Clincal Resarch Article
 
Role of Tenecteplase in Pulmonary Embolism
Sameer Shrivastava, Ankush Sachdeva, Biswajit Paul.
Escorts Heart Institute and Research Centre, Okhla, New Delhi

Abstract:
Patients presenting with pulmonary embolism have a wide spectrum of clinical severity. Although, some patients may present with frank hemodynamic collapse and cardiac arrest, others may present with asymptomatic pulmonary embolism that is discovered incidentally during work up of another condition. Fibrinolytic therapy is an option in the treatment of patients with pulmonary embolism. A rational approach to decide whether to indicate fibrinolytic therapy is based on assessment of benefits that each patient will derive from fibrinolytic therapy weighed against risk of major bleeding and intracranial hemmorage. There is a clear benefit/risk ratio for fibrinolytic therapy in patients with pulmonary embolism who present with cardiac arrest and in those who are hemodynamically unstable from a massive pulmonary embolism. With proper risk assessment selected patients with stable hemodynamics and right ventrical dysfunction may also benefit from fibrinolytic therapy. This article sets out to review the literature on tenecteplase in treatment of patients with pulmonary embolism.
Key words:
Thrombolytic therapy, Right ventricular dysfunction, Hemodynamic instability.

Introduction
The data regarding death due to cardiac arrest following pulmonary embolism cannot be over emphasized (1, 2). The condition is by no means less sinister in patients with massive or submassive pulmonary embolism (1, 2). Thromobolytic therapy has shown to improve survival in this category of patients (3). This article aims to discuss the role of tenecteplase in pulmonary embolism.

Spectrum of disease severity
The benefit/risk ratio of treatment with tenecteplase changes dramatically with each particular patient depending upon clinical presentation.

a) Cardiac arrest:
Two to 20% of patients with pulmonary embolism present in cardiac arrest and have a mortality rate of 66 to 95% (1, 2)
Use of thrombolytic therapy offers a clear benefit/risk ratio and has no absolute contraindications in this patient population. It has shown to improve the return of spontaneous circulation and may improve survival to hospital discharge (3)

b) Massive pulmonary embolism:
Patients with hemodynamic instability (SBP < 90 mmHg) or respiratory distress constitutes approximately 5% of patients with mortality rate of 22%-53% (1, 2). Early treatment with thrombolytic therapy offers the best benefit/risk ratio in these patients. Contraindications are mostly relative.

c) Sub-massive pulmonary embolism:
Twenty three to 40% patients with normal hemodynamics (SBP > 90 mmHg) and no signs of shock but may have signs and symptoms suggestive right ventricular dysfunction or may have occult right ventricular dysfunction (1, 4)

Mortality rate is 8%-13% with higher rates of in hospital complications and potential for long term pulmonary arterial hypertension and cardiolulmonary disease. (5,6) Thrombolytic therapy decreases right ventricular outlet tract

obstruction, decreases right ventricular wall tension and returns interventricular septum to normal location resuting in improvement in left ventricular preload, volume and cardiac output.


Fibrinolytic dosing regimens in pulmonary embolism: (7)

Cardiac Arrest:

Massive and sub-massive pulmonary embolism:
  1. Alteplase (FDA-appointed)
    1. 50 mg IV bolus
    2. May repeat 50 mg IV bolus in 15 min if no return of spontaneous circulation
  1. Alteplase (FDA Approved)
    1. 10 mg IV Bolus
    2. Followed by 90 mg IV infusion over 2 hrs.
  1. Reteplase
    1. 20 U IV Bolus

 
  1. Reteplase
    1. 10U IV Bolus
    2. Followed in 30 min. by another 10U IV bolus
  1. Tenecteplase
    1. 0.5 mg/kg IV Bolus (maximum 50 mg)

 
  1. Tenecteplase
    1. 0.5 mg/kg IV Bolus (maximum – 50 mg)

 

Evidence for fibrinolytics in pulmonary embolism
We discuss the data available in support of fibrinolysis in pulmonary embolism

Correspomdence: Dr.Sameer Shrivastava, EscortsHeart Institute and Research Centre,Okhla, New Delhi, India
Email: sameer_rashmi@hotmail.com
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Indian Heart J. 2009; 61: 464-466
Satyavan Sharma
 
Role of Tenecteplase in Pulmonary Embolism
 

Registries:
The ICOPER (International Cooperative Pulmonary Embolism Registry) (2) and MAPPET (Management Strategy and Prognosis of Pulmonary Embolism)(8) Registry suggests that patients with objectively confirmed pulmonary embolism, normal blood pressure and echocardiographic evidence of right ventricular dysfunction have high incidence of adverse effects and may potentially benefit more aggressive treatment.
Trials of other fibrinolytic agents in pulmonary embolism:
Numerous studies have shown that patients with pulmonary embolism who receive fibrinolytic have more rapid decrease in pulmonary arterial hypertension and improvement in right ventricular function than those who receive anticoagulation alone.
In 1970 the first prospective and randomized trial was urokinase pulmonary embolism trial (UPET) (9) wherein the effect of urokinase and heparin was compared in acute pulmonary embolism. Within 24 hrs improved lung scans, pulmonary angiogram and right ventricular pressure improvement was seen with urokinase. However, no significant difference was noted in longer follow up. In 2nd phase – urokinase was compared with streptokinase, both of which showed similar results on lung scan and were superior to heparin.
Numerous other randomized trials (10-14) comparing fibrinolytic therapy with streptokinase and alteplase with heparin showed clear benefit in terms of mortality and recurrent pulmonary embolism in patient receiving alteplase in comparison to anticoagulation alone.

