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Original Contribution |

Costs and Effectiveness of Ximelagatran for Stroke Prophylaxis in Chronic Atrial Fibrillation FREE

Cara L. O’Brien, MD; Brian F. Gage, MD, MSc
[+] Author Affiliations

Author Affiliations: Washington University School of Medicine, St Louis, Mo.

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JAMA. 2005;293(6):699-706. doi:10.1001/jama.293.6.699.
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Context Recent trials have found that ximelagatran and warfarin are equally effective in stroke prevention for patients with atrial fibrillation. Because ximelagatran can be taken in a fixed, oral dose without international normalized ratio monitoring and may have a lower risk of hemorrhage, it might improve quality-adjusted survival compared with dose-adjusted warfarin.

Objective To compare quality-adjusted survival and cost among 3 alternative therapies for patients with chronic atrial fibrillation: ximelagatran, warfarin, and aspirin.

Design Semi-Markov decision model.

Patients Hypothetical cohort of 70-year-old patients with chronic atrial fibrillation, varying risk of stroke, and no contraindications to anticoagulation therapy.

Main Outcome Measures Quality-adjusted life-years (QALYs) and costs in US dollars.

Results For patients with atrial fibrillation but no additional risk factors for stroke, both ximelagatran and warfarin cost more than $50 000 per QALY compared with aspirin. For patients with additional stroke risk factors and low hemorrhage risk, ximelagatran modestly increased quality-adjusted survival (0.12 QALY) at a substantial cost ($116 000 per QALY) compared with warfarin. For ximelagatran to cost less than $50 000 per QALY it would have to cost less than $1100 per year or be prescribed to patients who have an elevated risk of intracranial hemorrhage (>1.0% per year of warfarin) or a low quality of life with warfarin therapy.

Conclusion Assuming equal effectiveness in stroke prevention and decreased hemorrhage risk, ximelagatran is not likely to be cost-effective in patients with atrial fibrillation unless they have a high risk of intracranial hemorrhage or a low quality of life with warfarin.

Figures in this Article

The 2.3 million persons in the United States with atrial fibrillation1,2 have a 5-fold increased risk of ischemic stroke.3,4 Randomized controlled trials have found that warfarin reduces the risk of ischemic stroke in atrial fibrillation by 65%.5 However, warfarin is prescribed for only half of patients with atrial fibrillation who are appropriate anticoagulation candidates.68 Warfarin therapy is hampered by drug and food interactions, slow onset of action, requirement of regular monitoring, and individual variability in metabolism.9,10

Ximelagatran, an oral, direct thrombin inhibitor, has been developed to address these shortcomings. Unlike warfarin, ximelagatran has no known food or drug interactions and has a consistent pharmacokinetic profile.1114 Ximelagatran does not therefore require dose adjustment. Recently, 2 large randomized trials showed that ximelagatran is as effective as warfarin in stroke prevention and may cause less bleeding among patients with chronic atrial fibrillation.15,16 However, both trials noted that 6% to 7% of patients taking ximelagatran developed liver function abnormalities and 3 of 6948 participants died with possible liver failure.17

With a more favorable pharmacokinetic profile, equal efficacy in stroke prevention, and probable lower risk of bleeding, ximelagatran may increase quality-adjusted survival compared with warfarin. However, it is unclear whether this improvement justifies the additional cost and offsets rare liver toxicity. In this analysis, we compare the projected quality-adjusted survival and costs of ximelagatran, warfarin, and aspirin in patients with chronic atrial fibrillation.

Decision Model

Using a semi-Markov model,18 we performed a decision analysis comparing 3 treatments: aspirin, adjusted-dose warfarin with an international normalized ratio (INR) of 2 to 3, and fixed-dose ximelagatran (36 mg twice per day) in patients with atrial fibrillation. We expressed our results in terms of risk of adverse events, quality-adjusted life expectancy, 2003 US dollars, and incremental cost-effectiveness ratios. Our base case consisted of a hypothetical cohort of 70-year-old patients with atrial fibrillation, a moderate risk of stroke, and no contraindications to anticoagulant therapy.

The permanent health states in the model included healthy with atrial fibrillation, ischemic stroke (fatal, major, mild, or reversible), transient ischemic attack (TIA), hemorrhage (fatal, intracranial [ICH], or major or minor noncerebral), recurrent or combined events, and death (Figure 1). As described below, utilities and costs were applied to each of the outcomes over their expected duration. For all treatments, we quantified quality-adjusted life expectancy, risk of adverse events, and net cost over a maximum of 20 years.

Figure 1. Semi-Markov Model Showing Possible Transitions Between Permanent Health States
Graphic Jump Location

Patients start out with uncomplicated atrial fibrillation, then cycle between health states until death occurs or the 20-year period ends. The length of each cycle is 30 days. Temporary health states (eg, elevated liver function tests and minor hemorrhages) are not depicted. The health states are equivalent for aspirin, warfarin, and ximelagatran treatment, but the probabilities, costs, and quality of life vary with treatment. Any health state could lead to death, including death from liver failure (not shown).

