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Catheter-directed ultrasound-accelerated thrombolysis for the treatment of acute pulmonary embolism
Thrombosis Research 128 (2011) 149–154
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Regular Article
Catheter-directed ultrasound-accelerated thrombolysis for the treatment of acute pulmonary embolism Tod C. Engelhardt a,⁎, Allen J. Taylor b, Lauren A. Simprini b, Nils Kucher c a b c
Thoracic Surgery, Louisiana Heart, Lung and Vascular Institute, Metairie, LA USA Department of Medicine, Cardiovascular Research Institute, Washington Hospital Center, Washington DC USA Venous Thromboembolism Research Group, Swiss Cardiovascular Center, University Hospital Bern, Switzerland
a r t i c l e
i n f o
Article history: Received 22 March 2011 Received in revised form 3 May 2011 Accepted 3 May 2011 Available online 8 June 2011 Keywords: Pulmonary embolism Thrombolysis Ultrasound accelerated thrombolysis
a b s t r a c t Background: Systemic thrombolysis rapidly improves right ventricular (RV) dysfunction in patients with acute pulmonary embolism (PE) but is associated with major bleeding complications in up to 20%. The efficacy of low-dose, catheter-directed ultrasound-accelerated thrombolysis (USAT) on the reversal of RV dysfunction is unknown. Materials and methods: We performed a retrospective analysis of 24 PE patients (60 ± 16 years) at intermediate (n = 19) or high risk (n = 5) from the East Jefferson General Hospital who were treated with USAT (mean rt-PA dose 33.5 ± 15.5 mg over 19.7 hours) and received multiplanar contrast-enhanced chest computed tomography (CT) scans at baseline and after USAT at 38 ± 14 hours. All CT measurements were performed by an independent core laboratory. Results: The right-to-left ventricular dimension ratio (RV/LV ratio) from reconstructed CT four-chamber views at baseline of 1.33 ± 0.24 was significantly reduced to 1.00 ± 0.13 at follow-up by repeated-measures analysis of variance (p b 0.001). The CT-angiographic pulmonary clot burden as assessed by the modified Miller score was significantly reduced from 17.8 ± 5.3 to 8.7 ± 5.1 (p b 0.001). All patients were discharged alive, and there were no systemic bleeding complications but four major access site bleeding complications requiring transfusion and one suspected recurrent massive PE event. Conclusions: In patients with intermediate and high risk PE, low-dose USAT rapidly reverses right ventricular dilatation and pulmonary clot burden. © 2011 Elsevier Ltd. All rights reserved.
Introduction Pulmonary embolism (PE) is a potentially life-threatening condition that afflicts an estimated 600,000 patients and between 50,000 to 200,000 deaths each year in the United States [1–3]. A majority of PE patients have a benign clinical course once therapeutic levels of anticoagulation are established. However, high-risk PE involving circulatory collapse or systemic arterial hypotension is associated with an early mortality rate of approximately 50%, in part from right ventricular failure [4]. Normotensive PE patients presenting with right ventricular dilatation or dysfunction are at intermediate risk of death or recurrent venous thromboembolism [4]. Abbreviations: RV, right ventricular; PE, pulmonary embolism; USAT, ultrasound accelerated thrombolysis; CDT, catheter-directed thrombolysis; rt-PA, recombinant tissue plasminogen activator; CT, computed tomography; RV/LV ratio, right-to-left ventricular dimension ratio; LOS, length-of-stay; IDDC, intelligent drug delivery catheter; MSD, microSonic device. ⁎ Corresponding author at: Thoracic Surgery (Cardiothoracic Vascular Surgery), Louisiana Heart, Lung and Vascular Institute, 4228 Houma Blvd Ste 300, Metairie, LA 70006 USA. Tel.: + 1 504 454 2222. E-mail address: [email protected] (T.C. Engelhardt). 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.05.014
Patients with high-risk PE and a low risk of bleeding should receive thrombolysis, as may patients with intermediate-risk PE [5]. In comparison to anticoagulation alone, systemic thrombolysis can reverse right ventricular dilatation within 24 hours of treatment [6,7]. Despite these effects, adverse effects including major hemorrhage (in up to 20%) and intracranial hemorrhage (in up to 3%) limit the use of thrombolysis [8]. Surgical pulmonary artery thrombectomy represents another high-risk treatment alternative, but carries a substantial risk of morbidity. Thus, there is a need for effective treatment alternatives for acute PE that facilitate the reversal of right ventricular dysfunction without causing an excess in systemic bleeding complications. The purpose of this study was to assess the hemodynamic effects of catheter-directed, ultrasound-accelerated thrombolysis (USAT) in patients with high- and intermediate-risk PE. Materials and methods Patients At the East Jefferson General Hospital, catheter-directed thrombolysis (CDT) is a standard procedure for patients with high and
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intermediate-risk PE. This report describes the treatment of 27 consecutive patients with high and intermediate-risk PE using combined treatment with catheter-directed USAT (EkoSonic Endovascular System, EKOS Corporation; Bothell; WA) and rt-PA (Genentech; San Francisco, CA) between February 2009 and July 2010. Patients were treated if they fulfilled all of the following criteria: a) dyspnea, hypoxia, or hemodynamic instability, b) evidence of PE by multi-detector contrast-enhanced computed tomography (CT), and c) right ventricular dysfunction by echocardiography or right-to-left ventricular dimension ratio N0.9 by CT. Written informed consent for catheter-directed thrombolysis was obtained in all patients prior to the procedure. Medical records were reviewed and clinical data including symptoms, risk factors for venous thromboembolism, treatment details, and length-of-stay (LOS) were recorded. Telephone followup was obtained in all 27 patients at 269 ± 139 days (minimum 64 days; maximum 584 days) following hospital discharge. Three patients were excluded from the analysis because no post-treatment contrast-enhanced CT was available; two were alive at follow-up and one had died from cancer. Retrospective data collection for this observational experience was approved by the local Institutional Review Board (EJ - TE-1002).
