- Email: [email protected]
Counterpoint: Should Systemic Lytic Therapy Be Used for Submassive Pulmonary Embolism? No
Financial/nonfinancial disclosures: The author has reported to CHEST the following conflict of interest: Dr Jiménez is a member of the Steering Committee of the Pulmonary Embolism International Thrombolysis Trial. Correspondence to: David Jiménez, MD, PhD, Respiratory Department, Ramón y Cajal Hospital, Instituto Ramón y Cajal de Investigación Sanitaria, 28034 Madrid, Spain; e-mail: djc_69_98@ yahoo.com © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2447
References 1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162): 1386-1389. 2. 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. 3. 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(5):1165-1171. 4. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002;121(3):877-905. 5. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med. 2005;165(15):1777-1781. 6. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;315(18):1109-1114. 7. Torbicki A, Perrier A, Konstantinides SV, 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. 8. Jiménez D, Aujesky D, Yusen RD. Risk stratification of normotensive patients with acute symptomatic pulmonary embolism. Br J Haematol. 2010;151(5):415-424. 9. 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(8844):507-511. 10. 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(3): 520-526. 11. 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(2)(suppl):e419S-e494S. 12. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary
13.
14.
15.
16.
17.
18.
19.
20.
Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150. 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. 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(12):1569-1577. Jiménez D, Aujesky D, Moores L, et al. Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism. Thorax. 2011;66(1):75-81. Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll Cardiol. 2011;57(6):700-706. Jiménez D, Lobo JL, Otero R, Monreal M, Yusen RD. Prognostic significance of multidetector computed tomography in normotensive patients with pulmonary embolism: rationale, methodology and reproducibility for the PROTECT study. J Thromb Thrombolysis. 2012;34(2):187-192. 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. 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(6):744-749. Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012;163(1):33-38.
Counterpoint: Should Systemic Lytic Therapy Be Used for Submassive Pulmonary Embolism? No outcome of acute pulmonary embolism (PE) Thedepends on both the severity of the PE (clot bur-
den) and the presence and severity of preexisting cardiopulmonary disease in the patient. Patients who develop shock or hypotension related to acute PE have a higher mortality than do patients with PE who are hemodynamically stable. Mortality from acute PE ranges from 70% in patients with cardiopulmonary arrest, to 30% in patients with cardiogenic shock, to 15% in patients with hypotension.1-3 Consensus guidelines recommend treatment with thrombolysis, if not contraindicated, in hemodynamically unstable patients based on their high mortality rate and the
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physiologic rationale that they should benefit from the more rapid dissolution of the clot and resultant relief of the vascular obstruction that is known to occur with administration of lytic agents.4,5 In contrast, patients without hypotension have a mortality ranging from 0% to 10%,1,6 and guidelines recommend that they be treated with anticoagulation alone.4,5 Within the group of patients with hemodynamically stable PE is a subgroup characterized as having submassive PE, variably defined on the basis of right ventricular (RV) enlargement, dysfunction, ischemia, or strain, as assessed by echocardiography, CT scan, serum markers (troponin or brain natriuretic peptide [BNP] levels), ECG criteria, or other means.7-11 Multiple studies, including large registries, have reported a two to 2.5-fold increased risk of mortality in patients with normal BP and RV dysfunction compared with those without RV dysfunction.1,3,8,12 Based on this elevated risk, some experts have advocated that patients with submassive PE be treated more aggressively and have recommended the use of thrombolytic therapy.13,14 However, although patients with hemodynamically stable PE and RV dysfunction and/or ischemia may have a worse prognosis, not a single study has been published that demonstrates that normotensive patients with PE-induced RV dysfunction have a lower mortality when treated with thrombolysis. Furthermore, although carefully selected patients with submassive PE (deemed to be at low risk of bleeding) may benefit from thrombolysis, there is no validated prediction rule that allows us to select these patients up front. Thus, any blanket recommendation to treat all patients with submassive PE with thrombolysis cannot be supported. Studies have generally defined submassive PE on the basis of RV dysfunction, which has, itself, been defined in a wide variety of ways. Depending on the definition used, RV dysfunction can be identified in 27% to 55% of normotensive patients with PE.7,15,16 Many, but not all, studies have identified higher short-term mortality in this population.6,8-10,12,17 Among 1,035 patients with PE and systolic BP . 