title: Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: I. Reduced flow velocity in the left atrial appendage (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study). Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators. Should Stroke Subtype Influence Anticoagulation Decisions to Prevent Recurrence in Stroke Patients With Atrial Fibrillation? Stroke Prevention in Atrial Fibrillation Study: Final Results Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. Efficacy of anticoagulation for secondary stroke prevention in older people with non-valvular atrial fibrillation: a prospective case series study. Gender Differences in the Risk of Ischemic Stroke and Peripheral Embolism in Atrial Fibrillation: The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) Study A randomized trial of anticoagulants versus aspirin after cerebral ischemia of presumed arterial origin Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. Transesophageal Echocardiography To Assess Embolic Risk in Patients with Atrial Fibrillation Risk factors for stroke in patients with nonrheumatic atrial fibrillation: a case-control study. Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. Anticoagulation therapy for stroke prevention in atrial fibrillation: how well do randomized trials translate into clinical practice?
abstract: Stroke associated with atrial fibrillation ( AF ) is mainly due to embolism of thrombus formed during stasis of blood in the left atrial appendage ( LAA ) . Pathophysiologic correlates of appendage flow velocity as assessed by transesophageal echocardiography ( TEE ) in patients with AF have not been defined . To evaluate the hypothesis that reduced velocity is associated with spontaneous echocardiographic contrast and thrombus in the LAA and with clinical embolic events , we measured LAA flow velocity by TEE in 721 patients with nonvalvular AF entering the Stroke Prevention in Atrial Fibrillation ( SPAF-III ) study . Patient features , TEE findings , and subsequent cardioembolic events were correlated with velocity by multivariate analysis . Patients in AF during TEE displayed lower peak ante grade ( emptying ) flow velocity ( Anu(p ) ) than those with intermittent AF in sinus rhythm during TEE ( 33 cm/s vs 61 cm/s , respectively , P < .0001 ) . Anu(p ) < 20 cm/s was associated with dense spontaneous echocardiographic contrast ( P < .001 ) , appendage thrombus ( P < .01 ) , and subsequent cardioembolic events ( P < .01 ) . Independent predictors of Anu(p ) < 20 cm/s included age ( P = .009 ) , systolic blood pressure ( P < .001 ) , sustained AF ( P = .01 ) , ischemic heart disease ( P = .01 ) , and left atrial area ( P = .04 ) . Multivariate analysis found both Anu(p ) < 20 cm/s ( relative risk 2.6 , P = .02 ) and clinical risk factors ( relative risk 3.3 , P = .002 ) independently associated with LAA thrombus . LAA Anu(p ) is reduced in AF and associated with spontaneous echocardiographic contrast , appendage thrombus , and cardioembolic stroke . Systolic hypertension and aortic atherosclerosis , independent clinical predictors of stroke in patients with AF , also correlated with LAA Anu(p ) . Our results support the role of reduced LAA Anu(p ) in the generation of stasis , thrombus formation , and embolism in patients with AF , although other mechanisms also contribute to stroke Stroke incidence in Copenhagen , Denmark was recorded in a r and om population sample of 19,327 persons invited for two health examinations with 5 years ' interval from 1976 to 1983 . Stroke incidence increased exponentially with age . After adjustment to the age and sex distribution of the Danish population in 1980 , the estimated incidence of first stroke was 1.41/1000 women and 2.48/1000 men ; the total incidence was 1.94/1000 population . Risk factor analysis was based on the initial examination of 13,088 persons greater than 35 years old without previous stroke who responded to the first invitation , in whom 295 first strokes were subsequently observed . We used the regression model of Cox . However , our use of this model differs from the somewhat automatic procedures normally used to develop prognostic models . Evaluation of the causative effect of a particular risk factor requires that the direction of mutual influences between the factor in question and other risk factors is established/postulated . Among the 16 potential risk factors for stroke we examined , significant effects were found for age , sex , household income , smoking habits , systolic blood pressure , diabetes , plasma cholesterol concentration , ischemic heart disease , and atrial fibrillation . No significant effect could be demonstrated for a positive family history of stroke , years of school education , marital status , alcohol consumption , daily use of tranquilizers , body mass index , or postmenopausal hormone treatment BACKGROUND AND PURPOSE Nonvalvular atrial fibrillation ( AF ) is a strong , independent risk factor for stroke , but the absolute rate of stroke varies widely among AF patients , importantly influencing the potential benefit of antithrombotic prophylaxis . We explore factors associated with ischemic stroke in AF patients taking aspirin .  