- Email: [email protected]
Anticoagulation in atrial fibrillation: A contemporary viewpoint
Anticoagulation in atrial fibrillation: A contemporary viewpoint D. George Wyse, MD, PhD From the Libin Cardiovascular Institute of Alberta, University of Calgary, and Calgary Health Region, Calgary, Alberta, Canada. Anticoagulation therapy in patients with atrial fibrillation is important. This review consists of three parts: chronic anticoagulation, anticoagulation for cardioversion, and a brief comment on anticoagulation around the time of left atrial radiofrequency ablation. The risk stratification scheme of the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for chronic anticoagulation is briefly reviewed. Although there are several other similar schemes, they are not identical. The key point is the balance between benefit and risk. Some emerging controversies are outlined. Two specific questions explored are: is well-controlled hypertension a risk factor, and does paroxysmal atrial fibrillation confer the same risk as continuous atrial fibrillation? Differences in the risk of bleeding while taking a vitamin K antagonist noted in recent compared with older data are discussed. Risk of bleeding in the elderly and combined antithrombotic therapy with a vitamin K antagonist and an antiplatelet agent in high-risk patients are briefly discussed. Recent failures of studies attempting to find a
suitable alternative to vitamin K antagonists are outlined. The treatment guidelines for anticoagulation for cardioversion are briefly reviewed. The risk of thromboembolism according to international normalized ratio and use of low-molecular-weight heparin as an alternative to warfarin are discussed. Anticoagulation before and after left atrial radiofrequency ablation is empirical, and long-term anticoagulation seems advisable for high risk patients at the present time. The two most pressing needs for further investigation are (1) clarification, simplification, and consolidated of risk stratification schemes and treatment recommendations and (2) discovery of alternatives to warfarin.
Introduction
of AF,2 characteristics predisposing to thromboembolism were weighted and subdivided into “high,” “moderate,” and “weaker” risk factors (Table 1). Based on the presence or absence of high and moderate risk factors, patients are categorized as “high,” “moderate,” or “low” risk. Aspirin is advised for patients with “low” risk, an oral vitamin K antagonist (international normalized ratio [INR] 2.0 –3.0) is advised for those with “high” risk, and either aspirin or oral vitamin K antagonist is advised for those with “moderate” risk. Such risk classification schemes and treatment recommendations are helpful, but physicians also must take into account even the lesser risk factors and the risk of bleeding. No therapy is totally effective and without risk so good judgment is needed.
Anticoagulation is an integral part of the therapy for all patients with atrial fibrillation (AF). It continues to be an area of therapy about which there is controversy and confusion.
Chronic anticoagulation Risk stratification Current fundamentals of risk stratification A fundamental tenet of chronic anticoagulation for thromboembolism prophylaxis in AF, arising from early randomized trials of warfarin therapy,1 is individualization of therapy on the basis of risk stratification. Prosthetic heart valves and mitral stenosis were identified earlier as risk factors and were not included in those trials. Several factors predisposing to thromboembolism in nonvalvular AF thus were identified. In the recent update of the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for management Dr. Wyse is a member of the Scientific Advisory Board for Boehringer Ingelheim and Sanofi Aventis. Address reprint requests and correspondence: Dr. D. George Wyse, Libin Cardiovascular Institute of Alberta, University of Calgary, Department of Cardiac Sciences, 3330 Hospital Drive NW, Room G009, Calgary, Alberta T2N 4N1, Canada. E-mail address: [email protected].
KEYWORDS Atrial fibrillation; Anticoagulation; Antiplatelet agents; Thromboembolic risk; Bleeding risk; Risk stratification; Randomized controlled trials; Treatment guidelines; Radiofrequency ablation (Heart Rhythm 2007;4:S34 –S39) © 2007 Heart Rhythm Society. All rights reserved.
Confusion and controversies Several points of controversy contribute to confusion concerning risk stratification for antithrombotic therapy in AF. Consequently, both underuse and overuse of anticoagulation occurs.3,4 The confusion about risk stratification is partly related to the existence of many similar, but not identical, schemes. One commonly used scheme for nonvalvular AF (prosthetic valves and mitral stenosis excluded) is the so-called CHADS2 scheme (Figure 1).5 The CHADS2 scheme is simple to remember and use at the bedside and provides a more
1547-5271/$ -see front matter © 2007 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2006.12.001
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Table 1 Summary of risk stratification and recommendations for antithrombotic therapy from the 2006 ACC/AHA/ESC Guidelines Risk factors for stroke and systemic embolus in patients with atrial fibrillation Weaker risk
Moderate risk
Female gender Age ⱖ75 years Age 65–74 Hypertension years Coronary Left ventricular artery disease ejection fraction ⱕ0.35 or congestive heart failure Thyrotoxicosis Diabetes mellitus
S35 differently. Furthermore, the annual risk of some of the designated “high risk” patients was just over 3% while taking aspirin. The CHADS2 scheme stood out as most clearly identifying a truly high risk group (annual risk ⬎5%) in this analysis. Further work is needed to validate and consolidate the multiple schemes defining who is
High risk Mitral stenosis Prosthetic heart valve Stroke, transient ischemic attack, or systemic embolus
Table 2 Mean systolic blood pressure, proportion of patients with PAF at enrollment, and annual risk of stroke or systemic embolus in several trials Comparison of BP and risk of stroke or systemic embolus on vitamin K antagonist
Risk stratification and therapy recommendation Category
Recommendation
No risk factors One moderate risk factor
ASA (81–325 mg/day) ASA (81–325 mg/day) or warfarin (INR ⫽ 2.0–3.0) Warfarin (INR ⫽ 2.0 –3.0)*
Any high risk factor or ⱖ2 moderate risk factors
ACC/AHA/ESC ⫽ American College of Cardiology/American Heart Association/European Society of Cardiology; ASA ⫽ acetylsalicylic acid (aspirin); INR ⫽ international normalized ratio. Modified from Fuster et al.2 *Prosthetic heart valve, INR ⫽ 2.5 –3.5.
