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HomeHealth articlesischemic strokeWhat Are the Safety Concerns for Using Tenecteplase?

Safety Concerns for Tenecteplase in Acute Ischemic Stroke

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Tenecteplase is a form of native tissue-type plasminogen activator that catalyzes the production of the serine protease plasmin to promote thrombolysis quickly.

Medically reviewed by

Dr. Muhammad Zohaib Siddiq

Published At May 18, 2023
Reviewed AtJanuary 29, 2024

Introduction

Acute ischemic stroke (AIS) patients who present within the window for treatment are typically treated with Alteplase. Additionally, cardiac arrest caused by suspected pulmonary embolism (PE) and myocardial infarction (MI) can all be treated with Alteplase. Tenecteplase comes with a proven indication in MI, looking to expand its use to ischemic stroke, whereas Alteplase made a name for itself in the brain and heart.

Tenecteplase should be seriously considered as an alternative to Alteplase due to its superior pharmacokinetic and pharmacodynamic profile when compared to Alteplase. Tenecteplase is more effective than Alteplase in terms of a number of significant outcomes. Even for nonsignificant outcomes, Tenecteplase administration has a tendency to be beneficial. Read the article to know more.

What Are the Benefits of Tenecteplase?

Tenecteplase has theoretical advantages over Alteplase because it has a longer half-life and a higher level of fibrin specificity. In contrast to Alteplase, which requires a bolus followed by a one-hour infusion, this enables the administration of a single dose over five to ten seconds. Tenecteplase has extensive data for this off-label use and is currently approved by the Food and Drug Administration (FDA) for the treatment of ST-segment elevated myocardial infarction. Tenecteplase has also been studied in the treatment of acute ischemic stroke. The TNK-S2B, Australian TNK, ATTEST, Nor test, and TNK-S2 are the trials that have evaluated the use of Tenecteplase in acute ischemic stroke. Following its greater rate of early neurological recovery and non-inferiority in terms of safety results, TNK in the dose of 0.25 milligrams is a favorable alternative to Alteplase as the standard of care in patients with AIS (acute ischemic stroke) who present within 4.5 hours of symptom onset. However, evidence for TNK's potential in AIS presenting after 4.5 hours, wake-up stroke, and minor stroke or TIA (transient ischemic attack) is still lacking, necessitating the conduct of additional double-blind, large-scale, and pragmatic RCTs.

What Are the Safety Concerns for Using Tenecteplase?

It is safe and effective to use Tenecteplase, a modified recombinant tissue plasminogen activator, to treat acute ischemic stroke. The only thrombolytic medication with FDA approval for thrombolysis in AIS is Alteplase. When administered within the four to five window, Alteplase can result in a 28 percent reduction in disability at 90 days and quick symptom improvement. Implementation of Alteplase is limited despite its potential for a recovery devoid of disability because of the limited time window and unfavorable side effects, such as a six percent chance of symptomatic hemorrhage. Additionally, Alteplase has only mild fibrinolytic efficacy, with less than 50 percent of patients experiencing arterial recanalization. Only 50 percent of patients who achieve recanalization do so within two hours of drug administration. Alteplase’s adverse effects on the ischemic brain, including cytotoxicity and increased permeability of the blood-brain barrier, have also been a growing source of worry.

In this situation, the acceptance of thrombolytic therapy for stroke can be increased by developing thrombolytic medicines that are secure, simple to use, and efficient. Following reports from the ASSENT 2 trial, the FDA has approved Tenecteplase (TNK), a genetically altered form of Alteplase, for thrombolysis in acute myocardial infarction. TNK induces coronary reperfusion more quickly than Alteplase while having comparable mortality rates, according to numerous clinical traits comparing the two drugs in acute MI. The success of treatments for acute MI and animal models of the disease has sparked interest in substituting Alteplase for TNK therapy in AIS. TNK is an appealing substitute due to a number of benefits, including its generally low cost, high fibrin specialty, prolonged plasma half-life, and improved plasminogen activator inhibitor.

