Abstract
Introduction Early discharge of patients with acute low-risk pulmonary embolism requires validation by prospective trials with clinical and quality-of-life outcomes.
Methods The multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) single-arm management trial investigated early discharge followed by ambulatory treatment with rivaroxaban. The study was stopped for efficacy after the positive results of the predefined interim analysis at 50% of the planned population. The present analysis includes the entire trial population (576 patients). In addition to 3-month recurrence (primary outcome) and 1-year overall mortality, we analysed self-reported disease-specific (Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire) and generic (five-level five-dimension EuroQoL (EQ-5D-5L) scale) quality of life as well as treatment satisfaction (Anti-Clot Treatment Scale (ACTS)) after pulmonary embolism.
Results The primary efficacy outcome occurred in three (0.5%, one-sided upper 95% CI 1.3%) patients. The 1-year mortality was 2.4%. The mean±sd PEmb-QoL decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months, a mean change (improvement) of −9.1% (p<0.0001). Improvement was consistent across all PEmb-QoL dimensions. The EQ-5D-5L was 0.89±0.12 at 3 weeks after enrolment and improved to 0.91±0.12 at 3 months (p<0.0001). Female sex and cardiopulmonary disease were associated with poorer disease-specific and generic quality of life; older age was associated with faster worsening of generic quality of life. The ACTS burden score improved from 40.5±6.6 points at 3 weeks to 42.5±5.9 points at 3 months (p<0.0001).
Conclusions Our results further support early discharge and ambulatory oral anticoagulation for selected patients with low-risk pulmonary embolism. Targeted strategies may be necessary to further improve quality of life in specific patient subgroups.
Abstract
The results of the complete primary outcome analysis of the HoT-PE study, as well as long-term mortality and quality-of-life data, support early discharge and ambulatory oral anticoagulation with rivaroxaban for selected patients with acute low-risk PE https://bit.ly/32qX0mu
Introduction
The severity spectrum of acute pulmonary embolism is broad, ranging from asymptomatic, incidentally diagnosed events to cases in which pulmonary embolism compromises the patient's haemodynamic status and represents an immediately life-threatening condition. Initial risk assessment is mandatory for optimising initial treatment and deciding on the most appropriate setting in which this treatment will be delivered. As proposed by the recent 2019 European Society of Cardiology guidelines for the diagnosis and management of acute pulmonary embolism, developed in collaboration with the European Respiratory Society, such a risk-adjusted management strategy consists of a stepwise approach combining clinical findings, imaging and biochemical markers [1]. Criteria for identifying the group of patients whose risk is “sufficiently low” to permit early discharge and ambulatory treatment have been tested in prospective management studies, and include the absence of severe comorbidities, the absence of signs of right ventricular dysfunction, and adequate social and familiar support [2–7]. Despite these efforts, registry data indicate that only 10% of patients admitted to large European centres with acute pulmonary embolism are discharged “immediately” and more than half of the patients spend ≥5 days in hospital [8]. Early discharge and home treatment may minimise hospitalisation-related complications [9], reduce healthcare costs [10, 11] and improve the quality of life of affected patients [12].
Over the past decade, non-vitamin-K-dependent oral anticoagulants (NOACs) became the standard of care for the treatment of acute pulmonary embolism [1]. The fact that their use requires no periodic blood testing explains, at least in part, the higher patient-reported treatment satisfaction [13, 14]. Furthermore, early transition from hospital to ambulatory care may be facilitated, since at least some of the NOACs do not require an initial lead-in treatment with parenteral low-molecular-weight heparin and thus offer an appealing perspective both for (selected) patients and for caregivers.
In 2019, the results of the predefined interim analysis of the multinational Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) trial were published [5]. Initiation of anticoagulation with rivaroxaban followed by early discharge and continuation of treatment at home was shown to be effective and safe in patients with acute low-risk pulmonary embolism based on a combination of clinical criteria and the absence of right ventricular dysfunction on imaging. These findings permitted premature termination of the study after completion of the 3-month follow-up of the first 525 patients. The present study provides the results of the complete analysis of the HoT-PE study, including the patients enrolled while the interim analysis was being performed and focusing on the evaluation of key long-term outcomes, such as quality of life and treatment satisfaction, along with 12-month mortality.
