Abstract
Aims
The aim of this study is to compare the Hestia rule vs. the simplified Pulmonary Embolism Severity Index (sPESI) for triaging patients with acute pulmonary embolism (PE) for home treatment.
Methods and results
Normotensive patients with PE of 26 hospitals from France, Belgium, the Netherlands, and Switzerland were randomized to either triaging with Hestia or sPESI. They were designated for home treatment if the triaging tool was negative and if the physician-in-charge, taking into account the patient’s opinion, did not consider that hospitalization was required. The main outcomes were the 30-day composite of recurrent venous thrombo-embolism, major bleeding or all-cause death (non-inferiority analysis with 2.5% absolute risk difference as margin), and the rate of patients discharged home within 24 h after randomization (NCT02811237). From January 2017 through July 2019, 1975 patients were included. In the per-protocol population, the primary outcome occurred in 3.82% (34/891) in the Hestia arm and 3.57% (32/896) in the sPESI arm (P = 0.004 for non-inferiority). In the intention-to-treat population, 38.4% of the Hestia patients (378/984) were treated at home vs. 36.6% (361/986) of the sPESI patients (P = 0.41 for superiority), with a 30-day composite outcome rate of 1.33% (5/375) and 1.11% (4/359), respectively. No recurrent or fatal PE occurred in either home treatment arm.
Conclusions
For triaging PE patients, the strategy based on the Hestia rule and the strategy based on sPESI had similar safety and effectiveness. With either tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home with a low incidence of complications.
Keywords: Pulmonary embolism, Emergency department, Home treatment, Randomized controlled trial, Clinical decision-making, Risk assessment
Graphical abstract
The international randomized HOME-PE study demonstrates that, for triaging patients with acute pulmonary embolism for home treatment, the Hestia rule and the simplified Pulmonary Embolism Severity Index, complemented by the physician's overruling, are equally safe and efficient.
See page 3158 for the editorial comment on this article (doi:10.1093/eurheartj/ehab491)
Introduction
International guidelines suggest home treatment in patients with low-risk acute pulmonary embolism (PE), when home circumstances are adequate.1 , 2 However, current evidence is mainly based on cohort studies using different sets of eligibility criteria.3 , 4 Therefore, controversy persists about the optimal triaging strategy and eligibility criteria for home treatment.3
The approach proposed by the European Society of Cardiology firstly refers to a 30-day all-cause mortality risk assessment using the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI)1 , 5 , 6 (Table 1). The Hestia rule, a checklist of medical and social criteria precluding home treatment, is proposed as an alternative1 , 7 (Table 2). Although the Hestia rule was not primarily designed as a risk assessment model, the rate of complications in patients treated at home on the basis of a negative Hestia rule was low in prospective cohort studies, the 3-month mortality rate ranging from 0.5% to 1%.7–9 Moreover, the strategy based on the Hestia rule may lead to a higher proportion of PE patients treated at home than the strategy based on the sPESI.10 Indeed, around 50% of normotensive PE patients were discharged home within 24 h of diagnosis in studies applying the Hestia rule alone.7–9 Conversely, in studies using the PESI or the sPESI, medical or social exclusion criteria complemented the index, leading to a proportion of patients treated at home of <30%.11 , 12 However, the two strategies had never been prospectively compared head-to-head.
Table 1.
The simplified Pulmonary Embolism Severity Index
sPESI criteria | Points |
---|---|
Age >80 years | 1 |
History of cancer | 1 |
Chronic cardiopulmonary disease | 1 |
Systolic blood pressure <100 mmHg | 1 |
Heart rate ≥110 b.p.m. | 1 |
Arterial oxygen saturation <90% | 1 |
The sPESI score is the sum of the assigned points for each criterion. If the sPESI score is 0 points, i.e. the patient classified as low 30-day risk of death, patient qualification is home treatment. If the sPESI score is >0, i.e. the patient classified as high 30-day risk of death, patient qualification is in-hospital treatment.
sPESI, simplified Pulmonary Embolism Severity Index.
Table 2.
The Hestia rule
Checklist questions of the Hestia rule |
---|
|
If the answer to all the questions is no, i.e. the Hestia rule is negative, patient qualification is home treatment. If the answer to one of the questions is yes, i.e. the Hestia rule is positive, patient qualification is in-hospital treatment.
Include the following criteria but leave these to the discretion of the clinician: systolic blood pressure <100 mmHg with heart rate >100 b.p.m.; condition requiring admission to an intensive care unit.
Gastrointestinal bleeding in the preceding 14 days, recent stroke (<4 weeks ago), recent operation (<2 weeks ago), bleeding disorder or thrombocytopenia (platelet count <75 × 109/L), uncontrolled hypertension (systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg).
Calculated creatinine clearance according to the Cockcroft–Gault formula.
Left to the discretion of the physician.
The aim of the present trial was to compare the safety and effectiveness of the Hestia rule vs. the sPESI for triaging PE patients for home treatment, in the way they are applied in routine practice, i.e. with the possibility of the physician to overrule the triaging tool result and to take into account the patient’s opinion in a shared decision-making. Our research hypothesis was that the 30-day rate of complications of a triaging strategy based on the Hestia rule would be non-inferior to a strategy based on the sPESI and that the Hestia strategy would lead to a higher rate of patients treated at home than the sPESI strategy.
Methods
Trial design
HOME-PE study was an international randomized open-label non-inferiority trial, to compare a triaging strategy based on the Hestia rule with a strategy based on the sPESI for home treatment of patients with acute PE. The detailed trial protocol is available in the Supplementary material online. The trial was conducted in 26 hospitals from France (n = 15), Belgium (n = 5), the Netherlands (n = 5), and Switzerland (n = 1). Among them, 18 (69%) were university hospitals and 8 (31%) general hospitals. Prior to study initiation, 9 (35%) centres had a very-low level, 8 (31%) a low level, 5 (19%) an intermediate level and 4 (15%) a high level of experience in home treatment of patients with PE according to local investigators. There was no difference between university hospitals and general hospitals, 12/18 (67%) and 5/8 (62%) having a low or very-low level of experience, respectively. The study was approved by the relevant regulatory authorities and by the ethics committee CPP—Ouest II (France) for all the hospitals in France and by the ethics committee of the participating hospitals for Belgium, Switzerland, and the Netherlands. An independent Data and Safety Monitoring Board provided a timely review of data quality and safety of the clinical trial.
Patients
Patients presenting to the emergency department or just admitted in a clinical observation unit were eligible if they were 18 years or older, had objectively confirmed acute symptomatic PE [either by (i) a high-probability ventilation/perfusion lung scan, (ii) a new contrast segmental or more proximal filling defect on spiral computed tomography or on pulmonary angiography, or (iii) a new proximal deep vein thrombosis (DVT), i.e. thrombus in the popliteal vein or above, on venous compression ultrasonography along with clinical signs of PE]13 and provided oral and written informed consent. Patients were excluded if PE had been diagnosed more than 24 h prior to enrolment, if they had been admitted for more than 48 h, had shock or hypotension (defined as a systolic blood pressure <90 mmHg or a systolic blood pressure drop by ≥40 mmHg for more than 15 min, and not caused by a new-onset arrhythmia, hypovolaemia, or sepsis), or had conditions precluding 30-day follow-up (e.g. short life expectancy or geographical inaccessibility).
