Reperfusion therapy and outcomes in high-risk pulmonary embolism: A multicenter registry study from the Tokyo Cardiovascular Care Unit Network

Reperfusion therapy and outcomes in high-risk pulmonary embolism: A multicenter registry study from the Tokyo Cardiovascular Care Unit Network | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Reperfusion therapy and outcomes in high-risk pulmonary embolism: A multicenter registry study from the Tokyo Cardiovascular Care Unit Network Takeshi Yamamoto, Hiroyuki Yamamoto, Toshihiro Nozato, Atsushi Mizuno, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8387707/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background High-risk pulmonary embolism (PE) carries substantial mortality, but comprehensive real-world data encompassing the entire high-risk population are limited. Reperfusion therapy is recommended for these patients, yet its use in routine practice appears to be less consistent than expected. The present study evaluated current management and outcomes of high-risk PE within the Tokyo Cardiovascular Care Unit (CCU) Network. Methods We analyzed patients with high-risk PE enrolled in the Tokyo CCU Network registry between 2020 and 2022. High-risk PE was defined as shock, sustained hypotension, or cardiac arrest. Reperfusion therapies included systemic thrombolysis, catheter-based therapy, and surgical embolectomy. A multivariable logistic regression model was constructed to identify factors associated with in-hospital mortality. Results Among 1,217 patients with PE, 185 (15.2%) met the criteria for high-risk PE. Reperfusion therapy was performed in 43.8% of these patients (systemic thrombolysis 27.6%, surgical embolectomy 13.0%, catheter-based therapy 3.2%). Venoarterial extracorporeal membrane oxygenation (VA-ECMO) was initiated in 29.7% of patients. Overall in-hospital mortality was 14.6%. Mortality was lower with reperfusion therapy than without (8.6% vs 19.2%), whereas major bleeding did not differ significantly. In multivariable analysis, cardiac arrest (odds ratio [OR] 3.73, 95% confidence interval [CI] 1.33–10.46), VA-ECMO use (OR 3.08, 95% CI 1.01–8.93), and receipt of reperfusion therapy (OR 0.35, 95% CI 0.12–0.95) were independently associated with in-hospital mortality. Conclusions This study described real-world use and outcomes of reperfusion therapy among patients with high-risk PE within a large regional emergency network. Reperfusion therapy was independently associated with lower in-hospital mortality after adjustment for cardiac arrest and VA-ECMO use. These findings highlight the importance of timely implementation of reperfusion therapy in the modern management of high-risk PE. high-risk pulmonary embolism reperfusion therapy extracorporeal membrane oxygenation in-hospital mortality cardiac arrest outcomes surgical embolectomy outcomes systemic thrombolysis outcomes catheter-based therapy emergency cardiovascular care Figures Figure 1 Background High-risk pulmonary embolism (PE) is a life-threatening condition associated with substantial morbidity and mortality [ 1 ]. A recent report from the U.S. Pulmonary Embolism Response Team (PERT) registry showed in-hospital mortality rates of 42.1% among patients with circulatory collapse and 17.2% among those without [ 2 ]. Systemic thrombolysis is recommended as first-line reperfusion therapy; when contraindicated, surgical embolectomy or catheter-based therapy serves as an alternative [ 3 ]. Despite these recommendations, reperfusion therapy remains underused in routine clinical practice [ 4 , 5 ]. The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) has increased in recent years [ 6 ], prompting questions regarding its optimal integration with reperfusion strategies [ 6 – 8 ]. Several administrative-database studies have examined high-risk PE [ 5 , 9 , 10 ], yet contemporary analyses capturing the full clinical spectrum of high-risk patients remain limited [ 2 , 11 ]. The Tokyo Cardiovascular Care Unit (CCU) Network is a regional cardiovascular emergency transport system that coordinates ambulance triage and rapid transfer to acute cardiovascular care facilities in collaboration with the Tokyo Fire Department [ 12 , 13 ]. High-risk PE constitutes one of the emergency conditions prioritized within this system [ 12 , 14 , 15 ]. This study explored current management practices and in-hospital outcomes of high-risk PE using Tokyo CCU Network data, with a focus on real-world application of reperfusion therapy. Methods The Tokyo CCU Network database is an ongoing multicenter registry that prospectively collects information on emergency admissions to acute cardiovascular facilities, based on data provided by emergency medical services and investigators at participating hospitals [ 13 , 15 , 16 ]. The registry is listed in the University Hospital Medical Information Network (UMIN000013128). As of December 2022, it included 76 hospitals serving approximately 14 million residents. Data were anonymized before analysis, and informed consent was waived in accordance with national ethical guidelines. The study protocol was approved by the Institutional Review Board of the Tokyo CCU Network Scientific Committee (approval number 16 − 002). This analysis included data collected between 2020 and 2022. Among 1,217 patients diagnosed with PE during this period, 185 with high-risk PE and complete management and outcome data were included (Fig. 1 ). PE diagnosis required confirmation by contrast-enhanced computed tomography, a high-probability ventilation–perfusion scan, or pulmonary angiography. High-risk PE was defined by shock, sustained hypotension, or cardiac arrest at presentation. Treatment decisions followed Japanese Circulation Society or European Society of Cardiology guidelines [ 3 , 17 ] and were determined at the treating clinicians’ discretion. Reperfusion strategies included systemic thrombolysis, catheter-based therapy, and surgical embolectomy. When multiple modalities were applied, patients were categorized according to the final therapy to reflect treatment escalation [ 7 ]. In-hospital outcomes comprised all-cause mortality, PE-related mortality, and major bleeding, defined as intracranial hemorrhage or bleeding requiring transfusion. Dichotomous variables were compared using the chi-square or Fisher’s exact test, as appropriate. An exploratory multivariable logistic regression model assessed independent predictors of in-hospital mortality, focusing on variables representing early disease severity and initial