Chapter 69: Thrombolytic Therapy for Submassive Pulmonary Embolism

Acute pulmonary embolism (PE) remains the most frequent and potentially fatal venous thromboembolic event. It is estimated that 100,000 to 180,000 deaths occur annually in the United States from acute PE. The outcome of acute PE depends on both the severity of pulmonary arterial obstruction and the presence and severity of preexisting cardiopulmonary disease in the patient. Acute PE can be classified as massive or submassive. Massive PE accounts for 5% of patients with acute PE and is associated with hypotension (defined as systolic blood pressure [SBP] less than 90 mm Hg or a decrease in SBP of 40 mm Hg or more from baseline) and frequently results in acute right ventricular (RV) failure. Submassive PE accounts for approximately 20% to 25% of patients with acute PE and is associated with normotension and evidence of RV dysfunction including RV enlargement documented by transthoracic echocardiography or computed tomographic (CT) pulmonary angiography and elevated biomarkers of myocardial injury (troponins I or T- and B-type natriuretic peptide [BNP]).^1,2,3

The recent guidelines from the American College of Chest Physicians and American Heart Association recommend treatment with thrombolytic agents for patients with acute massive PE who present with persistent hypotension and do not have a high bleeding risk.^4,5 Several studies have demonstrated that thrombolytic therapy offers angiographic and hemodynamic benefits compared with standard heparin anticoagulation for patients with acute PE.^4,5 The most studied thrombolytic agents for the treatment of PE are recombinant-tissue-type plasminogen activator (TPA, alteplase), streptokinase, and recombinant human urokinase. Other agents include tenecteplase, and reteplase. Absolute contraindications include any prior intracranial hemorrhage, known structural intracranial cerebrovascular disease (eg, arteriovenous malformation), known malignant intracranial neoplasm, ischemic stroke within 3 months, suspected aortic dissection, active bleeding or bleeding diathesis, recent surgery encroaching on the spinal canal or brain, and recent significant closed-head or facial trauma with radiographic evidence of bony fracture or brain injury.⁴

The use of thrombolytic therapy in patients with submassive PE remains controversial. This chapter will discuss the role of thrombolytic therapy in submassive PE focusing on risk stratification and the complex decision to administer systemic thrombolysis in patients with acute submassive PE.

In recent years, there has been an increased appreciation of the need for risk stratification of patients with acute submassive PE who are hemodynamically stable but with evidence of RV dysfunction.⁶ In these patients, RV dysfunction is defined as the presence of at least one of the following: RV dilatation (apical 4-chamber RV diameter/left ventricular [LV] diameter more than 0.9 on echocardiography or chest CT, or RV systolic dysfunction on echocardiography); elevation of BNP more than 90 pg/mL or N-terminal pro-BNP more than 500 pg/mL; or electrocardiographic changes including new complete or incomplete right bundle branch block, anteroseptal ST-segment elevation or depression, or anteroseptal T-wave inversion. Myocardial necrosis is defined as either elevation of troponin I (> 0.4 ng/mL) or troponin T (> 0.1 ng/mL).^4,5 Several studies have shown a 2- to 2.5-fold increased risk of mortality in patients with normal BP and RV dysfunction compared with those without RV dysfunction.^4,5

Imaging of the RV with echocardiography detects the changes occurring in the morphology and function of the RV as a result of acute pressure overload in PE.⁶ Echocardiography also allows for estimation of pulmonary artery pressure. Echocardiographic findings in patients with acute PE include RV hypokinesis and dilatation, interventricular septal flattening and paradoxical motion toward the left ventricle, tricuspid regurgitation, pulmonary hypertension, and loss of inspiratory collapse of the inferior vena cava.¹ Several studies including registries have demonstrated an association between echocardiographic parameters of RV dysfunction and a poor in-hospital outcome.^6,7,8 Nevertheless, the prognostic value of echocardiography in hemodynamically stable patients appears moderate at best, primarily due to the poor standardization of echocardiographic criteria.^7,8 In a prospective randomized trial, Konstantinides et al reported that normotensive patients with submassive PE defined by echocardiography appeared to have a low early mortality risk, regardless of whether they received thrombolysis plus heparin or heparin alone.⁹

Four-chamber views of the heart on multidetector-row chest CT may, besides visualizing the thrombi in the pulmonary vasculature, also detect RV enlargement and (indirectly) dysfunction.⁷ In an international prospective cohort study, Becattini et al confirmed the prognostic value of an enlarged right ventricle on CT in patients with acute PE.¹⁰ However, RV dilatation on CT has been shown to have resulted in only a small ability to classify risk in these patients.¹¹

Elevated levels of cardiac biomarkers (troponins I or T and BNP), in combination with the presence of RV dilatation or hypokinesis on echocardiography significantly helps with risk stratification for acute PE.^{12,13,14,15,16} Elevated troponins are often found in hemodynamically stable patients with echocardiographic signs of RV overload suggesting myocardial injury.² Pruszczyk and colleagues found that an elevated troponin T level more than 0.01 ng/mL was the only parameter to predict adverse events in normotensive patients with acute PE.¹³ In a multicenter, multinational study, the high-sensitivity troponin was examined in 526 normotensive patients with PE and demonstrated a high negative predictive value (98%).¹⁴ Similarly, a meta-analysis of 1132 patients showed that 51% of patients with an acute PE had elevated BNP or NT-pro-BNP and were associated with increased early death and complications during hospitalization.¹⁵ However, the positive predictive value of BNP or NT-pro-BNP for higher risk has been rather low.

