Early Discharge and Ambulatory Treatment of Selected Patients with Acute Low-Risk Pulmonary Embolism

Acute pulmonary embolism (PE) is a frequent cause of cardiovascular mortality around the world.1,2 However, not all cases of PE are potentially life-threatening. Due to the broad spectrum of PE severity, risk assessment is necessary for defining when to escalate management and considered advanced interventions.3 The guidelines of the European Society of Cardiology (ESC) propose a risk assessment model combining clinical findings, imaging of the right ventricle (RV), and cardiac biomarkers, to classify patients into a high, intermediate, and low risk category of early death.4 Hemodynamically unstable patients with high-risk (massive) PE and those at risk of imminent decompensation may be candidates for early reperfusion (systemic fibrinolysis, surgical embolectomy, or catheter-directed treatment). At the other end of the severity spectrum, it is equally important to identify, within the large group of normotensive and apparently stable patients, those whose risk is sufficiently low to permit early discharge and ambulatory treatment. Such an approach offers the potential to reduce early complications related to hospitalization and health care costs, and it may also improve patient satisfaction and quality of life.5,6

In the era of the vitamin K antagonists (VKA), a number of small- or moderate-size management studies and randomized open-label trials investigated whether ambulatory treatment of acute PE might be feasible, effective and safe. The largest of these trials, which are summarized in Table 1, used clinical, laboratory, and social criteria to determine eligibility for early discharge. Although the results were generally promising, the optimal criteria and treatment regimen to support early discharge strategies for patients with PE remained controversial and the concept did not gain broad international acceptance. For example, a retrospective analysis of 6,746 patients from the Veterans Health Administration population in the United States found that as many as 36% of the patients with low-risk PE (as defined by the simplified Pulmonary Embolism Severity Index) had a shorter length of hospital stay.5 By contrast, a real world registry of 11,473 patients in 25 European countries reported that only one out of 13 patients eligible for home treatment was actually treated at home and more than 50% of the low-risk patients were hospitalized for more than 5 days.7

Recent advances in PE risk stratification and anticoagulation, and the results of a multinational management trial presented at the 2019 Scientific Sessions of the American College of Cardiology and published a few weeks later8, may help to increase interest in early discharge of selected patients with acute PE. Non-vitamin K antagonist oral anticoagulants (NOACs) are now the standard of care for the treatment and secondary prevention of acute PE, and two of these agents, the factor Xa inhibitors apixaban and rivaroxaban, can be administered without the need for lead-in parenteral anticoagulation. Simplification of early anticoagulation has facilitated early transition from hospital to ambulatory care. In parallel, evolving risk assessment strategies may offer improved safety by better identifying patients with 'truly low-risk' PE.9

The Home Treatment of Patients with Low-Risk Pulmonary Embolism with the Oral Factor Xa Inhibitor Rivaroxaban (HoT-PE) study, an international multicenter single-arm phase 4 management trial, investigated whether early discharge and ambulatory anticoagulation treatment is effective and safe. Patients were selected on the basis of clinical criteria combined with the absence of RV dysfunction on admission.10 This approach was stricter than that of most previous studies, in which clinical criteria were considered sufficient to define low risk and eligibility (Table 1). It was based on the notion that exclusion of RV dysfunction by imaging or laboratory testing can, when used on top of clinical prediction rules (rather being restricted to patients with elevated clinical severity scores), ensure the lowest risk of early mortality and PE-related adverse events.11

The HoT-PE study design and patient eligibility criteria are summarized in Table 1. The trial protocol mandated that patients be discharged from the hospital within 48 hours of initial presentation for PE; it tolerated up to two nights of hospital stay. Rivaroxaban was given at the approved dose for treatment of venous thromboembolism (VTE)/PE for at least 3 months. The primary outcome was symptomatic recurrent VTE or PE-related death within 3 months of enrollment. An interim analysis was planned after the first 525 patients, with prespecified early termination of the study if the null hypothesis could be rejected at the level of α=0.004 (< 6 primary outcome events).

