Mortality, Recurrent Thromboembolism and Major Bleeding in Cancer-Associated and Non-Cancer Pulmonary Embolism Patients Treated With Direct Oral Anticoagulants

Abstract

Background: Pulmonary embolism (PE) is a potentially fatal form of venous thromboembolism (VTE). This study compares the mortality, incidence of recurrent VTE, and incidence of major bleeding between non-cancer and cancer-associated PE patients treated with direct oral anticoagulants (DOACs).

Methods and Results: This was a retrospective, observational, single-center study involving 130 consecutive patients (87 with active cancer; 43 without cancer) who received DOAC treatment for PE between January 2016 and December 2019. Kaplan-Meier analysis showed significantly higher mortality in cancer-associated PE patients than in non-cancer patients (35/87 [40%] vs. 1/43 [2%], P < 0.001, log-rank test, HR 18.6 [95% CI: 2.5–136.0]). In contrast, the cumulative incidences of recurrent VTE and major bleeding were comparable between the 2 groups. Among the cancer-associated PE patients, the incidence for the composite outcome of recurrent VTE or major bleeding was significantly higher in patients undergoing chemotherapy than in those not undergoing chemotherapy (9/37 [24%] vs. 2/50 [4%], P=0.004, log-rank test, HR 6.9 [95% CI: 1.5–32.0]).

Conclusions: Although cancer-associated PE patients treated with DOACs showed higher mortality compared with non-cancer patients, presumably because of the presence of cancer, the risk of recurrent VTE or major bleeding was comparable between the 2 groups. Thus, DOAC is an important treatment option for cancer-associated PE, although underlying cancer-related risks (e.g., chemotherapy) remain.

Acute pulmonary embolism (PE) is a potentially life-threatening disease with sudden onset. The 30-day and 1-year case fatality rate of patients with PE in a Canadian cohort is reported to be 3.9% and 12.9%, respectively.¹ Because PE is predominantly caused by deep vein thrombosis (DVT), PE and DVT are collectively called venous thromboembolism (VTE). In an international prospective cohort, patients with symptomatic PE are reported to have a 5.42-fold higher risk of suffering a fatal PE event compared with patients with DVT only.²

From the case control study in The Netherlands, patients with cancer are reported to have a higher risk of developing thrombus formation, and a 4.6-fold higher incidence of PE, compared with non-cancer patients.³ In addition, the incidence of recurrent PE in the international cohort is 1.9-fold higher in cancer-associated PE patients than in cancer-associated DVT patients.⁴ Moreover, active cancer is not only a known major risk factor of recurrent VTE, but also a risk factor of major bleeding after the initial PE event.⁵

Direct oral anticoagulants (DOACs), especially anti-factor Xa inhibitors, are now widely used for the treatment of VTE.^6–9 In cancer-associated VTE patients, anti-factor Xa inhibitors (e.g., edoxaban, rivaroxaban, and apixaban) are proven to be effective, showing efficacies that are comparable to that of the anticoagulant, dalteparin (low-molecular-weight heparin).^10–12 However, few studies have evaluated the efficacy and safety of DOACs in cancer-associated VTE patients in Japan.^13,14 Here, we focused on PE and compared the mortality, incidence of recurrent VTE, and incidence of major bleeding in non-cancer and cancer-associated PE patients treated with DOACs.

Methods

Study Population and PE Diagnosis

This was a single-center, retrospective, observational study conducted at Nagoya University Hospital, Nagoya, Japan. A total of 130 consecutive patients diagnosed with PE and treated with a DOAC from January 2016 to December 2019 were enrolled; 87 of these patients had cancer and 43 did not (Figure 1). All the patients enrolled in the study were hospitalized in Nagoya University Hospital at the beginning of their anticoagulation therapy. This study was approved by the human research ethics committee of Nagoya University Hospital (no. 2020-0335) and performed in accordance with the Declaration of Helsinki and ethical standards of the institutional committee on human experimentation.

Figure 1.

Flowchart of the enrollment process. PE, pulmonary embolism; DOAC, direct oral anticoagulant.

PE was objectively diagnosed upon detection of a thrombus on contrast-enhanced computed tomography or lung perfusion scintigraphy images. Patients were diagnosed with symptomatic PE when they presented with sudden onset of dyspnea at rest or on exertion, syncope, chest pain, or hemoptysis. In addition, patients with a sudden vital sign abnormality (e.g., decreased oxygen saturation or blood pressure) were likewise considered to be symptomatic. The follow-up period of each patient was defined as the number of days from the diagnosis of PE to the date of death or latest date of consultation until the end of the study period.

