Dr. Coleman has received research funding from Janssen Pharmaceuticals Inc. and is a member of their Speaker's Bureau. No other authors have any conflicts of interest to report.
Conceived and designed the experiments: SL CC. Performed the experiments: SL RM JB CC. Analyzed the data: SL RM JB CC. Contributed reagents/materials/analysis tools: SL RM JB CC. Wrote the paper: SL RM CC.
Apixaban was shown to be superior to adjusted-dose warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation (AF) and at least one additional risk factor for stroke, and associated with reduced rates of hemorrhage. We sought to determine the cost-effectiveness of using apixaban for stroke prevention.
Based on the results from the Apixaban Versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial and other published studies, we constructed a Markov model to evaluate the cost-effectiveness of apixaban versus warfarin from the Medicare perspective. The base-case analysis assumed a cohort of 65-year-old patients with a CHADS2 score of 2.1 and no contraindication to oral anticoagulation. We utilized a 2-week cycle length and a lifetime time horizon. Outcome measures included costs in 2012 US$, quality-adjusted life-years (QALYs), life years saved and incremental cost-effectiveness ratios.
Under base case conditions, quality adjusted life expectancy was 10.69 and 11.16 years for warfarin and apixaban, respectively. Total costs were $94,941 for warfarin and $86,007 for apixaban, demonstrating apixaban to be a dominant economic strategy. Upon one-way sensitivity analysis, these results were sensitive to variability in the drug cost of apixaban and various intracranial hemorrhage related variables. In Monte Carlo simulation, apixaban was a dominant strategy in 57% of 10,000 simulations and cost-effective in 98% at a willingness-to-pay threshold of $50,000 per QALY.
In patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%, treatment with apixaban may be a cost-effective alternative to warfarin.
Atrial fibrillation (AF) is the most common cardiac arrhythmia in the United States (US), affecting about 2.7 million people
Warfarin has been shown to prevent up to 64% of strokes in patients AF; however, despite recommendations for its use by consensus guidelines (Class I; Level of Evidence A)
The Apixaban versus Warfarin in Patients with Atrial Fibrillation (ARISTOTLE) trial compared apixaban with adjusted-dose warfarin for the prevention of stroke or systemic embolism in patients with AF and at least one additional risk factor for stroke. Results of the ARISTOTLE trial revealed that apixaban statistically significantly decreased the risk of stroke and by 21%; driven by a 49% reduction in hemorrhagic stroke (p<0.001). In addition, apixaban was associated with a 31% reduced rate of major bleeding (p<0.001), a 38% reduction in ICH (p<0.001) and an 11% reduction in all-cause mortality (p = 0.047)
Although apixaban has been deemed a reasonable therapeutic alternative to warfarin, its adoption, usage, and clinical application will heavily depend on its perceived economic value. While assessing the cost of a new therapy based purely on its acquisition costs may provide some insight, the costs or savings associated with such therapies often extend far beyond these baseline figures, especially considering anticoagulation therapy is warranted for a lifetime in patients with AF. Whether the reduction is hemorrhagic stroke and intracranial bleeding with apixaban and the absence of a need for anticoagulation monitoring offsets some or all of the drug's additional cost is unclear. Therefore, we used decision analytic modeling to estimate the costs, quality-adjusted life years (QALYs), life-years saved (LYS) and cost-effectiveness of apixaban compared to adjusted-dose warfarin for the prevention of stroke in patients with AF and at least one additional risk factor for stroke.
We constructed a Markov model to evaluate the cost-effectiveness of two treatment strategies for the prevention of stroke in patients with AF: apixaban 5 mg twice daily and adjusted-dose warfarin with a target INR of 2 to 3. The base-case assumed a hypothetical cohort of 65-year-old patients with AF who had a CHADS2 score of 2 and no contraindications to oral anticoagulation. The following health states were modeled: well with AF, reversible ischemic neurologic disease (RIND), ischemic stroke (fatal, major, minor), ICH (fatal, major, minor), extracranial hemorrhage (ECH) (fatal and non-fatal), minor hemorrhage, myocardial infarction (MI) (fatal and non-fatal), and death (
All patients started at age 65 in the “well” with atrial fibrillation health state and then cycled between health states until death occurred or lifetime follow-up period ended (whichever came first). Only certain transitions were allowed and patients could never transition to a more favorable health state. The length of each cycle was 2 weeks and patients could only experience one event of any kind per cycle. Any health state could lead directly to death (not depicted). A second minor ischemic stroke resulted in a major ischemic stroke and that a second major ischemic stroke resulted in death. Temporary health states (e.g., minor bleed and non-fatal extracranial bleed) are not depicted in the figure. The health states were equivalent for apixaban and warfarin, but the probabilities, costs and utilities (quality-of-life) varied with treatment.
