2021 Volume 85 Issue 12 Pages 2201-2207
Background: A post-marketing surveillance study (STANDARD-VTE) evaluated the real-world safety and effectiveness of apixaban in Japanese patients prescribed for either the treatment of venous thromboembolism (VTE) or prevention of recurrent VTE.
Methods and Results: Patients newly initiated on apixaban were followed up for 52 weeks or 28 days post-discontinuation. Subgroup analysis was performed on patients with and without active cancer, and on patients with provoked VTE and with unprovoked VTE. A total of 1,119 patients were enrolled. Of these, 43.1% were aged ≥75 years, 46.4% had body weight ≤60 kg, and 21.3% had active cancer; mean serum creatinine was 0.76 mg/dL. The incidence of adverse drug reactions (ADRs) was 8.85%, and that of severe ADRs was 3.22%. Incidence of any bleeding, major bleeding, and recurrent VTE was 6.70%, 3.40%, and 0.80%, respectively. In patients starting apixaban 10 mg twice daily, THE incidence of any bleeding and major bleeding was 7.72% and 3.86%, respectively. In patients with active cancer, THE incidence of any bleeding and major bleeding was 16.81% and 9.24%, respectively.
Conclusions: No new safety signals of apixaban were identified in Japanese patients with VTE. In this study, the safety and effectiveness of apixaban in real-world practice was consistent with the results of the apixaban phase III trial.
Venous thromboembolism (VTE) presents clinically as deep vein thrombosis (DVT), pulmonary embolism (PE),1 or both. Historically, the prevalence of VTE in Japan has been lower than in Western countries; however, its incidence has increased in recent years.2 Common risk factors for thrombosis are congenital (e.g., protein C deficiency, protein S deficiency, and antithrombin deficiency) or acquired (e.g., surgery, obesity, congestive heart failure, chronic lung disease, cerebrovascular disease, antiphospholipid syndrome, use of drugs [e.g., estrogen, oral contraceptives, and corticosteroids], and traveler’s thrombosis).2
Although warfarin has been the primary oral treatment for VTE in Japan, it has a narrow therapeutic index with a highly individualized dose-response effect that requires routine monitoring of the international normalized ratio (target of 1.5–2.5 in Japanese) to assess individual fluctuations in the risk of bleeding.2–4 Further, demographic factors (e.g., age, race, body weight, sex, comorbidities, and genetics) and both food-drug and drug-drug interactions may influence the dose response of warfarin.4–6 In addition, East Asians, including the Japanese, bleed more frequently than non-East Asians; therefore, treatment with warfarin requires careful safety monitoring.7
In an attempt to address the unmet needs of patients receiving traditional anticoagulants, several novel nonvitamin K antagonist oral anticoagulants (NOACs) have been developed, including apixaban, a highly specific factor Xa inhibitor that is well tolerated and has a favorable safety profile over traditional anticoagulants.8–12
Apixaban is one of the NOACs that are administered as a single oral drug regimen from the initial treatment phase to the maintenance phase. The AMPLIFY study,13 a phase III trial, compared apixaban with conventional therapy (subcutaneous enoxaparin followed by warfarin) in 5,395 patients (apixaban, 2,691 patients) with acute VTE. The study found that apixaban was noninferior to conventional therapy for the treatment of acute VTE and was associated with significantly less bleeding. These results were also consistent with those of the AMPLIFY-J study12 in 80 patients (apixaban, 40 patients). In Japan, apixaban was approved in December 2015 for both treatment of VTE and prevention of recurrent VTE at a dose of 10 mg twice daily (BID) for the initial phase followed by 5 mg BID,14 and this regimen focuses on initial treatment to prevent recurrence of VTE. Apixaban is also recommended by the Japanese Circulation Society (JCS) Guidelines for the treatment of VTE and prevention of recurrent VTE.2
However, to date, no large-scale study has evaluated the safety and effectiveness of apixaban in the Japanese real-world setting. The objective of the STANDARD-VTE study (Post-Marketing Surveillance of Anticoagulant Drug Apixaban Real-World Data in Patients With VTE) was to investigate the safety and effectiveness of apixaban in Japanese patients for whom apixaban had been prescribed for treatment of VTE or prevention of recurrent VTE in real-world clinical practice by collecting data from a large sample population (planned, 1,000 patients). Here, we report the results of the final analysis.