90 mm Hg in the International Cooperative Pulmonary Embolism Registry (ICOPER), the presence of RV hypokinesis was associated with a nearly twofold risk of death (hazard ratio, 1.94).12 A systematic review of 12 studies of RV dysfunction in normotensive patients with PE suggested that RV dysfunction as assessed by echocardiography and spiral CT scan or elevated cardiac biomarkers is associated with a higher risk of shortterm mortality;8 the OR for short-term mortality based on echocardiography and spiral CT scan studies was 2.4 (95% CI, 1.3-4.4). A meta-analysis of 20 studies in patients with acute PE showed that high levels of troponins were associated with a high risk of shortterm death compared with normal levels (OR, 5.24;
95% CI, 3.28-8.38).10 Separate analysis of the seven studies that only included normotensive patients still showed an association between elevated troponin levels and mortality (OR, 4.98; 95% CI, 2.64-9.39).10 Similarly, a meta-analysis of 13 studies in patients with acute PE demonstrated that high BNP or N-terminalpro-BNP levels were at a higher risk of a complicated in-hospital course (OR, 6.8; 95% CI, 4.4-10) and 30-day mortality (OR, 7.6; 95% CI, 3.4-17).9 In contrast, a review of 157 patients in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II study with stable BP and RV enlargement (measured on CT pulmonary angiogram) showed no difference in the in-hospital rate of death from PE or all-cause mortality between 78 patients with RV enlargement and 79 patients without RV enlargement.17 Bova and colleagues6 prospectively evaluated the usefulness of six prognostic markers for predicting in-hospital adverse events related to PE and 3-month mortality in 201 consecutive patients with acute PE and normal BP. Only one patient (0.5%) died of PE during hospitalization, and in-hospital and 3-month all-cause mortality were 2% and 9%, respectively. None of the prognostic markers (RV dysfunction, troponin I, BNP, a validated clinical score, hypoxemia, or D-dimer) predicted the primary study outcome, which was in-hospital PE-related death or clinical deterioration, suggesting these prognostic markers are not useful for risk stratification of normotensive patients with acute PE and should not be used to select patients for aggressive treatment. The most convincing reason for not recommending thrombolysis for patients with submassive PE is that no study has shown a mortality benefit from doing so, and thrombolysis carries a significant risk of bleeding with a reported fatal hemorrhage rate of 2%.18,19 Although thrombolysis is associated with more rapid clot resolution and more rapid improvements in RV function and mean pulmonary artery pressure, these short-term benefits do not result in any long-term hemodynamic improvement.20-23 In fact, after 1 week, the percentage of lung perfusion resolution in patients treated with heparin is similar to that in patients treated with thrombolysis.20 Likewise, echocardiographic findings were similar after 7 days in patients treated with heparin compared with those treated with a thrombolytic agent.22 Results of the clinical trials that compared treatment of acute PE with thrombolysis with treatment with anticoagulation failed to show any benefit of thrombolytic therapy.24-26 A meta-analysis of 11 randomized trials comparing thrombolytic therapy with heparin in 748 patients showed no significant difference in mortality or major bleeding between groups.24 A subgroup analysis of trials that included hemodynamically unstable patients with acute PE (five trials)
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Point/Counterpoint Editorials
did show a significant reduction in PE or death in patients treated with thrombolysis compared with heparin. However, no benefit was seen in the six trials that excluded unstable patients. A meta-analysis of all clinical trials directly comparing recombinant tissue plasminogen activator with heparin in hemodynamically stable patients with acute PE was published in 2009. Five studies involving 464 patients were included. No difference in death related to PE or PE recurrence was seen, even in the subgroup of patients with RV dysfunction.25 An updated Cochrane Review concluded that thrombolytics compared with heparin did not reduce death or PE recurrence in patients with acute PE.26 Recently published guidelines have indicated similar conclusions. In the ninth edition of the Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, the expert panel reviewed 13 randomized trials that compared thrombolytic therapy alone to anticoagulant therapy alone and concluded that thrombolysis may be associated with a reduction in mortality and recurrent PE but is associated with an increase in major bleeding.5 Based on the poor quality of the evidence, the panel issued a weak recommendation for thrombolysis in patients with acute PE associated with hypotension who do not have a high risk of bleeding. They reasoned that the high mortality of patients in shock from acute PE justifies the risk of fatal