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1369-6998 doi:10.3111/13696998.2014.950670
Vol. 17, No. 11, 2014, 763–770
Article 0061.R1/950670 All rights reserved: reproduction in whole or part not permitted
Original article Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients
Alpesh Amin
Abstract
University of California, Irvine, CA, USA
Yonghua Jing Bristol-Myers Squibb, Plainsboro, NJ, USA
Jeffrey Trocio
Objective: This study evaluated differences in medical costs associated with clinical end-points from randomized clinical trials that compared the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, to standard therapy for treatment of patients with venous thromboembolism (VTE).
Pfizer, Inc., New York, NY, USA
Jay Lin Melissa Lingohr-Smith Novosys Health, Flemington, NJ, USA
John Graham Bristol-Myers Squibb, Plainsboro, NJ, USA Address for correspondence: Alpesh Amin, MD, Chair, Department of Medicine, Executive Director, Hospitalist Program, School of Medicine University of California, Irvine, UCIMC; 101 The City Drive South, Building 58, Room 110, ZC4076H, Mail Code: 4076, Irvine, CA 92868, USA. [email protected] Keywords: Economic models – Healthcare costs – Anticoagulants – Venous thromboembolism Accepted: 29 July 2014; published online: 12 August 2014 Citation: J Med Econ 2014; 17:763–70
Research design and methods: Event rates of efficacy and safety end-points from the clinical trials (RE-COVER, RE-COVER II, EINSTEINPooled, AMPLIFY, Hokusai-VTE trial) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical end-points for the NOACs vs standard therapy were then estimated. One-way and Monte Carlo sensitivity analyses were carried out. Results: A lower rate of major bleedings was associated with use of any of the NOACs vs standard therapy. Except for dabigatran, use of NOACs was also associated with a lower rate of recurrent VTE/death. As a result of the reduction in clinical event rates, the overall medical cost differences were $146, $482, $918, and $344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, vs patients treated with standard therapy. Conclusions: When any of the four NOACs are used instead of standard therapy for acute VTE, treatment medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety end-points. Further evaluation may be needed to validate these results in the real-world setting.
Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular diseaserelated deaths and was estimated in 2011 to annually cost between $13.5–$27.2 billion in the US1,2. VTE can lead to substantial morbidity and can be fatal, yet it is a preventable and treatable condition with use of anticoagulation therapy.
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Current guidelines recommend initial treatment for acute DVT or PE, with parenteral low-molecular-weight heparin (LMWH) or anticoagulation with rivaroxaban and additional anticoagulation therapy (such as a vitamin K antagonist (VKA), LMWH, rivaroxaban, etc.) for 3 months or longer, depending on bleeding risk and whether the event was provoked, unprovoked, or associated with active cancer3. The clinical trials, RE-COVER4, RE-COVER II5, EINSTEIN-DVT6, EINSTEIN-PE7, AMPLIFY8, and the Hokusai-VTE trial9 demonstrated that each of the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are non-inferior to standard therapies for treatment of acute symptomatic VTE without increasing the risk of major bleeding events. The relative risks for the primary efficacy outcome, which was the composite of recurrent VTE or VTE-related death in all NOAC VTE trials, were non-inferior or lower for each of the NOACs vs standard therapies4–10. The relative risks for the safety outcome, major bleeding, were significantly lower for rivaroxaban and apixaban vs standard therapies, but not for dabigatran or edoxaban vs standard therapies4–10. Of the four NOACs, dabigatran and rivaroxaban are approved by the FDA for the indication of acute VTE treatment. Apixaban and edoxaban manufacturers have submitted new drug applications for the indication of acute VTE to the FDA and they are currently under review. Since treatment of VTE patients with the NOACs was associated with differences in the risks for clinical end-points relative to standard therapies in the NOAC VTE trials it is important to determine the amount of medical costs that are avoided among these patient populations. The objective of this study was to evaluate the differences in medical costs when each of the NOACs are used for treatment of acute VTE vs standard therapies based on the differences in clinical event rates reported in the clinical trials.
Methods Estimation of clinical event rates The clinical events evaluated included recurrent VTE/ VTE-related death as defined in the clinical trials, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and other minor bleeding. The event rates of recurrent VTE/VTE-related death, MB, and CRNMB among VTE patients treated with dabigatran, rivaroxaban, apixaban, edoxaban, and standard therapies were estimated from the published data of the corresponding clinical trials as the percentage of patients with each of the clinical events during the trial periods. Event rates of other minor bleedings were derived from the calculation of any bleeding rate minus MB or CRNMB rate. 764
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Estimation of medical cost differences Incremental annual costs, defined as the incremental costs to a US health payer of a VTE patient experiencing a clinical event during 1 year following the initial event were obtained from the literature or healthcare claims databases. In this analysis the cost for recurrent VTE was obtained from Lefebvre et al.11. The incremental annual costs of MB and CRNMB were derived from a retrospective analysis of MarketScan database claims of patients with a diagnosis of VTE (January 1, 2008–December 31, 2011)12. The incremental annual cost of a minor bleeding was assumed to be the cost of one office visit obtained from the Medicare Fee Schedule, Payment and Reimbursement Benefit Guideline13. The medical costs associated with clinical events were inflation adjusted to 2013 cost levels via the CPI Medical Care Index14. Based on the absolute event rates for each of the clinical end-points, the differences in total medical costs associated with use of each the NOACs vs standard therapies were determined. Our study focused on the medical cost reduction driven by clinical outcomes, with drug costs and other additional monitoring related expenses not included in this analysis.