EkoSonic device The EKOS EkoSonic® Endovascular system (Fig. 1) delivers lowintensity ultrasound for the purpose of facilitated thrombolysis using low-dose fibrinolytic therapy. The ultrasound disaggregates fibrin strands, increases permeability of the clot, and disperses the fibrinolytic drug into clot through acoustic microstreaming effects [9,10]. The EkoSonic Endovascular System includes an Intelligent Drug Delivery Catheter (IDDC), MicroSonic Device (MSD) containing a series of miniature ultrasound transducers positioned along the treatment zone, and a Control Unit. The IDDC is a 5.2Fr multi-lumen sideport infusion catheter, with infusion lengths ranging from 6 to 50 cm, which accommodates the coaxial 0.035” MSD to deliver uniform radial ultrasound energy (2.2 MHz) to the entire infusion zone with simultaneous rt-PA infusion. The Control Unit continuously monitors treatment zone temperature measured by the IDDC's thermocouples and automatically adjusts delivered ultrasound power to optimize thrombolysis. The EkoSonic System has been previously cleared by the US FDA for the infusion of solutions into the
pulmonary arteries (K073166, April 22, 2008). Intravenous infusion of rt-PA is the approved route of administration for rt-PA. Treatment regimen All patients received low molecular weight heparin (Lovenox, Sanofi-Aventis, Bridgewater, NJ) using a standard weight-based algorithm (1 mg/kg/12 hours, subcutaneous) prior to, during, and after USAT treatment. The placement of the EkoSonic Endovascular System was performed in the cardiac catheterization laboratory. Venous access was obtained via the common femoral vein. In the first 14 patients, venous access was maintained with a 6 Fr introducer sheath (Boston Scientific; Natick, MA) and both right and left femoral veins were accessed in patients requiring placement of two EkoSonic devices. Beginning in February 2010 a 10 Fr dual lumen introducer sheath (FastCath Duo; St. Jude Medical; St. Paul, MN) was used requiring only one venous access site in patients receiving two EkoSonic devices. Following placement of the introducer sheath, a 260 cm guide wire (Cook, Inc.; Bloomington, IN) and 5 Fr angled pigtail catheter (Boston Scientific; Natick, MA) were advanced into the desired location in the pulmonary artery. The pigtail catheter was then removed and the EkoSonic IDDC was advanced over the guide wire until the treatment zone of the catheter was in the correct location directly within the embolus. The guide wire was then removed and replaced by the MSD containing the ultrasound transducers. Heparinized saline was infused through the central lumen of the IDDC and ultrasound delivery was initiated. Patients were transported to the Intensive Care Unit while rt-PA was being infused with simultaneous ultrasound delivery. Patients treated early in the series received rt-PA and ultrasound for approximately 24 hours. Infusion was discontinued when the cardiac catheterization laboratory was available for follow-up or if an adverse event occurred. In the last 7 patients, upon reaching maximum total dose of 20 mg rt-PA at 12 hours, the infusion and ultrasound were turned off and the EkoSonic devices were removed at bedside. Follow-up CT scans were performed after completion of treatment and removal of the EkoSonic Devices at 38 ± 14 hours (minimum 16 hours, maximum 79 hours). Definitions and endpoints Technical success was defined as successful placement of the EkoSonic device and initiation of the rt-PA infusion with simultaneous ultrasound delivery. The change from baseline to follow-up of the right-to-left ventricular dimension ratio (RV/LV ratio) was obtained
Fig. 1. EKOS EkoSonic® Endovascular system.
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from reconstructed CT four-chamber views [11,12]. The change from baseline to follow-up of the CT-angiographic pulmonary clot burden was assessed by the modified Miller score [13]. Major bleeding complications were defined as intracranial bleeding or bleeding severe enough to warrant cessation of therapy or blood transfusion. Minor bleeding complications were defined as bleeding manageable with local compression, sheath upsizing or fibrinolytic dose reduction. Data acquisition and statistical analysis CT images were acquired on a 64 slice helical CT scanner at one slice per second. Angiographic contrast material (Isovue 370) was infused at 5 ml per second for a total of 135 ml. For the baseline and follow-up CT measurements of RV/LV ratio and the modified Miller score, CT images were provided to an independent core laboratory for analysis (MedStar Health Research Institute, Washington Hospital, Washington, DC). The ungated contrast-enhanced helical CT scans were acquired and reconstructed at a 2 mm slice width with a B40f convolution kernel. Images were displayed on an off-line CT workstation (iCT; Philips Healthcare; Cleveland, OH) for analysis at a window width of 800–1000 and center of 50. Minimum intensity projections were viewed in axial and multiplanar reformats at a slice width of 2–10 mm. Subannular right and left ventricular dimensions were obtained from reconstructed four-chamber views, perpendicular to the interventricular septum and one centimeter apart from the atrioventricular annulus [11,12]. The pulmonary arteries were visually evaluated and semi-quantitated within each pulmonary artery segment (main, right or left, lobar or segmental) for the presence of clot (non-occlusive or occlusive). For the measurement of the modified Miller score (range 0 to 36), non-occlusive emboli were assigned a score of 1 and the number of emboli in an occluded vessel was multiplied by two [13]. Emboli in proximal pulmonary arteries were scored based on the number of supplied segmental pulmonary arteries. Discrete variables are reported as numbers with percentages and continuous data as mean and standard deviation. The change from baseline to follow-up of both the subannular RV/LV ratio and of the modified Miller score was assessed using one-way, repeatedmeasures analysis or variance (ANOVA). Analyses were performed using STATISTICA (version 8.0). Results Demographics and procedural details Mean age was 62 years and 46% of patients were male (Table 