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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.  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
3.  Anticoagulation and atrial fibrillation. Putting the results of clinical trials into practice. 
Western Journal of Medicine  1995;163(2):145-152.
The thromboembolic risk of atrial fibrillation varies with the underlying cause, associated heart disease, and history of previous embolism. Decisions regarding warfarin anticoagulation therapy require a careful assessment of relative risks of thromboembolism and bleeding. Anticoagulation is strongly indicated for valvular atrial fibrillation and to prevent recurrent stroke in patients with atrial fibrillation and previous stroke or transient ischemic attack. Several randomized trials have consistently shown a reduction of the risk with the use of warfarin in nonvalvular atrial fibrillation, and anticoagulation is recommended. With a careful selection of patients, the risk of major bleeding on warfarin therapy is 2% to 4% per year. Aspirin therapy is less efficacious but also less risky than warfarin. Patients younger than 60 with lone atrial fibrillation do not require anticoagulation.
PMCID: PMC1303009  PMID: 7571562
4.  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
5.  Anticoagulation for non-valvular atrial aibrillation – towards a new beginning with ximelagatran 
Ximelagatran is a novel oral direct thrombin inhibitor. It has favorable pharmacodynamic properties, with a broad therapeutic range without the need for anticoagulation monitoring. We aimed to discover whether ximelagatran offers a genuine future replacement to warfarin for patients in persistent atrial fibrillation (AF).
Materials and methods
We provide an evidence-based review of the relative merits and disadvantages of warfarin and aspirin. We subsequently present an overview of the evidence for the utility of ximelagatran in the treatment of AF.
Adjusted dose warfarin is recommended over aspirin for patients in AF at high risk of future stroke. Some of this benefit is partially offset by the higher bleeding risks associated with warfarin therapy. The SPORTIF III and V studies have shown that ximelagatran is not inferior to warfarin in the prevention of all strokes in patients with AF (both persistent and paroxysmal). This benefit was partially offset by the finding of a significant elevation of liver transaminases (>3 × normal) in 6% of patients.
Current data would suggest that ximelagatran might represent a future alternative to warfarin. The lack of need for anticoagulant monitoring has been partially offset by a need for regular monitoring of liver function. Further data from randomized clinical trials is clearly needed.
PMCID: PMC420263  PMID: 15104801
6.  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
7.  Antithrombotic therapy in atrial fibrillation: aspirin is rarely the right choice 
Postgraduate Medical Journal  2013;89(1052):346-351.
Atrial fibrillation, the commonest cardiac arrhythmia, predisposes to thrombus formation and consequently increases risk of ischaemic stroke. Recent years have seen approval of a number of novel oral anticoagulants. Nevertheless, warfarin and aspirin remain the mainstays of therapy. It is widely appreciated that both these agents increase the likelihood of bleeding: there is a popular conception that this risk is greater with warfarin. In fact, well-managed warfarin therapy (INR 2-3) has little effect on bleeding risk and is twice as effective as aspirin at preventing stroke. Patients with atrial fibrillation and a further risk factor for stroke (CHA2DS2-VASc >0) should therefore either receive warfarin or a novel oral agent. The remainder who are at the very lowest risk of stroke are better not prescribed antithrombotic therapy. For stroke prevention in atrial fibrillation; aspirin is rarely the right choice.
PMCID: PMC3664370  PMID: 23404744
Atrial Fibrillation; Aspirin; Antithrombotic; Anticoagulant; Warfarin
8.  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
9.  Use of antithrombotic measures for stroke prevention in atrial fibrillation 
Heart  1999;82(5):570-574.
OBJECTIVE—To evaluate appropriateness of antithrombotic use to prevent stroke in atrial fibrillation.
DESIGN, PATIENTS—344 patients with atrial fibrillation, stratified by age, were assessed clinically for contraindications to anticoagulation and stroke risk. The use of warfarin and aspirin was compared with recommendations for anticoagulation derived from pooled clinical trial data.
RESULTS—Low risk of stroke was seen in 47 (14%) patients, moderate risk in 213 (62%), and high risk in 84 (24%) patients included in the sample (mean (SD) age 68.4 (17.2) years, 42% men). The proportion of patients requiring anticoagulation varied from 258/344 (75%) to 72/344 (21%) depending upon criteria used, of whom 86/258 (33%) and 36/72 (50%) were receiving warfarin, respectively. Warfarin or aspirin were not being used in 124/297 (42%) patients with moderate to high risk, whereas anticoagulation was being undertaken in 13/47 (27%) patients at low risk of stroke. Antithrombotic use (warfarin or aspirin) was significantly less common in patients over 75 years of age, regardless of absence of contraindications and eligibility according to various criteria (p < 0.001).
