Original Article
Is Rivaroxaban Associated With Shorter Hospital Stays and Reduced Costs Versus Parenteral Bridging to Warfarin Among Patients With Pulmonary Embolism?
Clinical and Applied Thrombosis/Hemostasis 2017, Vol. 23(7) 830-837 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1076029616661415 journals.sagepub.com/home/cat
Craig I. Coleman, PharmD1, Gregory J. Fermann, MD2, Erin R. Weeda, PharmD1, Philip S. Wells, MD3, Veronica Ashton, MPH4, Concetta Crivera, PharmD, MPH4, Thomas J. Bunz, PharmD, PhD5, Peter Wildgoose, PhD4, Jeff R. Schein, DrPH, MPH4, and W. Frank Peacock, MD6
Abstract Objective: We sought to compare the length of stay (LOS) and total costs for patients with pulmonary embolism (PE) treated with either rivaroxaban or parenterally bridged warfarin. Methods: This retrospective claims analysis was performed in the Premier Database from November 2012 to March 2015. Adult patients were included if they had a hospital encounter for PE (an International Classification of Diseases, Ninth Revision code ¼ 415.1) in the primary position, a claim for 1 diagnostic test for PE on day 0 to 2, and initiated rivaroxaban or parenteral anticoagulation/warfarin. Rivaroxaban users (allowing 2 days of prior parenteral therapy) were 1:1 propensity score matched to patients receiving parenterally bridged warfarin. Length of stay, total costs, and readmission for venous thromboembolism (VTE) or major bleeding during the same or subsequent 2 months following the index event were compared between cohorts. Analysis restricted to patients with low-risk PE was also performed. Results: Characteristics of the matched PE cohorts (n ¼ 3466 per treatment) were well balanced. Rivaroxaban use was associated with a 1.36-day shorter LOS and $2304 reduction in total costs compared to parenterally bridged warfarin (P < .001 for both). Rates of readmission for VTE were similar between cohorts (1.7% vs 1.6%; P ¼ .64). No difference was observed between treatments for readmission for major bleeding (0.2% vs 0.2%; P > .99). In analyses restricted to low-risk patients (n ¼ 1551 per treatment), rivaroxaban was associated with a 1.01-day and a $1855 reduction in LOS and costs, respectively (P < .001 for both). Rates of readmission were again similar between treatments (P > .56 for all). Conclusion: Rivaroxaban significantly reduced hospital LOS and costs compared to parenterally bridged warfarin, without increasing the risk of readmission. Keywords rivaroxaban, warfarin, bridging therapy, pulmonary embolism, anticoagulation
Introduction Traditional long-term oral anticoagulation therapy for patients presenting with acute symptomatic pulmonary embolism (PE) consisted of warfarin.1 However, because warfarin requires several days to become therapeutic, ‘‘bridging’’ therapy (transition from an immediate acting agent to warfarin) is required. During this time period, patients receive both agents and often remain in the hospital for close anticoagulation monitoring. Rivaroxaban is a direct, oral factor Xa inhibitor approved to treat and reduce the risk of recurrent venous thromboembolism (VTE) and does not require bridging therapy or anticoagulation monitoring. In the North American patient subset of the pivotal EINSTEIN randomized clinical trial (RCT), rivaroxaban significantly reduced index hospitalization length of stay (LOS) in
1
School of Pharmacy, University of Connecticut, Storrs, CT, USA Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, USA 3 Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada 4 Janssen Scientific Affairs, LLC, Raritan, NJ, USA 5 New England Health Analytics, LLC, Granby, CT, USA 6 Department of Emergency Medicine, Baylor College of Medicine, Houston, TX, USA 2
Corresponding Author: Craig I. Coleman, School of Pharmacy, University of Connecticut, 69 North Eagleville Road, Storrs, CT 06269, USA. Email:
[email protected]
Coleman et al PE patients by a mean of 1.7 days (P ¼ .0002).2 To date, no real-world study has confirmed these clinical trial results. The primary objective of this study was to determine whether rivaroxaban was associated with a reduced hospital LOS compared to parenteral bridging to warfarin in patients with PE treated outside of a clinical trial setting. Secondary objectives included total hospital costs and readmission for recurrent VTE or major bleeding.