METHODS We performed multivariate logistic regression analysis of 2012 participants given aspirin alone or in combination with low , inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I-III trials followed for a mean of 2.0 years , during which 130 ischemic strokes were observed . RESULTS Age ( relative risk [RR]=1.8 per decade , P<0.001 ) , female sex ( RR=1.6 , P=0.01 ) , history of hypertension ( RR=2.0 , P<0.001 ) , systolic blood pressure > 160 mm Hg ( RR=2.3 , P<0.001 ) , and prior stroke or transient ischemic attack ( RR=2.9 , P<0.001 ) were independently associated with increased stroke risk . Regular consumption of > /=14 alcohol-containing drinks per week was associated with reduced stroke risk ( adjusted RR=0.4 , P=0.04 ) . Among SPAF III participants , estrogen hormone replacement therapy was associated with a higher risk of ischemic stroke ( adjusted RR=3.2 , P=0.007 ) . With the use of these variables , a risk stratification scheme for primary prevention separated participants into those with high ( 7.1%/y , 22 % of the cohort ) , moderate ( 2.6%/y , 37 % of the cohort ) , and low ( 0.9%/y , 41 % of the cohort ) rates of stroke . Ischemic strokes in low-risk participants were less often disabling ( P<0.001 ) . CONCLUSIONS Patients with AF who have high and low rates of stroke during treatment with  aspirin can be identified . However , validation of our risk stratification scheme is necessary before it can be applied with confidence to clinical management . Postmenopausal estrogen replacement therapy and moderate alcohol consumption may additionally modify the risk of stroke in AF , but these findings require confirmation Background and Purpose — Long-term anticoagulation is routinely used for secondary stroke prevention in atrial fibrillation , often regardless of stroke subtype . Although the role of warfarin in cardioembolic stroke is established , it may not prevent recurrence in other stroke subtypes , even in the presence of atrial fibrillation . Methods — This was a 2-year , prospect i ve , intervention study conducted in a district general hospital . Participants included 386 acute stroke patients with atrial fibrillation . Subjects were characterized for stroke subtype on clinical , neuroimaging , carotid ultrasonographic , and echocardiographic criteria . Eligible patients were treated with adjusted-dose warfarin ( international normalized ratio , 2.0 to 3.0 ) . Aspirin ( 75 to 300 mg/d ) was used in patients with contraindications or those who refused anticoagulation . The main outcome measures were rate of recurrent stroke by subtype and major and minor bleeding complications . Results — The  aspirin group ( n=172 ) was comparable to the  warfarin group ( n=214 ) in terms of age , sex , risk factors , and initial stroke subtype . The rate of recurrent stroke was higher ( 9.5 % versus 4.9 % , P < 0.02 ) but that of major bleeding was lower ( 0.6 % versus 2.5 % , P < 0.05 ) with aspirin . The increased stroke rate with aspirin was due predominantly to cardioembolic recurrence in patients presenting initially with cardioembolic stroke ( 8.4 % versus 1.9 % , P < 0.01 ) . The recurrence rate in aspirin-treated patients who presented with lacunar stroke and atrial fibrillation was similar to that seen in patients receiving warfarin ( 8.8 % versus 8.9 % ) . Conclusions — In this cohort of stroke patients with atrial fibrillation , anticoagulation was superior to aspirin in preventing cardioembolic but not lacunar recurrence . Determination of stroke subtype may be important in anticoagulation decisions for secondary prevention , and further studies are required Background Atrial fibrillation in the absence of rheumatic valvular disease is associated with a fivefold to sevenfold increased risk of ischemic stroke . Methods and Main Results . The Stroke Prevention in Atrial Fibrillation Study , a multicenter , r and omized trial , compared 325 mg/day aspirin ( double-blind ) or warfarin with placebo for prevention of ischemic stroke and systemic embolism ( primary events ) , and included 1,330 in patients and out patients with constant or intermittent atrial fibrillation . During a mean follow-up of 1.3 years , the rate of primary events in patients assigned to placebo was 6.3 % per year and was reduced by 42 % in those assigned to aspirin ( 3.6 % per year , p = 0.02 ; 95 % confidence interval , 9–63 % ) . In the subgroup of  warfarin-eligible patients ( most less than 76 years old ) , warfarin dose-adjusted to prolong prothrombin time to 1.3-fold to 1.8-fold that of control reduced the risk of primary events by 67 % ( warfarin versus placebo , 2.3 % versus 7.4 % per year , p = 0.01 ; 95 % confidence interval , 27–85 % ) . Primary events or death were reduced 58 % ( p = 0.01 ) by warfarin and 32 % ( p = 0.02 ) by aspirin . The risk of significant bleeding was 1.5 % , 1.4 % , and 1.6%o per year in patients assigned to warfarin , aspirin , and placebo , respectively . Conclusions Aspirin and warfarin are both effective in reducing ischemic stroke and systemic embolism in patients with atrial fibrillation . Because warfarin-eligible patients composed a subset of all aspirin-eligible patients , the magnitude of reduction in events by warfarin versus aspirin can not be compared . Too few events occurred in warfarin-eligible patients to directly assess the relative benefit of aspirin compared with warfarin , and the trial is continuing to address this issue . Patients with nonrheumatic atrial fibrillation who can safely take either aspirin or warfarin should receive prophylactic antithrombotic therapy to reduce the risk of stroke BACKGROUND Atherosclerotic intracranial arterial stenosis is an important cause of stroke . Warfarin is commonly used in preference to aspirin for this disorder , but these therapies have not been compared in a r and omized trial . METHODS We r and omly assigned patients with transient ischemic attack or stroke caused by angiographically verified 50 to 99 percent stenosis of a major intracranial artery to receive warfarin ( target international normalized ratio , 2.0 to 3.0 ) or aspirin ( 1300 mg per day ) in a double-blind , multicenter clinical trial . The primary end point was ischemic stroke , brain hemorrhage , or death from vascular causes other than stroke . RESULTS After 569 patients had undergone r and omization , enrollment was stopped because of concerns about the safety of the patients who had been assigned to receive warfarin .  During a mean follow-up period of 1.8 years , adverse events in the two groups included death ( 4.3 percent in the aspirin group vs. 9.7 percent in the warfarin group ; hazard ratio for aspirin relative to warfarin , 0.46 ; 95 percent confidence interval , 0.23 to 0.90 ; P=0.02 ) , major hemorrhage ( 3.2 percent vs. 8.3 percent , respectively ; hazard ratio , 0.39 ; 95 percent confidence interval , 0.18 to 0.84 ; P=0.01 ) , and myocardial infa rct ion or sudden death ( 2.9 percent vs. 7.3 percent , respectively ; hazard ratio , 0.40 ; 95 percent confidence interval , 0.18 to 0.91 ; P=0.02 ) . The rate of death from vascular causes was 3.2 percent in the aspirin group and 5.9 percent in the warfarin group ( P=0.16 ) ; the rate of death from nonvascular causes was 1.1 percent and 3.8 percent , respectively ( P=0.05 ) . The primary end point occurred in 22.1 percent of the patients in the aspirin group and 21.8 percent of those in the warfarin group ( hazard ratio , 1.04 ; 95 percent confidence interval , 0.73 to 1.48 ; P=0.83 ) . CONCLUSIONS Warfarin was associated with significantly higher rates of adverse events and provided no benefit over aspirin in this trial . Aspirin should be used in preference to warfarin for patients with intracranial arterial stenosis BACKGROUND AND PURPOSE Despite large r and omised trials that demonstrated the efficacy of oral anticoagulants in the primary and secondary prevention of stroke in patients with non-valvular atrial fibrillation ( AF ) , anticoagulation therapy remains largely under-used in older patients , who are at risk of first ever or recurrent stroke . The aim of the present study was to assess the influence of anticoagulation therapy on long-term prognosis in the oldest old stroke patients with AF after adjusting for baseline risk factors . METHODS We evaluated prospect ively a consecutive series of 207 older people ( > 75 years ) with AF and first ever ischaemic stroke . During the follow-up period ( mean 88.4 months , range 3 - 120 ) , the study population was under either oral anticoagulants ( n = 72 ) or aspirin ( n = 135 ) . Death and recurrent vascular events ( stroke and systemic embolism ) were documented . Statistical analyses were performed by means of the Kaplan-Meier product limit method and the Cox proportional hazards model . RESULTS The cumulative 10 year mortality and recurrence rate were 92.5 % ( 95 % CI 85.7 - 99.3 ) and 66.1 % ( 95 % CI 43.1 - 89.1 ) , respectively . Cox regression analysis revealed increasing age , functional dependency at hospital discharge and antiplatelet versus anticoagulation therapy as independent determinants of mortality . Antiplatelet versus anticoagulation therapy was the sole determinant of vascular recurrence .  