March 07, 2019
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Ultrasound-assisted, catheter-directed therapy for pulmonary embolism: Breaking down the evidence

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Acute pulmonary embolism is a serious, potentially life-threatening disease with a continuum of symptoms and clinical outcomes that vary based on the severity and extent of artery occlusion.

Massive PE is associated with hemodynamic instability and right ventricular dysfunction, resulting in a high mortality rate. Submassive PE refers to patients presenting with RV dysfunction without systemic hypotension but potential for clinical deterioration as well as significant morbidity, including chronic pulmonary hypertension, persistent RV dysfunction and recurrent PE.

Dustin D. Spencer

Systemic thrombolysis

Systemic thrombolysis improves hemodynamic parameters and restores RV function in patients with massive PE, but causes major bleeding in up to 20% of patients treated. Although guidelines support the use of systemic thrombolysis for massive PE, its use for submassive PE is less clear due to the associated bleeding risk (Table).

The use of systemic thrombolysis in patients with submassive PE has been evaluated in large, prospective studies.

In the PEITHO randomized trial of 1,005 patients, tenecteplase (TNKase, Genentech) combined with unfractionated heparin (UFH) significantly reduced the incidence of death or hemodynamic compromise, but increased the risk for major hemorrhage and stroke compared with UFH alone. In fact, the 2% rate of hemorrhagic stroke with systemic thrombolysis in this trial approaches the overall mortality of submassive PE.

Reduced-dose systemic thrombolysis has also been studied for the treatment of submassive PE to improve the safety profile. In the MOPETT trial, 121 patients were randomly assigned to reduced-dose alteplase ( 50% of standard dose) plus anticoagulation (UFH or subcutaneous enoxaparin) or anticoagulation alone. Benefits of reduced-dose thrombolysis included a more marked reduction in pulmonary artery pressures (PAP) at 48 hours and a lower incidence of pulmonary hypertension or recurrent PE at 28 months compared with anticoagulation alone. There were no in-hospital bleeding events in either group, but these events were not followed long term. Results of this trial demonstrate superiority of thrombolysis for prevention of longer-term morbidity associated with submassive PE, and emphasize the potential benefit of a safe, thrombolytic dosing strategy for these patients.

Catheter-directed interventions

Various catheter-directed interventions have also been evaluated for PE treatment, including drug-only catheter-directed thrombolysis (CDT), device-only percutaneous mechanical thrombectomy and drug plus device pharmacomechanical CDT.

CDT offers the advantage of thrombolytic delivery directly into the pulmonary circulation, allowing use of lower doses and thus a potentially lower risk for bleeding compared with systemic therapy. Additionally, CDT may be performed with or without low-power ultrasound energy. Ultrasound-assisted CDT (USCDT) accelerates thrombolytic delivery by using a catheter system (EkoSonic Endovascular System, EKOS Corp.) to deploy ultrasound waves to disaggregate fibrin and promote penetration of the thrombolytic agent into the thrombus. Use of USCDT has demonstrated promising results as a primary therapeutic option for submassive PE in prospective, randomized trials. Based on the results of these trials, the FDA approved use of the EkoSonic system in 2014 to deliver USCDT for the treatment of patients with PE.

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Clinical trials

ULTIMA was the first prospective, multicenter study to investigate whether UFH with adjunctive fixed-dose USCDT was superior to UFH alone. Fifty-nine patients with submassive PE were randomly assigned to UFH with alteplase 10 mg over 15 hours (1 mg per hour for 5 hours, then 0.5 mg per hour for 10 hours) per treated lung. Administration of USCDT resulted in significantly better reversal of RV dilatation at 24 hours compared with UFH alone (mean decrease in RV/LV ratio, 0.3 ± 0.2 vs. 0.03 ± 0.16; P < .001). Improvements in RV/LV ratio, PAP and cardiac index were similar in magnitude to those seen in prior systemic thrombolysis trials. There were no differences in rates of death, major or minor bleeding, or recurrent venous thromboembolism at 90 days.

