{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T17:10:50Z","timestamp":1793380250658,"version":"4.5.0"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001734","name":"Copenhagen University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001734","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Intermediate-high risk pulmonary embolism (PE) carries a significant risk of hemodynamic deterioration or death. Treatment should balance efficacy in reducing clot burden with the risk of complications, particularly bleeding. Previous studies on high-dose, short-term thrombolysis with alteplase (rtPA) showed a reduced risk of hemodynamic deterioration but no change in mortality and increased bleeding complications. Catheter-based techniques, including ultrasound-assisted thrombolysis (USAT), and low-dose thrombolysis may offer reasonable efficacy with lower risk. However, studies comparing these methods have been few. This trial aims to address this gap by randomizing patients to three treatment modalities.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Multicenter, randomized trial with 1:1:1 allocation of 210 patients with acute intermediate-high risk PE, excluding those with absolute contraindications to thrombolysis. Patients are eligible for inclusion if they are\u2009&gt;\u200918\u00a0years of age, have had symptoms\u2009&lt;\u200914\u00a0days, and are able to give informed consent. Patients are allocated 1:1:1 into three treatment strategies: (1) unfractionated heparin (UFH)\/low molecular weight heparin (LMWH), (2) UFH\/LMWH\u2009+\u200920\u00a0mg rtPA\/6\u00a0h intravenously (IV), or (3) UFH\u2009+\u200920\u00a0mg rtPA\/6\u00a0h via USAT. Co-primary outcomes include reduction in clot burden as assessed by refined Miller score from pre-treatment to follow-up (48\u201396\u00a0h) computed tomography pulmonary angiogram (CTPA) comparing low-dose rtPA (\u00b1\u2009USAT) groups to UFH\/LMWH group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01, <jats:italic>N<\/jats:italic>\u2009=\u2009210) and reduction in refined Miller score on follow-up CT angiography comparing low-dose rtPA by USAT to intravenous rtPA, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.04, <jats:italic>N<\/jats:italic>\u2009=\u2009140). Secondary outcomes comprise bleeding complications, duration of index admission, FiO<jats:sub>2<\/jats:sub>, blood pressure, respiratory and heart rate at the time of follow-up CT angiography, mortality in the three groups, incidence of tricuspid regurgitation pressure gradient\u2009&lt;\u200940\u00a0mmHg at 3\u00a0months follow-up echocardiography, 6-min walk test at 3\u00a0months comparing the three groups, and health-related quality of life at 3\u00a0months follow-up comparing the three groups.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>We hypothesize that in patients with intermediate-high risk PE (1) administration of 20\u00a0mg rtPA leads to a greater reduction in clot burden compared to heparins and (2) administration of 20\u00a0mg rtPA via USAT results in a greater reduction in clot burden compared to 20\u00a0mg rtPA intravenous.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ClinicalTrials.gov NCT04088292. Registered in September 2019 (retrospectively registered).<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-024-08688-4","type":"journal-article","created":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T19:21:48Z","timestamp":1735413708000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["A randomized trial of low-dose thrombolysis, ultrasound-assisted thrombolysis, or heparin for intermediate-high risk pulmonary embolism\u2014the STRATIFY trial: design and statistical analysis plan"],"prefix":"10.1186","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5244-0399","authenticated-orcid":false,"given":"Jesper","family":"Kj\u00e6rgaard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f8rn","family":"Carlsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Sonne-Holm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Wiberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lene","family":"Holmvang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Flensted","family":"Lassen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rikke","family":"S\u00f8rensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"H\u00f8fsten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter Sommer","family":"Ulriksen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samir","family":"Jawad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pernille","family":"Palm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens Jakob","family":"Thune","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hassager","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole P.","family":"Kristiansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Eskesen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f8ren","family":"Fan\u00f8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lia E.","family":"Bang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,28]]},"reference":[{"issue":"4","key":"8688_CR1","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1093\/eurheartj\/ehz405","volume":"41","author":"SV Konstantinides","year":"2020","unstructured":"Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, et al. 2019 ESC guidelines on the diagnosis and management of acute pulmonary embolism. EurHeart J. 2020;41(4):543\u2013603.","journal-title":"EurHeart J"},{"issue":"15","key":"8688_CR2","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1056\/NEJMoa1302097","volume":"370","author":"G Meyer","year":"2014","unstructured":"Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402\u201311.","journal-title":"N Engl J Med"},{"issue":"3","key":"8688_CR3","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1161\/01.CIR.96.3.882","volume":"96","author":"S Konstantinides","year":"1997","unstructured":"Konstantinides S, Geibel A, Olschewski M, Heinrich F, Grosser K, Rauber K, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation. 