For patients who do choose antithrombotic therapy, we suggest aspi- rin (75 mg to 325 mg once daily) rather than www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e533S For patients with AF at low to intermediate risk of stroke (eg, CHADS2 score of 0 or 1) during the rst 12 months after placement of an intracoronary stent (bare metal or drug eluting), we suggest dual antiplatelet ther- apy rather than triple therapy (Grade 2C). At 12 months after intracoronary stent place- ment, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). Remarks: Patients who place an exceptionally high value on stroke reduction and a low value on avoid- ing bleeding and the burden associated with antico- agulant therapy are likely to choose triple therapy rather than dual antiplatelet therapy. Other factors that may in uence this choice are a consideration of bleeding risk and the presence of additional non- CHADS2 risk factors for stroke (see section 2.1.12). 3.3. For patients with AF at intermediate to high risk of stroke (eg, CHADS2 score of 1 or greater) who experience an acute coronary syndrome and do not undergo intracoronary stent place- ment, we suggest for the rst 12 months, adjusted-dose VKA therapy (INR 2.0-3.0) plus single antiplatelet therapy rather than dual antiplatelet therapy (eg, aspirin and clopidogrel) or triple therapy (eg, warfarin, aspirin, and clopidogrel) (Grade 2C). After the rst 12 months, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1).


After the rst 12 months, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). For patients with AF at low risk of stroke (eg, CHADS2 score of 0), we suggest dual anti- platelet therapy (eg, aspirin and clopidogrel) rather than adjusted-dose VKA therapy (INR 2.0-3.0) plus single antiplatelet therapy or triple therapy (eg, warfarin, aspirin, and clopid- ogrel) (Grade 2C). After the rst 12 months, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). Remarks: Patients who place an exceptionally high value on stroke reduction and a low value on avoiding bleeding and the burden associated with anticoagu- lant therapy are likely to choose adjusted-dose VKA therapy plus single antiplatelet therapy rather than dual antiplatelet therapy. Other factors that may in uence this choice are a consideration of bleeding risk and the presence of additional non-CHADS2 risk factors for stroke (see section 2.1.12). 3.4. For patients with AF being managed with a rhythm control strategy (pharmacologic or about major bleeding), we recommend combi- nation therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) (Grade 1B). 2.1.11. For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation (including 2.1.9, suggest dabigatran 150 mg twice daily rather than adjusted-dose vitamin K antagonist (VKA) therapy (target INR range, 2.0-3.0) (Grade 2B). Remarks: Dabigatran is excreted primarily by the kidney. It has not been studied and is contraindi- cated in patients with severe renal impairment (esti- mated creatinine clearance of 30 mL/min or less). Clinicians should be aware that there is no antidote for dabigatran. 2.2.


Clinicians should be aware that there is no antidote for dabigatran. 2.2. For patients with AF and mitral stenosis, we recommend adjusted-dose VKA therapy (target INR range, 2.0-3.0) rather than no therapy, aspirin (75 mg to 325 mg once daily), or combi- nation therapy with aspirin and clopidogrel (all Grade 1B). For patients with AF and mitral ste- nosis who are unsuitable for or choose not to take adjusted-dose VKA therapy (for reasons other than concerns about major bleeding), we recommend combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) alone (Grade 1B). 3.1. For patients with AF and stable coronary artery disease (eg, no acute coronary syndrome within the previous year) and who choose oral anticoagulation, we suggest adjusted-dose VKA therapy alone (target international normal- ized ratio [INR] range, 2.0-3.0) rather than the combination of adjusted-dose VKA therapy and aspirin (Grade 2C). 3.2. For patients with AF at high risk of stroke (eg, CHADS2 score of 2 or greater) during the rst month after placement of a bare-metal stent or the rst 3 to 6 months after place- ment of a drug-eluting stent, we suggest triple therapy (eg, VKA therapy, aspirin, and clopid- ogrel) rather than dual antiplatelet therapy (eg, aspirin and clopidogrel) (Grade 2C). After this initial period of triple therapy, we suggest a VKA (INR 2.0-3.0) plus a single antiplatelet drug rather than VKA alone (Grade 2C). At 12 months after intracoronary stent placement, antithrom- botic therapy is suggested as for patients with AF and stable coronary artery disease (see sec- tion 3.1). e534S Antithrombotic Therapy for Atrial Fibrillation (Grade 2C), but that initiation of anticoagulation must not delay any emergency intervention (Grade 2C).


e534S Antithrombotic Therapy for Atrial Fibrillation (Grade 2C), but that initiation of anticoagulation must not delay any emergency intervention (Grade 2C). After successful cardioversion to sinus rhythm, we suggest therapeutic antico- agulation for at least 4 weeks after successful cardioversion to sinus rhythm rather than no anticoagulation, regardless of baseline stroke risk (Grade 2C). Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk-based recommendations for long- term antithrombotic therapy in section 2.1. 4.3. For patients with atrial utter undergo- ing elective or urgent pharmacologic or elec- trical cardioversion, we suggest that the same approach to thromboprophylaxis be used as for patients with atrial brillation undergoing cardioversion. Atrial brillation (AF) is the most common sus- tained cardiac arrhythmia. One in four individ- uals aged 40 years will develop AF during his or her lifetime, and it has been estimated that by the year 2050, up to 16 million Americans will have AF.1,2 Nonrheumatic AF is a strong, independent predictor of ischemic stroke associated with a vefold increase in risk.3 Without thromboprophylaxis, the risk of ischemic stroke in patients with nonrheumatic AF, as seen in the control arms of the original trials of antithrombotic therapy in AF, is 5% per year.4 Over the past 2 decades, considerable work has been done to evaluate antithrombotic therapies to prevent stroke in patients with AF, and the eld continues to evolve with the emergence of a new generation of oral anticoagulants. This article begins with a discussion of the methods used to develop our recommendations for antithrombotic therapy in patients with AF. Next, we provide our treatment recommendations, divided into the following sections: 1. Antithrombotic therapy in patients with AF in general (includes patients with permanent, per- sistent, or paroxysmal AF [PAF]) 2.


Antithrombotic therapy in patients with AF in general (includes patients with permanent, per- sistent, or paroxysmal AF [PAF]) 2. Antithrombotic therapy in patients with AF in special situations: Stable coronary artery disease Acute coronary syndrome (ACS) Intracoronary artery stent Acute ischemic stroke Management with a rhythm control strategy Chronic atrial utter 3. Antithrombotic therapy for patients with AF undergoing cardioversion catheter ablation), we suggest that antithrom- botic therapy decisions follow the general risk- based recommendations for patients with AF in section 2.1, regardless of the apparent persis- tence of normal sinus rhythm (Grade 2C). 3.5. For patients with atrial utter, we sug- gest that antithrombotic therapy decisions follow the same risk-based recommendations as for AF. 4.1.1. For patients with AF of greater than 48 h or unknown duration undergoing elective electri- cal or pharmacologic cardioversion, we recom- mend therapeutic anticoagulation (adjusted-dose VKA therapy, target INR range 2.0-3.0, low- molecular-weight heparin at full venous throm- boembolism treatment doses, or dabigatran) for at least 3 weeks before cardioversion or a transesophageal echocardiography (TEE)- guided approach with abbreviated antico- agulation before cardioversion rather than no anticoagulation (Grade 1B). We recommend therapeutic anticoagulation for at least 4 weeks after successful cardioversion to sinus rhythm rather than no anticoagulation, regardless of the baseline risk of stroke (Grade 1B). Decisions about anticoagulation beyond 4 weeks should be made in accordance with our risk-based rec- ommendations for long-term antithrombotic therapy in section 2.1. 4.1.2. For patients with AF of documented duration of 48 h or less undergoing elective cardioversion (electrical or pharmacologic), we suggest starting anticoagulation at presentation (low-molecular-weight heparin or unfraction- ated heparin at full venous thromboembolism treatment doses) and proceeding to cardio- version rather than delaying cardioversion for 3 weeks of therapeutic anticoagulation or a TEE-guided approach (Grade 2C).


For patients with AF of documented duration of 48 h or less undergoing elective cardioversion (electrical or pharmacologic), we suggest starting anticoagulation at presentation (low-molecular-weight heparin or unfraction- ated heparin at full venous thromboembolism treatment doses) and proceeding to cardio- version rather than delaying cardioversion for 3 weeks of therapeutic anticoagulation or a TEE-guided approach (Grade 2C). After suc- cessful cardioversion to sinus rhythm, we rec- ommend therapeutic anticoagulation for at least 4 weeks rather than no anticoagulation, regard- less of baseline stroke risk (Grade 2C). Decisions about long-term anticoagulation after cardio- version should be made in accordance with our risk-based recommendations for long-term antithrombotic therapy in section 2.1. 4.2. For patients with AF and hemodynamic instability undergoing urgent cardioversion (electrical or pharmacologic), we suggest that therapeutic-dose parenteral anticoagulation be started before cardioversion, if possible www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e535S frequent blood testing and clinic visits. For recommendations about patients with AF and stable coronary artery disease, intra- coronary stent placement, or recent ACS (sections 3.1-3.3), we also considered the effect of different treatment options on the outcome of nonfatal myocardial infarction (MI). 1.2 Patient Values and Preferences In developing our treatment recommendations, we attempted to account for patient values and preferences regarding these health states. In this guideline, a systematic review of studies assessing values and preferences related to antithrombotic therapy found that values for health states and preferences for treatments vary appreciably among individuals (MacLean et al9). The avail- able literature has several limitations. The studies eliciting prefer- ences were small and used different methods and tools, and most included a sizeable proportion of participants who had previ- ously taken or were currently taking VKAs.