Heart-type fatty acid-binding protein and growth differentiation factor-15 are 2 promising new cardiac biomarkers that have been shown to provide relevant prognostic information in patients with non-high-risk PE.⁶ Both of these biomarkers increase sharply after pressure overload or myocardial ischemia and are undergoing further study.

The most extensively validated clinical score for risk stratification of patients presenting with PE is the Pulmonary Embolism Severity Score (PESI).^17,18 The PESI allows the clinician to rule out an adverse outcome by having a high negative predictive value at the lowest level of PESI classes. The score is however complex to calculate. A more practical approach is the use of the simplified PESI (sPESI) score with 6 parameters: age more than 80 years, history of cancer, history of either heart failure or chronic lung disease, systolic BP less than 100 mm Hg, heart rate more than 110 beats/min, and an arterial oxyhemoglobin saturation less than 90%.¹⁹

The hemodynamic status of the patient with PE is the most significant predictor of mortality in the short term. Early mortality rates for PE range from 3% in clinically stable patients to 58% in patients with cardiogenic shock.²⁰ If the patient survives the initial presentation of PE, the most common cause of death during the first month is PE-associated RV dysfunction.²¹ Cardiac failure from PE is due to a combination of the increased wall stress and cardiac ischemia that compromise RV function and impair LV output.²² The development of recurrent PE or progression of RV dysfunction in patients with submassive PE may lead to hemodynamic collapse, even though these patients may have initially presented with hemodynamic stability. Thus the practice of evaluating risk in patients with PE based solely upon the presence of hypotension may neglect key prognostic features and may delay further prognostic testing and initiation of more appropriate therapy.²² Risk stratification is therefore, paramount to differentiate between subsets of patients.

The outcomes of patients with PE who have received thrombolytic therapy have been reviewed from 4 large registries: Management Strategy And Prognosis of Pulmonary Embolism Registry (MAPPET), International Cooperative Pulmonary Embolism Registry, Registro Informatizado de la Enfermedad TromboEmbolica, and Emergency Medicine Pulmonary Embolism in the Real-World Registry (EMPEROR).^4,5,20,23 These registries have reported a trend toward a decrease in all-cause mortality from PE, especially massive PE in those patients who received thrombolytic therapy. The 30-days mortality from PE in normotensive patients in the EMPEROR was 0.9% (95%CI: 0%-1.6%).²³ The recently completed Prognostic Value of Multidetector CT Scan in Hemodynamically Stable Patients With Acute Symptomatic Pulmonary Embolism study of normotensive patients with acute PE showed a 30-days PE-related mortality of 1.3% (95%CI: 0.5%-2.1%).²⁴ Overall, these studies have showed that short-term mortality directly attributable to submassive PE in patients treated with heparin anticoagulation is less than 3%. The investigators have concluded that even if adjunctive thrombolytic therapy has an extremely high efficacy (eg, 30% relative reduction in mortality), the effect size on mortality due to submassive PE is probably less than 1%. They propose that secondary outcome measures such as persistent RV dysfunction and chronic thromboembolic pulmonary hypertension (CTEPH), and impaired quality of life be used as important surrogate goals of treatment.^4,22 CTEPH is a rare but serious complication, affecting patients who survive acute PE. It can cause severe RV dysfunction and is often lethal. The etiology of CTEPH is unclear but proposed mechanisms include intricate and complex interactions involving thrombotic and thrombolytic processes and cellular remodeling confounded by various predisposing risk factors.^4,25

A prospective evaluation of RV function and functional status 6 months after acute submassive PE showed that in patients who received heparin only, 27% demonstrated an increase in RV systolic pressures (RVSP) at 6-months follow-up, and 46% had either dyspnea at rest or exercise intolerance.²⁶ Interestingly, not a single patient treated with TPA showed an increase in RVSP suggesting that thrombolytic therapy may have benefit in reducing the incidence of CTEPH. More recently, the results of the Moderate Pulmonary Embolism Treated with Thrombolysis trial showed that the incidence of pulmonary hypertension was lower in patients who received TPA and concomitant anticoagulation with reduced-dose enoxaparin or unfractionated heparin than in the standard anticoagulation group (16% vs 57%, P < 0.001). There were no in-hospital bleeding events reported in either group.²⁷

Three randomized controlled trials (RCTs) were specifically aimed to address the patients with submassive PE benefit from thrombolytic therapy: MAPPET-3, Tenecteplase Italian Pulmonary Embolism Study (TIPES), and the Pulmonary Embolism Thrombolysis (PEITHO) trials.^9,28,29 Of note, tenecteplase is not approved by the Food and Drug Administration in the United States for the treatment of PE.

