The primary aim of the study is to evaluate whether treatment with the EKOS device on top of anticoagulation in patients with severe pulmonary embolism results in a better clinical outcome than treatment with anticoagulation alone. The primary…
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Source
Brief title
Condition
- Pulmonary vascular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the occurrence of pulmonary embolism-related mortality,
cardiorespiratory decompensation or collapse or non-fatal symptomatic and
objectively confirmed recurrent pulmonary embolism within 7 days of
randomization.
Cardiorespiratory decompensation or collapse is defined as:
a) cardiac arrest or the need for cardiopulmonary resuscitation (CPR) at any
time between randomization and day 7;
b) Signs of shock: first-onset persistent hypotension (SBP below 90 mmHg or
decrease in SBP of at least 40 mmHg for at least 15 minutes, and despite
adequate filling status; or vasopressors/inotropics required to maintain an SBP
of at least 90 mmHg ), along with end-organ hypoperfusion (altered mental
status; oliguria/anuria; increased serum lactate) at any time between
randomization and day 7;
c) placement of ECMO at any time between randomization and day 7;
d) intubation or initiation of non-invasive mechanical ventilation at any time
between randomization and day 7;
e) National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7
days after randomization, confirmed on at least 2 measurements spaced at least
15 minutes apart.
Secondary outcome
1. Change in the right ventricular (RV) to left ventricular (LV) end diastolic
diameter ratio (RV/LV) as measured by echocardiography between baseline
and 48±6 hours;
2. PE-related death within 7 days;
3. Cardiorespiratory decompensation within 7 days;
4. Placement on ECMO or mechanical ventilation within 7 days
5. Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)
bleeding scale major (moderate and severe) bleeding within 7 days;
6. International Society on Thrombosis and Haemostasis (ISTH) major
bleeding within 7 days, 30 days, and 6 months;
7. Ischemic or hemorrhagic stroke within 7 days and 30 days;
8. All-cause mortality within 7 days, 30 days, 6 months, and 12 months;
9. Serious adverse events within 30 days;
10. All-cause mortality, cardiorespiratory collapse or recurrence of PE within
30 days;
11. Symptomatic PE recurrence within 30 days and 6 months;
12. Change from baseline in RV dysfunction on echocardiography at 6 months;
13. Duration of hospitalization for the index PE event;
14. Duration of stay at the intensive, intermediate or coronary care unit during
hospitalization for the index PE event;
15. Functional status: World Health Organization (WHO) functional class and
Post-Venous Thromboembolism (VTE) Functional Status (PVFS) scale at
discharge, 30 days, 6 and 12 months; 6-Minute Walk Test (6MWT) at 30
days, 6 and 12 months;
16. Quality of life: Pulmonary Embolism Quality of Life (PEmb-QOL), Short
Form 36 (SF-36), EuroQuol-5 Dimension (EQ-5D) at 6 and 12 months;
17. Diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH)
within 12 months;
18. Health economic analysis (length of hospital stay, resource utilization,
indirect costs) at 30 days and at 12 months (selected sites and countries)
Background summary
Intravenous thrombolysis is the "prototyped standard" for reperfusion therapy
in severe acute pulmonary embolism. This is only administered in case of
haemodynamic instability due to the pulmonary embolism (*high risk pulmonary
embolism*); although patients recover faster haemodynamically and have a better
survival after administration of thrombolysis, there is also a greatly
increased risk of major bleeding. Also in patients with a so-called
intermediate-high risk pulmonary embolism, defined as maintained blood pressure
with signs of right ventricular overload and cardiac ischaemia, thrombolysis
also protects against progression to shock or death due to pulmonary embolism.
Due to the large number of bleeding events, thrombolysis in this patient group
does not protect against death from any cause. For this reason, it is not the
standard treatment for this group.
