Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　― A Predetermined Companion Report From the ONCO PE Trial ―

Abstract

Background: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.

Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0–9.6%]) in the home treatment group and in 2 patients (1.8% [0.0–4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0–9.6%]), and 2 patients (3.0% [0.0–7.2%]) required hospitalization due to bleeding events.

Conclusions: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

Currently, many cancer patients live longer due to the advancements in early diagnosis and treatment.^1,2 Therefore, complications during the course of cancer treatment have become increasingly clinically relevant in cardio-oncology and pulmonary embolism (PE) is one of the major complications.³ Because of the high acute mortality rate of PE, traditionally patients have been treated in hospital. However, previous studies reported that appropriately selected low-risk PE patients could be treated safely and effectively at home.^4,5 In the era of using direct oral anticoagulants (DOACs) for treatment of PE, a single-drug approach without administering intravenous anticoagulant, which would be suitable for home treatment, has been reported.^6–8 Cancer is considered as a risk factor of acute adverse outcomes, and a standard risk stratification model for PE, the simplified version of the Pulmonary Embolism Severity Index (sPESI) score, includes cancer as a score component,^9,10 which suggests that patients with cancer would not be good candidates for home treatment.

PE was found in 3.6% of routine computed tomography (CT) scans of the chest for evaluation of cancer,¹¹ and cancer patients with low-risk PE, including minor and incidental PE, have become quite common in current daily clinical practice. In this context, it has been actively debated whether all PE patients with cancer should be treated in hospital. A previous study reported a relatively low acute PE-related mortality in cancer patients with PE of sPESI score=1 who had no score components of sPESI other than cancer,¹² which suggests potential feasibility of home treatment for such patients. However, the limited number of prospective clinical trials specifically investigating this issue prompted us to explore the feasibility of home treatment for cancer patients with potential low-risk PE using data from a prospective clinical trial, the ONCO PE trial.^4,5

Methods

Trial Design and Oversight

This predetermined companion report from the ONCO PE trial evaluated 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment, which was predetermined in the protocol before the start of the study outside the scheme of a randomized clinical trial (RCT) as an exploratory type of subanalysis after completing the collection of 3-month follow-up data. The ONCO PE trial (NCT 04724460) was an investigator-initiated, industry-sponsored, multicenter, open-label, adjudicator-blinded RCT among 32 institutions in Japan designed to compare 18-month rivaroxaban treatment with 6-month rivaroxaban treatment in cancer patients with PE of sPESI score=1. Funding was provided by Bayer Yakuhin Co., Ltd., which had no role in the design of the trial, collection or analysis of the data, or writing the report. Data were reviewed by an independent data and safety monitoring committee (Supplementary Appendix 1). The trial was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Kyoto University Institutional Review Board, as well as with the institutional review boards of all participating institutions (Supplementary Appendix 2).

Study Population

Patients with active cancer who were newly diagnosed with PE confirmed by contrast CT examination were eligible for inclusion if they had sPESI score=1 (no component of sPESI score other than cancer). The key exclusion criteria were being anticoagulation therapy at the time of the diagnosis, having a contraindication for rivaroxaban, and life prognosis £6 months according to the treating physicians. All patients provided written informed consent. The detailed inclusion and exclusion criteria are provided in Supplementary Appendix 3.

Treatment

Rivaroxaban was administered in accordance with the policies at each institution, and no restrictions were set, providing the treatment did not contravene the exclusion criteria. Treatment with a parenteral anticoagulant was allowed before enrolment, but after enrolment, patients received the first dose of rivaroxaban based on the label of the marketed product for the treatment of acute PE in Japan: 15 mg twice daily for the first 3 weeks followed by 15 mg once daily thereafter. No implementation of the initial intensive dose of 30 mg/day was allowed at the discretion of the treating physician for patients who were considered at high risk of bleeding. The selection of home treatment or in-hospital treatment in patients with out-of-hospital onset was at the discretion of clinicians in charge based on the patient’s characteristics and preference.

Definition of the Baseline Characteristics

Home treatment was defined as discharge directly from the emergency department or the outpatient clinic within 12 h after the first visit to the hospital among those patients diagnosed with out-of-hospital PE. All other management was defined as in-hospital treatment, including treatment in hospital of patients who were diagnosed with PE in hospital.