CONCLUSIONS—A clear need for anticoagulation using clinical criteria existed in about 25% of patients in atrial fibrillation presenting to medical clinics who were at high risk of stroke. Of these, only 50% of eligible patients were being anticoagulated. Appropriate anticoagulation needs to be based on risk assessment rather than age. Consensus is therefore needed on appropriate antithrombotic use in clinical practice.

Keywords: stroke prevention; atrial fibrillation; warfarin; aspirin; antithrombotics
PMCID: PMC1760775  PMID: 10525511
10.  Novel oral anticoagulants for stroke prevention in atrial fibrillation: a focus on the older patient 
Atrial fibrillation (AF) is a common arrhythmia that is associated with an increased risk of stroke, particularly in the elderly. Traditionally, a vitamin K antagonist such as warfarin is prescribed for stroke prevention. Warfarin is effective at lowering stroke risk but has several limitations due to food restrictions, drug interactions, and a narrow therapeutic window. Various novel oral anticoagulants (NOACs) are available or under development to provide alternative treatment options. This article reviews the efficacy and safety of three NOACs (dabigatran etexilate, rivaroxaban, and apixaban) in addition to warfarin and aspirin, for prevention of stroke in patients with AF, focusing on the elderly population. Results of clinical trials demonstrate that the efficacy of NOACs for stroke prevention in patients with AF is as good as or better than that of warfarin. The NOACs are also associated with an equivalent or lower risk of bleeding. Regardless of the medication chosen, older patients with AF must be treated cautiously due to an increased risk of stroke and bleeding, as well as potential challenges related to drug interactions and monitoring requirements. NOACs may be suitable alternatives to warfarin for stroke prevention in older patients due to several advantages, including a faster onset of action, few drug or food interactions, and no requirement for regular monitoring. However, dose adjustments may be required for certain patients, such as those with severe renal impairment or in the setting of drug interactions.
PMCID: PMC3610436  PMID: 23687449
aspirin; warfarin; dabigatran etexilate; rivaroxaban; apixaban
11.  Patterns of warfarin use and subsequent outcomes in atrial fibrillation in primary care practices 
Warfarin is recommended for stroke prevention in high-risk patients with atrial fibrillation. However, it is often underutilized and inadequately managed in actual clinical practice.
To examine the patterns of warfarin use and their relationship with stroke and bleeding in atrial fibrillation patients in community-based primary care practices.
Retrospective longitudinal cohort study.
A total of 1141 atrial fibrillation patients were selected from 17 primary care practices with a shared electronic medical record and characterized by stroke risk, potential barriers to anticoagulation, and comorbid conditions.
Main measures
Duration and number of warfarin exposures, interruptions in warfarin exposure > 45 days, stroke, and bleeding events.
Among 1141 patients with a mean age of 70 years (standard deviation 13.3) and mean follow-up of 3.4 years (standard deviation 3.0), 764 (67%) were treated with warfarin. Warfarin was discontinued within 1 year in 194 (25.4%), and 349 (45.7%) remained on warfarin at the end of follow-up. Interruptions in warfarin use were common, occurring in 32.6% (249 of 764) of patients. Those with two or more interruptions were younger and at lower baseline stroke risk when compared to those with no interruptions. There were 76 first strokes and 73 first-bleeding events in the follow-up period. When adjusted for baseline stroke risk, time to warfarin start, and total exposure time, two or more interruptions in warfarin use was associated with an increased risk of stroke (relative risk, 2.29; 95% confidence interval: 1.29–4.07). There was no significant association between warfarin interruptions and bleeding events.
Warfarin was underutilized in a substantial portion of eligible atrial fibrillation patients in these community-based practices. In addition, prolonged interruptions in anticoagulation were common in this population, and multiple interruptions were associated with over twice the risk of stroke when compared to those treated continuously.
PMCID: PMC3480279  PMID: 23112579
cardiovascular disease; primary care; quality assessment; outcomes
12.  Values and preferences in oral anticoagulation in patients with atrial fibrillation, physicians' and patients' perspectives: protocol for a two-phase study 
Oral anticoagulation prevents strokes in patients with atrial fibrillation but, for reasons that remain unclear, less than 40% of all patients with atrial fibrillation receive warfarin. The literature postulates that patient and clinician preferences may explain this low utilization.