Definitions and Clinical Outcomes

Active cancer was defined as any cancer, including locally recurrent, regionally advanced, or metastatic cancer, which had been diagnosed in the 6 months prior to the diagnosis of PE.

The details about deaths from all causes were collected and classified as being caused by cancer, PE, cardiac event, bleeding event, non-cardiac event, or other (data not shown).

A composite outcome consisting of either recurrent VTE or major bleeding event was also collected. Recurrent VTE was defined as newly diagnosed or exacerbation of DVT and/or PE with or without symptoms, as confirmed by detection of new or exacerbating thrombus on imaging examination. Major bleeding was diagnosed when at least one of the following criteria of the International Society on Thrombosis and Haemostasis was met: bleeding associated with ≥2 g/dL decrease in hemoglobin level; bleeding leading to ≥2 units of blood transfusion; symptomatic bleeding in a critical area or organ; or fatal bleeding.¹⁵

Statistical Analysis

Categorical variables are presented as numbers and percentages (%), and continuous variables are presented as mean±standard deviation or median and interquartile range. Categorical variables were compared with the chi-squared test or Fisher’s exact test. Continuous variables were compared with the Student’s t-test or the Mann-Whitney U-test depending on the distribution of the data. Cumulative survival and incidence of recurrent VTE or major bleeding were estimated by using the Kaplan-Meier method and the log-rank test was used to compare differences between groups. The Cox proportional hazards model was used to determine the hazard ratio (HR) and 95% confidence intervals (CI) of all-cause death, recurrent VTE, and major bleeding between groups. Gray’s test was also used to analyze the cumulative incidence of recurrent VTE and major bleeding, taking into consideration the competing risk of death.

A P value of <0.05 was considered to be statistically significant. All statistical analyses were conducted using the SPSS statistical software program (version 24.0 for Windows; SPSS Inc., Chicago, IL, USA).

Results

Baseline Patient Characteristics

In the overall cohort, the median follow-up period was 373 (IQR: 119–643) days, mean age was 64.2±15.6 years, 54% were female, mean body weight was 58.3±14.9 kg, and mean body mass index was 22.6±4.6 kg (Table 1). Concurrent DVT was diagnosed in 68% of the patients. Anticoagulation therapy was started with unfractionated heparin in 44% of the patients, whereas a single-drug approach of DOAC was applied in 56% of the patients.

Table 1.

Baseline Patient Characteristics

	Overall (n=130)	Cancer-associated PE patients (n=87)	Non-cancer PE patients (n=43)	P value
Follow-up period, days	373 (119–643)	367 (128–604)	386 (94–747)	0.34
Age, years	64.2±15.6	64.6±16.0	63.6±14.9	0.74
Female, n (%)	70 (54)	44 (51)	26 (60)	0.35
Body weight, kg	58.3±14.9	56.6±13.9	61.7±16.4	0.07
BMI, kg/m2	22.6±4.6	22.0±4.3	23.9±5.1	0.03
Concomitant use of antiplatelet agents, n (%)	7 (5)	4 (5)	3 (7)	0.68
History of heart failure, n (%)	3 (2)	2 (2)	1 (2)	–
History of chronic lung disease, n (%)	3 (2)	3 (3)	0	–
Hypertension, n (%)	24 (18)	15 (17)	9 (21)	0.64
Diabetes mellitus, n (%)	8 (6)	5 (6)	3 (7)	1.00
Stroke, n (%)	4 (3)	1 (1)	3 (7)	0.11
History of VTE, n (%)	5 (4)	1 (1)	4 (9)	0.04
History of major bleeding, n (%)	10 (8)	6 (7)	4 (9)	0.73
Thrombophilia, n (%)	3 (2)	2 (2)	1 (2)	–
Transient risk factor,† n (%)	–	–	20 (49)	–
Incidentally diagnosed, n (%)	95 (73)	70 (80)	25 (58)	0.01
Concurrent DVT, n (%)	89 (68)	57 (66)	32 (74)	0.33
High-risk PE, n (%)‡	5 (4)	1 (1)	4 (9)	0.04
sPESI score, n (%)				<0.001
0	29 (22)	0	29 (67)
1	62 (48)	54 (62)	8 (19)
2	26 (20)	24 (28)	2 (5)
≥3	13 (10)	9 (10)	4 (9)
Laboratory data
eGFR, mL/min/1.73 m2	76.6±25.5	80.8±26.5	68.1±21.4	0.01
Hgb, g/dL	11.0±1.9	10.7±1.9	11.6±2.0	0.01
Plt, ×104	22.6±9.3	22.9±10.1	22.0±7.8	0.61
D-dimer, μg/mL§	14.2 (5.6–27.8)	13.2 (5.5–24.6)	16.2 (6.8–31.9)	0.28
BNP, pg/mL§	33.4 (12.0–74.1)	31.6 (11.8–70.8)	36.2 (14.2–90.9)	1.00
Troponin T, ng/mL§	0.011 (0.008–0.023)	0.010 (0.007–0.018)	0.017 (0.009–0.034)	1.00
Initial anticoagulants used, n (%)				0.46
Unfractionated heparin	57 (44)	40 (44)	21 (48)
DOACs	73 (56)	51 (54)	22 (51)
DOACs at discharge, n (%)				0.68
Edoxaban	60 (46)	40 (46)	20 (47)
Rivaroxaban	28 (22)	18 (21)	10 (23)
Apixaban	42 (32)	29 (33)	13 (43)
Other initial treatments, n (%)
IVC filter	2 (2)	2 (2)	0	–
Thrombolysis	1	0	1	–
Duration of anticoagulation therapy, days	240 (90–450)	235 (91–441)	251 (81–497)	0.83

