Society of Interventional Radiology Position Statement on Catheter-Directed Therapy for Acute Pulmonary Embolism
2018; Elsevier BV; Volume: 29; Issue: 3 Linguagem: Inglês
10.1016/j.jvir.2017.10.024
ISSN1535-7732
AutoresWilliam T. Kuo, Akhilesh K. Sista, Salomão Faintuch, Sean R. Dariushnia, Mark O. Baerlocher, R. Lookstein, Ziv J. Haskal, Boris Nikolic, Joseph J. Gemmete,
Tópico(s)Ultrasound in Clinical Applications
ResumoThe Society of Interventional Radiology (SIR) considers the use of catheter-directed therapy (CDT) or thrombolysis to be an acceptable treatment option for carefully selected patients with massive (ie, high-risk) pulmonary embolism (PE) involving the proximal pulmonary arterial vasculature, in accordance with multidisciplinary guidelines (1Mozaffarian D. Benjamin E.J. Go A.S. et al.Heart disease and stroke statistics–2015 update: a report from the American Heart Association.Circulation. 2015; 131: e29-e322Crossref PubMed Scopus (5711) Google Scholar, 2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar, 3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar, 4Meyer G. Vicaut E. Danays T. et al.Fibrinolysis for patients with intermediate-risk pulmonary embolism.N Engl J Med. 2014; 370: 1402-1411Crossref PubMed Scopus (949) Google Scholar). SIR defines acute proximal PE as new main or lobar emboli identified on radiographic imaging within 14 days of PE symptoms. In addition, SIR encourages the investigative use of CDT and new endovascular techniques in prospective outcomes studies and clinical trials, with particular attention to patients with acute submassive (ie, intermediate-risk) PE. Acute PE is a common life-threatening condition that represents a severe manifestation along the spectrum of venous thromboembolic disease, and PE is the third leading cause of cardiovascular mortality in the United States (1Mozaffarian D. Benjamin E.J. Go A.S. et al.Heart disease and stroke statistics–2015 update: a report from the American Heart Association.Circulation. 2015; 131: e29-e322Crossref PubMed Scopus (5711) Google Scholar). Acute PE is currently classified into three categories: low-risk, submassive (ie, intermediate-risk), and massive (ie, high-risk) (2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar). Low-risk PE is defined by the absence of right heart strain and systemic arterial hypotension. The majority of patients diagnosed with PE present to the hospital without hypotension or heart strain, and these patients with low-risk PE (< 1% short-term mortality rate) can be successfully managed with prompt initiation of therapeutic anticoagulation (3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar). Submassive or intermediate-risk PE is defined by the presence of right heart dysfunction in the setting of normal blood pressure, and this represents as many as 25% of all cases of acute PE. Currently, the greatest uncertainty in the PE treatment algorithm concerns the risk stratification and management of submassive PE. A recent randomized controlled trial (RCT) (4Meyer G. Vicaut E. Danays T. et al.Fibrinolysis for patients with intermediate-risk pulmonary embolism.N Engl J Med. 2014; 370: 1402-1411Crossref PubMed Scopus (949) Google Scholar) in patients with submassive PE demonstrated a 5.6% rate of clinical deterioration (ie, death or hemodynamic decompensation) within 7 days and a 3% 30-day mortality rate with anticoagulation alone. In interpreting these findings against the background of previous studies, it should be noted that, for conventional and aggressive PE therapies, contemporary studies report lower mortality rates than older studies. In addition, RCTs have tended to report lower mortality rates than observational studies, which may result in part from selection of healthier populations (ie, strict inclusion/exclusion criteria) and closer subject monitoring in the RCTs. As such, earlier observational studies reported higher rates of mortality and rapid clinical deterioration in submassive PE populations treated with anticoagulation alone (5Goldhaber S.Z. Visani L. De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).Lancet. 1999; 353: 1386-1389Abstract Full Text Full Text PDF PubMed Scopus (2390) Google Scholar, 6Fremont B. Pacouret G. Jacobi D. Puglisi R. Charbonnier B. de Labriolle A. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients.Chest. 2008; 133: 358-362Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar). Nevertheless, considering all the studies to date, it is clear that the estimated mortality risk from submassive PE is substantially higher than that associated with low-risk PE, but that the vast majority of patients survive, perhaps as a result of contemporary advances in medical care (5Goldhaber S.Z. Visani L. De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).Lancet. 