Randomization
Included patients were centrally randomized via a secure interactive web response system in a 1:1 ratio to one of the two triaging arms, with variable-size block stratification according to the hospital.
Procedures
In patients randomized to the Hestia group, the physician assessed the 11 criteria of the rule (Table 2) and patients qualified for home treatment if all criteria were negative. Patients in whom a positive criterion with a 24-h time window improved within 24 h, also qualified for home treatment. All other patients qualified for hospitalization. As per-protocol, the physician-in-charge could overrule the Hestia qualification. They assessed if there was a major reason requiring an overruling of the result of the Hestia rule and took into account the patient’s preference in a shared decision-making. A justification explaining the cause of overruling was required.
In the patients randomized to the sPESI group, the physician assessed the six criteria of the index and patients qualified for home treatment if the sPESI was 0 points. They qualified otherwise for hospitalization. As per-protocol, the physician-in-charge could overrule the sPESI qualification in the same way as performed in the Hestia arm. They assessed if there was a major reason requiring an overruling of the result of sPESI and took into account the patient’s preference in a shared decision-making. A justification explaining the cause of overruling was required.
In both groups, patients designated for home treatment were to be discharged home within 24 h following randomization.
In all participating hospitals, a specific patient pathway was set up prior to study initiation to organize home treatment. A dedicated clinical team, consisting of physicians who normally were responsible for the treatment and follow-up of PE patients in each hospital, conducted the follow-up of patients and offered a telephone service in case of suspected complications. The patients received therapeutic anticoagulation according to international guidelines, the choice of which was left to the discretion of the physician-in-charge.2 , 13 All patients were followed for 90 days. They were contacted within 3 days following randomization and at 14 ± 3, 30 ± 5, and 90 ± 15 days.
Outcomes
The primary outcome of the study was the composite rate of recurrent venous thrombo-embolism (VTE), major bleeding or all-cause death within 30 days after randomization. Recurrent VTE was defined as symptomatic, objectively confirmed DVT, non-fatal or fatal PE. Major bleeding was defined according to the criteria proposed by the International Society on Thrombosis and Hemostasis.14 All clinical events were adjudicated by an independent event adjudication committee, whose members were unaware of group assignments.
The first secondary outcome was home treatment, strictly defined as patients discharged home within 24 h following randomization. The exact times of discharge were extracted from the patients’ administrative report forms, independently of patient allocation and whether the patient qualified for home treatment. The second secondary outcome was qualification for home treatment according to the allocated rule, i.e. patients meeting no criteria of the Hestia rule, or patients with an sPESI of 0 points.
We further assessed and compared the rate of the 30-day composite outcome in patients treated at home. Lastly, we determined and compared the applicability of both triaging tools defined as the proportion of patients who left the hospital in the first 24 h after randomization among those who qualified for home treatment.
Statistical analysis
The analyses were performed in compliance with the CONSORT statement. The analyses for the primary outcome and the two main secondary outcomes followed a hierarchical approach in three steps. The 1st step was a non-inferiority analysis of the primary outcome for the Hestia vs. the sPESI strategy and was performed in the per-protocol population by logistic regression adjusted for hospital organization regarding PE.15 The 2nd and 3rd steps were two-sided difference superiority analyses, with an alpha level set at 5% and were performed in the randomized population with application of the intention-to-treat principle, using the same model as for the primary outcome.
Protocol deviations were defined as disregarding of an inclusion and/or exclusion criterion and/or of the recommended delay for home discharge (patients designated for home treatment but discharged home more than 24 h after the randomization or patients designated for hospitalization but discharged within 24 h following randomization).
The absolute risk difference of the primary outcome was calculated and the upper limit of the one-sided 95% confidence interval (CI), i.e. two-sided 90% CI, was compared with the pre-specified non-inferiority margin of 2.5%. This non-inferiority margin is consistent with the International Conference on Harmonization Guidelines and lower than those used in previous studies of home treatment in acute PE.8 , 11 Considering this non-inferiority margin, a 5% rate of the primary outcome in each study arm,16 , 17 and a dropout rate of 5%, 1975 patients were needed to achieve an 80% power using a one-sided alpha level at 5%.
For all outcomes based on categorical variables, results are presented as the adjusted absolute difference in rates between the two strategies and their 95% CI. Missing data were not imputed and no adjustment for competing risk of death was performed for the secondary outcomes, recurrent VTE, and major bleeding, when assessed as binary variables at 14, 30, or 90 days of follow-up.
All statistical analyses were performed with SAS software (SAS Institute, Cary, NC, USA) and R software (R Core Team, R Foundation for Statistical Computing, Vienna, Austria). Details including patients’ recruitment, definition of the populations, and other pre-specified subgroup analyses are provided in the protocol and the statistical analysis plan of the trial (Supplementary material online).
Role of the funding source
The trial was funded by a grant from the French Health Ministry (PHRC-N-15-0480) and by an unrestricted grant of the participating hospitals in the Netherlands. Angers University Hospital sponsored the participating hospitals in France, Belgium, and Switzerland, and the Leiden University Medical Center was the sponsor for the participating hospitals in the Netherlands. The sponsors had no role in the study design, analysis of the data or in the preparation of the manuscript.
Results
Patients
Between 2 January 2017 and 7 July 2019, 1974 patients were randomized. Four patients withdrew their consent after randomization, leaving 984 patients in the Hestia arm and 986 in the sPESI arm (Figure 1). The baseline characteristics of the randomized patients are presented in Table 3. A total of 72.6% of patients in the Hestia arm and 74.1% in the sPESI arm were treated with a direct oral anticoagulant.
Figure 1.
Enrolment, randomization, and follow-up. Among randomized patients, three subsequently withdrew consent in the Hestia arm and one in the sPESI arm; 77 patients were excluded from the per-protocol population in the Hestia arm: 13 for disregard of the inclusion or exclusion criteria (for 6 patients the initial diagnosis of acute pulmonary embolism was subsequently refuted, 2 patients had systolic blood pressure <90 mmHg at baseline, 2 had a time interval between emergency department presentation and inclusion >48 h, and 3 patients had a time interval between pulmonary embolism diagnosis and inclusion >24 h), 63 for disregard of the protocol strategy (32 were designated for home treatment but discharged home more than 24 h after randomization and 31 were designated for hospitalization but discharged within 24 h following randomization), and 1 for both protocol deviations (unconfirmed pulmonary embolism diagnosis and designated for hospitalization but discharged within 24 h following randomization); 85 patients were excluded from the per-protocol population in the sPESI arm: 18 for disregard of the inclusion or exclusion criteria (for 12 patients, the initial diagnosis of acute pulmonary embolism was subsequently refuted, 3 had a time interval between emergency department presentation and inclusion >48 h, and 3 patients had a time interval between pulmonary embolism diagnosis and inclusion >24 h), 64 for disregard of the protocol strategy (31 were designated for home treatment but discharged home more than 24 h after randomization and 33 were designated for hospitalization but discharged within 24 h following randomization), and 3 for both protocol deviations (2 with unconfirmed pulmonary embolism diagnosis and designated for hospitalization but discharged within 24 h following randomization, and 1 with a time interval between emergency department presentation and inclusion >48 h, and designated for home treatment but discharged home more than 24 h after randomization).