continuous scale of risk. CHADS2 is compatible with the ACC/AHA/ESC scheme by considering scores of 0 ⫽ low risk, 1 ⫽ moderate risk, and ⱖ2 ⫽ high risk in Table 1. CHADS2 and four other schemes have been applied to a cohort of AF patients taking aspirin.6 Patients were divided into low, moderate, and high risk subgroups using each of the schemes. The five schemes divide the same cohort very
Study
Mean systolic BP
Higher BP Studies (⬎135 mmHg) AFASAK I† 153 mmHg BAATAF† 139 mmHg SPAF I† 137 mmHg CAFA† 142 mmHg SPAF II† 139 mmHg AFASAK II† 149 mmHg SPORTIF III 139 mmHg Lower BP Studies (ⱕ135 mmHg) SPINAF† 134 mmHg AFFIRM 135 mmHg SPORTIF V 133 mmHg ACTIVE W 133 mmHg
2.0% 0.4% 2.3% 2.5% 1.9% 2.8% 1.9% 0.9% 1.2% 1.1% 1.4%
Comparison of Proportion with PAF and Risk of Stroke or systemic embolus on vitamin K antagonist
Study
Percent PAF
Higher Percentage of PAF Studies* AFFIRM 31% SPORTIF V 14% ACTIVE W 18% Lower Percentage of PAF Studies* AFASAK I† 0% SPINAF† 0% CAFA† 7% AFASAK II† 0% SPORTIF III 8%
Figure 1 Annual risk of stroke with 95% confidence intervals in the presence of atrial fibrillation using the CHADS2 risk stratification scheme of assigning points. Congestive heart failure ⫽ 1 point; hypertension ⫽ 1 point; age ⱖ75 years ⫽ 1 point; diabetes mellitus ⫽ 1 point; stroke, transient ischemic attack, or systemic embolus ⫽ 2 points. (Based on data from Gage et al.5)
Annual risk of stroke or systemic embolus on vitamin K antagonist
Annual risk of stroke or systemic embolus on vitamin K antagonist 1.2% 1.1% 1.4% 2.0% 0.9% 2.5% 2.8% 1.9%
BP ⫽ blood pressure; PAF ⫽ paroxysmal atrial fibrillation. Trials: ACTIVE W ⫽ Atrial fibrillation with Clopidogrel Trial with Irbesartan for prevention of Vascular Events W (warfarin vs clopidogrel/aspirin); AFASAK ⫽ Copenhagen Atrial Fibrillation, Aspirin and Anticoagulation Study; AFFIRM ⫽ Atrial Fibrillation Follow-up Investigation of Rhythm Management trial; BAATAF ⫽ Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA ⫽ Canadian Atrial Fibrillation Anticoagulation study; SPAF ⫽ Stroke Prophylaxis in Atrial Fibrillation trial; SPINAF ⫽ Stroke Prevention In Nonrheumatic Atrial Fibrillation study; SPORTIF ⫽ Stroke Prevention with the Oral diRect Thrombin Inhibitor ximelagatran in atrial Fibrillation trial. *Earlier studies, such as SPAF, included “intermittent” atrial fibrillation, which is not the same as paroxysmal atrial fibrillation. †Data provided by Dr. Carl van Walraven, University of Ottawa.
