Abstract
Objectives:
Based on clinical trials the oral anticoagulants (OACs) apixaban, dabigatran, and rivaroxaban are efficacious for reducing stroke risk for non-valvular atrial fibrillation (NVAF) patients. Based on the clinical trials, this study evaluated the medical costs for clinical events among NVAF patients ≥75 and <75 years of age treated with individual OACs vs warfarin.
Methods:
Rates for primary and secondary efficacy and safety outcomes (i.e., clinical events) among NVAF patients receiving warfarin or each of the OACs were determined for NVAF populations aged ≥75 years and <75 years of age from the OAC vs warfarin trials. One-year incremental costs among patients with clinical events were obtained from published literature and inflation adjusted to 2010 costs. Medical costs, excluding medication costs, for clinical events associated with each OAC and warfarin were then estimated and compared.
Results:
Among NVAF patients aged ≥75, compared to warfarin, use of either apixaban or rivaroxaban was associated with a reduction in medical costs per patient year (apixaban = −$825, rivaroxaban =−$23), while dabigatran use was associated with increased medical costs of $180 per patient year. Among NVAF patients <75 years of age medical costs per patient year were estimated to be reduced −$254, −$367, and −$88, for apixaban, dabigatran, and rivaroxaban, respectively, in comparison to warfarin.
Limitations:
This economic analysis was based on clinical trial data and, therefore, the direct application of the results to routine clinical practice will require further assessment.
Conclusions:
Difference in medical costs between OAC and warfarin treated NVAF patients vary by age group and individual OACs. Although reductions in medical costs for NVAF patients aged ≥75 and <75 were observed for those using either apixaban or rivaroxaban vs warfarin, the reductions were greater per patient year for both the older and younger NVAF populations using apixaban.
Introduction
The most common significant cardiac rhythm disorder in the US is atrial fibrillation (AF), which affects more than 5 million Americans, of which 45% are 75 years of age or olderCitation1,Citation2. The vast majority of persons with AF have non-valvular AF (NVAF), with <5% having valvular heart diseaseCitation2. The risk of stroke is greater for people with NVAF and this risk increases with age, with persons between the ages of 60–69 having a 2.6-fold increased stroke risk, persons between the ages of 70–79 having a 3.3-fold increased stroke risk, and persons aged 80–89 having a 4.5-fold increased stroke riskCitation3. With the growing population of older persons in the US and a continued increase in the age-adjusted incidence of AF, its prevalence is expected to continue to increase over time and by 2050 have an annual economic burden of $30 billionCitation2,Citation4,Citation5.
Warfarin is a broad spectrum anticoagulant that has been used for over 50 years for stroke prophylaxis among NVAF patients, and multiple trials have demonstrated its efficacy for stroke prevention, which can approach 64% relative to placebo, when maintained in its therapeutic rangeCitation6,Citation7. In clinical practice where monitoring and care is proportionately less for NVAF patients on warfarin therapy in comparison to patients participating in clinical trials, the efficacy of warfarin for stroke prevention is reported to be about half (35% vs 64%) of that observed in clinical trialsCitation8. Moreover, warfarin therapy is under-utilized, particularly among older patients, as they frequently are at increased risk for major bleeding and, therefore, there is a reluctance to prescribe warfarin to these patientsCitation9,Citation10. Better therapeutic options without the limitations of warfarin therapy are needed to lower stroke risk among the AF population, especially for those at greater risk for stroke, such as those who are ≥75 years of ageCitation9.
Clinical trials have demonstrated that the oral anticoagulants (OACs) are as efficacious or superior to warfarin for reducing the risk of stroke among NVAF patientsCitation11–13. In the randomized, double-blind trial, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), apixaban, at a dose of 5 mg twice daily, was shown to be superior to warfarin for reducing the risk of stroke and systemic embolism (hazard ratio (HR) = 0.79, p = 0.01) in patients with NVAF and significantly reduced the risk for major bleedings (HR = 0.69, p < 0.001), relative to warfarin therapyCitation11. In the open-labeled trial, Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) dabigatran, at a dose of 150 mg twice daily, was shown to be superior to warfarin for preventing stroke and systemic embolism (HR = 0.66, p < 0.001) in patients with NVAF and major bleeding rates (HR = 0.93, p = 0.31) were similar for both treatmentsCitation12. In the double-blind Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) rivaroxaban, at a dose of 20 mg once daily, was similar in efficacy to warfarin for the prevention of stroke and systemic embolism (HR = 0.88, p = 0.12) among NVAF patients, who had greater stroke risks in comparison to study populations of the other trialsCitation13. Also, there was no significant difference in the risk of major bleeding (HR = 1.04, p = 0.58) between patient groups treated with rivaroxaban or warfarinCitation13. In the ARISTOTLE, RE-LY, and ROCKET-AF trials 31%, 40%, and 44% of NVAF patients were ≥75 years of age, respectively, and rates of clinical events were higher in this population than in those under the age of 75Citation11–13.