The sPESI score includes the following variables: age >80 years, history of cancer, history of chronic cardiopulmonary disease, heart rate ≥110 beats/min, systolic blood pressure <100 mmHg, and arterial oxygen saturation <90% at the time of diagnosis.⁹ Chronic cardiopulmonary disease included heart failure or chronic lung disease. Heart failure was diagnosed if the patient had a history of hospitalization for heart failure, if the patient had symptoms due to heart failure (New York Heart Association functional class ≥2), or if the left ventricular ejection fraction was <40%. Chronic lung disease was defined as persistent lung disorders such as asthma, chronic obstructive pulmonary disease, and restrictive lung diseases. Right ventricular (RV) dysfunction was defined as findings of enlarged RV (right ventricular/left ventricular ≥0.9) on CT, or the existence of estimated systolic pulmonary arterial pressure ≥40 mmHg by echocardiography. In the current study, all patients were evaluated for RV dysfunction by CT scan at diagnosis. The details of other patient characteristics are described in Supplementary Appendix 4.

Follow-up and Endpoints

All patients were followed for 3 months with an on-site visit scheduled beyond 90 days after enrolment, at which they were also additionally assessed for routine clinical care as needed. Detailed follow-up methodology is provided in Supplementary Appendix 5.

The primary endpoint was a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding at 3 months. PE-related death was defined as death due to PE diagnosed at autopsy, death following clinically severe PE, or death unexplained by causes other than PE. Recurrent VTE included PE and/or deep vein thrombosis (DVT), which was defined as the appearance of new or worsening thrombus images in the pulmonary arteries and deep veins on imaging (ultrasonography of lower limb vein system, CT examination, pulmonary perfusion scintigraphy, pulmonary angiography, venography) irrespective of symptoms. Major bleeding was defined according to the International Society on Thrombosis and Haemostasis (ISTH) criteria, which consisted of fatal bleeding, symptomatic bleeding in a critical area or organ, and bleeding causing a reduction in the hemoglobin level by ≥2 g/dL or leading to a transfusion of ≥2 units of whole blood or red blood cells.¹³

Other endpoints were PE-related death, recurrent VTE, major bleeding, all clinically relevant bleeding, all-cause death, and hospitalization due to recurrent VTE or bleeding events at 3 months. All clinically relevant bleeding included major bleeding and clinically relevant non-major bleeding, which were classified according to the ISTH criteria.¹³ Detailed definitions of the other endpoints are provided in Supplementary Appendix 6.

During the follow-up period, the anticoagulation status was obtained, including the discontinuation and initiation of anticoagulants with the reasons and types of anticoagulants. Persistent rivaroxaban discontinuation was defined as a discontinuation according to the study protocol or lasting for >14 days for any reason.

Statistical Analysis

Categorical variables are presented as numbers and percentages. Continuous variables are presented as the mean and standard deviation (SD) or the median and interquartile range (IQR) based on their distributions. Categorical variables were compared with the chi-square test when appropriate; otherwise, Fisher’s exact test was used. Continuous variables were compared using Student’s t-test or Wilcoxon’s rank sum test based on their distributions. Considering the exploratory nature of this subanalysis, the clinical endpoints at 3 months are presented as descriptive data, which consisted of numbers of events and cumulative incidences with the 95% confidence intervals (CI) in both the home treatment and in-hospital treatment groups. We used the Kaplan-Meier method to estimate the cumulative incidences and explore the differences with a log-rank test. We also exploratively calculated the hazard ratios (HR) with 95% CIs of home treatment compared with in-hospital treatment for clinical endpoints using Cox proportional hazard models. Additionally, because there could be potential differences between outpatients and inpatients, we performed a sensitivity analysis that included only patients who were diagnosed with out-of-hospital PE. Furthermore, we also performed analyses after excluding patients with initial parenteral therapy with heparin before enrolment. Physicians (R.C. and Y.Y.) and a statistician (T.M.) performed all statistical analyses using SPSS ver. 23 (IBM Japan, Tokyo), JMP version 15.2.0 (SAS Institute Inc., Cary, NC, USA) and SAS version 9.4 (SAS Institute Inc) software. The reported P values are 2-tailed, and P<0.05 was considered statistically significant.

Results

Patient Enrolment and Characteristics

From February 2021 to March 2023, a total of 179 patients were enrolled and randomized at 32 institutions in Japan (Figure 1). After excluding 1 patient who withdrew consent during the follow-up period within 3 months, 178 patients were included in the current 3-month analysis. There were 66 patients (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group.

Figure 1.

