Early Versus Delayed Use of Ultrasound-Assisted Catheter-Directed Thrombolysis in Patients With Acute Submassive Pulmonary Embolism

Abstract: Objectives. The effect of early vs delayed use of ultrasound-assisted catheter-directed thrombolysis (USAT) on invasive hemodynamics and in-hospital outcomes in patients with acute submassive pulmonary embolism (PE) is not well known. Methods. We evaluated 41 patients with submassive PE to study the association of early USAT (≤24 hours; n = 21) vs delayed USAT (>24 hours; n = 20) with change in invasive hemodynamic measures from pre USAT to post USAT. Results. Significantly greater improvement was observed in the early USAT group compared to the delayed group for median cardiac index (0.6 L/min/m² [IQR, 0.4-1.1 L/min/m²] vs 0.4 L/min/m² [IQR, 0.1-0.6 L/min/m²]; P=.03), median pulmonary vascular resistance (3.4 Wood units [IQR, 2.5-4.1 Wood units] vs 0.5 Wood units [IQR, 0.2-1.3 Wood units]; P<.001), and mean right ventricular stroke work index (3.5 ± 2.0 g-m/m²/beat vs 2.3 ± 1.6 g-m/m²/beat; P=.04). Although not statistically significant, a trend in favor of early treatment was found for improvement in mean right ventricle to left ventricle diameter ratio (0.38 ± 0.17 vs 0.33 ± 0.21; P=.40), mean pulmonary artery pressure (8.4 ± 7.1 mm Hg vs 5.3 ± 5.2 mm Hg; P=.13), and median pulmonary artery pulsatility index (1.14 [IQR, 2.01-0.45] vs 0.65 [IQR, 0.22-1.78]; P=.49). The mean postprocedural length of stay was significantly lower in the early-USAT group (6.0 ± 2.7 days vs 10.1 ± 7.0 days; P=.02). Three patients experienced moderate bleeding (2 patients in the early-USAT group and 1 patient in the delayed-USAT group) and no major bleeds or in-hospital mortality occurred. Conclusion. Early USAT was associated with greater improvement in pulmonary hemodynamics and shorter postprocedural length of stay compared with delayed USAT in patients with acute submassive PE.

J INVASIVE CARDIOL 2018;30(5):157-162.

Key words: submassive, pulmonary embolism, PE, ultrasound-assisted catheter-directed thrombolysis

Pulmonary embolism (PE) accounts for an estimated 300,000 annual hospitalizations in the United States and, despite advances in diagnosis and treatment, is associated with a mortality rate in excess of 80,000 deaths per year.^1,2 Systemic thrombolysis is the current treatment of choice for massive PE, with the benefit of reduced mortality exceeding the risk of major bleeds.^3,4 In contrast, systemic thrombolysis is not routinely utilized for submassive PE, as any mortality benefit is offset by a considerably higher risk of life-threatening bleeding.^5,6 Recent interest has centered on ultrasound-assisted catheter-directed thrombolysis (USAT).⁷ In this procedure, the ultrasound-enabled thrombolysis catheter is placed directly into the clot, which allows for much smaller doses of thrombolytics to be administered compared with systemic therapy, thereby reducing the risk of major bleeding events.⁸ Prior studies have shown improvement in pulmonary pressures and right ventricular size with USAT in patients with acute submassive PE treated within 14 days of symptom onset.^9,10 Many institutions have established PE response teams (PERT) to tackle PE early and efficiently using a multidisciplinary approach.¹¹ However, the association of timing of USAT with pulmonary hemodynamics and in-hospital outcomes in acute submassive PE remains unknown. Accordingly, the goal of our study was to evaluate the association of early use of USAT (≤24 hours from diagnosis) vs delayed use of USAT (>24 hours from diagnosis) with pulmonary hemodynamic and echocardiographic parameters and in-hospital outcomes in patients with acute submassive PE.

Methods

Study design. We assessed 41 patients who were treated with USAT using the Ekosonic endovascular system (EKOS) for symptomatic acute submassive PE per hospital protocol between January 2015 and February 2016. Data were collected retrospectively by reviewing the hospital electronic health records, which included patient demographics, comorbidities, presenting symptoms, procedural details, echocardiographic and hemodynamic parameters, and in-hospital outcomes. For the purpose of this analysis, patients were categorized into two groups: those who received USAT within or at 24 hours of diagnosis of PE (early-USAT group) and those who received USAT after 24 hours of diagnosis (delayed-USAT group). The study was approved by the St. John Hospital and Medical Center Institutional Review Board in Detroit, Michigan. 

