CLINICAL STUDY
Ultrasound-Accelerated Catheter-Directed Thrombolysis for Acute Submassive Pulmonary Embolism Sandeep Bagla, MD, John B. Smirniotopoulos, MD, Arletta van Breda, MSN, Michael J. Sheridan, ScD, and Keith M. Sterling, MD
ABSTRACT Purpose: To evaluate the safety and efficacy of ultrasound-accelerated catheter-directed thrombolysis (USAT) in patients with submassive pulmonary embolism (PE). Materials and Methods: This retrospective study comprised 45 consecutive patients (15 prospective, 30 retrospective) who underwent USAT for submassive PE from June 2012–May 2014. Inclusion criteria were right ventricular dysfunction (RVD) as indicated by right ventricle-to-left ventricle (RV:LV) ratio 4 0.9, symptoms of o 2 weeksʼ duration, and absence of absolute contraindication to thrombolysis. All patients underwent pulmonary artery catheterization with a standardized protocol (24 mg recombinant tissue plasminogen activator). Hemodynamic evaluation immediately after USAT, RV:LV ratio evaluation at 48– 72 hours after USAT by computed tomography angiography and echocardiography, and adverse event reporting for a minimum of 30 days were performed. Outcomes and complications are reported as per the Society of Interventional Radiology Reporting Standards for Endovascular Treatment of Pulmonary Embolism. Results: USAT was technically successful in 100% (n ¼ 45) of patients. Main pulmonary artery pressure significantly decreased from 49.8 mm Hg to 31.1 mm Hg (P o .0001). RVD significantly improved with mean RV:LV ratios decreasing from 1.59 to 0.93 (P o .0001). There were 6 complications: 4 minor bleeding episodes at access sites and 2 major bleeding complications (flank and arm hematoma). All-cause mortality at 30 days was 0%. There were no readmissions for PE at 30 days after discharge. Conclusions: Ultrasound-accelerated catheter-directed thrombolysis using a standardized low-dose protocol is a safe and efficacious method of treatment of submassive PE to reduce acute pulmonary hypertension and RVD.
ABBREVIATIONS CDT = catheter-directed thrombolysis, PE = pulmonary embolism, RVD = right ventricular dysfunction, RV:LV = right ventricle-toleft ventricle, USAT = ultrasound-accelerated catheter-directed thrombolysis
Pulmonary embolism (PE) is the third most common cause of cardiovascular-related death in the United States, following myocardial infarction and stroke (1).
From the Association of Alexandria Radiologists, PC (S.B., K.M.S.), Cardiovascular and Interventional Radiology Department, Inova Alexandria Hospital, 4320 Seminary Road, Alexandria, VA 22304; and Inova Health System (J.B.S., A.v.B., M.J.S.), Falls Church, Virginia. Received August 7, 2014; final revision received December 7, 2014; accepted December 10, 2014. Address correspondence to S.B.; E-mail: [email protected] K.M.S. is a paid consultant for BTG. None of the other authors have identified a conflict of interest. & SIR, 2015 J Vasc Interv Radiol 2015; 26:1001–1006 http://dx.doi.org/10.1016/j.jvir.2014.12.017
Submassive PE, which exhibits right ventricular dysfunction (RVD) without hemodynamic instability, is associated with escalation of therapy (cardiopulmonary resuscitation, intubation, vasopressor support), short- and intermediate-term mortality and chronic thromboembolic pulmonary hypertension (2–6). RVD as defined by a right ventricle-to-left ventricle (RV:LV) end-diastolic diameter ratio of greater than 0.9 is an independent predictor of mortality secondary to PE (7–9). Currently, there are no uniformly accepted recommendations for systemic thrombolysis in the treatment of submassive PE (10–12). There is growing evidence that systemic thrombolysis in submassive PE reduces hemodynamic collapse, improves RVD and decreases late onset pulmonary hypertension, however, this is at the expense of increased bleeding complications (13–16).
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Studies involving catheter-directed thrombolysis (CDT) with and without ultrasound have demonstrated a significant comparative improvement with RVD and pulmonary artery pressures without increased risk of major bleeding complication (17–22). Some authors have suggested that catheter directed therapy be utilized in patients with contraindications to systemic thrombolysis as this population is at intermediate to high risk of death (23,24), however a variety of treatment algorithms were reported. We present our retrospective experience of ultrasound-accelerated catheter-directed thrombolysis (USAT) in the treatment of submassive PE using a standardized low-dose treatment protocol.
