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1.  The Net Clinical Benefit of Warfarin Anticoagulation in Atrial Fibrillation 
Annals of internal medicine  2009;151(5):297-305.
Guidelines recommend warfarin use in patients with atrial fibrillation solely on the basis of risk for ischemic stroke without antithrombotic therapy. These guidelines rely on ischemic stroke rates observed in older trials and do not explicitly account for increased risk for hemorrhage.
To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation.
Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003.
An integrated health care delivery system.
13559 adults with nonvalvular atrial fibrillation.
Warfarin exposure, patient characteristics, and outcome events were ascertained from health plan records and databases. Outcome events were validated by formal physician review. Net clinical benefit was defined as the annual rate of (ischemic strokes and systemic emboli prevented by warfarin) minus (intracranial hemorrhages attributable to warfarin multiplied by an impact weight). For the base case, the impact weight was 1.5, reflecting the greater clinical impact of intracranial hemorrhage versus thromboembolism.
Patients accumulated more than 66000 person-years of follow-up. The adjusted net clinical benefit of warfarin for the cohort overall was 0.68% per year (95% CI, 0.34% to 0.87%). Adjusted net clinical benefit was greatest for patients with a history of ischemic stroke (2.48% per year [CI, 0.75% to 4.22%]) and for those 85 years or older (2.34% per year [CI, 1.29% to 3.30%]). The net clinical benefit of warfarin increased from essentially zero in CHADS2 (congestive heart failure/hypertension/age/diabetes/prior stroke2) stroke risk categories 0 and 1, to 2.22% per year (CI, 0.58% to 3.75%) in CHADS2 categories 4 to 6. The patterns of results were preserved using weighting factors for intracranial hemorrhage of 1.0 and 2.0.
Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable.
Expected net clinical benefit of warfarin therapy is highest among patients with the highest untreated risk for stroke, which includes the oldest age category. Risk assessment that incorporates both risk for thromboembolism and risk for intracranial hemorrhage provides a more quantitatively informed basis for the decision on antithrombotic therapy in patients with atrial fibrillation.
Primary Funding Source
National Institute on Aging; National Heart, Lung, and Blood Institute; and Massachusetts General Hospital.
PMCID: PMC2777526  PMID: 19721017
2.  30-day Mortality after Ischemic Stroke and Intracranial Hemorrhage in Patients with Atrial Fibrillation On and Off Anticoagulants 
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 vs. ICH in a large community-based cohort of patients with atrial fibrillation.
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 (INR) at presentation with 30-day mortality was modeled using multivariable logistic regression, adjusting for clinical factors.
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 odds ratio and 95% confidence interval [OR] = 0.64 [0.45, 0.91]), but a higher mortality from ICH (OR = 1.62 [0.88, 2.98]). Therapeutic INRs (2-3) were associated with an especially low ischemic stroke mortality (OR = 0.38 [0.20, 0.70]) while INRs > 3 increased the odds of dying of ICH by 2.66 fold (95% confidence interval: 1.21, 5.86).
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.
PMCID: PMC3383879  PMID: 22539546
Acute stroke; Intracranial hemorrhage; Anticoagulants; Warfarin; Atrial fibrillation
3.  Stroke in Heart Failure in Sinus Rhythm: The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial 
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial found no difference between warfarin and aspirin in patients with low ejection fraction in sinus rhythm for the primary outcome: first to occur of 84 incident ischemic strokes (IIS), 7 intracerebral hemorrhages or 531 deaths. Prespecified secondary analysis showed a 48% hazard ratio reduction (p = 0.005) for warfarin in IIS. Cardioembolism is likely the main pathogenesis of stroke in heart failure. We examined the IIS benefit for warfarin in more detail in post hoc secondary analyses.
We subtyped IIS into definite, possible and noncardioembolic using the Stroke Prevention in Atrial Fibrillation method. Statistical tests, stratified by prior ischemic stroke or transient ischemic attack, were the conditional binomial for independent Poisson variables for rates, the Cochran-Mantel-Haenszel test for stroke subtype and the van Elteren test for modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS) distributions, and an exact test for proportions.
Twenty-nine of 1,142 warfarin and 55 of 1,163 aspirin patients had IIS. The warfarin IIS rate (0.727/100 patient-years, PY) was lower than for aspirin (1.36/100 PY, p = 0.003). Definite cardioembolic IIS was less frequent on warfarin than aspirin (0.22 vs. 0.55/100 PY, p = 0.012). Possible cardioembolic IIS tended to be less frequent on warfarin than aspirin (0.37 vs. 0.67/100 PY, p = 0.063) but noncardioembolic IIS showed no difference: 5 (0.12/100 PY) versus 6 (0.15/100 PY, p = 0.768). Among patients experiencing IIS, there were no differences by treatment arm in fatal IIS, baseline mRS, mRS 90 days after IIS, and change from baseline to post-IIS mRS. The warfarin arm showed a trend to a lower proportion of severe nonfatal IIS [mRS 3–5; 3/23 (13.0%) vs. 16/48 (33.3%), p = 0.086]. There was no difference in NIHSS at the time of stroke (p = 0.825) or in post-IIS mRS (p = 0.948) between cardioembolic, possible cardioembolic and noncardioembolic stroke including both warfarin and aspirin groups.