Alternative scenario and sensitivity analyses The default cost comparison was done for a 1-year time frame as an annual perspective is a commonly used time frame by US payers to assess the cost consequence of new therapies. Since treatment durations differed among the trials (163–250 days)4–10, an alternative scenario analysis was conducted in which the clinical event rates were normalized to a 6-month duration by extrapolation. Additionally, univariate (one-way) sensitivity analyses were conducted to determine the effects of varying a single clinical event rate or the corresponding incremental cost on the medical cost differences associated with each NOAC vs standard therapy comparison. In the univariate sensitivity analysis, clinical event rates (rates of VTE, MB, CRNMB, and minor bleeding) and cost estimates (incremental costs of VTE, MB, and CRNMB) were varied between the ranges of their respective 95% confidence intervals when such confidence intervals were known. For the incremental cost estimates where the corresponding confidence intervals (e.g., cost of minor bleeding) were not known, the estimates were varied 30% in the univariate sensitivity analysis. In the univariate sensitivity analysis, a new medical cost avoidance estimate from the model was generated when the lower end or upper end estimates of a single variable was used in the economic model. Such univariate sensitivity analysis is used to help evaluate the sensitivity of the overall medical cost avoidance with the variation of a single model parameter variable. Furthermore, since these variables are often inter-dependent, Monte Carlo analyses were also www.informahealthcare.com/jme ! 2014 Informa UK Ltd
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conducted as multivariate sensitivity analyses. Gaussian distributions were assumed for the estimates of clinical event rates and the corresponding cost estimates. For each cycle of a Monte Carlo analysis, the values of the clinical event rates were taken randomly from a Gaussian distribution of the mean and standard deviation of the corresponding variables. When standard deviations of the cost estimates (e.g. cost of minor bleeding) were not known, they were estimated based on the assumption that the confidence intervals of such parameters were 30% as in the univariate sensitivity analysis. Ten thousand such Monte Carlo iterations were conducted for each NOAC vs standard therapy comparison. Descriptive statistics of the total medical cost differences were measured from the results of such 10,000 random Monte-Carlo cycles. The 95% confidence intervals of the mean medical cost differences were evaluated as the range between the 2.5–97.5 percentile of medical costs evaluated from the 10,000 random cycles of Monte-Carlo simulation for each NOAC vs standard therapy comparison.
Results
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Medical cost differences The incremental annual medical costs of patients with clinical events relative to patients who did not have a clinical event in 2013 dollars were estimated as the following: recurrent VTE ¼ $58,17411, MB ¼ $45,36712, CRNMB ¼ $214012, other minor bleedings (CPT code 99214: level 4 established office patient visit) ¼ $10213. The annual total medical cost differences associated with NOAC use in comparison to standard therapy were $146, $482, $918, and $344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively (negative numbers indicate cost reduction, Table 2). In the alternative scenario analysis when treatment durations were normalized, annual total medical cost differences associated with NOAC use in comparison to standard therapy were $153, $454, $1108, and $261 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively (Table 3). The medical cost reductions for dabigatran and apixaban vs standard therapies were greater in this analysis with normalized treatment duration, while they were less for rivaroxaban and edoxaban vs standard therapies.
Univariate and multivariate sensitivity analyses
Differences in absolute clinical event rates The differences (NOAC - standard therapy) in clinical event rates (per patient-year) for the efficacy outcome, recurrent VTE/VTE-related death, were 0.20%, 0.23%, 0.43%, and 0.34% for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively (Table 1). The absolute risks and differences in clinical event rates for all evaluated clinical end-points are reported in Table 1.
Univariate sensitivity analysis was carried out to assess the impact of each single model parameter on the total medical cost differences estimated from the model. Figure 1 indicates how such variations in clinical event rates and event costs influenced the estimated cost differences of NOACs vs standard therapies. For dabigatran, rivaroxaban, apixaban, and edoxaban, variations in event rates of VTE and MB had the greatest impact on the medical cost
Table 1. Clinical event rates (per patient-year) among venous thromboembolism (VTE) patients treated with new oral anticoagulants (NOACs) and standard therapies (Control). Outcome
Efficacy end-point Recurrent VTE* Difference [CI] Safety end-points Major bleedings Difference [CI] Clinically relevant non-major bleedings Difference [CI] Other minor bleedings Difference [CI]
Dabigatran vs Control (per patient year)
Rivaroxaban vs Control (per patient year)
Apixaban vs Control (per patient year)
Edoxaban vs Control (per patient year)
2.07 vs 2.30% 0.23% [0.78%, 0.44%]
2.26% vs 2.69% 0.43% [1.08%, 0.49%]
1.60% vs 1.94% 0.34% [0.78%, 0.27%]
1.37% vs 1.80% 0.43% [0.91%, 0.32%] 4.01% vs 6.87%
0.97% vs 1.75% 0.78% [1.10%, 0.37%] 8.57% vs 8.41%
0.56% vs 1.82% 1.26% [1.51%, 0.82%] 3.85% vs 8.00%
1.36% vs 1.60% 0.24% [0.66%, 0.34%] 7.24% vs 8.93%
2.87% [4.01%, 1.26%] 12.50% vs 16.79% 4.29% [5.86%, 2.50%]
0.17% [0.97%, 1.47%] 18.91% vs 18.00% 0.91% [0.73%, 2.70%]
4.15% [4.96%, 3.20%] 11.21% vs 16.14% 4.93% [6.37%, 3.28%]
1.69% [2.86%, 0.62%] 13.26% vs 15.36% 2.10% [3.43%, 0.61%]
2.35% vs 2.15% 0.20% [0.52%, 1.22%]
*Included recurrent VTE and VTE-related death as defined in the clinical trials; Difference ¼ NOAC Control. CI, confidence interval.
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Table 2. Medical cost differences among venous thromboembolism (VTE) patients treated with new oral anticoagulants (NOACs) vs standard therapies. Outcome
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Efficacy end-point Recurrent VTE Safety end-points Major bleedings Clinically relevant non-major bleedings Other minor bleedings Total medical cost
Dabigatran ($/patient-year)
Rivaroxaban ($/patient-year)
Apixaban ($/patient-year)
Edoxaban ($/patient-year)
$114
$132
$252
$197
$195 $61 $4 $146
$354 $4 $1 $482
$572 $89 $5 $918
$109 $36 $2 $344
Negative numbers indicate cost reduction vs. standard therapies.
