What data are available for systemic tenecteplase in submassive pulmonary embolism?
Background
Pulmonary embolism (PE) occurs in an estimated 1 in 1000 persons per year, and can lead to significant morbidity and mortality.1 Up to 100,000 people in the United States die from venous thromboembolism (VTE) each year, and the vast majority of VTE-related deaths occur in patients with PE.2,3 Patients who survive PE are at risk for recurrence and chronic complications such as chronic thromboembolic pulmonary hypertension (CTEPH).4
The presentation of PE varies widely; some patients may be asymptomatic, while others will present with symptoms ranging from shortness of breath to circulatory collapse.4 Pulmonary embolism may be classified as low risk, intermediate risk (submassive), or high risk (massive) depending on the severity of illness on presentation.1 If a patient presents with hypotension, the patient’s PE is considered high risk or massive; hypotension is typically defined as a systolic blood pressure less than 90 mm Hg or a drop in blood pressure greater than 40 mm Hg not explained by another cause. Patients without hypotension but with signs of myocardial injury (ie, elevated troponin levels) or right ventricular (RV) dysfunction (ie, RV hypokinesis, dilation, or overload on echocardiography; elevated brain natriuretic peptide [BNP]) are classified as having intermediate-risk or submassive PE. Patients with high-risk or intermediate-risk PE have a higher 30-day mortality rate than patients with low-risk PE. The 30-day mortality risk with low-risk PE is estimated at 2%, while intermediate-risk PE carries a mortality risk of 3% to 15% and high-risk PE carries a mortality risk greater than 15%.
Pulmonary embolism is typically treated with anticoagulants (ie, unfractionated heparin, low-molecular-weight heparin).4 However, anticoagulants do not break up existing emboli; they simply prevent the formation or extension of existing clots.5 Thrombolytics such as alteplase and tenecteplase lyse clots that have already formed, allowing them to quickly reestablish tissue perfusion. However, bleeding is a significant adverse effect of these agents; major bleeding may occur in as many as 21.7% of patients who receive thrombolytics in clinical practice, and intracranial hemorrhage may occur in up to 3.3%.4 In light of these potential risks, thrombolytics must be used cautiously, and only in patient populations most likely to benefit from their use.
Alteplase is the only thrombolytic with an approved indication for the treatment of acute PE.6 However, because of its short half-life, alteplase must be administered as a continuous intravenous (IV) infusion over 2 hours.1 Although tenecteplase is not labeled for use in PE, it may be an attractive alternative to alteplase because it can be administered as an IV bolus. This article will explore the literature supporting the use of tenecteplase in acute PE, with a focus on its use in patients with intermediate-risk or submassive PE.
Guideline recommendations on systemic thrombolytic use in acute submassive PE
The American College of Chest Physicians (ACCP) published an updated guideline on the treatment of VTE in 2021.7 This guideline recommends against systemic thrombolytics in most patients with acute PE not associated with hypotension (eg, systolic blood pressure less than 90 mm Hg). However, systemic thrombolytics are suggested for select patients with acute PE who have deteriorated after starting anticoagulant therapy but have yet to develop hypotension; signs of clinical deterioration may include a progressive decrease in heart rate, a decrease in systolic blood pressure (but not to values lower than 90 mm Hg), an increase in jugular venous pressure, worsening gas exchange, signs of shock (eg, cold sweaty skin, reduced urine output, confusion), progressive right heart dysfunction on echocardiography, or an increase in cardiac biomarkers. Patients must have an acceptable bleeding risk for systemic thrombolysis to be considered. No specific thrombolytic agent is recommended by this guideline.
The American Society of Hematology (ASH) also published a guideline on the treatment of VTE in 2020.8 This guideline suggests anticoagulation alone over the routine use of thrombolysis in addition to anticoagulation in patients with submassive PE (ie, PE with echocardiography and/or biomarkers compatible with RV dysfunction but without hemodynamic compromise). Hemodynamic compromise is defined as systolic blood pressure less than 90 mm Hg or a decrease in systolic blood pressure of 40 mm Hg or greater from baseline. However, the guideline does state that thrombolysis is reasonable to consider for selected younger patients with submassive PE and low risk of bleeding; thrombolysis may also be considered for patients with submassive PE at high risk for decompensation due to concomitant cardiopulmonary disease. As in the ACCP guideline, no specific thrombolytic agent is recommended.