Several steps have been taken to improve the treatment of the group of patients
with an intermediate-high risk pulmonary embolism. First of all, safer ways of
reperfusion therapy have been developed, namely catheter-guided treatment with
thrombosuction and/or local low-dose thrombolysis. Both techniques are known to
restore right heart function more quickly compared to anticoagulation alone,
and have a low risk of bleeding. In addition, better selection criteria have
been developed to identify hemodynamically stable patients with a risk of
progression to shock and death greater than 20%, by adding clinical signs of
severity on top of cardiac imaging and biomarkers of ischemic heart damage. The
researchers of the HI-PEITHO study are testing the hypothesis that reperfusion
therapy using catheter-guided low-dose thrombolysis in the latter group of
patients will lead to better outcomes (less death from pulmonary embolism or
progression to shock) than treatment with anticoagulation alone.
Study objective
The primary aim of the study is to evaluate whether treatment with the EKOS
device on top of anticoagulation in patients with severe pulmonary embolism
results in a better clinical outcome than treatment with anticoagulation alone.
The primary endpoint is the occurrence of pulmonary embolism-related mortality,
cardiorespiratory decompensation or collapse or non-fatal symptomatic and
objectively confirmed recurrent pulmonary embolism within 7 days of
randomization. Secondary endpoints are to determine the effect of the
intervention on the individual components of the primary endpoint, quality of
life, and speed of physical recovery. The safety and cost-effectiveness of the
treatment is also examined.
Study design
The study is a Phase 4, randomized, controlled, adaptive, open-label,
multicenter, parallel group, blinded assessment of primary composite outcome.
Subjects are randomized 1:1 to treatment with EKOS plus anticoagulation or
anticoagulation alone. The randomization is stratified by age (< 75 years
versus >= 75 years) and RV/LV ratio on CTPA (< 1.5 versus >= 1.5). After
randomization to the intervention arm, EKOS treatment should start within 6
hours of determining eligibility to participate in the study. In both study
arms, the first 24 hours is treated with unfractionated or twice daily dosed
low molecular weight heparin. In the intervention arm, this treatment is
continued until 24 hours after the end of the intervention. The local
investigator can then proceed to oral anticoagulation according to the
applicable international guideline and local protocol.
The target number of study patients is 406. These patients are being recruited
from approximately 65 hospitals in the United States and Europe. Based on the
interim analysis after 50% of the intended inclusions, there is a possibility
to increase the sample size to a maximum of 544 patients. All patients are
followed for 12 months; it is expected that the study can be completed 3 to 4
years after the start.
Intervention
Patients meeting all of the inclusion criteria and none of the exclusion
criteria will be included in the study upon written informed consent. They are
randomized in a 1:1 ratio to receive ultrasound-facilitated catheter-directed
thrombolysis (USCDT) in combination with anticoagulants or anticoagulants
alone. Randomization and initiation of assigned treatment should be followed as
soon as possible, but no later than six (6) hours after confirmation of the
diagnosis of intermediate to high risk pulmonary embolism, as defined in
inclusion criteria 2-5. Randomization should be performed as soon as
practicable after the investigator confirms the diagnosis. The assigned
treatment should be started as soon as possible after randomization. For
subjects assigned to the USCDT group, it is strongly recommended that the
intervention be initiated within two (2) hours of randomization.
Study burden and risks
The intervention is associated with a higher risk of bleeding due to
thrombolysis, and procedure-related risks such as bleeding at the insertion
site, damage to the heart or bypassed blood vessels, pneumothorax and
haemoptysis. However, the absolute risk of this is low (<3%) and should be
viewed in the context of the estimated risk of developing shock or death (20%).
If a patient in the control arm of the study, or who is not included, becomes
hemodynamically unstable, reperfusion therapy should still be administered,
whereby the risk of bleeding and complications is higher than that 3% due to
the acute setting.