MATERIALS AND METHODS This study included 45 consecutive patients (25 men and 20 women; mean age, 56.5 y) with submassive PE treated at a single institution from June 2012–May 2014. Demographics are presented in Table 1, and risk factors for venous thromboembolism are listed in Table 2 (25). The first 15 patients were enrolled in a prospective multicenter trial (SEATTLE II [A Prospective, Single-arm, Multi-center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism], ClinicalTrials.gov Identifier: NCT01513759), and the subsequent 30 patients were retrospectively evaluated. The treatment protocol was identical for all patients. All patients signed informed consent form, and the study was performed in compliance with the Health Insurance Portability and Accountability Act with institutional review board approval of prospective and retrospective cohorts. Inclusion criteria were acute PE documented by computed tomography (CT) with symptom onset o 2 weeks, RVD indicated by an RV:LV ratio of 4 0.9 on CT angiography (26), and systemic systolic blood pressure 490 mm Hg without the need for vasopressor support. Patients were excluded if they had a contraindication to receiving thrombolytic medication (27). All patients underwent right heart and pulmonary artery catheterization with hemodynamic evaluation followed by USAT (12 h, n ¼ 3; 24 h, n ¼ 42) with a total dose of 24 mg of recombinant tissue plasminogen activator (tPA). Concomitant anticoagulation with heparin was administered with a target partial thromboplastin time of 40–60 seconds. When a single unilateral catheter (n ¼ 3) was placed, a 24-hour of infusion of 24 mg of tPA alteplase (Activase; Genentech, Inc, South San Francisco, California) was performed at a rate of 1 mg/h (24 mg in 250 mL normal saline); when bilateral catheters (n ¼ 42) were placed, a 12-hour infusion was performed via two catheters at a rate of 1 mg/h each (12 mg tPA in 250 mL normal saline for two bags). Venous access was via a transfemoral route in 3 patients and transjugular route in 42. EkoSonic Endovascular System thrombolytic infusion
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Table 1 . Demographics Baseline demographics Age, y, mean ⫾ SD
56.5 ⫾ 13.6
Body mass index, mean ⫾ SD
32.5 ⫾ 8.2
Men, n (%) Women, n (%)
25/45 20/45
(55.6%) (44.4%)
23/45 17/45
(51.1%) (37.8%)
Comorbidities and risk factors Systemic hypertension, n (%) Hyperlipidemia, n (%) Tobacco use, n (%)
7/45
(15.6%)
Diabetes mellitus, n (%) Obesity, n (%)
6/45 18/45
(13.3%) (40.0%)
Renal insufficiency (GFR o 60
17/45
(37.8%)
mL/min), n (%) Chronic obstructive pulmonary
3/45
(6.7%)
Cancer, n (%) Congestive heart failure, n (%)
8/45 0/45
(17.8%) (0.0%)
Coronary artery disease, n (%)
4/45
(8.9%)
Prior stroke, n (%) Prior deep vein thrombosis, n (%)
1/45 6/45
(2.2%) (13.3%)
Prior PE, n (%)
6/45
(13.3%)
disease, n (%)
PE severity Tachycardia 4 100 beats/min, n (%)
18/43
(41.9%)
Systolic arterial pressure, mm Hg,
135.8 ⫾ 16.3
mean ⫾ SD Diastolic arterial pressure, mm Hg,
76.8 ⫾ 10.1
mean ⫾ SD Heart rate, beats/min, mean ⫾ SD Respiratory rate, breaths/min, mean ⫾ SD Oxygen supplementation, n (%)
90.8 ⫾ 17.0 21.3 ⫾ 4.9 20/38
supplement, mean ⫾ SD Troponin test positive, n (%)
(52.6%) 97% ⫾ 2.7
Oxygen saturation during oxygen 29/43
(67.4%)
RV:LV ratio by CT, before
1.59 ⫾ 0.54
procedure, mean ⫾ SD RV:LV ratio by CT, after procedure,
0.93 ⫾ 0.17
mean ⫾ SD Bilateral main pulmonary artery embolism, n (%)
43/45
(93.3%)
Unilateral main pulmonary artery
3/45
(6.7%)
embolism, n (%) Pulmonary pressure, before
49.8 ⫾ 13.76
procedure, mm Hg, mean ⫾ SD 31.1 ⫾ 9.9
Pulmonary pressure, after procedure, mm Hg, mean ⫾ SD Hospital stay, days (range) 30-day follow-up
5.64
(2–6)
No readmissions
CT ¼ computed tomography, GFR ¼ glomerular filtration rate, PE ¼ pulmonary embolism, RV:LV ¼ right ventricle-to-left ventricle.
catheters (EKOS Corp, Bothell, Washington) were placed in all patients with the operator-dependent decision for placement of unilateral versus bilateral
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Table 2 . Risk Factors for Venous Thromboembolism by the American Heart Association (25) Strong risk factors Fracture (hip or leg), n (%) Hip or knee replacement, n (%)
2/45 1/45
(4.4%) (2.2%)
Major general surgery, n (%)
1/45
(2.2%)
Major trauma, n (%) Spinal cord injury, n (%)
0/45 0/45
(0.0%) (0.0%)
Arthroscopic knee surgery, n (%) Central venous lines, n (%)
0/45 0/45
(0.0%) (0.0%)
Chemotherapy, n (%)
0/45
(0.0%)
Congestive heart or respiratory failure, n (%)
0/45
(0.0%)
Hormone replacement therapy,
1/45
(2.2%)
n (%) Malignancy, n (%)
8/45
(17.8%)
Oral contraceptive therapy, n (%)
2/45
(4.4%)
Paralytic stroke, n (%) Pregnancy (postpartum), n (%)
0/45 0/45
(0.0%) (0.0%)
Previous venous thromboembolism,
12/45
(26.7%)
n (%) Thrombophilia, n (%)
20/45
(44.4%)
2/45 10/45
(4.4%) (22.2%)
40/45 1/45
(88.9%) (2.2%)
Obesity, n (%) Pregnancy (antepartum), n (%)
18/45 0/45
(40.0%) (0.0%)
Varicose veins, n (%)
0/45
(0.0%)
Moderate risk factors
Weak risk factors Bed rest 4 3 days, n (%) Immobility from sitting (eg, prolonged car or air travel), n (%) Age 4 40 y, n (%) Laparoscopic surgery (eg, cholecystectomy), n (%)
catheter placement based on thrombus location. Inferior vena cava filters were not placed in any of the patients at the time of the procedure. Patients underwent repeat hemodynamic evaluation immediately after USAT. Pressures were measured via the thrombolytic catheters in the following manner. The coolant and drug delivery ports were capped, the MicroSonic (EKOS Corp) ultrasound core was removed, and a pressure transducer was connected to an Intelligent Drug Delivery Catheter (EKOS Corp). The first three patients also underwent catheter exchange using fluoroscopic guidance with placement of a 5-F pigtail catheter and connection of a pressure transducer. RV:LV ratio evaluation was performed in all patients at 48–72 hours by CT angiography and echocardiography. Adverse event reporting was performed for a minimum of 30 days, and outcomes and complications were reported as per the Society of Interventional Radiology (SIR) Reporting Standards for Endovascular Treatment of Pulmonary Embolism (28). Primary study outcomes of interest were differences in main pulmonary artery pressure and RV:LV ratio before
and after the procedure. Paired t tests were employed to evaluate these differences, using SAS software (version 9.3; SAS Institute, Inc, Cary, North Carolina). P values o .05 were considered to indicate statistical significance.