From May 2014 through June 2018, HoT-PE enrolled consecutive patients in seven European countries. Of the 525 patients included in the interim analysis, three (0.6%; one-sided upper 99.6% confidence interval [CI], 2.1%) suffered symptomatic nonfatal PE recurrence, a number sufficiently low to fulfil the condition for early termination of the trial.8 Further results of the interim analysis are summarized in Table 2. More than 95% of the study patients enrolled were hospitalized for two nights or less, and 54% were either discharged immediately or hospitalized for one night after presentation.8 Of note, approximately 20% of the HoT-PE population were elderly (>80 years), or had active cancer or chronic cardiopulmonary disease, all of which are considered to indicate a 'high risk' in the (simplified) Pulmonary Embolism Severity Index.12 Thus, the selection criteria and the management strategy validated in HoT-PE may be applicable to a larger number of patients in the 'real world' of aged patients with comorbidity. On the other hand, it needs to be mentioned that approximately 20% of the screened patients with acute PE were ultimately included in the trial. This fact highlights the complexity and need for individualization of management decisions concerning early discharge of patients with PE. In this regard, it is important that, in contrast to most previous studies shown in Table 1, HoT-PE was performed in seven European countries with different health care systems, social infrastructure, geography, and physicians'/patients' preferences. These important aspects should always be taken into account when implementing management strategies which involve the interaction and synergy of various stakeholders in a given country and center. Decisions on early discharge are never purely medical decisions.

In conclusion, and with all the above limitations and caveats in mind, HoT-PE as well as the other studies shown in Table 1 indicate that early discharge with continuation of anticoagulant treatment at home can be effective and safe, and that it should therefore be considered in carefully selected patients with acute low-risk PE.9 Implementation of validated early discharge strategies may help to reduce the need for hospitalization and use of health care resources.

TABLE 1: Design, selection criteria, and management strategy followed in home treatment trials published since 2010

  Aujesky et al13 Zondag et al14 Agterof et al15 Otero et al 16 den Exter et al.17 Barco et al (HoT-PE)8
Design Randomized, open-label, non-inferiority (outpatient versus inpatient treatment) Prospective cohort (single-arm) management trial Prospective cohort (single-arm) management trial Randomized, open-label trial (early discharge versus standard hospitalization) Randomized, open-label, non-inferiority (discharge after versus without NT-proBNP testing) Prospective cohort (single-arm), phase 4 management trial
Study sites, countries n=19; Switzerland,
France, Belgium, USA
n=12; The Netherlands n=5; The Netherlands n=9; Spain n=17; The Netherlands n=49, Germany, Italy, The Netherlands, Spain, Portugal, Finland, Greece
Patients enrolled 344 (of 1,557 screened) 297 (of 581 screened) 152 (of 351 screened) 132 (of 1,016 screened) 550 (of 1,102 screened) 525 (of 2,917 screened)
Main eligibility criteria*
Systolic blood pressure ≥ 100 mm Hg ≥ 100 mm Hg (included in Hestia criteria) ≥ 90 mm Hg ≥ 90 mm Hg ≥ 100 mm Hg (included in Hestia criteria) ≥ 100 mm Hg
Clinical prediction rule for PE severity PESI class I or II Hestia exclusion criteria† - Uresandi score‡ 0-2 Hestia exclusion criteria† Modified Hestia exclusion criteria
Biochemical markers (not required) (not required) NT-proBNP < 500 pg/mL Troponin T < 0.01 ng/mL Randomized to NT-proBNP versus no NT-proBNP testing (not required)
Absence of RV dysfunction (not required) (not required) (not required) TTE (no imaging of RV required) CTPA or TTE
Absence of severe renal impairment CrCl ≥ 30 mL/min CrCl ≥ 30 mL/min (included in Hestia criteria) Creatinine < 150 µmol/L (not required) CrCl ≥ 30 mL/min (included in Hestia criteria) CrCl ≥ 15 mL/min
Minimum platelet count ≥75 000/mm3 - - - -  
Body weight ≤ 150 kg - - BMI < 30 kg/m2 - -
No arterial hypoxemia or respiratory disorder O2 saturation ≥ 90%, or arterial PO2 ≥ 60 mmHg Included in Hestia criteria No need for O2 supply for maintaining O2 saturation > 90% O2 ≥ 93%; NYHA I or II; no severe COPD or asthma Included in Hestia criteria No need for O2 supply to maintain O2 saturation > 90%
Additional criteria No history of HIT   - No recent surgery (< 15 days)    
Duration of hospital stay / time of discharge Mean stay 0.5 ± 1.0 days (outpatients) versus 3.9 ± 3.1 days (inpatient group) Direct discharge from ER (77%), or < 24 h stay (23%) Direct discharge from ER (69.1%), or 6-24 h stay (30.9%) Discharge after 3.4 ± 1.1 days (early) versus 9.3 ± 5.7 days (standard) Mean stay, 10 hours without NT-proBNP versus 18 hours with NT-proBNP testing Median stay, 34 hours (IQR, 23-47 hours)
Anticoagulation treatment Enoxaparin bid + VKA started early Nadroparin od + VKA started early LMWH od + VKA started early LMWH bid + VKA started on day 10 LMWH + VKA started early Rivaroxaban 15 mg bid for 3 weeks, followed by 20 mg od over 3 months
* Eligibility criteria common to all studies include: Hemodynamically stable adults with acute, objectively confirmed PE; no active bleeding or high risk of bleeding; no requirement for parenteral analgesics; index PE not occurring during anticoagulation, pregnancy, or hospitalization for another illness; absence of other reasons for hospitalization; no familial or social barriers to home treatment; anticipated good compliance of the patient; life expectancy longer than 3 months.
† The Hestia criteria include the following questions, all of which must be answered with 'no': Is the patient hemodynamically unstable? Is thrombolysis or embolectomy necessary? Active bleeding or high risk of bleeding? More than 24 h of oxygen supply to maintain oxygen saturation > 90%? Is PE diagnosed during anticoagulant treatment? Severe pain needing intravenous pain medication for more than 24 h? Medical or social reason for treatment in the hospital for more than 24 h (infection, malignancy, no support system)? Does the patient have a creatinine clearance of < 30 mL/min? Does the patient have severe liver impairment? Is the patient pregnant? Does the patient have a documented history of heparin-induced thrombocytopenia?
‡ The Uresandi score includes the following variables: recent major bleeding (4 points); metastatic cancer (4 points); non-metastatic cancer (2 points); serum creatinine >2 mg/dL (3 points); immobility due to a recent medical condition (2 points); absence of surgery in the past 2 months (1 point); and age >60 years (1 point).
bid, bis in die (twice daily); BMI, body mass index; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; CTPA, computed tomographypulmonary angiography; ER, emergency room; HIT, heparin-induced thrombocytopenia; HoT-PE, Home Treatment of Pulmonary Embolism trial; IQR, interquartile range; LMWH, low molecular weight heparin; NT-proBNP, N-terminal pro-brain natriuretic peptide; NYHA, New York Heart Association class; od, omni die (once daily); PESI, Pulmonary Embolism Severity Index; PO2, partial oxygen pressure; RV, right ventricle/ventricular; TTE, transthoracic echocardiography; VKA, vitamin K antagonist(s).

