Randomized Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism Nils Kucher, Peter Boekstegers, Oliver Müller, Christian Kupatt, Jan Beyer-Westendorf, Thomas Heitzer, Ulrich Tebbe, Jan Horstkotte, Ralf Müller, Erwin Blessing, Martin Greif, Philipp Lange, Ralf-Thorsten Hoffmann, Sebastian Werth, Achim Barmeyer, Dirk Härtel, Henriette Grünwald, Klaus Empen and Iris Baumgartner Circulation. published online November 13, 2013; Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2013 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539
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DOI: 10.1161/CIRCULATIONAHA.113.005544
Randomized Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism Running title: Kucher et al.; Ultrasound thrombolysis for pulmonary embolism Nils Kucher, MD1; Peter Boekstegers, MD2; Oliver Müller, MD3; Christian Kupatt, MD4; Jan Beyer-Westendorf, MD5; Thomas Heitzer, MD6; Ulrich Tebbe, MD7; Jan Horstkotte, MD2; Ralf Müller, MD2; Erwin Blessing, MD3; Martin Greif, MD4; Philipp Lange, MD4; Ralf-Thorsten Hoffmann, MD5; Sebastian Werth, MD5; Achim Barmeyer, MD6; Dirk Härtel, MD7; Henriette Grünwald, MD8; Klaus Empen, MD8; Iris Baumgartner Baumgartner, err, MD1 1
Division of Vascular Medicine, Swiss Cardiovascular Center, University Hospital Bern, Bern,
Switzerland; Sw wit itze zerl rlan lan and; d 2He d; Helios Hel lios Hospital Siegburg, Siegbu lio Siegburg, urg r , Germany; 3In Internal nte t rn nal M Medicine edicine III, University Hospital Hospital al H Heidelberg, eide ei delb de berg, erg, H Heidelberg, e de ei delb lber lb errg, G Germany; erma erma many ny;; 4Gr Großhadern G oßßha hade dern de rn n Hospital, Hos o pi pita tal, ta l, L Ludwig-Maximiliansuddwi wigg-Ma Maxi Ma xiimili mili lian ansan s-University Munich, Germany; Uni U niversity iv M unnic ichh, Munich, Municch, G erma er maanyy; 5Un University niv versiity yH Hospital ospi os pita pi t l Ca Carl arll Gus Gustav staav C Carus arus u off tthe he T Technical ech hniical Univ Un University iver iv ersi er sity si ty D Dresden, resd re sden sd en,, Dresden, en Dreesdeen, Dr n, Germany; Germa ermany ny;; 6Do ny Dortmund Dort rtmu rt mund mu n H nd Hospital, ospi os pita pi tall, D ta Dortmund, ortm or tm mun und, d G Germany; erma er many ma ny;; 7Ho Hospital Hosp spit sp ital it a al Lippe-Detmold, Lippe-Detm tm mol o d, D Detmold, ettmo m ld ld,, Ge Germ Germany; rman rm any; an y;; 8Un University Univ iver iv ersi er siity Hospital Hosspi p ta tall of Ernst-Moritz-Arndt-University, Ern nstt-Mo Mori Mo ritz ri t -A tz Arn rndt dt-U dt -U University, Greifswald, Germany
Address for Correspondence: Nils Kucher, MD Division of Vascular Medicine, Swiss Cardiovascular Center University Hospital Bern 3010 Bern, Switzerland Tel: +41 31 632 7963 Fax: +41 31 632 4380 E-mail: [email protected] Journal Subject Code: Thrombosis:[160] Fibrinolysis
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DOI: 10.1161/CIRCULATIONAHA.113.005544
Abstract
Background—In patients with acute pulmonary embolism (PE), systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized controlled trial investigated whether ultrasoundassisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Methods and Results—Fifty-nine patients (63r14 years) with acute main or lower lobe PE and echocardiographic right-to-left ventricular dimension (RV/LV) ratio t1.0 were randomized to receive unfractionated heparin (UFH) and an USAT regimen of 10-20 mg rt-PA over 15 hours (N = 30, USAT group), or UFH alone (N = 29, heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes include ed de ddeath, ath, at h, m ajor aj o included major and minor bleeding, and recurrent venous thromboembolism (VTE) at 90 days. In n tthe he U SAT SA T USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours p10 mm) right atrial or right ventricular thrombus; hemodynamic decompensation defined as the need d for cardiopulmonary resuscitation, or systolicc blood blo d pressure bloo pres pr essu es s re su r < 90 mm Hg for at least 15 min, orr drop of systolic blood pressure by at least 40 mm Hg for at least 15 5m in w ithh ssigns it ign ns of of end organ hypoperfusion (co co old extremities orr low l w urinary lo uriinary ur in output < 30 mL/h or o min with (cold m enntal nt confusi sion on n),, oorr need need ffor or ccatecholamine or ateecho at echo h la lam minee aadministration dm min iniistrrattio ionn to om aint ai ntai aiin aadequate deq qua uate te oorgan rg gan pperfusion erfu erfu fusiion mental confusion), maintain an nd a ssystolic ysto ys to oli licc bl bloo oood pr ppressure res esssu suree off > 90 9 m mH g;; se ssevere verre ve re hhypertension yper yp erte er tens nsiion oon ns n rrepeated eppeat peat ated ed rreadings eaadi ding nggs (sys ((systolic syssto toli lic and blood mm Hg; > 180 mmHg Hgg oorr di dias asto as to oliic > 10 05 mm mmHg Hg); Hg ); ppregnancy, reegn gnan ancy an cy y, la lact ctat ct atio at ionn or pparturition io a tu ar turi riti ri tion ti on < 330 0 da days y ; diastolic 105 mmHg); lactation days; participation in any other investigational drug or device study; life expectancy < 90 days; inability to comply with study assessments. During the enrollment period, investigators registered screening failure patients with objectively confirmed PE. Overall, the screening failure rate was 84%, with anatomically small PE and an RV/LV rato < 1 as the main reasons (Figure 1). The study was approved by the ethics committees of the participating institutions, and all patients provided written informed consent prior to enrollment. ULTIMA is registered at ClinicalTrials.gov (NCT01166997).
