The optimal treatment for intermediate-risk pulmonary embolism (PE) remains unclear. Our goal was to describe the safety and efficacy of the EkoSonic ultrasound-assisted catheter-directed thrombolysis system (EKOS Corporation, Bothell, Washington) in a real-world registry of patients with intermediate-risk PE. Fifty-three consecutive patients with intermediate-risk PE treated with ultrasound-assisted catheter-directed thrombolysis at Brigham and Women’s Hospital from 2010 to 2014 were analyzed. The primary outcome was a change in directly measured pulmonary artery pressures as assessed using logistic regression with generalized estimating equations to account for serial measurements. Patients received an average of 24.6 ± 9 mg of alteplase using the EKOS catheter with an average treatment time of 15.9 ± 3 hours. After treatment, there was a 7.2- and a 11.4-mm Hg reduction in mean and systolic pulmonary artery pressure (95% confidence interval 4.7 to 9.7 mm Hg, p <0.001, and 95% confidence interval 7.8 to 15.0 mm Hg, p <0.001), respectively. In this cohort, 9.4% had any bleeding complication noted during their hospital stay. One patient’s alteplase was prematurely discontinued for access site bleeding although no other interventions were required related to bleeding complications.
Of patients diagnosed with pulmonary embolism (PE), 40% have evidence of right-sided cardiac strain without hemodynamic collapse —often referred to as intermediate-risk or submassive PE. Estimates of all-cause inhospital mortality for such patients range from 2% to 3% in contemporary series although mortality rates up to 8% have been observed in the setting of positive cardiac biomarkers. Although the appropriate treatment for these patients remains uncertain, there is growing interest in developing therapies that maybe more effective than standard anticoagulation. A large trial of systemic tenecteplase versus standard anticoagulation demonstrated a significant reduction in the risk of hemodynamic collapse and progression to massive PE in the thrombolytic arm, but this came at the expense of significantly more bleeding events including major bleeds. Catheter-directed thrombolysis has the advantage of delivering smaller total doses of thrombolytic therapy in a more concentrated manner directly to the effected vessel. The EkoSonic catheter (EKOS Corporation, Bothell, Washington) is a catheter-directed thrombolytic system that also emits intravascular ultrasound to facilitate thrombolysis. A randomized controlled trial of EKOS thrombolysis plus anticoagulation versus anticoagulation alone demonstrated good early efficacy and an excellent safety profile albeit in a small number of patients. However, patients enrolled in randomized trials tend to be highly selected. We therefore sought to analyze and report on the safety and efficacy of the EKOS ultrasound-assisted catheter-directed thrombolysis system in a real-world population of patients with intermediate-risk PE.
Methods
The analytic cohort comprised 53 consecutive patients who received ultrasound-assisted catheter-directed thrombolysis plus anticoagulation for an intermediate-risk PE at Brigham and Women’s Hospital from November 2010 through February 2014. Intermediate-risk patients were defined by hemodynamic stability with evidence of right ventricular (RV) strain or failure by transthoracic echocardiography or computed tomography (CT). Elevated cardiac biomarkers (e.g., troponin) were not required for treatment but were frequently considered when determining treatment strategy. Per protocol, all patients had had symptoms for <14 days at the time of their procedure. (Patients with symptoms for >2 weeks were not offered the therapy.) Patients with perceived or relative contraindications to thrombolytics, such as active bleeding, recent major surgical procedures, and intracerebral malignancies or metastases, were treated or declined for treatment at the discretion of the consulting interventional cardiologist.
EkoSonic ultrasound-accelerated infusion catheters were all placed through the internal jugular vein in the cardiac catheterization laboratory after pulmonary artery pressure measurements and bilateral pulmonary angiography. One or two EKOS catheters were placed as dictated by the location and volume of pulmonary emboli seen on the angiogram at the operator’s discretion. In most cases, the catheters were positioned in the lateral or posterior basal segmental arteries. When bilateral treatment was required, both catheters were positioned through a single 12Fr Fast-Cath Duo sheath (St. Jude Medical, Minnetonka, Minnesota). After placement, a small (average 2 ± 1.4 mg) bolus of alteplase was delivered per EKOS catheter followed by a constant infusion of alteplase at a rate of 0.75 to 2 mg/hour/strand for an intended goal of approximately 20 mg of total alteplase. Infusion rates were adjusted such that the target dose would be reached during standard working hours the following day to facilitate prompt device removal once complete. During alteplase infusion, the patients also received intravenous unfractionated heparin for a goal partial thromboplastin time of 40 to 60. After the treatment period, pulmonary artery pressures were again transduced through the infusion catheters before removal. After removal of the EKOS catheters, all patients received intravenous unfractionated heparin for a goal partial thromboplastin time of 60 to 80 followed by transition to a long-term anticoagulation strategy dictated by the treating physician.
