Do patients with submassive pulmonary embolism benefit from thrombolytic therapy?
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.
KEY POINTS
- 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.
THROMBOLYTIC AGENTS
Thrombolytic agents are the cornerstone of management for patients presenting with pulmonary embolism who are at high risk. As noted above, these agents are recommended in massive pulmonary embolism, but their role in submassive pulmonary embolism remains controversial.
Thrombolytics work by activating endogenous plasminogen. The resulting plasmin promotes clot lysis, reducing the size of the thrombus, decreasing pulmonary vasculature resistance, and improving right ventricular function.23
To date, three thrombolytic agents have received US Food and Drug Administration approval for use in massive pulmonary embolism: alteplase, urokinase, and streptokinase. But only alteplase is still available in the United States. Alteplase is also the best tolerated, whereas streptokinase is highly antigenic and may cause further deterioration in an already unstable patient. Alteplase is also the most fibrin-specific and is considered the most potent of the three agents.24
Additional thrombolytic agents under investigation for use in acute pulmonary embolism include reteplase, tenecteplase, and desmoteplase. These agents are more fibrin-specific than alteplase. Reteplase is a second-generation recombinant tissue-type plasminogen activator with a quicker onset of action and longer half-life than alteplase, allowing for bolus dosing. Tenecteplase, a variant of alteplase, is cleared more slowly and is 14 times more fibrin-specific than alteplase, also allowing for bolus dosing. Desmoteplase, a fibrin-specific agent currently in phase 2 trials, also has a longer half-life and appears to be more potent than alteplase. Table 2 lists the dosing and the degree of fibrin specificity of these agents.
Complications of thrombolytic therapy
Submassive pulmonary embolism has a low death rate, and the benefit of systemic thrombolytic therapy for this condition is controversial. Therefore, risk stratification is very important before pursuing this therapy.
A meta-analysis25 of 16 randomized controlled trials included 2,125 patients with pulmonary embolism:
- 210 (9.88%) in the low-risk category
- 1,499 (70.54%) in the submassive category
- 31 (1.46%) in the massive category
- 385 (18.11%) whose disease severity could not be determined.
Major bleeding occurred in:
- 98 (9.24%) of 1,061 patients receiving anticoagulation plus thrombolytics
- 36 (3.42%) of 1,054 patients receiving anticoagulation without thrombolytics (odds ratio [OR] 2.73, 95% confidence interval [CI] 1.91–3.91; number needed to harm [NNH] 18, 95% CI 13–27).
Intracranial hemorrhage occurred in:
- 15 (1.46%) of 2,014 patients on thrombolytic therapy
- 2 (0.19%) of 1,019 patients not on thrombolytic therapy (OR 4.63, 95% CI 1.78–12.04; NNH 78, 95% CI 48–206).
Of note, the incidence of major bleeding was not significantly increased in those age 65 or younger receiving thrombolytics (OR 1.25, 95% CI 0.5–3.14).
Comments. Definitions of major bleeding varied in the individual trials. Additionally, intracranial hemorrhage was included as a major bleeding end point in any trial in which it was not prespecified.
These findings emphasize the importance of risk stratification before pursuing thrombolytic therapy in submassive pulmonary embolism.
Table 3 lists absolute and relative contraindications to thrombolytic therapy.
MAJOR STUDIES IN SUBMASSIVE PULMONARY EMBOLISM
The MAPPET-3 trial
The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) trial,26 in 2002, was the first major trial to study thrombolytic therapy in submassive pulmonary embolism.
In this prospective, randomized, double-blinded trial conducted in Germany, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. The primary end point was in-hospital death or clinical deterioration requiring escalation of treatment. Secondary outcomes included recurrent pulmonary embolism, major bleeding, and stroke. Major bleeding was defined as fatal bleeding, hemorrhagic stroke, or drop in the hemoglobin concentration by more than 4 g/dL, with or without the need for red blood cell transfusion.
Right ventricular dysfunction was diagnosed by echocardiography in 30% of the participants, and the rest of the patients were classified as having submassive pulmonary embolism on the basis of electrocardiographic criteria alone. It is likely that the latter group had a less severe form of the disease and did not benefit from thrombolytic therapy as much as patients with echocardiographic findings of right ventricular dysfunction and elevated serum cardiac biomarkers.