Three molecular substitutions separate Tenecteplase from Alteplase, altering the drug’s pharmacokinetic and pharmacodynamic characteristics. These modifications led to an increase in the half-life of Alteplase and Tenecteplase from four minutes to 20 and 24 minutes, respectively. Tenecteplase’s long half life allows for single bolus administration rather than one hour-long infusion, which prolongs the time the drug is exposed to the clot. A higher affinity to fibrin-rich clots and platelet-rich thrombi, as well as greater thrombolytic potency when compared to Alteplase, are both made possible by changes in the molecular structure. And finally, it has been discovered that Tenecteplase consumes less fibrinogen, plasminogen, and alpha-two antiplasmins, which lowers the risk of bleeding.

What Are the Results of the Study of Tenecteplase Over Alteplase?

It is FDA approved indication based on studies that finished between 1997 and 1999. Tenecteplase 0.5 mg per kg and Alteplase 1.1 mg per kg were compared in a randomized, double-blind fashion (blinds both the subjects and the researchers to the treatment allocation) in patients with acute MI by researchers in the historic trial ASSENT-2. However, the rates of mortality and symptomatic intracerebral hemorrhage were similar in both groups. The Tenecteplase group had lower rates of cerebral bleeding and blood transfusions.

The first Tenecteplase for the AIS study was released about six years after the release of ASSENT-2. Tenecteplase 0.1 to 0.4 mg per kg was found to be safe for treating acute ischemic stroke in a dose escalation study. Five years after the completion of this study, the first randomized phase 2 trial comparing Tenecteplase at doses of 0.1, 0.25, and 0.4 mg per kg to Alteplase at the recommended dose was published. While the slow enrollment in this phase-2 trial led to early termination, preliminary findings that showed increased frequency in symptomatic intracerebral hemorrhage in the Tenecteplase of 0.4 mg per kg group were still published.

What Are the Contraindications of Tenecteplase?

The contraindications include:

  • Cerebrovascular accident history.

  • Active internal bleeding.

  • Intracranial neoplasm.

  • Uncontrolled hypertension.

  • Within two months of intracranial or intraspinal surgery or trauma.

  • Arteriovenous malformation.

Conclusion

Tenecteplase, which shares a similar safety profile with Alteplase, is associated with higher rates of both excellent functional outcomes and early neurological improvement when administered at a dose of 0.25 mg per kilogram. Tenecteplase may be a good substitute for Alteplase due to its superior pharmacokinetics. A direct comparison of Tenecteplase with thrombectomy and the effect of NIHSS (National Institute of Health Stroke Scale) scores on the efficacy and safety profiles of Tenecteplase is just a couple of the unanswered questions that require further research.

Frequently Asked Questions

1.

What Factors or Conditions Prohibit the Use of Thrombolysis?

Several conditions impose limitations on the use of thrombolysis. These restrictions include instances of recent intracranial hemorrhage, the presence of intracranial neoplasms, a history of ischemic stroke within the preceding three months, recent spinal or intracranial surgery, ongoing active bleeding, uncontrolled hypertension, the existence of structural brain lesions, head trauma within the last three months, and recent use of anticoagulant medications.

2.

What Factors Prevent the Use of Tenecteplase in STEMI?

Several factors can restrict the use of Tenecteplase in ST-segment elevated myocardial infarction (STEMI). While it is most effective when administered as swiftly as possible, one limiting factor is the necessity to use Tenecteplase within 12 hours of symptom onset. Contraindications also come into play in scenarios involving a history of bleeding, recent trauma, uncontrolled hypertension, brain tumors, brain hemorrhages, known allergies to Tenecteplase, prior transient ischemic attacks within the preceding six months, pregnancy, or administration within one week of postpartum recovery.

3.

What Are the Potential Adverse Effects Associated With Tenecteplase?

Tenecteplase comes with potential adverse effects, with bleeding being a primary concern, especially in individuals who have recently undergone surgery or experienced trauma, as this elevates the risk. Additionally, allergic reactions, characterized by symptoms like swelling and itching, can manifest in response to Tenecteplase. Other adverse effects may encompass a decrease in blood pressure and irregular heart rates, making it crucial to monitor patients for these potential side effects.

4.

What Is the Administration Procedure for Tenecteplase in the Context of Stroke?

Tenecteplase serves as a medication specifically designed to dissolve blood clots. In the context of acute ischemic stroke, characterized by a disruption in the brain's blood flow caused by a clot, Tenecteplase is administered as a single intravenous bolus. This bolus typically consists of 0.1133 mg/Ib, with a maximum dose capped at 25 mg. Notably, Tenecteplase boasts a half-life of approximately 30 minutes.

