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The role of thrombolysis in submassive PE remains controversial to date. In this podcast, Dr Chacko & I dive deeper to explore the current evidence on this topic.
What is Submassive PE and what are the key differences between Submissive and Massive PE
The terms massive, submassive, and low-risk PE have been coined to risk stratify PE based on the likelihood of mortality. Massive PE is characterized by sustained hypotension with a systolic pressure of < 90 mm for >15 minutes or the requirement for vasopressor support. A submassive PE does not cause hypotension but causes right heart strain, dilation, dysfunction, or ischemia. The RV function is assessed by echocardiography; RV dilation (RV/LV ratio of > 0.9) may be assessed by CT or echocardiography. Raised levels of biomarkers (brain natriuretic peptide or troponin) also categorize PE as being submassive. Submassive PE may also lead to electrocardiographic changes including a new-onset complete or incomplete right bundle branch block, anteroseptal ST changes, or anteroseptal T-wave inversion. Low-risk PE is characterized by normal blood pressure and right heart function.
What are the different options to treat submissive PE?
There is an ongoing debate regarding how best to risk stratify and escalate treatment in patients with submassive PE. Submassive PE is associated with normal blood pressure and lower mortality risk compared to massive PE. However, RV involvement may be associated with higher mortality. It is challenging to identify patients who may improve with anticoagulation alone and those who might deteriorate and might require treatment escalation. Treatment escalation with thrombolysis carries a higher risk and adds to the cost of care. Thus, a fine balance needs to be struck between the benefit of therapy vs. harm. If escalation of treatment is warranted, the options available include thrombolytic therapy with alteplase or tenecteplase, surgical embolectomy, and catheter-directed thrombolysis.
What are the advantages and disadvantages of using thrombolysis for submissive PE?
Thrombolytic therapy for massive PE is supported by robust evidence and is a widely established modality of care. The thrombolytic strategy has been clearly shown to reduce mortality and prevent recurrence of PE compared to anticoagulation alone. However, thrombolytic therapy for submassive PE is steeped in controversy.
What are the possible benefits of thrombolytic therapy in submassive PE? One of the putative benefits is an early reduction in the pulmonary vascular resistance, relief of RV strain, thereby reducing the risk of RV failure. Preservation of RV function may prevent cardiovascular collapse and reduce the risk of death. However, the use of thrombolysis may be associated with a significant risk of bleed, especially, intracranial hemorrhage. The actual risk of intracranial bleed is difficult to quantify from the evidence available and would depend on the clinical situation and the presence of a predisposing risk for hemorrhage. There is also an emerging school of thought that suggests that a lower thrombolytic dose (alteplase, 12–50 mg) may mitigate the rise in PA pressure and reduce the risk of death. From the available evidence, the risk of intracranial bleed is roughly around 1%. Overall, patients at a high risk of death from submassive PE (>5%) may benefit from thrombolytic therapy. However, predicting mortality risk by the bedside may not be easy.
What’s the evidence out there either in favor of or against the use of thrombolysis in submissive PE?
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 combined with heparin alone in acute PE. This study enrolled 1006 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.1 Three-year follow-up data from the PEITHO study showed no long-term mortality benefit or difference in the incidence of chronic thromboembolic pulmonary hypertension in either group.
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.2
Meta-analyses of thrombolytic therapy in submassive PE have come up with contrasting findings. Chatterjee et al., in a meta-analysis of 1,775 patients, showed a mortality benefit with thrombolysis with an increased risk of major bleeding (9.24%) and intracranial hemorrhage (1.46%).3 In another meta-analysis, which included 1,833 patients, no mortality benefit was observed with an increased risk of major bleeding (5.9%) and intracranial hemorrhage (1.74%).4
These studies suggest that among patients with acute PE who are not hypotensive, the decision to thrombolysis needs to be individualized. Thrombolytic therapy may benefit patients with submassive PE in the higher risk strata with severe or worsening right ventricular dysfunction and an increase in cardiac biomarkers.
What’s your current practice?
We try to individualize treatment based on a balance between benefit vs. possible harm. If there is clear evidence of RV dilatation or dysfunction on echocardiography, we would generally thrombolysis them, provided there are no obvious contraindications. The RV function is assessed using TAPSE on echocardiography. We would also use thrombolysis as a rescue measure in patients who had normal RV at initial presentation but show evidence of deterioration while on anticoagulant treatment. Besides, we have also been using reduced-dose thrombolytic therapy in submassive PE with alteplase 50 mg in some patients based on the risk profile on clinical presentation.
There is not enough evidence to recommend thrombolysis in submassive PE. New avenues such as embolectomy with or without partial thrombolysis depending upon close monitoring of RV strain may be the future treatment. However, we strongly recommend individualizing this treatment rather than applying one size fits all approach.
1. 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
2. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost JTH. 2014;12(4):459-468. doi:10.1111/jth.12521
3. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-2421. doi:10.1001/jama.2014.5990
4. Riera-Mestre A, Becattini C, Giustozzi M, Agnelli G. Thrombolysis in hemodynamically stable patients with acute pulmonary embolism: a meta-analysis. Thromb Res. 2014;134(6):1265-1271. doi:10.1016/j.thromres.2014.10.004