bleeding even if the efficacy of thrombolysis is modest. In most patients with PE without hypotension, the panel recommends against thrombolytic therapy. They do make allowance for physician judgment, however, through the following recommendation: “In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypotension, we suggest administration of thrombolytic therapy.”5 The panel recognizes that there is no explicit prediction rule to identify this subgroup of patients, however, and suggests that such patients be identified on the basis of clinical instability and failure to improve on anticoagulant therapy. Although parameters of RV size and function, as well as cardiac biomarkers, can assist the physician in selecting such patients for thrombolysis, they do not have sufficient predictive power to serve as independent selection criteria. In fact, the panel advises against their routine measurement. The American Heart Association guidelines parallel those of the American College of Chest Physicians. Fibrinolysis is reasonable in patients with massive PE (systolic BP , 90 mm Hg) and acceptable risk of bleeding complications.4 For patients with submassive PE, their recommendation is as follows:
“Fibrinolysis may be considered for patients with submassive PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and low risk of bleeding complications.”4 The facts are that most patients with submassive PE treated with anticoagulation alone have a low risk of dying (probably , 3%).4 The risk of fatal hemorrhage caused by the administration of a thrombolytic agent is on the order of 2%.18,19 Thus, thrombolysis should be used only in patients with more severe compromise, the need for cardiopulmonary capacity, and at low risk of intracranial hemorrhage. Current methodologies are overly sensitive in classifying many patients without substantial compromise as having “submassive PE,” and thus this population, broadly defined, does not clearly benefit from thrombolytic therapy. To date, not a single randomized controlled trial has identified the subgroup of patients with submassive PE whose survival is improved by the administration of thrombolytic therapy. Until that subgroup is defined, patients with submassive PE are best served when the decision to administer a thrombolytic agent is made on a case-by-case basis by thoughtful, wellinformed physicians who carefully weigh the risks and benefits and consider patient preferences, clot burden, acute physiology, comorbidities, need for maximal cardiopulmonary capacity, and bleeding risk. Our position is not contrary to ever giving thrombolytic therapy for submassive PE, but contrary to ever giving thrombolytic therapy for submassive PE as a matter of routine. Kathryn L. Bilello, MD, FCCP Fresno, CA Susan Murin, MD, FCCP Sacramento, CA Affiliations: From the Department of Medicine (Dr Bilello), University of California San Francisco-Fresno Program; the Department of Medicine (Dr Murin), Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, School of Medicine; and the Veterans Affairs Northern California Health Care System (Dr Murin). Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Susan Murin, MD, FCCP, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, School of Medicine, 4150 V St, Ste 3400, Sacramento, CA 95817; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2449
References 1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative
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2. 3.
4.
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6.
7. 8.
9.
10. 11.
12.
13. 14. 15.
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17.
Pulmonary Embolism Registry (ICOPER) . Lancet. 1999; 353(9162):1386-1389. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113(4):577-582. 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(5):1165-1171. 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. 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(2)(suppl):e419S-494S. Bova C, Pesavento R, Marchiori A, et al; TELESIO Study Group. Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up. J Thromb Haemost. 2009;7(6):938-944. Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest. 2004;125(4):1539-1545. 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(12):1569-1577. 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 metaanalysis. Am J Respir Crit Care Med. 2008;178(4):425-430. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116(4):427-433. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med. 2005;165(15):1777-1781. Goldhaber SZ. Pulmonary embolism thrombolysis: broadening the paradigm for its administration. Circulation. 1997; 96(3):716-718. Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs heparin in the treatment of pulmonary embolism: a clinical outcomebased meta-analysis. Arch Intern Med. 2002;162(22):2537-2541. Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation. 2000;101(24):2817-2822. Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H. Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart. 1997;77(4):346-349. Stein PD, Beemath A, Matta F, et al. Enlarged right ventricle without shock in acute pulmonary embolism: prognosis. Am J Med. 2008;121(1):34-42.