1). Twenty-three patients (96%) had a symptom duration of less than 14 days. Nineteen patients were at intermediate risk (normotensive, right ventricular dysfunction or dilatation) and 5 patients at high risk (transient or prolonged systemic hypotension). Two patients were receiving inotropic support prior to treatment. Fifteen (15) patients (62.5%) had at least one risk factor for bleeding complications, including age N70 years (n = 7), recent surgery (n = 7), cancer (n = 6), recent trauma (n = 2), severe renal dysfunction (n = 1) or pancreatitis (n = 1). Baseline mean right ventricular end diastolic diameter was 51.0 ± 8.0 mm and baseline mean left ventricular end diastolic diameter was 39.1 ± 5.7 mm. Technical success was achieved in all 24 patients. Nineteen patients (79%) presented with bilateral PE and received two EkoSonic devices. Five patients (21%) presented with unilateral PE and were treated with a single EkoSonic device. Overall, an initial bolus of 8.1 ± 2.3 mg rt-PA was administered followed by a continuous infusion of 0.8 ± 0.3 mg. Total mean rt-PA dose was 33.5 ± 15.5 mg administered over a mean infusion duration of 19.7 ± 8.1 hours via the EkoSonic device. The EkoSonic device was
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Table 1 Baseline characteristics. N = 24 Age, mean (range) Male (%) Comorbidities (%) Concomitant deep vein thrombosis Hypertension Hypercholesterolemia Recent major surgery Diabetes Cancer Coronary artery disease Tobacco use Recent trauma Congestive heart failure Hepatic or renal insufficiency Pancreatitis Prior PE Symptoms and hemodynamic status Dyspnea Hypoxemia Tachycardia Chest pain Hemoptysis Transient systemic hypotension Prolonged systemic hypotension Syncope Cough Cardiogenic shock Mechanical ventilation
61.7 ± 15.9 (32–85) 11 (46%) 21 12 9 7 6 6 4 3 2 1 1 1 1
(88%) (50%) (38%) (29%) (25%) (25%) (17%) (13%) (8%) (4%) (4%) (4%) (4%)
21 13 11 4 3 3 2 2 1 1 1
(88%) (54%) (46%) (17%) (13%) (13%) (8%) (8%) (4%) (4%) (4%)
removed promptly when the infusion was completed. In the first 13 patients, no upper limits on the bolus or total rt-PA dose and the infusion duration were planned. After the occurrence of bleeding complications, the rt-PA bolus was reduced, the maximum allowed total rt-PA dose was limited to 24 mg and the maximum allowed infusion duration to 24 hours (Table 2). End-point analyses Follow-up contrast enhanced CT studies were performed after 38 ± 14 hours. No patients were receiving inotropic support at follow-up CT. The RV/LV ratio decreased from 1.33 ± 0.24 to 1.00 ± 0.13 at follow-up (pb 0.001) (Figs. 2 and 3). The mean right ventricular end diastolic diameter was reduced from 51.0 ± 8.0 mm to 43.7 ± 6.4 mm and the mean left ventricular end diastolic diameter increased from 39.1 ± 5.7 mm to 43.8 ± 6.7 mm. The modified Miller score was significantly reduced from 17.8 ± 5.3 to 8.7 ± 5.1 (pb 0.001). Clinical outcomes All patients survived to hospital discharge with an average length of hospital stay of 11 ± 10 days (range, 2 – 46 days; median 7 days). The average duration of stay in the intensive care unit was 4 days
Table 2 Dose regimens for recombinant tissue plasminogen activator administered via the EkoSonic devices.
Total bolus, mean ± SD, mg Bolus per device, mean ± SD, mg Total infusion rate, mean ± SD, mg Infusion duration, mean ± SD, hours Total dose, mean ± SD, mg
High dose group* (N = 13)
Low dose group** (N = 11)
7.9 ± 2.9 5.2 ± 1.5 1.0 ± 0.0 21 ± 8 47.4 ± 18.9
8.4 ± 1.3 4.2 ± 0.6 0.5 ± 0.2 15 ± 4 20.2 ± 2.6 mg
* In the high dose group, 8 patients had 2 EkoSonic devices and 5 patients had 1 device. ** The maximum allowed total rt-PA dose was limited to 24 mg and the maximum allowed infusion duration to 24 hours. In this group, all 11 patients had 2 catheters.
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Fig. 2. Paired chart of pre and post RV/LV ratio.
(median 2 days). One patient had suspected recurrent massive PE one day after completed USAT and received rescue thrombolysis with 100 mg rt-PA administered intravenously over 2 hours. There were no systemic bleeding complications but 4 patients (16.7%) from the high-dose rt-PA group suffered major access-site bleeding and required transfusion of packed red blood cells. The 4 patients requiring transfusion received an average total rt-PA dose of 45 mg infused over 22.5 hours. Two additional patients from the highdose rt-PA group (8.3%) had inguinal puncture-site hematoma requiring no intervention. No minor or major bleeding complications occurred in the low-dose rt-PA patients. Improvement in RV/LV ratio and modified Miller score was similar in the low-dose and high-dose rt-PA patients. (Figs. 4 and 5). At the time of follow up, five patients had died, four from cancer and one from pre-existing chronic lung disease. There were no diagnosed recurrent clinical venous thromboembolic events during follow-up.
Discussion This study demonstrates the rapid reversal of right ventricular dilation and reduction in pulmonary clot burden among patients with intermediate and high risk PE who were treated with catheterdirected USAT. Other than access site bleeding, the device appeared to be associated with a favorable side effect profile. This study provides the first demonstration of the feasibility and clinical effects of a pharmacomechanical catheter intervention using low-dose thrombolysis and ultrasound to rapidly improve right ventricular dysfunction in patients with acute PE. Guidelines support the use of thrombolysis in the management of high and intermediate risk PE [5]. In a randomized study of patients with intermediate risk PE, the Tenecteplase Italian Pulmonary Embolism (TIPES) trial, weight-adjusted intravenous tenecteplase reduced the RV/LV ratio from 1.36 at baseline to 1.04 over 24 hours
Fig. 3. Paired chart of pre and post modified Miller index.
T.C. Engelhardt et al. / Thrombosis Research 128 (2011) 149–154
Fig. 4. Bar and whisker plots of the mean change of RV/LV ratio from baseline to followup for the high-dose and low-dose rt-PA groups. The mean change of RV/LV ratio of 0.34 ± 0.049 for the high-dose group was similar to the mean change of RV/LV ratio of 0.29 ± 0.087 for the low-dose group (p = 0.54).
