Current Medical Research & Opinion
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0300-7995 doi:10.1185/03007995.2015.1037728
2015, 1–5
Article FT-0057.R1/1037728 All rights reserved: reproduction in whole or part not permitted
Brief report Shortened length of hospital stay with rivaroxaban in patients with symptomatic venous thromboembolism in Japan: the J-EINSTEIN pulmonary embolism and deep vein thrombosis program
Hiroshi Matsuo
Abstract
Matsuo Clinic, Osaka, Japan
Martin Prins University of Maastricht, Maastricht, The Netherlands
Anthonie W.A. Lensing Bayer HealthCare Pharmaceuticals, Wuppertal, Germany
Emi Watanabe Fujinuma Yuki Miyamoto Mariko Kajikawa Bayer Yakuhin Ltd, Osaka, Japan Address for correspondence: Hiroshi Matsuo MD PhD, Matsuo Clinic, 2-15-25 Kitahonmachi, Yao-city, Osaka, Japan 581-0802. Tel: +81 72-991-6586; [email protected] Keywords: Deep vein thrombosis – Japan – Length of stay – Pulmonary embolism – Randomized trial – Rivaroxaban – Unfractionated heparin – Venous thromboembolism – Warfarin Accepted: 31 March 2015; published online: 11 May 2015 Citation: Curr Med Res Opin 2015; 1–5
Background: In Japan, the standard of care for the treatment of pulmonary embolism (PE) and/or deep vein thrombosis (DVT) consists of intravenous unfractionated heparin (UFH) followed by warfarin, which was recently compared with rivaroxaban, an oral factor Xa inhibitor, in randomized trials. Aim: To examine the length of hospital stay in patients with PE and/or DVT receiving rivaroxaban compared to Japanese standard therapy in the Japanese (J)-EINSTEIN PE and DVT program. Methods: Open-label, randomized clinical trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in patients with acute, confirmed symptomatic proximal PE and/or DVT. Decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Analyses were conducted in the intention-to-treat (ITT) population. Results: In the ITT population (N ¼ 97), overall patient characteristics were similar in both treatment arms. The median length of stay in rivaroxaban patients was 10.0 days (interquartile range [IQR] 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0) for patients on standard therapy (p ¼ 0.016). All of the four DVT patients who were not hospitalized for the index event were in the rivaroxaban arm. Conclusions: Our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. The limitations of our study include small sample size and the generalizability of the findings to the real-world setting. Further research is warranted to identify PE and/or DVT patients in Japanese clinical practice who may potentially be managed as outpatients. Trial registration: Clinicaltrials.gov: NCT01516814 and NCT01516840.
Introduction Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disorder associated with ! 2015 Informa UK Ltd www.cmrojournal.com
Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
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Current Medical Research & Opinion
2015
significant mortality and morbidity1,2. In Japan, awareness of the disease in the general public remains low, and the clinical, economic, and societal burden of the disease has not been well established3. The recommended regimen of therapy for the treatment of VTE according to the Japanese guidelines consists of intravenous unfractionated heparin (UFH) overlapping with and followed by warfarin, with a target international normalized ratio (INR) range of 1.5–2.54. This treatment regimen is complex and associated with a number of limitations, including intravenous administration of UFH, and the need for laboratory monitoring and dose adjustment for both UFH and warfarin5,6. The most important difference between the recommended therapy in Japan and other parts of the world is the use of intravenously administered UFH instead of subcutaneously injected low molecular weight heparin (LMWH) or fondaparinux as the initial treatment4. Indeed, according to a recent VTE treatment registry (JAVA), the majority (i.e., over 90%) of patients with VTE in Japan received in-hospital treatment with intravenous UFH3. Rivaroxaban is an oral, specific, direct inhibitor of activated Factor X that does not require dose adjustment or laboratory monitoring7. It was evaluated in a large, global clinical program in patients with symptomatic PE with or without DVT (EINSTEIN PE) or symptomatic DVT without PE (EINSTEIN DVT)8,9,10. Rivaroxaban was found to be non-inferior in VTE recurrence to standard treatment with LMWH overlapping with and followed by a vitamin K antagonist. In addition, it was associated with a reduced incidence of major bleeding10,11. In this global program, rivaroxaban was also associated with a significant reduction in length of hospital stay for the index PE or DVT despite the option to use LMWH which can be easily administered at home for initial treatment12. Consequently, a larger proportion of patients who received rivaroxaban were discharged within the first 5 days of initial hospitalization compared to those who received enoxaparin/vitamin K antagonist treatment, reducing the burden of treatment for patients on rivaroxaban12. In the Japanese (J)-EINSTEIN PE and DVT program that compared rivaroxaban to the Japanese standard therapy, rivaroxaban had a similar efficacy and safety profile compared to the control treatment13. In the current analysis, we examined the length of hospital stay in Japanese patients receiving rivaroxaban compared to Japanese standard therapy in this program.