Probability of Adverse Outcomes in the Decision Model

Mortality rates in the model were adjusted for aging (beginning at age 70 years), presence of atrial fibrillation, and antithrombotic therapy. Median survival was 11.7 years with aspirin, 13.3 years with warfarin, and 13.4 years with ximelagatran.7,1926

Risk of Liver Function Abnormalities. We estimated the rate of elevated liver function test results on ximelagatran to be 1.0% per month for the first 6 months and 0.08% per month subsequently.1517 We assumed that 1 in 2300 patients taking ximelagatran would develop fatal hepatic damage17 and that there would be a monthly 0.035% risk of elevated liver function test results with warfarin15 or aspirin.

Hemorrhage Risk. We quantified hemorrhage risk based on rates in the SPORTIF (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) trials. In our analysis, ICH included hemorrhagic strokes and subdural hematomas. The annual rate of ICH in SPORTIF III and V was 0.4% in participants randomized to receive warfarin (22 ICHs in 5652 patient-years of warfarin).15,16 The rate of major hemorrhage was 2.5% per year of warfarin therapy. Based on the pooled SPORTIF III and V data, the relative risk of major hemorrhage (including ICH) with ximelagatran vs warfarin was 0.74 (95% confidence interval [CI], 0.57-0.97), and the combined rate of major and minor hemorrhages with ximelagatran was 32.0% vs 39.1% with warfarin.15,16

In other randomized trials, the relative risk of major hemorrhage with aspirin compared with warfarin was 0.59.27 In our baseline model, patients who had a major hemorrhage while taking ximelagatran or warfarin stopped the anticoagulant and began aspirin.28

Ischemic Stroke Risk. We quantified stroke risk based on a validated prediction rule, CHADS2, in which stroke rate depends on the presence of the following risk factors: congestive heart failure, hypertension, age older than 75 years, diabetes mellitus, and history of stroke or TIA (Table 1).29,55 In the base case, stroke rates were 52% lower for patients treated with warfarin rather than aspirin,27 and ximelagatran and warfarin had identical stroke rates.15,16 In the base case, we assumed a moderate risk of stroke (4.5% per year with aspirin therapy) and that 28% of neurologic ischemic events were TIAs.3033 The rate of stroke and TIA increased by a factor of 1.4 per decade of life, compounded monthly.21

Table Graphic Jump LocationTable 1a. Model Variables: Base-Case Values and Ranges Used in Sensitivity Analyses

Stroke and Hemorrhage Severity. We classified initial ischemic stroke in 4 categories of severity: fatal, moderate to severe neurologic residua, mild neurologic residua, and no residual deficit (Table 1).3039 Similarly, we classified major hemorrhage as fatal, nonfatal ICH, nonfatal extracranial major hemorrhage, and nonfatal extracranial minor hemorrhage (Table 1).3037,39,5663 Nonfatal extracranial major hemorrhages affected quality of life for 1 month, while ICH had neurologic residua (or was fatal). In the model, minor hemorrhages decreased quality of life for only 2 days.

Quality-of-Life Estimates

To calculate quality-adjusted survival, we multiplied the probabilities of adverse events by quality-of-life estimates, known as utilities (Table 1).45 By definition, death from any cause had a utility of 0. We obtained the utility for warfarin from our previous survey of 83 patients with atrial fibrillation. Seventy of these patients were able to rate their quality of life while taking warfarin, including prothrombin time monitoring and changes in diet or lifestyle, with a mean value of 0.987.45 The average utility of aspirin therapy was 0.998.

To estimate the utility of ximelagatran therapy, we conducted a 1-time e-mail survey of the Anticoagulation-Thromboembolism Research Consortium, a group of approximately 30 physicians involved in antithrombotic clinical management and research, of whom 12 responded. We also surveyed 7 decision-analysts who have published in the area of antithrombotic therapy, of whom 3 responded; 2 of these respondents had usable results. Respondents gave 2 estimates for the utility of ximelagatran, 1 for the first 6 months of therapy (with monthly liver function monitoring) and 1 for subsequent therapy (with liver function monitoring every 3 months). Based on the values of 0.987 for warfarin utility and 0.998 for aspirin utility, respondents recommend a mean utility for ximelagatran of 0.989 (95% CI, 0.986-0.991) during the first 6 months and 0.994 (95% CI, 0.993-0.996) thereafter. For patients who developed liver function abnormalities, 0.002 quality-adjusted life-year (QALY) was subtracted to account for additional blood tests and physician visits.