treatment decisions. Variables included in the model were age, sex, cardiac arrest, VA-ECMO use, and reperfusion therapy; analyses were limited to complete cases. Two-tailed P-values < 0.05 indicated statistical significance. Results Patient characteristics and overall outcomes Baseline characteristics, management strategies, and in-hospital outcomes are presented in Table 1. The median age was 65 years (interquartile range 52–78), and 42.7% of patients were men. Active cancer was present in 8.7%; major transient venous thromboembolism (VTE) risk factors in 20.7%; minor transient risk factors in 27.7%; permanent risk factors in 6.0%; and unprovoked PE in 40.8%. In-hospital or healthcare-facility onset occurred in 26.5%. Cardiac arrest occurred in 17.8%, including 7.0% on arrival. Residual deep vein thrombosis was identified in 74.3%. Reperfusion therapy was administered to 81 patients (43.8%), including systemic thrombolysis in 27.6%, surgical embolectomy in 13.0%, and catheter-based therapy in 3.2%. VA-ECMO was used in 29.7%, and inferior vena cava filters in 6.6%. In-hospital mortality was 14.6%, PE-related mortality was 12.4%, and major bleeding occurred in 11.9%. Reperfusion therapy vs no reperfusion Patients who received reperfusion therapy were more often men and obese and more likely to have unprovoked PE, whereas in-hospital onset was less frequent. Heparin bolus use was lower, while inferior vena cava filter placement was more common. All-cause mortality was significantly lower among patients receiving reperfusion therapy (8.6% vs 19.2%, P = 0.043). PE-related mortality also tended to be lower (7.4% vs 16.3%, P = 0.068). Rates of major bleeding did not differ significantly (Table 1). Comparison among reperfusion modalities Among patients undergoing reperfusion therapy, 62.9% received systemic thrombolysis, 29.6%underwent surgical embolectomy, and 7.4% received catheter-based therapy. Mortality was lowest among patients treated with thrombolysis, followed by surgical embolectomy and catheter-based therapy. Overall major bleeding rates did not differ significantly among groups; however, intracranial hemorrhage occurred exclusively in the thrombolysis group (5.9%). Procedure-site bleeding was most frequent among patients receiving catheter-based therapy (Table 2). VA-ECMO vs no VA-ECMO Patients requiring VA-ECMO were younger (median age 58 vs 70.5 years; P = 0.002), more often men, and more likely to have major transient VTE risk factors or unprovoked PE. Cardiac arrest and arrest on arrival were significantly more common. Reperfusion therapy was used at comparable rates in patients with and without VA-ECMO (52.7% vs 40.0%). All-cause mortality (29.1% vs 8.5%), PE-related mortality (27.3% vs 6.2%), and major bleeding (27.3% vs 5.4%) were significantly higher among patients requiring VA-ECMO (all P < 0.001). Procedure-site bleeding was also more frequent (Supplemental Table 1). Cardiac arrest vs no cardiac arrest Patients with cardiac arrest were more often receiving chronic dialysis and more likely to have an in-hospital onset. The use of any reperfusion therapy tended to be lower among patients with cardiac arrest (30.3% vs 46.7%, P = 0.085). Thrombolysis was used less frequently (9.1% vs 31.6%, P = 0.009), whereas catheter-based therapy was more common (12.1% vs 1.3%, P = 0.010). Surgical embolectomy rates were similar between groups. All-cause mortality (39.4% vs 9.2%) and PE-related mortality (36.4% vs 7.2%) were markedly higher in the cardiac arrest group (both P < 0.001). Major bleeding showed a nonsignificant increase (P = 0.068), and procedure-site bleeding was more common (Supplemental Table 2). Survivors vs non-survivors Non-survivors were more often men and exhibited substantially higher rates of cardiac arrest and arrest on arrival. Reperfusion therapy, particularly systemic thrombolysis, was used less frequently (7.4% vs 31.0%, P = 0.010), whereas VA-ECMO use was significantly higher (59.3% vs 24.7%, P < 0.001). Non-survivors more frequently experienced clinical deterioration or recurrent PE (19.2% vs 4.5%, P = 0.016) and had higher rates of major bleeding (29.6% vs 8.9%, P = 0.002) (Supplemental Table 3). In multivariable analysis, cardiac arrest (OR 3.73, 95% CI 1.33–10.46, P = 0.012), VA-ECMO use (OR 3.08, 95% CI 1.01–8.93, P = 0.038), and reperfusion therapy (OR 0.34, 95% CI 0.12–0.95, P = 0.039) were independently associated with in-hospital mortality (Table 3). Discussion This study characterized current use and outcomes of reperfusion therapy across the full spectrum of patients with high-risk PE in Japan using data from the Tokyo CCU Network. Comprehensive real-world evidence encompassing all presentations of high-risk PE remains limited. A recent study analyzed 991 patients with high-risk PE but included only those who received reperfusion therapy or ECMO [ 12 ]. Similarly, the U.S. PERT registry enrolled 1,442 high-risk patients but was restricted to centers with established PERT programs [ 2 ]. In this cohort, reperfusion therapy was performed in 43.8% of patients and was associated with lower in-hospital mortality without an increase in major bleeding. In multivariable analysis, cardiac arrest, VA-ECMO use, and absence of reperfusion therapy independently predicted mortality, highlighting the potential benefit of active reperfusion therapy in this population. Compared with the PERT registry [ 2 ], the overall reperfusion rate was similar, although catheter-based therapy was used far less frequently, likely reflecting limited availability of dedicated PE devices in Japan. A recent systematic review (27 studies, 1,517 patients; 2010–2020) reported pooled in-hospital mortality, major bleeding, and intracranial hemorrhage rates of 28.3%, 13.8%, and 3.6%, respectively [ 18 ], broadly consistent with these findings. Earlier reports indicated reperfusion therapy use of approximately 30% in hemodynamically unstable PE [ 4 , 5 ], whereas both this cohort and the PERT registry reported rates near 40% [ 2 ]. This difference may reflect higher intervention rates in specialized care settings; nevertheless, overall utilization likely remains suboptimal. Barriers to thrombolysis include perceived bleeding risk, frequent relative contraindications, and heterogeneity in clinical presentation. Catheter-based therapy has gained attention with the introduction of large-bore aspiration devices, but supporting evidence largely derives from intermediate-high-risk PE [ 19 , 20 ], and reliance on specialized centers limits