Margaret C. Fang

Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack

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.

Antithrombotic Therapy for Atrial Fibrillation Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. RESULTS For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS(2) [congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS(2) score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS(2) score of ≥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. CONCLUSIONS Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS(2) score of ≥ 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach.

Antithrombotic Therapy in Atrial Fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)

This chapter about antithrombotic therapy in atrial fibrillation (AF) is part of the American College of Chest Physicians Evidence-Based Guidelines Clinical Practice Guidelines (8th Edition). Grade 1 recommendations indicate that most patients would make the same choice and Grade 2 suggests that individual patients values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following (all vitamin K antagonist [VKA] recommendations have a target international normalized ratio [INR] of 2.5; range 2.0-3.0, unless otherwise noted). In patients with AF, including those with paroxysmal AF, who have had a prior ischemic stroke, transient ischemic attack (TIA), or systemic embolism, we recommend long-term anticoagulation with an oral VKA, such as warfarin, because of the high risk of future ischemic stroke faced by this set of patients (Grade 1A). In patients with AF, including those with paroxysmal AF, who have two or more of the risk factors for future ischemic stroke listed immediately below, we recommend long-term anticoagulation with an oral VKA (Grade 1A). Two or more of the following risk factors apply: age >75 years, history of hypertension, diabetes mellitus, moderately or severely impaired left ventricular systolic function and/or heart failure. In patients with AF, including those with paroxysmal AF, with only one of the risk factors listed immediately above, we recommend long-term antithrombotic therapy (Grade 1A), either as anticoagulation with an oral VKA, such as warfarin (Grade 1A), or as aspirin, at a dose of 75-325 mg/d (Grade 1B). In these patients at intermediate risk of ischemic stroke we suggest a VKA rather than aspirin (Grade 2A). In patients with AF, including those with paroxysmal AF, age < or =75 years and with none of the other risk factors listed above, we recommend long-term aspirin therapy at a dose of 75-325 mg/d (Grade 1B), because of their low risk of ischemic stroke. For patients with atrial flutter, we recommend that antithrombotic therapy decisions follow the same risk-based recommendations as for AF (Grade 1C). For patients with AF and mitral stenosis, we recommend long-term anticoagulation with an oral VKA (Grade 1B). For patients with AF and prosthetic heart valves we recommend long-term anticoagulation with an oral VKA at an intensity appropriate for the specific type of prosthesis (Grade 1B). See CHEST 2008; 133(suppl):593S-629S. For patients with AF of > or =48 h or of unknown duration for whom pharmacologic or electrical cardioversion is planned, we recommend anticoagulation with an oral VKA, such as warfarin, for 3 weeks before elective cardioversion and for at least 4 weeks after sinus rhythm has been maintained (Grade 1C). For patients with AF of > or = 48 h or of unknown duration undergoing pharmacological or electrical cardioversion, we also recommend either immediate anticoagulation with unfractionated IV heparin, or low-molecular-weight heparin (LMWH), or at least 5 days of warfarin by the time of cardioversion (achieving an INR of 2.0-3.0) as well as a screening multiplane transesophageal echocardiography (TEE). If no thrombus is seen, cardioversion is successful, and sinus rhythm is maintained, we recommend anticoagulation for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. We recommend obtaining a repeat TEE before attempting later cardioversion (Grade 1B addressing the equivalence of TEE-guided vs non-TEE-guided cardioversion). For patients with AF of known duration <48 h, we suggest cardioversion without prolonged anticoagulation (Grade 2C). However, in patients without contraindications to anticoagulation, we suggest beginning IV heparin or LMWH at presentation (Grade 2C).

Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation

Context The appropriate level of warfarin anticoagulation in elderly patients with atrial fibrillation has been debated because of an age-associated increase in intracerebral hemorrhage. Contribution Patients with atrial fibrillation and intracerebral hemorrhage who were receiving anticoagulation were matched with similar patients who did not develop intracerebral hemorrhage. Although intracerebral hemorrhage was associated with increasing age (especially > 85 years) and increasing international normalized ratios (INRs) (especially > 3.5), the incidence of intracerebral hemorrhage was not statistically different in patients with INRs less than 2.0 and those with INRs between 2.0 and 3.0. This was true even among those older than 75 years of age. Implications Risk for intracerebral hemorrhage is not diminished in elderly patients with atrial fibrillation when anticoagulation is maintained below an INR of 2.0. The Editors Intracranial hemorrhage is the most dangerous complication of warfarin anticoagulant therapy because of its high short-term risk for death and severe neurologic deficit (1-5). Warfarin is extremely effective in reducing the risk for ischemic stroke associated with atrial fibrillation (6, 7). However, fear of hemorrhage may prompt some physicians to avoid prescribing anticoagulation (8), especially in elderly patients, who appear to have a higher risk for hemorrhage (8-13). Prominent recent guidelines recommend using lower-intensity anticoagulation for the primary prevention of stroke in patients older than 75 years of age who have atrial fibrillation (14) and suggest a target international normalized ratio (INR) range of 1.6 to 2.5, despite evidence that the risk for ischemic stroke increases sharply at INRs less than 2.0 (15, 16). Previous studies have not thoroughly addressed the relationship of age and anticoagulation intensity to the risk for intracranial hemorrhage among patients with atrial fibrillation (1, 2). A study of 121 patients with warfarin-associated intracranial hemorrhage used the now-outdated prothrombin time ratio as a measure of anticoagulation intensity and did not specifically address risk in patients with atrial fibrillation (1). Earlier studies also included patients receiving anticoagulation for mechanical valves, whose risk-to-benefit ratio is different from that of patients with atrial fibrillation (1, 2, 17). As the number of individuals with atrial fibrillation increases (18-21) and as a greater proportion of older adults receive anticoagulant therapy (22), more precise data are needed about the association of age, INR, and risk for intracranial hemorrhage. Intracranial hemorrhage, although critically important, is an uncommon complication among patients with atrial fibrillation who are receiving anticoagulation. As a result, randomized trials and cohort studies have difficulty accumulating enough hemorrhage events to powerfully assess risk factors. To address these limitations, we performed a large casecontrol study to evaluate the relationship of increasing age and INR to the risk for intracranial hemorrhage among patients with nonvalvular atrial fibrillation. Methods Case-Patients We performed a casecontrol study comparing 2 groups: 1) case-patients with nonvalvular atrial fibrillation who developed intracranial hemorrhage while taking warfarin and 2) controls who were receiving anticoagulation for nonvalvular atrial fibrillation but did not develop intracranial hemorrhage. We found potential case-patients using the Partners HealthCare System Research Patient Data Registry, which can identify patients with specific International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnoses by searching the Massachusetts General Hospital billing system. We searched for patients 18 years of age or older who had diagnoses of atrial fibrillation (ICD-9-CM code 427.31) and intracranial hemorrhage (ICD-9-CM codes 430, 431, 432.0, 432.1, 432.9) at any time from October 1993 to June 2002. By 1993, nearly all prothrombin time ratios at the hospital were reported as INRs. We reviewed medical records to confirm whether patients were eligible, that is, whether they had intracranial hemorrhage documented by computed tomography or magnetic resonance imaging and documentation of warfarin therapy for atrial fibrillation at the time of the event. We excluded patients who were not taking warfarin at the time of hemorrhage; those who were receiving anticoagulation for rheumatic heart disease, mitral stenosis, or mechanical valve placement; those whose event was an ischemic stroke with hemorrhagic conversion; or those in whom clinical factors may have led to hemorrhage independent of warfarin therapy. These factors included underlying anatomic brain abnormalities (such as tumors or aneurysms), antecedent major head trauma (skull fracture, trauma with loss of consciousness, motor vehicle injury, or neurosurgical