All data were obtained from the medical records. Hemodynamic data were collected prospectively. Measures of RV function were collected from echocardiographic and CT reports. All pre- and post-EKOS echocardiographic parameters were measured and analyzed retrospectively (JMM and PHH) on the basis of the captured images available. The primary end points of interest were changes in mean and systolic pulmonary artery pressures and inhospital bleeding complications. The change in pulmonary artery pressures were defined as the differences in directly measured pressures pre-EKOS therapy as compared with pressures measured directly after cessation of EKOS therapy.
Simple comparisons of normally and nonnormally distributed data were performed using the Student t test and Wilcoxon rank sum test, respectively. We used generalized estimating equations for analyses of effect comparing pre- and post-EKOS outcomes while accounting for nested time series measures per patient. All analyses were performed with Stata version 11 (StataCorp, College Station, Texas). Data are presented as means ± standard deviation or median and twenty-fifth and seventy-fifth interquartile range. This project was approved by the Partners Healthcare Institutional Review Board.
Results
Fifty-three patients with intermediate-risk PE underwent treatment with the EKOS ultrasound-assisted catheter-directed thrombolysis system and form our analytic cohort. As demonstrated in Table 1 , 15% of patients had active cancer and 11% had had a previous PE. Eight of the 53 patients were in the hospital for other conditions at the time of diagnosis of PE. Additionally, our cohort was generally hemodynamically stable. The average PE Severity Index (PESI) score of 74 reflects that most patients were in the intermediate-risk category for 30-day mortality. Fifty-eight percent of patients had evidence of moderate or severe RV dysfunction. Nine patients (17%) had undergone surgery in the previous 14 days for breast lumpectomy, gastric banding, cesarean section, total abdominal hysterectomy and bilateral salpingo-oophorectomy, sigmoidectomy, retinal surgery, bunionectomy, Achilles tendon repair, and ventriculoperitoneal shunt placement. The baseline pulmonary artery pressures and RV dimensions by transthoracic echocardiographic apical 4-chamber view are listed in Table 2 .
| N = 53 | |
|---|---|
| Age (Years) | 57.6 ± 16.2 |
| Men | 27 (51%) |
| Body Mass Index (kg/m 2 ) | 32.6 ± 8 |
| Hypertension | 30 (57%) |
| Diabetes Mellitus | 7 (13%) |
| Congestive Heart Failure | 2 (4%) |
| Chronic Obstructive Pulmonary Disease | 5 (9%) |
| History of Pulmonary Hypertension | 0 (0%) |
| Active Cancer | 8 (15%) |
| History of Pulmonary Embolus | 6 (11%) |
| History of Deep Venous Thrombosis | 11 (21%) |
| Smoker | 6 (12%) |
| Mean systolic blood pressure, mmHg | 134.2 ± 22 |
| Mean heart rate, beats/minute | 88 ± 20 |
| Mean respiratory rate, breaths/min | 18 ± 6 |
| Mean oxygen saturation | 96.5 ± 3% |
| Median supplemental Oxygen, liters [IQR] | 4 [3-4] |
| Mean Left Ventricular Ejection Fraction ∗ | 59.4 ± 7.6 |
| Right Ventricular Function ∗ | |
| Normal | 8 (15%) |
| Mild dysfunction | 16 (30%) |
| Moderate dysfunction | 18 (35%) |
| Severe dysfunction | 11 (20%) |
| Pulmonary Embolism Severity Index (PESI) Score † | 73.6 ± 23.6 |
∗ As determined by qualitative echocardiography assessment.
| Pressures (mmHg) | Baseline | Post | p value |
|---|---|---|---|
| Pulmonary Artery Systolic Pressure | 51.4 ± 15.5 | 40.7 ± 10.8 | <0.001 |
| Mean Pulmonary Artery Pressure | 33.8 ± 10.5 | 27 ± 7.6 | <0.001 |
| Right Ventricular Diameter: Left Ventricular Diameter Ratio | 1.12 ± 0.30 | 0.98 ± 0.20 | p = 0.03 |
| Right Ventricular End-Diastolic Dimension | 4.66 ± 0.80 | 4.48 ± 0.88 | p = 0.41 |
Table 3 outlines procedural details including hemodynamic and echocardiographic results. After accounting for repeated measures per patient, there was a significant 11.4-mm Hg reduction in systolic pulmonary artery pressure (p <0.001, 95% confidence interval [CI] 7.8 to 15.0 mm Hg) and 7.2-mm Hg reduction in mean pulmonary artery pressure (p <0.001, 95% CI 4.7 to 9.7 mm Hg). Figure 1 demonstrates the changes in systolic and mean pulmonary artery pressures per patient. Additionally, there was a reduction of 19% in RV/left ventricular diameter ratio (p <0.001, 95% CI 10% to 28%).
| Total Infusion Time (hours) | 15.9 ± 3.0 |
| Total Lytic Dose (mg) | 24.6 ± 9 |
| Lytic Infusion Rate (mg/hr) | 1.5 [1.0 – 1.5] |
| Peak activated partial thromboplastin time (aPTT) during treatment | 42.5 [38.5-55.6] |
| Fibrinogen during treatment | 406 ± 141 |
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