The proposed research seeks to answer the following questions: i) When assessed systematically, do patients' and clinicians' preferences explain the utilization of warfarin to prevent strokes associated with atrial fibrillation? ii) To what extent do patients' and clinicians' treatment preferences differ? iii) What factors explain any differences that exist in treatment preferences between patients and clinicians? To answer these questions we will conduct a two-phase study of patient and clinician preferences for health states and treatments. In the first phase of this study we will conduct structured interviews to determine their treatment preferences for warfarin vs. aspirin to prevent strokes associated with atrial fibrillation using the probability trade-off technique. In the same interview, we will conduct preference-elicitation exercises using the feeling thermometer to identify the utilities that patients place on taking medication (warfarin and aspirin), and on having a mild stroke, a severe stroke, and a major bleed. In the second phase of the study we will convene focus groups of clinicians and patients to explore their answers to the exercises in the first phase.
This is a study of patient and clinician preferences for health states and treatments. Because of its clinical importance and our previous work in this area, we will conduct our study in the clinical context of the decision to use antithrombotic agents to reduce the risk of stroke in patients with non-valvular chronic atrial fibrillation
PMCID: PMC2613147  PMID: 18954427
13.  The use of warfarin in veterans with atrial fibrillation 
Warfarin therapy is effective for the prevention of stroke in patients with atrial fibrillation. However, warfarin therapy is underutilized even among ideal anticoagulation candidates. The purpose of this study was to examine the use of warfarin in both inpatients and outpatients with atrial fibrillation within a Veterans Affairs (VA) hospital system.
This retrospective medical record review included outpatients and inpatients with atrial fibrillation. The outpatient cohort included all patients seen in the outpatient clinics of the VA Connecticut Healthcare System during June 2000 with a diagnosis of atrial fibrillation. The inpatient cohort included all patients discharged from the VA Connecticut Healthcare System West Haven Medical Center with a diagnosis of atrial fibrillation during October 1999 – March 2000. The outcome measure was the rate of warfarin prescription in patients with atrial fibrillation.
A total of 538 outpatients had a diagnosis of atrial fibrillation and 73 of these had a documented contraindication to anticoagulation. Among the 465 eligible outpatients, 455 (98%) were prescribed warfarin. For the inpatients, a total of 212 individual patients were discharged with a diagnosis of atrial fibrillation and 97 were not eligible for warfarin therapy. Among the 115 eligible inpatients, 106 (92%) were discharged on warfarin.
Ideal anticoagulation candidates with atrial fibrillation are being prescribed warfarin at very high rates within one VA system, in both the inpatient and outpatient settings; we found warfarin use within our VA was much higher than that observed for Medicare beneficiaries in our state.
PMCID: PMC526776  PMID: 15498102
Atrial fibrillation; warfarin; anticoagulation; preventive medicine; guideline adherence
14.  Current issues in patient adherence and persistence: focus on anticoagulants for the treatment and prevention of thromboembolism 
Warfarin therapy reduces morbidity and mortality related to thromboembolism. Yet adherence to long-term warfarin therapy remains challenging due to the risks of anticoagulant-associated complications and the burden of monitoring. The aim of this paper is to review determinants of adherence and persistence on long-term anticoagulant therapy for atrial fibrillation and venous thromboembolism. We evaluate what the current literature reveals about the impact of warfarin on quality of life, examine warfarin trial data for patterns of adherence, and summarize known risk factors for warfarin discontinuation. Studies suggest only modest adverse effects of warfarin on quality of life, but highlight the variability of individual lifestyle experiences of patients on warfarin. Interestingly, clinical trials comparing anticoagulant adherence to alternatives (such as aspirin) show that discontinuation rates on warfarin are not consistently higher than in control arms. Observational studies link a number of risk factors to warfarin non-adherence including younger age, male sex, lower stroke risk, poor cognitive function, poverty, and higher educational attainment. In addition to differentiating the relative impact of warfarin-associated complications (such as bleeding) versus the lifestyle burdens of warfarin monitoring on adherence, future investigation should focus on optimizing patient education and enhancing models of physician–patient shared-decision making around anticoagulation.
