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. 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. 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. 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. 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. 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 . 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. 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. 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) 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. 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 ). 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). 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 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. 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). 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. 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. 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. 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). 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). 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. 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. 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 . 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. 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. h Rate of nonfatal major extracranial bleeding on warfarin is from observational cohorts of patients receiving adjusted-dose VKA therapy (median, 1.3%/y). i 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 for systemic embolism of with VKA vs aspirin ( Table ). e554S 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. 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 Imprecise 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 Imprecise a Undetected d e RR CHADS points Moderate per f fewer strokes per (from fewer to more) CHADS point per fewer strokes per (from fewer to more) CHADS points per fewer strokes per (from fewer to more) CHADS points per fewer strokes per (from fewer to more) 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 fewer bleeds per (from fewer to more) Moderate www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e555S 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 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 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 See Table and legends for expansion of 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. 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. h Rate of nonfatal major extracranial bleeding on warfarin is from observational cohorts of patients receiving adjusted-dose VKA therapy (median, 1.3%/y). i 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 for systemic embolism of with VKA vs aspirin ( Table ). e556S Antithrombotic Therapy for Atrial Fibrillation no reduction in all-cause mortality. However, because absolute rates of stroke may have fallen over the past 2 decades, we may be overestimating the abso- lute reduction in nonfatal stroke achieved with VKA therapy. Moreover, the true extent of bleeding risk with VKA therapy compared with aspirin therapy is unclear because the pooled estimate of the relative risk of bleeding from the relevant RCTs is imprecise (Table 5). The limited ability of CHADS2 to accu- rately predict stroke risk (C statistic, 0.6-0.7), the considerable variability in patient values and pref- erences, and the burden and lifestyle limitations associated with adjusted-dose VKA therapy, intro- duce further uncertainty. Compared with combination therapy with aspirin and clopidogrel, VKA therapy is expected to result in six fewer nonfatal strokes per 1,000 patients over a 1-year period, anywhere from four fewer to three more nonfatal major extracranial bleeds, and no reduction in all-cause mortality (Table 6). Uncertainty regarding the small net clinical bene t at a CHADS2 score of 1 arises as a result of the limitations of the CHADS2 score in estimating stroke risk and the pos- sibility of declining absolute stroke rates over time. Uncertainty regarding the value of the small net bene t arises from the variability in patient values and preferences and the burden and lifestyle limita- tions associated with adjusted-dose VKA therapy. For patients at intermediate risk of stroke with a CHADS2 score of 1 who are unsuitable for or choose not to take an oral anticoagulant for reasons other than concerns about major bleeding (eg, dif culty maintaining a stable INR, lifestyle limitations of regular INR monitoring, dietary restrictions that are too burdensome, or costs of new anticoagulant drugs that are too high), combination therapy with aspirin and clopidogrel provides additional bene t of stroke reduction at the cost of additional bleeding (ACTIVE A trial) (Table 7). Patients opting for com- bination antiplatelet therapy rather than treatment with an oral anticoagulant should be informed that they are choosing an inferior treatment with regard to stroke prevention. Recommendation 2.1.9. For patients with AF, including those with paroxysmal AF, who are at intermediate risk of stroke (eg, CHADS2 score51), we recommend oral anticoagulation rather than no therapy (Grade 1B). We suggest oral anticoagulation rather than aspirin (75 mg to 325 mg once daily) (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B). For patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns then the already small bene ts of antithrombotic therapy (number needed to treat for 1 year to prevent one nonfatal stroke of 500 for aspirin and 200 for VKA therapy) will be even smaller. For patients who do choose antithrombotic therapy, the potential choices are aspirin, dual antiplatelet therapy with aspirin and clopidogrel, or oral antico- agulation. For every 1,000 patients with a CHADS2 score of 0, treatment for 1 year with adjusted-dose VKA therapy or with combination aspirin and clopid- ogrel therapy compared with aspirin is anticipated to result in small reductions in nonfatal stroke and an increase in nonfatal major extracranial bleeding such that the net bene ts of either VKA therapy or dual antiplatelet therapy with aspirin and clopidogrel would be small, particularly given the possibility of declining stroke rates over time (Tables 5, 7). Recommendation 2.1.8. For patients with AF, including those with paroxysmal AF, who are at low risk of stroke (eg, CHADS2 score50), we suggest no therapy rather than antithrombotic therapy (Grade 2B). For patients who do choose antithrombotic therapy, we suggest aspirin (75 mg to 325 mg once daily) rather than oral anticoagulation (Grade 2B) or combination therapy with aspirin and clopidogrel (Grade 2B). Remarks: Patients who place an exceptionally high value on stroke reduction and a low value on avoid- ing bleeding and the burden associated with anti- thrombotic therapy are likely to choose antithrombotic therapy rather than no antithrombotic therapy. Other factors that may in uence the choices above are a consideration of patient-speci c bleeding risk and the presence of additional risk factors for stroke, including age 65 to 74 years and female sex, which have been more consistently validated, and vascu- lar disease, which has been less well validated (see section 2.1.12). The presence of multiple non- CHADS2 risk factors for stroke may favor oral anti- coagulation therapy. 2.1.9 Recommendations for Patients With AF at Intermediate Risk of Stroke (eg, CHADS2 Score of 1): For patients at intermediate risk of stroke with a CHADS2 score of 1, compared with no therapy, 1 year of VKA therapy is expected to result in 15 fewer deaths and 15 fewer nonfatal strokes per 1,000 patients at the cost of eight more nonfatal major extracranial bleeds (Table 3). Regarding the choice between VKA therapy and aspirin, VKA therapy is anticipated to prevent nine nonfatal strokes for every 1,000 patients treated for 1 year compared with aspirin but will result in three additional bleeds and www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e557S stroke (eg, CHADS2 score 2), we recommend oral anticoagulation rather than no therapy (Grade 1A), aspirin (75 mg to 325 mg once daily) (Grade 1B), or combination therapy with aspirin and clopidogrel (Grade 1B). For patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns 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 Recommendation Regarding Dabigatran vs Adjusted-Dose VKA Therapy: The RE-LY trial showed that dabigatran, at the higher dose of 150 mg bid, leads to reductions in nonfatal stroke, probable reductions in all-cause mortality, and no apparent increase in the risk of nonfatal major extracranial bleeding compared with VKA therapy (Table 9), whereas there was no evidence that dabigatran 110 mg bid leads to a signi cant reduction in relevant outcomes compared with VKA therapy (Table 10). In the United States, the Food and Drug Administra- tion approved the use of dabigatran for the preven- tion of thromboembolism in patients with AF at a dose of 150 mg bid but not at a dose of 110 mg bid. However, the Food and Drug Administration did approve, based on pharmacokinetic considerations rather than direct evidence from RCTs in AF popula- tions, a dose of 75 mg bid for patients with severe renal insuf ciency (de ned as a creatinine clearance For the question of whether to use dabigatran vs adjusted-dose VKA therapy, the evidence suggests net clinical bene t at the 150-mg dose. At the time of this writing, however, knowledge regarding the ef cacy and safety of the new oral anticoagulants for patients with AF is still limited to one large ran- domized trial per agent. Uncommon but serious adverse effects may emerge with large-scale use of the drugs. Performance in usual clinical care may deteriorate because of less-restricted patient selec- tion and suboptimal adherence to the unmonitored drug. For patients who do experience bleeding com- plications, clinicians need to be aware that there is no antidote to reverse the anticoagulant effects of dabigatran.90 Given these concerns, it would be rea- sonable for VKA-experienced patients who are well controlled (ie, INR within therapeutic range a high proportion of the time) to continue on VKA therapy if they are satis ed with it and are tolerating it well rather than switching to dabigatran. There is evidence from meta-analyses of RCTs92 that home monitoring of VKA therapy reduces throm- boembolic events by 42% compared with usual monitoring (see also Holbrook et al91), which is about major bleeding), we suggest combination therapy with aspirin and clopidogrel rather than aspirin (75 mg to 325 mg once daily) (Grade 2B). Remarks: Patients who place an exceptionally high value on stroke reduction and a low value on avoiding bleeding and the burden associated with anticoag- ulant therapy are likely to choose oral anticoagula- tion rather than antiplatelet therapy. Other factors that may in uence the choice among antithrombotic therapies are a consideration of bleeding risk and the presence of additional risk factors for stroke, including age 65 to 74 years and female gender, which have been more consistently validated, and vascular disease, which has been less well validated (see sec- tion 2.1.12). The presence of multiple non-CHADS2 risk factors for stroke may favor oral anticoagulation therapy. 