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Alteplase
Clinical data
Trade namesActivase, others
Other namest-PA, rt-PA
AHFS/Drugs.comMonograph
MedlinePlusa625001
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Intravenous
Drug classTissue plasminogen activator
ATC code
Legal status
Legal status
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
FormulaC2569H3928N746O781S40
Molar mass59042.52 g·mol−1

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.[5] Alteplase is given by injection into a vein or artery.[5] Alteplase is the same as the normal human plasminogen activator produced in vascular endothelial cells[6] and is synthesized via recombinant DNA technology in Chinese hamster ovary cells (CHO). Alteplase causes the breakdown of a clot by inducing fibrinolysis.[7]

It is on the World Health Organization's List of Essential Medicines.[8]

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

Medical uses

[edit]

Alteplase is indicated for the treatment of acute ischemic stroke, acute myocardial infarction, acute massive pulmonary embolism, and blocked catheters.[5][2][3] Similar to other thrombolytic drugs, alteplase is used to dissolve clots to restore tissue perfusion, but this can vary depending on the pathology.[9][10] Generally, alteplase is delivered intravenously into the body.[7] To treat blocked catheters, alteplase is administered directly into the catheter.[7]

Ischemic stroke

[edit]

In adults diagnosed with acute ischemic stroke, thrombolytic treatment with alteplase is the standard of care.[10][11] Administration of alteplase is associated with improved functional outcomes and reduced incidence of disability.[12] Alteplase used in conjunction with mechanical thrombectomy is associated with better outcomes.[13][14]

Pulmonary embolism

[edit]

As of 2019, alteplase is the most commonly used medication to treat pulmonary embolism.[15] Alteplase has a short infusion time of 2 hours and a half-life of 4–6 minutes.[15] Alteplase has been approved by the US Food and Drug Administration, and treatment can be done via systemic thrombolysis or catheter-directed thrombolysis.[15][16]

Systemic thrombolysis can quickly restore right ventricular function, heart rate, and blood pressure in patients with acute PE.[17] However, standard doses of alteplase used in systemic thrombolysis may lead to massive bleeding, such as intracranial hemorrhage, particularly in older patients.[15] A systematic review has shown that low-dose alteplase is safer than and as effective as the standard amount.[18]

Blocked catheters

[edit]

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.[3][12] Catheter obstruction is commonly observed with a central venous catheter.[19] Currently, the standard treatment for catheter obstructions in the United States is alteplase administration.[6] Alteplase is effective and low risk for treating blocked catheters in adults and children.[6][19] Overall, adverse effects of alteplase for clearing blood clots are rare.[20] Novel alternatives to treat catheter occlusion, such as tenecteplase, reteplase, and recombinant urokinase, offer the advantage of shorter dwell times than alteplase.[19]

Contraindications

[edit]

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.[10] 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.[14] Active internal bleeding and high blood pressure are additional contraindications for alteplase.[14] The safety of alteplase in the pediatric population has not been determined definitively.[14] Additional contraindications for alteplase when used specifically for acute ischemic stroke include current intracranial hemorrhage and subarachnoid hemorrhage.[21] Contraindications for use of alteplase in people with a STEMI are similar to those of acute ischemic stroke.[9] People with an acute ischemic stroke may also receive other therapies including mechanical thrombectomy.[10]

Adverse effects

[edit]

Given that alteplase is a thrombolytic medication, a common adverse effect is bleeding, which can be life-threatening.[22] Adverse effects of alteplase include symptomatic intracranial hemorrhage and fatal intracranial hemorrhage.[22]

Angioedema is another adverse effect of alteplase, which can be life-threatening if the airway becomes obstructed.[2] Other side effects may rarely include allergic reactions.[5]

Mechanism of action

[edit]
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.[7] Alteplase cleaves plasminogen at the site of its Arg561-Val562 peptide bond to form plasmin.[7] 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.[7]

Regulation and inhibition

[edit]

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.[7] Fibrinolysis by plasmin is extremely short-lived due to plasmin inhibitors, which inactivate and regulate plasmin activity.[7]

History

[edit]

In 1995, a study by the National Institute of Neurological Disorders and Stroke showed the effectiveness of administering intravenous alteplase to treat ischemic stroke.[23] 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.[23]

Society and culture

[edit]

Alteplase was added to the World Health Organization's List of Essential Medicines in 2019, for use in ischemic stroke.[24][25]

[edit]

In May 1987, the US Food and Drug Administration (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,[26] and it generated significant criticism of the FDA.[27][28]

After results from two additional trials were obtained,[27] Alteplase was approved for medical use in the United States in November 1987 for the treatment of myocardial infarction.[5][2][29][30] 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.[30]

Economics

[edit]

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.[31] However, alteplase continues to be cost-effective.[31]

Brand names

[edit]

Alteplase is sold under the brand names Actilyse,[32] Activase,[2] and Cathflo Activase.[3][33]

Controversies

[edit]

Alteplase is underused in low- and middle-income countries.[34] This may be due to its high cost and the fact that it is often not covered by health insurance.[34]

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.[35]

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.[36] However, this difference has been improving since 2008.[36]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Alteplase

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from Grokipedia
Alteplase is a recombinant tissue (tPA), a produced via technology in Chinese hamster ovary cells, that binds to in thrombi and converts plasminogen to , initiating to dissolve blood clots. It is administered intravenously as a thrombolytic agent primarily for acute thrombotic emergencies, including ST-elevation (STEMI) to reduce mortality and congestive incidence, acute ischemic within a 3- to 4.5-hour window from symptom onset to improve neurologic outcomes, massive to enhance and reduce right ventricular dysfunction, and restoration of patency in occluded central venous access devices. First approved by the U.S. in 1987 for acute based on trials demonstrating significant mortality reduction through coronary reperfusion, alteplase's indications expanded to ischemic following the 1995 NINDS trial, which established a 30% higher likelihood of minimal or no at three months despite a 6.4% absolute increase in symptomatic . In , randomized trials like the 2002 NEJM study showed accelerated resolution of hemodynamic instability when combined with , though without overall mortality benefit in submassive cases. Its defining characteristics include high fibrin specificity minimizing systemic fibrinogen depletion compared to older thrombolytics like , yet this is tempered by well-documented hemorrhagic risks—major bleeding occurs in 5-10% of STEMI patients and up to 6% symptomatic in —necessitating rigorous contraindications such as active bleeding, recent trauma, or uncontrolled . Guidelines from bodies like the restrict its use to eligible patients within precise time frames, reflecting empirical trade-offs where timely reperfusion causally outweighs bleeding hazards in select cohorts, but overuse in extended windows or contraindicated cases amplifies adverse events without proportional gains.