RESULTS Endovascular placement of catheters and infusion were technically successful in 100% (n ¼ 45) of patients. There were no complications related to catheter placement (ie, perforation, sustained arrhythmia, dissection). Compared with baseline, main systolic pulmonary artery pressure significantly decreased from 49.8 mm to 31.1 mm, and the difference before and after the procedure was highly statistically significant (18.9 mm; 95% confidence interval, 14.9–22.8 mm, P o .0001). Complete concordance was noted in the first three patients who underwent measurements performed via the angiographic catheter and the Intelligent Drug Delivery Catheter on the EkoSonic system. In addition, RVD improved with mean RV:LV ratio decreasing from 1.59 to 0.93, being highly significant (0.66; 95% confidence interval, 0.50– 0.80, P o .0001) (Figs 1–4). There were four minor venous access site hemorrhagic complications, which did not require additional therapy. One major hemorrhagic complication (flank hematoma) occurred 3 days after cessation of USAT, which required blood transfusion; however, this was believed to be secondary to supratherapeutic anticoagulation (partial thromboplastin time 4130 s) after the cessation of thrombolysis. A second major event (forearm hematoma) occurred in a patient who underwent brachial artery puncture for arterial
Figure 1. CT angiogram depicts saddle PE (arrow) extending into the right and left main pulmonary arteries.
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Figure 4. RV:LV ratio improved to o 0.9 (right ventricle, dashed line; left ventricle, solid line), indicating resolution of RVD. Figure 2. RV:LV ratio is 2.1 (right ventricle, dashed line; left ventricle, solid line), with associated septal bowing (arrow) to the left. Findings of RVD.
Figure 3. There is improvement in the thrombus burden within the main pulmonary arteries 48 hours after thrombolysis. Only small nonobstructive distal left main pulmonary artery thrombus remains (arrow).
blood gas testing before the procedure. Surgical decompression was required. In-hospital and all-cause mortality at 30 days was 0%. The mean length of hospitalization was 5.6 days. There were no readmissions for PE at 30 days after discharge in all patients.
DISCUSSION Investigators are working to identify the ideal therapy, one with the lowest potential risk of hemorrhagic complications while decreasing RVD and subsequent
mortality, in patients presenting with submassive PE. A recently published European double-blind randomized controlled trial (14) evaluating systemic thrombolysis with a single weight-based bolus of tenecteplase ranging from 30–50 mg versus placebo in intermediate-risk PE revealed a 66% reduction in hemodynamic collapse and all-cause mortality in the tenecteplase group (2.6% vs 5.6%). However, this significant benefit was at the expense of a 4-fold increase in major bleeding and a 10-fold increase in intracranial hemorrhage in the fibrinolysis arm. In an attempt to reduce bleeding complications associated with systemic thrombolysis, the MOPPETT (Moderate Pulmonary Embolism Treated with Thrombolysis) trial (15) evaluated half-dose systemic thrombolysis with 50 mg of alteplase versus placebo. The investigators concluded that this “safe dose” thrombolysis is safe and effective in the treatment of moderate PE, with a significant immediate reduction in the pulmonary artery pressure that was maintained at 28 months. Several studies have been published evaluating the use of CDT and USAT in patients with acute massive and submassive PE (17–22). An initial report by Chamsuddin et al (18) evaluated USAT with various thrombolytics and reported a 76% rate of complete thrombus removal after a median of 24 hours without any major hemorrhagic complications. Lin et al (19) evaluated 25 patients with acute massive PE who underwent treatment with either USAT or CDT. The authors reported 100% thrombus removal in all 11 patients in the USAT group with a mean tPA dose rate of 0.86 mg/h (range, 8–28 mg) after a mean infusion time of 17.4 hours (range, 13–38 h). There were no hemorrhagic complications; however, there was a single mortality secondary to multiorgan system failure. The use of USAT
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compared favorably with the CDT group, in which only 50% of the patients had complete thrombus removal with a significantly longer thrombolytic infusion time of 26.7 hours and a hemorrhagic complication rate of 21.4%. Quintana et al (20) reported using tPA with USAT in 10 patients with acute massive or submassive PE. The median tPA dose and infusion time in their cohort was 18 mg (range, 7–38 mg) and 20.8 hours (range, 12–49 h), respectively. Cessation of thrombolysis in these three studies was determined by the adequacy of thrombus removal on repeat pulmonary angiography (18,19) or repeat CT angiography (20). Dumantepe et al (21) used one of three endpoints at the time of repeat pulmonary angiography to discontinue USAT in their group of 22 patients with either acute massive or submassive PE: no change in clot burden after 24 hours, resolution of all symptoms despite the presence of residual clot, or a decrease in the mean pulmonary arterial pressure of 50%. The authors used a mean dose of tPA of 21 mg with a range of 16–35 mg. This dose was associated with a significant decrease in RVD, pulmonary artery pressure, and obstructive index and no significant hemorrhagic complications. Kennedy et al (22) reported the use of a tPA infusion of 1 mg/h/ catheter in 54 of 60 patients with either acute massive or submassive PE. Patients underwent repeat pulmonary angiography and pulmonary artery pressure measurements, and the decision to discontinue treatment was based on improvement of baseline clinical symptoms and interval angiographic evidence of thrombolysis. The investigators used an average dose of 35.1 mg of tPA over a mean 19.6 hours of infusion time. Their study demonstrated that USAT provides an effective means of resolving clot burden and reversing hemodynamic compromise in patients with acute massive and submassive PE (22). Most recently, the ULTIMA (ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism) trial prospectively randomly assigned 59 patients with intermediate-risk PE to USAT or heparin alone. The USAT arm used a standard tPA dose of 1 mg/h via unilateral or bilateral catheters for 5 hours followed by 0.5 mg/h for 10 hours. The maximum tPA dose was 20 mg for bilateral PE and 10 mg for unilateral PE over 15 hours. The patients treated with USAT demonstrated a significant comparative improvement with RVD and pulmonary artery pressures without increased risk of major bleeding complications (29). Following the lead of the ULTIMA trial and the SEATTLE II investigators and the experience of effective results with low-dose USAT by Engelhart et al (17) and Kennedy et al (22), we sought to use a standardized protocol limiting the thrombolytic dose (24 mg tPA) and infusion time (12 h or 24 h as determined by the laterality of the PE). This protocol contrasts with previous use of angiography or CT angiography endpoints to terminate thrombolysis and may allow for wider adoption of CDT. In addition, our series is limited to
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patients with submassive PE, who face a unique risk to progress to complete cardiovascular compromise. Lastly, we identified prompt concordance between the EKOS catheter and standard pulmonary arterial catheters in measuring pressures, which obviated the need for repeat angiography or return to the catheterization laboratory. The current experience with standardized reduced dose USAT demonstrates safety with an efficacious rapid improvement in pulmonary hypertension and RVD in patients with acute submassive PE. Hemorrhagic complications are presumably reduced when using the current USAT treatment protocol because the dose is 25% of that used in standard systemic thrombolysis and 50% of that used in the MOPPETT trial. USAT also offers certain potential advantages, including local drug and ultrasonic energy deposition, where obstructive thrombus may limit local drug exposure to the intended target site because of flow shifts to patent vasculature. This system delivers high-frequency low-energy ultrasound during infusion, which disaggregates fibrin strands, increases permeability of the clot, and disperses the fibrinolytic drug into clot through acoustic microstreaming effects (30,31). The current experience also used a “standardized protocol,” which allows for more uniformity. Recent approval of the U.S. Food and Drug Administration for the EkoSonic Endovascular System in the pulmonary circulation may allow for further widespread experience by endovascular specialists and subsequent publication. The present study is limited by its lack of long-term follow-up and evaluation of long-term mortality. Other limitations include the lack of randomization or a comparative arm. In addition, although this standardized protocol demonstrated safety and efficacy, alternative dose protocols may be equally efficacious; however this was not evaluated in this study. The degree of clot lysis using a calculated obstructive index was not reported because we thought that changes in cathetermeasured pulmonary artery pressures and RVD were more significant measurements of success, and prior studies did not demonstrate this as an independent predictor of mortality (32). A final limitation of the standardized dose protocol is that cessation of USAT was not determined by hemodynamic assessment or imaging assessment of clot burden. Use of these parameters during treatment may more accurately dictate the thrombolytic dose and duration of USAT. In conclusion, USAT is a safe and efficacious method of treatment of submassive PE to reduce acute pulmonary hypertension and RVD. Future studies should be aimed at examining the long-term effect of USAT on mortality, exercise tolerance, and pulmonary hypertension.
REFERENCES 1. Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012; 379:1835–1846.
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2. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353:1386–1389. 3. Jerjes Sanchez C, Gutierrez-Fajardo P, Ramirez-Rivera A, et al. Acute infarct of the right ventricle secondary to a massive pulmonary thromboembolism. Arch Inst Cardiol Mex 1995; 65:65–73. 4. Becattini C, Casazza F, Forgione C, et al. Acute pulmonary embolism: external validation of an integrated risk stratification model. Chest 2013; 144:1539–1545. 5. Casazza F, Becattini C, Bongarzoni A, et al. Clinical features and short term outcomes of patients with acute pulmonary embolism. The Italian Pulmonary Embolism Registry. Thromb Res 2012; 130:847–852. 6. Ribeiro A, Lindmarker P, Johnson H, et al. Pulmonary embolism: oneyear follow-up with echocardiography Doppler and five-year survival analysis. Circulation 1999;99:1352–1330. 7. Quiroz R, Kucher N, Schoepf UJ, et al. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation 2004; 109:2401–2404. 8. Frémont B, Pacouret G, Jacobi D, et al. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients. Chest 2008; 133:358–362. 9. Schoepf UJ, Kucher N, Kipfmueller F, et al. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation 2004; 110:3276–3280. 10. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. Chest 2012; 141:e419S–e494S. 11. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism. Iliofemoral deep venous thrombosis and chronic pulmonary hypertension: A scientific statement from the American Heart Association. Circulation 2011; 123:1788–1830. 12. Fasullo S, Scalzo S, Maringhini G, et al. Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin. Am J Med Sci 2011; 341:33–39. 13. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347:1143–1150. 14. Meyer G, Vicaut E, Danays T. Fibrinolysis for patients with intermediaterisk pulmonary embolism. N Engl J Med 2014; 370:1402–1411. 15. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013; 111:273–277. 16. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding and intracranial hemorrhage: a meta-analysis. JAMA 2014; 311: 2414–2421. 17. Engelhardt TC, Taylor AJ, Simprini LA, et al. Catheter-directed ultrasound-accelerated thrombolysis for the treatment of acute pulmonary embolism. Thromb Res 2011; 128:149–154.