Costs

For each treatment, we projected net cost over 20 years. Future costs and life-years were discounted at 3% per year. Because we were interested in the incremental cost-effectiveness of one option vs another, rather than absolute costs, we excluded medical costs unrelated to antithrombotic therapy, hemorrhage, or neurological ischemia. Costs reflected the perspective of a health maintenance organization or insurance company that covered inpatient and outpatient medical care and prescription costs but did not pay for indirect costs (eg, lost wages). Costs were expressed in 2003 US dollars.64

Adverse Events. Cost of a minor hemorrhage was based on remuneration for an expanded problem-focused physician visit (Current Procedural Terminology [CPT ] code 99213).49 We estimated the cost of a major extracranial hemorrhage based on Medicare remuneration for the diagnosis-related group associated with gastrointestinal hemorrhage.51 We calculated costs for stroke, TIA, and ICH by using the median value of published studies and Medicare remuneration, and we estimated the cost of fatal hepatic failure (Table 1).5154

Drug Costs. We calculated the $545 annual cost of warfarin therapy by combining its annual prescription cost48 with Medicare reimbursement for 14 INR tests and minimal established patient office visits (CPT code 99211) per year (Table 1).49 In sensitivity analyses, we examined patients initiating warfarin, to whom we added a cost of up to 8 INRs and up to 8 physician visits during the first month based on our experience and recommendations.65

Based on the cost of clopidogrel (average US price, $4.39 per day) and the cost of ximelagatran in Germany (Exanta, AstraZeneca, London, England; €4.50 per day), we estimated the drug cost of ximelagatran to be $5 per day ($1825 per year).48 The total annual cost of ximelagatran therapy included a liver function test50 and minimal established patient office visit on initiation of treatment, then monthly visits and liver function measurements for 6 months. After the initial 6 months of therapy, the cost of ximelagatran included only 1 liver function test and minimal established patient office visits every 2 to 3 months. The cost associated with elevated liver function test results included 2 problem-oriented physician office visits (CPT code 99212)49 and 2 additional liver function tests (Table 1).

Sensitivity Analyses

We performed 1-way sensitivity analyses of the variables in the decision model over their plausible ranges (Table 1). In a 2-way sensitivity analyses analysis, we calculated cost-effectiveness ratios of ximelagatran over combinations of stroke and ICH risk. In first-order Monte Carlo simulations, we randomly sampled (with replacement) 10 000 times a set of utilities from 70 patients we have previously reported on who had atrial fibrillation and usable utility values45 and simulated outcomes using uniform distributions of all variables.

All analyses were performed with SMLTREE.66

Base-Case Analysis

Under base-case conditions, the quality-adjusted life expectancy in 70-year-old atrial fibrillation patients at moderate risk of stroke (4.5% per year of aspirin) and lower risk of ICH (0.4% per year of warfarin) was 9.51 QALYs with ximelagatran therapy, 9.39 QALYs with warfarin therapy, and 8.58 QALYs with aspirin therapy. The use of ximelagatran would yield only 0.12 QALY more than warfarin, at a cost of approximately $116 000 per QALY (Table 2).

Table Graphic Jump LocationTable 2. Projected Costs and QALYs in Patients at Moderate Risk of Stroke and Varying Risk of ICH*
Sensitivity Analyses

We examined how each variable affected quality-adjusted survival and cost for all plausible values (Figure 2). The most influential variables were ICH risk, effectiveness of stroke prophylaxis, risk of hepatic damage from ximelagatran, patient utilities for warfarin, and cost of ximelagatran.

Figure 2. One-Way Sensitivity Analyses on Influential Variables in the Model
Graphic Jump Location

Bars indicate range of cost per additional quality-adjusted life-year (QALY) of ximelagatran compared with warfarin as determined in sensitivity analyses over plausible ranges for variables. Upper and lower limits of variables examined in sensitivity analyses are indicated. Arrows indicate that the cost per QALY exceeds $200 000. INR indicates international normalized ratio.

ICH Risk. As risk of ICH increased, the marginal cost per QALY of ximelagatran compared with warfarin decreased from $116 000 to $44 000 (Table 2). Using $50 000 per additional QALY as a threshold for cost-effectiveness, we found that ximelagatran was cost-effective compared with warfarin for patients with an ICH risk greater than 1% per year of warfarin (Figure 3). If, however, ximelagatran did not reduce the risk of hemorrhage relative to warfarin, then the cost of ximelagatran exceeded $250 000 per QALY compared with warfarin, regardless of hemorrhage risk. In contrast, for patients at high risk of ICH who would otherwise be prescribed aspirin, ximelagatran could improve survival by approximately 0.8 QALY (Table 2), at a cost of $17 400 per QALY.

Figure 3. Two-Way Sensitivity Analysis Showing Which Antithrombotic Therapy Is Cost-effective at Varying Rates of Stroke and Intracranial Hemorrhage
Graphic Jump Location

Above the horizontal line, ximelagatran costs less than $50 000 per quality-adjusted life-year (QALY); below the line, warfarin costs less than $50 000 per QALY. To the left of the nearly vertical line, both of these anticoagulants cost more than $50 000 per QALY but aspirin is cost-effective.

Ischemic Stroke Risk. The cost-effectiveness of ximelagatran was extremely sensitive to its effectiveness: if ximelagatran reduced the relative risk of stroke by greater than 6% vs warfarin, then it would cost less than $50 000 per QALY. Assuming equal effectiveness, for patients with atrial fibrillation with the lowest risks of stroke (0.8% per year of aspirin) and ICH (0.4% per year of warfarin), ximelagatran modestly increased survival (by 0.12 QALY) compared with aspirin, at a cost of $167 000 per QALY. For these low-risk patients, warfarin yielded the fewest QALYs (10.43). For patients with a higher risk of stroke (5.5% per year of aspirin), warfarin cost $1000 or less per QALY compared with aspirin, and ximelagatran cost $9000 per QALY compared with aspirin but more than $100 000 per QALY compared with warfarin.

