Author S Jay Mathews 1 Affiliation 1 Bradenton Cardiology Center, Manatee . This combination of intelligent aspiration and large-lumen catheter engineering forms Lightning 12: the latest generation in clot removal technology. 1. Precautions The device is intended or single use only. Maintain a constant infusion of appropriate flush solution. Editors choiceEuropean Society for Vascular Surgery (ESVS) 2020 clinical practice guidelines on the management of acute limb ischemia. Schwartz-Buckley Professor of Surgery, Vascular Division Precautions The device is intended or single use only. Penumbra has changed the landscape of healthcare by providing truly innovative solutions for a wide realm of medical challenges. Use the INDIGO Aspiration System in conjunction with fluoroscopic visualization. The Indigo System with Lightning Aspiration Tubing is an intelligent aspiration system powered by Penumbra ENGINE. The combination of intelligent aspiration and large-lumen catheter engineering form Lightning 7 and Lightning 12: the latest generation in clot removal technology. Sponsored by Penumbra, Inc. Perspectives on PE Care Using Penumbra's Indigo System With Lightning Intelligent Aspiration. Lightning 12 and Lightning 8 expand the already broad offering of CAT8, CATD, CAT6, CAT5, and CAT3 and are paired with Penumbra ENGINE, the companys proprietary continuous, mechanical vacuum aspiration pump. Equipment is not safe for MR use. Next Article Lightning 12 combines the Indigo System CAT 12 Aspiration Catheter with Lightning Intelligent Aspiration, enabling physicians to focus on optimizing thrombus removal using the system's unique clot detection mechanism. All Rights Reserved Privacy Policy, With Frank R. Arko III, MD; Patrick E. Muck, MD, RVT, FACS; Ripal T. Gandhi, MD, FSIR, FSVM; Robert Lookstein, MD, MHCDL, FSIR, FAHA, FSVM; Michael S. Rosenberg, MD, FSIR, FACR; Eric Moldestad, MD; Gianmarco de Donato, MD; Thomas S. Maldonado, MD; D. Chris Metzger, MD, Robert Lookstein, MD, MHCDL, FSIR, FAHA, FSVM. doi: 10.14503/THIJ-21-7571. The Next Generation of Thrombus Removal | Penumbra Inc Do not use in the presence of a flammable anesthetic mixture with air or nitrous oxide. Executive Vice Chairman IVUS image showing a widely patent lumen after thrombectomy and stenting. Do not advance, retract or use any component of the INDIGO Aspiration System against resistance without careful assessment of the cause using fluoroscopy. rosen011@umn.edu Using the Lightning 12 and SEP12 (Penumbra, Inc.), we removed a huge clot from the iliac vein with a retrograde approach to the thrombus. For bilateral occlusions where thrombus is laced throughout the SFA in both legs and with potential for acute-to-chronic occlusion distally, the Indigo System provides a frontline treatment option that potentially preserves limb viability. To ensure the most secure and best overall experience on our website we recommend the latest versions of, Internet Explorer is no longer supported. The Indigo System with Lightning Intelligent Aspiration is available in the United States in the following configurations: Lightning 12, Lightning 8 and Lightning 7. Department of Medicine, Surgery and Neuroscience Do not position the PENUMBRA ENGINE so that it is difficult to remove the power cord. With contributions from Edoardo Pasqui, MD; Carlo Setacci, MD; and Giancarlo Palasciano, MD, Surgical management of lower extremity acute limb ischemia (ALI) has been considered the preferred treatment for years. Lightning Aspiration Tubing has dual pressure sensors for real-time blood flow monitoring. INDIGO Aspiration Tubing: As part of the INDIGO Aspiration System, the INDIGO Sterile Aspiration Tubing is indicated to connect the INDIGO Aspiration Catheters to the Penumbra Aspiration Pump. With automatic valve control, Lightning can help the physician focus on optimizing thrombus removal procedures. A preliminary analysis of the first 143 patients showed a technical success (defined as complete or near-complete revascularizationTIMI 2-3 flow) after thromboaspiration procedure alone in 89.5%. Stainless steel hypotube; Large lumen size and circumferential sweep enables maximized thrombus engagement; Immediately after, Lightning with the Indigo System Catheter CAT8 was used to aspirate thrombus in the left PA (, Due to increased amounts of thrombus in the right lobe, the SEP8 was introduced to clear the lumen of the catheter (. Lightning 12 combines the new Indigo System CAT12 Aspiration Catheter with Lightning Intelligent Aspiration, enabling physicians to focus on optimizing thrombus removal using the system's unique clot detection mechanism . investors@penumbrainc.com The Lightning 12 addition to the Indigo Aspiration System is a formative development in the thrombectomy space. When performing aspiration, ensure that the INDIGO Aspiration Tubing is open for only the minimum time needed to remove the thrombus. Use of LIGHTNING Aspiration Tubing adjacent to other equipment should be avoided because it could result in improper operation. Do not use kinked or damaged devices. 