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.
BACKGROUND: Submassive pulmonary embolism (PE) has a low mortality rate but can degrade functional capacity.
OBJECTIVE: The present study aims to provide rationale, methodology, and initial findings of a multicentre, randomised trial of fibrinolysis for PE that used a composite end-point, including quality of life measures.
METHODS: This investigator-initiated study was funded by a contract between a corporate partner and the investigator's hospital (the prime site). The investigator was the Food and Drug Administration (FDA) sponsor. The prime site subcontracted, indemnified, and trained consortia members. Consenting, normotensive patients with PE and right ventricular strain (by echocardiography or biomarkers) received low-molecular-weight heparin and random assignment to a single bolus of tenecteplase or placebo in double-blinded fashion. The outcomes were: (i) in-hospital rate of intubation, vasopressor support, and major haemorrhage, or (ii) at 90 days, death, recurrent PE, or composite that defined poor quality of life (echocardiography, 6 min walk test and surveys). The planned sample size was n = 200.
RESULTS: Eight sites enrolled 87 patients over 5 years. The ratio of patients screened for each enrolled was 7.4 to 1, equating to 11 h screening time per patient enrolled. Primary barrier to enrolment was the cost of screening. Two patients died (2.5%, 95%CI [0-8%]), one developed shock, but 18 (22%, 95%CI: [13-30%]) had a poor quality of life.
CONCLUSIONS: An investigator-initiated, FDA-regulated, multicentre trial of fibrinolysis for submassive PE was conducted, but was limited by screening costs and a low mortality rate. Quality of life measurements might represent a more important patient-centred end-point.
BACKGROUND: Acute submassive pulmonary embolism (PE) with right ventricular (RV) injury and/or concomitant deep venous thrombosis can cause persistent symptoms that degrade quality of life. We tested the hypothesis that intravenous tenecteplase would improve the probability of a favorable outcome at three months after submassive PE. METHODS: Multicenter randomized double-blind, placebo controlled trial. Eligible patients were ambulatory at baseline, had image-proven acute PE, a systolic blood pressure > 90 mm Hg and RV dysfunction (abnormal echocardiography, troponin or brain natriuretic peptide). Patients received anticoagulation with low molecular weight heparin (LMWH) and either tiered-dose tenecteplase or saline in an opaque syringe. Composite favorable outcome: 5 day survival to hospital discharge without shock, intubation, or major hemorrhage (any intracranial bleed or need for surgical or medical intervention for acute anemia), and at 90 days, normal RV on resting echocardiography, 6 minute walk distance>330 m, no dyspnea at rest, and no recurrent PE or DVT. Self-perception of wellness was assessed by the SF-16, VEINES-QOL and rank on 1-10 ordinal scale. RESULTS: 83 patients were enrolled, including 33 women, 52 Caucasians, mean age 55+/-14 years, 43 received placebo, 40 received tenecteplase, and 38 had concomittant DVT. A favorable composite outcome occurred in 17/43(40%, 95% CI: 25-56%) treated with placebo, versus 26/40 (65%, 95% CI: 48-79%) treated with tenecteplase, p=0.02 Fisher’s exact. Acute deterioration occurred in 3 patients treated with placebo: fatal PE (1), intubation (1), thrombectomy (1) and in one patient treated with tenecteplase who had a fatal intracranial hemorrhage. At three months, a nonfavorable outcome was found in 23 additional patients treated with placebo, versus 13 patients treated with tenecteplase. Assessments of wellness were consistently higher in the tenecteplase group (e.g., p=0.03 for ordinal scale rank). CONCLUSIONS: In this randomized trial, patients with submassive PE treated with LMWH and tenecteplase were more likely to have a favorable patient-oriented outcome at three months than patients treated with LMWH and saline placebo.
BACKGROUND: Acute pulmonary embolism (PE) can worsen quality of life due to persistent dyspnea or exercise intolerance.
OBJECTIVE: Test if tenecteplase increases the probability of a favorable composite patient-oriented outcome after submassive PE.
METHODS: Normotensive patients with PE and right ventricular (RV) strain (by echocardiography or biomarkers) were enrolled from eight hospitals. All patients received low-molecular-weight heparin followed by random assignment to either a single weight-based bolus of tenecteplase or placebo, administered in a double-blinded fashion. The primary composite outcome included: (i) death, circulatory shock, intubation or major bleeding within 5 days or (ii) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36(®) Physical Component Summary (PCS) score < 30 at 90-day follow-up.
RESULTS: Eighty-three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. Within 5 days, adverse outcomes occurred in three placebo-treated patients (death in one and intubation in two) and one tenecteplase-treated patient (fatal intracranial hemorrhage). At 90 days, adverse outcomes occurred in 13 unique placebo-treated patients and five unique tenecteplase-treated patients Thus, 16 (37%) placebo-treated and six (15%) tenecteplase-treated patients had at least one adverse outcome (exact two-sided P = 0.017).
CONCLUSIONS: Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome.
: Previous studies have associated biomarkers indicative of acute inflammation with pulmonary embolism, which may amplify coagulation, inhibit fibrinolysis and increase risk of venous thromboembolism (VTE) recurrence. The aim of this study was to measure inflammatory and hemostatic biomarkers in acute submassive pulmonary embolism at diagnosis and 3-month follow-up and to test the impact of treatment with fibrinolysis. Secondary analysis of a multicenter, double-blinded, randomized controlled trial including patients with submassive pulmonary embolism. Blood samples were obtained within 24 h of diagnosis and prior to bolus-dose tenecteplase (TNK) or placebo; all patients received standard anticoagulation and blood was redrawn 3 months later. Plasma concentrations of inflammatory [Interleukin 6 (IL-6), C-reactive protein (CRP), myeloperoxidase (MPO)] and hemostatic [plasminogen activator inhibitor-1 (PAI-1), fibrinogen, thrombin-activatable fibrinolysis inhibitor and D-dimer] biomarkers were quantified. The median values of the biomarkers of inflammation (IL-6, CRP, MPO) were all significantly decreased at 3-month follow-up, ranging from a 60 to 91% reduction over this time period. Concentrations of PAI-1 and fibrinogen did not change significantly. D-dimer concentration at 3-month follow-up was lower in patients treated with fibrinolysis vs. placebo and appeared to have a trend toward significance (placebo 310 vs. TNK 220 ng/ml, P = 0.051). Acute pulmonary embolism causes marked but transient inflammation, as demonstrated by the significant elevation in the inflammatory biomarkers at diagnosis, followed by their reduction in more than 80% of patients at 3-month follow-up.
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.
