Leila H. Borowsky

Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study.

Atrial fibrillation is the most common, potent risk factor for ischemic stroke. Nonrheumatic atrial fibrillation, the predominant form in the United States, occurs in nearly 6% of persons 65 years of age or older (1). Atrial fibrillation is an independent risk factor for stroke, increasing the annual risk by fivefold and accounting for approximately 15% of all strokes in the United States (2). Over the past decade, multiple randomized trials have demonstrated that warfarin therapy can reduce the average annual risk for ischemic stroke by two thirds, from 4.5% to 1.4%, in patients with nonvalvular atrial fibrillation (2). This benefit was accompanied by a relatively low annual bleeding rate (1.3%) (2-4). However, recent data suggest that these dramatic findings have not been adequately implemented in clinical practice (5-9). Previous studies of warfarin use in atrial fibrillation have primarily been performed among hospitalized patients (10-17) or those in long-term care facilities (18-20). By focusing on hospitalized patients or those receiving long-term care, who may be older and have more comorbid illnesses than ambulatory patients, previous estimates of warfarin use may not be generalizable to the majority of patients with atrial fibrillation, who are treated primarily in outpatient clinics. The few studies that have assessed the outpatient use of warfarin for atrial fibrillation have yielded widely varying results (5, 7, 10, 21, 22). Temporal trend data reveal an increase in warfarin use among outpatients with atrial fibrillation, from 7% in 1980-1981 (before the publication of randomized trials demonstrating the efficacy of anticoagulation [23-27]) to 33% to 50% in 1996 (5, 7). Available studies of ambulatory patients with atrial fibrillation have generally included relatively small numbers of patients (5, 8, 10, 21, 28-30), used varying methods for identifying patients with atrial fibrillation (5, 8, 10, 21, 28-30), or estimated warfarin use on the basis of clinic visits rather than person-level analyses (7, 22). Furthermore, despite the rapid growth of managed care, especially in terms of increased use by elderly persons, little is known about the quality of care for atrial fibrillation provided by these organizations. To address these issues, we assembled a large, contemporary sample of ambulatory patients with nonvalvular atrial fibrillation treated in a health maintenance organization and assessed the prevalence and determinants of warfarin use for stroke prevention. Methods Data Sources and Study Sample Between 1 July 1996 and 31 December 1997, we assembled a cohort of ambulatory patients with atrial fibrillation in the Kaiser Permanente Medical Care Program in Northern California. Kaiser Permanente is a group-model health maintenance organization in which 52% of the 1.9 million adult members were women; 16% of adult men and 15% of adult women were 65 years of age or older. Our goal was to identify patients with atrial fibrillation who were eligible for warfarin therapy. To that end, we identified all patients who had 1) a diagnosis of atrial fibrillation (code 427.31 from the International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9]] recorded in an automated outpatient database plus an electrocardiogram showing atrial fibrillation found in an electrocardiographic database or 2) more than one outpatient diagnosis of atrial fibrillation during the study period. For each of these groups, the date of the first diagnosis of atrial fibrillation (according to outpatient visit or electrocardiogram) was considered the index date. The electrocardiographic database included physician-confirmed diagnoses obtained since 1994 by using the same model of electrocardiograph (Hewlett-Packard model no. XLi) throughout all facilities in clinics, emergency departments, and inpatient wards. We also reviewed the medical records of a random sample of 50 patients in the subgroup who had serial outpatient diagnoses of atrial fibrillation but no electrocardiogram showing atrial fibrillation in the available database (23% of the total cohort). A high proportion of these patients (80%) had at least one 12-lead electrocardiogram demonstrating atrial fibrillation in their records. Almost all of the electrocardiograms with atrial fibrillation found in medical records were dated before the electrocardiographic database was developed. Therefore, we estimate that nearly all of the cohort identified by the above approaches had atrial fibrillation. In addition, according to review of the medical records of a random sample of 115 patients with nonvalvular atrial fibrillation and serial electrocardiograms, 21% had paroxysmal atrial fibrillation. The target population for warfarin analyses was ambulatory adult patients with nonvalvular atrial fibrillation who were receiving outpatient care after their index date. Therefore, we excluded patients who met any of the following criteria: no health plan