Medical Uses

Acute Ischemic Stroke

Intravenous alteplase, a recombinant tissue plasminogen activator, is indicated for the treatment of acute ischemic in adults exhibiting symptoms consistent with , provided treatment is initiated within 3 hours of symptom onset, as per FDA approval based on the NINDS trials. The recommended dose is 0.9 mg/kg body weight, not exceeding 90 mg total, administered as a 10% bolus over 1 minute followed by infusion of the remainder over 60 minutes, after confirmation of ischemic stroke via non-contrast CT to exclude hemorrhage. The NINDS rt-PA Stroke Study Group trials, conducted in the 1990s, provided level 1 evidence that alteplase improves neurologic recovery when given within 3 hours, with treated patients 30% to 50% more likely to achieve minimal disability ( score of 0-1) at 3 months compared to , despite a 6.4% risk of symptomatic . Subsequent pooled analyses of major trials (NINDS, ECASS, ATLANTIS, EPITHET) confirmed a time-dependent benefit, with earlier treatment correlating to better functional outcomes up to 4.5 hours post-onset. The ECASS III trial extended eligibility to a 3- to 4.5-hour window for select patients (age <80 years, no extensive ischemia on imaging, NIHSS score ≤25, without diabetes and prior stroke), demonstrating an odds ratio of 1.34 for favorable outcomes (modified Rankin Scale 0-1) at 90 days versus placebo. Although the FDA label specifies the 3-hour window, AHA/ASA guidelines endorse up to 4.5 hours for eligible patients without absolute contraindications, emphasizing rapid door-to-needle times under 60 minutes to maximize recanalization and neuroprotection. Recent meta-analyses reaffirm alteplase's net benefit in reducing disability, though with higher hemorrhage rates in extended windows, underscoring the need for individualized risk assessment.

Pulmonary Embolism

Alteplase is indicated for systemic thrombolysis in high-risk (massive) pulmonary embolism (PE), defined by sustained hypotension with systolic blood pressure below 90 mm Hg or requiring inotropic support, as per American Heart Association and European Society of Cardiology guidelines. This therapy aims to accelerate clot dissolution, improving right ventricular function and hemodynamics to reduce mortality, which approaches 25-50% in untreated massive PE without reperfusion. The standard dose is 100 mg administered intravenously over 2 hours, with concurrent unfractionated heparin infusion initiated after thrombolysis to avoid early rethrombosis. In intermediate-risk (submassive) PE, characterized by right ventricular dysfunction without hypotension, routine use of alteplase is not recommended due to net harm from bleeding risks outweighing benefits in hemodynamically stable patients. The PEITHO trial, evaluating thrombolysis (using tenecteplase, with analogous effects to alteplase) in 1,005 such patients, demonstrated a reduction in the composite endpoint of death or hemodynamic decompensation (2.6% vs. 5.6% with anticoagulation alone) at 7 days, but at the cost of higher rates of major extracranial bleeding (6.3% vs. 1.2%) and hemorrhagic stroke (2.4% vs. 0.2%). Long-term follow-up from PEITHO confirmed no mortality benefit at 3 years despite early hemodynamic gains. Guidelines reserve thrombolysis for intermediate-risk cases with clinical deterioration during initial anticoagulation. Studies on reduced-dose alteplase (e.g., 50 mg over 2 hours) in PE suggest comparable efficacy to full-dose in resolving clots and stabilizing hemodynamics, potentially with lower bleeding incidence, particularly in Asian populations or select high-risk patients. However, full-dose remains the evidence-based standard for massive PE, supported by FDA approval for this indication based on trials showing improved pulmonary perfusion and survival. Overall, alteplase outperforms older thrombolytics in reducing PE recurrence and pulmonary artery systolic pressure, though major hemorrhage occurs in 9-20% of treated patients, necessitating careful patient selection excluding active bleeding or recent surgery.

Acute Myocardial Infarction

Alteplase, a recombinant tissue plasminogen activator, is indicated for the treatment of acute ST-elevation myocardial infarction (STEMI) to achieve coronary thrombolysis and reduce mortality as well as the incidence of congestive heart failure. The U.S. Food and Drug Administration approved alteplase for this use in 1987 based on early trials demonstrating improved patency and survival. In clinical practice, it serves as an alternative to primary percutaneous coronary intervention (PCI) when PCI cannot be performed within 120 minutes of first medical contact, particularly in patients with symptom onset within 12 hours. The standard accelerated dosing regimen for patients weighing 67 kg or more is a 15 mg intravenous bolus, followed by 50 mg infused over the next 30 minutes, and then 35 mg over the subsequent 60 minutes, for a total dose of 100 mg. For patients under 67 kg, the total dose is adjusted to 1.25 mg/kg, with the bolus remaining 15 mg and subsequent infusions scaled accordingly to not exceed 100 mg. Administration should occur as soon as possible after symptom onset, ideally within 30 minutes of hospital arrival, and is typically accompanied by adjunctive therapies such as aspirin, heparin, and clopidogrel. The efficacy of alteplase was established in the GUSTO-I trial, a randomized study of 41,021 patients with acute myocardial infarction, which compared accelerated alteplase plus intravenous heparin to streptokinase regimens. This regimen reduced 30-day mortality to 6.3% versus 7.3% with streptokinase and subcutaneous heparin (p=0.001), with an absolute risk reduction of 1% and number needed to treat of 100. Angiographic substudies confirmed higher rates of TIMI grade 3 flow (artery fully patent) at 90 minutes with alteplase (53-54%) compared to streptokinase (32-37%). The LATE trial further extended the therapeutic window, showing a 25% relative mortality reduction when alteplase was given 6-12 hours after symptom onset. In current guidelines, primary PCI remains the reperfusion strategy of choice due to lower mortality and reinfarction rates compared to thrombolysis, but alteplase is recommended as a class I intervention in appropriate STEMI candidates without timely PCI access. Recent studies explore adjunctive low-dose intracoronary alteplase during PCI to enhance microvascular perfusion, though systemic intravenous use predominates in non-PCI settings. Overall, thrombolytic therapy with alteplase has contributed to a historical decline in AMI mortality, though its role has diminished with widespread PCI availability.