Previously, we reported that, in a patient year, the medical cost reductions associated with OAC use instead of warfarin were estimated to be −$485, −$179, and −$89 for apixaban, dabigatran, and rivaroxaban, respectivelyCitation14. Increasing age increases the risk for developing NVAF and also for NVAF-related clinical eventsCitation3. Additionally, in the OAC vs warfarin trials the OACs and warfarin were reported to have different efficacy and safety profiles among AF patients ≥75 and <75 years of age. Therefore, this study estimated and then compared the medical costs for clinical events among NVAF patients ≥75 years of age and also for those <75 years of age treated with the individual OACs vs warfarin in the US.
Methods
Estimation of clinical event rates
Clinical event rates (i.e., absolute risks) for NVAF patients aged ≥75 and separately for those <75 years of age treated with individual OACs or warfarin were determined from the three published OAC trials, ARISTOTLE, RE-LY, and ROCKET-AFCitation11–13. For all three clinical trials the primary outcome was stroke or systemic embolism and primary and secondary outcome events were adjudicated. Clinical events evaluated included stroke and systemic embolism (SSE), myocardial infarction (MI), pulmonary embolism or deep vein thrombosis (PE/DVT), major bleedings excluding hemorrhagic stroke (MBEHS), and non-major bleedings. Hemorrhagic stroke (HS) was considered both as an efficacy end-point and a safety end-point in the OAC vs warfarin clinical trials. In order to avoid costing HS twice, HS events in this cost analysis were excluded from major bleeding (MBEHS), but kept grouped with SSE. Major bleeding excluding hemorrhagic stroke (MBEHS) was estimated as the difference between the clinical event rates of major bleeding and HS. When the event rate for a particular clinical event was not reported in a clinical trial, the rate of an end-point containing this clinical event was usedCitation14. The event rates of non-major bleedings, including clinically relevant non-major bleedings and other minor bleedings, were not reported by age groups in the original clinical trial publications. In this analysis we assumed the relative risks of these non-major bleedings for the age groups to be the same as those for major bleedings reported for each trial. These estimated relative risks of non-major bleedings in combination with the absolute event rates of non-major bleedings from the overall trial population were used to estimate the event rates of non-major bleedings for the age groups. The event rates of the secondary end-points, MI and PE/DVT, were assumed to be the same as those of the overall population since such age group specific data were not reported in the OAC vs warfarin clinical trials.
Estimation of medical costs of clinical events
Values for incremental medical costs, defined as the incremental costs to a US payer of an NVAF patient experiencing a clinical event during 1 year following the event, were obtained from published literature or based on input from clinical experts when such literature was not availableCitation14. The costs of clinical events were inflation-adjusted to 2010 cost levels via the CPI Medical Care IndexCitation15. Based on the absolute risks determined for each of the clinical events for NVAF patients of the different age groups, the medical costs associated with use of warfarin and each of the OACs were determined, as well as the differences in medical costs for each OAC, relative to warfarin. Drug costs and other additional monitoring-related expenses were not included in the analysis.
Results
Estimated absolute risks for clinical events
Rates of SSE per patient year among the NVAF patient population ≥75 years of age treated with individual OACs were estimated to be numerically lower in comparison to those treated with warfarin (apixaban = 1.60% vs 2.20%, dabigatran = 1.43% vs 2.14%, rivaroxaban = 2.24% vs 2.78%) (). Rates of MBEHS in a patient year among the NVAF patient populations ≥75 years of age treated with individual OACs were estimated to be numerically greater for dabigatran (4.97% vs 3.89%) and rivaroxaban (4.13% vs 3.35%), but less for apixaban (3.00% vs 4.56%), relative to those treated with warfarin (). For the NVAF patient population <75 years of age SSE event rates in a patient year were numerically reduced for patients treated with individual OACs vs warfarin (). For the older and younger NVAF populations only apixaban treatment, relative to warfarin treatment, was consistently associated with reductions in both SSE and MBEHS rates. The estimated event rates for all evaluated clinical events are reported in .
Table 1. Estimated absolute risks for clinical events among NVAF patients treated with warfarin and individual oral anticoagulants (OACs).