Methods
Study design and participants
HoT-PE (EudraCT identifier 2013-001657-28) is a prospective multicentre single-arm investigator-initiated phase 4 interventional trial sponsored by the University Medical Center Mainz, Mainz, Germany [15]. The institutional Ethics Review Board of each participating site approved the study and patients provided written informed consent for participation. A description of the study rationale and background for the eligibility criteria has been published previously [15]. Briefly, adult patients were eligible for inclusion if they had objectively confirmed acute pulmonary embolism without right ventricular enlargement or dysfunction (right/left ventricular diastolic diameter ratio ≥1.0) and no free-floating thrombi in the right atrium or ventricle by echocardiography or computed tomographic pulmonary angiography (CTPA). Patients were also excluded if they had haemodynamic instability at presentation; active bleeding or known significant bleeding risk; need for supplemental oxygen administration; chronic treatment with anticoagulant drugs; pain requiring parenteral administration of analgesic agents; other medical conditions requiring hospitalisation; noncompliance or inability to adhere to the treatment or the follow-up visits, or lack of a family environment or support system; and contraindications to rivaroxaban therapy.
Treatment
Initiation of treatment with an approved parenteral or oral anticoagulant (unfractionated heparin, low-molecular-weight heparin, fondaparinux, rivaroxaban or apixaban) no later than 3 h after pulmonary embolism diagnosis was allowed before enrolment in the study. Patients received the first dose of the study medication, rivaroxaban, within 2 h of the next due dose of subcutaneous injection of low-molecular-weight heparin or fondaparinux (or oral rivaroxaban or apixaban), or at the time of discontinuation of intravenous unfractionated heparin. The rivaroxaban regimen corresponded to the label of the marketed product, consisting of 15 mg twice daily for 3 weeks followed by the maintenance regimen of 20 mg once daily for at least 3 months. Reduction of the maintenance dose to 15 mg once daily was allowed in patients estimated to have a high risk of bleeding, including those with a creatinine clearance <50 mL·min−1. The trial protocol mandated discharge within 48 h of admission or a maximum of 2 nights in hospital [15].
Study outcomes
The primary efficacy outcome was symptomatic recurrent venous thromboembolism or pulmonary embolism-related death within 3 months of enrolment. The secondary efficacy outcomes included all-cause death within 3 months and 1 year of enrolment, rehospitalisation due to pulmonary embolism or to a bleeding event within 3 months as well as the assessment of validated quality-of-life and treatment satisfaction questionnaires. The safety outcomes included major bleeding (defined by the criteria of the International Society on Thrombosis and Haemostasis) [16], clinically relevant nonmajor bleeding and serious adverse events. All efficacy and safety outcomes were adjudicated by an independent clinical events committee.
Quality of life and treatment satisfaction questionnaires
We analysed the data on the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire for the assessment of disease-specific quality of life [17]; the five-level five-dimension EuroQoL (EQ-5D-5L) scale for generic quality of life measured 3 weeks and 3 months after enrolment [18]; and the Anti-Clot Treatment Scale (ACTS), a patient-reported measure of anticoagulant treatment satisfaction [13].
The PEmb-QoL is composed of 40 items and serves to quantify health-related quality of life across six health dimensions: 1) frequency of complaints, 2) activities of daily living limitations, 3) work-related problems, 4) social limitations, 5) intensity of complaints and 6) emotional complaints. Two questions of the questionnaire focus on the time of the day at which the symptoms appear and the state of the patient's current condition compared with 1 year before, and do not contribute to the total score. The six dimensions contributing scores are summed, weighted and transformed to a percentage scale (0–100%), with higher scores indicating worse quality of life and lower scores indicating better quality of life.
The EQ-5D-5L (EuroQol Research Foundation) is a validated instrument designed to provide a simple and direct profile of the patient's generic health status. It comprises a short descriptive system questionnaire covering five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a visual analogue scale (VAS) ranging from 0 (“the worst health the patient can imagine”) to 100 (“the best health the patient can imagine”). Each of the five dimensions is composed of five levels of severity. EQ-5D-5L can also be analysed after conversion and weighting of the results of these dimensions into a single summary index value. Calculation of the EQ-5D-5L index score was based on the coding available at https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation-standard-value-sets/crosswalk-index-value-calculator.