Study flow chart. In the ONCO PE trial, the current analysis evaluated the 3-month clinical outcomes of 178 patients with active cancer who were newly diagnosed with PE of sPESI score=1, comparing patients with home treatment or in-hospital treatment. PE, pulmonary embolism; sPESI, simplified pulmonary embolism severity index.

In the entire study population, the mean age was 65.7 years, 53% of the patients were women, and the mean body weight and body mass index were 60.1 kg and 23.0 kg/m², respectively. The baseline characteristics were generally comparable between the groups (Table 1). The home treatment group less often showed symptoms for PE at baseline (4.5% vs. 17%, P=0.02). The thrombus location and prevalence of concomitant DVT were also similar between the groups, although the home treatment group less often showed RV dysfunction (1.5% vs. 13%, P=0.01). The comorbidities were comparable between the groups except for a history of VTE and transient risk factors for VTE (Table 1). The mean values of hemoglobin, creatinine clearance and platelet count were also similar between the groups. The most common type of cancer was colon cancer (12%), followed by uterine cancer (12%) and ovarian cancer (11%) (Supplementary Table 1).

Table 1.

Baseline Clinical Characteristics of the Patients

	Home treatment (n=66)	In-hospital treatment (n=112)	P value
Baseline characteristics
Age, years	66.2±9.5	65.5±11.0	0.67
≥65 years, n (%)	37 (56)	68 (61)	0.64
≥75 years, n (%)	13 (20)	27 (24)	0.58
Women, n (%)	34 (52)	61 (55)	0.76
Body weight, kg	60.4±10.9	60.0±11.7	0.81
<60 kg, n (%)	40 (61)	56 (50)	0.21
Body mass index, kg/m2	23.1±2.9	22.9±4.2	0.75
≥30 kg/m2	1 (1.5)	7 (6.3)	0.26
Presentation
Systolic blood pressure, mmHg	130.2±19.0	124.5±15.2	0.03
Diastolic blood pressure, mmHg	79.5±11.3	75.6±12.0	0.03
Heart rate, beats/min	82.5±12.5	80.4±11.9	0.29
Oxygen saturation, %	97.6±1.3	97.0±1.5	0.30
Symptoms for PE at baseline, n (%)	3 (4.5)	19 (17)	0.02
Place of onset
Out-of-hospital, n (%)	66 (100)	31 (28)	<0.001
Length of hospitalization, days	–	9 [5, 14]	–
In-hospital onset after surgery, n (%)	–	29 (26)	–
In-hospital onset other than after surgery, n (%)	–	52 (46)	–
PE characteristics
Thrombus location
Central, n (%)	3 (4.5)	11 (9.8)	0.62
Main, n (%)	7 (11)	15 (13)
Lobar, n (%)	20 (30)	34 (30)
Segmental, n (%)	23 (35)	30 (27)
Subsegmental, n (%)	13 (20)	22 (20)
RV dysfunction	1 (1.5)	14 (13)	0.01
RV/LV ≥0.9 on computed tomography, n (%)	1 (1.5)	11 (9.8)	0.03
Echocardiography evaluation, n (%)	28 (42)	83 (74)	<0.001
Estimated systolic PAP ≥40 mmHg by echocardiography, n (%)	0/28 (0)	4/83 (4.8)	0.57
Concomitant DVT, n (%)	40 (61)	64 (57)	0.75
Comorbidities
Hypertension, n (%)	22 (33)	45 (40)	0.42
Diabetes, n (%)	6 (9.1)	21 (19)	0.09
Dyslipidemia, n (%)	14 (21)	24 (21)	1.0
History of stroke, n (%)	0 (0)	1 (0.6)	1.0
History of VTE, n (%)	6 (9.1)	1 (0.9)	0.01
History of major bleeding, n (%)	5 (7.6)	5 (4.5)	0.50
Autoimmune disorder	5 (7.6)	7 (6.2)	0.76
Transient risk factors for VTE, n (%)	9 (14)	33 (30)	0.02
Surgery within past 2 months, n (%)	2 (3.0)	27 (24)	<0.001
Cancer status
Diagnosis within past 6 months, n (%)	28 (42)	74 (66)	0.003
Under chemotherapy, n (%)	53 (80)	54 (48)	<0.001
Under radiotherapy, n (%)	4 (6.1)	9 (8.0)	0.77
Scheduled to be operated, n (%)	15 (23)	54 (48)	0.001
Local invasion, n (%)	27 (41)	27 (24)	0.015
Metastatic disease, n (%)	27 (41)	40 (36)	0.53
Recurrent cancer, n (%)	11 (17)	16 (14)	0.67
ECOG performance status, n (%)
0	40 (61)	39 (35)	0.002
1	25 (38)	57 (51)
≥2	1 (1.5)	16 (14)
Laboratory tests at diagnosis
Hemoglobin, g/dL	11.5±1.9	11.3±2.1	0.55
Anemia, n (%)	45 (68)	73 (65)	0.74
Creatinine clearance, mL/min	81.2±26.0	87.2±30.3	0.18
Creatinine clearance ≤50 mL/min, n (%)	3 (4.5)	8 (7.1)	0.75
Platelet count, /μL	21.8±9.0	24.1±11.7	0.17
Platelet count <100,000/μL, n (%)	5 (7.6)	6 (5.4)	0.54
D-dimer, μg/mL	6.0 [3.0, 11.3]	10.0 [4.3, 18.0]	0.002
BNP, pg/mL (n=59)	18.0 [7.5, 33.5]	18.0 [10.5, 32.0]	0.34
NT-proBNP, pg/mL (n=48)	69.5 [46.0, 61.8]	108 [61.8, 229.0]	0.40
Troponin I, pg/dL (n=45)	10.0 [10.0, 21.0]	10.0 [10.0, 10.8]	0.14
Troponin T, pg/dL (n=38)	10.0 [7.5, 11.5]	10.0 [8.0, 14.5]	0.15
Concomitant medications
Antiplatelet, n (%)	2 (3.0)	3 (2.7)	1.0
Steroid, n (%)	12 (18)	12 (11)	0.18
Statin, n (%)	6 (9.1)	15 (13)	0.48
Proton pump inhibitor, n (%)	25 (38)	56 (50)	0.12