2019;140:e774-e801. Potential Adverse Events Possible complications include, but are not limited to, the following: allergic reaction and anaphylaxis from contrast media; acute occlusion; air embolism; arrhythmia; arteriovenous fistula; cardiac injury; cardio-respiratory arrest; death; device malfunction; distal embolization; emboli; excessive blood loss; false aneurysm formation; hematoma or hemorrhage at access site; inability to completely remove thrombus; infection; hemorrhage; ischemia; kidney damage from contrast media; neurological deficits including stroke; vessel spasm, thrombosis, dissection, or perforation; intimal disruption; myocardial infarction; emergent surgery; fibrillation; hypotension; hemoptysis; respiratory failure; thromboembolic events. The Indigo Aspiration System with Lightning 12 removes these difficult-to-access, life-threatening clots, potentially reducing the need for thrombolytics and their associated ICU stays. Do not use in oxygen rich environment. Many of the first-generation mechanical endovascular devices for thrombus removal have failed to be adequately successful or have been associated with unacceptable complication rates. This combination of intelligent aspiration and large-lumen catheter engineering makes Lightning 12 Penumbras most advanced clot removal technology for the treatment of pulmonary embolism. Remove and service the PENUMBRA ENGINE if liquids or solids have been drawn into the PENUMBRA ENGINE. doi: 10.1161/CIR.0000000000000707. Contraindications The INDIGO Aspiration System is contraindicated in: The removal of fibrous, adherent or calcified material (e.g. 5. INDIGO CAT RX Aspiration Catheters and INDIGO SEPARATOR 4 Indication for Use As part of the INDIGO Aspiration System, the INDIGO CAT RX Aspiration Catheters and INDIGO SEPARATOR 4 are indicated for the removal of fresh, soft emboli and thrombi from vessels in the coronary and peripheral vasculature. The patients right leg was completely cold, insensate, and immobile from the thigh down. From syringe aspiration to sustained aspiration and now to intelligent aspiration, the aspiration thrombectomy field has grown leaps and bounds, now finding itself at a place where the Indigo System with the Lightning Intelligent Aspiration optimizes the thrombus removal procedure by differentiating between thrombus and blood. Warnings The INDIGO Aspiration System should only be used by physicians who have received appropriate training in interventional techniques. The Indigo System Lightning 12 is the company's next generation aspiration system for peripheral thrombectomy. As part of the Indigo Aspiration System, Lightning 12 (Indigo System CAT 12 Aspiration Catheter with Lightning Intelligent Aspiration) and Separator 12 are now indicated for the removal of fresh, soft emboli and thrombi from vessels of the peripheral arterial and venous systems as well as for the treatment of pulmonary embolism. The Indigo System has been designed to address the limitations of traditional treatment options. The Penumbra Indigo System Separator is intended for use with our Indigo System's CAT family of catheters to enable the removal of a wide range of thrombus. Powered by the Penumbra ENGINE , Lightning 7 and Lightning 12 combine the new Indigo System CAT7 and CAT12 Aspiration Catheters with Lightning Intelligent Aspiration, a unique computer-aided clot detection technology that can differentiate between clot and blood, designed to reduce blood loss and the need for clot-dissolving drugs, which . This website is intended for US audience only. The new HTORQ angle is complemented by the large lumen when accessing wall-adherent thrombus in the venous space. Precautions The device is intended for single use only. To ensure the most secure and best overall experience on our website, we recommend the latest versions of, https://www.penumbrainc.com/indigo-lightning/, http://www.penumbrainc.com/healthcare-professionals. No modification of this equipment is allowed. Use prior to the Use By date. Catheters & Separators. Do not use open or damaged packages. The goal of this study is to create a prospective multicenter study that provides safety and performance data on the Indigo System as a frontline percutaneous aspiration thrombectomy approach for ALI patients for whom immediate treatment and revascularization can