The observed benefits in the reduction of IIS for warfarin compared to aspirin are most significant for cardioembolic IIS among patients with low ejection fraction in sinus rhythm. This is supported by trends to lower frequencies of severe IIS and possible cardioembolic IIS in patients on warfarin compared to aspirin.
PMCID: PMC4256381  PMID: 23921215
Aspirin; Cardiac embolism; Heart failure; Stroke prevention
4.  Moving the Tipping Point: The Decision to Anticoagulate Patients with Atrial Fibrillation 
The rate of ischemic stroke associated with traditional risk factors for patients with atrial fibrillation has declined over the past two decades. Further, new and potentially safer anticoagulants are on the horizon. Thus, the balance between risk factors for stroke and benefit of anticoagulation may be shifting.
Methods and Results
Markov state transition decision model to analyze the CHADS2 score above which anticoagulation is preferred, first using the stroke rate predicted for the CHADS2 derivation cohort, and then using the stroke rate from the more contemporary ATRIA cohort for any CHADS2 score. Base case was a 69-year-old man with atrial fibrillation. Interventions included: oral anticoagulant therapy with warfarin or a hypothetical “new and safer” anticoagulant (based on dabigatran), no antithrombotic therapy, or aspirin.
Warfarin is preferred above a stroke rate of 1.7%/year, while aspirin is preferred at lower rates of stroke. Anticoagulation with warfarin is preferred even for a score of 0 using the higher rates of the older CHADS2 derivation cohort. Using more contemporary and lower estimates of stroke risk, raises the threshold for use of warfarin to a CHADS2 score ≥ 2. However, anticoagulation with a “new, safer” agent, modeled on the results of the RE-LY trial of dabigatran, leads to a lowering of the threshold for anticoagulation to a stroke rate of just 0.9%/year.
Use of a more contemporary estimate of stroke risk shifts the “tipping point” such that anticoagulation is preferred at a higher CHADS2 score, reducing the number of patients for whom anticoagulation is recommended. The introduction of “new, safer” agents, however, would shift the tipping point in the opposite direction.
PMCID: PMC3058150  PMID: 21139092
anticoagulants; atrial fibrillation; health services research; stroke prevention; decision analysis
5.  Should We Test for CYP2C9 Before Initiating Anticoagulant Therapy in Patients with Atrial Fibrillation? 
Genetic variants of the warfarin sensitivity gene CYP2C9 have been associated with increased bleeding risk during warfarin initiation. Studies also suggest that such patients remain at risk throughout treatment.
Would testing patients with non-valvular atrial fibrillation (AF) for CYP2C9 before initiating warfarin improve outcomes?
Markov state transition decision model.
Ambulatory or inpatient settings necessitating new initiation of anticoagulation.
The base case was a 69-year-old man with newly diagnosed non-valvular AF. Interventions included: (1) warfarin, (2) aspirin, or (3) no antithrombotic therapy without genetic testing; and genetic testing followed by (4) aspirin or (5) no antithrombotic therapy in those with culprit CYP2C9 alleles.
Quality-adjusted life years (QALYs).
In the base case, testing and treating patients with CYP2C9*2 and/or CYP2C9*3 with aspirin rather than warfarin was best (8.97 QALYs). However, warfarin without genetic testing was a close second (8.96 QALYs), a difference of roughly 5 days. Sensitivity analyses demonstrated that genetic testing followed by aspirin was best for patients at lower risk of embolic events. Warfarin without testing was preferred if the rate of embolic events was greater than 5% per year, or the risk of major bleeding while receiving warfarin was lower.
For patients at average risk for ischemic stroke due to AF and at average risk for major hemorrhage, treatment based on genetic testing offers no benefit compared to warfarin initiation without testing. The gain from testing may be larger in patients at lower risk of embolic events or at greater risk of bleeding.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-009-0927-7) contains supplementary material, which is available to authorized users.
PMCID: PMC2669861  PMID: 19255811
anticoagulant therapy; warfarin; genetic testing; pharmacogenetics; decision analysis; atrial fibrillation; stroke
6.  Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation? The ATRIA Study 
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 (AF). 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 9,217 AF 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 2.0-2.5. We identified 396 TE cases and 164 ICH cases during follow-up. Each case was compared with four 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 to INR 2.0-2.5, the relative odds of TE increased strikingly at INR <1.8 (e.g., OR=3.72; 95% CI: 2.67-5.19, at INR 1.4-1.7). The odds of ICH increased markedly at INR values >3.5 (e.g., OR=3.56; 95% CI: 1.70-7.46, at INR 3.6-4.5). 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.
Our results confirm that the current standard of INR 2.0-3.0 for AF falls in the optimal INR range. Our findings do not support adjustment of INR targets according to previously defined stroke risk factors.
PMCID: PMC2801892  PMID: 20031854
atrial fibrillation; anticoagulation; stroke prevention
7.  Cost-Effectiveness of Apixaban Compared with Warfarin for Stroke Prevention in Atrial Fibrillation 
PLoS ONE  2012;7(10):e47473.
Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention.
Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS2 score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios.
Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY.
In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.
PMCID: PMC3467203  PMID: 23056642
8.  Dabigatran etexilate versus warfarin in management of non-valvular atrial fibrillation in UK context: quantitative benefit-harm and economic analyses 
Objectives To determine the incremental net health benefits of dabigatran etexilate 110 mg and 150 mg twice daily and warfarin in patients with non-valvular atrial fibrillation and to estimate the cost effectiveness of dabigatran in the United Kingdom.
Design Quantitative benefit-harm and economic analyses using a discrete event simulation model to extrapolate the findings of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study to a lifetime horizon.
Setting UK National Health Service.
Population Cohorts of 50 000 simulated patients at moderate to high risk of stroke with a mean baseline CHADS2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes mellitus, previous Stroke/transient ischaemic attack) score of 2.1.
Main outcome measures Quality adjusted life years (QALYs) gained and incremental cost per QALY of dabigatran compared with warfarin.
Results Compared with warfarin, low dose and high dose dabigatran were associated with positive incremental net benefits of 0.094 (95% central range −0.083 to 0.267) and 0.146 (−0.029 to 0.322) QALYs. Positive incremental net benefits resulted for high dose dabigatran in 94% of simulations versus warfarin and in 76% of those versus low dose dabigatran. In the economic analysis, high dose dabigatran dominated the low dose, had an incremental cost effectiveness ratio of £23 082 (€26 700; $35 800) per QALY gained versus warfarin, and was more cost effective in patients with a baseline CHADS2 score of 3 or above. However, at centres that achieved good control of international normalised ratio, such as those in the UK, dabigatran 150 mg was not cost effective, at £42 386 per QALY gained.
Conclusions This analysis supports regulatory decisions that dabigatran offers a positive benefit to harm ratio when compared with warfarin. However, no subgroup for which dabigatran 110 mg offered any clinical or economic advantage over 150 mg was identified. High dose dabigatran will be cost effective only forpatients at increased risk of stroke or for whom international normalised ratio is likely to be less well controlled.
PMCID: PMC3204867  PMID: 22042753
9.  Warfarin Discontinuation after Starting Warfarin for Atrial Fibrillation 
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 people newly starting warfarin for atrial fibrillation.
Methods and Results
We identified 4,188 subjects newly starting warfarin in the ATRIA Study and tracked longitudinal warfarin use using 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 one 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 and 95%CI [HR] 1.33 [1.03-1.72] compared to age ≥ 85 years), patients with poorer anticoagulation control (HR 1.46 [1.42-1.49] for every 10% decrease in time in therapeutic INR range) and lower stroke risk (HR 2.54 [1.86-3.47] for CHADS2 stroke risk index of 0 compared to 4-6).
More than one in four individuals 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 upon determining which patients are most appropriately initiated and maintained on therapy.
PMCID: PMC3063305  PMID: 20959565
anticoagulation; atrial fibrillation; discontinuation; stroke prevention; warfarin
10.  Antithrombotic therapy for atrial fibrillation and coronary artery disease in older patients 
American heart journal  2012;164(4):607-615.
Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important.
From the Duke Databank for Cardiovascular Disease, we identified patients with AF ≥65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS2) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported.
Of 2,122 patients ≥65 years old with AF and CAD, 477 (22.5%) were ≥80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ≥80 years old were at high stroke risk (CHADS2 ≥2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS2 scores and decreased with higher ATRIA scores. Of patients ≥80 years old with CHADS2 ≥2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes.
Among older patients with AF and CAD, overall warfarin use was low. Patients ≥80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.
PMCID: PMC3777661  PMID: 23067921
11.  Analysis of Antithrombotic Therapy After Cardioembolic Stroke Due to Atrial Fibrillation or Flutter 
Hospital Pharmacy  2013;48(2):127-133.
Guidelines recommend that all patients with atrial fibrillation and a history of ischemic stroke should receive an anticoagulant. Prior analyses show that warfarin is underutilized in most populations.
To examine the use of antithrombotic and anticoagulant therapy in patients with atrial fibrillation or flutter during the index hospitalization for acute, ischemic stroke.
Retrospective electronic medical record review of 200 patients treated at a tertiary care hospital with a primary ICD-9 code for ischemic stroke and a secondary ICD-9 code for atrial fibrillation or flutter. Exclusion criteria were active bleeding, pregnancy, age less than 18, pre-existing warfarin allergy, or dabigatran use.
Fifty-two percent of patients received at least one dose of warfarin during the index hospitalization. There was no relationship between CHADS2 score and likelihood of receiving warfarin (P > .05). There was no significant difference in adverse event rate in patients receiving warfarin compared to those receiving aspirin (3.8% vs 9.1%; P = .14), but the rate of hemorrhagic transformation was lower in patients receiving warfarin (1% vs 7%; P = .03). The composite of hemorrhagic stroke or hemorrhagic transformation was significantly lower in patients receiving bridging therapy (0% vs 11%; P = .03). Sixteen patients were readmitted for stroke within 3 months of discharge. Ten were readmitted for ischemic stroke, 3 for hemorrhagic stroke or hemorrhagic transformation, and 3 for systemic bleeding. Ten patients (62.5%) were receiving warfarin at readmission, but only one of these patients had a therapeutic INR.