Categorical variables are presented as numbers (n) and percentages, and continuous variables are presented as the mean and standard deviation or the median and interquartile range based on their distributions. RV dysfunction was defined as enlarged RV (RV/LV ≥0.9) on computed tomography, or the existence of estimated systolic PAP ≥40 mmHg by echocardiography. Eastern Cooperative Oncology Group (ECOG) performance status values range from 0 to 4, with higher values indicating greater disability. Transient risk factors for VTE included recent surgery, recent immobilization, long-distance travel, central venous catheter use, pregnancy or puerperium, recent leg trauma, fracture or burn, severe infection, and estrogen use. Anemia was diagnosed if hemoglobin <13 g/dL for men and <12 g/dL for women. DVT, deep vein thrombosis; LV, left ventricular; PAP, pulmonary arterial pressure; PE, pulmonary embolism; RV, right ventricular; VTE, venous thromboembolism.

Treatment Strategies

No patient received initial parenteral therapy with heparin in the home treatment group (Table 2). There was no significant difference between the groups in the prevalence of rivaroxaban with an initial intensive dose of 30 mg/day (52% vs. 57%, P=0.53) or in the median duration of initial intensive treatment periods (21 vs. 21 days, P=0.49). During the follow-up period, the proportion of premature discontinuation of rivaroxaban within 3 months was similar between the groups (9.1% vs. 9.8%, P=1.00).

Table 2.

Treatment Strategies

	Home treatment (n=66)	In-hospital treatment (n=112)	P value
Initial parenteral therapy with heparin, n (%)	0 (0)	29 (26)	<0.001
Rivaroxaban with initial intensive dose of 30 mg/day, n (%)	34 (52)	64 (57)	0.53
Duration of intensive period, days	21 [18, 21]	21 [12, 21]	0.49
Premature discontinuation of rivaroxaban within 3 months, n (%)	6 (9.1)	11 (9.8)	1.0
Discontinuation due to bleeding event, n (%)	2/6 (33)	4/11 (36)	0.43
Discontinuation due to invasive procedure, n (%)	2/6 (33)	2/11 (18)
Patient’s decision, n (%)	1/6 (17)	0/11 (0)
Physician’s decision, n (%)	0/6 (0)	1/11 (9.1)
Discontinuation due to cancer progression, n (%)	1/6 (17)	4/11 (36)

Categorical variables are presented as numbers (n) and percentages, and continuous variables are presented as the median and interquartile range.