Procedure protocol. Diagnosis of acute PE was made by computed tomography (CT) angiography with duration of symptoms ≤14 days, and categorized as submassive if evidence of right ventricular (RV) dysfunction was present in the absence of hemodynamic compromise (systolic blood pressure of ≥90 mm Hg).⁶ A right ventricle to left ventricle (RV/LV) diameter ratio >0.9 on CT angiography was used as a marker of RV dysfunction.¹² Once acute PE was suspected, and provided there were no contraindications to its use, unfractionated heparin was initiated with an intravenous bolus dose of 80 IU/kg followed by infusion with a targeted activated partial thromboplastin time of 1.5 to 2 times the laboratory control. A transthoracic echocardiogram was routinely performed to further assess RV/LV ratio and RV function; if no contraindications to administration of tissue plasminogen activator were present,¹³ the patient was taken to the catheterization laboratory for placement of USAT catheters. Right heart catheterization was performed prior to insertion of these catheters. Invasive hemodynamic measurements included mean pulmonary artery pressure (MPAP), cardiac index, pulmonary vascular resistance, right ventricular stroke work index (RVSWI), and pulmonary artery pulsatility index. Right or left femoral venous access was obtained and USAT catheters were inserted bilaterally into the pulmonary arteries under fluoroscopic guidance and left in place with slow infusion of tissue plasminogen activator through each catheter at 1 mg/hour/catheter for 12 hours. During and after the procedure, intravenous heparin was continued and monitored closely in the cardiovascular intensive care unit. Right heart catheterization was repeated to obtain post-USAT hemodynamic measurements immediately after removal of the catheters. Intravenous heparin was resumed after acceptable hemostasis of the access site was achieved. A transthoracic echocardiogram was repeated 48 hours after insertion of the USAT catheters for evaluation of RV/LV ratio post USAT, in line with previously published trials.¹⁰ Patients were bridged either to warfarin using enoxaparin or to novel oral anticoagulants prior to discharge based on patient candidacy. The timing of discharge was at the discretion of the treating physician.

Outcome measures. We evaluated six different parameters as surrogate outcome measures: one echocardiographic (RV/LV ratio) and five invasive (MPAP, cardiac index, pulmonary vascular resistance, RVSWI, and pulmonary artery pulsatility index). The cardiac index was calculated using Fick’s principle. Pulmonary vascular resistance was calculated in Wood units as (mean pulmonary artery pressure – pulmonary capillary wedge pressure)/cardiac output. RVSWI was calculated as stroke volume index × (mean pulmonary artery pressure – right atrial pressure) × 0.0136 g-m/m²/beat. The pulmonary artery pulsatility index was calculated as (pulmonary artery systolic pressure – pulmonary artery diastolic pressure)/right atrial pressure. These variables were measured before and after USAT in all 41 patients.

We also assessed the following clinical outcomes: postprocedural length of stay, in-hospital all-cause mortality, recurrent PE, bleeding, and procedure-related complications, even though we were not powered to detect any meaningful differences in these outcomes. Our goal was to detect specifically whether there were any major safety signals in this small cohort. Bleeding events were classified per GUSTO definition.¹⁴ 

Statistical analysis. Data were described as the mean with standard deviation for normally distributed variables and median with interquartile ranges (IQR; 25%-75%) for non-normally distributed variables. The normality of distributions was assessed using the Kolmogorov-Smirnov test as well as by assessing stem and leaf plots. Differences in demographic and clinical characteristics between the early and delayed groups were assessed using Student’s t-test and the Chi-square test. Differences in all pre-USAT to post-USAT measurements for the entire study group were assessed using the paired t-test. To assess the changes stratified by time, the difference in the pre-USAT to post-USAT measurement (the delta) was computed for each individual and then the median delta was compared between the early USAT and the delayed USAT groups using Student’s t-test or the Mann-Whitney U-test. All data were analyzed using SPSS version 24.0 and a P-value of ≤.05 was considered to indicate statistical significance.

Results

Demographic and clinical characteristics are presented in Table 1. Early USAT was utilized in 21 patients and delayed USAT was utilized in 20 patients. The mean age was 57.6 ± 12.9 years in the early group vs 63.6 ± 11.7 years in the delayed group (P=.13). Common risk factors for PE included obesity, immobility within preceding 30 days of diagnosis, family history of venous thromboembolism, and prior history of deep vein thrombosis or PE. Right femoral venous access was used in 38 patients and left femoral venous access was used 3 patients. Ultrasound-guided venous access was obtained in 36 patients. Bilateral USAT catheters were successfully placed during the first attempt in all 41 patients. The mean total dose of tissue plasminogen activator administered during USAT was 24 ± 1.1 mg.

