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Point: Should Systemic Lytic Therapy Be Used for Submassive Pulmonary Embolism? YesLytic Therapy for Pulmonary Embolism? Yes FREE TO VIEW

David Jiménez, MD, PhD
Author and Funding Information

From the Respiratory Department, Ramón y Cajal Hospital, Instituto Ramón y Cajal de Investigación Sanitaria.

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


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.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2013;143(2):296-299. doi:10.1378/chest.12-2447
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Early mortality rates for pulmonary embolism (PE) range from <3% in clinically stable patients to 58% in patients with cardiogenic shock.1 The various mortality rates reported among studies illustrate the heterogeneous clinical and prognostic spectrum in patients with PE.

Studies have provided evidence of PE-associated right ventricular (RV) dysfunction as the most common cause of death during the first 30 days after the diagnosis of PE.2,3 The initial PE, recurrent PE, or underlying cardiopulmonary disease may initiate or exacerbate the cascade of events. Cardiac failure from PE results from a combination of the increased wall stress and cardiac ischemia that compromise RV function and impair left ventricular output. The degree of increase in RV impedance is related predominantly to the interaction of the mechanical obstruction and the underlying cardiopulmonary status.4

An understanding of the pathophysiology of PE provides the rationale for some components of the risk stratification of patients with acute PE. Hemodynamic status at the time of presentation with acute PE has the strongest prognostic implications for short-term mortality.1 Massive PE (ie, high-risk PE), characterized by the presence of PE-associated arterial hypotension or shock, accounts for 5% of all cases of PE and has a short-term mortality of at least 15%.3 However, a subset of patients who initially present with hemodynamic stability have a mortality risk similar to that of patients who present with shock.5 The development of recurrent PE or the progression of RV dysfunction may lead to hemodynamic compromise and death in these patients, who had hemodynamic stability on initial presentation.6 Thus, the long-standing approach to assessing risk in patients with PE based solely on systemic arterial pressure may miss the identification of key prognostic features and may delay further prognostic testing and implementation of more appropriate therapy. In this scenario, risk stratification becomes critical to distinguish among these different categories of patients.7,8

The application of risk stratification tools may help guide therapy for patients with acute PE. Patients at high risk of death may potentially benefit from thrombolytic therapy. Patients treated with a systemic IV fibrinolytic agent for acute PE have faster restoration of lung perfusion than do those treated with IV heparin.9,10 At 24 h after the initiation of thrombolytic therapy, patients treated with IV heparin and adjunctive IV fibrinolysis manifest a 30% to 35% reduction in total perfusion defect, whereas patients treated with IV heparin alone have no substantial improvement in pulmonary blood flow. However, by day 7, blood flow improves to a similar degree (65%-70% reduction in total defect) in those treated with heparin. Although thrombolysis has angiographic and hemodynamic benefits compared with standard therapy with IV heparin for patients with acute PE, studies have not convincingly demonstrated the superiority of thrombolysis on clinical outcomes.

In the absence of large randomized clinical trials that demonstrate the benefit of thrombolytic therapy on mortality, the 2012 American College of Chest Physicians guidelines suggested the use of thrombolytic therapy for patients with acute symptomatic PE and hemodynamic instability who do not have major contraindications owing to bleeding risk (grade 2C).11 For patients with submassive (ie, intermediate-risk) PE, controversy exists regarding the use of thrombolytics.

