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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Prevention of stroke in patients with atrial fibrillation: current strategies and future directions

Stefan H. Hohnloser1,*, Gabor Z. Duray1, Usman Baber2 and Jonathan L. Halperin2

1 Division of Electrophysiology, Department of Cardiology, J.W. Goethe University, Theodor Stern Kai 7, 60590 Frankfurt, Germany
2 Mount Sinai Medical Center, The Zena and Michael A. Wiener Cardiovascular Institute, New York, NY 10029-6574, USA

* Corresponding author. Tel: +49 69 6301 7404; fax: +49 69 6301 7017. E-mail address: hohnloser{at}em.uni-frankfurt.de


   Abstract
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The morbidity and mortality associated with atrial fibrillation (AF) are related mainly to ischaemic stroke, and the prevention of thrombo-embolism is an important component of the patient management. The choice of optimum antithrombotic therapy for a given patient depends on the risk of thrombo-embolism, and the assessment of thrombo-embolic risk using validated stratification schemes, such as the CHADS2 score, is a critical step. Improved stratification schemes are needed that take into account the risk of intracerebral haemorrhage, which is the most worrisome complication of anticoagulant therapy. The pattern of AF (paroxysmal, persistent, or permanent) should not influence the selection of antithrombotic treatment. Similarly, successful rhythm control is not a sound basis for withdrawing antithrombotic treatment, and whether this situation differs after successful catheter ablation of AF has not been established. At present, oral vitamin K antagonists alone are recommended for patients with AF at moderate-to-high risk of stroke. A combination of anticoagulant and antiplatelet drugs is necessary in patients with AF undergoing percutaneous coronary intervention and stent implantation, but the optimal therapeutic management of these patients has not been defined. The development of new antithrombotic agents that are easier to use and have a superior benefit-to-risk ratio will extend treatment to a greater proportion of the AF population at risk. The large number of phase III trials currently investigating specific inhibitors of thrombin or factor Xa that do not require laboratory monitoring suggests that this goal is within reach.

Key Words: Aspirin • Atrial fibrillation • Stroke • Thrombo-embolism • Vitamin K antagonists • Warfarin

Much of the morbidity and mortality associated with atrial fibrillation (AF) is due to thrombo-embolic complications, mainly involving the cerebrovascular system and resulting in ischaemic stroke.1 This is explained by the deterioration of atrial mechanical function, which favours thrombus formation in zones of stasis, especially in the left atrial appendage (LAA).2 Overall, the risk of stroke is increased four- to five-fold in patients with AF.2 Thus, AF is responsible for up to 15% of all strokes and represents the most important cause of ischaemic stroke in women >75 years old.2,3 Beyond the treatment of the cardiac arrhythmia, the prevention of thrombo-embolic complications is a vital aspect of management for patients with AF. Despite a sound basis in clinical evidence derived from randomized trials, many aspects of antithrombotic therapy in patients with AF remain controversial. In this review, we address some of these issues and indicate possible directions for the evolution of antithrombotic therapy in the future.


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This review is based on the results of a workshop on unresolved issues in antithrombotic therapy for stroke prevention in patients with AF, held in Berlin in October 2007, and a systematic search of published literature on the key issues discussed. This document summarizes the results of this consensus conference.

Efficacy and safety of antithrombotic therapy for patients with atrial fibrillation
Current antithrombotic strategies for patients with AF include anticoagulant drugs, notably the coumarin class of vitamin K antagonists (VKAs), such as warfarin, and antiplatelet agents, such as aspirin. In a recent meta-analysis of clinical trials involving the prevention of stroke in patients with non-valvular AF, adjusted-dose VKA therapy reduced stroke by 64% (95% CI 49–74) compared with control (placebo or no treatment); the absolute increase in major extracranial haemorrhage in patients treated with VKAs was small (≤3% per year).4 Moreover, adjusted-dose VKAs were substantially more effective than antiplatelet therapy, with a stroke risk reduction of 39% (95% CI 22–52); the risk of intracranial haemorrhage doubled with adjusted-dose VKAs, but the absolute increase in risk was small (0.2% per year).4 The superior efficacy of VKAs was also demonstrated in the subgroup of patients with non-valvular AF with no history of stroke or transient ischaemic attack (TIA): compared with antiplatelet therapy, the administration of VKAs significantly reduced the risk of all strokes by 32% [odds ratio (OR) 0.68; 95% CI 0.54–0.85].5 Furthermore, in another meta-analysis, VKAs were more effective than antiplatelet drugs for the prevention of systemic embolism (OR 0.50; 95% CI 0.33–0.75) without increasing the risk of major bleeding (OR 1.07; 95% CI 0.85–1.34).6 Aspirin appears to reduce the risk of non-cardioembolic strokes more than cardioembolic strokes, whereas adjusted-dose VKAs are much more effective than aspirin for the prevention of cardioembolic events.2

