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. After the initial period of triple therapy, patients may be given VKA therapy plus a single antiplatelet drug until 12 months have elapsed from the time of stent placement (particu- larly if stent placement was performed in the setting of a recent ACS [see section 3.3] or if a drug-eluting stent was used). It should be noted that patients with AF who have received a drug-eluting stent and who are at increased risk of late stent thrombosis (eg, ACS at presenta- tion, diabetes, long lesions, narrow diameter of tar- get vessel)123 may choose to continue triple therapy for a full 12 months after stent placement if they place a low value on avoiding bleeding. At 12 months after stent placement, antithrombotic therapy can be given according to our recommendations for AF and stable coronary artery disease (section 3.1). Recommendation 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 placement of a drug-eluting stent, we suggest triple therapy (eg, VKA therapy, aspirin, and clopidogrel) rather than dual antiplatelet therapy (eg, aspi- rin 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, antithrombotic therapy is suggested as for patients with AF and stable coronary artery disease (see section 3.1). 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 intra- coronary stent (bare metal or drug eluting), we suggest dual antiplatelet therapy rather than triple therapy (Grade 2C). At 12 months after intracoronary stent placement, 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 trials including 2,436 patients found that a 30- to 42-day course of ticlopidine plus aspirin vs warfa- rin plus aspirin reduced the 30- to 42-day risk of nonfatal MI (relative risk, 0.50; 95% CI, 0.30-0.83; number needed to treat, 55) and revascularization (relative risk, 0.29; 95% CI, 0.16-0.56; number needed to treat, 33) with a possible reduction in major bleed- ing (relative risk, 0.36; 95% CI, 0.14-1.02) (see Table 11 in Vandvik et al,108 sections 3.1-3.5).114 Based on these data, we recommend aspirin and clopidogrel over warfarin plus aspirin for a nite period following stent placement. For patients with AF receiving oral anticoagulation who undergo place- ment of an intracoronary stent, the dilemma arises about whether patients should be continued on oral anticoagulation during the time they are recom- mended to be on dual antiplatelet therapy, given the lack of direct evidence from RCTs addressing this question. Treatment decisions in this scenario must balance the effect of each drug combination on (1) the risk of stroke, systemic embolism, and mortality due to AF; (2) the risk of recurrent MI (including stent throm- bosis); and (3) the risk of bleeding related to anti- thrombotic therapy. Because of the very high risk for bias in the available observational studies that com- pare cardiovascular event rates in patients receiving triple therapy vs dual antiplatelet therapy after stent placement,115-120 we have instead used indirect evi- dence from relevant RCTs to inform our recommen- dations. We assumed that the relative impact of triple therapy on death, nonfatal MI, and nonfatal major extracranial bleeds compared with dual antiplatelet therapy would be similar to that seen in 10 RCTs of warfarin plus aspirin compared with aspirin in patients with ACS.121 For nonfatal stroke and systemic embo- lism, we assumed that the relative impact of triple therapy vs dual therapy would be similar to that seen in the ACTIVE W trial, which compared war- farin vs aspirin plus clopidogrel in patients with AF (Table 6).80 This assumption may be underestimating the true effect of triple therapy on stroke and systemic embolism compared with dual therapy. We used the same annual baseline event rates (ie, on dual antiplatelet therapy) for death, nonfatal stroke, and systemic embolism as were used in the evidence pro le comparing VKA to aspirin plus clo- pidogrel in the general AF population (Table 6). For the annual risk of nonfatal MI and nonfatal major extracranial bleeding on aspirin plus clopidogrel, we used the rates reported in the clopidogrel arm of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial, which compared ticagrelor to clopid- ogrel in patients with ACS receiving aspirin.122 The indirect data summarized in Table 12 suggest that triple therapy may be associated with net clinical e562S Antithrombotic Therapy for Atrial Fibrillation Table [Sections Should Triple Therapy Rather Than Dual Antiplatelet Therapy Be Used in Patients With AF After Intracoronary Stent Placement? 