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Contrast-enhanced chest computed tomography Digitized copies of the baseline chest CT scans were transferred to the CT core laboratory which confirmed the presence of PE in all enrolled patients. In addition, the core laboratory calculated the pulmonary occlusion score using the Qanadli index (range 0 to 40 points, maximum 20 points per lung).19 Non-obstructive embolus located in a lobar or main pulmonary artery received score points equal to the number of arising segmental branches (maximum 10 points per lung). A segmental artery containing non-obstructive embolus without thrombus in a proximal feeder artery received one score point. Score points were multiplied by two in case of obstructive embolus. Anticoagulation therapy Unfractionated heparin (UFH) was administered immediately after randomization as an ntrrav aven enou en ouus bo bbolus lu us of o 80 IU/Kg, followed by an in infu fu usion of 18 IU/ U/kg k /h h ((with with a maximum initial intravenous infusion IU/kg/h infusion nfu usi s on rate off 11800 800 IU IU/h IU/h). /h)). /h ). F For or ppatients or a ie at i ntss alre already eady rreceiving ecceivvin ving ng U UFH, F , lo FH low ow mole m molecular olecu cu ula larr w weight eig ight ig ht hheparin eparin epar in n LMW MWH) H)) oorr fond ffondaparinux onddap apar arin inux u bbefore ux e orre ra ef rand ndom omiz om izaatio iz io on, th he iinitial he niti ni tial ti al U FH bolus bol olus uss was was omitted. omitt mittted ed. P atiien entts (LMWH) randomization, the UFH Patients who had rece eiv ived e L ed MWH or ffondaparinux MW on nda d pa p riinu nuxx at a w e gh ei ght--ad adju just ju s ed ttherapeutic st heera rape peut pe utic ut icc do ose se,, th thee start of thee received LMWH weight-adjusted dose, UFH infusion was delayed until 8-12 hours after the last LMWH injection and until 20-24 hours after the last fondaparinux injection. The UFH infusion was adjusted in order to achieve and maintain aPTT corresponding with therapeutic heparin levels (equivalent to 0.3 to 0.7 IU/mL by factor Xa inhibition). The minimum duration of the UFH infusion was 24 hours for all patients. Post-procedure anticoagulation therapy was left to the discretion of the investigators. Initiation of vitamin K antagonist or switch from UFH to LMWH or fondaparinux was allowed 36 hours after randomization. The minimum suggested duration of anticoagulation therapy was 3 months. Standardized procedure of ultrasound-assisted catheter-directed thrombolysis (USAT)
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In the USAT group, the time between the baseline echocardiogram and initiation of the catheter procedure had to be less than 4 hours. All patients were treated using EkoSonic MACH4e Endovascular Systems (EKOS Corporation; Bothell, WA).20 Bilateral device placement was suggested in case of embolus located in both main or proximal lower lobe pulmonary arteries. The EkoSonic Endovascular System consists of three components: an Intelligent Drug Delivery Catheter (IDDC); a removable MicroSonic Device (MSD) containing multiple small ultrasound transducers distributed over the treatment zone; and the EkoSonic control unit. The insertion of the catheter system was performed at the cardiac catheterization laboratory with continuous haemodynamic and electrocardiographic monitoring. Venous access was obtained at he common femoral vein using a 6 French introducer sheath for patients who we eree sch ched ch edul ed uled ul ed fo the were scheduled for unilateral EkoSonic device placement or a 10 French double-lumen introducer sheath for those who were were scheduled sch ched dul uleed ed for bilateral EkoSonic device devic icee insertion. ic insertion. Invasive Invas assivee pressure preessure tracings and a pr who bblood loood sample ffor orr tthe he m ix xed vvenous enouus ox enou oxyg yggen ssaturation aturaatiion w eree obta er oobtained btain ined ed ffrom rom m th he ma ain ppulmonary u mona ul monaary y mixed oxygen were the main artery. arrte tery ry.. Sy ry Syst Systemic sttem emic ic ar arterial rteriiall ox rter oxyg oxygen yggen n sa satu saturation tura tu raati tion on w was as rrecorded ecord eco orded ded ei eit either ther fr ther from om m a pperipheral erip erip phe hera r l ar ra art arterial teri riiall bblood lo ood d ample or transcutaneous tran an nsc scut uttan aneo eo ous u ooxygen xyge xy geen sa atu t ra rati tiion m eassur u em e en ent. t.. T heere reaf affte ter, r, a 00.035 .00355 iinch nchh gu nc guidewire sample saturation measurement. Thereafter, and a standard diagnostic angiographic catheter were used to cross the embolic occlusion. The main and lower lobe pulmonary arteries were considered for catheter insertion only. With the guidewire tip in a safe position within a large lower lobe segmental branch, the angiographic catheter was exchanged for the IDDC. Finally, the guidewire was removed and the MSD was inserted into the IDDC. A continuous infusion of rt-PA at 1 mg/hour and saline coolant at 35 ml/hour per catheter and intravascular ultrasound delivery were then initiated. After catheter placement, patients were transferred for continuous monitoring to the intermediate or intensive care unit. After 5 hours of
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treatment, the infusion rate of rt-PA was reduced to 0.5 mg/hour per catheter for 10 hours. The maximum t-PA dose was 20 ± 1 mg for patients for patients with bilateral device placement and 10 ± 0.5 mg for patients with unilateral device placement. At 15 ± 1 hours, the rt-PA infusion and ultrasound delivery was discontinued. Thereafter, the EkoSonic devices were removed in the intermediate or intensive care unit. After removal of the MSD, invasive pressure tracings were recorded from the IDDC. Once a typical pressure tracing of the main pulmonary artery trunk was obtained, a blood sample for the follow-up mixed venous oxygen saturation was taken. Follow-up systemic arterial oxygen saturation was taken as described above. Finally, the IDDC and the introducer sheath were removed and the puncture site ite manually compressed until local haemostasis was achieved. Echocardiography Prior instructions obtaining Pr rio or to the the recruitment recru uit itm ment phase, core laboratory in nstructions for obt bttai a niing ddigitized igitized echocardiographic cardiac with ec choocardiograp aphi h c images im mag ages es from fro rom m standardized