The studies eliciting prefer- ences were small and used different methods and tools, and most included a sizeable proportion of participants who had previ- ously taken or were currently taking VKAs. Furthermore, there are inconsistencies across studies that often are dif cult to explain, leaving considerable uncertainty about average patient values. Nevertheless, to make our recommendations, we required an esti- mate of average patient values for the relevant outcomes so that we could judge whether the trade-offs between bene t and harm would favor one course of treatment over another. As described by Guyatt et al10 in this guideline, to obtain our estimates of average patient values, we have used ratings of key health states from participating guideline panelists informed by our systematic review of the relevant literature. The results of the panelist value rating exercise suggest that on average, patients would nd a typical nonfatal stroke (ischemic or hemorrhagic) approximately three times as aversive as a nonfatal major extra- cranial bleed (typically a GI bleed) and a typical nonfatal MI as aversive as a nonfatal major extracranial bleed. With the exception of the choice between VKA therapy and no therapy, the choice of one antithrombotic treatment over another for long-term stroke prevention in AF will not lead to differences in all-cause mortality (section 2). Thus, for these choices that are not expected to result in a difference in mor- tality, for every 1,000 patients treated for 1 year, if the number of nonfatal strokes prevented is less than one-third of the number of nonfatal major extracranial bleeds caused by a given antithrom- botic therapy, we have recommended against that intervention.


Thus, for these choices that are not expected to result in a difference in mor- tality, for every 1,000 patients treated for 1 year, if the number of nonfatal strokes prevented is less than one-third of the number of nonfatal major extracranial bleeds caused by a given antithrom- botic therapy, we have recommended against that intervention. If the number of nonfatal strokes prevented is appreciably more than one-third of the number of nonfatal major extracranial bleeding events that result from a given antithrombotic therapy, we have recommended in favor. Making these trade-offs requires not only estimates regarding average patient values for the relevant outcomes but also best esti- mates of (1) the effect of a given treatment on these outcomes against a given comparator (ie, relative risk) and (2) the absolute event rates for these outcomes in untreated patients (or, for PICO questions of a treatment vs an active comparator, the absolute event rates in patients receiving the active comparator). In the following section, we present the methods used to obtain these estimates for our guidelines. 1.3 Estimating the Magnitude of Treatment Effect For each clinical question, we extracted data regarding the previously discussed outcomes from the relevant clinical trials. When there were multiple randomized controlled trials (RCTs) addressing the same clinical question, we conducted meta- analyses using random-effects models and the Mantel-Haenszel method to obtain pooled estimates of treatment effect, expressed as relative risk. For studies that did not report the proportion of strokes that were fatal and nonfatal, we used all available data in the published report to obtain a best estimate of the effect of The article ends with a discussion of practical issues in the use of adjusted-dose vitamin K antago- nist (VKA) therapy in patients with AF and sugges- tions for future research.


For studies that did not report the proportion of strokes that were fatal and nonfatal, we used all available data in the published report to obtain a best estimate of the effect of The article ends with a discussion of practical issues in the use of adjusted-dose vitamin K antago- nist (VKA) therapy in patients with AF and sugges- tions for future research. Table 1 speci es the clinical question being addressed in this article (in PICO [population, inter- vention, comparator, outcomes] format) and the types of studies used. This article does not give recommen- dations for antithrombotic therapy in patients with AF around the time of surgical or invasive proce- dures (see Douketis et al5), at the time of presen- tation with acute stroke (see Lansberg et al6), or in patients with AF who have prosthetic heart valves (see Whitlock et al7). This article does not give recom- mendations for patients with AF who are pregnant. For general recommendations on antithrombotic ther- apy during pregnancy (ie, not speci c to AF), see Bates et al.8 Finally, the recommendations in this article apply to patients with persistent and perma- nent AF and to patients with PAF but do not apply to patients with a single, transient, self-limited episode of AF associated with acute illness. To inform our guideline development, we searched for relevant articles published since the last literature search performed for the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Speci cally, for literature regarding the assess- ment of stroke risk in patients with AF, we searched Medline for articles published from January 1, 2005, to October 2009 using the search terms atrial brillation, atrial utter, risk assess- ment, risk factors, risk strati cation, stroke, and thrombo- embolism.


Speci cally, for literature regarding the assess- ment of stroke risk in patients with AF, we searched Medline for articles published from January 1, 2005, to October 2009 using the search terms atrial brillation, atrial utter, risk assess- ment, risk factors, risk strati cation, stroke, and thrombo- embolism. For literature regarding prevention of stroke and thromboembolism in patients with AF, we searched Medline for articles published from January 1, 2005, to October 2009 using the search terms coumarins, warfarin, dicumarol, phenprocoumon, acenocoumarol, fondaparinux, idraparinux, aspirin, tri usal, indobufen, dabigatran, ximelagatran, rivaroxaban, apixaban, ticlopidine, clopidogrel, catheter ablation, watchman, PLAATO, cardioversion, atrial bril- lation, and atrial utter. 1.1 Outcomes of Interest The outcomes most relevant to patients with AF include death, nonfatal stroke, systemic embolism, nonfatal major extracranial bleeding, and the burden and lifestyle limitations associated with outpatient antithrombotic therapy. To facilitate decision-making, the term stroke in this article includes ischemic stroke and intra- cranial hemorrhage (intracerebral, subdural, and subarachnoid hemorrhage). Although there may be some differences in the impact of these intracranial events (eg, subdural hemorrhage) on quality of life, we judged that on average, the impact would be similar. We also explicitly considered that outpatient antithrom- botic therapy was associated with a burden to the patient, which in some cases, such as aspirin, is a requirement to take a daily medication, or in other cases, such as adjusted-dose VKA therapy, is not only a requirement to take a daily medication but also a requirement to limit one s lifestyle, restrict one s diet, and undergo e536S Antithrombotic Therapy for Atrial Fibrillation Table [Introduction] Clinical Questions Addressed in This Article Section Population Intervention Comparator Outcomes of Interest Available Methodology 2.


We also explicitly considered that outpatient antithrom- botic therapy was associated with a burden to the patient, which in some cases, such as aspirin, is a requirement to take a daily medication, or in other cases, such as adjusted-dose VKA therapy, is not only a requirement to take a daily medication but also a requirement to limit one s lifestyle, restrict one s diet, and undergo e536S Antithrombotic Therapy for Atrial Fibrillation Table [Introduction] Clinical Questions Addressed in This Article Section Population Intervention Comparator Outcomes of Interest Available Methodology 2. Patients with AF in general Patients with nonrheumatic AF Adjusted-dose VKA No therapy Death Nonfatal strokes Nonfatal major extracranial bleeds Systemic embolism Procedural complications (for percutaneous closure of left atrial appendage only) RCTs Antiplatelet monotherapy (eg, aspirin) No therapy VKA Antiplatelet monotherapy (eg, aspirin) VKA Aspirin clopidogrel Aspirin clopidogrel Aspirin New oral anticoagulants VKA Dabigatran VKA Percutaneous closure of left atrial appendage VKA RCTs Cohort studies Patients with AF and mitral stenosis VKA No therapy, antiplatelet monotherapy (eg, aspirin), or aspirin clopidogrel Cohort studies 3. Management of antithrombotic therapy for patients with AF in special situations Patients with AF and stable coronary artery disease VKA aspirin VKA Death Nonfatal strokes Nonfatal MI Nonfatal major extracranial bleeds Systemic embolism Cohort studies Patients with AF and placement of an intracoronary stent (with or without recent ACS) VKA aspirin clopidogrel Aspirin clopidogrel Patients with AF and ACS who do not undergo intracoronary stent placement VKA aspirin Aspirin clopidogrel VKA aspirin clopidogrel Patients with AF being managed with a rhythm control strategy VKA No VKA Death Nonfatal strokes Nonfatal major extracranial bleeds Systemic embolism Patients with chronic atrial utter Antithrombotic therapy options as per section 4. Patients with AF undergoing cardioversion Patients with AF of .


Patients with AF undergoing cardioversion Patients with AF of . h or unknown duration undergoing elective cardioversion Minimum wk anticoagulation before and wk after cardioversion No anticoagulation Death Nonfatal strokes Nonfatal major extracranial bleeds Systemic embolism Cohort studies Abbreviated precardioversion anticoagulation TEE-guided cardioversion No anticoagulation RCTs Cohort studies Patients with AF of h duration undergoing elective cardioversion Anticoagulation before cardioversion No anticoagulation before cardioversion Cohort studies Patients undergoing urgent cardioversion for hemodynamically unstable AF Anticoagulation before cardioversion No anticoagulation before cardioversion Cohort studies Patients undergoing elective or urgent cardioversion for atrial utter Anticoagulation before and after cardioversion No anticoagulation Cohort studies ACS acute coronary syndrome; AF atrial brillation; MI myocardial infarction; RCT randomized controlled trial; TEE transesophageal echocardiography; VKA vitamin K antagonist. www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e537S tic plaque in the descending aorta seen on transesophageal echo- cardiography [TEE] or a history of peripheral arterial disease) independently predicts stroke risk among patients with AF.21-23 1.4.3 Stroke Risk Strati cation Schema: Many risk strati - cation schema, which use various combinations of the risk fac- tors discussed previously, have been developed to aid clinicians in the assessment of stroke risk in patients with nonrheumatic AF (Table S13).12 Despite substantial efforts in this eld over the past several decades, all available schema have only modest ability to predict stroke in patients with AF, with C statistics typi- cally between 0.55 and 0.70.4,24-43 (A C statistic of 0.50 indicates a model that does not discriminate better than chance alone, and a C statistic of 1.00 indicates perfect discrimination.)


www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e537S tic plaque in the descending aorta seen on transesophageal echo- cardiography [TEE] or a history of peripheral arterial disease) independently predicts stroke risk among patients with AF.21-23 1.4.3 Stroke Risk Strati cation Schema: Many risk strati - cation schema, which use various combinations of the risk fac- tors discussed previously, have been developed to aid clinicians in the assessment of stroke risk in patients with nonrheumatic AF (Table S13).12 Despite substantial efforts in this eld over the past several decades, all available schema have only modest ability to predict stroke in patients with AF, with C statistics typi- cally between 0.55 and 0.70.4,24-43 (A C statistic of 0.50 indicates a model that does not discriminate better than chance alone, and a C statistic of 1.00 indicates perfect discrimination.) The CHADS2 score is the most validated risk scheme, having been independently tested in at least 10 separate cohorts after its original derivation.24,32,35-46 The CHADS2 score gives a single point for each of congestive heart failure (originally de ned as a recent exacerbation of congestive heart failure), hypertension (de ned as a history of hypertension, rather than a presence of elevated BP), age 75 years, and diabetes mellitus and two points for prior stroke or TIA (Table 2).30 Despite its widespread adoption and ease of use, the CHADS2 score has limitations. First, congestive heart failure is not a consis- tently demonstrated independent predictor of stroke.