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 Dual Therapy With Triple Therapy With Dual Antiplatelet Therapy With Triple Therapy CI) Quality of Evidence Death (critical outcome) RCTs No serious limitations No serious inconsistency Very serious indirectness a Imprecise b Undetected RR per c more deaths per (from fewer to more) Low Nonfatal stroke (critical outcome) median follow-up y; ischemic stroke and intracranial hemorrhage RCT No serious limitations No serious inconsistency Very serious indirectness d No serious imprecision Undetected RR CHADS points Low per e 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 MI (important outcome) RCTs No serious limitations No serious inconsistency Very serious indirectness a No serious imprecision Undetected RR per f fewer MI per (from fewer to fewer) Low Nonfatal major extracranial bleeds (important outcome) RCTs No serious limitations No serious inconsistency Very serious indirectness a No serious imprecision Undetected RR per g more bleeds per (from more to more) Moderate Systemic embolism (important outcome) median follow-up y RCT No serious limitations No serious inconsistency Very serious indirectness d No serious imprecision Undetected RR per h fewer systemic emboli per (from fewer to fewer) Low (Continued) www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e563S 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 Dual Therapy With Triple Therapy With Dual Antiplatelet Therapy With Triple Therapy 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 Triple therapy . dual therapy Triple therapy: daily medication, lifestyle limitations, dietary restrictions, frequent blood testing and clinic visits High Dual antiplatelet therapy: daily medication only PLATO Study of Platelet Inhibition and Patient Outcomes; TIMI Thrombolysis In Myocardial Infarction. See Table legends for expansion of other abbreviations. a We used the relative risk for all-cause mortality, nonfatal MI, and nonfatal major extracranial bleeding associated with warfarin aspirin therapy vs aspirin alone in RCTs of patients with acute coronary syndrome (Rothberg et al ) to estimate the effect of triple therapy vs dual antiplatelet therapy on all-cause mortality in patients with AF and acute coronary syndrome. b The CI does not exclude important harm or bene t with triple therapy. c We used the same baseline estimates of mortality as for the general AF population receiving aspirin clopidogrel. This was 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 We used data from an RCT of warfarin vs aspirin clopidogrel in patients with AF (ACTIVE W) to estimate the relative effect of triple therapy vs dual antiplatelet therapy on nonfatal stroke and systemic embolism in patients with AF and acute coronary syndrome. This assumption may be underestimating the potential bene t of triple therapy vs dual antiplatelet therapy in reducing nonfatal stroke. e 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. f From clopidogrel (plus aspirin) arm of the PLATO trial of ticagrelor vs clopidogrel in patients with acute coronary syndrome. g Based on the absolute rate of non-coronary artery bypass graft-related major bleeding (TIMI de nition) reported in the clopidogrel (plus aspirin) arm of the PLATO trial minus the rate of fatal bleeding reported in this arm of the PLATO trial. h Estimate is derived from rate of systemic embolism on aspirin per patient-y) reported in the individual patient data 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 ). e564S Antithrombotic Therapy for Atrial Fibrillation these issues are not relevant for patients already receiving warfarin for AF. Finally, there are no studies comparing warfarin plus aspirin to triple therapy (eg, warfarin, aspirin, and clopidogrel) in patients with AF and recent ACS. Use of triple therapy in this situation would be appropriate only if the risk reduction in MI and stroke achieved by adding the second antiplatelet agent is greater than the increase in bleeding risk. This seems unlikely in patients who are not under- going stent placement and, thus, where there is no concern regarding stent thrombosis. Given the lack of direct evidence and mindful of the principle to rst do no harm, we do not advocate the use of triple therapy in patients with AF who experience ACS but do not receive an intracoronary stent. However, patients placing a high value on MI and stroke reduc- tion and a low value on avoiding bleeding may opt for an initial period of triple therapy (eg, 3-6 months) followed by warfarin plus aspirin. Recommendation 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 placement, we suggest, for the rst 12 months, adjusted- dose VKA therapy (INR 2.0-3.0) plus single anti- platelet 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, antithrom- botic