Methods The J-EINSTEIN PE and DVT program included openlabel, randomized controlled trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in 2
Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
patients older than 20 years who had acute, objectively confirmed symptomatic PE and/or proximal DVT. Patients with PE received rivaroxaban 15 mg twice daily for 3 weeks followed by 15 mg once daily. Patients with DVT received rivaroxaban 10 mg or 15 mg twice daily for a total of 3 weeks in a double-blind fashion, followed by open-label rivaroxaban 15 mg once daily. The dose of rivaroxaban in the maintenance phase was lower in the J-EINSTEIN PE/DVT program compared with that in the global EINSTEIN PE/DVT program, as the exposure levels to the corresponding doses were estimated to be comparable in Japanese and Caucasian patients. Patients assigned to control treatment received intravenous UFH for at least 5 days, with the dose adjusted to prolong the activated partial thromboplastin time 1.5–2.5-fold that of controls. UFH was overlapping with and followed by warfarin which was titrated to an INR range of 1.5 to 2.5. Treatment was continued for 3, 6, or 12 months, as decided by the attending physician, and decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Admission and discharge dates were recorded. The program was sponsored by Bayer Yakuhin Ltd, Japan. The protocols were approved by the local institutional review boards, and written informed consent was obtained from all patients. The details of the program have been described elsewhere13.
Statistical analysis Analyses were conducted in the intention-to-treat (ITT) population. For nine patients whose data indicated no hospitalization throughout the trial period, the respective attending physicians or trial coordinators were contacted to verify the data based on the hospital records or trial monitoring records. Chi-square and Student’s t tests were used for the analysis of categorical and continuous variables, respectively. Non-parametric statistical analysis was performed using a Mann–Whitney U test comparing the two treatment groups. The results were considered statistically significant at the level of p50.05.
Results Patients A total of 97 patients were included in the ITT population, with 78 in the rivaroxaban arm (30 patients with PE with or without DVT, and 48 patients with DVT only) and 19 in the UFH/warfarin arm (7 patients with PE, and 12 patients with DVT) (Table 1). Overall, patient characteristics were similar in both treatment arms. www.cmrojournal.com ! 2015 Informa UK Ltd
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Table 1. Baseline characteristics of enrolled patients (ITT population).
Sex, male, n (%) Age, years, mean (SD) Body weight 570 kg, n (%) Creatinine clearance 580 ml/min, n (%) DVT only, n (%) Unprovoked VTE, n (%) Provoked VTE, n (%) Previous VTE, n (%) Recent surgery or trauma, n (%) Active cancer, n (%) Prolonged immobilization, n (%) Mean treatment duration, days (SD)
Rivaroxaban 10 mg bid/15 mg qd (N ¼ 23)
Rivaroxaban 15 mg bid/15 mg qd (N ¼ 55)
UFH/warfarin (N ¼ 19)
16 (69.6) 65.0 (9.9) 15 (65.2) 9 (39.1) 23 (100.0) 11 (47.8) 12 (52.2) 0 6 (26.1) 2 (8.7) 3 (13.0) 191.8 (106.9)
25 (45.5) 68.8 (12.2) 41 (74.5) 36 (65.5) 25 (45.5) 31 (56.4) 24 (43.6) 8 (14.5) 11 (20.0) 3 (5.5) 8 (14.5) 196.6 (121.7)
10 (52.6) 63.4 (18.3) 15 (78.9) 11 (57.9) 12 (63.2) 8 (42.1) 11 (57.9) 1 (5.3) 2 (10.5) 2 (10.5) 4 (21.1) 199.8 (101.9)
bid, twice daily; DVT, deep vein thrombosis; qd, once daily; SD, standard deviation; UFH, unfractionated heparin; VTE, venous thromboembolism.
