Objective of the study: Primary objective: to determine whether early discharge and out-of-hospital treatment of patients with low-risk acute PE (as defined by the inclusion and exclusion criteria) with the new oral factor Xa inhibitor rivaroxaban…
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy outcome is symptomatic recurrent venous thromboembolism
(VTE) or death related to pulmonary embolism within 3 months after enrolment.
Secondary outcome
1) All-cause mortality within 7 days;
2) All-cause mortality within 3 weeks;
3) All-cause mortality within 3 months;
4) Overall duration of hospital stay (index event and repeated hospitalizations
due to PE [index or recurrent event] or to a bleeding event) within 3 months;
5) Rehospitalization due to PE (index or recurrent event) or to a bleeding
event within 3 months;
6) Generic and disease-specific quality of life at baseline, 1 week, 3 weeks,
and 3 months;
7) Treatment satisfaction using the Anti-Clot Treatment Scale (ACTS) at 3 weeks
and 3 months;
8) Utilization of medical resources at 1 week, 3 weeks, and 3 months (based on
data from patients recruited at German study sites);
9) All-cause mortality at one year.
Safety outcomes:
1) Major bleeding, based on the ISTH definition, within 7 days, 3 weeks, and 3
months;
2) Clinically relevant bleeding, defined as a composite of major or clinically
relevant non- major bleeding, within 7 days, 3 weeks, and 3 months;
3) Serious adverse events (SAE) within 7 days, 3 weeks, and 3 months
A Serious Adverse Event is defined as an event that at any dose (including
overdose):
Results in death;
Is life-threatening;
Requires subject hospitalization or prolongation of existing hospitalization;
Results in persistent or significant disability/incapacity;
Is a congenital anomaly/birth defect;
Is an important medical event.
Background summary
In all home-treatment single-armed (management) and randomized trials performed
thus far, conventional regimens of anticoagulation using subcutaneous low
molecular-weight heparin followed by oral anticoagulants (vitamin K
antagonists) were used; the bleeding risks and logistical problems associated
with the latter drugs have repeatedly been emphasized (19-22).
The EINSTEIN-PE study (23) tested the new oral factor Xa inhibitor rivaroxaban
in 4,832 patients at 263 sites in 38 countries. Recurrent symptomatic (or
lethal) venous thromboembolism occurred in 2.1% of patients receiving
rivaroxaban compared with 1.8% of those on standard enoxaparin/warfarin
therapy. Rivaroxaban was thus non-inferior to standard therapy (P=0.003).
Importantly, major bleeding was observed in only 1.1% of patients taking
rivaroxaban compared with 2.2% of those on enoxaparin/warfarin (P=0.003). In
particular, intracranial bleeding occurred in one rivaroxaban patient compared
with 10 patients receiving standard therapy. Based on the results of the
EINSTEIN trial, rivaroxaban was approved for use as oral monotherapy for acute
PE in Europe and North America in 2012.
New oral anticoagulants may provide a safe, user-friendly, and cost effective
alternative to standard regimens; in particular, they offer the potential to
radically change the management of acute PE at the low-risk end of the severity
spectrum and facilitate home treatment for a large number of patients eligible
for early discharge. Proof (or rejection) of this important concept is the aim
of the present trial.
Study objective
Objective of the study:
Primary objective: to determine whether early discharge and out-of-hospital
treatment of patients with low-risk acute PE (as defined by the inclusion and
exclusion criteria) with the new oral factor Xa inhibitor rivaroxaban is
feasible, effective, and safe.
Secondary objectives:
- determine whether early discharge and out-of-hospital treatment of low-risk
acute PE with the new oral factor Xa inhibitor rivaroxaban can result in good
quality of life and patient satisfaction; and
- To obtain valid health economic variables as the basis for a description of
health care resource utilization compared to standard in-hospital care. This
includes validation of a disease-specific quality of life questionnaire,
validation of existing Markov models, and comparison to published data on
in-hospital care patients.
Study design
Study design: HoT-PE is a prospective, multicenter, single-arm phase 4
management (cohort) study.
In patients clinically suspected of having acute PE, the diagnostic workup will
be completed within 24 hours of admission. Treatment with an approved
parenteral anticoagulant (unfractionated heparin administered intravenously, or
low-molecular-weight heparin (LMWH), fondaparinux (administered
subcutaneously), or rivaroxaban (administered orally) may be started before
screening and enrolment. Anticoagulant treatment should be started upon
clinical suspicion of PE and no later than 3 hours after confirmation of PE.
Patients who fulfill all the inclusion criteria and meet none of the exclusion
criteria will be enrolled in the study after providing written informed
consent. The first dose of the study drug (rivaroxaban) will be given
in-hospital, 2 hours or less before the time that the next (second)
subcutaneous dosage of LMWH would have been due, or at the time of
discontinuation of intravenous unfractionated heparin.
Additional baseline tests such as echocardiography and compression
ultrasonography of the leg veins will be performed before discharge. These
tests are recommended but not compulsory.
Patients will be discharged from the hospital within 48 hours of presentation.
A 24-hour emergency number will be provided by the study site.
Rivaroxaban will be taken for a total of at least 3 months. After that period,
continuation of
anticoagulation and the anticoagulant drug to be used will be at the discretion
of the patient*s
physician.
Follow-up will be performed at 8 days, 3 weeks, 3 months, and one year.
