Accelerated Thrombolysis for Pulmonary Embolism: Will Clinical Benefit Be ULTIMAtely Realized? Michael R. Jaff and Ido Weinberg 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
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.113.007132
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DOI: 10.1161/CIRCULATIONAHA.113.007132
Accelerated Thrombolysis for Pulmonary Embolism: Will Clinical Benefit Be ULTIMAtely Realized?
Running title: Weinberg et al.; Accelerated Thrombolysis for Pulmonary Embolism
Ido Weinberg, MD and Michael R. Jaff, DO
In nst stit itut it utee for ut fo Heart Hear He art Vascular and Stroke Care,, Massachusetts M ssachusetts General Ma Genera raal Hospital, Hospital, Boston, MA Institute
Ad ddr dres ess for for Correspondence: C rr Co rres esp ponden nd ncee: Address Mich chael R. Jaff, Jaf aff, f,, D O Michael DO nst s itut u e fo or He H artt Va ar V scul sc ular ar and and S trok tr okee Ca C are re Institute for Heart Vascular Stroke Care Massachusetts General Hospital 55 Fruit St., Warren 905 Boston, MA Tel: 617-726-3784 Fax: 617-724-0371 E-mail: [email protected]
Journal Subject Code: Thrombosis:[160] Fibrinolysis
Key words: Editorial, Ultrasound assisted thrombolysis
1 Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
Over the past 25 years, thrombolytic therapy has consistently demonstrated improvement in hemodynamic parameters in patients with pulmonary embolism (PE)1. Clinically, while resulting in reduced mortality in patients with massive PE2 thrombolytic therapy is not beneficial in unselected PE patients3. Major societal guidelines support systemic thrombolysis for massive PE, and recommend catheter-based interventions for rescue therapy in centers with appropriate expertise4-6. For patients with submassive PE, selected guidelines suggest considering systemic thrombolysis in a limited population of PE patients4,5, while others recommend against its use in these patients6. Recently, several studies have addressed thrombolytic therapy in patients with submassive PE. The Pulmonary Embolism International Thrombolysis (PEITHO) trial reported a substantial reduction in the combined endpoint of early mortality or hemodyna hemodynamic amic mic co collapse oll llap apse ap se iin n patients receiving systemic thrombolysis (as compared to heparin alone) at the expense of a significant ign nif ific ican ic an nt in inc increase crea eaase in major hemorrhage (includ (including din i g intracranial hhemorrhage). e orrrh em rhag a e). This was particularly part tic i ularly evi evident vide d nt among de amo mong ngg elderly eld ldeerl rlyy patients patients over pat over the the age ag ge of 7557. In In the the much much uch smaller smal alle l r TOPCOAT le TOPC TO PCOA PC OAT OA study tud udyy (Tenecteplase (Ten (T en nec ecte tepl pllasse or Placebo: Pla laceebo bo:: Cardiopulmonary Carrdio Ca rdio opu pulm lmon lm onnar a yO Outcomes ut omes utco mes At A T Three hree hr eee M Months), on nth ths) s),, wh s) whichh was wa s terminated erminated pprematurely, reema m tu ture r ly re ly,, th the he co ccomposite mpos mp ossit i e pr prim primary imar im arry ou outc outcome tcom tc o e (55 dday om ay ssurvival urrvi v va vall to hhospital osspi pita tall di ta ddischarge scharge without shock, intubation, or major hemorrhage; 90 day rate of normal right ventricular (RV) function, 6 minute walk distance>330 meters, no dyspnea at rest, and no recurrent PE or deep vein thrombosis) was positive in the patients randomized to thrombolysis as compared to the low molecular weight heparin patients8. Another small study comparing thrombolytic therapy to heparin alone demonstrated a decrease in the composite endpoint of death, recurrent venous thromboembolism, RV dysfunction and major hemorrhage at 6 months in the group randomized to thrombolytic therapy9. In the MOPPETT trial, half-dose systemic thrombolytic therapy resulted in long-term reduction in the incidence of pulmonary hypertension compared to
