Author + information
- Received April 17, 2015
- Accepted April 23, 2015
- Published online August 24, 2015.
- Gregory Piazza, MD, MS1,∗ (, )
- Benjamin Hohlfelder, PharmD1,
- Michael R. Jaff, DO2,
- Kenneth Ouriel, MD3,
- Tod C. Engelhardt, MD4,
- Keith M. Sterling, MD5,
- Noah J. Jones, MD6,
- John C. Gurley, MD7,
- Rohit Bhatheja, MD8,
- Robert J. Kennedy, MD9,
- Nilesh Goswami, MD10,
- Kannan Natarajan, MD11,
- John Rundback, MD12,
- Immad R. Sadiq, MD13,
- Stephen K. Liu, MD14,
- Narinder Bhalla, MD15,
- M. Laiq Raja, MD16,
- Barry S. Weinstock, MD17,
- Jacob Cynamon, MD18,
- Fakhir F. Elmasri, MD19,
- Mark J. Garcia, MD20,
- Mark Kumar, MD21,
- Juan Ayerdi, MD22,
- Peter Soukas, MD23,
- William Kuo, MD24,
- Ping-Yu Liu, PhD25,
- Samuel Z. Goldhaber, MD2,
- SEATTLE II Investigators
- 1Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- 2Cardiovascular Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- 3Syntactx, New York, New York
- 4East Jefferson General Hospital, Metairie, Louisiana
- 5Cardiovascular and Interventional Associates, INOVA Alexandria Hospital, Alexandra, Virginia
- 6Mt. Carmel East Hospital, Columbus, Ohio
- 7Gill Heart Institute, University of Kentucky, Lexington, Kentucky
- 8Florida Heart Group, Florida Hospital, Orlando, Florida
- 9Holmes Regional Medical Center, Melbourne, Florida
- 10Prairie Heart Institute, St. John’s Hospital, Springfield, Illinois
- 11St. Vincent Medical Group, Indianapolis, Indiana
- 12Holy Name Medical Center, Teaneck, New Jersey
- 13Vascular Medicine Division, Hartford Hospital, Hartford, Connecticut
- 14Lifelink Interventional Center, Memorial Medical Center, Modesto, California
- 15River Region Cardiology Associates, Baptist Medical Center, Montgomery, Alabama
- 16El Paso Cardiology Associates, PA, Providence Memorial Hospital and Sierra Medical Hospital, El Paso, Texas
- 17Leesburg Regional Medical Center, Leesburg, Florida
- 18Division of Vascular Intervention Radiology, Department of Radiology, Montefiore Medical Center, Bronx, New York
- 19Radiology and Imaging Specialists of Lakeland, Lakeland Regional Medical Center, Lakeland, Florida
- 20Christiana Care Center for Heart and Vascular Health, Newark, Delaware
- 21The Cardiovascular Care Group, Overlook Medical Center, Summit, New Jersey
- 22Macon Cardiovascular Institute, Medical Center of Georgia, Macon, Georgia
- 23Miriam Cardiology Inc., The Miriam Hospital, Providence, Rhode Island
- 24Stanford University, Stanford, California
- 25Fred Hutchinson Cancer Center, Seattle, Washington
- ↵∗Reprint requests and correspondence:
Dr. Gregory Piazza, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115.
Objectives This study conducted a prospective, single-arm, multicenter trial to evaluate the safety and efficacy of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, using the EkoSonic Endovascular System (EKOS, Bothell, Washington).
Background Systemic fibrinolysis for acute pulmonary embolism (PE) reduces cardiovascular collapse but causes hemorrhagic stroke at a rate exceeding 2%.
Methods Eligible patients had a proximal PE and a right ventricular (RV)-to-left ventricular (LV) diameter ratio ≥0.9 on chest computed tomography (CT). We included 150 patients with acute massive (n = 31) or submassive (n = 119) PE. We used 24 mg of tissue-plasminogen activator (t-PA) administered either as 1 mg/h for 24 h with a unilateral catheter or 1 mg/h/catheter for 12 h with bilateral catheters. The primary safety outcome was major bleeding within 72 h of procedure initiation. The primary efficacy outcome was the change in the chest CT–measured RV/LV diameter ratio within 48 h of procedure initiation.