2.1.10 Recommendations for Patients With AF at High Risk of Stroke (eg, CHADS2 Score of 2, Which Includes Prior Ischemic Stroke or TIA): Patients at high risk of ischemic stroke, which includes patients with a history of ischemic stroke or TIA, can antici- pate large bene ts (ie, 15 fewer deaths and 30 fewer nonfatal strokes per 1,000 patients during 1 year of VKA therapy) with anticoagulation (Table 3). For every 1,000 patients with a CHADS2 score of 2 treated for 1 year with VKA therapy rather than aspirin, we anticipate 19 fewer nonfatal strokes at the expense of three more nonfatal major extracra- nial bleeds (Table 5). For every 1,000 such patients treated with VKA rather than combination therapy with aspirin and clopidogrel, we anticipate 11 fewer strokes and anywhere between four fewer to three more nonfatal major extracranial bleeds (Table 6). There is therefore a substantial net clinical bene t with oral anticoagulation. For patients at high risk of ischemic stroke with a CHADS2 score of 2 who are unsuitable for or who choose not to take an oral anticoagulant for reasons other than concerns about major bleeding (eg, dif - culty maintaining a stable INR, lifestyle limitations of regular INR monitoring, dietary restrictions that are too burdensome, or costs of new anticoagulant drugs that are too high), aspirin and clopidogrel therapy will result in a substantial reduction in stroke com- pared with aspirin alone (ACTIVE A trial) (Table 7). Patients opting for combination antiplatelet therapy rather than treatment with an oral anticoagulant should be informed that they are choosing an inferior treatment with regard to stroke prevention. Recommendation 2.1.10. For patients with AF, including those with paroxysmal AF, who are at high risk of e558S Antithrombotic Therapy for Atrial Fibrillation bleeding risk because there are insuf cient data to estimate reliably the absolute bleeding rates for patients in different categories of bleeding risk on different antithrombotic regimens. However, the following evidence regarding bleeding risk assess- ment may help to guide individualized treatment decisions for patients with AF. One challenge in bleeding risk assessment for patients with AF is that many of the factors associ- ated with an increased risk of major bleeding are also risk factors for ischemic stroke. For instance, older age, hypertension, congestive heart failure, and prior history of ischemic stroke all of which are compo- nents of the CHADS2 score have been found in various studies of patients with AF to be indepen- dent predictors of bleeding while on VKA therapy.94 Several bleeding risk scores have been evaluated in cohorts of patients with AF (see Table 11).53,95-98 However, these scores have not been extensively validated. Their ability to predict major bleeding is modest, with comparable C statistics across exter- nal validation studies (range, 0.61-0.66).53,97-99 In sce- narios where we make weak recommendations in favor of oral anticoagulation (eg, patients with a CHADS2 score of 1), patients at high risk of major bleeding may decline oral anticoagulation. Additional Risk Factors for Stroke in Patients With AF In addition to consideration of bleeding risk and patient values and preferences, for patients with a CHADS2 score of 0 or 1, clinicians may wish to consider additional stroke risk factors when indi- vidualizing decisions about antithrombotic therapy. For instance, there is high-quality evidence that stroke risk increases continuously with age (rather than as a dichotomous function of age ,75 or 75 years) and moderate-quality evidence that female sex is an independent predictor of stroke risk in patients with AF.18,20 Thus, patients may be inclined to choose the more aggressive treatment option (eg, antithrom- botic therapy rather than no therapy for patients with a CHADS2 score of 0 and oral anticoagulation rather than aspirin for patients with a CHADS2 score of 1) when these additional risk factors for stroke are present. The presence of multiple non-CHADS2 risk factors for stroke may favor oral anticoagulation therapy. There is less-consistent evidence support- ing an independent association between vascular disease (ie, prior MI, complex aortic plaque seen on TEE, and peripheral arterial disease) and the risk of stroke in patients with AF (section 1.4.2).21-23 2.1.13 Percutaneous Closure of the Left Atrial Appendage: Percutaneous closure of the left atrial appendage (LAA) has recently been evaluated as a nondrug alternative for stroke prevention in patients with AF. The PROTECT-AF (WATCHMAN Left similar to the 33% relative reduction in stroke achieved with dabigatran 150 mg bid compared with VKA therapy (Table 9).84 Therefore, any advan- tages of