Table 3. Alternative scenario analysis: medical cost differences among venous thromboembolism (VTE) patients treated with new oral anticoagulants (NOACs) vs standard therapies—with treatment duration normalized to 6 months. Outcome
Efficacy end-point Recurrent VTE Safety end-points Major bleedings Clinically relevant non-major bleedings Other minor bleedings Total medical cost
Dabigatran ($/patient-year)
Rivaroxaban ($/patient-year)
Apixaban ($/patient-year)
Edoxaban ($/patient-year)
$130
$135
$317
$148
$211 $67 $5 $153
$320 $0 $1 $454
$680 $105 $6 $1108
$83 $28 $2 $261
Negative numbers indicate cost reduction vs. standard therapies.
differences between NOACs and standard therapies, with corresponding medical cost difference ranges of ($561, $450) and ($366, $194), ($805, $96) and ($628, $294), ($1293, $384) and ($1032, $718), and ($599, $10) and ($533, $82), respectively. In the case of dabigatran, variations in both VTE and MB event rates caused the medical cost difference vs standard therapy to no longer be a cost reduction (cost difference 4$0). In the case of edoxaban, variation in VTE event rates caused the medical cost difference vs standard therapy to no longer be a cost reduction, since the higher VTE cost from the variation range of VTE rate more than offset the cost reduction associated with the bleeding events. Variations in CRNMB event rate and costs of MB and VTE had much smaller influences on the medical cost differences associated with NOACs vs standard therapies. Variations in CRNMB cost, minor bleeding event rate, and cost of minor bleeding had very small influences on the medical cost differences associated with NOACs vs standard therapies. Monte-Carlo multivariate analyses, in which each variable of the univariate analyses were allowed to vary simultaneously for 10,000 random cycles, were used to further test the consistency of the estimates of medical cost differences for NOACs relative to standard therapies (Figure 2). The mean (95% confidence interval (CI)) medical cost reductions associated with NOAC use vs standard therapy were as follows: dabigatran: $145 (95% CI ¼ $731 to $438), rivaroxaban: $483 (95% CI ¼ $876 to $88), 766
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apixaban: $918 (95% CI ¼ $1413 to $440), edoxaban: $345 (95% CI ¼ $730 to $30). Of the 10,000 random Monte-Carlo simulation cycles, 68.55%, 99.32%, 100.00%, and 96.29% had a cost reduction 5$0 for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. The means of such 10,000 random cycles of Monte Carlo simulations were very close to the estimated cost avoidances in the default model analysis. This showed that the results of the original estimated cost avoidances are relatively robust to random variations.
Discussion Based on our economic analysis using clinical trial data, annual medical costs were estimated to be lower for VTE patients taking any of the NOACs vs a standard therapy for acute VTE treatment. Standard therapies in the RECOVER trials, EINSTEIN trials, AMPLIFY trial, and Hokusai-VTE trial were a parenteral anticoagulant followed by warfarin, a parenteral anticoagulant followed by warfarin or acenocoumarol, enoxaparin followed by warfarin, and enoxaparin or unfractionated heparin followed by warfarin, respectively4–10. In particular, the annual medical cost differences per patient associated with use of dabigatran, rivaroxaban, apixaban, and edoxaban vs a standard therapy were $146, $482, $918, and $344, respectively. Since the treatment durations differed among the NOAC VTE trials, we also conducted www.informahealthcare.com/jme ! 2014 Informa UK Ltd
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Figure 1. Univariate sensitivity analyses of medical cost differences of new oral anticoagulants (NOACs) vs standard therapies.
an alternative scenario analysis in which all treatment durations were normalized to 6 months. In this analysis the estimated medical cost reductions were similar for NOACs, with those associated with dabigatran and apixaban being more favorable than estimated in the default analysis. Our estimates of the medical cost differences between NOACs and standard therapies were consistent under additionally evaluated scenarios. From the 10,000 random variations in each of the Monte-Carlo multivariate analyses the mean cost reductions associated with use of the NOACs vs standard therapies were similar to that estimated in the default analysis, with use of apixaban associated with the greatest medical cost reduction vs standard therapy. Apixaban was associated with a cost reduction in 100% of the 10,000 Monte-Carlo iterations, while approximately one-third of the iterations for dabigatran showed a medical cost difference 4$0 (cost increase). Rivaroxaban and edoxaban showed a medical cost difference 5$0 in 99% and 96% of the 10,000 Monte Carlo ! 2014 Informa UK Ltd www.informahealthcare.com/jme
iterations, respectively. Our economic analysis was based on clinical trial data and, therefore, the direct application of the results to the real-world setting, where many other factors, including local healthcare cost, drug adherence, population risk, and health behaviors may vary, will require further assessment. However, prior to the broad exposure of NOACs to the real world, clinical trial results are considered the best basis for conducting this type of research15,16. The incidences of recurrent VTE and MB may be higher in real-world settings in comparison to that measured in the clinical trials, which were 53% for recurrent VTE and 52% for MB among the trials for NOACs vs standard therapy for acute VTE treatment4–10,17. The Worcester VTE study, which had a mean follow-up period of 1216 days of 1567 persons with first-time VTE, reported cumulative rates of 16% for recurrent VTE and 12% for MB17. The Worcestor VTE study also noted that the cumulative incidence of MB was 8% in the month following the initial VTE event17. Studies with longer NOACs vs standard therapy for VTE treatment Amin et al.
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Figure 2. Distribution of total medical cost differences from 10,000 cycles of Monte Carlo simulation: new oral anticoagulants (NOACs) vs standard therapies.