Results Mean RV/LV diameter ratio decreased from baseline to 48 h post-procedure (1.55 vs. 1.13; mean difference, −0.42; p < 0.0001). Mean pulmonary artery systolic pressure (51.4 mm Hg vs. 36.9 mm Hg; p < 0.0001) and modified Miller Index score (22.5 vs. 15.8; p < 0.0001) also decreased post-procedure. One GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries)–defined severe bleed (groin hematoma with transient hypotension) and 16 GUSTO-defined moderate bleeding events occurred in 15 patients (10%). No patient experienced intracranial hemorrhage.
Conclusions Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE. (A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (PE) [SEATTLE II]; NCT01513759)
- catheter embolectomy
- catheter thrombolysis
- pulmonary embolism
- right ventricular failure
The Surgeon General estimates that 100,000 to 180,000 deaths occur annually from pulmonary embolism (PE) in the United States (1). Advanced therapies, such as systemic fibrinolysis and embolectomy, have the potential to reduce right ventricular (RV) pressure overload in massive (2) and submassive PE (3,4) and lower mortality by reversing pulmonary arterial obstruction and RV failure.
In the largest study of full-dose systemic fibrinolysis, tenecteplase reduced the risk of death or cardiovascular collapse by 56% in 1,006 submassive PE patients (5). However, this benefit was offset by a nearly 5-fold increased risk of major bleeding and a 10-fold increased risk of hemorrhagic stroke. Meta-analyses of trials of systemic fibrinolysis for acute PE have demonstrated similar findings (6,7).
Concern over the risk of intracranial hemorrhage, which approaches 3% to 5% outside of clinical trials (8,9), has dampened clinician enthusiasm for full-dose systemic fibrinolysis and has sparked development of alternative advanced therapies with lower bleeding risk. Pharmacomechanical catheter-directed therapy combines fibrinolytic therapy with mechanical disruption of the thrombus (10–12). The high-frequency, low-power ultrasound component of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis is hypothesized to disaggregate fibrin fibers, potentially allowing greater penetration of the fibrinolytic agent (13). This therapeutic strategy requires only a fraction of the systemic fibrinolytic dose. This dose reduction might improve the safety of fibrinolysis for PE. In a randomized, controlled trial of 59 patients with submassive PE in Europe, there were no major bleeding complications with ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, which rapidly improved RV function compared with anticoagulation alone (14).
To expand our understanding of the efficacy and safety of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis to reverse RV dysfunction in acute massive or submassive PE, we conducted a prospective, single-arm, multicenter trial (Central Illustration) (NCT01513759).
From June 2012 to February 2013, we screened 159 hospitalized patients with acute massive or submassive PE and enrolled 150 in this prospective, single-arm trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis (Figure 1). Study patients were recruited at 22 sites across the United States, including urban, nonurban, teaching, and nonteaching hospitals. Institutional review board approval was obtained at all sites, and written informed consent was obtained for every patient. The results of this prospective, single-arm, multicenter trial were presented in abstract form on March 30, 2014, at the American College of Cardiology Annual Scientific Sessions in Washington, DC. The trial was designed and led by an Executive Committee (G.P. and S.Z.G.) from the Study Coordinating Center. The Executive Committee established the data analysis plan and participated in the statistical analysis.
Patients were potentially eligible to participate if they had a proximal PE (filling defect in at least 1 main or lobar pulmonary artery), age 18 years or older, PE symptom duration ≤14 days, and RV/LV diameter ratio ≥0.9 on contrast-enhanced chest computed tomography (CT). We included patients with massive (defined as syncope, systemic arterial hypotension, cardiogenic shock, or resuscitated cardiac arrest) or submassive (defined as a normotensive patient with PE and evidence of RV dysfunction) PE. Major exclusion criteria were stroke or transient ischemic attack, head trauma, or other active intracranial or intraspinal disease within 12 months; major surgery within 7 days; recent active bleeding from a major organ; hematocrit <30%; platelets <100,000/μl; International Normalized Ratio >3; serum creatinine >2 mg/dl; and systolic blood pressure <80 mm Hg despite vasopressor or inotropic support (Online Appendix). Obesity was defined as a clinical diagnosis of obesity in the medical record.
Anticoagulation was initiated with full-dose intravenous unfractionated heparin with a target activated partial thromboplastin time of 60 to 80 s. For patients who had already received low-molecular weight heparin or fondaparinux, the initiation of intravenous unfractionated heparin was delayed by 12 h. After completion of the procedure, all subjects received full anticoagulation. The drug, dose, frequency, and duration of anticoagulation were selected by the attending physician.
Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis
The EkoSonic Endovascular System (EKOS, Bothell, Washington) comprises 3 components: the Intelligent Drug Delivery Catheter, a removable MicroSonic device, and a reusable EkoSonic control unit. The procedure was performed by an experienced operator from Interventional Cardiology, Interventional Radiology, Vascular Surgery, or Cardiothoracic Surgery. Venous access was obtained, most often with ultrasound guidance, via the common femoral or internal jugular vein. After catheter placement but before activation of ultrasound and infusion of fibrinolytic therapy, baseline right heart pressures were transduced through the catheters. Because the catheters are placed in or adjacent to the PE, the fibrinolytic agent is delivered directly to the thrombus.
The fixed-dose regimen of tissue-plasminogen activator (t-PA) (Genentech, South San Francisco, California) was 24 mg at 1 mg/h with saline coolant at 35 ml/h for both unilateral and bilateral PEs. The fibrinolytic agent is not infused under pressure, but rather drips out of microscopic side holes. For patients with predominantly unilateral PE, a single continuous catheter-directed pulmonary artery infusion of t-PA was used for 24 h. For patients with bilateral PE, 2 drug delivery devices were placed, and a continuous infusion of t-PA was administered in each catheter for 12 h. No adjunctive interventional techniques to assist thrombus removal or dissolution were permitted. During the procedure, intravenous unfractionated heparin was continued at intermediate intensity with a target aPTT of 40 to 60 s. After removal of the drug delivery device(s), the access site was manually compressed for at least 5 min. Fifteen minutes after achieving hemostasis, full therapeutic anticoagulation was restarted.
After completion of the procedure but before catheter removal, right heart pressures were measured. Right heart pressure measurements were transduced once before activation of ultrasound and infusion of fibrinolytic therapy and once after completion of the procedure. The post-procedure invasive hemodynamic assessment was performed at either 12 or 24 h after the initiation of fibrinolysis. In the 86% of patients with bilateral PEs who underwent ultrasound-facilitated, catheter-directed, low-dose fibrinolysis via bilateral catheters, the post-procedure hemodynamic assessment was performed at 12 h after initiation of the procedure, before catheter removal. For the remaining patients who had unilateral ultrasound-facilitated, catheter-directed, low-dose fibrinolysis via a single catheter, the post-procedure hemodynamic assessment was performed at 24 h after initiation of the procedure, before catheter removal. Multiple right heart pressure measurements or “averaging” values were not allowed for assessment of baseline and post-procedure pressures. Follow-up contrast-enhanced chest CT and transthoracic echocardiography were performed within 48 ± 6 h after initiation of the procedure. The changes in the RV/LV diameter ratio and modified Miller angiographic obstruction index score (15) were assessed by the contrast-enhanced chest CT performed at baseline and at 48 h. The maximal modified Miller Index score is 40, corresponding with occlusion of all pulmonary artery segments. Echocardiography was performed to estimate pulmonary artery systolic pressure at 48 ± 6 h. All CT scans and echocardiograms were analyzed at a dedicated, blinded imaging core laboratory (Syntactx, New York, New York).
Bleeding complications were assessed for 72 h after the procedure. Patients were assessed clinically for recurrent, symptomatic PE at 30 days after the procedure. Recurrent PE was defined as symptomatic and objectively confirmed with contrast-enhanced chest CT, ventilation-perfusion lung scanning, or invasive contrast pulmonary angiography. Overall, 149 of 150 patients (99.3%) completed the required clinical follow-up.
The primary efficacy outcome was the core laboratory–measured change in the RV/LV diameter ratio from baseline, as assessed by contrast-enhanced chest CT at baseline and at 48 ± 6 h after initiation of procedure (16). A secondary efficacy outcome was the change in pulmonary artery systolic pressure, as assessed by baseline right heart catheterization compared with measurements obtained at the conclusion of the procedure and as estimated by transthoracic echocardiography at 48 h. An additional secondary outcome was the change in the modified Miller angiographic obstruction index score, as assessed by the baseline contrast-enhanced chest CT and the follow-up scan performed at 48 h.
The primary safety outcome was major bleeding within 72 h of initiation of the procedure. Bleeding events were classified by the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) bleeding criteria (Online Appendix) (17). Severe or life-threatening bleeding was defined as either intracranial hemorrhage or bleeding that caused hemodynamic compromise and required intervention. Moderate bleeding required blood transfusion but did not result in hemodynamic compromise. Mild bleeding did not meet criteria for either severe/life-threatening or moderate bleeding. We defined major bleeding as either a GUSTO moderate or a GUSTO severe/life-threatening bleeding event. All monitoring for major bleeding within 72 h was performed during the hospitalization.
