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Background

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.

Objective

To quantify the net clinical benefit of warfarin therapy in a cohort of patients with atrial fibrillation.

Design

Mixed retrospective and prospective cohort study of patients with atrial fibrillation between 1996 and 2003.

Setting

An integrated health care delivery system.

Patients

13559 adults with nonvalvular atrial fibrillation.

Measurements

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.

Results

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.

Limitations

Residual confounding is a possibility. Some outcome events were probably missed by the screening algorithm or when medical records were unavailable.

Conclusion

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.

Background

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.

Conclusions

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.

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.

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Objective

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).

Methods

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).

Results

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.

Conclusions

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.

Objectives

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.

Results

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.

Conclusions

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.

Background

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.

Background

Randomized trials and observational studies support using an international normalized ratio (INR) target of 2.0 to 3.0 for preventing ischemic stroke in atrial fibrillation (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.

Conclusions

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.

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

Background

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.

Objectives

To examine the patterns of warfarin use and their relationship with stroke and bleeding in atrial fibrillation patients in community-based primary care practices.

Design

Retrospective longitudinal cohort study.

Participants

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.

Results

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.

Conclusion

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.

Background

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.

Design

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.

Discussion

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

Background

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.

Methods

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.

Results

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.

Conclusions

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.

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.

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.

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.

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.

Background

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.

Aim

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.

Setting

Twenty-seven general practices in southwest Scotland.

Method

Case note review of 601 patients previously identified as having atrial fibrillation by GPs.

Results

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%).

Conclusion

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.

Objective

Warfarin is a medication commonly prescribed to prevent strokes associated with certain medical conditions such as atrial fibrillation; however, little is known about how people taking warfarin perceive the goal of therapy and how they describe strokes. We assessed the stroke-related health literacy of anticoagulated patients to inform ways in which to improve health communication among people taking warfarin.

Methods

We conducted a mixed-methods study of an ethnically and linguistically diverse sample of people taking warfarin to prevent stroke (N=183) and measured literacy using the short-form Test of Functional Health Literacy in Adults. We asked participants to (1) describe their indication for warfarin, and (2) describe a stroke. Transcribed answers were coded as concordant or discordant with established indications for warfarin and definitions of stroke.

Results

Forty-three percent of participants provided a discordant response when describing their indication for warfarin. Only 9.3% reported that the purpose of taking warfarin was to prevent stroke. Not speaking English [OR = 2.4 (1.1–5.6)] and less than a college education [OR = 3.3 (1.4–7.3)] were independently associated with discordant answers about warfarin. Nearly 40% of subjects had inaccurate perceptions of stroke, and only one-third of subjects described a symptom or sign of stroke. Among English and Spanish-speaking participants, inadequate literacy was strongly associated with discordant responses about stroke [OR = 5.8 (2.1–15.6)].

Conclusion

Among high risk people taking warfarin to prevent stroke, significant gaps in stroke-related health literacy exist. These gaps likely represent mismatches in the ways clinicians teach and patients learn.

Practice implications

Since stroke risk awareness and early recognition of the signs and symptoms of stroke are critical aspects of stroke prevention and treatment, clinicians should more strongly link warfarin therapy to stroke prevention and ensure that patients know the presenting symptoms and signs of stroke. Public health communication strategies regarding stroke prevention need to target individuals with limited literacy and limited English proficiency.

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.

Atrial fibrillation (AF) is strongly associated with cardioembolic stroke, and thromboprophylaxis is an established means of reducing stroke risk in patients with AF. Oral vitamin K antagonists such as warfarin have been the mainstay of therapy for stroke prevention in patients with AF. However, they are associated with a number of limitations, including excessive bleeding when not adequately controlled. Antiplatelet agents do not match vitamin K antagonists in terms of their preventive efficacy. Dual-antiplatelet therapy (clopidogrel and acetylsalicylic acid) or combined antiplatelet–vitamin K antagonist therapy in AF has also failed to provide convincing evidence of their additional benefit over vitamin K antagonists alone. Novel oral anticoagulants, including the direct thrombin inhibitor dabigatran and direct Factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban, have now been approved or are currently in late-stage clinical development in AF. These newer agents may provide a breakthrough in the optimal management of stroke risk.

The aim of the study was to assess the extent to which published recommendations on the antithrombotic management of atrial fibrillation had been adopted into clinical practice in a busy district general hospital, and the impact of clinical audit on subsequent management. In the initial audit, 185 consecutive patients with atrial fibrillation were studied using their case notes to identify any further clinical risk factors for stroke. A management algorithm stratified patients with atrial fibrillation into high, moderate, or low risk of stroke according to the individual stroke risk factors. For patients at high risk, the correct treatment is warfarin unless there are specific contraindications. For patients at moderate risk, the correct management is aspirin unless there are specific contraindications. Patients at low risk should receive no thromboprophylaxis. The clinical risks of stroke and thromboprophylaxis on discharge from hospital were recorded. An extensive education programme on stroke prevention in atrial fibrillation was undertaken. Six months later a further 185 consecutive patients with atrial fibrillation were audited. Overall, a large proportion (306/370; 83%) of patients were at high risk of stroke. In the initial audit, antithrombotic management was correct in 89 patients (48%). In the follow up audit, antithrombotic management was correct in 135 patients (73%) (p < 0.00001). If this improvement in management were extrapolated to all hospital patients in the United Kingdom, approximately 1400 strokes/year could be avoided. Despite broad consensus in recent publications, antithrombotic management of atrial fibrillation remains imperfect, with many patients exposed to unnecessarily high risk of stroke.