maintain limb viability. The means of mains disconnect is to remove the power cord. Associate Professor of Radiology and Surgery This website is intended for US audience only. An intuitive clicking sound is made by the device that signals that one is in free-flowing blood. The catheter is robust and trackable, and the large lumen allows for thrombectomy either with a guidewire in place or without a guidewire. right-arrow Cat 12 is a large-lumen aspiration catheter that incorporates laser-cut hypotube-based catheter to provide deliverability and torqueability within the body. Utility of a power aspiration-based extraction technique as an initial and secondary approach in the treatment of peripheral arterial thromboembolism: results of the multicenter PRISM trial. Hemoglobin and hematocrit levels should be monitored in patients with >700 mL blood loss from the clot aspiration procedure. Figure 4. right-arrow Heart disease and stroke statistics2020 update: a report from the American Heart Association. The primary outcome is the rate of TIMI 2-3 revascularization after treatment using the Indigo System. Icahn School of Medicine at Mount Sinai COVID has increased the awareness of the need for therapies that remove blood clots, and we are thrilled with the FDA clearance of the PE treatment indication for Lightning 12.. The INDIGO SEPARATOR is not intended for use as a guidewire. The latest addition to the catheter line, the CAT12, is Penumbras most torqueable and trackable catheter to date. Do not use in an oxygen rich environment. Restored distal flow to the left TPT. Prior to use, please refer to Instructions for Use for complete product indications, contraindications, warnings, precautions, potential adverse events and detailed instructions for use. The PRISM trial, a retrospective case analysis assessing the rate of TIMI 2-3 flow after the use of Indigo and specifically the XTRACT technique, showed an 87.2% rate of revascularization post-Indigo and subsequent treatment of underlying stenosis in the same setting.1 The newly completed study studying the same primary outcome as PRISM, the INDIAN registry, showed an even higher rate of revascularization, 88.7%.2 Sustained aspiration for ALI could potentially increase the revascularization rate by serving as an effective single-session frontline option. Created with Sketch. February 2022. Disclosures: None. Indigo System | Penumbra Inc Dr. Benenati will join Penumbra on September 1, 2020, and will contribute to clinical and medical affairs strategies and advise upon global commercialization and market development activities. Dr. Arko is chief, Division of Vascular and Endovascular Surgery, Sanger Heart and Vascular Institute in Charlotte, North Carolina. Penumbra (PEN) Launches INDIGO System Lightning 7 in US At Penumbra, I have a profound opportunity to change the course of healthcare delivery for people living with vascular disease. Only use replacement fuse with correct rating (see Table 1 for fuse rating). Return all damaged devices and packaging to the manufacturer/distributor. Penumbra's Indigo Aspiration System Lightning 12 received FDA clearance for the treatment of pulmonary embolism. In PE cases, patients are often emergent and need interventions that provide immediate relief. For more information on the personal data that is collected by this website, please refer to Penumbras Privacy Notice. NYU Langone Health Percutaneous manual thromboaspiration was the first technique proposed, followed by a series of percutaneous mechanical thrombectomy devices based on a different mechanism of action (mechanical fragmentation, aspiration, rheolytic thrombectomy, and their combinations). Do not resterilize or reuse. Created with Sketch. Do not use in an oxygen rich environment. Penumbra continues to strive to bring innovative therapies to the medical community, and this is another important milestone that will help advance pulmonary embolism intervention, said Adam Elsesser, president and chief executive officer, Penumbra. For more information, visit https://www.penumbrainc.com/indigo-lightning/. Do not resterilize or reuse. Reuse may result in canister cracking or vacuum filter blockages, which may result in the inability to aspirate. Disclaimer: The opinions and clinical experiences presented herein are for informational purposes only. Warnings/Precautions The canister is intended for single use only. Preliminary data from the INDIAN registry is promising regarding early safety and efficacy for the revascularization of acute peripheral arterial occlusions with thromboaspiration as primary therapy. This site is protected by reCAPTCHA and the Google, Mechanical clot engagement with proprietary Separator