal of Cardiology has revealed that over the 5-year period from 2004 to 2008, hospitalisations for AF increased by 33% compared with 20% for all cardiovascular causes.4 The total number of AF-related patient bed days also increased by 15%, with a longer mean duration of inpatient stay than for other cardiovascular conditions (10.9 vs 8.7 days). The consensus conference of the Royal College of Physicians of Edinburgh called for a national programme to screen for AF in individuals aged over 65 years.5 The Atrial Fibrillation Association, an influential charity for patients with AF, launched the campaign ‘1 million 1 mission’ in order to secure 1 million pledges worldwide, in a bid to increase awareness of AF-related stroke.6 As the Deputy Editor of the British Medical Journal pointed out in his editorial, ‘Suddenly ... atrial fibrillation is ... everywhere.’7

It was only 2 years ago that the Task Force Committee on AF of the European Society of Cardiology (ESC) released a new set of recommendations on arrhythmia management,8 but shortly after its publication, the Committee believed that rapidly accumulating evidence for novel and more effective therapies for AF demanded an update. The 2012 focused update of the guideline incorporated the results of several large-scale randomised controlled trials and registries, and developed more comprehensive recommendations for the management of AF. The update covered several areas:9

  • risk stratification for stroke and bleeding
  • use of novel oral anticoagulants
  • left atrial appendage occlusion
  • pharmacological cardioversion (vernakalant)
  • oral antiarrhythmic therapy (dronedarone)
  • left atrial catheter ablation.

The strength of recommendation of particular treatment options are graded, as outlined in Table 1.

Table 1: Classes of recommendations9
Classes of recommendations Definition Suggested wording to use
Class I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective Is recommended/is indicated
Class II Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure
Class IIa
Weight of evidence/opinion is in favour of usefulness/efficacy Should be considered
Class IIb
Usefulness/efficacy is less well established by evidence/opinion May be considered
Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful Is not recommended
Camm A, Lip G, De Caterina R et al. Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33: 2719–2747, by permission of Oxford University Press.

Screening for AF

The updated ESC guideline on AF advocates the need for early and proactive diagnosis of the arrhythmia, which includes opportunistic screening of individuals aged 65 years and over for the presence of AF (recommendation class I).9 Many cases of AF in the community may remain unrecognised because of the absence of symptoms in patients and a lack of awareness in GPs; and essential life-saving treatment, for example, oral anticoagulation with warfarin, may not be administered until a devastating complication of AF, such as stroke, has occurred. It has been estimated that asymptomatic or silent AF may be present in up to 40%–60% of these patients.10 Data from the Framingham Study revealed that at least 25% of patients presenting with acute ischaemic stroke have undiagnosed AF.11 Opportunistic screening during GP visits for unrelated issues is crucial in identifying such individuals in the community, and initiating appropriate antithrombotic prophylaxis.


New trial data prompt update of the ESC guideline on AF continued

Assessment of risk of stroke and bleeding

Predictably, stratification of risk in the prevention of stroke occupied a significant part of the 2012 focused update. Over the past few years, the medical community embraced the CHADS2 score, mainly because of its simplicity and clinical relevance;12 one point is assigned to each of the following: Congestive heart failure (or left ventricular systolic dysfunction), Hypertension, Age 75 years and older, and Diabetes, and 2 points are assigned to previous Stroke or a transient ischaemic attack (TIA). However, the CHADS2 score offers a relatively crude estimation of risk and may render a non-negligible proportion of patients as ‘low-risk’, resulting in unjustified withholding of anticoagulation.

The 2012 focused update of the ESC guideline advocates use of the CHA2DS2-VASc score (see Table 2), which emphasises the significance of older age—2 points are assigned for people aged 75 years or older and 1 point for those aged 65 to 74 years. It also includes atherosclerotic disease in the coronary, aortic, and peripheral arterial circulation as a risk factor (1 point); and acknowledgement of female gender as a contributor to risk (1 point), but only if other components of the stratification system are present.8,9 The annual rates of stroke are under 1% for patients with a CHA2DS2-VASc score of 0 and 1%–2% in those with a CHA2DS2-VASc score of 1, but increase progressively to 4%–9% for patients with scores 2–4 and to 15%–20% for those with higher scores.13 In contrast to CHADS2, the CHA2DS2-VASc score identifies more at-risk patients and prompts anticoagulation therapy in a greater number of cases. Therefore, the ESC guideline recommends that the latter score is used to assess stroke risk in non-valvular AF.9

The 2010 ESC guideline on AF also introduced a HAS-BLED score for assessment of bleeding risk. A score of ≥3 is considered as high risk (~4% per year; see Table 3).8,9,14 It is, however, important, that the HAS-BLED score is not used to deter anticoagulation, but to modify risk factors, such as uncontrolled hypertension; guide the anticoagulation strategy with regard to the choice of an antithrombotic agent and dose; institute more intense follow up; and offer patient education on bleeding risks and ways to avoid them.