First, congestive heart failure is not a consis- tently demonstrated independent predictor of stroke. Second, the risk associated with a history of hypertension may differ among patients with well-treated vs poorly treated hypertension.46-48 Third, in most studies, the CHADS2 score has only a modest ability to predict stroke in patients with AF (C statistic, 0.56-0.70).24,32,35-46 Finally, the threshold of stroke risk at which treatment with oral anticoagulation will be preferred is likely to decrease with the emergence of new oral anticoagulants that do not require reg- ular monitoring of the international normalized ratio (INR) and that may be associated with greater reductions in stroke and less risk of bleeding compared with adjusted-dose VKA therapy.49 Thus, stroke risk strati cation schema will need to evolve to more accurately identify patients who are at suf ciently low risk of stroke and can be treated with aspirin or no antithrombotic ther- apy, whereas all other patients with AF can be considered for oral anticoagulation. The CHA2DS2-VASc (congestive heart failure [or left ventric- ular systolic dysfunction], hypertension, age ,75 years; diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex) score is a new risk scheme that combines the CHADS2 score with additional moderate risk fac- tors, which were also included in the 2006 American College of Cardiology/American Heart Association/European Society of Cardiology and National Institute for Health and Clinical Excel- lence AF practice guidelines.29,50 Speci cally, the CHA2DS2-VASc score assigns points as in the original CHADS2 score (Table 2) with the exception of age 75 years, which is assigned two points.


The CHA2DS2-VASc (congestive heart failure [or left ventric- ular systolic dysfunction], hypertension, age ,75 years; diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65 to 74 years, female sex) score is a new risk scheme that combines the CHADS2 score with additional moderate risk fac- tors, which were also included in the 2006 American College of Cardiology/American Heart Association/European Society of Cardiology and National Institute for Health and Clinical Excel- lence AF practice guidelines.29,50 Speci cally, the CHA2DS2-VASc score assigns points as in the original CHADS2 score (Table 2) with the exception of age 75 years, which is assigned two points. It also assigns a single point for each of the following additional treatment on nonfatal stroke by assuming a case fatality rate of 50% for hemorrhagic stroke and 25% for ischemic stroke based on population-based stroke registry data and the case fatality rates observed in the RCTs of patients with AF that reported such data.11 For nonfatal major extracranial bleeding, we accepted the de nition of major bleeding from the individual studies, and when the proportion of major extracranial bleeds that were fatal vs nonfatal was not reported, we applied the average case fatality rate for major extracranial bleeding reported across the relevant clinical trials (15%). For the outcome of systemic embolism, we used the total number of events (fatal and nonfatal) because systemic embolism was an infrequent event and typically not reported as fatal vs nonfatal. 1.4 Deriving Baseline Risk of Stroke in Patients With AF The risk of stroke varies considerably across different groups of patients with AF.12 Simple validated tools for the assessment of stroke risk in patients with AF help in identifying those who are more likely to bene t than be harmed from antithrombotic therapy.


1.4 Deriving Baseline Risk of Stroke in Patients With AF The risk of stroke varies considerably across different groups of patients with AF.12 Simple validated tools for the assessment of stroke risk in patients with AF help in identifying those who are more likely to bene t than be harmed from antithrombotic therapy. 1.4.1 Pattern of AF: Guidelines have categorized the pat- tern of AF into (1) PAF, in which recurrent episodes terminate spontaneously within 7 days and usually in ,48 h; (2) persistent AF, in which the episode of AF does not self-terminate within 7 days or is terminated by cardioversion; and (3) permanent AF, in which AF is present for some time and cardioversion either has failed or has not been attempted.13 For patients with PAF, periods of sinus rhythm theoretically should lessen the risk of stroke, yet transitions from AF to sinus rhythm may acutely heighten risk in a manner similar to the increase in risk caused by cardioversion. Although some studies suggest that PAF is associated with a lower risk of stroke than persistent or permanent AF, patients with PAF generally are younger and have a lower prevalence of other stroke risk factors, and clinical trial data suggest that PAF confers a relative risk of stroke similar to persistent or permanent AF when controlling for associated stroke risk factors.14-17 Pending further evidence, it seems reasonable to treat patients with PAF in a manner similar to those with persistent and permanent AF; thus, our risk-based treatment recommendations apply to patients with PAF and per- sistent and permanent AF.


Although some studies suggest that PAF is associated with a lower risk of stroke than persistent or permanent AF, patients with PAF generally are younger and have a lower prevalence of other stroke risk factors, and clinical trial data suggest that PAF confers a relative risk of stroke similar to persistent or permanent AF when controlling for associated stroke risk factors.14-17 Pending further evidence, it seems reasonable to treat patients with PAF in a manner similar to those with persistent and permanent AF; thus, our risk-based treatment recommendations apply to patients with PAF and per- sistent and permanent AF. 1.4.2 Independent Risk Factors for Stroke in Patients With AF: Two recent systematic reviews have identi ed clinical and echo- cardiographic factors that are independently associated with an increased risk of stroke in patients with AF.18,19 The individual studies from these systematic reviews, in addition to articles identi ed in an updated literature search performed for this guideline, are summarized in Tables S1 through S12 (tables that contain an S before the number denote supplementary tables not contained in the body of the article and available instead in an online data supplement; see the Acknowledgments for more information). In terms of clinical applicability, the most consistently identi ed risk factors for ischemic stroke among patients with AF are a history of ischemic stroke or transient ischemic attack (TIA) the strongest dichotomous predictor of stroke risk older age, hypertension, and diabetes. Although impaired left ventricular systolic function is a risk factor for stroke in AF, there are con icting data about whether a history of congestive heart failure per se raises the risk of ischemic stroke in AF.


Although impaired left ventricular systolic function is a risk factor for stroke in AF, there are con icting data about whether a history of congestive heart failure per se raises the risk of ischemic stroke in AF. Although age thresholds often are used in stroke risk schemes, stroke risk in AF increases contin- uously with age, appreciably rising from age 65 years onward.20 There is moderate-quality evidence that women face a higher risk of stroke than men.18 A history of coronary artery disease has not consistently been found to be an independent risk factor for stroke in patients with AF.18 However, there is low-quality evidence that the presence of atherosclerotic vascular disease (eg, complex aor- Assessment of Stroke Risk in Patients With Nonrheumatic AF Risk Factor Points Recent Congestive heart failure exacerbation 1 History of Hypertension 1 Diabetes mellitus 1 Prior history of Stroke or transient ischemic attack 2 CHADS2 5congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischemic attack. See Table 1 legend for expansion of other abbreviation. e538S Antithrombotic Therapy for Atrial Fibrillation score of 1.5, and a substantial majority (78%) of patients in the cohort had a CHADS2 score of 1.44 Although CHADS2-speci c rates of all-cause mortality are not available from this cohort, the risk of death is expected to be lower in low-risk patients with a CHADS2 score of 0 because of their younger age, lower preva- lence of vascular risk factors, and lower rates of fatal ischemic stroke. 1.6 Deriving Baseline Risk of Nonfatal Major Extracranial Bleeding To develop our recommendations, we also required estimates of the baseline risk of nonfatal major extracranial bleeding in patients with AF.


1.6 Deriving Baseline Risk of Nonfatal Major Extracranial Bleeding To develop our recommendations, we also required estimates of the baseline risk of nonfatal major extracranial bleeding in patients with AF. We obtained this estimate from observational studies of VKA therapy in cohorts that included exclusively or predominantly patients with AF (median rate of 1.3% per year across these studies).44,53,54 To estimate the baseline risk of non- fatal major extracranial bleeding off VKA therapy, we used this median rate of bleeding on VKA therapy from the observa- tional studies (1.3% per year) and divided by the pooled relative risk (2.58) of nonfatal major extracranial bleeding associated with VKA therapy, as obtained from RCTs of VKA therapy vs no therapy. Therefore, our estimate of the baseline risk of nonfatal major extracranial bleeding off therapy was 0.5% per year. 2.0 Antithrombotic Therapy for Patients With AF in General Over the past 2 decades, numerous RCTs have investigated antithrombotic therapies to reduce the risk of thromboembolism, principally ischemic stroke, in patients with AF. In this section, we summarize the evidence and give treatment recommendations for VKA therapy, antiplatelet monotherapy (eg, aspirin), dual antiplatelet therapy with aspirin and clopid- ogrel, and new oral anticoagulants (eg, dabigatran) in patients with AF.


In this section, we summarize the evidence and give treatment recommendations for VKA therapy, antiplatelet monotherapy (eg, aspirin), dual antiplatelet therapy with aspirin and clopid- ogrel, and new oral anticoagulants (eg, dabigatran) in patients with AF. 2.1 Patients With Nonrheumatic AF 2.1.1 VKAs vs No Therapy: Six RCTs that enrolled a total of 2,584 patients and address the primary pre- vention (Atrial Fibrillation Aspirin and Anticoagulation [AFASAK] 1, Boston Area Anticoagulation Trial for Atrial Fibrillation [BAATAF], Canadian Atrial Fibril- lation Anticoagulation [CAFA], Stroke Prevention in Atrial Fibrillation [SPAF] I, Stroke Prevention in Nonrheumatic Atrial Fibrillation [SPINAF]) and sec- ondary prevention (European Atrial Fibrillation Trial [EAFT]) of stroke in patients with AF provide high- quality evidence that VKA therapy reduces the risk of death by one-fourth and the risk of nonfatal stroke by two-thirds compared with no therapy (Table 3).55-61 For patients with a CHADS2 score of 0, the studies provide moderate-quality evidence that VKA therapy increases the risk of nonfatal major extracranial bleeding due to imprecision of the esti- mate (wide CIs). The studies provide high-quality evidence for patients with higher CHADS2 scores. risk factors: female sex, age 65 to 74 years, and vascular disease (de ned as a history of MI, peripheral arterial disease, or complex aortic plaque). The CHA2DS2-VASc score has been evaluated in at least ve separate cohorts since its original description.


