Semin Respir Crit Care Med 2017; 38(01): 056-065
DOI: 10.1055/s-0036-1597560
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Systemic Thrombolytic Therapy for Acute Pulmonary Embolism: Who Is a Candidate?

Stavros V. Konstantinides
1   Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
2   Department of Cardiology, Democritus University of Thrace, Alexandroupolis, Greece
,
Stefano Barco
1   Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
16 February 2017 (online)

Abstract

Pulmonary embolism (PE) is a major cause of both acute and long-term morbidity for a large number of patients worldwide, and massive PE is frequently fatal. Right ventricular (RV) dysfunction is a key determinant of prognosis in the acute phase of PE. Patients with clinically overt RV failure, that is, with cardiogenic shock or persistent hypotension at presentation (acute high-risk PE), are clearly in need of immediate reperfusion treatment with systemic thrombolysis or, alternatively, surgical or catheter-directed techniques. On the other hand, within the large group of patients presenting without hemodynamic instability, the bleeding risk of full-dose intravenous thrombolytic treatment has been shown to outweigh its benefits, even if they present with evidence of both RV dysfunction and myocardial injury. Thus, current guidelines agree in proposing a strategy of effective anticoagulation and “watchful waiting” (with initial hemodynamic monitoring notably over the first 48–72 hours) in intermediate-risk PE, with an indication for rescue thrombolysis if signs of hemodynamic decompensation appear. Recently published trials suggest that catheter-directed, ultrasound-assisted, low-dose local fibrinolysis may provide an effective and particularly safe treatment option for some of these patients. Ongoing or planned studies are expected to resolve the controversy on the efficacy and safety or reduced-dose systemic thrombolysis and to address the possible impact of thrombolytic therapy on long-term outcomes after acute PE.