Because of low efficacy and the appreciable bleeding risk with aspirin, the ESC guideline does not encourage its use for prevention of stroke in patients with AF, unless they refuse any form of anticoagulation,15 in which case dual antiplatelet therapy with aspirin and clopidogrel or, less effectively, aspirin alone, can be considered as a last resort.

Table 2: CHA2DS2-VASc score8
Risk factor
Score (points)
Congestive heart failure/left ventricular dysfunction
1
Hypertension
1
Age &g3; 75 years
2
Diabetes mellitus
1
Stroke/transient ischaemic attack thromboembolism
2
Vascular disease*
1
Age 65–74 years
1
Sex category (i.e. female sex)
1
Maximum score is 9 since age may contribute 0, 1, or 2 points.

*Prior myocardial infarction, peripheral artery disease, aortic plaque

Camm A, Kirchhof P, Lip G et al. Guidelines for the management of atrial fibrillation: the Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC).
Eur Heart J 2010; 31: 2369–2429, by permission of Oxford University Press.
Table 3: HAS-BLED bleeding risk score8
Clinical characteristic
Points awarded
H
Hypertension (SBP >160 mmHg)
1
A
Abnormal renal and liver function
(1 point each)
1 or 2
S
Stroke
1
B
Previous bleeding history or predisposition to bleeding
1
L
Labile INRs
1
E
Elderly—age >65 years
1
D
Drugs* or alcohol abuse
1 or 2
Maximum 9 points
*Includes aspirin and non-steroidal anti-inflammatory agents SBP=systolic blood pressure; INR=international normalised ratio
Camm A, Kirchhof P, Lip G et al. Guidelines for the management of atrial fibrillation: the Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429, by permission of Oxford University Press.

New trial data prompt update of the ESC guideline on AF continued

New oral anticoagulants

For many years, warfarin has been the mainstream therapy for stroke prevention in AF, but several new oral anticoagulant drugs have recently become licensed or will soon become available. These include a direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors, rivaroxaban and apixaban, all of which have been granted European regulatory approval. A large randomised controlled trial on a fourth agent, edoxaban, is nearing completion (see Table 4).15–21Compared with warfarin, these new drugs:22

  • have greater specificity (single versus multiple targets within the clotting cascade)
  • have a more rapid onset of action (time to peak concentration: 2–4 hours versus 72–96 hours)
  • have shorter half-lives (5–17 hours versus 40 hours)
  • have considerably fewer interactions with other drugs
  • have no food interactions or need for dietary restrictions
  • are more predictable in pharmacokinetic terms than warfarin
  • can be administered at fixed doses without the requirement for anticoagulation monitoring.

Compared with warfarin, the novel oral anticoagulant drugs have been shown to reduce the occurrence of stroke or systemic embolism by 20%–22%, any stroke by ~23%, ischaemic or unidentified stroke by 13%, haemorrhagic stroke and intracranial haemorrhage by 50%–55%, major bleeding by ~13%, and all-cause mortality by ~12%.23,24 In other words, they are more effective, safe, and convenient than warfarin. On these grounds, the updated ESC guideline recommends that any of the three new oral anticoagulants should be considered instead of warfarin in most patients with AF who should receive oral anticoagulation (recommendation class of IIa; see Figure 1).9

However, the use of these new anticoagulants is not without caveats. Firstly, their anticoagulant activity cannot be reversed, and no antidote is available (currently in development).9 If bleeding occurs during therapy, the drug should be discontinued and standard supportive treatment, such as mechanical compression, surgical haemostasis, blood volume replacement, and blood products, should be initiated as appropriate. Activated charcoal can be given by mouth if dabigatran has been taken within the last 4–6 hours.9 Prothrombin complex concentrate can be administered to partially reverse anticoagulant activity,9 and because of its low protein binding, dabigatran can be dialysed.

Secondly, because of the potential for reduced elimination and increased plasma drug levels in patients with renal impairment, the new anticoagulants should be used with caution in patients with abnormal renal function. It is advised that renal function is assessed in all patients prior to therapy and periodically during therapy.9 A reduced drug dose is recommended for patients with creatinine clearance of 30–49 ml/min; use of the new anticoagulants in people with creatinine clearance below 30 ml/min is not recommended by the ESC guideline.9

Finally, the new oral anticoagulant drugs cannot be used in patients with valvular disease, usually defined as significant mitral stenosis and prosthetic mechanical valves.9 There is also no consensus on the management of patients taking new anticoagulants should they require cardioversion or intervention, including ablation for AF, or if they develop acute coronary syndrome.