Estimation of stroke risk in atrial fibrillation patients
The risk of stroke is not homogeneous among all patients with AF, varying 20-fold depending on clinical features.7,8 As underlined in the latest joint European (ESC) and US (ACC/AHA) guidelines for the management of patients with AF, optimum antithrombotic therapy depends on the risk of thrombo-embolism in a given patient.1 Schematically, VKA treatment is recommended for stroke prevention in patients at moderate-to-high risk (~50–70% of patients with AF). For patients with AF at lower risk, aspirin is recommended, though this offers only modest protective efficacy compared with warfarin.

Assessing the thrombo-embolic risk in a given patient with AF is a critical step which, in practice, is based on risk-stratification schemes that integrate a number of independent risk factors identified in randomized trials and population-based studies. In these studies, the most consistent predictors of stroke were a history of stroke, TIA or systemic embolism, hypertension, advanced age, diabetes mellitus, and heart failure or left ventricular systolic dysfunction.7 The predictive value of female gender is less well validated. In the EuroHeart Survey, which enrolled 5333 patients with AF in 35 countries in 2003 and 2004, 90% of patients had at least one risk factor for stroke; >60% had a history of hypertension, the most prevalent stroke risk factor.9

The various stroke risk-stratification schemes available have comparable, but relatively limited, ability to predict thrombo-embolism in persons with AF.10 One of the best validated and most user-friendly tools is the CHADS2 score (Table 1),11,12 which incorporates five clinical features to assess stroke risk: age ≥75 years, heart failure, hypertension, diabetes, and a history of stroke or TIA. A score of 1 point is allotted for each of the first four features and 2 points for a history of stroke or TIA. Clinical studies have confirmed that thrombo-embolic risk increases in proportion to the CHADS2 score (Table 2).13,14 Furthermore, VKA treatment reduces the stroke risk in all individuals, apart from those with a CHADS2 score of 0, in whom the risk of bleeding associated with anticoagulation may exceed benefit.13 Among such low-risk patients, aspirin monotherapy may confer sufficient protection against ischaemic stroke.15 In contrast, therapy with either aspirin or VKA is reasonable in patients with a CHADS2 score of 1; the choice should be based on individual assessment of bleeding risk, availability of high-quality anticoagulation management resources, and patient preference. Long-term treatment with VKAs is recommended for those with a CHADS2 score ≥ 2 who are not at excessive bleeding risk.


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  		Table 1 The CHADS2 score and the prevalence of risk factors9,11,12

 

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  		Table 2 The CHADS2 score, the risk of thrombo-embolism and the efficacy of vitamin K antagonist therapy13,14

 
Since the combination of anticoagulant and antiplatelet therapy proved more effective than antiplatelet therapy alone in patients with acute coronary syndromes,16 it was hypothesized that the combination of VKAs and aspirin might also be valuable in patients at high risk of stroke (CHADS2 score ≥ 5). However, a meta-analysis of randomized trials involving patients with various indications for anticoagulation, comparing VKAs with the combination of aspirin plus VKAs, found that combination therapy reduced the risk of thrombo-embolism only among patients with mechanical heart valves.17 Among patient cohorts with AF, there was no significant reduction in the rate of thrombo-embolism (OR 0.98; 95% CI 0.77–1.25), and the combination of aspirin and VKA therapy was associated with a markedly increased risk of bleeding (OR 1.43; 95% CI 1.00–2.02; P = 0.05). Hence, the combined use of anticoagulant and antiplatelet drugs is not routinely recommended for patients with AF.18,19

