Ultrasound-Accelerated Thrombolysis: An Optimal Solution for Undertreated Patients With Intermediate-Risk PE

For a large majority of patients with acute intermediate-risk pulmonary embolism (PE), the usual standard of care of anticoagulation alone falls far short of saving lives and avoiding long-term sequelae, such as chronic thromboembolic pulmonary hypertension. We can and should offer these patients more aggressive treatment with ultrasound-enhanced thrombolysis, which quickly clears the clot without the large dose of tPA used in systemic fibrinolytic treatment. 

Patients with intermediate risk, or submassive, PE are hemodynamically stable but have right heart strain consistent with imminent right heart failure. Submassive PEs, which typically present with thrombosis in one or both of the left and right pulmonary arteries, account for 40% of all PEs. Only 5% of PE patients have the high risk, or massive, type; these patients present with hemodynamic collapse and cardiogenic shock. 

The problem with treating submassive PEs with anticoagulation alone, as is currently recommended by the American College of Chest Physicians’ treatment guidelines¹, is that anticoagulants prevent thrombus propagation, but don’t resolve the existing clot. The body’s endogenous fibrinolysis can take weeks to months to dissolve a clot, and often the process is incomplete. Complications from the clot left behind may not emerge for as long as 10 years, but can result in severe disability and the need for pulmonary thromboendarterectomy. 

Undertreatment of submassive PE with anticoagulants alone also increases mortality risk. In one study, as many as 5.6% of patients with submassive PEs treated with anticoagulation alone demonstrated hemodynamic deterioration, which led to significant mortality.² Another study found that mortality risk increases 11-fold for PE patients treated only with anticoagulant therapy when their pulmonary obstructive index is 40% or greater.³ 

Aggressive reperfusion therapy using ultrasound-accelerated thrombolysis rapidly reverses right ventricular dilation and reduces the pulmonary clot burden in patients with right ventricular enlargement who are at risk of developing increased pulmonary resistance, leading to a massive PE. Patients with submassive PE in danger of becoming hemodynamically unstable typically require a 100mg bolus dose of tPA delivered over 2 hours. Large-dose systemic thrombolysis, however, carries a 20% risk of major hemorrhage and up to a 3% risk of intracranial hemorrhage. 

Ultrasound-directed thrombolysis significantly reduces the risk of bleeding by clearing the clot with a much lower dose of tPA than with systemic thrombolysis. Low-intensity ultrasound, delivered via the EkoSonic Endovascular System (EKOS Corporation), conditions the clot, separating fibrin strands and exposing plasminogen receptor sites. Ultrasonic pressure waves force the tPA deep into the clot, which is now more permeable and receptive to the drug. Our protocol is to administer 1mg tPA per hour in bilateral catheters for 12 hours. The total 24mg of tPA, one-fifth of the systemic dose, is tolerated very well. None of our 115 patients who have had ultrasound-enhanced thrombolysis since 2009 have experienced bleeding or intracranial hemorrhage. 

Case presentation

We aggressively treat as many as 75% of patients with submassive PEs with ultrasound-directed thrombolysis. One such recent patient is a 37-year-old male in active military duty with no prior medical history. On a flight from Louisiana to North Carolina, he noticed some minor leg pain. Flying again a few days later, he became short of breath and, upon landing, immediately went to the emergency room, where he was diagnosed with acute submassive PE. 

The patient had a deep venous thrombosis (DVT) of his right lower extremity involving the right common femoral vein, popliteal vein, and tibial veins, but ultrasound showed no iliofemoral thrombus. A computed tomography (CT) scan showed a saddle PE with extensive bilateral involvement and an enlarged right ventricle with a right ventricular/left ventricular (RV/LV) ratio of 2.2 (normal RV/LV ratio is 0.6 to 0.8). He was tachycardic at 110 bpm, normotensive, and had an elevated troponin level. His pulmonary artery pressures were 53/32mmHg with a mean pressure of 41mmHg. PE patients with an RV/LV >0.9 have a significantly higher chance of adverse events within 30 days. His simplified pulmonary embolism severity index was >1, necessitating urgent aggressive reperfusion therapy and making him an excellent candidate for ultrasound-enhanced thrombolysis.⁴