18. Levine MN. Thrombolytic therapy for venous thromboembolism. Complications and contraindications. Clin Chest Med. 1995;16(2):321-328. 19. Kanter DS, Mikkola KM, Patel SR, Parker JA, Goldhaber SZ. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest. 1997;111(5):1241-1245. 20. Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970;214(12):2163-2172. 21. 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(8844):507-511. 22. 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(8):966-970. 23. Fasullo S, Scalzo S, Maringhini G, et al. 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(1):33-39. 24. 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(6):744-749. 25. Tardy B, Venet C, Zeni F, Coudrot M, Guyomarc’h S, Mismetti P. Short term effect of recombinant tissue plasminogen activator in patients with hemodynamically stable acute pulmonary embolism: results of a meta-analysis involving 464 patients. Thromb Res. 2009;124(6):672-677. 26. Dong BR, Hao Q, Yue J, Wu T, Liu GJ. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2009(3):CD004437.
Rebuttal From Dr Jiménez colleagues Drs Bilello and Murin contend that Mythrombolytics should not be used for submas1
sive pulmonary embolism (PE) using two arguments: (1) Studies have not demonstrated a survival benefit from thrombolysis in patients with acute submassive PE, and (2) studies have not validated an explicit prediction rule for identifying the subgroup of normotensive patients with PE who are at high risk of PE-related complications, in contrast to hemodynamically unstable patients “based upon their high mortality rate and the physiologic rationale that they should benefit from the more rapid dissolution of the clot, and resultant relief of vascular obstruction….”1 I concede that trials have not demonstrated a survival benefit from thrombolysis in patients with submassive PE. However, only one randomized controlled trial (by Jerjes-Sanchez and colleagues2) has provided evidence of a survival benefit of lytic therapy compared with heparin for the initial treatment of patients with PE and cardiogenic shock. In this study of eight randomized patients, none of the four patients who received intrapulmonary streptokinase died, compared with four of the four patients who received intrapulmonary heparin. Interestingly, the four patients in
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References 1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162): 1386-1389. 2. 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. 3. 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(5):1165-1171. 4. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002;121(3):877-905. 5. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med. 2005;165(15):1777-1781. 6. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;315(18):1109-1114. 7. Torbicki A, Perrier A, Konstantinides SV, 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. 8. Jiménez D, Aujesky D, Yusen RD. Risk stratification of normotensive patients with acute symptomatic pulmonary embolism. Br J Haematol. 2010;151(5):415-424. 9. 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(8844):507-511. 10. 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(3): 520-526. 11. 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(2)(suppl):e419S-e494S. 12. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary
13.
14.
15.
16.
17.
18.
19.
20.
Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150. 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. 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(12):1569-1577. Jiménez D, Aujesky D, Moores L, et al. Combinations of prognostic tools for identification of high-risk normotensive patients with acute symptomatic pulmonary embolism. Thorax. 2011;66(1):75-81. Pollack CV, Schreiber D, Goldhaber SZ, et al. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry). J Am Coll Cardiol. 2011;57(6):700-706. Jiménez D, Lobo JL, Otero R, Monreal M, Yusen RD. Prognostic significance of multidetector computed tomography in normotensive patients with pulmonary embolism: rationale, methodology and reproducibility for the PROTECT study. J Thromb Thrombolysis. 2012;34(2):187-192. 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. 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(6):744-749. Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012;163(1):33-38.