Warfarin was underutilized as secondary stroke prophylaxis in these high-risk patients. Bridging therapy appeared to be safe and was not associated with an increase in adverse events.
PMCID: PMC3839477  PMID: 24421450
anticoagulant; atrial fibrillation; atrial flutter; stroke; warfarin
12.  Amino terminal pro–B-type natriuretic peptide, secondary stroke prevention, and choice of antithrombotic therapy 
Background and Purpose
Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro–B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin–Aspirin Recurrent Stroke Study (WARSS), diagnosed with inferred non-cardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events.
NT-proBNP was measured in stored serum collected at baseline from participants enrolled in WARSS, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over two years was compared based on NT-proBNP concentrations.
About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the two-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, while for 979 patients with NT-proBNP ≤750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval 0.12 to 0.84, p-value=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (p-value=0.01).
For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents.
Clinical Trial Registration
This trial was not registered because enrollment began prior to 2005.
PMCID: PMC3583375  PMID: 23339958
aspirin; warfarin; NT-proBNP; secondary stroke prevention
13.  National Utilization Patterns of Warfarin Use in Older Patients with Atrial Fibrillation: A Population-Based Study of Medicare Part D Beneficiaries 
The Annals of pharmacotherapy  2013;47(1):35-42.
Although warfarin therapy reduces stroke incidence in patients with atrial fibrillation (AF), the rate of warfarin use in this population remains low. In 2008, the Medicare Part D program was expanded to pay for medications for Medicare enrollees.
To examine rates and predictors of warfarin use in Medicare Part D beneficiaries with AF.
This population-based retrospective cohort study used claims data from 41,447 Medicare beneficiaries aged 66 and older with at least 2 AF diagnoses in 2007 and at least 1 diagnosis in 2008. All subjects had continuous Medicare Part D prescription coverage in 2008. Statistical analysis using χ2 was used to examine differences in warfarin use by patient characteristics (age, ethnicity, sex, Medicaid eligibility, comorbidities, contraindications to warfarin, and whether they visited a cardiologist or a primary care physician [PCP]), CHADS2 score (congestive heart failure, hypertension, age, diabetes, and stroke or transient ischemic attack; higher scores indicate higher risks of stroke), and geographic regions. Using hierarchical generalized linear models restricted to subjects without warfarin contraindications (n = 34,947), we examined the effect of patient characteristics and geographic regions on warfarin use.
The overall warfarin use rate was 66.8%. The warfarin use rates varied between hospital referral regions, with highest rates in the Midwestern states and lowest rates in the South. The regional variation persisted even after adjustment for patient characteristics. Multivariable analysis showed that the odds of being on warfarin decreased significantly with age and increasing comorbidity, in blacks, and among those with low income. Seeing a cardiologist (OR 1.10; 95% CI 1.05–1.16), having a PCP (OR 1.23; 95% CI 1.17–1.29), and CHADS2 score of 2 or greater (OR 1.09; 95% CI 1.01–1.17) were associated with increased odds of warfarin use.
Warfarin use rates vary by patient characteristics and region, with higher rates among residents of the Midwest and among patients seen by cardiologists and PCPs. Preventing stroke-related disability in AF requires implementation of evidence-based initiatives to increase warfarin use.
PMCID: PMC4006962  PMID: 23324508
14.  Cost-effectiveness of apixaban vs. current standard of care for stroke prevention in patients with atrial fibrillation 
European Heart Journal  2014;35(28):1897-1906.
Warfarin, a vitamin K antagonist (VKA), has been the standard of care for stroke prevention in patients with atrial fibrillation (AF). Aspirin is recommended for low-risk patients and those unsuitable for warfarin. Apixaban is an oral anticoagulant that has demonstrated better efficacy than warfarin and aspirin in the ARISTOTLE and AVERROES studies, respectively, and causes less bleeding than warfarin. We evaluated the potential cost-effectiveness of apixaban against warfarin and aspirin from the perspective of the UK payer perspective.
Results and methods
A lifetime Markov model was developed to evaluate the pharmacoeconomic impact of apixaban compared with warfarin and aspirin in VKA suitable and VKA unsuitable patients, respectively. Clinical events considered in the model include ischaemic stroke, haemorrhagic stroke, intracranial haemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, cardiovascular hospitalization and treatment discontinuations; data from the ARISTOTLE and AVERROES trials and published mortality rates and event-related utility rates were used in the model. Apixaban was projected to increase life expectancy and quality-adjusted life years (QALYs) compared with warfarin and aspirin. These gains were expected to be achieved at a drug acquisition-related cost increase over lifetime. The estimated incremental cost-effectiveness ratio was £11 909 and £7196 per QALY gained with apixaban compared with warfarin and aspirin, respectively. Sensitivity analyses indicated that results were robust to a wide range of inputs.
Based on randomized trial data, apixaban is a cost-effective alternative to warfarin and aspirin, in VKA suitable and VKA unsuitable patients with AF, respectively.