technology, Tip directionality for circumferential aspiration, The Indigo System is an integrated system for use only with other components of the Indigo System including the CAT family of catheters, Separators, Dynamic Aspiration Tubing, Lightning, Penumbra ENGINE, and Penumbra ENGINE Canister, Lightning Intelligent Aspiration comes packaged with CAT7, CAT8 or CAT12, Live feedback during the procedure with integrated clot catcher, Penumbra ENGINE is capable of delivering and maintaining nearly pure vacuum (-29 inHg or 98.2 kPa) with the disposable Penumbra ENGINE Canister. Notably, Lightning 7 is designed . Poor flow through the left TPT. The Penumbra Indigo System Separator is intended for use with our Indigo Systems CAT family of catheters to enable the removal of a wide range of thrombus. Earlier in November 2020, Penumbra announced the receipt of 510(k) FDA clearance for an expanded indication of the latest iteration of the Indigo Aspiration System, Lightning 12. The latest generation of Penumbras continuous aspiration thrombectomy system features Indigo System Lightning 12 which combines the new Indigo System CAT 12 Aspiration Catheter with Lightning Intelligent Aspiration powered by Penumbra ENGINE, enabling physicians to focus on optimizing thrombus removal using the systems unique clot detection mechanism. Penumbra Augments Vascular Franchise With Latest Indigo System Launch The device is intended for single use only. Penumbra, the Penumbra P logo, Indigo, CAT, Separator, Lightning, and Penumbra ENGINE are trademarks of Penumbra, Inc. For more information, visit www.penumbrainc.com and connect on Twitter and LinkedIn. Professor, Cardiovascular Surgery Venogram showing stents in the left CIV and EIV. The Indigo System with . Associate Clinical Professor, University of South Florida College of Medicine D. Chris Metzger, MD Otherwise, this could result in degradation of the performance of this equipment. In addition to Lightning 12, the Indigo System also now includes Lightning 8 which combines the Indigo System CAT 8 Aspiration Catheter with Lightning Intelligent Aspiration for the removal of fresh, soft emboli and thrombi from the peripheral arterial and venous systems, and for the treatment of pulmonary embolism. Learn more about Lightning. Carrera LA, Reddy R, Pamoukian VN, et al. Resterilization and/or reuse may result in ineffective catheter coating lubrication, which may result in high friction and the inability to access the target vasculature location. CAT12 is a large-lumen aspiration catheter that incorporates novel laser-cut hypotube-based catheter engineering to . Executive Medical Director of Interventional Radiology & Vascular Imaging o The Indigo catheters vary in diameters from 3.4Fr to 12Fr. Indigo, now with Lightning, utilizes a unique mechanism of action to help optimize thrombus removal procedures by differentiating between thrombus and blood. Thomas S. Maldonado, MD Use of LIGHTNING Aspiration Tubing adjacent to other equipment should be avoided because it could result in improper operation. Miami, Florida Disclosures: None. Hemoglobin and hematocrit levels should be monitored in patients with >700 mL blood loss from the clot aspiration procedure. Lightning 12: 12 F (4.04 mm) HTORQ (100 cm, 115 cm lengths) XTORQ (100 cm length) Lightning 7: 7 F (2.3 mm) XTORQ (130 cm length) CAT . Placing guidewire too distal in the pulmonary vasculature or excessive manipulation of aspiration/ guiding catheter in the smaller, peripheral, and segmental pulmonary artery branches can result in vessel perforation. Designed for single session arterial thrombus removal, New angled tip shape for maximized clot extraction, Dual pressure sensors for real-time flow monitoring, Large lumen size and circumferential sweep enables maximized thrombus engagement, Multi-pitch hypotube for 1:1 torque transfer and advanced deliverability, Indicated for the treatment of pulmonary embolism. The INDIAN registry is a prospective, multicenter registry designed to investigate, in a controlled setting, the safety and initial efficacy of the Indigo System in the treatment of acute peripheral arterial thromboembolism. In summary, Lightning 12 is an excellent addition to the peripheral thrombectomy armamentarium and may allow for successful treatment of complex patients. As PE treatment options continue to grow, the EXTRACT-PE results with the Indigo System serve as a promising data set in helping move the PE landscape forward. Lightning 12 combines the new Indigo System CAT12 aspiration catheter with Lightning intelligent aspiration, enabling physicians to focus on optimising thrombus removal using the system's clot detection mechanism. on behalf of the American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. The major adverse event rate in EXTRACT-PE was 1.7%, and patients had a median intensive care unit stay of < 1 day. Warnings The INDIGO Aspiration System should only be used by physicians who have received appropriate training in interventional techniques. The Indigo System Lightning 12 is the company's next generation aspiration system for peripheral thrombectomy. Figure 2. 