Counterpoint: Should Systemic Lytic Therapy Be Used for Submassive Pulmonary Embolism? No outcome of acute pulmonary embolism (PE) Thedepends on both the severity of the PE (clot bur-
den) and the presence and severity of preexisting cardiopulmonary disease in the patient. Patients who develop shock or hypotension related to acute PE have a higher mortality than do patients with PE who are hemodynamically stable. Mortality from acute PE ranges from 70% in patients with cardiopulmonary arrest, to 30% in patients with cardiogenic shock, to 15% in patients with hypotension.1-3 Consensus guidelines recommend treatment with thrombolysis, if not contraindicated, in hemodynamically unstable patients based on their high mortality rate and the
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physiologic rationale that they should benefit from the more rapid dissolution of the clot and resultant relief of the vascular obstruction that is known to occur with administration of lytic agents.4,5 In contrast, patients without hypotension have a mortality ranging from 0% to 10%,1,6 and guidelines recommend that they be treated with anticoagulation alone.4,5 Within the group of patients with hemodynamically stable PE is a subgroup characterized as having submassive PE, variably defined on the basis of right ventricular (RV) enlargement, dysfunction, ischemia, or strain, as assessed by echocardiography, CT scan, serum markers (troponin or brain natriuretic peptide [BNP] levels), ECG criteria, or other means.7-11 Multiple studies, including large registries, have reported a two to 2.5-fold increased risk of mortality in patients with normal BP and RV dysfunction compared with those without RV dysfunction.1,3,8,12 Based on this elevated risk, some experts have advocated that patients with submassive PE be treated more aggressively and have recommended the use of thrombolytic therapy.13,14 However, although patients with hemodynamically stable PE and RV dysfunction and/or ischemia may have a worse prognosis, not a single study has been published that demonstrates that normotensive patients with PE-induced RV dysfunction have a lower mortality when treated with thrombolysis. Furthermore, although carefully selected patients with submassive PE (deemed to be at low risk of bleeding) may benefit from thrombolysis, there is no validated prediction rule that allows us to select these patients up front. Thus, any blanket recommendation to treat all patients with submassive PE with thrombolysis cannot be supported. Studies have generally defined submassive PE on the basis of RV dysfunction, which has, itself, been defined in a wide variety of ways. Depending on the definition used, RV dysfunction can be identified in 27% to 55% of normotensive patients with PE.7,15,16 Many, but not all, studies have identified higher short-term mortality in this population.6,8-10,12,17 Among 1,035 patients with PE and systolic BP . 90 mm Hg in the International Cooperative Pulmonary Embolism Registry (ICOPER), the presence of RV hypokinesis was associated with a nearly twofold risk of death (hazard ratio, 1.94).12 A systematic review of 12 studies of RV dysfunction in normotensive patients with PE suggested that RV dysfunction as assessed by echocardiography and spiral CT scan or elevated cardiac biomarkers is associated with a higher risk of shortterm mortality;8 the OR for short-term mortality based on echocardiography and spiral CT scan studies was 2.4 (95% CI, 1.3-4.4). A meta-analysis of 20 studies in patients with acute PE showed that high levels of troponins were associated with a high risk of shortterm death compared with normal levels (OR, 5.24;
95% CI, 3.28-8.38).10 Separate analysis of the seven studies that only included normotensive patients still showed an association between elevated troponin levels and mortality (OR, 4.98; 95% CI, 2.64-9.39).10 Similarly, a meta-analysis of 13 studies in patients with acute PE demonstrated that high BNP or N-terminalpro-BNP levels were at a higher risk of a complicated in-hospital course (OR, 6.8; 95% CI, 4.4-10) and 30-day mortality (OR, 7.6; 95% CI, 3.4-17).9 In contrast, a review of 157 patients in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II study with stable BP and RV enlargement (measured on CT pulmonary angiogram) showed no difference in the in-hospital rate of death from PE or all-cause mortality between 78 patients with RV enlargement and 79 patients without RV enlargement.17 Bova and colleagues6 prospectively evaluated the usefulness of six prognostic markers for predicting in-hospital adverse events related to PE and 3-month mortality in 201 consecutive patients with acute PE and normal BP. Only one patient (0.5%) died of PE during hospitalization, and in-hospital and 3-month all-cause mortality were 2% and 9%, respectively. None of the prognostic markers (RV dysfunction, troponin I, BNP, a validated clinical score, hypoxemia, or D-dimer) predicted the primary study outcome, which was in-hospital PE-related death or clinical deterioration, suggesting these prognostic markers are not useful for risk stratification of normotensive patients with acute PE and should not be used to select patients for aggressive treatment. The most convincing reason for not recommending thrombolysis for patients with