Alteplase

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Alteplase, sold under the brand name Activase among others, is a biosynthetic form of human tissue-type plasminogen activator (t-PA). It is a thrombolytic medication used to treat acute ischemic stroke, acute ST-elevation myocardial infarction (a type of heart attack), pulmonary embolism associated with low blood pressure, and blocked central venous catheter.<ref name="AHFS2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Alteplase is given by injection into a vein or artery.<ref name=AHFS2019/> Alteplase is the same as the normal human plasminogen activator produced in vascular endothelial cells<ref name=":5">Template:Cite journal</ref> and is synthesized via recombinant DNA technology in Chinese hamster ovary cells (CHO). Alteplase causes the breakdown of a clot by inducing fibrinolysis.<ref name=":6" />

It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref>

File:"Localisation du thrombus et conséquences 2" by Servier Medical Art is licensed under CC BY 2.0.jpg

Blood flow obstructed by coagulated blood that could potentially be reversed with alteplase.

Medical uses

Alteplase is indicated for the treatment of acute ischemic stroke, acute myocardial infarction, acute massive pulmonary embolism, and blocked catheters.<ref name="AHFS2019" /><ref name="Activase FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Cathflo Activase FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Similar to other thrombolytic drugs, alteplase is used to dissolve clots to restore tissue perfusion, but this can vary depending on the pathology.<ref name=":1">Template:Cite journal</ref><ref name = "Powers_2019">Template:Cite journal</ref> Generally, alteplase is delivered intravenously into the body.<ref name=":6" /> To treat blocked catheters, alteplase is administered directly into the catheter.<ref name=":6">Template:Cite book</ref>

Ischemic stroke

In adults diagnosed with acute ischemic stroke, thrombolytic treatment with alteplase is the standard of care.<ref name = "Powers_2019" /><ref name=":23">Template:Cite journal</ref> Administration of alteplase is associated with improved functional outcomes and reduced incidence of disability.<ref name=":7" /> Alteplase used in conjunction with mechanical thrombectomy is associated with better outcomes.<ref>Template:Cite journal</ref><ref name="pmid 26696642">Template:Cite journal</ref>

Pulmonary embolism

As of 2019, alteplase is the most commonly used medication to treat pulmonary embolism (PE).<ref name=":0">Template:Cite journal</ref> Alteplase has a short infusion time of 2 hours and a half-life of 4–6 minutes.<ref name=":0" /> Alteplase has been approved by the FDA, and treatment can be done via systemic thrombolysis or catheter-directed thrombolysis.<ref name=":0" /><ref>Template:Cite journal</ref>

Systemic thrombolysis can quickly restore right ventricular function, heart rate, and blood pressure in patients with acute PE.<ref name=":3">Template:Cite journal</ref> However, standard doses of alteplase used in systemic thrombolysis may lead to massive bleeding, such as intracranial hemorrhage, particularly in older patients.<ref name=":0" /> A systematic review has shown that low-dose alteplase is safer than and as effective as the standard amount.<ref>Template:Cite journal</ref>

Blocked catheters

Alteplase can be used in small doses to clear blood clots that obstruct a catheter, reopening the catheter so it can continue to be used.<ref name="Cathflo Activase FDA label" /><ref name=":7">Template:Cite book</ref> Catheter obstruction is commonly observed with a central venous catheter.<ref name=":4">Template:Cite journal</ref> Currently, the standard treatment for catheter obstructions in the United States is alteplase administration.<ref name=":5" /> Alteplase is effective and low risk for treating blocked catheters in adults and children.<ref name=":5" /><ref name=":4" /> Overall, adverse effects of alteplase for clearing blood clots are rare.<ref>Template:Cite journal</ref> Novel alternatives to treat catheter occlusion, such as tenecteplase, reteplase, and recombinant urokinase, offer the advantage of shorter dwell times than alteplase.<ref name=":4" />

Contraindications

A person should not receive alteplase treatment if testing shows they are not suffering from an acute ischemic stroke or if the risks of treatment outweigh the likely benefits.<ref name="Powers_2019" /> Alteplase is contraindicated in those with bleeding disorders that increase a person's tendency to bleed and in those with an abnormally low platelet count.<ref name="pmid 26696642" /> Active internal bleeding and high blood pressure are additional contraindications for alteplase.<ref name="pmid 26696642" /> The safety of alteplase in the pediatric population has not been determined definitively.<ref name="pmid 26696642" /> Additional contraindications for alteplase when used specifically for acute ischemic stroke include current intracranial hemorrhage and subarachnoid hemorrhage.<ref>Template:Cite journal</ref> Contraindications for use of alteplase in people with a STEMI are similar to those of acute ischemic stroke.<ref name=":1" /> People with an acute ischemic stroke may also receive other therapies including mechanical thrombectomy.<ref name="Powers_2019" />