Hepatic Failure. If only 1 in 10 000 patients initiating ximelagatran developed permanent hepatic failure (rather than our base-case estimate of 1 in 2300), then the cost per QALY of ximelagatran compared with warfarin would be $82 290. Even if none of the patients taking ximelagatran develop permanent hepatic failure, the cost per QALY of ximelagatran compared with warfarin would slightly exceed $75 000.

Patient Utility. In 58 of 70 patients we previously surveyed,45 ximelagatran cost greater than $50 000 per QALY gained compared with either aspirin or warfarin therapy. In these patients, the average utility for warfarin was 0.996 (range, 0.97-1.00). The 12 patients whose cost per additional QALY for ximelagatran was less than $50 000 compared with warfarin had a median utility for warfarin of 0.954 (range, 0.50-0.96).

Monitoring. If the cost of performing an INR test was only $5 or if only 6 INRs per year were required to monitor warfarin therapy, then ximelagatran would cost approximately $140 000 per QALY gained vs warfarin. If the INR test cost $50 or if 24 INRs per year were required, then ximelagatran would cost approximately $70 000 per QALY gained. Neither cost nor frequency of liver function monitoring had a significant impact on cost-effectiveness.

Age. We considered patients aged 65 to 90 years. The quality-adjusted survival of a 65-year-old patient was 11.1 years with ximelagatran, and the cost per QALY with ximelagatran vs warfarin was $100 020. The quality-adjusted survival of a 90-year-old was only 3.49 years with ximelagatran, 3.47 years with warfarin, and 3.34 years with aspirin. In nonagenarians, ximelagatran cost more than $150 000 per QALY compared with warfarin, and warfarin cost $8400 per QALY compared with aspirin.

Costs. The costs and utilities of adverse events, including major and minor stroke, major and minor hemorrhage, TIA, liver failure, and elevation of liver function parameters did not significantly affect cost-effectiveness. In contrast, ximelagatran would cost less than $50 000 per QALY compared with warfarin if its annual price was less than $1100 and less than $75 000 per QALY if its annual price was $1300 or less.

2- and 3-Way Sensitivity Analyses. We examined 2- and 3-way sensitivity analyses of key variables. These analyses confirmed that low stroke rates favored aspirin therapy and that high ICH risks favored ximelagatran (Figure 3). The most important 3-way sensitivity analysis corroborated the relevance of variability in utilities for patients at moderate risk of stroke (4.5% per year of aspirin) and high ICH risk (1.2% per year of warfarin). On average, ximelagatran was cost-effective ($44 000 per QALY) in these patients (Figure 3), but when we examined the 70 patients whom we previously surveyed,45 ximelagatran cost $75 000 or less per QALY in 44 of them; the other 26 had high utilities for warfarin.

To assess the combined effect of the precision of the model variables, we compared ximelagatran with warfarin in Monte Carlo simulations. In the base case, ximelagatran had a greater quality-adjusted survival 49% of the time and warfarin was better 51% of the time. For patients with a higher ICH risk, ximelagatran had a greater quality-adjusted survival 52% of the time.

We found that switching therapy for a patient with atrial fibrillation and low bleeding risk from warfarin to ximelagatran would increase survival modestly (0.12 QALY) at a substantial cost. In the base case, the cost per QALY gained would be $116 000, which exceeds the usual limits for a cost-effective therapy.67 However, in sensitivity analyses, we identified 2 important subgroups of patients with atrial fibrillation for whom ximelagatran would be cost-effective: patients whose utility for warfarin was low (<0.97) and patients whose risk of ICH was greater than 1.0% per year. For these patients, ximelagatran is likely to cost less than $50 000 per QALY.

Previous work has shown that the major risk factors for ICH are hypertension, tobacco use, high fall risk, advanced age, prior stroke, prior bleeding, white-matter hyperintensities (leukoaraiosis) on brain imaging, and neuropsychiatric impairment (eg, dementia).6770 Patients with 2 or more of these risk factors are likely to have an ICH risk exceeding 1% per year of warfarin therapy.71 In these patients, ximelagatran would be cost-effective compared with warfarin (assuming that ximelagatran does reduce the risk of ICH compared with warfarin). Presently, many patients with these factors take aspirin (or avoid antithrombotic therapy),8 and they have the greatest potential gain from ximelagatran—almost 1.0 QALY compared with aspirin therapy.

Estimating the risk of ICH is one way clinicians could identify patients who may derive benefit from ximelagatran. Quantifying the utility of warfarin is another way. In patients with a low risk of ICH, ximelagatran was cost-effective in 12 (17%) of 70 patients, all of whom rated the utility of warfarin to be less than 0.97. Clinicians could estimate their patients’ preferences qualitatively or quantify them formally using the standard gamble, the time-tradeoff method,45 or a decision aid.72,73

Although risk of ICH and patient preference for warfarin were key determinants of the tradeoff between ximelagatran and warfarin, patient stroke risk was relatively unimportant, except that at the lowest stroke rate, neither anticoagulant was cost-effective compared with aspirin. At all other stroke rates, warfarin and ximelagatran were cost-effective compared with aspirin.

