Outcomes of Catheter-Directed Therapy Plus Anticoagulation Versus Anticoagulation Alone for Submassive and Massive Pulmonary Embolism

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Outcomes of Catheter Directed Therapy Plus Anticoagulation Versus Anticoagulation Alone for Submassive and Massive Pulmonary Embolism with Subgroup Analysis Charles Hennemeyer MD , Abdul Khan MD , Hugh McGregor MD , Cheyenne Moffett B.S , Gregory Woodhead MD, PhD PII: DOI: Reference:

S0002-9343(18)31032-5 https://doi.org/10.1016/j.amjmed.2018.10.015 AJM 14876

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The American Journal of Medicine

Please cite this article as: Charles Hennemeyer MD , Abdul Khan MD , Hugh McGregor MD , Cheyenne Moffett B.S , Gregory Woodhead MD, PhD , Outcomes of Catheter Directed Therapy Plus Anticoagulation Versus Anticoagulation Alone for Submassive and Massive Pulmonary Embolism with Subgroup Analysis, The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.10.015

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Outcomes of Catheter Directed Therapy Plus Anticoagulation Versus Anticoagulation Alone for Submassive and Massive Pulmonary Embolism with Subgroup Analysis

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Charles Hennemeyer, MD ; Abdul Khan, MD ; Hugh McGregor, MD ; Cheyenne Moffett, 1

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B.S. ; Gregory Woodhead, MD, PhD .

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Department of Medical Imaging, University of Arizona, Tucson, AZ, USA

*Corresponding Author: Charles Hennemeyer, MD. Division Chief, Vascular and Interventional Radiology, University of Arizona. 1501 N. Campbell Ave, Room 1343, Tucson, AZ 85724-

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5058, USA. Phone: (520) 626-1957. [email protected]

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Funding: None

Conflict of Interest: Dr. Charles Hennemeyer reports being a consultant for Penumbra Inc.. The

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other authors report no conflicts.

All authors noted above had access to data used in the research study and participated in writing

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the manuscript being submitted.

Article Type: Retrospective Clinical Research Study Key Words: Pulmonary Embolism Running Head: Outcomes of CDT in Massive and Submassive PE

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Highlights:  Catheter Directed Therapy improves RV/LV ratio, a measure of heart dysfunction, in patients with massive and submassive pulmonary embolism more significantly than anticoagulation alone, hereby directing clinicians to potential life-saving treatment  Mechanical Aspiration with the Penumbra Indigo device is a safe and effective catheter treatment, and may combined with Ultrasound-Assisted Local Thrombolysis for a more favorable outcome  Catheter Directed Therapy improves heart dysfunction more significantly at RV/LV ratios <1.9 Abstract

Background: Catheter directed therapy (CDT) offers an alternative treatment to systemic

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thrombolysis for patients with massive and submassive pulmonary embolism.

Methods: A retrospective review of 105 consecutive massive and submassive pulmonary embolisms over two years was performed. Thirty-six patients (9 massive, 27 submassive) were

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treated with CDT, consisting of aspiration thrombectomy (18), ultrasound-assisted thrombolysis (8) or both (10). Forty-three patients (8 massive, 35 submassive) were treated with heparin

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anticoagulation alone. Primary outcome was improvement of RV/LV ratio 24-48 hours after treatment. Safety outcomes included 90-day mortality, bleeding complications, and hospital

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readmissions. Subgroup analysis based on severity of RV dilation was performed.

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Results: Mean RV/LV ratio decreased from 1.910.61 to 1.280.45 (p<0.001) in the CDT group and from 1.400.37 to 1.250.32 (p=0.01) in the anticoagulation group. In submassive

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pulmonary embolisms with mild and moderate RV dilation (RV/LV ratio 0.9-1.9), RV/LV ratio was significantly lower in the CDT group at 24-48 hours (1.050.38 vs 1.200.31, p<0.001. In submassive pulmonary embolisms with severe RV dilation (RV/LV ratio >1.9), no difference was noted between the two treatment groups. Ninety-day mortality (11% and 14%, p=0.7) and incidence of major bleeding complications did not significantly differ between the groups.

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Thirty-day readmission rates were 8% in the CDT group and 26% in the anticoagulation group (p=0.04). Conclusion: CDT for acute massive and submassive pulmonary embolism significantly improves RV/LV ratio at 24-48 hours compared to anticoagulation alone and may lower hospital

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readmission rates. CDT may be more advantageous in patients with mild to moderate RV dilation.