Results. At 30 days, 11% of the alteplase-plus-heparin group had met the primary end point, compared with 24.6% of the placebo-plus-heparin group (P = .006). The difference was mostly driven by the need for secondary thrombolysis (7.6% vs 23.2%, P = .001), since 32 (23.2%) of the 138 patients in the control group required secondary thrombolysis, accounting for 94% of the 34 patients in this group who required escalation of treatment. Most cases of clinical deterioration in this group occurred within the first 5 days.
Mortality rates were 3.4% in the heparin-plus-alteplase group and 2.2% in the heparin-plus-placebo group, but the difference was not statistically significant (P = .71).
Major bleeding occurred in 1 patient in the heparin-plus-alteplase group and 5 patients in the heparin-plus-placebo group, but the trial’s definition of major bleeding may have resulted in underestimation of this event. The definition put forth by the International Society on Thrombosis and Haemostasis is less strict, defining bleeding in nonsurgical patients as major if it is fatal, symptomatic in a critical area or organ, or causing a fall in hemoglobin level of 2.0 g/dL or more, leading to transfusion of two or more units of whole blood or red cells.27
MOPETT trial
The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial28 was a single-center, randomized trial in 121 normotensive patients with “moderate” pulmonary embolism and right ventricular dysfunction. Moderate pulmonary embolism was defined as signs and symptoms of pulmonary embolism with evidence on computed tomographic angiography of greater than 70% involvement with thrombus in two or more lobes or left or right main pulmonary arteries, or by a high-probability ventilation-perfusion scan showing a mismatch in two or more lobes.
The authors defined right ventricular dysfunction by elevated cardiac markers or by findings on echocardiography. Only 20% of the participants were enrolled on the basis of right ventricular dysfunction on echocardiography, whereas almost 60% had elevated cardiac biomarkers.
The primary outcome was the development of pulmonary hypertension, based on echocardiography.
Patients were randomized to either anticoagulation alone (unfractionated heparin or low-molecular-weight heparin) or anticoagulation plus half-dose alteplase (0.5 mg/kg, to a maximum of 50 mg). Echocardiography was performed within 2 hours of study entry, at 48 hours, and every 6 months thereafter. The mean duration of follow-up was 28 months.
Results. Pulmonary hypertension developed in 16% of the anticoagulation-plus-alteplase group vs 57% of the anticoagulation-only group (P < .001). However, the clinical relevance of elevated right-sided pressures observed by echocardiography in asymptomatic patients is uncertain. Alteplase had no impact on the rates of death or recurrent pulmonary embolism.
PEITHO trial
The 2014 Pulmonary Embolism Thrombolysis (PEITHO) trial29 was a prospective, randomized, double-blinded, placebo-controlled trial conducted in 13 countries between 2007 and 2012. A total of 1,005 patients with submassive pulmonary embolism received unfractionated heparin and were randomized to also receive either tenecteplase or placebo.
The primary end point was death from any cause or hemodynamic compromise within 7 days of randomization. Secondary end points included death within 30 days, recurrence of pulmonary embolism, major bleeding, and stroke.
Echocardiography was strongly recommended for diagnosing right ventricular dysfunction in all patients. When this was unavailable, computed tomographic images were used to assess right ventricular dysfunction. Major bleeding was characterized as moderate or severe, and bleeding events were reported using the International Society on Thrombosis and Haemostasis criteria.
Results. The tenecteplase group had a lower rate of the primary end point at 7 days (2.6% vs 5.6%, P = .02), but no significant reduction in all-cause mortality at 30 days (2.4% vs 3.2%, P = .42). In addition, the tenecteplase group had higher rates of major extracranial bleeding (6.3% vs 1.2%, P < .001) and stroke (2.4% vs 0.2%, P = .004) at 7 days.
Although the PEITHO trial showed no reduction in mortality rates and showed a higher rate of major bleeding, this may have been related to using a higher dose of tenecteplase than needed in this population. Further studies should be conducted to confirm this theory.