follow-up periods have reported 5-year cumulative incidence rates of recurrent VTE ranging between 21.5–29.1%18,19. The potentially greater event rates of recurrent VTE and MB in real-world settings implies the differences in medical costs between VTE patients who use NOACs vs standard therapies estimated in this study, which were based on clinical trial data, are likely under768
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estimated, thus making the impact of the cost differences even greater in favor of the NOACs. Lefebvre et al.11 conducted a study in which patients with an initial VTE and a recurrent VTE within 1 year were matched to patients with an initial VTE, but no recurrent VTE. The total annual healthcare costs among patients with recurrent VTE were $86,744 per patient vs www.informahealthcare.com/jme ! 2014 Informa UK Ltd
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$37,525 for patients who had an initial VTE but no recurrent VTE11. These high healthcare costs of recurrent VTE patients are reflective of much greater healthcare utilization and poor outcomes and are pointedly suggestive of the need for better management of VTE patients. Since none of the NOACs require frequent monitoring and dose adjustments and are administered orally they may simplify the treatment of VTE and potentially improve patient outcomes. Furthermore, the risk of MB is an important factor and concern for patients receiving acute VTE treatments. Dabigatran, rivaroxaban, and apixaban are priced similarly, with a wholesale acquisition cost in the US of $8.35 per day20. Edoxaban is currently not marketed in the US yet, but may likely be priced similar to the other NOACs. Thus, the drug prices of NOACs are not likely to affect the relative cost differences among the four NOACs. Standard therapies for acute VTE treatment in comparison to NOACs are less expensive when only drug costs are taken into account. However, the avoidance of VTErelated clinical events and, hence, lower healthcare costs, should assist clinicians and health policy-makers in determining the most cost-effective pharmacotherapies for prevention of VTE recurrence. 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 all US health expenditures21.
Limitations This economic analysis has limitations in that monitoringrelated 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 VTE were not taken into account. Further studies incorporating all of these costs, as well as drug costs, will provide valuable information for healthcare providers, patients, and health policy-makers, and will likely be best accomplished using a real-world observational study design. The cost model was based on data obtained from clinical trials that had similar efficacy and bleeding outcomes, but the VTE patient populations might have differed in VTE recurrence risk, pre-existing conditions, and other characteristics, which may have influenced the clinical event rates and, hence, the estimates of medical cost differences. On the other hand, the differences of such patient characteristics might have been balanced out between control arms and interventional drug arms through the randomization process of the clinical trials. Additionally, in some patients PE could not be confirmed or excluded, but the death was included in the end-point count and, hence, the event rate. We used such clinical event rates from the original trial data to be consistent with the primary findings from the original trials. ! 2014 Informa UK Ltd www.informahealthcare.com/jme
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The incremental annual medical costs for patients with clinical events were based upon those obtained from published studies or database claims, which estimated costs from different US health insurers. Therefore, the medical costs are generalized and may not apply to specific payers of US health plans. Additionally, the costs of MB and CRNMB were obtained from a retrospective database claims study, which was presented at the International Society on Thrombosis and Haemostasis 60th Annual Scientific and Standardization Committee Meeting and not published in a peer-reviewed journal yet. Since rates of VTE recurrence and MB may be greater in real-world settings17–19, the estimated medical cost differences associated with NOAC use relative to standard therapies may be under-estimated. Thus, the direct application of the results to routine clinical practice, where many factors including population risk may vary, will require further assessment.
Conclusions When any of the four NOACs are used instead of standard therapy for acute VTE treatment, medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety endpoints. The estimated medical cost reductions associated with NOAC use, relative to standard therapies, may be helpful in determining the overall cost impacts of the use of NOACs for VTE patients in the US, although further evaluation may be needed to validate these results in the real-world setting.
Transparency Declaration of funding This research was supported by Bristol-Myers Squibb and Pfizer. Declaration of financial/other relationships Alpesh Amin is a consultant for Novosys Health in connection with conducting this study. Yonghua Jing and John Graham are employees of Bristol-Myers Squibb and own stock in the company. Jeffrey Trocio is an employee of Pfizer and owns stock in the company. Jay Lin and Melissa Lingohr-Smith are employees of Novosys Health, which has received research funds from BristolMyers Squibb and Pfizer in connection with conducting this study and development of this manuscript. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References 1. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012;379:1835-46
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2. Mahan CE, Borrego ME, Woersching AL, et al. Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates. Thromb Haemost 2012; 108:291-302 3. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl): e419S-94S 4. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52 5. Clinicaltrials.gov. Phase III Study Testing Efficacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symp Venous Thromboembolism (VTE) (RE-COVER II). http://clinicaltrials.gov/ct2/show/ NCT00680186?term¼re-Coverþdabigatran&rank¼1. Accessed March 3, 2014 6. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510 7. EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97 8. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808 9. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15 10. Prins MH, Lensing AWA, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21 11. Lefebvre P, Laliberte´ F, Nutescu EA, et al. All-cause and disease-related health care costs associated with recurrent venous thromboembolism. Thromb Haemost 2013;110:1288-97
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12. Amin A, Jing Y, Trocio J, et al. Incremental healthcare burden of bleeding among patients with venous thromboembolism in the US. The International Society on Thrombosis and Haemostasis 60th Annual Scientific and Standardization Committee (SSC) Meeting. Milwaukee, WI, June 23–26, 2014 13. Medicare Fee Schedule, Payment and Reimbursement Benefit Guideline, CPT Code Billing. Centers for Medicare and Medicaid Services. Baltimore, MD. http://www.medicarepaymentandreimbursement.com/2013/12/medicareschedule-update-important.html. Accessed March 3, 2014 14. US Department of Labor. Consumer Price Index December 2013. USDL14-0037. Washington D.C.: Bureau of Labor Statistics US Department of Labor; 2013. http://www.bls.gov/news.release/archives/cpi_01162014.pdf. Accessed March 3, 2014 15. Chiong JR, Kim S, Lin J, et al. Evaluation of costs associated with tolvaptanmediated length of stay reduction among heart failure patients with hyponatremia in the US, based on the EVEREST trial. J Med Econ 2012;15:1-9 16. Dasta JF, Chiong JR, Christian R, et al. Evaluation of costs associated with tolvaptan- mediated hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials. Hospit Pract 2013;40:1-8 17. Spencer FA, Emery C, Joffe SW, et al. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J Thromb Thrombolysis 2009;28:401-9 18. Hansson PO, So¨rbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160:769-74 19. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1626 patients. Haematologica 2007;92:199-205 20. Analy$ource Online. San Francisco, CA: First Databank Inc.; 2013 21. Health Care Costs: A Primer. Menlo Park, CA: Kaiser Family Foundation; 2012. http://kff.org/report-section/health-care-costs-a-primer-2012-report/
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1369-6998 doi:10.3111/13696998.2014.950670
Vol. 17, No. 11, 2014, 763–770
Article 0061.R1/950670 All rights reserved: reproduction in whole or part not permitted
Original article Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients
Alpesh Amin
Abstract
University of California, Irvine, CA, USA
Yonghua Jing Bristol-Myers Squibb, Plainsboro, NJ, USA
Jeffrey Trocio
Objective: This study evaluated differences in medical costs associated with clinical end-points from randomized clinical trials that compared the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, to standard therapy for treatment of patients with venous thromboembolism (VTE).