Study burden and risks
HoT-PE is a phase 4 clinical trial; rivaroxaban has been shown to be effective
and safe for the treatment of acute PE and has been approved for use in this
indication. This means that no additional harm can be expected for patients
with acute PE who will be treated with the (already approved) rivaroxaban
regimen. Of note, the current indication, by the European Medicines Agency, for
rivaroxaban in acute PE does not explicitly mention (i.e. neither recommends
nor excludes) immediate/early discharge and out-of-hospital treatment of the
disease, but the evidence to support this strategy is very weak at present,
since the vast majority (90%) of patients included in the EINSTEIN-PE trial
were hospitalized during the initial phase (23).
If the hypothesis of HoT-PE is confirmed, early discharge (within 24 to 48
hours) and home treatment will become an attractive option for a large
proportion of patients with acute PE. Based on the existing data, these may be
as many as 50% of all patients with the disease (26). Considering the fact that
venous thromboembolism is the third most frequent acute cardiovascular syndrome
(after acute coronary syndrome and stroke) with an annual incidence rate of
23-69 cases per 100,000 population (27), the absolute number of patients to
benefit from such a major change in paradigm will be very large. Home
treatment, if confirmed to be effective and safe, could not only result in
increased patient satisfaction and improved quality of life (these parameters
will be assessed using standardized, validated questionnaires in the present
trial), but it could also prove to be a cost effective approach by reducing
hospitalization costs (a systematic pharmaco-economic analysis will be
performed based on patient data collected at the German study sites). The
potential socioeconomic implications of such a change are considerable and may
include changes in the hospital reimbursement system which currently assumes
(based on old data with injectable agents for the initial anticoagulation
period along with the lack of a risk stratification concept and robust home
treatment trials) that patients with acute PE need to be hospitalized for
several days.
In addition, proposed clinical, imaging and laboratory criteria for identifying
low-risk PE will be validated for the first time in a large therapeutic trial.
Thus, HoT-PE will be the largest-ever trial to translate a risk stratification
model into clinical management of acute PE.
If, on the other hand, the hypothesis of HoT-PE is rejected and home treatment
is found to be either ineffective or unsafe, then hospitalization will remain
the gold standard for the initial treatment of the disease for the years to
come.
The investigator will be informed about any relevant or new finding including
AEs relating to treatment with the investigational medicinal product.
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Mainz 55131
DE
Listed location countries
Age
Inclusion criteria
1) Age *18 years;
2) Ability of subject to understand character and individual consequences of clinical trial;
3) Signed and dated informed consent of the subject available before the start of any specific trial procedures;
4) Women of childbearing potential have to practice a medically accepted contraception (non-hormonal intrauterine device, two independent barriers, female or male surgical sterilization, or two years postmeno-pausal) during the trial, and a negative pregnancy test (serum or urine) should be available before inclusion in the trial;
5) Objectively confirmed diagnosis of acute PE by multidetector computed tomographic (CT) pulmonary angiography, pulmonary angiography, or V/Q lung scan according to established diagnostic criteria, with or without symptomatic deep vein thrombosis;
6) Absence of right ventricular (RV) enlargement or dysfunction, and of free floating thrombi
in the right atrium or right ventricle on echocardiography or computed tomography.
On echocardiography, RV enlargement/dysfunction is absent when both criteria listed
below are met:
- Right/left ventricular end-diastolic diameter ratio < 0.9 (apical or subcostal 4-chamber
view)
- No paradoxical motion of the interventricular septum
On CT angiography, RV enlargement/dysfunction is absent when the following criterion is
met:
- Right/left short-axis diameter ratio < 0.9 (transverse plane)
Exclusion criteria
-Hemodynamic instability at presentation, indicated by at least one of the following: (i) systolic blood pressure (SBP) < 100 mm Hg, or heart rate >100 beats per minute, or SBP drop by > 40 mm Hg, for > 15 min; (ii) need for catecholamines to maintain adequate organ perfusion and a systolic blood pressure of >100 mm Hg; (iii) need for cardiopulmonary resuscitation;
-Right ventricular (RV) enlargement or dysfunction, or free floating thrombi in the right atrium or right ventricle, detected by echocardiography or computed tomography;
-Treatment with low-molecular-weight heparin, fondaparinux, or unfractionated heparin for more than 48 hours, or more than a single dose of a vitamin K antagonist prior to inclusion in the study;
-Treatment with rivaroxaban, dabigatran, apixaban, edoxaban or any other new generation antithrombotics on admission;
-Use of a fibrinolytic agent, surgical thrombectomy, interventional (transcatheter) thrombus aspiration or lysis, or use of a cava filter to treat the index episode of PE;
- Need for supplemental oxygen administration to maintain oxygen saturation >90%;
-Pain requiring parenteral administration of analgesic agents;
-Other medical conditions/comorbidities requiring hospitalization;
- Acute PE diagnosed in a patient already hospitalized for another condition;
- Pregnancy or lactation;
- Active bleeding or known significant bleeding risk;
-Severe renal insufficiency (estimated GFR <15 ml/min/1.73m2) or end-stage renal disease;
-Severe hepatic failure;
-Known allergy or intolerance to rivaroxaban;
-Concomitant administration of strong inhibitors of P-gp and CYP3A4 such as azole antimycotic agents or HIV protease inhibitors;
-Need for long-term treatment vitamin K antagonists, or for antiplatelet agents except acetylsalicylic acid at a dosage <100 mg/day;
-Non-compliance or inability to adhere to treatment or to the follow-up visits; or lack of a family environment or support system for home treatment;
-Life expectancy less than 3 months.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-001657-28-NL |
| CCMO | NL58418.101.16 |