Catheter Occlusion

Alteplase, marketed as Cathflo Activase for this indication, is FDA-approved for restoring function to central venous access devices (CVADs), including central venous catheters and ports, occluded by thrombus. This approval, granted in October 2001, followed clinical trials demonstrating efficacy in clearing thrombotically occluded devices without systemic thrombolysis. The agent is instilled directly into the occluded lumen, targeting localized clot dissolution via conversion of plasminogen to plasmin, which degrades fibrin in the thrombus. Standard dosing involves reconstituting alteplase to 1 mg/mL and instilling 2 mg (2 mL) into each occluded catheter lumen, allowing a dwell time of up to 2 hours before aspiration and flushing with saline. If function is not restored, a second identical dose may be administered after an additional 2-hour dwell. Lower doses of 1 mg have shown comparable efficacy to 2 mg in retrospective studies, with success rates exceeding 80% and reduced drug volume, though 2 mg remains the FDA-recommended regimen. Clinical trials confirm high restoration rates: in a multicenter study of 426 adults with occluded CVADs, up to two 2-mg doses restored function in 88% of cases, with 73% success after the first dose. Pediatric trials, including a prospective open-label study of 100 children, reported 85-90% efficacy for central venous catheter occlusions, with rapid clearance often within 30-120 minutes. Overall clearance rates across studies range from 86% to 95% for thrombotic occlusions, outperforming urokinase (a previously used agent withdrawn in 1999 due to contamination concerns). Alteplase is ineffective for non-thrombotic causes, such as mechanical kinking or malposition, requiring diagnostic confirmation via aspiration attempts or imaging. Safety profiles indicate low systemic exposure due to localized administration, with serious bleeding events in fewer than 1% of cases and no intracranial hemorrhages reported in pivotal trials. Minor adverse events, including catheter-related infections or transient bacteremia, occur at rates below 5%, comparable to untreated occlusions. Guidelines from organizations like the Oncology Nursing Society recommend alteplase as first-line therapy for CVAD occlusions after ruling out other etiologies.

Contraindications and Precautions

Absolute Contraindications

Absolute contraindications to alteplase administration are conditions in which the potential for severe, life-threatening hemorrhage substantially outweighs any therapeutic benefit due to the drug's fibrinolytic mechanism, which promotes systemic clot dissolution and plasmin activation. These are delineated in the FDA-approved prescribing information for Activase (alteplase) and corroborated by clinical guidelines from organizations such as the . Common to all indications (acute myocardial infarction, pulmonary embolism, and acute ischemic stroke) are:
  • Active internal bleeding.
  • Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or ischemic stroke.
  • Presence of intracranial conditions increasing bleeding risk, such as neoplasm, arteriovenous malformation, or aneurysm.
  • Bleeding diathesis, including but not limited to current anticoagulant use with elevated INR (>1.7), within 48 hours with prolonged aPTT, or platelet count <100,000/mm³.
  • Severe uncontrolled hypertension (systolic >180 mm Hg or diastolic >110 mm Hg despite treatment).
For acute ischemic stroke specifically, additional absolute contraindications include current (confirmed by CT or MRI) and , as these directly contraindicate due to near-certain hemorrhagic transformation. Prior to administration, must exclude hemorrhage, and eligibility requires weighing these risks against time-sensitive benefits within therapeutic windows (e.g., 3-4.5 hours for ). to alteplase or its components also precludes use across indications.

Relative Contraindications and Risk Factors

Relative contraindications to alteplase therapy encompass patient-specific factors that substantially increase the likelihood of adverse events, particularly symptomatic (sICH), but do not categorically preclude treatment when the anticipated benefits—such as restored in acute ischemic , myocardial infarction (MI), or (PE)—outweigh the risks. These are delineated in guidelines from organizations like the /American Stroke Association (AHA/ASA), where decisions hinge on individualized risk-benefit evaluation rather than absolute exclusion. Common across indications include recent major or severe trauma within 14 days, due to potential hemorrhage at operative or injury sites, with limited registry data showing variable sICH rates (e.g., 0-12.5% in small cohorts). For acute ischemic stroke, relative contraindications specifically include advanced age over 80 years, associated with higher overall mortality (odds ratio up to 1.6) and less favorable functional outcomes despite comparable sICH incidence to younger patients; mild or rapidly improving symptoms ( Stroke Scale [NIHSS] score ≤4), where 20-30% may still face substantial without intervention; and severe stroke (NIHSS >25), linked to elevated sICH risk (up to 15% in some trials) though not precluding use within 3-4.5 hours if benefits are deemed superior. Additional stroke-specific factors are at onset with postictal deficits, risking misdiagnosis of stroke mimics like Todd's paralysis (sICH in <1% of reported cases); recent gastrointestinal or genitourinary hemorrhage within 21 days; recent MI within 3 months, with rare reports of cardiac rupture; pregnancy; and arterial puncture at a noncompressible site within 7 days, posing uncontrollable bleeding hazards. Key risk factors amplifying bleeding propensity with alteplase include older age (incremental sICH odds increase per decade), low body weight (<50 kg), Asian ethnicity, and high stroke severity, as evidenced by meta-analyses showing 4-fold overall ICH elevation post-thrombolysis and 2.3% absolute excess fatal intracerebral hemorrhage in the first week. Uncontrolled hypertension (systolic >185 mmHg or diastolic >110 mmHg despite treatment) and borderline (international normalized ratio 1.7-1.9 or platelet count 100,000-150,000/μL) further heighten risks, often warranting caution or alternative strategies. In PE and MI contexts, overlapping risks like recent or similarly apply, with emphasis on extracranial hemorrhage monitoring. These factors underscore the need for pre-administration imaging, laboratory assessment, and multidisciplinary consultation to mitigate complications.

Adverse Effects

Hemorrhagic Risks

Alteplase administration carries a substantial of hemorrhagic complications due to its fibrinolytic mechanism, which degrades clots and can impair normal , leading to both intracranial and systemic bleeding. The most critical concern is symptomatic (sICH), defined as parenchymal , , or causing neurological deterioration within 36 hours of treatment. In acute ischemic patients, sICH rates following intravenous alteplase range from 2% to 7%, with higher incidences observed in real-world registries compared to controlled trials. For instance, individual studies report sICH in 1.7% to 8.8% of thrombolyzed patients, often associated with a exceeding 40%. This is dose-dependent and exacerbated by delayed treatment initiation or overly rapid administration, though faster door-to-needle times may marginally reduce sICH odds by approximately 4% per 15-minute decrement. In pivotal trials such as NINDS, alteplase increased incidence to 6.4% versus 0.6% with , highlighting a net absolute risk elevation despite overall functional benefits. Meta-analyses confirm this proportional hazard, with alteplase elevating odds across populations, though absolute risks remain low in carefully selected patients without contraindications. Risk prediction models incorporating factors like age, stroke severity (NIHSS score), and imaging findings (e.g., early infarct signs) aid in estimating individual probability, with scores such as SPAN-100 or iScore demonstrating modest predictive accuracy (AUC 0.6-0.7). Hemorrhagic transformation without symptoms occurs more frequently (up to 30-40% in imaging follow-up) but rarely alters management unless progressing to . Systemic non-intracranial , including gastrointestinal, genitourinary, and retroperitoneal sites, affects 5-10% of patients, with major events (e.g., requiring transfusion or intervention) in 1-5% depending on indication. In , major rates reach 9.24% with alteplase versus 3.42% with anticoagulation alone, often at access sites or mucosae. Less severe manifestations include ecchymosis (1%), gingival (<1%), and epistaxis (<1%). The FDA prescribing information warns of delayed hemorrhage (beyond 24 hours) during concurrent anticoagulation, emphasizing monitoring and avoidance of intramuscular injections or recent arterial punctures. Overall, while alteplase's risks are mitigated by patient selection, they contribute to treatment withholding in up to 30% of eligible cases.