The secondary safety outcomes included symptomatic recurrent PE up to 30 days after the initiation of the procedure, all-cause mortality at hospital discharge and through 30 days, and technical procedural complications. Mortality was further classified as related to cancer, myocardial infarction, PE, or other causes. Death was attributed to PE if it was either sudden or unsuspected or if there was evidence to support an association with PE. All safety outcomes, including bleeding complications, were adjudicated by a designated independent Study Safety Monitor (M.R.J.).
We estimated that at 48 h after the procedure, there would be at least a 0.27 mean decrease from baseline in the RV/LV diameter ratio, based on a study that compared RV/LV diameter ratios at baseline and after reperfusion in patients undergoing systemic fibrinolysis or surgical pulmonary embolectomy for acute PE (18). A 20% decrease in the RV/LV diameter ratio was observed in a previous systemic fibrinolysis study (19) and served as the basis for our sample size estimate. With recruitment of 118 evaluable subjects in our present study, the power was ∼0.89 to detect a >0.2 mean RV/LV diameter ratio decrease, with a SD of 0.24, at a 2-sided p < 0.05 significance level by t test.
Results for continuous variables were compared with baseline using a paired t test or Wilcoxon signed rank test. For 2-group comparisons, a 2-sample t test or Wilcoxon rank sum test was used for continuous data, and the Fisher exact test was used for binary data. All reported p values were 2-sided, and a p value <0.05 was considered statistically significant. An intercept-only mixed model repeated measures analysis was conducted with change in RV/LV diameter ratio as the dependent variable and study site (n = 22) fitted as a random effect to assess the variance in the change in RV/LV diameter ratio across the study sites. All statistical analyses were performed using SAS statistical software version 9.2 (SAS Institute, Cary, North Carolina).
Role of funding
The sponsor had no role in data interpretation or writing the manuscript. G.P. and S.Z.G. had full access to the data and had final responsibility for the decision to submit for publication. The sponsor of the trial was in possession of the database.
Baseline demographics and clinical characteristics
The mean age was 59 years (Table 1). The mean body mass index (35.6 kg/m2) was consistent with an obese patient population. Common risk factors for PE included obesity (55%), immobility within 30 days of PE diagnosis (30%), family history of venous thromboembolism (21%), and personal history of deep vein thrombosis (DVT) (20%) or PE (10%). Mean serum creatinine was 1.0 mg/dl.
Characteristics of a PE
All patients had symptomatic PEs (Table 2). The duration of PE symptoms was 14 days or less, with the exception of a single patient who was subsequently found to have symptoms for more than 14 days. Submassive PE and massive PE were observed in 79% and 21% of patients, respectively.
The mean total dose of t-PA was 24 mg (Table 3). Of 285 devices that were attempted to be placed, 98% were successfully placed. Right femoral venous access was most frequently used for device placement (64%). Ultrasound guidance was used in 73% of vascular access procedures for catheter placement. Bilateral devices were placed in 86% of patients. Bilateral catheters to treat bilateral PE were placed through a single-access site in the majority of patients (57%).
Thirty-five patients did not have follow-up chest CT performed within the 48 ± 6-h window. The mean RV/LV diameter ratio decreased from 1.55 at baseline to 1.13 at 48 ± 6 h after initiation of the procedure (mean difference, −0.42; p < 0.0001) (Table 4, Figure 2). Invasively measured mean pulmonary artery systolic pressure decreased from 51.4 mm Hg at baseline to 37.5 mm Hg at the completion of the procedure (mean difference, −14 mm Hg; p < 0.0001). The decrease in mean pulmonary artery systolic pressure was sustained from baseline to 48 ± 6 h, as estimated by transthoracic echocardiography (51.4 mm Hg vs. 36.9 mm Hg; mean difference, −14.4; p < 0.0001). Mean modified Miller angiographic obstruction index score decreased from 22.5 at baseline to 15.8 at 48 ± 6 h (mean difference, −6.6; p < 0.0001).
