The aim of this updated guideline is to provide comprehensive and timely evidence-based recommendations on the prevention of future stroke among survivors of ischemic stroke or transient ischemic attack. The guideline is addressed to all clinicians who manage secondary prevention for these patients. Evidence-based recommendations are provided for control of risk factors, intervention for vascular obstruction, antithrombotic therapy for cardioembolism, and antiplatelet therapy for noncardioembolic stroke. Recommendations are also provided for the prevention of recurrent stroke in a variety of specific circumstances, including aortic arch atherosclerosis, arterial dissection, patent foramen ovale, hyperhomocysteinemia, hypercoagulable states, antiphospholipid antibody syndrome, sickle cell disease, cerebral venous sinus thrombosis, and pregnancy. Special sections address use of antithrombotic and anticoagulation therapy after an intracranial hemorrhage and implementation of guidelines.

BACKGROUND The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results. METHODS We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy. RESULTS At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy. CONCLUSIONS Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy. (Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)

OBJECTIVES-To assess whether older age is independently associated with hemorrhage risk in patients with atrial fibrillation, whether or not they are taking warfarin therapy. DESIGN-Cohort study.SETTING-Integrated healthcare delivery system. PARTICIPANTS-Thirteen thousand five hundred fifty-nine adults with nonvalvular atrial fibrillation.MEASUREMENTS-Patient data were collected from automated clinical and administrative databases using previously validated search algorithms. Medical charts were reviewed from patients hospitalized were for major hemorrhage (intracranial, fatal, requiring ≥2 units of transfused blood, or involving a critical anatomic site). Age was categorized into four categories (<60, 60-69, 70-79, and ≥80), and multivariable Poisson regression was used to assess whether major hemorrhage rates increased with age, stratified by warfarin use and adjusted for other clinical risk factors for hemorrhage.RESULTS-A total of 170 major hemorrhages were identified during 15,300 person-years of warfarin therapy and 162 major hemorrhages during 15,530 person-years off warfarin therapy. Hemorrhage rates rose with older age, with an average increase in hemorrhage rate of 1.2 (95% confidence interval (CI) 1.0-1.4) per older age category in patients taking warfarin and 1.5 (95% CI=1.3-1.8) in those not taking warfarin. Intracranial hemorrhage rates were significantly higher in those aged 80 and older (adjusted rate ratio=1.8, 95% CI=1.1-3.1 for those taking warfarin, adjusted rate ratio=4.7, 95% CI=2.4-9.2 for those not taking warfarin) than in those younger than 80. Author Contributions: Margaret Fang, Alan Go, Elaine Hylek, and Daniel Singer contributed to study concept and design, data analysis and interpretation, and preparation of manuscript. Yuchiao Chang contributed to data analysis and interpretation, and preparation of manuscript. Lori Henault and Nancy Jensvold contributed to study concept and design and acquisition of subjects and data. Anticoagulation therapy with warfarin effectively reduces the risk of ischemic stroke associated with atrial fibrillation but also increases the risk for major hemorrhage. [1][2][3][4] Although previous randomized trials of warfarin for atrial fibrillation reported low rates of hemorrhage, these studies included few patients aged 80 and older and selected their patients more rigorously than in actual clinical practice. 1,5 It is uncertain whether the low bleeding rates observed in trial settings apply to patients with atrial fibrillation in usual clinical care. Prior studies have also provided conflicting evidence as to whether older age is an independent risk factor for warfarin-associated hemorrhage. 6-8 As increasing numbers of elderly patients take warfarin for atrial fibrillation, 9 more-precise data are needed on hemorrhage rates in the oldest patients. NIH Public AccessMost observational studies of warfarin did not specifically address the risk of hemorrhage in patients with atrial fibrillation. Studies generally included patients taking warfarin for m...

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 prospectively 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 searching validated computerized databases 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.