Anticoagulation was associated with decreased risk of death ( hazards ratio ( HR ) 0.47 , 95 % CI 0.31 - 0.72 , P = 0.001 ) ) and recurrent thromboembolism ( HR 0.31 , 95 % CI 0.16 - 0.62 , P = 0.002 ) . CONCLUSIONS Our results suggest that the benefits of anticoagulation for secondary stroke prevention in AF patients extend to the oldest old . Prospect i ve r and omised clinical trials are needed to verify the potential benefit of anticoagulation in such patients Background —Previous studies provide conflicting results about whether women are at higher risk than men for thromboembolism in the setting of atrial fibrillation ( AF ) . We examined data from a large contemporary cohort of AF patients to address this question . Methods and Results —We prospect ively studied 13 559 adults with AF and recorded data on patients ’ clinical characteristics and the occurrence of incident hospitalizations for ischemic stroke , peripheral embolism , and major hemorrhagic events through search ing vali date d computerized data bases and medical record review . We compared event rates by patient sex using multivariable log-linear regression , adjusting for clinical risk factors for stroke , and stratifying by warfarin use . We identified 394  ischemic stroke and peripheral embolic events during 15 494 person-years of follow-up off warfarin . After multivariable analysis , women had higher annual rates of thromboembolism off warfarin than did men ( 3.5 % versus 1.8 % ; adjusted rate ratio [ RR ] , 1.6 ; 95 % CI , 1.3 to 1.9 ) . There was no significant difference by sex in 30-day mortality after thromboembolism ( 23 % for both ) . Warfarin use was associated with significantly lower adjusted thromboembolism rates for both women and men ( RR , 0.4 ; 95 % CI , 0.3 to 0.5 ; and RR , 0.6 ; 95 % CI , 0.5 to 0.8 , respectively ) , with similar annual rates of major hemorrhage ( 1.0 % and 1.1 % , respectively ) . Conclusions —Women are at higher risk than men for AF-related thromboembolism off warfarin . Warfarin therapy appears be as effective in women , if not more so , than in men , with similar rates of major hemorrhage . Female sex is an independent risk factor for thromboembolism and should influence the decision to use anticoagulant therapy in persons with AF Aspirin is only modestly effective in the secondary prevention after cerebral ischemia . Studies in other vascular disorders suggest that anticoagulant drugs in patients with cerebral ischemia of presumed arterial ( noncardiac ) origin might be more effective . The aim of the Stroke Prevention in Reversible Ischemia Trial ( SPIRIT ) therefore was to compare the efficacy and safety of 30 mg aspirin daily and oral anticoagulation ( international normalized ratio [ INR ] 3.0–4.5 ) . Patients referred to a neurologist in one of 58 collaborating centers because of a transient ischemic attack or minor ischemic stroke ( Rankin grade $ 3 ) were eligible . R and omization was concealed , treatment assignment was open , and assessment of outcome events was masked . The primary measure of outcome was the composite event “ death from all vascular causes , nonfatal stroke , nonfatal myocardial infa rct ion , or nonfatal major bleeding complication . ” The trial was stopped at the first interim analysis . A total of 1,316 patients participated ; their mean follow‐up was 14 months . There was an excess of the primary outcome event in the anticoagulated group ( 81 of 651 ) versus 36 of 665 in the aspirin group ( hazard ratio , 2.3 ; 95 % confidence interval [ CI ] , 1.6–3.5 ) . This excess could be attributed to 53 major bleeding complications ( 27 intracranial ; 17 fatal ) during anticoagulant therapy versus 6 on aspirin ( 3 intracranial ; 1 fatal ) . The bleeding incidence increased by a factor of 1.43 ( 95 % CI , 0.96–2.13 ) for each 0.5 unit increase of the achieved INR . Anticoagulant therapy with an INR range of 3.0 to 4.5 in patients after cerebral ischemia of presumed arterial origin is not safe . The efficacy of a lower intensity anticoagulation regimen remains to be determined CONTEXT In patients with nonvalvular atrial fibrillation , warfarin prevents ischemic stroke , but dose adjustment , coagulation monitoring , and bleeding limit its use . OBJECTIVE To compare the efficacy of the oral direct thrombin inhibitor ximelagatran with warfarin for prevention of stroke and systemic embolism . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , multicenter trial ( 2000 - 2001 ) conducted at 409 North American sites , involving 3922 patients with nonvalvular atrial fibrillation and additional stroke risk factors . INTERVENTIONS Adjusted-dose warfarin ( aim ing for an international normalized ratio [ INR ] 2.0 to 3.0 ) or fixed-dose oral ximelagatran , 36 mg twice daily . MAIN OUTCOME MEASURES The primary end point was all strokes ( ischemic or hemorrhagic ) and systemic embolic events . The primary analysis was based on demonstrating noninferiority within an absolute margin of 2.0 % per year according to the intention-to-treat model . RESULTS During 6405 patient-years ( mean 20 months ) of follow-up , 88 patients experienced primary events . The mean ( SD ) INR with warfarin ( 2.4 [ 0.8 ] ) was within target during 68 % of the treatment period . The primary event rate with ximelagatran was 1.6 % per year and with warfarin was 1.2 % per year ( absolute difference , 0.45 % per year ; 95 % confidence interval , -0.13 % to 1.03 % per year ; P<.001 for the predefined noninferiority hypothesis ) . When all-cause mortality was included in addition to stroke and systemic embolic events , the rate difference was 0.10 % per year ( 95 % confidence interval , -0.97 % to 1.2 % per year ; P = .86 ) . There was no difference between treatment groups in rates of major bleeding , but total bleeding ( major and minor ) was lower with ximelagatran ( 37 % vs 47 % per year ; 95 % confidence interval for the difference , -14 % to -6.0 % per year ; P<.001 ) . Serum alanine aminotransferase levels rose to greater than 3 times the upper limit of normal in 6.0 % of patients treated with ximelagatran , usually within 6 months and typically declined whether or not treatment continued ; however , one case of documented fatal liver disease and one other suggestive case occurred . CONCLUSIONS The results establish the efficacy of fixed-dose oral ximelagatran without coagulation monitoring compared with well-controlled warfarin for prevention of thromboembolism in patients with atrial fibrillation requiring chronic anticoagulant therapy , but the potential for hepatotoxicity requires further investigation Transesophageal echocardiography visualizes the left atrium and its appendage and is more sensitive than transthoracic echocardiography for diagnosing thrombi of the left atrium and the left atrial appendage and spontaneous echocardiographic contrast of the left atrium [ 1 - 3 ] . The left atrium and especially the left atrial appendage are the presumed sites of thrombus formation and sources of arterial emboli in patients with atrial fibrillation [ 4 ] . Patients with atrial fibrillation and a history of stroke or embolism were shown to have a higher prevalence of thrombi of the left atrium or the left atrial appendage , a higher prevalence of spontaneous echocardiographic contrast , and a larger left atrial appendage than patients with no history of stroke or embolism [ 2 , 5 , 6 ] . However , whether these abnormalities are predictors for stroke or embolism remains controversial [ 7 , 8 ] . Furthermore , no studies have determined whether transesophageal echocardiography helps to assess risk for stroke or embolism in out patients with atrial fibrillation who have no history of stroke or embolism or whether transesophageal echocardiography is useful in the decision to initiate anticoagulation . We therefore performed a prospect i ve , multicenter study of out patients with atrial fibrillation who had not recently had stroke . We sought to determine whether thrombi of the left atrium or the left atrial appendage , spontaneous echocardiographic contrast , and size of the left atrial appendage are associated with stroke or embolism . Our hypothesis was that patients with thrombi of the left atrium or the left atrial appendage , spontaneous echocardiographic contrast , and enlargement of the left atrial appendage have a higher rate of stroke or embolism than do patients without these abnormalities . The baseline clinical and echocardiographic characteristics of our study sample have been reported elsewhere [ 9 ] . Methods Patient Recruitment Our study was conducted in Austria and Slovakia . At the beginning of the study , general practitioners and internists from surrounding participating centers were informed about the study and were asked to refer patients who had constant or intermittent atrial fibrillation . At each patient 's first visit , a cardiologist recorded baseline data , associated illnesses , clinical characteristics ( definitions of which are listed in Appendix 2 ) , and the cause of atrial fibrillation . A 12-lead electrocardiogram was recorded on 2 separate days . We excluded patients with prosthetic valves and those who were already receiving anticoagulation . Current therapy with aspirin was not an exclusion criterion . Patients who had mitral valve stenosis or had recently had stroke were excluded because anticoagulation was indicated for such conditions . For the definition of recent stroke , we chose a cutoff value of 1 year because a previous study reported that the risk for recurrent stroke was increased in patients who had had an ischemic event in the previous year [ 10 ] . Echocardiography For transthoracic echocardiography , 2.5- or 3.5-MHz probes were used . For M-mode measurements , we applied the recommendations of the American Society of Echocardiography [ 11 ] . M-mode measurements were performed on-line and were documented on printouts . Regional wall-motion and valvular abnormalities were recorded . In patients without regional wall-motion abnormalities , left ventricular systolic function was assessed by calculation of left ventricular fractional shortening . For transesophageal echocardiography , biplane 5-MHz probes were used in 64 % of the patients and monoplane 5-MHz probes were used in 36 % . After local anesthesia with lidocaine spray was administered , the probe was introduced into the nonse date d patients , who lay on their left side . The entire study was recorded on S-VHS videotapes . The cardiac chambers and valves were investigated by using all obtainable views [ 12 , 13 ] . Special care was taken to visualize the whole cavity of the left atrium and its appendage from different planes , with the tip of the probe slightly flexed . The size of the left atrial appendage was measured off-line . A frame that best visualized the left atrial appendage with respect to