Length of stay The median length of stay in rivaroxaban patients was 10.0 days (IQR 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0 days) for patients on standard therapy (Table 2). This difference was highly statistically significant (p ¼ 0.016). The minimum and maximum lengths of stay for rivaroxaban patients were 0.0 days and 52.0 days, while they were 5.0 days and 29.0 days for UFH/warfarin patients, respectively. There were 4 (5.1%) patients who were not hospitalized for the index event in the rivaroxaban arm, and all of them were DVT patients. All patients in UFH/warfarin arm were hospitalized for their index PE or DVT events. Thirteen (16.7%) of the 78 patients treated with rivaroxaban and 1 (5.3%) of the 19 treated with standard therapy were discharged within 5 days (p ¼ 0.059). When PE and DVT patients were analyzed separately, the median length of stay for DVT patients in the rivaroxaban arm was 8.0 days (IQR 4.0 to 15.0 days), and that in the UFH/warfarin arm was 15.5 days (IQR 9.5 to 19.5 days). In PE patients, the median length of stay in the rivaroxaban arm was 11.0 days (IQR 9.0 to 16.0 days), while that in the UFH/warfarin arm was 13.0 days (IQR 9.0 to 22.0 days).
Discussion The results of this study showed a significant reduction in length of hospital stay in patients with acute symptomatic PE and/or DVT who received rivaroxaban compared with those who received UFH/warfarin in the Japanese EINSTEIN PE/DVT trials. This reduction in the length of stay may be due to the high proportion of patients in the UFH/warfarin arm who remained in hospital until an adequate INR level was achieved12. Indeed, only 1 of 19 patients on standard treatment with intravenous UFH and warfarin versus approximately 1 in 5 patients on rivaroxaban were discharged within 5 days. Moreover, 4 DVT patients who were not hospitalized for the index event ! 2015 Informa UK Ltd www.cmrojournal.com
Table 2. Descriptive comparison of length of initial hospitalization. Rivaroxaban (N ¼ 78) Median length of stay 10.0 (6.0–15.0) (days, IQR) Min–max (days) 0.0–52.0 Length of hospitalization Not hospitalized 4 (5.1%) 1-5 days 13 (16.7%) 6-13 days 34 (43.6%) 13þ days 27 (34.6%)
UFH/warfarin (N ¼ 19)
p Value
15.0 (9.0–22.0)
0.016
5.0–29.0 0.059 0 (0.0%) 1 (5.3%) 8 (42.1%) 10 (52.6%)
IQR, interquartile range; min, minimum; max, maximum. One patient who was randomized to rivaroxaban did not receive rivaroxaban and stayed in the hospital for 11 days.
were all in the rivaroxaban arm. This may indicate the potential benefit of rivaroxaban in enabling outpatient treatment of DVT throughout the treatment regimen. The reduction in length of stay in favor of rivaroxaban was consistent with that observed in the global program, although the length of stay in Japan was considerably longer compared to the global EINSTEIN PE/DVT program (Table 3). In addition to the structure of hospital payments in Japan which incentivizes prolonged hospital stay14, it is likely that cultural differences in treatment behavior have also played an important role in the length of hospital stay. The median length of stay in the EINSTEIN PE and DVT trials were 6.0 and 5.0 days for rivaroxaban patients, respectively, and 7.0 and 8.0 days for enoxaparin/warfarin patients, respectively (both p50.0001). However, in the Asian region, patients of the global EINSTEIN PE and DVT studies had a far longer median length of stay, with 13.0 and 12.0 days in the rivaroxaban arm, and 16.5 and 15.0 days in enoxaparin/warfarin arm, respectively (data not shown)12,15. The strengths of our study include its randomized design with comparable patient groups in each arm and a Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
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Table 3. Length of stay in EINSTEIN PE and DVT trials. EINSTEIN PE
Not hospitalized Hospitalized Median length of stay (days, IQR)
EINSTEIN DVT
Rivaroxaban (n ¼ 2412)
Enoxaparin/warfarin (n ¼ 2409)
Rivaroxaban (n ¼ 1723)
Enoxaparin/warfarin (n ¼ 1711)
249 (10.3%) 2163 (89.7%) 6.0y (4.0–9.0)
244 (10.1) 2409 (89.9%) 7.0 (5.0–10.0)
851 (49.4%) 872 (50.6%) 5.0y (3.0–9.0)
802 (46.9%) 909 (53.1%) 8.0 (4.0–10.0)
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IQR, interquartile range. yp50.0001.