PMCID: PMC2846139  PMID: 20361065
anticoagulation; warfarin; adherence; persistence; thromboembolism
15.  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
16.  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
17.  Antithrombotic and interventional treatment options in cardioembolic transient ischaemic attack and ischaemic stroke 
Peer‐reviewed data pertaining to anti‐thrombotic and interventional therapy for transient ischaemic attack (TIA) or ischaemic stroke patients with non‐valvular atrial fibrillation, atrial flutter, interatrial septal abnormalities, or left ventricular thrombus were reviewed. Long‐term oral anticoagulant therapy with warfarin is the treatment of choice for secondary stroke prevention following TIA or minor ischaemic stroke in association with persistent or paroxysmal non‐valvular atrial fibrillation or atrial flutter. If warfarin is contraindicated, long‐term aspirin is a safe, but much less effective alternative treatment option in this subgroup of patients with cerebrovascular disease. Management of young patients with TIA or stroke in association with an interatrial septal defect is controversial. Various treatment options are outlined, but readers are encouraged to include these patients in one of the ongoing randomised clinical trials in this area. It is reasonable to consider empirical anticoagulation in patients with TIA or ischaemic stroke in association with left ventricular thrombus formation following myocardial infarction or in association with idiopathic dilated cardiomyopathy. If warfarin is prescribed, one should aim for a target international normalised ratio of 2.5 (range 2–3) to achieve the best balance between adequate secondary prevention of cardioembolic events and the risk of major haemorrhagic complications.
PMCID: PMC2117792  PMID: 17172564
18.  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
19.  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
20.  Battle of oral anticoagulants in the field of atrial fibrillation scrutinized from a clinical practice (the real world) perspective 
Thrombosis Journal  2011;9:12.
Warfarin has a long history of benefit and has become the gold standard medication for the prevention of ischemic stroke in patients with atrial fibrillation. Nevertheless, it is far from perfect and there is no doubt that new drugs must be found to replace warfarin. The new oral anticoagulants that are on the market or awaiting approval or under research offer some benefits but not enough to replace warfarin until results of additional studies can show an adequate balance between effectiveness/safety and cost/benefit. There are several issues concerning the new oral anticoagulants. It is essential that the effect of any anticoagulant can be measured in plasma. But to date, there is no test to assess the effect or therapeutic range for the new oral anticoagulants. There is no antidote to neutralize the action of the new drugs in cases of bleeding or when acute surgical intervention is necessary. Dabigatran requires dose adjustment in patients with moderate renal impairment and is contraindicated in patients with severe renal failure. Rivaroxaban should be used with caution in patients with severe renal impairment. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not yet been determined. How anticoagulant bridging can be done before surgery has not yet been established. In conclusion, although thousands of patients have been treated in phase III studies, additional data are necessary before conclusions can be drawn on the potential for these new anticoagulant drugs to replace warfarin in patients with atrial fibrillation.
PMCID: PMC3161913  PMID: 21794130
Atrial fibrillation; Oral anticoagulants; Antiplatelet drugs; Aspirin; Dabigatran; Rivaroxaban; Apixaban
21.  New Oral Anticoagulants May Be Particularly Useful for Asian Stroke Patients 
Journal of Stroke  2014;16(2):73-80.
Atrial fibrillation (AF) is an emerging epidemic in both high-income and low-income countries, mainly because of global population aging. Stroke is a major complication of AF, and AF-related ischemic stroke is more disabling and more fatal than other types of ischemic stroke. However, because of concerns about bleeding complications, particularly intracranial hemorrhage, and the limitations of a narrow therapeutic window, warfarin is underused. Four large phase III randomized controlled trials in patients with non-valvular AF (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) demonstrated that new oral anticoagulants (NOACs) are superior or non-inferior to warfarin as regards their efficacy in preventing ischemic stroke and systemic embolism, and superior to warfarin in terms of intracranial hemorrhage. Among AF patients receiving warfarin, Asians compared to non-Asians are at higher risk of stroke or systemic embolism and are also more prone to develop major bleeding complications, including intracranial hemorrhage. The extra benefit offered by NOACs over warfarin appears to be greater in Asians than in non-Asians. In addition, Asians are less compliant, partly because of the frequent use of herbal remedies. Therefore, NOACs compared to warfarin may be safer and more useful in Asians than in non-Asians, especially in stroke patients. Although the use of NOACs in AF patients is rapidly increasing, guidelines for the insurance reimbursement of NOACs have not been resolved, partly because of insufficient understanding of the benefit of NOACs and partly because of cost concerns. The cost-effectiveness of NOACs has been well demonstrated in the healthcare settings of developed countries, and its magnitude would vary depending on population characteristics as well as treatment cost. Therefore, academic societies and regulatory authorities should work together to formulate a scientific healthcare policy that will effectively reduce the burden of AF-related stroke in this rapidly aging society.