Clinical Endpoint

The primary endpoint of a composite of PE-related death, recurrent VTE and major bleeding occurred in 3 of 66 patients (4.6% [0.0–9.6%]) in the home treatment group and in 2 of 112 patients (1.8% [0.0–4.3%]) in the in-hospital treatment group at 3 months (Table 3). There was no significant difference in the cumulative 3-month incidence of the primary endpoint between the groups (4.6% vs. 1.8%, log-rank P=0.28) (Figure 2).

Table 3.

Clinical Outcomes at 3 Months

	Event number (CUMULATIVE incidence [95% CI])		HR (95% CI)
	Home treatment (n=66)	In-hospital treatment (n=112)
Primary endpoint
Composite outcome of PE-related death, recurrent VTE and major bleeding	3 (4.6% [0.0–9.6%])	2 (1.8% [0.0–4.3%])	2.58 (0.43–19.59)
Secondary endpoint
PE-related death	0 (0% [0.0–0.0%])	0 (0% [0.0–0.0%])	–
Recurrent VTE	0 (0% [0.0–0.0%])	1 (0.9% [0.0–2.7%])	–
Major bleeding	3 (4.6% [0.0–9.6%])	1 (0.9% [0.0–2.7%])	5.23 (0.67–105.59)
All clinically relevant bleeding	6 (9.2% [2.2–16.2%])	12 (10.8% [5.0–16.7%])	0.84 (0.29–2.16)
Deaths from all causes	4 (6.1% [0.3–11.8%])	5 (4.5% [0.6–8.3%])	1.36 (0.34–5.13)
Death due to PE	0 (0% [0.0–0.0%])	0 (0% [0.0–0.0%])	–
Death due to bleeding event	0 (0% [0.0–0.0%])	0 (0% [0.0–0.0%])	–
Death due to cancer	4 (6.1% [0.3–11.8%])	5 (4.5% [0.6–8.3%])	1.36 (0.34–5.13)
Hospitalization due to recurrent VTE or bleeding event	2 (3.0% [0.0–7.2%])	–	–
Hospitalization due to recurrent VTE	0 (0% [0.0–0.0%])	–	–
Hospitalization due to bleeding event	2 (3.0% [0.0–7.2%])	–	–

Clinical outcomes were presented as event number and 90-day cumulative incidence with 95% CI. Cumulative incidences were estimated by the Kaplan-Meier method. Crude HRs and 95% CIs were estimated by the Cox proportional hazard models using patients with in-hospital treatment as the reference. PE-related death was defined as death due to PE diagnosed at autopsy, death followed a clinically severe PE, or death unexplained by the causes other than PE. All clinically relevant bleeding included major bleeding and clinically relevant non-major bleeding, which were classified according to the criteria of the International Society on Thrombosis and Hemostasis. Recurrent VTE was defined as appearance of new or worsening thrombus images in the pulmonary arteries and deep veins on imaging tests. CI, confidence interval; HR, hazard ratio; PE, pulmonary embolism; VTE, venous thromboembolism.

Figure 2.

Kaplan-Meier curves for the primary endpoints of the composite of PE-related death, recurrent VTE or major bleeding in patients with home treatment or in-hospital treatment. PE, pulmonary embolism; VTE, venous thromboembolism.

In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0–9.6%]) at 3 months (Table 3). In the in-hospital treatment group, recurrent VTE and major bleeding occurred in 1 patient each (0.9% [0.0–2.7%] and 0.9% [0.0–2.7%], respectively). There was no significant difference in the cumulative 3-month incidence of recurrent VTE or major bleeding between the groups (recurrent VTE: 0.0% vs. 0.9%, log-rank P=0.44; major bleeding: 4.6% vs. 0.9%, log-rank P=0.11) (Figure 3A,B). There were no major bleeding events during the initial intensive dose period in either group. There were no significant factors associated with major bleeding except for local invasion as the cancer status (Supplementary Table 2).

Figure 3.

Kaplan-Meier curves for (A) recurrent VTE and (B) major bleeding in patients with home treatment or in-hospital treatment. VTE, venous thromboembolism.

Clinically relevant bleeding events occurred in 6 patients (9.2% [2.2–16.2%]) in the home treatment group and in 12 patients (10.8% [5.0–16.7%]) in the in-hospital treatment group. Clinically relevant bleeding during the initial intensive dose period occurred in 1 patient in the home treatment group and in 2 patients in the in-hospital treatment group. All-cause death occurred in 4 patients (6.1% [0.3–11.8%]) in the home treatment group and in 5 patients (4.5% [0.6–8.3%]) in the in-hospital treatment group at 3 months (Table 3); all 9 deaths were due to cancer. In the home treatment group, 2 patients (3.0% [0.0–7.2%]) required hospitalization for bleeding events at 3 months. Details of the clinical outcomes are shown in Supplementary Table 3.