its orifice , extension , and delineation of borders was selected just before the QRS complex . The length of the left atrial appendage was defined as the distance between the limbus of the left superior pulmonary vein and the apex of the left atrial appendage ; the width of the left atrial appendage was defined as the longest distance between the lateral and ventricular left atrial appendage wall , measured in a line perpendicular to the course of the left atrial appendage curvature ; and the left atrial appendage area was defined as described elsewhere [ 14 ] . For the assessment of intra- and interobserver deviations , left atrial appendage size was measured 1 year after the initial measurement in 20 r and omly selected video recordings by the same observer and in 60 r and omly selected video recordings by three observers from different centers . A thrombus of the left atrium or left atrial appendage was considered definite if at least three of the following five criteria were present : clear borders , echogenicity different from that of surrounding structures , independent mobility , longest diameter greater than 15 mm , and evidence of thrombus in more than one imaging plane [ 15 ] . A second observer from a different center review ed video recordings to confirm diagnosis of thrombus of the left atrium or left atrial appendage . A thrombus was considered probable if only two criteria were present or if the observers disagreed . Spontaneous echocardiographic contrast was diagnosed in the presence of dynamic smoke-like echoes within the left atrium or left atrial appendage with a characteristic swirling motion that was distinct from white noise artifact [ 16 ] . When spontaneous echocardiographic contrast was suspected , the gain setting s were decreased in a stepwise manner to exclude artifact caused by excessive gain . The compression and gain controls were then adjusted to ensure the best possible visualization . Spontaneous echocardiographic contrast was not quantified . A second observer from a different center checked the diagnosis of spontaneous echocardiographic contrast by review ing all video recordings . When the observers disagreed about the presence or absence of spontaneous echocardiographic contrast , the decision made at the time of examination was chosen . This was done because spontaneous echocardiographic contrast was not always visible on review of the video recordings . Outcome Events Primary events were stroke and embolism that extended to viscera or extremities . Stroke was defined as acute onset of a focal neurologic deficit that lasted more than 24 hours and was consistent with a vascular event . Severity and subtypes of stroke were assessed according to established criteria [ 17 ] . Embolism extending to viscera or extremities was defined as a sudden onset of pain that was associated with typical findings on Doppler ultrasonography , angiography , surgery , or autopsy . Secondary events were the need for anticoagulation during follow-up in patients who were primarily receiving aspirin and death not caused by stroke or embolism . Death not caused by stroke or embolism was classified as cardiac or noncardiac on the basis of information from the treating physician and the patient 's family . Follow-up Visits took place 3 , 6 , 12 , 18 , and 24 months after study entry . After a follow-up period of at least 2 years ( ending in February 1994 ) , it was evident that the number of primary outcome events was low . We therefore prolonged the follow-up period and planned further visits , one to be held in 1994 and one to be held in 1995 . Patients who were unwilling or unable to attend the visits were contacted by telephone . Medical records were obtained for patients who had been admitted to a hospital . If a patient had died , an autopsy report or death certificate was obtained . Treatment and Ethical Considerations Although our study was design ed to be observational , we recommended antithrombotic treatment to the patients because of ethical considerations . Because patients with thrombi of the left atrium or left atrial appendage are considered to have a high risk for embolism , we recommended that they receive anticoagulation . The target range for the international normalized ratio was 2.0 to 3.0 , and the treating physicians monitored the ratio [ 5 , 18 ] . We recommended that the remaining patients receive aspirin , 160 mg/d , because preliminary data indicated that aspirin reduces the risk for stroke or embolism in patients with atrial fibrillation [ 19 ] . The institutional review board of the participating centers approved the study . Patients were informed about the background and the procedures of the trial , and informed consent was obtained according to the rules of each center . Statistical Analysis For baseline data , group comparisons were done by analysis of variance for normally distributed data and by the nonparametric Kruskal-Wallis test for data that were not normally distributed . If appropriate , we used the Scheffe post hoc test . The