Three points concerning the CHADS2 score are open to debate. The first is how to score a history of stroke or TIA, the strongest independent predictor of stroke in patients with AF. Absolute stroke rates for patients with AF who are not anticoagulated are in the range of 6–9% per year, compared with 1.5–3.5% for each other component of the CHADS2 score.7 Under the current scheme, a patient with AF whose only stroke risk factor is prior thrombo-embolism, although uncommon, is assigned a CHADS2 score of 2. This underestimates the risk and leaves optimum antithrombotic therapy uncertain.20 This was evident in the EuroHeart Survey, in which a history of stroke or TIA was not a uniform determinant of prescription of VKA therapy.21

Second, the CHADS2 score does not incorporate information obtained by cardiovascular imaging. Markers of stasis detected by transoesophageal echocardiography, such as reduced LAA flow velocity, dense spontaneous echo contrast, and atrial thrombus, are associated with increased embolic risk. The value of integrating these characteristics into stroke-risk stratification has not been evaluated.22–24

Third, the CHADS2 score does not account for the risk of bleeding associated with antithrombotic therapy, which has been partly defined for patients with AF.25 Gage et al.26 proposed a classification scheme to quantify the risk of major bleeding in elderly patients with AF that included the following predictors: previous bleeding, hepatic or renal disease, ethanol abuse, malignancy, age > 75 years, reduced platelet count or function, uncontrolled hypertension, anaemia, genetic factors, risk of falling, and stroke. Clinical application of such schemes is complicated, however, by the fact that many risk factors for bleeding (e.g. advanced age, hypertension, and cerebrovascular disease) are also predictors of ischaemic stroke. When considering the risk of bleeding in patients with AF, it may be pertinent to focus on the risk of intracerebral haemorrhage (the consequences of which are often devastating) rather than on major bleeding in general.27 Advanced age and high INR values are notably associated with an increased risk of intracranial haemorrhage.28 Thus, a risk-stratification scheme is needed that is specific to patients with AF and takes into account the risks of both thrombo-embolism and intracranial haemorrhage.

Management of patients with atrial fibrillation using available antithrombotic drugs
With VKA anticoagulants, balance between the prevention of ischaemic stroke and avoidance of haemorrhagic complications is best achieved, in most patients, with a target intensity corresponding to INR 2.0–3.0. Compared with adjusted-dose VKA therapy, fixed low-dose therapy is associated with a higher rate of thrombo-embolic events without reducing the risk of bleeding.29 In the EuroHeart survey, undertreatment was associated with a higher risk of thrombo-embolism than adherence to guideline recommendations (OR 1.97; 95% CI 1.29–3.01; P = 0.004).30

Optimal anticoagulation entails the need for frequent INR monitoring, which can be cumbersome for many patients. The quality of anticoagulation control may be improved through patient education literature30 and programmes.31–33 In selected patients, home monitoring may be valuable: compared with standard care, self-monitoring of the intensity of VKA therapy resulted in significant reductions in the rates of thrombo-embolic events (OR 0.45; 95% CI 0.30–0.68) and major haemorrhages (OR 0.65; 95% CI 0.42–0.99).34 Combining self-monitoring and self-dosing was even more successful in preventing thrombo-embolic events.34 The implementation of these procedures is not feasible for all patients and requires careful identification and education of suitable candidates.

The possibility that dual antiplatelet therapy might represent a safe and simpler alternative to oral anticoagulation was evaluated in the prospective ACTIVE-W trial,35 in which 6706 patients with AF at high risk of stroke were randomized to treatment with either aspirin + clopidogrel or VKA (target INR 2.0–3.0). The trial was stopped early because of the superiority of VKA therapy, with an annual risk of the composite of stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death of 3.93% in the VKA group vs. 5.60% in patients receiving aspirin + clopidogrel (relative risk 1.44; 95% CI 1.18–1.76; P = 0.0003). The VKA group exhibited less minor bleeding and a comparable number of major bleed events and slightly more fatal haemorrhages. In a secondary analysis, the benefit of VKA therapy was limited to those already receiving this type of treatment at entry. This result suggests that trial data obtained in patients already successfully anticoagulated prior to participation may not be directly applied to VKA-naïve patients.