Pfizer, Inc., New York, NY, USA
Jay Lin Melissa Lingohr-Smith Novosys Health, Flemington, NJ, USA
John Graham Bristol-Myers Squibb, Plainsboro, NJ, USA Address for correspondence: Alpesh Amin, MD, Chair, Department of Medicine, Executive Director, Hospitalist Program, School of Medicine University of California, Irvine, UCIMC; 101 The City Drive South, Building 58, Room 110, ZC4076H, Mail Code: 4076, Irvine, CA 92868, USA. [email protected] Keywords: Economic models – Healthcare costs – Anticoagulants – Venous thromboembolism Accepted: 29 July 2014; published online: 12 August 2014 Citation: J Med Econ 2014; 17:763–70
Research design and methods: Event rates of efficacy and safety end-points from the clinical trials (RE-COVER, RE-COVER II, EINSTEINPooled, AMPLIFY, Hokusai-VTE trial) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical end-points for the NOACs vs standard therapy were then estimated. One-way and Monte Carlo sensitivity analyses were carried out. Results: A lower rate of major bleedings was associated with use of any of the NOACs vs standard therapy. Except for dabigatran, use of NOACs was also associated with a lower rate of recurrent VTE/death. As a result of the reduction in clinical event rates, the overall medical cost differences were $146, $482, $918, and $344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, vs patients treated with standard therapy. Conclusions: When any of the four NOACs are used instead of standard therapy for acute VTE, treatment medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety end-points. Further evaluation may be needed to validate these results in the real-world setting.
Introduction Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cause of vascular diseaserelated deaths and was estimated in 2011 to annually cost between $13.5–$27.2 billion in the US1,2. VTE can lead to substantial morbidity and can be fatal, yet it is a preventable and treatable condition with use of anticoagulation therapy.
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Current guidelines recommend initial treatment for acute DVT or PE, with parenteral low-molecular-weight heparin (LMWH) or anticoagulation with rivaroxaban and additional anticoagulation therapy (such as a vitamin K antagonist (VKA), LMWH, rivaroxaban, etc.) for 3 months or longer, depending on bleeding risk and whether the event was provoked, unprovoked, or associated with active cancer3. The clinical trials, RE-COVER4, RE-COVER II5, EINSTEIN-DVT6, EINSTEIN-PE7, AMPLIFY8, and the Hokusai-VTE trial9 demonstrated that each of the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, are non-inferior to standard therapies for treatment of acute symptomatic VTE without increasing the risk of major bleeding events. The relative risks for the primary efficacy outcome, which was the composite of recurrent VTE or VTE-related death in all NOAC VTE trials, were non-inferior or lower for each of the NOACs vs standard therapies4–10. The relative risks for the safety outcome, major bleeding, were significantly lower for rivaroxaban and apixaban vs standard therapies, but not for dabigatran or edoxaban vs standard therapies4–10. Of the four NOACs, dabigatran and rivaroxaban are approved by the FDA for the indication of acute VTE treatment. Apixaban and edoxaban manufacturers have submitted new drug applications for the indication of acute VTE to the FDA and they are currently under review. Since treatment of VTE patients with the NOACs was associated with differences in the risks for clinical end-points relative to standard therapies in the NOAC VTE trials it is important to determine the amount of medical costs that are avoided among these patient populations. The objective of this study was to evaluate the differences in medical costs when each of the NOACs are used for treatment of acute VTE vs standard therapies based on the differences in clinical event rates reported in the clinical trials.
Methods Estimation of clinical event rates The clinical events evaluated included recurrent VTE/ VTE-related death as defined in the clinical trials, major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and other minor bleeding. The event rates of recurrent VTE/VTE-related death, MB, and CRNMB among VTE patients treated with dabigatran, rivaroxaban, apixaban, edoxaban, and standard therapies were estimated from the published data of the corresponding clinical trials as the percentage of patients with each of the clinical events during the trial periods. Event rates of other minor bleedings were derived from the calculation of any bleeding rate minus MB or CRNMB rate. 764
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Estimation of medical cost differences Incremental annual costs, defined as the incremental costs to a US health payer of a VTE patient experiencing a clinical event during 1 year following the initial event were obtained from the literature or healthcare claims databases. In this analysis the cost for recurrent VTE was obtained from Lefebvre et al.11. The incremental annual costs of MB and CRNMB were derived from a retrospective analysis of MarketScan database claims of patients with a diagnosis of VTE (January 1, 2008–December 31, 2011)12. The incremental annual cost of a minor bleeding was assumed to be the cost of one office visit obtained from the Medicare Fee Schedule, Payment and Reimbursement Benefit Guideline13. The medical costs associated with clinical events were inflation adjusted to 2013 cost levels via the CPI Medical Care Index14. Based on the absolute event rates for each of the clinical end-points, the differences in total medical costs associated with use of each the NOACs vs standard therapies were determined. Our study focused on the medical cost reduction driven by clinical outcomes, with drug costs and other additional monitoring related expenses not included in this analysis.