1999; 353: 1386-1389Abstract Full Text Full Text PDF PubMed Scopus (2390) Google Scholar, 6Fremont B. Pacouret G. Jacobi D. Puglisi R. Charbonnier B. de Labriolle A. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients.Chest. 2008; 133: 358-362Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar, 7Chatterjee S. Chakraborty A. Weinberg I. et al.Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.JAMA. 2014; 311: 2414-2421Crossref PubMed Scopus (495) Google Scholar). Massive or high-risk PE is characterized by the presence of sustained systemic arterial hypotension defined by a systolic blood pressure < 90 mm Hg for at least 15 minutes or requiring inotropic support (2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar), and these patients carry a mortality risk of 25%–65% (8Kasper W. Konstantinides S. Geibel A. et al.Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry.J Am Coll Cardiol. 1997; 30: 1165-1171Crossref PubMed Scopus (857) Google Scholar). As a result of the critical nature of high-risk PE, there is a current consensus that aggressive clot removal strategies be considered including systemic thrombolysis, CDT, and/or surgical embolectomy in select patients depending on risk/benefit assessment, presence of contraindications to such therapies, and available local expertise (2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar, 3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar, 9Konstantinides S.V. Torbicki A. Agnelli G. et al.2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) endorsed by the European Respiratory Society (ERS).Eur Heart J. 2014; 35: 3033-3073Crossref PubMed Scopus (86) Google Scholar). Although systemic thrombolysis is currently indicated for the treatment of acute massive PE, many patients cannot receive systemic thrombolytic therapy because of contraindications. Even when patients with acute PE are prescreened for absolute contraindications, the rate of major hemorrhage associated with systemic thrombolysis has been estimated at 9.2%, with a 1.5% risk of intracranial hemorrhage reported in a metaanalysis of RCTs (7Chatterjee S. Chakraborty A. Weinberg I. et al.Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.JAMA. 2014; 311: 2414-2421Crossref PubMed Scopus (495) Google Scholar), and observational studies (4Meyer G. Vicaut E. Danays T. et al.Fibrinolysis for patients with intermediate-risk pulmonary embolism.N Engl J Med. 2014; 370: 1402-1411Crossref PubMed Scopus (949) Google Scholar, 5Goldhaber S.Z. Visani L. De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).Lancet. 1999; 353: 1386-1389Abstract Full Text Full Text PDF PubMed Scopus (2390) Google Scholar, 10Fiumara K. Kucher N. Fanikos J. Goldhaber S.Z. Predictors of major hemorrhage following fibrinolysis for acute pulmonary embolism.Am J Cardiol. 2006; 97: 127-129Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 11Goldhaber S.Z. Integration of catheter thrombectomy into our armamentarium to treat pulmonary embolism.Chest. 1998; 114: 1237-1238Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar) have shown that these bleeding risks may be higher among real-world populations. Although systemic thrombolysis can be initiated in a shorter time frame than CDT, the full dose generally takes 2 hours to deliver, and possible advantages of CDT could include the ability to use a lower thrombolytic drug dose and obtain faster lysis as a result of the targeted intrathrombus drug delivery and the addition of mechanical treatment (ie, pharmacomechanical CDT) (3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar, 12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). In a meta-analysis of 594 patients with acute massive PE treated with modern CDT (ie, use of low-profile devices < 10 F, mechanical fragmentation, and/or aspiration of emboli with or without the use of thrombolytic drugs) (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar), clinical success was achieved in 86.5%, with success defined as the stabilization of hemodynamic parameters, resolution of hypoxia, and survival to hospital discharge. The analysis was limited because most of the identified studies were retrospective in design, most were small with heterogenous methods, and there were no randomized trials (although RCTs might pose an ethical challenge in patients with massive PE); nevertheless, there was no significant difference in clinical success rates between the prospective and retrospective study groups. In the same study (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar), 