Table 3.
Demographic and clinical characteristics of the randomized patients at baseline
Hestia strategy (N = 984) | sPESI strategy (N = 986) | |
---|---|---|
Characteristics | ||
Age, years, median ± IQ | 63.5 ± 17.7 | 62.3 ± 17.5 |
>80 years, n (%) | 185 (18.8) | 161 (16.3) |
Female sex, n (%) | 475 (48.3) | 473 (48.0) |
ED presentation to randomization, h, median ± IQ | 15.7 ± 16.2 | 14.5 ± 16.2 |
Medical history, n (%) | ||
Previous venous thrombo-embolism | 253 (25.9) | 257 (26.3) |
Current oestrogen therapy | 54 (5.5) | 55 (5.6) |
Bed rest >72 h within past 3 months | 122 (12.5) | 110 (11.2) |
Surgery within past 3 months | 94 (9.6) | 86 (8.8) |
Current pregnancy | 4 (0.8) | 2 (0.4) |
Active cancer or remission <1 year | 148 (15.1) | 101 (10.3) |
History of cancer or active cancer | 217 (22.2) | 183 (18.7) |
Chronic heart failure | 42 (4.3) | 38 (3.9) |
Chronic lung disease | 101 (10.3) | 92 (9.4) |
PE diagnosed during anticoagulation | 44 (4.5) | 40 (4.1) |
Signs and symptoms, n (%) | ||
Syncope | 59 (6.0) | 42 (4.3) |
Systolic blood pressure <100 mmHg | 23 (2.4) | 10 (1.0) |
Heart rate ≥110 b.p.m. | 178 (18.2) | 157 (16.0) |
Oxygen saturation <90% | 57 (5.9) | 87 (8.9) |
Right ventricular dilatationa | 221 (22.4) | 225 (22.8) |
High level of troponin b | 294 (29.9) | 268 (27.2) |
High level of BNP or NT-proBNPc | 190 (19.3) | 187 (18.8) |
Anticoagulant treatmentd, n (%) | ||
Direct oral anticoagulant | 714 (72.6) | 731 (74.1) |
Vitamin K antagonist | 50 (5.1) | 52 (5.3) |
Low molecular weight or unfractionated heparin | 180 (18.3) | 154 (15.6) |
Miscellaneous | 40 (4.1) | 49 (5.0) |
Right ventricle/left ventricle >1 on computed tomography pulmonary angiography or on transthoracic echocardiography; assessed in 819 (83%) patients in the Hestia group and (84%) patients in the sPESI group.
Troponin level >99th percentile according to local technique; assessed in 729 (74%) patients in the Hestia group and 719 (73%) patients in the sPESI group.
BNP (B-type natriuretic peptide) >100 ng/L or NT-proBNP (N-terminal proBNP) >600 ng/L; assessed in 562 (57%) patients in the Hestia group and 539 (55%) patients in the sPESI group.
Main anticoagulant treatment, i.e. drug prescribed ≥90% of the time, within 30 days following inclusion.
Primary outcome and clinical events
In the overall randomized population, a protocol deviation occurred in 162 patients, 9 patients opted out of the study and 12 patients were lost to follow-up at Day 30, leaving 891 patients in the Hestia arm and 896 in the sPESI arm for the per-protocol main analysis (Figure 1). The 30-day primary composite outcome occurred in 3.82% (34/891) in the Hestia arm and in 3.57% (32/896) in the sPESI arm, for an adjusted absolute difference of 0.20% (upper limit of the one-sided 95% CI 1.43%; P = 0.004 for non-inferiority; Table 4). Similar results were observed in the overall intention-to-treat population: 3.93% (38/966) in the Hestia arm and 3.37% (33/978) in the sPESI arm, for an adjusted absolute difference of 0.49% (upper limit of the one-sided 95% CI 1.68%; P = 0.0076 for non-inferiority) (Table 4). The rate of the primary composite outcome and each of its components, i.e. recurrent VTE, major bleeding, and all-cause death, was comparable between the study arms at Days 14, 30, and 90 (Table 4). Likewise, the time-to-event curves were comparable (Supplementary material online, eFigures S1–4).
Table 4.
Outcomes in per-protocol and intention-to-treat populations
Hestia strategy (N = 984) | sPESI strategy (N = 986) | ||||
---|---|---|---|---|---|
Main outcome In the per-protocol population |
n° of patients with event/total n° of patients (%) |
Adjusted absolute differencea (90% CI) |
|||
Composite of recurrent VTE, major bleeding and all-cause death at Day 30 | 34/891 (3.82) | 32/896 (3.57) | +0.20% (−1.03 to 1.43) | P = 0.004b | |
In the intention-to-treat population | |||||
Composite of recurrent VTE, major bleeding and all-cause death at Day 30 | 38/966 (3.93) | 33/978 (3.37) | +0.49% (−0.71 to 1.68) | P = 0.008b | |
Major secondary outcomes In the intention-to-treat population |
n° of patients with event/total n° of patients (%) |
Adjusted absolute differencea (95%CI) |
|||
Rate of patients actually treated at home | 378/984 (38.4) | 361/986 (36.6) | +1.78% (−2.40 to 5.96) | P = 0.41c | |
Rate of patients qualified for home treatment according to the rule | 388/984 (39.4) | 477/986 (48.4) | −8.91% (−13.3 to −4.56) | – | |
Applicability of the triaging strategy | |||||
Patients treated at home among qualified patients according to the rule | 343/388 (88.4) | 309/477 (64.8) | +25.3 % (19.5 to 31.1) | ||
Clinical events at Day 14 | |||||
Composite of recurrent VTE, major bleeding and all-cause death | 18/974 (1.85) | 24/981 (2.45) | −0.47% (−1.50 to 0.55) | ||
Recurrent VTE | 3/967 (0.31) | 4/969 (0.41) | +0.07% (−0.47 to 0.32) | ||
Major bleeding | 9/967 (0.93) | 8/960 (0.83) | +0.10% (−0.67 to 0.86) | ||
All-cause death | 8/974 (0.82) | 13/981 (1.33) | −0.37% (−1.05 to 0.31) | ||
Clinical events at Day 30 | |||||
Composite of recurrent VTE, major bleeding and all-cause death | 38/966 (3.93) | 33/978 (3.37) | +0.49% (−0.94 to 1.92) | ||
Recurrent VTE | 4/946 (0.42) | 5/959 (0.52) | +0.07% (−0.50 to 0.36) | ||
Major bleeding | 15/947 (1.58) | 10/960 (1.04) | +0.54% (−0.48 to 1.56) | ||
All-cause death | 22/966 (2.28) | 19/978 (1.94) | +0.28% (−0.78 to 1.35) | ||
Clinical events at Day 90 | |||||
Composite of recurrent VTE, major bleeding and all-cause death | 74/959 (7.72) | 61/972 (6.28) | +1.34% (−0.77 to 3.45) | ||
Recurrent VTE | 8/910 (0.88) | 13/934 (1.39) | −0.49% (−1.43 to 0.44) | ||
Major bleeding | 24/912 (2.63) | 15/937 (1.60) | +1.05% (−0.30 to 2.40) | ||
All-cause death | 51/959 (5.32) | 38/972 (3.91) | +1.24% (−0.40 to 2.90) |
The total number of patients (denominator) corresponds to the number of patients in the subgroup minus the number of patients who had withdrawn their consent or who were lost to follow-up.
