Curr Treat Options Cardio Med (2014) 16:336 DOI 10.1007/s11936-014-0336-z

Vascular Disease (R Schainfeld, Section Editor)

Acute Pulmonary Embolus: The Next Frontier in Venous Thromboembolic Interventions Tod C. Engelhardt, MD, FACS Address Cardiovascular and Thoracic Surgery, Louisiana Heart, Lung and Vascular Institute, East Jefferson General Hospital, 4228 Houma Blvd Ste 300, Metairie, LA 70006, USA Email: [email protected]

* Springer Science+Business Media New York 2014

This article is part of the Topical Collection on Vascular Disease Keywords Ultrasound I Pulmonary embolism I rt-PA I Thrombus I Catheter I Infusion I Massive I Submassive I Catheter-directed therapy I Thrombolytic I Thrombolysis I RV dysfunction I RV/LV ratio I Hemodynamic

Opinion statement Submassive pulmonary embolism (PE) represents a patient population that is under-recognized and under-treated. Recent clinical trials demonstrated the hemodynamic benefit of IV thrombolytic therapy among these patients; however, it came at the cost of a significantly increased risk of major, particularly intracranial, hemorrhage. Catheter-based treatment modalities have garnered considerable clinical interest in recent years. In particular, ultrasound accelerated thrombolysis, a catheter-based technology that enhances the process of thrombolytic delivery into the thrombus, has emerged as a treatment modality with an increasing number of singlecenter studies, as well as randomized, controlled clinical trials. Results from these experiences are consistent in achieving outcomes of thrombus resolution and hemodynamic recovery with a low dose thrombolytic infusion protocol, but without the high risk of bleeding complications associated with IV thrombolysis. The clinical data will hopefully be impactful to the development of the next edition of the treatment guidelines, in support of overall recommendations for catheter-based interventions. When available and with appropriate expertise, this modality should be considered as the preferred treatment of both massive and submassive PE.

Introduction Pulmonary embolism (PE) is a prevalent life-threatening condition that affects 600,000 patients annually in the United States (U.S.) and leads to an estimated

50,000 to 200,000 deaths each year [1]. PE when untreated is associated with an overall mortality rate of approximately 30 % [2]. Current practice guidelines

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provide definitions for patient risk stratification [3•]. Massive PE, representing 5 % of the patient population, is characterized by the presence of systemic arterial hypotension, cardiogenic shock, or cardiac arrest [2]. Submassive PE patients are systemically normotensive, but present with right ventricular (RV) dysfunction. This group reportedly represents up to 40 % of the patient population [2]. Patients who have normal systemic arterial blood pressure and no evidence of RV dysfunction are considered minor PE. The 90-day mortality rates are substantial, reaching 58 % for massive, 22 % for submassive and 15 % for minor PE patients [2]. For massive PE patients, the goal of treatment is to rapidly improve systemic arterial perfusion pressure by relieving RV overload and avert impending hemodynamic collapse and death due to progressive RV failure [4]. For submassive PE patients, recent studies have examined treatment endpoints of resolution of thrombus and recovery of RV dysfunction [5, 6]. RV

dysfunction is typically characterized by the right-ventricular-to-left-ventricular diameter (RV/LV) ratio at end-diastole [7, 8]. Previously, Fremont et al. have reported that a ratio of 0.9 or higher measured on echocardiography is an independent predictor for inhospital mortality [9]. Additionally, van der Meer et al. identified that, based on chest computed tomography (CT) measurement, the RV/LV ratio increases with PE-related mortality at 3-month follow-up [10]. RV dysfunction is further characterized by presence of RV hypokinesis, which has also been demonstrated as a prognostic indicator of poor outcomes [2]. Importantly, PE patients with RV dysfunction unresolved at discharge suffered more than four times the mortality rate and eight times the rate of recurrent VTE than patients whose RV dysfunction was resolved at time of discharge [11]. These studies prompt consideration of treatment that allows resolution of clot burden and reversal of RV dysfunction.

