Alteplase (rtPA)

Aka. t-PA, rt-PA, Actilyse, Activase, Cathflo

CLASS

• Thrombolytic

INDICATIONS

1. Acute STEMI
2. Acute Ischaemic stroke
   • Last seen well within 4.5 hours
   • In potentially disabling ischaemic stroke who meet perfusion mismatch in addition to clinical criteria can be administered up to 9 hours after last seen well (see Stroke Foundation Guidelines) unless planned for endovascular clot retrieval
3. Acute massive pulmonary embolism
   • Including Cardiac arrest due to suspected PE
4. Central venous catheter occlusion

ADMINISTRATION / DOSING

• Intravenous (IV)
• Adults:
  • Acute STEMI:
    • 3-hour infusion: 10mg bolus, then 50 mg over 1st hour, then 40 mg over the following 2 hours (if < 65 kg, adjust the dose so total is < 1.5 mg/kg)
    • Accelerated infusion (90mins) total dose not to exceed 100 mg:
      • 15 mg bolus then,
      • 0.75 mg/kg (up to 50mg) over 30 mins then,
      • 0.5 mg/kg (up to 35 mg) over 60 minutes.
  • Acute massive PE
    • IV bolus of 10 mg, then 90 mg infused over 2 hours (if <65 kg, adjust so the total dose is <1.5 mg/kg)
  • Acute Ischaemic stroke
    • 0.9 mg/kg (max. dose 90 mg), give 10% as a bolus, then the rest over 60 mins.
  • Cardiac arrest with suspected PE:
    • 50mg bolus, consider further 50 mg 15 mins after initial bolus. Then you should continue CPR for 50-90 mins.
  • Central venous catheter occlusion:
    • >30 kg: 2 mg in 2 mL into the occluded catheter, consider second dose 120 mins later
    • <30kg: dose equal to 110% of catheter lumen volume, MAX 2 mg in 2mL
• Children:
  • Refer to paediatric guidelines.
• Administration-specific things:
  • Precipitates in 5% dextrose, must be drawn up in water for injection or 0.9% sodium chloride (Actilyse (Australian version) comes with diluent in package)
  • It comes in a set-up not-unlike Prothrombinex with a diluent and a transfer device. Don’t shake it up, swirl gently.

MECHANISM OF ACTION

• It is a tissue plasminogen activator (tPA)
• It enhances the conversion of plasminogen to plasmin by binding to fibrin initiating fibrinolysis with limited systemic proteolysis.
• The circulating plasminogen that has been activated will cause a systemic lytic state
• Alteplase requires fibrin as a cofactor for the activation of plasminogen

PHARMACEUTICS

• Produced by recombinant DNA technology
• Excipients:
  • Arginine, phosphoric acid, polysorbate 80 and nitrogen
• White lyophilised powder for reconstitution
• When reconstituted it is a colourless to pale yellow transparent solution with a pH of 7.3 and osmolality of 215 mOsm/kg
• Comes with preservative-free sterile water for injection with a transfer device
• Once reconstituted, it must be kept between 2 – 30^oC and then used within 8 hours

PHARMACOKINETICS

• Absorption
  • Initial response: ~30 mins
  • Peak plasma: ~60 mins
• Distribution
  • Distribution half-life: 4.4 – 7 mins
  • Volume of distribution: 8.1 L
• Metabolism
  • Liver – degraded to constituent amino acids
• Elimination
  • Total body clearance: 380 – 570 mL/min
  • Parent compound cleared in 26.5 – 46 mins
  • Initial plasma half-life < 5 mins
  • Following 90 min infusion, T_1/2  26.5 – 46 mins

PHARMACODYNAMICS

• CNS
  • Post-lysis cerebral oedema in the infarcted zone
• CVS
  • Transient drop in blood pressure during administration
  • Arrhythmias with reperfusion after lysis for a myocardial infarction
• RESP
  • Bronchospasm
• OTHER
  • Massive haemorrhage

CONTRAINDICATIONS
RELATIVE

• Everything is a relative contraindication when you’re doing CPR on someone with a massive PE…
• Age >80 review risk vs benefits given the increased risk of ICH