Patient adherence to long-term therapy with the novel oral anticoagulants, some of which need be taken twice daily, is important, and patient education on the effects and side-effects of these agents is crucial. Unlike warfarin, the new anticoagulants do not require monitoring, and some physicians may feel uneasy about the lack of laboratory testing. The latter may sometimes be needed to assess patient compliance with treatment or to detect anticoagulant activity if the patient requires surgery or intervention. Several laboratory tests are available to assess the effect of new anticoagulants. For example, the prothrombin time appears to be sensitive to the presence of rivaroxaban and apixaban, whereas the ecarin clotting time (ECT), or activated partial thromboplastin time if ECT cannot be analysed, can be used to determine the activity of dabigatran. However, these tests can only indicate the presence of such drugs, but not the exact anticoagulant activity.


New trial data prompt update of the ESC guideline on AF continued

Table 4: Clinical trials of new oral anticoagulants for atrial fibrillation15-21
Drug Action Phase III trial Comparator Design n Status Approval
Dabigatran Direct thrombin inhibitor RE-LY Warfarin Non-inferiority 18,113 Completed Approved by EMA and FDA
Rivaroxaban Factor Xa inhibitor ROCKET-AF Warfarin Non-inferiority 14,264 Completed Approved by EMA and FDA
Apixaban Factor Xa inhibitor AVERROES Aspirin Superiority 5599 Completed Approved by EMA and FDA
ARISTOTLE Warfarin Non-inferiority 18,201 Completed
Edoxaban Factor Xa inhibitor ENGAGE-AF Warfarin Non-inferiority ~20,500 Ongoing Not applicable
Biotinylated idraparinux Anti Xa BOREALIS-AF Warfarin Non-inferiority 9600 Stopped Not applicable
Tecarfarin Vitamin K antagonist EMBRACE-AC Warfarin Superiority 612 Completed Not applicable
Other factor Xa inhibitors include: betrixaban (EXPLORE-Xa), darexaban (OPAL-1), and AZD0837
EMA=European Medicines Agency; FDA=Food and Drug Administration

Figure 1: Choice of anticoagulant9

graph

Colour: CHA2DS2-VASc; blue=1, red=≥2
Line: solid=best option; dashed=alternative option
*Includes rheumatic valvular disease and prosthetic valves
†Antiplatelet therapy with aspirin plus clopidogrel, or—less effectively—aspirin only, should be considered in patients who refuse any OAC, or cannot tolerate anticoagulants for reasons unrelated to bleeding. If there are contraindications to OAC or antiplatelet therapy, left atrial appendage occlusion, closure, or excision may be considered
AF=atrial fibrillation; NOAC=novel oral anticoagulant; VKA=vitamin K antagonist; OAC=oral anticoagulant
Camm A, Lip G, De Caterina R et al. Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33: 2719–2747, by permission of Oxford University Press.

New trial data prompt update of the ESC guideline on AF continued

Which new anticoagulant should be used?

There have been no randomised head-to-head studies of the new anticoagulants, but several indirect comparisons found no marked differences between the three agents.23,24 Apixaban and dabigatran 110 mg were associated with a lower incidence of major bleeding compared with dabigatran 150 mg and rivaroxaban, and several other incidental differences have been reported, such as a superior efficacy of dabigatran 150 mg in preventing ischaemic stroke in some analyses.23-25 However, because of the inherent dissimilarities between the studies, such as the mean CHADS2 score and the prevalence and distribution of its components and cardiovascular risk in general, the evidence from indirect comparison studies is insufficient to develop definitive recommendations on the choice of new oral anticoagulant in specific patient groups.

Left atrial appendage occlusion

Interventional, percutaneous left atrial appendage closure may be considered in patients with a high stroke risk and contraindications for long-term oral anticoagulation.9 However, this recommendation is supported by a single randomised controlled study with a relatively short follow up (1 year) and a registry that specifically concerns patients for whom vitamin K antagonists are contraindicated.9,26,27 More evidence on long-term efficacy and safety is warranted before this approach can be adopted in wider patient populations, particularly as, although these devices exclude the main source of thromboemboli from the left atrial appendage, they do not address thrombogenic mechanisms.