The ACTS (Bayer AG) includes 12 items assessing perceived burden and three items assessing perceived benefits from treatment. Each item can be rated from the lowest intensity 1 (not at all) to the highest intensity 5 (extremely) with totals in the range 12–60 (burdens) and 3–15 (benefits). After reversing of the scale, higher ACTS scores indicate greater treatment satisfaction.
Sample size calculation
The null hypothesis (H0) that p≥0.03 (p being the probability of recurrent venous thromboembolism or pulmonary embolism-related death within 3 months) was tested against the alternative hypothesis (H1) that p<0.03, using a binomial test (two-stage adaptive design based on an O'Brien–Fleming design) and assuming a 3-month symptomatic venous thromboembolism recurrence rate of 1.7%, similar to that reported in a meta-analysis of studies dating back to the vitamin K antagonist era [19] and to the 3-month recurrence rate observed in the EINSTEIN-PE rivaroxaban phase 3 trial [20]. The study was stopped after the pre-planned interim analysis performed after enrolment and 3-month evaluation of the first 525 patients, as H0 could be rejected at the local level of α=0.004 (less than six patients developing the primary efficacy outcome) in the intention-to-treat (ITT) population [5].
Statistical analysis
The primary and secondary outcome analyses were done in the ITT population, consisting of patients who signed the informed consent. Safety analysis was conducted in the safety population, including all patients who received at least one dose of study drug. Per-protocol analysis was carried out as a sensitivity analysis for the primary outcome, including all patients who received at least one dose of study drug and fulfilled the protocol requirements for early discharge from the hospital.
Differences of the quality-of-life scores between 3-week and 3-month visits were determined using paired t-tests in the case of normally distributed data or using the Wilcoxon signed-rank test. To check for associations between baseline predefined explanatory variables characterised by low multicollinearity and an outcome variable (PEmb-QoL and EQ-5D-5L VAS), a linear regression model was fitted for the 3-week and 3-month visits as well as for the difference between 3 weeks and 3 months. For each linear regression model, the assumption of normal distributed residuals was confirmed. In case the number of missing values for both the explanatory and outcome variable(s) was low (<5%), an imputation technique was not deemed to be crucial.
Results
From May 2014 through June 2018, a total of 576 patients signed informed consent for participation in the HoT-PE trial at 49 centres in seven countries and were included in the ITT population. The mean (range) age was 57 (18–90) years and 266 (46.2%) were female. Table 1 shows the baseline characteristics of the study population. Dyspnoea (61.3%), pleuritic pain (40.6%), cough (10.7%) and retrosternal pain (20.7%) represented the most frequent symptoms of pulmonary embolism, followed by fever (7.5%), haemoptysis (4.9%) and syncope (3.0%). Unilateral leg pain and unilateral oedema were present in 24.8% and 15.6% of patients, respectively. The onset of symptoms preceded the diagnosis of acute pulmonary embolism by a median (interquartile range (IQR)) of 4 (2–8) days. CTPA was the most frequently used imaging test for diagnosis (n=528 (91.7%)). Deep vein thrombosis was present in 241 (53.2%) of the 453 patients in whom compression ultrasound was performed.
Baseline characteristics of the study population
A total of 569 (98.8%) patients who received at least one dose of rivaroxaban were included in the safety population. The median (IQR) length of hospitalisation was 33 (23–47) h and 551 patients were hospitalised for up to 2 nights in compliance with the study protocol. A total of 547 (95.0%) patients were included in the per-protocol population.
Rivaroxaban 15 mg twice daily was given for a mean±sd period of 21±5 days after the diagnosis of acute pulmonary embolism. Patients received the maintenance dosage of rivaroxaban over an additional period of 69±10 days. Continuation of anticoagulant treatment beyond the study period was at the discretion of the patient's physician [15].
Primary efficacy outcome
The primary efficacy outcome, i.e. symptomatic recurrent venous thromboembolism or pulmonary embolism-related death, occurred in three (0.5%, one-sided upper 95% CI 1.3%; one-sided p<0.0001) of the 576 patients of the ITT population within 3 months of enrolment (table 2). All three recurrent events were nonfatal recurrent pulmonary embolism (supplementary table S1). The primary outcome occurred in two (0.4%, two-sided 95% CI 0.04–1.3%; two-sided p<0.0001) of the 547 patients included in the per-protocol population.