Estimated medical costs and their differences
Incremental 1-year medical costs of patients with a clinical event vs without a clinical event in the US were estimated as follows: SSE = $40,613Citation16,Citation17, MI = $37,446Citation18, PE/DVT = $19,532Citation19, MBEHS = $34,617Citation16, and non-major bleedings = $130 (assumed to be the cost of one office visit with CPT code 99215)Citation20.
For the ≥75 and <75 years of age NVAF patient populations treated with warfarin and individual OACs, medical costs for the evaluated clinical events and the sum of these medical costs are reported in . In a year, the total medical cost differences associated with OAC use instead of warfarin among the NVAF population ≥75 years of age were estimated to be −$825, $180, and −$23 and among the NVAF population <75 years of age were estimated to be −$254, −$367, and −$88 for apixaban, dabigatran, and rivaroxaban, respectively ().
Figure 1. Differences in One Year Medical Costs for Clinical Events Among NVAF Patients Treated with Individual Oral Anticoagulants (OACs) Relative to Warfarin-treated Patients.
Table 2. Medical costs for clinical events among NVAF patients treated with warfarin and individual oral anticoagulants (OACs).
Sensitivity analysis
We further carried out a sensitivity analysis in which rates of clinical events for warfarin were estimated as weighted averages from the three OAC trials and those of individual OACs as relative risks to the estimated common warfarin event rates. For this analysis, the total medical cost differences in a year associated with OAC usage instead of warfarin among the NVAF population ≥75 years of age were estimated to be −$812, $191, and $77 and among the NVAF population <75 years of age were estimated to be −$298, −$326, and −$58 for apixaban, dabigatran, and rivaroxaban, respectively.
Discussion
This analysis, based on clinical trial data, shows that differences in medical costs, excluding costs of medications, for clinical events compared with warfarin are dependent on the specific OAC used and age of the NVAF population. It was previously reported that among the overall NVAF population use of any of the OACs was estimated to be associated with reduced medical costs relative to warfarinCitation14. In the current analysis use of either rivaroxaban or apixaban was associated with reduced medical costs relative to warfarin for NVAF patient populations ≥75 and those who were <75 years of age. However, in comparison to rivaroxaban, apixaban use was associated with greater reductions in medical costs for both the older (36-fold vs rivaroxaban) and younger (3-fold vs rivaroxaban) NVAF populations. For apixaban and dabigatran the results were directionally consistent under an additional scenario in which clinical event rates for warfarin-treated patients were estimated as weighted averages from the three OAC trials and those of individual OACs as relative risks to the estimated common warfarin event rates. However, the small reduction in medical costs observed for NVAF patients ≥75 years of age treated with rivaroxaban (−$23) relative to warfarin was reversed ($77), which is likely attributed to differences in MBEHS event rates.
Individuals ≥75 years of age have a greater risk of stroke, which are more frequently deadly, recurrent, require longer recovery periods, and exacerbate concomitant illnessesCitation9. In the US in the near future (2020) the AF population is predicted to increase to 7.5 million individuals, with an expected prevalence of 13.5% among individuals ≥75 years of age, and 18.2% for those ≥85 years of ageCitation1. Based on the Framingham study, the stroke risk attributed to AF (24%) is greatest for persons aged between 80–89 yearsCitation3. Therefore, the healthcare and economic burdens of AF-related stroke, particularly among older persons, are projected to increase, and better treatment options may potentially lessen these burdensCitation2,Citation4,Citation5.
The risk for major bleeding events also increases with age and new phamacotherapies for stroke prophylaxis among NVAF patients ≥75 years of age will likely be better options only if they also demonstrate superior safety relative to warfarin. The greater risk for a major bleeding event among NVAF patients ≥75 years of age using dabigatran or rivaroxaban in comparison to those treated with warfarin contributed to the reversal or partial reversal of the estimated total medical cost reductions previously predicted for the general NVAF populationCitation14. However, use of apixaban, which is estimated to reduce the risk for a major bleeding event by 35% (≥75 years of age), relative to warfarin treatment among NVAF patients was associated with an even greater overall medical cost reduction for those ≥75 (−$825) vs the general NVAF population (−$485)Citation14. Similarly, in the AVERROES trial apixaban use among NVAF patients was more efficacious in comparison to aspirin for stroke prevention among those ≥75 years of age (6.1% vs 2.0%) than the overall NVAF population (3.7% vs 1.6%)Citation21. Although more frequent among NVAF patients, medical costs for non-major bleeding events per patient year contributed relatively little to the overall differences in medical costs between OACs and warfarin.