Introduction

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Acute pulmonary embolism is a leading cause of cardiovascular morbidity and death. PE has been described by the Surgeon General as the most common preventable cause of death among hospitalized patients. Massive and submassive pulmonary embolism, accounting for 5-10% and

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20-25% of cases respectively, and are associated with increased mortality [1, 2, 3]. The International Cooperative Pulmonary Embolism Registry (ICOPER) reported 90 day mortalities

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of up to 52.4% for massive pulmonary embolism and up to 19% for submassive pulmonary embolism [4]. Systemic thrombolysis improves pulmonary perfusion and reverses acute right

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heart failure in patients with PE, but is associated with an overall major bleeding risk of 10% and

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a 3-5% risk of hemorrhagic stroke [5]. Systemic thrombolysis is FDA approved for massive pulmonary embolism, but its use for submassive pulmonary embolism remains controversial.

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Catheter directed therapy (CDT) represents an alternative treatment option for massive and submassive pulmonary embolism PE, utilizing intrapulmonary administration of low dose of thrombolytics and in some cases mechanical clot removal [6,7,8] As a result, major bleeding complications are reduced in CDT compared to systemic thrombolysis [9]. CDT options have expanded with new device development and now includes ultrasound-assisted thrombolysis

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(USAT), mechanical aspiration thrombectomy, and direct clot-retrieval systems. Several devices are currently being studied, including the Penumbra Indigo aspiration system [10, 11, 12]. Current literature provides preliminary safety data on mechanical aspiration, but efficacy data is needed. The purpose of this study was to assess the efficacy and safety of the USAT and

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mechanical aspiration and compare outcomes of CDT to anticoagulation alone in patients with acute massive and submassive PE.

Materials and Methods

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This study was conducted as an IRB approved single center, retrospective review that included 105 consecutive patients with pulmonary embolism associated with right heart strain from October 2016 to September 2018. Patients were treated with CDT or anticoagulation alone.

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CDT included aspiration mechanical thrombectomy, USAT, bolus intrapulmonary delivery of Tissue Plasminogen Activator (tPA), or a combination of these therapies. Anticoagulation

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included treatment with IV heparin and subsequent warfarin, lovenox, or vitamin K-independent oral anticoagulation treatment. Inclusion criteria were acute massive or submassive pulmonary

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embolism diagnosed with computed tomography (CT) angiography, evidence of right heart strain

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on CT angiography, echocardiogram or magnetic resonance imaging (MRI), completion of catheter based therapy if initiated, and follow up imaging 24-48 hours after treatment. Exclusion

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criteria were failure to complete catheter treatment if initiated, the presence of septic emboli, or patients treated with systemic tPA. Acute massive pulmonary embolism was defined as an acute pulmonary embolism with hypotension or requiring inotropic support and submassive pulmonary embolism was defined as an acute pulmonary embolism with signs of right heart strain on CTA or echocardiography [2]. Criteria for right heart strain included elevated RV/LV ratio (>0.9). All

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patients received systemic heparin as standard treatment for acute pulmonary embolism. A total of 42 patients underwent catheter directed therapy during the two-year interval. Thirty-six patients (9 massive, 27 submassive) were included in this study; 6 patients were excluded from statistical analysis as post treatment imaging was not completed. A total of 63 patients were

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treated with anticoagulation alone. Forty-three patients (8 massive, 35 submassive) were

included in this study; 20 patients were excluded as post treatment imaging was not completed.

Treatment Procedure and Devices:

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All patients included in the analysis undergoing catheter directed intervention had treatment within 24-48 hours of pulmonary embolism diagnosis. Mechanical aspiration thrombectomy was performed with use of the Penumbra Indigo System (CAT8, Penumbra, CA, USA). In patients

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receiving USAT, the EkoSonic MACH4e Endovascular System (EKOS Corporation, WA, USA) was used. Venous access was obtained via the right common femoral or right internal jugular

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vein with the aid of ultrasound guidance. The pulmonary arterial system was accessed and pulmonary angiography was performed via standard catheterization techniques. In patients

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receiving mechanical aspiration, an intrapulmonary bolus of 7-15mg of tPA was given in each

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pulmonary artery in patients without absolute contraindications to thrombolytics. Aspiration was performed in all lobar branches of both pulmonary arteries. Angiography was repeated until no

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evidence of lobar clot burden remained. In patients undergoing EKOS treatment, infusion catheters placed in the lobar branch with the most clot burden and run at 0.5 mg of tPa/hour/catheter. Patients were observed in the ICU and the EKOS catheters were removed 1522 hours later.