The cost-effectiveness of ximelagatran was sensitive to the effectiveness of ximelagatran vs warfarin in stroke prevention (Figure 2). Taken together, SPORTIF III and V found equal stroke rates in patients with atrial fibrillation randomized to receive either ximelagatran or warfarin.15,16 Thus, we assumed equal effectiveness in the decision model. Individually, however, the 2 trials had conflicting results. In SPORTIF III, ximelagatran had a 29% lower rate of ischemic stroke or systemic embolism15; in SPORTIF V, which was double-blind, warfarin had a 28% lower rate of ischemic stroke or systemic embolism.16 In sensitivity analysis, if ximelagatran reduced the rate of ischemic stroke by more than 6% vs warfarin, as is possible with poor warfarin management, then ximelagatran would cost less than $50 000 per year.

The probability of permanent hepatic failure during ximelagatran use also significantly affected cost and benefits. Three possible hepatic deaths of 6948 ximelagatran-treated patients have been reported from clinical trials.17 However, trial participants were ideal candidates for ximelagatran therapy—patients with known liver disease were excluded. In clinical practice, where patients are less carefully selected and monitored, the risk of liver failure is probably greater.

Ximelagatran has been approved for use in several European countries (primarily for short-term use in the prevention of venous thromboembolism in orthopedic surgery) but was denied US Food and Drug Administration (FDA) approval in October 2004. After reviewing the SPORTIF trials and other data, the FDA Advisory Committee concluded that the risks of ximelagatran outweigh the benefits.74 We found that ximelagatran could improve the quality-adjusted survival of patients who had a low utility for warfarin or a high bleeding risk at an acceptable cost, but this assumes that it is prescribed only in patients with low risk of hepatotoxicity and is carefully monitored. Not only would patients with alcoholism or liver disease need to avoid ximelagatran, but so would patients with impaired renal function because the active metabolites of ximelagatran are renally cleared.

Our analysis has a number of important potential limitations. The efficacies used in the base case are based on randomized, controlled clinical trials in which compliance, monitoring, and follow-up are better than in general clinical practice. Therefore, we may have overestimated the benefits of both anticoagulants, because lapses in compliance are common, especially among the very elderly.75 Additionally, because ximelagatran has a shorter half-life than warfarin or aspirin, noncompliant patients taking ximelagatran may be especially susceptible to lapses in adherence. A final limitation is our extrapolation of results from clinical trials lasting only 1 to 3 years. Rates of adverse events may vary over the long term.

In conclusion, although we found that ximelagatran can increase quality-adjusted survival compared with warfarin, the increment is modest in patients at low risk of ICH. At a price of $1700 per year or greater, ximelagatran would cost more than $100 000 per QALY compared with warfarin in patients with atrial fibrillation who have a moderate risk of stroke and low ICH risk. Our study yielded these findings despite assuming equal effectiveness in stroke prevention and a decreased ICH risk with ximelagatran therapy over 20 years. Unless ximelagatran costs less than $1100 per year, it will be cost-effective only in patients with very low utility for warfarin (<0.97) or in patients at high risk of ICH. If additional randomized trials with ximelagatran are conducted in the atrial fibrillation population, they should preferentially recruit these populations.

Corresponding Author: Brian F. Gage, MD, MSc, General Medical Sciences, Washington University School of Medicine, Campus Box 8005, 660 S Euclid Ave, St Louis, MO 63110 (bgage@im.wustl.edu).

Author Contributions: Drs O’Brien and Gage had full access to their Markov model and the data they collected and had access to summary data from the SPORTIF trials. Both authors take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: O’Brien, Gage.

Acquisition of data: O’Brien, Gage.

Analysis and interpretation of data: O’Brien, Gage.

Drafting of the manuscript: O’Brien, Gage.

Critical revision of the manuscript for important intellectual content: O’Brien, Gage.

Statistical analysis: O’Brien, Gage.

Obtained funding: Gage.

Study supervision: Gage.

Financial Disclosures: None reported.

Funding/Support: This study was supported by Agency for Healthcare Research and Quality grant R01 HS10133 and by the Aetna Quality Care Research Fund.

Role of the Sponsors: The study’s sponsors had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript.

Acknowledgment: We thank Deepak Voora, MD, and Paul Milligan, RPh, who critiqued an early version of the manuscript.