Evidence for tenecteplase in acute submassive PE
Several randomized controlled trials (RCTs) have examined the use of systemic tenecteplase in patients with acute submassive PE (Table 1).9-12 However, the majority of these trials were too small to demonstrate a specific, clinically relevant benefit or adverse outcome with tenecteplase as compared to placebo. The largest RCT examining tenecteplase use in this patient population is the double-blind, placebo-controlled PEITHO trial, which enrolled 1005 patients.9 This trial did find a benefit for tenecteplase with respect to the composite primary endpoint of death from any cause or hemodynamic decompensation/collapse within 7 days of treatment; however, this result was primarily driven by a reduction in the risk of hemodynamic decompensation/collapse, with secondary endpoint analyses finding no significant differences in mortality between tenecteplase and placebo. Additionally, tenecteplase was associated with a significantly increased risk of major extracranial bleeding and hemorrhagic stroke. Authors of the trial concluded that caution is warranted when considering systemic tenecteplase for a patient with acute intermediate-risk PE. A recent meta-analysis of 4 RCTs by Zhang and colleagues similarly found that tenecteplase improves RV insufficiency at 24 hours post-administration and reduces the incidence of hemodynamic failure but does not impact mortality in patients with submassive PE and likely increases the risk of bleeding.13
| Table 1. Overview of RCTs examining systemic tenecteplase for submassive PE.9-12 |
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| Study design and duration | Subjects | Interventions | Results | Conclusions |
| Meyer 20149 PEITHO MC, DB, PC, RCT Follow-up: 30 days post-intervention Konstantinides 201710 Long-term follow-up study to PEITHO Follow-up at 24 months or more after randomization (median 37.8 months) | N=1005 patients aged ≥18 years with acute intermediate-risk PE, RV dysfunction confirmed on echocardiography or chest CT, and myocardial injury confirmed by a positive troponin test Median age: 70 years All patients were normotensive at the time of randomization N=709 patients from the PEITHO trial participated in long-term follow-up | Weight-based tenecteplase 30 to 50 mg administered as an IV bolus over 5 to 10 seconds (n=506) Placebo (n=499) Both groups also received IV UFH titrated to maintain aPTT 2 to 2.5 times the ULN | Primary: Composite of death from any cause or hemodynamic decompensation or collapse within 7 days: 2.6% in the tenecteplase group vs. 5.6% in the placebo group (OR, 0.44; 95% CI, 0.23 to 0.87; p=0.02) Secondary: Death within 7 days: 1.2% in the tenecteplase group vs. 1.8% in the placebo group (OR, 0.65; 95% CI, 0.23 to 1.85; p=0.42) Hemodynamic decompensation or collapse within 7 days: 1.6% in the tenecteplase group vs. 5% in the placebo group (OR, 0.30; 95% CI, 0.14 to 0.68; p=0.002) Symptomatic recurrence of PE within 7 days: 0.2% in the tenecteplase group vs. 1% in the placebo group (OR, 0.20; 95% CI, 0.02 to 1.68; p=0.12) Death within 30 days: 2.4% in the tenecteplase group vs. 3.2% in the placebo group (OR, 0.73; 95% CI, 0.34 to 1.57; p=0.42) Safety: Major extracranial bleeding within 7 days: 6.3% in the tenecteplase group vs. 1.2% in the placebo group (OR, 5.55; 95% CI, 2.3 to 13.39; p<0.001) Ischemic or hemorrhagic stroke within 7 days: 2.4% in the tenecteplase group vs. 0.2% in the placebo group (OR, 12.10; 95% CI, 1.57 to 93.39; p=0.003); most strokes were hemorrhagic Serious AEs within 30 days: 10.9% in the tenecteplase group vs. 11.8% in the placebo group (OR, 0.91; 95% CI, 0.62 to 1.34; p=0.63) Long-term outcomes: Death from any cause between randomization and long-term follow-up: 20.3% in the tenecteplase group vs. 18% in the placebo group (p=0.43) Persistent clinical symptoms at long-term follow-up: 36% in the tenecteplase group vs. 30.1% in the placebo group (p=0.23); the major symptom reported was mild exertional dyspnea One or more indicators of pulmonary hypertension and/or RV dysfunction were recorded in 44.1% of the tenecteplase group vs. 36.6% of the placebo group (p=0.20) CTEPH diagnosis at long-term follow-up: 2.1% of the tenecteplase group vs. 3.2% of the placebo group (p=0.79) | Tenecteplase reduced the risk of hemodynamic decompensation or collapse compared to placebo in patients with acute intermediate-risk PE; however, treatment with tenecteplase had no significant effect on mortality and increased the risk of major extracranial bleeding and hemorrhagic stroke. |