Hylek et al.Citation22 conducted a retrospective study on AF patients admitted to the Massachusetts General Hospital between January 2001 and June 2003 and reported a major hemorrhage event rate of 13.1 per 100 person-years for AF patients on warfarin therapy ≥80 years of age and 4.7 per 100 person-years for those <80 years of age, suggesting that the risk of major hemorrhage for patients using warfarin may be greater in routine clinical practice, especially for older patientsCitation22. The greater risk of major bleedings among the older AF patient population in clinical practice is one factor contributing to the reluctance to prescribe and/or use warfarin among them even when they are at a high risk for strokeCitation22. As the analysis presented here is based on clinical trial data and does not account for the greater risk for major bleedings among warfarin treated NVAF patients in routine clinical practiceCitation22, the total medical cost reduction associated with use of apixaban as an alternative to warfarin may be under-estimated. Furthermore, apixaban may more often be utilized in clinical practice due to its lower risk for major bleedings and may potentially improve stroke management among older NVAF patients who are not prescribed warfarin or who are intolerant to warfarin therapy.
All three OACs are priced similarly with a wholesale acquisition cost in the US of $8.35 per day (yearly = $3048)Citation23. Thus, the drug prices of OACs are not likely to affect the relative cost differences among the three OACs. When compared to the OACs, generic warfarin with a yearly cost of $164 is an inexpensive drug when only drug costs are consideredCitation23. However, the cost of warfarin treatment also involves monitoring-related expenses which, based on current procedural terminology codes, Harrington et al.Citation24 estimated a yearly cost of $84 for INR testing and $408 for monthly physician visits. In that publication, also included in warfarin treatment-related costs was the economic value of patient time for INR testing, which was estimated at $1751 annuallyCitation24. Such monitoring-related costs were not included in the scope of this study, although the general expectation is that warfarin is associated with greater needs for monitoring than required for OAC use. The inclusion of monitoring costs may enhance the economic benefits of OAC use vs warfarin, but this will require additional future assessment, especially in the read-world setting.
In our analysis we have provided the differences in medical costs for clinical events among older and younger NVAF patients treated with each of the OACs vs warfarin and these data may further assist clinicians and other healthcare decision-makers in choosing treatments for NVAF patients. Having the medical costs for clinical events avoided as a component of overall drug cost is highly relevant given the fact that hospitalizations and physician/clinical services account for 51% of US health expendituresCitation25.
Limitations
Drug costs and other additional monitoring-related expenses, as well as the long-term burden of clinical events, indirect costs, and quality-of-life, all of which may be impacted by more efficacious pharmacotherapy for stroke prophylaxis, were not taken into account. Due to a substantial overlap between patients with clinical events (e.g., stroke, major bleedings) and patient deaths, patient death was not included as an end-point for cost estimate. This economic analysis was based on data obtained from clinical trials that had similar efficacy and bleeding outcomes, but the AF patient populations differed in stroke risk, pre-existing conditions, and other characteristics, which were not adjusted for, and these covariates may affect the indirect comparison of the medical cost differences associated with individual OACs vs warfarinCitation11–13. Also, the direct application of the results to routine clinical practice, where many factors including local healthcare cost, drug adherence, and population risk may vary, will require further assessment. Additionally, incremental annual medical costs for patients with clinical events were based upon those obtained from published studies, which estimated costs from different US health insurers including Medicare and multiple managed care organizations. Therefore, the medical costs are generalized and may not apply to specific payers of US health plans. Since the occurrences of stroke and major bleedings may be greater in routine clinical practiceCitation16,Citation21, our cost estimates may have under-estimated the medical cost changes associated with OAC use, relative to warfarin.
Conclusions
Of the three OACs evaluated vs warfarin, the use of apixaban and rivaroxaban were estimated to be associated with reduced medical costs relative to warfarin among NVAF patients ≥75 and <75 years of age, with apixaban having the greater cost reductions. Reductions in both stroke and major bleeding event rates across age groups were the primary drivers of the medical cost reductions associated with apixaban.
Transparency
Declaration of funding
This research was supported by Bristol-Myers Squibb and Pfizer.
Declaration of funding
SD and AA are paid consultants for Novosys Health in connection with conducting this study. YJ, DM, and JG are employees of Bristol-Myers Squibb and own stock in the company. DW is an employee of Pfizer and owns stock in the company. JL is an employee of Novosys Health, which has received financial support from Bristol-Myers Squibb and Pfizer in connection with conducting this study and development of this manuscript.
Acknowledgments
Editorial support was provided by Melissa Lingohr-Smith at Novosys Health and was funded by Bristol-Myers Squibb and Pfizer.
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