2. Warnings Do not use the INDIGO Aspiration System with a pump other than a Penumbra Aspiration Pump. Las Vegas, Nevada Device Problem Adverse Event Without Identified Device or Use Problem (2993) The product was not returned for evaluation. July 14, 2020Penumbra, Inc. announced the United States commercial availability of the Indigo System Lightning 12, which is the companys next-generation aspiration system for peripheral thrombectomy. Lightning 7 a and Lightning 12 a are made of laser-cut hypotube technology, designed to increase trackability and torqueability. Only use replacement fuse with correct rating (see Table 1 for fuse rating). betsy@merrymancommunications.com MHealth Fairview System Medical Director for Interventional Radiology Operations Figure 3. Stay informed on the week's top stories including literature summaries, device approvals, guideline changes, and more. should be used no closer than 12 inches (30 cm) to any part of LIGHTNING Aspiration Tubing. Ask the Experts: How Do You Treat (and Avoid) Recurrent Varicose Veins? Lightning 12 combines the new Indigo System CAT12 Aspiration Catheter with . Giri J, Sista A, Weinberg I, et al. Do not use petroleum based compounds, acids, caustics, or chlorinated solvents to clean or lubricate any parts. Potential adverse . Do not use automated high-pressure contrast injection equipment with the INDIGO Aspiration Catheter because it may damage the device. INDIGO Aspiration System with LIGHTNING Aspiration Tubing Indication for Use Figure 7. Miami Vascular Specialists The patient also had a history of bilateral PE dating back to October 2017, at which point rivaroxaban was prescribed. Lightning 12 combines the new Indigo System CAT12 Aspiration Catheter with Lightning Intelligent Aspiration, enabling physicians to focus on optimizing thrombus removal using the system's unique clot detection mechanism. The PENUMBRA ENGINE is indicated as a vacuum source for Penumbra Aspiration Systems. Created with Sketch. The on-table PA pressures were statistically reduced, and the median device time was 37 minutes. According to the American Heart Association, PE affects roughly 367,000 Americans per year.1. Lightning 12 and Separator 12 are designed for the removal of fresh, soft emboli and thrombi from the peripheral arterial and venous systems, and for the treatment of pulmonary embolism. 2023 Bryn Mawr Communications II, LLC. Bjrck M, Earnshaw JJ, Acosta S, et al. Pulmonary embolism (PE) is a condition that occurs when blood clots, typically traveling from the veins in the legs, get caught in the arteries of the lungs. Director, Venous Thromboembolic Center and Aortic Center If the cause cannot be determined, withdraw the device or system as a unit. The Indigo System with Lightning Intelligent Aspiration and Separators is indicated for the removal of fresh, soft emboli and thrombi from the peripheral arterial and venous . doi: 10.1111/j.1525-139X.2012.01104.x. 310-560-8176. Penumbra Aspiration Pump: The Penumbra Aspiration Pump is indicated as a vacuum source for Penumbra Aspiration Systems. We opted for aspiration thrombectomy with the Indigo System Lightning 12 with the 100-cm HTORQ tip (Penumbra, Inc.). The CAT familyof catheters is the foundation of Penumbras Indigo System. The built-in microprocessor features a proprietary thrombus removal algorithm that automatically controls a valve in the tubing to provide continuous or intermittent aspiration. When performing aspiration, ensure that the INDIGO Aspiration Tubing is open for only the minimum time needed to remove the thrombus. Available in a selection of sizes, the CAT family can provide access to distal peripheral vessels of the upper and lower extremities, including below the knee. It is a welcome addition to our existing endovascular technologies for the treatment of acute PE. Professor of Radiology and Surgery Do not use automated high-pressure contrast injection equipment with the INDIGO Aspiration Catheter because it may damage the device. Potential Adverse Events Possible complications include, but are not limited to, the following: allergic reaction and anaphylaxis from contrast media; acute occlusion; air embolism; arrhythmia/fibrillation; arteriovenous fistula; death; device malfunction; distal embolization; emergent