2 Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
anticoagulation alone without excess bleeding10. In this issue of Circulation, Kucher and colleagues compared the use of heparin and ultrasound accelerated thrombolysis (USAT) utilizing the EkoSonic (EKOS Corporation, Bothell, WA, USA) catheter to heparin alone in patients presenting with submassive PE11. The primary outcome was change in the ratio of right ventricle to left ventricle size 24 hours following treatment, while the primary safety outcome was a composite of death, major and minor bleeding, recurrent venous thromboembolism and serious adverse events at 90 days. The authors report a significant reduction in the primary outcome in the USAT group compared to the heparin group. This was coupled with a significant reduction in surrogates of pulmonary ildd RV artery hypertension. At 90 days the majority off patients in both groups had no orr m mild m baseline, and while there was a difference dysfunction, representing an improvement from beetw wee eenn groups grou gr oups favoring ou fav avooring USAT (overall 100% vs. vs 93% 93% in the USAT USA SA AT an andd heparin groups, between esppec e tively, p= p=0. 0 003) 003) 3), im impo port po rtan rt antt cl clin iniicaal co orrrelattess (s suc uchh aass ex exe erttion onal a ddyspnea) al yspn ys pnea pn ea)) we were re nnot ot ot respectively, p=0.003), important clinical correlates (such exertional epo port rted rt e . The ed The authors auth au thor orss also also s acknowledge ack ckno ck no owl wleedg edge ge a late latee “catch-up” “caatcchh-up up”” by up by tthe h hheparin he epar ep arrin ggroup, ro oup up,, wh whi ich may ich may rresult essult su reported. which n less difference differren nce c after aft fter err further fur u th ther er follow-up. fol ollo l wlo w up up.. It It iss for forr this thi hiss reason reeas ason on that tha hatt some soome gguidelines uide ui d li de line ness su ne sugg g est in suggest following PE patients for 6 months before re-assessing measures of RV function and pulmonary arterial pressure12. Catheter directed thrombolysis has the potential to offer benefits of systemic thrombolysis while minimizing bleeding risk due to a lower dose of the thrombolytic agent. More information about the safety of USAT may come from the SEATTLE II study, a singlearm prospective trial examining the safety of USAT in 150 patients with massive and submassive PE, which has completed enrollment, but has not yet reported results13. Further complicating clinical decision making is the lack of reliable and well-validated bleeding-risk assessment tools
3 Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
in patients with PE. It is often that bleeding risk is inferred from scoring systems developed for other indications 14. Results from the ULTIMA trial must be considered with the understanding that most PE patients treated with anticoagulation alone will achieve embolus resolution at 4 weeks 15. While clot resolution can be accelerated with the use of thrombolytic therapy, the volume of residual thrombosis does not seem to differ between patients treated with thrombolytic therapy or anticoagulation. Mortality following submassive PE is uncommon. The number of patients with massive PE to receive thrombolytic therapy in order to demonstrate a mortality benefit has been estimated to be as low as 10 3. To demonstrate a mortality benefit in patients with submassive PE would require a much larger sample size, suggesting that an appropriately powere powered ed pr prospective rosspe pect ctiv ct ivee iv study tudy may never be completed. Furthermore, the feared consequence of resultant chronic thromboembolic hro omb mboe oemb mboolicc ppulmonary mb ul ulmonary hypertension16, 17 occ occurs cur u s in only 0.1% % tto o 3. 