Date Published: February 6, 2019
Publisher: Public Library of Science
Author(s): Darshan C. Patel, Ron C. Gaba, Li Liu, R. Peter Lokken, Yoshiaki Taniyama.
The purpose of this study is to assess the incremental effect of tissue plasminogen activator (t-PA) dose on pulmonary artery pressure (PAP) and bleeding during catheter directed thrombolysis (CDT) of submassive pulmonary embolism (PE).
Records of 46 consecutive patients (25 men, 21 women, mean age 55±14 y) who underwent CDT for submassive PE between September 2009 and February 2017 were retrospectively reviewed. Mean t-PA rate was 0.7±0.3 mg/h. PAP was measured at baseline and daily until CDT termination. Mixed-effects regression modeling was performed of repeated PAP measures in individual patients. Bleeding events were classified by Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) and t-PA dose at onset.
Mean t-PA dose was 43.0±30.0 mg over 61.9± 28.8 h. Mean systolic PAP decreased from 51.7±15.5 mmHg at baseline to 35.6±12.7 mmHg at CDT termination (p<0.001). Mixed-effects regression revealed a linear decrease in systolic PAP over time (β = -0.37 (SE = 0.05), p<0.001) with reduction in mean systolic PAP to 44.8±1.9 mmHg at 12 mg t-PA/20 h, 39.5±2.0 mmHg at 24 mg t-PA/40 h, and 34.9±2.1 mmHg at 36 mg/60 h. No severe, one moderate, and 8 mild bleeding events occurred; bleeding onset was more frequent at ≤24 mg t-PA (p <0.001). One patient expired from cardiopulmonary arrest after 16 h of CDT (15.4 mg t-PA); no additional intra-procedural fatalities occurred. Increased total t-PA dose and CDT duration were associated with greater PAP reduction without increased bleeding events.
Prospective trials investigating catheter directed thrombolysis (CDT) of submassive pulmonary embolism (PE) demonstrated reduction of pulmonary artery pressure (PAP)  and right heart strain [2, 3] in CDT treatment arms. These results are corroborated by findings from the prospective multicenter Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT) registry  and retrospective studies [5–12]. However, thrombolytic dose and duration were limited to 4–24 mg tissue-plasminogen activator (t-PA) over 2–24 h in the prospective trials [1–3]; patients in PERFECT received a mean t-PA dose of 28±11 mg over 23.2±8.1 h using ultrasound assisted thrombolysis (USAT) or 20.8±11.5 h with standard CDT . The ULTIMA study  reported a 10% minor bleeding complication rate and no major bleeding; the SEATTLE II study [1, 13] reported a 20%, 10.7% and 0.7% incidence of mild, moderate and severe bleeding events respectively. In the OPTALYSE PE study, four patients (4%) suffered 5 major bleeding events, included one intracranial hemorrhage attributed to CDT; this patient had been randomized to receive 12–24 mg t-PA over 6 h, a higher dose over a shorter duration compared to the ULTIMA (10–20 mg t-PA over 15 h) and SEATTLE II (24 mg t-PA over 12–24 h) trials . The highest rates of major bleeding in these trials have occurred with t-PA dosage of ≥2 mg/h, raising the possibility that administration rates above 1 mg/h may decrease safety of CDT .
This single-center retrospective cohort study was compliant with the Health Insurance Portability and Accountability Act. Institutional Review Board approval was obtained with waiver of informed consent for review of records.
Meta-analyses of prospective clinical trials evaluating systemic fibrinolysis for submassive PE have suggested a decrease in all-cause mortality  or clinical deterioration [23, 24] compared to anticoagulation alone, at the expense of an increased risk of major bleeding. Direct instillation of a lower dose of fibrinolytic agent into the PA via CDT has been investigated with the goal of achieving therapeutic benefit while minimizing bleeding complications. However, the optimal dose, duration, and technique of CDT is not established. The higher rates of major bleeding in the SEATTLE II study, in which the majority of patients received 2 mg t-PA/h, and in the OPTALYSE PE trial arm receiving 12–24 mg/t-PA over 6 h, suggest that a dose rate of over 1 mg t-PA/h may result in greater hemorrhagic complications [1, 3, 14]. The majority of prospective and retrospective studies have assessed CDT with ≤24 mg t-PA; [1–5, 7–9, 11] the impact of t-PA dose >24 mg, administered at a low (≤1 mg/h) dose rate, upon PAP reduction and bleeding risk is unclear.