Another barrier to long-term anticoagulation is that patients often cannot or will not sustain VKA therapy for a variety of medical, social, and personal reasons. In this context, ACTIVE-A is an ongoing randomized trial of aspirin + clopidogrel vs. aspirin alone in patients not tolerating or unwilling to pursue anticoagulant therapy.36

The genotypes of the cytochrome p450 isoform CYP2C9 and the vitamin K epoxide reductase complex subunit 1 VKORC1 conjointly influence the liver metabolism of VKAs, and thereby the inter-individual dose variability of VKAs.37 The determination of these genotypes may improve the initial estimate of VKA dose, as highlighted in the US product labelling for warfarin,37 but the clinical value of pharmacogenetically guided VKA treatment remains unproven.38

Pattern of atrial fibrillation and indication for an antithrombotic treatment
It is widely perceived that patients with paroxysmal AF exhibit a lower risk of stroke than those with permanent or persistent AF.21 As a result, VKA therapy is less often prescribed for patients with paroxysmal AF than for those with chronic AF.21 The pattern of AF should not influence the selection of antithrombotic treatment, however, which should instead be selected on the basis of associated risk factors for thrombo-embolism and bleeding.1 Data from clinical trials support this recommendation, as thrombo-embolic risk was similar among patients with paroxysmal and persistent AF. Furthermore, in the ACTIVE-W study, VKA treatment was similarly superior to the combination of aspirin + clopidogrel in patients with either pattern of AF.39

In patients with paroxysmal AF, the perception of the frequency and duration of episodes often underestimates the true burden of AF, as many recurrences are asymptomatic.40 Indeed, the risk of thrombo-embolism is independent of the presence or absence of symptoms such as palpitations.41 To clarify this issue, two prospective trials involving patients with implanted cardiac devices who are not receiving anticoagulant medication are examining the association between asymptomatic atrial high-rate episodes and ischaemic events,42,43 and an interventional trial is testing a strategy of guiding antithrombotic therapy both on stroke risk factors and on the detection of AF by implanted devices.

Anticoagulation in patients with atrial fibrillation managed with rhythm control
As the reduction of blood flow velocity in the LAA in patients with AF is linked to the risk of thrombo-embolism,44 it has been hypothesized that restoring normal sinus rhythm may reduce stasis, thrombus formation, and the risk of stroke. Whether restoration and maintenance of sinus rhythm is a clinically effective alternative to anticoagulation, however, may depend on the method and success of rhythm control. The decision to adopt a management strategy of rhythm control does not eliminate the need for effective antithrombotic therapy, except perhaps in patients at lowest thrombo-embolic risk (CHADS2 score ≤ 1). AF frequently recurs after initial restoration of sinus rhythm, and these recurrences may be symptomatic.40 Moreover, AF may create an inherently pro-thrombotic state45 and patients with AF often harbour co-morbidity, such as hypertension, valvular heart disease or cerebrovascular disease, left ventricular dysfunction, or aortic arch atheroma that increases their risk of stroke.46 In fact, the ESC/ACC/AHA guidelines recommend long-term anticoagulation for most patients with AF who have risk factors for thrombo-embolism, regardless of treatment strategy (rate control vs. rhythm control) and whether or not recurrent AF is documented.1

In some patients, catheter ablation of AF has been more effective than antiarrhythmic drug therapy in maintaining sinus rhythm.47–49 The A4 trial, in which patients with symptomatic paroxysmal AF who had failed treatment with at least one class I or class III antiarrhythmic drug were randomized to either antiarrhythmic drug therapy or catheter ablation, revealed that significantly more patients treated with catheter ablation were free of recurrent AF at 1 year follow-up (75 vs. 6%; P < 0.0001).49,50 Anticoagulation was stopped in 60% of patients in the ablation group, compared with 34% of those receiving antiarrhythmic drug therapy. In an analysis of 755 consecutive patients with paroxysmal (n = 490) or persistent (n = 265) AF undergoing percutaneous left atrial radiofrequency ablation, 522 were in sinus rhythm after catheter ablation. Warfarin was safely discontinued in 79% of the 256 patients without risk factors and in 68% of the 266 patients with ≥1 risk factor for thrombo-embolism. None of these patients experienced thrombo-embolic events during 25 ± 8 months of follow-up.48 These observations suggest that anticoagulation may be stopped in low-risk patients following successful AF ablation. For those at moderate risk, however, the appropriate strategy is not clear, and, until further evidence is available, the prudent option is to continue anticoagulation. Continued anticoagulation may be necessary in high-risk patients, even if AF ablation is successful. Larger prospective trials are needed to further clarify the issues surrounding the safety and timing of VKA discontinuation after catheter ablation of AF.

