Do patients with submassive pulmonary embolism benefit from thrombolytic therapy?

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ABSTRACTDespite growing interest in thrombolytic agents to treat submassive pulmonary embolism, their role in this scenario remains controversial. Needed is a way to identify patients with this condition who are at risk of clinical deterioration and who would benefit from thrombolytic therapy. Here, we review the use of thrombolytic agents in submassive pulmonary embolism to help distinguish the risk and benefits of this therapy.


  • Most patients with submassive pulmonary embolism do not need thrombolytic therapy.
  • Identifying patients with submassive pulmonary embolism at highest risk of clinical deterioration can guide physicians to consider thrombolytic therapy.
  • In clinical trials, thrombolytic therapy reduced the rates of secondary outcomes but did not reduce the rate of death in this patient population.



For patients with submassive acute pulmonary embolism—the intermediate category between massive and low-risk—whether to give thrombolytic therapy is controversial. In general, patients with massive pulmonary embolism need this therapy, whereas those with low-risk pulmonary embolism do not—and neither do most of those with submassive embolism. But where should we draw the line?

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More than 600,000 patients suffer pulmonary embolisms every year in the United States, and 50,000 to 200,000 people die of them.1–3 In various studies,4–6 within 1 year, 12.9% of patients had another pulmonary embolism, 7.3% developed chronic venous insufficiency, and 3.8% developed chronic thromboembolic pulmonary hypertension.


Episodes of acute pulmonary embolism are classified as low-risk (about 70% of cases), hemodynamically unstable or massive (5%), or submassive (25%).7,8

Low-risk acute pulmonary embolism is defined by the absence of right ventricular dysfunction and the absence of myocardial necrosis. The death rate in such cases is less than 1%.9 Its pharmacologic management includes parenteral anticoagulation and early initiation of long-term anticoagulation therapy, which the American College of Chest Physicians (ACCP) gives a grade IB recommendation (strong, based on moderate-quality evidence).10

Massive or hemodynamically unstable pulmonary embolism is characterized by any of the following, in the absence of other causes8:

  • Sustained hypotension (systolic blood pressure < 90 mm Hg for ≥ 15 minutes)
  • An absolute decrease in systolic blood pressure of 40 mm Hg or more
  • Need for inotropic support
  • Cardiac arrest
  • Bradycardia (heart rate < 40 beats per minute).

The death rate is more than 30% in patients presenting with shock and approaches 70% in those presenting with cardiac arrest.11,12 Therefore, the consensus is that this category of pulmonary embolism merits aggressive treatment. Systemic thrombolytic therapy is recommended in those who are not at high risk of major bleeding, though the ACCP gives it only a grade 2C recommendation (weak, based on low-quality evidence).10

Submassive pulmonary embolism is defined by evidence of right ventricular dysfunction with normal blood pressure. According to the ACCP guidelines, thrombolytic therapy should be considered (grade 2C recommendation) for patients with acute pulmonary embolism without hypotension and with a low bleeding risk (with no renal failure and not on dual antiplatelet therapy), but at high risk of developing hypotension.10


In managing acute pulmonary embolism, it is critical to recognize whether a patient is at high risk of clinical deterioration.

Blood pressure

The systolic blood pressure not only indicates whether the patient has hypotension (systolic blood pressure < 90 mm Hg) and therefore massive rather than submassive or low-risk pulmonary embolism; it is also important as a baseline value. A decrease in systolic blood pressure of 40 mm Hg or more is associated with worse outcomes.12

Right ventricular dysfunction

The physiologic response to occlusion of the pulmonary arteries can result in early myocardial injury and right ventricular dysfunction, which can be assessed by various methods (Table 1).

Electrocardiographic signs. Right heart strain may be recognized on electrocardiography as:

  • Evidence of new complete or incomplete right bundle branch block
  • T-wave inversion in the anterolateral leads V1 to V4
  • S1Q3T3 (a large S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III, the classic pattern of acute cor pulmonale).13

These findings add incremental prognostic value to echocardiographic findings in patients with submassive pulmonary embolism.14

Cardiac biomarkers such as B-type natriuretic peptide (BNP), N-terminal-pro-BNP (NT-pro-BNP), cardiac troponins, and heart-type fatty acid-binding protein (H-FABP) are also markers of right-sided myocardial damage and strain and can be used to identify patients with submassive pulmonary embolism.15 Abnormal levels of these substances are as follows:

  • Troponin T greater than 0.1 ng/mL
  • Troponin I greater than 0.4 ng/mL
  • BNP greater than 90 pg/mL
  • NT-pro-BNP greater than 500 pg/mL
  • H-FABP less than 6 ng/mL.

These levels have prognostic value, identifying patients with submassive pulmonary embolism at risk of deterioration or death,14,16,17

Echocardiographic signs. Right ventricular dysfunction can be assessed quickly at the bedside with portable transthoracic echocardiography. A meta-analysis showed that close to 37% of hemodynamically stable patients with pulmonary embolism had echocardiographic evidence of right ventricular dysfunction on presentation and a higher short-term mortality rate.18 Evidence of right ventricular dysfunction includes the following:

  • New-onset hypokinesis or akinesis
  • Right ventricular dilation
  • Right ventricular free-wall hypokinesis with apical sparing (the McConnell sign)
  • Paradoxical movement of the interventricular septum
  • Newly increased right ventricular systolic pressure
  • Pulmonary hypertension, defined as tricuspid regurgitation jet velocity greater than 2.8 m/s.15,19

Computed tomographic (CT) angiography is widely available. Findings that have prognostic value in determining those at higher risk of death include the following20,21:

  • A dilated right ventricle—ratio of right ventricle to left ventricle diameter (RV:LV ratio) greater than 0.9
  • Interventricular septal bowing.

PESI and sPESI scores. The European Society of Cardiology 2014 guidelines stratify the risk in normotensive patients with pulmonary embolism according to their score on the Pulmonary Embolism Severity Index (PESI) or the simplified PESI (sPESI). There are five PESI classes. Those in PESI class III or IV or with an sPESI score of 1 or more (on a scale of 0 to 6) are considered at intermediate risk of clinical deterioration and are then further risk-stratified according to whether they have right ventricular dysfunction (based on echocardiography or computed tomography) and elevated cardiac biomarkers. These scoring systems are based on easily obtainable clinical information such as age, male sex, history of cancer, history of heart failure, history of chronic lung disease, heart rate, systolic blood pressure, respiratory rate, temperature, and altered mental status, and calculators are readily available.

Anticoagulation for all, plus thrombolysis for some

Patients with neither right ventricular dysfunction nor elevated cardiac biomarkers are at intermediate to low risk of clinical deterioration, and it is recommended that they be given anticoagulation therapy in an inpatient setting.

On the other hand, patients with both right ventricular dysfunction and elevated cardiac biomarkers are considered at intermediate to high risk of clinical deterioration; they should also be managed with anticoagulation and monitored closely for the need for rescue reperfusion therapy with thrombolytics.22

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