Non-Hemorrhagic Adverse Events

Orolingual , a potentially life-threatening swelling of the or oropharynx, occurs in approximately 1% to 5.1% of patients receiving intravenous alteplase for acute ischemic , with higher rates observed in those with recent inhibitor (ACEI) use or insular cortex . This anaphylactoid reaction typically manifests within 2 hours of infusion and is attributed to bradykinin-mediated mechanisms exacerbated by alteplase's fibrinolytic activity, rather than IgE-mediated . Management involves airway monitoring, epinephrine, antihistamines, and corticosteroids, though may be required in severe cases. Hypersensitivity reactions, including urticaria, , laryngeal , and rare , have been reported in clinical trials and post-marketing surveillance across indications, with an estimated incidence below 0.02% for overt . These events are generally mild but can progress to anaphylactoid shock, as evidenced by case reports of , , and shortly after infusion. Allergic-type reactions necessitate immediate discontinuation and supportive care, though true IgE-mediated to alteplase remains unconfirmed in most instances. Other non-hemorrhagic events include fever, , and /, observed in post-marketing reports particularly during acute treatment, where reperfusion may contribute to arrhythmias or . Cholesterol embolization, a rare complication presenting as or renal failure, has been linked to alteplase in case reports but lacks defined incidence due to underreporting and factors like catheterization. In acute ischemic , post-marketing data also note seizures and , potentially related to rather than direct toxicity. Overall, these events underscore the need for close monitoring, though their causality is often confounded by underlying acute conditions.

Pharmacology and Mechanism of Action

Biochemical Mechanism

Alteplase, a recombinant variant of human tissue plasminogen activator (tPA), functions as a that catalyzes the conversion of plasminogen to , the primary fibrinolytic , in a process highly dependent on the presence of . This fibrin-enhanced activation occurs because alteplase binds directly to polymerized within thrombi via its N-terminal domain (residues 4-50) and kringle 2 domain (residues 175-261), which possess high-affinity binding sites for exposed residues on . The binding induces a conformational change in alteplase, accelerating its catalytic rate for plasminogen cleavage by up to 500- to 1000-fold compared to free solution conditions. The catalytic mechanism involves the triad (His322, Asp371, Ser478) in the C-terminal domain of alteplase, which cleaves plasminogen at the specific Arg561-Val562 to generate active two-chain . , in turn, proteolytically degrades the cross-linked scaffold of the by hydrolyzing internal bonds adjacent to and residues, leading to the solubilization of fibrin degradation products (FDPs) such as D-dimers. This localized amplification is further potentiated as exposes additional plasminogen binding sites ( residues) on partially degraded , recruiting more plasminogen and perpetuating at the clot surface. In the absence of fibrin, alteplase demonstrates low intrinsic activity toward free plasminogen due to rapid inhibition by (PAI-1) and poor substrate affinity, minimizing systemic lytic effects and conferring relative specificity. The single-chain form of alteplase (scu-PA equivalent in activity) can undergo limited autocleavage to a two-chain form upon binding, enhancing its efficiency without significant circulating activation.

Pharmacokinetics and Pharmacodynamics

Alteplase, a recombinant form of human tissue plasminogen activator, promotes primarily by binding to in thrombi, which facilitates the conversion of plasminogen to and subsequent degradation of cross-links. This action is mediated through high-affinity interactions with lysine-binding sites on and plasminogen, conferring relative specificity for fibrin-bound plasminogen over free circulating plasminogen at endogenous concentrations. At pharmacologic doses, however, systemic activation of plasminogen occurs, leading to measurable fibrinogen depletion and increased circulating degradation products, though less extensively than with . Following intravenous administration, alteplase demonstrates complete due to direct entry into the systemic circulation. Its distribution is characterized by rapid binding to within thrombi and , with a approximating plasma volume. Pharmacokinetic profiles reveal biphasic elimination: an initial alpha half-life of fewer than 5 minutes, reflecting rapid plasma clearance, and a beta terminal of up to 40 minutes, influenced by ongoing hepatic uptake and thrombus binding. Total plasma clearance ranges from 380 to 570 mL/min in patients with acute , primarily via in the liver, with minimal renal . Liver blood flow significantly impacts clearance rates, as reduced perfusion prolongs elimination in conditions like . No dose proportionality is observed beyond certain thresholds due to saturable hepatic clearance mechanisms.

Endogenous Regulation and Inhibition

Tissue plasminogen activator (tPA), the endogenous counterpart to recombinant alteplase, is primarily synthesized and secreted by vascular endothelial cells in response to stimuli such as , , or , ensuring localized activation of at sites of deposition. Its production is transcriptionally regulated by , hypoxia-inducible factors, and cytokines, maintaining basal plasma levels of approximately 5-10 ng/mL in healthy individuals. The activity of endogenous tPA is predominantly inhibited by (PAI-1), the principal physiological regulator of the fibrinolytic system, which forms an irreversible 1:1 stoichiometric complex with tPA, leading to its rapid inactivation and hepatic clearance. PAI-1, secreted by endothelial cells, platelets, adipocytes, and hepatocytes, circulates in plasma at concentrations of 5-50 ng/mL, with elevated levels associated with thrombotic risk due to impaired ; its expression is upregulated by factors including insulin, II, and tumor necrosis factor-alpha. Plasminogen activator inhibitor-2 (PAI-2), primarily intracellular and placenta-derived, provides secondary inhibition but is less relevant in plasma-mediated regulation. Fibrin-bound tPA exhibits enhanced plasminogen activation and partial protection from PAI-1 inhibition due to conformational changes that reduce inhibitor access, thereby promoting clot-specific while free tPA in circulation is swiftly neutralized to prevent systemic . Downstream, generated is antagonized by α2-antiplasmin, which irreversibly binds free plasmin with high affinity (Ki ≈ 10^{-8} M), though fibrin-associated plasmin evades this inhibition more effectively, sustaining localized . Additional attenuation occurs via thrombin-activatable inhibitor (TAFI), which, upon activation by thrombin-thrombomodulin complex, carboxypeptidase-activates to cleave C-terminal lysines from partially degraded , diminishing plasminogen recruitment and thus dampening tPA-mediated amplification of . This multilayered endogenous control—spanning tPA inhibition, neutralization, and substrate modification—balances thrombolytic potential against hemorrhagic risk, with dysregulation (e.g., high PAI-1) linked to arterial in observational studies.