submassive PE is that no study has shown a mortality benefit from doing so, and thrombolysis carries a significant risk of bleeding with a reported fatal hemorrhage rate of 2%.18,19 Although thrombolysis is associated with more rapid clot resolution and more rapid improvements in RV function and mean pulmonary artery pressure, these short-term benefits do not result in any long-term hemodynamic improvement.20-23 In fact, after 1 week, the percentage of lung perfusion resolution in patients treated with heparin is similar to that in patients treated with thrombolysis.20 Likewise, echocardiographic findings were similar after 7 days in patients treated with heparin compared with those treated with a thrombolytic agent.22 Results of the clinical trials that compared treatment of acute PE with thrombolysis with treatment with anticoagulation failed to show any benefit of thrombolytic therapy.24-26 A meta-analysis of 11 randomized trials comparing thrombolytic therapy with heparin in 748 patients showed no significant difference in mortality or major bleeding between groups.24 A subgroup analysis of trials that included hemodynamically unstable patients with acute PE (five trials)
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Point/Counterpoint Editorials
did show a significant reduction in PE or death in patients treated with thrombolysis compared with heparin. However, no benefit was seen in the six trials that excluded unstable patients. A meta-analysis of all clinical trials directly comparing recombinant tissue plasminogen activator with heparin in hemodynamically stable patients with acute PE was published in 2009. Five studies involving 464 patients were included. No difference in death related to PE or PE recurrence was seen, even in the subgroup of patients with RV dysfunction.25 An updated Cochrane Review concluded that thrombolytics compared with heparin did not reduce death or PE recurrence in patients with acute PE.26 Recently published guidelines have indicated similar conclusions. In the ninth edition of the Antithrombotic Therapy and Prevention of Thrombosis: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, the expert panel reviewed 13 randomized trials that compared thrombolytic therapy alone to anticoagulant therapy alone and concluded that thrombolysis may be associated with a reduction in mortality and recurrent PE but is associated with an increase in major bleeding.5 Based on the poor quality of the evidence, the panel issued a weak recommendation for thrombolysis in patients with acute PE associated with hypotension who do not have a high risk of bleeding. They reasoned that the high mortality of patients in shock from acute PE justifies the risk of fatal bleeding even if the efficacy of thrombolysis is modest. In most patients with PE without hypotension, the panel recommends against thrombolytic therapy. They do make allowance for physician judgment, however, through the following recommendation: “In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypotension, we suggest administration of thrombolytic therapy.”5 The panel recognizes that there is no explicit prediction rule to identify this subgroup of patients, however, and suggests that such patients be identified on the basis of clinical instability and failure to improve on anticoagulant therapy. Although parameters of RV size and function, as well as cardiac biomarkers, can assist the physician in selecting such patients for thrombolysis, they do not have sufficient predictive power to serve as independent selection criteria. In fact, the panel advises against their routine measurement. The American Heart Association guidelines parallel those of the American College of Chest Physicians. Fibrinolysis is reasonable in patients with massive PE (systolic BP , 90 mm Hg) and acceptable risk of bleeding complications.4 For patients with submassive PE, their recommendation is as follows:
“Fibrinolysis may be considered for patients with submassive PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and low risk of bleeding complications.”4 The facts are that most patients with submassive PE treated with anticoagulation alone have a low risk of dying (probably , 3%).4 The risk of fatal hemorrhage caused by the administration of a thrombolytic agent is on the order of 2%.18,19 Thus, thrombolysis should be used only in patients with more severe compromise, the need for cardiopulmonary capacity, and at low risk of intracranial hemorrhage. Current methodologies are overly sensitive in classifying many patients without substantial compromise as having “submassive PE,” and thus this population, broadly defined, does not clearly benefit from thrombolytic therapy. To date, not a single randomized controlled trial has identified the subgroup of patients with submassive PE whose survival is improved by the administration of thrombolytic therapy. Until that subgroup is defined, patients with submassive PE are best served when the decision to administer a thrombolytic agent is made on a case-by-case basis by thoughtful, wellinformed physicians who carefully weigh the risks and benefits and consider patient preferences, clot burden, acute physiology, comorbidities, need for maximal cardiopulmonary capacity, and bleeding risk. Our position is not contrary to ever giving thrombolytic therapy for submassive PE, but contrary to ever giving thrombolytic therapy for submassive PE as a matter of routine. Kathryn L. Bilello, MD, FCCP Fresno, CA Susan Murin, MD, FCCP Sacramento, CA Affiliations: From the Department of Medicine (Dr Bilello), University of California San Francisco-Fresno Program; the Department of Medicine (Dr Murin), Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, School of Medicine; and the Veterans Affairs Northern California Health Care System (Dr Murin). Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Correspondence to: Susan Murin, MD, FCCP, Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, School of Medicine, 4150 V St, Ste 3400, Sacramento, CA 95817; e-mail: [email protected] © 2013 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.12-2449
References 1. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative
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Pulmonary Embolism Registry (ICOPER) . Lancet. 1999; 353(9162):1386-1389. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation. 2006;113(4):577-582. 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(5):1165-1171. 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. 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(2)(suppl):e419S-494S. Bova C, Pesavento R, Marchiori A, et al; TELESIO Study Group. Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up. J Thromb Haemost. 2009;7(6):938-944. Kreit JW. The impact of right ventricular dysfunction on the prognosis and therapy of normotensive patients with pulmonary embolism. Chest. 2004;125(4):1539-1545. 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(12):1569-1577. 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 metaanalysis. Am J Respir Crit Care Med. 2008;178(4):425-430. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis. Circulation. 2007;116(4):427-433. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med. 2002;347(15):1143-1150. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med. 2005;165(15):1777-1781. Goldhaber SZ. Pulmonary embolism thrombolysis: broadening the paradigm for its administration. Circulation. 1997; 96(3):716-718. Agnelli G, Becattini C, Kirschstein T. Thrombolysis vs heparin in the treatment of pulmonary embolism: a clinical outcomebased meta-analysis. Arch Intern Med. 2002;162(22):2537-2541. Grifoni S, Olivotto I, Cecchini P, et al. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation. 2000;101(24):2817-2822. Kasper W, Konstantinides S, Geibel A, Tiede N, Krause T, Just H. Prognostic significance of right ventricular afterload stress detected by echocardiography in patients with clinically suspected pulmonary embolism. Heart. 1997;77(4):346-349. Stein PD, Beemath A, Matta F, et al. Enlarged right ventricle without shock in acute pulmonary embolism: prognosis. Am J Med. 2008;121(1):34-42.
18. Levine MN. Thrombolytic therapy for venous thromboembolism. Complications and contraindications. Clin Chest Med. 1995;16(2):321-328. 19. Kanter DS, Mikkola KM, Patel SR, Parker JA, Goldhaber SZ. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest. 1997;111(5):1241-1245. 20. Urokinase pulmonary embolism trial. Phase 1 results: a cooperative study. JAMA. 1970;214(12):2163-2172. 21. 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(8844):507-511. 22. 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(8):966-970. 23. Fasullo S, Scalzo S, Maringhini G, et al. 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(1):33-39. 24. 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(6):744-749. 25. Tardy B, Venet C, Zeni F, Coudrot M, Guyomarc’h S, Mismetti P. Short term effect of recombinant tissue plasminogen activator in patients with hemodynamically stable acute pulmonary embolism: results of a meta-analysis involving 464 patients. Thromb Res. 2009;124(6):672-677. 26. Dong BR, Hao Q, Yue J, Wu T, Liu GJ. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2009(3):CD004437.
Rebuttal From Dr Jiménez colleagues Drs Bilello and Murin contend that Mythrombolytics should not be used for submas1
sive pulmonary embolism (PE) using two arguments: (1) Studies have not demonstrated a survival benefit from thrombolysis in patients with acute submassive PE, and (2) studies have not validated an explicit prediction rule for identifying the subgroup of normotensive patients with PE who are at high risk of PE-related complications, in contrast to hemodynamically unstable patients “based upon their high mortality rate and the physiologic rationale that they should benefit from the more rapid dissolution of the clot, and resultant relief of vascular obstruction….”1 I concede that trials have not demonstrated a survival benefit from thrombolysis in patients with submassive PE. However, only one randomized controlled trial (by Jerjes-Sanchez and colleagues2) has provided evidence of a survival benefit of lytic therapy compared with heparin for the initial treatment of patients with PE and cardiogenic shock. In this study of eight randomized patients, none of the four patients who received intrapulmonary streptokinase died, compared with four of the four patients who received intrapulmonary heparin. Interestingly, the four patients in
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Point/Counterpoint Editorials