3.8% .8% of patients with PE16, 18 and an nd me m mechanisms chanisms ms too id identify den nti tiffy fy tthis hiss su hi subset ubse bset ooff pa patients atiientss a priori prrio ori are are not noot available. av vaiila labl ble. e.. It It is is unfortunate unfo un f rtunat fo unatte that tha clinical cl lin inic iccal outcomes outtco come mes were were wer re not not reported rep epor orte or rte tedd inn ULTIMA, ULT LTIM IM MA, but but mean mea eann hospital hosp ho sppittal length leng le ngth ng th of of stay s ay was st wass more mor oree than th han a 8 days in both th h groups, gro oup ups, s,, suggesting sug ugge gest ge s in st ng limited liimi m te tedd clinically clin cl inic in ical ic allly y apparent app p ar aren entt benefit en bene be n fiit in the ne the short shoort term. ter erm. m m. Realistically, thrombolytic therapy is not considered an option for many patients. Estimated bleeding risk is the main concern prior to administering thrombolytic therapy, especially in older patients and those with active malignancy. These are the exact populations that have the greatest potential to benefit from thrombolytic therapy. In ULTIMA many patients with submassive PE failed randomization (84%) for a multitude of reasons, most commonly increased bleeding risk, prolonged symptom duration, advanced age, and inadequate PE distribution on imaging. The authors also cite a potential selection bias, acknowledging that not all eligible patients were subject to randomization. This suggests limited applicability in a real
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DOI: 10.1161/CIRCULATIONAHA.113.007132
world setting. While USAT is appealing, there are other catheter-based PE treatments including thrombus fragmentation, suction thrombectomy and rotational thrombectomy19. As noted by the authors, direct comparison to varying techniques was not available in the current study. In the interim, as more information about various treatment options is being gathered, registry data may be useful. Applicable information may soon become available by pulmonary embolism response teams (PERT) which are becoming more commonplace in major clinical centers20. ULTIMA is extremely valuable in that it represents the first randomized trial to test a standardized, commonly used catheter-based intervention in patients with acute PE. For upporters of thrombolytic therapy in submassive PE, ULTIMA proves that inte erv rven en ntiion onal al supporters interventional reatments for submassive PE offer objective improvement in important hemodynamic treatments pa araame metters ters with withh very ver low risk of major and mort rttal hemorrhage. hemorrhage. Until U tiil meaningful Un meaningful clinical me parameters mortal outc com o es are rreported ep porteed fo or pa pati tien ti ents tss rreceiving e ei ec eivving g aadvanced dvaancced d ttherapy heraapy iin hera n rrandomized and nd dom omiz ized ed cclinical linnica li nicaal ttrials riaals ls outcomes for patients ag agai ains ai nstt st ns stan an nda dard rd an nticoa ntic oagu g laati gu t on n, cl cli inicciaans m inic ay pu ppursue urrsue ue iinterventional nteerve nt vent ve nttio ona nall th thro r mbol ro mbol o yt ytic ic the heeraapi piees ffor o or against standard anticoagulation, clinicians may thrombolytic therapies patients withh hi hhigh-risk gh-r gh -rris i k PE P w h lee av hi aavoiding o diing tthem oi hem he m inn low-risk low ow-r -rris iskk patients. pati pa tieent ti n s. Patients Pati Pa tien ti ents en t felt ts fel eltt too be be at while intermediate risk must be individually stratified by multispecialty “teams” while understanding the current literature gap.
Conflict of Interest Disclosures: IW – None. MRJ – Non-compensated Data Safety and Monitoring Board, Ekos Corporation; Board member of VIVA physicians, a 501 c 3 non for profit education and research organization References: 1. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet.