Wilk-Shapiro test was used to check for normality . Contingency table methods , including the chi-square test and the Fisher exact test , were used to analyze categorical data . We used the Cox proportional-hazards model to obtain estimates of relative risk and 95 % CIs for all univariate and multivariate analyses of time-to-event data . All tests were two-sided . The level of significance assumed was an level of 0.05 . We used SAS software ( SAS Institute , Cary , North Carolina ) for analyses . Role of Funding Sources The funding sources had no role in the collection , analysis , or interpretation of the data ; did not review the manuscript at any time ; and were not involved in su bmi tting the paper for publication . Results Patients Patients were recruited between January 1990 and February 1992 . Of the 474 PURPOSE R and omized controlled trials have demonstrated that anticoagulant therapy is very effective at preventing stroke among patients with nonrheumatic atrial fibrillation . However , these trials have reported too few strokes for powerful risk factor analysis . Observational studies may provide additional information . The purpose of this study was to identify risk factors in a larger number of patients with stroke and nonrheumatic atrial fibrillation , using case-control methodology . PATIENTS AND METHODS We identified all patients discharged from one hospital over an 8-year period who met our case definition of nonrheumatic atrial fibrillation and ischemic stroke ( n = 134 ) , and compared them with contemporaneous control subjects who were discharged with nonrheumatic atrial fibrillation without stroke ( n = 131 ) . RESULTS Cases and controls were similar in terms of duration of atrial fibrillation ; proportion with paroxysmal atrial fibrillation ; percentage with a past medical history of angina , myocardial infa rct ion , congestive heart failure , diabetes , or smoking ; and mean left atrial size . In contrast , cases were significantly older than controls ( 78.5 versus 74.8 years , p = 0.002 ) and more likely to have a history of hypertension ( 55 % versus 38 % , p = 0.0093 ) . The relative odds for stroke was 1.91 for patients with hypertension , 1.73 for patients older than 75 years , and 3.26 for patients with both factors . CONCLUSIONS Our analysis suggests that age and hypertension should be considered when deciding upon long-term anticoagulant therapy to prevent stroke in patients with nonrheumatic atrial fibrillation BACKGROUND Clinical features that consistently predict ischemic stroke in patients with nonvalvular atrial fibrillation have been identified , while echocardiographic risk factors are less well defined . OBJECTIVE To determine whether the results of transthoracic echocardiography add independent information to the clinical risk factors for stroke in patients with atrial fibrillation . METHODS Transthoracic echocardiographic findings and clinical features from 1066 patients with atrial fibrillation assigned to placebo or control in 3 r and omized trials ( Boston Area Anticoagulation Trial for Atrial Fibrillation , Stroke Prevention in Atrial Fibrillation I Study , and Veterans Affairs Prevention in Atrial Fibrillation Study ) were correlated with subsequent ischemic stroke by multivariate analysis . RESULTS The mean + SD age of patients was 67 + /- 10 years , 78 % were men , 55 % had a history of hypertension , 19 % had a history of diabetes , 7 % had a previous transient ischemic attack or stroke , and 27 % had a history of heart failure . During a mean follow-up of 1.6 years , 78 ischemic strokes occurred ( annual rate , 4.7 % ) . Moderate to severe left ventricular systolic dysfunction shown via 2-dimensional echocardiography was a strong independent predictor of stroke ( relative risk , 2.5 ; P<.001 ) in the 1010 patients in whom echocardiographic values for left ventricular function were available . Left atrial diameter by M-mode echocardiography did not predict stroke ( relative risk , 1.02/mm ; P = .10 ) . Of 163 patients categorized as low risk based on clinical features ( annual stroke rate , 0.8 % ; 95 % confidence interval , 0.2%-3.0 % ) , 10 had moderate to severe left ventricular dysfunction shown via 2-dimensional echocardiography and a 9.3 % per year risk of stroke ( 95 % confidence interval , 1.3%-66 % ) . Conversely , 728 of the 847 patients at high risk for stroke based on clinical criteria had normal or mildly abnormal left ventricular function ; their stroke rate was 4.4 % ( 95 % confidence interval , 3.4%-5.8 % ) . CONCLUSIONS Left ventricular systolic dysfunction shown via 2-dimensional transthoracic echocardiography independently predicts risk of stroke in patients with atrial fibrillation . Echocardiography may prove most useful in a small group of patients who have a low risk of stroke according to clinical factors BACKGROUND Despite the use of antiplatelet agents , usually aspirin , in patients who have had an ischemic stroke , there is still a substantial rate of recurrence . Therefore , we investigated whether warfarin , which