ABSOLUTE

• Known hypersensitivity/anaphylaxis reactions to the medication or related excipients (increased risk with ACEi use)
• Active internal bleeding
• Current intracranial haemorrhage
• Intracranial neoplasm, arteriovenous malformation, aneurysm, or other conditions that may increase haemorrhage
• Bleeding diathesis (e.g. von Willebrand disease, haemophilia, advanced liver disease etc.)
• Recent (i.e. within 3 months) intracranial or intraspinal surgery, major surgery
• Recent (i.e. within 3 months) serious head trauma
• Recent (i.e. within 3 months) stroke, for patients with acute myocardial infarction or pulmonary embolism
• Severe uncontrolled hypertension
• Subarachnoid haemorrhage
• Active peptic ulcer disease
• Prolonged CPR

IN ACUTE ISCHAEMIC STROKE
In addition to the above:

• Symptoms began >4.5 hours prior to infusion start, or when time onset is unknown (or >9 hours in specific circumstances, see Stroke Foundation Guidelines)
• Seizure
• Platelets <100
• Already anticoagulated
• Rapid resolution of symptoms or only minor neurological deficit
• SBP >185 / SBP >110
• Blood glucose <2.8 mmol or >22.2 mmol/L
• Patients < 18 years
• History of prior stroke and Diabetes Mellitus
• Severe stroke as assessed by NIHSS >25 or imaging techniques as higher risk of ICH

IN ACUTE MYOCARDIAL INFARCTION
In addition to the above:

• Ischaemic stroke or TIA in the preceding 6 months, except a current stroke with onset of < 4.5 hours

RISKS

• Reperfusion arrhythmias (in myocardial infarction) – 10%
• Severe haemorrhage 1.8%
• Moderate haemorrhage ~10% (requiring transfusion, but not hemodynamically compromising)
• Gastrointestinal haemorrhage – ~5%
• Intracranial haemorrhage – ~0.5-2% (increases to ~4% for >75 y/o patients)
  • With ~25-50% of those ICH being fatal
• Orolingual angioedema (increased risk with ACEi use): 1-8%
• Rare:
  • Anaphylaxis
  • Seizure
  • Dysphagia
  • Retroperitoneal haemorrhage

• Post-stroke modified Rankin Score (mRS) for those treated within 3 hours from the ITT population (NINDS, ECASS-1, ECASS-II, ATLANTIS):
  • mRS 0 – 1 (favourable): 42% vs 29% (alteplase vs placebo)
  • mRS 0 – 2 (independent): 50% vs 40%
  • mRS 5 – 6 (disability or death): 24% vs 25%
  • Death (all causes): 17.6% vs 17.2%ICH: 34% vs 31.6%
  • Symptomatic ICH: 7.9% vs 1.6%

REVERSAL

• See haemorrhage post-thrombolysis

EVIDENCE

• See STEMI Management
• See Stroke Thrombolysis
• See Pulmonary Embolism
  • Briefly: Associated with reduced pulmonary artery pressure, and faster reduction in thrombus size

References and Links

• Australian Injectable Drugs Handbook, 8th Edition. (2023). Retrieved 28 April 2023, from https://aidh.hcn.com.au/
• Australian Medicines Handbook. (2023). Retrieved 28 April 2023 from https://amhonline.amh.net.au/       
• IBM Micromedex. (2023). Retrieved 28 April 2023, from https://www.micromedexsolutions.com
• MIMS Online. (2023). Retrieved 28 April 2023, from https://www.mimsonline.com.au
• Stroke Foundation. (2022). Clinical Guidelines for Stroke Management. Living Clinical Guidelines for Stroke Management. https://informme.org.au/guidelines/living-clinical-guidelines-for-stroke-management

FOAMED

• Resus Review — TPA mixing tutorial (2013)

LITFL

• Drugs for cardiac arrest
• Haemorrhage post-thrombolysis
• Pharm 101: Thrombolytic Agents
• STEMI management
• Tenecteplase
• Thrombolytic Agents
• Thrombolysis for PE
• Thrombolysis for Stroke
• A three-part series into the use of thrombolysis in stroke
  • Part 1 – Why we should be very wary of using clot busting drugs to treat acute strokes
  • Part 2 – the use of thrombolysis as a treatment for acute stroke
  • Part 3 – Schrödinger’s Fence  

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