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Dries D, Exner D, Gersh B, Domanski M, Waclawiw M, Stevenson L. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials.  J Am Coll Cardiol. 1998;32:695-703
PubMed   |  Link to Article
Wyse DG, Love JC, Yao Q.  et al.  Atrial fibrillation: a risk factor for increased mortality—an AVID registry analysis.  J Interv Card Electrophysiol. 2001;5:267-273
PubMed   |  Link to Article
Dennis MS, Burn JPS, Sandercock PAG, Bamford JM, Wade DT, Warlow C. Long-term survival after first-ever stroke: the Oxfordshire community stroke project.  Stroke. 1993;24:796-800
PubMed   |  Link to Article
Antithrombotic Trialists' Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;324:71-86
PubMed   |  Link to Article
Miniño A, Arias E, Kochanek K, Murphy S, Smith B. Deaths: final data for 2000.  Natl Vital Stat Rep. 2002;50:1-119
PubMed
van Walraven C, Hart RG, Singer DE.  et al.  Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis.  JAMA. 2002;288:2441-2448
PubMed   |  Link to Article
Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.  Stroke. 2003;34:1710-1716
PubMed   |  Link to Article
Gage BF, van Walraven C, Pearce L.  et al.  Selecting patients with atrial fibrillation for anticoagulation: validation of risk stratification schemes.  Circulation. 2004;110:2287-2292
Link to Article
Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study.  Lancet. 1989;1:175-179
PubMed   |  Link to Article
Gullov AL, Koefoed BG, Petersen P.  et al.  Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.  Arch Intern Med. 1998;158:1513-1521
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.  Lancet. 1994;343:687-691
PubMed
Stroke Prevention in Atrial Fibrillation Investigators.  Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.  Lancet. 1996;348:633-638
PubMed   |  Link to Article
Hellemons BS, Langenberg M, Lodder J.  et al.  Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin.  BMJ. 1999;319:958-964
PubMed   |  Link to Article
The European Atrial Fibrillation Trial Study Group.  Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.  Lancet. 1993;342:1255-1262
PubMed
Connolly SJ. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study.  J Am Coll Cardiol. 1991;18:349-355
PubMed   |  Link to Article
Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators.  The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.  N Engl J Med. 1990;323:1505-1511
PubMed   |  Link to Article
Hylek EM, Go AS, Chang Y.  et al.  Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.  N Engl J Med. 2003;349:1019-1026
PubMed   |  Link to Article
Ezekowitz MD, Bridgers SL, James KE.  et al.  Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation.  N Engl J Med. 1992;327:1406-1412
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Stroke Prevention in Atrial Fibrillation (SPAF) Study: final results.  Circulation. 1991;84:527-539
PubMed   |  Link to Article
Gage BF, Yan Y, Milligan PE.  et al.  Validation of clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation.  Am Heart JIn press
Evans A, Kalra L. Are the results of randomized controlled trials on anticoagulation in patients with atrial fibrillation generalizable to clinical practice?  Arch Intern Med. 2001;161:1443-1447
PubMed   |  Link to Article
Copland M, Walker ID, Tait RC. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation.  Arch Intern Med. 2001;161:2125-2128
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Bleeding during antithrombotic therapy in patients with atrial fibrillation.  Arch Intern Med. 1996;156:409-416
PubMed   |  Link to Article
Gage BF, Cardinalli AB, Owens D. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life.  Arch Intern Med. 1996;156:1829-1836
PubMed   |  Link to Article
Thomson R, Parkin D, Eccles M, Sudlow M, Robinson A. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation.  Lancet. 2000;355:956-962
PubMed   |  Link to Article
Fryback DG, Dasbach EJ, Klein R.  et al.  The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors.  Med Decis Making. 1993;13:89-102
PubMed   |  Link to Article
 2003 Drug Topics Red Book10th ed. Montvale, NJ: Thomson PDR; 2003
 Coaguchek Systems 2003 Medicare Reimbursement Handbook for Health Care ProfessionalsIndianapolis, Ind: Roche Diagnostics; 2003
Gyrd-Hansen D. Willingness to pay for a QALY.  Health Econ. 2003;12:1049-1060
PubMed   |  Link to Article
Agency for Healthcare Research and Quality.  HCUPnet, healthcare cost and utilization. Available at: http://hcup.ahrq.gov/HCUPnet.asp. Accessed January 14, 2003, 2004
Leibson CL, Hu T, Brown RD, Hass SL, O'Fallon WM, Whisnant JP. Utilization of acute care services in the year before and after first stroke: a population-based study.  Neurology. 1996;46:861-869
PubMed
Holloway RG, Witter DM Jr, Lawton KB, Lipscomb J, Samsa G. Inpatient costs of specific cerebrovascular events at five academic medical centers.  Neurology. 1996;46:854-860
PubMed   |  Link to Article
Matchar DB, Samsa GP. Secondary and Tertiary Prevention of Stroke: Patient Outcomes Research Team (PORT) Final Report—Phase 1. Rockville, Md: Agency for Healthcare Research and Quality; 2000. AHRQ publication 00-N0001
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford M. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.  JAMA. 2001;285:2864-2870
PubMed   |  Link to Article
Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study: Atrial Fibrillation Aspirin and Anticoagulation.  Arch Intern Med. 1999;159:1322-1328
PubMed   |  Link to Article
Wehinger C, Stollberger C, Langer T, Schneider B, Finsterer J. Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation.  Stroke. 2001;32:2246-2252
PubMed   |  Link to Article
Palareti G, Leali N, Coccheri S.  et al.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT).  Lancet. 1996;348:423-428
PubMed   |  Link to Article
Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White R. The risk for and severity of bleeding complications in elderly patients treated with warfarin: the National Consortium of Anticoagulation Clinics.  Ann Intern Med. 1996;124:970-979
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Casais P, Luceros AS, Meschengieser S, Fondevila C, Santarelli MT, Lazzari MA. Bleeding risk factors in chronic oral anticoagulation with acenocoumarol.  Am J Hematol. 2000;63:192-196
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Gitter MJ, Jaeger TM, Petterson TM, Gersh BJ, Silverstein MD. Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota.  Mayo Clin Proc. 1995;70:725-733
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Gorter JW.European Atrial Fibrillation Trial (EAFT) Study Groups.  Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors: Stroke Prevention In Reversible Ischemia Trial (SPIRIT).  Neurology. 1999;53:1319-1327
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Launbjerg J, Egeblad H, Heaf J, Nielsen NH, Fugleholm AM, Ladefoged K. Bleeding complications to oral anticoagulant therapy: multivariate analysis of 1010 treatment years in 551 outpatients.  J Intern Med. 1991;229:351-355
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Ariesen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in the general population: a systematic review.  Stroke. 2003;34:2060-2065
PubMed   |  Link to Article
Lee SH, Bae HJ, Kwon SJ.  et al.  Cerebral microbleeds are regionally associated with intracerebral hemorrhage.  Neurology. 2004;62:72-76
PubMed   |  Link to Article
Beyth RJ, Milligan PE, Gage BF. Risk factors for bleeding in patients taking coumarins.  Curr Hematol Rep. 2002;1:41-49
PubMed
Gage BF, Birman-Deych E, Kerzner R, Radford MJ, Nilasena DS, Rich MW. Incidence of intracranial hemorrhage and the role of warfarin in patients with atrial fibrillation who are prone to fall.  Am J MedIn press
Man-Son-Hing M, Laupacis A, O’Connor AM.  et al.  A patient decision aid regarding antithrombotic therapy for stroke prevention in atrial fibrillation: a randomized controlled trial.  JAMA. 1999;282:737-743
PubMed   |  Link to Article
Johnston JA, Eckman MH. Use of regression modeling to simulate patient-specific decision analysis for patients with nonvalvular atrial fibrillation.  Med Decis Making. 2003;23:361-368
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Figures