consistent clinical care setting. The randomized design also excludes the possibility of treatment selection based on clinical severity, which could have caused bias. In addition, the protocols did not give guidance for hospitalization practices, which was left to the discretion of the attending physician. The main limitation of this study is the small sample size, which only allowed descriptive analyses that were not stratified by factors that could have affected the length of stay, such as pre-specified intended periods of treatment, age or comorbidity. However, the findings were similar to those reported in the global EINSTEIN PE and DVT program, and length of hospital stay and rate of hospitalization in the initial treatment did not differ by the intended treatment period in these trials. Another limitation is the generalizability of our findings from randomized clinical trials to the real-world setting. Patients included in our trials may not be representative of the Japanese PE and DVT population, and their characteristics and care provided in the participating hospitals may differ from those in hospitals that did not participate in the trials. Patient care was likely more strictly monitored and controlled in the trials than in the real-world setting, which may have affected clinical decisions, such as hospital admissions, discharges and timing of treatments.
Declaration of financial/other relationships H.M. has disclosed that he was a paid consultant of Bayer Yakuhin Ltd, Japan in the current analysis, and a member of the J-EINSTEIN data monitoring committee. M.P. has disclosed that he is a consultant advisor for Bayer HealthCare Pharmaceuticals AG. A.W.A.L. has disclosed that he is an employee of Bayer HealthCare Pharmaceuticals AG. E.W.F., Y.M. and M.K. have disclosed that they are employees of Bayer Yakuhin Ltd, Japan. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose. Acknowledgments Members of the J-EINSTEIN study group and affiliations are as follows. Coordinate investigator: Norikazu Yamada, Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Mie, Japan. Central independent adjudication committee (CIAC): Martin H. Prins, Maastricht University Medical Center, Maastricht, The Netherlands. Data monitoring committee (DMC): Shotai Kobayashi, Shimane University Faculty of Medicine, Matsue, Japan; Hiroshi Matsuo, Matsuo Vascular Ultrasound Laboratory, Matsuo Clinic, Suita, Osaka, Japan; Hideki Origasa, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan. We thank Adelphi Values LLC for performing statistical analyses in the current study.
References Conclusion In conclusion, our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. Further research is warranted to identify PE and DVT patients in Japanese clinical practice who may potentially be managed as outpatients.
Transparency Declaration of funding The program was funded by Bayer Yakuhin Ltd, Japan. 4
Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
1. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7 2. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64 3. Nakamura M, Miyata T, Ozeki Y, et al. Current venous thromboembolism management and outcomes in Japan: nationwide the Japan venous thromboembolism treatment registry observational study. Circ J 2014;78:708-71 4. JCS Joint Working Group. Guidelines for the diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2009). Circ J 2011;75:1258-81 5. Simonneau G, Sors H, Charbonnier B, et al. A comparison of lowmolecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997;337:663-9 6. Bu¨ller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695-702
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12. Van Bellen B, Bamber L, Correa de Carvalho F, et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014;30: 829-37 13. Yamada N, Hirayama A, Maeda H, et al. Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism – the J-EINSTEIN DVT and PE program. Thromb J 2015;13:2 14. OECD. Health at a Glance 2011: OECD Indicators. Paris: OECD Publishing, 2011. Available at: DOI: http://dx.doi.org/10.1787/health_glance-2011-en [Last accessed February 2015] 15. Wang Y, Wang C, Chen Z, et al. Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies. Thromb J 2013;11:25-32
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7. Sarich TC, Peters G, Berkowitz SD, et al. Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions. Ann NY Acad Sci 2013;1291:42-55 8. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510 9. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97 10. Prins MH, Lensing AWA, Bauersachs R, et al; on behalf of the EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEINDVT and PE randomized studies. Thromb J 2013;11:21-30 11. Prins MH, Lensing AWA. Derivation of the non-inferiority margin for the evaluation of direct oral anticoagulants in the treatment of venous thromboembolism. Thromb J 2013;11:13-18
2015
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0300-7995 doi:10.1185/03007995.2015.1037728
2015, 1–5
Article FT-0057.R1/1037728 All rights reserved: reproduction in whole or part not permitted
Brief report Shortened length of hospital stay with rivaroxaban in patients with symptomatic venous thromboembolism in Japan: the J-EINSTEIN pulmonary embolism and deep vein thrombosis program