therapy is suggested as for patients with AF and stable coronary artery disease (see sec- tion 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 tri- ple 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 avoid- ing bleeding and the burden associated with antico- agulant 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 bleed- ing risk and the presence of additional non-CHADS2 risk factors for stroke (see section 2.1.12). bleeding and the burden associated with anticoag- ulant therapy are likely to choose triple therapy rather than dual antiplatelet therapy. Other fac- tors that may in uence this choice are a consider- ation of bleeding risk and the presence of additional non-CHADS2 risk factors for stroke (see section 2.1.12). 3.3 Patients With AF and ACS Who Do Not Undergo Intracoronary Stent Placement Dual antiplatelet therapy (eg, with aspirin and clopidogrel) rather than aspirin alone is recommended during the rst 12 months after an ACS, regardless of whether patients also receive an intracoronary stent (Vandvik et al108). Many patients with AF (eg, CHADS2 score of 1) will choose VKA therapy (eg, warfarin) to prevent future stroke (section 2.1). Therefore, treatment options in patients with AF and recent ACS may include warfarin plus dual antiplatelet therapy (ie, triple therapy), dual antiplatelet therapy, or warfarin plus single antiplatelet therapy. In this section, we speci cally address patients with AF and ACS who do not undergo placement of an intracoro- nary stent. The indirect data summarized in Table 12 sug- gest that triple therapy may not be associated with net clinical bene t compared with dual antiplatelet therapy unless patients are at substantially high risk of stroke (eg, CHADS2 score of 2), whereas the net bene t at lower levels of stroke risk is uncertain. Rather than triple therapy, a third therapeutic option in this clinical scenario (where stent thrombosis is not a concern) is to use a VKA plus single antiplatelet therapy. Unfortunately, there are no RCTs com- paring warfarin plus single antiplatelet therapy to dual antiplatelet therapy. As described in Author et al (section 2.4) in this guideline, warfarin plus aspirin is associated with a signi cant reduction in risk of sub- sequent MI (relative risk, 0.69; 95% CI, 0.54-0.88) and stroke (relative risk, 0.56; 95% CI, 0.39-0.82) compared with aspirin alone in patients post-ACS.121 The point estimates for these reductions in MI and stroke are greater than those seen with clopidogrel plus aspirin (relative risk, 0.77; 95% CI, 0.67-0.89) vs aspirin alone (relative risk, 0.86; 95% CI, 0.63-1.18) in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial.124 These data sug- gest that warfarin plus aspirin is at least as effec- tive, and potentially more effective, than clopidogrel plus aspirin for the prevention of cardiovascular events after ACS. Warfarin plus aspirin was not given a recommendation in Author et al either as an alterna- tive or in preference to dual antiplatelet therapy for patients post-ACS because of pragmatic issues (physician reluctance, burden of use, etc). However, www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e565S clinical trials, but because these patients often have concomitant AF or are at increased risk of devel- oping AF, it is reasonable to base decisions regard- ing antithrombotic therapy on the risk strati cation schemes used for AF (section 1.1). Recommendation 3.5. For patients with atrial utter, we suggest that antithrombotic therapy decisions follow the same risk-based recommendations as for AF. 4.0 Antithrombotic Therapy for Patients With AF Undergoing Cardioversion To minimize the risk of stroke and systemic embolism associated with cardioversion, therapeutic anticoagulation (eg, with adjusted-dose oral VKAs; INR 2.0-3.0) conventionally is recommended for a minimum of 3 weeks before, during, and for a min- imum of 4 weeks after the procedure. For some patients with AF of documented short duration (eg, 48 h), a common practice is to cardiovert with- out prolonged precardioversion anticoagulation. For patients with AF duration of .48 h or unknown duration, a TEE-guided approach is an alternative strategy that can simplify anticoagulation manage- ment before cardioversion. In this section, we sum- marize the evidence and give recommendations for the use of antithrombotic therapy in patients under- going electrical or pharmacologic cardioversion for AF (or atrial utter). 