Systemic thrombolysis Systemic thrombolysis improves hemodynamic parameters and reverses right ventricular dysfunction [12–14]. For massive PE patients, the U.S. Food and Drug Administration (FDA) has approved thrombolytic therapy with 100 mg recombinant tissue plasminogen activator (rt-PA) infused intravenously (IV) over two hours. The 2012 American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines recommend thrombolysis for patients with evidence of hemodynamic compromise unless there are major contraindications related to bleeding risk [15]. This is considered a life-saving intervention due to the high mortality associated with massive PE. However, systemic thrombolysis also carries significant bleeding risks, reaching as much as 20 % of major bleeding complications and 3 % of intracranial hemorrhage [16, 17]. In clinical practice, this aggressive therapy is withheld in more than two-thirds of massive PE patients [18]. For hemodynamically stable PE patients, systemic thrombolysis remains controversial. Recently, a single-center prospective study (MOPETT) has investigated the benefit of reduced-dose thrombolytic therapy in patients with ‘moderate’ PE, defined as the presence of signs and symptoms of PE plus involvement of970 % of thrombus in at least two lobar or left and right main pulmonary arteries on chest computed tomography (CT) or by a high probability ventilation/perfusion scan showing ventilation/perfusion mismatch in two lobes [19]. RV dysfunction was not an inclusion criterion. In total, 121 patients were randomized to the control group (anticoagulation alone) (n=60) or the thrombolysis group (anticoagulation plus a maximum dose of 50 mg rt-PA) (n=61). Results showed a reduction of both primary

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endpoints, which are pulmonary hypertension (16 % vs. 57 %; pG0.001) and the combined endpoint of pulmonary hypertension (defined as pulmonary artery systolic pressure of 40 mmHg or higher) or recurrent PE at 28 months (16 % vs. 63 %; pG0.001), among patients in the thrombolysis group compared with those in the control group. Additionally, patients receiving thrombolysis had fewer hospital days, with 2.2±0.5 days as compared to 4.9 ±0.8 days in the control group (pG0.001). There were no reports of major or minor bleeding in either group. As secondary outcomes, the combination of death plus recurrent PE was 1.6 % in the thrombolytic group versus 10 % in the control group (p=0.049), although no significant difference was noted in the rate of individual outcomes of death and recurrent PE when assessed independently. These findings demonstrated the clinical evidence of using rtPA in the treatment of moderate PE. The TOPCOAT study is a multicenter, randomized, prospective clinical trial comparing Tenecteplase (TNK) with placebo for the treatment of submassive PE patients [20]. The study was planned to enroll 150 patients, but discontinued after enrolling 83 patients (40 in TNK group, 43 in placebo group), due to challenges associated with reestablishing the prime research site upon transfer of the primary investigator to a new institution. The primary composite outcome included: 1) death, circulatory shock, intubation or major bleeding with 5 days; or 2) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36® Physical Component Summary score less than 30 at 90-day follow-up. Adverse outcomes within 5 days were reported in three patients in the placebo group (death in one and intubation in two patients) compared to one patient in the TNK group (fatal intracranial hemorrhage). Data from both 5-day and 90-day follow-up revealed 16 (37 %) placebo-treated and six (15 %) TNK-treated patients with at least one adverse outcome (p=0.017). The proportion of patients that remained in the intensive care unit on day 2 was significantly higher with placebo (20.5 %) than with TNK (5 %, p=0.03). Overall, this trial demonstrated evidence of increased probability of a favorable composite outcome associated with thrombolytic treatment for submassive PE patients. The PEITHO study (ClinicalTrials.gov Identifier: NCT00639743) was recently completed to evaluate the safety and efficacy of systemic thrombolysis for the treatment of submassive PE. A total of 1,006 patients were enrolled in 31 sites in 12 countries, randomized between IV TNK bolus with heparin and placebo with heparin [21, 22••]. Bolus TNK dose was determined based on weight, ranging between 30 mg to 50 mg. Inclusion criteria included confirmation of PE by CT, RV dysfunction by echocardiography and systemic normotension. Results demonstrated a statistically significant reduction of the combined endpoint of all-cause mortality or hemodynamic collapse within 7 days of randomization among patients treated with thrombolysis compared to those in the placebo group (2.6 % vs. 5.6 %; p=0.015). However, patients in the thrombolysis group reported substantially higher rates of bleeding complications than those of the placebo group (non-intracranial major bleeding: 6.3 % vs. 1.5 %; pG0.001). In particular, there were 12 cases of strokes in the thrombolytic group, compared to only one in the placebo group (p=0.003). The authors concluded that the study results confirm the benefit of thrombolytic therapy in preventing clinical deterioration in pa-

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Curr Treat Options Cardio Med (2014) 16:336 tients with evidence of RV dysfunction. However, such benefit came at the cost of significantly increased risk of major bleeding complications, particularly intracranial hemorrhage.