Study outcomes
Safety and secondary efficacy outcomes
Of the 569 patients included in the safety population, six (1.1%, two-sided 95% CI 0.4–2.3%) had a major bleeding episode during rivaroxaban treatment within 3 months of enrolment. Clinically relevant nonmajor bleeding was recorded in 30 (5.3%, two-sided 95% CI 3.6–7.4%) patients. The median (IQR) duration of first rehospitalisation was 6 (3–9) days. Serious adverse events within 3 months of enrolment occurred in 68 (12.0%) patients, of which 64 required rehospitalisation. An overview of these events is provided in supplementary table S2. 12 (2.1%) patients were hospitalised for suspected pulmonary embolism recurrence or bleeding within 3 months of enrolment, which was then confirmed in seven (1.2%) patients.
14 patients died after a median (IQR) of 6.8 (4.7–11.4) months, corresponding to a 1-year mortality rate of 2.4% (95% CI 1.3–4.0%). Cancer was the most frequent cause of death and was recorded in nine patients. The 3-month mortality rate was 0.4% (95% CI 0.04–1.25%) and both deaths were due to progressive metastatic cancer.
Analysis of quality-of-life questionnaires
The PEmb-QoL analysis was conducted on a total of 425 patients who completed the questionnaire at both visits. The formulas for the calculation of the PEmb-QoL score are given in the supplementary material. The mean±sd PEmb-QoL score decreased from 28.9±20.6% at 3 weeks to 19.9±15.4% at 3 months; this corresponds to a mean±sd reduction of −9.1±15.4% (paired t-test; p<0.0001), indicating a significant improvement in the patients' self-reported quality of life. As shown in figure 1, the improvement was consistent across all PEmb-QoL dimensions. In our multivariable linear regression model (table 3), female sex, higher body mass index and the presence of cardiopulmonary disease were associated with a poorer quality of life (indicated by a higher PEmb-QoL score) at both week 3 and month 3 of follow-up. Of note, older age and the presence of cancer were not associated with worse quality of life at these time-points, but they were associated with “faster worsening” of disease-specific quality of life over time. Specifically, we documented a +0.2% relative increase in the slope (per unit increase) between week 3 and month 3 per year of age (p=0.001), and a +6.4% relative increase in patients with (versus without) cancer (p=0.001).
Improvement of quality of life after acute pulmonary embolism according to the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire score. ADL: activities of daily living. The radar plot illustrates the evolution in disease-specific quality of life for each of the PEmb-QoL dimensions and for the total PEmb-QoL score between week 3 and month 3. The six dimensions contributing scores are summed, weighted and transformed to a percentage scale (0–100%), with higher scores (larger area of the polygon) indicating worse quality of life and lower scores (smaller area of the polygon) indicating better quality of life.
Association between baseline clinical characteristics and quality-of-life scores 3 weeks and 3 months after enrolment
In supplementary tables S3 and S4, we separately show the results of the two PEmb-QoL dimensions not included in the calculation of the score, which serve to qualitatively assess the time of the day when the patient's symptoms were perceived as being more intense (Dimension 2) and whether symptoms are more severe compared with 1 year before (Dimension 3). The characteristics of the patients with and without complete PEmb-QoL assessment at both visits are reported in supplementary table S5.
The EQ-5D-5L analysis was conducted in a total of 473 patients who completed the questionnaire at both visits. The mean±sd EQ-5D-5L index score was 0.89±0.12 at week 3 and improved to 0.91±0.12 at month 3 (paired t-test for difference; p<0.0001). The percentage of patients reporting “no problems” in any of the five dimensions increased from 61.2% at week 3 to 72.0% at month 3, paralleled by a consistent reduction of the proportion of patients with slight (from 25.7% to 18.4%), moderate (from 10.3% to 7.4%), severe (from 1.9% to 1.8%) or extreme (from 0.3% to 0.2%) problems. As shown in figure 2, these positive changes were consistent across all five EQ-5D-5L dimensions.