Hiroshi Matsuo
Abstract
Matsuo Clinic, Osaka, Japan
Martin Prins University of Maastricht, Maastricht, The Netherlands
Anthonie W.A. Lensing Bayer HealthCare Pharmaceuticals, Wuppertal, Germany
Emi Watanabe Fujinuma Yuki Miyamoto Mariko Kajikawa Bayer Yakuhin Ltd, Osaka, Japan Address for correspondence: Hiroshi Matsuo MD PhD, Matsuo Clinic, 2-15-25 Kitahonmachi, Yao-city, Osaka, Japan 581-0802. Tel: +81 72-991-6586; [email protected] Keywords: Deep vein thrombosis – Japan – Length of stay – Pulmonary embolism – Randomized trial – Rivaroxaban – Unfractionated heparin – Venous thromboembolism – Warfarin Accepted: 31 March 2015; published online: 11 May 2015 Citation: Curr Med Res Opin 2015; 1–5
Background: In Japan, the standard of care for the treatment of pulmonary embolism (PE) and/or deep vein thrombosis (DVT) consists of intravenous unfractionated heparin (UFH) followed by warfarin, which was recently compared with rivaroxaban, an oral factor Xa inhibitor, in randomized trials. Aim: To examine the length of hospital stay in patients with PE and/or DVT receiving rivaroxaban compared to Japanese standard therapy in the Japanese (J)-EINSTEIN PE and DVT program. Methods: Open-label, randomized clinical trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in patients with acute, confirmed symptomatic proximal PE and/or DVT. Decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Analyses were conducted in the intention-to-treat (ITT) population. Results: In the ITT population (N ¼ 97), overall patient characteristics were similar in both treatment arms. The median length of stay in rivaroxaban patients was 10.0 days (interquartile range [IQR] 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0) for patients on standard therapy (p ¼ 0.016). All of the four DVT patients who were not hospitalized for the index event were in the rivaroxaban arm. Conclusions: Our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. The limitations of our study include small sample size and the generalizability of the findings to the real-world setting. Further research is warranted to identify PE and/or DVT patients in Japanese clinical practice who may potentially be managed as outpatients. Trial registration: Clinicaltrials.gov: NCT01516814 and NCT01516840.
Introduction Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common disorder associated with ! 2015 Informa UK Ltd www.cmrojournal.com
Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
1
Curr Med Res Opin Downloaded from informahealthcare.com by Nyu Medical Center on 05/13/15 For personal use only.
Current Medical Research & Opinion
2015
significant mortality and morbidity1,2. In Japan, awareness of the disease in the general public remains low, and the clinical, economic, and societal burden of the disease has not been well established3. The recommended regimen of therapy for the treatment of VTE according to the Japanese guidelines consists of intravenous unfractionated heparin (UFH) overlapping with and followed by warfarin, with a target international normalized ratio (INR) range of 1.5–2.54. This treatment regimen is complex and associated with a number of limitations, including intravenous administration of UFH, and the need for laboratory monitoring and dose adjustment for both UFH and warfarin5,6. The most important difference between the recommended therapy in Japan and other parts of the world is the use of intravenously administered UFH instead of subcutaneously injected low molecular weight heparin (LMWH) or fondaparinux as the initial treatment4. Indeed, according to a recent VTE treatment registry (JAVA), the majority (i.e., over 90%) of patients with VTE in Japan received in-hospital treatment with intravenous UFH3. Rivaroxaban is an oral, specific, direct inhibitor of activated Factor X that does not require dose adjustment or laboratory monitoring7. It was evaluated in a large, global clinical program in patients with symptomatic PE with or without DVT (EINSTEIN PE) or symptomatic DVT without PE (EINSTEIN DVT)8,9,10. Rivaroxaban was found to be non-inferior in VTE recurrence to standard treatment with LMWH overlapping with and followed by a vitamin K antagonist. In addition, it was associated with a reduced incidence of major bleeding10,11. In this global program, rivaroxaban was also associated with a significant reduction in length of hospital stay for the index PE or DVT despite the option to use LMWH which can be easily administered at home for initial treatment12. Consequently, a larger proportion of patients who received rivaroxaban were discharged within the first 5 days of initial hospitalization compared to those who received enoxaparin/vitamin K antagonist treatment, reducing the burden of treatment for patients on rivaroxaban12. In the Japanese (J)-EINSTEIN PE and DVT program that compared rivaroxaban to the Japanese standard therapy, rivaroxaban had a similar efficacy and safety profile compared to the control treatment13. In the current analysis, we examined the length of hospital stay in Japanese patients receiving rivaroxaban compared to Japanese standard therapy in this program.