sttan anda daard dizeed transthoracic trannsthorraccic ca ardiacc vviews ardi iews ie ws w ithh it electrocardiographic were during investigator meeting. Pulsed el lec ectr trroc o ar ardi diog di ogra raph phic ph ic ttracing raci ra c ng w ci ere pprovided rovvide ro vide dedd du uri ring ng aan n in inve vesstig ve st gat a or or m eeetinng. ng Pu Puls l ed ls d aand ndd continuous-waved Doppler were captured still frames Doppler images continuous-w wav aved ed dD oppl op p err sstudies pl t di tu dies e w es erre ca capt p ur pt ured ed bby y st stil illl fr il fram ames am es and nd 22D D or ccolor olor ol or D oppler image op es by cine loops of at least 3 cardiac cycles from standardized cardiac views. Because RV/LV ratio > 1 was an inclusion criteria and the difference in RV/LV ratio from baseline to 24 hours the primary endpoint, particular attention was paid to obtain at least 3 adequate cine loops from the apical four-chamber view for the measurement of RV/LV ratio. Dicom-formatted echocardiographic images from the examinations at baseline, 24 ± 2 hours, and 90 days were transferred to the core laboratory for data acquisition. Echocardiographic measurements from the apical four-chamber view included the subannular end-diastolic RV/LV ratio (Figure 2) and tricuspid annular plane systolic excursion (TAPSE); from the parasternal short-axis and apical
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four-chamber views, RV systolic dysfunction (none, mild, moderate, severe) was graded and the pressure gradient between the right ventricle and the right atrium obtained; the minimum diameter of the intrahepatic inferior vena cava was obtained from a subcostal view. The core laboratory was blinded to group assignment and reported the number of evaluable patients for the primary outcome measure to the Data Safety Monitoring Board (DSMB). The DSMB terminated patient enrollment after at least 25 patients in each group were known to be evaluable for the primary endpoint (Figure 1). Data on baseline RV/LV ratio measured by the investigator were not available to the core laboratory but were compared to the data obtained by the core laboratory to assess interobserver agreement. Outcome measures The primary difference RV/LV Th he pr prim imar im aryy eendpoint ar ndp dpooint dp oi of ULTIMA was the diffe ere r nce in the RV/ /LV L rratio atio at io from baseline to 24 hours, laboratory. hours, hou ur evaluated evaluatted d by by the the blinded bli lind nded nd ed ccore ore la ore aborattory. Patients were clinical Pati Pa tiien ents ts w ere sscheduled ere chhedu hedule l d fo le forr a 90-d 990-day 0-d -day ay ffollow-up oll l ow ow-u -upp cl clin inic in ical al vvisit issit aand nd rrepeated ep pea eate t d te echocardiography. Safety decompensation echocardiogr grap aphy ap hy.. Sa hy S f ty fe t ooutcomes utco ut co ome m s in iincluded clud cl uded ud ed ddeath, eath ea th, he th hhemodynamic mody mo dyna dy nami na m c de mi deco comp co mpen mp e sa en sati tion ti on aass defined in n the exclusion criteria, major and minor bleeding, recurrent venous thromboembolism (VTE), and serious adverse events up to 90 days post randomization. Major bleeding was defined as overt bleeding associated with a fall in the hemoglobin level of at least 2.0 g/dl or with transfusion of 2 units of red blood cells, or involvement of a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome). Clinically overt bleeding not fulfilling the criteria of a major bleeding was classified as a minor bleeding complication. There was routine surveillance for recurrent VTE during 90-day follow-up. Recurrent VTE was diagnosed if suspected symptoms or signs of deep vein thrombosis or acute PE
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were objectively confirmed by an imaging test (new filling defect by pulmonary angiography or contrast-enhanced chest CT, new high-probability perfusion defect revealed by lung scan, or positive compression ultrasound study for deep vein thrombosis). There was no routine surveillance for asymptomatic recurrent VTE. Patient chart documents and case report forms were verified by independent data monitors. All clinical adverse events and secondary endpoints were adjudicated by the DSMB and the Clinical Event Reviewer. Statistical analysis Sample size assumptions were based on the Tenecteplase Italian Pulmonary Embolism Study (TIPES) in which therapy with weight-adjusted intravenous tenecteplase significantly reduced the he RV/LV ratio at 24 hours by mean 0.31 (standard deviation: 0.20) and therapyy with wit i h UF UFH H alone resulted in a non-significant reduction in RV/LV ratio by mean 0.10 (standard deviation: 0.30). 0. .30 0).9 We We assumed asssume medd that USAT would have a similar me sim im millar effect on reducing red ed ducin in ng RV/LV RV/LV ratio at 24 hours as compared com o pared with wiith t tenecteplase ten necte tepl te plas pl asee and as and used used use ed thee mean meann and and standard stand tand dard deviations deviat devi atio i ns io ns ooff the the di ddifference ffer ff eren nce iin n RV/LV ratio tenecteplase sample calculation. The RV V/L /LV V ra rati tioo fr ti from om m tthe he te enecte ene teepl plaase aand nd d hheparin epaarin ep in n ggroups roups rou ups fo forr sa sam mple mple l ssize izee ca iz alc lcuulat ulat atio ionn. n. T hee eestimated stim st im mated ate sample ample size wa wass 24 pper e ggroup er ro oup uusing sing si ng a ppower ower ow er ooff 80 80% 0% at a a ttwo-sided wo-s wo -ssid ided ed p vvalue a ue ooff 0. al 0.05 05 bby y t-test. Continuous data are presented as means ± standard deviations (SD) or in case of a skewed distribution as median values with ranges. Comparison of binary data between the groups was performed using the Fisher’s exact test. Within-group comparison of continuous data was performed using the two-sided paired t-test. Within-group ordinal data were compared using the two-sided Wilcoxon signed-rank test. Between-group continuous data were compared using the two-sided unpaired t-test or Wilcoxon rank sum test. Between-group ordinal data were compared using the exact Mantel-Haenszel chi-square test. Interobserver agreement for the echocardiographic baseline RV/LV ratio between the investigator and core laboratory
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measurements was assessed by Bland-Altman analysis. All statistical analyses were performed using SAS software version 9.2.