Catheter-drected therapy Initial interest in catheter-based intervention for acute PE consisted of local catheter-directed delivery of thrombolytic agent directly into the occluded pulmonary artery. This provides a treatment option when full-dose thrombolysis has either failed or is contraindicated. Additionally, catheter-directed delivery of the thrombolytic agent was believed to result in more rapid and complete thrombolysis than systemic thrombolytic therapy because of higher local drug concentrations. The 2011 American Heart Association (AHA) Scientific Statement on the management of PE recommended both systemic thrombolysis and catheter-based interventions for massive and submassive PE patients [3]. Experience of catheter-based techniques for treating PE was evaluated in a meta-analysis of 594 patients in 35 studies [23], which collectively featured applications of a variety of techniques, including local thrombolytic infusion, manual (pigtail) fragmentation, and rheolytic and rotational thrombectomy, among others. Interventionalists conducting these studies often combined mechanical thrombectomy with local thrombolytic therapy. This strategy may offer the potential benefit of increased efficacy of thrombus removal due to the combined effects of higher local concentrations of thrombolytic agent and facilitated drug penetration of the thrombus via mechanical disruption. Because the higher local drug concentration is achieved with a lower overall dose of thrombolytic agent, catheter-based thrombectomy may also hold the promise of decreased hemorrhagic complications. Results showed an overall pooled clinical success rate of 86.5 % and pooled procedural complication rate of 7.9 %. However, the study also revealed unacceptably high complication rates associated with rheolytic thrombectomy, with reports of bradyarrhythmia, heart block, hemoptysis, major hemorrhages and procedure-related deaths associated with use of the device. The physiological basis of bradyarrhythmia remains unclear; however, it can be attributed to the release of neurohormonal substances such as bradykinins and adenosine from hemolysis induced by the hydrodynamic mechanism.

Ultrasound accelerated thrombolysis Ultrasound accelerated thrombolysis (USAT) is enabled by the EKOS EkoSonic® Endovascular System (EKOS Corporation; Bothell, WA), which combines a side-hole drug infusion catheter with a multi-element ultrasound device. The thrombolytic drug is delivered through the infusion catheter while the intraluminal ultrasound device produces high-frequency, low energy intravascular ultrasound into the entire treatment zone. The ultrasound prepares the thrombus by unwinding the fibrin strands and increasing the permeability of the thrombus [24, 25]. Acoustic pressure waves and microstreaming force the delivered thrombolytic drug into the thrombus. As the thrombolytic agent permeates the thrombus, it binds with exposed plas-

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minogen receptor sites. Once bound by the thrombus, the fibrinolytic drug is no longer free to migrate through the circulatory system, does not pass through the liver, and is not metabolized. These mechanisms contribute to enhance the thrombolytic process by increasing the rate of thrombus dissolution with a reduced amount of total drug dose.

Retrospective studies Several recent single-center studies have evaluated USAT for the treatment of acute PE. Kennedy and colleagues reported a single-center experience of 60 consecutive PE patients, of which 48 were submassive and 12 were massive PE [5]. Treatment resulted in thrombus clearance (≥90 %) in 57 % and near-complete (50–90 %) clearance in 41 % of patients after infusion of 35.1 mg±11.1 of rt-PA over 19.6±6 hours. Analysis also showed statistically significant decrease in pulmonary artery pressure (systolic: 47±15 mmHg to 38±12 mm Hg; pG0.001), as well as clot burden and perfusion based on the Miller Score 25±3 to 17± 6; pG0.001). There were 57 patients who survived to discharge. All three patients who died in the hospital presented with massive PE. Engelhardt et al have previously reported a retrospective series of 32 consecutive patients treated with USAT [6]. In this study, there were five patients with massive PE and the remaining 27 patients with submassive PE. Overall, the treatment required a mean rt-PA dose of 33.5 mg infused over 19.7 hours. Core laboratory analysis demonstrated that the RV/LV ratio of 1.37±0.28 at baseline was significantly reduced to 1.02±0.13 at 48 hours follow-up (pG0.001). Additionally, the modified Miller Score was also significantly reduced from 18.8±5.8 to 9.1±5.2 (pG0.001). Four cases of bleeding complications requiring blood transfusion were observed early in the patient series with a high target lytic dose, while none were reported among those treated using the low dose protocol of 20– 24 mg rt-PA. Since then, the patient series has been extended to include, to date, an additional 32 patients, resulting in a total of 64 (eight massive and 56 submassive). Analysis demonstrated that, for the entire patient population, the RV/LV ratio decreased from 1.55±0.44 to 0.97±0.18 (pG 0.001) and the modified Miller Score from 18.0±5.1 to 9.7±5.3 (pG 0.001). No additional bleeding complications have been observed in the newly documented patients. Interestingly, additional chest CT at an intermediate time point (30 days) was available in a small subset of patients (n=6). The corresponding RV/LV ratio among them decreased from 1.63 at baseline to 1.03 at 48 hours to 0.77 at 30 days follow-up, in support of a trend of continuing resolution of RV dysfunction with time.