S36 truly in need of therapy with warfarin in contemporary AF patient populations. The issue of contemporary risk is under discussion because of a number of empirical observations. Among others, two emerging questions are topical. Is well-controlled hypertension really a moderate risk factor? And, does paroxysmal AF truly confer the same risk as persistent or permanent AF? The blood pressure issue has emerged partly in comparison of the two SPORTIF (Stroke Prevention with the Oral diRect Thrombin Inhibitor ximelagatran in atrial Fibrillation Trial) studies: SPORTIF III and SPORTIF V.7,8 There has been much speculation about possible explanations for the lower risk of stroke while being treated with warfarin in SPORTIF V. It has been noted that the average systolic blood pressure at entry to SPORTIF III was 139 mmHg but was 133 mmHg in SPORTIF V. A comparison of these two studies and several other trials on the basis of blood pressure at entry is given in Table 2. In general, studies with higher blood pressures at entry had higher risk of stroke in the anticoagulation-treated arms (Table 2). Furthermore, most of the trials with higher blood pressures are older, and it is these trials that identified hypertension as a risk factor. These observations, among others, have led to speculation that the definition of hypertension and contemporary control of blood pressure are different than they were years ago, and consequently history of hypertension should be a “weaker” risk factor. The second issue is the current recommendation that paroxysmal AF be considered to confer the same risk as persistent or permanent AF. The key definition of paroxysmal AF is that it is self-terminating within a short period of time, often less than 24 hours.2 Some of the original trials specifically excluded self-terminating AF,9 whereas others included only small numbers of such patients.10 A subanalysis of the SPAF (Stroke Prophylaxis in Atrial Fibrillation) trials looked at the risk of stroke in patients having “intermittent” AF in comparison with those having contin-
Heart Rhythm, Vol 4, No 3, March Supplement 2007 uous AF.11 In that analysis, the definitions of intermittent AF11 are starkly different from what we now agree is paroxysmal AF. Emerging evidence suggests that brief episodes of self-terminating AF do not constitute the same risk as long-lasting AF (Figure 2).12 Comparison of stroke rates in the anticoagulation-treated arms of several trials in relation to proportion with paroxysmal AF is shown in Table 2. Those trials with a higher proportion of patients with paroxysmal AF usually have a lower risk of stroke. Two large studies examining the relevance of duration of AF (“burden”) to the risk of thromboembolism using device telemetry are currently in progress.13,14 Another emerging controversy is the contemporary risk of a major bleeding complication. The risk was previously stated as being between 1% and 1.5% per year.1 One recent trial suggests the risk may be closer to 4% in the first year and even higher in “warfarin-naïve” patients.15 The increased risk of bleeding has been noted previously with the first episode of AF and starting warfarin.16 The risk of bleeding from warfarin in AF patients in the Framingham Study is also higher, perhaps because of increased risk in women (see later).17 Patients in contemporary trials may have more risk factors for bleeding and greater concurrent use of antiplatelet agents (see later). If the level of bleeding risk is higher than previously thought, it is imperative that the contemporary risk of thromboembolic events be accurately defined.
Some other controversies Risk of bleeding in the elderly The fear of bleeding is of even greater concern in the elderly, in whom the risk of bleeding while taking warfarin is believed to be greater.18 Increased risk of bleeding in older patients is particularly unfortunate because they generally have greater risk of stroke. However, an analysis of the Framingham data found that although female gender increased the risk of a bleeding complica-
Figure 2 Risk of thromboembolism according to duration of atrial fibrillation detected by device telemetry. (Reproduced with permission from Capucci et al.12)
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Anticoagulation in Atrial Fibrillation
tion, after adjustment for gender age did not.17 Because the risk of stroke is much greater in women than in men,19 the benefit/risk of warfarin is still believed to be favorable in elderly women. A cohort analysis suggested that, for intracranial bleeding, the increased risk is independently related to age and INR.20 Although no statistical interaction between age and INR was found, the numbers are small, and it is generally more difficult to precisely control the INR in the elderly. The guidelines suggest use of a lower INR in the elderly, who have difficulties with warfarin.2 It may be preferable to use the same target INR for the elderly but to monitor it more closely. Combination of vitamin K antagonists and antiplatelet agents Use of the combination of a vitamin K antagonist and an antiplatelet agent is increasingly common. There is no clear consensus about the correctness of such therapy. Certainly SPAF III showed that addition of aspirin does not permit a target INR within a lower range.21 After a recent myocardial infarction, warfarin alone is superior to aspirin alone, and the combination is better with respect to future ischemic events, although the risk of bleeding is greater with the combination.22 The combination of a vitamin K antagonist and an antiplatelet agent for treatment of AF was examined in a randomized clinical trial, albeit with agents not used in North America.23 That trial showed increased efficacy but also increased risk of bleeding with the combination. Thus, the combination probably should be used only in high risk patients, such as patients who recently underwent percutaneous coronary intervention with stent deployment or who had a recent myocardial infarction. Consideration should be given to discontinuation of the antiplatelet agent at some point. It is unfortunate that the patients at highest risk for thromboembolism also are at increased risk of bleeding from combination therapy.
