Thrombolysis for acute pulmonary embolism: one size may not fit all!

Thrombolytic agents lead to the activation of plasminogen to plasmin, resulting in accelerated clot lysis. They have been used in a variety of thrombotic disorders, including acute pulmonary embolism (PE). Thrombolytic therapy in acute PE has been clearly established to improve arterial oxygenation, reduce pulmonary artery pressure, and results in resolution of filling defects on the perfusion scan.1 However, thrombolysis carries a relatively increased risk of life-threatening hemorrhagic events compared to anticoagulation alone. How do we decide upon when may thrombolytic therapy be more appropriate compared to anticoagulation alone in patients with acute pulmonary embolism? 

Early, benchmark studies

Several early randomized controlled trials have evaluated the efficacy of thrombolytic therapy in acute pulmonary embolism.2,3 Most of these early studies used streptokinase and demonstrated a consistent mortality benefit with thrombolytic therapy compared to anticoagulation alone. In a subgroup of patients with massive PE, a meta-analysis that included these benchmark studies demonstrated that systemic thrombolytic therapy significantly reduced the composite endpoint of death and recurrent PE.4

Thrombolysis in hypotensive patients

There is a general consensus that thrombolytic therapy is beneficial in patients with acute PE who are hemodynamically unstable. Thrombolytic therapy may also be appropriate in patients who become hemodynamically unstable following an initial period of stability after the commencement of anticoagulant therapy. There are several early studies that compared thrombolysis with anticoagulation alone in patients with acute pulmonary embolism;  these studies demonstrated a consistent benefit with thrombolytic therapy. A recent meta-analysis enrolled patients with acute PE from prospective registries. Among the 1574 patients included in this meta-analysis, the authors found a significant association between hemodynamic instability and short-term all-cause and pulmonary embolism-related mortality. Thrombolytic therapy was associated with lower short term mortality among patients who were hemodynamically unstable.5 Based on available evidence, there is a strong indication for thrombolytic therapy in patients with acute PE who are hypotensive and do not have an increased risk of bleeding. 

Thrombolysis in patients without hypotension

In contrast to patients with acute PE who present with hemodynamic instability, the administration of thrombolytic agents in patients with stable blood pressure is contentious. The Pulmonary Embolism Thrombolysis (PEITHO) trial investigated the effect of a single dose tenecteplase and heparin compared with with heparin alone in acute PE. This study enrolled normotensive patients with right ventricular dysfunction and evidence of myocardial injury suggested by positive cardiac troponin I or troponin T levels. The primary composite outcome of all-cause mortality or hemodynamic decompensation within 7 days of randomization was significantly lower among patients who received the tenecteplase-heparin combination compared to heparin alone. The incidence of extracranial hemorrhage and hemorrhagic stroke was significantly higher among patients who received tenecteplase. Furthermore, rescue thrombolytic therapy seemed to benefit patients who became hemodynamically unstable after initial treatment with anticoagulation alone.6

Kline et al. performed a randomized controlled trial, including 83 patients with acute PE across eight centers in the US. Patients were normotensive, with evidence of right ventricular strain on echocardiography or the presence of elevated levels of biomarkers. Patients received tenecteplase combined with low molecular weight or unfractionated heparin or anticoagulation alone. The primary composite outcome included death, circulatory shock, the requirement for intubation, major bleeding within 5 days, recurrent pulmonary embolism, or an adverse SF36 Physical Component Summary score at 90 days. The composite primary outcome was significantly worse in patients who received anticoagulation alone. This study suggested that thrombolytic therapy with tenecteplase leads to improved clinical outcomes in normotensive patients with submassive pulmonary embolism.

These studies suggest that among patients with acute PE who are not hypotensive, the decision to thrombolyze needs to be individualized. Thrombolytic therapy may benefit patients with submassive PE who develop severe or worsening right ventricular dysfunction and an increase in cardiac biomarkers.

Thrombolysis during cardiopulmonary resuscitation

Does thrombolysis improve outcomes during cardiopulmonary resuscitation? In a retrospective study, acute PE was found to be the underlying cause of cardiac arrest in 4.8% of patients. Return of spontaneous circulation was significantly higher among those who received thrombolytic therapy with tissue plasminogen activator (tPA) compared to those who did not.7 In another retrospective study, patients with cardiac arrest and pulseless electrical activity due to massive PE were administered 50 mg of tPA as an intravenous bolus. Return of spontaneous circulation was observed in all except one of 23 patients who underwent thrombolytic therapy. Besides, a significant reduction in the right ventricular size and pulmonary artery pressure were also observed.8

Abu-Laban et al. randomized patients who suffered cardiac arrest with pulseless electrical activity as the presenting rhythm to receive 100 mg tPA or placebo. There was no difference in the number of patients who had return of spontaneous circulation; only one patient in the study cohort survived to hospital discharge.9

In light of the equivocal evidence, the administration of thrombolytic agents cannot be routinely recommended as part of therapy during cardiopulmonary resuscitation. 