Clinical Evidence and Efficacy

Evidence from Key Trials for Stroke

The National Institute of Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) Stroke Trial, conducted between 1991 and 1994, was a randomized, double-blind, placebo-controlled study involving 624 patients with acute ischemic stroke treated within 3 hours of symptom onset. Patients received intravenous alteplase at 0.9 mg/kg (maximum 90 mg) or placebo. The primary outcome was neurological recovery, assessed by the National Institutes of Health Stroke Scale (NIHSS) at 24 hours and minimal or no disability (modified Rankin Scale [mRS] score of 0-1) at 3 months. Alteplase resulted in a 12% absolute increase in the proportion of patients achieving minimal or no disability at 3 months (39% vs. 26% with placebo; odds ratio [OR] 1.7, 95% CI 1.2-2.6), with benefits persisting at 1 year. Symptomatic intracranial hemorrhage (sICH) occurred in 6.4% of alteplase-treated patients versus 0.6% in placebo (p<0.001), but overall mortality at 3 months was similar (17% vs. 21%). This trial established alteplase's efficacy for reducing disability despite hemorrhagic risks, leading to FDA approval in 1996 for use within 3 hours. Subsequent trials extended the time window. The European Cooperative Acute Stroke Study III (ECASS III), a 2008 randomized, placebo-controlled trial of 821 patients with ischemic treated 3-4.5 hours post-onset, used the same alteplase dose. At 90 days, 52.4% of alteplase patients had an mRS score of 0-1 versus 45.2% with (OR 1.34, 95% CI 1.02-1.76; number needed to treat [NNT] 14), indicating improved functional outcomes. sICH rates were higher with alteplase (2.4% vs. 0.2%; OR 27.7, 95% CI 3.3-230.9), and mortality was comparable (8.2% vs. 10.3%). ECASS III supported guideline extensions to 4.5 hours for eligible patients without major imaging exclusions. Earlier ECASS trials (I and II) yielded mixed results, with ECASS I (1995) showing no overall benefit due to high protocol violations and hemorrhagic transformations in patients with early CT hypodensity, while ECASS II (1998) suggested potential efficacy but failed primary endpoints amid inclusion of mismatched cases.08020-9/abstract) The trial (1998-2003), evaluating alteplase 3-5 hours post-onset in 613 patients, did not demonstrate efficacy, with no significant difference in excellent neurological recovery at 90 days ( 0; 32% vs. 29%; p=0.625) and higher (7.0% vs. 1.1%). A of , ECASS, and NINDS data confirmed time-dependent benefits, with odds of good outcome decreasing sharply beyond 3 hours (OR 2.8 within 90 minutes vs. 1.5 at 3-4.5 hours). The Third International Trial (IST-3, 2000-2011), involving 3035 patients randomized within 6 hours (many beyond 3 hours), found alteplase increased the proportion alive and independent at 6 months (52.4% vs. 46.3%; OR 1.29, 95% CI 1.10-1.51; NNT 8 overall, but 4.6 for 0-3 hours). was elevated (7% vs. 1%), with early mortality hazard (OR 1.44, 95% CI 1.15-1.81), but long-term survival favored alteplase in prognostic subgroups. These trials collectively affirm alteplase's net benefit in select acute ischemic patients, primarily within 4.5 hours, balancing recanalization gains against risks, though real-world adherence to exclusion criteria influences outcomes.15692-4/fulltext)60768-5/fulltext)

Evidence for Myocardial Infarction and Pulmonary Embolism

Alteplase, administered as an accelerated infusion with intravenous , demonstrated superior efficacy over in treating acute ST-elevation (STEMI) in the Global Utilization of and Tissue for Occluded Coronary Arteries (GUSTO-I) trial, a randomized study of 41,021 patients conducted from to 1993. The 30-day was 6.3% in the alteplase group compared to 7.3% in the group (p=0.001), representing a 1% absolute and 14% relative reduction, primarily due to improved early coronary reperfusion and reduced reinfarction rates. One-year follow-up data confirmed sustained benefit, with alteplase saving approximately 10 lives per 1,000 treated patients compared to . These outcomes established alteplase as a standard thrombolytic for STEMI in settings without timely primary (PCI) access, though subsequent trials have shown PCI achieves higher reperfusion rates and lower mortality without the hemorrhagic risks of . Despite its efficacy, alteplase's use in carries significant risks, including a 0.72% incidence of in GUSTO-I, higher than streptokinase's 0.54% (p=0.02), underscoring the need for careful patient selection based on age, infarct location, and absence of contraindications. Real-world applications have reinforced these findings, with meta-analyses of early thrombolytic trials indicating a 25-30% mortality reduction overall when administered within 6 hours of symptom onset, though benefits diminish beyond 12 hours. Current guidelines prioritize alteplase in resource-limited environments where PCI delays exceed 120 minutes, reflecting its causal role in clot dissolution via plasminogen activation but tempered by the shift toward mechanical reperfusion strategies that avoid systemic . For (PE), alteplase is primarily evidenced for massive PE with hemodynamic instability, where it rapidly reduces pressure and improves right ventricular function. In a prospective study of 25 patients with massive PE and shock treated in the , a 100 mg bolus of alteplase over 2 hours achieved hemodynamic stabilization in 90% of cases within 2 hours, with no major events reported, supporting its in acute decompensation. Similarly, bolus regimens have shown comparable thrombolytic effects to infusions in resolving thrombi, with faster administration linked to quicker symptom relief in hemodynamically unstable patients. In submassive (intermediate-risk) PE, a randomized trial of 256 patients found that alteplase plus , versus heparin alone, reduced the combined endpoint of death or hemodynamic deterioration from 24.7% to 11% at 7 days (p=0.03), driven by improved echocardiographic right ventricular function, though without mortality benefit and with doubled major bleeding risk (21.1% vs 9.8%). Meta-analyses affirm hemodynamic benefits in high-risk PE but highlight net uncertainty in lower-risk cases due to outweighing gains in stable patients. Lower doses (e.g., 50 mg) have shown equivalent to full 100 mg in some observational data for massive PE, potentially mitigating hemorrhage while preserving clot .