Alternatives to vitamin K antagonists—What went wrong? There has been substantial enthusiasm and interest in finding alternatives to warfarin. The ideal agent would be as effective as vitamin K antagonists, have less risk of bleeding, and be simpler to use. In spite of a great deal of early promise, the comparative studies have been a major disappointment. Ximelagatran The first agent to be studied in large trials is the oral direct thrombin inhibitor ximelagatran. The key studies are SPORTIF III and SPORTIFV.7,8 Although the results of these two trials seemed promising, a number of problems emerged. The first was the setting of the noninferiority trial boundaries.24 A full discussion of this problem is beyond the scope of this article. Strict analysis suggests that SPORTIF V in particular did not demonstrate that ximelagatran was noninferior to warfarin.24 The second problem
S37 was liver toxicity.7,8 Initially it was hoped that careful monitoring of liver function tests could avert overt liver failure. However, when liver failure developed in a patient taking ximelagatran in an extended-duration venous thromboembolism prophylaxis trial, without prior elevation of serum liver function tests, further attempts to market this drug were abandoned. Combination of aspirin and clopidogrel The combination of clopidogrel and aspirin was studied in ACTIVE W (Atrial fibrillation with Clopidogrel Trial with Irbesartan for prevention of Vascular Events W [warfarin vs clopidogrel/aspirin], which was prematurely terminated because of clear superiority of warfarin to the combination of clopidogrel plus aspirin.16 A comparison of clopidogrel plus aspirin to aspirin alone continues in patients with stroke risk factors who are ineligible (due to contraindications) or unwilling to take warfarin in ACTIVE A (Atrial fibrillation with Clopidogrel Trial with Irbesartan for prevention of Vascular Events [aspirin vs clopidogrel/aspirin]).25 Idraparinux The other agent of interest that has been recently evaluated in a large randomized trial is the factor Xa inhibitor idraparinux, administered as a subcutaneous injection once per week. The results of the AMADEUS trial (which compared once per week subcutaneous idraparinux to adjusted-dose warfarin in AF patients with stroke risk factors) have not yet been presented or published. This trial was prematurely terminated because of excess bleeding, particularly intracranial bleeding, in the idraparinux arm, although the noninferiority criteria were met. It remains to be seen whether this agent will be tested in a modified dosage. Dabigatran This drug is an oral antithrombin inhibitor, and two doses currently are being compared with warfarin in a trial with a noninferiority design. It is hoped that liver toxicity will not be a problem as it was for ximelagatran.
Anticoagulation for cardioversion The use of anticoagulation around the time of cardioversion is independent of the considerations for chronic anticoagulation, except that the need for it probably is greatest in those who have stroke risk factors. The need for continuation of anticoagulation beyond cardioversion itself is dependent on the likelihood of recurrence of AF and the patient’s stroke risk profile (discussed earlier).
Fundamentals Based on observational studies, there is an increased risk of stroke and systemic embolus around the time of cardioversion. Accordingly, there is a need for anticoagulation to reduce that risk. There is an interval of time from the onset of AF before the risk of a thromboembolic event from cardioversion is evident. In the guidelines the interval is said to be 48 hours, although the duration of AF probably is a continuous variable as far as the risk of stroke is con-
S38 cerned,26 and consideration should be given for anticoagulation for shorter periods of AF in high risk patients. When the duration of AF is longer than 48 hours or is unknown, anticoagulation for reducing the risk of thromboembolism is recommended prior to and after cardioversion.2 Two approaches are deemed acceptable. The first is anticoagulation with warfarin at a therapeutic INR for at least 3 weeks prior to cardioversion and for 4 weeks after cardioversion. The second is immediate administration of either intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin followed by transesophageal echocardiography. In the absence of clot in the left atrium, cardioversion then can be undertaken, but anticoagulation must be continued for 4 weeks after cardioversion. The latter strategy is based largely on the results of the ACUTE (Assessment of Cardioversion Using Transesophageal Echocardiography) trial.27 However, a clear trend for increased risk of death using the latter approach in ACUTE should be noted. In the guidelines, no distinction is made for the need for antithrombotic therapy between electrical and pharmacologic cardioversion.
Recent information The exact magnitude of the risk of thromboembolism at the time of cardioversion is not known with any certainty and has been assessed only in retrospective cohort studies. These cohort studies often contain a mixture of patients with and without a variety of antithrombotic therapies. The most recent cohort data of this type examined INR and risk (Figure 3).28 It was noted that when the INR is between 1.5 and 1.9 at the time of cardioversion, the risk of thromboembolism is approximately 1%, falling to less than 1% when the INR is 2.0 –2.4 and is close to zero when the INR is ⱖ2.5. The alternative of using low-molecular-weight heparin subcutaneously around the time of cardioversion is a rela-
Heart Rhythm, Vol 4, No 3, March Supplement 2007 tively recent recommendation. It is based on a randomized controlled trial that compared low-molecular-weight heparin subcutaneously before and after cardioversion to intravenous unfractionated heparin followed by a vitamin K antagonist in a noninferiority design.29 The composite endpoint examined thromboembolism, death, or major hemorrhage, and using this endpoint, the two types of anticoagulation were similar.
Anticoagulation for left atrial radiofrequency ablation There are no randomized controlled trials of the use of anticoagulation around the time of left atrial ablation procedures. It is usual, however, for anticoagulation to be given for a period of time prior to ablation, for unfractionated heparin to be administered during the procedure, and for anticoagulation to be resumed for a period of time after ablation.30 Given reports of periprocedural strokes,31 these precautions seem prudent. In the presence of guiding sheaths and catheters, which may activate a different limb of the anticoagulation cascade,32 and with the burden of endocardial damage associated with the ablation procedure, unfractionated heparin would seem to be the preferred anticoagulant during the procedure. There is no evidence that anticoagulation can be safely stopped after an apparently successful procedure in high risk patients (CHADS2 score ⱖ3).31 Because some patients will continue to have asymptomatic episodes of AF,33 it seems prudent to continue anticoagulation indefinitely in such patients.