generalizability; notably, these devices are unavailable in Japan. Surgical embolectomy enables definitive clot removal but remains constrained by procedural invasiveness and the need for immediate access to experienced cardiovascular surgeons. VA-ECMO use was relatively high in this cohort, consistent with Japanese practice patterns [ 6 , 21 ]. Although ECMO serves as supportive rather than definitive therapy, it can rapidly unload the right ventricle and stabilize hemodynamics. In this study, VA-ECMO was used in 29.7% of patients; those receiving ECMO more frequently presented with cardiac arrest, more often underwent surgical embolectomy, and experienced higher mortality and bleeding rates. In the United States, ECMO use was 6.3% in the PERT registry [ 2 ] and 2.3% in a recent Nationwide Inpatient Sample analysis [ 7 ]. The latter suggested that ECMO combined with reperfusion therapy may improve survival after cardiac arrest. Regarding reperfusion strategies during ECMO, a systematic review of 17 studies (327 VA-ECMO–treated PE patients; 2010–2020) reported mortality rates of 22.6% with mechanical reperfusion, primarily surgical embolectomy, and 42.8% with other strategies, yielding an absolute difference of 20.2% (95% CI 5.2%–27.6%) [ 8 ]. Similarly, a Japanese registry of 2,035 patients with symptomatic PE reported the lowest 30-day mortality after surgical embolectomy (6.3%), compared with thrombolysis (25%), anticoagulation alone (39.3%), and catheter-based therapy (43.8%) [ 9 ]. Given the relatively high ECMO utilization in Japan, further research should define optimal timing and combinations of ECMO and reperfusion therapy in high-risk PE management. Limitations This study has several limitations. First, although the Tokyo CCU Network captures real-world, all-comer practice across multiple centers, the absolute number of high-risk PE cases was modest. Second, detailed bleeding-risk profiles and data on right-heart thrombi, which may influence severity and management, were unavailable. Third, procedural details of reperfusion therapy and timing of ECMO initiation were not recorded. Treatment selection, particularly in the setting of cardiac arrest, likely reflected clinician judgment and institutional resources, introducing potential confounding. Finally, the exploratory multivariable model excluded several established prognostic markers, such as baseline right ventricular function, lactate levels, comorbidity burden, and embolic burden, which may have resulted in residual confounding. Conclusions This study described real-world use and outcomes of reperfusion therapy among patients with high-risk PE within a large regional emergency network. Reperfusion therapy was independently associated with lower in-hospital mortality after adjustment for cardiac arrest and VA-ECMO use. These findings emphasize the importance of timely implementation of reperfusion therapy in contemporary high-risk PE management. Abbreviations • BMI body mass index • CCU cardiovascular care unit • CI confidence interval • ECMO extracorporeal membrane oxygenation • OR odds ratio • PE pulmonary embolism • PERT Pulmonary Embolism Response Team • UMIN University Hospital Medical Information Network • VA ECMO –venoarterial extracorporeal membrane oxygenation • VTE venous thromboembolism Declarations Ethics approval and consent to participate All data were anonymized before analysis, and the requirement for informed consent was waived in accordance with national ethical guidelines. The study protocol was approved by the Institutional Review Board of the Tokyo CCU Network Scientific Committee (approval number 16 − 002). Consent for publication Not applicable Competing interests Dr. Kohsaka has received research grants from Pfizer and has received lecture fees from Novartis and Bristol Myers Squibb, outside the submitted work. The other authors report no conflicts of interest. Funding The Tokyo CCU Network data registry is financially supported by the Tokyo Metropolitan Government, Japan. The funders had no role in study design or data interpretation. This work was partially supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (Grant Number: 24K12164). Author Contribution TY performed material preparation, data collection, and analysis and wrote the first draft. TY, HY, TN, AM, NH, SH, KA, SK, and MT contributed to study conception, design, manuscript review, and approval of the final version. Acknowledgement The authors thank the members of the Tokyo CCU Network, as well as Ms. Kozue Murayama (Tokyo CCU Network Secretariat) for their assistance with data collection. Data Availability The anonymized data supporting the findings of this study are available from the corresponding author upon reasonable request. References Yamamoto T. Management of patients with high-risk pulmonary embolism: A narrative review. J Intensive Care. 2018;6:16. Kobayashi T, Pugliese S, Sethi SS, Parikh SA, Goldberg J, Alkhafan F, et al. Contemporary management and outcomes of patients with high-risk pulmonary embolism. J Am Coll Cardiol. 2024;83:35–43. Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020. 2019;41:543–603 Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: Saves lives but underused. Am J Med. 2012;125:465–70. Zuin M, Rigatelli G, Zuliani G, Zonzin P, Ramesh D, Roncon L. Thrombolysis in hemodynamically unstable patients: Still underused: A review based on multicenter prospective registries on acute pulmonary embolism. J Thromb Thrombolysis. 2019;48:323–30. Nishimoto Y, Ohbe H, Matsui H, Nakajima M, Sasabuchi Y, Sato Y, et al. Trends in treatment patterns and outcomes of patients with pulmonary embolism in Japan, 2010 to 2020: A nationwide inpatient database study. J Am Heart Assoc. 