Methods This retrospective claims study used Premier Perspective Comparative Hospital Database data from November 2012 to March 2015. The Premier database captures *20% of all acute care hospital discharges in the United States. This database was chosen as it provides highly granular data regarding the hospital encounters including a date-stamped listing of all charged items at the individual patient level including medications, laboratory and diagnostic tests, therapeutic services, discharge status, and subsequent hospital encounters or readmissions over time. Data in this database are deidentified and fully compliant with all Health Insurance Portability and Accountability Act (HIPAA) privacy and security requirements to protect participant anonymity and confidentiality. We included adult patients (18 years of age) if they had a hospital encounter for PE (including those restricted to the emergency department [ED], coded as an observation stay, or that resulted in an admission to an inpatient bed), an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code for PE (ICD-9-CM: 415.1x) in the primary position, 1 claim for a diagnostic test for PE (computed tomography, ventilation-perfusion scan, or pulmonary angiography) on day 0 to 2 and treated with either rivaroxaban or parenteral anticoagulation (unfractionated [UFH], low-molecular-weight heparin, or fondaparinux) and warfarin. Consistent with the EINSTEIN PE RCT,3 rivaroxaban patients were allowed to receive 10%. In the full PE analysis cohort, rivaroxaban use was associated with a 1.36-day shorter LOS (P < .001) and US$2304 reduction in total costs (P < .001) compared to parenteral bridging to warfarin (Table 3). Rates of readmission for VTE were similar between cohorts (P ¼ .64) as were rates of readmission due to major bleeding (P > .99). The mean hospital LOS for the low-risk cohort was lower than that of the overall cohort (3.35 + 2.2 vs 3.92 + 2.87); however, the association between rivaroxaban use and LOS and costs remained similar. Rivaroxaban users had a 1.01day and US$1857 reduction in LOS and total costs,
respectively (P < .001 for both). The rates of readmission for VTE or major bleeding were similar between rivaroxaban users and those bridged to warfarin (P ¼ .90 for VTE and P ¼ .56 for major bleeding).
Discussion This large claims database analysis of nearly 7000 patients with acute PE suggests rivaroxaban use was associated with significantly reduced length of hospital stay and total costs compared to parenteral bridging to warfarin. Moreover, the reductions in LOS and costs were achieved without increasing the short-term risk of adverse events including in readmission for VTE or major bleeding. The benefits of rivaroxaban remained even
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Table 2. Patient Demographics, Clinical, and Hospital Characteristics of Low-Risk Matched Rivaroxaban and Parenteral Bridging to Warfarin Users.
Characteristics Demographics Age 18-24 years 25-34 years 35-44 years 45-54 years 55-64 years Male gender Race White Black Other Marital status Married Single Other Payer Managed care Medicare Medicaid Commercial Self-pay Other Year of admission 2012 2013 2014 2015 Hospital characteristics Urban Large (500 beds) Teaching Region South Midwest Northeast West Admitting physician specialty Internal medicine Cardiology Emergency medicine Pulmonary Other Degree of severitya Minor Moderate Major Extreme Other Comorbid conditions, included in claimsbased rule Myocardial infarction Chronic lung disease Cerebrovascular disease (stroke) Prior major bleeding