Methods The J-EINSTEIN PE and DVT program included openlabel, randomized controlled trials that compared 3, 6, or 12 months of rivaroxaban with UFH and warfarin in 2
Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
patients older than 20 years who had acute, objectively confirmed symptomatic PE and/or proximal DVT. Patients with PE received rivaroxaban 15 mg twice daily for 3 weeks followed by 15 mg once daily. Patients with DVT received rivaroxaban 10 mg or 15 mg twice daily for a total of 3 weeks in a double-blind fashion, followed by open-label rivaroxaban 15 mg once daily. The dose of rivaroxaban in the maintenance phase was lower in the J-EINSTEIN PE/DVT program compared with that in the global EINSTEIN PE/DVT program, as the exposure levels to the corresponding doses were estimated to be comparable in Japanese and Caucasian patients. Patients assigned to control treatment received intravenous UFH for at least 5 days, with the dose adjusted to prolong the activated partial thromboplastin time 1.5–2.5-fold that of controls. UFH was overlapping with and followed by warfarin which was titrated to an INR range of 1.5 to 2.5. Treatment was continued for 3, 6, or 12 months, as decided by the attending physician, and decisions regarding hospital admission and/or discharge were left to the clinical judgment of attending physicians. Admission and discharge dates were recorded. The program was sponsored by Bayer Yakuhin Ltd, Japan. The protocols were approved by the local institutional review boards, and written informed consent was obtained from all patients. The details of the program have been described elsewhere13.
Statistical analysis Analyses were conducted in the intention-to-treat (ITT) population. For nine patients whose data indicated no hospitalization throughout the trial period, the respective attending physicians or trial coordinators were contacted to verify the data based on the hospital records or trial monitoring records. Chi-square and Student’s t tests were used for the analysis of categorical and continuous variables, respectively. Non-parametric statistical analysis was performed using a Mann–Whitney U test comparing the two treatment groups. The results were considered statistically significant at the level of p50.05.
Results Patients A total of 97 patients were included in the ITT population, with 78 in the rivaroxaban arm (30 patients with PE with or without DVT, and 48 patients with DVT only) and 19 in the UFH/warfarin arm (7 patients with PE, and 12 patients with DVT) (Table 1). Overall, patient characteristics were similar in both treatment arms. www.cmrojournal.com ! 2015 Informa UK Ltd
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2015
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Table 1. Baseline characteristics of enrolled patients (ITT population).
Sex, male, n (%) Age, years, mean (SD) Body weight 570 kg, n (%) Creatinine clearance 580 ml/min, n (%) DVT only, n (%) Unprovoked VTE, n (%) Provoked VTE, n (%) Previous VTE, n (%) Recent surgery or trauma, n (%) Active cancer, n (%) Prolonged immobilization, n (%) Mean treatment duration, days (SD)
Rivaroxaban 10 mg bid/15 mg qd (N ¼ 23)
Rivaroxaban 15 mg bid/15 mg qd (N ¼ 55)
UFH/warfarin (N ¼ 19)
16 (69.6) 65.0 (9.9) 15 (65.2) 9 (39.1) 23 (100.0) 11 (47.8) 12 (52.2) 0 6 (26.1) 2 (8.7) 3 (13.0) 191.8 (106.9)
25 (45.5) 68.8 (12.2) 41 (74.5) 36 (65.5) 25 (45.5) 31 (56.4) 24 (43.6) 8 (14.5) 11 (20.0) 3 (5.5) 8 (14.5) 196.6 (121.7)
10 (52.6) 63.4 (18.3) 15 (78.9) 11 (57.9) 12 (63.2) 8 (42.1) 11 (57.9) 1 (5.3) 2 (10.5) 2 (10.5) 4 (21.1) 199.8 (101.9)
bid, twice daily; DVT, deep vein thrombosis; qd, once daily; SD, standard deviation; UFH, unfractionated heparin; VTE, venous thromboembolism.