membership after diagnosis of atrial fibrillation, age younger than 18 years, transient atrial fibrillation secondary to a recent cardiac surgery, mitral stenosis or mitral or aortic valve repair or replacement, concomitant hyperthyroidism, or no outpatient internal medicine or cardiology care during the 12 months after index date. Inpatient diagnoses used for exclusion purposes were identified by using comprehensive databases of discharge diagnoses from Kaiser Permanente hospitalizations and billing claims for members treated on an emergent basis at non-Kaiser Permanente facilities. Outpatient diagnoses were identified by using a database of assigned diagnoses for all ambulatory encounters (outpatient clinics, urgent care, and emergency department). Transient, perioperative atrial fibrillation was defined as having one of the following procedures up to 30 days before a single diagnosis of atrial fibrillation: coronary artery bypass surgery (ICD-9 codes 36.10 to 36.19), pericardial surgery (ICD-9 codes 37.10 to 37.12, 37.31 to 37.33, or 37.40), or structural cardiac repair (ICD-9 codes 35.00 to 35.04, 35.31 to 35.39, 35.41 to 35.42, 35.50 to 35.56, 35.60 to 35.63, or 35.70 to 35.73). Valvular heart disease was defined as an inpatient or outpatient diagnosis of mitral stenosis or prosthetic heart valve (ICD-9 codes 394.0, 394.2, 396.0, 396.1, 396.8, V43.3, or V42.2) or mitral or aortic valve repair or replacement (ICD-9 codes 35.10 to 35.14 or 35.20 to 35.28). Concomitant hyperthyroidism was defined as having any of the following factors within 12 months before the index date: an inpatient or outpatient diagnosis of hyperthyroidism or thyrotoxicosis (ICD-9 codes 242.0 to 242.9); a low serum level of thyroid-stimulating hormone (<0.03 g/mL) found in laboratory databases; or a prescription for an antithyroid agent (methimazole or propylthiouracil) found in pharmacy databases. Predictor Variables Patient age and sex at the index date were identified from administrative files. On the basis of the corresponding ICD-9 codes, we searched the ambulatory visit database between 1 June 1994 and 31 December 1997 and hospital discharge and billing claims databases in the 5 years before the index date to identify risk factors for stroke (besides older age) (31) and potential contraindications to warfarin therapy. For risk factors for stroke, inpatient and outpatient sources were used to identify previous stroke and congestive heart failure and outpatient sources were used to detect hypertension. Information on diabetes mellitus and ischemic heart disease (possible risk factors for stroke) was obtained from outpatient sources only. For potential contraindications to warfarin, inpatient and outpatient databases were used to detect a history of cirrhosis, hepatitis, or seizure disorder; inpatient sources were used to detect previous intracranial hemorrhage, gastrointestinal hemorrhage, hospitalization for other bleeding, and hospitalizations involving a mechanical fall; and the outpatient database was used to detect dementia. Renal insufficiency was determined on the basis of diagnoses in the outpatient database or a serum creatinine concentration of 221 mol/L or more ( 2.5 mg/dL) in the laboratory database. To assess the utility of the outpatient database, we used the statistic to compare selected diagnoses (previous stroke, congestive heart failure, hypertension, diabetes, ischemic heart disease, and dementia) found in this database with data from outpatient medical records in 295 randomly selected patients with atrial fibrillation (32). Warfarin Use Warfarin use was defined as having either a filled prescription for warfarin or dicumarol in the pharmacy database, more than one outpatient international normalized ratio (based on prothrombin time measurement), or a diagnosis of Coumadin therapy (ICD-9 code V58.61) in the ambulatory visit database in the 3 months before or after the first identified diagnosis of atrial fibrillation during the study period, or any combination of these factors. More than 99% of prescriptions were for warfarin; thus, use of warfarin or dicumarol was referred to as warfarin use. More than 95% of the patients had a pharmacy benefit, and all patients were fully covered by insurance for laboratory tests. The 1% of patients without a pharmacy benefit or an outpatient international normalized ratio were considered to have unknown warfarin status and were excluded from all analyses. We used the statistic to validate our approach to assigning warfarin status by chart review of 98 randomly sampled patients (45 users and 53 nonusers) (32). Statistical Analysis The Student t-test or Wilcoxon rank-sum test for continuous variables and the chi-square test for proportions were used to compare demographic characteristics and the prevalence of risk factors for stroke and potential contraindications to therapy in warfarin users and nonusers. Descriptive analyses of warfarin use were confined to eligible patients who h

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.