PMCID: PMC4060270  PMID: 24949312
Atrial fibrillation; Warfarin; Stroke; Intracranial hemorrhage; Asians; New oral anticoagulants
22.  Cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in atrial fibrillation 
Neurology  2012;79(14):1428-1434.
To compare the cost-effectiveness of apixaban vs warfarin for secondary stroke prevention in patients with atrial fibrillation (AF).
Using standard methods, we created a Markov decision model based on the estimated cost of apixaban and data from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and other trials of warfarin therapy for AF. We quantified the cost and quality-adjusted life expectancy resulting from apixaban 5 mg twice daily compared with those from warfarin therapy targeted to an international normalized ratio of 2–3. Our base case population was a cohort of 70-year-old patients with no contraindication to anticoagulation and a history of stroke or TIA from nonvalvular AF.
Warfarin therapy resulted in a quality-adjusted life expectancy of 3.91 years at a cost of $378,500. In comparison, treatment with apixaban led to a quality-adjusted life expectancy of 4.19 years at a cost of $381,700. Therefore, apixaban provided a gain of 0.28 quality-adjusted life-years (QALYs) at an additional cost of $3,200, resulting in an incremental cost-effectiveness ratio of $11,400 per QALY. Our findings were robust in univariate sensitivity analyses varying model inputs across plausible ranges. In Monte Carlo analysis, apixaban was cost-effective in 62% of simulations using a threshold of $50,000 per QALY and 81% of simulations using a threshold of $100,000 per QALY.
Apixaban appears to be cost-effective relative to warfarin for secondary stroke prevention in patients with AF, assuming that it is introduced at a price similar to that of dabigatran.
PMCID: PMC3525294  PMID: 22993279
23.  The safety and adequacy of antithrombotic therapy for atrial fibrillation: a regional cohort study 
Atrial fibrillation is a common problem in older people. The evidence base for the safety of warfarin and aspirin in atrial fibrillation is largely derived from selective research studies and secondary care. Further assessment of the safety of warfarin in older people with atrial fibrillation in routine primary care is needed.
To measure the complication rates and adequacy of warfarin control in a cohort of patients with atrial fibrillation managed in primary care and compare them with published data from controlled trials and community patients with atrial fibrillation not receiving warfarin.
Design of study
Retrospective review of regional cohort.
Twenty-seven general practices in southwest Scotland.
Case note review of 601 patients previously identified as having atrial fibrillation by GPs.
The average age of our cohort was 77 years at recruitment. Two hundred and sixty-four (44%) patients died within 5 years of follow up. Three hundred and nine of the 601 (51%) patients with atrial fibrillation took warfarin at some stage during this study. INR (international normalised ratio) was maintained between 2 and 3 for 68% of the time. Bleeding risk was higher in patients taking warfarin than in those on aspirin or no antithrombotic therapy (warfarin 9.0% per year versus aspirin 4.7% per year versus no therapy 4.6% per year). The annual risk of any bleeding complication on warfarin (9%) was similar to that recorded in randomised trials (9.2%) whereas the annual risk of severe bleeding was approximately double (2.6 versus 1.3%).
Adequacy of anticoagulant control was broadly comparable to that reported in clinical trials, whereas the risk of severe bleeding was higher, possibly reflecting the older age and the comorbidities of our unselected cohort.
PMCID: PMC1876637  PMID: 16954003
anticoagulation; antithrombotic therapy; atrial fibrillation; cohort study
24.  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
25.  Current strategies to minimize the bleeding risk of warfarin 
For many decades, the vitamin K antagonist warfarin has been the mainstay of treatment for various conditions that require anticoagulation, including atrial fibrillation. Although the efficacy of warfarin in both prevention and treatment of thrombosis has been demonstrated in numerous randomized clinical studies, one of the major concerns that remains is the risk of bleeding. Although the net benefit of warfarin has been demonstrated in large clinical trials, physicians and patients alike are often reluctant to use warfarin because of the bleeding risk. Bleeding in patients on warfarin is generally minor requiring no intervention, but the development of a major bleeding complication is associated with significant morbidity and can even be fatal. Numerous risk factors that increase the probability of having a hemorrhage while on warfarin have been identified, and bleeding risk scores have been developed. Various strategies to reduce bleeding risks have been developed and have become more important, since the use of warfarin and other anticoagulants continues to increase. This paper provides a concise review of bleeding risk factors, while outlining recommendations both physician and patients can incorporate to help reduce the risk of bleeding.
PMCID: PMC3760283  PMID: 24019755
hemorrhage; warfarin; thrombosis; anticoagulants; dabigatran; vitamin K antagonist

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