2023;12:e028981. Farmakis IT, Sagoschen I, Barco S, Keller K, Valerio L, Wild J, et al. Extracorporeal membrane oxygenation and reperfusion strategies in high-risk pulmonary embolism hospitalizations. Crit Care Med. 2024;52:e512–21. Chopard R, Nielsen P, Ius F, Cebotari S, Ecarnot F, Pilichowski H, et al. Optimal reperfusion strategy in acute high-risk pulmonary embolism requiring extracorporeal membrane oxygenation support: A systematic review and meta-analysis. Eur Respir J. 2022;60:2102977. Takabayashi K, Yamashita Y, Morimoto T, Chatani R, Kaneda K, Nishimoto Y, et al. Clinical characteristics and short-term outcomes of patients with critical acute pulmonary embolism requiring extracorporeal membrane oxygenation: From the COMMAND VTE Registry-2. J Intensive Care. 2024;12:45. Nishimoto Y, Ohbe H, Matsui H, Nakajima M, Sasabuchi Y, Sato Y, et al. Effectiveness of systemic thrombolysis on clinical outcomes in high-risk pulmonary embolism patients with venoarterial extracorporeal membrane oxygenation: A nationwide inpatient database study. J Intensive Care. 2023;11:4. Ishida K, Nishimoto Y, Ohbe H, Ikeda N, Sugiura T, Suda R, et al. Short-term outcomes of thrombolysis versus surgical pulmonary embolectomy in patients with high-risk pulmonary embolism. J Thorac Cardiovasc Surg. 2025:S0022-5223(25)00646-4. Stadlbauer A, Verbelen T, Binzenhöfer L, Goslar T, Supady A, Spieth PM, et al. Management of high-risk acute pulmonary embolism: An emulated target trial analysis. Intensive Care Med. 2025;51:490–505. Tokyo CCU Network Scientific Committee. Latest management and outcomes of major pulmonary embolism in the cardiovascular disease early transport system: Tokyo CCU Network. Circ J. 2010;74:289–93. Yamamoto T, Otsuka T, Yoshida N, Kobayashi Y, Komiyama N, Hara K, et al. Hospital performance in a large urban acute myocardial infarction emergency care system: Tokyo Cardiovascular Care Unit network. J Cardiol. 2021;78:177–82. Mizuno A, Yamamoto T, Tanabe Y, Obayashi T, Takayama M, Nagao K, et al. Pulmonary embolism severity index and simplified pulmonary embolism severity index risk scores are useful to predict mortality in Japanese patients with pulmonary embolism. Circ J. 2015;79:889–91. Tanabe Y, Obayashi T, Yamamoto T, Takayama M, Nagao K. Predictive value of biomarkers for the prognosis of acute pulmonary embolism in Japanese patients: Results of the Tokyo CCU Network registry. J Cardiol. 2015;66:460–5. JCS Joint Working Group. Guidelines for diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2017). [Japanese]. https://js-phlebology.jp/wp/wp-content/uploads/2019/03/JCS2017_ito_h.pdf Accessed 17 Dec 2025 Silver MJ, Giri J, Duffy Á, Jaber WA, Khandhar S, Ouriel K, et al. Incidence of mortality and complications in high-risk pulmonary embolism: A systematic review and meta-analysis. J Soc CardioVasc Angiogr Interv. 2023;2:100548. Jaber WA, Gonsalves CF, Stortecky S, Horr S, Pappas O, Gandhi RT, et al. Large-bore mechanical thrombectomy versus catheter-directed thrombolysis in the management of intermediate-risk pulmonary embolism: Primary results of the PEERLESS randomized controlled trial. Circulation. 2025;151:260–73. Lookstein RA, Konstantinides SV, Weinberg I, Dohad SY, Rosol Z, Kopeć G, et al. Randomized controlled trial of mechanical thrombectomy with anticoagulation versus anticoagulation alone for acute intermediate-high risk pulmonary embolism: Primary outcomes from the STORM-PE trial. Circulation. 2025. https://doi.org/10.1161/CIRCULATIONAHA.125.077232 [Epub ahead of print] Yamashita Y, Morimoto T, Kadota K, Takase T, Hiramori S, Kim K, et al. Severity of pulmonary embolism at initial diagnosis and long-term clinical outcomes: From the COMMAND VTE Registry. Int J Cardiol. 2021;343:107–13. Tables Table 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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1","display":"","copyAsset":false,"role":"figure","size":23227,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of patient selection\u003c/p\u003e","description":"","filename":"HRAPECCUneworkFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8387707/v1/d1ac79b500b9b8669ef5dfb3.png"},{"id":99522891,"identity":"5a53b3c7-9f59-428f-8e22-63bf371a5f37","added_by":"auto","created_at":"2026-01-05 11:24:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":606041,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8387707/v1/8c578567-05c3-4a30-95c0-a51c1b87ca6e.pdf"},{"id":99188528,"identity":"ee216372-f7ca-4831-a1a0-3f44de9faa0f","added_by":"auto","created_at":"2025-12-30 00:19:16","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18412,"visible":true,"origin":"","legend":"","description":"","filename":"Table13.docx","url":"https://assets-eu.researchsquare.com/files/rs-8387707/v1/0add0b65a9946fbe91d89a1a.docx"},{"id":99188530,"identity":"decbaeb7-5ad1-458b-be13-5082591eb56a","added_by":"auto","created_at":"2025-12-30 00:19:16","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":22961,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable13.docx","url":"https://assets-eu.researchsquare.com/files/rs-8387707/v1/027e24504eff18af9fd3beaf.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Reperfusion therapy and outcomes in high-risk pulmonary embolism: A multicenter registry study from the Tokyo Cardiovascular Care Unit Network","fulltext":[{"header":"Background","content":"\u003cp\u003eHigh-risk pulmonary embolism (PE) is a life-threatening condition associated with substantial morbidity and mortality [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. A recent report from the U.S. Pulmonary Embolism Response Team (PERT) registry showed in-hospital mortality rates of 42.1% among patients with circulatory collapse and 17.2% among those without [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Systemic thrombolysis is recommended as first-line reperfusion therapy; when contraindicated, surgical embolectomy or catheter-based therapy serves as an alternative [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Despite these recommendations, reperfusion therapy remains underused in routine clinical practice [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) has increased in recent years [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], prompting questions regarding its optimal integration with reperfusion strategies [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSeveral administrative-database studies have examined high-risk PE [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], yet contemporary analyses capturing the full clinical spectrum of high-risk patients remain limited [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The Tokyo Cardiovascular Care Unit (CCU) Network is a regional cardiovascular emergency transport system that coordinates ambulance triage and rapid transfer to acute cardiovascular care facilities in collaboration with the Tokyo Fire Department [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. High-risk PE constitutes one of the emergency conditions prioritized within this system [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis study explored current management practices and in-hospital outcomes of high-risk PE using Tokyo CCU Network data, with a focus on real-world application of reperfusion therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe Tokyo CCU Network database is an ongoing multicenter registry that prospectively collects information on emergency admissions to acute cardiovascular facilities, based on data provided by emergency medical services and investigators at participating hospitals [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The registry is listed in the University Hospital Medical Information Network (UMIN000013128). As of December 2022, it included 76 hospitals serving approximately 14\u0026nbsp;million residents. Data were anonymized before analysis, and informed consent was waived in accordance with national ethical guidelines. The study protocol was approved by the Institutional Review Board of the Tokyo CCU Network Scientific Committee (approval number 16\u0026thinsp;\u0026minus;\u0026thinsp;002).