Efficacy and Safety of Flow-Directed Pulmonary Artery Catheter Thrombolysis for Treatment of Submassive Pulmonary Embolism

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1 Vascular and Interventional Radiology Original Research Gaba et al. Catheter Thrombolysis of Submassive PE Vascular and Interventional Radiology Original Research Ron C. Gaba 1 Madhu S. Gundavaram 2 Ahmad Parvinian 1 M. Grace Knuttinen 1 Jeet Minocha 1 Charles A. Owens 1 James T. Bui 1 Gaba RC, Gundavaram MS, Parvinian A, et al. Keywords: catheter-directed thrombolysis, efficacy, pulmonary embolism (PE), safety, submassive DOI: /AJR Received June 12, 2013; accepted after revision October 10, Presented at the 2013 annual meeting of the American Thoracic Society, Philadelphia, PA. 1 Department of Radiology, Division of Interventional Radiology, University of Illinois Hospital and Health Sciences System, 1740 W Taylor St, MC 931, Chicago, IL Address correspondence to R. C. Gaba (rgaba@uic.edu). 2 Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Allergy Medicine, University of Illinois Hospital and Health Sciences System, Chicago, IL. AJR 2014; 202: X/14/ American Roentgen Ray Society Efficacy and Safety of Flow-Directed Pulmonary Artery Catheter Thrombolysis for Treatment of Submassive Pulmonary Embolism OBJECTIVE. The purpose of this study was to assess the efficacy and safety of flow-directed catheter thrombolysis for treatment of submassive pulmonary embolism (PE). MATERIALS AND METHODS. In this single-institution retrospective study, 19 patients (nine men and 10 women; mean age [± SD], 54 ± 13 years) with submassive PE underwent catheter-directed thrombolysis between 2009 and Presenting symptoms included dyspnea in 18 of 19 (95%) cases. Submassive PE was diagnosed by pulmonary CT arteriography and right ventricular strain. PE was bilateral in 17 of 19 (89%) and unilateral in two of 19 (11%) cases. Thrombolysis was performed via a pulmonary artery (PA) catheter infusing mg alteplase per hour and was continued to complete or near complete clot dissolution with reduction in PA pressure. IV systemic heparin was administered. Measured outcomes included procedural success, PA pressure reduction, clinical success, survival, and adverse events. RESULTS. Procedural success, defined as successful PA catheter placement, fibrinolytic agent delivery, PA pressure reduction, and achievement of complete or near complete clot dissolution, was achieved in 18 of 19 (95%) cases. Thrombolysis required 57 ± 31 mg of alteplase administered over 89 ± 32 hours. Initial and final PA pressures were 30 ± 10 mm Hg and 20 ± 8 mm Hg (p < 0.001). All 18 (100%) technically successful cases achieved clinical success because all patients experienced symptomatic improvement. Eighteen of 19 (95%) patients survived to hospital discharge; 18 of 19 (95%) and 15 of 16 (94%) patients had documented 1-month and 3-month survival. One fatal case of intracranial hemorrhage was attributed to supratherapeutic anticoagulation because normal fibrinogen levels did not suggest remote fibrinolysis; procedural success was not achieved in this case because of early thrombolysis termination. No other complications were encountered. CONCLUSION. Among a small patient cohort, flow-directed catheter thrombolysis with alteplase effectively dissolved submassive PE and reduced PA pressure. Postprocedure short-term survival was high, and patients undergoing thrombolysis required close observation for bleeding events. P ulmonary embolism (PE) is a deadly disease that results in significant morbidity and mortality in the United States; up to 600,000 cases of PE are diagnosed annually and yearly deaths approximate 50, ,000 nationwide [1 4]. Massive and submassive PE which are PE subtypes associated with right ventricular (RV) dysfunction with or without systemic arterial hypotension, cardiogenic shock, or cardiac arrest are particularly deadly; 30-day mortality rates for these PE varieties may approximate 60% and 20%, respectively [5]. Although systemic anticoagulation can reduce overall PE mortality, this therapy neither dissolves existing clot nor prevents thrombus propaga- tion. Therefore, the American College of Chest Physicians (ACCP) and American Heart Association (AHA) recommend consideration of fibrinolytic therapy for massive acute PE [6, 7]. IV administration of fibrinolytic agents offers ease of delivery, but the high dose and uncontrolled distribution with systemic or remote lytic effects may complicate this approach and contribute to a major hemorrhage rate approximating 10% [7]; however, higher [5, 8] and lower rates have been reported [9]. In contrast, targeted catheter-based fibrinolytic agent delivery for treatment of massive PE has been associated with complication rates under 2.5% as well as 86.5% efficacy measured by stabiliza- AJR:202, June