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DOI: 10.1161/CIRCULATIONAHA.113.007132
1993;341:507-511. 2. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125:465-470. 3. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004;110:744-749. 4. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK, American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation, American Heart Association Council on Peripheral Vascular Disease, American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788-1830. 5. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Z, Nelson Nel e soon ME, ME, Chest Physicians. Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR, American College of C heest P hysi hy sici si cian ans n s. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Physicians Thrombosis,, 9th ed: American College of Chest Phys y icians Evidence-Based Clinical Practice Guidelines. Chest. Guid Gu idel id elin el ines in es.. Ch es C esst. t. 2012;141:e419S-94S. 2 12;141:e419S-94S. 20 66.. National Nat a ional Institute In nst stit itutte for it fo He Heal Health alth al th aand nd Care Caree Excellence. Ex xceellen ncee. Venous Veno Ve nouus us thromboembolic thrrom mbo boem embo em boolic lic diseases: dise di seaases se asess: Th Thee management m annagement na nt ooff ve ven venous nouus tthromboembolic hroomboem embo b licc dis bo diseases seaases aand nd tthe nd he rrole ole off th thrombophilia hrom mbop ophhil hilia lia tes testing. stinng. 22012. 0122. CG144. CG G1444. 4 London: Lon ondo donn: National Nat atiional nal Institute In nst s it itut utee for ut for Health Heal He alth al th aand nd dC Care arre Ex Exce Excellence. cell llen ll en ncee. 7. Konstantini niide des, s, S ehal eh a f of tthe h P he EITH EI THO TH O in nve vest s ig st gat a or ors. s F ibriino ib noly lysi ly siss fo si fforr no norm rmot rm oten ot e sive Konstantinides, S.. On bbehalf PEITHO investigators. Fibrinolysis normotensive pati pa tien ents ts with wit ithh acute acut ac utee submassive subm su bmas assi sive ve pulmonary pul ulmo mona nary ry embolism. emb mbooli lism sm Pr Pres esen ente tedd at tthe he aannual nnua nn uall me meet etin ingg of tthe he patients Presented meeting American College of Cardiology on March 9, 2013. Abstract. 8. Kline J, Hernandez J, Kabrhel C, Courtney C, Jones A, Nordenholtz K, Diercks D, Klinger J. Randomized trial of tenecteplase or placebo with low molecular weight heparin for acute submassive pulmonary embolism: Assessment of patient-oriented cardiopulmonary outcomes at three months. Presented at the annual meeting of the Americal College of Cardiology on March 9, 2013. Abstract. 9. Fasullo S, Scalzo S, Maringhini G, Ganci F, Cannizzaro S, Basile I, Cangemi D, Terrazzino G, Parrinello G, Sarullo FM, Baglini R, Paterna S, Di Pasquale P. Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin. Am J Med Sci. 2011;341:33-39. 10. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, "MOPETT" Investigators. Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). Am J Cardiol. 2013;111:273-277.
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11. Kucher N, Boekstegers P, Müller O, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Müller R, Blessing E, Greif M, Lange P, Hoffmann R-T, Werth S, Barmeyer A, Härtel D, Grünwald H, Empen K, Baumgartner I. Randomized Controlled Trial of UltrasoundAssisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism. Circulation. 2013;XX:XX-XXX. 12. Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009;30:2493-2537. 13. A Prospective, Single-arm, Multi-center Trial of EkoSonic® Endovascular System and Activase for Treatment of Acute Pulmonary Embolism (PE). (SEATTLE II). Available at: http://clinicaltrials.gov/show/NCT01513759. Accessed 11/13/2013. 14. Nieto JA, Solano R, Trapero Iglesias N, Ruiz-Gimenez N, Fernandez-Capitan Fernandez-Capitaan C, C, Valero Val aler ero er o B, B, Tiberio G, Bura-Riviere A, Monreal M, RIETE Investigators. Validation of a score for predicting fatal bleeding g in pa patients receiving anticoagulation for venous thromboembolism. Thromb Res. 2013;132:175-179. 20 013 13;1 ;132 ;1 32:1 32 :175 :1 75-179 75 79. 79 115. 5. K Kearon earon C. Nat N Natural atura rall hi history istor sttor oryy of vvenous en nous thro thromboembolism. omboeembooli olism ism. Ci Circulation. C rcculat atio ion.. 20 io 2003; 003 03;; 107: 1007: I22-30. I22 2 -3 -30. 0. 16. M,, Po Poggio R,, T Taliani Ageno 16 6. Becattini Becattin ni C, C Agnelli Agneellii G, Pesavento Pesa Pe s ve v ntto R, Silingardi Sillinngarddi di M Pogg ggiio R aliaani ani MR MR, Ag A enoo W. en W Incidence episode nci cide denc de n e of cchronic nc hron hr onic on ic tthromboembolic hromb mbooemb mbol olic ol ic ppulmonary ulmo ul mona mo nary na ry hhypertension yperte ype tennsio ns on aafter fte teer a ffirst irrst ep epis isod is odde ooff ppulmonary ulmo ulmo onaary embolism. Chest. 2006;130:172-175. embo boli lism m. Ch C est. 20 es 2006 06;1 130 30:1 172 72-1 -175 7 . 17. Pe 17 Pepk Pepke-Zaba pkee-Za Zaba ba JJ, De Delc Delcroix lcro roix ix M M, La Lang ng II, Ma Maye Mayer yerr E E, Ja Jans Jansa nsaa P P, A Ambroz mbro mb rozz D D, T Treacy reac re acyy C C, D D'Armini 'A Arm rmin inii AM AM, Morsolini M, Snijder R, Bresser P, Torbicki A, Kristensen B, Lewczuk J, Simkova I, Barbera JA, de Perrot M, Hoeper MM, Gaine S, Speich R, Gomez-Sanchez MA, Kovacs G, Hamid AM, Jais X, Simonneau G. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124:1973-1981. 18. Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, Albanese P, Biasiolo A, Pegoraro C, Iliceto S, Prandoni P, Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350:2257-2264. 19. Engelberger RP, Kucher N. Catheter-based reperfusion treatment of pulmonary embolism. Circulation. 2011;124:2139-2144. 20. Kabrhel C, Jaff MR, Channick RN, Baker JN, Rosenfield K. A multidisciplinary pulmonary embolism response team. Chest. 2013;144:1738-1739.