This regulatory post-marketing surveillance study, conducted between July 2016 and July 2018, was a prospective, observational, noncontrolled, multicenter, single-arm study. Patients were registered by the Patient Registration Center System. Patients newly initiated on apixaban were followed up for 52 weeks or, after discontinuation, for another 28 days. Discontinuation was defined as the patient not receiving apixaban for more than 28 days after the last dose/cessation. Patients were observed for occurrence of adverse drug reactions (ADRs), any bleeding, major bleeding, and recurrent VTE. Decisions on initiation of apixaban, duration of treatment, and treatment discontinuation were made at the physician’s discretion. The STANDARD-VTE study was conducted in accordance with Japanese Good Post-marketing Study Practice (GPSP).
PatientsJapanese patients newly initiated on apixaban for treatment of VTE or prevention of recurrent VTE were included in this study. Patients with nonvalvular atrial fibrillation treated with apixaban and patients who had received prior treatment with apixaban were excluded.
Safety and Effectiveness OutcomesADRs were coded by treating physicians using the Medical Dictionary for Regulatory Activities/Japanese version 20.1, and causality and seriousness of ADRs were evaluated at the investigator’s/physician’s discretion. Severe ADRs included events whose association with apixaban could not be ruled out (including unknown) and which were determined as serious by the attending physician. Any bleeding was defined as all major and non-major bleeding events. Major bleeding was defined as per the criteria of the International Society of Thrombosis and Haemostasis,15 with a modification in the number of concentrated red blood cell transfusion units, and included (a) fatal bleeding, (b) bleeding with a decrease in hemoglobin levels ≥2 g/dL, (c) bleeding requiring concentrated red blood cell transfusion of ≥4 units, and (d) bleeding in a critical region or organ, including intracranial, intraspinal, intraocular, pericardial, intra-articular, and retroperitoneal bleedings, and intramuscular bleeding with compartment syndrome. The causal relationship between apixaban and bleeding was not considered. Effectiveness was assessed in terms of recurrent VTE, which was defined as symptomatic DVT or PE that occurred after administration of apixaban.
SubgroupsBecause the risk of recurrence differs according to predisposition to developing VTE, the JCS Guidelines set a recommended period for anticoagulation therapy for each type of risk factor for VTE. Following this, we created subgroups by the type of VTE risk factor. We classified and tabulated VTE as “with active cancer” and “without active cancer.” Active cancer was defined as patients with comorbid cancer at enrollment.
We further categorized the patients without active cancer into provoked and unprovoked VTE groups. The “provoked” group comprised patients with surgery, trauma, fracture, pregnancy, childbirth, and long-term bed rest, and the “unprovoked” group comprised the remaining patients.
Statistical AnalysisOn the basis of the incidence rate of major bleeding or clinically relevant non-major bleeding (7.5%) observed in the AMPLIFY-J study, a target sample size of 1,000 was set to detect a risk ratio of 2.0 at the 5% significance level and 80% power between VTE patients exposed to high and low levels of background risk factors. Data are expressed as mean±standard deviation (SD), median, or percentage. The incidence (in percentage) of ADRs was tabulated. The incidence (in percentage) of major bleeding, any bleeding, and recurrent VTE was calculated. The cumulative incidence of major bleeding was analyzed using a Kaplan-Meier curve and evaluated by a log-rank test among those with vs. without active cancer. In each subgroup, patient characteristics and the incidence of major bleeding, any bleeding, and recurrent VTE were also analyzed.
A total of 289 centers participated in this survey. Of 1,134 patients enrolled, 5 were excluded owing to misregistration (n=4) or double registration (n=1), and case report forms were not collected from 3 patients. Additionally, 7 patients were not included in the analysis; therefore, 1,119 patients were analyzed for safety and effectiveness. The patient disposition is presented in Figure 1. The mean±SD and median treatment duration was 234.9±138.5 days and 286 days, respectively. Overall, 53.3% of patients discontinued apixaban treatment before the 52-week follow-up period. Of these, 26.7% discontinued apixaban owing to resolution of the disease or stabilization of symptoms, and 10.2% failed to return to the hospital (Table 1).
Patient disposition. *Protocol violation.