dabigatran with respect to thromboembo- lism would likely not exist for motivated patients who are able to participate in home monitoring of their VKA therapy. Although home monitoring will reduce the burden of INR testing and VKA dose adjustment, the burdens of VKA therapy related to dietary restrictions and drug interactions will still exist, and there will be a cost for the home monitoring device and test strips. Therefore, depend- ing on how patients value these burdens, some may choose dabigatran rather than home monitoring of VKA therapy. Before prescribing dabigatran, clinicians need to judge whether the patient is similar enough to those enrolled in RE-LY that the clinical trial results are still likely to apply. In particular, the RE-LY study excluded patients with severe renal impairment (estimated creatinine clearance 30 mL/min or less).84 The cost-effectiveness of the new anticoagulants compared with VKA therapy is another consider- ation. An economic analysis based on pricing of dabigatran in the United Kingdom (US $13 per day) estimated that dabigatran 150 mg bid would cost $45,372 more per quality-adjusted life year gained compared with warfarin for patients with AF aged 65 years with risk factors for stroke (CHADS2 score of 1). The cost-effectiveness estimates in this model were sensitive to the pricing of dabigatran.93 Recommendation 2.1.11. For patients with AF, including those with paroxysmal AF, for recommendations in favor of oral anticoagulation (including 2.1.9, gest dabigatran 150 mg twice daily rather than adjusted-dose 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 (estimated creatinine clearance of 30 mL/min). Clinicians should be aware that there is no antidote for dabigatran. 2.1.12 Tailoring These Recommendations to Indi- vidual Patients: As with all weak recommendations, treatment decisions should be individualized based on patient values and preferences, and in this case, an assessment of bleeding risk, and a consideration of additional risk factors for stroke. Bleeding Risk Assessment We have not made separate recommendations depending on patient www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e559S no formal recommendations regarding LAA clo- sure devices, pending more de nitive research in this eld. 2.2 Patients With AF and Mitral Stenosis Patients with AF in the setting of rheumatic mitral valve disease, particularly mitral stenosis, are at high risk of stroke. Most RCTs of adjusted-dose VKA therapy in AF excluded such patients. We believe that the results of randomized clinical trials in patients with nonrheumatic AF can be generalized to patients with mitral stenosis. Recommendation 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 stenosis 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 Atrial Appendage System for Embolic PROTECTion in Patients With Atrial Fibrillation) study randomized 707 patients with AF to percutaneous closure of the LAA using the WATCHMAN device (Atritech, Inc) or adjusted-dose warfarin to achieve a target INR of 2.0 to 3.0.100 Percutaneous LAA closure was associ- ated with a statistically nonsigni cant reduction in the risk of their primary ef cacy outcome of stroke (ischemic or hemorrhagic), cardiovascular or unex- plained death, or systemic embolism compared with warfarin (absolute risk reduction, 1.9% per year; 95% CI, 3.2% per year less to 1.2% per year more, with percu- taneous LAA closure compared with adjusted-dose warfarin). However, there was a signi cantly higher rate of adverse events (excessive bleeding, procedure- related complications) in the percutaneous LAA clo- sure arm (absolute risk increase, 3.0% per year). In particular, serious pericardial effusion (ie, requiring percutaneous or surgical drainage) occurred in 4.8% of patients in the percutaneous LAA closure arm. Another occlusion device, PLAATO [percutaneous LAA transcatheter occlusion], has not been tested in a randomized trial but has been evaluated in prospective, multicenter cohort studies in patients ineligible for warfarin.101,102 At this time, we make Table 11 [Section 2.1.12] Bleeding Risk Scores Low Moderate High Calculation of Bleeding Risk Score Outpatient Bleeding Risk Age 65 y GI bleed in past 2 wk Previous stroke Comorbidities (recent MI, Hct,30%, diabetes, or creatinine.1.5 mg/dL) Hepatic or renal disease Ethanol abuse Malignancy Older age (.75 yr) Reduced platelet count or function Hypertension (uncontrolled) Anemia Genetic factors (CYP2C9 polymorphisms) Excessive fall risk Stroke 2 points for: Rebleeding risk (ie, prior bleed) (0.273diabetes)1(0.863anemia)1(0.323antiplatelet drug use), with 1 point for presence of each and 0 if absent Abnormal renal/liver function (1 point each) Stroke Bleeding history or predisposition Labile INR Elderly (eg, age.65 y) Drugs (eg, concomitant antiplatelet/NSAID) or alcohol (1 point each) Maximum 9 points Hct5hematocrit; NSAID5nonsteroidal antiin ammatory drug. See Table 1 and 8 legends for expansion of other abbreviations. e560S Antithrombotic Therapy for Atrial Fibrillation conjunction with either warfarin (INR 2.0-3.0) or dabigatran.105 Analyses of observational data from a large population-based registry of hospitalized patients with AF also found a nearly twofold increase in the risk of bleeding requiring hospitalization or causing death when patients with AF received com- bination