[6]. The control group of this study received unfractionated heparin without thrombolysis, and there was no significant reversal of right ventricular dilatation with an RV/LV ratio of 1.32 at baseline and 1.22 at 24 hours (RV/LV ratio mean absolute reduction 0.10). The observed hemodynamic effect of USAT including low dose thrombolysis appears to be similar to the effect seen with full-dose intravenous thrombolysis. Notably, the baseline extent of right ventricular dilatation in the TIPES (RV/LV ratio 1.36) and our study (RV/LV ratio 1.33) were similar, as was the effect of the thrombolysis intervention on reversing right ventricular dilatation. However, the hemodynamic effects in the TIPES and our study should be compared with caution because 1) different imaging techniques of measuring RV/LV ratio (echocardiography in TIPES, non-gated CT in our study), and 2) different intervals of the follow-up imaging (24 hours in TIPES and 38 hours in our study) were used. An ongoing randomized controlled clinical trial (NCT01166997) is comparing the effectiveness of USAT and anticoagulation alone for reversing right ventricular dilatation within 24 hours in patients with intermediate risk PE.
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Although all patients were discharged alive in our study, the clinical efficacy and safety of USAT in patients with acute PE can only be investigated with a large clinical trial. The finding of several accessrelated bleeding complications suggests that the total rt-PA dose should be kept ≤24 mg during 15 hours infusion time. Complications of pulmonary catheter interventions have not been reported with the EkoSonic System but may include perforation or dissection of cardiovascular structures, pericardial tamponade, pulmonary hemorrhage, and distal thrombus embolization [14]. Other potential complications include blood loss, arrhythmia, contrast-induced nephropathy, anaphylactic reaction to iodine contrast, and vascular access complications such as hematoma, pseudoaneurysm, or AV fistula [14]. Early in vitro studies have demonstrated that vascular blood clots dissolve more rapidly when exposed to ultrasound and urokinase or rt-PA, with no thrombolytic effect observed from ultrasound alone [9,10,15–17]. Ultrasound accelerates thrombolysis by disaggregating fibrin stands and increasing the permeability of the clot. Acoustic pressure waves and micro-streaming effects force infused thrombolytic agent into the thrombus, permeating throughout the thrombus and binding with exposed plasminogen receptor sites. The bound rt-PA is then protected from deactivation by anti-plasmin proteins. The EKOS system has been used in patients with stroke [18], peripheral arterial occlusion [19], DVT [20] and PE [21,22]. Chamsuddin et al. reported successful USAT treatment in 10 acute PE patients [21]. Lin et al. reported results of a retrospective study in 25 patients with massive PE that suggested higher treatment success, reduced thrombolytic infusion times, lower thrombolytic dosage and fewer complications compared to non-ultrasound assisted CDT [22]. This study has several limitations. The retrospective nature of the study indicates the findings should be interpreted cautiously; particularly because the number of patients is small (24) and there are no controls. A prospective trial is underway to determine the comparative effectiveness of this intervention to standard of care. Changes in RV/LV ratio represent a surrogate for outcomes in the treatment of acute PE. Although such measurements have been associated with favorable outcomes, clinical endpoint trials are needed to understand the net health effects of this intervention. Finally, our study was not designed to investigate the contribution of single treatment components, i.e., thrombolysis, ultrasound, and anticoagulation therapy, on the recovery of right ventricular dilatation and clot burden. In conclusion, low-dose USAT rapidly improved right ventricular dilatation and thrombus size in studied patients with intermediate and high risk PE. Future prospective randomized, controlled studies are needed to determine the clinical efficacy and safety of USAT for patients with acute PE. Conflict of Interest Statement EKOS Corporation provided payment for the independent core laboratory analysis (MedStar, Washington Hospital, Washington DC). Dr. Kucher reports receiving honoraria from Boehringer Ingelheim, EKOS Corporation, GlaxoSmithKline, and Sanofi-Aventis. Drs. Engelhardt, Taylor, and Simprini have no conflict of interest to report. Acknowledgements We are thankful for editorial support provided by Elise Wolf. References
Fig. 5. Box and whisker plots of pre and post modified Miller index from baseline to follow-up for the high-dose and low-dose rt-PA groups. The mean change of the modified Miller index of 9.3 ± 2.0 for the high-dose group was similar to the mean change of Miller index of 8.5 ± 1.9 for the low-dose group (p = 0.45).
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[3] Dalen JE, Alper JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:259–70. [4] Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–9. [5] Kearon C, Kahn S, Agnelli G, Goldhaber G, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence based clinical practice guidelines. Chest, 8th edition, 133(6 Suppl); 2008. p. 454S–545S. [6] Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res 2010;125:e82–6. [7] Konstantinides S, Tiede N, Geibel A, Olschewski M, Just H, Kasper W. Comparison of alteplase versus heparin for resolution of major pulmonary embolism. Am J Cardiol 1998;82:966–70. [8] Goldhaber SZ. Pulmonary embolism. N Engl J Med 1998;339:93–104. [9] Braaten JV, Goss RA, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost 1997;78:1063–8. [10] Francis C, Blinc A, Lee S, Cox C. Ultrasound accelerates transport of recombinant of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol 1995;21:419–24. [11] Quiroz R, Kucher N, Schoepf UJ, et al. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation 2004;109:2401–4. [12] Schoepf UJ, Kucher N, Kipfmueller F, Quiroz R, Costello P, Goldhaber SZ. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation 2004;110:3276–80.