Analysis of the six surrogate outcome measures in all 41 patients before and after USAT is illustrated in Figure 1. We noted a statistically significant reduction in all six parameters after USAT treatment. Mean time interval between diagnosis and initiation of the procedure was 13.3 ± 5.6 hours and 46.4 ± 10.1 hours in the early-USAT and delayed-USAT groups, respectively. The comparison of surrogate outcome measures between the early-USAT and delayed-USAT groups is displayed in Table 2. The comparison of the median change in these variables between the two groups is illustrated in Figure 2. Statistically significant differences in the improvement in cardiac index, pulmonary vascular resistance, and RVSWI were noted between the two groups, in favor of the early-USAT group. No significant difference was noted for the improvement in RV/LV ratio, MPAP, and pulmonary artery pulsatility index.

There were no deaths and no severe or life-threatening bleeding as defined by the GUSTO definition¹⁴ among any of the 41 patients. Three patients (7.3%) were noted to have GUSTO moderate bleeding (2 patients in the early-USAT group and 1 patient in the delayed-USAT group), each related to access-site hematomas and requiring 2 units of packed red blood cells. There were no episodes of recurrent PE and no major complications from the device placement itself. The mean postprocedure length of stay in all 41 patients was 8 ± 5.8 days. The length of stay was significantly shorter in the early-USAT group vs the delayed USAT group (6.0 ± 2.6 days vs 10.1 ± 6.9 days, respectively; P=.02).

Discussion

In our single-center study of 41 patients with acute submassive PE treated with USAT, we demonstrated rapid and significant improvement in all six surrogate outcome measures from baseline to post-USAT treatment. Furthermore, the early use of USAT within or at 24 hours of diagnosis was associated with a significantly greater improvement in cardiac index, pulmonary vascular resistance, and RVSWI when compared to delayed administration (>24 hours). Although not statistically significant, a trend in favor of early treatment was noted for the improvement in RV/LV ratio, MPAP, and pulmonary artery pulsatility index. These improvements were attained with no deaths or major bleeding events in any patient in either group. Three patients (7%) experienced moderate bleeding requiring transfusions (2 in the early-USAT group and 1 in the delayed-USAT group). Finally, the postprocedural length of stay was significantly shorter in the early-USAT compared with the delayed-USAT group.

Management of patients with submassive PE remains challenging. The Pulmonary Embolism Thrombolysis (PEITHO) trial⁵ compared the efficacy and safety of systemic thrombolysis with tenecteplase plus heparin vs heparin alone in 1006 patients with submassive PE. Although systemic thrombolysis showed a lower risk of hemodynamic decompensation (1.6% vs 5.0%; P<.01), there was a 10-fold increase in hemorrhagic stroke (2.0% vs 0.2%; P<.01). This has spurred considerable interest in USAT, where direct placement of the catheter into the clot, in addition to ultrasound-facilitated deeper clot penetration of tissue plasminogen activator,¹⁵ could reduce the thrombolytic dose to a fraction of that used systemically, potentially decreasing the risk of major bleeding while retaining the benefits of thrombolysis.^9,10

Few prior studies have evaluated the use of USAT for patients with submassive PE. ULTIMA⁹ (Randomized Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) was the first major randomized trial to compare USAT with heparin vs heparin alone in 59 patients diagnosed with acute submassive PE. Treatment with USAT was superior to heparin alone in reversing RV dilation (mean decrease in LV/RV ratio from 0.30 at baseline to 0.03 at 24 hours; P<.001) and RV-to-right atrial pressure gradient (surrogate for pulmonary artery systolic pressure; 9.8 mm Hg vs 0.3 mm Hg; P<.05). Even though there was a late “catch-up” in RV size in the heparin-treated group at 3-month follow-up, a significant difference in RV-to-right atrial pressure gradient persisted in favor of the USAT group. SEATTLE II¹⁰ (A Prospective, Single-arm, Multi-center Trial of EkoSonic Endovascular System and Activase for Treatment of Acute Pulmonary Embolism) was a study of 150 patients with massive and submassive PE treated with USAT. It showed significant improvement in RV/LV ratio (1.55 vs 1.13; P<.001) and pulmonary artery systolic pressure (51.4 mm Hg vs 36.9 mm Hg; P<.001) in the immediate postprocedure period.

