Abstract
Early discharge and home treatment of acute pulmonary embolism in fragile patients appears to be feasible and acceptably safe. Caution is warranted due to the higher risk of major bleeding among fragile patients. https://bit.ly/2YtStiU
To the Editor:
Pulmonary embolism is the third most frequent acute cardiovascular disease with an annual incidence of approximately 100 cases per 100 000 population and an annual mortality of ≥7 deaths per 100 000 population in the European region [1, 2]. Initial management is adjusted to the risk of in-hospital death or early complications, which depend both on the severity of pulmonary embolism and the presence of comorbidities [3].
In recent years, significant progress was made in the validation of clinical, biochemical and haemodynamic criteria, which can be used to identify patients with low-risk pulmonary embolism [3]. Some of these patients may be candidates for early or immediate discharge from the hospital after pulmonary embolism diagnosis, to be followed by continuation of anticoagulant treatment on an ambulatory basis. In this regard, non-vitamin-K antagonist oral anticoagulants (NOACs) have simplified the regimens of initial anticoagulation and offer the potential of facilitating the transition from hospital to ambulatory care. These considerations justify the assumption that home treatment strategies may be implemented effectively and safely in selected patients with pulmonary embolism, and that they may increase treatment satisfaction and the patients’ quality of life while reducing the risk of in-hospital complications. Besides, home treatment may help to reduce some of the substantial costs related to early treatment of pulmonary embolism [4].
Pulmonary embolism incidence and mortality peak among the elderly, who often have (serious) comorbidities and are at increased risk of early death [1, 2]. Existing data based on phase III trials suggest that NOACs are effective and safe in “fragile” patients with acute venous thromboembolism, as defined by older age, renal dysfunction or low body weight [5, 6]. Consequently, we investigated the efficacy and safety of early discharge and home treatment of acute pulmonary embolism in fragile low-risk patients, performing a subgroup analysis of the Home Treatment of Pulmonary Embolism (HoT-PE) trial [7].
HoT-PE was a prospective multicentre multinational management trial. Normotensive patients with acute pulmonary embolism were included based on a combination of clinical and imaging criteria indicating a low-risk status [8]. The first dose of rivaroxaban was given in hospital following diagnosis of acute pulmonary embolism, and patients were discharged within 48 h of presentation. Rivaroxaban was taken for at least 3 months at standard approved doses. The primary efficacy outcome was symptomatic recurrent venous thromboembolism, or pulmonary embolism-related death, within 3 months of enrolment. The safety outcomes included major bleeding, serious adverse outcomes and all-cause death. The trial was stopped following the predefined interim analysis after inclusion of the first 525 patients, as only three of these patients (0.6%) reached the primary efficacy outcome; this rate was sufficiently low to allow the early termination of the study based on the trial protocol [8]. For the present subgroup analysis, patients with acute low-risk pulmonary embolism were further stratified based on the presence of at least one criterion of “fragility” corresponding to those used in prior studies: age >75 years, renal dysfunction (creatinine clearance <50 mL·min−1 based on the Modification of Diet in Renal Disease, MDRD, equation), and body mass index <18.5 kg·m−2 (used in place of a body weight <50 kg). We compared the 3-month rate of the primary efficacy and safety outcome, and of other serious adverse events, as recorded by the HoT-PE investigators, between fragile and non-fragile patients calculating absolute risk differences and the corresponding 95% confidence intervals. A sensitivity analysis was performed using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to estimate the glomerular filtration rate.
A total of 524 patients with complete information (one patient was excluded due to missing values) were included in this analysis; of these, 112 (21.4%) were categorised as being fragile. Median (interquartile range) age of fragile and non-fragile patients was 77 (74–80) and 53 (43–65) years, respectively. Table 1 provides an overview of the demographic and baseline characteristics of the two groups. Overall, 104 of 112 (92.9%) fragile and 397 of 412 (96.4%) non-fragile patients spent a maximum of two nights in hospital in compliance with the study protocol; the median hospital stay was 42 (25–47) and 32 (23–46) h, respectively. The primary efficacy outcome of symptomatic recurrent venous thromboembolism or pulmonary embolism-related death within 3 months occurred in one (0.9%) fragile and two (0.5%) non-fragile patients (absolute risk difference +0.4%; 95% CI −1.1% to +4.4%; table 1). Major bleeding occurred in three (2.7%) fragile and three (0.7%) non-fragile patients for an absolute risk difference of +2.0% (table 1). One patient in each group suffered intracranial haemorrhage. In the fragile patient population, all of the bleeding events and recurrent episodes of venous thromboembolism occurred after the first 30 days following the diagnosis of acute pulmonary embolism. Among fragile patients who experienced major bleeding, the main risk factors appeared to be older age (n=3), male sex (n=2), moderate renal dysfunction (n=3) and arterial hypertension (n=1); none of the patients had (active) cancer, a history of alcohol abuse or recent trauma/surgery. The 3-month rate of serious adverse events did not differ between the two groups. All-cause 3-month mortality was low in both groups (0.9% versus 0.2%; table 1), and all deaths were cancer-related.