Specific agents, dosing strategies

Recombinant tPA, streptokinase, and recombinant human urokinase have been the most studied thrombolytic agents in acute PE. Tenecteplase and reteplase have also been used in acute pulmonary embolism. Fibrin specific agents bind preferentially to clot-bound plasminogen. Although the superiority of one agent over the other has not been established in acute PE, fibrin specific agents are commonly preferred (Table 1). Thrombolytic therapy is typically administered as an intravenous infusion through a peripheral IV line. Anticoagulant therapy is discontinued during the administration of the thrombolytic agent and commenced when clot lysis occurs and the APTT is less than twice the upper limit of normal. 

Table 1. The dose of commonly used fibrin specific thrombolytic agents in acute PE

Alteplase 100 mg IV over 2 hours
Reteplase 10 units IV bolus, two doses, 30 minutes apart 
Tenecteplase  Less than 60 kg: 30 mg 
60–70 kg: 35 mg
70–80 kg: 40 mg
80–90 kg: 45 mg
More than 90 kg: 50 mg 

Catheter-directed treatment with or without thrombolysis may be appropriate in patients with a high risk of bleeding, when death seems imminent before thrombolytic therapy can take effect, and as rescue therapy after failure of systemic thrombolysis. 

Low-dose thrombolysis

The MOPETT trial addressed the benefit of low-dose thrombolytic therapy in patients with moderate PE (clinical features of PE with more than 70% involvement of 2 or more lobar or main pulmonary arteries on CT-pulmonary angiogram or a high probability ventilation/perfusion scan showing ventilation/perfusion mismatch in 2 or more lobes). Patients were randomized to receive heparin alone or in combination with low-dose tPA. The dose of tPA was 50% of the conventionally accepted dose. Low-dose thrombolytic therapy resulted in a lower incidence of pulmonary hypertension, lower pulmonary systolic pressures, and a more rapid resolution of pulmonary hypertension, with similar rates of bleeding.10 Kiser et al. performed a retrospective cohort study among patients who received half dose (50 mg) compared to a full dose of alteplase. Propensity matching was carried out to eliminate confounders and hospital-level clustering. The use of half dose alteplase did not result in a significant difference in mortality or the incidence of major bleeding; however, escalation of therapy was more often required with the lower dose.11  The use of reduced-dose thrombolytic therapy requires more robust evidence of efficacy before it can be recommended as a routine treatment modality. 

The bottom line

  • In hypotensive patients with acute PE, without an increase in the risk of bleeding, there is robust evidence to support thrombolytic therapy. 
  • Among patients who are not hypotensive, the decision to thrombolyze needs to be individualized. Thrombolytic therapy may benefit in patients with submassive PE with severe or worsening right ventricular dysfunction and an increase in cardiac biomarkers. It may also be appropriate to administer thrombolytic therapy among patients who remain normotensive but deteriorate otherwise after the commencement of anticoagulant therapy.
  • Patients with acute PE who remain normotensive following cardiopulmonary resuscitation may also benefit from thrombolytic therapy. 
  • Extensive clot burden or the presence of a free-floating thrombus in the right atrium or ventricle are unsubstantiated, but possibly beneficial indications for thrombolysis.
  • It may be reasonable to consider thrombolytic agents in patients who develop recurrent PE while on anticoagulant therapy. 

References

1.         Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026

2.         Jerjes-Sanchez  null, Ramírez-Rivera  null, de Lourdes García M  null, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis. 1995;2(3):227-229. doi:10.1007/bf01062714

3.         Ly B, Arnesen H, Eie H, Hol R. A controlled clinical trial of streptokinase and heparin in the treatment of major pulmonary embolism. Acta Med Scand. 1978;203(6):465-470. doi:10.1111/j.0954-6820.1978.tb14909.x

4.         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. doi:10.1161/01.CIR.0000137826.09715.9C

5.         Quezada CA, Bikdeli B, Barrios D, et al. Meta-analysis of prevalence and short-term prognosis of hemodynamically unstable patients with symptomatic acute pulmonary embolism. Am J Cardiol. 2019;123(4):684-689. doi:10.1016/j.amjcard.2018.11.009

6.         Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. doi:10.1056/NEJMoa1302097

7.         Kürkciyan I, Meron G, Sterz F, et al. Pulmonary embolism as a cause of cardiac arrest: presentation and outcome. Arch Intern Med. 2000;160(10):1529-1535. doi:10.1001/archinte.160.10.1529

8.         Sharifi M, Berger J, Beeston P, et al. Pulseless electrical activity in pulmonary embolism treated with thrombolysis (from the “PEAPETT” study). Am J Emerg Med. 2016;34(10):1963-1967. doi:10.1016/j.ajem.2016.06.094

9.         Abu-Laban RB, Christenson JM, Innes GD, et al. Tissue plasminogen activator in cardiac arrest with pulseless electrical activity. N Engl J Med. 2002;346(20):1522-1528. doi:10.1056/NEJMoa012885

10.       Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. doi:10.1016/j.amjcard.2012.09.027

11.       Kiser TH, Burnham EL, Clark B, et al. Half-Dose Versus Full-Dose Alteplase for Treatment of Pulmonary Embolism*: Crit Care Med. 2018;46(10):1617-1625. doi:10.1097/CCM.0000000000003288

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