Graphic representation of the course of the five-level five-dimension EuroQoL (EQ-5D-5L) assessed 3 weeks and 3 months after enrolment. The stacked bar plots show the percentage of patients reporting “no problems”, “slight problems”, “moderate problems”, “severe problems” or “extreme problems” in each of the five dimensions of the EQ-5D-5L health-related quality-of-life questionnaire and in the overall questionnaire at week 3 and month 3.
The mean±sd VAS of the EQ-5D-5L increased from 76.2±16.1 to 80.2±16.4 points (paired t-test for difference; p<0.0001). In our multivariable linear regression model (table 3), female sex and the presence of cardiopulmonary disease were associated with a lower VAS, indicating a poorer quality of life, at both week 3 and month 3. Older age was associated with faster worsening of generic quality of life according to the VAS (−0.1% relative decrease per year of age between week 3 and month 3; p=0.02). The characteristics of the patients with and without complete EQ-5D-5L assessment are reported in supplementary table S6.
Anti-Clot Treatment Scale
The ACTS analysis was conducted on a total of 421 patients who completed the questionnaire at both visits. After 3 weeks, the percentage of patients not reporting any of the ACTS burden items was 56.9% and increased to 66.0% after 3 months. The mean±sd ACTS burden score increased from 40.5±6.6 at week 3 to 42.5±5.9 at month 3, indicating an improvement in terms of treatment satisfaction (paired t-test; p<0.0001). At 3 weeks after acute pulmonary embolism, 26.3% of the patients reported being “extremely satisfied” based on the ACTS benefit items; this percentage increased to 31.7% at 3 months. The mean±sd ACTS benefit score was 11.4±2.9 at week 3 and 11.4±3.1 at month 3 (paired t-test; p=0.4189).
Discussion
This report presents a comprehensive analysis of clinical outcomes and self-reported quality of life in the entire population of the HoT-PE study, a prospective multinational investigator-initiated and academically sponsored phase 4 trial. The results of the predefined interim analysis yielded low rates of the primary outcome, i.e. symptomatic recurrent venous thromboembolism or pulmonary embolism-related death, at the 3-month follow-up [5] and thus allowed for early termination of the trial. The present analysis focuses on long-term survival as well as quality of life and its change over time following early discharge of patients with acute low-risk pulmonary embolism. Our results, obtained in 576 patients, confirm the low rate of the primary efficacy outcome and show low all-cause mortality at the 12-month follow-up (2.4%). Moreover, and importantly, the HoT-PE study quantitatively assessed the course of the patients' disease-specific and generic quality of life, as measured by established standardised scores, over the first 3 months of oral anticoagulant treatment for pulmonary embolism. By identifying predictors of a poor or worsening score among the patients' key baseline characteristics, our data may help to design future research on targeted strategies aiming to improve the quality of life of specific patient subgroups after acute pulmonary embolism.
The rate of the efficacy outcome in the entire population of our trial is in agreement with the low rates reported in phase 3 anticoagulation trials which enrolled patients with venous thromboembolism [21] and in pragmatic management studies of patients with low-risk pulmonary embolism [4, 7]. This is also true for the rate of safety outcomes, notably major haemorrhage [4, 7, 21]. We recently reported that, within this low-risk population, “fragile” patients defined by age >75 years, low body mass index (<18.5 kg·m−2) or creatinine clearance <50 mL·min−1, exhibited a higher rate of major bleeding (2.7% compared with 0.7% among patients with none of these characteristics) [22]. While these characteristics do not, by themselves, represent contraindications to early discharge and home treatment of acute low-risk pulmonary embolism, closer surveillance may be warranted for prevention or early detection of bleeding complications.
The notion that our study successfully defined and enrolled a patient population with “truly” low-risk pulmonary embolism is supported by the very low 12-month (2.4%) overall mortality rates; in fact, out of 14 total deaths recorded over the entire 1-year follow-up period, nine were due to active cancer as the underlying disease of the patient's index episode of pulmonary embolism. These numbers are in sharp contrast to the rates previously reported in the literature; in those earlier reports, the 1-year mortality rate overall exceeded 15% among unselected patients with pulmonary embolism [23, 24] or venous thromboembolism in the broader sense [25–27], ranging between 40% among patients with cancer and 10% among those without it.