4.1 Patients Undergoing Elective Cardioversion of AF 4.1.1 Cardioversion of AF of More Than 48 h or Unknown Duration: Evidence favoring the ef cacy of pericardioversion anticoagulation is based on observational studies in mostly patients undergoing electrical rather than pharmacologic cardioversion. There is moderate-quality evidence from a system- atic review of 18 observational studies suggesting that the risk of stroke or thromboembolism is sub- stantially lower in patients receiving pericardiover- sion anticoagulation than in those who receive no anticoagulation (0.3% vs 2.0%), translating to a rela- tive risk of 0.16 (95% CI, 0.05-0.48) in favor of anti- coagulation.139 No data regarding major hemorrhagic events were reported in this systematic review. The conventional duration of a minimum of 3 weeks therapeutic anticoagulation before cardioversion and a minimum 4 weeks afterward is based on indirect pathophysiologic data and evidence from observa- tional studies and remains arbitrary. Observational data showing that thromboembolism was signi - cantly more common at an INR of 1.5 to 2.4 before 3.4 Patients With AF Managed by a Rhythm Control Strategy Some patients with AF will be managed with anti- arrhythmic drugs (AADs) to achieve and maintain normal sinus rhythm. Increasingly, patients with AF are also receiving catheter radiofrequency abla- tion procedures (pulmonary vein isolation) to main- tain normal sinus rhythm. In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, in which many patients in the rhythm control arm did not receive anticoagulation, patients in a rhythm control strategy had a similar risk of stroke compared with patients in a rate control strategy (see also section 4.1.1).125 There are several RCTs of catheter ablation vs AAD therapy in patients with AF, typically those who have failed rst-line therapy with AADs.126-132 All trials found a signi cant reduction in AF recurrence at 1 year of follow-up. However, AF recurrence in the catheter ablation arms ranged from 11% to 44% at 1 year. The studies rarely reported on stroke outcomes, and all were underpowered to address this question. Given the results of the AFFIRM trial, the lack of longer-term follow-up data from catheter ablation RCTs regarding AF recurrence rates, and poor reporting of stroke outcomes, it would be pru- dent to base decisions about long-term antithrom- botic therapy on a patient s underlying risk for stroke as recommended in section 2.1, and not on their underlying rhythm. Recommendation 3.4. For patients with AF being managed with a rhythm control strategy (pharmacologic or cath- eter ablation), we suggest that antithrombotic therapy decisions follow the general risk-based recommendations for patients with AF in sec- tion 2.1, regardless of the apparent persistence of normal sinus rhythm (Grade 2C). 3.5 Patients With Atrial Flutter Many patients with persistent atrial utter have periods of atrial utter alternating with periods of AF.133,134 The prevalence of thrombus in the body of the atria and atrial appendage on TEE in patients with atrial utter ranges from 1% to 21%.135-138 There are few data from longitudinal studies assessing the risk of thromboembolism with well-documented sustained atrial utter. A study describing a series of 191 consecutive, unselected patients hospitalized for treatment of atrial utter reported thromboembo- lism in 7% of patients during a mean follow-up of 26 months.134 The role of anticoagulant therapy for patients with atrial utter has not been evaluated in e566S Antithrombotic Therapy for Atrial Fibrillation bolism. If no thrombus is seen, the patient proceeds immediately to cardioversion. A TEE-guided strategy requires an experienced echocardiographer because accurate visualization of thrombus may be operator dependent. The Assessment of Cardioversion Using Transesoph- ageal Echocardiography (ACUTE) RCT compared a TEE-guided strategy of abbreviated therapeutic anti- coagulation with IV unfractionated heparin (started 24 h before cardioversion) or warfarin (INR 2.0-3.0) (started 5 days before cardioversion) to a strategy of therapeutic anticoagulation for at least 3 weeks before cardioversion.145 The evidence is of low quality given the wide 95% CIs around the point estimates of effect on patient-important outcomes (Table 13). Thus, the results do not exclude with con dence the possibility of important bene t or harm with a TEE- guided approach compared with a conventional approach of 3 weeks anticoagulation precardioversion. Acknowledging these uncertainties, a TEE-guided approach may be best suited for patients who are very symptomatic while in AF because cardioversion can be done sooner if the TEE is negative for thrombus. It may also suit patients who would prefer to avoid prolonged oral anticoagulation before cardioversion and those at increased risk for bleeding. However, the ability