2 Gaba et al. tion of hemodynamics, resolution of hypoxia, and survival to hospital discharge [10]. Although such advanced fibrinolytic therapy can thus be lifesaving in the setting of massive PE, its use remains unverified in patients with submassive PE [11], and practical application may be limited to those patients judged to have clinical evidence for an adverse prognosis [7]. With this in mind, this study was undertaken to assess the efficacy and safety of flow-directed catheter thrombolysis, or targeted clot dissolution, performed with fibrinolytic agent infusion into the pulmonary artery (PA) proximal to the embolus for treatment of submassive PE. Materials and Methods This retrospective study was in compliance with HIPAA, and the institutional review board at our institution granted approval with waiver of consent for inclusion in the study. All patients provided written informed consent for catheter-directed thrombolysis procedures, which were performed for the medical indication of PE fibrinolysis. Clinical Setting and Study Design Between September 2009 and May 2013, 19 consecutive patients with large clot burden and physiologic changes of submassive PE who underwent catheter-directed thrombolysis at a single tertiary care academic university hospital in a large metropolitan area were identified via medical record review and selected for retrospective study. Submassive PE was defined as PE associated with RV dysfunction without systemic arterial hypotension, cardiogenic shock, or cardiac arrest. Indications for PE thrombolysis included imaging confirmation of thrombus within the main or lobar pulmonary arteries; RV strain; and clinical symptoms such as dyspnea, chest pain, syncope, or dizziness. Submassive PE was diagnosed by pulmonary CT arteriography in 19 patients by the use of RV to left ventricular (LV) diameter ratio [12] and defined by RV strain on echocardiography in 17 patients. Submassive PE was evidenced by RV hypokinesis (n = 6), dilatation (n = 11), flattening of the interventricular septum (n = 7), and tricuspid regurgitation (n = 17) [13]. An intensive care physician evaluated all patients, and the decision to pursue catheter-directed fibrinolysis was determined by consensus discussion between critical care and interventional radiology physicians. Standard contraindications to thrombolytic agent administration [14] were considered in patient selection, and none of the patients in the current cohort had such contraindications. Catheter-Directed Thrombolysis Technique Catheter-directed thrombolysis was performed in the interventional radiology suite using IV moderate sedation anesthesia. For these procedures, patients were prepared and draped in standard sterile fashion while supine on the angiographic procedure table. Routine single-wall puncture venous access was gained via the right or left common femoral vein using direct sonographic guidance and a 21-gauge needle (Micropuncture Introducer Set, Cook Medical). Vascular access was dilated to accept an 8-French vascular sheath (Pinnacle, Terumo). A 7-French multisidehole pigtail catheter (APC, Cook Medical) was then advanced into the main pulmonary trunk. The APC catheter, or Van Aman pulmonary pigtail with APC tip configuration (a modification of the Grollman pulmonary pigtail), is a 100-cmlong inch internal diameter multisidehole (12 total) catheter with a 90 curve of its distal 5 cm as well as a distal pigtail with an end hole. Mean PA pressure was then recorded; right atrial and RV pressures were not measured. From the main pulmonary trunk, digital subtraction pulmonary arteriography was performed with iohexol (Omnipaque 300, GE Healthcare) injection at a flow rate of ml/s for a total injection volume of ml; flow rates were selected at the discretion of the primary operating interventional radiology on the basis of perceived PA flow velocity on hand injections of contrast material (notably, injection at a reduced flow rate is preferable in the presence of pulmonary hypertension and RV dysfunction associated with submassive PE so as not to provoke right heart failure). Catheter-directed thrombolysis using