Figure 1. Semi-Markov Model Showing Possible Transitions Between Permanent Health States
Graphic Jump Location

Patients start out with uncomplicated atrial fibrillation, then cycle between health states until death occurs or the 20-year period ends. The length of each cycle is 30 days. Temporary health states (eg, elevated liver function tests and minor hemorrhages) are not depicted. The health states are equivalent for aspirin, warfarin, and ximelagatran treatment, but the probabilities, costs, and quality of life vary with treatment. Any health state could lead to death, including death from liver failure (not shown).

Figure 2. One-Way Sensitivity Analyses on Influential Variables in the Model
Graphic Jump Location

Bars indicate range of cost per additional quality-adjusted life-year (QALY) of ximelagatran compared with warfarin as determined in sensitivity analyses over plausible ranges for variables. Upper and lower limits of variables examined in sensitivity analyses are indicated. Arrows indicate that the cost per QALY exceeds $200 000. INR indicates international normalized ratio.

Figure 3. Two-Way Sensitivity Analysis Showing Which Antithrombotic Therapy Is Cost-effective at Varying Rates of Stroke and Intracranial Hemorrhage
Graphic Jump Location

Above the horizontal line, ximelagatran costs less than $50 000 per quality-adjusted life-year (QALY); below the line, warfarin costs less than $50 000 per QALY. To the left of the nearly vertical line, both of these anticoagulants cost more than $50 000 per QALY but aspirin is cost-effective.

Tables

Table Graphic Jump LocationTable 1a. Model Variables: Base-Case Values and Ranges Used in Sensitivity Analyses
Table Graphic Jump LocationTable 2. Projected Costs and QALYs in Patients at Moderate Risk of Stroke and Varying Risk of ICH*