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18. Chamsuddin A, Nazzal L, Kang B, et al. Catheter-directed thrombolysis with the Endowave system in the treatment of acute massive pulmonary embolism: a retrospective multicenter case series. J Vasc Interv Radiol 2008; 19:372–376. 19. Lin PH, Annambhotla S, Bechara CF, et al. Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular 2009; 17:S137–S147. 20. Quintana D, Salsamendi J, Fourzali R, et al. Ultrasound-assisted thrombolysis in submassive and massive pulmonary embolism: assessment of lung obstruction before and after catheter-directed therapy. Cardiovasc Intervent Radiol 2014; 37:420–426. 21. Dumantepe M, Uyar I, Teymen B, et al. Improvements in pulmonary artery pressure and right ventricular function after ultrasound-accelerated catheter-directed thrombolysis for the treatment of pulmonary embolism. J Card Surg 2014; 29:455–463. 22. Kennedy RJ, Kenney HH, Dunfee BL. Thrombus resolution and hemodynamic recovery using ultrasound-accelerated thrombolysis in acute pulmonary embolism. J Vasc Interv Radiol 2013; 24:841–848. 23. Kuo WT, Gould MK, Louie JD, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and metaanalysis of modern techniques. J Vasc Interv Radiol 2009; 20:1431–1440. 24. Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010; 122:1124–1129. 25. Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107(23Suppl1):I9–I16. 26. Ghaye B, Ghuysen A, Bruyere PJ, et al. Can CT pulmonary angiography allow assessment of severity and prognosis in patients presenting with pulmonary embolism? What the radiologist needs to know. Radiographics 2006; 26:23–39. 27. Antman EM, Anbe DT, Armstrong PW, et al. American College of Cardiology; American Heart Association; Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with STelevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2004; 4:671–719. 28. Banovac F, Buckley DC, Kuo WT, et al. Reporting standards for endovascular treatment of pulmonary embolism. J Vasc Interv Radiol 2010; 21:44–53. 29. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014; 129:479–486. 30. Braaten JV, Goss RA, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost 1997; 78:1063–1068. 31. Francis C, Blinc A, Lee S, et al. Ultrasound accelerates transport of recombinant of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol 1995; 21:419–424. 32. Furlan A, Aghayev A, Chang CCH, et al. Short-term mortality in acute pulmonary embolism: clot burden and signs of right heart dysfunction at CT pulmonary angiography. Radiology 2012; 265:283–293.
Ultrasound-Accelerated Catheter-Directed Thrombolysis for Acute Submassive Pulmonary Embolism Sandeep Bagla, MD, John B. Smirniotopoulos, MD, Arletta van Breda, MSN, Michael J. Sheridan, ScD, and Keith M. Sterling, MD
ABSTRACT Purpose: To evaluate the safety and efficacy of ultrasound-accelerated catheter-directed thrombolysis (USAT) in patients with submassive pulmonary embolism (PE). Materials and Methods: This retrospective study comprised 45 consecutive patients (15 prospective, 30 retrospective) who underwent USAT for submassive PE from June 2012–May 2014. Inclusion criteria were right ventricular dysfunction (RVD) as indicated by right ventricle-to-left ventricle (RV:LV) ratio 4 0.9, symptoms of o 2 weeksʼ duration, and absence of absolute contraindication to thrombolysis. All patients underwent pulmonary artery catheterization with a standardized protocol (24 mg recombinant tissue plasminogen activator). Hemodynamic evaluation immediately after USAT, RV:LV ratio evaluation at 48– 72 hours after USAT by computed tomography angiography and echocardiography, and adverse event reporting for a minimum of 30 days were performed. Outcomes and complications are reported as per the Society of Interventional Radiology Reporting Standards for Endovascular Treatment of Pulmonary Embolism. Results: USAT was technically successful in 100% (n ¼ 45) of patients. Main pulmonary artery pressure significantly decreased from 49.8 mm Hg to 31.1 mm Hg (P o .0001). RVD significantly improved with mean RV:LV ratios decreasing from 1.59 to 0.93 (P o .0001). There were 6 complications: 4 minor bleeding episodes at access sites and 2 major bleeding complications (flank and arm hematoma). All-cause mortality at 30 days was 0%. There were no readmissions for PE at 30 days after discharge. Conclusions: Ultrasound-accelerated catheter-directed thrombolysis using a standardized low-dose protocol is a safe and efficacious method of treatment of submassive PE to reduce acute pulmonary hypertension and RVD.
ABBREVIATIONS CDT = catheter-directed thrombolysis, PE = pulmonary embolism, RVD = right ventricular dysfunction, RV:LV = right ventricle-toleft ventricle, USAT = ultrasound-accelerated catheter-directed thrombolysis
Pulmonary embolism (PE) is the third most common cause of cardiovascular-related death in the United States, following myocardial infarction and stroke (1).
From the Association of Alexandria Radiologists, PC (S.B., K.M.S.), Cardiovascular and Interventional Radiology Department, Inova Alexandria Hospital, 4320 Seminary Road, Alexandria, VA 22304; and Inova Health System (J.B.S., A.v.B., M.J.S.), Falls Church, Virginia. Received August 7, 2014; final revision received December 7, 2014; accepted December 10, 2014. Address correspondence to S.B.; E-mail: [email protected] K.M.S. is a paid consultant for BTG. None of the other authors have identified a conflict of interest. & SIR, 2015 J Vasc Interv Radiol 2015; 26:1001–1006 http://dx.doi.org/10.1016/j.jvir.2014.12.017
Submassive PE, which exhibits right ventricular dysfunction (RVD) without hemodynamic instability, is associated with escalation of therapy (cardiopulmonary resuscitation, intubation, vasopressor support), short- and intermediate-term mortality and chronic thromboembolic pulmonary hypertension (2–6). RVD as defined by a right ventricle-to-left ventricle (RV:LV) end-diastolic diameter ratio of greater than 0.9 is an independent predictor of mortality secondary to PE (7–9). Currently, there are no uniformly accepted recommendations for systemic thrombolysis in the treatment of submassive PE (10–12). There is growing evidence that systemic thrombolysis in submassive PE reduces hemodynamic collapse, improves RVD and decreases late onset pulmonary hypertension, however, this is at the expense of increased bleeding complications (13–16).