procedures), or platelet count less than 50 109 cells/L. Starting in July 1994, consecutive patients with intracerebral hemorrhage have been enrolled through the Massachusetts General Hospital emergency department as part of a longitudinal cohort study (23). To validate our automated search strategy, we compared our case-patient list with the list of patients identified through the cohort study and found that our search strategy missed only 4 patients with intracerebral hemorrhage. We obtained data on patient date of birth, sex, and ethnicity from computerized records. The type of hemorrhage (intracerebral, subdural, subarachnoid, intraventricular, or epidural) was determined through review of radiology reports. Data on presenting symptoms, history of minor head trauma, concomitant aspirin use, and disposition status were obtained from review of the admission medical record and were recorded on a standardized data collection form. We recorded the INR measurement obtained closest to the onset of symptoms. If an INR was not available or fresh frozen plasma or vitamin K was administered before the measurement, we considered INR data missing. We reviewed medical charts for documentation of the following comorbid conditions: history of cerebrovascular disease (defined as previous ischemic stroke or carotid artery disease), hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, and cancer (excluding nonmelanoma skin cancer). Controls Controls were sampled from patients managed by the Massachusetts General Hospital Anticoagulation Management Services clinic, which followed approximately 1000 patients receiving anticoagulation for atrial fibrillation at any given time during the study period. All patients who were followed in the anticoagulation clinic, received anticoagulation for atrial fibrillation, and had an INR measurement obtained in the same month and year as the given case date were assigned a random number. Six controls per case-patient were then randomly selected. We matched case-patients to controls by INR date to account for any technical changes in INR testing that may have occurred over time. Because of this sampling method, an individual patient could potentially serve as a control for more than 1 case-patient (24). Like case-patients, controls were 18 years of age or older; were receiving anticoagulation for atrial fibrillation; and had no documented rheumatic heart disease, mitral stenosis, or valve replacement. We sought data on potential confounders of the association of age, INR, and risk for intracranial hemorrhage, focusing on relevant comorbid conditions and combined use of aspirin with warfarin. We reviewed available computerized discharge summaries, outpatient clinic notes, and medication lists from up to 2 years before the admission date. If combination warfarin and aspirin use was not documented, patients were considered to not be taking aspirin. Statistical Analysis Case-patients were categorized by type of hemorrhage: intracerebral, subdural, and other (subarachnoid, intraventricular, or epidural). Clinical differences between types of hemorrhage were compared by using the KruskalWallis test for continuous variables (age and INR) and chi-square tests for categorical variables. We compared case-patients with controls by using multivariable conditional logistic regression, matching on INR date. Patient age was divided into 5-year intervals that were coded as indicator variables, and the odds of intracranial hemorrhage for each interval were compared with the odds of hemorrhage at a referent age of 70 to 74 years. The INR was divided into a set of ordered intervals that were coded as indicator variables. The relative odds for intracranial hemorrhage at each interval were calculated by using an INR of 2.0 to 3.0 as the referent category. In addition to age, INR, sex, and ethnicity, the following variables were included in the multivariable models to control for potential confounding effects of clinical factors and aspirin use: cerebrovascular disease, hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, cancer, and concomitant aspirin use. If no records were available for review, comorbid conditions and aspirin use were coded as missing. We used multiple imputations for missing data on ethnicity, comorbid conditions, and aspirin use (25). We tested for interactions between age and INR and comorbid conditions using 2-way interactions. None of the interaction terms were included in the model if they were not statistically significant when tested collectively. We tested the models goodness of fit using the HosmerLemeshow method (26). Because the hospitals anticoagulation clinic did not follow some case-patients before the event, and since factors relating to differences in outpatient care and monitoring could have confounded our analyses, we repeated these analyses in the subgroup of case-patients managed by the anticoagulation clinic. These restricted analyses approximated