An analysis was conducted to determine whether there was any difference in the change in RV/LV diameter ratio between patients who had a follow-up CT scan performed with the 48 ± 6-h window and those who had a follow-up CT scan performed but it fell outside of the 48 ± 6-h window. There was no difference in the change in RV/LV diameter ratio in patients who had a follow-up CT scan performed within the 48 ± 6-h window and those who had a follow-up CT scan performed but it fell outside of the 48 ± 6-h window (mean percentage of change, −24% vs. −29%; p = 0.29). Similarly, there was no difference in the change in pulmonary artery systolic pressure in patients who had follow-up echocardiography performed within the 48 ± 6-h window and those who had echocardiography performed outside of the 48 ± 6-h window (mean percentage of change, −14.4 mm Hg vs. −17.5 mm Hg; p = 0.24).
A random-effects model analysis was performed to assess whether there was significant variance in the change in RV/LV diameter ratio according to study site. There was no indication of significant study site variance (p = 0.24), and the 2-sided p value for comparing the mean change in RV/LV diameter ratio with the pre-specified control value of −0.2 remained significant (p < 0.0001).
Three patients died while hospitalized, and 1 patient died after hospital discharge within 30 days of the procedure (Table 5). One patient died of massive PE before the procedure could be completed; 1 patient changed her code status and elected to receive hospice care after multisystem organ failure developed during a prolonged admission; 1 patient died of sepsis unrelated to the procedure; and 1 patient died of PE resulting in progressive respiratory failure. The patient who died before the procedure could be completed was a 61-year-old woman with diabetes, obesity, and recent infectious illness who presented hemodynamically stable with acute bilateral PEs to a local medical center and was started on heparin. Her initial RV/LV diameter ratio was 1.68, and her modified Miller Index score was 30. The following day, she was transferred to another medical center and enrolled in the SEATTLE II study. While the left infusion catheter was being placed, respiratory failure developed and the patient was intubated. She subsequently became bradycardic, experienced cardiac arrest, and could not be resuscitated.
Few serious adverse events were adjudicated to either the device (2%) or t-PA (1.3%). No patient experienced intracranial hemorrhage. There were 17 major bleeding events within 30 days of the procedure observed in 15 patients (10%) (Table 5). All but 1 took place within 72 h of the procedure. One of these major bleeding events was a GUSTO severe/life-threatening hemorrhage (a right groin vascular access site hematoma with transient hypotension requiring vasopressor support). The remainder (94%) were GUSTO moderate bleeds, 3 of which were related to vascular access (Table 6). Immobility within 30 days of PE diagnosis (57.1% vs. 27.8%, p = 0.03), recent trauma (21.4% vs. 3.7%, p = 0.03), and multiple vascular access attempts (25.9% vs. 4.0%, p < 0.001) were more frequent in patients with major bleeding compared with those who did not have major bleeding.
There was no significant difference in the proportion of major bleeding within 72 h of the procedure across the 22 study sites (p = 0.91).
Massive versus submassive PE
The decrease in mean RV/LV diameter ratio from baseline to 48 ± 6 h was similar in massive and submassive PE patients (−0.51 vs. −0.43, p = 0.31). Likewise, the decrease in mean pulmonary artery systolic pressure from baseline to procedure completion (−12.6 vs. −14.3, p = 0.61) and from baseline to 48 ± 6 h (−14.2 vs. −15.0, p = 0.81) was also similar in massive and submassive PE patients. Massive PE patients were more likely to experience major bleeding than submassive PE patients (23% vs. 7%, p = 0.02).
In our study, ultrasound-facilitated, catheter-directed, low-dose fibrinolysis resulted in no episodes of intracranial hemorrhage. We observed a 25% decrease in CT-measured RV/LV diameter ratio over 48 h, a 30% decrease in pulmonary arterial systolic pressure by the end of the procedure, and a 30% decrease in pulmonary artery angiographic obstruction over 48 h.
Systemic full-dose fibrinolysis has been the most extensively studied advanced therapy for patients with acute massive and submassive PE. However, its use even in the highest risk patients has decreased over the past 2 decades (20), presumably due to the high rate of intracranial hemorrhage. Clinical practice guidelines recommend against the use of full-dose systemic fibrinolytic therapy for acute submassive PE in all but the lowest bleeding risk patients (21–23).