[13] Araoz PA, Gotway MB, Harrington JR, Harmsen WS, Mandrekar JN. Pulmonary embolism: prognostic CT findings. Radiology 2007;242:889–97. [14] Kucker N, Goldhaber SZ. Management of massive pulmonary embolism. Circulation 2005;112:e28–32. [15] Siddiqi F, Odrljin TM, Fay PJ, Cox C, Francis CW. Binding of tissue-plasminogen activator to fibrin: Effect of ultrasound. Blood 1997;91:2019–25. [16] Lauer CG, Burge R, Tang DB, Bass BG, Gomez ER, Alving BM. Effect of ultrasound on tissue-type plasminogen activator-induced thrombolysis. Circulation 1992;86: 1257–64. [17] Harpaz D, Chen X, Francis CW, Marder VJ, Meltzer RS. Ultrasound enhancement of thrombolysis and reperfusion in vitro. J Am Coll Cardiol 1993;21:1507–11. [18] IMS II Trial Investigators. Interventional Management of Stroke (IMS) II Study. Stroke 2007;38:2127–35. [19] Wissgott C, Richter A, Kamsuella P, Steinkamp HJ. Treatment of critical limb ischemia using ultrasound enhanced thrombolysis (PARES-Trial): final results. J Endovasc Ther 2007;14:438–43. [20] Parikh S, Motarjeme A, McNamara T, et al. Ultrasound accelerated thrombolysis for the treatment of deep vein thrombosis: initial clinical experience. J Vasc Interv Radiol 2008;19:521–3. [21] Chamsuddin A, Nazzal L, Kang B, et al. Catheter-directed Thrombolysis with the Endowave System in the Treatment of Acute Massive Pulmonary Embolism: A Retrospective Multicenter Case Series. J Vasc Interv Radiol 2008;19:372–6. [22] Lin PH, Annambhotla S, Bechara CF, et al. Comparison of percutaneous ultrasoundaccelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular 2009;17(Suppl 3):S137–47.
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Regular Article
Catheter-directed ultrasound-accelerated thrombolysis for the treatment of acute pulmonary embolism Tod C. Engelhardt a,⁎, Allen J. Taylor b, Lauren A. Simprini b, Nils Kucher c a b c
Thoracic Surgery, Louisiana Heart, Lung and Vascular Institute, Metairie, LA USA Department of Medicine, Cardiovascular Research Institute, Washington Hospital Center, Washington DC USA Venous Thromboembolism Research Group, Swiss Cardiovascular Center, University Hospital Bern, Switzerland
a r t i c l e
i n f o
Article history: Received 22 March 2011 Received in revised form 3 May 2011 Accepted 3 May 2011 Available online 8 June 2011 Keywords: Pulmonary embolism Thrombolysis Ultrasound accelerated thrombolysis
a b s t r a c t Background: Systemic thrombolysis rapidly improves right ventricular (RV) dysfunction in patients with acute pulmonary embolism (PE) but is associated with major bleeding complications in up to 20%. The efficacy of low-dose, catheter-directed ultrasound-accelerated thrombolysis (USAT) on the reversal of RV dysfunction is unknown. Materials and methods: We performed a retrospective analysis of 24 PE patients (60 ± 16 years) at intermediate (n = 19) or high risk (n = 5) from the East Jefferson General Hospital who were treated with USAT (mean rt-PA dose 33.5 ± 15.5 mg over 19.7 hours) and received multiplanar contrast-enhanced chest computed tomography (CT) scans at baseline and after USAT at 38 ± 14 hours. All CT measurements were performed by an independent core laboratory. Results: The right-to-left ventricular dimension ratio (RV/LV ratio) from reconstructed CT four-chamber views at baseline of 1.33 ± 0.24 was significantly reduced to 1.00 ± 0.13 at follow-up by repeated-measures analysis of variance (p b 0.001). The CT-angiographic pulmonary clot burden as assessed by the modified Miller score was significantly reduced from 17.8 ± 5.3 to 8.7 ± 5.1 (p b 0.001). All patients were discharged alive, and there were no systemic bleeding complications but four major access site bleeding complications requiring transfusion and one suspected recurrent massive PE event. Conclusions: In patients with intermediate and high risk PE, low-dose USAT rapidly reverses right ventricular dilatation and pulmonary clot burden. © 2011 Elsevier Ltd. All rights reserved.
Introduction Pulmonary embolism (PE) is a potentially life-threatening condition that afflicts an estimated 600,000 patients and between 50,000 to 200,000 deaths each year in the United States [1–3]. A majority of PE patients have a benign clinical course once therapeutic levels of anticoagulation are established. However, high-risk PE involving circulatory collapse or systemic arterial hypotension is associated with an early mortality rate of approximately 50%, in part from right ventricular failure [4]. Normotensive PE patients presenting with right ventricular dilatation or dysfunction are at intermediate risk of death or recurrent venous thromboembolism [4]. Abbreviations: RV, right ventricular; PE, pulmonary embolism; USAT, ultrasound accelerated thrombolysis; CDT, catheter-directed thrombolysis; rt-PA, recombinant tissue plasminogen activator; CT, computed tomography; RV/LV ratio, right-to-left ventricular dimension ratio; LOS, length-of-stay; IDDC, intelligent drug delivery catheter; MSD, microSonic device. ⁎ Corresponding author at: Thoracic Surgery (Cardiothoracic Vascular Surgery), Louisiana Heart, Lung and Vascular Institute, 4228 Houma Blvd Ste 300, Metairie, LA 70006 USA. Tel.: + 1 504 454 2222. E-mail address: [email protected] (T.C. Engelhardt). 0049-3848/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2011.05.014
Patients with high-risk PE and a low risk of bleeding should receive thrombolysis, as may patients with intermediate-risk PE [5]. In comparison to anticoagulation alone, systemic thrombolysis can reverse right ventricular dilatation within 24 hours of treatment [6,7]. Despite these effects, adverse effects including major hemorrhage (in up to 20%) and intracranial hemorrhage (in up to 3%) limit the use of thrombolysis [8]. Surgical pulmonary artery thrombectomy represents another high-risk treatment alternative, but carries a substantial risk of morbidity. Thus, there is a need for effective treatment alternatives for acute PE that facilitate the reversal of right ventricular dysfunction without causing an excess in systemic bleeding complications. The purpose of this study was to assess the hemodynamic effects of catheter-directed, ultrasound-accelerated thrombolysis (USAT) in patients with high- and intermediate-risk PE. Materials and methods Patients At the East Jefferson General Hospital, catheter-directed thrombolysis (CDT) is a standard procedure for patients with high and
150
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intermediate-risk PE. This report describes the treatment of 27 consecutive patients with high and intermediate-risk PE using combined treatment with catheter-directed USAT (EkoSonic Endovascular System, EKOS Corporation; Bothell; WA) and rt-PA (Genentech; San Francisco, CA) between February 2009 and July 2010. Patients were treated if they fulfilled all of the following criteria: a) dyspnea, hypoxia, or hemodynamic instability, b) evidence of PE by multi-detector contrast-enhanced computed tomography (CT), and c) right ventricular dysfunction by echocardiography or right-to-left ventricular dimension ratio N0.9 by CT. Written informed consent for catheter-directed thrombolysis was obtained in all patients prior to the procedure. Medical records were reviewed and clinical data including symptoms, risk factors for venous thromboembolism, treatment details, and length-of-stay (LOS) were recorded. Telephone followup was obtained in all 27 patients at 269 ± 139 days (minimum 64 days; maximum 584 days) following hospital discharge. Three patients were excluded from the analysis because no post-treatment contrast-enhanced CT was available; two were alive at follow-up and one had died from cancer. Retrospective data collection for this observational experience was approved by the local Institutional Review Board (EJ - TE-1002).
