clot dissolving treatment for blood clots in the lungs

Conditions: Pulmonary Embolism

Summary: 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.

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 \ 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.

Eligibility criteria:
inclusion criteria: * pulmonary vascular imaging positive for pe within the previous 24 hours * ability to provide written informed consent and comply with study assessments for the full duration of the study * age \>17 years * evidence of severe pe: rv hypokinesis on echocardiography, abnormal troponin i or t (any non-normal including indeterminate values, using local reference thresholds) or bnp measurement \>90 pg/ml or nt probnp \>900 pg/ml (not more than 6 hours prior to ct angiography and not more than 30 hours before enrollment) or a pulse oximetry reading \<95% within previous two hours (\<93% in denver). exclusion criteria: * systolic blood pressure \< 90 mm hg at time of informed consent * do not resuscitate or do not intubate order * systemic fibrinolytic treatment within previous 7 days * inability to follow-up at 3 months * documented gastrointestinal bleeding within previous 30 days * active hemorrhage in any of the following sites at the time of enrollment: intraperitoneal, retroperitoneal, pulmonary, uterine, bladder, or nose. * head trauma causing loss of consciousness within previous 7 days * any history of hemorrhagic stroke * ischemic stroke within the past year * prior history of heparin-induced thrombocytopenia * history of intraocular hemorrhage * intracranial metastasis * known inherited bleeding disorder, e.g., hemophilia * platelet count \< 50,000/ul * prothrombin time with an inr \>1.7 * chest, abdominal, intracranial or spinal surgery within the previous 14 days * subacute bacterial endocarditis * pregnancy (positive pregnancy test) * prior enrollment in the study * current treatment with fondiparinux, dalteparin, a direct thrombin inhibitor or administration of a glycoprotein inhibitor within the previous 48 hours. * known pericarditis * allergy to heparins,or tenecteplase * elapsed time that would preclude drug or placebo administration within 24 hours after diagnosis * evidence of non-end stage kidney injury (creatinine clearance \< 30 ml/min without chronic hemodialysis treatment; chronic hemodialysis-treated patients are eligible) * preexisting end-stage cardiopulmonary disease (heart failure with left ventricular ejection fraction \<20%, known severe pulmonary hypertension or other lung disease causing permanent dependence upon oxygen) * any other condition that the investigator believes would pose a significant hazard to the subject

Keywords: pulmonary embolism tenecteplase enoxaparin thrombosis fibrinolytics