\u003c/p\u003e \u003cp\u003eThis analysis included data collected between 2020 and 2022. Among 1,217 patients diagnosed with PE during this period, 185 with high-risk PE and complete management and outcome data were included (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). PE diagnosis required confirmation by contrast-enhanced computed tomography, a high-probability ventilation\u0026ndash;perfusion scan, or pulmonary angiography. High-risk PE was defined by shock, sustained hypotension, or cardiac arrest at presentation. Treatment decisions followed Japanese Circulation Society or European Society of Cardiology guidelines [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and were determined at the treating clinicians\u0026rsquo; discretion. Reperfusion strategies included systemic thrombolysis, catheter-based therapy, and surgical embolectomy. When multiple modalities were applied, patients were categorized according to the final therapy to reflect treatment escalation [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In-hospital outcomes comprised all-cause mortality, PE-related mortality, and major bleeding, defined as intracranial hemorrhage or bleeding requiring transfusion.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDichotomous variables were compared using the chi-square or Fisher\u0026rsquo;s exact test, as appropriate. An exploratory multivariable logistic regression model assessed independent predictors of in-hospital mortality, focusing on variables representing early disease severity and initial treatment decisions. Variables included in the model were age, sex, cardiac arrest, VA-ECMO use, and reperfusion therapy; analyses were limited to complete cases. Two-tailed P-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics and overall outcomes\u003c/h2\u003e \u003cp\u003eBaseline characteristics, management strategies, and in-hospital outcomes are presented in Table\u0026nbsp;1. The median age was 65 years (interquartile range 52\u0026ndash;78), and 42.7% of patients were men. Active cancer was present in 8.7%; major transient venous thromboembolism (VTE) risk factors in 20.7%; minor transient risk factors in 27.7%; permanent risk factors in 6.0%; and unprovoked PE in 40.8%. In-hospital or healthcare-facility onset occurred in 26.5%. Cardiac arrest occurred in 17.8%, including 7.0% on arrival. Residual deep vein thrombosis was identified in 74.3%.\u003c/p\u003e \u003cp\u003eReperfusion therapy was administered to 81 patients (43.8%), including systemic thrombolysis in 27.6%, surgical embolectomy in 13.0%, and catheter-based therapy in 3.2%. VA-ECMO was used in 29.7%, and inferior vena cava filters in 6.6%. In-hospital mortality was 14.6%, PE-related mortality was 12.4%, and major bleeding occurred in 11.9%.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eReperfusion therapy vs no reperfusion\u003c/h3\u003e\n\u003cp\u003ePatients who received reperfusion therapy were more often men and obese and more likely to have unprovoked PE, whereas in-hospital onset was less frequent. Heparin bolus use was lower, while inferior vena cava filter placement was more common. All-cause mortality was significantly lower among patients receiving reperfusion therapy (8.6% vs 19.2%, P\u0026thinsp;=\u0026thinsp;0.043). PE-related mortality also tended to be lower (7.4% vs 16.3%, P\u0026thinsp;=\u0026thinsp;0.068). Rates of major bleeding did not differ significantly (Table\u0026nbsp;1).\u003c/p\u003e\n\u003ch3\u003eComparison among reperfusion modalities\u003c/h3\u003e\n\u003cp\u003eAmong patients undergoing reperfusion therapy, 62.9% received systemic thrombolysis, 29.6%underwent surgical embolectomy, and 7.4% received catheter-based therapy. Mortality was lowest among patients treated with thrombolysis, followed by surgical embolectomy and catheter-based therapy. Overall major bleeding rates did not differ significantly among groups; however, intracranial hemorrhage occurred exclusively in the thrombolysis group (5.9%). Procedure-site bleeding was most frequent among patients receiving catheter-based therapy (Table\u0026nbsp;2).\u003c/p\u003e\n\u003ch3\u003eVA-ECMO vs no VA-ECMO\u003c/h3\u003e\n\u003cp\u003ePatients requiring VA-ECMO were younger (median age 58 vs 70.5 years; P\u0026thinsp;=\u0026thinsp;0.002), more often men, and more likely to have major transient VTE risk factors or unprovoked PE. Cardiac arrest and arrest on arrival were significantly more common. Reperfusion therapy was used at comparable rates in patients with and without VA-ECMO (52.7% vs 40.0%). All-cause mortality (29.1% vs 8.5%), PE-related mortality (27.3% vs 6.2%), and major bleeding (27.3% vs 5.4%) were significantly higher among patients requiring VA-ECMO (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Procedure-site bleeding was also more frequent (Supplemental Table\u0026nbsp;1).