A total of 207 (39.4%) patients were classified as fragile using the CKD-EPI formula for the glomerular filtration rate. The primary efficacy outcome occurred in two (1.0%) fragile and one (0.3%) non-fragile patient. Major bleeding occurred in three (1.5%) fragile and three (1.0%) non-fragile patients. All-cause 3-month mortality was 0.5% and 0.3%, respectively.
The present analysis of the population of HoT-PE, a multinational prospective management trial, support the feasibility and safety of early discharge and home treatment of carefully selected patients with acute low-risk pulmonary embolism, based on the modified Hestia criteria and the absence of signs of right ventricular dysfunction, but with characteristics of fragility (or frailty). Of note, the 3-month rate of recurrent venous thromboembolism observed in the HoT-PE trial was almost identical to that observed among patients with acute pulmonary embolism included in a large European registry (0.9% versus 0.8%, respectively) [9]. Our results also indicate that fragile patients have higher rates of major bleeding compared with non-fragile patients. This has been previously described in phase III trials and cohort studies [9, 10] and is most likely related to older age itself along with a higher prevalence of concomitant diseases, such as renal impairment (one of the items defining frailty), arterial hypertension, active malignancy and diabetes, which are known to affect the risk of bleeding [11]. Rivaroxaban use may be associated with up to 70% lower risk of major bleeding compared with vitamin K antagonist therapy among fragile patients [6]; nevertheless, careful follow-up of the patients and family/social support remains necessary to monitor renal function, the prescription of new co-medications and drug compliance. This is irrespective of whether the patient may be a candidate for early discharge and home treatment.
In the population of HoT-PE, we found that the patients’ outcome, particularly mortality, was similar to that reported in earlier studies of patients with acute low-risk pulmonary embolism [12–15]. Thus, the results available to date support the recommendation of the 2019 European guidelines [3] to employ careful risk stratification and patient selection based on validated criteria as a prerequisite for early discharge. We also showed that the use of different formulas to estimate renal function may lead to discrepancies in the classification of a patient as fragile. This, however, might not have a major impact on efficacy and safety in the context of a low-risk patient population [16].
In conclusion, early discharge and home treatment of fragile patients with acute low-risk pulmonary embolism appears to be feasible and safe. Our results support the notion that these patients should not be a priori excluded from early discharge strategies. At the same time, caution is warranted due to a possibly higher risk of major bleeding on anticoagulant treatment in the presence of frailty.
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Footnotes
The HoT-PE Investigators: 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, 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, Jörg Herold, 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, Walter Lehmacher, Stanislav Gorbulev and Kai Kronfeld.
Conflict of interest: L. Hobohm reports grants from German Federal Ministry of Education and Research (BMBF 01EO1503), during the conduct of the study; personal fees from MSD and Actelion, outside the submitted work.
Conflict of interest: T. Anušic reports grants from German Federal Ministry of Education and Research (BMBF 01EO1503), during the conduct of the study.
Conflict of interest: S.V. Konstantinides reports grants from German Federal Ministry of Education and Research (BMBF 01EO1503), during the conduct of the study; grants and personal fees from Boehringer Ingelheim, Bayer, Daiichi-Sankyo and Pfizer – Bristol-Myers Squibb, personal fees from MSD, grants from Actelion, outside the submitted work.
Conflict of interest: S. Barco reports grants from German Federal Ministry of Education and Research (BMBF 01EO1503), during the conduct of the study; personal fees for lectures and travel costs from Bayer Health Care, personal fees for lectures from BTG Pharmaceuticals, Leo Pharma and Daiichi-Sankyo, outside the submitted work.
Support statement: The work of Lukas Hobohm, Stavros V. Konstantinides and Stefano Barco is supported by the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503). The sponsor, the University Medical Center Mainz (Germany), obtained the study drug and a grant from Bayer AG, the market authorisation holder of rivaroxaban. The authors were entirely responsible for the design and conduct of the study, statistical analysis, interpretation of results and drafting of the manuscript. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received March 12, 2020.
- Accepted April 29, 2020.
- Copyright ©ERS 2020