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Imaging Review and Data Analysis: RV/LV ratios were measured from a combination of echocardiography (75), CTA (74), and MRA (4) completed 24-48-hours after diagnosis of pulmonary embolism. If multiple imaging studies were completed, a mean RV/LV ratio was taken. Measurements were taken using an

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apical four chamber view and included sub-annular end-diastolic right and left ventricular

diameters [7]. Two fellowship-trained Cardiothoracic Imaging physicians (each with greater than 7 years of experience) were blinded to treatment group and outcomes and evaluated CT, MRI, and echocardiography images. The mean of their measurements was used in the analysis. Patient

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clinical data, outcomes, and complications were assessed with a chart review and outpatient follow up. Primary safety outcomes included 90-day mortality and major and minor bleeding complications [13]. Data were expressed as mean  standard deviation. Pearson’s correlation was

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used to analyze the association between all studied parameters. Comparisons of RV/LV ratio as well as patient demographics and outcomes were completed using a 2-tailed, paired sample t test.

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P values < 0.05 was considered statistically significant.

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Results

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Clinical and procedural data

Our analysis included 36 patients treated with CDT plus anticoagulation and 43 patients treated

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with anticoagulation alone. Nine massive and 27 submassive pulmonary embolisms were included in the CDT group. Eight massive and 35 submassive PEs were in anticoagulation group. Patient demographics and clinical characteristics are summarized in Table 1. In the CDT group 18 patients were treated with mechanical aspiration, 8 patients with USAT, and 10 patients with both aspiration and USAT. Fifteen of 18 patients treated with mechanical aspiration alone

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received an intrapulmonary bolus of tPA (mean dose 30 mg). One of 8 patients treated with USAT alone received an intrapulmonary bolus of 30 mg tPA. Eight of 10 patients treated with both mechanical aspiration and USAT received an intrapulmonary bolus of tPA (mean dose 29.2±17.11)). Mean estimated blood loss for the CDT group was 308±271 and mean fluoroscopy

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time was 32.95 ± 20.04 minutes. Procedural data is summarized in Table 2.

Imaging

Any reduction in RV/LV ratio was achieved in 33 of 36 patients treated with CDT and 35 of 43

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patients treated with anticoagulation alone. A comparison of RV/LV reduction categorized by type of PE and treatment modality is presented in Table 3. In all patients treated with CDT, the mean RV/LV ratio decreased from 1.91 to 1.28 at 24-48 hours’ post-procedure with an absolute

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difference of -0.62  0.59 (p <0.001). The mean RV/LV ratio in the anticoagulation group decreased from 1.40 to 1.25 at 24-48 hours’ post-procedure with an absolute difference of -0.14

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 0.31 (p=0.01). The mean reduction in RV/LV ratio for the CDT group was 31% compared to

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8% for the anticoagulation alone group (p value <0.001).

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The absolute reduction in RV/LV ratio for patients with massive and submassive pulmonary embolism who underwent CDT was - 0.67  0.85 (p=0.04) and -0.61  0.60 (p < 0.001)

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respectively. The absolute reduction in RV/LV ratio for patients with massive and submassive pulmonary embolism treated with anticoagulation was -0.16 ± 0.31 (p=0.17) and -0.14 ± 0.32 (p=0.02). The mean reduction in RV/LV ratio in patients with massive pulmonary embolism treated with CDT was 24% and 9% in patients treated with anticoagulation alone (p=0.17). Patients with submassive pulmonary embolisms treated with CDT had a mean reduction of

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RV/LV ratio of 33% compared to 7% in patients treated with anticoagulation alone (p < 0.001). In patients who underwent mechanical aspiration, the mean RV/LV ratio decreased from 1.73 to 1.19 with an absolute reduction of -0.54  0.46 (p < 0.001). In patients who underwent USAT alone treatment, the average RV/LV ratio decreased from 1.81 to 1.49 with an absolute reduction

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of -0.32  0.46 (p= 0.09). In patients who underwent both USAT and mechanical aspiration treatments, the mean RV/LV ratio decreased from 2.32 to 1.30 with an absolute reduction of -

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1.02  0.73 (p=0.002).