The sensitivity analysis that included only patients who were diagnosed with out-of-hospital PE essentially showed results consistent with the main analysis (Supplementary Tables 4–6). The sensitivity analysis after excluding patients with initial parenteral therapy with heparin also showed similar results to those from the main analysis (Supplementary Table 7).

Discussion

The current study provided some insights on the feasibility of home treatment with rivaroxaban for cancer patients with low-risk PE of sPESI score=1. First, 37% of cancer patients with PE of sPESI score=1 were treated at home and they less often had RV dysfunction compared with those treated in hospital. Second, patients having home treatment did not develop any thrombotic events at 3 months, although 4.6% had bleeding events at 3 months. Third, the prevalence of switching from home treatment to in-hospital treatment due to PE-related adverse outcomes was only 3.0% at 3 months.

The strengths of the current study are the prospective design with predetermined analysis and inclusion of specifically potentially low-risk PE patients (sPESI score=1), compared with a previous report.¹⁴ When considering home treatment for PE, appropriate selection of patients with low-risk PE is a very important issue. The HoT-PE trial evaluating the efficacy and safety of home treatment with rivaroxaban for low-risk PE included patients without hemodynamic instability, RV dysfunction, intracardiac thrombi, or serious comorbidities according to the Hestia criteria, and the number of patients with active cancer was only 32 (6.2%).⁵ In the HOME-PE trial that compared a triaging strategy based on the Hestia criteria and the sPESI score for home treatment of patients with acute PE, patients with active cancer comprised only 34 (9.1%) in the Hestia strategy and 17 (4.8%) in the sPESI strategy among the patients treated at home.⁴ Currently, active cancer is categorized as a serious comorbidity, which makes them less likely to be considered as good candidates for home treatment. However, in the current study more than one-third of active cancer patients with PE of sPESI score=1 were treated at home, and in particular, clinicians selected home treatment for patients without RV dysfunction, which was in line with a previous study that evaluated all types of PE patients.¹⁰ The current guidelines recommend RV assessment in addition to the clinical severity of PE and serious comorbidities based on sPESI score when planning home treatment.¹⁰ Therefore, absence of RV dysfunction may be important factor beyond the score component of sPESI, even in patients with active cancer.

In the HoT-PE trial, the 3-month event rates of recurrent VTE, major bleeding and clinically relevant bleeding in patients treated at home were 0.6%, 1.2% and 6.0%, respectively.⁵ In the HOME-PE trial, the 3-month event rates of recurrent VTE and major bleeding in patients treated at home were respectively 0.8% and 2.4% in the Hestia strategy and 0.8% and 0.6% in the sPESI strategy.⁴ Compared with these findings in patients mainly without active cancer, the current study, which included only patients with active cancer, showed no signs of a higher event rate of recurrent VTE in the home treatment group than in the hospital treatment group. However, there was a numerically higher event rate of bleeding events in the home treatment group than in the hospital treatment group. Previous RCTs evaluating DOACs for cancer-associated VTE reported that DOACs were noninferior to low-molecular-weight heparin for preventing recurrent VTE without an increased risk of major bleeding, although DOACs were associated with a higher risk of clinically relevant bleeding, including bleeding events requiring hospitalization.^15–17 In terms of home treatment for cancer patients with PE, clinicians should monitor not only for thrombotic events but also bleeding events that may require hospitalization. Notably, the current study included a number of patients with incidental PE (87.6%), which was significantly different from the Hot-PE and HOME-PE trials that focused on patients with symptomatic PE.^4,5 Although active cancer patients with symptomatic PE could be at a higher risk of recurrent VTE events than those with incidental PE,¹⁸ a previous study reported that the risks of death and readmission were consistent between symptomatic and incidental PE.¹⁴ The current study showed a relatively low proportion of intensive treatment with rivaroxaban (55.1%). A previous study reported that Asian patients were at higher risk of bleeding than non-Asian patients with anticoagulation therapy,¹⁹ and a recent large Japanese registry reported a relatively low proportion of intensive treatment with rivaroxaban for active cancer-associated VTE (70.7%).²⁰ Thus, physicians were assumed to be more concerned about bleeding risk with intensive treatment among patients with low-risk PE. The current study also showed that only local invasion as the cancer status was significantly associated with major bleeding events. Appropriate selection of home treatment from the perspective of risk for bleeding events might be also important.