VTE, venous thrombo-embolism.
Differences are expressed as absolute rate differences adjusted for hospital organization regarding PE.
P-value of one-sided non-inferiority analysis with a non-inferiority limit fixed to 2.5% in absolute risk difference.
P-value of two-sided superiority analysis.
First secondary outcome
In the Hestia arm, 38.4% (378/984) of the patients were treated at home vs. 36.6% (361/986) in the sPESI arm, for an adjusted absolute difference of 1.78% (95% CI −2.40 to 5.96; P = 0.41 for superiority; Table 4). Similar results between the study arms were observed in the per-protocol population (Supplementary material online, eTable S1).
Second secondary outcome and selection for home treatment
The Hestia rule was negative in 39.4% (388/984) of patients and the sPESI was 0 points in 48.4% of patients (477/986), for an adjusted absolute difference of −8.91% (95% CI: −13.3 to −4.56; Table 4 and Figure 2).
Figure 2.
Selection for home treatment. The selection for home treatment included three steps. Step 1: Qualification for home treatment according to the allocated triaging tool. Patients randomized to the Hestia arm qualified for home treatment if all answers were negative. Patients randomized to the sPESI arm qualified for home treatment if the sPESI was 0 points. Step 2: Designation for home treatment according to the physician-in-charge. In both study arms, for designation for home treatment and as per-protocol, the physician-in-charge could overrule the qualification issued from the allocated triaging tool in case of imperative medical or social reasons, or patient’s refusal. The reasons are mentioned in the lateral boxes. Step 3: Final management. Patients were considered to have been treated at home if they were actually discharged within 24 h following randomization, calculated from the patients’ administrative report forms. Protocol deviations were defined as patients designated for home treatment who were discharged after the 24-h limit, or vice versa, as patients designated for hospitalization who were discharged before the 24-h limit. DOAC, direct oral anticoagulant; LMWH, low molecular weight heparin.
The negative Hestia rule was overruled in 3.4% of patients (13/388): 10 patients refused home treatment and 3 had a contra-indication to a low molecular weight heparin and a direct oral anticoagulant. A positive Hestia rule was overruled in 0.5% of patients (3/596): all those patients refused to be hospitalized. The sPESI of 0 points was overruled in 28.5% of patients (136/477): 96 patients had a concomitant illness necessitating hospitalization and 13 patients a social reason for hospitalization; 13 patients required specific PE treatment, including reperfusion therapy or vena cava filter insertion according to the physician-in-charge; 11 patients refused home treatment; and 3 patients had a contra-indication to low molecular weight heparin or direct oral anticoagulant. An sPESI of 1 point or more was overruled in 3.3% of patients (17/509): all 17 patients refused to be hospitalized. Therefore, 38.4% (378/984) of the patients in the Hestia arm and 36.3% (358/986) in the sPESI arm were designated by the physician-in-charge for home treatment (Figure 2).
Applicability of the triaging tools
The applicability of the triaging tools, i.e. the proportion of patients with a negative Hestia rule or an sPESI of 0 points, who were discharged to home in the first 24 h after randomization, was 88.4% (343/388) for the Hestia rule and 64.8% (309/477) for the sPESI, for an adjusted absolute difference of +25.3% in favour of the Hestia rule (95% CI 19.5 to 31.1; Table 4).
Patients treated at home
The baseline characteristics of the patients treated at home are presented in Table 5. The median in-hospital length of stay between emergency department presentation and discharge to home was 19.2 h in the Hestia arm and 16.7 h in sPESI arm (Supplementary material online, eTable S2). In the Hestia arm, the proportion of patients older than 80 years (absolute difference +4.72%, 95% CI 1.31 to 8.14), with active cancer (+4.77%, 95% CI 0.66 to 8.87), history of cancer (+8.55%, 95% CI 3.46 to 13.63), chronic lung disease (+3.55%, 95% CI 0.31 to 6.80), and heart rate ≥110 b.p.m. (+4.63%, 95% CI 0.38 to 8.89) was higher than in the sPESI arm (Supplementary material online, eTable S3). Within 14 days following home discharge, 9 (2.4%) and 17 (4.7%) patients had an unscheduled hospitalization in the Hestia arm and in the sPESI arm, respectively (Supplementary material online, eTable S2).
Table 5.
Demographic and clinical characteristics of patients treated at home
Hestia strategy (N = 378) | sPESI strategy (N = 361) | |
---|---|---|
Characteristics | ||
Age, years, mean ± SD | 57.9 ± 16.7 | 55.4 ± 15.5 |
>80 years, n (%) | 26 (6.9) | 9 (2.5) |
Female sex, n (%) | 177 (46.8) | 164 (45.4) |
ED presentation to randomization, h, median ± IQ | 13.1 ± 15.3 | 10.0 ± 15.1 |
Medical history, n (%) | ||
Previous venous thrombo-embolism | 83 (22.3) | 106 (29.9) |
Current oestrogen therapy | 32 (8.6) | 32 (9.0) |
Bed rest >72 h within past 3 months | 31 (8.3) | 25 (7.0) |
Surgery within past 3 months | 38 (10.2) | 29 (8.2) |
Current pregnancy | 2 (1.1) | 1 (0.6) |
Active cancer or remission <1 year | 34 (9.1) | 17 (4.8) |
History of cancer or active cancer | 59 (15.9) | 28 (7.9) |
Chronic heart failure | 7 (1.9) | 1 (0.3) |
Chronic lung disease | 26 (7.0) | 12 (3.4) |
PE diagnosed during anticoagulant treatment | 7 (1.9) | 10 (2.8) |
Signs and symptoms at baseline, n (%) | ||
Syncope | 10 (2.7) | 8 (2.2) |
Systolic blood pressure <100 mmHg | 2 (0.5) | 2 (0.6) |
Heart rate ≥110 b.p.m. | 42 (11.3) | 24 (6.7) |
Oxygen saturation <90% | 1 (0.5) | 2 (0.6) |
Right ventricular dilatation a | 46 (12.2) | 44 (12.2) |
High level of troponin b | 54 (14.3) | 37 (10.2) |
High level of BNP or NT-proBNPc | 19 (5.0) | 11 (3.0) |
Anticoagulant treatmentd, n (%) | ||
Direct oral anticoagulant treatment | 321 (84.9) | 315 (87.3) |
Vitamin K antagonist | 7 (1.9) | 12 (3.3) |
Low molecular weight heparin | 37 (9.8) | 24 (6.6) |
Miscellaneous | 13 (3.4) | 10 (2.8) |
Right ventricle/left ventricle >1 on computed tomography pulmonary angiography or on transthoracic echocardiography; assessed in 312 (82%) patients in the Hestia arm and 304 (84%) patients in the sPESI arm of outpatients.