OBJECTIVES-Little is known about the outcomes of patients who have hemorrhagic complications while receiving warfarin therapy. We examined the rates of death and disability resulting from warfarin-associated intracranial and extracranial hemorrhages in a large cohort of patients with atrial fibrillation.METHODS-We assembled a cohort of 13,559 adults with nonvalvular atrial fibrillation and identified patients hospitalized for warfarin-associated intracranial and major extracranial hemorrhage. Data on functional disability at discharge and 30-day mortality were obtained from a review of medical charts and state death certificates. The relative odds of 30-day mortality by hemorrhage type were calculated using multivariable logistic regression.RESULTS-We identified 72 intracranial and 98 major extracranial hemorrhages occurring in more than 15,300 person-years of warfarin exposure. At hospital discharge, 76% of patients with intracranial hemorrhage had severe disability or died, compared with only 3% of those with major extracranial hemorrhage. Of the 40 deaths from warfarin-associated hemorrhage that occurred within 30 days, 35 (88%) were from intracranial hemorrhage. Compared with extracranial hemorrhages, intracranial events were strongly associated with 30-day mortality (odds ratio 20.8 [95% confidence interval, 6.0-72]) even after adjusting for age, sex, anticoagulation intensity on admission, and other coexisting illnesses. CONCLUSIONS-Among anticoagulated patients with atrial fibrillation, intracranialhemorrhages caused approximately 90% of the deaths from warfarin-associated hemorrhage and the majority of disability among survivors. When considering anticoagulation, patients and clinicians need to weigh the risk of intracranial hemorrhage far more than the risk of all major hemorrhages. Atrial fibrillation is the most common clinically significant cardiac arrhythmia and increases the risk for ischemic stroke 4-to 5-fold. 1 Anticoagulation therapy with warfarin can reduce the risk for ischemic stroke by 68% but also increases the risk for major hemorrhagic complications. 2 Clinical decision-making regarding the appropriateness of warfarin therapy for patients with atrial fibrillation has generally relied on balancing the risk of ischemic strokes without warfarin therapy with the risk of all major hemorrhage with warfarin therapy. KeywordsRates of ischemic stroke in patients with atrial fibrillation who are not taking warfarin can be as high as 12% per year, 2,3 and the proportion of patients who have major functional disability after an atrial fibrillation-related ischemic stroke is substantial, as high as 59%. 4 Yet multiple studies demonstrate that patients with atrial fibrillation are frequently not prescribed warfarin despite its benefits in ischemic stroke risk reduction. [5][6][7] The primary deterrent to prescribing warfarin is the fear of inducing life-threatening hemorrhage. 8 Although concerns about hemorrhage prevent many patients from receiving warfarin, there are relatively little data a...

BackgroundMore accurate and reliable stroke risk prediction tools are needed to optimize anticoagulation decision making in patients with atrial fibrillation (AF). We developed a new AF stroke prediction model using the original Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) AF cohort and externally validated the score in a separate, contemporary, community‐based inception AF cohort, ATRIA–Cardiovascular Research Network (CVRN) cohort.Methods and ResultsThe derivation ATRIA cohort consisted of 10 927 patients with nonvalvular AF contributing 32 609 person‐years off warfarin and 685 thromboembolic events (TEs). The external validation ATRIA‐CVRN cohort included 25 306 AF patients contributing 26 263 person‐years off warfarin and 496 TEs. Cox models identified 8 variables, age, prior stroke, female sex, diabetes mellitus, heart failure, hypertension, proteinuria, and eGFR<45 mL/min per 1.73 m2 or end‐stage renal disease, plus an age×prior stroke interaction term for the final model. Point scores were assigned proportional to model coefficients. The c‐index in the ATRIA cohort was 0.73 (95% CI, 0.71 to 0.75), increasing to 0.76 (95% CI, 0.74 to 0.79) when only severe events were considered. In the ATRIA‐CVRN, c‐indexes were 0.70 (95% CI, 0.67 to 0.72) and 0.75 (95% CI, 0.72 to 0.78) for all events and severe events, respectively. The C‐index was greater and net reclassification improvement positive comparing the ATRIA score with the CHADS2 or CHA2DS2‐VASc scores.ConclusionsThe ATRIA stroke risk score performed better than existing risk scores, was validated successfully, and showed improvement in predicting severe events, which is of greatest concern. The ATRIA score should improve the antithrombotic decision for patients with AF and should provide a secure foundation for the addition of biomarkers in future prognostic models.

Objective To develop a risk stratification score to predict warfarin-associated hemorrhage Background Optimal decision-making regarding warfarin use for atrial fibrillation requires estimation of hemorrhage risk. Methods We followed 9,186 patients with atrial fibrillation contributing 32,888 person-years of follow-up on warfarin, obtaining data from clinical databases and validating hemorrhage events using medical record review. We used Cox regression models to develop a hemorrhage risk stratification score, selecting candidate variables using bootstrapping approaches. The final model was internally validated via split-sample testing and compared to six published hemorrhage risk schemes. Results We observed 461 first major hemorrhages during follow-up (1.4% annually). Five independent variables were included in the final model and weighted by regression coefficients: anemia (3 points), severe renal disease (e.g., glomerular filtration rate < 30 ml/min or dialysis-dependent, 3 points), age ≥ 75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Major hemorrhage rates ranged from 0.4% (0 points) to 17.3% per year (10 points). Collapsed into a 3-category risk score, major hemorrhage rates were 0.8% in the low risk group (0-3 points), 2.6% in intermediate risk (4 points), and 5.8% in high risk (5-10 points). The c-index for the continuous risk score was 0.74 and 0.69 for the 3-category score, higher than in the other risk schemes. There was net reclassification improvement versus all six comparators (from 27% to 56%). Conclusions A simple 5-variable risk score was effective in quantifying the risk of warfarin-associated hemorrhage in a large community-based cohort of patients with atrial fibrillation.

The risk for intracranial hemorrhage increases at age 85 years. International normalized ratios less than 2.0 were not associated with lower risk for intracranial hemorrhage compared with INRs between 2.0 and 3.0. Therefore, anticoagulation management should focus on maintaining INRs in the 2.0 to 3.0 range, even in elderly patients with atrial fibrillation, rather than targeting INRs less than 2.0. Similarly, INRs of 3.5 or greater should be avoided.