 
  • References

  • 1 Cohen AT, Agnelli G, Anderson FA , et al; VTE Impact Assessment Group in Europe (VITAE). Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thromb Haemost 2007; 98 (4) 756-764
  • 2 Becattini C, Agnelli G, Lankeit M , et al. Acute pulmonary embolism: mortality prediction by the 2014 European Society of Cardiology risk stratification model. Eur Respir J 2016;
  • 3 Klok FA, van der Hulle T, den Exter PL, Lankeit M, Huisman MV, Konstantinides S. The post-PE syndrome: a new concept for chronic complications of pulmonary embolism. Blood Rev 2014; 28 (6) 221-226
  • 4 Lang IM, Pesavento R, Bonderman D, Yuan JX. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J 2013; 41 (2) 462-468
  • 5 Barco S, Woersching AL, Spyropoulos AC, Piovella F, Mahan CE. European Union-28: an annualised cost-of-illness model for venous thromboembolism. Thromb Haemost 2016; 115 (4) 800-808
  • 6 Mahan CE, Borrego ME, Woersching AL , et al. Venous thromboembolism: annualised United States models for total, hospital-acquired and preventable costs utilising long-term attack rates. Thromb Haemost 2012; 108 (2) 291-302
  • 7 Konstantinides SV, Torbicki A, Agnelli G , et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35 (43) 3033-3069 , 3069a–3069k
  • 8 Konstantinides SV. Trends in incidence versus case fatality rates of pulmonary embolism: good news or bad news?. Thromb Haemost 2016; 115 (2) 233-235
  • 9 Laporte S, Mismetti P, Décousus H , et al; RIETE Investigators. 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 (13) 1711-1716
  • 10 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 (8) 1041-1046
  • 11 Jiménez D, Aujesky D, Moores L , et al; RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170 (15) 1383-1389
  • 12 Righini M, Roy PM, Meyer G, Verschuren F, Aujesky D, Le Gal G. The Simplified Pulmonary Embolism Severity Index (PESI): validation of a clinical prognostic model for pulmonary embolism. J Thromb Haemost 2011; 9 (10) 2115-2117
  • 13 Harjola VP, Mebazaa A, Čelutkienė J , et al. Contemporary management of acute right ventricular failure: a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016; 18 (3) 226-241
  • 14 Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med 2008; 359 (26) 2804-2813
  • 15 Marti C, John G, Konstantinides S , et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2015; 36 (10) 605-614
  • 16 Chatterjee S, Chakraborty A, Weinberg I , et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014; 311 (23) 2414-2421
  • 17 Meyer G, Vicaut E, Danays T , et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014; 370 (15) 1402-1411
  • 18 Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med 2012; 125 (5) 465-470
  • 19 Jiménez D, de Miguel-Díez J, Guijarro R , et al; RIETE Investigators. Trends in the management and outcomes of acute pulmonary embolism: analysis from the RIETE Registry. J Am Coll Cardiol 2016; 67 (2) 162-170
  • 20 Wang C, Zhai Z, Yang Y , et al; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest 2010; 137 (2) 254-262
  • 21 Torbicki A, Perrier A, Konstantinides S , et al; ESC Committee for Practice Guidelines (CPG). 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 (18) 2276-2315
  • 22 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 (2) 273-277
  • 23 Armstrong PW, Gershlick AH, Goldstein P , et al; STREAM Investigative Team. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013; 368 (15) 1379-1387
  • 24 Engelberger RP, Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J 2014; 35 (12) 758-764
  • 25 Kucher N, Boekstegers P, Müller OJ , et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014; 129 (4) 479-486
  • 26 Piazza G, Hohlfelder B, Jaff MR , et al; SEATTLE II Investigators. A prospective, single-arm, multicenter trial of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II study. JACC Cardiovasc Interv 2015; 8 (10) 1382-1392
  • 27 Kuo WT, Banerjee A, Kim PS , et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): initial results from a prospective multicenter registry. Chest 2015; 148 (3) 667-673
  • 28 Engelberger RP, Spirk D, Willenberg T , et al. Ultrasound-assisted versus conventional catheter-directed thrombolysis for acute iliofemoral deep vein thrombosis. Circ Cardiovasc Interv 2015; 8 (1) 8
  • 29 Stevinson BG, Hernandez-Nino J, Rose G, Kline JA. Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients. Eur Heart J 2007; 28 (20) 2517-2524
  • 30 Chung T, Emmett L, Mansberg R, Peters M, Kritharides L. Natural history of right ventricular dysfunction after acute pulmonary embolism. J Am Soc Echocardiogr 2007; 20 (7) 885-894
  • 31 Guérin L, Couturaud F, Parent F , et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost 2014; 112 (3) 598-605
  • 32 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 (4) 459-468
  • 33 Coutance G, Cauderlier E, Ehtisham J, Hamon M, Hamon M. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011; 15 (2) R103
  • 34 Becattini C, Agnelli G, Vedovati MC , et al. Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test. Eur Heart J 2011; 32 (13) 1657-1663
  • 35 Aviram G, Soikher E, Bendet A , et al. Prediction of mortality in pulmonary embolism based on left atrial volume measured on CT pulmonary angiography. Chest 2016; 149 (3) 667-675
  • 36 Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008; 178 (4) 425-430
  • 37 Lankeit M, Jiménez 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 (6) 1669-1677
  • 38 Bajaj A, Rathor P, Sehgal V , et al. Prognostic value of biomarkers in acute non-massive pulmonary embolism: a systematic review and meta-analysis. Lung 2015; 193 (5) 639-651
  • 39 Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation 2007; 116 (4) 427-433
  • 40 Lankeit M, Jiménez 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 (24) 2716-2724
  • 41 Kaeberich A, Seeber V, Jiménez D , et al. Age-adjusted high-sensitivity troponin T cut-off value for risk stratification of pulmonary embolism. Eur Respir J 2015; 45 (5) 1323-1331
  • 42 Dellas C, Puls M, Lankeit M , et al. Elevated heart-type fatty acid-binding protein levels on admission predict an adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol 2010; 55 (19) 2150-2157
  • 43 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 (5) 996-1003
  • 44 Hellenkamp K, Schwung J, Rossmann H , et al. Risk stratification of normotensive pulmonary embolism: prognostic impact of copeptin. Eur Respir J 2015; 46 (6) 1701-1710
  • 45 Becattini C, Agnelli G, Salvi A , et al; TIPES Study Group. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res 2010; 125 (3) e82-e86
  • 46 Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest 2009; 136 (5) 1202-1210
  • 47 Kearon C, Akl EA, Ornelas J , et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (2) 315-352
  • 48 Jaff MR, McMurtry MS, Archer SL , et al; 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 (16) 1788-1830
  • 49 Agarwal S, Menon V, Jaber WA. Residential zip code influences outcomes following hospitalization for acute pulmonary embolism in the United States. Vasc Med 2015; 20 (5) 439-446
  • 50 Tsai J, Grosse SD, Grant AM, Hooper WC, Atrash HK. Trends in in-hospital deaths among hospitalizations with pulmonary embolism. Arch Intern Med 2012; 172 (12) 960-961
  • 51 Yang S, Yang Y, Zhai Z , et al. Incidence and risk factors of chronic thromboembolic pulmonary hypertension in patients after acute pulmonary embolism. J Thorac Dis 2015; 7 (11) 1927-1938
  • 52 de Miguel-Díez J, Jiménez-García R, Jiménez D , et al. Trends in hospital admissions for pulmonary embolism in Spain from 2002 to 2011. Eur Respir J 2014; 44 (4) 942-950
  • 53 Dentali F, Ageno W, Pomero F, Fenoglio L, Squizzato A, Bonzini M. Time trends and case fatality rate of in-hospital treated pulmonary embolism during 11 years of observation in Northwestern Italy. Thromb Haemost 2016; 115 (2) 399-405
  • 54 Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med 2011; 171 (9) 831-837
  • 55 Shiraev TP, Omari A, Rushworth RL. Trends in pulmonary embolism morbidity and mortality in Australia. Thromb Res 2013; 132 (1) 19-25
  • 56 Smith SB, Geske JB, Kathuria P , et al. Analysis of national trends in admissions for pulmonary embolism. Chest 2016; 150 (1) 35-45