Troponin level >99th percentile according to local technique; assessed in 242 (64%) patients in the Hestia subgroup and 218 (60%) in the sPESI subgroup of outpatients.
BNP (B-type natriuretic peptide) >100 ng/L or NT-proBNP (N-terminal proBNP) > 600 ng/L; assessed in 185 (49%) patients in the Hestia subgroup and 145 (40%) patients in the sPESI subgroup of outpatients.
Main anticoagulant treatment, i.e. drug prescribed ≥90% of the time, within 30 days following inclusion.
Among patients treated at home, the 30-day primary composite outcome occurred in 1.33% (5/375) of patients assigned to the Hestia arm and in 1.11% (4/359) in patients assigned to the sPESI arm (adjusted absolute difference 0.19%, 95% CI −1.15 to 1.52; Table 6). No patient suffered from fatal PE, recurrent non-fatal PE, or haemodynamic collapse in either study arm. Four out of five non-fatal major bleedings were metro- or menorrhagia, all in women receiving direct oral anticoagulant treatment. Two patients had a symptomatic extension, objectively confirmed by compression ultrasonography, of a pre-existing DVT despite anticoagulation (Supplementary material online, eTable S4).
Table 6.
Outcomes in patients treated at home
Hestia strategy (N = 378) | sPESI strategy (N = 361) | Adjusted absolute difference (95% CI)a | |
---|---|---|---|
Clinical events at Day 14 | n° of patients with event/total n° of patients (%) | ||
Composite of recurrent VTE, major bleeding, and all-cause death | 3/376 (0.80) | 2/360 (0.56) | +0.20% (−0.76 to 1.16) |
Recurrent VTE | 0/376 (–) | 2/360 (0.56) | −0.26% (−0.62 to 0.10) |
Major bleeding | 3/376 (0.80) | 0/360 (–) | +0.81% (−0.34 to 1.96) |
All-cause death | 1/376 (0.27) | 0/360 (–) | +0.13% (−0.12 to 0.37) |
Clinical events at Day 30 | |||
Composite of recurrent VTE, major bleeding, and all-cause death | 5/375 (1.33) | 4/359 (1.11) | +0.19% (−1.15 to 1.52) |
Recurrent VTE | 0/374 (–) | 2/358 (0.56) | −0.26% (−0.63 to 0.10) |
Major bleeding | 5/375 (1.33) | 1/358 (0.28) | +1.07% (−0.38 to 2.53) |
All-cause death | 1/375 (0.27) | 1/359 (0.28) | −0.01% (−0.36 to 0.35) |
Clinical events at Day 90 | |||
Composite of recurrent VTE, major bleeding, and all-cause death | 11/371 (2.96) | 5/357 (1.40) | +1.07% (−0.43 to 2.57) |
Recurrent VTE | 3/369 (0.81) | 3/356 (0.84) | −0.03% (−1.38 to 1.32) |
Major bleeding | 9/370 (2.43) | 2/356 (0.56) | +1.45% (−0.07 to 2.97) |
All-cause death | 2/371 (0.54) | 1/357 (0.28) | +0.12% (−0.31 to 0.56) |
The total number of patients (denominator) corresponds to the number of patients in the subgroup minus the number of patients who opted out of the trial or who were lost to follow-up.
VTE, venous thrombo-embolism.
Differences are expressed as absolute rate differences adjusted for hospital organization regarding PE.
Further subgroup analysis
Characteristics and outcomes of patients (i) qualified for home treatment by Hestia and sPESI, (ii) designated for home treatment after physician-in-charge overruling, and (iii) treated in hospital are shown in Supplementary material online, eTables S5, S6, eTables S7, S8, and eTables S9, S10, respectively. The outcomes were similar between the two study arms in all of these subgroup analyses.
Discussion
Principal findings
In the HOME-PE study, the Hestia rule strategy was non-inferior to the sPESI strategy for triaging normotensive PE patients for home treatment, with respect to the 30-day composite complication rate. Compared with the sPESI, the Hestia rule qualified fewer patients as eligible for home treatment but its applicability was higher, because fewer home treatment qualifications were overruled by the physician-in-charge taking into account the patient’s preference. Despite differences in the characteristics of patients treated at home, the proportion of patients discharged home within the 24 h following inclusion, did not differ between the two strategies. More than a third of PE patients were treated at home using either the Hestia rule or the sPESI, with a low 30-day rate of complications (Graphical abstract).
Meaning of the study and comparison with other studies
Several studies have previously evaluated these two triaging tools, but most of them were single-arm cohort studies precluding direct comparison of their safety, applicability, and effectiveness.3 , 4 To our knowledge, only two studies previously compared the sPESI and the Hestia rule. The first one was retrospective,18 and the other a single-centre observational prospective study where the investigators did not use the triaging tools for decision-making of home treatment.19 The aim of the present trial was to compare the two triaging strategies as they would be applied in routine practice, to directly guide clinical decision-making. In light of the 30-day rates of the main primary composite outcome and its individual components, our data demonstrate that, while the patients managed at home differed between the two strategies in several aspects, their safety was comparable in both the per-protocol and intention-to-treat populations. Of note, the rates of recurrent VTE and all-cause death in the overall HOME-PE population were lower than reported in historical cohorts of normotensive PE patients.16 , 17 Improvement of hospital adherence to evidence-based guidelines, e.g. the introduction of risk stratification-based initial management and direct oral anticoagulants, may have contributed to a clear decrease in PE mortality over time.20 , 21
Contrary to our hypotheses, a lower proportion of patients was qualified for home treatment with the Hestia rule than with the sPESI and a similar proportion of patients was actually treated at home. The 39.4% rate of patients with a negative Hestia rule was lower in our study than in Dutch hospitals, which first described and used the Hestia rule (51–55%),7 , 8 but higher than in two other studies (27%).19 , 22 Conversely, the 48% rate of patients with an sPESI of 0 points was higher than the 28% rate in two other recent studies.19 , 23 Possible reasons for these discrepancies are differences in hospital settings and patient characteristics as well as the way the triaging tools are used. Indeed, both tools include measurements of three vital signs: systolic blood pressure, pulse rate, and oxygen saturation. Vital signs are dynamic and the use of one or another measurement in the triaging assessment may change the qualification. Moreover, some criteria of the Hestia rule, such as ‘high risk for bleeding’ and ‘medical or social reason for admission’, leave some room for the physician’s interpretation.19
One important feature of our trial is its pragmatic design allowing reliable assessment of the effectiveness of the two triaging tools as they are applied in everyday clinical practice.24 Indeed, the physician-in-charge had the possibility to overrule the qualification issued by the triaging tool and to take into account the patient’s opinion in the decision-making process. This overruling occurred in 28.5% of patients with an sPESI of 0 points, vs. in 3.4% of patients with a negative Hestia rule. As a result, the applicability of the Hestia rule was higher than that of the sPESI. This difference is likely related to the divergent original purposes of the two triaging rules, i.e. to predict 30-day mortality for the sPESI6 and to identify conditions precluding home treatment for the Hestia rule.7 The sPESI cannot be applied as a standalone rule to decide on the feasibility of home treatment. It requires an implicit assessment of medical or social conditions precluding home treatment. The addition of these implicit criteria to the sPESI criteria could have resulted in a lower proportion of patients sent home than when only the explicit Hestia criteria would have been used. For instance, according to sPESI, patients older than 80 years or with cancer or cardiorespiratory disease are precluded from home treatment. The proportion of these patients treated at home was therefore higher in the Hestia arm than in the sPESI arm. The same findings were observed in a retrospective assessment of the Hestia study.18 However, despite these differences in patients’ characteristics, the rate of patients managed at home was not higher with the Hestia strategy than with the sPESI strategy. This unexpected result emphasizes the relevance and importance of physicians’ and patients’ related factors in the real-world applicability and effectiveness of the two triaging tools.