We assigned the baseline rate of ischemic stroke on warfarin based on data from ARISTOTLE (1.05%/year, a mean CHADS2 score of 2.1±1.1)
Variable | Base-Case | Range | References |
|
|||
Warfarin, 2 weeks (Tablets Only) | 15 | 1–24 | 42 |
Cost of INR Laboratory (Per Test) | 6 | 4–10 | 41 |
Total Cost of Warfarin and INR Monitoring, 2 weeks | 18 | 3–28 | 41,42 |
Apixaban, 2 weeks | 95 | 51–154 | 43 |
Aspirin, 2 weeks | 0.3 | 0.07–2.8 | 42 |
Event Cost of RIND | 6,562 | 3,500–13,000 | 33–39 |
Event Cost of Minor Stroke | 9,956 | 4,500–18,000 | 33–39 |
Event Cost of Moderate to Severe Stroke | 14,783 | 11,000–27,500 | 33–39 |
Bi-weekly Cost of Minor Stroke | 1,232 | 500–2,000 | 32–39 |
Bi-weekly Cost of Moderate to Severe Stroke | 2,683 | 1,000–4,500 | 32–39 |
Event Cost of ICH | 41,645 | 16,500–71,000 | 33–39 |
Bi-weekly Cost of ICH | 2,835 | 1,000–4,500 | 32–39 |
Bi-weekly Cost of Stroke and ICH | 3,595 | 1,600–7,000 | 32–39 |
Event Cost of Extracranial Bleed | 5,830 | 2,000–9,000 | 33–39 |
Event Cost of Minor Bleed | 42 | 0–200 | 32–34 |
Event Cost of MI | 20,357 | 16,500–24,000 | 39,40 |
Bi-weekly Cost of MI | 152 | 69–300 | 39,40 |
Event Cost of Non-Event Death | 5,000 | 0–10,000 | Estimate |
Annual Discount Rate (%) | 3 | 0–5 | 14 |
|
|||
Healthy on Warfarin | 0.987 | 0.940–1 | 12.29 |
Healthy on Apixaban | 0.994 | 0.975–1 | 7,11,29 (Estimation) |
Healthy on Aspirin | 0.998 | 0.994–1 | 12,29 |
Major Neurological Event | 0.39 | 0–1 | 29 |
Minor Neurological Event | 0.75 | 0–1 | 29 |
Disutility of Major Bleed (2 weeks) | −0.16 | −0.3 to 0 | 10–12 |
Disutility of Minor Bleed (2 days) | −0.16 | −0.3 to 0 | 10–12 |
MI | 0.84 | 0.5–1 | 30,31 |
|
|||
Baseline Rate of Stroke on Warfarin, %/year (CHADS2 Score) | 1.05 (2.1) | 0.92–1.24 | 7 |
HR of Stroke on Apixaban versus Warfarin | 1 | 0.74–1.13 | 7 (Estimate) |
RR of Stroke on Aspirin versus Warfarin | 2.08 | 1.59–2.70 | 21 |
RR of Stroke per 10-Years of Life | 1.4 | N/A | 9 |
Percentage of Strokes with Apixaban or Warfarin that were | |||
Fatal, % | 8.2 | 8.2–10.1 | 7,10,23 |
Major, % | 40.2 | 40.2–41.7 | 7,10,23 |
Minor, % | 42.5 | 34.8–42.5 | 7,10,23 |
No Residual Deficit, % | 9.1 | 9.1–13.3 | 7,10,23 |
Percentage of Strokes with Aspirin that were | |||
Fatal, % | 17.9 | 10.1–17.9 | 10 |
Major, % | 30.0 | 30.0–41.1 | 10 |
Minor, % | 41.0 | 34.8–41.0 | 10 |
No Residual Deficit, % | 11.0 | 11.0–13.3 | 10 |
Baseline Rate of ICH on Warfarin, %/year | 0.80 | 0.63–0.89 | 7 |
HR of ICH on Apixaban versus Warfarin | 0.42 | 0.30–0.58 | 7 |
RR of ICH per 10-Years of Life | 1.97 | N/A | 20 |
Percentage of ICH with Apixaban, Warfarin, and Aspirin that were | |||
Fatal, % | 36.4 | 28.3–45.2 | 19 |
Major, % | 14.1 | 9.0–21.4 | 19 |
Minor, % | 49.5 | N/A | 19 |
Baseline Rate of ECH on Warfarin, %/year | 3.09 | 2.59–3.16 | 7 |
HR of ECH on Apixaban versus Warfarin | 0.69 | 0.60–0.80 | 7 |
Baseline Rate of Clinically Relevant Minor Bleeding on Warfarin, %/year | 2.55 | 2.32–2.80 | 7 (Estimate) |
RR of Clinically Relevant Minor Bleeding on Apixaban | 0.69 | 0.59–0.80 | 7(Estimate) |
RR of Hemorrhage (ICH, ECH, and minor) on Aspirin versus Warfarin | 0.87 | 0.59–0.90 | 21–23 |
Baseline Rate of MI on Warfarin, %/year | 0.61 | 0.51–0.76 | 7 |
HR of MI on Apixaban | 1.0 | 0.66–1.17 | 7 |
RR of MI on Aspirin | 1.42 | 0.84–2.39 | 25 |
RR of MI per Decade of Life | 1.3 | N/A | 12,24 |