to avoid anticoagulation with a TEE-guided strategy is most relevant for patients without stroke risk factors and at low risk of recurrent AF in whom long-term anticoagulation beyond 4 weeks after car- dioversion would not be required. For patients undergoing a TEE-guided approach, low-molecular-weight heparin at full VTE treatment doses or IV unfractionated heparin (to maintain an activated partial thromboplastin time prolongation cardioversion than an INR of 2.5 (0.93% vs 0%, P 5 .012) suggests the importance of maintaining a therapeutic INR in the pericardioversion period.140 After cardioversion, results of observational studies suggest that the highest risk of stroke and thrombo- embolism is in the rst 72 h after cardioversion and that the majority of thromboembolic complications will occur within 10 days of cardioversion.141 How- ever, TEE studies have demonstrated that despite restoration of sinus rhythm on the ECG, atrial mechanical dysfunction may persist for several weeks A nonrandomized comparison of 1,270 patients enrolled in the RE-LY trial who underwent 1,983 car- dioversions suggests that there may be no excess harm with dabigatran compared with warfarin when used for pericardioversion anticoagulation. Most cardioversions in this study (80%) were performed after the protocol-assigned study anticoagulant was given for a minimum of 3 weeks before the proce- dure, and rates of stroke and systemic embolism at 30 days after cardioversion were low when oral anti- coagulation with either warfarin or dabigatran was with dabigatran 110 mg bid, dabigatran 150 mg bid, and warfarin, respectively).143 A TEE-guided approach with abbreviated antico- agulation before cardioversion is an alternative to the conventional approach of using a minimum of 3 weeks therapeutic precardioversion anticoagulation.144 Under a TEE-guided strategy, patients receive anticoagula- tion and once therapeutic, undergo screening TEE. If thrombus is seen in either atrial appendage or atrium at the time of TEE, cardioversion is post- poned, given the presumed high risk of thromboem- Table 13 [Section 4.1] Abbreviated Anticoagulation With TEE-Guided Cardioversion vs Conventional Anticoagulation for at Least 3 Weeks Before Cardioversion Anticipated Absolute Effects (Time Frame Is 8 wk) Outcomes Risk With Conventional Anticoagulation Risk Difference With Anticoagulationa (95% CI) Relative Effect No. of Participants (Studies), Follow-up Quality of The Evidence (GRADE) (0 more to 52 more) Nonfatal strokes 3 per 1,000b 5 more strokes per 1,000 (2 fewer to 38 more) Nonfatal major extracranial bleedsd (12 fewer to 9 more) ACUTE 5 Assessment of Cardioversion Using Transesophageal Echocardiography; GRADE 5 Grades of Recommendations, Assessment, Development, and Evaluation; TEE5transesophageal echocardiography. See Tables 1 and 8 for expansion of other abbreviations. aAbbreviated anticoagulation refers to either IV unfractionated heparin (started 24 h before cardioversion) or adjusted-dose warfarin (INR 2.0-3.0) (started 5 d before cardioversion). bAssumed risk is the observed event rate from the control arm (ie, conventional anticoagulation) of the RCT by Klein et al145 (ACUTE trial). cNo statistically signi cant effect, and CIs are very wide. Trial was not suf ciently large to demonstrate comparable safety between conventional and TEE-based strategies. dMost of these were GI bleeds. www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e567S recommendations for long-term antithrombotic therapy in section 2.1. 4.1.2 Cardioversion of AF of 48 h Duration or Less: There is uncertainty over the precise duration of AF necessary for thrombus to develop and, hence, the threshold of AF duration below which precar- dioversion anticoagulation can be safely avoided. For AF of short duration (eg, 48 h), a common practice is to cardiovert without a TEE or prolonged precardioversion anticoagulation. However, observa- tional studies have found left atrial thrombus on TEE in as many as 14% of patients with acute AF of short duration.158,159 Moreover, because many indi- viduals develop AF asymptomatically, it is often dif cult to accurately determine a patient s dura- tion of AF, making the 48-h rule dif cult to apply.160 No RCTs have compared different anticoagulation strategies in patients with AF of documented dura- tion of 48 h. Observational data suggest that the risk of stroke or thromboembolism in these patients is similar to those who have received conventional anticoagulation for a minimum of 3 weeks before Recommendation 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 presenta- tion (low-molecular-weight heparin or unfrac- tionated heparin at full venous thromboembolism treatment doses) and proceeding to cardiover- sion 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 anti- thrombotic therapy in section 2.1. 