Alternative scenario and sensitivity analyses The default cost comparison was done for a 1-year time frame as an annual perspective is a commonly used time frame by US payers to assess the cost consequence of new therapies. Since treatment durations differed among the trials (163–250 days)4–10, an alternative scenario analysis was conducted in which the clinical event rates were normalized to a 6-month duration by extrapolation. Additionally, univariate (one-way) sensitivity analyses were conducted to determine the effects of varying a single clinical event rate or the corresponding incremental cost on the medical cost differences associated with each NOAC vs standard therapy comparison. In the univariate sensitivity analysis, clinical event rates (rates of VTE, MB, CRNMB, and minor bleeding) and cost estimates (incremental costs of VTE, MB, and CRNMB) were varied between the ranges of their respective 95% confidence intervals when such confidence intervals were known. For the incremental cost estimates where the corresponding confidence intervals (e.g., cost of minor bleeding) were not known, the estimates were varied 30% in the univariate sensitivity analysis. In the univariate sensitivity analysis, a new medical cost avoidance estimate from the model was generated when the lower end or upper end estimates of a single variable was used in the economic model. Such univariate sensitivity analysis is used to help evaluate the sensitivity of the overall medical cost avoidance with the variation of a single model parameter variable. Furthermore, since these variables are often inter-dependent, Monte Carlo analyses were also www.informahealthcare.com/jme ! 2014 Informa UK Ltd
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conducted as multivariate sensitivity analyses. Gaussian distributions were assumed for the estimates of clinical event rates and the corresponding cost estimates. For each cycle of a Monte Carlo analysis, the values of the clinical event rates were taken randomly from a Gaussian distribution of the mean and standard deviation of the corresponding variables. When standard deviations of the cost estimates (e.g. cost of minor bleeding) were not known, they were estimated based on the assumption that the confidence intervals of such parameters were 30% as in the univariate sensitivity analysis. Ten thousand such Monte Carlo iterations were conducted for each NOAC vs standard therapy comparison. Descriptive statistics of the total medical cost differences were measured from the results of such 10,000 random Monte-Carlo cycles. The 95% confidence intervals of the mean medical cost differences were evaluated as the range between the 2.5–97.5 percentile of medical costs evaluated from the 10,000 random cycles of Monte-Carlo simulation for each NOAC vs standard therapy comparison.
Results
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Medical cost differences The incremental annual medical costs of patients with clinical events relative to patients who did not have a clinical event in 2013 dollars were estimated as the following: recurrent VTE ¼ $58,17411, MB ¼ $45,36712, CRNMB ¼ $214012, other minor bleedings (CPT code 99214: level 4 established office patient visit) ¼ $10213. The annual total medical cost differences associated with NOAC use in comparison to standard therapy were $146, $482, $918, and $344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively (negative numbers indicate cost reduction, Table 2). In the alternative scenario analysis when treatment durations were normalized, annual total medical cost differences associated with NOAC use in comparison to standard therapy were $153, $454, $1108, and $261 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively (Table 3). The medical cost reductions for dabigatran and apixaban vs standard therapies were greater in this analysis with normalized treatment duration, while they were less for rivaroxaban and edoxaban vs standard therapies.
Univariate and multivariate sensitivity analyses
Differences in absolute clinical event rates The differences (NOAC - standard therapy) in clinical event rates (per patient-year) for the efficacy outcome, recurrent VTE/VTE-related death, were 0.20%, 0.23%, 0.43%, and 0.34% for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively (Table 1). The absolute risks and differences in clinical event rates for all evaluated clinical end-points are reported in Table 1.
Univariate sensitivity analysis was carried out to assess the impact of each single model parameter on the total medical cost differences estimated from the model. Figure 1 indicates how such variations in clinical event rates and event costs influenced the estimated cost differences of NOACs vs standard therapies. For dabigatran, rivaroxaban, apixaban, and edoxaban, variations in event rates of VTE and MB had the greatest impact on the medical cost
Table 1. Clinical event rates (per patient-year) among venous thromboembolism (VTE) patients treated with new oral anticoagulants (NOACs) and standard therapies (Control). Outcome
Efficacy end-point Recurrent VTE* Difference [CI] Safety end-points Major bleedings Difference [CI] Clinically relevant non-major bleedings Difference [CI] Other minor bleedings Difference [CI]
Dabigatran vs Control (per patient year)
Rivaroxaban vs Control (per patient year)
Apixaban vs Control (per patient year)
Edoxaban vs Control (per patient year)
2.07 vs 2.30% 0.23% [0.78%, 0.44%]
2.26% vs 2.69% 0.43% [1.08%, 0.49%]
1.60% vs 1.94% 0.34% [0.78%, 0.27%]
1.37% vs 1.80% 0.43% [0.91%, 0.32%] 4.01% vs 6.87%
0.97% vs 1.75% 0.78% [1.10%, 0.37%] 8.57% vs 8.41%
0.56% vs 1.82% 1.26% [1.51%, 0.82%] 3.85% vs 8.00%
1.36% vs 1.60% 0.24% [0.66%, 0.34%] 7.24% vs 8.93%
2.87% [4.01%, 1.26%] 12.50% vs 16.79% 4.29% [5.86%, 2.50%]
0.17% [0.97%, 1.47%] 18.91% vs 18.00% 0.91% [0.73%, 2.70%]
4.15% [4.96%, 3.20%] 11.21% vs 16.14% 4.93% [6.37%, 3.28%]
1.69% [2.86%, 0.62%] 13.26% vs 15.36% 2.10% [3.43%, 0.61%]
2.35% vs 2.15% 0.20% [0.52%, 1.22%]
*Included recurrent VTE and VTE-related death as defined in the clinical trials; Difference ¼ NOAC Control. CI, confidence interval.
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Table 2. Medical cost differences among venous thromboembolism (VTE) patients treated with new oral anticoagulants (NOACs) vs standard therapies. Outcome
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Efficacy end-point Recurrent VTE Safety end-points Major bleedings Clinically relevant non-major bleedings Other minor bleedings Total medical cost
Dabigatran ($/patient-year)
Rivaroxaban ($/patient-year)
Apixaban ($/patient-year)
Edoxaban ($/patient-year)
$114
$132
$252
$197
$195 $61 $4 $146
$354 $4 $1 $482
$572 $89 $5 $918
$109 $36 $2 $344
Negative numbers indicate cost reduction vs. standard therapies.