The CHA2DS2-VASc score has been evaluated in at least ve separate cohorts since its original description. With the exception of a recent study by Olesen et al,24 all other studies have found that the predictive ability of CHA2DS2-VASc is similar to that of the CHADS2 score (C statistics of each risk score is 0.6 across the various studies) and not statistically signi cantly greater than that of CHADS2.36,40-43 Because the CHADS2 score has been extensively validated and is easy for clinicians to remember and use, we use the CHADS2 score as the principal approach for our risk-based treatment recommendations. 1.4.4 Estimating the Baseline Risk of Nonfatal Stroke by CHADS2 Score: To develop our recommendations, we required estimates of the absolute rate of nonfatal stroke (ischemic or hem- orrhagic) for patients according to their underlying risk of stroke, as characterized by their CHADS2 score. Ideally, we would obtain these estimates of baseline risk from published annual rates of stroke, by CHADS2 score, among untreated patients. However, such data are not available. Therefore, to obtain estimates of annual stroke risk, we used pooled data from aspirin-treated patients enrolled in six clinical trials of antithrombotic therapy for stroke prevention in AF.37 This published report presented data regarding ischemic stroke rates (fatal and nonfatal combined) on aspirin, strati ed by CHADS2 score. We used the following calculations to estimate the annual risk of nonfatal stroke (ie, ischemic and hemorrhagic) on aspirin: (1) multiplication of reported rates of ischemic stroke by 1.08 to account for additional hemorrhagic strokes on aspirin therapy (based on the observed ratio of ischemic:hemorrhagic strokes in aspirin arms of RCTs in patients with AF) and (2) an estimation that 50% and 25% of hemorrhagic and ischemic strokes, respec- tively, were fatal.


We used the following calculations to estimate the annual risk of nonfatal stroke (ie, ischemic and hemorrhagic) on aspirin: (1) multiplication of reported rates of ischemic stroke by 1.08 to account for additional hemorrhagic strokes on aspirin therapy (based on the observed ratio of ischemic:hemorrhagic strokes in aspirin arms of RCTs in patients with AF) and (2) an estimation that 50% and 25% of hemorrhagic and ischemic strokes, respec- tively, were fatal. Depending on the clinical question being addressed by a par- ticular recommendation, we adjusted these absolute rates of nonfatal stroke on aspirin to re ect the clinical scenario being addressed. For the recommendation addressing VKA therapy vs no treatment, for example, to estimate absolute rates of non- fatal stroke on no treatment, we increased our estimates of the rate of nonfatal stroke on aspirin by 21% to account for the esti- mated ef cacy of aspirin in preventing stroke in AF). We there- fore used the following absolute rates of nonfatal stroke in untreated patients to develop our recommendations: 0.8%, 2.2%, 4.5%, and 9.6% per year for patients with CHADS2 scores of 0, 1, 2, and 3 to 6, respectively. We have chosen to base our treatment recommendations on absolute rates of stroke derived from clinical trials, recognizing that these data have important limitations.


We have chosen to base our treatment recommendations on absolute rates of stroke derived from clinical trials, recognizing that these data have important limitations. Less than 10% of patients screened were enrolled in these historical trials, there was limited racial and ethnic diversity, and there is some evi- dence suggesting that stroke rates may now be lower than at the time these RCTs were conducted 2 decades ago possibly because of improved treatment of cardiovascular risk factors, such as hypertension.51,52 However, despite these limitations, these clinical trial-based data regarding stroke events were systemati- cally and prospectively collected, and they remain the best avail- able source of stroke rates strati ed by CHADS2 score. 1.5 Deriving Baseline Risk of Death in Patients With AF We used data from an observational health plan database study of 11,526 patients with nonvalvular AF (the Anticoagula- tion and Risk Factors in Atrial Fibrillation [ATRIA] Study) to obtain an estimate of the risk of all-cause mortality in patients with AF not treated with warfarin (53 deaths per 1,000 patient- years). Untreated patients in this cohort had a mean CHADS2 www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e539S Table [Sections Should VKAs Rather Than No Therapy Be Used in Patients With AF? a Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Estimation of Absolute Effects y Time Frame No.


a Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Estimation of Absolute Effects y Time Frame No. of Studies With No Therapy With VKA Relative Effect CI) With No Therapy With VKA CI) Quality of Evidence Death (critical outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected RR per b fewer deaths per c (from fewer to fewer) High Nonfatal stroke (critical outcome) mean follow-up y; ischemic stroke and intracranial hemorrhage d RCTs No serious limitations No serious inconsistency No serious Indirectness No serious imprecision Undetected e f RR CHADS points High per g fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected RR per h more bleeds per (from more to more) High i Systemic embolism (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious Indirectness Imprecise j Undetected RR per k fewer systemic emboli per (from fewer to more) Moderate (Continued) e540S Antithrombotic Therapy for Atrial Fibrillation Table Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Estimation of Absolute Effects y Time Frame No. of Studies With No Therapy With VKA Relative Effect CI) With No Therapy With VKA CI) Quality of Evidence Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA .


of Studies With No Therapy With VKA Relative Effect CI) With No Therapy With VKA CI) Quality of Evidence Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA . no therapy Warfarin: daily medication, lifestyle limitations, dietary restrictions, frequent blood testing and clinic visits High AFASAK Atrial Fibrillation Aspirin and Anticoagulation; ATRIA Anticoagulation and Risk Factors in Atrial Fibrillation; BAATAF Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA Canadian Atrial Fibrillation Anticoagulation; EAFT European Atrial Fibrillation Trial; IPD individual patient data; N/A not applicable; RR risk ratio; SPAF Stroke Prevention in Atrial Fibrillation; SPINAF Stroke Prevention in Nonrheumatic Atrial Fibrillation. See Table and legends for expansion of other abbreviations. a Pooled estimates of treatment effect in this evidence pro le are from a meta-analysis conducted for these guidelines, including data from RCTs of adjusted-dose VKA therapy vs no antithrombotic therapy (AFASAK I, BAATAF, CAFA, EAFT, SPAF I, SPINAF). b From Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort). The majority of the patients in ATRIA had a CHADS score of 1. c VKA therapy likely does not lead to any reductions in all-cause mortality compared with no therapy in low-risk patients with a CHADS score of because there is evidence suggesting that absolute reductions in ischemic stroke heavily depend on stroke risk (eg, small reductions at low CHADS score), whereas the absolute increase in intracranial hemorrhage is relatively consistent across CHADS categories (Singer et al ). d Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds.


The majority of the patients in ATRIA had a CHADS score of 1. c VKA therapy likely does not lead to any reductions in all-cause mortality compared with no therapy in low-risk patients with a CHADS score of because there is evidence suggesting that absolute reductions in ischemic stroke heavily depend on stroke risk (eg, small reductions at low CHADS score), whereas the absolute increase in intracranial hemorrhage is relatively consistent across CHADS categories (Singer et al ). d Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds. For studies that did not report the number of strokes that were fatal and nonfatal (CAFA, EAFT), we imputed values for the number of fatal and nonfatal strokes to estimate the pooled relative risk for nonfatal stroke across all eligible studies. Assumptions underlying these estimates are detailed in the section of this article. e Of the nonfatal strokes on no therapy, an estimated were ischemic, and two were hemorrhagic. f Of the nonfatal strokes on VKA therapy, an estimated were ischemic, and two were hemorrhagic. g We estimated the annual rates of nonfatal stroke (ischemic and hemorrhagic) on no therapy by extrapolating from observed annual rates of ischemic stroke (fatal nonfatal), strati ed by CHADS score, in the aspirin arms of six historical RCTs in patients with AF (Gage et al ). Assumptions underlying these estimates are detailed in the section of this article. h Estimate of the rate of nonfatal major extracranial bleeding on no therapy is derived from rates in observational cohorts of predominantly patients with AF receiving adjusted-dose VKA therapy (median, and dividing by the relative risk of major bleeding on adjusted-dose VKA therapy observed in the RCTs (see section of this article).


h Estimate of the rate of nonfatal major extracranial bleeding on no therapy is derived from rates in observational cohorts of predominantly patients with AF receiving adjusted-dose VKA therapy (median, and dividing by the relative risk of major bleeding on adjusted-dose VKA therapy observed in the RCTs (see section of this article). i Quality of evidence is moderate for patients with a CHADS score of because the recommendation would differ if the true increase in nonfatal major extracranial bleeding was one vs bleeds per patients in a given year. j The CI does not exclude the possibility of no effect. k Based on rate of systemic embolism on aspirin of per patient-y reported in the IPD meta-analysis of warfarin vs aspirin by van Walraven et al and a relative risk of for aspirin vs no therapy for systemic embolism. www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e541S 2.1.2 implies that adjusted-dose warfarin is far supe- rior to aspirin for the prevention of stroke in patients with AF but is likely to be associated with a greater risk of bleeding complications.


www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e541S 2.1.2 implies that adjusted-dose warfarin is far supe- rior to aspirin for the prevention of stroke in patients with AF but is likely to be associated with a greater risk of bleeding complications. Direct evidence regarding this clinical question comes from 11 RCTs (total of 6,526 patients) comparing adjusted-dose VKA therapy to antiplatelet monotherapy (AFASAK 1, AFASAK 2, Birmingham Atrial Fibrillation Treat- ment of the Aged [BAFTA], EAFT, National Study for Prevention of Embolism in Atrial Fibrillation [NASPEAF], Primary Prevention of Arterial Throm- boembolism in Nonrheumatic AF in Primary Care Trial [PATAF], Studio Italiano Fibrillazione Atriale [SIFA], SPAF II, SPAF III, Vemmos et al,69 and War- farin vs Aspirin for Stroke Prevention in Octogenar- ians With AF [WASPO]) (Table 5).55,60,70-77 Antiplatelet therapy was typically with aspirin 75 to 325 mg/d, but in the SIFA and NASPEAF studies, it was with indobufen and tri usal, respectively.72,74 In SPAF III and one of the two antiplatelet arms of AFASAK II, aspirin was given in combination with xed mini- dose (ineffective) warfarin.70,76 These trials provide high-quality evidence that adjusted-dose VKA therapy reduces by one-half the risk of nonfatal stroke compared with antiplatelet monotherapy. These trials suggest that VKA therapy increases the risk of nonfatal major extracranial bleeding by about 50% compared with aspirin (pooled risk ratio, 1.42; 95% CI, 0.89-2.29), but the quality of evidence was rated down to moderate because of imprecision.