the flowdirected technique, which is a form of pharmacologic thrombolysis in which the infusion is administered through a catheter positioned in the PA proximal to the location of PA thrombus, was then pursued. The catheter was positioned in the PA with the greater clot burden (preprocedure pulmonary CT arteriography can assist in this regard) immediately proximal to the location of PA thrombus, with administration of 0.5 mg (n = 14) or 1.0 mg (n = 5) alteplase (Activase, Genentech) per hour (infusion rate of 60 ml/h of 8 mg alteplase/1000 ml saline preparation, 120 ml/h of 4 mg alteplase/1000 ml saline preparation, or 120 ml/h of 8 mg alteplase/1000 ml saline preparation); these preparations and infusion rates are the same as those used for peripheral catheter-directed thrombolysis at our institution. Alteplase dosing was at the discretion of the operating interventional radiology physician; the term low dose refers to PA infusion of mg alteplase per hour, whereas high dose denotes IV infusion with 100 mg alteplase administered over 2 hours. Systemic IV heparin was also administered to prevent thrombus propagation and was titrated to achieve a partial thromboplastin time (PTT) of seconds; subtherapeutic doses of heparin have been deemed acceptable when used in combination with thrombolytic therapy [15]. Patients were continuously monitored in an ICU setting during the entirety of thrombolytic therapy. Laboratory values, including hematologic parameters such as CBC, coagulation profile including prothrombin time (PT) and PTT, and fibrinogen levels, were monitored every 4 6 hours. Although the clinical progress of catheter-directed thrombolysis may be assessed by evaluating patient hemodynamic status, oxygen saturation, and pulmonary artery pressure, daily pulmonary arteriography was performed in the interventional radiology suite in accordance with our institutional protocol to monitor the progress of thrombolytic therapy and to ensure catheter positional stability and enable catheter repositioning as needed. Catheter repositioning into the contralateral PA was pursued when complete or near complete clot dissolution was achieved in the initially treated PA. This methodology was used with the intent of minimizing vascular access punctures and maintaining a low thrombolytic agent dose with a single rather than dual infusion. Moreover, prior in vitro and in vivo studies have shown contralateral flow of thrombolytic agent administered into a large embolus-containing PA [16], theoretically allowing some simultaneous contralateral clot dissolution. Thrombolysis was continued until PA pressure reduction and concomitant resolution of patient symptoms were achieved; complete or near complete clot dissolution in both PAs was considered a secondary termination endpoint. No mechanical clot disruption techniques were pursued in any case. After completion of thrombolytic therapy, the PA catheter was removed over a guidewire under fluoroscopic guidance, the vascular access sheath was removed, and hemostasis was achieved at the common femoral venotomy site with manual compression. Of note, patients were generally maintained on a 6-month course of systemic anticoagulation after completion of catheter-directed thrombolysis. Measured Outcomes Electronic medical records were reviewed to obtain patient demographic information, risk factors for venous thromboembolism (VTE), patient comorbidities, presenting signs and symptoms, procedure data, clinical outcomes including symptomatic improvement or resolution after treatment, ICU length of stay, hospital length of stay, survival to discharge, 30-day survival, and 1356 AJR:202, June 2014

3 Catheter Thrombolysis of Submassive PE 90-day survival. Patient mortality was confirmed using the United States Social Security Death Index. Data were collected for each patient using a standardized data collection form. Measured study outcomes included procedure technical success, procedural success, clinical success, survival to hospital discharge, and C A 30- and 90-day survival. Technical success was defined as successful PA catheter placement and effective fibrinolytic agent delivery [17]. Procedural success was defined as technical success plus achievement of the intended interventional therapeutic goal, in this case PA pressure reduction and complete ( 90% clearance) or near complete (70 90% clearance) clot dissolution [2]. Clot dissolution was visually estimated on a per-case basis via analysis of initial