Results Clinical characteristics Among the 59 patients, mean age was 63 r 14 years and 53% were women. The most frequent comorbidities were systemic hypertension (59%), diabetes mellitus (17%), renal insufficiency (15%), and cancer (12%), with no difference between the study groups (Table 1). Baseline vital parameters including systemic arterial pressure, heart and respiratory rates, and oxygen saturation aturation were similar between the groups, as well as core laboratory chest CT findings finddin fi ngs of of the t e th pulmonary occlusion score and RV/LV ratio. Treatment details Tr Trea eatm ea tmen tm nt d eta ail ilss Prior P rio or to enrollment, enrollm lmeent ent, 11 11 (37%) (37% (37% 7%)) patients pati pa tiien ents ts inn thee USAT USAT AT group gro rooup and and 9 (31%) (3 31% 1%)) iin n tthe he hheparin he epar ep a in ar i ggroup ro oup hhad ad received eceeiv ved antithrombotic ant ntit ithr it hrom ombo om b tic bo tic treatment t ea tr e tm tmen en nt with w th wi h weight wei eigh ghtt adjusted gh adju ad just ju s ed doses st dos osess of LMWH LMW MWH H or fondaparinux fonnda dapa pari rinnux nux (p = total UFH randomization hours lower USAT 0.78). The mean mea eann to ota tall UF U H do dosee ffrom ro om ra rand ndom nd omiz om izzat atio io on to 224 4 ho hour urss wa ur wass lo lowe werr in we n tthe he U S T group SA than in the heparin group (29,045 ± 7,712 versus 32,873 ± 5,917 units; p = 0.04). In the USAT group, placement of the EKOS catheters was technically successful in all patients with a median procedure time of 42 (range 15-102) minutes. Twenty-six (87%) patients received a bilateral USAT procedure (one device per lung) with a mean total r-tPA dose of 20.8 ± 3.0 mg. Four (13%) patients received an unilateral USAT procedure (only one lung treated) with a mean total r-tPA dose of 10.5 ± 0.6 mg. The mean hospital stay was 8.9 ± 3.4 days in the USAT group and 8.6 ± 3.9 days in the heparin group (p = 0.80). Interobserver agreement in baseline RV/LV ratio
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In 54 (98%) of 55 analyzed patients, there was agreement between investigators and core laboratory for identifying patients with a baseline RV/LV ratio 1. The mean (± SD) difference in the baseline echocardiographic RV/LV ratio between investigator and core laboratory measurements was 0.02 ± 0.15 (Figure 3). Primary endpoint analysis In the USAT group, the mean RV/LV ratio was reduced from 1.28 ± 0.19 at baseline to 0.99 ± 0.17 at 24 hours (p 10 100 00 be beat beats atss per p r mi pe minute, nute, nu e, N (%) % Systolic lic aarterial rter rt eria er iall pr ia pres pressure e su sure ree ((mm mm Hg Hg) Hg), ), m mean e n ± SD ea Diastolic arterial Hg), mean oli licc ar arte teri rial al ppressure ress re ssur uree (m ((mm m Hg g), m eann ± SD ea Heart rate (beats per mi minu minute), n tee), nu ) m mean eann ± SD ea Respiratory minute), irat ir ator oryy ra rate te ((per perr mi pe minu nute te)), me mean an ± SD SD Oxygen saturation during oxygen supplement (%), mean ± SD Troponin test positive, N (%) RV/LV ratio by computed tomography, mean ± SD Pulmonary occlusion score by computed tomography, median (min-max) Bilateral main pulmonary artery embolism, N (%) Bilateral lower lobe pulmonary artery embolism, N (%) Unilateral main pulmonary artery embolism, N (%) Unilateral lower lobe pulmonary artery embolism, N (%)
USAT group N = 30
Heparin group N = 29
p
64 ± 15 31 ± 7 19 (63%)
62 ± 13 29 ± 7 12 (41%)
0.58 0.28 0.12
20 (67%) 4 (13)% 6 (20%) 4 (13%) 5 (17%) 2 (7%) 2 (7 ((7%) %) (0%) 0 (0%) 4 (1 (13% (13%) 3%)) 3% 4 (13% 13 ) (13%)
15 (5 ((52%) 2%)) 2% 7 (2 ((24%) 4%) 4% 4 (1 (14% (14%) 14% 4%)) 5 (17%) 2 (7%) 1 (3%) 1 (3%) 1 (3 (3%) %) 9 (3 (31% (31%) 1% %) 2 (7 ((7%) % %)
00. 0.29 29 00.33 0. 33 00.73 0. 7 73 0.7 0.73 0.42 1.00 1.00 00.49 .49 00.13 0. 13 00.67 .67
8 (2 (27% (27%) 7%)) 7% 137 37 ± 199 80 ± 113 3 88 ± 113 3 20 ± 6 96 ± 3 16/20 (80%) 1.4 ± 0.3 27 (9-36) 12 (40%) 22 (73%) 8 (27%) 6 (20%)
7 (2 (24% (24%) 24% 4%) 1131 31 ± 118 8 77 ± 113 3 86 ± 112 2 20 ± 8 96 ± 3 17/22 (77%) 1.3 ± 0.2 24 (13-38) 5 (17%) 25 (86%) 10 (34%) 2 (7%)
1.00 00.20 0. 2 20 0.36 0.3 0. 3 0.6 0.65 6 0.75 0.77 0.92 1.00 0.56 0.24 0.08 0.33 0.58 0.25
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Table 2. Echocardiographic core laboratory data Difference: Difference: Baseline - 24 hours Baseline - 90 days USAT Heparin USAT Heparin USAT Heparin USAT Heparin USAT Heparin 1.28±0.19 1.20±0.14 0.99±0.17 1.17±0.20 0.92±0.15 0.96±0.16 0.30±0.19 0.03±0.16 0.35±0.22 0.24±0.19 26 29 28 28 26 27 25 28 23 27 0.07 0.001 0.36 p
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/early/2013/11/13/CIRCULATIONAHA.113.005544
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/
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DOI: 10.1161/CIRCULATIONAHA.113.005544