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eCardiac arrest vs no cardiac arrest\u003c/h2\u003e \u003cp\u003ePatients with cardiac arrest were more often receiving chronic dialysis and more likely to have an in-hospital onset. The use of any reperfusion therapy tended to be lower among patients with cardiac arrest (30.3% vs 46.7%, P\u0026thinsp;=\u0026thinsp;0.085). Thrombolysis was used less frequently (9.1% vs 31.6%, P\u0026thinsp;=\u0026thinsp;0.009), whereas catheter-based therapy was more common (12.1% vs 1.3%, P\u0026thinsp;=\u0026thinsp;0.010). Surgical embolectomy rates were similar between groups. All-cause mortality (39.4% vs 9.2%) and PE-related mortality (36.4% vs 7.2%) were markedly higher in the cardiac arrest group (both P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Major bleeding showed a nonsignificant increase (P\u0026thinsp;=\u0026thinsp;0.068), and procedure-site bleeding was more common (Supplemental Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvivors vs non-survivors\u003c/h3\u003e\n\u003cp\u003eNon-survivors were more often men and exhibited substantially higher rates of cardiac arrest and arrest on arrival. Reperfusion therapy, particularly systemic thrombolysis, was used less frequently (7.4% vs 31.0%, P\u0026thinsp;=\u0026thinsp;0.010), whereas VA-ECMO use was significantly higher (59.3% vs 24.7%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Non-survivors more frequently experienced clinical deterioration or recurrent PE (19.2% vs 4.5%, P\u0026thinsp;=\u0026thinsp;0.016) and had higher rates of major bleeding (29.6% vs 8.9%, P\u0026thinsp;=\u0026thinsp;0.002) (Supplemental Table\u0026nbsp;3). In multivariable analysis, cardiac arrest (OR 3.73, 95% CI 1.33\u0026ndash;10.46, P\u0026thinsp;=\u0026thinsp;0.012), VA-ECMO use (OR 3.08, 95% CI 1.01\u0026ndash;8.93, P\u0026thinsp;=\u0026thinsp;0.038), and reperfusion therapy (OR 0.34, 95% CI 0.12\u0026ndash;0.95, P\u0026thinsp;=\u0026thinsp;0.039) were independently associated with in-hospital mortality (Table\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study characterized current use and outcomes of reperfusion therapy across the full spectrum of patients with high-risk PE in Japan using data from the Tokyo CCU Network. Comprehensive real-world evidence encompassing all presentations of high-risk PE remains limited. A recent study analyzed 991 patients with high-risk PE but included only those who received reperfusion therapy or ECMO [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Similarly, the U.S. PERT registry enrolled 1,442 high-risk patients but was restricted to centers with established PERT programs [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this cohort, reperfusion therapy was performed in 43.8% of patients and was associated with lower in-hospital mortality without an increase in major bleeding. In multivariable analysis, cardiac arrest, VA-ECMO use, and absence of reperfusion therapy independently predicted mortality, highlighting the potential benefit of active reperfusion therapy in this population.\u003c/p\u003e \u003cp\u003eCompared with the PERT registry [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], the overall reperfusion rate was similar, although catheter-based therapy was used far less frequently, likely reflecting limited availability of dedicated PE devices in Japan. A recent systematic review (27 studies, 1,517 patients; 2010\u0026ndash;2020) reported pooled in-hospital mortality, major bleeding, and intracranial hemorrhage rates of 28.3%, 13.8%, and 3.6%, respectively [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], broadly consistent with these findings.\u003c/p\u003e \u003cp\u003eEarlier reports indicated reperfusion therapy use of approximately 30% in hemodynamically unstable PE [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], whereas both this cohort and the PERT registry reported rates near 40% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This difference may reflect higher intervention rates in specialized care settings; nevertheless, overall utilization likely remains suboptimal. Barriers to thrombolysis include perceived bleeding risk, frequent relative contraindications, and heterogeneity in clinical presentation. Catheter-based therapy has gained attention with the introduction of large-bore aspiration devices, but supporting evidence largely derives from intermediate-high-risk PE [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and reliance on specialized centers limits generalizability; notably, these devices are unavailable in Japan. Surgical embolectomy enables definitive clot removal but remains constrained by procedural invasiveness and the need for immediate access to experienced cardiovascular surgeons.\u003c/p\u003e \u003cp\u003eVA-ECMO use was relatively high in this cohort, consistent with Japanese practice patterns [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Although ECMO serves as supportive rather than definitive therapy, it can rapidly unload the right ventricle and stabilize hemodynamics. In this study, VA-ECMO was used in 29.7% of patients; those receiving ECMO more frequently presented with cardiac arrest, more often underwent surgical embolectomy, and experienced higher mortality and bleeding rates. In the United States, ECMO use was 6.3% in the PERT registry [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and 2.3% in a recent Nationwide Inpatient Sample analysis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The latter suggested that ECMO combined with reperfusion therapy may improve survival after cardiac arrest.\u003c/p\u003e \u003cp\u003eRegarding reperfusion strategies during ECMO, a systematic review of 17 studies (327 VA-ECMO\u0026ndash;treated PE patients; 2010\u0026ndash;2020) reported mortality rates of 22.6% with mechanical reperfusion, primarily surgical embolectomy, and 42.8% with other strategies, yielding an absolute difference of 20.2% (95% CI 5.2%\u0026ndash;27.6%) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Similarly, a Japanese registry of 2,035 patients with symptomatic PE reported the lowest 30-day mortality after surgical embolectomy (6.3%), compared with thrombolysis (25%), anticoagulation alone (39.3%), and catheter-based therapy (43.8%) [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Given the relatively high ECMO utilization in Japan, further research should define optimal timing and combinations of ECMO and reperfusion therapy in high-risk PE management.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study has several limitations. First, although the Tokyo CCU Network captures real-world, all-comer practice across multiple centers, the absolute number of high-risk PE cases was modest. Second, detailed bleeding-risk profiles and data on right-heart thrombi, which may influence severity and management, were unavailable. Third, procedural details of reperfusion therapy and timing of ECMO initiation were not recorded. Treatment selection, particularly in the setting of cardiac arrest, likely reflected clinician judgment and institutional resources, introducing potential confounding. Finally, the exploratory multivariable model excluded several established prognostic markers, such as baseline right ventricular function, lactate levels, comorbidity burden, and embolic burden, which may have resulted in residual confounding.