EkoSonic device The EKOS EkoSonic® Endovascular system (Fig. 1) delivers lowintensity ultrasound for the purpose of facilitated thrombolysis using low-dose fibrinolytic therapy. The ultrasound disaggregates fibrin strands, increases permeability of the clot, and disperses the fibrinolytic drug into clot through acoustic microstreaming effects [9,10]. The EkoSonic Endovascular System includes an Intelligent Drug Delivery Catheter (IDDC), MicroSonic Device (MSD) containing a series of miniature ultrasound transducers positioned along the treatment zone, and a Control Unit. The IDDC is a 5.2Fr multi-lumen sideport infusion catheter, with infusion lengths ranging from 6 to 50 cm, which accommodates the coaxial 0.035” MSD to deliver uniform radial ultrasound energy (2.2 MHz) to the entire infusion zone with simultaneous rt-PA infusion. The Control Unit continuously monitors treatment zone temperature measured by the IDDC's thermocouples and automatically adjusts delivered ultrasound power to optimize thrombolysis. The EkoSonic System has been previously cleared by the US FDA for the infusion of solutions into the
pulmonary arteries (K073166, April 22, 2008). Intravenous infusion of rt-PA is the approved route of administration for rt-PA. Treatment regimen All patients received low molecular weight heparin (Lovenox, Sanofi-Aventis, Bridgewater, NJ) using a standard weight-based algorithm (1 mg/kg/12 hours, subcutaneous) prior to, during, and after USAT treatment. The placement of the EkoSonic Endovascular System was performed in the cardiac catheterization laboratory. Venous access was obtained via the common femoral vein. In the first 14 patients, venous access was maintained with a 6 Fr introducer sheath (Boston Scientific; Natick, MA) and both right and left femoral veins were accessed in patients requiring placement of two EkoSonic devices. Beginning in February 2010 a 10 Fr dual lumen introducer sheath (FastCath Duo; St. Jude Medical; St. Paul, MN) was used requiring only one venous access site in patients receiving two EkoSonic devices. Following placement of the introducer sheath, a 260 cm guide wire (Cook, Inc.; Bloomington, IN) and 5 Fr angled pigtail catheter (Boston Scientific; Natick, MA) were advanced into the desired location in the pulmonary artery. The pigtail catheter was then removed and the EkoSonic IDDC was advanced over the guide wire until the treatment zone of the catheter was in the correct location directly within the embolus. The guide wire was then removed and replaced by the MSD containing the ultrasound transducers. Heparinized saline was infused through the central lumen of the IDDC and ultrasound delivery was initiated. Patients were transported to the Intensive Care Unit while rt-PA was being infused with simultaneous ultrasound delivery. Patients treated early in the series received rt-PA and ultrasound for approximately 24 hours. Infusion was discontinued when the cardiac catheterization laboratory was available for follow-up or if an adverse event occurred. In the last 7 patients, upon reaching maximum total dose of 20 mg rt-PA at 12 hours, the infusion and ultrasound were turned off and the EkoSonic devices were removed at bedside. Follow-up CT scans were performed after completion of treatment and removal of the EkoSonic Devices at 38 ± 14 hours (minimum 16 hours, maximum 79 hours). Definitions and endpoints Technical success was defined as successful placement of the EkoSonic device and initiation of the rt-PA infusion with simultaneous ultrasound delivery. The change from baseline to follow-up of the right-to-left ventricular dimension ratio (RV/LV ratio) was obtained
Fig. 1. EKOS EkoSonic® Endovascular system.