Randomized Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism Running title: Kucher et al.; Ultrasound thrombolysis for pulmonary embolism Nils Kucher, MD1; Peter Boekstegers, MD2; Oliver Müller, MD3; Christian Kupatt, MD4; Jan Beyer-Westendorf, MD5; Thomas Heitzer, MD6; Ulrich Tebbe, MD7; Jan Horstkotte, MD2; Ralf Müller, MD2; Erwin Blessing, MD3; Martin Greif, MD4; Philipp Lange, MD4; Ralf-Thorsten Hoffmann, MD5; Sebastian Werth, MD5; Achim Barmeyer, MD6; Dirk Härtel, MD7; Henriette Grünwald, MD8; Klaus Empen, MD8; Iris Baumgartner Baumgartner, err, MD1 1
Division of Vascular Medicine, Swiss Cardiovascular Center, University Hospital Bern, Bern,
Switzerland; Sw wit itze zerl rlan lan and; d 2He d; Helios Hel lios Hospital Siegburg, Siegbu lio Siegburg, urg r , Germany; 3In Internal nte t rn nal M Medicine edicine III, University Hospital Hospital al H Heidelberg, eide ei delb de berg, erg, H Heidelberg, e de ei delb lber lb errg, G Germany; erma erma many ny;; 4Gr Großhadern G oßßha hade dern de rn n Hospital, Hos o pi pita tal, ta l, L Ludwig-Maximiliansuddwi wigg-Ma Maxi Ma xiimili mili lian ansan s-University Munich, Germany; Uni U niversity iv M unnic ichh, Munich, Municch, G erma er maanyy; 5Un University niv versiity yH Hospital ospi os pita pi t l Ca Carl arll Gus Gustav staav C Carus arus u off tthe he T Technical ech hniical Univ Un University iver iv ersi er sity si ty D Dresden, resd re sden sd en,, Dresden, en Dreesdeen, Dr n, Germany; Germa ermany ny;; 6Do ny Dortmund Dort rtmu rt mund mu n H nd Hospital, ospi os pita pi tall, D ta Dortmund, ortm or tm mun und, d G Germany; erma er many ma ny;; 7Ho Hospital Hosp spit sp ital it a al Lippe-Detmold, Lippe-Detm tm mol o d, D Detmold, ettmo m ld ld,, Ge Germ Germany; rman rm any; an y;; 8Un University Univ iver iv ersi er siity Hospital Hosspi p ta tall of Ernst-Moritz-Arndt-University, Ern nstt-Mo Mori Mo ritz ri t -A tz Arn rndt dt-U dt -U University, Greifswald, Germany
Address for Correspondence: Nils Kucher, MD Division of Vascular Medicine, Swiss Cardiovascular Center University Hospital Bern 3010 Bern, Switzerland Tel: +41 31 632 7963 Fax: +41 31 632 4380 E-mail: [email protected] Journal Subject Code: Thrombosis:[160] Fibrinolysis
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DOI: 10.1161/CIRCULATIONAHA.113.005544
Abstract
Background—In patients with acute pulmonary embolism (PE), systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized controlled trial investigated whether ultrasoundassisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Methods and Results—Fifty-nine patients (63r14 years) with acute main or lower lobe PE and echocardiographic right-to-left ventricular dimension (RV/LV) ratio t1.0 were randomized to receive unfractionated heparin (UFH) and an USAT regimen of 10-20 mg rt-PA over 15 hours (N = 30, USAT group), or UFH alone (N = 29, heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes include ed de ddeath, ath, at h, m ajor aj o included major and minor bleeding, and recurrent venous thromboembolism (VTE) at 90 days. In n tthe he U SAT SA T USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours p10 mm) right atrial or right ventricular thrombus; hemodynamic decompensation defined as the need d for cardiopulmonary resuscitation, or systolicc blood blo d pressure bloo pres pr essu es s re su r < 90 mm Hg for at least 15 min, orr drop of systolic blood pressure by at least 40 mm Hg for at least 15 5m in w ithh ssigns it ign ns of of end organ hypoperfusion (co co old extremities orr low l w urinary lo uriinary ur in output < 30 mL/h or o min with (cold m enntal nt confusi sion on n),, oorr need need ffor or ccatecholamine or ateecho at echo h la lam minee aadministration dm min iniistrrattio ionn to om aint ai ntai aiin aadequate deq qua uate te oorgan rg gan pperfusion erfu erfu fusiion mental confusion), maintain an nd a ssystolic ysto ys to oli licc bl bloo oood pr ppressure res esssu suree off > 90 9 m mH g;; se ssevere verre ve re hhypertension yper yp erte er tens nsiion oon ns n rrepeated eppeat peat ated ed rreadings eaadi ding nggs (sys ((systolic syssto toli lic and blood mm Hg; > 180 mmHg Hgg oorr di dias asto as to oliic > 10 05 mm mmHg Hg); Hg ); ppregnancy, reegn gnan ancy an cy y, la lact ctat ct atio at ionn or pparturition io a tu ar turi riti ri tion ti on < 330 0 da days y ; diastolic 105 mmHg); lactation days; participation in any other investigational drug or device study; life expectancy < 90 days; inability to comply with study assessments. During the enrollment period, investigators registered screening failure patients with objectively confirmed PE. Overall, the screening failure rate was 84%, with anatomically small PE and an RV/LV rato < 1 as the main reasons (Figure 1). The study was approved by the ethics committees of the participating institutions, and all patients provided written informed consent prior to enrollment. ULTIMA is registered at ClinicalTrials.gov (NCT01166997).
