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Thromb Haemost 2015; 113(06): 1202-1209
DOI: 10.1160/TH14-11-0998
Theme Issue Article
Schattauer GmbH

Acute phase treatment of venous thromboembolism: advanced therapy

Systemic fibrinolysis and pharmacomechanical therapy
Stavros V. Konstantinides
1   Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Mainz, Germany
2   Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
,
Simone Wärntges
1   Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Mainz, Germany
› Author Affiliations
Further Information

Publication History

Received: 30 November 2014

Accepted after major revision: 01 February 2015

Publication Date:
22 November 2017 (online)

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Summary

Venous thromboembolism, which encompasses deep-vein thrombosis and acute pulmonary embolism (PE), represents a major contributor to global disease burden worldwide. For patients who present with cardiogenic shock or persistent hypotension (acute high-risk PE), there is consensus that immediate reperfusion treatment applying systemic fibrinolysis or, in the case of a high bleeding risk, surgical or catheterdirected techniques, is indicated. On the other hand, for the large, heterogeneous group of patients presenting without overt haemodynamic instability, the indications for advanced therapy are less clear. The recently updated guidelines of the European Society of Cardiology emphasise the importance of clinical prediction rules in combination with imaging procedures (assessment of right ventricular function) and laboratory biomarkers (indicative of myocardial stress or injury) for distinguishing between an intermediate and a low risk for an adverse early outcome. In intermediate-high-risk PE defined by the presence of both right ventricular dysfunction on echocardiography (or computed tomography) and a positive troponin (or natriuretic peptide) test, the bleeding risks of full-dose fibrinolytic treatment have been shown to outweigh its potential clinical benefits unless clinical signs of haemodynamic decompensation appear (rescue fibrinolysis). Recently published trials suggest that catheter-directed, ultrasoundassisted, low-dose local fibrinolysis may provide an effective and particularly safe treatment option for some of these patients.

Keywords

Pulmonary embolism - risk-adjusted treatment - fibrinolysis - catheter-directed treatment - pharmacomechanical therapy
 