Reasons for Discontinuation of Apixaban
| n (%) | |
|---|---|
| Total | 596 (53.3)* |
| Resolution of disease or stabilization of symptoms | 299 (26.7) |
| Failure to return to the hospital | 114 (10.2) |
| Adverse event | 91 (8.1) |
| Patient request | 22 (2.0) |
| Death | 21 (1.9) |
| Insufficient effect | 14 (1.3) |
| Surgical operation and other procedures | 13 (1.2) |
| Other | 31 (2.8) |
*Multiple answers.
Patient Demographics and Baseline Characteristics
The mean±SD age of the patients was 68.9±14.8 years (≥75 years, 43.1%), 60.1% of patients were women, 46.4% had body weight ≤60 kg, median serum creatinine was 0.720 mg/dL, and 18.1% had creatinine clearance (CrCl) ≤50 mL/min. The reason for using apixaban was PE, DVT, and both DVT and PE in 11.8%, 53.3%, and 34.9% of patients, respectively, and the purpose of apixaban administration was for initial treatment and for recurrence prevention during the extended period in 82.7% and 17.3% of patients, respectively. In terms of prior medication, 26.5% of patients were on anticoagulants (unfractionated heparin, 16.4%; warfarin, 5.1%), 2.7% of patients were on thrombolytic drugs (monteplase, 1.2%; urokinase, 1.5%), and 8.9% of patients had an inferior vena cava filter. Furthermore, 21.3% of patients had active cancer as a comorbidity, and the risk factors of VTE were unprovoked in 42.3% of patients (Table 2).
Patient Demographics and Baseline Characteristics
| Parameter | n (%) (n=1,119) |
|---|---|
| Sex, female | 673 (60.1) |
| Age (years) | |
| Mean±SD | 68.9±14.8 |
| ≥75 | 482 (43.1) |
| Weight (kg) | |
| Mean±SD | 59.9±12.9 |
| ≤60 | 519 (46.4) |
| BMI | |
| Mean±SD | 23.92±4.11 |
| Serum creatinine (mg/dL) | |
| Mean±SD | 0.760±0.237 |
| Creatinine clearance (mL/min) | |
| Mean±SD | 77.4±34.9 |
| <30 | 19 (1.7) |
| 30–50 | 183 (16.4) |
| >50–80 | 388 (34.7) |
| >80 | 367 (32.8) |
| Hb (g/dL), below standard value* | 486 (43.4) |
| D-dimer (μg/mL) | |
| Mean±SD | 11.99±18.57 |
| Min–max | 0.1–416.9 |
| Median | 7.4 |
| <1.0 | 56 (5.0) |
| ≥1.0 | 901 (80.5) |
| Unknown/not given | 162 (14.5) |
| Liver disorder | 105 (9.4) |
| Renal disorder** | 121 (10.8) |
| History of VTE | 16 (1.4) |
| Active cancer | 238 (21.3) |
| Risk factors of VTE | |
| Provoked | 386 (34.5) |
| Unprovoked | 473 (42.3) |
| Reason for prescription of apixaban | |
| PE | 132 (11.8) |
| DVT | 596 (53.3) |
| Both | 391 (34.9) |
| Purpose of apixaban administration | |
| Initial treatment | 925 (82.7) |
| Recurrence prevention | 194 (17.3) |
| Initial dose of apixaban | |
| 10 mg BID | 725 (64.8) |
| 5 mg BID | 331 (29.6) |
| Other | 63 (5.6) |
| Prior anticoagulants*** | 297 (26.5) |
| Warfarin | 57 (5.1) |
| Unfractionated heparin | 184 (16.4) |
| Fondaparinux | 6 (0.5) |
| Rivaroxaban | 16 (1.4) |
| Edoxaban | 30 (2.7) |
| Unspecified | 4 (0.4) |
| Prior medication (thrombolytic drugs) | 30 (2.7) |
| Monteplase | 13 (1.2) |
| Urokinase | 17 (1.5) |
| Pretreatment (non-drug treatment) | 194 (17.3) |
| Inferior vena cava filter | 100 (8.9) |
| Catheter treatment | 9 (0.8) |
| Surgical treatment | 4 (0.4) |
| Physical therapy**** | 95 (8.5) |
| Other | 5 (0.4) |
| Antiplatelets | 127 (11.3) |
| NSAIDs | 150 (13.4) |
*Hb values of 13 g/dL in men and 12 g/dL in women (WHO standard) were used to judge whether the level was below or above the standard value. **Renal disorder was judged by the physician using the standard classification to assess severity of renal disease. ***If there were pretreatments but it was unclear whether those were the treatment immediately prior to the apixaban treatments, those patients were categorized as “Unspecified.” ****Physical therapy refers to compression therapy (including elastic stockings and elastic bandages). BID, twice daily; BMI, body mass index; DVT, deep vein thrombosis; Hb, hemoglobin; Max, maximum; Min, minimum; NSAID, non-steroidal anti-inflammatory drug; PE, pulmonary embolism; SD, standard deviation; VTE, venous thromboembolism; WHO, World Health Organization.