4.2 Patients Undergoing Urgent Cardioversion for Hemodynamically Unstable AF There are no published data regarding the opti- mal anticoagulation strategy to use before or dur- ing urgent cardioversion for patients with AF and hemodynamic instability. Initiation of anticoag- ulation immediately before urgent cardioversion (eg, with IV unfractionated heparin or low-molecular- weight heparin) would be expected to reduce the risk of stroke or thromboembolism based on studies that corresponds to plasma heparin levels of 0.3-0.7 International Units/mL antifactor Xa activity) should be started at the time of TEE and cardioversion per- formed within 24 h of the TEE if no thrombus is seen. A few observational studies and one RCT have suggested that low-molecular-weight heparin has similar ef cacy compared with heparin or warfarin for immediate anticoagulation before TEE.146-150 Out- patients undergoing a TEE-guided approach may be started on a VKA (INR 2.5; range, 2.0-3.0) and the TEE and subsequent cardioversion scheduled for 5 days later (if the INR is in therapeutic range at that time). The new oral anticoagulants may also be suitable for outpatient treatment before TEE-guided cardioversion given their ease of use (eg, dabigatran achieves steady-state concentrations in 2-3 days after bid administration),151 but they have not yet been studied for this purpose. There is no direct evidence to guide decisions about the long-term management of anticoagula- tion in patients who appear to be in sinus rhythm 4 weeks after cardioversion. Several observational studies indicate that approximately one-half of patients will have recurrence of AF at 1 year after cardioversion.152-156 The AFFIRM study, in which many patients stopped anticoagulation after initial (apparently) successful restoration of sinus rhythm, found similar rates of thromboembolism with a rhythm control strategy compared with a rate con- trol strategy.125 Finally, patients with PAF often are asymptomatic during episodes of AF recurrence, with one series suggesting that only one in every 12 paroxysms are symptomatic.157 These observations suggest that decisions about long-term antithrom- botic therapy should be primarily based on a patient s risk for stroke (see section 2.1) rather than on the prevailing rhythm at 4 weeks postcardioversion. Recommendation 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 TEE- guided approach with abbreviated anticoagu- lation 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 e568S Antithrombotic Therapy for Atrial Fibrillation ies assessed oral anticoagulation at very-low INR targets or xed low doses compared with adjusted- dose anticoagulation targeted at an INR of 2.0 to 3.0 and found that anticoagulation targeted at an INR of 2.0 to 3.0 was more effective in reducing the risk of stroke.164 Observational studies have shown that the risk of ischemic stroke is much greater once INR levels are , 2.0 and that there are no appre- ciable gains in ef cacy with levels . 2.0. However, there is a sharp increase in the risk of bleeding com- plications, particularly intracranial hemorrhage, as INR levels rise to . 3.0 to 4.0.165-169 A target INR value of 2.0 will result in patients spending a substan- tial proportion of time at subtherapeutic INR levels (ie, ,2.0).170 Given that bleeding risk does not rise substantially until INR levels are .3.0, and particu- larly .4.0, these data from AF populations support an optimal target INR range of 2.0 to 3.0, with a tar- get value of 2.5 to maximize the time spent in the optimal INR range.165-170 5.2 Time in Therapeutic Range For a full discussion of the importance of time in therapeutic range while on adjusted-dose VKA therapy, see Ageno et al171 regarding oral antico- agulation in this guideline. With respect to patients with AF, there are several observational studies indi- cating that increasing time out of range is associated with poorer outcomes (eg, mortality, ischemic stroke, thromboembolism, major bleeding).172-175 6.0 Future Research Approximately one in every three patients with AF also has coronary artery disease.51 However, the opti- mal approach to antithrombotic therapy in these patients is unclear. Research is needed to determine the effect of treatment with oral anticoagulation and aspirin compared with oral anticoagulation alone on patient-important outcomes of vascular death, nonfa- tal stroke, nonfatal MI, nonfatal major extracranial bleeding, and nonfatal systemic embolism. Research is also needed to inform