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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.113.007132
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/
Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
Accelerated Thrombolysis for Pulmonary Embolism: Will Clinical Benefit Be ULTIMAtely Realized?
Running title: Weinberg et al.; Accelerated Thrombolysis for Pulmonary Embolism
Ido Weinberg, MD and Michael R. Jaff, DO
In nst stit itut it utee for ut fo Heart Hear He art Vascular and Stroke Care,, Massachusetts M ssachusetts General Ma Genera raal Hospital, Hospital, Boston, MA Institute
Ad ddr dres ess for for Correspondence: C rr Co rres esp ponden nd ncee: Address Mich chael R. Jaff, Jaf aff, f,, D O Michael DO nst s itut u e fo or He H artt Va ar V scul sc ular ar and and S trok tr okee Ca C are re Institute for Heart Vascular Stroke Care Massachusetts General Hospital 55 Fruit St., Warren 905 Boston, MA Tel: 617-726-3784 Fax: 617-724-0371 E-mail: [email protected]
Journal Subject Code: Thrombosis:[160] Fibrinolysis
Key words: Editorial, Ultrasound assisted thrombolysis
1 Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
Over the past 25 years, thrombolytic therapy has consistently demonstrated improvement in hemodynamic parameters in patients with pulmonary embolism (PE)1. Clinically, while resulting in reduced mortality in patients with massive PE2 thrombolytic therapy is not beneficial in unselected PE patients3. Major societal guidelines support systemic thrombolysis for massive PE, and recommend catheter-based interventions for rescue therapy in centers with appropriate expertise4-6. For patients with submassive PE, selected guidelines suggest considering systemic thrombolysis in a limited population of PE patients4,5, while others recommend against its use in these patients6. Recently, several studies have addressed thrombolytic therapy in patients with submassive PE. The Pulmonary Embolism International Thrombolysis (PEITHO) trial reported a substantial reduction in the combined endpoint of early mortality or hemodyna hemodynamic amic mic co collapse oll llap apse ap se iin n patients receiving systemic thrombolysis (as compared to heparin alone) at the expense of a significant ign nif ific ican ic an nt in inc increase crea eaase in major hemorrhage (includ (including din i g intracranial hhemorrhage). e orrrh em rhag a e). This was particularly part tic i ularly evi evident vide d nt among de amo mong ngg elderly eld ldeerl rlyy patients patients over pat over the the age ag ge of 7557. In In the the much much uch smaller smal alle l r TOPCOAT le TOPC TO PCOA PC OAT OA study tud udyy (Tenecteplase (Ten (T en nec ecte tepl pllasse or Placebo: Pla laceebo bo:: Cardiopulmonary Carrdio Ca rdio opu pulm lmon lm onnar a yO Outcomes ut omes utco mes At A T Three hree hr eee M Months), on nth ths) s),, wh s) whichh was wa s terminated erminated pprematurely, reema m tu ture r ly re ly,, th the he co ccomposite mpos mp ossit i e pr prim primary imar im arry ou outc outcome tcom tc o e (55 dday om ay ssurvival urrvi v va vall to hhospital osspi pita tall di ta ddischarge scharge without shock, intubation, or major hemorrhage; 90 day rate of normal right ventricular (RV) function, 6 minute walk distance>330 meters, no dyspnea at rest, and no recurrent PE or deep vein thrombosis) was positive in the patients randomized to thrombolysis as compared to the low molecular weight heparin patients8. Another small study comparing thrombolytic therapy to heparin alone demonstrated a decrease in the composite endpoint of death, recurrent venous thromboembolism, RV dysfunction and major hemorrhage at 6 months in the group randomized to thrombolytic therapy9. In the MOPPETT trial, half-dose systemic thrombolytic therapy resulted in long-term reduction in the incidence of pulmonary hypertension compared to
2 Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
