Catheter directed thrombolysis for submassive PE: better than heparin? (RCT)

Image: EKOS

Patients with acute pulmonary embolism (PE) fall into three general clinical categories:

Massive PE, most often defined as hypotension due to right ventricular dysfunction. Short-term mortality is high (more than 1 in 7 die in-hospital). Systemic thrombolytic therapy (tissue plasminogen activator or tPA) is considered standard care by AHA and ACCP, because it improves RV function and blood pressure. A definite mortality reduction has not yet been demonstrated for tPA in massive PE.

Low-risk patients have blood pressure at or near their baseline and no right heart dysfunction. Normal troponin, BNP and oxygenation add to a favorable prognosis. These patients should be treated with systemic anticoagulation, but may not even require hospital admission. With appropriate treatment, their mortality is low. The Pulmonary Embolism Severity Index (PESI) can help identify low risk patients.

Intermediate risk patients (including "submassive" pulmonary embolism) have preserved blood pressure, but adverse risk factors such as right ventricular dysfunction, "looking sick," dyspnea and hypoxemia, elevated troponins, or severe tachycardia. These patients exist on an uncomfortable spectrum of risk from ~4% to ~15% in-hospital mortality.

The AHA and ACCP both recommend giving thrombolytic therapy (tPA) to those with massive PE without contraindications, and weakly suggest giving tPA to intermediate risk patients who are at low risk for bleeding. But since risk for bleeding is fuzzy and subjective, and devastating intracranial hemorrhage may occur in up to 3% of patients receiving tPA, physicians commonly withhold thrombolytics even from patients with massive PE, and rarely give tPA to hemodynamically stable, intermediate risk patients with PE.

Interventionalists can approach a clot with a catheter tip and use ultrasound to agitate fibrin fibers inside blood clots and create pressure waves, creating pockets into which thrombolytics can penetrate. This technique has been called ultrasound assisted catheter directed thrombolysis.

To date, catheter directed thrombolysis with various devices (with and without ultrasound) has been tested in small studies, but has not shown benefit in any randomized trial. With the publication of the industry-funded ULTIMA trial in a recent issue of Circulation, this niche of interventional vascular medicine gets an interesting lift.

Investigators enrolled 59 patients with acute pulmonary embolism affecting a main or lower lobe pulmonary artery who also had right ventricular dysfunction on echocardiogram (but preserved blood pressure) and a low or average bleeding risk. They were recruited from 8 hospitals in Germany and Switzerland, and randomized to be treated with heparin infusion alone, or heparin infusion along with ultrasound assisted catheter directed thrombolysis Interventionalists used the EkoSonic MACH4e Endovascular System and gave 10-20 mg tPA over 15 hours, depending on whether they got 1 or 2 catheters placed. EKOS funded the study, and Dr. Kucher reports being a paid consultant for EKOS.

Within 24 hours, those receiving catheter directed thrombolysis had significant reductions in pulmonary artery pressure and RV dilation; those receiving heparin alone did not. After 3 months, there was a “catch up” effect among the heparin-treated patients, with their right ventricular dilation disappearing (equal to the tPA group). However, at 90 days, most patients receiving heparin only continued to have mild RV systolic dysfunction (by TAPSE) on echocardiogram, while most receiving tPA had normal RV function.

There was no significant bleeding in either arm, and no recurrent DVT or PE at 90 days of follow-up. One patient in the heparin-only arm died, from pancreatic cancer. Three minor bleeding episodes occurred in the intervention arm (1 in the heparin arm).

This trial is provocative and should give a boost to centers and physicians performing catheter directed thrombolysis, and to future research in this area. But since there were no clinically meaningful benefits established here, and the patients treated with heparin alone did well, one could also question the significance of the echocardiographic benefits seen in the tPA arm.

Did the heparin patients’ RV dysfunction persist at 6 or 12 months? Were there residual symptoms, or recurrence of DVT/PE? If not, one could question whether even the low marginal excess risk of thrombolysis (surely there is some) is worth it.

Also, keep in mind the devices available for catheter directed thrombolysis vary significantly in their design and function. Some perform clot fragmentation with suction (embolectomy or thrombectomy). Results may vary.

Given the efficacy and lack of bleeding risk signal, some physicians may be tempted to use catheter directed thrombolysis for patients with massive PE as well, or for submassive PE with elevated risk for bleeding; those questions were not tested in ULTIMA. Another trial on the EKOS device called SEATTLE II has been completed; no results yet on clinicaltrials.gov. The NIH-funded ATTRACT study at Washington University (n=692) is studying outcomes after catheter directed thrombolysis for DVT.

Clinical Takeaway: Catheter directed thrombolysis might safely improve right ventricular function in people with intermediate risk pulmonary embolism. Larger trials with longer followup and clinically relevant endpoints are needed before adopting this promising therapy as standard care.

Nils Kucher et al. Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism. Circulation 2014;  129: 479-486.