Keywords: atrial fibrillation; anticoagulation

Background:

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.

Methods:

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).

Results:

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.

Interpretation:

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.

Antithrombotics have been shown to decrease the risk of stroke in patients with atrial fibrillation (AF). However they are associated with an increased risk of bleeding. We assessed the frequency and appropriateness of antithrombotic therapy in patients admitted to our service with stroke and AF. A retrospective case study of 219 patients (mean age 77.2 years) admitted between January 1999 and 31 December 2001 with a diagnosis of stroke and AF was done. Patient characteristics, presence of comorbid conditions, knowledge of preadmission AF, medication history and appropriateness of antithrombotic treatment were recorded. One hundred and fifty patients were known to have had AF prior to admission. Forty-one presented with an intracranial hemorrhage (19 on warfarin, 10 on aspirin). Of those patients with known AF only 43 were on treatment consistent with the guidelines. Warfarin was recommended in 144 of the whole cohort, but only 39 were taking it. Fifty-three patients were receiving aspirin although warfarin was the recommended treatment. Fifty-four with known AF were not on any antithrombotic treatment. Factors significantly associated with the use of antithrombotic treatment were history of AF (p = 0.0004), valvular heart disease (p = 0.02), venous thromboembolism (p = 0.04), risk of thromboembolism (p = 0.003) and presentation with a nonischemic infarct (p = 0.008). Antithrombotic therapy use in our patients differs significantly from guideline recommendations.

Nonvalvular atrial fibrillation is an increasingly common condition. It may cause disabling symptoms and is an important risk factor for stroke. The goals of treatment include the relief and prevention of rate- and rhythm-related symptoms and the prevention of stroke and systemic emboli. Three principal treatments should be considered: pharmacologic rate control, cardioversion and antiarrhythmic therapy to restore and maintain sinus rhythm, and prophylactic anticoagulation or antiplatelet therapy to reduce the risk of stroke. The risks and benefits of each of these therapies have been reviewed. Symptoms, if present, can often be managed safely with rate-directed therapy alone. Until issues regarding safety and long-term efficacy are resolved, cardioversion and antiarrhythmic therapy should be limited to those patients whose symptoms cannot otherwise be controlled. The benefits of warfarin anticoagulation for the primary and secondary prevention of stroke in nonvalvular atrial fibrillation have been demonstrated convincingly by several randomized clinical trials. These benefits must be weighed against the real risk of major hemorrhage. For patients at low risk of stroke, the use of aspirin may be an acceptable alternative to warfarin sodium therapy.

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Opinion statement

Atrial fibrillation (AF) is the most common cardiac arrhythmia in the elderly, affecting 1 in 20 adults over the age of 70 years. Stroke is a major yet highly preventable complication of AF, and the strokes related to AF often are disabling and fatal. Warfarin is the treatment of choice in high-risk patients with AF, and its superior efficacy over aspirin for preventing stroke in these patients is widely recognized. However, several eligible patients with AF are not being treated with warfarin or are being treated inadequately, largely because of concerns regarding the attendant strict monitoring, drug interactions, and risk of major bleeding. As such, alternative antithrombotic therapies that can rival or exceed the efficacy of warfarin, yet compare favorably with its administration and side effect profile, are being sought. One such strategy, the use of a combination antiplatelet regimen, for stroke prevention in high-risk patients with nonvalvular AF was investigated recently in two clinical trials. This article reviews the role of combination antiplatelet regimens in stroke prevention for patients with AF. Other therapies discussed include oral anticoagulation, single antiplatelet therapies, oral anticoagulation plus antiplatelet treatment, direct thrombin inhibitors, and factor Xa inhibitors.

Atrial fibrillation is the most common cardiac arrhythmias, and a major cause of morbidity and mortality due to cardioembolic stroke. The left atrial appendage is the major site of thrombus formation in non-valvular atrial fibrillation. Loss of atrial systole in atrial fibrillation and increased relative risk of associated stroke point strongly toward a role for stasis of blood in left atrial thrombosis, although thrombus formation is multifactorial, and much more than blood flow irregularities are implicated. Oral anticoagulation with vitamin-K-antagonists is currently the most effective prophylaxis for stroke in atrial fibrillation. Unfortunately, this treatment is often contraindicated, particularly in the elderly, in whom risk of stroke is high. Moreover, given the risk of major bleeding, there is reason to be skeptical of the net benefit when warfarin is used in those patients. This work reviews the pathophysiology of cardioembolic stroke and critically spotlights the current status of preventive anticoagulation therapy. Various techniques to exclude the left atrial appendage from circulation were discussed as a considerable alternative for stroke prophylaxis.