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.

Implications of Stroke Risk Criteria on the Anticoagulation Decision in Nonvalvular Atrial Fibrillation The Anticoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study

BACKGROUND Warfarin dramatically reduces the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF) but increases the likelihood of bleeding. Accurately identifying patients who need anticoagulation is critical. We assessed the potential impact of prominent stroke risk classification schemes on this decision in a large sample of patients with NVAF. METHODS AND RESULTS We used clinical and electrocardiographic databases to identify 13 559 ambulatory patients with NVAF from July 1996 through December 1997. We compared the proportion of patients classified as having a low enough stroke risk to receive aspirin using published criteria from the Atrial Fibrillation Investigators (AFI), American College of Chest Physicians (ACCP), and the Stroke Prevention in Atrial Fibrillation Investigators (SPAF). In this cohort, AFI criteria classified 11% as having a low stroke risk, compared with 23% for ACCP and 29% for SPAF (kappa range, 0.44 to 0.85). This 2- to-3-fold increase in low stroke risk patients by ACCP and SPAF criteria primarily resulted from the inclusion of many older subjects (65 to 75 years+/-men >75 years) with no additional clinical stroke risk factors. CONCLUSIONS The age threshold for assigning an increased stroke risk has a dramatic impact on whether to recommend warfarin in populations of patients with NVAF. Large, prospective studies with many stroke events are needed to precisely determine the relationship of age to stroke risk in AF and to identify which AF subgroups are at a sufficiently low stroke risk to forego anticoagulation.

Warfarin Discontinuation After Starting Warfarin for Atrial Fibrillation

Background—Although warfarin is widely recommended to prevent atrial fibrillation-related thromboembolism, many eligible patients do not take warfarin. The objective of this study was to describe factors associated with warfarin discontinuation in patients newly starting warfarin for atrial fibrillation. Methods and Results—We identified 4188 subjects newly starting warfarin in the Anticoagulation and Risk Factors in Atrial Fibrillation Study and tracked longitudinal warfarin use through pharmacy and laboratory databases. Data on patient characteristics, international normalized ratio (INR) tests, and incident hospitalizations for hemorrhage were obtained from clinical and laboratory databases. Multivariable Cox regression analysis was used to identify independent predictors of prolonged warfarin discontinuation, defined as ≥180 consecutive days off warfarin. Within 1 year after warfarin initiation, 26.3% of subjects discontinued therapy despite few hospitalizations for hemorrhage (2.3% of patients). The risk of discontinuation was higher in patients aged <65 years (adjusted hazard ratio [HR], 1.33 [95% CI, 1.03 to 1.72] compared to those aged ≥85 years), patients with poorer anticoagulation control (HR, 1.46 [95% CI, 1.42 to 1.49] for every 10% decrease in time in therapeutic INR range), and patients with lower stroke risk (HR, 2.54 [95% CI, 1.86 to 3.47] for CHADS2 stroke risk index of 0 compared to 4 to 6). Conclusions—More than 1 in 4 patients newly starting warfarin for atrial fibrillation discontinued therapy in the first year despite a low overall hemorrhage rate. Individuals deriving potentially less benefit from warfarin, including those with younger age, fewer stroke risk factors, and poorer INR control, were less likely to remain on warfarin. Maximizing the benefits of anticoagulation for atrial fibrillation depends on determining which patients are most appropriately initiated and maintained on therapy.

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

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 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. 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.

Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation?: The ATRIA Study

Background—Randomized trials and observational studies support using an international normalized ratio (INR) target of 2.0 to 3.0 for preventing ischemic stroke in atrial fibrillation. We assessed whether the INR target should be adjusted based on selected patient characteristics. Methods and Results—We conducted a case–control study nested within the ATRIA cohort’s 9217 atrial fibrillation patients taking warfarin to define the relationship between INR level and the odds of thromboembolism (TE; mainly stroke) and of intracranial hemorrhage (ICH) relative to INR 2.0 to 2.5. We identified 396 TE cases and 164 ICH cases during follow-up. Each case was compared with 4 randomly selected controls matched on calendar date and stroke risk factors using matched univariable analyses and conditional logistic regression. We explored modification of the INR–outcome relationships by the following stroke risk factors: prior stroke, age, and CHADS2 risk score. Overall, the odds of TE were low and stable above INR 1.8. Compared with INR 2.0 to 2.5, the relative odds of TE increased strikingly at INR <1.8 (eg, odds ratio, 3.72; 95% CI, 2.67 to 5.19, at INR 1.4 to 1.7). The odds of ICH increased markedly at INR values >3.5 (eg, odds ratio, 3.56; 95% CI: 1.70 to 7.46, at INR 3.6 to 4.5). The relative odds of ICH were consistently low at INR <3.6. There was no evidence of lower ICH risk at INR levels <2.0. These patterns of risk did not differ substantially by history of stroke, age, or CHADS2 risk score. Conclusions—Our results confirm that the current standard of INR 2.0 to 3.0 for atrial fibrillation falls in the optimal INR range. Our findings do not support adjustment of INR targets according to previously defined stroke risk factors.

Thirty-Day Mortality After Ischemic Stroke and Intracranial Hemorrhage in Patients With Atrial Fibrillation On and Off Anticoagulants

Background and Purpose— Prescribing warfarin for atrial fibrillation depends in large part on the expected reduction in ischemic stroke risk versus the expected increased risk of intracranial hemorrhage (ICH). However, the anticoagulation decision also depends on the relative severity of such events. We assessed the impact of anticoagulation on 30-day mortality from ischemic stroke versus ICH in a large community-based cohort of patients with atrial fibrillation. Methods— We followed 13 559 patients with atrial fibrillation enrolled in an integrated healthcare delivery system for a median 6 years. Incident ischemic strokes and ICHs were identified from computerized databases and validated through medical record review. The association of warfarin and international normalized ratio at presentation with 30-day mortality was modeled using multivariable logistic regression adjusting for clinical factors. Results— We identified 1025 incident ischemic strokes and 299 ICHs during follow-up. Compared with no antithrombotic therapy, warfarin was associated with reduced Rankin score and lower 30-day mortality from ischemic stroke (adjusted OR, 0.64; 95% CI, 0.45–0.91) but a higher mortality from ICH (OR, 1.62; 95% CI, 0.88–2.98). Therapeutic international normalized ratios (2–3) were associated with an especially low ischemic stroke mortality (OR, 0.38; 95% CI, 0.20–0.70), whereas international normalized ratios >3 increased the odds of dying of ICH by 2.66-fold (95% CI, 1.21–5.86). Conclusions— Warfarin reduces 30-day mortality from ischemic stroke but increases ICH-related mortality. Both effects on event severity as well as on event rates need to be incorporated into rational decision-making about anticoagulants for atrial fibrillation.

Change in physician knowledge and attitudes after implementation of a pneumonia practice guideline.

OBJECTIVE: To assess physicians’ response to implementation of an emergency department (ED) pneumonia practice guideline and determine if the guideline changed physicians’ knowledge and attitudes about pneumonia care.DESIGN: Prospective intervention study with cross-sectional and longitudinal physician surveys.SETTING: An urban, university teaching hospital ED.PARTICIPANTS: One hundred forty physicians who were responsible for the triage of at least one of 166 patients presenting to the ED with community-acquired pneumonia.MEASUREMENTS: Physician characteristics, attitudes about pneumonia care and guidelines, and ratings of guideline helpfulness and effects on patient care were obtained by self administered questionnaire before, during, and after a yearlong intervention.MAIN RESULTS: More than 73% of the physicians reported the guideline as helpful and more than 94% wanted it to be continued in the future. Most reported that the guideline would decrease costs and improve quality without any increase in adverse outcomes. Two thirds said they were more likely to treat patients with pneumonia as outpatients in the future because of the guideline. Among the 58 physicians with matching preintervention and postintervention survey data, the guideline decreased the beliefs that “all patients >65 years old with pneumonia should be admitted,” from 52% to 14% (p<.001), and that “patients with pneumonia have a >15% mortality rate,” from 11% to 5% (p<.007). The intervention did not significantly change general attitudes about practice guidelines. House officers rated the guideline as more helpful than attending physicians (p<.02).CONCLUSIONS: This locally developed, actively implemented guideline was well regarded by physicians. Guidelines can change practice and also alter underlying knowledge and attitudes about disease management. They may be most useful to those with less experience.