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USAT for Treatment of Acute Submassive PE
Studies involving catheter-directed thrombolysis (CDT) with and without ultrasound have demonstrated a significant comparative improvement with RVD and pulmonary artery pressures without increased risk of major bleeding complication (17–22). Some authors have suggested that catheter directed therapy be utilized in patients with contraindications to systemic thrombolysis as this population is at intermediate to high risk of death (23,24), however a variety of treatment algorithms were reported. We present our retrospective experience of ultrasound-accelerated catheter-directed thrombolysis (USAT) in the treatment of submassive PE using a standardized low-dose treatment protocol.
MATERIALS AND METHODS This study included 45 consecutive patients (25 men and 20 women; mean age, 56.5 y) with submassive PE treated at a single institution from June 2012–May 2014. Demographics are presented in Table 1, and risk factors for venous thromboembolism are listed in Table 2 (25). The first 15 patients were enrolled in a prospective multicenter trial (SEATTLE II [A Prospective, Single-arm, Multi-center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism], ClinicalTrials.gov Identifier: NCT01513759), and the subsequent 30 patients were retrospectively evaluated. The treatment protocol was identical for all patients. All patients signed informed consent form, and the study was performed in compliance with the Health Insurance Portability and Accountability Act with institutional review board approval of prospective and retrospective cohorts. Inclusion criteria were acute PE documented by computed tomography (CT) with symptom onset o 2 weeks, RVD indicated by an RV:LV ratio of 4 0.9 on CT angiography (26), and systemic systolic blood pressure 490 mm Hg without the need for vasopressor support. Patients were excluded if they had a contraindication to receiving thrombolytic medication (27). All patients underwent right heart and pulmonary artery catheterization with hemodynamic evaluation followed by USAT (12 h, n ¼ 3; 24 h, n ¼ 42) with a total dose of 24 mg of recombinant tissue plasminogen activator (tPA). Concomitant anticoagulation with heparin was administered with a target partial thromboplastin time of 40–60 seconds. When a single unilateral catheter (n ¼ 3) was placed, a 24-hour of infusion of 24 mg of tPA alteplase (Activase; Genentech, Inc, South San Francisco, California) was performed at a rate of 1 mg/h (24 mg in 250 mL normal saline); when bilateral catheters (n ¼ 42) were placed, a 12-hour infusion was performed via two catheters at a rate of 1 mg/h each (12 mg tPA in 250 mL normal saline for two bags). Venous access was via a transfemoral route in 3 patients and transjugular route in 42. EkoSonic Endovascular System thrombolytic infusion
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Table 1 . Demographics Baseline demographics Age, y, mean ⫾ SD
56.5 ⫾ 13.6
Body mass index, mean ⫾ SD
32.5 ⫾ 8.2
Men, n (%) Women, n (%)
25/45 20/45
(55.6%) (44.4%)
23/45 17/45
(51.1%) (37.8%)
Comorbidities and risk factors Systemic hypertension, n (%) Hyperlipidemia, n (%) Tobacco use, n (%)
7/45
(15.6%)
Diabetes mellitus, n (%) Obesity, n (%)
6/45 18/45
(13.3%) (40.0%)
Renal insufficiency (GFR o 60
17/45
(37.8%)
mL/min), n (%) Chronic obstructive pulmonary
3/45
(6.7%)
Cancer, n (%) Congestive heart failure, n (%)
8/45 0/45
(17.8%) (0.0%)
Coronary artery disease, n (%)
4/45
(8.9%)
Prior stroke, n (%) Prior deep vein thrombosis, n (%)
1/45 6/45
(2.2%) (13.3%)
Prior PE, n (%)
6/45
(13.3%)
disease, n (%)
PE severity Tachycardia 4 100 beats/min, n (%)
18/43
(41.9%)
Systolic arterial pressure, mm Hg,
135.8 ⫾ 16.3
mean ⫾ SD Diastolic arterial pressure, mm Hg,
76.8 ⫾ 10.1
mean ⫾ SD Heart rate, beats/min, mean ⫾ SD Respiratory rate, breaths/min, mean ⫾ SD Oxygen supplementation, n (%)
90.8 ⫾ 17.0 21.3 ⫾ 4.9 20/38
supplement, mean ⫾ SD Troponin test positive, n (%)
(52.6%) 97% ⫾ 2.7
Oxygen saturation during oxygen 29/43
(67.4%)
RV:LV ratio by CT, before
1.59 ⫾ 0.54
procedure, mean ⫾ SD RV:LV ratio by CT, after procedure,
0.93 ⫾ 0.17
mean ⫾ SD Bilateral main pulmonary artery embolism, n (%)
43/45
(93.3%)
Unilateral main pulmonary artery
3/45
(6.7%)
embolism, n (%) Pulmonary pressure, before
49.8 ⫾ 13.76
procedure, mm Hg, mean ⫾ SD 31.1 ⫾ 9.9
Pulmonary pressure, after procedure, mm Hg, mean ⫾ SD Hospital stay, days (range) 30-day follow-up
5.64
(2–6)
No readmissions
CT ¼ computed tomography, GFR ¼ glomerular filtration rate, PE ¼ pulmonary embolism, RV:LV ¼ right ventricle-to-left ventricle.