5.

Has the FDA Granted Approval for Tenecteplase in the Treatment of Strokes?

The FDA (Food and Drug Administration) has not bestowed its approval upon Tenecteplase for the management of strokes involving cerebral blood flow blockages. Nevertheless, it is noteworthy that the American Heart Association and the National Institute of Neurological Disorders have granted their approvals for its use in this context.

6.

Which tPA Is Considered the Most Effective for Stroke Management?

Alteplase stands out as the most commonly employed tissue plasminogen activator (tPA) for managing strokes. It is crucial to administer Alteplase within a narrow time window of 4.5 hours from the onset of the stroke. Early administration is pivotal in facilitating the dissolution of the blood clot and thereby mitigating potential damage.

7.

In Stroke Patients, Is Tenecteplase Superior to Alteplase?

Numerous clinical trials have consistently demonstrated that Tenecteplase is on par with Alteplase in terms of efficacy. What sets Tenecteplase apart is its status as a genetically modified iteration of Alteplase, offering several notable advantages. These advantages include a prolonged half-life, simplified administration procedures, a reduced risk of bleeding complications, and enhanced specificity for fibrin.

8.

Is Tenecteplase Considered a Safer Alternative to Alteplase?

Both Tenecteplase and Alteplase belong to the category of thrombolytic medications, designed to facilitate the dissolution of blood clots. Interestingly, the efficacy of these medications often appears to be comparable. Numerous clinical trials have indicated that Tenecteplase's effectiveness is non-inferior to that of Alteplase. However, it is important to note that, despite these findings, the FDA has granted approval for the use of Alteplase exclusively in the management of stroke, restricting Tenecteplase's approved indications.

9.

Is Tenecteplase More Effective Than Streptokinase?

Tenecteplase and Streptokinase are both classified as thrombolytic medications, instrumental in the dissolution of blood clots. Notably, Tenecteplase often emerges as the more effective choice when compared to Streptokinase. This heightened efficacy can be attributed to Tenecteplase's extended half-life and superior fibrin specificity. In contrast, Streptokinase has a shorter half-life and carries a greater risk of bleeding complications and a propensity for allergic reactions due to its bacterial protein composition.

10.

What Is the Recommended Treatment for Reversing the Effects of TPA?

Reversing the effects of tissue plasminogen activator (tPA) poses a challenge since no specific antidotes are available. Typically, healthcare professionals turn to alternative strategies, such as anti-fibrinolytic therapy, which includes the use of medications like aminocaproic acid or tranexamic acid. These drugs serve to inhibit fibrinolytic activity. Alongside this, supportive measures come into play, encompassing actions like halting bleeding, considering platelet transfusions, and vigilant monitoring of vital signs.

11.

How Long Does Tenecteplase Remain Detectable in the System?

Tenecteplase exhibits an initial half-life ranging from 20 to 24 minutes, with a terminal half-life spanning approximately 90 to 130 minutes. However, it is important to note that metabolism and renal function can significantly influence the drug's clearance from the body. Given its extended half-life, tenecteplase is typically administered as a single intravenous bolus to ensure effective and sustained therapeutic action.

12.

Which Medication Is Employed to Counteract the Effects of Alteplase?

When it comes to reversing alteplase's effects, there is no specific antidote available. In the event of complications, addressing bleeding cessation is of paramount importance. This involves stabilizing blood pressure and providing essential supportive care, including monitoring vital signs and neurological status. In cases of severe bleeding complications, the use of blood products like platelet transfusions may be considered. Additionally, antifibrinolytic medications can be employed as an option.

13.

What Is the Success Rate Associated With the Use of Tenecteplase?

The effectiveness of tenecteplase hinges on the particular medical condition it is addressing. Tenecteplase achieves a success rate of approximately 90.93 percent when used in managing acute myocardial infarction. Notably, its success rate rises even further to 93 percent when administered within the critical window of three hours from the onset of symptoms.
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Dr. Muhammad Zohaib Siddiq
Dr. Muhammad Zohaib Siddiq

Cardiology

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tenecteplaseischemic stroke
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