Subgroup analysis

Patients were stratified by severity of RV dilation (Table 4). Mild RV dilation was defined as an RV/LV ratio of 0.9-1.3, moderate as an RV/LV ratio of 1.3-1.9, and severe as an RV/LV ratio

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>1.9). Among patients with mild RV dilation, the mean RV/LV ratio in the CDT group decreased from 1.14 to 0.86 (p<0.004) compared to no significant decrease in the anticoagulation

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alone group. With moderate RV dilation, the mean RV/LV ratio of CDT patients decreased from 1.68 to 1.21 (p<0.001) compared again to no significant decrease in the anticoagulation alone

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group. In severe RV dilation, the mean RV/LV ratio of CDT patients decreased from 2.36 to 1.50

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(p<0.001) compared to a reduction from 2.04 to 1.50 (p=0.002) in the anticoagulation alone group. A parallel sub-category analysis based on pre-procedure RV/LV severity, was performed

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on the submassive- pulmonary embolism patient group and yielded similar results (Table 3). Demographics and clinical data of the patients categorized in the severe group compared to mild and moderate group were analyzed and the results are presented in Table 5. Of note, patients in the severe group had a higher mean age, higher proportion of patients taking antihypertensive medication, and a higher proportion of troponin leak at pulmonary embolism diagnosis.

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Clinical outcomes Clinical outcomes are presented in Table 2. There were no significant differences between the CDT group and the anticoagulation alone group with regards to mortality, length of hospital stay,

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length of ICU stay, recurrent thromboembolism and major and minor bleeding complications. Three patients in the CDT group were readmitted within 30 days and 11 in the anticoagulation alone group were readmitted within 30 days (p=0.04).

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Discussion

CDT for acute pulmonary embolism is a topic of increasing interest. Trials including ULTIMA, SEATTLE II, and PERFECT provide evidence that USAT is safe and efficacious in the

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treatment of patients with submassive pulmonary embolism [7-9,14]. Specifically, markers of RV strain significantly improve with USAT compared to anticoagulation alone. These studies

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however, did not attempt to identify specific subgroups which may receive greater benefit from CDT. In addition, these studies do not include mechanical thrombectomy devices, which have

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the advantages of direct thrombus extraction, potentially obviating the need for high-dose tPA.

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The Penumbra Indigo System is an aspiration mechanical thrombectomy system that utilizes intermittent suction and a clot-separator device to facilitate breakdown and extraction of

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pulmonary embolism [15]. Preliminary studies have demonstrated the safety of the Indigo system in the treatment of patients with submassive PE [10, 11, 12].

The present study compares CDT and anticoagulation versus anticoagulation alone for the treatment of acute submassive and massive pulmonary embolism and provides safety and

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efficacy data for several different CDT techniques, alone, or in combination. This study also provides subgroup analysis of massive and submassive pulmonary embolisms based on degree of RV dilation and identifies patients who may have greater benefit from CDT.

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Patients in the CDT group underwent treatment with aspiration mechanical thrombectomy using the Penumbra Indigo system, USAT using EKOS, or a combination of the two therapies.

Baseline RV/LV ratio in the CDT group was significantly higher than the anticoagulation alone group and patients treated with CDT were less likely to have had recent surgery. This data

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provides insight into patient selection, with RV/LV ratio likely being used as surrogate for pulmonary embolism severity and need for advanced treatment (CDT) and reflects an

appropriate hesitancy to use thrombolytics in patients with recent surgery. Additionally, the

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anticoagulation alone group was more likely to have isolated segmental pulmonary embolisms,

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reflecting bias towards treating only lobar and main pulmonary embolisms with CDT.

An important prognostic indicator in acute pulmonary embolism is RV dilation. Increased

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RV/LV ratio has been shown to have a strong association with pulmonary embolism related

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mortality [16]. Specifically, an RV/LV ratio >0.9 have been shown to predict clinical outcomes in pulmonary embolism and is an acceptable assessment of right heart function after reperfusion

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therapy for acute pulmonary embolism [17]. CDT in this study demonstrated significantly greater reductions in RV/LV ratio for patients with massive and submassive pulmonary embolism treated with CDT compared to those patients treated with anticoagulation. Specifically, significant reductions in RV/LV ratio with sole use of Penumbra Indigo system and a combination of Penumbra Indigo System and EKOS system were noted. USAT alone did not

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significantly reduce RV/LV ratio, however, there were only 8 patients in this subgroup. As the baseline RV/LV ratio in the CDT and anticoagulation alone groups differed, subgroup analysis of outcomes based on severity of RV/LV ratio was performed.