Antiarrhythmic drug therapy: dronedarone

Rhythm control with antiarrhythmic drugs remains an essential part of AF management.28 The choice of an antiarrhythmic agent is determined by the presence and nature of underlying heart disease.9 Dronedarone dominated the 2010 ESC AF guideline recommendations for long-term prophylactic antiarrhythmic drug therapy.8 Although this drug is only moderately effective for prevention of recurrent AF, the reduction in cardiovascular mortality and hospitalisations and a trend towards lower all-cause mortality, as demonstrated in the ATHENA (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg b.i.d. for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) study in patients with paroxysmal and persistent AF,29 prompted dronedarone to be recommended in many clinical settings. This trend was reversed in the PALLAS (Permanent Atrial fibriLLAtion outcome Study) trial, which used dronedarone on top of standard therapy, in permanent AF: more patients in the dronedarone arm experienced stroke, systemic embolism, myocardial infarction, and cardiovascular death; there was also higher a rate of hospitalisations, including admissions for heart failure.30

The updated ESC guideline restricts the use of dronedarone to patients with non-permanent AF. The drug is contraindicated in permanent AF and in unstable or advanced heart failure (class III–IV), and its use is also discouraged in class I–II heart failure.9 There have been cases of severe hepatotoxicity associated with dronedarone, and monitoring of liver function is required in patients on long-term therapy.31 The revised European summary of product characteristics for this drug advises that the use of dronedarone is supervised by hospital or office-based staff familiar with the use of antiarrhythmic drugs.32

Pharmacological cardioversion: vernakalant

Vernakalant acts preferentially in the atria by blocking several ion channels, but has little impact on currents involved in ventricular repolarisation.9 In several randomised controlled and phase IV open-label studies, vernakalant has proven effective for cardioversion of patients with AF ≤7 days or AF ≤3 days after cardiac surgery.33 Despite relatively modest overall efficacy, the major advantage of vernakalant is its rapid antiarrhythmic effect, with approximately 50% of patients converting within 90 minutes after the start of treatment, with a median time to conversion of 8–14 minutes.9,33 Unlike Class IC drugs, vernakalant can be safely used in patients with stable coronary artery disease (recommendation class IIb), but should be used with caution in patients with class I–II heart failure because of a higher risk of hypotension and ventricular ectopics; this drug is not recommended in class III–IV heart failure, acute coronary syndrome, or in patients with severe aortic stenosis or QT interval prolongation.9


New trial data prompt update of the ESC guideline on AF continued

Left atrial ablation

There were two significant upgrades to the class of recommendation for the management of ablation in AF:9

  • ablation for symptomatic paroxysmal AF that cannot be controlled on at least one antiarrhythmic drug was granted a class I recommendation (up from IIa)
  • ablation as first-line therapy in selected patients with lone paroxysmal AF was given a class IIa recommendation (up from IIb, based on two new studies34,35).

All studies comparing drugs and ablation for management of recurrent AF demonstrated more sustainable rhythm control and improvement in quality of life with ablation, although not all of them reached statistical significance with regard to the primary endpoint. Thus, in the MANTRA-PAF (Medical ANtiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) study, although the overall AF burden was lower in the ablation group, the difference was not statistically significant.34 However, AF recurrence was significantly reduced in the ablation group. There are three large ongoing trials that will address an important issue on whether AF ablation confers any benefit with respect to ‘hard’ endpoints such as stroke and mortality:

  • CASTLE-AF (Catheter Ablation versus Standard conventional Treatment in patients with LEft ventricular dysfunction and Atrial Fibrillation)—all-cause mortality and heart-failure hospitalisations (n=420)36
  • CABANA (Catheter ABlation versus ANtiarrhythmic drug therapy for Atrial fibrillation)—all-cause mortality (n=3000)37
  • EAST (Early Atrial fibrillation Stroke prevention Trial)—all-cause mortality and cardiovascular hospitalisations (n=2810).38

Patient preferences should be considered when choosing the strategy for rhythm control in AF (see Figure 2).

Figure 2: Ablation and antiarrhythmic drugs for rhythm control in atrial fibrillation9

graph

AF=atrial fibrillation; HF=heart failure
aUsually pulmonary vein isolation is appropriate
bMore extensive left atrial fibrillation may be needed
cCaution with coronary heart disease
dNot recommended with left ventricular hypertrophy. Heart failure due to AF=tachycardiomyopathy

Camm A, Lip G, De Caterina R et al. Focused update of the ESC guidelines for the management of atrial fibrillation: an update of the 2010 ESC guidelines for the management of atrial fibrillation. Eur Heart J 2012; 33: 2719–2747, by permission of Oxford University Press.