These trials suggest that VKA therapy increases the risk of nonfatal major extracranial bleeding by about 50% compared with aspirin (pooled risk ratio, 1.42; 95% CI, 0.89-2.29), but the quality of evidence was rated down to moderate because of imprecision. Indirect evidence from RCTs of adjusted- dose VKA therapy vs aspirin in other populations suggest that VKA therapy is likely associated with a true twofold to 2.5-fold increase in major bleeding risk.78,79 For the outcomes of death and systemic embolism, pooled estimates of treatment effect from trials of VKA therapy in patients with AF were impre- cise, leaving uncertainty about the impact of VKA therapy on these outcomes compared with antiplate- let monotherapy. 2.1.4 VKAs vs Dual Antiplatelet Therapy With Aspirin and Clopidogrel: The Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) W trial assessed dual antiplatelet therapy with aspirin and clopidogrel as a potential alternative to VKA therapy (INR 2.0-3.0).80 The trial was stopped early because of ndings of superiority of VKA therapy (for their primary out- come of stroke, systemic embolism, MI, or vascular death) and did not nd evidence of a difference in the risk of major bleeding (Table 6). Most patients (77%) were receiving VKA therapy before randomi- zation, raising some concerns about generalizability of these ndings to patients with AF who are being newly started on VKA therapy (ie, by enrolling mostly The studies also provide moderate-quality evidence that VKA therapy reduces the risk of systemic embo- lism (rated down for imprecision). 2.1.2 Antiplatelet Monotherapy (Aspirin) vs No Therapy: Several RCTs of antiplatelet monotherapy vs no therapy in patients with AF have shown that antiplatelet therapy leads to, at best, a modest reduc- tion in the risk of nonfatal stroke.


2.1.2 Antiplatelet Monotherapy (Aspirin) vs No Therapy: Several RCTs of antiplatelet monotherapy vs no therapy in patients with AF have shown that antiplatelet therapy leads to, at best, a modest reduc- tion in the risk of nonfatal stroke. Antiplatelet mono- therapy in these trials was either with aspirin alone (AFASAK 1; SPAF I; EAFT; United Kingdom Tran- sient Ischaemic Attack Aspirin trial [UK-TIA]; Low- Dose Aspirin, Stroke, Atrial Fibrillation [LASAF]; European Stroke Prevention Study [ESPS]-2; and Japan Atrial Fibrillation Stroke Trial [JAST]), aspirin in combination with xed (ineffective) minidose warfarin (Swedish Atrial Fibrillation Trial [SAFT]), or dipyridamole (ESPS-2).55,58,60,62-66 Aspirin dosing in these trials typically ranged from 50 to 325 mg/d. In the LASAF, JAST, and SAFT trials, aspirin was compared with a no-treatment control arm, whereas in the remaining trials, comparison was to placebo.63,64,66 ESPS-2 and UK-TIA were stroke prevention trials conducted primarily in non-AF populations, and only the data from the subset of patients with AF are con- Pooled data from these trials provide moderate- quality evidence (rated down for imprecision) that antiplatelet monotherapy is associated with a 21% relative reduction in risk of nonfatal stroke com- pared with no treatment (Table 4). Although our con- dence in the bene ts of aspirin therapy is moderate, our con dence in its bleeding risk is high. Although the trials of antiplatelet monotherapy in patients with AF were underpowered to precisely estimate the risk of nonfatal major extracranial bleeding, trials of aspirin for the primary and secondary prevention of cardiovascular disease have conclusively demon- strated that aspirin is associated with an increased risk of major hemorrhage.


Although the trials of antiplatelet monotherapy in patients with AF were underpowered to precisely estimate the risk of nonfatal major extracranial bleeding, trials of aspirin for the primary and secondary prevention of cardiovascular disease have conclusively demon- strated that aspirin is associated with an increased risk of major hemorrhage. An individual patient data meta-analysis combining data from six cardiovas- cular primary prevention trials (95,000 subjects) and a meta-analysis of 60 cardiovascular secondary pre- vention trials (94,000 subjects) found that aspirin is associated with a signi cant 50% to 60% relative increase, respectively, in the risk of major extracra- nial bleeding.67,68 For the outcomes of death and systemic embolism, pooled estimates of treatment effect from trials of antiplatelet monotherapy in patients with AF were imprecise, leaving uncer- tainty about the impact of antiplatelet monotherapy on these outcomes when compared with no treat- ment (Table 4). 2.1.3 VKAs vs Antiplatelet Monotherapy (Aspirin): The evidence summarized in sections 2.1.1 and e542S Antithrombotic Therapy for Atrial Fibrillation (Continued) Table [Section Should Antiplatelet (Aspirin) Monotherapy Rather Than No Therapy Be Used in Patients With AF? a,b Quality Assessment Summary of Findings No.


2.1.3 VKAs vs Antiplatelet Monotherapy (Aspirin): The evidence summarized in sections 2.1.1 and e542S Antithrombotic Therapy for Atrial Fibrillation (Continued) Table [Section Should Antiplatelet (Aspirin) Monotherapy Rather Than No Therapy Be Used in Patients With AF? a,b Quality Assessment Summary of Findings No. of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects y Time Frame Quality of Evidence With No Therapy With Antiplatelet With No Therapy With Antiplatelet CI) Death (critical outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise c Undetected RR per d fewer deaths per (from fewer to more) Moderate Nonfatal stroke (critical outcome) mean follow-up y; ischemic stroke and intracranial hemorrhage e RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise f Undetected g h RR CHADS points Moderate per i fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) j RCTs No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected RR per k more bleeds per (from more to more) High www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e543S Table Quality Assessment Summary of Findings No.


of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects y Time Frame Quality of Evidence With No Therapy With Antiplatelet With No Therapy With Antiplatelet CI) Death (critical outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise c Undetected RR per d fewer deaths per (from fewer to more) Moderate Nonfatal stroke (critical outcome) mean follow-up y; ischemic stroke and intracranial hemorrhage e RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise f Undetected g h RR CHADS points Moderate per i fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) j RCTs No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected RR per k more bleeds per (from more to more) High www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e543S Table Quality Assessment Summary of Findings No. of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects y Time Frame Quality of Evidence With No Therapy With Antiplatelet With No Therapy With Antiplatelet CI) Systemic embolism (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise l Undetected RR per m fewer systemic embolism per (from fewer to more) Moderate ESPS European Stroke Prevention Study; JAST Japan Atrial Fibrillation Stroke Trial; LASAF Low-dose Aspirin, Stroke, Atrial Fibrillation; SAFT Swedish Atrial Fibrillation Trial; UK-TIA United Kingdom Transient Ischaemic Attack Aspirin Trial. See Table legends for expansion of other abbreviations.


of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects y Time Frame Quality of Evidence With No Therapy With Antiplatelet With No Therapy With Antiplatelet CI) Systemic embolism (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise l Undetected RR per m fewer systemic embolism per (from fewer to more) Moderate ESPS European Stroke Prevention Study; JAST Japan Atrial Fibrillation Stroke Trial; LASAF Low-dose Aspirin, Stroke, Atrial Fibrillation; SAFT Swedish Atrial Fibrillation Trial; UK-TIA United Kingdom Transient Ischaemic Attack Aspirin Trial. See Table legends for expansion of other abbreviations. a Pooled estimates of treatment effect in this evidence pro le, with the exception of nonfatal major extracranial bleeding b , are from a meta-analysis conducted for these guidelines, including data from RCTs of antiplatelet monotherapy (typically aspirin) vs no therapy (AFASAK I, SPAF I, EAFT, UK-TIA, LASAF, JAST, SAFT). b To obtain a best estimate of the risk of nonfatal major extracranial bleeding on antiplatelet monotherapy, we used data from the Antithrombotic Trialists Collaboration meta-analysis of aspirin for the secondary prevention of cardiovascular disease. c The CI does not exclude the possibility of no effect. d From Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort). e Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds. For studies that did not report the number of strokes that were fatal and nonfatal (EAFT, UK-TIA, JAST), we imputed values for the number of fatal and nonfatal strokes to estimate the pooled relative risk for nonfatal stroke across all eligible studies. Assumptions underlying these estimates are detailed in section of this article.