  • References

  • 1 Raskob GE, Angchaisuksiri P, Blanco AN. et al. Thrombosis: A major contributor to global disease burden. Thromb Haemost 2014; 112: 843-852.
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Cohen AT, Agnelli G, Anderson FA. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756-764.
    Thieme ConnectPubMedSearch in Google Scholar
  • 3 Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999; 353: 1386-1389.
    CrossrefPubMedSearch in Google Scholar
  • 4 Kasper W, Konstantinides S, Geibel A. et al. Management strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry. J Am Coll Cardiol 1997; 30: 1165-1171.
    CrossrefPubMedSearch in Google Scholar
  • 5 Kasper W, Konstantinides S, Geibel A. et al. Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart 1997; 77: 346-349.
    CrossrefPubMedSearch in Google Scholar
  • 6 British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Research Committee of the British Thoracic Society. Lancet 1992; 340: 873-876.
    PubMedSearch in Google Scholar
  • 7 Carson JL, Kelley MA, Duff A, Weg JG, Fulkerson WJ, Palevsky HI. et al. The clinical course of pulmonary embolism. N Engl J Med 1992; 326: 1240-1245.
    CrossrefPubMedSearch in Google Scholar
  • 8 Aujesky D, Jimenez D, Mor MK, Geng M, Fine MJ, Ibrahim SA. Weekend versus weekday admission and mortality after acute pulmonary embolism. Circulation 2009; 119: 962-968.
    CrossrefPubMedSearch in Google Scholar
  • 9 Laporte S, Mismetti P, Decousus H. et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117: 1711-1716.
    CrossrefPubMedSearch in Google Scholar
  • 10 Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J 2012; 33: 3014-3022.
    CrossrefPubMedSearch in Google Scholar
  • 11 Konstantinides SV, Torbicki A, Agnelli G. et al. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)Endorsed by the European Respiratory Society (ERS). Eur Heart J 2014; 35: 3033-3073.
    CrossrefPubMedSearch in Google Scholar
  • 12 Aujesky D, Obrosky DS, Stone RA. et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172: 1041-1046.
    CrossrefPubMedSearch in Google Scholar
  • 13 Aujesky D, Roy PM, Verschuren F. et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet 2011; 378: 41-48.
    CrossrefPubMedSearch in Google Scholar
  • 14 Jimenez D, Aujesky D, Moores L. et al. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170: 1383-1389.
    CrossrefPubMedSearch in Google Scholar
  • 15 Righini M, Roy PM, Meyer G. et al. The Simplified Pulmonary Embolism Severity Index (PESI): validation of a clinical prognostic model for pulmonary embolism. J Thromb Haemost 2011; 09: 2115-2117.
    CrossrefPubMedSearch in Google Scholar
  • 16 Lankeit M, Gomez V, Wagner C. et al. A strategy combining imaging and laboratory biomarkers in comparison with a simplified clinical score for risk stratification of patients with acute pulmonary embolism. Chest 2012; 141: 916-922.
    CrossrefPubMedSearch in Google Scholar
  • 17 Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest 2004; 125: 1539-1545.
    CrossrefPubMedSearch in Google Scholar
  • 18 Coutance G, Cauderlier E, Ehtisham J. et al. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011; 15: R103.
    CrossrefPubMedSearch in Google Scholar
  • 19 Sanchez O, Trinquart L, Colombet I. et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008; 29: 1569-1577.
    CrossrefPubMedSearch in Google Scholar
  • 20 Becattini C, Agnelli G, Germini F. et al. Computed tomography to assess risk of death in acute pulmonary embolism: a meta-analysis. Eur Respir J 2014; 43: 1678-1690.
    CrossrefPubMedSearch in Google Scholar
  • 21 Kucher N, Boekstegers P, Muller OJ. et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014; 129: 479-486.
    CrossrefPubMedSearch in Google Scholar
  • 22 Meyer G, Vicaut E, Danays T. et al. Fibrinolysis for patients with intermediaterisk pulmonary embolism. N Engl J Med 2014; 370: 1402-1411.
    CrossrefPubMedSearch in Google Scholar
  • 23 Becattini C, Agnelli G, Salvi A. et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res 2010; 125: e82-e86.
    CrossrefPubMedSearch in Google Scholar
  • 24 Lankeit M, Jimenez D, Kostrubiec M. et al. Predictive value of the high-sensitivity troponin T assay and the simplified pulmonary embolism severity index in hemodynamically stable patients with acute pulmonary embolism: a prospective validation study. Circulation 2011; 124: 2716-2724.
    CrossrefPubMedSearch in Google Scholar
  • 25 Lankeit M, Jimenez D, Kostrubiec M. et al. Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism. Eur Respir J 2014; 43: 1669-1677.
    CrossrefPubMedSearch in Google Scholar
  • 26 Dellas C, Tschepe M, Seeber V. et al. A novel H-FABP assay and a fast prognostic score for risk assessment of normotensive pulmonary embolism. Thromb Haemost 2014; 111: 996-1003.
    Thieme ConnectPubMedSearch in Google Scholar