Length of stay The median length of stay in rivaroxaban patients was 10.0 days (IQR 6.0 to 15.0 days) while it was 15.0 days (IQR 9.0 to 22.0 days) for patients on standard therapy (Table 2). This difference was highly statistically significant (p ¼ 0.016). The minimum and maximum lengths of stay for rivaroxaban patients were 0.0 days and 52.0 days, while they were 5.0 days and 29.0 days for UFH/warfarin patients, respectively. There were 4 (5.1%) patients who were not hospitalized for the index event in the rivaroxaban arm, and all of them were DVT patients. All patients in UFH/warfarin arm were hospitalized for their index PE or DVT events. Thirteen (16.7%) of the 78 patients treated with rivaroxaban and 1 (5.3%) of the 19 treated with standard therapy were discharged within 5 days (p ¼ 0.059). When PE and DVT patients were analyzed separately, the median length of stay for DVT patients in the rivaroxaban arm was 8.0 days (IQR 4.0 to 15.0 days), and that in the UFH/warfarin arm was 15.5 days (IQR 9.5 to 19.5 days). In PE patients, the median length of stay in the rivaroxaban arm was 11.0 days (IQR 9.0 to 16.0 days), while that in the UFH/warfarin arm was 13.0 days (IQR 9.0 to 22.0 days).
Discussion The results of this study showed a significant reduction in length of hospital stay in patients with acute symptomatic PE and/or DVT who received rivaroxaban compared with those who received UFH/warfarin in the Japanese EINSTEIN PE/DVT trials. This reduction in the length of stay may be due to the high proportion of patients in the UFH/warfarin arm who remained in hospital until an adequate INR level was achieved12. Indeed, only 1 of 19 patients on standard treatment with intravenous UFH and warfarin versus approximately 1 in 5 patients on rivaroxaban were discharged within 5 days. Moreover, 4 DVT patients who were not hospitalized for the index event ! 2015 Informa UK Ltd www.cmrojournal.com
Table 2. Descriptive comparison of length of initial hospitalization. Rivaroxaban (N ¼ 78) Median length of stay 10.0 (6.0–15.0) (days, IQR) Min–max (days) 0.0–52.0 Length of hospitalization Not hospitalized 4 (5.1%) 1-5 days 13 (16.7%) 6-13 days 34 (43.6%) 13þ days 27 (34.6%)
UFH/warfarin (N ¼ 19)
p Value
15.0 (9.0–22.0)
0.016
5.0–29.0 0.059 0 (0.0%) 1 (5.3%) 8 (42.1%) 10 (52.6%)
IQR, interquartile range; min, minimum; max, maximum. One patient who was randomized to rivaroxaban did not receive rivaroxaban and stayed in the hospital for 11 days.
were all in the rivaroxaban arm. This may indicate the potential benefit of rivaroxaban in enabling outpatient treatment of DVT throughout the treatment regimen. The reduction in length of stay in favor of rivaroxaban was consistent with that observed in the global program, although the length of stay in Japan was considerably longer compared to the global EINSTEIN PE/DVT program (Table 3). In addition to the structure of hospital payments in Japan which incentivizes prolonged hospital stay14, it is likely that cultural differences in treatment behavior have also played an important role in the length of hospital stay. The median length of stay in the EINSTEIN PE and DVT trials were 6.0 and 5.0 days for rivaroxaban patients, respectively, and 7.0 and 8.0 days for enoxaparin/warfarin patients, respectively (both p50.0001). However, in the Asian region, patients of the global EINSTEIN PE and DVT studies had a far longer median length of stay, with 13.0 and 12.0 days in the rivaroxaban arm, and 16.5 and 15.0 days in enoxaparin/warfarin arm, respectively (data not shown)12,15. The strengths of our study include its randomized design with comparable patient groups in each arm and a Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
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Table 3. Length of stay in EINSTEIN PE and DVT trials. EINSTEIN PE
Not hospitalized Hospitalized Median length of stay (days, IQR)
EINSTEIN DVT
Rivaroxaban (n ¼ 2412)
Enoxaparin/warfarin (n ¼ 2409)
Rivaroxaban (n ¼ 1723)
Enoxaparin/warfarin (n ¼ 1711)
249 (10.3%) 2163 (89.7%) 6.0y (4.0–9.0)
244 (10.1) 2409 (89.9%) 7.0 (5.0–10.0)
851 (49.4%) 872 (50.6%) 5.0y (3.0–9.0)
802 (46.9%) 909 (53.1%) 8.0 (4.0–10.0)
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IQR, interquartile range. yp50.0001.