Conclusion Antithrombotic therapy for thromboembolism prophylaxis in patients with AF continues to be controversial and confusing in spite of nearly 2 decades of productive research. The two currently pressing needs are (1) contemporary validation and consolidation of all the major treatment
Figure 3 Risk of thromboembolism from cardioversion according to international normalized ratio (INR) at the time of cardioversion. (Reproduced with permission from Klein et al.27)
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guidelines, and (2) continuation of the quest for safer, simpler, and effective alternatives to vitamin K antagonists.
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suitable alternative to vitamin K antagonists are outlined. The treatment guidelines for anticoagulation for cardioversion are briefly reviewed. The risk of thromboembolism according to international normalized ratio and use of low-molecular-weight heparin as an alternative to warfarin are discussed. Anticoagulation before and after left atrial radiofrequency ablation is empirical, and long-term anticoagulation seems advisable for high risk patients at the present time. The two most pressing needs for further investigation are (1) clarification, simplification, and consolidated of risk stratification schemes and treatment recommendations and (2) discovery of alternatives to warfarin.
Introduction
of AF,2 characteristics predisposing to thromboembolism were weighted and subdivided into “high,” “moderate,” and “weaker” risk factors (Table 1). Based on the presence or absence of high and moderate risk factors, patients are categorized as “high,” “moderate,” or “low” risk. Aspirin is advised for patients with “low” risk, an oral vitamin K antagonist (international normalized ratio [INR] 2.0 –3.0) is advised for those with “high” risk, and either aspirin or oral vitamin K antagonist is advised for those with “moderate” risk. Such risk classification schemes and treatment recommendations are helpful, but physicians also must take into account even the lesser risk factors and the risk of bleeding. No therapy is totally effective and without risk so good judgment is needed.
Anticoagulation is an integral part of the therapy for all patients with atrial fibrillation (AF). It continues to be an area of therapy about which there is controversy and confusion.
Chronic anticoagulation Risk stratification Current fundamentals of risk stratification A fundamental tenet of chronic anticoagulation for thromboembolism prophylaxis in AF, arising from early randomized trials of warfarin therapy,1 is individualization of therapy on the basis of risk stratification. Prosthetic heart valves and mitral stenosis were identified earlier as risk factors and were not included in those trials. Several factors predisposing to thromboembolism in nonvalvular AF thus were identified. In the recent update of the American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for management Dr. Wyse is a member of the Scientific Advisory Board for Boehringer Ingelheim and Sanofi Aventis. Address reprint requests and correspondence: Dr. D. George Wyse, Libin Cardiovascular Institute of Alberta, University of Calgary, Department of Cardiac Sciences, 3330 Hospital Drive NW, Room G009, Calgary, Alberta T2N 4N1, Canada. E-mail address: [email protected].
KEYWORDS Atrial fibrillation; Anticoagulation; Antiplatelet agents; Thromboembolic risk; Bleeding risk; Risk stratification; Randomized controlled trials; Treatment guidelines; Radiofrequency ablation (Heart Rhythm 2007;4:S34 –S39) © 2007 Heart Rhythm Society. All rights reserved.
Confusion and controversies Several points of controversy contribute to confusion concerning risk stratification for antithrombotic therapy in AF. Consequently, both underuse and overuse of anticoagulation occurs.3,4 The confusion about risk stratification is partly related to the existence of many similar, but not identical, schemes. One commonly used scheme for nonvalvular AF (prosthetic valves and mitral stenosis excluded) is the so-called CHADS2 scheme (Figure 1).5 The CHADS2 scheme is simple to remember and use at the bedside and provides a more
1547-5271/$ -see front matter © 2007 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2006.12.001
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Table 1 Summary of risk stratification and recommendations for antithrombotic therapy from the 2006 ACC/AHA/ESC Guidelines Risk factors for stroke and systemic embolus in patients with atrial fibrillation Weaker risk
Moderate risk
Female gender Age ⱖ75 years Age 65–74 Hypertension years Coronary Left ventricular artery disease ejection fraction ⱕ0.35 or congestive heart failure Thyrotoxicosis Diabetes mellitus
S35 differently. Furthermore, the annual risk of some of the designated “high risk” patients was just over 3% while taking aspirin. The CHADS2 scheme stood out as most clearly identifying a truly high risk group (annual risk ⬎5%) in this analysis. Further work is needed to validate and consolidate the multiple schemes defining who is
High risk Mitral stenosis Prosthetic heart valve Stroke, transient ischemic attack, or systemic embolus
Table 2 Mean systolic blood pressure, proportion of patients with PAF at enrollment, and annual risk of stroke or systemic embolus in several trials Comparison of BP and risk of stroke or systemic embolus on vitamin K antagonist
Risk stratification and therapy recommendation Category
Recommendation
No risk factors One moderate risk factor
ASA (81–325 mg/day) ASA (81–325 mg/day) or warfarin (INR ⫽ 2.0–3.0) Warfarin (INR ⫽ 2.0 –3.0)*
Any high risk factor or ⱖ2 moderate risk factors
ACC/AHA/ESC ⫽ American College of Cardiology/American Heart Association/European Society of Cardiology; ASA ⫽ acetylsalicylic acid (aspirin); INR ⫽ international normalized ratio. Modified from Fuster et al.2 *Prosthetic heart valve, INR ⫽ 2.5 –3.5.