Importantly, the rate of adverse events in patients treated at home in our study was low and similar between the two triaging strategies. It compares well to that in recent studies on this topic, supporting the external validity of our study.12 , 25 , 26 Notably, the most commonly occurring complication was major uterine bleeding in women treated with a direct oral anticoagulant.27
Nearly, a quarter of our patients had right ventricular dilatation as assessed by echocardiography or computed tomography pulmonary angiography. How the presence of right ventricular dilatation should influence the decision to treat normotensive PE patients at home is an ongoing debate.28 The HOME-PE study was not designed to solve this issue and assessment of right ventricular function was not compulsory. However, none of the 90 patients, who had right ventricular dilatation at presentation and were treated at home, returned to the hospital because of haemodynamic deterioration or experienced a PE recurrence or PE-related death. Similar results have been reported in another study.29
Strengths and limitations of this study
HOME-PE is the largest trial of PE home treatment to date, providing robust results with a narrow 95% CI on the rate of adverse events. Several strengths reinforce the generalizability of its results. HOME-PE was performed in four European countries with different health-care organization and in 26 hospitals with, for most of them, a very low or low level of experience in home treatment of PE patients prior to study initiation. Although we had a strict randomization process, the trial was designed and conducted in real-world clinical practice. Especially, the physician-in-charge had the possibility to overrule the qualification issued from the triaging tool in each study arm and could involve the patient’s preference in the decision-making, as would occur in daily practice.
Our study also has limitations. First, we chose a pragmatic trial design over an explanatory design, since the goal of HOME-PE was to provide clinicians with robust evidence to safely triage PE patients for home treatment directly transferable into their everyday clinical practice.24 Second, HOME-PE was not formally powered to compare the rate of adverse events in the subgroups of patients treated at home, but the very low rate of complications reinforces the validity of using either triage tool. Third, participating hospitals had to set up a specific patient pathway for home treatment that may be difficult to organize in lack of local expert availability, especially in community hospitals. Finally, as a double-blind study design was not feasible, physicians may have incorporated some criteria of one rule when assessing patients randomized to the other one. Nonetheless, the characteristics of patients treated at home were different between the two study arms, confirming that the physicians made different decisions in patients assigned to the Hestia triaging strategy or to the sPESI triaging strategy.
Implications for policy and practice
Our findings add evidence to current guidelines supporting home treatment with either the Hestia rule or the sPESI. The sPESI consists of fewer and exclusively objective criteria but requires an additional assessment of the suitability of home treatment. The Hestia rule includes medical and social conditions that preclude home treatment. Its applicability is better but certain criteria leave room for the physician’s judgement. In our study, both strategies safely led to home treatment in more than one-third of patients. Widespread implementation of either Hestia or sPESI triaging strategy could therefore result in considerable cost savings, as more than 90% of PE patients are currently hospitalized in several European countries and in the USA.30 , 31 One important feature is that all participating hospitals had set up a specific patient pathway based on local experts, to organize home treatment, with timely follow-up and clear instructions for discharged patients. This may have contributed to the low rate of complications. In our view, and in line with current guidelines1 , 2 and with the organization in place in the countries that have a wide experience in home treatment of PE patients,9 , 32 , 33 such an organization should optimally be in place before home treatment is implemented.
Conclusions
For triaging normotensive PE patients for home treatment, the strategy based on the Hestia rule and the strategy based on the sPESI had similar safety and effectiveness. With either triaging tool complemented by the overruling of the physician-in-charge, more than a third of patients were treated at home, with a low rate of complications.
Supplementary material
Supplementary material is available at European Heart Journal online.
Supplementary Material
Acknowledgements
The authors thank the patients for their participation in the trial, all the investigators of the HOME-PE study group, and all the members of the different study committees. They dedicate HOME-PE to our late friend and inspirator Guy Meyer, who greatly contributed to its design and chaired the steering committee of the study.
HOME-PE study group
Investigators: In addition to the authors, the following investigators participated in the HOME-PE study. France—Paris HEGP (350): Anne-Laure Feral, Jean Pastré, Anne Roche; Toulon CHITS (214): Dimitri Cornand, Pauline Martinez, Jean-Noël Poggi, Sarah Rezkallah; Angers CHU (139): Cristina Belizna, Yannick Bigou, Quentin Carraro, Emilie Friou, Anne-Sophie Gourdier, Camille Palous; Brest CHU (85): David Goetghebeur; Rouen CHU: Guillaume Armengol, Cédric Tzebia; Paris Cochin (66): Florence Dumas; Grenoble CHU (64): Maxime Maignan; Clermont-Ferrand CHU (62): Farès Moustafa; Toulouse CHU (57): Sandrine Charpentier, Alessandra Bura-Rivière; Paris Louis Mourier(53): Florent Maillet, Ludovic Plaisance; Montpellier CHU (42): Jean-Philippe Galanaud, Pierrick Henneton, Riad Jreige, Bruno Lehodey; Dijon CHU (39): Didier Honnart, Riadh Tfifha; Le Mans CH (38): Thibault Schotte; Paris APHP Lariboisière (15): Ghanima Al Dandachi, Guy Simoneau; Brest HIA (9): Anne Le Coat. Belgium—Bruxelles Cliniques Universitaires Saint-Luc (164): Chiara Casarin, Anda Cismas, Boris Germeau, Charles Grégoire, Philippe Hainaut, Cédric Hermans, Catherine Lambert, Francoise Steenebrugge; Liege CHU (80): Marie Muriel, Sprynger Moonen; Saint-Pierre CHU (46): Maria Gabrovska, Bernard Kreps, Diane de Longueville, Pierre Mols; Namur CHR (25): Philippe Delvaux; Bruxelles ERASME (6): Marc Van Nuffelen, Serge Motte. Switzerland—Lausanne CHUV (90). The Netherlands—Hilversum-Tergooiziekenhuizen (51): Pieter Willem Kamphuisen; Beverwijk—Rode Kruis Ziekenhuis (60): Carlinda Bresser; Den Haag-Hagaziekenhuis (36): Stephan Hendriks, Albert T.A. Mairuhu, Liselotte van der Pol; Leiden University Medical Center (35): Anne J Fogteloo; Utrecht-UMC (12): Mathilde Nijkeuter, Micha de Winter.