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Age
Inclusion criteria
1) Age 18-80 years, inclusive
2) Objectively confirmed acute PE, based on CTPA showing a filling defect in at
least one main or proximal lobar pulmonary artery (PA)
3) Elevated risk of early death/hemodynamic collapse, indicated by at least two
of the following new-onset clinical criteria:
i) Electrocardiogram (ECG)-documented tachycardia with heart rate >= 100 beats
per minute, not due to hypovolemia, arrhythmia, or sepsis;
ii) SBP <= 110 mm Hg for at least 15 minutes;
iii) respiratory rate > 20 x min-1 or oxygen saturation on pulse oximetry
(SpO2) < 90% (or partial arterial oxygen pressure < 60 mmHg) at rest while
breathing room air;
4) Right-to-left ventricular (RV/LV) diameter ratio >= 1.0 on CTPA
5) Serum troponin I or T levels above the upper limit of normal
6) Signed informed consent
Exclusion criteria
1) Hemodynamic instability*, i.e. at least one of the following present:
a) cardiac arrest or need for cardiopulmonary resuscitation;
b) need for ECMO, or ECMO initiated before randomization;
c) PE-related shock, defined as: (i) SBP < 90 mmHg, or vasopressors required to
achieve
SBP >= 90 mmHg, despite an adequate volume status; and (ii) end-organ
hypoperfusion (altered mental status; oliguria/anuria; increased serum lactate);
d) isolated persistent hypotension (SBP < 90 mmHg, or a systolic pressure drop
by at
least 40 mmHg for at least 15 minutes), not caused by new-onset arrhythmia,
hypovolemia, or sepsis.
* Patients who presented with temporary need for fluid resuscitation and/or
low-dose
catecholamines may be included, provided that they could be stabilized within 2
hours
of admission and maintain SBP of >= 90 mmHg and adequate organ perfusion without
catecholamine infusion.
2) Need for admission to an intensive care unit for a reason other than the
index PE episode.
Note: Patients who test positive for SARS-CoV-2 can be enrolled where the
investigator
believes that the pulmonary embolism is the dominant pathology in the patient*s
clinical
presentation and qualifying cardiorespiratory parameters.
3) Temperature above 39oC / 102.2oF
4) Logistical reasons limiting the rapid availability of interventional
procedures to treat
acute PE (e.g., during the outbreak of an epidemic)
5) Index PE symptom duration > 14 days
6) Active bleeding
7) History of intracranial or intraocular bleeding at any time
8) Stroke or transient ischemic attack within the past 6 months, or previous
stroke at any
time if associated with permanent disability
9) Central nervous system neoplasm, or metastatic cancer
10) Major neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or
orthopedic
surgery or trauma (including syncope-associated with head strike or skeletal
fracture)
within the past 3 weeks
11) Platelet count < 100 x 109 x L-1
12) Patients who have received a once-daily therapeutic dose of LMWH or a
therapeutic dose
of fondaparinux within 24 hours prior to randomization
13) Patients who have received one of the direct oral anticoagulants apixaban
or rivaroxaban
within 12 hours prior to randomization
14) Patients who have received one of the direct oral anticoagulants dabigatran
or edoxaban
for the index PE episode, as these drugs are not approved for patients who have
not
received heparin for at least 5 days
15) Administration of a thrombolytic agent or a glycoprotein IIb/IIIa receptor
antagonist
during the current hospital stay and/or within 30 days, for any reason
16) Chronic treatment with antiplatelet agents other than low-dose
acetylsalicylic acid or
clopidogrel 75 mg once daily (but not both). Dual antiplatelet therapy is
excluded
17) Chronic treatment with a direct oral anticoagulant (apixaban, dabigatran,
edoxaban or
rivaroxaban)
18) Chronic treatment with a vitamin K antagonist, or known coagulopathy
including severe
hepatic dysfunction, with an International Normalized Ratio (INR) > 1.5
19) Pregnancy or lactation
20) Previous inclusion in the study
21) Known hypersensitivity to alteplase, LMWH, UFH, or to any of the excipients
22) Life expectancy less than 6 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 |
|---|---|
| ClinicalTrials.gov | NCT04790370 |
| CCMO | NL81278.041.22 |