and final pulmonary arteriograms. Incremental per day clot dissolution rates were not reported because visual estimation of small changes in clot size was thought to be subject to significant error that may introduce Fig year-old man with acute onset of dyspnea associated with oxygen saturation of 87% on room air. A, Axial contrast-enhanced chest CT image shows large bilateral pulmonary embolisms (PEs) (arrowheads). B and C, Right (B) and left (C) pulmonary arteriograms (10-mL/s iodinated contrast medium injection) show significant right-sided PE (arrowheads, B) as large filling defect with poor flow in lower lobe pulmonary artery (PA) branch (arrow, B) and reduced parenchymal perfusion as well as multiple emboli in left-sided branches (arrowheads, C). D, Pulmonary arteriogram (15 ml/s iodinated contrast medium injection) obtained after 96 hours of catheter-directed thrombolysis to right pulmonary artery using 0.5 mg of alteplase per hour displays greater than 90% clot dissolution, with marked progressive reduction in PE size (arrowheads) and only minimal residual PE as well as significant improvement in PA perfusion (arrow). E, Pulmonary arteriogram shows left-sided PE similarly resolved, although without direct alteplase infusion. PA pressure decreased from mean of 52 to 18 mm Hg, and oxygen saturation improved to 96% on room air. D B E AJR:202, June

4 Gaba et al. inaccuracy into the clot dissolution outcome measure. Of note, although the diagnosis of submassive PE is not based on embolus burden, clearance of thrombus was considered to be an appropriate and valuable therapeutic endpoint in conjunction with PA pressure reduction in this study because the intent of thrombolytic therapy was to pursue active thrombus clearance to bring about PA reduction. Clinical success was defined by improvement in patient clinical signs and symptoms as well as adverse events, graded according to the Society of Interventional Radiology classification of complications [17]. Statistical Analysis Descriptive statistics were used to check for erroneous entries, assess for normalcy of the data, and characterize demographic features of the study population. Comparisons for continuous normally distributed variables were performed by the unpaired or paired samples Student t test. Statistical analysis was performed using a commercially available software package (SPSS version 18), and p values 0.05 were considered statistically significant. Results Patient Cohort and Pulmonary Embolism Characteristics The study cohort consisted of 19 patients, including nine men and 10 women with a mean age ± SD of 54 ± 13 years (range, years). VTE risk factors included obesity (11/19, 58%), hypertension (10/19, 53%), immobility (3/19, 16%), malignancy (3/19, 16%), and smoking (2/19, 11%). Mean body mass index was 36.3 ± 12.6 kg/m 2 (range, kg/m 2 ). Presenting symptoms included new onset of dyspnea (18/19, 95%), chest pain (6/19, 32%), syncope (4/19, 21%), or dizziness (2/19, 11%). PE location was saddle or bilateral in 17 of 19 (89%) cases and unilateral in two of 19 (11%) cases. CT showed a mean RV to LV ratio of 1.5 ± 0.3 (range, ). Twelve of 19 (63%) patients had lower extremity deep venous thrombosis on presentation diagnosed by lower extremity Duplex sonography. Catheter-Directed Thrombolysis Procedures The time from initial patient presentation to medical attention to initiation of catheter-directed thrombolysis was 30 ± 28 hours (range, 4 96 hours). Thrombolysis required a mean of 57 ± 31 mg (range, mg) of alteplase administered over a mean of 89 ± 32 hours (range, hours). There was no statistically significant difference in thrombolysis procedure length when alteplase was dosed at 0.5 mg per hour compared with 1.0 mg per hour (91 vs 82 hours, p = 0.517). Systemic fibrinogen levels averaged 480 ± 167 mg/dl (range, mg/dl) during treatment. No patients had fibrinogen levels that dropped below 200 mg/dl. Technical success was achieved in all 19 (100%) cases. Among these patients, 18 (95%) achieved procedural success (Fig. 1), in whom complete thrombolysis was achieved in 11 (61%) patients and near-complete thrombolysis was achieved in seven (39%) patients. Catheter repositioning to the contralateral PA was necessary to achieve contralateral clot dissolution in four cases. Contralateral thrombus dissolution without catheter repositioning was seen in 11 cases. A statistically significant decrease in PA pressure was detected; mean initial and final PA pressures were 30 ± 10 mm Hg (range, mm Hg) and 20 ± 8 mm Hg (range, 8 37 mm Hg), respectively (p < 0.001). Mean PA pressure reduction was 10 ± 9 mm Hg (minimum reduction, 1 mm Hg, maximum reduction, 34 mm Hg). Eight of 19 (42%) patients had complete normalization of PA pressure (mean 18 mm Hg). Of note, no patients experienced a catheter-induced cardiac arrhythmia during the course of thrombolytic agent infusion. Clinical Outcomes Eighteen of the 18 (100%) technically successful cases achieved clinical success; all patients experienced symptomatic improvement with resolution of their initially presenting symptom on completion of catheterdirected thrombolysis. Of these patients, 17 (94%) had symptomatic improvement before resolution of thrombus (mean time to symptomatic improvement was 49 hours and mean PA pressure at the time of symptomatic improvement was 24 mm Hg). Mean length of ICU stay (inclusive of time before thrombolysis initiation) was 4.7 ± 2.3 days (range, 2 10 days), and mean length of hospital stay was 10.5 ± 7.8 days (range, 2 34 days). Eighteen of 19 (95%) patients survived to hospital discharge. The 30-day survival rate was 95% (18/19) and 90-day survival was 94% (15/16) (three patients had not reached 90 days postprocedure at the time of this writing). There were no minor or major complications among surviving patients. One patient (5%) developed cerebral hemorrhage 24 hours after catheter-directed thrombolysis initiation and subsequently died because of intracranial bleeding. However, systemic anticoagulation in this patient was complicated by labile PTT with elevation to greater than 200 seconds for approximately 2 hours. Fibrinogen levels in this patient ranged from 386 to 486 mg/dl during thrombolysis, indicating no systemic alteplase thrombolytic effect. Supratherapeutic anticoagulation was thus determined to be the cause of the patient s hemorrhagic event. Discussion The application of thrombolytic therapy for treatment of submassive PE is currently considered controversial [18, 19]. Data for the use of fibrinolytic agents in this setting are sparse despite the considerable shortterm mortality associated with submassive PE [5], poor prognosis of PE patients with RV dysfunction and PA pressure elevation [20], and significant incidence of chronic pulmonary hypertension among survivors of submassive PE events [21]. In the 256-patient prospective randomized Management Strategies and Prognosis of Pulmonary Embolism Trial-3 reported by Konstantinides et al. [9] in 2002, a statistically significant decrease in the rate of in-hospital death or clinical deterioration requiring an escalation of treatment (11.0% vs 24.6%) was observed in patients with acute submassive PE treated with systemic anticoagulation plus bolus alteplase versus systemic anticoagulation alone. Although the effects of thrombolytic therapy for PA pressure reduction have not been specifically investigated, a 2009 study by Kline et al. [21] suggested greater PA pressure reduction and more durable reduction of RV systolic pressure in patients treated with systemic anticoagulation plus bolus alteplase versus systemic anticoagulation alone, although this study was significantly limited by dissimilar sample sizes and disparate study populations. Thus, with limited supporting data, current clinical practice guidelines recommend that application of thrombolysis be reserved for only those submassive PE patients judged to have clinical evidence for an adverse prognosis [7]. In the current study, we investigated the efficacy and safety of flow-directed catheter thrombolysis for treatment of acute submassive PE. In examining the procedure outcomes of 19 patients who underwent targeted thrombolytic therapy, we found that catheter-based fibrinolysis effectively dissolved clot, reestablished PA perfusion, and reduced PA pressure. Complete or near-complete clot dissolution was efficiently achieved 1358 AJR:202, June 2014

