Daniel E. Singer

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

BACKGROUND The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

Risk Factors for Intracranial Hemorrhage in Outpatients Taking Warfarin

Intracranial hemorrhage is the most feared complication of anticoagulant therapy. Outcomes are frequently catastrophic, often resulting in death or severe neurologic disability. The effect of intracranial hemorrhage is as great as that of the thromboembolic events warfarin is used to prevent. As a result, the risk for intracranial hemorrhage is a critical feature of the decision to use anticoagulation [1]. The indications for use of anticoagulants are expanding, particularly among older patients. For example, anticoagulant therapy is now recommended to prevent stroke in patients with atrial fibrillation [2-6], and it has been found to significantly improve outcome in patients after myocardial infarction [7]. Clinical trials of warfarin as primary preventive therapy for ischemic heart disease are ongoing [8]. With this increase in the use of long-term warfarin therapy, there is a pressing need to identify clinical features that raise the risk of its most severe bleeding complications. No previous study has identified independent risk factors for intracranial hemorrhage among patients taking warfarin. Previous prospective analytic studies that focused on the entire spectrum of major bleeding complications have contained few cases of intracranial hemorrhage [9-11]. We designed a casecontrol study focused exclusively on intracranial hemorrhage occurring among outpatients taking warfarin. We drew on an 11-year experience of one general hospital to provide case-patients and used the same hospitals large anticoagulant therapy unit to provide contemporaneous controls who were also taking warfarin. This design was chosen to increase statistical power for detecting risk factors for intracranial hemorrhage while reducing possible bias. Methods Case-Patient Identification and Eligibility Using a discharge log of consecutive admissions to the Massachusetts General Hospital during the period from 1 January 1981 through 31 December 1991, we identified 1881 patients with a principal diagnosis of intracranial hemorrhage (ICD-9 codes 430, 431, 432.0, 432.1, and 432.9). Forty-one (2%) medical records for these patients could not be located. In the remaining 1840 case-patients, warfarin use was determined from review of the neurologist, neurosurgery resident, and attending staff physician admission notes. Intracranial hemorrhage was verified by computed tomographic (CT) scanning, lumbar puncture, or postmortem examination in all but one case-patient. In this latter case-patient, the diagnosis was based on clinical grounds because the patient died before diagnostic studies were done and no autopsy was performed. To be eligible for the study, patients had to be at least 18 years old and taking warfarin as an outpatient. Patients with an anatomic abnormality or underlying bleeding diathesis predisposing to intracranial hemorrhage, regardless of anticoagulant therapy, were not included. Hemorrhages sustained as a result of major head trauma (with skull fracture and loss of consciousness) also were not eligible. Of 131 patients with intracranial hemorrhage identified, 10 were excluded as ineligible: Four patients had subarachnoid hemorrhage resulting from angiographically identified intracranial aneurysms; 2 had hemorrhage into primary or metastatic tumors; 2 had acute subdural hemorrhage after major head trauma; 1 bled after multiple craniotomies and radiation therapy for a recurrent craniopharyngioma; and another patient had aplastic anemia. Controls: Source and Matching Controls were selected from the registry of the Massachusetts General Hospitals anticoagulant therapy unit. During the study period, this unit managed warfarin dosing for approximately 8000 patients referred from all hospital clinical services. The most common indications for anticoagulation were atrial fibrillation, previous stroke, presence of prosthetic heart valves, and venous thromboembolism. Approximately 40% of the patients managed by the anticoagulant therapy unit have prothrombin time tests done at the Massachusetts General Hospital. An additional 20% have their prothrombin times measured at one large commercial laboratory (via home phlebotomy services). The remaining 40% have their tests done at various local laboratories. Each case-patient was matched to three randomly selected controls taking warfarin at the time of the case-patients intracranial hemorrhage. Matching was accomplished by first identifying all patients managed by the anticoagulant therapy unit at the date of hospital admission for the given case-patient. Each potential control was assigned a random number. The three controls with the lowest random numbers were selected. No control was used more than once. Three controls subsequently became case-patients. Matching was done to control for any change in background risk over the 11-year study period (for example, from changes in