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      A New Risk Scheme to Predict Ischemic Stroke and Other Thromboembolism in Atrial Fibrillation: The ATRIA Study Stroke Risk Score

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          Abstract

          Background

          More 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 Results

          The 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 m 2 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 CHADS 2 or CHA 2DS 2‐VASc scores.

          Conclusions

          The 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.

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          Most cited references13

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          Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials.

          Atrial fibrillation is associated with an increased risk of ischemic stroke. Data on individual patients were pooled from five recently completed randomized trials comparing warfarin (all studies) or aspirin (the Atrial Fibrillation, Aspirin, Anticoagulation Study and the Stroke Prevention in Atrial Fibrillation Study) with control in patients with atrial fibrillation. The purpose of the analysis was to (1) identify patient features predictive of a high or low risk of stroke, (2) assess the efficacy of antithrombotic therapy in major patient subgroups (eg, women), and (3) obtain the most precise estimate of the efficacy and risks of antithrombotic therapy in atrial fibrillation. For the warfarin-control comparison there were 1889 patient-years receiving warfarin and 1802 in the control group. For the aspirin-placebo comparison there were 1132 patient-years receiving aspirin and 1133 receiving placebo. The daily dose of aspirin was 75 mg in the Atrial Fibrillation, Aspirin, Anticoagulation Study and 325 mg in the Stroke Prevention in Atrial Fibrillation Study. To monitor warfarin dosage, three studies used prothrombin time ratios and two used international normalized ratios. The lowest target intensity was a prothrombin time ratio of 1.2 to 1.5 and the highest target intensity was an international normalized ratio of 2.8 to 4.2. The primary end points were ischemic stroke and major hemorrhage, as assessed by each study. At the time of randomization the mean age was 69 years and the mean blood pressure was 142/82 mm Hg. Forty-six percent of the patients had a history of hypertension, 6% had a previous transient ischemic attack or stroke, and 14% had diabetes. Risk factors that predicted stroke on multivariate analyses in control patients were increasing age, history of hypertension, previous transient ischemic attack or stroke, and diabetes. Patients younger than 65 years who had none of the other predictive factors (15% of all patients) had an annual rate of stroke of 1.0%, 95% confidence interval (CI) 0.3% to 3.0%. The annual rate of stroke was 4.5% for the control group and 1.4% for the warfarin group (risk reduction, 68%; 95% CI, 50% to 79%). The efficacy of warfarin was consistent across all studies and subgroups of patients. In women, warfarin decreased the risk of stroke by 84% (95% CI, 55% to 95%) compared with 60% (95% CI, 35% to 76%) in men. The efficacy of aspirin was not as consistent. The risk reduction with 75 mg of aspirin in the Atrial Fibrillation, Aspirin, Anticoagulation Study was 18% (95% CI, 60% to 58%), and with 325 mg of aspirin in the Stroke Prevention in Atrial Fibrillation Study the risk reduction was 44% (95% CI, 7% to 66%). When both studies were combined the risk reduction was 36% (95% CI, 4% to 57%). The annual rate of major hemorrhage (intracranial bleeding or a bleed requiring hospitalization or 2 units of blood) was 1.0% for the control group, 1.0% for the aspirin group, and 1.3% for the warfarin group. In these five randomized trials warfarin consistently decreased the risk of stroke in patients with atrial fibrillation (a 68% reduction in risk) with virtually no increase in the frequency of major bleeding. Patients with atrial fibrillation younger than 65 years without a history of hypertension, previous stroke or transient ischemic attack, or diabetes were at very low risk of stroke even when not treated. The efficacy of aspirin was less consistent. Further studies are needed to clarify the role of aspirin in atrial fibrillation.
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            Leukocyte count and coronary heart disease: implications for risk assessment.