Adverse effects

Given that alteplase is a thrombolytic medication, a common adverse effect is bleeding, which can be life-threatening.<ref name=":9">Template:Cite journal</ref> Adverse effects of alteplase include symptomatic intracranial hemorrhage and fatal intracranial hemorrhage.<ref name=":9" />

Angioedema is another adverse effect of alteplase, which can be life-threatening if the airway becomes obstructed.<ref name="Activase FDA label" /> Other side effects may rarely include allergic reactions.<ref name="AHFS2019" />

Mechanism of action

File:Fibrinolysis.svg

Depiction of the pathway that alteplase (t-PA) uses to promote the degradation of a blood clot (fibrin).

Alteplase binds to fibrin in a blood clot and activates the clot-bound plasminogen.<ref name=":6" /> Alteplase cleaves plasminogen at the site of its Arg561-Val562 peptide bond to form plasmin.<ref name=":6" /> Plasmin is a fibrinolytic enzyme that cleaves the cross-links between polymerized fibrin molecules, causing the blood clot to break down and dissolve, a process called fibrinolysis.<ref name=":6" />

Regulation and inhibition

Plasminogen activator inhibitor 1 stops alteplase activity by binding to it and forming an inactive complex, which is removed from the bloodstream by the liver.<ref name=":6" /> Fibrinolysis by plasmin is extremely short-lived due to plasmin inhibitors, which inactivate and regulate plasmin activity.<ref name=":6" />

History

In 1995, a study by the National Institute of Neurological Disorders and Stroke showed the effectiveness of administering intravenous alteplase to treat ischemic stroke.<ref name=":02">Template:Cite journal</ref> This sparked a medical paradigm shift as it redesigned stroke treatment in the emergency department to allow for timely assessment and therapy for ischemic stroke patients.<ref name=":02" />

Society and culture

Alteplase was added to the World Health Organization's List of Essential Medicines in 2019, for use in ischemic stroke.<ref name="WHO21st2">Template:Cite book</ref><ref>Template:Cite book</ref>

Legal status

In May 1987, the United States FDA requested additional data for the drug rather than approve it outright, causing Genentech stock prices to fall by nearly one quarter. The decision was described as a surprise to the company as well as many cardiologists and regulators,<ref>Template:Cite journal</ref> and it generated significant criticism of the FDA, including from The Wall Street Journal editorial board.<ref name = "Daniels">Template:Cite book</ref><ref>Template:Cite news</ref>

After results from two additional trials were obtained,<ref name = "Daniels"/> Alteplase was approved for medical use in the United States in November 1987 for the treatment of myocardial infarction.<ref name="AHFS2019" /><ref name="Activase FDA label" /><ref name="Activase: FDA-Approved Drugs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":8">Template:Cite journal</ref> This was just seven years after the first efforts were made to produce recombinant t-PA, making it one of the fastest drug developments in history.<ref name=":8" />

Economics

The cost of alteplase in the United States increased by 111% between 2005 and 2014, despite there being no proportional increase in the costs of other prescription drugs.<ref name=":33">Template:Cite journal</ref> However, alteplase continues to be cost-effective.<ref name=":33" />

Brand names

Alteplase is sold under brand names Actilyse,<ref name=":03">Template:Cite journal</ref> Activase,<ref name="Activase FDA label" /> and Cathflo Activase.<ref name="Cathflo Activase FDA label" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Controversies

Alteplase is extremely underused in low- and middle-income countries.<ref name=":07">Template:Cite journal</ref> This may be due to its high cost and the fact that it is often not covered by health insurance.<ref name=":07" />

There may be citation bias in the literature on alteplase in ischemic stroke, as studies reporting positive results for tissue plasminogen activator are more likely to be cited in following studies than those reporting negative or neutral results.<ref>Template:Cite journal</ref>

There is a sex difference in the use of intravenous tissue plasminogen activator, as it is less likely to be used for women with acute ischemic stroke than men.<ref name=":12">Template:Cite journal</ref> However, this difference has been improving since 2008.<ref name=":12" />