Two trials have specifically assessed the effect of thrombolysis in patients with submassive PE: Management Strategies and Prognosis of Pulmonary Embolism Trial-3 (MAPPET-3)12 and Tenecteplase Italian Pulmonary Embolism Study (TIPES)13 (Table 1). In the MAPPET-3 multicenter, randomized, double-blind, placebo-controlled study, Konstantinides and colleagues12 evaluated the effect of alteplase on the clinical outcome of patients with submassive PE. The study randomized 256 hemodynamically stable patients with acute PE and either pulmonary hypertension (defined as a tricuspid regurgitant jet velocity >2.8 m/s, present in 68.8% of the enrolled patients) or RV dysfunction (defined as RV enlargement combined with loss of inspiratory collapse of the inferior vena cava, present in 31.2% of the enrolled patients) to receive IV recombinant tissue plasminogen activator, 100 mg over 2 h, followed by unfractionated heparin infusion, or placebo tissue plasminogen activator plus heparin anticoagulation. The study used in-hospital death or clinical deterioration requiring escalation of therapy (defined as catecholamine infusion, rescue fibrinolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy) as the primary end point. Compared with heparin anticoagulation alone, fibrinolysis resulted in a significant reduction in the primary end point (10.2% vs 24.6%, P = .004). Mortality did not differ between the randomized treatment groups. The study attributed the difference to a higher frequency of escalation of therapy in patients randomized to anticoagulation with heparin alone compared with those treated with fibrinolysis. Both randomized treatment groups had low rates of major bleeding, although the heparin treatment group, surprisingly, had a trend toward more major bleeding compared with the thrombolysis treatment group (3.6% vs 0.8%, P = .29).

Table Graphic Jump Location
Table 1 —Randomized Clinical Trials Comparing Thrombolytics and Heparin in Patients With Acute Submassive PE

PE = pulmonary embolism; RR = relative risk.

In the TIPES multicenter, randomized, double-blind, placebo-controlled study, Becattini et al13 evaluated the effect of tenecteplase on RV dysfunction assessed by echocardiography in hemodynamically stable patients with submassive PE. The study defined RV dysfunction as the right/left ventricle end-diastolic dimension ratio >1 in the apical four-chamber view and/or >0.7 in the parasternal long axis, both in the absence of right ventricle hypertrophy. The study randomized patients to receive weight-adjusted single-bolus IV tenecteplase or placebo. All patients received IV unfractionated heparin. An independent committee, blinded to treatment allocation, evaluated echocardiograms for the primary efficacy end point of reduction of RV dysfunction at 24 h. In the 58 randomized patients, the tenecteplase group had a 0.31±0.08 reduction of the right to left ventricle end-diastolic dimension ratio at 24 h in comparison with a reduction of 0.10±0.07 in the placebo group (P = .04). At 30 days, one patient randomized to tenecteplase suffered a clinical event (recurrent PE), in comparison with three patients randomized to placebo (one recurrent PE, one clinical deterioration, and one non-PE-related death). Two nonfatal major bleedings occurred with tenecteplase (one intracranial), and one occurred with placebo. Because the published randomized trials have not shown a survival benefit of thrombolysis for patients with submassive acute PE (hemodynamically stable, but associated with RV dysfunction), why do some physicians favor this approach?

Different groups of investigators have not agreed on standard definitions for echocardiographic findings of RV dysfunction14 (Table 2). In most thrombolytic trials, investigators used a single echocardiographic criterion to assess RV dysfunction, which demonstrated a low positive predictive value for PE-related in-hospital death. Thus, researchers should combine echocardiographic criteria to identify those patients with more severe RV dysfunction at the highest risk of clinical deterioration and PE-related mortality.

Table Graphic Jump Location
Table 2 —Echocardiographic Criteria for Right Ventricular Dysfunction

Patients with acute PE in association with RV dysfunction and preserved systemic arterial BP should undergo further risk stratification to identify subgroups at the highest risk of clinical deterioration because they may benefit the most from the administration of thrombolytic therapy. Some studies have investigated the prognostic role of the combination of a simple laboratory test (ie, measurement of the levels of a cardiac biomarker) and a noninvasive imaging method such as echocardiography. A study of 591 normotensive patients given a diagnosis of PE assessed the test characteristics of cardiac troponin I, transthoracic echocardiography, and lower-limb ultrasound testing for prediction of 30-day PE-related mortality.15 A three-test strategy that combined all modalities (echocardiography, troponin, and lower-limb ultrasound testing) and assessed RV dysfunction, myocardial injury, and thrombus burden had a trend toward improved prediction of PE-related death in comparison with the use of any test by itself.