anticoagulation alone without excess bleeding10. In this issue of Circulation, Kucher and colleagues compared the use of heparin and ultrasound accelerated thrombolysis (USAT) utilizing the EkoSonic (EKOS Corporation, Bothell, WA, USA) catheter to heparin alone in patients presenting with submassive PE11. The primary outcome was change in the ratio of right ventricle to left ventricle size 24 hours following treatment, while the primary safety outcome was a composite of death, major and minor bleeding, recurrent venous thromboembolism and serious adverse events at 90 days. The authors report a significant reduction in the primary outcome in the USAT group compared to the heparin group. This was coupled with a significant reduction in surrogates of pulmonary ildd RV artery hypertension. At 90 days the majority off patients in both groups had no orr m mild m baseline, and while there was a difference dysfunction, representing an improvement from beetw wee eenn groups grou gr oups favoring ou fav avooring USAT (overall 100% vs. vs 93% 93% in the USAT USA SA AT an andd heparin groups, between esppec e tively, p= p=0. 0 003) 003) 3), im impo port po rtan rt antt cl clin iniicaal co orrrelattess (s suc uchh aass ex exe erttion onal a ddyspnea) al yspn ys pnea pn ea)) we were re nnot ot ot respectively, p=0.003), important clinical correlates (such exertional epo port rted rt e . The ed The authors auth au thor orss also also s acknowledge ack ckno ck no owl wleedg edge ge a late latee “catch-up” “caatcchh-up up”” by up by tthe h hheparin he epar ep arrin ggroup, ro oup up,, wh whi ich may ich may rresult essult su reported. which n less difference differren nce c after aft fter err further fur u th ther er follow-up. fol ollo l wlo w up up.. It It iss for forr this thi hiss reason reeas ason on that tha hatt some soome gguidelines uide ui d li de line ness su ne sugg g est in suggest following PE patients for 6 months before re-assessing measures of RV function and pulmonary arterial pressure12. Catheter directed thrombolysis has the potential to offer benefits of systemic thrombolysis while minimizing bleeding risk due to a lower dose of the thrombolytic agent. More information about the safety of USAT may come from the SEATTLE II study, a singlearm prospective trial examining the safety of USAT in 150 patients with massive and submassive PE, which has completed enrollment, but has not yet reported results13. Further complicating clinical decision making is the lack of reliable and well-validated bleeding-risk assessment tools
3 Downloaded from http://circ.ahajournals.org/ at Universitaet Duesseldorf on November 24, 2013
DOI: 10.1161/CIRCULATIONAHA.113.007132
in patients with PE. It is often that bleeding risk is inferred from scoring systems developed for other indications 14. Results from the ULTIMA trial must be considered with the understanding that most PE patients treated with anticoagulation alone will achieve embolus resolution at 4 weeks 15. While clot resolution can be accelerated with the use of thrombolytic therapy, the volume of residual thrombosis does not seem to differ between patients treated with thrombolytic therapy or anticoagulation. Mortality following submassive PE is uncommon. The number of patients with massive PE to receive thrombolytic therapy in order to demonstrate a mortality benefit has been estimated to be as low as 10 3. To demonstrate a mortality benefit in patients with submassive PE would require a much larger sample size, suggesting that an appropriately powere powered ed pr prospective rosspe pect ctiv ct ivee iv study tudy may never be completed. Furthermore, the feared consequence of resultant chronic thromboembolic hro omb mboe oemb mboolicc ppulmonary mb ul ulmonary hypertension16, 17 occ occurs cur u s in only 0.1% % tto o 3. 