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Patients were sub-categorized into three degrees of RV/LV ratio: mild (0.9-1.3), moderate (1.31.9), severe (>1.9). Patients with mild and moderate RV/LV ratio treated with CDT showed statistically significant reductions in RV/LV ratio while those treated with anticoagulation did not. Patients with severe RV/LV ratio treated with CDT also showed statistically significant

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reductions in RV/LV ratio. However, anticoagulation alone demonstrated similar reductions in RV/LV in the severe subgroup. Patients in the severe RV/LV ratio subgroup were significantly older, had a higher prevalence of outpatient anti-hypertensive treatment, and a higher prevalence

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of troponin leak at time of pulmonary embolism diagnosis. Patients with a severe RV/LV ratio may have a higher pre-existing cardiopulmonary disease burden, which may result in a more

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accentuated response to acute pulmonary embolism (greater RV dilation) and a limited capacity for improvement of RV dilation after treatment. This data suggests that patients with mild or

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moderate RV/LV ratio characterization may be more likely to benefit from CDT than patients

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with severe RV/LV ratio and that severity of RV/LV ratio should be considered when assessing patients for CDT. However, the goal of early CDT for acute pulmonary embolism is not only to

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improve RV/LV ratio, but also to improve markers of long-term health, such as overall survival (OS), right ventricular function, and pulmonary reserve. A future prospective randomized controlled trial with long-term outcomes comparing CDT with anticoagulation alone will be essential to address these questions.

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There was no significant difference in bleeding complications in this study between the CDT group and the anticoagulation alone group. The mean dose of intra-pulmonary tPA given in the CDT group (28 mg) is less than common systemic tPA regimens of 50 -100mg IV. There were 3 readmissions in the CDT group compared to 11 readmissions in the anticoagulation group.

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Reasons for readmission in the CDT group included evaluation of palpitations that were found to be clinically insignificant, acute cholecystitis, and hematemesis related to a gastric arteriovenous malformation. Reasons for readmission in the anticoagulation group included recurrent

pulmonary embolism, gastrointestinal bleed, recurrent deep vein thrombosis, acute dyspnea, and

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substance abuse. The possibility of decreasing thirty day readmissions in patients with

pulmonary embolism treated with CDT may represent another advantage of CDT, albeit economic. A systematic analysis of patients hospitalized for venous thromboemolism by

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Secemsky et al. reported a median cost of $9781.70 for hospital readmissions [18]. The current study did not analyze the cost burden of readmission, but future studies may be prompted to

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include a cost burden analysis.

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Of note, there were two patients with submassive pulmonary emboli in which CDT was unable

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to be initiated due to issues with procedural sedation. Each patient went into cardiac arrest with the administration of pre-procedural sedatives. Interventionists should exercise caution when

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administering sedative medications in patients with submassive and massive pulmonary embolism, because these medications may have accentuated hemodynamic effects in this population given their complex cardiopulmonary status. Further research is needed on the impact of procedural sedation in patients with submassive and massive pulmonary embolism. We propose that operators consider avoiding sedation entirely if possible.

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The present study has limitations including a small sample size, heterogeneity of data, and minimal long term follow up data. A larger study conducted as a prospective trial would allow a more thorough analysis of CDT. Another limitation is the use of RV/LV ratio as a primary

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outcome measure. Right heart function may be better assessed by other metrics, such as right ventricular ejection fraction. Further studies and longer follow up are needed to examine the long term physiological effects of CDT as well as impact on long term functional status and

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quality of life.

Conclusion

CDT using mechanical aspiration thrombectomy and/or ultrasound assisted thrombolysis for

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acute massive and submassive pulmonary embolism demonstrates similar safety profiles to anticoagulation alone and superior improvement in RV/LV ratio at 24-48 hours. Catheter based

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therapy may be more advantageous to patients with mild and moderate characterizations of

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References

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3. Kucher N, Rossi E, De rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113(4):577-82. 4. Goldhaber SZ, Visani L, De rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet.

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7. Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and

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8. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation,

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Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015;148(3):667-73.