Recent clinical trials Very recently, two influential clinical trials on catheter-based therapy for acute PE have been completed. The ULTIMA study (ClinicalTrials.gov Identifier:NCT01166997), which is a prospective, multicenter, randomized, controlled clinical trial, compared outcomes between submassive PE patients treated with USAT and heparin and those treated with heparin only [26••]. Inclusion criteria for the study were PE confirmed by chest CT with embolus located in at least one main or proximal lobe or pulmonary artery and an RV/LV ratio91.0 on echocardiography. Primary

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Curr Treat Options Cardio Med (2014) 16:336 endpoint for the study was reduction of RV/LV ratio (based on echo) from baseline to 24 hours post-treatment, evaluated by a blinded core laboratory. A total of 59 patients were randomized to the USAT arm (30 patients) or the heparin only arm (n=29). Patients treated with USAT received rt-PA infusion at 1 mg/hr/catheter for the first 5 hours, followed by 0.5 mg/hr/catheter for 10 hours. Results show that patients in the USAT group exhibited a reduction of RV/LV ratio from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (pG0.001). However, patients receiving heparin only did not show a significant reduction in RV/LV ratio from 1.20±0.14 at baseline to 1.17±0.20 at 24 hours. Importantly, patients treated with USAT in addition to heparin did not exhibit statistically increased rate of bleeding complications or recurrent thromboembolic episodes compared to patients treated with heparin only, in support of the safety profile of USAT among PE patients. This study represents the first and only randomized clinical trial to compare a catheter-based treatment modality with the standard of care therapy of anticoagulation. Additionally, the SEATTLE II study, a prospective, single-arm, controlled study with 21 clinical sites in the U.S., has also been recently completed (ClinicalTrials.gov Identifier:NCT01513759). Both massive and submassive PE patient confirmed by chest CT with embolus located in at least one or proximal lobar PA and an RV/LV ratio of90.9 on CT are included in the study. Primary efficacy endpoint for the study was the reduction of RV/LV ratio based on chest CT. Primary safety endpoint was major bleeding within 72 hours from the initiation of thrombolysis. The trial began in June 2012 and enrollment of 150 patients in 21 clinical sites was complete by February 2013. Data analysis is currently in progress. This will be the largest prospective, U.S.-based, multicenter clinical trial investigating a catheter-based treatment modality for the treatment of PE.

Summary Acute PE is a serious and potentially life-threatening condition, afflicting a broad spectrum of the population. Recent practice guidelines have defined a three-tier risk stratification scale, characterized as massive, submassive and minor PE. Massive PE patients present with systemic hypotension and/or cardiogenic shock and require immediate intervention. Submassive PE patients are systemically normotensive, but exhibit signs of RV dysfunction. Typically, these patients are not managed aggressively; however, there is mounting evidence that failure to resolve RV dysfunction predicts poor outcomes, including mortality. Available treatment options include both systemic and catheter-based approaches. Systemic thrombolysis with 100 mg of rt-PA is indicated for the treatment of massive PE, although it carries a high risk of bleeding complications, including intracranial hemorrhage. Recent randomized, controlled, clinical trials have demonstrated the benefit of systemic thrombolysis for the treatment of submassive PE in improving RV function, although the high bleeding risks remain a serious concern. Available catheter-based therapies are largely driven by principles of mechanical

