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

The 2.3 million persons in the United States with atrial fibrillation^1- 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.^6- 8 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.^11- 14 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.

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.

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.^7,19- 26

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.^15- 17 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.^30- 33 The rate of stroke and TIA increased by a factor of 1.4 per decade of life, compounded monthly.²¹

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).^30- 39 Similarly, we classified major hemorrhage as fatal, nonfatal ICH, nonfatal extracranial major hemorrhage, and nonfatal extracranial minor hemorrhage (Table 1).^{30- 37,39,56- 63} 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.

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.

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).^51- 54

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).

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

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).

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.

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.

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).^67- 70 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.