96% of patients received CDT as the first adjunct to heparin with no previous systemic tissue plasminogen activator (TPA) infusion, and 33% of cases were initiated with mechanical treatment alone (ie, fragmentation and/or aspiration of emboli) without local thrombolytic agent infusion. In addition, the estimated rate of major complications associated with modern CDT was 2.4%, and most complications were attributed to the use of rheolytic thrombectomy with the use of an AngioJet (Possis Medical, Minneapolis, Minnesota) device (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). The highest complication rates occurred in the 68 patients who underwent CDT with the AngioJet rheolytic thrombectomy device, including 27 minor complications (40%) and 19 major complications (28%), with 5 procedure-related deaths (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar); 76% of all major complications recorded in the study (19 of 25) were directly attributed to AngioJet rheolytic thrombectomy despite the fact that it was used in only a small percentage (11%) of the 594 patients studied (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar). In this meta-analysis (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar), use of the AngioJet device was the only catheter-based treatment associated with procedure-related deaths, and the device currently carries a black-label warning from the Food and Drug Administration (13AngioJet Xpeedior [product insert]. Minneapolis: Possis Medical, 2008.Google Scholar), stating "There are reports of serious adverse events, including death, associated with cases where the [AngioJet] catheter was used in treatment of pulmonary embolism." Among patients with submassive PE, the initial goal of treatment escalation with thrombolysis is to reduce mortality from PE without increasing the risk of treatment-related complications. Although a recent meta-analysis of randomized trials (7Chatterjee S. Chakraborty A. Weinberg I. et al.Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.JAMA. 2014; 311: 2414-2421Crossref PubMed Scopus (495) Google Scholar) demonstrated a survival benefit with use of systemic thrombolytic therapy in submassive PE, these data also revealed a much higher risk of major bleeding complications compared with anticoagulation alone. Therefore, the risk-to-benefit ratio of systemic thrombolysis in the submassive PE population is uncertain with regard to clinical decision-making. It is reasonable to hypothesize that delivering a lower overall thrombolytic agent dose via catheter could mitigate the risk of major bleeding complications (14Kuo W.T. Endovascular therapy for acute pulmonary embolism.J Vasc Interv Radiol. 2012; 23: 167-179Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Interestingly, a previous study on flow dynamics (15Schmitz-Rode T. Kilbinger M. Günther R.W. Simulated flow pattern in massive pulmonary embolism: significance for selective intrapulmonary thrombolysis.Cardiovasc Intervent Radiol. 1998; 21: 199-204Crossref PubMed Scopus (66) Google Scholar) demonstrated that a systemically administered drug makes little contact with an obstructing embolus, and most of the drug flows away from the obstructing clot (ie, Venturi effect) toward the open nontarget vessels. Pharmacologic CDT overrides the Venturi effect because a soft, flexible catheter with multiple side holes is directly inserted under image guidance into the thrombosed target vessel to provide direct intraclot drug infusion. A potential advantage with CDT is targeted drug delivery into the clot to achieve low-dose thrombolysis, which may reduce bleeding risk (14Kuo W.T. Endovascular therapy for acute pulmonary embolism.J Vasc Interv Radiol. 2012; 23: 167-179Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). Therefore, relative to systemic drug therapy, local CDT may improve drug effectiveness, allow a lower drug dose to be used, and result in fewer bleeding complications. Despite some limitations of available evidence (12Kuo W.T. Gould M.K. Louie J.D. Rosenberg J.K. Sze D.Y. Hofmann L.V. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques.J Vasc Interv Radiol. 