Beyond delivering data on recurrence, bleeding and overall mortality, HoT-PE is the largest study that has prospectively evaluated, using established standardised questionnaires, patients' quality of life 3 weeks and 3 months after acute (low-risk) pulmonary embolism. Both the disease-specific and the generic tools measuring quality of life indicated a significant improvement over time, although no definitive conclusion can be drawn that a causal association exists between early discharge followed by home oral rivaroxaban anticoagulation on quality-of-life parameters in the absence of a control group. Seen from a different perspective, however, our results also show that pulmonary embolism continues to represent, over a considerable period of several weeks or months, a source of major discomfort, and it may interfere with several aspects of the patient's work, daily activities and social life, even if the index episode fulfilled strict criteria of “low risk”. The degree of improvement over time was similar across different scales and dimensions of quality of life. Female sex, higher body mass index and a history of cardiac or pulmonary disease were associated with a poorer quality of life at a given time-point in follow-up according to the validated disease-specific PEmb-QoL score; female sex and cardiac or pulmonary disease also correlated with a lower generic quality of life according with the VAS (table 3). Older age correlated with a faster worsening of both indexes over time. This analysis in a large low-risk population is generally in line with the results of prior studies reporting on follow-up after pulmonary embolism [28–30]. In fact, studies of patients suffering stroke or myocardial infarction have also pointed to a similar direction, particularly concerning age, sex and body mass index [31–33], indicating that the impact of specific baseline characteristics on quality of life over time is consistent across a broad spectrum of acute cardiovascular syndromes.
Our study has some limitations. Routine assessment of right ventricular function has been proposed to possess added value for risk stratification of pulmonary embolism independently from clinical assessment tools [34], but the optimal imaging method, i.e. CTPA versus transthoracic echocardiography, remains unclear. Moreover, it is sometimes argued that the latter imaging modality may not be available on a continuous basis in all hospitals. In HoT-PE, CTPA was performed for diagnosis of initial acute pulmonary embolism in the vast majority (>90%) of the study patients. It has been shown that a simple parameter of right ventricular function on CTPA, i.e. the calculation of the right/left ventricular diameter ratio, was accurate and reproducible after minimal training [35]. These facts argue against feasibility problems in following the strategy tested in HoT-PE. A further limitation of our study is that complete data for self-reported quality of life or treatment satisfaction were available, for both follow-up visits, in only ∼75% of the study patients. For absolute transparency, we have included, in the supplementary material, two tables showing the baseline characteristics of the patients with versus those without complete questionnaire data. Other potential limitations of our trial, including the “cautiousness” of the eligibility criteria, have previously been addressed in detail [5]. The strengths of the prospective HoT-PE study lie in the rigorous monitoring, the independent adjudication of the efficacy and safety outcomes, the large size of the study for this particular patient population, and most of all in the fact that it can be considered a representative European management trial, having included 49 centres in seven countries with different population characteristics and healthcare systems.
In conclusion, the results of the complete analysis of the HoT-PE trial support the early discharge and ambulatory oral anticoagulation treatment of carefully selected patients with acute low-risk pulmonary embolism. Anticoagulation with rivaroxaban initiated in the hospital and continued over at least 3 months was effective and safe. All-cause mortality was extremely low over the entire 12-month follow-up period. The patients' quality of life improved early during follow-up as assessed on the basis of standardised, disease-specific and generic quality-of-life questionnaires. Future early-discharge strategies may need to target individuals with specific baseline characteristics such as female sex, an increased body mass index and a history of cardiac or pulmonary disease.
Supplementary material
Supplementary Material
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Supplementary material I: supplementary tables ERJ-02368-2020.Supplement_I
Supplementary material II: formulas for the calculation of the PEmb-QoL questionnaire ERJ-02368-2020.Supplement_II
Committees and lists of participating centres ERJ-02368-2020.Committees
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Supplementary Material
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Acknowledgements
We would like to thank Dorothea Becker and Nadine Martin (Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany), Kai Kronfeld and Stanislav Gorbulec (Interdisciplinary Center for Clinical Studies, University Medical Center of the Johannes Gutenberg University Mainz), and Luigi Visani and Chiara Colombo (EXOM Group – the Human and Digital CRO, Milano, Italy), for their help.