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study described real-world use and outcomes of reperfusion therapy among patients with high-risk PE within a large regional emergency network. Reperfusion therapy was independently associated with lower in-hospital mortality after adjustment for cardiac arrest and VA-ECMO use. These findings emphasize the importance of timely implementation of reperfusion therapy in contemporary high-risk PE management.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eBMI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebody mass index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eCCU\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecardiovascular care unit\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eCI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003econfidence interval\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eECMO\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eextracorporeal membrane oxygenation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eOR\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eodds ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003ePE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epulmonary embolism\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003ePERT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePulmonary Embolism Response Team\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eUMIN\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUniversity Hospital Medical Information Network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eVA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003e \u003cb\u003eECMO\u003c/b\u003e\u0026ndash;venoarterial extracorporeal membrane oxygenation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u0026bull; \u003cb\u003eVTE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003evenous thromboembolism\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003e All data were anonymized before analysis, and the requirement for informed consent was waived in accordance with national ethical guidelines. The study protocol was approved by the Institutional Review Board of the Tokyo CCU Network Scientific Committee (approval number 16\u0026thinsp;\u0026minus;\u0026thinsp;002).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eDr. Kohsaka has received research grants from Pfizer and has received lecture fees from Novartis and Bristol Myers Squibb, outside the submitted work. The other authors report no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThe Tokyo CCU Network data registry is financially supported by the Tokyo Metropolitan Government, Japan. The funders had no role in study design or data interpretation.\u003c/p\u003e \u003cp\u003eThis work was partially supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (Grant Number: 24K12164).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eTY performed material preparation, data collection, and analysis and wrote the first draft. TY, HY, TN, AM, NH, SH, KA, SK, and MT contributed to study conception, design, manuscript review, and approval of the final version.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors thank the members of the Tokyo CCU Network, as well as Ms. Kozue Murayama (Tokyo CCU Network Secretariat) for their assistance with data collection.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe anonymized data supporting the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYamamoto T. Management of patients with high-risk pulmonary embolism: A narrative review. J Intensive Care. 2018;6:16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobayashi T, Pugliese S, Sethi SS, Parikh SA, Goldberg J, Alkhafan F, et al. Contemporary management and outcomes of patients with high-risk pulmonary embolism. J Am Coll Cardiol. 2024;83:35\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKonstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, et al. ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020. 2019;41:543\u0026ndash;603\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: Saves lives but underused. Am J Med. 2012;125:465\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZuin M, Rigatelli G, Zuliani G, Zonzin P, Ramesh D, Roncon L. Thrombolysis in hemodynamically unstable patients: Still underused: A review based on multicenter prospective registries on acute pulmonary embolism. J Thromb Thrombolysis. 2019;48:323\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishimoto Y, Ohbe H, Matsui H, Nakajima M, Sasabuchi Y, Sato Y, et al. Trends in treatment patterns and outcomes of patients with pulmonary embolism in Japan, 2010 to 2020: A nationwide inpatient database study. J Am Heart Assoc. 2023;12:e028981.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFarmakis IT, Sagoschen I, Barco S, Keller K, Valerio L, Wild J, et al. Extracorporeal membrane oxygenation and reperfusion strategies in high-risk pulmonary embolism hospitalizations. Crit Care Med. 2024;52:e512\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChopard R, Nielsen P, Ius F, Cebotari S, Ecarnot F, Pilichowski H, et al. Optimal reperfusion strategy in acute high-risk pulmonary embolism requiring extracorporeal membrane oxygenation support: A systematic review and meta-analysis. Eur Respir J. 2022;60:2102977.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTakabayashi K, Yamashita Y, Morimoto T, Chatani R, Kaneda K, Nishimoto Y, et al. Clinical characteristics and short-term outcomes of patients with critical acute pulmonary embolism requiring extracorporeal membrane oxygenation: From the COMMAND VTE Registry-2. J Intensive Care. 2024;12:45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNishimoto Y, Ohbe H, Matsui H, Nakajima M, Sasabuchi Y, Sato Y, et al. Effectiveness of systemic thrombolysis on clinical outcomes in high-risk pulmonary embolism patients with venoarterial extracorporeal membrane oxygenation: A nationwide inpatient database study. J Intensive Care. 2023;11:4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIshida K, Nishimoto Y, Ohbe H, Ikeda N, Sugiura T, Suda R, et al. Short-term outcomes of thrombolysis versus surgical pulmonary embolectomy in patients with high-risk pulmonary embolism. J Thorac Cardiovasc Surg. 2025:S0022-5223(25)00646-4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStadlbauer A, Verbelen T, Binzenh\u0026ouml;fer L, Goslar T, Supady A, Spieth PM, et al. Management of high-risk acute pulmonary embolism: An emulated target trial analysis. Intensive Care Med. 2025;51:490\u0026ndash;505.