catheters (EKOS Corp, Bothell, Washington) were placed in all patients with the operator-dependent decision for placement of unilateral versus bilateral
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Table 2 . Risk Factors for Venous Thromboembolism by the American Heart Association (25) Strong risk factors Fracture (hip or leg), n (%) Hip or knee replacement, n (%)
2/45 1/45
(4.4%) (2.2%)
Major general surgery, n (%)
1/45
(2.2%)
Major trauma, n (%) Spinal cord injury, n (%)
0/45 0/45
(0.0%) (0.0%)
Arthroscopic knee surgery, n (%) Central venous lines, n (%)
0/45 0/45
(0.0%) (0.0%)
Chemotherapy, n (%)
0/45
(0.0%)
Congestive heart or respiratory failure, n (%)
0/45
(0.0%)
Hormone replacement therapy,
1/45
(2.2%)
n (%) Malignancy, n (%)
8/45
(17.8%)
Oral contraceptive therapy, n (%)
2/45
(4.4%)
Paralytic stroke, n (%) Pregnancy (postpartum), n (%)
0/45 0/45
(0.0%) (0.0%)
Previous venous thromboembolism,
12/45
(26.7%)
n (%) Thrombophilia, n (%)
20/45
(44.4%)
2/45 10/45
(4.4%) (22.2%)
40/45 1/45
(88.9%) (2.2%)
Obesity, n (%) Pregnancy (antepartum), n (%)
18/45 0/45
(40.0%) (0.0%)
Varicose veins, n (%)
0/45
(0.0%)
Moderate risk factors
Weak risk factors Bed rest 4 3 days, n (%) Immobility from sitting (eg, prolonged car or air travel), n (%) Age 4 40 y, n (%) Laparoscopic surgery (eg, cholecystectomy), n (%)
catheter placement based on thrombus location. Inferior vena cava filters were not placed in any of the patients at the time of the procedure. Patients underwent repeat hemodynamic evaluation immediately after USAT. Pressures were measured via the thrombolytic catheters in the following manner. The coolant and drug delivery ports were capped, the MicroSonic (EKOS Corp) ultrasound core was removed, and a pressure transducer was connected to an Intelligent Drug Delivery Catheter (EKOS Corp). The first three patients also underwent catheter exchange using fluoroscopic guidance with placement of a 5-F pigtail catheter and connection of a pressure transducer. RV:LV ratio evaluation was performed in all patients at 48–72 hours by CT angiography and echocardiography. Adverse event reporting was performed for a minimum of 30 days, and outcomes and complications were reported as per the Society of Interventional Radiology (SIR) Reporting Standards for Endovascular Treatment of Pulmonary Embolism (28). Primary study outcomes of interest were differences in main pulmonary artery pressure and RV:LV ratio before
and after the procedure. Paired t tests were employed to evaluate these differences, using SAS software (version 9.3; SAS Institute, Inc, Cary, North Carolina). P values o .05 were considered to indicate statistical significance.
RESULTS Endovascular placement of catheters and infusion were technically successful in 100% (n ¼ 45) of patients. There were no complications related to catheter placement (ie, perforation, sustained arrhythmia, dissection). Compared with baseline, main systolic pulmonary artery pressure significantly decreased from 49.8 mm to 31.1 mm, and the difference before and after the procedure was highly statistically significant (18.9 mm; 95% confidence interval, 14.9–22.8 mm, P o .0001). Complete concordance was noted in the first three patients who underwent measurements performed via the angiographic catheter and the Intelligent Drug Delivery Catheter on the EkoSonic system. In addition, RVD improved with mean RV:LV ratio decreasing from 1.59 to 0.93, being highly significant (0.66; 95% confidence interval, 0.50– 0.80, P o .0001) (Figs 1–4). There were four minor venous access site hemorrhagic complications, which did not require additional therapy. One major hemorrhagic complication (flank hematoma) occurred 3 days after cessation of USAT, which required blood transfusion; however, this was believed to be secondary to supratherapeutic anticoagulation (partial thromboplastin time 4130 s) after the cessation of thrombolysis. A second major event (forearm hematoma) occurred in a patient who underwent brachial artery puncture for arterial
Figure 1. CT angiogram depicts saddle PE (arrow) extending into the right and left main pulmonary arteries.
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Figure 4. RV:LV ratio improved to o 0.9 (right ventricle, dashed line; left ventricle, solid line), indicating resolution of RVD. Figure 2. RV:LV ratio is 2.1 (right ventricle, dashed line; left ventricle, solid line), with associated septal bowing (arrow) to the left. Findings of RVD.
Figure 3. There is improvement in the thrombus burden within the main pulmonary arteries 48 hours after thrombolysis. Only small nonobstructive distal left main pulmonary artery thrombus remains (arrow).
blood gas testing before the procedure. Surgical decompression was required. In-hospital and all-cause mortality at 30 days was 0%. The mean length of hospitalization was 5.6 days. There were no readmissions for PE at 30 days after discharge in all patients.