References

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PubMed   |  Link to Article
Dries D, Exner D, Gersh B, Domanski M, Waclawiw M, Stevenson L. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials.  J Am Coll Cardiol. 1998;32:695-703
PubMed   |  Link to Article
Wyse DG, Love JC, Yao Q.  et al.  Atrial fibrillation: a risk factor for increased mortality—an AVID registry analysis.  J Interv Card Electrophysiol. 2001;5:267-273
PubMed   |  Link to Article
Dennis MS, Burn JPS, Sandercock PAG, Bamford JM, Wade DT, Warlow C. Long-term survival after first-ever stroke: the Oxfordshire community stroke project.  Stroke. 1993;24:796-800
PubMed   |  Link to Article
Antithrombotic Trialists' Collaboration.  Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ. 2002;324:71-86
PubMed   |  Link to Article
Miniño A, Arias E, Kochanek K, Murphy S, Smith B. Deaths: final data for 2000.  Natl Vital Stat Rep. 2002;50:1-119
PubMed
van Walraven C, Hart RG, Singer DE.  et al.  Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis.  JAMA. 2002;288:2441-2448
PubMed   |  Link to Article
Eckman MH, Rosand J, Knudsen KA, Singer DE, Greenberg SM. Can patients be anticoagulated after intracerebral hemorrhage? a decision analysis.  Stroke. 2003;34:1710-1716
PubMed   |  Link to Article
Gage BF, van Walraven C, Pearce L.  et al.  Selecting patients with atrial fibrillation for anticoagulation: validation of risk stratification schemes.  Circulation. 2004;110:2287-2292
Link to Article
Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK Study.  Lancet. 1989;1:175-179
PubMed   |  Link to Article
Gullov AL, Koefoed BG, Petersen P.  et al.  Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study.  Arch Intern Med. 1998;158:1513-1521
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study.  Lancet. 1994;343:687-691
PubMed
Stroke Prevention in Atrial Fibrillation Investigators.  Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial.  Lancet. 1996;348:633-638
PubMed   |  Link to Article
Hellemons BS, Langenberg M, Lodder J.  et al.  Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin.  BMJ. 1999;319:958-964
PubMed   |  Link to Article
The European Atrial Fibrillation Trial Study Group.  Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.  Lancet. 1993;342:1255-1262
PubMed
Connolly SJ. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study.  J Am Coll Cardiol. 1991;18:349-355
PubMed   |  Link to Article
Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators.  The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.  N Engl J Med. 1990;323:1505-1511
PubMed   |  Link to Article
Hylek EM, Go AS, Chang Y.  et al.  Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation.  N Engl J Med. 2003;349:1019-1026
PubMed   |  Link to Article
Ezekowitz MD, Bridgers SL, James KE.  et al.  Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation.  N Engl J Med. 1992;327:1406-1412
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Stroke Prevention in Atrial Fibrillation (SPAF) Study: final results.  Circulation. 1991;84:527-539
PubMed   |  Link to Article
Gage BF, Yan Y, Milligan PE.  et al.  Validation of clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation.  Am Heart JIn press
Evans A, Kalra L. Are the results of randomized controlled trials on anticoagulation in patients with atrial fibrillation generalizable to clinical practice?  Arch Intern Med. 2001;161:1443-1447
PubMed   |  Link to Article
Copland M, Walker ID, Tait RC. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation.  Arch Intern Med. 2001;161:2125-2128
PubMed   |  Link to Article
Stroke Prevention in Atrial Fibrillation Investigators.  Bleeding during antithrombotic therapy in patients with atrial fibrillation.  Arch Intern Med. 1996;156:409-416
PubMed   |  Link to Article
Gage BF, Cardinalli AB, Owens D. The effect of stroke and stroke prophylaxis with aspirin or warfarin on quality of life.  Arch Intern Med. 1996;156:1829-1836
PubMed   |  Link to Article
Thomson R, Parkin D, Eccles M, Sudlow M, Robinson A. Decision analysis and guidelines for anticoagulant therapy to prevent stroke in patients with atrial fibrillation.  Lancet. 2000;355:956-962
PubMed   |  Link to Article
Fryback DG, Dasbach EJ, Klein R.  et al.  The Beaver Dam Health Outcomes Study: initial catalog of health-state quality factors.  Med Decis Making. 1993;13:89-102
PubMed   |  Link to Article
 2003 Drug Topics Red Book10th ed. Montvale, NJ: Thomson PDR; 2003
 Coaguchek Systems 2003 Medicare Reimbursement Handbook for Health Care ProfessionalsIndianapolis, Ind: Roche Diagnostics; 2003
Gyrd-Hansen D. Willingness to pay for a QALY.  Health Econ. 2003;12:1049-1060
PubMed   |  Link to Article
Agency for Healthcare Research and Quality.  HCUPnet, healthcare cost and utilization. Available at: http://hcup.ahrq.gov/HCUPnet.asp. Accessed January 14, 2003, 2004
Leibson CL, Hu T, Brown RD, Hass SL, O'Fallon WM, Whisnant JP. Utilization of acute care services in the year before and after first stroke: a population-based study.  Neurology. 1996;46:861-869
PubMed
Holloway RG, Witter DM Jr, Lawton KB, Lipscomb J, Samsa G. Inpatient costs of specific cerebrovascular events at five academic medical centers.  Neurology. 1996;46:854-860
PubMed   |  Link to Article
Matchar DB, Samsa GP. Secondary and Tertiary Prevention of Stroke: Patient Outcomes Research Team (PORT) Final Report—Phase 1. Rockville, Md: Agency for Healthcare Research and Quality; 2000. AHRQ publication 00-N0001
Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford M. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation.  JAMA. 2001;285:2864-2870
PubMed   |  Link to Article
Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study: Atrial Fibrillation Aspirin and Anticoagulation.  Arch Intern Med. 1999;159:1322-1328
PubMed   |  Link to Article
Wehinger C, Stollberger C, Langer T, Schneider B, Finsterer J. Evaluation of risk factors for stroke/embolism and of complications due to anticoagulant therapy in atrial fibrillation.  Stroke. 2001;32:2246-2252
PubMed   |  Link to Article
Palareti G, Leali N, Coccheri S.  et al.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT).  Lancet. 1996;348:423-428
PubMed   |  Link to Article
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