Categorical variables are presented as numbers and percentages, and continuous variables are presented as mean±standard deviation or median and interquartile range. ^†Transient risk factor was defined as follows: recent immobilization more than 4 days (patients with non-surgical bed-ridden in the previous 2 months), recent surgery (in the previous 2 months), recent trauma which required immobilization (in the previous 2 months), recent long-distance travel lasting more than 6 hours (in the previous 3 weeks), use of the central venous catheter, severe infection, pregnancy, or use of estrogen (in the previous 2 months). ^‡High risk PE patient is defined as follows: PE patients with hemodynamic instability and evidence of RV dysfunction on trans-thoracic echocardiogram or computed tomography pulmonary angiography at presentation. Hemodynamic instability in PE patient is defined as any of the following clinical manifestations: cardiac arrest, obstructive shock, or persistent hypotension. ^§Limited numbers of patients were tested: D-dimer was tested in 117 patients, BNP in 73 patients, and troponin T in 61 patients. BMI, body mass index; BNP, brain natriuretic peptide; DOACs, direct oral anticoagulants; DVT, deep vein thrombosis; eGFR, estimated glomerular filtration rate; Hgb, hemoglobin; IVC, inferior vena cava; PE, pulmonary embolism; Plt, platelet; sPESI, simplified pulmonary embolism severity index; VTE, venous thromboembolism; –, data not applicable.

Comparing the patients with or without cancer, although median follow-up period, mean age, sex, and body weight were comparable between the 2 groups, body mass index was significantly lower in the cancer-associated PE patients than in the non-cancer PE patients (P=0.03). History of VTE was detected significantly more frequently in cancer-associated PE patients (P=0.04). From the laboratory findings, estimated glomerular filtration rate (eGFR) was significantly higher and hemoglobin levels were significantly lower in cancer-associated PE patients (P=0.01 and P=0.01, respectively). In addition, significantly more cancer-associated PE patients than non-cancer PE patients were diagnosed incidentally (i.e., without PE symptoms) (80% vs. 58%, P<0.01).

Baseline Characteristics of the Cancer-Associated PE Patients

All 87 patients with cancer-associated PE were categorized as having active cancer. The 3 most frequent primary cancer sites were lung, colon, and pancreas (Table 2). At diagnosis of PE, cancer metastasis was observed in 43% of the patients. Cancer treatment was ongoing (defined as cancer treatment within the previous 4 weeks) in 61% of the patients at the time of PE diagnosis, and the remaining patients were either in the terminal stage or had received a new cancer diagnosis before treatment.

Table 2.