RR of Non-Event Death with NVAF | 1.3 | 1.12–1.62 | 27 |
RR of Non-Event Death with NVAF and Stroke | 2.3 | 1.3–3.0 | 28 |
ECH = extracranial hemorrhage; HR = hazard ratio; ICH = intracranial hemorrhage; INR = international normalized ratio; MI = myocardial infarction; NA = not applicable; NVAF = nonvalvular atrial fibrillation; RIND = reversible ischemic neurologic event; RR = relative risk.
We also quantified the baseline rate of hemorrhage (ICH, ECH, or minor hemorrhage) based upon rates observed in patients during the ARISTOTLE trial
Our base-case analysis assumed a baseline rate of MI on warfarin as reported in ARISTOTLE, and assumed no difference in the hazard of MI between patients treated with warfarin and rivaroxaban as observed in ARISTOTLE
Age-adjusted mortality rates for non-event (non- ischemic or major hemorrhage) death were derived from the most recent published U.S. Census Bureau estimates and multiplied by a factor of 1.3 to reflect mortality rates in patients with AF [26.27]. We further assumed the risk of non-event death was 2.3 times higher in patients with AF who also developed a stroke
We calculated QALYs by multiplying the time spent in each health state by corresponding utilities (quality-of-life) estimates derived from the medical literature (where utility scores range from zero to one; zero representing death and 1 representing perfect health). The inconvenience of INR monitoring in addition to required diet or lifestyle changes were considered when assigning a base case utility value of 0.987 to warfarin
The utility weight of neurologic events (ischemic stroke or ICH), other major bleeding and MI were derived from the published literature
Our cost-effectiveness analysis examined direct costs only (inpatient, outpatient and drug); excluding costs due to lost productivity since patients started the model at an age where many are retired from the work force. Healthcare costs were based on data from the Agency of Healthcare Research and Quality's (AHRQ's) Healthcare Cost and Utilization Project (HCUP), the Centers of Medicare and Medicaid Services (CMS), and previously published estimates
We performed one-way sensitivity analyses of all variables over their plausible ranges along with structural parameters (i.e., time horizon). We derived the ranges of clinical events from the 95% confidence intervals of the event rates reported in the ARISTOTLE trial and from other published literature. To explore the relationship between various risk of ischemic stroke and ICH, we varied these two parameters in a two-way sensitivity analysis. Historical rates of ischemic stroke observed in a national registry of Medicare beneficiaries (baseline rate of stroke on warfarin of 0.61%–5.82% for patients with a CHADS2 score of 0–6) were used in this two-way sensitivity analysis
Under base-case assumptions, the quality-adjusted life expectancy of 65-year-old AF patients with a CHADS2 score of 2.1 was 10.89 and 11.23 years for warfarin and apixaban, respectively. Total costs were $90,225 for warfarin and $87,592 for apixaban, demonstrating apixaban to be a dominant (less costly, more effective) economic strategy compared to warfarin. In analysis not adjusted for utility, the net gain in life-years with apixaban compared to warfarin was 0.20 (11.64 life-years versus 11.44 life-years for apixaban and warfarin, respectively).