surgery; false aneurysm formation; hematoma, hemorrhage, or blood loss at access site; hematoma, hemorrhage, or blood loss; hypotension; inability to completely remove thrombus or control blood flow; infection; ischemia; kidney damage from contrast media; myocardial infarction; neurological deficits including stroke; respiratory failure; thromboembolic events; vascular complications (including vessel spasm, thrombosis, intimal disruption, dissection, or perforation). In my radiology practice, Ive seen firsthand the challenges medical practitioners face while treating difficult medical conditions, stated Dr. Teigen in the announcement. Otherwise, this could result in degradation of the performance of this equipment. Otherwise, this could result in degradation of the performance of this equipment. Atrium Health At discharge, there have been no adverse device events, and clinical success at 1 month (defined as the absence of death and limb loss) is 98.6%.4. Using the HTORQ angle on CAT12 to torque the catheter, several passes were made through the affected area, from the left popliteal to the external iliac vein (EIV) and internal iliac vein. When in free-flowing blood, this technology automatically stops aspirating blood and hence limits unnecessary loss of blood. Access was gained using an 8-F sheath in the left popliteal vein, which was then upsized to a 12-F sheath. Lightning 12 combines the Indigo System CAT12 aspiration catheter with lightning intelligent aspiration, enabling physicians to focus on optimising thrombus removal using the system's unique clot detection mechanism. Aspiration may also be performed in conjunction with an Indigo System Separator (Penumbra, Inc.) to allow for constant clearing of thrombus from the lumen of the catheter. Our business and operations are subject to a variety of risks and uncertainties and, consequently, actual results may differ materially from those projected by any forward-looking statements. Director of Interventional Radiology Scans revealed a left lower extremity venous thrombus extending from the calf to the common iliac vein (CIV) (Figure 1). If such use is necessary, this equipment and the other equipment should be observed to verify that they are operating normally. Penumbra's Indigo System With Lightning Intelligent Aspiration We gained access through the right CFV using a 14-F sheath. Created with Sketch. If repositioning of the INDIGO CAT RX Aspiration Catheter is necessary during the revascularization procedure, such repositioning should be performed over an appropriate guidewire using standard guidewire techniques. Do not re-infuse blood or fluid from the canister back into the patient. 1. Do not use kinked or damaged devices. After adjunctive endovascular (angioplasty, stenting, or lysis), TIMI 2-3 was reached in up to 95.3% of patients. The clot detection algorithm paired with the audiovisual cues lets the physician know when the catheter is in thrombus versus when it is in blood. Rotational thrombectomy of acute peripheral vascular occlusions using the ThromCat XT device: techniques, indications, and initial results. Mechanical Thrombectomy of Pulmonary Emboli With Use of the Indigo CAT3 advanced through the pedal loop (C). A venogram was performed via left popliteal vein access, which demonstrated thrombosis of the left femoral vein (FV) and common femoral vein (CFV) (Figure 1) and the previously stented left common iliac vein (CIV) and external iliac vein (EIV) (Figure 2). Real-world case examples of Indigo System Lightning 12 Intelligent Aspiration for pulmonary embolism, plus insight into the science behind computer-aided mechanical aspiration and outlooks on PERT development in 2022. CAT12 is a large-lumen aspiration catheter that incorporates novel laser-cut hypotube-based catheter engineering to provide advanced deliverability and torqueability within the body. INDIGO Aspiration System with LIGHTNING Aspiration Tubing - Indication for Use . Potential Adverse Events Possible complications include, but are not limited to, the following: allergic reaction and anaphylaxis from contrast media; acute occlusion; air embolism; arrhythmia; arteriovenous fistula; cardiac injury; cardio-respiratory arrest; death; device malfunction; distal embolization; emboli; excessive blood loss; false aneurysm formation; hematoma or hemorrhage at access site; inability to completely remove thrombus; infection; hemorrhage; ischemia; kidney damage from contrast media; neurological deficits including stroke; vessel spasm, thrombosis, dissection, or perforation; intimal disruption; myocardial infarction; emergent surgery; fibrillation; hypotension; hemoptysis; respiratory failure; thromboembolic events.