Characteristics of Patients With Active Cancer

Primary cancer site, n
Lung	13
Colon	10
Pancreas	10
Uterus	9
Ovary	8
Bile duct	8
Stomach	7
Esophagus	5
Other	19
Metastasis, n (%)	37 (43)
Performance status, 0 / 1 / 2 / 3 / 4	26 / 30 / 17 / 7 / 7 (30 / 34 / 20 / 8 / 8)
Cancer treatment within previous 4 weeks, n (%)	53 (61)
Chemotherapy	37 (43)
Cisplatin*	10 (27)
Taxane anti-cancer agents (paclitaxel and docetaxel)*	10 (27)
VEGF inhibitor (bevacizumab)*	4 (10)
Surgery	19 (22)

Categorical variables are presented as numbers and percentages. *Each percentage is calculated as follows: each number is divided by 37 (total number of patients who received chemotherapy prior to the PE diagnosis). VEGF, vascular endothelial growth factor.

Clinical Outcomes for the Overall Cohort

In the overall cohort, 36 patients died at a median of 160 days from the diagnosis of PE (Table 3). All the deaths were unrelated to PE, and all the patients with cancer died from a cancer-related cause. Patients with cancer showed significantly higher mortality than non-cancer patients (Figure 2, P<0.001). Recurrent VTE occurred in 5 patients. Although there was no statistical difference in incidence between the cancer and non-cancer groups, all the recurrent VTE events occurred in cancer-associated PE patients (Figure 3). In the overall cohort, major bleeding events occurred in 12 patients and there was no statistical difference in incidence between the cancer and non-cancer groups (Figure 3).

Table 3.

Incidences of Mortality, Recurrent Venous Thromboembolism, and Major Bleeding in the Present Cohort

	Overall (n=130)	Cancer-associated PE (n=87)	Non-cancer PE (n=43)
All-cause death, n (%)	36 (28)	35 (40)	1 (2)
Median no. of days from diagnosis of PE	160 (467–371)	167 (67–373)	–
Recurrent venous thromboembolism, n (%)	5	5	0
Median no. of days from diagnosis of PE	134 (64–135)	134 (64–135)	–
Incidental DVT only	1	1	–
Symptomatic DVT only	2	2	–
Incidental PE only	1	1	–
Incidental DVT and PE	1	1	–
Major bleeding, n (%)	12	6	6
Median no. of days from diagnosis of PE	209 (47–241)	234 (180–340)	120 (26–220)
Bleeding associated with ≥2 g/dL decrease in hemoglobin level	5	1	4
Leading to ≥2 units of blood transfusion	3	2	1
Symptomatic bleeding in a critical area or organ	5	3	2
Fatal bleeding	0	0	0

Categorical variables are presented as numbers and percentages, and continuous variables are presented as median and interquartile range. Abbreviations as in Table 1.

Figure 2.

Cumulative survival in pulmonary embolism (PE) patients with or without cancer. HR, hazard ratio.

Figure 3.

Cumulative incidence of recurrent venous thromboembolism or major bleeding in pulmonary embolism (PE) patients with or without cancer. In 2 of the non-cancer PE patients, major bleeding occurred during the use of continuous intravenous infusion of unfractionated heparin within 40 days from the diagnosis of PE.

Clinical Outcomes in the Cancer-Associated PE Patients

Although hemoglobin level tended to be lower in patients who had received chemotherapy in the 4 weeks prior to the diagnosis of PE (chemotherapy group) compared to those who had not (non-chemotherapy group), there was no significant difference in the baseline factors between the 2 groups (Supplementary Table 1). In the patients with cancer-associated PE, a significantly higher cumulative incidence for the composite outcome (recurrent VTE or major bleeding) was found between the chemotherapy group and non-chemotherapy group (9/37 [24%] vs. 2/50 [4%], P=0.004, log-rank test, HR 6.9 [95% CI: 1.5–32.0]; Figure 4). Similarly, the cumulative incidence of recurrent VTE tended to be higher in the chemotherapy group than the non-chemotherapy group (Figure 5 Left; P=0.079, log-rank test), and higher in patients with concomitant DVT than in those without (Supplementary Figure; P=0.094, log-rank test), although these findings were not statistically significant. In addition, the cumulative incidence of major bleeding was significantly higher in the chemotherapy group than in the non-chemotherapy group (Figure 5 Right; P=0.036, log-rank test, Supplementary Table 2), and significantly higher in the patients with anemia than in those without (Supplementary Figure; P=0.038, log-rank test).