| Kline 201411 TOPCOAT MC, DB, PC, RCT Follow-up for 90 days | N=83 patients aged >17 years with PE, normal systolic blood pressure, and evidence of RV strain based on echocardiography, troponin test, or BNP level Mean age: 54 years in the tenecteplase group and 57 years in the placebo group | Tiered-dose tenecteplase dosed according to the prescribing information (n=40) Placebo (n=43) All patients received full-dose LMWH prior to receipt of study drug | A total of 16 patients (37%) in the placebo group and 6 patients (15%) in the tenecteplase group had a study-defined adverse outcome at some point during follow-up (difference, 22%; 95% CI, 3.2% to 40%; two-sided p=0.017; Fisher’s exact p=0.027) Adverse outcomesa within 5 days occurred in 1 patient who received tenecteplase (death) and 3 patients who received placebo (death, n=1; shock/intubation, n=2) At 90-day follow-up, 13 patients (30%) in the placebo group and 5 patients (12.5%) in the tenecteplase group reported adverse outcomesb; none of these patients had previously experienced an adverse outcome during the study Adverse outcomes at 90-day follow-up included poor functional capacity only (tenecteplase, n=3; placebo, n=2), recurrent VTE only (n=1 in each group), poor physical health-related quality of life only (tenecteplase, n=0; placebo, n=2), poor functional capacity plus poor physical health-related quality of life (tenecteplase, n=1; placebo, n=5), recurrent VTE plus poor physical health-related quality of life (tenecteplase, n=0; placebo, n=2), and recurrent VTE plus poor functional capacity plus poor physical health-related quality of life (tenecteplase, n=0; placebo, n=1) | Use of tenecteplase was associated with decreased probability of a composite adverse outcome compared to placebo; however, the small sample size of the trial did not allow for detection of significant differences in individual adverse outcomes. |
| Becattini 201012 TIPES MC, DB, PC, RCT Follow-up for 30 days | N=58 patients aged 18 to 85 years with acute PE, systolic blood pressure ≥100 mm Hg, and RV dysfunction on echocardiography Mean age: 72.1 years in the tenecteplase group and 64.5 years in the placebo group (p=0.01) Mean RV end-diastolic dimension at baseline: 49 in the tenecteplase group and 47 in the placebo group Mean right/left end-diastolic dimension ratio at baseline: 1.36 in the tenecteplase group and 1.32 in the placebo group | Weight-based tenecteplase 30 to 50 mg administered as an IV bolus over 5 seconds (n=28) Placebo (n=30) Both groups also received IV UFH titrated to maintain aPTT 2 to 2.5 times the ULN | Primary: At 24 hours post-randomization, both RV end-diastolic dimension and right/left end-diastolic dimension ratio were significantly lower in patients who received tenecteplase compared to those who received placebo (mean RV end-diastolic dimension: 40 vs. 45 respectively; p=0.04; mean right/left end-diastolic dimension ratio: 1.04 vs. 1.22 respectively; p=0.02) Secondary: At 7 days post-randomization, between-group differences in right/left end-diastolic dimension ratio were not statistically significant Clinical deterioration requiring escalation of treatment occurred in 1 patient randomized to placebo and 0 patients randomized to tenecteplase Two patients (one in each treatment group) had symptomatic recurrent PE within 30 days post-randomization; 1 patient in the placebo group died, and 0 tenecteplase-treated patients died Safety: Major bleeding occurred in 1 placebo-treated patient and 2 tenecteplase-treated patients Minor bleeding occurred in 1 placebo-treated patient and 13 tenecteplase-treated patients | Tenecteplase is associated with an early reduction in RV dysfunction at 24 hours; however, it is unclear whether this benefit is associated with improved clinical outcome. |
| Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BNP=brain natriuretic peptide; CI=confidence interval; CT=computed tomography; CTEPH=chronic thromboembolic pulmonary hypertension; DB=double-blind; IV=intravenous; LMWH=low-molecular-weight heparin; MC=multicenter; OR=odds ratio; PC=placebo-controlled; PE=pulmonary embolism; RCT=randomized controlled trial; RV=right ventricular; SF-36= Standard Form 36; UFH=unfractionated heparin; ULN=upper limit of normal; VTE=venous thromboembolism. aAdverse outcomes at 5 days could include adverse outcomes from PE or adverse outcomes from treatment. Adverse outcomes from PE were death, circulatory shock (hypotension requiring vasopressor infusion), or need for intubation. Adverse outcomes from treatment were death from hemorrhage, any intracranial or intraspinal hemorrhage, active bleeding with >2 g/dL drop in hemoglobin within 24 hours requiring transfusion, and any bleeding that required surgery, endoscopic treatment, or intravascular treatment. bAdverse outcomes measured at 90 days were VTE recurrence, poor functional capacity, and poor physical health-related quality of life. Poor functional capacity was defined as RV dysfunction on echocardiography plus exercise intolerance (defined as the inability to walk 330 m in a 6-minute walk test) or dyspnea at rest (defined as a New York Heart Association functional class of 3 or 4). Poor physical health-related quality of life was defined as an SF-36 physical component summary score <30. |