recommendations about dif- ferent antithrombotic therapy regimens for patients with AF undergoing placement of an intracoronary artery stent or who experience an ACS (eg, triple therapy with oral anticoagulation, clopidogrel, and aspirin; dual antiplatelet therapy with clopidogrel and aspirin; or combination oral anticoagulation and aspirin or clopidogrel). Finally, all existing stroke risk strati cation and bleeding risk strati cation schema for patients with AF have modest predictive value, and development of more-accurate risk strati cation systems is needed to facilitate a more-accurate esti- mation of net clinical bene t for individual patients. of elective cardioversion. It is important to note that the initiation of anticoagulation therapy should not delay any emergency interventions to stabilize the patient. Recommendation 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 (Grade 2C), but that initiation of anticoagulation must not delay any emergency intervention (Grade 2C). After successful cardioversion to sinus rhythm, we suggest therapeutic anticoag- ulation for at least 4 weeks after successful car- dioversion 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 Patients Undergoing Elective or Urgent Cardioversion for Atrial Flutter There are no published data regarding the optimal anticoagulation strategy to use for patients under- going cardioversion for atrial utter. Although some observational studies suggest that the risk of throm- boembolism after cardioversion for atrial utter is low, even without anticoagulation, other studies have documented a similar risk of thromboembolism in patients after cardioversion for atrial utter and AF.140,162,163 This may be because AF and atrial utter often coexist. Recommendation 4.3. For patients with atrial utter undergo- ing elective or urgent pharmacologic or electri- cal cardioversion, we suggest that the same approach to thromboprophylaxis be used as for patients with atrial brillation undergoing cardioversion. 5.0 Practical Issues in the Management of VKA Therapy 5.1 Optimal Target INR Range For a full discussion of optimal target INR range with VKA therapy across a variety of indications, see Holbrook et al91 regarding evidence-based man- agement of anticoagulation in this guideline. With respect to patients with AF speci cally, several stud- www.chestpubs.org CHEST / 141 / 2 / FEBRUARY, 2012 SUPPLEMENT e569S and the Thrombosis Research Institute. She has also received support (travel and accommodation) to attend conferences from Astra- Zeneca and Boehringer Ingelheim GmbH. Dr Eckman has received a number of grants, including university grants for Using Decision Analytic Modeling to Guide the ACCP Guideline Development Process for Antithrombotic Therapy in Atrial Fibrilla- tion (Foundation for Informed Medical Decision Making; $185,000) and has the following industry grants: Cost-Effectiveness of Screening for Chronic Hepatitis C Infection (Merck/Schering- Plough; September 2012; $58,000) and Cost-Effectiveness of Screening for Chronic Hepatitis B Infection (Gilead Sciences Inc; $56,000). He served as a consultant for Savient Pharmaceuticals ($300). Dr Hylek has participated in a symposium sponsored by Boehringer Ingelheim, served on advisory boards (Bayer Healthcare Pharmaceuticals; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Daiichi-Sankyo, Inc; Johnson & Johnson; Merck and Co, Inc; Ortho-McNeil Pharmaceutical, Inc; and P zer Inc) for amounts totaling ,$10,000 and participated at the steering committee level for several pharmaceutical-sponsored studies (ARISTOTLE trial sponsored by Bristol-Myers Squibb and P zer Inc [, $10,000] and ORBIT-AF Registry sponsored by Ortho-McNeil Pharma- ceutical, Inc [,$10,000]). Dr Go has received research funding from the National Heart, Lung, and Blood Institute related to anti- thrombotic therapy in atrial brillation and was a site principal investigator for a clinical trial sponsored by Johnson & Johnson and Bayer Healthcare Pharmaceuticals. Dr Halperin has received consulting fees from the following pharmaceutical manufacturers for advisory activities involving the development of anticoagulant drugs, none of which are currently approved for clinical use in any indication in the United States: Astellas Pharma, US; Bayer AG HealthCare; Boehringer Ingelheim; Daiichi Sankyo; Johnson & Johnson; and Sano -Aventis. He has received honoraria from Portola Pharmaceuticals, Inc as a member of the Data Safety Monitoring Board of its Phase II EXPLORE-AF trial involving an investi- gational anticoagulant for prevention of thromboembolism in patients with atrial brillation. He has received consulting fees from Biotronik, Inc