3.8% .8% of patients with PE16, 18 and an nd me m mechanisms chanisms ms too id identify den nti tiffy fy tthis hiss su hi subset ubse bset ooff pa patients atiientss a priori prrio ori are are not noot available. av vaiila labl ble. e.. It It is is unfortunate unfo un f rtunat fo unatte that tha clinical cl lin inic iccal outcomes outtco come mes were were wer re not not reported rep epor orte or rte tedd inn ULTIMA, ULT LTIM IM MA, but but mean mea eann hospital hosp ho sppittal length leng le ngth ng th of of stay s ay was st wass more mor oree than th han a 8 days in both th h groups, gro oup ups, s,, suggesting sug ugge gest ge s in st ng limited liimi m te tedd clinically clin cl inic in ical ic allly y apparent app p ar aren entt benefit en bene be n fiit in the ne the short shoort term. ter erm. m m. Realistically, thrombolytic therapy is not considered an option for many patients. Estimated bleeding risk is the main concern prior to administering thrombolytic therapy, especially in older patients and those with active malignancy. These are the exact populations that have the greatest potential to benefit from thrombolytic therapy. In ULTIMA many patients with submassive PE failed randomization (84%) for a multitude of reasons, most commonly increased bleeding risk, prolonged symptom duration, advanced age, and inadequate PE distribution on imaging. The authors also cite a potential selection bias, acknowledging that not all eligible patients were subject to randomization. This suggests limited applicability in a real
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DOI: 10.1161/CIRCULATIONAHA.113.007132
world setting. While USAT is appealing, there are other catheter-based PE treatments including thrombus fragmentation, suction thrombectomy and rotational thrombectomy19. As noted by the authors, direct comparison to varying techniques was not available in the current study. In the interim, as more information about various treatment options is being gathered, registry data may be useful. Applicable information may soon become available by pulmonary embolism response teams (PERT) which are becoming more commonplace in major clinical centers20. ULTIMA is extremely valuable in that it represents the first randomized trial to test a standardized, commonly used catheter-based intervention in patients with acute PE. For upporters of thrombolytic therapy in submassive PE, ULTIMA proves that inte erv rven en ntiion onal al supporters interventional reatments for submassive PE offer objective improvement in important hemodynamic treatments pa araame metters ters with withh very ver low risk of major and mort rttal hemorrhage. hemorrhage. Until U tiil meaningful Un meaningful clinical me parameters mortal outc com o es are rreported ep porteed fo or pa pati tien ti ents tss rreceiving e ei ec eivving g aadvanced dvaancced d ttherapy heraapy iin hera n rrandomized and nd dom omiz ized ed cclinical linnica li nicaal ttrials riaals ls outcomes for patients ag agai ains ai nstt st ns stan an nda dard rd an nticoa ntic oagu g laati gu t on n, cl cli inicciaans m inic ay pu ppursue urrsue ue iinterventional nteerve nt vent ve nttio ona nall th thro r mbol ro mbol o yt ytic ic the heeraapi piees ffor o or against standard anticoagulation, clinicians may thrombolytic therapies patients withh hi hhigh-risk gh-r gh -rris i k PE P w h lee av hi aavoiding o diing tthem oi hem he m inn low-risk low ow-r -rris iskk patients. pati pa tieent ti n s. Patients Pati Pa tien ti ents en t felt ts fel eltt too be be at while intermediate risk must be individually stratified by multispecialty “teams” while understanding the current literature gap.
Conflict of Interest Disclosures: IW – None. MRJ – Non-compensated Data Safety and Monitoring Board, Ekos Corporation; Board member of VIVA physicians, a 501 c 3 non for profit education and research organization References: 1. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet.
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