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from reconstructed CT four-chamber views [11,12]. The change from baseline to follow-up of the CT-angiographic pulmonary clot burden was assessed by the modified Miller score [13]. Major bleeding complications were defined as intracranial bleeding or bleeding severe enough to warrant cessation of therapy or blood transfusion. Minor bleeding complications were defined as bleeding manageable with local compression, sheath upsizing or fibrinolytic dose reduction. Data acquisition and statistical analysis CT images were acquired on a 64 slice helical CT scanner at one slice per second. Angiographic contrast material (Isovue 370) was infused at 5 ml per second for a total of 135 ml. For the baseline and follow-up CT measurements of RV/LV ratio and the modified Miller score, CT images were provided to an independent core laboratory for analysis (MedStar Health Research Institute, Washington Hospital, Washington, DC). The ungated contrast-enhanced helical CT scans were acquired and reconstructed at a 2 mm slice width with a B40f convolution kernel. Images were displayed on an off-line CT workstation (iCT; Philips Healthcare; Cleveland, OH) for analysis at a window width of 800–1000 and center of 50. Minimum intensity projections were viewed in axial and multiplanar reformats at a slice width of 2–10 mm. Subannular right and left ventricular dimensions were obtained from reconstructed four-chamber views, perpendicular to the interventricular septum and one centimeter apart from the atrioventricular annulus [11,12]. The pulmonary arteries were visually evaluated and semi-quantitated within each pulmonary artery segment (main, right or left, lobar or segmental) for the presence of clot (non-occlusive or occlusive). For the measurement of the modified Miller score (range 0 to 36), non-occlusive emboli were assigned a score of 1 and the number of emboli in an occluded vessel was multiplied by two [13]. Emboli in proximal pulmonary arteries were scored based on the number of supplied segmental pulmonary arteries. Discrete variables are reported as numbers with percentages and continuous data as mean and standard deviation. The change from baseline to follow-up of both the subannular RV/LV ratio and of the modified Miller score was assessed using one-way, repeatedmeasures analysis or variance (ANOVA). Analyses were performed using STATISTICA (version 8.0). Results Demographics and procedural details Mean age was 62 years and 46% of patients were male (Table 1). Twenty-three patients (96%) had a symptom duration of less than 14 days. Nineteen patients were at intermediate risk (normotensive, right ventricular dysfunction or dilatation) and 5 patients at high risk (transient or prolonged systemic hypotension). Two patients were receiving inotropic support prior to treatment. Fifteen (15) patients (62.5%) had at least one risk factor for bleeding complications, including age N70 years (n = 7), recent surgery (n = 7), cancer (n = 6), recent trauma (n = 2), severe renal dysfunction (n = 1) or pancreatitis (n = 1). Baseline mean right ventricular end diastolic diameter was 51.0 ± 8.0 mm and baseline mean left ventricular end diastolic diameter was 39.1 ± 5.7 mm. Technical success was achieved in all 24 patients. Nineteen patients (79%) presented with bilateral PE and received two EkoSonic devices. Five patients (21%) presented with unilateral PE and were treated with a single EkoSonic device. Overall, an initial bolus of 8.1 ± 2.3 mg rt-PA was administered followed by a continuous infusion of 0.8 ± 0.3 mg. Total mean rt-PA dose was 33.5 ± 15.5 mg administered over a mean infusion duration of 19.7 ± 8.1 hours via the EkoSonic device. The EkoSonic device was
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Table 1 Baseline characteristics. N = 24 Age, mean (range) Male (%) Comorbidities (%) Concomitant deep vein thrombosis Hypertension Hypercholesterolemia Recent major surgery Diabetes Cancer Coronary artery disease Tobacco use Recent trauma Congestive heart failure Hepatic or renal insufficiency Pancreatitis Prior PE Symptoms and hemodynamic status Dyspnea Hypoxemia Tachycardia Chest pain Hemoptysis Transient systemic hypotension Prolonged systemic hypotension Syncope Cough Cardiogenic shock Mechanical ventilation
61.7 ± 15.9 (32–85) 11 (46%) 21 12 9 7 6 6 4 3 2 1 1 1 1
(88%) (50%) (38%) (29%) (25%) (25%) (17%) (13%) (8%) (4%) (4%) (4%) (4%)
21 13 11 4 3 3 2 2 1 1 1
(88%) (54%) (46%) (17%) (13%) (13%) (8%) (8%) (4%) (4%) (4%)
removed promptly when the infusion was completed. In the first 13 patients, no upper limits on the bolus or total rt-PA dose and the infusion duration were planned. After the occurrence of bleeding complications, the rt-PA bolus was reduced, the maximum allowed total rt-PA dose was limited to 24 mg and the maximum allowed infusion duration to 24 hours (Table 2). End-point analyses Follow-up contrast enhanced CT studies were performed after 38 ± 14 hours. No patients were receiving inotropic support at follow-up CT. The RV/LV ratio decreased from 1.33 ± 0.24 to 1.00 ± 0.13 at follow-up (pb 0.001) (Figs. 2 and 3). The mean right ventricular end diastolic diameter was reduced from 51.0 ± 8.0 mm to 43.7 ± 6.4 mm and the mean left ventricular end diastolic diameter increased from 39.1 ± 5.7 mm to 43.8 ± 6.7 mm. The modified Miller score was significantly reduced from 17.8 ± 5.3 to 8.7 ± 5.1 (pb 0.001). Clinical outcomes All patients survived to hospital discharge with an average length of hospital stay of 11 ± 10 days (range, 2 – 46 days; median 7 days). The average duration of stay in the intensive care unit was 4 days
Table 2 Dose regimens for recombinant tissue plasminogen activator administered via the EkoSonic devices.
Total bolus, mean ± SD, mg Bolus per device, mean ± SD, mg Total infusion rate, mean ± SD, mg Infusion duration, mean ± SD, hours Total dose, mean ± SD, mg
High dose group* (N = 13)
Low dose group** (N = 11)
7.9 ± 2.9 5.2 ± 1.5 1.0 ± 0.0 21 ± 8 47.4 ± 18.9
8.4 ± 1.3 4.2 ± 0.6 0.5 ± 0.2 15 ± 4 20.2 ± 2.6 mg
* In the high dose group, 8 patients had 2 EkoSonic devices and 5 patients had 1 device. ** The maximum allowed total rt-PA dose was limited to 24 mg and the maximum allowed infusion duration to 24 hours. In this group, all 11 patients had 2 catheters.
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Fig. 2. Paired chart of pre and post RV/LV ratio.
(median 2 days). One patient had suspected recurrent massive PE one day after completed USAT and received rescue thrombolysis with 100 mg rt-PA administered intravenously over 2 hours. There were no systemic bleeding complications but 4 patients (16.7%) from the high-dose rt-PA group suffered major access-site bleeding and required transfusion of packed red blood cells. The 4 patients requiring transfusion received an average total rt-PA dose of 45 mg infused over 22.5 hours. Two additional patients from the highdose rt-PA group (8.3%) had inguinal puncture-site hematoma requiring no intervention. No minor or major bleeding complications occurred in the low-dose rt-PA patients. Improvement in RV/LV ratio and modified Miller score was similar in the low-dose and high-dose rt-PA patients. (Figs. 4 and 5). At the time of follow up, five patients had died, four from cancer and one from pre-existing chronic lung disease. There were no diagnosed recurrent clinical venous thromboembolic events during follow-up.