  • 27 Lankeit M, Dellas C, Benz V. et al. The predictive value of heart-type fatty acidbinding protein is independent from symptom duration in normotensive patients with pulmonary embolism. Thromb Res 2013; 132: 543-547.
    CrossrefPubMedSearch in Google Scholar
  • 28 Becattini C, Casazza F, Forgione C. et al. Acute pulmonary embolism: external validation of an integrated risk stratification model. Chest 2013; 144: 1539-1545.
    CrossrefPubMedSearch in Google Scholar
  • 29 Jimenez D, Kopecna D, Tapson V. et al. Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 2014; 189: 718-726.
    CrossrefPubMedSearch in Google Scholar
  • 30 Bova C, Sanchez O, Prandoni P. et al. Identification of intermediate-risk patients with acute symptomatic pulmonary embolism. Eur Respir J 2014; 44: 694-703.
    CrossrefPubMedSearch in Google Scholar
  • 31 Miller GA, Sutton GC, Kerr IH. et al. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. Br Heart J 1971; 33: 616.
    PubMedSearch in Google Scholar
  • 32 The urokinase pulmonary embolism trial. A national cooperative study. Circulation 1973; 47: II1-II108.
    CrossrefPubMedSearch in Google Scholar
  • 33 Tibbutt DA, Davies JA, Anderson JA. et al. Comparison by controlled clinical trial of streptokinase and heparin in treatment of life-threatening pulmonay embolism. Br Med J 1974; 01: 343-347.
    CrossrefPubMedSearch in Google Scholar
  • 34 Ly B, Arnesen H, Eie H. et al. A controlled clinical trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta Med Scand 1978; 203: 465-470.
    PubMedSearch in Google Scholar
  • 35 Marini C, Di Ricco G, Rossi G. et al. Fibrinolytic effects of urokinase and heparin in acute pulmonary embolism: a randomized clinical trial. Respiration 1988; 54: 162-173.
    CrossrefPubMedSearch in Google Scholar
  • 36 Levine M, Hirsh J, Weitz J. 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: 1473-1479.
    CrossrefPubMedSearch in Google Scholar
  • 37 Tissue plasminogen activator for the treatment of acute pulmonary embolism. A collaborative study by the PIOPED Investigators. Chest 1990; 97: 528-533.
    CrossrefPubMedSearch in Google Scholar
  • 38 Dalla-Volta S, Palla A, Santolicandro A. et al. PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol 1992; 20: 520-526.
    CrossrefPubMedSearch in Google Scholar
  • 39 Goldhaber SZ, Haire WD, Feldstein ML. et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 341: 507-511.
    CrossrefPubMedSearch in Google Scholar
  • 40 Tebbe U, Bramlage P, Graf A. et al. Desmoteplase in acute massive pulmonary thromboembolism. Thromb Haemost 2009; 101: 557-562.
    Thieme ConnectPubMedSearch in Google Scholar
  • 41 Tebbe U, Graf A, Kamke W. et al. Hemodynamic effects of double bolus reteplase versus alteplase infusion in massive pulmonary embolism. Am Heart J 1999; 138: 39-44.
    CrossrefPubMedSearch in Google Scholar
  • 42 Meneveau N, Seronde MF, Blonde MC. et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest 2006; 129: 1043-1050.
    CrossrefPubMedSearch in Google Scholar
  • 43 Daniels LB, Parker JA, Patel SR. et al. Relation of duration of symptoms with response to thrombolytic therapy in pulmonary embolism. Am J Cardiol 1997; 80: 184-188.
    CrossrefPubMedSearch in Google Scholar
  • 44 Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med 2008; 359: 2804-2813.
    CrossrefPubMedSearch in Google Scholar
  • 45 Kline JA, Nordenholz KE, Courtney DM. et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014; 12: 459-468.
    CrossrefPubMedSearch in Google Scholar
  • 46 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic Therapy for VTE Disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419S-e494S.
    CrossrefPubMedSearch in Google Scholar
  • 47 Jaff MR, McMurtry MS, Archer SL. et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123: 1788-1830.
    CrossrefPubMedSearch in Google Scholar
  • 48 Wan S, Quinlan DJ, Agnelli G. et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 2004; 110: 744-749.
    CrossrefPubMedSearch in Google Scholar
  • 49 Marti C, John G, Konstantinides S. et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2014. Epub ahead of print
    Search in Google Scholar
  • 50 Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med 2012; 125: 465-470.
    CrossrefPubMedSearch in Google Scholar
  • 51 Rose PS, Punjabi NM, Pearse DB. Treatment of right heart thromboemboli. Chest 2002; 121: 806-814.
    CrossrefPubMedSearch in Google Scholar
  • 52 Chartier L, Bera J, Delomez M. et al. Free-floating thrombi in the right heart: diagnosis, management, and prognostic indexes in 38 consecutive patients. Circulation 1999; 99: 2779-2783.
    CrossrefPubMedSearch in Google Scholar
  • 53 Konstantinides S, Tiede N, Geibel A. et al. Comparison of alteplase versus heparin for resolution of major pulmonary embolism. Am J Cardiol 1998; 82: 966-970.
    CrossrefPubMedSearch in Google Scholar