Antithrombotic therapy in atrial fibrillation patients undergoing percutaneous coronary intervention
The management of patients with AF who undergo percutaneous coronary intervention (PCI) with stent implantation may be particularly problematic owing to the need for both dual-antiplatelet therapy and VKA. To date, there are no prospective randomized trial data to guide clinicians in the optimal management of such patients. Data from PCI registries support individualized approaches that incorporate inherent bleeding and stroke risks along with stent type.1,51–55 The ESC/ACC/AHA guidelines1 recommend interrupting the VKA for 2–4 weeks while continuing aspirin and clopidogrel to reduce bleeding risk immediately following PCI. Beyond this initial period, VKAs (INR 2–3) may be resumed, whereas aspirin should be stopped. Clopidogrel (75 mg daily) should be given for a minimum of 1 month after the implantation of a bare metal stent, for at least 3 months for a sirolimus-eluting stent, at least 6 months for a paclitaxel-eluting stent, and 12 months or longer in selected patients, following which the VKA may be continued as monotherapy in the absence of a subsequent coronary event. Since the publication of the guidelines for the management of patients with AF, however, have come a number of reports of thrombosis of drug-eluting coronary stents as late as 2 or 3 years after deployment when clopidogrel therapy was interrupted. The implication is that longer term treatment with clopidogrel is necessary, and for patients with both drug-eluting stents and AF requiring chronic anticoagulation, the risk of ischaemic events is high when either the platelet inhibitor or the anticoagulant is omitted, and the risk of major bleeding is high with the combination of both. No consensus has yet emerged, and the number of patients with AF who will require PCI is expected to increase over the next few years, highlighting the need for randomized trials to define the optimum antithrombotic regimen for this population. It is widely acknowledged, however, that when PCI is necessary, bare-metal stents may be preferable to drug-eluting stents3 in patients with AF who have risk factors for thrombo-embolism (CHADS2 score ≥ 2).

Alternatives to vitamin K antagonists or antiplatelet therapy in patients with atrial fibrillation
VKAs are currently the only oral anticoagulants available for stroke prevention in patients with AF. The search for new anticoagulant drugs with more favourable safety profiles that do not require frequent coagulation monitoring or dose adjustment is highly active. Among the many targets for novel anticoagulants, the two principal targets in the coagulation pathway are thrombin and factor Xa (Table 3).56


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  		Table 3 New anticoagulant drugs studied in phase III trials in atrial fibrillation

 
Ximelagatran was the first oral direct thrombin inhibitor tested in phase III trials in patients with AF. The SPORTIF III and V studies compared ximelagatran with warfarin for the prevention of stroke and systemic embolism in 3407 and 3922 patients with non-valvular AF, respectively.57,58 In a pre-specified analysis of the pooled data from both trials, the rates of stroke and systemic embolic events were almost identical with ximelagatran and warfarin (1.6% per year in both groups).59 Major bleeding events were marginally less frequent with ximelagatran than with warfarin (1.9% per year vs. 2.5% per year; risk ratio 0.76; 95% CI 0.56–1.03; P = 0.07). Although the development of this drug was subsequently stopped, mainly because of liver toxicity, these results were important because they showed for the first time that an oral anticoagulant drug can be used safely and effectively without coagulation monitoring in patients with AF.

Another oral direct thrombin inhibitor, dabigatran, is currently under investigation for various indications, including stroke prevention in patients with AF. Following a dose-finding study in patients with AF,60 the phase III RELY trial is comparing two blinded doses of dabigatran (110 and 150 mg) vs. warfarin in 18 000 patients with non-rheumatic AF who have at least one additional risk factor for stroke.