The similarities and differences of our findings with these studies merit some discussion. As in prior investigations,^9,10,16,17 there was a significant improvement in RV/LV ratio, pulmonary artery pressures, and cardiac index post USAT in our study. Unlike these studies, however, we also demonstrated improvement in other pulmonary hemodynamic parameters such as pulmonary vascular resistance, RVSWI, and pulmonary artery pulsatility index. Although the moderate bleeding event rate was similar to these studies, no deaths or major bleeding events were noted in our study. Finally, most prior studies evaluated patients with acute submassive PE patients who presented within 14 days of symptom onset. However, the impact of early vs delayed administration of USAT on these surrogate measures or in-hospital clinical outcomes has not yet been investigated. Our findings provided this previously missing insight into the timing of treatment from diagnosis and showed that compared with delayed use of USAT, early use was associated with a greater improvement in pulmonary hemodynamics.

These findings, specifically those favoring early treatment, support the implementation of PERTs by an increasing number of institutions to tackle massive and submassive PEs in a multidisciplinary fashion, early and efficiently.¹¹ Similar to the treatment of acute ST-elevation myocardial infarction, a recent clot may be more amenable to thrombolysis that, in turn, is likely to shorten the duration of RV strain and injury, thereby promoting early recovery of RV function and improvement in right-sided hemodynamics. Early use of USAT, as a result of enhanced thrombolysis, can also potentially lower the chronic thrombus burden and reduce the development of chronic thromboembolic pulmonary hypertension (CTEPH). However, given the varying results on long-term incidence of CTEPH in patients with acute PE treated with systemic thrombolytics,^18-20 the clinical implications of our findings need to be evaluated in future USAT studies.

Study limitations. Our study findings should be viewed in light of their limitations. This was an observational study rather than a prospective randomized study; thus, any conclusions derived here should be interpreted as hypothesis generating. We evaluated time to treatment as the time interval from diagnosis to the use of USAT. Thus, even if a patient presented late after symptom onset and was intervened within 24 hours, he/she was included in the early-USAT group and vice versa. The decision to intervene early vs delayed and the timing of discharge were solely based on the subjective discretion of the consultant cardiologist. Operators were aware of the initial invasive hemodynamic findings during insertion of the catheters and the possibility of bias during repeat measurement could not be excluded. Finally, we evaluated a small number of patients at a single institution and provided a mechanistic insight into surrogates rather than hard clinical events. However, all markers we evaluated have been previously shown to have prognostic value in patients with RV dysfunction secondary to PE and other cardiovascular diseases. Increased RV/LV diameter ratio of >0.9 is a well-validated predictor of 6-month mortality in acute PE (odds ratio, 2.5; 95% confidence interval, 1.8-3.5).²¹ Pulmonary vascular resistance has been studied extensively in systemic thrombolysis trials and has been shown to be a sensitive prognostic marker in acute PE.²² Similarly, improvement in pulmonary vascular resistance in patients with CTEPH undergoing pulmonary thromboendarterectomy has been shown to be associated with lower mortality.²³ RVSWI is used to evaluate RV contractility and is routinely used to predict RV failure in patients receiving LV assist devices or heart transplants.²⁴ Pulmonary artery pulsatility index has been shown to predict in-hospital mortality in patients with acute inferior-wall myocardial infarction.²⁵ These data lend credence to our choice of surrogate outcome measures, but require future studies to demonstrate that these improvements are associated with better clinical outcomes in patients with acute submassive PE.

Conclusion

The consistent improvement in pulmonary hemodynamic parameters with no serious complications of death or major bleeding found in our study reinforces the utility of USAT as a safe and effective procedure for the management of acute submassive PE. Furthermore, the greater improvement in hemodynamic profile with early use of USAT lends support to the investment in PERTs for early and efficient multidisciplinary management of acute PE. Future studies are needed to understand the implications of USAT timing on long-term clinical outcomes.

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From the ¹Division of Cardiology, ²Department of Internal Medicine, and ³Department of Medical Education, St. John Hospital and Medical Center, Detroit, Michigan; and ⁴Duke Clinical Research Institute, Durham, North Carolina.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted November 1, 2017, final version accepted January 8, 2018.

Address for correspondence: Sushruth Edla MD, VEP, 2nd Floor Cath Lab, 22101 Moross Road, Detroit, MI 48236. Email: esushruth@gmail.com