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DOI: 10.1161/CIRCULATIONAHA.113.005544
Contrast-enhanced chest computed tomography Digitized copies of the baseline chest CT scans were transferred to the CT core laboratory which confirmed the presence of PE in all enrolled patients. In addition, the core laboratory calculated the pulmonary occlusion score using the Qanadli index (range 0 to 40 points, maximum 20 points per lung).19 Non-obstructive embolus located in a lobar or main pulmonary artery received score points equal to the number of arising segmental branches (maximum 10 points per lung). A segmental artery containing non-obstructive embolus without thrombus in a proximal feeder artery received one score point. Score points were multiplied by two in case of obstructive embolus. Anticoagulation therapy Unfractionated heparin (UFH) was administered immediately after randomization as an ntrrav aven enou en ouus bo bbolus lu us of o 80 IU/Kg, followed by an in infu fu usion of 18 IU/ U/kg k /h h ((with with a maximum initial intravenous infusion IU/kg/h infusion nfu usi s on rate off 11800 800 IU IU/h IU/h). /h)). /h ). F For or ppatients or a ie at i ntss alre already eady rreceiving ecceivvin ving ng U UFH, F , lo FH low ow mole m molecular olecu cu ula larr w weight eig ight ig ht hheparin eparin epar in n LMW MWH) H)) oorr fond ffondaparinux onddap apar arin inux u bbefore ux e orre ra ef rand ndom omiz om izaatio iz io on, th he iinitial he niti ni tial ti al U FH bolus bol olus uss was was omitted. omitt mittted ed. P atiien entts (LMWH) randomization, the UFH Patients who had rece eiv ived e L ed MWH or ffondaparinux MW on nda d pa p riinu nuxx at a w e gh ei ght--ad adju just ju s ed ttherapeutic st heera rape peut pe utic ut icc do ose se,, th thee start of thee received LMWH weight-adjusted dose, UFH infusion was delayed until 8-12 hours after the last LMWH injection and until 20-24 hours after the last fondaparinux injection. The UFH infusion was adjusted in order to achieve and maintain aPTT corresponding with therapeutic heparin levels (equivalent to 0.3 to 0.7 IU/mL by factor Xa inhibition). The minimum duration of the UFH infusion was 24 hours for all patients. Post-procedure anticoagulation therapy was left to the discretion of the investigators. Initiation of vitamin K antagonist or switch from UFH to LMWH or fondaparinux was allowed 36 hours after randomization. The minimum suggested duration of anticoagulation therapy was 3 months. Standardized procedure of ultrasound-assisted catheter-directed thrombolysis (USAT)
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DOI: 10.1161/CIRCULATIONAHA.113.005544
In the USAT group, the time between the baseline echocardiogram and initiation of the catheter procedure had to be less than 4 hours. All patients were treated using EkoSonic MACH4e Endovascular Systems (EKOS Corporation; Bothell, WA).20 Bilateral device placement was suggested in case of embolus located in both main or proximal lower lobe pulmonary arteries. The EkoSonic Endovascular System consists of three components: an Intelligent Drug Delivery Catheter (IDDC); a removable MicroSonic Device (MSD) containing multiple small ultrasound transducers distributed over the treatment zone; and the EkoSonic control unit. The insertion of the catheter system was performed at the cardiac catheterization laboratory with continuous haemodynamic and electrocardiographic monitoring. Venous access was obtained at he common femoral vein using a 6 French introducer sheath for patients who we eree sch ched ch edul ed uled ul ed fo the were scheduled for unilateral EkoSonic device placement or a 10 French double-lumen introducer sheath for those who were were scheduled sch ched dul uleed ed for bilateral EkoSonic device devic icee insertion. ic insertion. Invasive Invas assivee pressure preessure tracings and a pr who bblood loood sample ffor orr tthe he m ix xed vvenous enouus ox enou oxyg yggen ssaturation aturaatiion w eree obta er oobtained btain ined ed ffrom rom m th he ma ain ppulmonary u mona ul monaary y mixed oxygen were the main artery. arrte tery ry.. Sy ry Syst Systemic sttem emic ic ar arterial rteriiall ox rter oxyg oxygen yggen n sa satu saturation tura tu raati tion on w was as rrecorded ecord eco orded ded ei eit either ther fr ther from om m a pperipheral erip erip phe hera r l ar ra art arterial teri riiall bblood lo ood d ample or transcutaneous tran an nsc scut uttan aneo eo ous u ooxygen xyge xy geen sa atu t ra rati tiion m eassur u em e en ent. t.. T heere reaf affte ter, r, a 00.035 .00355 iinch nchh gu nc guidewire sample saturation measurement. Thereafter, and a standard diagnostic angiographic catheter were used to cross the embolic occlusion. The main and lower lobe pulmonary arteries were considered for catheter insertion only. With the guidewire tip in a safe position within a large lower lobe segmental branch, the angiographic catheter was exchanged for the IDDC. Finally, the guidewire was removed and the MSD was inserted into the IDDC. A continuous infusion of rt-PA at 1 mg/hour and saline coolant at 35 ml/hour per catheter and intravascular ultrasound delivery were then initiated. After catheter placement, patients were transferred for continuous monitoring to the intermediate or intensive care unit. After 5 hours of
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DOI: 10.1161/CIRCULATIONAHA.113.005544
treatment, the infusion rate of rt-PA was reduced to 0.5 mg/hour per catheter for 10 hours. The maximum t-PA dose was 20 ± 1 mg for patients for patients with bilateral device placement and 10 ± 0.5 mg for patients with unilateral device placement. At 15 ± 1 hours, the rt-PA infusion and ultrasound delivery was discontinued. Thereafter, the EkoSonic devices were removed in the intermediate or intensive care unit. After removal of the MSD, invasive pressure tracings were recorded from the IDDC. Once a typical pressure tracing of the main pulmonary artery trunk was obtained, a blood sample for the follow-up mixed venous oxygen saturation was taken. Follow-up systemic arterial oxygen saturation was taken as described above. Finally, the IDDC and the introducer sheath were removed and the puncture site ite manually compressed until local haemostasis was achieved. Echocardiography Prior instructions obtaining Pr rio or to the the recruitment recru uit itm ment phase, core laboratory in nstructions for obt bttai a niing ddigitized igitized echocardiographic cardiac with ec choocardiograp aphi h c images im mag ages es from fro rom m standardized sttan anda