consistent clinical care setting. The randomized design also excludes the possibility of treatment selection based on clinical severity, which could have caused bias. In addition, the protocols did not give guidance for hospitalization practices, which was left to the discretion of the attending physician. The main limitation of this study is the small sample size, which only allowed descriptive analyses that were not stratified by factors that could have affected the length of stay, such as pre-specified intended periods of treatment, age or comorbidity. However, the findings were similar to those reported in the global EINSTEIN PE and DVT program, and length of hospital stay and rate of hospitalization in the initial treatment did not differ by the intended treatment period in these trials. Another limitation is the generalizability of our findings from randomized clinical trials to the real-world setting. Patients included in our trials may not be representative of the Japanese PE and DVT population, and their characteristics and care provided in the participating hospitals may differ from those in hospitals that did not participate in the trials. Patient care was likely more strictly monitored and controlled in the trials than in the real-world setting, which may have affected clinical decisions, such as hospital admissions, discharges and timing of treatments.
Declaration of financial/other relationships H.M. has disclosed that he was a paid consultant of Bayer Yakuhin Ltd, Japan in the current analysis, and a member of the J-EINSTEIN data monitoring committee. M.P. has disclosed that he is a consultant advisor for Bayer HealthCare Pharmaceuticals AG. A.W.A.L. has disclosed that he is an employee of Bayer HealthCare Pharmaceuticals AG. E.W.F., Y.M. and M.K. have disclosed that they are employees of Bayer Yakuhin Ltd, Japan. CMRO peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose. Acknowledgments Members of the J-EINSTEIN study group and affiliations are as follows. Coordinate investigator: Norikazu Yamada, Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Mie, Japan. Central independent adjudication committee (CIAC): Martin H. Prins, Maastricht University Medical Center, Maastricht, The Netherlands. Data monitoring committee (DMC): Shotai Kobayashi, Shimane University Faculty of Medicine, Matsue, Japan; Hiroshi Matsuo, Matsuo Vascular Ultrasound Laboratory, Matsuo Clinic, Suita, Osaka, Japan; Hideki Origasa, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan. We thank Adelphi Values LLC for performing statistical analyses in the current study.
References Conclusion In conclusion, our results suggest that treatment with rivaroxaban may significantly reduce the length of hospital stay in patients hospitalized for PE and/or DVT compared with the current standard of care in Japan, thereby reducing the burden on patients and the healthcare system. Further research is warranted to identify PE and DVT patients in Japanese clinical practice who may potentially be managed as outpatients.
Transparency Declaration of funding The program was funded by Bayer Yakuhin Ltd, Japan. 4
Shortened length of hospital stay with rivaroxaban in Japan Matsuo et al.
1. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7 2. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64 3. Nakamura M, Miyata T, Ozeki Y, et al. Current venous thromboembolism management and outcomes in Japan: nationwide the Japan venous thromboembolism treatment registry observational study. Circ J 2014;78:708-71 4. JCS Joint Working Group. Guidelines for the diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2009). Circ J 2011;75:1258-81 5. Simonneau G, Sors H, Charbonnier B, et al. A comparison of lowmolecular-weight heparin with unfractionated heparin for acute pulmonary embolism. The THESEE Study Group. Tinzaparine ou Heparine Standard: Evaluations dans l’Embolie Pulmonaire. N Engl J Med 1997;337:663-9 6. Bu¨ller HR, Davidson BL, Decousus H, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med 2003;349:1695-702
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12. Van Bellen B, Bamber L, Correa de Carvalho F, et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014;30: 829-37 13. Yamada N, Hirayama A, Maeda H, et al. Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism – the J-EINSTEIN DVT and PE program. Thromb J 2015;13:2 14. OECD. Health at a Glance 2011: OECD Indicators. Paris: OECD Publishing, 2011. Available at: DOI: http://dx.doi.org/10.1787/health_glance-2011-en [Last accessed February 2015] 15. Wang Y, Wang C, Chen Z, et al. Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies. Thromb J 2013;11:25-32
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7. Sarich TC, Peters G, Berkowitz SD, et al. Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions. Ann NY Acad Sci 2013;1291:42-55 8. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:2499-510 9. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97 10. Prins MH, Lensing AWA, Bauersachs R, et al; on behalf of the EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEINDVT and PE randomized studies. Thromb J 2013;11:21-30 11. Prins MH, Lensing AWA. Derivation of the non-inferiority margin for the evaluation of direct oral anticoagulants in the treatment of venous thromboembolism. Thromb J 2013;11:13-18
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