Real-World Outcomes and Meta-Analyses

A 2023 of randomized controlled trials (RCTs) pooling data from over 6,700 patients with acute ischemic treated with intravenous alteplase within 3-4.5 hours demonstrated an of 1.44 (95% CI 1.17-1.76) for achieving a score of 0-1 at 3 months compared to , alongside an increased risk of symptomatic (OR 3.45, 95% CI 2.24-5.32). Real-world registry data from the Safe Implementation of in -Monitoring Study (SITS-MOST), involving over 6,400 patients, reported a symptomatic rate of 7.1% and mortality of 17.3% within 3 months, with functional in 58.0% at 3 months, reflecting outcomes in broader populations beyond strict trial criteria. Long-term follow-up from Danish registries indicated that alteplase-treated patients had a of 0.58 (95% CI 0.50-0.68) for 5-year mortality compared to untreated ischemic patients, adjusted for confounders. For acute , a 2017 network of fibrinolytics in ST-elevation MI ranked alteplase highly for 30-day mortality reduction versus (OR 0.66, 95% CI 0.57-0.77), with comparable efficacy to but higher non-intracranial risk.31441-1/abstract) Real-world data from the Global Registry of Acute Coronary Events (GRACE) showed alteplase use associated with in-hospital mortality of 5.6% in eligible patients, lower than untreated cohorts, though with 1.2% major rates. In , a 2014 meta-analysis of RCTs found systemic with alteplase reduced all-cause mortality (OR 0.53, 95% CI 0.32-0.88) and recurrent (OR 0.40, 95% CI 0.17-0.93) compared to alone in hemodynamically stable patients, but increased major (OR 2.73, 95% CI 1.91-3.90) and (OR 4.97, 95% CI 1.20-20.5). Observational studies in submassive reported right ventricular function improvement in 70-80% of alteplase-treated cases, with in-hospital mortality under 3%, though complications occurred in up to 10%. A 2023 confirmed alteplase's in reducing hemodynamic instability but highlighted persistent risks relative to anticoagulation monotherapy.

History

Discovery and Early Development

Tissue-type plasminogen activator (t-PA), the endogenous enzyme mimicked by alteplase, was first identified in tissues in 1947 by Tage Astrup and Svend Permin, who described a plasminogen-activating factor distinct from other fibrinolytics. Progress stalled until the mid-1970s, when Désiré Collen and Arnold Billiau demonstrated high-level secretion of t-PA from the Bowes cell line, a variant obtained in 1975 that proved invaluable for isolation due to its prolific production. In 1979, Collen purified sufficient quantities of natural t-PA for detailed study, establishing its role as a with fibrin-binding domains that confer clot-specific activation of plasminogen. Concurrently, Desire Collen's group and D.C. Rijken independently isolated t-PA from culture fluids, characterizing it as a 70 kDa single-chain comprising 527 . The early development of alteplase as a recombinant form of t-PA addressed supply constraints of natural extraction, with Genentech initiating efforts in the early 1980s through collaboration with Collen. In 1982, Desiree Pennica's team cloned the full-length human t-PA cDNA from a library derived from Bowes melanoma mRNA and expressed it in Escherichia coli, yielding initial non-glycosylated recombinant t-PA (rt-PA). Production was soon optimized in Chinese hamster ovary (CHO) cells to generate glycosylated alteplase, mirroring the native protein's post-translational modifications essential for stability and activity. Preclinical validation followed rapidly, with 1980 studies by Collen and colleagues confirming rt-PA's thrombolytic potency in rabbit pulmonary embolism models at doses achieving rapid clot lysis without systemic hypofibrinogenemia. These milestones enabled progression to human pharmacokinetics and safety assessments by 1981.

Pivotal Clinical Trials and Regulatory Approvals

Alteplase, marketed as Activase, received initial U.S. (FDA) approval on November 13, 1987, for the management of acute (AMI), based on early clinical trials demonstrating its ability to achieve coronary artery reperfusion. Pivotal supporting evidence came from angiographic studies such as the in (TIMI) phase I trial, which reported recanalization rates of approximately 70% in occluded coronary arteries within 90 minutes of alteplase administration. Subsequent confirmation of mortality benefit arose from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial, a randomized study of 41,021 patients with AMI published in 1993, which showed that an accelerated 90-minute infusion regimen of alteplase reduced 30-day mortality by 1% (6.3% vs. 7.3% with ) compared to standard streptokinase therapy, despite a slightly higher risk. In 1990, the FDA expanded approval to include acute massive with unstable , supported by multicenter trials evidencing rapid reductions in pressure and improvements in right ventricular function, such as a 1987 study by Goldhaber et al. demonstrating hemodynamic stabilization in patients receiving 100 mg over 2 hours. These trials prioritized fibrin-specific over systemic effects seen with earlier agents like , though larger randomized mortality trials were not conducted prior to approval. The most contentious approval process culminated in 1996 for acute ischemic , following the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Study, a two-part randomized, placebo-controlled trial involving 624 patients treated within 3 hours of symptom onset. Part 1 assessed early neurological improvement, showing a higher proportion of alteplase-treated patients (47% vs. 39%) achieving minimal or no deficit at 24 hours, while Part 2 demonstrated a 30% relative increase in favorable functional outcomes at 3 months (defined as minimal or no disability on the ; 39% vs. 26%), despite a 6.4% absolute increase in symptomatic (6.4% vs. 0.6%). This approval, granted on June 18, 1996, marked the first evidence-based thrombolytic for , though debates persist over the trial's generalizability due to strict eligibility criteria and the balance of benefits against bleeding risks in real-world settings.

Comparisons with Alternative Thrombolytics

Tenecteplase

Tenecteplase is a genetically modified variant of recombinant tissue plasminogen activator (tPA), engineered with three key mutations in the alteplase molecule: asparagine-to-threonine substitution at position 103, threonine-to-isoleucine at positions 296-297, and lysine-to-arginine at position 333. These alterations confer a longer plasma of 20-24 minutes compared to 4-6 minutes for alteplase, enabling single-bolus intravenous administration rather than the 90-minute infusion required for alteplase. Additionally, exhibits 14- to 15-fold greater specificity and 80-fold increased resistance to inhibition by (PAI-1), potentially reducing systemic fibrinogen depletion and non-clot relative to alteplase. In acute ST-elevation (STEMI), , administered as a weight-based bolus (e.g., 30-50 mg depending on body weight), demonstrated noninferiority to accelerated alteplase in the 1999 ASSENT-2 trial, achieving similar 30-day mortality rates (approximately 6%) with comparable major bleeding risks but greater convenience due to bolus dosing. For acute ischemic (AIS), lacks U.S. FDA approval as of 2025 but has been evaluated in multiple trials as an off-label alternative to alteplase; meta-analyses of randomized controlled trials indicate similar functional outcomes ( 0-2 at 90 days) at doses of 0.25 mg/kg, with potentially lower rates of symptomatic (sICH; risk ratio 0.83) and mortality compared to alteplase 0.9 mg/kg. However, higher doses (0.4 mg/kg) showed inferior outcomes and increased sICH in trials like NOR-TEST-2A (2024), highlighting dose-dependent risks. Pharmacodynamic advantages of tenecteplase include faster initiation and reduced treatment delays in resource-limited settings, as bolus administration simplifies logistics versus alteplase's protocol. Real-world data and phase 3 trials like ACT (2023) support noninferiority in AIS reperfusion rates, though alteplase remains the standard due to longer-established evidence from NINDS (1995) and ECASS trials. Criticisms include limited head-to-head data in large, diverse populations and concerns over risk in tenecteplase, potentially higher than alteplase in some cohorts ( 3.12). Overall, tenecteplase's profile positions it as a promising successor for select indications, pending broader regulatory endorsement and cost analyses.