The current study showed that 3.0% of cancer patients with PE initially treated at home required hospitalization within 3 months, all cases being due to bleeding events. In the HoT-PE trial, 12 (2.3%) of 525 patients with PE initially treated at home required hospitalization within 3 months due to suspected recurrent PE in 7 patients or bleeding in 5 patients.⁵ The rate of hospitalization due to PE-related adverse outcomes in cancer patients with PE treated at home in the present study was comparable to that in the previous reports, which included mostly non-cancer patients with PE. Therefore, home treatment for cancer patients with potential low-risk PE might be feasible, but needs to be further investigated in future RCTs. Furthermore, the new anticoagulants, which have a potentially lower risk of anticoagulation-related bleeding, such as factor XIa inhibitors, could overcome this issue, and be more suitable for home treatment for cancer patients with low-risk PE.^21,22

Study Limitations

First, patients were not randomized into home treatment and in-hospital treatment, which is an important limitation inherent to the study design. Because the selection of home treatment or in-hospital treatment was left to the discretion of the attending physician, the current analysis was exploratory, and should be interpreted as hypothesis-generating. Second, because we specifically targeted active cancer patients with PE of sPESI score=1 and did not calculate the sample size based on evaluation of home treatment, the number of included patients was relatively small. Thus, there could be lack of statistical power for exploratory comparisons between the groups. Third, the latest Japanese Circulation Society Guidelines recommend risk assessment for PE using the sPESI score, which has become common in current daily clinical practice in Japan. Thus, we adopted sPESI score for risk assessment, although there are several other clinical scores such as the Hestia criteria. Fourth, we did not set restrictions for acute treatment strategies including parenteral anticoagulant if the treatment did not contravene the exclusion criteria, although the prevalence of rivaroxaban with initial intensive dose and duration of intensive periods were numerically comparable between the groups. Finally, all patients were evaluated for RV dysfunction based on CT findings, but not all patients were evaluated by echocardiography, which might lead to over-interpretation of RV dysfunction.

Conclusions

In the current analysis exploring the feasibility of home treatment for cancer patients with PE of sPESI score=1, patients with low-risk PE could potentially be treated at home.

Clinical Perspective

Active cancer patients with PE of sPESI score=1 could be treated at home, but would require bleeding-risk assessment. Further prospective clinical trials specifically investigating this issue are needed.

Acknowledgments

This study was an investigator-initiated study with financial support from Bayer Yakuhin Co., Ltd. We are grateful to all staff, particularly the Clinical Events Committee, Data Safety Monitoring Committee, and Clinical Research Organization (MID, Inc. and Department of Cardiovascular Medicine, Graduate School of Medicine and Faculty of Medicine Kyoto University) for their thorough work, to all site personnel who helped to enroll participants, and to all the healthcare professionals who took care of our patients during this study protocol. Finally, we thank all the participants, without whom this research would not have been possible.

Conflicts of Interest

Dr. Yamashita received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and grant support from Bayer Healthcare and Daiichi Sankyo. Dr. Morimoto reports lecturer’s fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer and Tsumura; manuscript fees from Bristol-Myers Squibb and Pfizer; advisory board for Novartis and Teijin. Dr. Shibata received lecture fees from Novartis Pharmaceuticals KK and Otsuka Pharmaceuticals Co. Ltd. Dr. Nishimoto received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo. Dr. Ogihara received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Pfizer, and Daiichi Sankyo, and research funds from Bayer Healthcare and Daiichi Sankyo. Dr. Ikeda received lecture fees from Bayer Healthcare, Bristol-Myers Squibb and Daiichi Sankyo. All other authors report that they have no relationships relevant to the contents of this paper to disclose.

Disclosures

Dr. Ono is a member of Circulation Journal’s Editorial Team.

Sources of Funding

Funding was provided by Bayer Yakuhin Co., Ltd., which had no role in the study design, data collection, analysis, interpretation, or writing of the report.

Ethics Approval Statement

The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Kyoto University Institutional Review Board, along with the institutional review boards of all participating institutions (approval no. jRCTs051200135).

Patient Consent Statement

All patients provided written informed consent.

Permission to Reproduce Material From Other Sources

N/A.

Trial Registration Number

NCT 04724460.

IRB Information

The present study was approved by Kyoto University Certified Review Board. Reference number: jRCTs051200135.