In the MAPPET-3 trial, 256 hemodynamically stable patients with acute submassive PE were randomized to receive intravenous (IV) recombinant TPA 100 mg over 2 hours followed by unfractionated heparin infusion or placebo TPA plus heparin anticoagulation.⁹ The primary endpoint was in-hospital death or clinical deterioration requiring escalation of therapy defined as catecholamine infusion, rescue fibrinolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy. The investigators found that compared with heparin anticoagulation alone, thrombolytic therapy resulted in a significant reduction in the primary endpoint (10.2% vs 24.6%, P = 0.004). They ascribed the difference in the primary endpoint to a higher frequency of escalation of therapy in patients randomized to heparin anticoagulation alone compared to those treated with TPA. Both groups had low rates of major bleeding, although the heparin treatment group, surprisingly, had a trend toward more major bleeding episodes compared to the TPA-treatment group (3.6% vs 0.8%, P = 0.29).⁹

The TIPES trial randomized 58 patients to receive weight-adjusted single-bolus IV tenecteplase or placebo.²⁸ The primary efficacy endpoint was reduction of RV dysfunction on echocardiography at 24 hours. The investigators found that in the tenecteplase group, there was a 0.31 ± 0.08 reduction of the right-to-left ventricle end-diastolic dimension ratio at 24 hours versus a reduction of 0.10 ± 0.07 in the placebo group (P = 0.04). At 30 days, 1 patient randomized to tenecteplase suffered a clinical event (recurrent PE), versus 3 patients randomized to placebo (1 recurrent PE, 1 clinical deterioration, and 1 non-PE-related death). Two nonfatal major bleedings occurred with tenecteplase (1 intracranial), and 1 occurred with placebo.

The PEITHO trial was a prospective, multicenter, double-blind, placebo-controlled randomized trial of thrombolysis with a single-bolus injection of tenecteplase plus heparin versus placebo plus heparin in normotensive patients with submassive PE.^29,30 Eligible patients were those with acute symptomatic PE confirmed by CT pulmonary angiography and RV dysfunction on echocardiography or CT plus evidence of myocardial injury with a positive troponin I or T value. The primary outcome was the composite of death from any cause or hemodynamic collapse within 7 days of randomization. A total of 1005 patients were included in the intention-to-treat analysis. The investigators found that a single-bolus injection of tenecteplase resulted in a significantly lower risk of early death or hemodynamic decompensation (2.6%) versus 5.6% in the placebo plus heparin group. However, tenecteplase was also associated with a 2% rate of hemorrhagic stroke and a 6.3% rate of major extracranial hemorrhage versus 0.2% and 1.2% in the placebo plus heparin group.

More recently, Kucher et al reported the results of the Ultrasound Accelerated Thrombolysis of Pulmonary Embolism trial.³¹ This trial randomized 59 patients with acute main or lower lobe PE and echocardiographic evidence of RV dysfunction to receive unfractionated heparin and an ultrasound-assisted catheter-directed thrombolysis (USAT) regimen of 10 to 20 mg recombinant TPA over 15 hours or unfractionated heparin alone. The primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. The authors found that a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications. However, the study had several limitations including the lack of a thrombolysis control group without ultrasound, possible selection bias, lack of monitoring of quality of anticoagulation therapy with dose adjustments of heparin (based on activated partial thromboplastin time levels) and of vitamin K antagonists (based on international normalized ratio values), poor quality of the echocardiographic images in some patients and the lack of assessment of residual embolic burden by repeated contrast-enhanced CT.³⁰

To date, there has been no adequately powered RCT that has demonstrated that the survival of patients with submassive PE is improved with the administration of thrombolytic therapy. Furthermore, there is currently no validated prediction rule that can identify the subgroup of patients with submassive PE who are at high risk for PE-related complications and who may benefit from thrombolysis. We believe that select patients with acute submassive PE who have severe RV dysfunction on echocardiography and myocardial injury (elevated troponin or BNP levels) and who are at low risk of bleeding complications may be considered for thrombolytic therapy. Ultimately, as other experts have suggested, clinicians should weigh the risks and benefits, consider the patients’ preferences, clot burden, acute physiology, comorbidities, and bleeding risk on a case-by-case basis when deciding to use thrombolytic therapy for patients with submassive PE.³¹