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9. Moriarty JM, Edwards M, Plotnik AN. Intervention in Massive Pulmonary Embolus: Catheter Thrombectomy/Thromboaspiration versus Systemic Lysis versus Surgical Thrombectomy. Semin Intervent Radiol. 2018;35(2):108-115.

10. Ciampi-dopazo JJ, Romeu-prieto JM, Sánchez-casado M, et al. Aspiration Thrombectomy for Treatment of Acute Massive and Submassive Pulmonary Embolism:

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Initial Single-Center Prospective Experience. J Vasc Interv Radiol. 2018;29(1):101-106. 11. Al-hakim R, Bhatt A, Benenati JF. Continuous Aspiration Mechanical Thrombectomy for the Management of Submassive Pulmonary Embolism: A Single-Center Experience. J Vasc Interv Radiol. 2017;28(10):1348-1352.

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12. Pieraccini M, Guerrini S, Laiolo E, et al. Acute Massive and Submassive Pulmonary Embolism: Preliminary Validation of Aspiration Mechanical Thrombectomy in Patients with Contraindications to Thrombolysis. Cardiovasc Intervent Radiol. 2018.

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Classification by the Society of Interventional Radiology Standards of Practice Committee. J Vasc Interv Radiol. 2017;28(10):1432-1437.e3.

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Embolism. Semin Intervent Radiol. 2018;35(2):122-128.

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Therapy in Pulmonary Embolism. Tech Vasc Interv Radiol. 2017;20(3):185-192. 16. Meinel FG, Nance JW, Schoepf UJ, et al. Predictive Value of Computed Tomography in

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Acknowledgments: The authors want to thank the following members for their contributions to this study: Stacey

Table 1. Acute Pulmonary Emboli Patient Characteristics Demographics

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Black, MD., Jessica Lee, MD., Paola Devis, MD., and Andrew Karellas, PhD.

Catheter Treatment group

P value 0.95 0.74 0.06

23 (53) 7 (16) 4 (9) 11 (26) 9 (22) 5 (12) 19 (44) 6 (14) 13 (30)

0.59 0.28 0.19 0.33 0.07 0.34 0.07 0.99 0.27

22 (51) 32 (74) 24 (56) 8 (17) 35 (81) 9 (21) 10 (23) 18 (42) 6 (14) 21 (49)

0.92 0.82 0.13 0.50 0.50 0.09 0.48 0.30 0.01 0.56

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Male, n (%) 17 (47) Age, meanSD 59  15.93 Body mass index, meanSD 35.2  10.56 Patient Comorbidities Hypertension, n (%) 17 (47) Coronary Artery Disease, n (%) 3 (8) Tobacco Use, n (%) 6 (17) Diabetes Mellitus, n (%) 6 (17) Recent Major Surgery, n (%) 3 (8) Prior stroke, n (%) 2 (5) Cancer, n (%) 9 (25) Prior deep vein thrombosis, n (%) 5 (14) Prior Pulmonary Embolus, n (%) 7 (19) Patient Characteristics at PE diagnosis Tachycardia, n (%) 18 (50) Requiring oxygen supplementation, n (%) 26 (72) Troponin Elevation, n (%) 26 (72) Massive pulmonary embolus, n (%) 9 (25) Submassive pulmonary embolus, n (%) 27 (75) *Saddle pulmonary embolus, n (%) 14 (39) *Main pulmonary embolus, n (%) 11 (31) *Lobar pulmonary embolus, n (%) 11 (31) *Segmental pulmonary embolus, n (%) 0 (0) Associated deep vein thrombosis, n (%) 20 (56) *Most central PE identified at the time of imaging

Anticoagulation Treatment Group 20 (47) 60  17.16 31.1  7.79

Table 2. CDT vs Anticoagulation Treatment Outcomes and Analysis Catheter Directed Therapy 27.5 ± 12.3

Average tPA Indigo

Heparin

p-value

25.4 ± 11.83

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26.8 ± 10.58 29.2 ± 17.11

EBL from procedure (cc)

308 ± 271

Indigo EKOS INDIGO+EKOS

480 ± 240 13 ± 5 234 ± 179

Mean fluoroscopy time (min)

32.95 ± 20.04

Indigo EKOS INDIGO+EKOS

34.1 ± 14.68 13.8 ± 6.93 46.3 ± 24.33 3.78 ± 6.09

1.93 ± 4.7

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Length of ICU stay (days)