PMCID: PMC4104492  PMID: 24513791
Vitamin K antagonist; Aspirin; Stroke prevention; Apixaban; Cost-effectiveness; Atrial fibrillation
15.  The Case for an Elderly Targeted Stroke Management 
Stroke is a leading cause of death and disability worldwide. The elderly, in whom atrial fibrillation (AF) is most prevalent, carry the greatest risk, undergoing more recurrent, deadlier strokes, with bigger deficits, slower recoveries, and more comorbidities. Evidence-based data on advanced age stroke management are scarce. Age-related cerebral changes might undermine the benefit of established stroke treatments. Nevertheless, the elderly should probably also undergo thrombolysis for ischemic stroke: they do not bleed more, and die not because of hemorrhage but of concomitant illnesses. Beyond natural bleeding risks, AF in advanced age has a high embolic potential if not anticoagulated. Standard or lower intensity warfarin anticoagulation prevents embolic stroke in the elderly with a hemorrhage risk even lower than aspirin. In fact, adverse effects seem to occur more often with aspirin. Excess anticoagulation hazards are prevented with lower starting doses, stricter corrections, more frequent International Normalized Ratio monitoring, and longer adjustment intervals. Validated prognostic scores such as CHADS2 help minimize bleeds. Direct inhibitors have recently shown a benefit similar to warfarin with fewer hemorrhages. Carefully tailoring antithrombotics to this age group is therefore useful. Antihypertensives probably help 80-plus stroke patients as well, but the risk/benefit of lowering blood pressure in secondary stroke prevention at that age is uncertain. Evidence-based data on diabetes management and use of lipid-lowering drugs are still lacking in this age group. In summary, emerging data suggest that stroke management should be specifically targeted to the elderly to better prevent its devastating consequences in the population at the highest risk.
PMCID: PMC3248648  PMID: 22232616
stroke management; elderly population; antithrombotics
16.  Application of a Decision Support Tool for Anticoagulation in Patients with Non-valvular Atrial Fibrillation 
Atrial fibrillation affects more than two million Americans and results in a fivefold increased rate of embolic strokes. The efficacy of adjusted dose warfarin is well documented, yet many patients are not receiving treatment consistent with guidelines. The use of a patient-specific computerized decision support tool may aid in closing the knowledge gap regarding the best treatment for a patient.
This retrospective, observational cohort analysis of 6,123 Ohio Medicaid patients used a patient-specific computerized decision support tool that automated the complex risk–benefit analysis for anticoagulation. Adverse outcomes included acute stroke, major gastrointestinal bleeding, and intracranial hemorrhage. Cox proportional hazards models were developed to compare the group of patients who received warfarin treatment with those who did not receive warfarin treatment, stratified by the decision support tool’s recommendation.
Our decision support tool recommended warfarin for 3,008 patients (49%); however, only 9.9% received warfarin. In patients for whom anticoagulation was recommended by the decision support tool, there was a trend towards a decreased hazard for stroke with actual warfarin treatment (hazard ratio 0.90) without significant increase in gastrointestinal hemorrhage (0.87). In contrast, in patients for whom the tool recommended no anticoagulation, receipt of warfarin was associated with statistically significant increased hazard of gastrointestinal bleeding (1.54, p = 0.03).
We have shown that our atrial fibrillation decision support tool is a useful predictor of those at risk of major bleeding for whom anticoagulation may not necessarily be beneficial. It may aid in weighing the benefits versus risks of anticoagulation treatment.
PMCID: PMC2359511  PMID: 18373138
atrial fibrillation; decision support; anticoagulation; decision aid
17.  Rates of hemorrhage during warfarin therapy for atrial fibrillation 
Although warfarin has been extensively studied in clinical trials, little is known about rates of hemorrhage attributable to its use in routine clinical practice. Our objective was to examine incident hemorrhagic events in a large population-based cohort of patients with atrial fibrillation who were starting treatment with warfarin.
We conducted a population-based cohort study involving residents of Ontario (age ≥ 66 yr) with atrial fibrillation who started taking warfarin between Apr. 1, 1997, and Mar. 31, 2008. We defined a major hemorrhage as any visit to hospital for hemorrage. We determined crude rates of hemorrhage during warfarin treatment, overall and stratified by CHADS2 score (congestive heart failure, hypertension, age ≥ 75 yr, diabetes mellitus and prior stroke, transient ischemic attack or thromboembolism).
We included 125 195 patients with atrial fibrillation who started treatment with warfarin during the study period. Overall, the rate of hemorrhage was 3.8% (95% confidence interval [CI] 3.8%–3.9%) per person-year. The risk of major hemorrhage was highest during the first 30 days of treatment. During this period, rates of hemorrhage were 11.8% (95% CI 11.1%–12.5%) per person-year in all patients and 16.7% (95% CI 14.3%–19.4%) per person-year among patients with a CHADS2 scores of 4 or greater. Over the 5-year follow-up, 10 840 patients (8.7%) visited the hospital for hemorrhage; of these patients, 1963 (18.1%) died in hospital or within 7 days of being discharged.