continuous scale of risk. CHADS2 is compatible with the ACC/AHA/ESC scheme by considering scores of 0 ⫽ low risk, 1 ⫽ moderate risk, and ⱖ2 ⫽ high risk in Table 1. CHADS2 and four other schemes have been applied to a cohort of AF patients taking aspirin.6 Patients were divided into low, moderate, and high risk subgroups using each of the schemes. The five schemes divide the same cohort very
Study
Mean systolic BP
Higher BP Studies (⬎135 mmHg) AFASAK I† 153 mmHg BAATAF† 139 mmHg SPAF I† 137 mmHg CAFA† 142 mmHg SPAF II† 139 mmHg AFASAK II† 149 mmHg SPORTIF III 139 mmHg Lower BP Studies (ⱕ135 mmHg) SPINAF† 134 mmHg AFFIRM 135 mmHg SPORTIF V 133 mmHg ACTIVE W 133 mmHg
2.0% 0.4% 2.3% 2.5% 1.9% 2.8% 1.9% 0.9% 1.2% 1.1% 1.4%
Comparison of Proportion with PAF and Risk of Stroke or systemic embolus on vitamin K antagonist
Study
Percent PAF
Higher Percentage of PAF Studies* AFFIRM 31% SPORTIF V 14% ACTIVE W 18% Lower Percentage of PAF Studies* AFASAK I† 0% SPINAF† 0% CAFA† 7% AFASAK II† 0% SPORTIF III 8%
Figure 1 Annual risk of stroke with 95% confidence intervals in the presence of atrial fibrillation using the CHADS2 risk stratification scheme of assigning points. Congestive heart failure ⫽ 1 point; hypertension ⫽ 1 point; age ⱖ75 years ⫽ 1 point; diabetes mellitus ⫽ 1 point; stroke, transient ischemic attack, or systemic embolus ⫽ 2 points. (Based on data from Gage et al.5)
Annual risk of stroke or systemic embolus on vitamin K antagonist
Annual risk of stroke or systemic embolus on vitamin K antagonist 1.2% 1.1% 1.4% 2.0% 0.9% 2.5% 2.8% 1.9%
BP ⫽ blood pressure; PAF ⫽ paroxysmal atrial fibrillation. Trials: ACTIVE W ⫽ Atrial fibrillation with Clopidogrel Trial with Irbesartan for prevention of Vascular Events W (warfarin vs clopidogrel/aspirin); AFASAK ⫽ Copenhagen Atrial Fibrillation, Aspirin and Anticoagulation Study; AFFIRM ⫽ Atrial Fibrillation Follow-up Investigation of Rhythm Management trial; BAATAF ⫽ Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA ⫽ Canadian Atrial Fibrillation Anticoagulation study; SPAF ⫽ Stroke Prophylaxis in Atrial Fibrillation trial; SPINAF ⫽ Stroke Prevention In Nonrheumatic Atrial Fibrillation study; SPORTIF ⫽ Stroke Prevention with the Oral diRect Thrombin Inhibitor ximelagatran in atrial Fibrillation trial. *Earlier studies, such as SPAF, included “intermittent” atrial fibrillation, which is not the same as paroxysmal atrial fibrillation. †Data provided by Dr. Carl van Walraven, University of Ottawa.