Similar results were also seen in the SEATTLE II trial, a prospective, single-arm trial that evaluated the safety and efficacy of USCDT in 150 patients with acute massive (n = 31) or submassive PE (n = 119). Patients received USCDT with alteplase (Activase, Genentech) 24 mg (1 mg per hour for 24 hours with unilateral catheter or 1 mg per hour for 12 hours with bilateral catheters). Use of USCDT in this trial improved the RV/LV ratio as well as PAP and thrombus burden at 48 hours. Major bleeding occurred in 10% of patients. Only one event, a groin hematoma, was defined as severe and there were no intracranial hemorrhages at 72 hours.

The most recent prospective, randomized USCDT trial, OPTALYSE PE, sought to determine the lowest effective dose and duration of alteplase using USCDT. In this trial, 101 patients with submassive PE were randomized into four cohorts based on the dose of alteplase per treated lung and the duration of treatment: 4 mg per 2 hours, 4 mg per 4 hours, 6 mg per 6 hours and 12 mg per 6 hours. All patients also received anticoagulation with UFH. There was a significant reduction in in the RV/LV ratio from baseline by approximately 23% to 26% for all cohorts at 48 hours measured by CT. The embolic burden, measured by refined modified Miller score, was also improved in all cohorts with greater improvements seen in the higher-dose cohorts. Four patients (4%) experienced a total of five major bleeding events, including two intracranial hemorrhages, one of which was attributed to alteplase delivery in the highest-dose cohort. At 1 year, RV/LV ratios continued to show improvement and both mortality and recurrent PE rates were maintained at 2%. The results of OPTALYSE PE appear to support the efficacy and safety of USCDT in patients with submassive PE, including with use of lower doses and shorter durations of alteplase than previously studied. However, unlike ULTIMA, this trial did not include a control group to prove reductions in RV/LV ratios were a result of USCDT and not endogenous thrombolysis.

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Another study evaluated the impact of a multidisciplinary PE response team (PERT) designed to individualize treatment strategies for patients with submassive PE who did not qualify for systemic thrombolysis. Patients were treated with surgical pulmonary embolectomy or USCDT with alteplase. Bleeding rates were higher in the USCDT group (9.7% vs. 1.4%; P = .025), but mortality was similar between treatment cohorts (3.1% vs. 7%; P = 0.448). Importantly, volumes of pulmonary embolectomy did not decrease after introduction of USCDT, highlighting the need for access to both surgical and pharmacologic strategies.

Finally, a meta-analysis evaluated use of USCDT with alteplase, including for both high-risk and intermediate-risk PE. Eleven trials (n = 553) were evaluated for the primary outcomes of mean PAP, RV/LV ratio and CT obstruction score, and secondary outcomes were evaluated in 15 trials (n = 655) and included all-cause and CV mortality, major and minor bleeding, and recurrent PE. Compared with systemic thrombolysis, USCDT significantly reduced mean PAP, RV/LV ratio and CT obstruction scores. Patients treated with USCDT also had lower rates of major bleeding (5.5% vs. 9.9%; P < .001), but similar mortality (3.2% vs. 2%; P = .18) compared with other meta-analyses in which patients received systemic thrombolysis.

Continued area of interest, investigation

Accumulated evidence suggests promise for use of USCDT as an option for submassive PE, although more adequately powered studies evaluating clinical endpoints over imaging surrogates could help further define its therapeutic potential. It is also unknown whether use of ultrasound with CDT is superior to standard CDT catheters due to the lack of prospective comparisons of these treatments. USCDT studies to date have almost exclusively utilized alteplase, although urokinase has also been evaluated in one prospective registry study.

Until more questions are answered, USCDT will likely continue as an area of interest for future research and remain a treatment approach for select patients, particularly in centers with expertise using this strategy.

Disclosure: Spencer reports no relevant financial disclosures.