In a randomized study (6, 7) done with streptokinase and urokinase compared with heparin in patients with chronic vascular obstruction, fibrinolytic were shown to reduce chronic vascular obstruction, potential for persistent pulmonary arterial hypertension and right ventricular dysfunction associated pulmonary embolism.
MAPPET-3 trial (15) addressed the possible benefits of thrombolysis in submassive pulmonary embolism. The combined end points (death or escalation of therapy) were significantly reduced in patients who received thrombolysis.

 

Chemistry of Tenecteplase
Tenecteplase is a tissue plasminogen activator (tPA) produced by recombinant DNA technology using established mamalian line (chinese hamster ovary cells). Tenecteplase is a 527 amino acid glycoprotein developed by introducing following modifications to the complementary DNA (cDNA) for natural human tPA: substitution of threonine 103 with aspaagine ,and substitution  of asparagines 117 with glutamine ,both within the Kringle 1 domain ,and a tetra-alanine substitution at amino acids 296-299.
Tenecteplase is a recombinant fibrin specific plasminogen that is derived from native tPA by modifications at three sites of protein structure. It binds to the fibrin component of thrombus and selectively converts thrombus bound plasminogen into plasmin, which degrades the matrix of thrombus. Tenecteplase has higher fibrin specificity and greater resistance to inactivation by its endogenous plasminogen activator inhibitor-1 (PAI-1) compared to native tPA.

 

Trials with tenecteplase in pulmonary embolism
Randomized Trials
A randomized, double blind placebo-controlled study done to asses the effect of tenecteplase on RV dysfunction showed that single bolus tenecteplase was associated with improved reduction of right to left ventricular end diastolic diameter ratio. One pulmonary embolism related death and three recurrent pulmonary embolism and intracranial bleeding were seen in tenecteplase group within 7 days from treatment administration (16).
Clot dissolving treatment for blood clots in the lungs is currently recruiting candidates. Purpose is to determine if tenecteplase and enoxaparin is safe and effective in patients with severe submassive pulmonary embolism.

Multicentre Trials:
A large European mulicentre, double blind trial, pulmonary embolism thrombolysis study (PEITHO) (17) is underway. This study will randomize patients with normotensive pulmonary embolism, RV enlargement on echocardiography (RV/LV > 0.9) and elevated level of cardiac troponin to receive either a bolus regimen of tenecteplase and heparin or tenecteplase alone.

After thrombolysis in cardiac arrest (TROICA) trial (18) which was set to determine whether tenecteplase in benefits in cardiac arrest scenario extend beyond the approved indications such as ST-elevation myocardial infaction and massive pulmonary embolism in a subset of one thousand five hundred patients,a metaanalysis including 926 patients from eight studies conclude that thrombolysis ,when given during cardiopulmonary resusiation significantly improved the return of spontaneous circulation ,24-hour survival ,survival to discharge and long term neurological function contrary to the results of TROICA trial.
There have been some case reports of treatment of massive pulmonary embolism with catheter directed tenecteplase (19). Clinical data is currently being collected.

Bleeding complications with thrombolytic therapy
Thrombolytic therapy carries a significant risk of bleeding especially when predisposing. Conditions or comorbidities exist. Summarized data from randomized trials (20-27) reveal a 13% cumulative rate of major bleeding and a 1.8% rate of intracranial /fatal haemorrage. In most recent trials, (27, 28) life threatening haemorrage has been less common. This appears to be in line with the observation that thrombolysis-related bleeding rates are lower when non-invasive imaging methods are used to confirm pulmonary embolism, (29) a strategy that has been adopted increasingly over the past 10 years.

Conclusions
Thrombolytic therapy is the first line of treatment in patients with high risk pulmonary embolism (30) presenting with cardiogenic shock and persistent arterial hypertension with few absolute contraindications.

 
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Indian Heart J. 2009; 61: 464-466
 
Sameer Shrivastava et al
 
Routine use of thrombolysis in non-high risk patients is not recommended but may be considered in selected patients with intermittent risk pulmonary embolism and after thorough consideration of conditions increasing the risk of bleeding. Thrombolytic therapy should not be used in patients with low risk pulmonary embolism. With currently available data tenecteplase does prove useful in its safety and efficacy to treat this condition.

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