Discussion This study demonstrates the rapid reversal of right ventricular dilation and reduction in pulmonary clot burden among patients with intermediate and high risk PE who were treated with catheterdirected USAT. Other than access site bleeding, the device appeared to be associated with a favorable side effect profile. This study provides the first demonstration of the feasibility and clinical effects of a pharmacomechanical catheter intervention using low-dose thrombolysis and ultrasound to rapidly improve right ventricular dysfunction in patients with acute PE. Guidelines support the use of thrombolysis in the management of high and intermediate risk PE [5]. In a randomized study of patients with intermediate risk PE, the Tenecteplase Italian Pulmonary Embolism (TIPES) trial, weight-adjusted intravenous tenecteplase reduced the RV/LV ratio from 1.36 at baseline to 1.04 over 24 hours
Fig. 3. Paired chart of pre and post modified Miller index.
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Fig. 4. Bar and whisker plots of the mean change of RV/LV ratio from baseline to followup for the high-dose and low-dose rt-PA groups. The mean change of RV/LV ratio of 0.34 ± 0.049 for the high-dose group was similar to the mean change of RV/LV ratio of 0.29 ± 0.087 for the low-dose group (p = 0.54).
[6]. The control group of this study received unfractionated heparin without thrombolysis, and there was no significant reversal of right ventricular dilatation with an RV/LV ratio of 1.32 at baseline and 1.22 at 24 hours (RV/LV ratio mean absolute reduction 0.10). The observed hemodynamic effect of USAT including low dose thrombolysis appears to be similar to the effect seen with full-dose intravenous thrombolysis. Notably, the baseline extent of right ventricular dilatation in the TIPES (RV/LV ratio 1.36) and our study (RV/LV ratio 1.33) were similar, as was the effect of the thrombolysis intervention on reversing right ventricular dilatation. However, the hemodynamic effects in the TIPES and our study should be compared with caution because 1) different imaging techniques of measuring RV/LV ratio (echocardiography in TIPES, non-gated CT in our study), and 2) different intervals of the follow-up imaging (24 hours in TIPES and 38 hours in our study) were used. An ongoing randomized controlled clinical trial (NCT01166997) is comparing the effectiveness of USAT and anticoagulation alone for reversing right ventricular dilatation within 24 hours in patients with intermediate risk PE.
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Although all patients were discharged alive in our study, the clinical efficacy and safety of USAT in patients with acute PE can only be investigated with a large clinical trial. The finding of several accessrelated bleeding complications suggests that the total rt-PA dose should be kept ≤24 mg during 15 hours infusion time. Complications of pulmonary catheter interventions have not been reported with the EkoSonic System but may include perforation or dissection of cardiovascular structures, pericardial tamponade, pulmonary hemorrhage, and distal thrombus embolization [14]. Other potential complications include blood loss, arrhythmia, contrast-induced nephropathy, anaphylactic reaction to iodine contrast, and vascular access complications such as hematoma, pseudoaneurysm, or AV fistula [14]. Early in vitro studies have demonstrated that vascular blood clots dissolve more rapidly when exposed to ultrasound and urokinase or rt-PA, with no thrombolytic effect observed from ultrasound alone [9,10,15–17]. Ultrasound accelerates thrombolysis by disaggregating fibrin stands and increasing the permeability of the clot. Acoustic pressure waves and micro-streaming effects force infused thrombolytic agent into the thrombus, permeating throughout the thrombus and binding with exposed plasminogen receptor sites. The bound rt-PA is then protected from deactivation by anti-plasmin proteins. The EKOS system has been used in patients with stroke [18], peripheral arterial occlusion [19], DVT [20] and PE [21,22]. Chamsuddin et al. reported successful USAT treatment in 10 acute PE patients [21]. Lin et al. reported results of a retrospective study in 25 patients with massive PE that suggested higher treatment success, reduced thrombolytic infusion times, lower thrombolytic dosage and fewer complications compared to non-ultrasound assisted CDT [22]. This study has several limitations. The retrospective nature of the study indicates the findings should be interpreted cautiously; particularly because the number of patients is small (24) and there are no controls. A prospective trial is underway to determine the comparative effectiveness of this intervention to standard of care. Changes in RV/LV ratio represent a surrogate for outcomes in the treatment of acute PE. Although such measurements have been associated with favorable outcomes, clinical endpoint trials are needed to understand the net health effects of this intervention. Finally, our study was not designed to investigate the contribution of single treatment components, i.e., thrombolysis, ultrasound, and anticoagulation therapy, on the recovery of right ventricular dilatation and clot burden. In conclusion, low-dose USAT rapidly improved right ventricular dilatation and thrombus size in studied patients with intermediate and high risk PE. Future prospective randomized, controlled studies are needed to determine the clinical efficacy and safety of USAT for patients with acute PE. Conflict of Interest Statement EKOS Corporation provided payment for the independent core laboratory analysis (MedStar, Washington Hospital, Washington DC). Dr. Kucher reports receiving honoraria from Boehringer Ingelheim, EKOS Corporation, GlaxoSmithKline, and Sanofi-Aventis. Drs. Engelhardt, Taylor, and Simprini have no conflict of interest to report. Acknowledgements We are thankful for editorial support provided by Elise Wolf. References
Fig. 5. Box and whisker plots of pre and post modified Miller index from baseline to follow-up for the high-dose and low-dose rt-PA groups. The mean change of the modified Miller index of 9.3 ± 2.0 for the high-dose group was similar to the mean change of Miller index of 8.5 ± 1.9 for the low-dose group (p = 0.45).
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