This figure depicts the effect of varying baseline intracranial hemorrhage rates on the ICER. Vertical dotted line demarcates the lower limit of the plausible range (i.e., 0.63% per year).
Variable | Low range | High range | Threshold value |
Apixaban drug cost, 2 weeks ($) | Dominant | 35,583 | 106 |
ICH bi-weekly costs, $ | 26,659 | Dominant | 2,418 |
ICH hazard ratio | Dominant | 12,049 | 0.49 |
Percentage of ICH that are fatal, % | Dominant | 1,111 | 44.0 |
Baseline rate of ICH on warfarin, % per year | 4,899 | Dominant | 0.70 |
Cost of warfarin treatment including cost of INR laboratory test, 2 weeks ($) | 2,156 | Dominant | 6.3 |
ICH = intracranial hemorrhage; INR = international normalized ratio.
Value of variable at which apixaban was no longer found to be a dominant economic strategy.
Two-way sensitivity analysis of various baseline risks of stroke and ICH demonstrated apixaban is cost-effective when stroke and ICH were varied jointly across plausible ranges (
The results of the 10,000 iteration MCS are presented in
Incremental cost-effectiveness plane showing Monte Carlo estimates of incremental costs and benefits of using apixaban for stroke prevention versus adjusted-dose warfarin. For each one of the 10,000 iterations, values for parameters are randomly selected from their distributions and an ICER is calculated. Points falling above the dotted line have an ICER of >$50,000 per QALY and those falling below the line have an ICER of <$50,000 per QALY. Apixaban was found to be a dominant strategy (less costly, more effective) in 57% of the simulations and cost-effective in 98% of simulations at willingness-to-pay thresholds of $50,000 per QALY. Four thousand of the 10,000 iterations, selected at random, are depicted. ICER = incremental cost-effectiveness ratio; QALYs = quality-adjusted life-years.
Our Markov model demonstrates the use of apixaban would modestly decrease the overall cost of treatment ($2,633) and increase quality-adjusted survival (0.34 QALY) among AF patients aged 65 years or older with at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%. These results were however sensitive to variability in a number of parameters estimated in the model. More than half of the time, MCS suggested apixaban would be “cost-saving” (less costly and more efficacious); with the probability of apixaban being cost-effective (assuming a willingness-to-pay threshold of $50,000/QALY) estimated to be over was 98%.
If approved by the Food and Drug Administration (FDA), apixaban will not be the first oral anticoagulant available as an alternative to warfarin for stroke prevention in AF in the United States. Current guidelines for stroke prevention published jointly by the American College of Cardiology Foundation/American Heart Association/Heart Rhythm Society as well as those from the American College of Chest Physicians
To our knowledge, ours is the first model to assess the cost-effectiveness of apixaban to warfarin. Our model suggests the economics of apixaban are somewhat similar to that of rivaroxaban. Apixaban was also not shown to reduce the risk of ischemic stroke compared to warfarin (HR, 0.92, 95% CI, 0.74–1.13), but did significantly reduce the risk of hemorrhagic stroke by 49% and ICH by 58%
There are limitations to our analysis that must be considered when interpreting results. First, drug specific transition probabilities were derived solely from ARISTOTLE
Our analysis suggests that apixaban is likely at minimum cost-effective in patients with AF and at least one additional risk factor for stroke and a baseline risk of ICH risk of about 0.8%. These results are sensitive to several model assumptions; particularly those related to ICH.