A total of 725 (64.8%) patients were initiated apixaban on the 10 mg BID dose; 331 (29.6%) were initiated on the 5 mg BID dose; and 63 (5.6%) were initiated on other doses, including 2.5 mg BID (58 patients), 10 mg once daily (OD; 3 patients), 2.5 mg OD (1 patient), and 5 mg 4 times daily (1 patient). Among patients who were initiated on the 10 mg BID dose, 90.1% (653/725) received a starting dose of 10 mg BID for 7–8 days, 37 patients received the 10 mg BID dose for 1–6 days, 31 patients received the 10 mg BID dose for 9–28 days, and 4 patients received the 10 mg BID dose for ≥29 days.
SafetyThe incidence of ADRs and severe ADRs was 8.85% (99/1,119) and 3.22% (36/1,119), respectively. Overall incidence of any bleeding and major bleeding was 6.70% (75/1,119) and 3.40% (38/1,119), respectively (Table 3). Incidence of major bleeding included gastrointestinal bleeding in 1.43% (16/1,119) of patients; intracranial bleeding in 0.36% (4/1,119) of patients; and each of intraocular bleeding, pericardial bleeding and intra-articular bleeding in 0.09% (1/1,119) of patients. The rates of any bleeding and major bleeding in patients initiated on apixaban 10 mg BID were 7.72% (56/725) and 3.86% (28/725), respectively, and in patients initiated on apixaban 5 mg BID were 4.53% (15/331) and 2.72% (9/331), respectively. The cumulative incidence of major bleeding is shown using Kaplan-Meier plots (Figure 2).
Incidence of Bleeding and Recurrent VTE
| Type of event | Any bleeding, n (%) |
Major bleeding, n (%) |
Recurrent VTE, n (%) |
|---|---|---|---|
| Overall (n=1,119) | 75 (6.70) | 38 (3.40) | 9 (0.80) |
| With active cancer (n=238) | 40 (16.81) | 22 (9.24) | 5 (2.10) |
| Without active cancer (n=881) | 35 (3.97) | 16 (1.82) | 4 (0.45) |
| Provoked (n=386) | 13 (3.37) | 6 (1.55) | 0 (0.00) |
| Unprovoked (n=473) | 20 (4.23) | 10 (2.11) | 4 (0.85) |
VTE, venous thromboembolism.
Cumulative incidence rate of major bleeding.
Effectiveness
The incidence of recurrent VTE was 0.80% (9/1,119) in the on-treatment population: 0.27% (3/1,119) for PE and 0.54% (6/1,119) for DVT. Although 1 patient had recurrent VTE after the end of follow-up (days from the start of apixaban, day 386), this event was included in this analysis. Recurrent VTE occurred in 8 patients initiated on the 10 mg BID apixaban dose and in 1 patient initiated on the 2.5 mg BID dose. After the occurrence of recurrent VTE, apixaban treatment was withdrawn in 2 patients, the dose was increased in 3 patients, and the dose was unchanged in the remaining 4 patients.
Subgroup AnalysisPatients With and Without Active Cancer Disposition, demographics, and baseline characteristics in patients with or without active cancer are presented in Supplementary Table 1. Among patients with active cancer, 95.4% (227/238) had solid cancers and 5.0% (12/238) had blood cancer. Among the patients with solid cancers, 18.9% had lower gastrointestinal cancer, followed by 16.8% with gynecological cancers and 14.7% with lung cancer (Supplementary Table 2). The mean±SD and median follow-up periods in patients with and without active cancer were 227.2±143.5 days and 280 days, and 236.9±137.2 days and 289 days, respectively. The incidence of any bleeding and major bleeding events was 16.81% (40/238) and 9.24% (22/238), respectively, in patients with active cancer. In patients without active cancer, the incidence of any bleeding and major bleeding events was 3.97% (35/881) and 1.82% (16/881), respectively (Table 3). Recurrent VTE occurred in 2.10% (5/238) of patients with active cancer and in 0.45% (4/881) of patients without active cancer.