daard dizeed transthoracic trannsthorraccic ca ardiacc vviews ardi iews ie ws w ithh it electrocardiographic were during investigator meeting. Pulsed el lec ectr trroc o ar ardi diog di ogra raph phic ph ic ttracing raci ra c ng w ci ere pprovided rovvide ro vide dedd du uri ring ng aan n in inve vesstig ve st gat a or or m eeetinng. ng Pu Puls l ed ls d aand ndd continuous-waved Doppler were captured still frames Doppler images continuous-w wav aved ed dD oppl op p err sstudies pl t di tu dies e w es erre ca capt p ur pt ured ed bby y st stil illl fr il fram ames am es and nd 22D D or ccolor olor ol or D oppler image op es by cine loops of at least 3 cardiac cycles from standardized cardiac views. Because RV/LV ratio > 1 was an inclusion criteria and the difference in RV/LV ratio from baseline to 24 hours the primary endpoint, particular attention was paid to obtain at least 3 adequate cine loops from the apical four-chamber view for the measurement of RV/LV ratio. Dicom-formatted echocardiographic images from the examinations at baseline, 24 ± 2 hours, and 90 days were transferred to the core laboratory for data acquisition. Echocardiographic measurements from the apical four-chamber view included the subannular end-diastolic RV/LV ratio (Figure 2) and tricuspid annular plane systolic excursion (TAPSE); from the parasternal short-axis and apical
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DOI: 10.1161/CIRCULATIONAHA.113.005544
four-chamber views, RV systolic dysfunction (none, mild, moderate, severe) was graded and the pressure gradient between the right ventricle and the right atrium obtained; the minimum diameter of the intrahepatic inferior vena cava was obtained from a subcostal view. The core laboratory was blinded to group assignment and reported the number of evaluable patients for the primary outcome measure to the Data Safety Monitoring Board (DSMB). The DSMB terminated patient enrollment after at least 25 patients in each group were known to be evaluable for the primary endpoint (Figure 1). Data on baseline RV/LV ratio measured by the investigator were not available to the core laboratory but were compared to the data obtained by the core laboratory to assess interobserver agreement. Outcome measures The primary difference RV/LV Th he pr prim imar im aryy eendpoint ar ndp dpooint dp oi of ULTIMA was the diffe ere r nce in the RV/ /LV L rratio atio at io from baseline to 24 hours, laboratory. hours, hou ur evaluated evaluatted d by by the the blinded bli lind nded nd ed ccore ore la ore aborattory. Patients were clinical Pati Pa tiien ents ts w ere sscheduled ere chhedu hedule l d fo le forr a 90-d 990-day 0-d -day ay ffollow-up oll l ow ow-u -upp cl clin inic in ical al vvisit issit aand nd rrepeated ep pea eate t d te echocardiography. Safety decompensation echocardiogr grap aphy ap hy.. Sa hy S f ty fe t ooutcomes utco ut co ome m s in iincluded clud cl uded ud ed ddeath, eath ea th, he th hhemodynamic mody mo dyna dy nami na m c de mi deco comp co mpen mp e sa en sati tion ti on aass defined in n the exclusion criteria, major and minor bleeding, recurrent venous thromboembolism (VTE), and serious adverse events up to 90 days post randomization. Major bleeding was defined as overt bleeding associated with a fall in the hemoglobin level of at least 2.0 g/dl or with transfusion of 2 units of red blood cells, or involvement of a critical site (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome). Clinically overt bleeding not fulfilling the criteria of a major bleeding was classified as a minor bleeding complication. There was routine surveillance for recurrent VTE during 90-day follow-up. Recurrent VTE was diagnosed if suspected symptoms or signs of deep vein thrombosis or acute PE
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DOI: 10.1161/CIRCULATIONAHA.113.005544
were objectively confirmed by an imaging test (new filling defect by pulmonary angiography or contrast-enhanced chest CT, new high-probability perfusion defect revealed by lung scan, or positive compression ultrasound study for deep vein thrombosis). There was no routine surveillance for asymptomatic recurrent VTE. Patient chart documents and case report forms were verified by independent data monitors. All clinical adverse events and secondary endpoints were adjudicated by the DSMB and the Clinical Event Reviewer. Statistical analysis Sample size assumptions were based on the Tenecteplase Italian Pulmonary Embolism Study (TIPES) in which therapy with weight-adjusted intravenous tenecteplase significantly reduced the he RV/LV ratio at 24 hours by mean 0.31 (standard deviation: 0.20) and therapyy with wit i h UF UFH H alone resulted in a non-significant reduction in RV/LV ratio by mean 0.10 (standard deviation: 0.30). 0. .30 0).9 We We assumed asssume medd that USAT would have a similar me sim im millar effect on reducing red ed ducin in ng RV/LV RV/LV ratio at 24 hours as compared com o pared with wiith t tenecteplase ten necte tepl te plas pl asee and as and used used use ed thee mean meann and and standard stand tand dard deviations deviat devi atio i ns io ns ooff the the di ddifference ffer ff eren nce iin n RV/LV ratio tenecteplase sample calculation. The RV V/L /LV V ra rati tioo fr ti from om m tthe he te enecte ene teepl plaase aand nd d hheparin epaarin ep in n ggroups roups rou ups fo forr sa sam mple mple l ssize izee ca iz alc lcuulat ulat atio ionn. n. T hee eestimated stim st im mated ate sample ample size wa wass 24 pper e ggroup er ro oup uusing sing si ng a ppower ower ow er ooff 80 80% 0% at a a ttwo-sided wo-s wo -ssid ided ed p vvalue a ue ooff 0. al 0.05 05 bby y t-test. Continuous data are presented as means ± standard deviations (SD) or in case of a skewed distribution as median values with ranges. Comparison of binary data between the groups was performed using the Fisher’s exact test. Within-group comparison of continuous data was performed using the two-sided paired t-test. Within-group ordinal data were compared using the two-sided Wilcoxon signed-rank test. Between-group continuous data were compared using the two-sided unpaired t-test or Wilcoxon rank sum test. Between-group ordinal data were compared using the exact Mantel-Haenszel chi-square test. Interobserver agreement for the echocardiographic baseline RV/LV ratio between the investigator and core laboratory
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DOI: 10.1161/CIRCULATIONAHA.113.005544
measurements was assessed by Bland-Altman analysis. All statistical analyses were performed using SAS software version 9.2.