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.03811-2020
This article has supplementary material available from erj.ersjournals.com
The HoT-PE Trial Investigators are: Stavros V. Konstantinides, Rupert Martin Bauersachs, Christoph Bode, Michael Christ, Christine Espinola-Klein, Annette Geibel, Mareike Lankeit, Michael Pfeifer, Sebastian Schellong, Philipp S. Wild, Harald Binder, Luca Valerio, Kurt Quitzau, Nadine Martin, Dorothea Becker, Stefano Barco, Irene Schmidtmann, Toni Anusic, Martin Schwaiblmair, Ursula Rauch-Kröhnert, Martin Möckel, Johannes Brachmann, Jan Beyer-Westendorf, Daniel Duerschmied, Sabine Blaschke, Marius M. Hoeper, Evangelos Giannitis, Klaus Empen, Rainer Schmiedel, Ulrich Hoffman, Ibrahim Akin, Andreas Meyer, Sabine Genth-Zotz, Joachim Ficker, Tobias Geisler, Matthias Held, Cecilia Becattini, Ludovica Cimini, Walter Ageno, Rodolfo Sbrojavacca, Enrico Bernardi, Giuseppe Bettoni, Roberto Cosentini, Paolo Moscatelli, Cinzia Nitti, Maria Pazzaglia, Raffaele Pesavento, Alessandra Ascani, Francesca Cortellaro, Nicola Montano, Peter E. Westerweel, Pedro Ruiz-Artacho, David Jiménez, Aitor Ballaz-Quincoces, Raquel Lopez Reyes, Remedios Otero, Candida Fonseca, Tiago Judas, Inês Araujo, Sergio Batista, Fabienne Goncalves, Veli-Pekka Harjola, Pirjo Mustonen, Georgios Hahalis, Athanassios Manginas, Konstantinos Gougoulianis, Athanasios Manolis, Michael Czihal, Tobias J. Lange, Raoul Stahrenberg, Thomas Meinertz, Menno V. Huisman, Paolo Prandoni and Walter Lehmacher.
This study is registered at EudraCT with identifier number 2013-001657-28. Individual participant data can be made available upon request for individual participant data meta-analysis. For information, please contact the corresponding author.
Conflict of interest: S. Barco reports personal fees from Biocompatibles Group UK, LEO Pharma, Bayer, nonfinancial support from Bayer HealthCare and Daiichi Sankyo, grants from Sanofi, outside the submitted work.
Conflict of interest: I. Schmidtmann reports grants from Merck Serono, outside the submitted work.
Conflict of interest: W. Ageno reports grants from Bayer, personal fees from Boehringer Ingelheim, Daiichi Sankyo and Bristol Myers Squibb/Pfizer, outside the submitted work.
Conflict of interest: T. Anušić has nothing to disclose.
Conflict of interest: R.M. Bauersachs reports personal fees for lectures and advisory board work from Bayer HealthCare, Bristol Myers Squibb/Pfizer and Daiichi Sankyo, during the conduct of the study.
Conflict of interest: C. Becattini reports personal fees for consultancy and lectures from Bayer HealthCare, Daiichi Sankyo and Bristol Myers Squibb, outside the submitted work.
Conflict of interest: E. Bernardi has nothing to disclose.
Conflict of interest: J. Beyer-Westendorf reports patient fees from the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, during the conduct of the study; grants and personal fees for advisory board work, lectures and travel support from Bayer, outside the submitted work.
Conflict of interest: L. Bonacchini has nothing to disclose.
Conflict of interest: J. Brachmann reports grants and personal fees from Medtronic, during the conduct of the study; grants from Medtronic, St Jude and Biotronik, outside the submitted work.
Conflict of interest: M. Christ reports grants from the University of Mainz, during the conduct of the study.
Conflict of interest: M. Czihal reports personal fees from Bayer HealthCare, Roche, AstraZeneca, MSD Sharp & Dohme and LEO Pharma, outside the submitted work.
Conflict of interest: D. Duerschmied reports personal fees for lectures and nonfinancial support (travel costs) from Bayer, Pfizer, Daiichi Sankyo and CytoSorbents, outside the submitted work.
Conflict of interest: K. Empen reports travel costs and personal fees for lectures from Bayer HealthCare, outside the submitted work.