The desire to reduce RV pressure overload and to minimize the risk of adverse outcomes, such as intracranial hemorrhage, spurred exploration of alternative lower-dose fibrinolytic strategies, including half-dose systemic fibrinolysis (24,25) and catheter-based pharmacomechanical therapy (26). In the European ULTIMA (Ultrasound Accelerated Thrombolysis of Pulmonary Embolism) trial of 59 patients with submassive PE, ultrasound-facilitated, catheter-directed, low-dose fibrinolysis plus anticoagulation improved RV function from baseline to 24 h to a greater extent than anticoagulation alone without causing major bleeding (14). Although both trials used the same equipment, the ULTIMA study used a slightly lower dose of t-PA (20 mg) than the current study (24 mg). The ULTIMA study evaluated the procedure in 30 patients with submassive PE, whereas the current study included 150 patients with submassive or massive PE. The difference in the definitions of major bleeding between the 2 trials may partly explain the variation in major bleeding with ultrasound-facilitated, catheter-directed, low-dose fibrinolysis (0% in the ULTIMA study vs. 10% in the current study). In contrast to the ULTIMA study, the current study also included massive PE patients who were more likely to experience major bleeding than those with submassive PE. Our study expands the experience of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis in patients with massive and submassive PE and demonstrates the potential of this technique. On May 21, 2014, based on the data from our trial and previous studies, the U.S. Food and Drug Administration approved the EkoSonic Endovascular System for treatment of PE (27).
Increased RV/LV diameter ratio is a reproducible and well-validated tool for identifying PE patients at risk of adverse outcomes, in particular, increased 30-day mortality (28). Although a decrease in RV/LV diameter ratio is an important surrogate marker for the efficacy of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis, the need for trials with clinical endpoints remains important (29). Clinical outcomes such as hemodynamic collapse, quality of life (30,31), and mortality will help guide the use of this technology.
Study limitations and strengths
The major limitation of our study was the lack of a comparator group. Because we did not include a comparator group, we cannot comment on the efficacy or safety of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis compared with full-dose systemic fibrinolysis, half-dose systemic fibrinolysis, or anticoagulation alone.
Another potential comparator was catheter-directed, low-dose fibrinolysis without the ultrasound turned “on.” A study evaluated the impact of ultrasound on catheter-directed, low-dose fibrinolysis for acute DVT and did not demonstrate that ultrasound bolstered efficacy (32). However, these findings in patients with DVT cannot be extrapolated to acute PE because PE thrombus is more acute, less organized, and less fibrotic than DVT.
An important statistical limitation relates to a subset of patients who did not undergo follow-up chest CT for assessment of RV/LV diameter ratio or echocardiography for estimation of pulmonary artery systolic pressure within the pre-specified 48 ± 6-h window. Missing data could have biased the results in favor of a greater treatment benefit by removing patients with a complicated post-procedure clinical course and limited improvement in our study outcomes. Alternatively, they or their physicians may have canceled follow-up imaging because they had excellent clinical improvement. We conducted an analysis to explore the possibility of important differences between the patients with and without missing follow-up imaging data. We observed no difference in baseline demographic, clinical characteristics, comorbid conditions, PE duration or subtype, anticoagulation, procedural characteristics, length of stay, or in-hospital mortality. Furthermore, we observed no difference in the change in RV/LV diameter ratio in patients who had a follow-up CT scan performed within the 48 ± 6-h window and those who had a follow-up CT scan performed but it fell outside of the 48 ± 6-h window.
In summary, we created a precise protocol for ultrasound-facilitated, catheter-directed, low-dose fibrinolysis with t-PA. Previously, there was no standardized approach. Our simplified study design facilitated expeditious enrollment of 150 patients within 9 months. One-half of the study population was female. The population was also racially and ethnically diverse, with substantial representation of African-American and Hispanic/Latino patients. We emphasized safety by using a definition of major bleeding (combining GUSTO severe/life-threatening and GUSTO moderate bleeds) that would capture a greater number of clinically relevant bleeding events.
Future areas of investigation
Future considerations include determining which patients among those with hemodynamically stable PE are optimal candidates for ultrasound-facilitated, catheter-directed, low-dose fibrinolysis. Clinical studies with comparator groups of anticoagulation alone, systemic fibrinolysis, or other catheter-based techniques will be critical in defining how ultrasound-facilitated, catheter-directed, low-dose fibrinolysis should be used in patients with acute PE. Strategies to reduce major bleeding related to the procedure should also be evaluated. Health economics and outcomes research will be critical for determining appropriate use of this technology.
Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis improved RV function in acute PE, decreased pulmonary artery angiographic obstruction, reduced pulmonary artery systolic pressure, and did not result in intracranial hemorrhage. Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis has the potential to improve outcomes and change treatment algorithms in higher risk PE patients.
WHAT IS KNOWN? Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive PE improved RV function, decreased pulmonary artery angiographic obstruction, and reduced pulmonary hypertension.
WHAT IS NEW? The discussion of advanced therapies for patients with massive or submassive PE should include the option of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis at medical centers with experience in the appropriate patient selection, performance of the procedure, and post-procedure care.
WHAT IS NEXT? Although ultrasound-facilitated, catheter-directed, low-dose fibrinolysis appeared to improve short-term, surrogate outcomes, subsequent studies focused on clinical and longer term outcomes will provide a better understanding of the optimal use of this therapy for acute PE. Subsequent studies with comparator groups of anticoagulation alone, systemic fibrinolysis, or other catheter-based techniques will be critical in defining how ultrasound-facilitated, catheter-directed, low-dose fibrinolysis should be applied to patients with acute PE.
For supplemental material, please see the online version of this article.
This study was funded by a research grant from EKOS, a BTG International group company. Dr. Piazza receives research support from EKOS, Bristol-Myers Squibb, Daiichi-Sankyo, and Janssen. Dr. Jaff is a noncompensated member of the Data Safety and Monitoring Board of EKOS and a Board member of VIVA Physicians, a 501(c)(3) not-for-profit education and research organization. Dr. Ouriel holds equity in and is an employee of Syntactx, which receives fees for core laboratory activities from EKOS. Dr. Jones receives honoraria for serving on the Speaker Bureau of Medtronic and EKOS; and receives consulting fees from Cordis. Drs. Engelhardt, Sterling, Gurley, Bhatheja, Kennedy, Goswami, Natarajan, Rundback, Sadiq, S.K. Liu, Bhalla, Raja, Weinstock, Cynamon, Elmasri, Garcia, Kumar, Ayerdi, Soukas, Kuo, and Goldhaber has received research support from EKOS, a BTG International Group company. Dr. P.-Y. Liu receives consulting fees from EKOS. Dr. Bhatheja is a speaker for St. Jude Medical and Cardiovascular Systems Inc. Dr. Goswami is a consultant for Boston Scientific. Dr. Gurley is a speaker for EKOS. Dr. Weinstock is a consultant for W.L. Gore. Dr. Hohfelder has reported that he has no relationships relevant to the contents of this paper to disclose.
The results of this prospective, single-arm, multicenter trial were presented in abstract form on March 30, 2014 at the American College of Cardiology Annual Scientific Sessions in Washington, DC.
- Abbreviations and Acronyms
- computed tomography
- deep vein thrombosis
- pulmonary embolism
- right ventricular
- right ventricular-to-left ventricular
- tissue-plasminogen activator
- Received April 17, 2015.
- Accepted April 23, 2015.
- American College of Cardiology Foundation
- ↵The surgeon general's call to action to prevent deep vein thrombosis and pulmonary embolism. U.S. Department of Health and Human Services. 2008. Available at: www.ncbi.nlm.nih.gov/books/NBK44178/. Accessed September 21, 2014.
- Kucher N.,
- Goldhaber S.Z.
- Piazza G.,
- Goldhaber S.Z.
- Marti C.,
- John G.,
- Konstantinides S.,
- et al.
- Kucher N.,
- Boekstegers P.,
- Muller O.,
- et al.
- Schoepf U.J.,
- Kucher N.,
- Kipfmueller F.,
- Quiroz R.,
- Costello P.,
- Goldhaber S.Z.
- Kipfmueller F.,
- Quiroz R.,
- Goldhaber S.Z.,
- Schoepf U.J.,
- Costello P.,
- Kucher N.
- Jaff M.R.,
- McMurtry M.S.,
- Archer S.L.,
- et al.
- Konstantinides S.V.,
- Torbicki A.,
- Agnelli G.,
- et al.
- ↵EkoSonic® Endovascular System receives FDA Clearance for the Treatment of Pulmonary Embolism in the USA. Cath Lab Digest. Available at: http://www.cathlabdigest.com/EkoSonic%C2%AE-Endovascular-System-receives-FDA-Clearance-Treatment-Pulmonary-Embolism-USA. Accessed June 27, 2015.
- Weinberg I.,
- Jaff M.R.
- Engelberger R.P.,
- Spirk D.,
- Willenberg T.,
- et al.