HOME-PE study committees
Steering committee: Gilles Chatellier (Methodologist; Hôpital Européen Georges Pompidou, Paris, France); Olivier Hugli (Coordinator for Switzerland; University Hospital of Lausanne, Lausanne, Switzerland). Menno Huisman (Coordinator for the Netherlands; Leiden University Medical Center, Leiden, the Netherlands); David Jimenez (Advisor; Ramon y Cajal Hospital, Madrid, Spain); Frederikus A. Klok (Advisor; Leiden University Medical Center, Leiden, the Netherlands); Guy Meyer (Chair; Hôpital Européen Georges Pompidou, Paris, France); Andrea Penaloza (Coordinator for Belgium; Cliniques Universitaires Saint Luc, Brussels, Belgium); Pierre-Marie Roy (Principal Investigator—coordinator of the study; CHU Angers, Angers, France); Olivier Sanchez (Coordinator for France; Hôpital Européen Georges Pompidou, Paris, France).
Independent adjudication of clinical events committee: Phillipe Girard (Chair; Institut Montsouris, Paris, France); Manuel Monreal (Hospital Universitari Germans Trias i Pujol, Barcelona, Spain); Paul den Exter (Leiden University Medical Center, Leiden, the Netherlands); Florence Parent (Hôpital Bicêtre, Le Kremlin Bicêtre France).
Independent Data Safety and Monitoring Board: Drahomir Aujesky (Hôpital Universitaire de Berne, Bern, Swithzerland); Henri Bounameaux (Chair, University Hospital of Geneva, Geneva, Switzerland); Silvy Laporte (CHU Saint Etienne, Saint Etienne, France); Hugo Ten Cate (Masstricht University, Masstricht, The Netherlands).
Study management staffs: International coordination (Angers): Béatrice Gable, Cindy Augereau. Data-management (Angers): Jean-Marie Chrétien, Adrien Goraguer, Elise Houssin. Research management assistants: France—Paris HEGP: Laurence Leconte, Siwar Smii, Fayza Lasri, Céline Haton, Amélie Marquette; Toulon CHITS: Matthias Mercier, Manon Abello, Fabien Mitri, Claudie Leclerq, Danielle Giansily; Angers CHU: Clothilde Aubert, Chloé Ragueneau, Nadine Baty; Brest CHU: Anne-Sophie Veillon, Bénédicte Le Gall; Rouen CHU: Caroline Bulte; Paris APHP Cochin Hospital: Gwenaëlle Pontdemé, Aziza Chibah, Youcef Atia; Grenoble CHU: Prudence Mabiala Makele, Fatima Bouchafa; Clermont-Ferrand CHU: Christelle Camminada; Toulouse CHU: Manon Hebrard, Brigitte Pelvet, Delphine Baudoin; Paris APHP Louis Mourier Hospital: Michèle Pinson, Hélène Helfer; Montpellier CHU: Sophie Lefebvre, Daniel Pontal; Dijon CHU: Barbara Lextreyt, Céline Bernard; Le Mans CH: Alain Robert; Brest HIA: Isabelle Pichon, Elisabeth Beuvard—Belgium—Bruxelles Cliniques Universitaires Saint-Luc: Anne-Charlotte Dekeister; Namur CHR: Christine Leon—Suisse—Lausanne CHU Vaudois: Hélène Gerhard-Donnet—The Netherlands—Hilversum-Tergooi: Sandra Moll, Martine de Bruijn.
Funding
This work was supported by a grant from the French Health Ministry (PHRC-N-15-0480) and by an unrestricted grant of the participating hospitals in the Netherlands. Angers University Hospital sponsored the participating hospitals in France, Belgium, and Switzerland, and the Leiden University Medical Center was the sponsor for the participating hospitals in the Netherlands. The sponsors had no role in the study design, analysis of the data or in the preparation of the manuscript.
Conflict of interest: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi.disclosure.pdf and declare no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other activities that could appear to have influenced the submitted work. The following authors report, outside the submitted work, to have served as an advisor, lecturer, or consultant and/or to have received grant or personal fees or non-financial support: P.M.R. from Bayer HealthCare, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Aspen, Daiichi Sankyo, and Sanofi-Aventis; A.P. from Bayer HealthCare, Boehringer Ingelheim, Bristol Myers Squibb, Roche, Aspen, Daiichi Sankyo, Sanofi-Aventis, and Stago; F.K. from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, MSD, Daiichi Sankyo, Actelion, the Dutch thrombosis association, the Dutch Heart foundation, and the Netherlands Organisation for Health Research and Development; A.A. from APHP; F.C. from Bayer HealthCare, Boehringer Ingelheim, Bristol Myers Squibb, Astra Zeneca, Leo Pharma, and Actelion; J.S. from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Leo Pharma; I.M. from Stago, Bayer HealthCare, Bristol Myers Squibb, and Leo Pharma; I.Q. from Bayer HealthCare, Bristol Myers Squibb, Pfizer, and Leo Pharma; Y.B. from Bayer HealthCare, Bristol Myers Squibb, Pfizer, and Leo Pharma; N.D. from Leo Pharma, Bayer HealthCare, and Molnlycke HealthCare; G.M. from Bayer HealthCare, Bristol Myers Squibb, Pfizer, and Leo Pharma; O.S. from Bayer HealthCare, Bristol Myers Squibb, Pfizer, Daiichi Sankyo, Sanofi-Aventis, Boehringer Ingelheim, Boston Scientifics, Chiesi, and MSD. O.H., A.E., L.M.J., R.L., L.F., M.D.-E., B.P., J.B., D.V., H.J., F.S., M.B., R.C., T.M., N.F., K.M., D.D., C.S., S.H., T.A.S., G.P., F.X.L., A.G., and M.S. had nothing to declare.
Ethics
This study complies with the Declaration of Helsinki. It was approved by the ethics committee CPP—Ouest II (France) for all the hospitals in France and by the ethic committee of the participating hospitals for Belgium, Switzerland, and the Netherlands.
Copyright
This study has not previously been published and is not currently submitted elsewhere.
Transparency
The corresponding author (P.M.R.) has access to the data and affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.