Assumptions underlying these estimates are detailed in section of this article. f Restricting meta-analysis exclusively to RCTs evaluating aspirin alone vs no antithrombotic therapy (ie, excluding SAFT, which used aspirin in combination with xed minidose warfarin, and excluding the dipyridamole monotherapy arm of results in an estimate of relative risk that includes no effect (relative risk, CI, 0.66-1.01). g Of the nonfatal strokes on no therapy, an estimated were ischemic, and four were hemorrhagic. h Of the nonfatal strokes on antiplatelet therapy, an estimated were ischemic, and four were hemorrhagic. i We estimated the annual rates of nonfatal stroke (ischemic and hemorrhagic) on no therapy by extrapolating from observed annual rates of ischemic stroke (fatal nonfatal), strati ed by CHADS score, in the aspirin arms of six historical RCTs in patients with AF (Gage et al ). Assumptions underlying these estimates are detailed in section of this article. j We used evidence from RCTs of aspirin for the secondary prevention of cardiovascular events to obtain a best estimate of the risk of major extracranial bleeding with antiplatelet monotherapy. Note that the study event rates and relative risk are for the outcome of all major extracranial bleeding (nonfatal and fatal events) because speci c data regarding nonfatal events were not reported. k Rates of nonfatal major extracranial bleeding on no therapy are extrapolated from rates observed in observational cohorts of patients receiving adjusted-dose VKA therapy (median, and dividing by the relative risk of major bleeding on adjusted-dose VKA therapy observed in the RCTs. l The CI does not exclude the possibility of appreciable harm or bene t with antiplatelet therapy.


l The CI does not exclude the possibility of appreciable harm or bene t with antiplatelet therapy. m Based on rate of systemic embolism on aspirin of per patient-y reported in the IPD meta-analysis of warfarin vs aspirin by van Walraven et al and a relative risk of for aspirin vs no therapy for systemic embolism. e544S Antithrombotic Therapy for Atrial Fibrillation Table [Sections Should VKAs Rather Than Aspirin Be Used in Patients With AF? a Quality Assessment Summary of Findings No.


e544S Antithrombotic Therapy for Atrial Fibrillation Table [Sections Should VKAs Rather Than Aspirin Be Used in Patients With AF? a Quality Assessment Summary of Findings No. of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA With VKA With ASA With VKA CI) Death (critical outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise b Undetected RR per c fewer death per (from fewer to more) Moderate Nonfatal stroke (critical outcome) mean follow-up y; ischemic stroke and intracranial hemorrhage d RCTs No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected e f RR CHADS points High per g fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise h Undetected RR per i more bleeds per (from fewer to more) Moderate Systemic embolism (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise j Undetected RR per k fewer systemic embolism per (from fewer to more) Moderate (Continued) www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e545S Table Quality Assessment Summary of Findings No.


of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA With VKA With ASA With VKA CI) Death (critical outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise b Undetected RR per c fewer death per (from fewer to more) Moderate Nonfatal stroke (critical outcome) mean follow-up y; ischemic stroke and intracranial hemorrhage d RCTs No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected e f RR CHADS points High per g fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise h Undetected RR per i more bleeds per (from fewer to more) Moderate Systemic embolism (important outcome) mean follow-up y RCTs No serious limitations No serious inconsistency No serious indirectness Imprecise j Undetected RR per k fewer systemic embolism per (from fewer to more) Moderate (Continued) www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e545S Table Quality Assessment Summary of Findings No. of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA With VKA With ASA With VKA CI) Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA .


of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA With VKA With ASA With VKA CI) Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA . aspirin Warfarin: daily medication, lifestyle limitations, dietary restrictions, frequent blood testing and clinic visits High Aspirin: daily medication only ASA acetylsalicyclic acid; BAFTA Birmingham Atrial Fibrillation of the Aged; NASPEAF National Study for Prevention of Embolism in Atrial Fibrillation; PATAF Primary Prevention of Arterial Thromboembolism in Nonrheumatic AF in Primary Care Trial; SIFA Studio Italiano Fibrillazione Artiale; WASPO Warfarin vs Aspirin for Stroke Prevention in Octogenarians With AF. See Table legends for expansion of other abbreviations. a Pooled estimates of treatment effect in this evidence pro le are from a new meta-analysis of data from RCTs which included a comparison of warfarin and antiplatelet monotherapy (typically aspirin). In SPAF III and AFASAK II, aspirin was combined with xed (ineffective) minidose warfarin (AFASAK I, AFASAK II, Vemmos et al , BAFTA, EAFT, NASPEAF, PATAF, SIFA, SPAF II, SPAF III, WASPO). b The CI does not exclude the possibility of appreciable harm or bene t with VKA therapy. c Based on data from Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort) and an estimated relative risk of mortality of for aspirin vs no therapy ( Table ). d Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds.


c Based on data from Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort) and an estimated relative risk of mortality of for aspirin vs no therapy ( Table ). d Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds. For SPAF II, which did not report the number of strokes that were fatal and nonfatal, we imputed values for the number of fatal and nonfatal strokes to estimate the pooled relative risk for nonfatal stroke across all eligible studies. Assumptions underlying these estimates are detailed in section of this article. e Of the nonfatal strokes on antiplatelet therapy, an estimated were ischemic, and seven were hemorrhagic. f Of the nonfatal strokes on VKA therapy, an estimated were ischemic, and were hemorrhagic. g We estimated the annual rates of nonfatal stroke (ischemic and hemorrhagic) on no therapy by extrapolating from observed annual rates of ischemic stroke (fatal nonfatal), strati ed by CHADS score, in the aspirin arms of six historical RCTs in patients with AF (Gage et al ). Assumptions underlying these estimates are detailed in section of this article. h The CI does not exclude appreciable harm with VKA therapy. i Rates of nonfatal major extracranial bleeding on aspirin are extrapolated from rates observed in observational cohorts of patients receiving adjusted-dose VKA therapy (median, and relative risks of major extracranial bleeding associated with VKA therapy (RR, and aspirin (RR, compared with no therapy. j The CI does not exclude the possibility of appreciable bene t or harm with VKA therapy. k Based on rate of systemic embolism on aspirin of per patient-y reported in the individual patient data meta-analysis of warfarin vs aspirin by van Walraven et al.


k Based on rate of systemic embolism on aspirin of per patient-y reported in the individual patient data meta-analysis of warfarin vs aspirin by van Walraven et al. e546S Antithrombotic Therapy for Atrial Fibrillation (Continued) Table [Sections Should VKAs Rather Than Aspirin Plus Clopidogrel Be Used in Patients With AF? Quality Assessment Summary of Findings No. of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA Clopid With VKA With ASA Clopid With VKA CI) Death (critical outcome) median follow-up y RCT No serious limitations a No serious inconsistency No serious indirectness Imprecise b Undetected RR per c fewer death per (from fewer to more) Moderate Nonfatal stroke (critical outcome) median follow-up y; ischemic stroke and intracranial hemorrhage d RCT No serious limitations a No serious inconsistency No serious indirectness No serious imprecision Undetected e f RR CHADS points High per g fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) median follow-up y h RCT No serious limitations a No serious inconsistency No serious indirectness of patients were receiving VKA at study entry) Imprecise i Undetected RR per j fewer bleeds per (from fewer to more) Moderate www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e547S Table Quality Assessment Summary of Findings No.


of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA Clopid With VKA With ASA Clopid With VKA CI) Death (critical outcome) median follow-up y RCT No serious limitations a No serious inconsistency No serious indirectness Imprecise b Undetected RR per c fewer death per (from fewer to more) Moderate Nonfatal stroke (critical outcome) median follow-up y; ischemic stroke and intracranial hemorrhage d RCT No serious limitations a No serious inconsistency No serious indirectness No serious imprecision Undetected e f RR CHADS points High per g fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) median follow-up y h RCT No serious limitations a No serious inconsistency No serious indirectness of patients were receiving VKA at study entry) Imprecise i Undetected RR per j fewer bleeds per (from fewer to more) Moderate www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e547S Table Quality Assessment Summary of Findings No. of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA Clopid With VKA With ASA Clopid With VKA CI) Systemic embolism (important outcome) median follow-up y RCT No serious limitations a No serious inconsistency No serious indirectness No serious imprecision Undetected RR per k fewer systemic emboli per (from fewer to fewer) High Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA .


of Studies Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame Quality of Evidence With ASA Clopid With VKA With ASA Clopid With VKA CI) Systemic embolism (important outcome) median follow-up y RCT No serious limitations a No serious inconsistency No serious indirectness No serious imprecision Undetected RR per k fewer systemic emboli per (from fewer to fewer) High Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA . ASA clopidogrel Warfarin: daily medication, lifestyle limitations, dietary restrictions, frequent blood testing and clinic visits High Aspirin clopidogrel: daily medication only ACTIVE Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events. Clopid clopidogrel. See Table and legends for expansion of other abbreviations. a Results are based on a single RCT (ACTIVE W) that was stopped early for bene t. b The CI does not exclude appreciable harm or bene t with VKA therapy. c Based on data from Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort), an estimated relative risk of for mortality with aspirin vs no therapy ( Table ), and an estimated relative risk of for mortality with aspirin clopidogrel vs aspirin ( Table ). d Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds. The published report did not provide the number of strokes that were fatal and nonfatal; therefore, we imputed values for the number of fatal and nonfatal strokes to estimate the relative risk for nonfatal stroke. Assumptions underlying these estimates are detailed in section of this article. e Of the nonfatal strokes on aspirin clopidogrel therapy, an estimated were ischemic, and ve were hemorrhagic.


e Of the nonfatal strokes on aspirin clopidogrel therapy, an estimated were ischemic, and ve were hemorrhagic. f Of the nonfatal strokes on VKA therapy, an estimated were ischemic, and were hemorrhagic. g We estimated the annual rates of nonfatal stroke (ischemic and hemorrhagic) on aspirin clopidogrel by extrapolating from observed annual rates of ischemic stroke (fatal nonfatal), strati ed by CHADS score, in the aspirin arms of six historical RCTs in patients with AF (Gage et al ). Assumptions underlying these estimates are detailed in section of this article. h The published report did not provide the number of major extracranial bleeds that were fatal and nonfatal; therefore, we imputed values for the number of fatal and nonfatal major extracranial bleeds to estimate the relative risk for nonfatal major extracranial bleeds. Assumptions underlying these estimates are detailed in section of this article. i The CI does not exclude appreciable harm or bene t with VKA therapy. j Rate of nonfatal major extracranial bleeding on aspirin clopidogrel is extrapolated from rates observed in observational cohorts of patients receiving VKA therapy (median, and estimated relative risks of nonfatal major extracranial bleeding associated with VKA therapy compared with no therapy (RR, aspirin compared with no therapy (RR, and aspirin clopidogrel compared with aspirin (RR, 1.50). k Estimate is derived from rate of systemic embolism on aspirin per patient-y) reported in the IPD meta-analysis by van Walraven et al and estimated relative risk of CI, for systemic embolism with combination aspirin clopidogrel therapy vs aspirin observed in ACTIVE A ( Table ).


k Estimate is derived from rate of systemic embolism on aspirin per patient-y) reported in the IPD meta-analysis by van Walraven et al and estimated relative risk of CI, for systemic embolism with combination aspirin clopidogrel therapy vs aspirin observed in ACTIVE A ( Table ). e548S Antithrombotic Therapy for Atrial Fibrillation results of a three-arm RCT of 18,113 patients with AF in which dabigatran 110 mg bid, and dabiga- tran 150 mg bid, were compared with open-label, adjusted-dose warfarin (target INR 2.0-3.0).84 Based on best estimates of the proportion of strokes and major extracranial bleeds that were nonfatal (the published report did not present the number or proportion of fatal and nonfatal events), dabigatran at a dose of 150 mg bid is associated with a statisti- cally signi cant one-third reduction in nonfatal stroke, with no evidence of a difference in the risk of nonfa- tal major extracranial bleeding compared with war- farin. Moreover, the data raised the possibility that dabigatran 150 mg bid may reduce all-cause mortality compared with warfarin (relative risk, 0.89; 95% CI, 0.79-1.01) (Table 9). In contrast, dabigatran at a dose of 110 mg bid was not associated with a signi cant difference in the risk of death, nonfatal stroke, nonfa- tal major extracranial bleeding, or systemic embolism (Table 10).