S36 truly in need of therapy with warfarin in contemporary AF patient populations. The issue of contemporary risk is under discussion because of a number of empirical observations. Among others, two emerging questions are topical. Is well-controlled hypertension really a moderate risk factor? And, does paroxysmal AF truly confer the same risk as persistent or permanent AF? The blood pressure issue has emerged partly in comparison of the two SPORTIF (Stroke Prevention with the Oral diRect Thrombin Inhibitor ximelagatran in atrial Fibrillation Trial) studies: SPORTIF III and SPORTIF V.7,8 There has been much speculation about possible explanations for the lower risk of stroke while being treated with warfarin in SPORTIF V. It has been noted that the average systolic blood pressure at entry to SPORTIF III was 139 mmHg but was 133 mmHg in SPORTIF V. A comparison of these two studies and several other trials on the basis of blood pressure at entry is given in Table 2. In general, studies with higher blood pressures at entry had higher risk of stroke in the anticoagulation-treated arms (Table 2). Furthermore, most of the trials with higher blood pressures are older, and it is these trials that identified hypertension as a risk factor. These observations, among others, have led to speculation that the definition of hypertension and contemporary control of blood pressure are different than they were years ago, and consequently history of hypertension should be a “weaker” risk factor. The second issue is the current recommendation that paroxysmal AF be considered to confer the same risk as persistent or permanent AF. The key definition of paroxysmal AF is that it is self-terminating within a short period of time, often less than 24 hours.2 Some of the original trials specifically excluded self-terminating AF,9 whereas others included only small numbers of such patients.10 A subanalysis of the SPAF (Stroke Prophylaxis in Atrial Fibrillation) trials looked at the risk of stroke in patients having “intermittent” AF in comparison with those having contin-
Heart Rhythm, Vol 4, No 3, March Supplement 2007 uous AF.11 In that analysis, the definitions of intermittent AF11 are starkly different from what we now agree is paroxysmal AF. Emerging evidence suggests that brief episodes of self-terminating AF do not constitute the same risk as long-lasting AF (Figure 2).12 Comparison of stroke rates in the anticoagulation-treated arms of several trials in relation to proportion with paroxysmal AF is shown in Table 2. Those trials with a higher proportion of patients with paroxysmal AF usually have a lower risk of stroke. Two large studies examining the relevance of duration of AF (“burden”) to the risk of thromboembolism using device telemetry are currently in progress.13,14 Another emerging controversy is the contemporary risk of a major bleeding complication. The risk was previously stated as being between 1% and 1.5% per year.1 One recent trial suggests the risk may be closer to 4% in the first year and even higher in “warfarin-naïve” patients.15 The increased risk of bleeding has been noted previously with the first episode of AF and starting warfarin.16 The risk of bleeding from warfarin in AF patients in the Framingham Study is also higher, perhaps because of increased risk in women (see later).17 Patients in contemporary trials may have more risk factors for bleeding and greater concurrent use of antiplatelet agents (see later). If the level of bleeding risk is higher than previously thought, it is imperative that the contemporary risk of thromboembolic events be accurately defined.
Some other controversies Risk of bleeding in the elderly The fear of bleeding is of even greater concern in the elderly, in whom the risk of bleeding while taking warfarin is believed to be greater.18 Increased risk of bleeding in older patients is particularly unfortunate because they generally have greater risk of stroke. However, an analysis of the Framingham data found that although female gender increased the risk of a bleeding complica-
Figure 2 Risk of thromboembolism according to duration of atrial fibrillation detected by device telemetry. (Reproduced with permission from Capucci et al.12)
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tion, after adjustment for gender age did not.17 Because the risk of stroke is much greater in women than in men,19 the benefit/risk of warfarin is still believed to be favorable in elderly women. A cohort analysis suggested that, for intracranial bleeding, the increased risk is independently related to age and INR.20 Although no statistical interaction between age and INR was found, the numbers are small, and it is generally more difficult to precisely control the INR in the elderly. The guidelines suggest use of a lower INR in the elderly, who have difficulties with warfarin.2 It may be preferable to use the same target INR for the elderly but to monitor it more closely. Combination of vitamin K antagonists and antiplatelet agents Use of the combination of a vitamin K antagonist and an antiplatelet agent is increasingly common. There is no clear consensus about the correctness of such therapy. Certainly SPAF III showed that addition of aspirin does not permit a target INR within a lower range.21 After a recent myocardial infarction, warfarin alone is superior to aspirin alone, and the combination is better with respect to future ischemic events, although the risk of bleeding is greater with the combination.22 The combination of a vitamin K antagonist and an antiplatelet agent for treatment of AF was examined in a randomized clinical trial, albeit with agents not used in North America.23 That trial showed increased efficacy but also increased risk of bleeding with the combination. Thus, the combination probably should be used only in high risk patients, such as patients who recently underwent percutaneous coronary intervention with stent deployment or who had a recent myocardial infarction. Consideration should be given to discontinuation of the antiplatelet agent at some point. It is unfortunate that the patients at highest risk for thromboembolism also are at increased risk of bleeding from combination therapy.
Alternatives to vitamin K antagonists—What went wrong? There has been substantial enthusiasm and interest in finding alternatives to warfarin. The ideal agent would be as effective as vitamin K antagonists, have less risk of bleeding, and be simpler to use. In spite of a great deal of early promise, the comparative studies have been a major disappointment. Ximelagatran The first agent to be studied in large trials is the oral direct thrombin inhibitor ximelagatran. The key studies are SPORTIF III and SPORTIFV.7,8 Although the results of these two trials seemed promising, a number of problems emerged. The first was the setting of the noninferiority trial boundaries.24 A full discussion of this problem is beyond the scope of this article. Strict analysis suggests that SPORTIF V in particular did not demonstrate that ximelagatran was noninferior to warfarin.24 The second problem
S37 was liver toxicity.7,8 Initially it was hoped that careful monitoring of liver function tests could avert overt liver failure. However, when liver failure developed in a patient taking ximelagatran in an extended-duration venous thromboembolism prophylaxis trial, without prior elevation of serum liver function tests, further attempts to market this drug were abandoned. Combination of aspirin and clopidogrel The combination of clopidogrel and aspirin was studied in ACTIVE W (Atrial fibrillation with Clopidogrel Trial with Irbesartan for prevention of Vascular Events W [warfarin vs clopidogrel/aspirin], which was prematurely terminated because of clear superiority of warfarin to the combination of clopidogrel plus aspirin.16 A comparison of clopidogrel plus aspirin to aspirin alone continues in patients with stroke risk factors who are ineligible (due to contraindications) or unwilling to take warfarin in ACTIVE A (Atrial fibrillation with Clopidogrel Trial with Irbesartan for prevention of Vascular Events [aspirin vs clopidogrel/aspirin]).25 Idraparinux The other agent of interest that has been recently evaluated in a large randomized trial is the factor Xa inhibitor idraparinux, administered as a subcutaneous injection once per week. The results of the AMADEUS trial (which compared once per week subcutaneous idraparinux to adjusted-dose warfarin in AF patients with stroke risk factors) have not yet been presented or published. This trial was prematurely terminated because of excess bleeding, particularly intracranial bleeding, in the idraparinux arm, although the noninferiority criteria were met. It remains to be seen whether this agent will be tested in a modified dosage. Dabigatran This drug is an oral antithrombin inhibitor, and two doses currently are being compared with warfarin in a trial with a noninferiority design. It is hoped that liver toxicity will not be a problem as it was for ximelagatran.