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EKOS INDIGO+EKOS

Indigo EKOS INDIGO+EKOS

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3.78±6.54 2.25±0.89 5.0±7.67

Length of hospital stay (days)

7.78 ± 5.64

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10.28±8.85 7±3.38 9.8±6.61

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Indigo EKOS INDIGO+EKOS

9.42 ± 7.30

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30-day Readmission, n (%) 3 (8) 11 (26) 0.04 IVC filter placed, n (%) 15 (42) 6 (14) 0.007 90-day Mortality, n (%) 4* (11) 6 (14) 0.71 Recurrent VTE, n (%) 0 3 (7) 0.08 Major bleeding, n (%) 2 (6) 3 (7) 0.80 Minor bleeding, n (%) 2 (6) 0 0.16 CDT = Catheter Directed Therapy; tPA= tissue plasminogen activator, ICU = intensive care unit, IVC = inferior vena cava, VTE = venous thromboembolism *not attributed to Catheter Treatment or Pulmonary Embolus

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Table 3. CDT vs Anticoagulation Outcomes

RV/LV ratio

Patient Description

Baseline

24-48 hr post procedure

All CDT Massive Submassive Indigo EKOS Indigo + EKOS

1.91±0.61 2.15±0.96 1.83±0.44 1.73±0.42 1.81±0.55 2.32±0.81

1.28±0.45 1.48±0.38 1.22±0.52 1.19±0.41 1.49±0.75 1.30±0.39 24-48 hr post diagnosis

Absolute Difference -0.62±0.59 -0.67±0.85 -0.61±0.50 -0.54±0.46 -0.32±0.46 -1.02±0.73

P value <0.001 0.04 <0.001 <0.001 0.09 0.002

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ACCEPTED MANUSCRIPT

Anticoagulation 1.40±0.37 1.25±0.32 -0.14±0.31 Massive 1.48±0.34 1.31±0.30 -0.16±0.30 Submassive 1.38±0.38 1.24±0.32 -0.14±0.32 CDT = Catheter Directed Therapy; RV = right ventricular; LV = left ventricular

0.01 0.17 0.02

Table 4. CDT vs Anticoagulation Outcomes Characterized by RV/LV ratio RV/LV ratio characterization

CDT

RV/LV ratios

Heparin P value

AN US

CR IP T

Baseline 24-48 hrs P value Baseline 24-48 hrs All PE patients Mild 0.9 – 1.3 1.14 0.86 0.004 1.10 1.09 Moderate 1.3 – 1.9 1.68 1.21 <0.001 1.60 1.43 Severe > 1.9 2.36 1.50 <0.001 2.04 1.50 Submassive PE only Mild 0.9 – 1.3 1.18 0.86 <0.001 1.10 1.09 Moderate 1.3 – 1.9 1.67 1.24 0.01 1.59 1.42 Severe > 1.9 2.18 1.46 0.003 2.07 1.50 RV = right ventricular; LV = left ventricular; CDT = catheter directed therapy

0.72 0.05 0.002 0.88 0.06 0.005

Table 5. Patient Demographics by RV/LV Characterization

AC

CE

PT

ED

M

RV/LV <1.9 p-value RV/LV  1.9 AGE 0.004 56.5717.18 66.8712.31 BMI 0.96 32.749.25 32.6210.30 HTN 25 (44) 16 (67) 0.04 Tobacco Use 7 (12) 3 (13) 0.95 DM 11 (19) 6 (25) 0.55 CAD 7 (12) 3 (13) 0.95 Pulmonary HTN 11 (19) 4 (17) 0.82 Previous CT Chest 14 (25) 3 (13) 0.20 History of Cardiac Cath 8 (14) 2 (8) 0.47 Previous DVT 7 (12) 4 (17) 0.60 Previous PE 16 (28) 4 (17) 0.27 Concurrent DVT 29 (51) 12 (50) 0.98 Troponin Leak 31 (54) 19 (79) 0.012 Requiring oxygen supplementation 39 (68) 19 (79) 0.21 Tachycardia 30 (53) 10 (42) 0.42 BMI = body mass index; HTN = hypertension; DM = Diabetes Mellitus; CAD = coronary artery disease; CT = computed tomography; DVT = deep vein thrombosis; PE = pulmonary embolism

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