Other Agents like Streptokinase and Urokinase

, derived from beta-hemolytic streptococci, functions as a non-fibrin-specific thrombolytic by forming a complex with plasminogen to activate systemically, leading to widespread fibrinogen depletion and increased risk compared to fibrin-specific agents like alteplase. In acute (MI), large trials such as GUSTO-I demonstrated that accelerated alteplase regimens achieved higher 90-minute coronary patency rates (54% vs. 37%) and lower 30-day mortality (6.3% vs. 7.3%) than , though overall mortality differences were modest when combined with . is associated with greater antigenicity, causing allergic reactions in up to 5% of patients and in 10-20%, precluding repeat use within 6-12 months due to neutralizing antibodies; alteplase lacks this . For ischemic , trials like ASK showed excessive (10.3% vs. 1.2% with ), rendering it unsuitable, whereas alteplase at 0.9 mg/kg within 4.5 hours remains the standard with a 6% symptomatic ICH rate in NINDS. Urokinase, a direct originally isolated from human and now often recombinant, also induces non-fibrin-specific , resulting in more pronounced systemic hypofibrinogenemia than alteplase and comparable or higher risks in peripheral arterial . In (PE), randomized comparisons indicate alteplase achieves faster clot resolution (e.g., improved right ventricular function within 24 hours) with similar overall efficacy to urokinase, but without the need for initial bolus priming; urokinase requires activation steps and longer infusions. For acute ischemic , limited data from recombinant prourokinase trials show functional outcomes akin to alteplase ( 0-2 at 90 days: ~50%), but with potentially higher ICH risk due to non-specificity; urokinase is rarely used systemically for stroke owing to these concerns. models predict urokinase's rapid but elevated intracranial hemorrhage probability from fibrinogen depletion, contrasting alteplase's targeted action at thrombi.
AgentFibrin SpecificityKey Adverse EffectsPrimary Indications vs. Alteplase Advantage
StreptokinaseLowAntigenicity (5%), hypotension (10-20%), major bleeds (higher non-stroke)MI: Alteplase superior patency/mortality; Stroke: Not used (high ICH)
UrokinaseLowSystemic fibrinogen drop, ICH riskPE/Peripheral: Alteplase faster; Stroke: Similar efficacy, higher bleed potential

Controversies and Criticisms

Debates on Net Benefit in Stroke Treatment

The approval of alteplase for acute ischemic stemmed primarily from the 1995 NINDS trial, which reported a 30% relative increase in the likelihood of minimal or no at three months ( 1.7; 95% CI 1.2-2.6), but this came with a 6.4% rate of symptomatic (sICH) compared to 0.6% in , alongside no significant mortality difference. Critics have highlighted methodological flaws, including baseline imbalances in stroke severity between treatment arms (with alteplase patients having slightly milder strokes in the 91-180 minute window) and reliance on a global treatment effect that masked potential harms in subgroups, such as those with severe strokes or uncertain diagnoses. These issues have fueled arguments that the trial's positive results may reflect statistical artifacts rather than robust causal , particularly given the absence of mandatory advanced to confirm ischemic , leading to potential inclusion of hemorrhagic or mimic strokes. Subsequent meta-analyses have quantified a modest absolute benefit—approximately 3.2% improvement in good neurologic outcomes ( 0-1) across nine randomized involving 6,756 patients—but at the cost of a 5.4% absolute increase in and 2.5% rise in mortality, yielding a number needed to treat of 8 for benefit alongside a number needed to harm of 19 for hemorrhage. Organizations like the American Academy of have cited such data to argue against routine use, asserting that the evidence fails to demonstrate a net patient-oriented benefit when weighing functional gains against life-threatening risks, especially in non- settings where patient selection is less rigorous. Real-world registries, contrasting with , often report lower and higher adverse events; for instance, observational studies indicate rates exceeding 7% in community practice, attributed to broader application beyond strict criteria like early presentation (<3 hours) and low NIHSS scores. Debates intensify over population-level net benefit, with proponents emphasizing time-dependent causal effects in highly selected early presenters (e.g., benefit confined to <4.5 hours in meta-analyses), while skeptics point to underpowered analyses and the dilution of gains in extended windows or comorbid patients, where harms predominate. For minor strokes (NIHSS ≤5), recent meta-analyses find no significant advantage of alteplase over best medical therapy alone for functional , questioning expansion to low-risk cases. Overall, while persists in aggregated data, the narrow therapeutic margin—coupled with diagnostic uncertainties and potential overtreatment—has led some experts to advocate for individualized risk-benefit assessment over universal guideline endorsement, prioritizing empirical outcomes over modeled projections.

Risks of Overuse and Diagnostic Errors

Alteplase administration in misdiagnosed cases poses significant risks, particularly when acute ischemic is incorrectly identified. misdiagnosis rates for symptoms range from 3% to 30%, with some tPA-treated cohorts showing up to 4% misdiagnosis, including conditions like seizures or intracranial tumors mistaken for ischemia. Failure to detect early or subtle on non-contrast CT, despite standard protocols, can result in exacerbating the bleed, leading to catastrophic outcomes such as rapid deterioration or death. Although the incidence of unsuspected hemorrhage prompting tPA is low due to requirements, reported cases highlight near-100% poor when occurs in confirmed primary hemorrhage. Stroke mimics, comprising up to 25-30% of tPA recipients in some series, often include benign entities like or metabolic disturbances, but confer no thrombolytic benefit while exposing patients to systemic bleeding risks. Inappropriate use in these patients amplifies harm without offsetting gains, as alteplase's net benefit in confirmed ischemic is modest (number needed to treat approximately 8 for functional improvement, versus number needed to harm 17 for symptomatic ). Overextension beyond strict evidence-based criteria, such as the 3-hour window from pivotal NINDS trials or in low-NIHSS cases, further contributes to overuse, where risks like or extracranial hemorrhage predominate absent clot . Dosing errors represent another facet of overuse, with overdose linked to heightened and mortality. Regional network analyses report tPA prescription and administration errors in 64% of cases, including overdoses in 4.6% associated with fatal intraparenchymal hematomas. Factors such as incorrect weight-based calculation or failure to adjust for -specific dosing (versus protocols) exacerbate these risks, underscoring the need for standardized verification to mitigate iatrogenic harm. Overall, these diagnostic and application pitfalls highlight alteplase's narrow , where overuse erodes potential benefits in eligible patients.

