Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis

Christophe Marti, Gregor John, Stavros Konstantinides, Christophe Combescure, Olivier Sanchez, Mareike Lankeit, Guy Meyer, Arnaud Perrier, Christophe Marti, Gregor John, Stavros Konstantinides, Christophe Combescure, Olivier Sanchez, Mareike Lankeit, Guy Meyer, Arnaud Perrier

Abstract

Aim: Thrombolytic therapy induces faster clot dissolution than anticoagulation in patients with acute pulmonary embolism (PE) but is associated with an increased risk of haemorrhage. We reviewed the risks and benefits of thrombolytic therapy in the management of patients with acute PE.

Methods and results: We systematically reviewed randomized controlled studies comparing systemic thrombolytic therapy plus anticoagulation with anticoagulation alone in patients with acute PE. Fifteen trials involving 2057 patients were included in our meta-analysis. Compared with heparin, thrombolytic therapy was associated with a significant reduction of overall mortality (OR; 0.59, 95% CI: 0.36-0.96). This reduction was not statistically significant after exclusion of studies including high-risk PE (OR; 0.64, 95% CI: 0.35-1.17). Thrombolytic therapy was associated with a significant reduction in the combined endpoint of death or treatment escalation (OR: 0.34, 95% CI: 0.22-0.53), PE-related mortality (OR: 0.29; 95% CI: 0.14-0.60) and PE recurrence (OR: 0.50; 95% CI: 0.27-0.94). Major haemorrhage (OR; 2.91, 95% CI: 1.95-4.36) and fatal or intracranial bleeding (OR: 3.18, 95% CI: 1.25-8.11) were significantly more frequent among patients receiving thrombolysis.

Conclusions: Thrombolytic therapy reduces total mortality, PE recurrence, and PE-related mortality in patients with acute PE. The decrease in overall mortality is, however, not significant in haemodynamically stable patients with acute PE. Thrombolytic therapy is associated with an increase of major and fatal or intracranial haemorrhage.

Keywords: Pulmonary embolism; Systematic review; Thrombolytic therapy.

© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Figure 1
Figure 1
Study flow chart.
Figure 2
Figure 2
Early mortality by pulmonary embolism severity, Forest plot.
Figure 3
Figure 3
Major bleeding by drug, Forest plot.
Figure 4
Figure 4
Early mortality, Funnel plot of included studies.

References

    1. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831–837.
    1. Kroger K, Moerchel C, Moysidis T, Santosa F. Incidence rate of pulmonary embolism in Germany: data from the federal statistical office. J Thromb Thrombolysis. 2010;29:349–353.
    1. Laporte S, Mismetti P, Decousus H, Uresandi F, Otero R, Lobo JL, Monreal M. 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.
    1. Aujesky D, Hughes R, Jimenez D. Short-term prognosis of pulmonary embolism. J Thromb Haemost. 2009;7(Suppl. 1):318–321.
    1. Stein PD, Kayali F, Olson RE. Estimated case fatality rate of pulmonary embolism, 1979 to 1998. Am J Cardiol. 2004;93:1197–1199.
    1. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, Klepetko W, Mayer E, Remy-Jardin M, Bassand JP. 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) Eur Heart J. 2008;29:2276–2315.
    1. 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. 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.
    1. Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970;214:2163–2172.
    1. Konstantinides S, Tiede N, Geibel A, Olschewski M, Just H, Kasper W. Comparison of alteplase versus heparin for resolution of major pulmonary embolism. Am J Cardiol. 1998;82:966–970.
    1. Becattini C, Agnelli G, Salvi A, Grifoni S, Pancaldi LG, Enea I, Balsemin F, Campanini M, Ghirarduzzi A, Casazza F. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res. 2010;125:e82–e86.
    1. Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, Zonzin P, Zanuttini D, Barbaresi F, Agnelli G, Morpurgo M, Giulia Marini M, Visani L. 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.
    1. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA, Mogtader A, McDonough TJ, Braunwald E. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet. 1993;341:507–511.
    1. 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.
    1. Dong BR, Hao Q, Yue J, Wu T, Liu GJ. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2009:CD004437. .
    1. 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.
    1. Thabut G, Thabut D, Myers RP, Bernard-Chabert B, Marrash-Chahla R, Mal H, Fournier M. Thrombolytic therapy of pulmonary embolism: a meta-analysis. J Am Coll Cardiol. 2002;40:1660–1667.
    1. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR. 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(2 Suppl):e419S–e494S.
    1. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the ‘MOPETT’ Trial) Am J Cardiol. 2013;111:273–277.
    1. Meyer G, vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebanne M, Sobkowicz B, Stefanovic BS, Thiele H, torbicki A, Verschuren F, Konstantinides SV. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402–1411.
    1. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694.
    1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.
    1. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–748.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560.
    1. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351–1375.
    1. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56:455–463.
    1. Kline J, Hernandez J, Kabrehl C, Courtney D, 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. J Am Coll Cardiol. 2013;61 E2074.
    1. Jerjes-Sanchez C, Ramirez-Rivera A, Lourdes Garcia M, Arriaga-Nava R, Valencia S, Rosado-Buzzo A, Pierzo JA, Rosas E. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis. 1995;2:227–229.
    1. Dotter CT, Seaman AJ, Rosch J, Porter JM. Streptokinase and heparin in the treatment of major pulmonary embolism: a randomised comparison. Vascu Surg. 1979;13:42–52.
    1. Ly B, Arnesen H, Eie H, Hol R. A controlled clinical trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta Med Scand. 1978;203:465–470.
    1. Marini C, Di Ricco G, Rossi G, Rindi M, Palla R, Giuntini C. Fibrinolytic effects of urokinase and heparin in acute pulmonary embolism: a randomized clinical trial. Respiration. 1988;54:162–173.
    1. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347:1143–1150.
    1. Levine M, Hirsh J, Weitz J, Cruickshank M, Neemeh J, Turpie AG, Gent M. 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.
    1. Stein PD, Matta F, Steinberger DS, Keyes DC. Intracerebral hemorrhage with thrombolytic therapy for acute pulmonary embolism. Am J Med. 2012;125:50–56.
    1. Kucher N, Boekstegers P, Muller O, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129:479–486.
    1. Stein PD, Matta F, Janjua M, Yaekoub AY, Jaweesh F, Alrifai A. Outcome in stable patients with acute pulmonary embolism who had right ventricular enlargement and/or elevated levels of troponin I. Am J Cardiol. 2010;106:558–563.
    1. Schoepf UJ, Kucher N, Kipfmueller F, Quiroz R, Costello P, Goldhaber SZ. Right ventricular enlargement on chest computed tomography: a predictor of early death in acute pulmonary embolism. Circulation. 2004;110:3276–3280.
    1. Sanchez O, Trinquart L, Colombet I, Durieux P, Huisman MV, Chatellier G, Meyer G. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J. 2008;29:1569–1577.
    1. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116:427–433.
    1. Lankeit M, Friesen D, Aschoff J, Dellas C, Hasenfuss G, Katus H, Konstantinides S, Giannitsis E. Highly sensitive troponin T assay in normotensive patients with acute pulmonary embolism. Eur Heart J. 2010;31:1836–1844.
    1. 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.

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