A Significant Clot

Last week our Journal Club focused on the treatment of hemodynamically significant pulmonary emboli.  These are pulmonary emboli causing either frank hypotension (sometimes called massive or high risk PEs) or causing significant right heart strain as evidenced by CT findings, cardiac biomarker elevation, or bedside Echo findings.  Drs. Grace Lagasse, Kari Gorder, and Claire O'Brien led us in a discussion of the 3 papers linked and explained below.  Read the papers yourself, listen to the podcast, read the summaries and get caught up on all things PE.

MS GPM, PharmD BH, DO MRJ, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. JACC: Cardiovascular Interventions 2015;8(10):1382–92. 

SEATTLE II was a prospective, single-arm study looking at the safety and efficacy of ultrasound-facilitated, catheter-guided treatment for submassive and massive PE with the proprietary EKOS device. This study enrolled patients who had acute PEs with signs of right heart strain or dysfunction, specifically those with an RV/LV ratio equal to or greater than 0.9. Patients received a standard dose of catheter-drected tPA, which was significantly lower than the systemic dose given in previous trials. They found a 25% decrease in the RV/LV diameter ratio at 48 hours, and a 30% decrease in pulmonary artery pressures by the end of the procedure. With regards to safety, even with a broad definition of a significant bleeding event, they found that no patients suffered an intracranial hemorrhage—- the dreaded complication of systemic thrombolysis — but that only one patient was hemodynamically unstable from a bleeding event.

While the study did demonstrate safety and efficacy of the device, it was a single-arm study with no comparator group, so no conclusions can be drawn about this method as compared to other available PE treatment protocols. Additionally, as this technology is relatively new, long-term data about patient-centered outcomes is not yet available.

William T Kuo MD F, BS AB, MD PSK, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT). CHEST 2015;148(3):667–73. 

The PERFECT trial was an international, prospective multicenter registry from 2011-2014, aimed at evaluating the safety and effectiveness of catheter-direct therapy (CDT) for massive and submassive pulmonary embolisms (PEs) in a prospective, multicenter real world population. The study enrolled 101 consecutive patients with either massive or submassive PE. Massive PE was defined as either sustained hypotension, SBP<90, or requiring inotropic support in the setting of CT evidence of proximal pulmonary embolism. Submassive PE was defined as RV dilation and hypokinesis based on echo or CT imaging in the setting of CT evidence of proximal pulmonary embolism. Patients who presented with massive PE received catheter-directed mechanical or pharmacomechanical therombectomy in addition to catheter-directed thrombolysis whereas those with submassive PE received catheter-directed thrombolysis via a low-dose hourly infusion of tPA or urokinase only. After CDT therapy patients were transitioned to long-term anticoagulation.

The authors defined clinical success as meeting three metrics: stabilization in hemodynamics, improvement in RV strain or pulmonary HTN, and survival to hospital discharge. Safety outcomes were also evaluated, looking at major procedure related complications and major bleeding events. The trial enrolled 73 patients with submassive PE and 28 with massive PE. The study found that there was clinical improvement in 71/73 in patients with submassive PE and in 24/28 of patients with massive PE. Six patients died, four in the massive PE group and two in the submassive PE group. 57/64 patients showed improvement in RV strain on echo and 78/92 showed improvement in PA pressures on invasive pulmonary monitoring both of which was statically significant. The study reported no major procedure related complications. There were 13/101 minor complications none of which required transfusion or additional interventions. The study was limited by its design as a registry; there was no control group for comparison. Additionally, there was no long-term monitoring of RV function or PA pressures. 

In conclusion, this study found that clinical success rates for CDT treatment of submassive and massive PEs in a “real world” population is consistent with previously reported rates.

Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med 2014;370(15):1402–11.

PEITHO was a multicenter, double blind, placebo controlled, randomized trial that was published in 2014 addressing the role of fibrinolytic therapy in patients with intermediate risk pulmonary embolism. The study randomized two groups with confirmed diagnosis of intermediate risk PE to receive either tenectaplase + heparin vs heparin alone.

1005 patients from 76 sites in 13 countries were included in an intention to treat analysis. Intermediate risk pulmonary embolism was defined as acute PE (with ≤15 days of symptoms) in normotensive patients, 18 or older, who had confirmed RV dysfunction on ECHO or CT, and evidence of myocardial injury by an elevated troponin. The primary endpoint was the composite of death from any cause or hemodynamic decompensation within 7 days. The secondary outcomes were death within 7 days, hemodynamic decompensation within 7 days, recurrent PE within 7 days, death within 30 days, and major adverse event within 30 days. Importantly, this study also looked at safety outcomes which included ischemic or hemorrhagic stroke and moderate/severe bleeding within 7 days. 

Patients were randomized within 2 hours of physician diagnosis of intermediate risk PE. The treatment group received a single weight-based IV bolus of tenectaplase while the control group received an IV bolus of the same volume and appearance of tenectaplase. Both groups were given a heparin bolus immediately after randomization and started on a heparin infusion.

The results demonstrated a statistically significant difference between the two groups for the primary outcome, death or hemodynamic collapse.  It is important to note that efficacy was driven by prevention of hemodynamic collapse and did not detect a statistically significant difference in rate of death.  Analysis of the safety outcomes demonstrated a statistically significant difference in the rate of both major bleeding and stroke – with higher rates occurring in the treatment group receiving tenectaplase. In this trial, fibrinolytic therapy was associated with a 2% risk of hemorrhagic stroke and a 6.3% risk of other major bleeding.

Ultimately, this was a well-designed study but it is important to evaluate the clinical significance of the primary outcome. Given the broad definition of HD decompensation used in the study, it is important to weigh the increased risk of intracranial hemorrhage and other serious bleeding against the benefit of reducing HD decompensation.

In conclusion, a single bolus of tenecteplase reduced the composite of early death or hemodynamic compromise in patients with intermediate risk PE, but was associated with an increased risk of intracranial and major bleeding. Our discussion group was very interested in potential long term outcomes that were not measured in this study such as chronic right heart failure, exercise tolerance, and chronic PE and whether the incidence of these long term complications would differ between the treatment and control groups.  We also felt it demonstrated the importance of considering other treatment options that may reduce the risk of hemodynamic decompensation while minimizing the risk of bleeding, such as catheter directed thrombolysis or low dose thrombolysis.