Table 3. Alternative scenario analysis: medical cost differences among venous thromboembolism (VTE) patients treated with new oral anticoagulants (NOACs) vs standard therapies—with treatment duration normalized to 6 months. Outcome
Efficacy end-point Recurrent VTE Safety end-points Major bleedings Clinically relevant non-major bleedings Other minor bleedings Total medical cost
Dabigatran ($/patient-year)
Rivaroxaban ($/patient-year)
Apixaban ($/patient-year)
Edoxaban ($/patient-year)
$130
$135
$317
$148
$211 $67 $5 $153
$320 $0 $1 $454
$680 $105 $6 $1108
$83 $28 $2 $261
Negative numbers indicate cost reduction vs. standard therapies.
differences between NOACs and standard therapies, with corresponding medical cost difference ranges of ($561, $450) and ($366, $194), ($805, $96) and ($628, $294), ($1293, $384) and ($1032, $718), and ($599, $10) and ($533, $82), respectively. In the case of dabigatran, variations in both VTE and MB event rates caused the medical cost difference vs standard therapy to no longer be a cost reduction (cost difference 4$0). In the case of edoxaban, variation in VTE event rates caused the medical cost difference vs standard therapy to no longer be a cost reduction, since the higher VTE cost from the variation range of VTE rate more than offset the cost reduction associated with the bleeding events. Variations in CRNMB event rate and costs of MB and VTE had much smaller influences on the medical cost differences associated with NOACs vs standard therapies. Variations in CRNMB cost, minor bleeding event rate, and cost of minor bleeding had very small influences on the medical cost differences associated with NOACs vs standard therapies. Monte-Carlo multivariate analyses, in which each variable of the univariate analyses were allowed to vary simultaneously for 10,000 random cycles, were used to further test the consistency of the estimates of medical cost differences for NOACs relative to standard therapies (Figure 2). The mean (95% confidence interval (CI)) medical cost reductions associated with NOAC use vs standard therapy were as follows: dabigatran: $145 (95% CI ¼ $731 to $438), rivaroxaban: $483 (95% CI ¼ $876 to $88), 766
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apixaban: $918 (95% CI ¼ $1413 to $440), edoxaban: $345 (95% CI ¼ $730 to $30). Of the 10,000 random Monte-Carlo simulation cycles, 68.55%, 99.32%, 100.00%, and 96.29% had a cost reduction 5$0 for dabigatran, rivaroxaban, apixaban, and edoxaban, respectively. The means of such 10,000 random cycles of Monte Carlo simulations were very close to the estimated cost avoidances in the default model analysis. This showed that the results of the original estimated cost avoidances are relatively robust to random variations.
Discussion Based on our economic analysis using clinical trial data, annual medical costs were estimated to be lower for VTE patients taking any of the NOACs vs a standard therapy for acute VTE treatment. Standard therapies in the RECOVER trials, EINSTEIN trials, AMPLIFY trial, and Hokusai-VTE trial were a parenteral anticoagulant followed by warfarin, a parenteral anticoagulant followed by warfarin or acenocoumarol, enoxaparin followed by warfarin, and enoxaparin or unfractionated heparin followed by warfarin, respectively4–10. In particular, the annual medical cost differences per patient associated with use of dabigatran, rivaroxaban, apixaban, and edoxaban vs a standard therapy were $146, $482, $918, and $344, respectively. Since the treatment durations differed among the NOAC VTE trials, we also conducted www.informahealthcare.com/jme ! 2014 Informa UK Ltd
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Figure 1. Univariate sensitivity analyses of medical cost differences of new oral anticoagulants (NOACs) vs standard therapies.
an alternative scenario analysis in which all treatment durations were normalized to 6 months. In this analysis the estimated medical cost reductions were similar for NOACs, with those associated with dabigatran and apixaban being more favorable than estimated in the default analysis. Our estimates of the medical cost differences between NOACs and standard therapies were consistent under additionally evaluated scenarios. From the 10,000 random variations in each of the Monte-Carlo multivariate analyses the mean cost reductions associated with use of the NOACs vs standard therapies were similar to that estimated in the default analysis, with use of apixaban associated with the greatest medical cost reduction vs standard therapy. Apixaban was associated with a cost reduction in 100% of the 10,000 Monte-Carlo iterations, while approximately one-third of the iterations for dabigatran showed a medical cost difference 4$0 (cost increase). Rivaroxaban and edoxaban showed a medical cost difference 5$0 in 99% and 96% of the 10,000 Monte Carlo ! 2014 Informa UK Ltd www.informahealthcare.com/jme
iterations, respectively. Our economic analysis was based on clinical trial data and, therefore, the direct application of the results to the real-world setting, where many other factors, including local healthcare cost, drug adherence, population risk, and health behaviors may vary, will require further assessment. However, prior to the broad exposure of NOACs to the real world, clinical trial results are considered the best basis for conducting this type of research15,16. The incidences of recurrent VTE and MB may be higher in real-world settings in comparison to that measured in the clinical trials, which were 53% for recurrent VTE and 52% for MB among the trials for NOACs vs standard therapy for acute VTE treatment4–10,17. The Worcester VTE study, which had a mean follow-up period of 1216 days of 1567 persons with first-time VTE, reported cumulative rates of 16% for recurrent VTE and 12% for MB17. The Worcestor VTE study also noted that the cumulative incidence of MB was 8% in the month following the initial VTE event17. Studies with longer NOACs vs standard therapy for VTE treatment Amin et al.
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Figure 2. Distribution of total medical cost differences from 10,000 cycles of Monte Carlo simulation: new oral anticoagulants (NOACs) vs standard therapies.