Anticoagulation for cardioversion The use of anticoagulation around the time of cardioversion is independent of the considerations for chronic anticoagulation, except that the need for it probably is greatest in those who have stroke risk factors. The need for continuation of anticoagulation beyond cardioversion itself is dependent on the likelihood of recurrence of AF and the patient’s stroke risk profile (discussed earlier).
Fundamentals Based on observational studies, there is an increased risk of stroke and systemic embolus around the time of cardioversion. Accordingly, there is a need for anticoagulation to reduce that risk. There is an interval of time from the onset of AF before the risk of a thromboembolic event from cardioversion is evident. In the guidelines the interval is said to be 48 hours, although the duration of AF probably is a continuous variable as far as the risk of stroke is con-
S38 cerned,26 and consideration should be given for anticoagulation for shorter periods of AF in high risk patients. When the duration of AF is longer than 48 hours or is unknown, anticoagulation for reducing the risk of thromboembolism is recommended prior to and after cardioversion.2 Two approaches are deemed acceptable. The first is anticoagulation with warfarin at a therapeutic INR for at least 3 weeks prior to cardioversion and for 4 weeks after cardioversion. The second is immediate administration of either intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin followed by transesophageal echocardiography. In the absence of clot in the left atrium, cardioversion then can be undertaken, but anticoagulation must be continued for 4 weeks after cardioversion. The latter strategy is based largely on the results of the ACUTE (Assessment of Cardioversion Using Transesophageal Echocardiography) trial.27 However, a clear trend for increased risk of death using the latter approach in ACUTE should be noted. In the guidelines, no distinction is made for the need for antithrombotic therapy between electrical and pharmacologic cardioversion.
Recent information The exact magnitude of the risk of thromboembolism at the time of cardioversion is not known with any certainty and has been assessed only in retrospective cohort studies. These cohort studies often contain a mixture of patients with and without a variety of antithrombotic therapies. The most recent cohort data of this type examined INR and risk (Figure 3).28 It was noted that when the INR is between 1.5 and 1.9 at the time of cardioversion, the risk of thromboembolism is approximately 1%, falling to less than 1% when the INR is 2.0 –2.4 and is close to zero when the INR is ⱖ2.5. The alternative of using low-molecular-weight heparin subcutaneously around the time of cardioversion is a rela-
Heart Rhythm, Vol 4, No 3, March Supplement 2007 tively recent recommendation. It is based on a randomized controlled trial that compared low-molecular-weight heparin subcutaneously before and after cardioversion to intravenous unfractionated heparin followed by a vitamin K antagonist in a noninferiority design.29 The composite endpoint examined thromboembolism, death, or major hemorrhage, and using this endpoint, the two types of anticoagulation were similar.
Anticoagulation for left atrial radiofrequency ablation There are no randomized controlled trials of the use of anticoagulation around the time of left atrial ablation procedures. It is usual, however, for anticoagulation to be given for a period of time prior to ablation, for unfractionated heparin to be administered during the procedure, and for anticoagulation to be resumed for a period of time after ablation.30 Given reports of periprocedural strokes,31 these precautions seem prudent. In the presence of guiding sheaths and catheters, which may activate a different limb of the anticoagulation cascade,32 and with the burden of endocardial damage associated with the ablation procedure, unfractionated heparin would seem to be the preferred anticoagulant during the procedure. There is no evidence that anticoagulation can be safely stopped after an apparently successful procedure in high risk patients (CHADS2 score ⱖ3).31 Because some patients will continue to have asymptomatic episodes of AF,33 it seems prudent to continue anticoagulation indefinitely in such patients.
Conclusion Antithrombotic therapy for thromboembolism prophylaxis in patients with AF continues to be controversial and confusing in spite of nearly 2 decades of productive research. The two currently pressing needs are (1) contemporary validation and consolidation of all the major treatment
Figure 3 Risk of thromboembolism from cardioversion according to international normalized ratio (INR) at the time of cardioversion. (Reproduced with permission from Klein et al.27)
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S39
guidelines, and (2) continuation of the quest for safer, simpler, and effective alternatives to vitamin K antagonists.
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