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disruption that allow immediate recanalization. A meta-analysis of 35 studies on these techniques demonstrated an overall pooled clinical success rate of 86.5 % with relatively low risk of complications. USAT is a promising modality, enabled by high frequency, low-power ultrasound that enhances thrombolytic delivery into the thrombus and is not mechanically disruptive by nature. ULTIMA is a recently completed, first of its kind, randomized clinical trial that demonstrated superiority of USAT and heparin over heparin alone in reversing RV dysfunction among submassive PE patients. Single center studies that included both massive and submassive PE patients have reported corroborative results, with rapid thrombus resolution and reduction of PA pressures. Notably, all of these experiences consistently demonstrated a low risk of bleeding complications associated with USAT using a low-dose rtPA infusion protocol. Continuing clinical studies with this modality will further establish the role of USAT in the treatment algorithm for acute PE.

Compliance with Ethics Guidelines Conflict of Interest Dr. Tod C. Engelhardt declares no potential conflicts of interest relevant to this article. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

Wood KE. Major Pulmonary Embolism: Review of a Pathophysiologic Approach to the Golden Hour of Hemodynamically Significant Pulmonary Embolism. Chest. 2002;121:877–905. 2. 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. 3.• Jaff MR, McMurtry MS, Archer SL, et al. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement from the American Heart Association. Circulation. 2011;123:1788–830. This is the first set of treatment guidelines that have provided a definition for risk stratification of acute PE patients. 4. Piazza G, Goldhaber SZ. Fibrinolysis for Acute Pulmonary Embolism. Vasc Med. 2010;15:419–28.

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Kennedy RJ, Kenney HH, Dunfee BL. Thrombus Resolution and Hemodynamic Recovery Using Ultrasound-Accelerated Thrombolysis in Acute Pulmonary Embolism. J Vasc Interv Radiol. 2013;24:841–8. Engelhardt TC, Taylor AJ, Simprini LA, Kucher N. Catheter-Directed Ultrasound-Accelerated Thrombolysis for the Treatment of Acute Pulmonary Embolism. Thromb Res 2011. 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. 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.

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Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive Pulmonary Embolism. Circulation. 2006;113:577–82. 19. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate Pulmonary Embolism Treated With Thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013;111:273–7. 20. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of Submassive Pulmonary Embolism With Tenecteplase or Placebo: Cardiopulmonary Outcomes at Three Months TOPCOAT): Multicenter Double-Blind, Placebo-Controlled Randomized Trial. J Thromb Haemost 2014. 21. Konstantinides S, Lankeit M. Pulmonary Embolism Hotline 2012. Recent and Expected Trials. Hamostaseologie. 2013;33:43–50. 22.•• The PEITHO Investigators. Pulmonary Embolism Thrombolysis Study: An Investigator-Initiated, Investigator-Sponsored Trial. 62nd Annual Meeting of the American College of Cardiology; San Francisco 2013. The PEITHO study is the largest prospective, randomized, controlled clinical trial to-date that evaluated IV thrombolysis against placebo for the treatment of submassive PE patients. 23. Kuo WT, Gould MK, Louie JD, Rosenberg JK, Sze DY, Hofmann LV. Catheter-Directed Therapy for the Treatment of Massive Pulmonary Embolism: Systematic Review and Meta-Analysis of Modern Techniques. J Vasc Interv Radiol. 2009;20:1431–40. 24. Francis CW, Blinc A, Lee S, Cox C. Ultrasound Accelerates Transport of Recombinant Tissue Plasminogen Activator into Clots. Ultrasound Med Biol. 1995;21:419–24. 25. Braaten JV, Goss RA, Francis CW. Ultrasound Reversibly Disaggregates Fibrin Fibers. Thromb Haemost. 1997;78:1063–8. 26.•• Kucher N, Boekstegers P, Muller OJ, et al. Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute IntermediateRisk Pulmonary Embolism. Circulation. 2014;129:479–86. The ULTIMA is the first prospective, randomized, controlled, clinical trial that evaluated an advanced catheter-based treatment modality against standard-of-care therapy for acute PE patients.

Acute pulmonary embolus: the next frontier in venous thromboembolic interventions.

Submassive pulmonary embolism (PE) represents a patient population that is under-recognized and under-treated. Recent clinical trials demonstrated the...
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