Influence of Industry and Guidelines

The development and promotion of alteplase (marketed as Activase by , a subsidiary) have been intertwined with industry funding to professional organizations that author treatment guidelines, raising concerns about potential in recommendations for its use in acute ischemic stroke. The (AHA) and American Stroke Association (ASA) have issued guidelines designating intravenous alteplase as a class I recommendation (strongly recommended) with level A evidence for eligible patients within 3-4.5 hours of symptom onset, based on pivotal trials like NINDS. However, analyses have identified extensive financial relationships between guideline authors and pharmaceutical sponsors, including , which has provided grants, educational funding, and support for initiatives like the AHA's Get With The Guidelines-Stroke program aimed at improving thrombolytic administration rates. Critics, including a 2004 BMJ investigation, documented that the AHA received over $1 million from between 1996 and 2000, coinciding with guideline endorsements of alteplase despite modest trial benefits (e.g., absolute risk reduction of about 13% for good outcomes in NINDS, offset by 6% symptomatic hemorrhage risk), and absence of published conflict-of-interest disclosures in early guidelines. A 2011 review of 72 influential thrombolytic studies found that 56% were industry-sponsored, with sponsored trials 3.4 times more likely to report positive outcomes favoring alteplase over non-sponsored ones, suggesting sponsorship bias shapes the evidentiary base underpinning guidelines. Subsequent AHA/ASA guidelines, such as the 2018 and 2019 updates, have improved disclosure requirements, but a 2019 analysis revealed that 56% of authors for the 2018 early management guidelines had industry ties, including to , prompting calls for stricter mitigation. AHA representatives have countered that funding does not influence content, asserting panelist independence and rigorous evidence review processes, as stated in responses to allegations. Nonetheless, independent meta-analyses, such as those questioning net benefit in broader real-world populations beyond trial criteria, highlight how guideline-driven "door-to-needle" time targets—promoted via industry-supported quality metrics—may encourage overuse, with U.S. registries showing hemorrhage rates up to 6-7% in routine practice versus 6.4% in NINDS. Genentech's ongoing support for education and trials, including for alteplase alternatives like (now FDA-approved for as of March 2025), continues to intersect with guideline evolution, though direct causation of recommendations remains debated.

Society and Culture

Brand Names and Manufacturers

Alteplase is marketed under several brand names worldwide, primarily as a recombinant tissue plasminogen activator for thrombolytic therapy. , the primary brand is Activase, produced by , Inc., a subsidiary of , for indications including acute ischemic , acute , and . A related formulation, Cathflo Activase, is also manufactured by specifically for restoring function to occluded central venous access devices. Internationally, alteplase is sold under the brand Actilyse by , particularly in and other regions, for similar thrombolytic uses. originally developed alteplase using technology, with initial FDA approval for Activase in 1987 for . As a biologic product, alteplase has limited generic competition due to manufacturing complexities, though active pharmaceutical (API) suppliers exist for potential biosimilars in select markets; however, no widely approved U.S. generics were available as of 2024. Supply constraints for Activase have occasionally arisen, with allocating product amid demand fluctuations.
Brand NamePrimary ManufacturerKey IndicationsRegions Primarily Marketed
ActivaseAMI, AIS, PE
Cathflo ActivaseCentral venous catheter occlusion
ActilyseAMI, AIS, PE and international
Alteplase, marketed as Activase in the United States, received initial approval from the U.S. (FDA) on November 13, 1987, for the management of acute to improve ventricular function and reduce the incidence of congestive , based on trials demonstrating reduced mortality. Subsequent FDA approval for acute ischemic occurred in June 1996, limited to administration within three hours of symptom onset, following the National Institute of Neurological Disorders and Stroke trial results. Additional indications include (approved concurrently with AMI in 1987) and restoration of function to central venous access devices (as Cathflo Activase, approved September 13, 2001). In , alteplase (as Actilyse) was authorized by the (EMA) for acute prior to indications, with EMA approval for acute ischemic granted on November 22, 2002, initially for use within three hours of onset following a referral procedure harmonizing member state authorizations. This was extended in to 4.5 hours based on pooled trial data showing net benefit in extended windows. The EMA has also assessed versions, confirming for products like those from various manufacturers since the reference product's long market presence. Globally, alteplase holds prescription-only status (Rx-only in the U.S., Schedule 4 in , and equivalent restrictions elsewhere), requiring administration by qualified healthcare professionals due to risks of hemorrhage and the need for rapid thrombolytic intervention. It is not classified as a under international narcotic conventions. In 2019, the added alteplase to its List of specifically for ischemic treatment, recognizing its role in resource-limited settings despite access challenges. Regulatory updates have included label revisions for safety monitoring, such as FDA's 2015 labeling emphasizing blood pressure control to mitigate risk. No major revocations or suspensions have occurred, though ongoing monitors post-marketing adverse events.

Economics, Cost-Effectiveness, and Access

Alteplase treatment for acute ischemic typically requires a dose of up to 90 mg, with the wholesale acquisition for a 100 mg in the United States exceeding $8,600 as of 2023 data, reflecting a more than doubling of prices over the prior decade from approximately $6,400 in 2017 under CMS reimbursement. This escalation has raised concerns about affordability, particularly as hospital charges can approach $20,000 per administration, though actual payer reimbursements vary by insurance and setting. In international markets, prices are lower, with 20 mg vials available for around $700 through verified pharmacies, but U.S. list prices remain a significant economic burden for healthcare systems. Cost-effectiveness analyses generally support alteplase's use in eligible acute ischemic patients within the treatment window, showing favorable incremental cost-effectiveness ratios from healthcare and societal perspectives. For instance, a Brazilian study reported 0.35 additional quality-adjusted life years (QALYs) gained versus standard care at an ICER of approximately $12,000 per QALY, while a U.K.-based model estimated net societal savings due to reduced long-term and rehabilitation costs. However, low-dose regimens do not yield overall healthcare cost reductions compared to standard dosing, and outcomes are sensitive to door-to-needle times and patient selection. Compared to , alteplase incurs higher medication costs—up to $1,700 more per case in some analyses—and less favorable lifetime QALYs and total expenses, with tenecteplase demonstrating dominance in multiple economic models for . Global access to alteplase remains uneven, with thrombolysis rates under 5% in low- and middle-income countries (LMICs) versus 10-15% in high-income settings, primarily due to high drug costs, inadequate , and prehospital exceeding the 4.5-hour . In LMICs, affordability barriers limit uptake, as alteplase's expense—often unsubsidized—exacerbates disparities, while issues and clinician training gaps compound underutilization. Even in the U.S., coverage variations affect equity, with distributional analyses highlighting higher costs per QALY in underserved populations, though Medicare and private payers generally reimburse eligible cases. Efforts to improve access include advocacy for generics and policy reforms, but persistent financial and logistical hurdles restrict broader implementation.

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