In this large cohort of older patients with atrial fibrillation, we found that rates of hemorrhage are highest within the first 30 days of warfarin therapy. These rates are considerably higher than the rates of 1%–3% reported in randomized controlled trials of warfarin therapy. Our study provides timely estimates of warfarin-related adverse events that may be useful to clinicians, patients and policy-makers as new options for treatment become available.
PMCID: PMC3563912  PMID: 23184840
18.  Utilization of Anticoagulation Therapy in Medicare Patients with Nonvalvular Atrial Fibrillation 
American Health & Drug Benefits  2012;5(3):157-168.
Clinical guidelines recommend oral anticoagulation for stroke prevention in patients with atrial fibrillation (AF) at moderate or high risk for stroke but not at high risk for bleeding; however, studies consistently report suboptimal use of such therapy. This study used Medicare Part D claims data to assess the use of warfarin in the Medicare population.
To compare real-world warfarin utilization with current treatment guideline recommendations, and to assess the effect of warfarin exposure level on patient outcomes in Medicare beneficiaries with nonvalvular AF (NVAF).
Patients who were recently diagnosed with NVAF were identified using a random 5% sample of Research Identifiable Files of Medicare beneficiaries in 2006 or 2007. Individuals with moderate-to-high stroke risk per CHADS2 but not at high bleeding risk per ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score were evaluated for warfarin use, as identified by the presence of ≥1 warfarin prescription claims within 12 months after the index diagnosis. Warfarin exposure level was assessed by the proportion of days covered during the 12-month follow-up period. The effect of warfarin exposure on ischemic stroke and major bleeding event rates during the 12-month follow-up period were assessed using multivariate logistic regression.
Data from 14,149 newly diagnosed patients with NVAF (mean age, 79 years; 58.7% female) were analyzed, and of these, 7524 (53.2%) patients were identified as having moderate-to-high stroke risk and not being at high bleeding risk. Of these patients, 3110 (41.3%) did not receive warfarin within 12 months of the index diagnosis. The risk for ischemic stroke was significantly lower in those with warfarin exposure versus no warfarin exposure (adjusted odds ratio [OR], 0.51; confidence interval [CI], 0.43–0.61; P <.001) and in patients with warfarin proportion of days covered ≥80% versus those with proportion of days covered <80% (adjusted OR, 0.59; 95% CI, 0.48–0.72; P<.001). Warfarin exposure was associated with a significantly higher major bleeding rate (adjusted OR, 1.19; 95% CI, 1.04–1.36; P = .013), with this significant difference being driven by patients aged >65 years.
Based on a risk-stratification scheme composed of previously published tools, such as CHADS2 and the ATRIA bleeding risk index, a significant proportion of Medicare beneficiaries with AF are not receiving guideline-recommended anticoagulation therapy, which leads to an excess rate of ischemic stroke in this patient population. These findings highlight quality-of-care issues for patients with AF and the need to improve compliance with anticoagulation guidelines in the Medicare population.
PMCID: PMC4046469  PMID: 24991318
19.  Atrial Fibrillation, Stroke, and Anticoagulation in Medicare Beneficiaries: Trends by Age, Sex, and Race, 1992–2010 
We evaluated temporal trends in ischemic stroke and warfarin use among demographic subsets of the US Medicare population that are not well represented in randomized trials of warfarin for stroke prevention in nonvalvular atrial fibrillation (AF).
Methods and Results
One‐year cohorts of Medicare–primary payer patients (1992–2010) were created using the Medicare 5% sample. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify AF and ischemic and hemorrhagic stroke; ≥3 consecutive prothrombin time claims were used to identify warfarin use. Ischemic stroke rates (per 1000 patient‐years) decreased markedly from 1992 to 2010. Among women, rates decreased from 37.1 to 13.6 for ages 65 to 74 years, from 55.2 to 16.5 for ages 74 to 84, and from 66.9 to 22.9 for age ≥85; warfarin use increased 31% to 59%, 27% to 63%, and 15% to 49%, respectively. Among men, rates decreased from 33.8 to 11.7 for ages 65 to 74 years, from 49.2 to 13.8 for ages 75 to 84, and from 51.5 to 18.0 for age ≥ 85; warfarin use increased 34% to 63%, 28% to 66%, and 15% to 55%, respectively. Rates decreased from 47.0 to 14.8 for whites and 73.0 to 29.3 for blacks; warfarin use increased 27% to 61% and 19% to 52%, respectively. In all age categories, the thromboembolic risk (CHADS [congestive heart failure, hypertension, age ≥75 years, diabetes, stroke]) score was significantly higher among women (versus men) and blacks (versus whites).
Ischemic stroke rates among Medicare AF patients decreased significantly in all demographic subpopulations from 1992–2010, coincident with increasing warfarin use. Ischemic stroke rates remained higher and warfarin use rates remained lower for women and blacks with AF, groups whose baseline CHADS scores were higher.
PMCID: PMC4309061  PMID: 24895161
anticoagulants; arrhythmia; stroke
20.  Bleeding complications associated with warfarin treatment in ischemic stroke patients with atrial fibrillation: a population-based cohort study 
Bleeding events are the major obstacle to the widespread use of warfarin for secondary stroke prevention. Previous studies have not examined the use of risk stratification scores to estimate lifetime bleeding risk associated with warfarin treatment in a population-based setting. The purpose of this study is to determine the lifetime risk of bleeding events in ischemic stroke patients with atrial fibrillation (AF) undergoing warfarin treatment in a population-based cohort and to evaluate the use of bleeding risk scores to identify patients at high-risk for lifetime bleeding events.