In the cardiac catheterization laboratory, we placed one EkoSonic Endovascular System (EKOS) catheter percutaneously via the right common femoral vein into the left lower lobar branch, draped across the pulmonary valve into the right ventricular outflow tract. A second EKOS catheter was placed into the right lower lobar branch. We administered tPA at 1mg/hour per catheter for 12 hours for a total of 24mg tPA. The intraoperative procedure was completed in 20 minutes. Three hours after therapy terminated, a transthoracic echocardiogram showed the patient’s heart had returned to a completely normal function and size. Eight hours post-infusion, his pulmonary artery pressure was significantly reduced to 18/8mmHg with a mean pressure of 12mmHg.

He spent a half day in the intensive care unit (ICU) and was discharged in 36 hours — a significantly shorter length of stay than the 5 to 7 days most submassive PE patients typically spend in the hospital.⁵ After two weeks, his CT scan showed a complete resolution of his embolism in the main and left pulmonary arteries, and a large reduction in RV/LV ratio to 0.8. A significant reduction in RV/LV ratio post-therapy has historically been a significant predictor of good long-term outcomes. Ultrasound-directed thrombolysis certainly prevented this young man’s death from PE, and it is expected that he will have no adverse outcomes.

A yet-unanswered question is whether submassive patients have better long-term outcomes with aggressive reperfusion therapy compared with the usual standard of care. A randomized, controlled trial comparing the two therapies isn’t likely, since, in our opinion, it would be unethical to enroll high-risk submassive PE patients to be randomly assigned to anticoagulation alone. Now that we have done the procedure on 115 patients, we plan to retrospectively study our patients to determine if they have a lower rate of long-term sequelae, such as chronic pulmonary hypertension, compared to a cohort of patients who have had anticoagulation alone. Four percent (4%) of patients with PE develop chronic pulmonary hypertension.^6,7 However, we believe the percentage is significantly greater in patients who have unresolved right ventricular dilatation at the time of discharge.

Ultrasound-accelerated thrombolysis offers the optimal treatment strategy for most patients with submassive PE and for a small subset of patients with massive PE who are hemodynamically stable enough to undergo the procedure. The only patients who are not good candidates for ultrasound-enhanced thrombolysis are those who have an absolute contraindication to tPA, such as patients with active gastrointestinal (GI) bleeding or those who have undergone a major surgery within the prior week. We have, however, treated patients two weeks post-operatively without inducing any bleeding complications, because of the low dose of tPA we use. The procedure is also not indicated for patients who are hypercoagulable due to metastatic cancer, or for patients with a life expectancy of less than 3 months.

Although the procedure has had an excellent safety profile in our patients, we will soon begin a clinical trial sponsored by EKOS Corporation, OPTALYSE PE (Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Pulmonary Embolism), to determine whether we can achieve the same results with even less tPA and a shorter infusion time. The four- to five-arm study will vary the amount of tPA and therapy time to find the optimal protocol.

References

1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb; 141(2 Suppl): 7S-47S. doi: 10.1378/chest.1412S3.
2. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014; 370(15): 1402-1411.
3. van der Meer RW, Pattynama PM, van Strijen MJ, van den Berg-Huijsmans AA, Hartmann IJ, Putter H, de Roos A, Huisman MV. Right ventricular dysfunction and pulmonary obstruction index at helical CT: prediction of clinical outcome during 3-month follow-up in patients with acute pulmonary embolism. Radiology. 2005 Jun; 235(3): 798-803.
4. Konstantinides SV. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014 Dec 1; 35(45): 3145-3146. doi: 10.1093/eurheartj/ehu393.
5. Aujesky D, Stone RA, Kim S, Crick EJ, Fine MJ. Length of hospital stay and postdischarge mortality in patients with pulmonary embolism: a statewide perspective. Arch Intern Med. 2008 Apr 14; 168(7): 706-712. doi: 10.1001/archinte.168.7.706.
6. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004 May 27; 350(22): 2257-2264.
7. Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011 Jan 27; 364(4): 351-360. doi: 10.1056/NEJMra0910203.