Idraparinux is a long-acting indirect inhibitor of factor Xa that must be administered parenterally once a week. In the AMADEUS trial involving 4576 patients with AF, idraparinux was non-inferior to warfarin for the prevention of stroke and systemic embolism (1.3% with warfarin vs. 0.9% with idraparinux), but clinically relevant bleeding was significantly more frequent and severe with idraparinux (19.7 vs. 11.3%; P < 0.001).61 A biotinylated form of idraparinux has been developed that allows rapid removal of the drug upon the administration of avidin. The BOREALIS-AF trial will determine the benefit–risk ratio of this new reversible anticoagulant in patients with AF.

Among the oral direct factor Xa inhibitors in development, two are currently being tested in phase III trials in patients with AF: apixaban in the ARISTOTLE and AVERROES trials and rivaroxaban in the ROCKET-AF trial. Both involve fixed dosing without anticoagulation monitoring in patients with AF at risk of stroke.

Mechanical antithrombotic approaches for the prevention of thrombo-embolism may represent an alternative to anticoagulation for patients with AF. The administration of an anticoagulant drug is problematic for many patients: it has been estimated that long-term VKA treatment is contraindicated in 14–44% patients with AF who are at risk of stroke.62 Even medically eligible patients face such barriers to anticoagulation that in clinical practice, VKAs are prescribed to only 15–65% of patients with AF who are considered at high risk for thrombo-embolic events.62 Approximately 90% of cardiogenic embolism events in patients with non-valvular AF are thought to arise from a thrombus that forms in the LAA,63 hence the occlusion of the appendage should theoretically reduce stroke. Surgical exclusion or amputation of the LAA is frequently performed during open-heart surgery.64 In addition, several catheter-borne devices have been designed to occlude the LAA via a percutaneous approach: the PLAATO and the WATCHMAN systems. Although preliminary experience with these approaches has been promising, safety and efficacy have yet not been verified. The WATCHMAN device is currently under investigation in the PROTECT-AF trial.62


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AF is associated with a risk of thrombo-embolism that may be reduced through judicious antithrombotic therapy, most importantly oral anticoagulation. Although the benefits of antithrombotic therapy for stroke prevention have been extensively demonstrated in patients with AF, treatment with VKA drugs is underused.21 This may be related to the underestimation of benefit or the overestimation of the associated bleeding risk, but withholding antithrombotic treatment is generally a greater problem than over-treatment.30,65 In addition, the antithrombotic therapy for individual patients is not always properly adapted to their stroke risk; in the EuroHeart Survey, VKA therapy was often used across all stroke risk categories, influenced by less relevant factors, such as the pattern of AF and availability of anticoagulation monitoring facilities, than by the patient’s intrinsic risk of thrombo-embolism.30

This means that physicians and patients need to know more about the benefit of appropriate antithrombotic therapy. Moreover, risk stratification schemes must be refined to incorporate data available from imaging studies that enhance predictive value for ischaemic events and risk factors for bleeding. At the same time, schemes must be simple enough to encourage broader use. The development of antithrombotic strategies that are easier to administer and are associated with superior benefit-to-risk ratios may improve the treatment of AF patients and prevent thousands of strokes. The introduction of novel antithrombotic agents into clinical trials suggests that this goal may be on the horizon.


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Funding for editorial support was provided by sanofi-aventis.

Conflict of interest: S.H.H., G.Z.D. and U.B. declare no conflict of interest. J.L.H. has received during the past two years consulting fees from Astellas Pharma, Bayer AG HealthCare, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi-Sankyo Pharma, GlaxoSmithKline, Johnson & Johnson and sanofi-aventis for advisory activities involving the development of new anticoagulant drugs, none of which are currently approved for clinical use in any indication. He receives consulting fees from Biotronik, Inc. for his role as Co-Chairman of the Steering Committee for the IMPACT clinical trial evaluating the use of ambulatory monitoring technology in approved implanted cardiac arrhythmia devices to guide anticoagulation therapy for stroke prevention.


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