A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study.

OBJECTIVES The purpose of this study was 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 up 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 by split-sample testing and compared with 6 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% for low risk (0 to 3 points), 2.6% for intermediate risk (4 points), and 5.8% for high risk (5 to 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 6 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.

A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

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.).

Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study.

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.

Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation.

OBJECTIVES We assessed 5 risk stratification schemes for their ability to predict atrial fibrillation (AF)-related thromboembolism in a large community-based cohort. BACKGROUND Risk schemes can help target anticoagulant therapy for patients at highest risk for AF-related thromboembolism. We tested the predictive ability of 5 risk schemes: the Atrial Fibrillation Investigators, Stroke Prevention in Atrial Fibrillation, CHADS(2) (Congestive heart failure, Hypertension, Age >or= 75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack) index, Framingham score, and the 7th American College of Chest Physicians Guidelines. METHODS We followed a cohort of 13,559 adults with AF for a median of 6.0 years. Among non-warfarin users, we identified incident thromboembolism (ischemic stroke or peripheral embolism) and risk factors from clinical databases. Each scheme was divided into low, intermediate, and high predicted risk categories and applied to the cohort. Annualized thromboembolism rates and c-statistics (to assess discrimination) were calculated for each risk scheme. RESULTS We identified 685 validated thromboembolic events that occurred during 32,721 person-years off warfarin therapy. The risk schemes had only fair discriminating ability, with c-statistics ranging from 0.56 to 0.62. The proportion of patients assigned to individual risk categories varied widely across the schemes. The proportion categorized as low risk ranged from 11.7% to 37.1% across schemes, and the proportion considered high risk ranged from 16.4% to 80.4%. CONCLUSIONS Current risk schemes have comparable, but only limited, overall ability to predict thromboembolism in persons with AF. Recommendations for antithrombotic therapy may vary widely depending on which scheme is applied for individual patients. Better risk stratification is crucially needed to improve selection of AF patients for anticoagulant therapy.

Impact of Proteinuria and Glomerular Filtration Rate on Risk of Thromboembolism in Atrial Fibrillation The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study

Background— Atrial fibrillation (AF) substantially increases the risk of ischemic stroke, but this risk varies among individual patients with AF. Existing risk stratification schemes have limited predictive ability. Chronic kidney disease is a major cardiovascular risk factor, but whether it independently increases the risk for ischemic stroke in persons with AF is unknown. Methods and Results— We examined how chronic kidney disease (reduced glomerular filtration rate or proteinuria) affects the risk of thromboembolism off anticoagulation in patients with AF. We estimated glomerular filtration rate using the Modification of Diet in Renal Disease equation and proteinuria from urine dipstick results found in laboratory databases. Patient characteristics, warfarin use, and thromboembolic events were ascertained from clinical databases, with validation of thromboembolism by chart review. During 33 165 person-years off anticoagulation among 10 908 patients with AF, we observed 676 incident thromboembolic events. After adjustment for known risk factors for stroke and other confounders, proteinuria increased the risk of thromboembolism by 54% (relative risk, 1.54; 95% CI, 1.29 to 1.85), and there was a graded, increased risk of stroke associated with a progressively lower level of estimated glomerular filtration rate compared with a rate ≥60 mL · min−1 · 1.73 m−2: relative risk of 1.16 (95% CI, 0.95 to 1.40) for estimated glomerular filtration rate of 45 to 59 mL · min−1 · 1.73 m−2 and 1.39 (95% CI, 1.13 to 1.71) for estimated glomerular filtration rate <45 mL · min−1 · 1.73 m−2 (P=0.0082 for trend). Conclusions— Chronic kidney disease increases the risk of thromboembolism in AF independently of other risk factors. Knowing the level of kidney function and the presence of proteinuria may improve risk stratification for decision making about the use of antithrombotic therapy for stroke prevention in AF.Background Atrial fibrillation (AF) substantially increases the risk of ischemic stroke but this risk varies among individual patients with AF. Existing risk stratification schemes have limited predictive ability. Chronic kidney disease is a major cardiovascular risk factor, but whether it independently increases the risk for ischemic stroke in persons with AF is unknown.

Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study.

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.