is effective and superior to aspirin in the prevention of cardiogenic embolism , would also prove superior in the prevention of recurrent ischemic stroke in patients with a prior noncardioembolic ischemic stroke . METHODS In a multicenter , double-blind , r and omized trial , we compared the effect of warfarin ( at a dose adjusted to produce an international normalized ratio of 1.4 to 2.8 ) and that of aspirin ( 325 mg per day ) on the combined primary end point of recurrent ischemic stroke or death from any cause within two years . RESULTS The two r and omized study groups were similar with respect to base-line risk factors . In the intention-to-treat analysis , no significant differences were found between the treatment groups in any of the outcomes measured . The primary end point of death or recurrent ischemic stroke was reached by 196 of 1103 patients assigned to warfarin ( 17.8 percent ) and 176 of 1103 assigned to aspirin ( 16.0 percent ; P=0.25 ; hazard ratio comparing warfarin with aspirin , 1.13 ; 95 percent confidence interval , 0.92 to 1.38 ) . The rates of major hemorrhage were low ( 2.22 per 100 patient-years in the warfarin group and 1.49 per 100 patient-years in the aspirin group ) . Also , there were no significant treatment-related differences in the frequency of or time to the primary end point or major hemorrhage according to the cause of the initial stroke ( 1237 patients had had previous small-vessel or lacunar infa rcts , 576 had had cryptogenic infa rcts , and 259 had had infa rcts design ated as due to severe stenosis or occlusion of a large artery ) . CONCLUSIONS Over two years , we found no difference between aspirin and warfarin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage . Consequently , we regard both warfarin and aspirin as reasonable therapeutic alternatives CONTEXT Warfarin has been shown to be highly efficacious for preventing  thromboembolism in atrial fibrillation in r and omized trials , but its effectiveness and safety in clinical practice is less clear . OBJECTIVE To evaluate the effect of warfarin on risk of thromboembolism , hemorrhage , and death in atrial fibrillation within a usual care setting . DESIGN Cohort study assembled between July 1 , 1996 , and December 31 , 1997 , and followed up through August 31 , 1999 . SETTING Large integrated health care system in Northern California . PATIENTS Of 13,559 adults with nonvalvular atrial fibrillation , 11,526 were studied , 43 % of whom were women , mean age 71 years , with no known contraindications to anticoagulation at baseline . MAIN OUTCOMES Ischemic stroke , peripheral embolism , hemorrhage , and death according to warfarin use and comorbidity status , as determined by automated data bases , review of medical records , and state mortality files . RESULTS Among 11,526 patients , 397 incident thromboembolic events ( 372 ischemic strokes , 25 peripheral embolism ) occurred during 25,341 person-years of follow-up , and warfarin therapy was associated with a 51 % ( 95 % confidence interval [ CI ] , 39%-60 % ) lower risk of thromboembolism compared with no warfarin therapy ( either no antithrombotic therapy or aspirin ) after adjusting for potential confounders and likelihood of receiving warfarin . Warfarin was effective in reducing thromboembolic risk in the presence or absence of risk factors for stroke . A nested case-control analysis estimated a 64 % reduction in odds of thromboembolism with warfarin compared with no antithrombotic therapy . Warfarin was also associated with a reduced risk of all-cause mortality ( adjusted hazard ratio , 0.69 ; 95 % CI , 0.61 - 0.77 ) . Intracranial hemorrhage was uncommon , but the rate was moderately higher among those taking vs those not taking warfarin ( 0.46 vs 0.23 per 100 person-years , respectively ; P = .003 , adjusted hazard ratio , 1.97 ; 95 % CI , 1.24 - 3.13 ) . However , warfarin therapy was not associated with an increased adjusted risk of nonintracranial major hemorrhage . The effects of warfarin were similar when patients with contraindications at baseline were analyzed separately or combined with those without contraindications ( total cohort of 13,559 ) . CONCLUSIONS Warfarin is very effective for preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small . Results of r and omized trials of anticoagulation translate well into clinical care for patients with atrial fibrillation
target: Female sex was inconsistently associated with stroke risk , whereas the evidence was inconclusive that either heart failure or coronary artery disease is independently predictive of stroke .
  Conclusions : Four clinical features ( prior stroke/TIA , advancing age , hypertension , diabetes ) are consistent independent risk factors for stroke in atrial fibrillation patients .
background: Background : Absolute stroke rates vary widely among patients with nonvalvular atrial fibrillation .
  To balance the benefits and risks of chronic antithrombotic prophylaxis , it is important to estimate the absolute risk of stroke for individual patients .