1997;96(3):882\u20138.","journal-title":"Circulation"},{"issue":"3","key":"8688_CR4","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1378\/chest.106.3.718","volume":"106","author":"SZ Goldhaber","year":"1994","unstructured":"Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolus alteplase vs conventional alteplase infusion for pulmonary embolism thrombolysis. An international multicenter randomized trial. The Bolus Alteplase Pulmonary Embolism Group. Chest. 1994;106(3):718\u201324.","journal-title":"Chest."},{"issue":"2","key":"8688_CR5","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1378\/chest.09-0765","volume":"137","author":"C Wang","year":"2010","unstructured":"Wang C, Zhai Z, Yang Y, Wu Q, Cheng Z, Liang L, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010;137(2):254\u201362.","journal-title":"Chest"},{"issue":"6","key":"8688_CR6","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1378\/chest.98.6.1473","volume":"98","author":"M Levine","year":"1990","unstructured":"Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AG, et al. A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest. 1990;98(6):1473\u20139.","journal-title":"Chest"},{"issue":"2","key":"8688_CR7","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.amjcard.2012.09.027","volume":"111","author":"M Sharifi","year":"2013","unstructured":"Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the \u201cMOPETT\u201d Trial). AmJCardiol. 2013;111(2):273\u20137.","journal-title":"AmJCardiol"},{"issue":"10","key":"8688_CR8","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1016\/j.jcin.2015.04.020","volume":"8","author":"G Piazza","year":"2015","unstructured":"Piazza G, Hohlfelder B, Jaff MR, Ouriel K, Engelhardt TC, Sterling KM, et al. Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC Cardiovasc Interv. 2015;8(10):1382\u201392.","journal-title":"JACC Cardiovasc Interv."},{"issue":"4","key":"8688_CR9","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1161\/CIRCULATIONAHA.113.005544","volume":"129","author":"N Kucher","year":"2014","unstructured":"Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479\u201386.","journal-title":"Circulation"},{"issue":"1","key":"8688_CR10","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1056\/NEJMicm1415847","volume":"374","author":"A Oguzhan","year":"2016","unstructured":"Oguzhan A. IMAGES IN CLINICAL MEDICINE. Percutaneous Rotational Pulmonary Thrombectomy. N Engl J Med. 2016;374(1):e1.","journal-title":"N Engl J Med."},{"issue":"3","key":"8688_CR11","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1378\/chest.15-0119","volume":"148","author":"WT Kuo","year":"2015","unstructured":"Kuo WT, Banerjee A, Kim PS, DeMarco FJ Jr, Levy JR, Facchini FR, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. Chest. 2015;148(3):667\u201373.","journal-title":"Chest"},{"issue":"5","key":"8688_CR12","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1177\/0003319716661446","volume":"68","author":"C Kaymaz","year":"2017","unstructured":"Kaymaz C, Ozturk S, Akbal O, Tanboga IH, Yilmaz F, Poci N, et al. Ultrasound-Assisted Catheter-Directed Thrombolysis in High-Risk and Intermediate-High-Risk Pulmonary Embolism: Results From a Single-Center Cohort. Angiology. 2017;68(5):433\u201340.","journal-title":"Angiology"},{"issue":"1","key":"8688_CR13","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1177\/1708538116645056","volume":"25","author":"K Ouriel","year":"2017","unstructured":"Ouriel K, Ouriel RL, Lim YJ, Piazza G, Goldhaber SZ. Computed tomography angiography with pulmonary artery thrombus burden and right-to-left ventricular diameter ratio after pulmonary embolism. Vascular. 2017;25(1):54\u201362.","journal-title":"Vascular"},{"issue":"4","key":"8688_CR14","first-page":"616","volume":"33","author":"GA Miller","year":"1971","unstructured":"Miller GA, Sutton GC, Kerr IH, Gibson RV, Honey M. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. Br Heart J. 1971;33(4):616.","journal-title":"Br Heart J"},{"issue":"6","key":"8688_CR15","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.2214\/ajr.176.6.1761415","volume":"176","author":"SD Qanadli","year":"2001","unstructured":"Qanadli SD, El HM, Vieillard-Baron A, Joseph T, Mesurolle B, Oliva VL, et al. New CT index to quantify arterial obstruction in pulmonary embolism: comparison with angiographic index and echocardiography. AJR Am J Roentgenol. 2001;176(6):1415\u201320.","journal-title":"AJR Am J Roentgenol."},{"issue":"20","key":"8688_CR16","doi-asserted-by":"publisher","first-page":"2401","DOI":"10.1161\/01.CIR.0000129302.90476.BC","volume":"109","author":"R Quiroz","year":"2004","unstructured":"Quiroz R, Kucher N, Schoepf UJ, Kipfmueller F, Solomon SD, Costello P, et al. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation. 2004;109(20):2401\u20134.","journal-title":"Circulation"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08688-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-024-08688-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-024-08688-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T20:02:27Z","timestamp":1735416147000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-024-08688-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,28]]},"references-count":16,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["8688"],"URL":"https:\/\/doi.org\/10.1186\/s13063-024-08688-4","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,28]]},"assertion":[{"value":"3 July 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 December 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Prior to initiation of the study, study protocol, written patient information, and consent forms were approved by the regional ethics committee of the Capital Region of Denmark (Approval id H-18013257) and the Danish Medicines Agency (Approval id 2017\u2013005075-91). A data handling agreement has been approved by the Data Protection Agency (Approval id VD-2019\u201352).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate {24}"}},{"value":"Consent forms have been approved by the regional ethical committee. The form can be found in the supplementary materials (In Danish).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication {32}"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests {28}"}}],"article-number":"853"}}