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Practical considerations for tenecteplase use in acute PE
Tenecteplase is typically administered as an IV bolus for the treatment of PE; the specific dose administered depends on the patient’s weight (see Table 2).4 There are a number of absolute and relative contraindications to the use of thrombolytics in patients with submassive PE; these conditions increase the risk for bleeding complications.1,4 Absolute contraindications to thrombolytic therapy include history of intracranial hemorrhage, ischemic stroke within the past 3 months, active bleeding, recent neurosurgical procedure, recent head trauma involving fracture or brain injury, bleeding diathesis, and structural intracranial disease. Relative contraindications to thrombolytic therapy include a blood pressure of 180/110 mm Hg or greater; recent bleeding, surgery, or invasive procedure; history of ischemic stroke at any time; anticoagulant therapy; traumatic cardiopulmonary resuscitation; pericarditis or pericardial fluid; diabetic retinopathy; pregnancy; age greater than 75 years; weight less than 60 kg; female sex; and African-American race.
| Table 2. Dosing of systemic tenecteplase in acute PE.4,14 | |
|---|---|
| Patient weight | Recommended dose |
| <60 kg | 30 mg |
| 60-69 kg | 35 mg |
| 70-79 kg | 40 mg |
| 80-89 kg | 45 mg |
| ≥90 kg | 50 mg |
Conclusion
Current guidelines do not recommend the routine use of any thrombolytic in patients with submassive PE; however, systemic thrombolytic therapy can be considered for select patients with a favorable bleeding risk who deteriorate despite anticoagulant therapy. Tenecteplase is a reasonable choice of thrombolytic agent if thrombolytic therapy is warranted. A large RCT found that tenecteplase decreased the risk of hemodynamic decompensation or collapse among patients with acute submassive PE, but it was also associated with an increased risk of intracranial and extracranial bleeding. The benefits and risks of systemic thrombolytic therapy should be carefully weighed, and the decision to administer thrombolytics should be individualized based on the patient’s clinical status and bleeding risk.
References
- Igneri LA, Hammer JM. Systemic thrombolytic therapy for massive and submassive pulmonary embolism. J Pharm Pract. 2020;33(1):74-89. doi:10.1177/0897190018767769
- Data and statistics on venous thromboembolism. Centers for Disease Control and Prevention. Updated June 9, 2022. Accessed December 20, 2022. https://www.cdc.gov/ncbddd/dvt/data.html
- Office of the Surgeon General (US), National Heart Lung and Blood Institute (US). The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism. Office of the Surgeon General (US); 2008. Accessed December 20, 2022. https://www.ncbi.nlm.nih.gov/books/NBK44178/
- Eberle H, Lyn R, Knight T, Hodge E, Daley M. Clinical update on thrombolytic use in pulmonary embolism: a focus on intermediate-risk patients. Am J Health Syst Pharm. 2018;75(17):1275-1285. doi:10.2146/ajhp170357
- Drugs that affect blood. In: Stringer J, ed. Basic Concepts in Pharmacology: What You Need to Know for Each Drug Class. 6th ed. McGraw Hill; 2022. Accessed December 16, 2022. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3136§ionid=263124011
- Clinical Pharmacology. Elsevier; 2022. Accessed December 16, 2022. https://www.clinicalkey.com/pharmacology/
- Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest. 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055
- Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
- 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
- Konstantinides SV, Vicaut E, Danays T, et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol. 2017;69(12):1536-1544. doi:10.1016/j.jacc.2016.12.039
- 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. 2014;12(4):459-468. doi:10.1111/jth.12521
- Becattini C, Agnelli G, Salvi A, et al. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res. 2010;125(3):e82-86. doi:10.1016/j.thromres.2009.09.017
- Zhang Z, Xi L, Zhang S, et al. Tenecteplase in pulmonary embolism patients: a meta-analysis and systematic review. Front Med (Lausanne). 2022;9:860565. doi:10.3389/fmed.2022.860565
- Lexicomp. Wolters Kluwer; 2022. Accessed December 20, 2022. http://online.lexi.com/lco/action/home
Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
January 2023
The information presented is current as of December 7, 2022. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.