prothrombin time targets or technique of measuring the prothrombin time). Data Collected Clinical features of case-patients and controls were extracted primarily from hospital records, with supplementation in a few instances from physician office records. Variables were entered on a predesigned data form and included indication for anticoagulant therapy; race; sex; age; prothrombin time ratio (PTR); duration of warfarin therapy; history of diagnosed hypertension, stroke, transient ischemic attack, diabetes mellitus, myocardial infarction, atrial fibrillation, and congestive heart failure; and medications. Clinical features of the intracranial hemorrhages were also recorded. Clinical data for the controls were current at the admission date of the matched case-patient with intracranial hemorrhage. The prothrombin time ratio was expressed as the ratio of the patients value divided by the simultaneously reported control value. For case-patients, we used the PTR on admission, or, if available, the PTR closest to the reported onset of symptoms. For controls, the PTR closest to that of the case-patient admission date was recorded from the anticoagulant therapy unit database. Because values for the international sensitivity index (ISI) for thromboplastins were not universally reported before 1988, we analyzed our data using the PTR rather than the international normalized ratio (INR). Since 1988, Massachusetts General Hospitals hematology laboratory has used Simplastin Automated (Organon Teknika Corporation, Durham, North Carolina), with values for the ISI ranging from 1.9 to 2.0. During the study period, this company (previously General Diagnostics) supplied the thromboplastin and assisted our laboratory in selecting lots of comparable sensitivity. Studies were routinely done to minimize year-to-year variation in thromboplastin sensitivity. Since 1988, the most frequently used commercial laboratory has used thromboplastins with ISI values ranging from 1.9 to 2.1. The PTR was missing for four case-patients; the data for case-patients and controls were otherwise complete. Selected Relevant Definitions Hypertension was defined as probable if the patient had such a diagnosis listed in the medical record and as definite if the patient was receiving antihypertensive medication. When hypertension was diagnosed, it was classified as definite 97% of the time for case-patients and 93% of the time for controls. All diagnoses of hypertension are used in the analyses. Patients with documented carotid or vertebrobasilar disease and those with a history of previous stroke were defined as having cerebrovascular disease. Diagnoses of carotid or vertebrobasilar disease or both were confirmed by angiography in 71% of case-patients and 93% of controls, by Doppler studies in 17% of case-patients and 2% of controls, and solely by assessment by a neurologist in 12% of case-patients and 5% of controls. Statistical Analysis Case-patients and controls were compared using chi-square tests and the Fisher exact test, where appropriate, for categorical variables and using the Student t-test for continuous variables. Univariate odds ratios were calculated using unmatched and matched techniques. The matched odds ratios were provided by the Mantel-Haenszel [12] summary statistic across matched sets. The unmatched and matched techniques provided very similar estimates of odds ratios. We report the unmatched results. Confidence intervals for odds ratios were calculated using the Taylor series method [13]. The test of trend was done using the Cochran-Mantel-Haenszel test [14]. Logistic regression models assessed the independent effect of multiple clinical features and the significance of interaction terms. Conditional logistic models [15] accounting for matching provided estimates similar to those of the unmatched logistic regression analyses. The estimates from the unmatched analyses are reported. Data were recorded in R:BASE (Microrim, Bellevue, Washington) from the paper data forms. Statistical analyses were done using SAS (SAS Institute Inc., Cary, North Carolina) and GLIM (Numerical Algorithms Group Limited, Oxford, United Kingdom). Results Clinical Course of Case-Patients During the 11-year study period, 121 patients with intracranial hemorrhage were eligible; 77 hemorrhages were intracerebral and 44 were subdural (Table 1). Three of the patients with subdural hemorrhage had a history of trivial head trauma; the others had no known antecedent head trauma. For the patients with intracerebral hemorrhages, headache was the most common presenting feature (53%), followed by nausea and vomiting (40%) and unresponsiveness (36%). Seventy-eight percent of the case-patients presented to the emergency department within 24 hours of the onset of symptoms and 87% within 48 hours. In contrast, only 36% of the patients with subdural bleeding came to medical attention within this same period. Forty-six percent of patients with intracerebral bleeding died, and 17% survived with major neurologic deficits that prevented subsequent independent living. Table 1. Clinical