            Inflammation is a key feature of atherosclerosis and its clinical manifestations. The leukocyte count is a marker of inflammation that is widely available in clinical practice. This paper reviews the available epidemiologic evidence for a relationship between the leukocyte count and coronary heart disease (CHD). Numerous epidemiologic and clinical studies have shown leukocytosis to be an independent predictor of future cardiovascular events, both in healthy individuals free of CHD at baseline and in patients with stable angina, unstable angina, or a history of myocardial infarction. This relationship has been observed in prospective and retrospective cohort studies, as well as in case-control studies. It is strong, consistent, temporal, dose-dependent, and biologically plausible. The relationship persists after adjustment for multiple CHD risk factors, including smoking. Elevated differential cell counts, including eosinophil, neutrophil, and monocyte counts, also predict the future incidence of CHD. Leukocytosis affects CHD through multiple pathologic mechanisms that mediate inflammation, cause proteolytic and oxidative damage to the endothelial cells, plug the microvasculature, induce hypercoagulability, and promote infarct expansion. In summary, leukocytosis has been consistently shown to be an independent risk factor and prognostic indicator of future cardiovascular outcomes, regardless of disease status. The leukocyte count is inexpensive, reliable, easy to interpret, and ordered routinely in inpatient and outpatient settings. However, its diagnostic and prognostic utility in CHD is widely unappreciated. Further studies are needed to assess the true impact of leukocytosis on CHD, compare it with other inflammatory markers such as C-reactive protein and lipoprotein phospholipase A(2) levels, and promote its use in CHD prediction.
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              Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.

              To characterize the efficacy and safety of anticoagulants and antiplatelet agents for prevention of stroke in patients with atrial fibrillation. Randomized trials identified by using the search strategy developed by the Cochrane Collaboration Stroke Review Group. All published randomized trials testing antithrombotic agents to prevent stroke in patients with atrial fibrillation. Data on interventions, number of participants, duration of exposure and occurrence of all stroke (ischemic and hemorrhagic), major extracranial bleeding, and death were extracted independently by two investigators. Sixteen trials included a total of 9874 participants (mean follow-up, 1.7 years). Adjusted-dose warfarin (six trials, 2900 participants) reduced stroke by 62% (95% CI, 48% to 72%); absolute risk reductions were 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeding was increased by warfarin therapy (absolute risk increase, 0.3% per year). Aspirin (six trials, 3119 participants) reduced stroke by 22% (CI, 2% to 38%); absolute risk reductions were 1.5% per year for primary prevention and 2.5% per year for secondary prevention. Adjusted-dose warfarin (five trials, 2837 participants) was more efficacious than aspirin (relative risk reduction, 36% [CI, 14% to 52%]). Other randomized comparisons yielded inconclusive results. Adjusted-dose warfarin and aspirin reduce stroke in patients with atrial fibrillation, and warfarin is substantially more efficacious than aspirin. The benefit of antithrombotic therapy was not offset by the occurrence of major hemorrhage among participants in randomized trials. Judicious use of antithrombotic therapy, tailored according to the inherent risk for stroke, importantly reduces stroke in patients with atrial fibrillation.
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                Author and article information

                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                ahaoa
                jah3
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                Blackwell Publishing Ltd
                2047-9980
                June 2013
                21 June 2013
                : 2
                : 3
                : e000250
                Affiliations
                [1 ]Clinical Epidemiology Unit, Massachusetts General Hospital, Boston, MA (D.E.S., Y.C., L.H.B.)
                [2 ]Department of Medicine, University of California San Francisco, San Francisco, CA (M.C.F., A.S.G.)
                [3 ]Division of Research, Kaiser Permanente of Northern California, Oakland, CA (N.K.P., N.U., A.S.G.)
                [4 ]Department of Research and Evaluation, Kaiser Permanente of Southern California, Pasadena, CA (K.R.)
                [5 ]Department of Epidemiology, University of California San Francisco, San Francisco, CA (A.S.G.)
                [6 ]Department of Biostatistics, University of California San Francisco, San Francisco, CA (A.S.G.)
                [7 ]Department of Health Research and Policy, Stanford University School of Medicine, Palo Alto, CA (A.S.G.)
                Author notes
                Correspondence to: Daniel E. Singer, MD, Clinical Epidemiology Unit, 50 Staniford St., 9th Floor, Massachusetts General Hospital, Boston, MA 02114. E‐mail: dsinger@ 123456partners.org
                Article
                jah3242
                10.1161/JAHA.113.000250
                3698792
                23782923
                caf94204-6ee3-4714-9a96-c9b20cb6bc6b
                © 2013 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley-Blackwell.

                This is an Open Access article under the terms of the Creative Commons Attribution Noncommercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 05 April 2013
                : 24 May 2013
                Categories
                Original Research
                Arrhythmia and Electrophysiology

                Cardiovascular Medicine
                anticoagulants,atrial fibrillation,risk score,stroke
                Cardiovascular Medicine
                anticoagulants, atrial fibrillation, risk score, stroke

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