Total n (%), N ¼ 3102
191 484 801 871 755 1516
(6.2) (15.6) (25.8) (28.1) (24.3) (48.9)
Rivaroxaban n (%), N ¼ 1551
96 238 407 432 378 750
(6.2) (15.3) (26.2) (27.9) (24.4) (48.4)
Parenteral Bridging to Warfarin, n (%) N ¼ 1551
95 246 394 439 377 766
Standardized Difference (%)
(6.1) (15.9) (25.4) (28.3) (24.3) (49.4)
0.42 1.65 1.83 0.89 0.23 2.00
2182 (70.3) 615 (19.8) 305 (9.8)
1069 (68.9) 316 (20.4) 166 (10.7)
1113 (71.8) 299 (19.3) 139 (9.0)
6.35 2.76 5.71
1463 (47.2) 1254 (40.4) 382 (12.3)
739 (47.6) 621 (40.0) 188 (12.1)
724 (46.7) 633 (40.8) 194 (12.5)
1.80 1.63 1.22
1567 296 437 446 198 158
(50.5) (9.5) (14.1) (14.4) (6.4) (5.1)
786 144 205 231 105 80
(50.7) (9.3) (13.2) (14.9) (6.8) (5.2)
781 152 232 215 93 78
(50.4) (9.8) (15.0) (13.9) (6.0) (5.0)
0.60 1.70 5.17 2.85 3.27 0.91
49 895 1690 468
(1.6) (28.9) (54.5) (15.1)
23 430 846 252
(1.5) (27.7) (54.5) (16.2)
26 465 844 216
(1.7) (30.0) (54.4) (13.9)
1.59 5.08 0.20 6.44
1285 (82.8) 302 (19.5) 504 (32.5)
5.15 4.22 6.96
2599 (83.8) 631 (20.3) 1059 (34.1)
1314 (84.7) 329 (21.2) 555 (35.8)
1736 708 364 294
(56.0) (22.8) (11.7) (9.5)
855 368 193 135
(55.1) (23.7) (12.4) (8.7)
881 340 177 159
(56.8) (21.9) (11.0) (10.3)
3.42 4.29 4.36 5.46
2519 51 99 64 369
(81.2) (1.6) (3.2) (2.1) (11.9)
1252 33 51 31 184
(80.7) (2.1) (3.3) (2.0) (11.9)
1267 18 48 33 185
(81.7) (1.2) (3.1) (2.1) (11.9)
2.56 7.07 1.14 0.71 0
1069 1138 318 22 555
(34.5) (36.7) (10.3) (0.7) (17.9)
549 559 153 6 284
(35.4) (36.0) (9.9) (0.4) (18.3)
520 579 165 16 271
(33.5) (37.3) (10.6) (1.0) (17.5)
4.00 2.70 2.31 7.20 2.09
2 259 2 5
(0.1) (8.3) (0.1) (0.2)
1 128 1 2
(0.1) (8.3) (0.1) (0.1)
1 131 1 3
(0.1) (8.4) (0.1) (0.1)
0 0.36 0 0 (continued)
Coleman et al
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Table 2. (continued)
Characteristics Atrial fibrillation Cognitive impairment (dysfunction) Heart failure Renal failure Liver disease (dysfunction) Coagulopathy Cancer Comorbid conditions, AHRQ-29 comorbidity measure AIDS Alcohol abuse Deficiency anemias Rheumatoid arthritis/collagen vascular diseases Chronic blood loss anemia Depression Diabetes, uncomplicated Diabetes, with chronic complications Drug abuse Hypertension Hypothyroidism Lymphoma Fluid and electrolyte disorders Metastatic cancer Other neurological disorders Obesity Paralysis Peripheral vascular disease Psychosis Solid tumor without metastasis Peptic ulcer disease excluding bleeding Valvular disease Weight loss Unmatched characteristics Diagnosis via CT Time to diagnosis, days (mean + SD) IMPACT estimated mortality risk, % (mean + SD)
Total n (%), N ¼ 3102
Rivaroxaban n (%), N ¼ 1551
Parenteral Bridging to Warfarin, n (%) N ¼ 1551
Standardized Difference (%)
21 0 15 8 23 21 0
(0.7) (0) (0.5) (0.3) (0.7) (0.7) (0)
14 0 8 3 10 14 0
(0.9) (0) (0.5) (0.2) (0.6) (0.9) (0)
7 0 7 5 13 7 0
(0.5) (0) (0.5) (0.3) (0.8) (0.5) (0)
4.80 0 0 2.00 2.40 4.80 0
3 54 203 81
(0.1) (1.7) (6.5) (2.6)
1 33 107 40
(0.1) (2.1) (6.9) (2.6)
2 21 96 41