2009; 20: 1431-1440Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar), CDT is currently considered an acceptable treatment option (as are systemic thrombolysis and surgical embolectomy) for highly selected patients with massive PE (2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar, 3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar, 9Konstantinides S.V. Torbicki A. Agnelli G. et al.2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) endorsed by the European Respiratory Society (ERS).Eur Heart J. 2014; 35: 3033-3073Crossref PubMed Scopus (86) Google Scholar). This largely reflects the imminent risk of death and the juxtaposition of a large degree of uncertainty with the estimates of safety and efficacy of CDT and surgical therapy versus the bleeding risk associated with systemic thrombolysis. However, the optimal treatment strategy for submassive PE is still evolving. The 2011 American Heart Association guidelines (2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar) state that "[systemic] Fibrinolysis may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe [right ventricular] RV dysfunction, or major myocardial necrosis) and low risk of bleeding complications… Either catheter embolectomy or surgical embolectomy may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis)." The 2014 European Society of Cardiology guidelines (9Konstantinides S.V. Torbicki A. Agnelli G. et al.2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) endorsed by the European Respiratory Society (ERS).Eur Heart J. 2014; 35: 3033-3073Crossref PubMed Scopus (86) Google Scholar) state that "Surgical pulmonary embolectomy or percutaneous catheter-directed treatment may be considered as alternative, 'rescue' procedures for patients with intermediate/high-risk PE, in whom hemodynamic decompensation appears imminent and the anticipated bleeding risk under systemic thrombolysis is high." The 2016 American College of Chest Physicians guidelines (3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar) state: "In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy… Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT are likely to choose CDT over systemic thrombolytic therapy." A complete summary of these guidelines is included in the Appendix. Because systemic thrombolysis carries a significant risk of major hemorrhage, current guidelines have tempered the indication for use of systemic thrombolysis for intermediate-risk PE, suggesting that it be used only when there is cardiac enzyme leak and/or impending hemodynamic collapse (2Jaff M.R. McMurtry M.S. Archer S.L. 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: 1788-1830Crossref PubMed Scopus (1585) Google Scholar, 3Kearon C. Akl E.A. Ornelas J. et al.Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report.Chest. 2016; 149: 315-352Abstract Full Text Full Text PDF PubMed Scopus (3364) Google Scholar, 9Konstantinides S.V. Torbicki A. Agnelli G. et al.2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: the task force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC) endorsed by the European Respiratory Society (ERS).Eur Heart J. 2014; 35: 3033-3073Crossref PubMed Scopus (86) Google Scholar). This causes a dilemma because patients with moderate to severe RV strain are still at risk of sudden cardiac collapse and death before the development of cardiac enzyme leak and impending life-threatening shock (5Goldhaber S.Z. Visani L. De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER).Lancet. 1999; 353: 1386-1389Abstract Full Text Full Text PDF PubMed Scopus (2390) Google Scholar, 6Fremont B. Pacouret G. Jacobi D. Puglisi R. Charbonnier B. de Labriolle A. Prognostic value of echocardiographic right/left ventricular end-diastolic diameter ratio in patients with acute pulmonary embolism: results from a monocenter registry of 1,416 patients.Chest. 2008; 133: 358-362Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar); by then, it may be too late to escalate treatment. Other patients with submassive PE may have severe and persistent pulmonary symptoms (eg, severe hypoxia, tachypnea, and dyspnea on exertion) that is not relieved by therapeutic anticoagulation. In such scenarios, the availability of a treatment option with a more favorable risk-to-benefit profile than systemic thrombolysis would be optimal. It is possible that CDT meets this criterion; however, current estimates of the safety and efficacy of CDT are based on exceedingly limited data and therefore carry major uncertainty. For this reason, even though it is reasonable to target escalation of care to individual patient circumstances (especially for cases bordering on massive PE physiology that are associated with a low risk of bleeding), CDT cannot be firmly recommended for these patient groups at present. Further prospective studies are needed to address these issues, following the lead of three early prospective studies (16Kucher N. Boekstegers P. Müller O.J. et al.Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.Circulation. 