follow-up periods have reported 5-year cumulative incidence rates of recurrent VTE ranging between 21.5–29.1%18,19. The potentially greater event rates of recurrent VTE and MB in real-world settings implies the differences in medical costs between VTE patients who use NOACs vs standard therapies estimated in this study, which were based on clinical trial data, are likely under768
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estimated, thus making the impact of the cost differences even greater in favor of the NOACs. Lefebvre et al.11 conducted a study in which patients with an initial VTE and a recurrent VTE within 1 year were matched to patients with an initial VTE, but no recurrent VTE. The total annual healthcare costs among patients with recurrent VTE were $86,744 per patient vs www.informahealthcare.com/jme ! 2014 Informa UK Ltd
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$37,525 for patients who had an initial VTE but no recurrent VTE11. These high healthcare costs of recurrent VTE patients are reflective of much greater healthcare utilization and poor outcomes and are pointedly suggestive of the need for better management of VTE patients. Since none of the NOACs require frequent monitoring and dose adjustments and are administered orally they may simplify the treatment of VTE and potentially improve patient outcomes. Furthermore, the risk of MB is an important factor and concern for patients receiving acute VTE treatments. Dabigatran, rivaroxaban, and apixaban are priced similarly, with a wholesale acquisition cost in the US of $8.35 per day20. Edoxaban is currently not marketed in the US yet, but may likely be priced similar to the other NOACs. Thus, the drug prices of NOACs are not likely to affect the relative cost differences among the four NOACs. Standard therapies for acute VTE treatment in comparison to NOACs are less expensive when only drug costs are taken into account. However, the avoidance of VTErelated clinical events and, hence, lower healthcare costs, should assist clinicians and health policy-makers in determining the most cost-effective pharmacotherapies for prevention of VTE recurrence. 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 all US health expenditures21.
Limitations This economic analysis has limitations in that monitoringrelated 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 VTE were not taken into account. Further studies incorporating all of these costs, as well as drug costs, will provide valuable information for healthcare providers, patients, and health policy-makers, and will likely be best accomplished using a real-world observational study design. The cost model was based on data obtained from clinical trials that had similar efficacy and bleeding outcomes, but the VTE patient populations might have differed in VTE recurrence risk, pre-existing conditions, and other characteristics, which may have influenced the clinical event rates and, hence, the estimates of medical cost differences. On the other hand, the differences of such patient characteristics might have been balanced out between control arms and interventional drug arms through the randomization process of the clinical trials. Additionally, in some patients PE could not be confirmed or excluded, but the death was included in the end-point count and, hence, the event rate. We used such clinical event rates from the original trial data to be consistent with the primary findings from the original trials. ! 2014 Informa UK Ltd www.informahealthcare.com/jme
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The incremental annual medical costs for patients with clinical events were based upon those obtained from published studies or database claims, which estimated costs from different US health insurers. Therefore, the medical costs are generalized and may not apply to specific payers of US health plans. Additionally, the costs of MB and CRNMB were obtained from a retrospective database claims study, which was presented at the International Society on Thrombosis and Haemostasis 60th Annual Scientific and Standardization Committee Meeting and not published in a peer-reviewed journal yet. Since rates of VTE recurrence and MB may be greater in real-world settings17–19, the estimated medical cost differences associated with NOAC use relative to standard therapies may be under-estimated. Thus, the direct application of the results to routine clinical practice, where many factors including population risk may vary, will require further assessment.
Conclusions When any of the four NOACs are used instead of standard therapy for acute VTE treatment, medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety endpoints. The estimated medical cost reductions associated with NOAC use, relative to standard therapies, may be helpful in determining the overall cost impacts of the use of NOACs for VTE patients in the US, although further evaluation may be needed to validate these results in the real-world setting.
Transparency Declaration of funding This research was supported by Bristol-Myers Squibb and Pfizer. Declaration of financial/other relationships Alpesh Amin is a consultant for Novosys Health in connection with conducting this study. Yonghua Jing and John Graham are employees of Bristol-Myers Squibb and own stock in the company. Jeffrey Trocio is an employee of Pfizer and owns stock in the company. Jay Lin and Melissa Lingohr-Smith are employees of Novosys Health, which has received research funds from BristolMyers Squibb and Pfizer in connection with conducting this study and development of this manuscript. JME peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
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2. Mahan CE, Borrego ME, Woersching AL, et al. Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates. Thromb Haemost 2012; 108:291-302 3. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl): e419S-94S 4. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52 5. Clinicaltrials.gov. Phase III Study Testing Efficacy & Safety of Oral Dabigatran Etexilate vs Warfarin for 6 m Treatment for Acute Symp Venous Thromboembolism (VTE) (RE-COVER II). http://clinicaltrials.gov/ct2/show/ NCT00680186?term¼re-Coverþdabigatran&rank¼1. Accessed March 3, 2014 6. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510 7. EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97 8. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808 9. The Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15 10. Prins MH, Lensing AWA, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21 11. Lefebvre P, Laliberte´ F, Nutescu EA, et al. All-cause and disease-related health care costs associated with recurrent venous thromboembolism. Thromb Haemost 2013;110:1288-97
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12. Amin A, Jing Y, Trocio J, et al. Incremental healthcare burden of bleeding among patients with venous thromboembolism in the US. The International Society on Thrombosis and Haemostasis 60th Annual Scientific and Standardization Committee (SSC) Meeting. Milwaukee, WI, June 23–26, 2014 13. Medicare Fee Schedule, Payment and Reimbursement Benefit Guideline, CPT Code Billing. Centers for Medicare and Medicaid Services. Baltimore, MD. http://www.medicarepaymentandreimbursement.com/2013/12/medicareschedule-update-important.html. Accessed March 3, 2014 14. US Department of Labor. Consumer Price Index December 2013. USDL14-0037. Washington D.C.: Bureau of Labor Statistics US Department of Labor; 2013. http://www.bls.gov/news.release/archives/cpi_01162014.pdf. Accessed March 3, 2014 15. Chiong JR, Kim S, Lin J, et al. Evaluation of costs associated with tolvaptanmediated length of stay reduction among heart failure patients with hyponatremia in the US, based on the EVEREST trial. J Med Econ 2012;15:1-9 16. Dasta JF, Chiong JR, Christian R, et al. Evaluation of costs associated with tolvaptan- mediated hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials. Hospit Pract 2013;40:1-8 17. Spencer FA, Emery C, Joffe SW, et al. Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study. J Thromb Thrombolysis 2009;28:401-9 18. Hansson PO, So¨rbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000; 160:769-74 19. Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1626 patients. Haematologica 2007;92:199-205 20. Analy$ource Online. San Francisco, CA: First Databank Inc.; 2013 21. Health Care Costs: A Primer. Menlo Park, CA: Kaiser Family Foundation; 2012. http://kff.org/report-section/health-care-costs-a-primer-2012-report/
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