(0.1) (1.4) (6.2) (2.6)
0 5.34 2.83 0
11 340 68 10 125 987 32 0 177 0 13 658 15 34 106 0 1 88 17
(0.4) (11.0) (2.2) (0.3) (4.0) (31.8) (1.0) (0) (5.7) (0) (0.4) (21.2) (0.5) (1.1) (3.4) (0) (0.1) (2.8) (0.5)
7 173 40 6 55 496 16 0 94 0 7 315 8 17 55 0 0 46 9
(0.5) (11.2) (2.6) (0.4) (3.5) (32.0) (1.0) (0) (6.1) (0) (0.5) (20.3) (0.5) (1.1) (3.5) (0) (0) (3.0) (0.6)
4 167 28 4 70 491 16 0 83 0 6 343 7 17 51 0 1 42 8
(0.3) (10.8) (1.8) (0.3) (4.5) (31.7) (1.0) (0) (5.4) (0) (0.4) (22.1) (0.5) (1.1) (3.3) (0) (0.1) (2.7) (0.5)
3.17 1.28 5.46 1.69 5.10 0.64 0 0 3.01 0 1.49 0.50 0 0 1.10 0 4.47 0.56 1.35
3003 (97.8) 0.94 + 0.4 1.0 + 0.3
1514 (97.6) 0.95 + 0.4 1.0 + 0.3
1519 (97.9) 0.92 + 0.4 1.0 + 0.3
– – –
Abbreviations: AHRQ-29, Agency for Healthcare Research and Quality 29; CT, computed tomography; IMPACT, in-hospital mortality for pulmonary embolism using claims data; MI, myocardial infarction; N, number; SD, standard deviation. a Determined by All Patient Refined Diagnosis-Related Groups (APR-DRG) coding.
when administered to PE patients classified as ‘‘low risk,’’ and by default, reduced LOS and treatment costs. The reductions in LOS seen with rivaroxaban versus parenteral bridging to warfarin in our study are consistent with prior research.2,3,7 van Bellen and colleagues7 evaluated the differences in LOS in the intention-to-treat population of EINSTEIN PE (n ¼ 4821 patients with acute symptomatic PE with or without deep vein thrombosis) randomized to receive either rivaroxaban (n ¼ 2419) or enoxaparin bridging to a vitamin K antagonist (VKA; n ¼ 2413). That analysis demonstrated LOS was significantly shorter in patients who received rivaroxaban than in those who received enoxaparin/VKA (exponentiated least square
mean of log-transformed LOS ¼ 6.6 vs 7.5 days, respectively; difference ¼ 0.9 days; P < .0001). Bookhart and colleagues2 evaluated the impact of rivaroxaban on LOS among 321 hospitalized acute symptomatic PE patients recruited into EINSTEIN PE in North American sites. In these patients with PE, rivaroxaban use resulted in a 1.7day mean reduction in LOS compared with enoxaparin/ VKA (4.5 vs 6.2 days; P ¼ .0002). The researcher’s further projected rivaroxaban use (vs enoxaparin/VKA) would reduce total hospital treatment costs by *$3000 per patient stay (based on estimated AHRQ Healthcare Cost and Utilization Project data suggesting the cost of an average hospital day to treat PE was $1842).
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Table 3. Outcomes in the Overall and Low-Risk Pulmonary Embolism–Matched Rivaroxaban and Parenteral Bridging to Warfarin Cohorts.
End Point All PE patients LOS, days (mean + SD) Total hospital costs, 2015 US$ (mean + SD) Readmission for recurrent VTE during the same or subsequent 2 months following the index PE, n (%) Re-admission for major bleeding during the same or subsequent 2 months following the index PE, n (%) Low-risk PE patients LOS, days (mean + SD) Total hospital costs, 2015 US$ (mean + SD) Readmission for VTE during the same or subsequent 2 months following the index PE, n (%) Readmission for major bleeding during the same or subsequent 2 months following the index PE, n (%)
Rivaroxaban
Parenteral Bridging to Warfarin
P Value
N ¼ 3466 N ¼ 3466 3.24 + 1.81 4.60 + 3.50