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTokyo CCU Network Scientific Committee. Latest management and outcomes of major pulmonary embolism in the cardiovascular disease early transport system: Tokyo CCU Network. Circ J. 2010;74:289\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamamoto T, Otsuka T, Yoshida N, Kobayashi Y, Komiyama N, Hara K, et al. Hospital performance in a large urban acute myocardial infarction emergency care system: Tokyo Cardiovascular Care Unit network. J Cardiol. 2021;78:177\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizuno A, Yamamoto T, Tanabe Y, Obayashi T, Takayama M, Nagao K, et al. Pulmonary embolism severity index and simplified pulmonary embolism severity index risk scores are useful to predict mortality in Japanese patients with pulmonary embolism. Circ J. 2015;79:889\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTanabe Y, Obayashi T, Yamamoto T, Takayama M, Nagao K. Predictive value of biomarkers for the prognosis of acute pulmonary embolism in Japanese patients: Results of the Tokyo CCU Network registry. J Cardiol. 2015;66:460\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJCS Joint Working Group. Guidelines for diagnosis, treatment and prevention of pulmonary thromboembolism and deep vein thrombosis (JCS 2017). [Japanese]. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://js-phlebology.jp/wp/wp-content/uploads/2019/03/JCS2017_ito_h.pdf\u003c/span\u003e\u003cspan address=\"https://js-phlebology.jp/wp/wp-content/uploads/2019/03/JCS2017_ito_h.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e Accessed 17 Dec 2025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSilver MJ, Giri J, Duffy \u0026Aacute;, Jaber WA, Khandhar S, Ouriel K, et al. Incidence of mortality and complications in high-risk pulmonary embolism: A systematic review and meta-analysis. J Soc CardioVasc Angiogr Interv. 2023;2:100548.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaber WA, Gonsalves CF, Stortecky S, Horr S, Pappas O, Gandhi RT, et al. Large-bore mechanical thrombectomy versus catheter-directed thrombolysis in the management of intermediate-risk pulmonary embolism: Primary results of the PEERLESS randomized controlled trial. Circulation. 2025;151:260\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLookstein RA, Konstantinides SV, Weinberg I, Dohad SY, Rosol Z, Kopeć G, et al. Randomized controlled trial of mechanical thrombectomy with anticoagulation versus anticoagulation alone for acute intermediate-high risk pulmonary embolism: Primary outcomes from the STORM-PE trial. Circulation. 2025. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1161/CIRCULATIONAHA.125.077232\u003c/span\u003e\u003cspan address=\"10.1161/CIRCULATIONAHA.125.077232\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e [Epub ahead of print]\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamashita Y, Morimoto T, Kadota K, Takase T, Hiramori S, Kim K, et al. Severity of pulmonary embolism at initial diagnosis and long-term clinical outcomes: From the COMMAND VTE Registry. Int J Cardiol. 2021;343:107\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"high-risk pulmonary embolism, reperfusion therapy, extracorporeal membrane oxygenation, in-hospital mortality, cardiac arrest outcomes, surgical embolectomy outcomes, systemic thrombolysis outcomes, catheter-based therapy, emergency cardiovascular care","lastPublishedDoi":"10.21203/rs.3.rs-8387707/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8387707/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHigh-risk pulmonary embolism (PE) carries substantial mortality, but comprehensive real-world data encompassing the entire high-risk population are limited. Reperfusion therapy is recommended for these patients, yet its use in routine practice appears to be less consistent than expected. The present study evaluated current management and outcomes of high-risk PE within the Tokyo Cardiovascular Care Unit (CCU) Network.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe analyzed patients with high-risk PE enrolled in the Tokyo CCU Network registry between 2020 and 2022. High-risk PE was defined as shock, sustained hypotension, or cardiac arrest. Reperfusion therapies included systemic thrombolysis, catheter-based therapy, and surgical embolectomy. A multivariable logistic regression model was constructed to identify factors associated with in-hospital mortality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong 1,217 patients with PE, 185 (15.2%) met the criteria for high-risk PE. Reperfusion therapy was performed in 43.8% of these patients (systemic thrombolysis 27.6%, surgical embolectomy 13.0%, catheter-based therapy 3.2%). Venoarterial extracorporeal membrane oxygenation (VA-ECMO) was initiated in 29.7% of patients. Overall in-hospital mortality was 14.6%. Mortality was lower with reperfusion therapy than without (8.6% vs 19.2%), whereas major bleeding did not differ significantly. In multivariable analysis, cardiac arrest (odds ratio [OR] 3.73, 95% confidence interval [CI] 1.33\u0026ndash;10.46), VA-ECMO use (OR 3.08, 95% CI 1.01\u0026ndash;8.93), and receipt of reperfusion therapy (OR 0.35, 95% CI 0.12\u0026ndash;0.95) were independently associated with in-hospital mortality.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study described real-world use and outcomes of reperfusion therapy among patients with high-risk PE within a large regional emergency network. Reperfusion therapy was independently associated with lower in-hospital mortality after adjustment for cardiac arrest and VA-ECMO use. These findings highlight the importance of timely implementation of reperfusion therapy in the modern management of high-risk PE.\u003c/p\u003e","manuscriptTitle":"Reperfusion therapy and outcomes in high-risk pulmonary embolism: A multicenter registry study from the Tokyo Cardiovascular Care Unit Network","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-30 00:19:12","doi":"10.21203/rs.3.rs-8387707/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c627da76-5712-4c23-8954-f7a665454d15","owner":[],"postedDate":"December 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-05T11:24:30+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-30 00:19:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8387707","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8387707","identity":"rs-8387707","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}