DISCUSSION Investigators are working to identify the ideal therapy, one with the lowest potential risk of hemorrhagic complications while decreasing RVD and subsequent
mortality, in patients presenting with submassive PE. A recently published European double-blind randomized controlled trial (14) evaluating systemic thrombolysis with a single weight-based bolus of tenecteplase ranging from 30–50 mg versus placebo in intermediate-risk PE revealed a 66% reduction in hemodynamic collapse and all-cause mortality in the tenecteplase group (2.6% vs 5.6%). However, this significant benefit was at the expense of a 4-fold increase in major bleeding and a 10-fold increase in intracranial hemorrhage in the fibrinolysis arm. In an attempt to reduce bleeding complications associated with systemic thrombolysis, the MOPPETT (Moderate Pulmonary Embolism Treated with Thrombolysis) trial (15) evaluated half-dose systemic thrombolysis with 50 mg of alteplase versus placebo. The investigators concluded that this “safe dose” thrombolysis is safe and effective in the treatment of moderate PE, with a significant immediate reduction in the pulmonary artery pressure that was maintained at 28 months. Several studies have been published evaluating the use of CDT and USAT in patients with acute massive and submassive PE (17–22). An initial report by Chamsuddin et al (18) evaluated USAT with various thrombolytics and reported a 76% rate of complete thrombus removal after a median of 24 hours without any major hemorrhagic complications. Lin et al (19) evaluated 25 patients with acute massive PE who underwent treatment with either USAT or CDT. The authors reported 100% thrombus removal in all 11 patients in the USAT group with a mean tPA dose rate of 0.86 mg/h (range, 8–28 mg) after a mean infusion time of 17.4 hours (range, 13–38 h). There were no hemorrhagic complications; however, there was a single mortality secondary to multiorgan system failure. The use of USAT
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compared favorably with the CDT group, in which only 50% of the patients had complete thrombus removal with a significantly longer thrombolytic infusion time of 26.7 hours and a hemorrhagic complication rate of 21.4%. Quintana et al (20) reported using tPA with USAT in 10 patients with acute massive or submassive PE. The median tPA dose and infusion time in their cohort was 18 mg (range, 7–38 mg) and 20.8 hours (range, 12–49 h), respectively. Cessation of thrombolysis in these three studies was determined by the adequacy of thrombus removal on repeat pulmonary angiography (18,19) or repeat CT angiography (20). Dumantepe et al (21) used one of three endpoints at the time of repeat pulmonary angiography to discontinue USAT in their group of 22 patients with either acute massive or submassive PE: no change in clot burden after 24 hours, resolution of all symptoms despite the presence of residual clot, or a decrease in the mean pulmonary arterial pressure of 50%. The authors used a mean dose of tPA of 21 mg with a range of 16–35 mg. This dose was associated with a significant decrease in RVD, pulmonary artery pressure, and obstructive index and no significant hemorrhagic complications. Kennedy et al (22) reported the use of a tPA infusion of 1 mg/h/ catheter in 54 of 60 patients with either acute massive or submassive PE. Patients underwent repeat pulmonary angiography and pulmonary artery pressure measurements, and the decision to discontinue treatment was based on improvement of baseline clinical symptoms and interval angiographic evidence of thrombolysis. The investigators used an average dose of 35.1 mg of tPA over a mean 19.6 hours of infusion time. Their study demonstrated that USAT provides an effective means of resolving clot burden and reversing hemodynamic compromise in patients with acute massive and submassive PE (22). Most recently, the ULTIMA (ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism) trial prospectively randomly assigned 59 patients with intermediate-risk PE to USAT or heparin alone. The USAT arm used a standard tPA dose of 1 mg/h via unilateral or bilateral catheters for 5 hours followed by 0.5 mg/h for 10 hours. The maximum tPA dose was 20 mg for bilateral PE and 10 mg for unilateral PE over 15 hours. The patients treated with USAT demonstrated a significant comparative improvement with RVD and pulmonary artery pressures without increased risk of major bleeding complications (29). Following the lead of the ULTIMA trial and the SEATTLE II investigators and the experience of effective results with low-dose USAT by Engelhart et al (17) and Kennedy et al (22), we sought to use a standardized protocol limiting the thrombolytic dose (24 mg tPA) and infusion time (12 h or 24 h as determined by the laterality of the PE). This protocol contrasts with previous use of angiography or CT angiography endpoints to terminate thrombolysis and may allow for wider adoption of CDT. In addition, our series is limited to
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patients with submassive PE, who face a unique risk to progress to complete cardiovascular compromise. Lastly, we identified prompt concordance between the EKOS catheter and standard pulmonary arterial catheters in measuring pressures, which obviated the need for repeat angiography or return to the catheterization laboratory. The current experience with standardized reduced dose USAT demonstrates safety with an efficacious rapid improvement in pulmonary hypertension and RVD in patients with acute submassive PE. Hemorrhagic complications are presumably reduced when using the current USAT treatment protocol because the dose is 25% of that used in standard systemic thrombolysis and 50% of that used in the MOPPETT trial. USAT also offers certain potential advantages, including local drug and ultrasonic energy deposition, where obstructive thrombus may limit local drug exposure to the intended target site because of flow shifts to patent vasculature. This system delivers high-frequency low-energy ultrasound during infusion, which disaggregates fibrin strands, increases permeability of the clot, and disperses the fibrinolytic drug into clot through acoustic microstreaming effects (30,31). The current experience also used a “standardized protocol,” which allows for more uniformity. Recent approval of the U.S. Food and Drug Administration for the EkoSonic Endovascular System in the pulmonary circulation may allow for further widespread experience by endovascular specialists and subsequent publication. The present study is limited by its lack of long-term follow-up and evaluation of long-term mortality. Other limitations include the lack of randomization or a comparative arm. In addition, although this standardized protocol demonstrated safety and efficacy, alternative dose protocols may be equally efficacious; however this was not evaluated in this study. The degree of clot lysis using a calculated obstructive index was not reported because we thought that changes in cathetermeasured pulmonary artery pressures and RVD were more significant measurements of success, and prior studies did not demonstrate this as an independent predictor of mortality (32). A final limitation of the standardized dose protocol is that cessation of USAT was not determined by hemodynamic assessment or imaging assessment of clot burden. Use of these parameters during treatment may more accurately dictate the thrombolytic dose and duration of USAT. In conclusion, USAT is a safe and efficacious method of treatment of submassive PE to reduce acute pulmonary hypertension and RVD. Future studies should be aimed at examining the long-term effect of USAT on mortality, exercise tolerance, and pulmonary hypertension.
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