Figure 4.

Cumulative incidence of the composite outcome of recurrent venous thromboembolism or major bleeding in cancerassociated pulmonary embolism (PE) patients undergoing chemotherapy or not. Cancer patients undergoing chemotherapy were defined as those who had received chemotherapy in the 4 weeks prior to the diagnosis of PE. HR, hazard ratio.

Figure 5.

Cumulative incidence of recurrent venous thromboembolism or major bleeding in cancer-associated pulmonary embolism (PE) patients undergoing chemotherapy or not. Cancer patients undergoing chemotherapy were defined as those who had received chemotherapy in the 4 weeks prior to the diagnosis of PE.

Discussion

There are 3 main findings from our study of non-cancer and cancer-associated PE patients treated with DOACs. First, the cumulative survival in the cancer-associated PE patients was significantly lower than that of the non-cancer PE patients; most likely due to the high mortality associated with cancer. Second, there were no statistical differences in the cumulative incidence of recurrent VTE or major bleeding between the cancer and non-cancer PE patients. Third, in the cancer-associated PE patients, the cumulative incidence of the composite outcome of recurrent VTE and major bleeding was significantly higher in those who had received chemotherapy in the 4 weeks prior to the diagnosis of PE.

The incidences of death, recurrent VTE, and major bleeding in Japanese patients with VTE conventionally treated with warfarin have been reported from the COMMAND VTE Registry.¹⁶ In the COMMAND VTE Registry, the cumulative 5-year incidences of all-cause death, recurrent VTE and major bleeding were reported as higher in the active cancer-associated VTE group than in the non-cancer VTE group (all-cause death: 73.1% vs.14.6%, P<0.001; recurrent VTE: 17.7% vs. 8.6%, P<0.001; major bleeding: 26.6% vs. 9.3%, P<0.001).¹⁷ Yamashita et al also reported the first 30-day clinical outcomes of cancer-associated PE patients from the VTE registry (all-cause death: 10.1%, recurrent VTE: 4.8%, and major bleeding: 5.3%).¹⁸ In the present study, the all-cause mortality in the cancer-associated PE patients was higher than that in the non-cancer PE patients; most likely due to the presence of cancer. The high mortality in cancer-associated PE patients in the present study was consistent with the findings of those in the previous studies, despite the used of DOACs in our patients.^16–18

In the cancer-associated PE patients, the median duration of anticoagulation was 251 days, the mean time to follow up was 367 days, and 5 patients (5.7%) were diagnosed with recurrent VTE; these findings are consistent with previous studies (SELECT-D trial: 4% in a 6-month period, HOKUSAI VTE cancer trial: 7.9% in a 12-month period, Caravaggio trial: 5.6% in 6-month period).^10–12 Although patients with cancer are at high risk of venous thrombus formation, we found no statistical difference in the cumulative incidence of recurrent VTE between the cancer-associated PE and non-cancer PE patients treated with DOACs. However, there are 3 findings that should be noted. First, no recurrent VTE was found in the non-cancer PE patients. Second, among the cancer-associated PE patients, recurrent VTE occurred after discontinuation of anticoagulants in 2 of the 5 cases, and another case was associated with self-interruption of anticoagulant therapy. In these 3 cases, recurrent VTE might have been prevented had the patients continued anticoagulation therapy. Indeed, a previous report has noted a high incidence of recurrent VTE in cancer VTE patients who stopped anticoagulant therapy (13.2% at a 3-year follow up after anticoagulants discontinuation).¹⁶ Third, in 3 of the 5 cases, the recurrent VTE was diagnosed incidentally. The prevalence of incidental PE diagnosed as a finding on oncological computed tomography scans was previously reported to be 3.6%, which suggests that our present study findings can be explained by the increased use of computed tomography in patients with cancer.¹⁹