Results Clinical characteristics Among the 59 patients, mean age was 63 r 14 years and 53% were women. The most frequent comorbidities were systemic hypertension (59%), diabetes mellitus (17%), renal insufficiency (15%), and cancer (12%), with no difference between the study groups (Table 1). Baseline vital parameters including systemic arterial pressure, heart and respiratory rates, and oxygen saturation aturation were similar between the groups, as well as core laboratory chest CT findings finddin fi ngs of of the t e th pulmonary occlusion score and RV/LV ratio. Treatment details Tr Trea eatm ea tmen tm nt d eta ail ilss Prior P rio or to enrollment, enrollm lmeent ent, 11 11 (37%) (37% (37% 7%)) patients pati pa tiien ents ts inn thee USAT USAT AT group gro rooup and and 9 (31%) (3 31% 1%)) iin n tthe he hheparin he epar ep a in ar i ggroup ro oup hhad ad received eceeiv ved antithrombotic ant ntit ithr it hrom ombo om b tic bo tic treatment t ea tr e tm tmen en nt with w th wi h weight wei eigh ghtt adjusted gh adju ad just ju s ed doses st dos osess of LMWH LMW MWH H or fondaparinux fonnda dapa pari rinnux nux (p = total UFH randomization hours lower USAT 0.78). The mean mea eann to ota tall UF U H do dosee ffrom ro om ra rand ndom nd omiz om izzat atio io on to 224 4 ho hour urss wa ur wass lo lowe werr in we n tthe he U S T group SA than in the heparin group (29,045 ± 7,712 versus 32,873 ± 5,917 units; p = 0.04). In the USAT group, placement of the EKOS catheters was technically successful in all patients with a median procedure time of 42 (range 15-102) minutes. Twenty-six (87%) patients received a bilateral USAT procedure (one device per lung) with a mean total r-tPA dose of 20.8 ± 3.0 mg. Four (13%) patients received an unilateral USAT procedure (only one lung treated) with a mean total r-tPA dose of 10.5 ± 0.6 mg. The mean hospital stay was 8.9 ± 3.4 days in the USAT group and 8.6 ± 3.9 days in the heparin group (p = 0.80). Interobserver agreement in baseline RV/LV ratio
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DOI: 10.1161/CIRCULATIONAHA.113.005544
In 54 (98%) of 55 analyzed patients, there was agreement between investigators and core laboratory for identifying patients with a baseline RV/LV ratio 1. The mean (± SD) difference in the baseline echocardiographic RV/LV ratio between investigator and core laboratory measurements was 0.02 ± 0.15 (Figure 3). Primary endpoint analysis In the USAT group, the mean RV/LV ratio was reduced from 1.28 ± 0.19 at baseline to 0.99 ± 0.17 at 24 hours (p 10 100 00 be beat beats atss per p r mi pe minute, nute, nu e, N (%) % Systolic lic aarterial rter rt eria er iall pr ia pres pressure e su sure ree ((mm mm Hg Hg) Hg), ), m mean e n ± SD ea Diastolic arterial Hg), mean oli licc ar arte teri rial al ppressure ress re ssur uree (m ((mm m Hg g), m eann ± SD ea Heart rate (beats per mi minu minute), n tee), nu ) m mean eann ± SD ea Respiratory minute), irat ir ator oryy ra rate te ((per perr mi pe minu nute te)), me mean an ± SD SD Oxygen saturation during oxygen supplement (%), mean ± SD Troponin test positive, N (%) RV/LV ratio by computed tomography, mean ± SD Pulmonary occlusion score by computed tomography, median (min-max) Bilateral main pulmonary artery embolism, N (%) Bilateral lower lobe pulmonary artery embolism, N (%) Unilateral main pulmonary artery embolism, N (%) Unilateral lower lobe pulmonary artery embolism, N (%)
USAT group N = 30
Heparin group N = 29
p
64 ± 15 31 ± 7 19 (63%)
62 ± 13 29 ± 7 12 (41%)
0.58 0.28 0.12
20 (67%) 4 (13)% 6 (20%) 4 (13%) 5 (17%) 2 (7%) 2 (7 ((7%) %) (0%) 0 (0%) 4 (1 (13% (13%) 3%)) 3% 4 (13% 13 ) (13%)
15 (5 ((52%) 2%)) 2% 7 (2 ((24%) 4%) 4% 4 (1 (14% (14%) 14% 4%)) 5 (17%) 2 (7%) 1 (3%) 1 (3%) 1 (3 (3%) %) 9 (3 (31% (31%) 1% %) 2 (7 ((7%) % %)
00. 0.29 29 00.33 0. 33 00.73 0. 7 73 0.7 0.73 0.42 1.00 1.00 00.49 .49 00.13 0. 13 00.67 .67
8 (2 (27% (27%) 7%)) 7% 137 37 ± 199 80 ± 113 3 88 ± 113 3 20 ± 6 96 ± 3 16/20 (80%) 1.4 ± 0.3 27 (9-36) 12 (40%) 22 (73%) 8 (27%) 6 (20%)
7 (2 (24% (24%) 24% 4%) 1131 31 ± 118 8 77 ± 113 3 86 ± 112 2 20 ± 8 96 ± 3 17/22 (77%) 1.3 ± 0.2 24 (13-38) 5 (17%) 25 (86%) 10 (34%) 2 (7%)
1.00 00.20 0. 2 20 0.36 0.3 0. 3 0.6 0.65 6 0.75 0.77 0.92 1.00 0.56 0.24 0.08 0.33 0.58 0.25
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DOI: 10.1161/CIRCULATIONAHA.113.005544
Table 2. Echocardiographic core laboratory data Difference: Difference: Baseline - 24 hours Baseline - 90 days USAT Heparin USAT Heparin USAT Heparin USAT Heparin USAT Heparin 1.28±0.19 1.20±0.14 0.99±0.17 1.17±0.20 0.92±0.15 0.96±0.16 0.30±0.19 0.03±0.16 0.35±0.22 0.24±0.19 26 29 28 28 26 27 25 28 23 27 0.07 0.001 0.36 p