Data Availability

The data, analytic methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-24-0004

References

• 1.   Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69: 7–34.
• 2.   Ito Y, Miyashiro I, Ito H, Hosono S, Chihara D, Nakata-Yamada K, et al. Long-term survival and conditional survival of cancer patients in Japan using population-based cancer registry data. Cancer Sci 2014; 105: 1480–1486.
• 3.   Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293: 715–722.
• 4.   Roy PM, Penaloza A, Hugli O, Klok FA, Arnoux A, Elias A, et al. Triaging acute pulmonary embolism for home treatment by Hestia or simplified PESI criteria: The HOME-PE randomized trial. Eur Heart J 2021; 42: 3146–3157.
• 5.   Barco S, Schmidtmann I, Ageno W, Bauersachs RM, Becattini C, Bernardi E, et al. Early discharge and home treatment of patients with low-risk pulmonary embolism with the oral factor Xa inhibitor Rivaroxaban: An international multicentre single-arm clinical trial. Eur Heart J 2020; 41: 509–518.
• 6.   Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499–2510.
• 7.   Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287–1297.
• 8.   Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369: 799–808.
• 9.   Jiménez D, Aujesky D, Moores L, Gómez V, Lobo JL, Uresandi F, et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170: 1383–1389.
• 10.   Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41: 543–603.
• 11.   Di Nisio M, Lee AY, Carrier M, Liebman HA, Khorana AA; Subcommittee on Haemostasis and Malignancy. Diagnosis and treatment of incidental venous thromboembolism in cancer patients: Guidance from the SSC of the ISTH. J Thromb Haemost 2015; 13: 880–883.
• 12.   Yamashita Y, Morimoto T, Amano H, Takase T, Hiramori S, Kim K, et al. Usefulness of simplified pulmonary embolism severity index score for identification of patients with low-risk pulmonary embolism and active cancer: From the COMMAND VTE Registry. Chest 2020; 157: 636–644.
• 13.   Schulman S, Kearon C, Bergqvist D, Eriksson B, Lassen MR, Fisher W; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692–694.
• 14.   Guman NAM, Kaptein FHJ, Lohle SB, Mairuhu ATA, Klok FA, Huisman MV, et al. Discharge from the emergency department and outpatient clinic in cancer patients with acute symptomatic and incidental pulmonary embolism: A multicenter retrospective cohort study. Thromb Res 2024; 233: 181–188.
• 15.   Young AM, Marshall A, Thirlwall J, Chapman O, Lokare A, Hill C, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol 2018; 36: 2017–2023.
• 16.   Sabatino J, De Rosa S, Polimeni A, Sorrentino S, Indolfi C. Direct oral anticoagulants in patients with active cancer: A systematic review and meta-analysis. JACC Cardiooncol 2020; 2: 428–440.
• 17.   Schrag D, Uno H, Rosovsky R, Rutherford C, Sanfilippo K, Villano JL, et al. Direct oral anticoagulants vs. low-molecular-weight heparin and recurrent VTE in patients with cancer: A randomized clinical trial. JAMA 2023; 329: 1924–1933.
• 18.   Delluc A, Wang TF. How to treat incidental pulmonary embolism in cancer patients? Recent advances. Kardiol Pol 2021; 79: 1305–1310.
• 19.   Kim HK, Tantry US, Smith SC Jr, Jeong MH, Park SJ, Kim MH, et al. The East Asian paradox: An updated Position Statement on the Challenges to the Current Antithrombotic Strategy in Patients with Cardiovascular Disease. Thromb Haemost 2021; 121: 422–432.
• 20.   Chatani R, Yamashita Y, Morimoto T, Mushiake K, Kadota K, Kaneda K, et al. Cancer-associated venous thromboembolism in the direct oral anticoagulants era: Insight from the COMMAND VTE Registry-2. Thromb Res 2024; 234: 86–93.
• 21.   Weitz JI, Strony J, Ageno W, Gailani D, Hylek EM, Lassen MR, et al. Milvexian for the prevention of venous thromboembolism. N Engl J Med 2021; 385: 2161–2172.
• 22.   Piccini JP, Caso V, Connolly SJ, Fox KAA, Oldgren J, Schuyler Jones W, et al. Safety of the oral factor XIa inhibitor asundexian compared with apixaban in patients with atrial fibrillation (PACIFIC-AF): A multicentre, randomised, double-blind, double-dummy, dose-finding phase 2 study. Lancet 2022; 399: 1383–1390.