  • 54 Konstantinides S, Geibel A, Heusel G. et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347: 1143-1150.
    CrossrefPubMedSearch in Google Scholar
  • 55 Kanter DS, Mikkola KM, Patel SR. et al. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest 1997; 111: 1241-1245.
    CrossrefPubMedSearch in Google Scholar
  • 56 Sors H, Pacouret G, Azarian R. et al. Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest 1994; 106: 712-717.
    CrossrefPubMedSearch in Google Scholar
  • 57 Goldhaber SZ, Kessler CM, Heit JA. et al. Recombinant tissue-type plasminogen activator versus a novel dosing regimen of urokinase in acute pulmonary embolism: a randomized controlled multicenter trial. J Am Coll Cardiol 1992; 20: 24-30.
    CrossrefPubMedSearch in Google Scholar
  • 58 Meyer G, Sors H, Charbonnier B. et al. Effects of intravenous urokinase versus alteplase on total pulmonary resistance in acute massive pulmonary embolism: a European multicenter double-blind trial. The European Cooperative Study Group for Pulmonary Embolism [see comments]. J Am Coll Cardiol 1992; 19: 239-245.
    CrossrefPubMedSearch in Google Scholar
  • 59 Goldhaber SZ, Kessler CM, Heit J. et al. Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 02: 293-298.
    PubMedSearch in Google Scholar
  • 60 Verstraete M, Miller GA, Bounameaux H. et al. Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism. Circulation 1988; 77: 353-360.
    CrossrefPubMedSearch in Google Scholar
  • 61 Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. J Am Med Assoc 1974; 229: 1606-1613.
    CrossrefPubMedSearch in Google Scholar
  • 62 Konstantinides S, Marder VJ. Thrombolysis in venous thromboembolism. In: Hemostasis and Thrombosis. Philadelphia: Lippincott Williams and Wilkins; 2006. pp. 1317-1329.
    Search in Google Scholar
  • 63 Mikkola KM, Patel SR, Parker JA. et al. Increasing age is a major risk factor for hemorrhagic complications after pulmonary embolism thrombolysis. Am Heart J 1997; 134: 69-72.
    CrossrefPubMedSearch in Google Scholar
  • 64 Wang C, Zhai Z, Yang Y. 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: 254-262.
    CrossrefPubMedSearch in Google Scholar
  • 65 Sharifi M, Bay C, Skrocki L. et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013; 111: 273-277.
    CrossrefPubMedSearch in Google Scholar
  • 66 Armstrong PW, Gershlick AH, Goldstein P. et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013; 368: 1379-1387.
    CrossrefPubMedSearch in Google Scholar
  • 67 Leacche M, Unic D, Goldhaber SZ. et al. Modern surgical treatment of massive pulmonary embolism: results in 47 consecutive patients after rapid diagnosis and aggressive surgical approach. J Thorac Cardiovasc Surg 2005; 129: 1018-1023.
    CrossrefPubMedSearch in Google Scholar
  • 68 Delnoij TS, Accord RE, Weerwind PW. et al. Atrial trans-septal thrombus in massive pulmonary embolism salvaged by prolonged extracorporeal life support after thrombo-embolectomy. A bridge to right-sided cardiovascular adaptation. Acute Card Care 2012; 14: 138-140.
    CrossrefPubMedSearch in Google Scholar
  • 69 Leick J, Liebetrau C, Szardien S. et al. Percutaneous circulatory support in a patient with cardiac arrest due to acute pulmonary embolism. Clin Res Cardiol 2012; 101: 1017-1020.
    CrossrefPubMedSearch in Google Scholar
  • 70 Taniguchi S, Fukuda W, Fukuda I. et al. Outcome of pulmonary embolectomy for acute pulmonary thromboembolism: analysis of 32 patients from a multicentre registry in Japan. Interact Cardiovasc Thorac Surg 2012; 14: 64-67.
    CrossrefPubMedSearch in Google Scholar
  • 71 Malekan R, Saunders PC, Yu CJ. et al. Peripheral extracorporeal membrane oxygenation: comprehensive therapy for high-risk massive pulmonary embolism. Ann Thorac Surg 2012; 94: 104-108.
    CrossrefPubMedSearch in Google Scholar
  • 72 Myers PO, Bounameaux H, Panos A. et al. Impending paradoxical embolism: systematic review of prognostic factors and treatment. Chest 2010; 137: 164-170.
    CrossrefPubMedSearch in Google Scholar
  • 73 Engelberger RP, Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J 2014; 35: 758-764.
    CrossrefPubMedSearch in Google Scholar
  • 74 Engelberger RP, Moschovitis A, Fahrni J. et al. Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate-and high-risk pulmonary embolism. Eur Heart J 2015; 36: 597-604.
    CrossrefPubMedSearch in Google Scholar
  • 75 Braaten JV, Goss RA, Francis CW. Ultrasound reversibly disaggregates fibrin fibers. Thromb Haemost 1997; 78: 1063-1068.
    Thieme ConnectPubMedSearch in Google Scholar
  • 76 Francis CW, Blinc A, Lee S. et al. Ultrasound accelerates transport of recombinant tissue plasminogen activator into clots. Ultrasound Med Biol 1995; 21: 419-424.
    CrossrefPubMedSearch in Google Scholar
  • 77 Kuo WT, Gould MK, Louie JD. et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009; 20: 1431-1440.
    CrossrefPubMedSearch in Google Scholar