In contrast, dabigatran at a dose of 110 mg bid was not associated with a signi cant difference in the risk of death, nonfatal stroke, nonfa- tal major extracranial bleeding, or systemic embolism (Table 10). ROCKET-AF (Rivaroxaban Once Daily Oral direct Factor Xa inhibition Compared with Vitamin K Antago- nism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was a double-blind, double- dummy RCT comparing rivaroxaban 20 mg once daily to adjusted-dose warfarin (INR 2.0-3.0) in 14,264 patients with AF at increased risk of stroke (mean CHADS2 score of 3.5).85 In the intention-to- treat analysis, rivaroxaban was noninferior to warfarin for the primary end point of stroke (ischemic or hem- orrhagic) or systemic embolism but was not superior to warfarin (hazard ratio, 0.88; 95% CI, 0.74-1.03). The trial did not nd evidence of a difference in major bleeding between rivaroxaban and warfarin (hazard ratio, 1.04; 95% CI, 0.90-1.20). Major GI bleeding was more common with rivaroxaban than with warfarin (3.2% and 2.2%, respectively, P,.001). Mortality was not signi cantly different between rivaroxaban and warfarin. The Apixaban vs Acetylsalicylic Acid to Prevent Strokes (AVERROES) RCT compared apixaban 5 mg bid to aspirin in 5,599 patients with AF who were demonstrated or expected to be unsuitable candi- dates for adjusted-dose VKA therapy.86 The trial was stopped early for bene t and was consistent with the trials of VKA therapy vs aspirin (section 2.1.3), reporting that apixaban reduces by one-half the occurrence of the primary outcome of stroke and systemic embolism compared with aspirin (hazard ratio, 0.45; 95% CI, 0.32-0.62).


The Apixaban vs Acetylsalicylic Acid to Prevent Strokes (AVERROES) RCT compared apixaban 5 mg bid to aspirin in 5,599 patients with AF who were demonstrated or expected to be unsuitable candi- dates for adjusted-dose VKA therapy.86 The trial was stopped early for bene t and was consistent with the trials of VKA therapy vs aspirin (section 2.1.3), reporting that apixaban reduces by one-half the occurrence of the primary outcome of stroke and systemic embolism compared with aspirin (hazard ratio, 0.45; 95% CI, 0.32-0.62). The trial failed to demonstrate or exclude a difference in the risk of major extracranial bleeding with apixaban compared with aspirin (hazard ratio, 1.23; 95% CI, 0.74-2.05), and the results were consistent with those of earlier trials of VKA therapy vs aspirin (section 2.1.3), which suggest an increase in the risk of major extracranial prior users of VKA therapy, the study sample may be more representative of patients in whom VKA therapy is well tolerated). In prespeci ed subgroup analyses, the investigators did not nd evidence of a difference in the effect of VKA therapy on primary outcome in patients who were and were not receiving VKA therapy at study entry. However, there was a signi - cant difference (interaction P5.03) in the effect on major bleeding, depending on whether patients were prior users of VKA therapy. For patients who were not receiving VKA therapy at study entry, VKA therapy was associated with a nonsigni cant trend toward a 69% relative increase in major bleeding compared with dual antiplatelet therapy, whereas in patients already receiving VKA therapy at study entry, VKA therapy was associated with a nonsigni cant trend toward a 24% relative decrease in major bleeding compared with dual antiplatelet therapy.


For patients who were not receiving VKA therapy at study entry, VKA therapy was associated with a nonsigni cant trend toward a 69% relative increase in major bleeding compared with dual antiplatelet therapy, whereas in patients already receiving VKA therapy at study entry, VKA therapy was associated with a nonsigni cant trend toward a 24% relative decrease in major bleeding compared with dual antiplatelet therapy. 2.1.5 Dual Antiplatelet Therapy With Aspirin and Clopidogrel vs Aspirin Alone: The ACTIVE A study compared combination aspirin and clopid- ogrel therapy with aspirin alone.81 The trial enrolled 7,554 patients considered unsuitable for VKA therapy (approximately one-half because of a physician s judg- ment that VKA was inappropriate, one-fourth because of a speci c risk of bleeding, and one-fourth because of the patient s preference not to take a VKA as the sole reason) and found that combination therapy is more effective in reducing the risk of nonfatal stroke in patients with AF but also increases the risk of non- fatal major extracranial bleeds compared with treat- ment with aspirin alone (Table 7). 2.1.6 New Oral Anticoagulants vs VKAs: Anti- thrombotic therapy for AF is evolving rapidly because of the development of new oral anticoagulants that directly target different parts of the coagulation path- way, have a more predictable anticoagulant effect, and do not require INR monitoring. Included in this new group of drugs are direct thrombin inhibitors (eg, dabigatran) and direct factor Xa inhibitors (apixa- ban, rivaroxaban, edoxaban). Results of large phase 3 clinical trials of these agents in patients with AF have been recently published or will be reported soon (Table 8).


Results of large phase 3 clinical trials of these agents in patients with AF have been recently published or will be reported soon (Table 8). Although ximelagatran is no longer approved for use by regulatory agencies because of concerns about severe liver toxicity, the Stroke Pre- vention Using an Oral Thrombin Inhibitor in Patients With AF (SPORTIF) III and V trials were a proof of principle that a direct thrombin inhibitor can achieve similar protection against stroke compared with war- farin (ie, ndings met the investigators prespeci ed noninferiority criterion) with no evidence of increased The Randomized Evaluation of Long-Term Anti- coagulation Therapy (RE-LY) trial reported the www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e549S (Continued) Table [Sections Should Aspirin Plus Clopidogrel Rather Than Aspirin Be Used in Patients With AF? Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame No.


Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame No. of Studies With ASA With ASA/Clopid With ASA With ASA/Clopid CI) Quality of Evidence Death (critical outcome) median follow-up y RCT No serious limitations No serious inconsistency No serious indirectness Imprecise a Undetected RR per b fewer death per (from fewer to more) Moderate Nonfatal stroke (critical outcome) median follow-up y; ischemic stroke and intracranial hemorrhage c RCT No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected d e RR CHADS points High per f fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) median follow-up y g RCT No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected RR per h more bleeds per (from more to more) High e550S Antithrombotic Therapy for Atrial Fibrillation Table Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame No. of Studies With ASA With ASA/Clopid With ASA With ASA/Clopid CI) Quality of Evidence Systemic embolism (important outcome) median follow-up y RCT No serious limitations No serious inconsistency No serious indirectness Imprecise i Undetected RR per j fewer systemic emboli per (from fewer to more) Moderate See Table and legends for expansion of abbreviations. a The CI does not exclude the possibility of no effect.


a The CI does not exclude the possibility of no effect. b Based on data from Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort) and an estimated relative risk of mortality of for aspirin vs no therapy ( Table ). c Hemorrhagic stroke not clearly de ned in published RCT report (ie, unclear whether subdural and subarachnoid bleeds were included in the de nition of hemorrhagic stroke). d The published RCT report did not present the proportion of nonfatal strokes in the aspirin arm that were ischemic vs hemorrhagic; however, of all strokes (fatal and nonfatal), were hemorrhagic, and were ischemic or of uncertain type. e The published RCT report did not present the proportion of nonfatal strokes in the combination aspirin clopidogrel arm that were ischemic vs hemorrhagic; however, of all strokes (fatal and nonfatal), were hemorrhagic, and were ischemic or of uncertain type. f We estimated the annual rates of nonfatal stroke (ischemic and hemorrhagic) on aspirin by extrapolating from observed annual rates of ischemic stroke (fatal nonfatal), strati ed by CHADS score, in the aspirin arms of six historical RCTs in patients with AF (Gage et al ). Assumptions underlying these estimates are detailed in section of this article. g The published report did not provide the number of major extracranial bleeds that were fatal and nonfatal; therefore, we imputed values for the number of fatal and nonfatal major extracranial bleeds to estimate the relative risk for nonfatal major extracranial bleeds. Assumptions underlying these estimates are detailed in section of this article.


Assumptions underlying these estimates are detailed in section of this article. h Rates of nonfatal major extracranial bleeding on aspirin are extrapolated from rates in observational cohorts of patients receiving adjusted-dose VKA therapy (median, and relative risks of major extracranial bleeding associated with VKA therapy (RR, and aspirin (RR, compared with no therapy. i The CI does not exclude the possibility of no effect. j Based on rate of systemic embolism on aspirin of per patient-y reported in the IPD meta-analysis of warfarin vs aspirin by van Walraven et al. www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e551S dabigatran over adjusted-dose VKA therapy in sec- tion 2.1.11. The data from RE-LY do not directly address the use of dabigatran in patients with AF and mitral ste- nosis (patients with hemodynamically relevant val- vular disease were excluded from this study), or in patients with AF in other special situations (sections 2.2 and 3.0). Therefore, we have not extrapolated the data from RE-LY to these clinical situations and have instead restricted those recommendations for oral anticoagulation to adjusted-dose VKA therapy. There is direct evidence from RE-LY regarding the use of dabigatran in patients with AF undergoing cardiover- sion, and these data are summarized in section 4.1.1. 2.1.8 Recommendations for Patients With AF at Low Risk of Stroke (eg, CHADS2 Score of 0): Patients at suf ciently low risk of ischemic stroke may opt for no treatment rather than antithrombotic therapy with either aspirin or an oral anticoagulant. For instance, for every 1,000 patients at low risk of stroke with a CHADS2 score of 0, VKA therapy compared with no treatment is anticipated to result in ve fewer nonfatal strokes at the expense of eight more nonfatal major extracranial bleeds and the additional burden of adjusted-dose VKA treatment (Table 3).