Provoked/Unprovoked VTE Among patients without active cancer, a total of 386 and 473 patients had provoked and unprovoked VTE, respectively; 22 patients were classified as unknown because they could not be classified under any of the definitions of active cancer or provoked or unprovoked VTE, or the cause of their VTE was unknown. The mean±SD and median follow-up periods in patients with provoked and unprovoked VTE were 204.5±141.1 days and 195 days, and 260.6±128.9 days and 364 days, respectively. Any bleeding and major bleeding occurred in 3.37% (13/386) and 1.55% (6/386) of patients with provoked VTE, respectively. Any bleeding and major bleeding occurred in 4.23% (20/473) and 2.11% (10/473) of patients with unprovoked VTE, respectively (Table 3). Recurrent VTE occurred in 0.85% (4/473) of patients with unprovoked VTE over the study period and in none of the patients with provoked VTE.
A comparison with the apixaban group of the AMPLIFY study showed that Japanese patients in the current study were older (68.9±14.8 vs. 57.2±16.0 years), and had lower body weight (59.9±12.9 vs. 84.6±19.8 kg), reduced renal function (CrCl ≤50 mL/min, 18.1% vs. 6.5%), and higher incidence of active cancer (21.3% vs. 2.5%). Therefore, patients in the current study were at higher risk of bleeding than those in the AMPLIFY study (major bleeding, 3.4% in the current study vs. 0.6% in the AMPLIFY study). On the other hand, the incidence of recurrent VTE in the current study was lower than in the AMPLIFY study (0.8% vs. 2.3%).
The AMPLIFY-J study12 (age, 64.3±13.4 years; body weight, 64.6±12.9 kg; CrCl ≤50 mL/min, 5.0%), conducted in Japan, evaluated the same apixaban regimen (10 mg BID for 7 days, followed by 5 mg BID for 23 weeks) as that used in the AMPLIFY study. The incidence of major or clinically relevant non-major bleeding in the apixaban group was 7.5%, and no patients developed major bleeding or recurrent VTE. Although the number of patients (n=40) was small and the follow-up duration was shorter (up to 168 days) than in the current study, the incidence of bleeding in AMPLIFY-J was higher.12
Based on these results, the safety and effectiveness profiles of apixaban observed in the current study were almost comparable to those reported in clinical trials.12,13 In addition, 90.1% of patients received a starting dose of 10 mg BID for 7–8 days as initial treatment of VTE, and the incidence of recurrent VTE was 0.80% (9/1,119) in the on-treatment population. Thus, oral administration of apixaban from the initial phase to the maintenance phase was well tolerated by the patients enrolled in the current study. The current study also confirmed that in clinical practice, apixaban was used not only as initial treatment but also as maintenance treatment. Because the background of patients may differ owing to the different purposes for using apixaban, it is necessary to do further analysis in the future.
Outcome of Apixaban in Patients With Active CancerCompared with patients without active cancer, patients with active cancer had a higher incidence of any bleeding (16.81% vs. 3.97%) and major bleeding (9.24% vs. 1.82%), which may be attributed to a higher risk of bleeding in the cancer group. Patients with active cancer in the current study showed a higher risk of bleeding, which might be associated with a higher occurrence of liver disorders (13.0% vs. 8.4%), and below standard value of hemoglobin (59.2% vs. 39.2%), than patients without active cancer (Supplementary Table 1). In addition, 5 of 9 patients who developed recurrent VTE had active cancer, which could be attributed to hypercoagulability and a decrease in mobility because of cancer.