5 Catheter Thrombolysis of Submassive PE in 100% of cases, and thrombolysis was associated with near normalization of PA pressures in all cases, with complete normalization of PA pressures in 42% of cases. Low material cost (consisting of standard sheaths, catheters, and guidewires) and simplicity of the flow-directed thrombolytic technique (requiring minimal catheter manipulation) represent additional benefits of the described approach. Most important, 95% of patients in the current series experienced symptomatic improvement and survived to hospital discharge and 90-day follow-up. The results obtained in our study suggest the potential utility of catheter-directed thrombolysis for primary treatment in submassive PE patients, who are at risk of short-term mortality and adverse outcome [10], and our findings may provide a basis for future large-scale prospective multiinstitutional registry or meta-analysis studies comparing catheterdirected thrombolysis outcomes to those of systemic anticoagulation or bolus fibrinolysis, which would be necessary before recommendation for clinical adoption. In the present series, targeted thrombolytic therapy required approximately half the total fibrinolytic agent dose (57 versus 100 mg) compared with that approved by the United States Food and Drug Administration for systemic thrombolysis of massive PE, but we used an off-label manner for treatment of submassive PE, theoretically reducing the risk for hemorrhagic complications. This bleeding risk is further reduced by slow delivery of low-dose alteplase over many hours (mean, 89 hours) compared with 2-hour systemic bolus delivery. Prior studies have confirmed the enhanced safety profile of catheter-directed thrombolytic agent delivery compared with systemic administration, including a nearly 10-fold reduction in major bleeding complications and intracranial hemorrhage [5, 8, 10]. In the sole hemorrhagic complication in the current study, supratherapeutic systemic anticoagulation certainly contributed to adverse event occurrence, whereas normal fibrinogen levels in this case suggested lack of remote lytic effects of alteplase. We thus highlight the need for vigilant anticoagulant management as well as attentive laboratory assessment in patients undergoing thrombolysis. In contrast to the technical approach to targeted therapy for massive PE, which is based on mechanical methods (catheter disruption, balloon fragmentation, and rheolytic thrombectomy) [10] aimed at debulking clot and acutely revascularizing the pulmonary outflow tract to relieve life-threatening heart strain and improve pulmonary perfusion (surgical embolectomy could similarly be used), we support a more conservative approach aimed at slow and steady clot dissolution in the setting of submassive PE. We believe there is no urgent need for acute mechanical thrombus disruption in hemodynamically stable PE patients given the potential to precipitate abrupt hemodynamic deterioration by increasing the cross-sectional area of obstructing embolus, PA pressure, and cardiac afterload [22 24]. In this study, our technical approach to local therapy of submassive PE successfully used flowdirected fibrinolysis without mechanical clot dislodgment and represents a methodology that has been advocated by other authors as well [10]. Notably, ultrasound-accelerated thrombolysis which hastens the penetration of fibrinolytic agent into clot has also been used with safety and efficacy in patients with acute PE [25]. There are limitations to this investigation. First, this study was retrospective and nonrandomized in nature and is subject to the inherent weaknesses of nonprospective studies. Second, our investigation represents the experience of a single institution and has a small sample size accrued without a power analysis to estimate a proper cohort volume. Third, this investigation did not compare outcomes of catheter-directed thrombolysis to those of a control group treated with systemic anticoagulation alone or with systemic fibrinolysis. Fourth, patients were not followed for longterm assessment of RV function or pulmonary hypertension after treatment. In conclusion, flow-directed catheter thrombolysis with low-dose alteplase is effective in dissolving submassive PE and reducing PA pressure and is associated with high rates of survival to hospital discharge as well as 30- and 90-day survival. However, patients undergoing thrombolysis require close observation for bleeding complications. Future studies should aim to collect and analyze prospective data for catheter-directed thrombolysis of submassive PE; further refine treatment protocols by defining optimal treatment approaches on the basis of patient characteristics and clinical circumstances; define favorable catheter-directed techniques that maximize patient safety, effectiveness at clot removal, and ease of use; and compare catheter-directed thrombolysis outcomes to those of systemic anticoagulation and bolus fibrinolysis. References 1. Wood KE. 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