Although dalteparin is conventionally recommended for the treatment of cancer-associated VTE throughout the world, dalteparin for the treatment of VTE is not covered by the national health insurance system in Japan; therefore, warfarin was conventionally used. However, under anticoagulation with warfarin, the risk of major bleeding in cancer-associated VTE patients is higher than that in non-cancer VTE patients (15.3% vs 4.0–6.0% at 1 year).¹⁶ In our DOAC-treated patients, major bleeding occurred in 6.9% of the cancer-associated PE patients, which is consistent with previous studies (SELECT-D trial: 6% in a 6-month period; HOKUSAI VTE cancer trial: 6.9% in a 12-month period; Caravaggio trial: 3.8% in a 6-month period).^10–12 Furthermore, there were no significant differences in the incidence of major bleeding between the cancer-associated PE patients and the non-cancer PE patients. In the present study, intracranial hemorrhage occurred in 5 patients; 1 patient with bleeding of a metastatic brain tumor, and 4 patients who were aged >70 years (2 patients with cancer-associated PE and 2 patients with non-cancer PE). Patients with a brain tumor were not eligible to participate in the SELECT-D trial, HOKUSAI VTE cancer trial, and Caravaggio trial because they were assumed to have high risk of severe bleeding. In addition, being elderly is a known risk factor for bleeding. Thus, the incidence of intracranial hemorrhage in the present study was expected, based on our knowledge of these previous risk factors.

The risk of VTE is reported to be 9-fold greater in cancer patients receiving chemotherapy compared with that in individuals without cancer.²⁰ Patients receiving chemotherapy are also at risk of bleeding caused by thrombocytopenia or the condition of the cancer. In addition, because warfarin is used in Japan for the treatment of cancer-associated VTE, patients receiving chemotherapy are at risk of bleeding due to drug–drug interactions (e.g., 5-fluorouracil, and capecitabine).²¹ In the present study, the incidence of the composite outcome of recurrent VTE and major bleeding was significantly higher in cancer-associated PE patients who had received chemotherapy in the 4 weeks prior to the diagnosis of PE than in those who had not. Similarly, the incidence of major bleeding was significantly higher in cancer-associated PE patients who had received chemotherapy in the 4 weeks prior to the diagnosis of PE than in those who had not, even though DOACs appear to be reasonable for VTE treatment without potential drug–drug interactions with chemotherapeutic drugs.²² Among the 37 cancer-associated PE patients receiving chemotherapy within 4 weeks prior to PE diagnosis, recurrent VTE occurred in 4 patients. In these 4 patients, taxane anti-cancer agents (paclitaxel and docetaxel) were used in 3 of the patients, Cisplatin in 1 patient, and a VEGF inhibitor (bevacizumab) in 1 patient. Thus, treatment strategies for cancer patients who are receiving chemotherapy at the time of PE diagnosis should take into account the potential risk of both recurrent VTE and major bleeding even when treated with DOACs.

Study Limitations

There are several limitations to the present study. First, this was a retrospective study conducted at a single institution that is the core hospital in the diagnosis and treatment of intractable diseases and is one of the largest designated cancer hospitals in the central region of Japan. Therefore, the background of the PE patients (e.g., incidence of incidental diagnosis) is likely to be different from that of the patients enrolled in previous studies. Also, the number of patients enrolled was limited because the present study was conducted in a single center, and further large studies are needed. Despite these limitations, the present study provides valuable information on the clinical outcomes of cancer-associated PE, including incidentally diagnosed PE, which will be useful for institutions in which cancer-associated PE is encountered in daily clinical practice. Second, all the patients enrolled in the present study were taking either of the 3 DOACs (edoxaban, rivaroxaban, or apixaban); however, the effects of the different DOACs on clinical outcome were not evaluated. Finally, the number of patients in the different primary cancer site categories varied; therefore, we were unable to examine the associations between primary cancer site and clinical outcome. We also could not examine the associations between cancer status or cancer treatment and clinical outcome because of the limited cases enrolled.

Conclusions

Although cancer-associated PE patients treated with DOACs showed increased mortality compared with non-cancer patients, primarily because of the presence of cancer, the risk of recurrent VTE or major bleeding was comparable between the 2 groups. However, among cancer-associated PE patients, the risk of recurrent VTE or major bleeding was higher in patients who had received chemotherapy in the 4 weeks prior to the diagnosis of PE than in those who had not. Thus, the present data suggest that care should be taken regarding the use of DOACs for patients undergoing chemotherapy.

Disclosures

T.M. is a member of Circulation Journal’s Editorial Team.

Y.N., T.K. belong to the endowed department of Actelion Pharmaceuticals Japan (now Janssen Pharmaceutical K.K.).

IRB Information

The human research ethics committee of Nagoya University Hospital (no. 2020-0335) approved this study.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-20-1247

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