The resources of the Rochester Epidemiology Project Medical Linkage System were used to identify acute ischemic stroke patients with atrial fibrillation undergoing warfarin treatment for secondary stroke prevention from 1980 to 1994. Medical information for patients seen at Mayo Clinic and at Olmsted Medical Center were used to retrospectively risk-stratify stroke patients according to bleeding risk scores (including the HAS-BLED and HEMORR2HAGES scores) prior to warfarin initiation. These scores were reassessed one and five years later, and compared with lifetime bleeding events.
One hundred patients (mean age, 79.3 years; 68% women) were studied. Ninety-nine patients were followed to death. Major bleeding events occurred in 41 patients at a median of 19 months following warfarin initiation. Patients with a history of hemorrhage before warfarin treatment were more likely to develop major hemorrhage (15% vs 3%, p=0.04). Patients with baseline HAS-BLED scores ≥2 had a higher lifetime risk of major bleeding events compared with those with scores ≤1 (53% vs 7%, p<0.01), while those with HEMORR2HAGES score ≥2 had a higher life-time risk of major bleeding events compared with those with scores ≤1 (52% vs 16%, p=0.03). Patients with an increase in the HAS-BLED and HEMORR2HAGES scores during follow-up had a higher remaining lifetime risk of major bleeding events compared to those with no change.
Our findings indicate high lifetime bleeding risk associated with warfarin treatment for patients with ischemic stroke. Risk stratification scores are useful to identify patients at high-risk of developing bleeding complications and should be recalculated at regular intervals to evaluate the bleeding risk in anticoagulated patients with ischemic stroke.
PMCID: PMC4080718  PMID: 23499334
stroke; atrial fibrillation; warfarin; bleeding complications
21.  Protocol for Birmingham Atrial Fibrillation Treatment of the Aged study (BAFTA): a randomised controlled trial of warfarin versus aspirin for stroke prevention in the management of atrial fibrillation in an elderly primary care population [ISRCTN89345269] 
Atrial fibrillation (AF) is an important independent risk factor for stroke. Randomised controlled trials have shown that this risk can be reduced substantially by treatment with warfarin or more modestly by treatment with aspirin. Existing trial data for the effectiveness of warfarin are drawn largely from studies in selected secondary care populations that under-represent the elderly.
The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) study will provide evidence of the risks and benefits of warfarin versus aspirin for the prevention of stroke for older people with AF in a primary care setting.
Study design
A randomised controlled trial where older patients with AF are randomised to receive adjusted dose warfarin or aspirin. Patients will be followed up at three months post-randomisation, then at six monthly intervals there after for an average of three years by their general practitioner. Patients will also receive an annual health questionnaire.
1240 patients will be recruited from over 200 practices in England. Patients must be aged 75 years or over and have AF. Patients will be excluded if they have a history of any of the following conditions: rheumatic heart disease; major non-traumatic haemorrhage; intra-cranial haemorrhage; oesophageal varices; active endoscopically proven peptic ulcer disease; allergic hypersensitivity to warfarin or aspirin; or terminal illness. Patients will also be excluded if the GP considers that there are clinical reasons to treat a patient with warfarin in preference to aspirin (or vice versa).
The primary end-point is fatal or non-fatal disabling stroke (ischaemic or haemorrhagic) or significant arterial embolism. Secondary outcomes include major extra-cranial haemorrhage, death (all cause, vascular), hospital admissions (all cause, vascular), cognition, quality of life, disability and compliance with study medication.
PMCID: PMC201020  PMID: 12939169
22.  Are family physicians using the CHADS2 score? 
Canadian Family Physician  2011;57(8):e305-e309.
To assess whether family physicians are using the CHADS2 (congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, and stroke or transient ischemic attack) score in the decision to initiate warfarin therapy to prevent stroke in patients with atrial fibrillation.
Retrospective analysis of the medical records of patients with atrial fibrillation.
Data were gathered from records at 3 clinics in a primary care network in Edmonton, Alta.
The medical records of patients with atrial fibrillation who were currently taking warfarin therapy.
Main outcome measures
Percentage of patients whose CHADS2 scores indicated warfarin therapy for stroke prophylaxis compared with the actual percentage of patients taking warfarin therapy. Data on patients’ age, number of medications, and number of comorbid conditions were also recorded.
Among these patients, 7% had a CHADS2 score of 0, for which no warfarin therapy was indicated; 21% had a score of 1, for which either acetylsalicylic acid or warfarin was indicated; and 72% had a score of 2 or greater, for which warfarin therapy was indicated. About 80% of patients were taking medication to control their heart rate.
The CHADS2 score is not being used in all cases to assess the need for warfarin therapy for preventing stroke in patients with atrial fibrillation. The CHADS2 score might be of limited use because it is not sensitive enough to stratify patients clearly into high-, intermediate-, and low-risk groups. Although guidelines for stroke prevention should be followed, the CHADS2 portion of the guidelines might not be the most effective way to assess patients’ risk of stroke.
