Tyree Kiser, PharmD, BCCCP, FCCM
Professor
University of Colorado Anschutz Medical Campus
Denver, CO
Disclosure information not submitted.
Peter Hountras, MD
Assistant Professor
University of Colorado School of Medicine
Aurora, Colorado, United States
Disclosure information not submitted.
Jonathan Lindquist, MD
Assistant Professor of Radiology
University of Colorado School of Medicine
Aurora, Colorado, United States
Disclosure information not submitted.
Todd Bull, MD
Professor
University of Colorado School of Medicine
Aurora, Colorado, United States
Disclosure information not submitted.
Title: Pharmacodynamic Evaluation of Varying Alteplase Dosages for the Treatment of Pulmonary Embolism
Introduction: Pulmonary embolism (PE) is associated with significant morbidity and mortality. Lower dose or catheter directed (CD) thrombolysis may be utilized in an attempt to better balance benefits with major bleeding risks. However, pharmacokinetic (PK) and pharmacodynamic (PD) data comparing these strategies to full dose (FD) are lacking. We therefore aimed to evaluate differences in PD response to FD and lower dose alteplase treatments.
Methods: We performed a single center prospective open-label PK/PD pilot study of adults (≥18 years) admitted to the University of Colorado Hospital with acute PE and prescribed intravenous alteplase at a dose of either 100mg (FD), 50mg (half-dose [HD]), or a CD approach (~1mg/hr). Peripheral blood sampling occurred immediately prior to alteplase administration and at 1, 2, and 4 hours after start of treatment. The primary outcome was maximum reduction in alpha-2 antiplasmin (A2A) activity from baseline. Additionally, percentage lysis at 30 minutes (LY30) via thromboelastography (TEG) and change in fibrinogen and D-dimer was evaluated.
Results: Five patients were included: median (range) age 64 years (29-82), 108.9 kg (77.7-158.8), 80% white, 60% female, high-risk PE (n=2), and intermediate high-risk PE (n=3). Alteplase 100mg (n=1), 50mg (n=3), and CD (0.5 mg/hr x 2 catheters x 12 hours; n=1) were the initial thrombolytic strategies. All FD and HD patients received a 10mg bolus with the remaining dose administered as an infusion. One HD patient received a second 50mg dose. Median baseline A2A activity in all patients was 121 (range 108-135) and reduced to a nadir of 23.5 (↓81%), 33 (↓73%), and 48 (↓60%) after FD, HD, and CD alteplase, respectively (FD vs. HD, p=0.2). TEG LY30 was increased to 89.4% in FD, 90.5% in HD, and < 5% in CD (FD vs. HD, p=0.85). Fibrinogen was reduced by 51%, 31%, 75% in FD, HD, and CD (p=0.54). Median baseline D-Dimer was 27625 (range 3000-50870) and increased to 207750 after FD, and > 400000 after HD and CD (p=NS).
Conclusion: Small differences in PD response were observed with FD and HD alteplase therapy. CD had the least effect on A2A and TEG LY30, however D-Dimer increases and fibrinogen decreases were similar. Our findings highlight the need for PK/PD evaluations of new thrombolytic strategies that can better retain benefits and minimize risk.