therapy with warfarin and aspirin vs war- A systematic review of RCTs in diverse (mostly non-AF) patient populations that compared aspirin plus VKA therapy with VKA therapy alone, in which VKAs were administered to achieve the same target INR or given at the same xed dose in both arms, found that combination VKA plus aspirin therapy was associated with a lower risk of cardiovascular events compared with VKA therapy alone but that this bene t was restricted to RCTs enrolling patients with mechanical heart valves. No bene t was seen with combination therapy in studies of patients with AF or coronary artery disease, although estimates of treatment effect were very imprecise. Combination therapy with VKA and aspirin was associated with a greater risk of major bleeding (pooled OR, 1.43; 95% CI, 1.00-2.02) compared with VKA therapy alone.107 Recommendation 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 INR range, 2.0-3.0) rather than the combination of adjusted-dose VKA therapy and aspirin (Grade 2C). 3.2 Patients With AF and Placement of an Intracoronary Stent (With or Without Recent ACS) Patients bene t from dual antiplatelet therapy (eg, aspirin and clopidogrel) for a nite duration following placement of an intracoronary stent (4 weeks after placement of a bare-metal stent; 3 to 6 months after placement of a drug-eluting stent [typically 3 months for -olimus stents and 6 months for -taxel stents]) (see Vandvik et al).108 The principal objec- tive of dual antiplatelet therapy after placement of an intracoronary stent is the prevention of stent thrombosis. Before the adoption of dual antiplatelet therapy in clinical practice, stent thrombosis occurred in 6% to 24% of patients after bare-metal stent place- ment and was associated with a high case fatality rate of nearly 50%.109-113 Concomitantly, a number of studies compared a new strategy, aspirin plus ticlopi- dine (a thienopyridine precursor to clopidogrel), to the previously most successful strategy of aspirin plus warfarin in patients undergoing stent placement. A Cochrane systematic review of four randomized and clopidogrel rather than aspirin (75 mg to 325 mg once daily) alone (Grade 1B). 3.0 Antithrombotic Therapy for Patients With AF in Special Situations 3.1 Patients With AF and Stable Coronary Artery Disease Approximately one-third of patients with AF also have coronary artery disease.51 A recurring question is whether patients with AF for whom oral antico- agulation is indicated because of a high risk of stroke (eg, CHADS2 score of 2) and who have concom- itant stable coronary artery disease should also use aspirin to prevent coronary heart disease events. In this article, we de ne stable coronary artery disease as the presence (or absence) of angina but no revas- cularization procedure (percutaneous coronary inter- vention or coronary artery bypass graft surgery) or hospitalization for ACS (ie, unstable angina, non-ST- segment elevation MI, or ST-segment elevation MI) in the past year. The studies discussed next provide low-quality evidence that combination therapy with adjusted-dose VKA therapy plus aspirin is not associ- ated with reductions in stroke or MI but that it does increase by 1.5 to 2 times the risk of major bleeding compared with adjusted-dose VKA therapy alone. The FFAACS (Fluindione, Fibrillation Auriculaire, Aspirin et Contraste Spontane) trial is the only RCT that directly compared adjusted-dose VKA therapy and aspirin to adjusted-dose VKA therapy alone. In this study, patients in both arms received uindi- one (INR 2.0-2.6), and patients in the combination therapy arm also received aspirin 100 mg/d. The trial was stopped early after enrollment of only 157 patients because of excessive hemorrhage in the group receiving uindione plus aspirin.103 No con- clusion can be drawn regarding ef cacy for preven- tion of stroke or MI because there were so few events during a short duration of follow-up. There is direct evidence from a nonrandomized comparison of patients enrolled in the SPORTIF trials that combination therapy (with warfarin [INR 2.0-3.0] plus aspirin) is associated with a nearly two- fold greater risk of major bleeding compared with warfarin alone, with no signi cant reduction in stroke or MI.104 Patients receiving aspirin were different from those not receiving aspirin (eg, those receiving aspirin more often had diabetes, coronary artery dis- ease, and previous stroke or TIA). Although the analy- ses were adjusted for baseline differences in patient characteristics, there remains a high risk for bias. A similar nonrandomized comparison of patients enrolled in the RE-LY trial reported that rates (likely unadjusted) of major bleeding were roughly 2 times higher for patients receiving aspirin in www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e561S bene t compared with dual antiplatelet therapy for patients at high risk of stroke (eg, CHADS2 score of 2), whereas the net bene t at lower levels of stroke risk is uncertain. The duration of triple therapy should be kept as brief as possible given the associ- ated increase in bleeding risk. Because the risk of stent thrombosis falls signi cantly after 30 days with bare-metal stents and 3 to 6 months after drug-eluting stents, triple therapy should be continued only dur- ing this high-risk period and only among patients at higher risk of stroke. 