For instance, for every 1,000 patients at low risk of stroke with a CHADS2 score of 0, VKA therapy compared with no treatment is anticipated to result in ve fewer nonfatal strokes at the expense of eight more nonfatal major extracranial bleeds and the additional burden of adjusted-dose VKA treatment (Table 3). Although VKA therapy is expected to reduce all-cause mortality in patients with AF in general, it is likely that this mortality bene t does not extend to low-risk patients. The absolute reduction in fatal ischemic stroke with VKA therapy will be far fewer such patients, whereas their absolute increase in fatal intracranial hemor- rhage will be similar to those with higher CHADS2 For patients with a CHADS2 score of 0, treatment with aspirin for 1 year may result in the prevention of two nonfatal strokes per 1,000 patients (moderate- quality evidence due to imprecision) at the expense of three additional nonfatal major extracranial bleeds per 1,000 patients compared with no treatment (Table 4). If stroke rates are truly declining over time, bleeding with oral anticoagulation compared with aspirin. ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) was a double-blind, double-dummy RCT comparing apixaban 5 mg bid to warfarin (INR 2.0-3.0) in 18,201 patients with AF (mean CHADS2 score of 2.1).87 Apixaban reduced by 21% the risk of the primary outcome of stroke (ischemic or hemorrhagic) or systemic embo- lism (hazard ratio, 0.79; 95% CI, 0.66-0.95) and reduced by 31% the risk of major bleeding (hazard ratio, 0.69; 95% CI, 0.60-0.80) compared with warfa- rin. There was no evidence of a difference in major GI bleeding between apixaban and warfarin (hazard was lower with apixaban compared with warfarin (hazard ratio, 0.89; 95% CI, 0.80-0.998).


There was no evidence of a difference in major GI bleeding between apixaban and warfarin (hazard was lower with apixaban compared with warfarin (hazard ratio, 0.89; 95% CI, 0.80-0.998). In all three recently completed trials of novel anticoagulants vs warfarin (RE-LY, ROCKET-AF, and ARISTOTLE), the rate of intracranial hemorrhage (including both hemorrhagic stroke and other intracranial bleeds) was lower in patients assigned to the novel anticoag- ulant than in patients assigned to warfarin.84,85,87,88 2.1.7 General Approach to Recommendations About New Oral Anticoagulants in This Article: Our guideline panel elected to make recommendations only for those drugs that have received regulatory approval for use in AF (ie, dabigatran).89 Although based on the results of a single trial, there is evidence from RE-LY that dabigatran is no worse than VKA therapy with respect to nonfatal major extracranial bleeding and that it is similar or superior to warfarin with respect to nonfatal stroke, systemic embolism, and all-cause mortality in patients with nonvalvular AF (section 2.1.6).


In all three recently completed trials of novel anticoagulants vs warfarin (RE-LY, ROCKET-AF, and ARISTOTLE), the rate of intracranial hemorrhage (including both hemorrhagic stroke and other intracranial bleeds) was lower in patients assigned to the novel anticoag- ulant than in patients assigned to warfarin.84,85,87,88 2.1.7 General Approach to Recommendations About New Oral Anticoagulants in This Article: Our guideline panel elected to make recommendations only for those drugs that have received regulatory approval for use in AF (ie, dabigatran).89 Although based on the results of a single trial, there is evidence from RE-LY that dabigatran is no worse than VKA therapy with respect to nonfatal major extracranial bleeding and that it is similar or superior to warfarin with respect to nonfatal stroke, systemic embolism, and all-cause mortality in patients with nonvalvular AF (section 2.1.6). Therefore, for patients with non- rheumatic AF, wherever we recommend (or suggest) VKA therapy, we also recommend (or suggest) the use of dabigatran, and in these situations, our rec- ommendations simply refer to oral anticoagulation.88 We address the speci c question of whether to use Table 8 [Section 2.1.6] Phase 3 RCTs of New Oral Anticoagulants in Patients With AF Trial Intervention Comparator Status SPORTIF III Ximelagatran Warfarin (INR, 2.0-3.0) Published82,83 SPORTIF V RE-LY Dabigatran (150 or 110 mg bid) Warfarin (INR, 2.0-3.0) Published84 AVERROES Apixaban (5 mg bid) Aspirin (81-324 mg daily) Published86 ROCKET-AF Rivaroxaban (20 mg once daily) Warfarin (INR, 2.0-3.0) Published85 ARISTOTLE Apixaban (5 mg bid) Warfarin (INR, 2.0-3.0) Published87 ENGAGE-AF TIMI 48 Edoxaban (high- and low-dose regimens) Warfarin (INR, 2.0-3.0) Currently recruiting ARISTOTLE5Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES5Apixaban versus Acetylsalicylic Acid to Prevent Strokes; ENGAGE-AF TIMI 485Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48; INR5international normalized ratio; RE-LY5Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF5Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; SPORTIF5Stroke Prevention Using an Oral Thrombin Inhibitor in Patients With AF.


Therefore, for patients with non- rheumatic AF, wherever we recommend (or suggest) VKA therapy, we also recommend (or suggest) the use of dabigatran, and in these situations, our rec- ommendations simply refer to oral anticoagulation.88 We address the speci c question of whether to use Table 8 [Section 2.1.6] Phase 3 RCTs of New Oral Anticoagulants in Patients With AF Trial Intervention Comparator Status SPORTIF III Ximelagatran Warfarin (INR, 2.0-3.0) Published82,83 SPORTIF V RE-LY Dabigatran (150 or 110 mg bid) Warfarin (INR, 2.0-3.0) Published84 AVERROES Apixaban (5 mg bid) Aspirin (81-324 mg daily) Published86 ROCKET-AF Rivaroxaban (20 mg once daily) Warfarin (INR, 2.0-3.0) Published85 ARISTOTLE Apixaban (5 mg bid) Warfarin (INR, 2.0-3.0) Published87 ENGAGE-AF TIMI 48 Edoxaban (high- and low-dose regimens) Warfarin (INR, 2.0-3.0) Currently recruiting ARISTOTLE5Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation; AVERROES5Apixaban versus Acetylsalicylic Acid to Prevent Strokes; ENGAGE-AF TIMI 485Effective Anticoagulation With Factor xA Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction Study 48; INR5international normalized ratio; RE-LY5Randomized Evaluation of Long-Term Anticoagulation Therapy; ROCKET-AF5Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; SPORTIF5Stroke Prevention Using an Oral Thrombin Inhibitor in Patients With AF. e552S Antithrombotic Therapy for Atrial Fibrillation (Continued) Table [Section Should Dabigatran mg bid Rather Than VKAs be Used in Patients With AF? Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame No.


Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame No. of Studies With VKA With Dabi mg With VKA With Dabigatran CI) Quality of Evidence Death (critical outcome) median follow-up y RCT No serious limitations No serious inconsistency No serious indirectness Serious imprecision a Undetected RR per b fewer deaths per (from fewer to more) Moderate Nonfatal stroke (critical outcome) median follow-up y; ischemic stroke and intracranial hemorrhage c RCT No serious limitations No serious inconsistency No serious indirectness No serious imprecision Undetected d e RR CHADS points High per f fewer strokes per (from fewer to fewer) CHADS point per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) CHADS points per fewer strokes per (from fewer to fewer) Nonfatal major extracranial bleeds (important outcome) median follow-up y g RCT No serious limitations No serious inconsistency No serious indirectness Imprecise a Undetected RR per h more bleed per (from fewer to more) Moderate Systemic embolism (important outcome) median follow-up y RCT No serious limitations No serious inconsistency No serious indirectness Imprecise a Undetected RR per i fewer systemic emboli per (from fewer to more) Moderate www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e553S Table Quality Assessment Summary of Findings Risk of Bias Inconsistency Indirectness Imprecision Publication Bias Study Event Rates (%) Relative Effect CI) Estimation of Absolute Effects Time Frame No. of Studies With VKA With Dabi mg With VKA With Dabigatran CI) Quality of Evidence Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA .


of Studies With VKA With Dabi mg With VKA With Dabigatran CI) Quality of Evidence Burden of treatment (important outcome) N/A No serious limitations No serious limitations No serious limitations No serious limitations N/A N/A N/A VKA . dabigatran Warfarin: daily medication, lifestyle limitations, dietary restrictions, frequent blood testing and clinic visits High Dabigatran: daily medication only Dabi dabigatran. See Table legends for expansion of other abbreviations. a The CI does not exclude the possibility of no effect. b Based on data from Go et al, which reported a mortality rate of per person-y in untreated (no warfarin) patients from an observational study (ATRIA cohort) and an estimated relative risk of mortality of for VKA vs no therapy ( Table ). c Intracranial hemorrhage includes intracerebral, subdural, and subarachnoid bleeds. The published report did not provide the number of strokes that were fatal and nonfatal; therefore, we imputed values for the number of fatal and nonfatal strokes to estimate the relative risk for nonfatal stroke. Assumptions underlying these estimates are detailed in section of this article. d Of the nonfatal strokes on VKA therapy, an estimated were ischemic, and were hemorrhagic. e Of the nonfatal strokes on dabigatran therapy, an estimated were ischemic, and were hemorrhagic. f We estimated the annual rates of nonfatal stroke (ischemic and hemorrhagic) on warfarin by extrapolating from observed annual rates of ischemic stroke (fatal nonfatal), strati ed by CHADS score, in the aspirin arms of six historical RCTs in patients with AF (Gage et al ). Assumptions underlying these estimates are detailed in section of this article.