Tissue plasminogen activator has a notoriously checkered past within emergency medicine, and its controversial use continues with the advent of targeted therapy for pulmonary embolism. Catheter-directed administration of tPA for PE is gaining traction, and the development of multidisciplinary PE Response Teams are popularizing and advocating this therapy. (Chest 2016;150:384.) The evidence for this treatment strategy, however, raises concerns about its early adoption.
Catheter-directed therapy (CDT) for PE involves placing a special catheter directly into the pulmonary artery, into or adjacent to the clot, followed by a continuous infusion of tPA. The thought is that by infusing the tPA directly into the pulmonary circulation, significantly lower doses can be used to achieve thrombolysis and to mitigate the risk of hemorrhage. Some of these catheters are specially equipped to provide ultrasound pulsations that are said to provide mechanical force to expose fibrin and improve tPA efficacy. The former is termed catheter-directed thrombolysis, the latter ultrasound-assisted catheter-directed thrombolysis. (Chest 2016;150:384; Circulation 2014;129:479; http://bit.ly/2CbgjUY; Chest 2015;148:667; J Vasc Interv Radiol 2018;29:293; http://bit.ly/2Ggqqfd.)
Proponents of this therapy tout reduced doses of thrombolytics and decreased major bleeding events as compelling reasons to adopt this groundbreaking therapy. Several studies have evaluated its feasibility and efficacy for various forms of PE, but only one randomized controlled trial has been done comparing catheter-directed thrombolysis to standard care. The remainder of the literature consists largely of cohort studies with no control groups and no patient-oriented outcomes.
The Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism (ULTIMA trial), funded by EKOS Corp., boasted a robust sample size of 59 patients with submassive PE. (Circulation 2014;129:479; http://bit.ly/2CbgjUY.) These patients were randomized to receive heparin or heparin plus CDT (10-20 mg of tPA over 15 hours). The CDT group demonstrated a statistically significant reduction in RV/LV diameter ratio at 24 hours (not a patient-oriented primary outcome) while the heparin group did not. No major bleeding episodes were seen in either group. (Circulation 2014;129:479; http://bit.ly/2CbgjUY.)
The ULTIMA study demonstrated a clear benefit in the CDT group compared with heparin alone for achieving the primary outcome of reduced RV strain. This should be no surprise because anticoagulant therapy and thrombolytic therapy have entirely different mechanisms of action. Of course, correlation does not prove causation. Patients who received CDT in the ULTIMA trial had significantly better outcomes than those receiving heparin, but the cause was likely not the sham procedure of CDT but the infusion of low-dose tPA.
No Proven Benefit
The fallacy in accepting catheter-directed therapy as effective is that clinicians conclude that the catheter delivery system is solely responsible for the improved outcomes. Two facts dispute this claim: Delivery of tPA directly into the pulmonary circulation has never been definitively proven to provide benefit compared with systemic delivery, and ultrasound therapy has not been shown to add benefit in conjunction with tPA for treating clots.
A 1988 study examined the effects of intrapulmonary tPA with standard intravenous tPA administration in a group with massive PE; clot burden and reduction in pulmonary arterial pressure were nearly identical in each group. (Circulation 1988;77:353.) This makes intuitive sense based on the pulmonary physiology. The pulmonary circulation receives the entire circulating blood volume, and any medication infused peripherally will make its way into the pulmonary circulation to exert its effects.
The addition of ultrasound to catheter-directed therapy likely confers no appreciable benefit based on the results of the 2015 PERFECT trial. This study enrolled consecutive patients who had either submassive or massive PE. A portion underwent CDT without ultrasound, while others underwent ultrasound-assisted CDT. There was no significant difference between PA pressure reduction or tPA requirement between the groups. (Chest 2015;148:667.) We see similar results reported in the DVT literature, where the addition of ultrasound to catheter-directed therapy does not seem to improve clot burden or reduce tPA requirement. (Circ Cardiovasc Interv 2015;8:1; http://bit.ly/2BlRrYW.)
A definitive trial would involve comparing catheter-directed tPA v. peripherally infused tPA at the same rate. I suspect that the outcomes would be no different and that we could start delivering effective therapy through a simple IV infusion right at the bedside, but the CDT manufacturers aren't in a hurry to fund that study.
The lack of high-quality evidence in the form of large patient populations, randomized controlled trial design, and long-term patient-oriented outcomes makes adopting catheter-directed therapy for pulmonary embolism questionable at best. Yet despite the dearth of quality data, the Society of Interventional Radiology actually considers catheter-directed thrombolysis an acceptable treatment for massive PE in “carefully selected” patients. (J Vasc Interv Radiol 2018;29:293; http://bit.ly/2Ggqqfd.)
The evidence for systemic thrombolytics in PE, especially submassive PE, is still fraught with controversy. The introduction of a costly, invasive, and poorly studied therapy such as CDT just serves to muddy the already murky waters in which we wade while caring for patients suffering from PE. Until more rigorous, methodologically sound research is presented, catheter-directed therapy is far from prime time, but it seems that the horse has already left the barn.Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.