AN ANALYSIS OF THE LOWEST EFFECTIVE INTENSITY OF PROPHYLACTIC ANTICOAGULATION FOR PATIENTS WITH NONRHEUMATIC ATRIAL FIBRILLATION

BACKGROUND To avert major hemorrhage, physicians need to know the lowest intensity of anticoagulation that is effective in preventing stroke in patients with atrial fibrillation. Since the low rate of stroke has made it difficult to perform prospective studies to resolve this issue, we conducted a case-control study. METHODS We studied 74 consecutive patients with atrial fibrillation who were admitted to our hospital from 1989 through 1994 after having an ischemic stroke while taking warfarin. For each patient with stroke, three controls with nonrheumatic atrial fibrillation who were treated as outpatients were randomly selected from the 1994 registry of the anticoagulant-therapy unit (222 controls). We used the international normalized ratio (INR) to measure the intensity of anticoagulation. For the patients with stroke, we used INR at admission; for the controls, we selected the INR that was measured closest to the month and day of the matched case patients hospital admission. RESULTS The risk of stroke rose steeply at INRs below 2.0. At an INR of 1.7, the adjusted odds ratio for stroke, as compared with the risk at an INR of 2.0, was 2.0 (95 percent confidence interval, 1.6 to 2.4); at an INR of 1.5, it was 3.3 (95 percent confidence interval, 2.4 to 4.6); and at an INR of 1.3, it was 6.0 (95 percent confidence interval, 3.6 to 9.8). Other independent risk factors were previous stroke (odds ratio, 10.4; 95 percent confidence interval, 4.4 to 24.5), diabetes mellitus (odds ratio, 2.95; 95 percent confidence interval, 1.3 to 6.5), hypertension (odds ratio, 2.5; 95 percent confidence interval, 1.1 to 5.7), and current smoking (odds ratio, 5.7; 95 percent confidence interval, 1.4 to 24.0). CONCLUSIONS Among patients with atrial fibrillation, anticoagulant prophylaxis is effective at INRs of 2.0 or greater. Since previous studies have indicated that the risk of hemorrhage rises rapidly at INRs greater than 4.0 to 5.0, tight control of anticoagulant therapy to maintain the INR between 2.0 and 3.0 is a better strategy than targeting lower, less effective levels of anticoagulation.

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).

Assessing health-related quality of life in patients with sciatica.

Study Design This study analyzed health-related quality-of-life measures and other clinical and questionnaire data obtained from the Maine Lumbar Spine Study, a prospective cohort study of persons with low back problems. Objective For persons with sciatica, back pain-specific and general measures of health-related quality-of-life were compared with regard to internal consistency, construct validity, reproducibility, and responsiveness in detecting small changes over a 3-month period. Summary of Background Data Data were collected from 427 participants with sciatica. Baseline in-person interviews were conducted with surgical and medical patients before treatment and by mail at 3 months. Methods Health-related quality-of-life measures included symptoms (frequency and bothersomeness of pain and sciatica) functional status and well-being (modified back pain-specific Roland scale and Medical Outcomes Study 36-item Short Form Health Survey (SF-36), and disability (bed rest, work loss, and restricted activity days). Results Internal consistency of measures was high. Reproducibility was moderate, as expected after a 3-month interval. The SF-36 bodily pain item and the modified Roland measure demonstrated the greatest amount of change and were the most highly associated with self-rated improvement. The specific and generic measures changed in the expected direction, except for general health perceptions, which declined slightly. A high correlation between clinical findings or symptoms and the modified Roland measure, SF-36, and disability days indicated a high degree of construct validity. Conclusions These measures performed well in measuring the health-related quality-of-life of patients with sciatica. The modified Roland and the physical dimension of the SF-36 were the measures most responsive to change over time, suggesting their use in prospective evaluation. Disability day measures, although valuable for assessing the societal impact of dysfunction, were less responsive to changes over this short-term follow-up of 3 months.

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

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.

Risk Variable Clustering in the Insulin Resistance Syndrome: The Framingham Offspring Study

Insulin resistance has been hypothesized to unify the clustering of hypertension, glucose intolerance, hyper-insulinemia, increased levels of triglyceride and decreased HDL cholesterol, and central and overall obesity. We tested this hypothesis with factor analysis, a statistical technique that should identify one factor if a single process underlies the clustering of these risk variables. From 2,458 nondiabetic subjects of the Framingham Offspring Study, we collected clinical data, fasting and 2-h postchallenge glucose and insulin levels, and fasting lipid levels. We performed factor analyses separately for men and women in the entire population and among subgroups with features of the insulin resistance syndrome. Subjects ranged in age from 26 to 82 years (mean age 54); 53% were women, 13.4% had impaired glucose tolerance, 27.6% had hypertension, 40% were obese, and 11.6% were hyperinsulinemic, defined by elevated fasting insulin levels. Underlying the clustering of these risk variables were three factors. Fasting and 2-h postchallenge insulin levels, fasting triglyceride and HDL cholesterol levels, BMI, and waist-to-hip ratio were associated with one factor. Fasting and 2-h levels of glucose and insulin were associated with a second factor. Systolic blood pressure, diastolic blood pressure, and BMI were associated with a third factor. Results were similar for men and women and for all subgroups. These results were consistent with more than one independent physiological process underlying risk variable clustering: a central metabolic syndrome (characterized by hyperinsulinemia, dyslipidemia, and obesity), glucose intolerance, and hypertension. Glucose intolerance and hypertension were linked to the central syndrome through shared correlations with insulin levels and obesity. Insulin resistance (reflected by hyperinsulinemia) alone did not appear to underlie all features of the insulin resistance syndrome.