as co-chair of the Steering Committee for the IMPACT clinical trial evaluating the use ambulatory monitoring technology in approved implanted cardiac arrhythmia devices to guide anticoagulation therapy for stroke prevention. He has received a consulting fee from the Bristol-Myers Squibb/Sano Partner- ship for advisory activities related to the use of the platelet inhibitor drug, clopidogrel, for prevention of thromboembolism in patients with atrial brillation. He has been a speaker at CME Symposia that derived partial funding from the following sponsors involved in the development of anticoagulants for potential use in patients with AF: Bayer AG HealthCare, Boehringer Ingelheim, and Sano - Aventis. Dr Lip has served as a consultant for Bayer, Astellas, Merck, Daiichi-Sankyo, AstraZeneca, Sano -Aventis, BMS/P zer, Biotronik, Portola, and Boehringer Ingelheim and has been on the speakers bureau for Bayer, Bristol-Myers Squibb/P zer, Boehringer Ingelheim, and Sano -Aventis. Drs You, Howard, Fang, Schulman, Hughes, Manning, and Spencer have reported that no potential con icts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors played no role in the develop- ment of these guidelines. Sponsoring organizations cannot rec- ommend panelists or topics, nor are they allowed prepublication access to the manuscripts and recommendations. Guideline panel members, including the chair, and members of the Health & Science Policy Committee are blinded to the funding sources. Further details on the Con ict of Interest Policy are available online at http://chestnet.org. Other contributions: We thank Louis Kuritzky, MD, for sharing his perspective as a frontline clinician during the development of our recommendations. Endorsements: This guideline is endorsed by the American Association for Clinical Chemistry, the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, the American Society of Hematology, and the International Soci- ety of Thrombosis and Hematosis. Additional information: The supplement Tables can be found in the Online Data Supplement at http://chestjournal.chestpubs.org/ content/141/2_suppl/e531S/suppl/DC1. Stroke is a serious complication of AF, but its risk varies considerably across different groups of patients with AF. Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treat- ment based on net clinical bene t for patients with AF at varying levels of stroke risk. Oral anticoag- ulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (eg, CHADS2 score 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach that takes into con- sideration patient values and preferences, bleeding risk, and the presence of non-CHADS2 stroke risk factors. The role of oral anticoagulation for the pre- vention of stroke in patients with AF will evolve as the results of large, ongoing, phase 3 RCTs of new oral anticoagulants are published and as experience with these new agents in clinical practice continues to grow. Acknowledgments Author contributions: As Topic Editor, Dr You oversaw the development of this article, including the data analysis and sub- sequent development of the recommendations contained herein. Dr You: contributed as Topic Editor. Dr Singer: contributed as a panelist. Dr Howard: contributed as a panelist. Dr Lane: contributed as a panelist. Dr Eckman: contributed as a resource consultant. Dr Fang: contributed as a panelist. Dr Hylek: contributed as a panelist. Dr Schulman: contributed as a panelist. Dr Go: contributed as a panelist. Dr Hughes: contributed as a panelist. Dr Spencer: contributed as a panelist. Dr Manning: contributed as a panelist. Dr Halperin: contributed as a panelist. Dr Lip: contributed as Deputy Editor and senior author. Financial/non nancial disclosures: The authors of this guide- line provided detailed con ict of interest information related to each individual recommendation made in this article. A grid of these disclosures is available online at http://chestjournal. chestpubs.org/content/141/2_suppl/e531S/suppl/DC1. In summary, the authors have reported to CHEST the following con icts of interest: Over the past 3 years, Dr Singer has received grant support from the Eliot B. and Edith C. Shoolman fund of Massachusetts General Hospital (MGH) to study stroke in atrial brillation. He has also received research grant support (through MGH) from Daiichi-Sankyo, Inc, to study hemorrhage risk in patients with atrial brillation taking warfarin. Dr Singer has been supported by the National Institutes of Health (National Heart, Lung, and Blood Institute and National Institute on Aging) grant funding to study stroke risk in patients with atrial brillation. 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