Conflict of interest: C. Espinola-Klein reports lecture fees from Bayer HealthCare, outside the submitted work.
Conflict of interest: J.H. Ficker reports personal fees for lectures from Daiichi Sankyo, outside the submitted work.
Conflict of interest: C. Fonseca reports personal fees for consultancy and lectures from Bayer, outside the submitted work
Conflict of interest: S. Genth-Zotz has nothing to disclose.
Conflict of interest: D. Jiménez has nothing to disclose.
Conflict of interest: V-P. Harjola reports personal fees for lectures from Bayer, personal fees for lectures and advisory board work from Boehringer Ingelheim and Pfizer, personal fees for advisory board work from MSD, outside the submitted work.
Conflict of interest: M. Held reports honoraria for advisory board work from Actelion, Bayer, Boehringer, MSD, Daiichi Sankyo and Roche, honoraria for lectures from Actelion, Bayer, Berlin-Chemie, Bristol Myers Squibb, MSD, Daichi Sankyo, Pfizer and OMT, grants from Actelion, outside the submitted work.
Conflict of interest: L. Iogna Prat has nothing to disclose.
Conflict of interest: T.J. Lange reports nonfinancial support for meeting attendance from the Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, during the conduct of the study; personal fees from Bayer and Pfizer, outside the submitted work.
Conflict of interest: M. Lankeit reports personal fees for lectures and nonfinancial support (travel costs) from Actelion, Bayer and Daiichi Sankyo, personal fees for lectures from MSD and Bristol Myers Squibb/Pfizer, grants from BRAHMS – Thermo Fisher Scientific, outside the submitted work.
Conflict of interest: A. Manolis has nothing to disclose.
Conflict of interest: A. Meyer has nothing to disclose.
Conflict of interest: T. Münzel has nothing to disclose.
Conflict of interest: P. Mustonen reports personal fees for lectures and advisory board work from Boehringer Ingelheim, Bayer, Sanofi-Anetis, LEO Pharma, Bristol Myers Squibb/Pfizer and MSD, outside the submitted work.
Conflict of interest: U. Rauch-Kroehnert reports grants from Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Interdisziplinäres Zentrum Klinische Studien (IZKS) during the conduct of the study; personal fees from Bayer Vital, outside the submitted work.
Conflict of interest: P. Ruiz-Artacho reports personal fees from Bayer, Daiichi Sankyo, Sanofi, Pfizer, LEO Pharma and Rovi, outside the submitted work.
Conflict of interest: S. Schellong reports personal fees for lectures and consultancy from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Aspen, grants and personal fees for lectures and consultancy from Bristol Myers Squibb, outside the submitted work.
Conflict of interest: M. Schwaiblmair has nothing to disclose.
Conflict of interest: R. Stahrenberg has nothing to disclose.
Conflict of interest: L. Valerio has nothing to disclose.
Conflict of interest: P.E. Westerweel has nothing to disclose.
Conflict of interest: P.S. Wild reports grants and personal fees from Boehringer Ingelheim, Sanofi-Aventis, Bayer Vital and Bayer HealthCare, grants from Philips Medical Systems and Daiichi Sankyo Europe, personal fees from AstraZeneca, personal fees and equipment provision from DiaSorin, equipment provision from IEM, outside the submitted work.
Conflict of interest: S.V. Konstantinides reports grants and provision of study drug from Bayer, during the conduct of the study; grants and personal fees for consultancy and lectures from Boehringer Ingelheim, Daiichi Sankyo, Biocompatibles Group UK and MSD, personal fees for consultancy and lectures from Bayer and Bristol Myers Squibb/Pfizer, grants and personal fees for lectures from Actelion, grants from Servier, outside the submitted work.
Support statement: HoT-PE is an independent, investigator-initiated trial with an academic sponsor (Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany). The work of S. Barco, M. Lankeit, L. Valerio, P.S. Wild and S.V. Konstantinides was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503). In addition, the sponsor has obtained the study drug (rivaroxaban) and a grant from the market authorisation holder of rivaroxaban, Bayer AG. The funding bodies had no influence on the design or conduct of the study; collection, management, analysis or interpretation of the data; preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 17, 2020.
- Accepted August 21, 2020.
- Copyright ©ERS 2021
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