PMCID: PMC3155466  PMID: 21841094
23.  Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation 
Heart  2012;98(7):573-578.
To assess the cost-effectiveness of dabigatran etexilate, a new oral anticoagulant, versus warfarin and other alternatives for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation (AF).
A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin, aspirin or no therapy. Two patient cohorts with AF (starting age of <80 and ≥80 years) were considered separately, in line with the UK labelled indication. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs).
Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years. Larger differences were observed comparing dabigatran etexilate with aspirin or no therapy. For patients initiating treatment at ages <80 and ≥80 years, the ICERs for dabigatran etexilate were £4831 and £7090/QALY gained versus warfarin with a probability of cost-effectiveness at £20 000/QALY gained of 98% and 63%, respectively. For the patient cohort starting treatment at ages <80 years, the ICER versus aspirin was £3457/QALY gained and dabigatran etexilate was dominant (ie, was less costly and more effective) compared with no therapy. These results were robust in sensitivity analyses.
This economic evaluation suggests that the use of dabigatran etexilate as a first-line treatment for the prevention of stroke and systemic embolism is likely to be cost-effective in eligible UK patients with AF.
PMCID: PMC3308473  PMID: 22422743
Anticoagulation; Dabigatran etexilate; warfarin; stroke; cost-effectiveness; atrial fibrillation
24.  Evidence-based study on antithrombotic therapy in patients at risk of a stroke with paroxysmal atrial fibrillation 
The aim of the present study was to determine the optimal intensity of anticoagulation therapy in elderly patients with paroxysmal atrial fibrillation (PAF), using aspirin and varied concentrations of warfarin. Elderly patients with PAF (n=1,162) who met the inclusion criteria of the study and were at middle or high-risk of a stroke were investigated. Patients were divided into six groups (four high-risk groups and two middle-risk groups). Patients were treated with aspirin or varied concentrations of warfarin. The primary endpoint events, secondary endpoint events, major bleeding events and minor bleeding events were observed and compared. In high-risk elderly patients, warfarin significantly reduced primary and secondary endpoint events, total primary events and total events compared with aspirin. In middle-risk elderly patients, for all the events warfarin demonstrated no significant difference compared with aspirin. In high-risk patients with PAF, when the concentration of warfarin was adjusted to target international normalized ratio (INR) range 1.7–2.5, the primary and secondary endpoint events, total primary events and total events were significantly lower (P<0.05), compared with aspirin and warfarin at INR 1.2–1.6. When the intensity of warfarin was adjusted to the target INR 2.6–3.0, the primary and secondary endpoint events were significantly lower (P<0.05) compared with aspirin and warfarin INR at 1.2–1.6. This study determined that in high-risk elderly patients with PAF, warfarin is recommended for anticoagulation with an optimal INR range of 1.7–2.5. In patients at a middle-risk of a stroke, aspirin is the recommended treatment as an antithrombotic as results have indicated that there is limited benefit in the use of warfarin.
PMCID: PMC3787006  PMID: 24137200
paroxysmal atrial fibrillation; aspirin; warfarin; middle risk; high risk
25.  Benefit of Warfarin Compared With Aspirin in Patients With Heart Failure in Sinus Rhythm 
Circulation. Heart failure  2013;6(5):988-997.
The Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial found no difference in the primary outcome between warfarin and aspirin in 2305 patients with reduced left ventricular ejection fraction in sinus rhythm. However, it is unknown whether any subgroups benefit from warfarin or aspirin.
Methods and Results
We used a Cox model stepwise selection procedure to identify subgroups that may benefit from warfarin or aspirin on the WARCEF primary outcome. A secondary analysis added major hemorrhage to the outcome. The primary efficacy outcome was time to the first to occur of ischemic stroke, intracerebral hemorrhage, or death. Only age group was a significant treatment effect modifier (P for interaction, 0.003). Younger patients benefited from warfarin over aspirin on the primary outcome (4.81 versus 6.76 events per 100 patient-years: hazard ratio, 0.63; 95% confidence interval, 0.48–0.84; P=0.001). In older patients, therapies did not differ (9.91 versus 9.01 events per 100 patient-years: hazard ratio, 1.09; 95% confidence interval, 0.88–1.35; P=0.44). With major hemorrhage added, in younger patients the event rate remained lower for warfarin than aspirin (5.41 versus 7.25 per 100 patient-years: hazard ratio, 0.68; 95% confidence interval, 0.52–0.89; P=0.005), but in older patients it became significantly higher for warfarin (11.80 versus 9.35 per 100 patient-years: hazard ratio, 1.25; 95% confidence interval, 1.02–1.53; P=0.03).
In patients <60 years, warfarin improved outcomes over aspirin with or without inclusion of major hemorrhage. In patients ≥60 years, there was no treatment difference, but the aspirin group had significantly better outcomes when major hemorrhage was included.
Clinical Trial Registration
URL: Unique identifier: NCT00041938.
PMCID: PMC4242511  PMID: 23881846
aspirin; heart failure; sinus rhythm; stroke; warfarin

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