This project is a phase III, six-center, randomized trial of tenecteplase to treat severe submassive (systolic blood pressure >90 mm Hg) pulmonary embolism (PE). Severe requires one of the following predictors of a adverse outcome: right ventricular (RV) hypokinesis on echocardiography, hypoxemia (pulse oximetry reading <95%, <1000 feet above sea level), serum troponin I (abnormal at local threshold) or brain natriuretic peptide concentration >90 pg/mL (or NT proBNP >900 pg/mL). Patients from the emergency department or inpatients can be enrolled within 24 hours of a diagnostic positive CT angiography. After informed consent, eligible patients will be randomized to the study or placebo arm. All patients will a receive a 1mg/kg enoxaparin, SQ followed by a syringe prepared in pharmacy containing either a body weight-adjusted dose of tenecteplase or a 0.9% saline placebo, given IV push. Patients will be followed for five days post-treatment for composite acute adverse outcomes: PE-related (death, any ACLS intervention, circulatory shock, respiratory failure, need for vasopressors with organ dysfunction) and hemorrhage-related (intracranial or intraspinal hemorrhage and any other hemorrhage requiring transfusion, surgical or endoscopic intervention or a hemostatic drug). Survivors will return at three months for assessment of a delayed adverse outcomes of death or cardiopulmonary functional limitation (CFL): interval medical care for dyspnea + RV dysfunction or pulmonary hypertension on echo + either a NYHA score ≥3 or a 6 minute walk distance <330 m. Together, the acute and delayed outcomes represent composite serious adverse outcomes (SAOs). We hypothesize an absolute 20% reduction in composite serious adverse outcomes in the study arm compared with the placebo arm. The six hospitals represent geographic diversity: Boston, Charlotte, Chicago, Denver, New Haven, and Springfield, MA. To help maintain balance between sites, the six sites will each enroll a maximum of 40 patients until the sample size of N=200 is reached, which allows the 20% effect size to be tested at α =0.05 and β=0.20 with 15% loss to follow-up. The study will employ an intent-to treat analysis. Secondary endpoints include recurrent venous thromboembolism within three months, scores from two validated quality of life questionnaire (VEINES-QOL and SF-36TM) at three months. Human subject safety include requirement that a study MD verify the presence of all inclusion and absence of exclusions in real-time, a method to allow unblinding to the clinical care team, an independent DSMB that will perform 6 interim analyses and will enforce predefined stopping criteria for either safety or efficacy.
The purpose of this study is to determine if tenecteplase plus enoxaparin is safe and effective in the treatment of patients with severe submassive pulmonary embolism.