New trial data prompt update of the ESC guideline on AF continued

Implementation

The main barrier to the implementation of the ESC guideline on AF relates to the substantial educational effort that is needed. In some cases entrenched views, such as prescription of aspirin for stroke prevention in AF, need to be overturned. Economic issues will prevent the easy and immediate implementation of recommendations relating to the preference of novel oral anticoagulants over dose-adjusted vitamin K antagonists.

Primary care

The ESC guideline is relevant to all healthcare professionals providing care for patients with AF. Much of the management of AF and its complications are being progressively devolved to primary care, such as:

  • opportunistic screening for AF by checking the pulse, and where appropriate, recording an electrocardiogram
  • the continuing management of patients who are prescribed antiarrhythmic drugs, especially dronedarone and amiodarone
  • the initiation and follow up of patients receiving thromboembolic protection with traditional and novel oral anticoagulants.

Conclusion

Developments in the field of AF have been rapid and considerable. In particular, the development of new and potentially safer anticoagulant drugs has stimulated a reappraisal of the risk stratification of patients with AF in order to identify truly low-risk patients who do not need any antithrombotic therapy (including aspirin), and to offer formal anticoagulation with novel oral anticoagulants or warfarin to the remainder. New options for rhythm control with antiarrhythmic drugs or ablation has stimulated renewed interest in maintaining sinus rhythm rather than pursuing a rate-control strategy. However, progress continues and it will probably be no longer than 2 years before further guideline revision is needed.


New trial data prompt update of the ESC guideline on AF continued

Key points
  • Opportunistic screening for AF is recommended in the general population aged 65 years and older
  • Risk stratification and prevention of stroke is a central component of AF management
  • The CHA2DS2-VASc score offers a more comprehensive risk assessment and should be used in favour of CHADS2
  • The HAS-BLED score allows quantification of bleeding risk and helps guide the stroke prevention strategy, but should not be used to deter anticoagulation in patients at risk
  • New oral anticoagulation drugs (dabigatran, rivaroxaban, and apixaban) are preferred to dose-adjusted warfarin and should be offered to a wider range of patients with non-valvular AF because of their many advantages including better efficacy and safety, particularly with regard to intracranial haemorrhage
  • Aspirin as monotherapy does not provide adequate protection against stroke in patients with AF and should not be used for this purpose unless there is no alternative
  • Kidney function tests at baseline and periodically during therapy with new oral anticoagulants is either mandatory or strongly advisable, depending on the agent
  • Implantation of a left atrial appendage occlusion device is a viable alternative for stroke prevention in patients with contraindications to oral anticoagulation, with either warfarin or new agents, but more long-term data on the efficacy and safety are required
  • Dronedarone can be used safely in patients with non-permanent AF provided they do not have unstable or advanced heart failure; the drug is best avoided or used with caution in individuals with milder forms of heart failure unless there is no alternative
  • Liver function should be monitored during therapy with dronedarone
  • Ablation therapy is a viable alternative in patients with paroxysmal symptomatic AF who have not responded to a trial of at least one drug, and can even be used as first-line therapy in selected patients with lone AF; the evidence is less impressive in patients with persistent AF
  • Patient preferences should be taken into consideration and, whenever possible, patients should be given an informed choice: when selecting the long-term anticoagulation strategy, rate versus rhythm control therapy, and drug therapy versus ablation.

AF=atrial fibrillation
GP commissioning take home messages for England

written by Dr David Jenner, NHS Alliance GMS contract/PBC Lead

  • The European Society of Cardiology recommends the use of a new risk stratification tool, which differs from the CHADS2 tool currently used in the QOF (CHA2DS2-VASc)
  • CCGs should encourage opportunistic screening for atrial fibrillation in primary care and encourage anticoagulation to avoid ischaemic stroke and other events, where appropriate and safe
  • The newer anticoagulants are significantly more expensive than warfarin and if used widely would have major impacts on CCG prescribing budgets
  • CCGs should consult carefully with specialist colleagues regarding the most effective and cost-efficient choices for inclusion in local formularies, taking into account the efficacies of the various treatments in preventing further morbidity and healthcare costs.
QOF=quality and outcomes framework; CCG=clinical commissioning group

New trial data prompt update of the ESC guideline on AF continued

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  38. ClinicalTrials.gov website. Early treatment of atrial fibrillation for stroke prevention trial. clinicaltrials.gov/show/NCT01288352 (accessed 14 March 2013). G

Dr Irene Savelieva
Clinical Lecturer in Cardiology St George’s University of London
Member of the AF Guideline Task Force

Professor John Camm
Professor of Clinical Cardiology St George’s University of London
Chairman of the AF Guideline Task Force

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