2014; 129: 479-486Crossref PubMed Scopus (617) Google Scholar, 17Piazza G. Hohlfelder B. Jaff M.R. et al.A prospective, single-arm, multicenter trial of ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute massive and submassive pulmonary embolism (SEATTLE II).JACC Cardiovasc Interv. 2015; 8: 1382-1392Crossref PubMed Scopus (509) Google Scholar, 18Kuo W.T. Banerjee A. Kim P.S. et al.Pulmonary embolism response to fragmentation, embolectomy, and catheter thrombolysis (PERFECT): initial results from a prospective multicenter registry.Chest. 2015; 148: 667-673Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). The ULTIMA RCT (16Kucher N. Boekstegers P. Müller O.J. et al.Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.Circulation. 2014; 129: 479-486Crossref PubMed Scopus (617) Google Scholar) enrolled 59 patients with submassive acute main or lower-lobe PE presenting within 14 days and an RV-to-left ventricle (LV) diameter ratio ≥ 1.0 on echocardiography. The study randomized patients to receive unfractionated heparin versus unfractionated heparin plus CDT with the use of an ultrasound (US)-assisted thrombolysis regimen and a maximum TPA dose of 10–20 mg over 15 hours. The ULTIMA trial showed that US-assisted CDT was superior to anticoagulation alone in reversing RV dilation at 24 hours, with no increase in bleeding complications. The trial was limited by selection of a small, idealized trial population, as 84% of screened patients were excluded and only 30 patients were enrolled in the treatment arm. The study was not designed to assess long-term outcomes of CDT and the risk of development of post-PE syndrome (PPS) or chronic thromboembolic pulmonary hypertension (CTEPH). The ULTIMA trial was also an industry-sponsored trial that did not compare US-assisted catheters versus standard CDT; therefore, the contribution of US was unclear. Nevertheless, the ULTIMA trial was the first RCT to test a standardized catheter intervention in patients with acute submassive PE and confirm that a low-dose CDT regimen is superior to anticoagulation alone in improving RV dilation at 24 hours (16Kucher N. Boekstegers P. Müller O.J. et al.Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.Circulation. 2014; 129: 479-486Crossref PubMed Scopus (617) Google Scholar). The SEATTLE II trial (17Piazza G. Hohlfelder B. Jaff M.R. et al.A prospective, single-arm, multicenter trial of ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute massive and submassive pulmonary embolism (SEATTLE II).JACC Cardiovasc Interv. 2015; 8: 1382-1392Crossref PubMed Scopus (509) Google Scholar) (a prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism) enrolled 119 patients with submassive PE and 31 patients with massive PE. Eligible patients had proven proximal PE and an RV:LV diameter ratio ≥ 0.9 confirmed on contrast-enhanced chest computed tomography (CT). The maximum dose of TPA was 24 mg infused via US-assisted catheter over 12–24 hours. During CDT, unfractionated heparin was infused at intermediate intensity (ie, subtherapeutic) with a target activated partial thromboplastin time of 40–60 seconds. The study concluded that low-dose CDT fibrinolysis improves RV function in acute PE, decreases angiographic pulmonary artery obstruction, and reduces systolic pulmonary artery pressure. There was an 11% major bleeding rate in the SEATTLE II trial (17Piazza G. Hohlfelder B. Jaff M.R. et al.A prospective, single-arm, multicenter trial of ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute massive and submassive pulmonary embolism (SEATTLE II).JACC Cardiovasc Interv. 2015; 8: 1382-1392Crossref PubMed Scopus (509) Google Scholar), which, despite the lack of catastrophic bleeding events, adds to the uncertainty concerning whether CDT is truly safer than systemic thrombolysis. In addition, the risk of major bleeding was associated with multiple venous access attempts (ie, access site complications) (19Sadiq I. Goldhaber S.Z. Liu P.Y. Piazza G. for the SEATTLE II investigatorsRisk factors for major bleeding in the SEATTLE II trial.Vasc Med. 2017; 22: 44-50Crossref PubMed Scopus (29) Google Scholar). The trial (17Piazza G. Hohlfelder B. Jaff M.R. et al.A prospective, single-arm, multicenter trial of ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute massive and submassive pulmonary embolism (SEATTLE II).JACC Cardiovasc Interv. 2015; 8: 1382-1392Crossref PubMed Scopus (509) Google Scholar) was limited by a nonrandomized design, even though this allowed more types of patients to be included compared with the ULTIMA trial (16Kucher N. Boekstegers P. Müller O.J. et al.Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.Circulation. 2014; 129: 479-486Crossref PubMed Scopus (617) Google Scholar). Th
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