Standard-dose Apixaban AFtEr Very Low-dose ThromboLYSis for Acute Intermediate-high Risk Acute Pulmonary Embolism
Condition: Pulmonary Embolism With Acute Cor Pulmonale; Pulmonary Embolism; Pulmonary Embolism With Pulmonary Infarction; Pulmonary Embolism Subacute Massive; Right Ventricular Dysfunction; Right Ventricular Failure
MeSH terms: Pulmonary Embolism; Pulmonary Infarction; Embolism; Ventricular Dysfunction; Ventricular Dysfunction, Right; Pulmonary Heart Disease; Infarction
Intervention: Alteplase; Unfractionated heparin; Placebo; Apixaban
Intervention description: Lyophilized powder for reconstitution in 50mg vials; Heparin sodium in 0.45% sodium chloride injection for intravenous use; Saline solution reconstituted to mimic Alteplase 50mg vial; Apixaban tablet
Intervention MeSH terms: Heparin; Calcium heparin; Tissue Plasminogen Activator; Plasminogen; Apixaban
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to examine the degree to which pulmonary embolism (clot) can be
      dissolved when treated with a very low dose of a systemic thrombolytic drug (clot buster)
      along with standard anticoagulant therapy as compared to the standard of care anticoagulant
      therapy alone.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Chest CT angiogram (CTA) evidence of proximal Pulmonary Embolism (PE) with a filling
             defect in at least one main pulmonary artery or lobar artery

          -  PE symptom duration ≤14 days

          -  Intermediate-high risk PE: defined as RV dysfunction with an RV/LV diameter ≥ 0.9,
             sPESI > 0, and either troponin > 0.05ng/mL or BNP > 100 pg/mL, and hemodynamically
             stable (systolic blood pressure > 90mmHg without the use of vasopressor support)

          -  Randomization within 24 + 4 hours of anticoagulation

          -  Signed and dated informed consent obtained from subject or legally authorized
             representative before initiation of any study procedures

        Exclusion Criteria:

          -  Weight > 130kg or < 40 kg on day of randomization

          -  Stroke or transient ischemic attack (TIA), head trauma, or other active intracranial
             or intraspinal disease within one year

          -  Recent (within one month) or active bleeding from a major organ

          -  Major surgery within 14 days

          -  Clinician deems the subject too high-risk for bleeding using HAS-BLED criteria

          -  History of any hematologic disease or coagulopathy

          -  Cirrhosis (as determined by Child-Pugh B or C)

          -  History of heparin-induced thrombocytopenia (HIT)

          -  Hemodynamic instability defined as systolic blood pressure (SBP) less than 90mmHg
             and/or use of vasopressors for greater than 15 minutes

          -  Severe hypertension as defined as SBP greater than 180mmHg

          -  Cardiac arrest or active cardiopulmonary resuscitation (CPR)

          -  Receiving neuraxial anesthesia or undergoing spinal puncture

          -  Patient with prosthetic heart valves

          -  Evidence of irreversible neurological compromise

          -  Evidence of poor functional status

          -  History of major gastrointestinal bleed within the last month

          -  Active gastric or duodenal ulcers

          -  Use of thrombolytics or glycoprotein IIb/IIIa antagonists within 3 days prior to
             diagnosis

          -  Lovenox administration within 12 hours of randomization

          -  Direct-acting oral anticoagulant use (dabigatran, rivaroxaban, apixaban, or edoxaban)
             with last known dose within 48 hours

          -  Hemoglobin < 10 g/dL

          -  Creatinine clearances < 60 mL/min

          -  Platelets < 100 thousand/µL

          -  INR > 1.4

          -  Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 2 times upper limit of
             normal (ULN)

          -  Total bilirubin (TBL) ≥ 1.5 times ULN (except due to confirmed Gilbert's syndrome)

          -  Patient is pregnant (positive pregnancy test; women of childbearing capacity must be
             tested prior to enrollment) or breast feeding

          -  Patient who is a prisoner, or if subject who becomes compulsory detained

          -  Active cancer defined as diagnosis of cancer within six months before the study
             inclusion, or receiving treatment for cancer at the time of inclusion or any treatment
             for cancer during 6 months prior to randomization, or recurrent locally advanced or
             metastatic cancer

          -  Known allergy, hypersensitivity or thrombocytopenia from heparin, tPA, or apixaban or
             iodinated contrast except for mild-moderate contrast allergies for which steroid
             pre-medication can be administered within 12 hours prior to the CTA

          -  HIV/AIDS