Data availability
All anonymized raw data on individual patients on which the analysis, results, and conclusions reported in the paper are based are available to a third-party auditor and to researchers on reasonable request to the corresponding author.
Contributor Information
Pierre-Marie Roy, Emergency Department, CHU Angers, 4 rue Larrey, Angers, France, F-49000; Univ. Angers, INSERM, CNRS, MITOVASC, Equipe CARME, SFR ICAT, Angers, France; F-CRIN, INNOVTE, Saint-Etienne, France.
Andrea Penaloza, F-CRIN, INNOVTE, Saint-Etienne, France; Emergency Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium; UCLouvain, Brussels, Belgium.
Olivier Hugli, Emergency Department, University Hospital of Lausanne, Lausanne, Switzerland.
Frederikus A Klok, Department of Medicine – Thrombosis and Hemostasis, DTN, Leiden University Medical Center, Leiden, the Netherlands.
Armelle Arnoux, Computing, Statistics and Public Health & CIC1418, Hôpital Européen Georges Pompidou, APHP, Paris, France; University of Paris, Paris, France.
Antoine Elias, F-CRIN, INNOVTE, Saint-Etienne, France; Department of Cardiology and Vascular Medicine, CH Sainte Musse – Toulon, Toulon, France.
Francis Couturaud, F-CRIN, INNOVTE, Saint-Etienne, France; Department of Internal Medicine and Chest Disease, CHU Brest, Brest, France; EA3878-GETBO, CIC-INSERM1412, Univ-Brest, Brest, France.
Luc-Marie Joly, Emergency Department, CHU Rouen, Normandy Univ, UNIROUEN, Rouen, France.
Raphaëlle Lopez, Emergency Department, Sart Tilman University Hospital, Liège, Belgium.
Laura M Faber, Department of Internal Medicine, Rode Kruis Hospital, Beverwijk, DTN, the Netherlands.
Marie Daoud-Elias, Department of Cardiology and Vascular Medicine, CH Sainte Musse – Toulon, Toulon, France.
Benjamin Planquette, F-CRIN, INNOVTE, Saint-Etienne, France; Department of Pneumology and Intensive Care, Hôpital Europeen Georges Pompidou, APHP, Paris, France; University of Paris, INSERM UMR-S 1140 Innovaties Therapies in Haemostasis, Paris, France.
Jérôme Bokobza, Emergency Department, Hôpital Cochin, APHP, Paris, France.
Damien Viglino, Emergency Department, CHU Grenoble Alpes, Grenoble, France; HP2 INSERM U 1042 Laboratory, University of Grenoble-Alpes, Grenoble, France.
Jeannot Schmidt, F-CRIN, INNOVTE, Saint-Etienne, France; Emergency Department, CHU Clermont-Ferrand, University of Clermont Auvergne, Clermont-Ferrand, France.
Henry Juchet, Emergency Department, CHU Toulouse, Toulouse, France.
Isabelle Mahe, F-CRIN, INNOVTE, Saint-Etienne, France; Internal Medicine Department, HU Paris Nord, Louis Mourier Hospital, APHP, Colombes, France; Inserm UMR_S1140 Hemostasis Therapeutical Innovations, University of Paris, Colombes, France.
Frits Mulder, Department of Internal Medicine, Tergooi Hospital, Hilversum, the Netherlands.
Magali Bartiaux, Emergency Department, Saint-Pierre Hospital, Brussels, Belgium.
Rosen Cren, Emergency Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
Thomas Moumneh, Emergency Department, CHU Angers, 4 rue Larrey, Angers, France, F-49000; Univ. Angers, INSERM, CNRS, MITOVASC, Equipe CARME, SFR ICAT, Angers, France; F-CRIN, INNOVTE, Saint-Etienne, France.
Isabelle Quere, F-CRIN, INNOVTE, Saint-Etienne, France; Vascular Medicine Department, CHU Montpellier, EA2992, CIC 1001, University of Montpellier, Montpellier, France.
Nicolas Falvo, Vascular Medicine Department, CHU Dijon, Dijon, France.
Karine Montaclair, F-CRIN, INNOVTE, Saint-Etienne, France; Department of Cardiology, CH Le Mans, Le Mans, France.
Delphine Douillet, Emergency Department, CHU Angers, 4 rue Larrey, Angers, France, F-49000; Univ. Angers, INSERM, CNRS, MITOVASC, Equipe CARME, SFR ICAT, Angers, France; F-CRIN, INNOVTE, Saint-Etienne, France.
Charlotte Steinier, Emergency Department, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.
Stephan V Hendriks, Department of Medicine – Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
Ygal Benhamou, Department of Internal Medicine, CHU Charles Nicolle, Rouen, France; Normandie University, UNIROUEN, INSERM U1096 EnVI, Rouen, France.
Tali-Anne Szwebel, Department of Internal Medicine, Cochin Hospital, APHP, Paris, France.
Gilles Pernod, F-CRIN, INNOVTE, Saint-Etienne, France; Department of Vascular Medicine, CHU Grenoble Alpes, Grenoble, France; University Grenoble Alpes, CNRS / TIMC-IMAG UMR 5525 / Themas, Grenoble, France.
Nicolas Dublanchet, Emergency Department, CHU Clermont-Ferrand, University of Clermont Auvergne, Clermont-Ferrand, France.
François-Xavier Lapebie, Vascular Medicine Department, CHU Toulouse, Toulouse, France.
Nicolas Javaud, Emergency Department, CréAk, Louis Mourier Hospital, APHP, University of Paris, Colombes, France.
Alexandre Ghuysen, Emergency Department, Sart Tilman University Hospital, Liège, Belgium.
Mustapha Sebbane, F-CRIN, INNOVTE, Saint-Etienne, France; Emergency Department, Lapeyronie Hospital, CHU Montpellier, University of Montpellier, Montpellier, France.
Gilles Chatellier, Computing, Statistics and Public Health & CIC1418, Hôpital Européen Georges Pompidou, APHP, Paris, France; University of Paris, Paris, France.
Guy Meyer, Department of Pneumology and Intensive Care, Hôpital Europeen Georges Pompidou, APHP, Paris, France; University of Paris, INSERM UMR-S 1140 Innovaties Therapies in Haemostasis, Paris, France.
David Jimenez, Respiratory Department and Medicine Department, Ramon y Cajal Hospital IRYCIS Alcal de Henares University, Madrid, Spain.
Menno V Huisman, Department of Medicine – Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
Olivier Sanchez, F-CRIN, INNOVTE, Saint-Etienne, France; University of Paris, INSERM UMR-S 1140 Innovaties Therapies in Haemostasis, Paris, France; Pneumology Department and Intensive Care, Hôpital Européen Georges Pompidou, APHP, 20-40 rue Leblanc, Paris, France, F-75908.
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Data Availability Statement
All anonymized raw data on individual patients on which the analysis, results, and conclusions reported in the paper are based are available to a third-party auditor and to researchers on reasonable request to the corresponding author.