TABLE 2: Early discharge strategies and 3-month outcomes in the HoT-PE trial8

Duration of hospitalization for index PE
Spent a maximum of two nights in hospital 502 of 523 patients (96.0%)
Discharged on the same day 61 patients (11.7%)
Hospitalized for one night 219 patients (41.8%)
Hospitalized for two nights 243 patients (46.5%)
Needed prolonged hospitalization due to adverse events 11 patients (2.1%)
Primary Efficacy Outcome
Recurrent venous thromboembolism or fatal PE 3 of 525 patients (0.6%; one-sided upper 99.6% CI, 2.1%)
Recurrent PE 3 patients (0.6%; 95% CI, 0.1%-1.7%)
Recurrent deep vein thrombosis 0
Death related to PE 0
Safety Outcomes
Major bleedinga 6 of 519 patients (1.2%; 95% CI, 0.4%-2.5%)
Any clinically relevant bleeding 31 patients (6.0%; 95% CI, 4.1%-8.4%)
Death of any cause within the first 3 months 2 of 525 patients (0.4%; 95% CI, 0.1%-1.4%)
Cause of death Advanced cancer in both cases
a As defined by the criteria of the International Society of Thrombosis and Haemostasis,18
CI, confidence interval; IQR, interquartile range; PE, pulmonary embolism.

Acknowledgments
The work of Stavros Konstantinides, Stefano Barco, and Mareike Lankeit was supported by the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503). The authors are responsible for the contents of this publication.

References

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Clinical Topics: Anticoagulation Management, Cardio-Oncology, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism, Lipid Metabolism, Novel Agents, Interventions and Vascular Medicine

Keywords: Factor Xa Inhibitors, Venous Thromboembolism, Anticoagulants, Patient Selection, Length of Stay, Factor Xa, Retrospective Studies, Veterans Health, Patient Preference, Confidence Intervals, Secondary Prevention, Patient Satisfaction, Patient Satisfaction, Heart Ventricles, Quality of Life, Pyridones, Pyrazoles, Pulmonary Embolism, Patient Discharge, Embolectomy, Ambulatory Care, Risk Assessment, Registries, Comorbidity, Clinical Protocols, Health Care Costs, Decision Support Techniques, Neoplasms, Vitamin K, ACC Annual Scientific Session, ACC19


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