The Multicenter Emergency Medicine Pulmonary Embolism in the Real World Registry (EMPEROR) of normotensive patients with acute PE demonstrated a 0.9% (95% CI, 0%-1.6%) 30-day mortality rate that the investigators directly attributed to PE.16 The recently completed Prognostic Value of Multidetector CT Scan in Hemodynamically Stable Patients With Acute Symptomatic Pulmonary Embolism (PROTECT) study of normotensive patients with acute PE showed a 30-day PE-related mortality of 1.3% (95% CI, 0.5%-2.1%).17 Data from these and other studies indicate that patients with submassive PE, treated with IV heparin in various settings throughout the world, have a short-term mortality rate directly attributable to PE of <3.0%. These data imply that even if adjunctive fibrinolytic therapy has extremely high efficacy (eg, a 30% relative reduction in mortality), it probably has a <1% effect size on mortality due to submassive PE. Thus, improvement in secondary outcomes, such as quality of life and quality-adjusted survival, and surrogate outcomes of decreases in escalation rates of therapy, persistent RV dysfunction, and chronic thromboembolic pulmonary hypertension represent other important goals of treatment.18

The risk of major bleeding, in particular intracranial hemorrhage, raises great concern about the use of thrombolytics. Pooled data from controlled thrombolysis trials of patients with acute PE, which compared either thrombolysis with heparin alone or different thrombolytic regimens with each other, revealed a 13% cumulative rate of major bleeding and a 1.8% rate of intracranial/fatal hemorrhage associated with thrombolysis.19 More recent trials have had lower rates of major hemorrhage in comparison with older trials,9,12 in agreement with the notion that thrombolysis-related bleeding rates may be lower when noninvasive imaging methods (instead of pulmonary angiography with a pulmonary artery catheter puncture site in a central vein such as the femoral vein) are used to diagnose PE.

The ongoing Pulmonary Embolism International Thrombolysis Trial (PEITHO) (NCT00639743) plans to enroll 1,000 normotensive patients who have an acute symptomatic PE associated with RV dysfunction (detected by echocardiography or CT scan) and evidence of myocardial injury (indicated by a positive troponin test).20 The study randomizes patients to treatment with (1) IV tenecteplase followed by IV heparin or (2) IV placebo followed by IV heparin. The study uses a primary clinical end point of all-cause mortality or hemodynamic collapse within 7 days after treatment.20

While awaiting the results of this trial, I consider using thrombolysis (of note, only in the absence of contraindications) for normotensive patients with acute PE who have severe RV dysfunction, myocardial injury, and concomitant proximal DVT at the time of PE diagnosis. This practice may prevent major complications, including the need for emergency thrombolysis due to rapid deterioration, within the first few days after the PE diagnosis.

Although studies have not shown a survival benefit from thrombolytic treatment in patients with acute submassive PE, one study does suggest that lysis prevents clinical deterioration and the need for escalation of care. Because of differences in patients’ preferences, values, and risk-benefit ratios, physicians should decide about the use of thrombolysis on a case-by-case basis. In patients with submassive PE, those who have signs of increased cardiac dysfunction and greater clot burden may have a greater likelihood of benefitting from thrombolytic therapy than do those without these findings.

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. [CrossRef] [PubMed]
 
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 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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Torbicki A, Perrier A, Konstantinides SV, et al;; ESC Committee for Practice Guidelines (CPG) 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. [CrossRef] [PubMed]
 
Jiménez D, Aujesky D, Yusen RD. Risk stratification of normotensive patients with acute symptomatic pulmonary embolism. Br J Haematol. 2010;151(5):415-424. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators 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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Steering CommitteeSteering 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. [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Randomized Clinical Trials Comparing Thrombolytics and Heparin in Patients With Acute Submassive PE

PE = pulmonary embolism; RR = relative risk.

Table Graphic Jump Location
Table 2 —Echocardiographic Criteria for Right Ventricular Dysfunction

References

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. [CrossRef] [PubMed]
 
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 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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Torbicki A, Perrier A, Konstantinides SV, et al;; ESC Committee for Practice Guidelines (CPG) 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. [CrossRef] [PubMed]
 
Jiménez D, Aujesky D, Yusen RD. Risk stratification of normotensive patients with acute symptomatic pulmonary embolism. Br J Haematol. 2010;151(5):415-424. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W; Management Strategies and Prognosis of Pulmonary Embolism-3 Trial Investigators 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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
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. [CrossRef] [PubMed]
 
Steering CommitteeSteering 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. [CrossRef] [PubMed]
 
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