These results are similar to those observed in several previous reports evaluating cancer patients with VTE.16–18 In a large population-based, case-control (Multiple Environmental and Genetic Assessment [MEGA] of risk factors for venous thrombosis) study of 3,220 consecutive patients with a first VTE and separate 2,131 control participants in the Netherlands, the overall risk of VTE was increased 7-fold in patients with a malignancy vs. those without a malignancy (odds ratio [OR], 6.7; 95% confidence interval [CI], 5.2–8.6).18 The COMMAND VTE Registry, which enrolled patients with consecutive acute symptomatic VTE in Japan between 2010 and 2014, reported significantly higher cumulative 5-year incidence of major bleeding and recurrent VTE in patients with active cancer compared with those with a history of cancer or without cancer (major bleeding: 26.6%, recurrent VTE: 17.7%).17
On the other hand, when comparing patients with active cancer, the COMMAND VTE Registry (88% of patients used warfarin) showed a higher incidence of major bleeding than the current study (cumulative 1-year incidence, 15.3% vs. 11.7%; Supplementary Figure). Although cancer types were similar between the 2 studies, this difference might be associated with the severity of patients’ condition and recruitment of patients with acute symptomatic VTE, and metastatic or terminal cancer in the COMMAND VTE Registry.17
In the CARAVAGGIO study, which compared apixaban treatment for 6 months with subcutaneous dalteparin in patients with VTE with active cancer,19 major bleeding and major or clinically relevant non-major bleeding occurred in 3.8% and 12.2% of patients, respectively, and recurrent VTE occurred in 5.6% of patients treated with apixaban. Patients in the current study, who had lower body weight (mean±SD: 57.9±11.3 kg vs. 75.7±16.1 kg) and poor renal function (CrCl ≤50 mL/min, 14.7% vs. 8.9%), were at higher risk of bleeding than those in CARAVAGGIO (major bleeding, 9.24% in the current study vs. 3.8% in CARAVAGGIO). On the other hand, the incidence of recurrent VTE in the current study was lower than that in the CARAVAGGIO study (2.1% vs. 5.6%).
Outcome of Apixaban in Patients With Provoked and Unprovoked VTEThe JCS Guidelines recommend a longer treatment duration for patients with unprovoked VTE because these patients have a higher risk of recurrent VTE than those with provoked VTE. The current study found that patients with unprovoked VTE were treated with apixaban for a longer duration than those with provoked VTE (mean, 260.6 vs. 204.5 days). Patients with unprovoked VTE had a higher incidence of bleeding and recurrent VTE compared with those with provoked VTE. The difference in bleeding frequency in the current study may be related to the duration of treatment with apixaban.
Study LimitationsFirst, the single-cohort design prevented comparisons with conventional therapy. Second, 53.3% of patients discontinued apixaban or were lost to follow-up at some stage over the 52-week follow-up period. Although the main reason for discontinuation was “disease resolution or symptom stability”, the shorter follow-up period would have underestimated the incidence in the current study. Third, possible misclassifications of events cannot be ruled out because events were assessed by treating physicians and were not confirmed by an independent adjudication committee. Fourth, adherence to apixaban was not evaluated. Finally, relative risk estimates or absolute incidence rates cannot be confirmed to be completely unbiased.
This post-marketing surveillance study confirmed that the real-world safety and effectiveness of apixaban in Japanese patients with VTE are consistent with those observed in apixaban phase III trials, with no new safety signals. The usefulness of apixaban, which is administered as a single oral drug from the initial treatment phase to the maintenance phase, was confirmed in clinical practice in Japan.
This study was sponsored by Pfizer Inc. and Bristol Myers Squibb K.K. Editorial support, in the form of medical writing, assembling tables and creating high-resolution images based on detailed directions from the authors, collating author comments, copyediting, fact-checking, and referencing, was provided by Annirudha Chillar, MD, PhD, of Cactus Communications and was funded by Pfizer Inc. and Bristol-Myers Squibb K.K.
Individual deidentified participant data (including data dictionaries) will not be shared.
A post-marketing surveillance study (the STANDARD-VTE study) was conducted in accordance with Japanese Good Post-marketing Study Practice (GPSP). Approval of the institutional review board of each participating institution and written informed consent were not required because this study was conducted as a regulatory and legal requirement in accordance with GPSP guidelines.
N. Yamada received remuneration as lecture fees and/or for attending meetings (presentations) from Daiichi Sankyo Co., Ltd., Bayer Yakuhin, Ltd., Bristol-Myers Squibb K.K., and Pfizer Japan Inc. M. Mo received consulting fees or honorarium from Pfizer Japan Inc. and Bayer Yakuhin, Ltd. M. Nakamura received consulting fees or honorarium from Daiichi Sankyo Co., Ltd. A. Ohsawa and D. Shima are employees of Pfizer Japan Inc. M. Sato is a former employee of Bristol-Myers Squibb K.K. M. Umeyama is an employee of Bristol-Myers Squibb K.K.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-20-0829
