Fibrinolytic Drugs

Synonyms: 'clot busters' and plasminogen activators.

Streptokinase (derived from haemolytic streptococci) has the longest history of use of drugs in this class. It combines with plasminogen to form an active complex which degrades fibrin, breaking up thrombus.

Newer drugs developed since the 1980s are alteplase (recombinant plasminogen activator), reteplase and tenecteplase. These are modified forms of plasminogen activator with the significant advantage that they can be given by rapid IV bolus rather than IV infusion. They also tend to have longer half-lives which again makes them easier to deliver.

Fibrinolytics are used when there is an urgent need to break down fibrin clot.

• Acute cardiac syndrome with ST elevation. A spectrum of acute cardiac syndrome (ACS) is now recognised bridging unstable coronary artery disease to unstable angina and myocardial infarction (MI). This recognises the common pathology of thrombus formation on complicated atheromatous plaque. Further definition depends on clinical presentation, ECG findings and cardiac biochemical markers. One variant of ACS, ST elevation MI (STEMI) has been shown to benefit from urgent thrombolysis. Non-ST ACS requires a different approach.
  • Thrombolysis can achieve rapid reperfusion of the infarcting myocardium and dramatically reverse ST changes, reducing mortality and morbidity.
  • Approximately 50,000 people receive it per annum in England and Wales.⁵
  • Mortality rates in ST-elevation MI are reduced with a NNT of 53, representing 18 fewer deaths per 1000 patients treated (using pooled data across the class).⁶
  • There is a non-linear time benefit to getting early treatment with little benefit beyond 12 hours of the start of the event. The NSF for coronary heart disease demanded a call-to-needle time of less than 60 minutes.⁷
  • Where primary percutaneous coronary intervention (PCI) and thrombolysis services are both available and can be carried out promptly, PCI is preferable as it confers a greater degree of myocardial salvage at all time points and is less time-dependent compared to thrombolysis. However, consensus opinion is that where primary PCI cannot be performed within 90 minutes of diagnosis, thrombolysis should be given.⁸
• Acute ischaemic stroke
  • Alteplase has the potential to improve outcome but it is a high risk treatment and should only be administered within 3 hours of the onset of the stroke symptoms, where haemorrhage has been definitively excluded (requiring neuroimaging) and in a specialist centre with the appropriate experience and expertise.⁹ It is not recommended in those over 80.
  • A large observational study (Safe Implementation of Thrombolysis in Stroke Monitoring Study or SITS-MOST) provided reassuring evidence of safety and benefit of alteplase in clinical practice, even when used by centres with little previous experience, and we move towards a future where 'brain attacks' will routinely be managed as medical emergencies like MIs.¹⁰
  • Thrombolysis significantly increases symptomatic and fatal intracranial haemorrhage but reduces survivors' end disability with a net reduction in the proportion of patients dependent in activities of daily living following an ischaemic stroke.¹¹
• Life-threatening venous thrombosis and pulmonary embolus - thrombolysis with tPA or streptokinase is sometimes considered in unstable patients with suspected or confirmed massive PE where cardiac arrest is imminent. The alternative is surgical thrombectomy. Expert guidance is required.
• Acute arterial thromboembolism.
• Intra-arterial thrombolysis has a place in the treatment of acute limb ischaemia.
• Treatment of central retinal arterial and venous thrombosis.^12,13
• Low dose intracoronary streptokinase used immediately post primary percutaneous coronary intervention (PCI) appears to improve myocardial perfusion but not long term left ventricular size or function.¹⁴
• Less acutely:
  • Loculated pleural empyema or effusion. Fibrinolytics (streptokinase, urokinase and tPA), administered via a chest drain, have been used in the treatment of complicated parapneumonial effusions.¹⁵ Persistent pleural effusions typically become fibrinous and loculated and the use of intrapleural fibrinolytics appears safe¹⁶ and may improve drainage. However the largest randomised trial to date showed no benefit.¹⁷ They are also used palliatively to treat malignant pleural effusions where they provide symptomatic relief, improve effusion drainage and enable pleurodesis.¹⁸
  • Blocked venous catheters - recombinant urokinase restored total patency in 75% of an unselected cohort of occluded central venous access devices.¹⁹ Alteplase achieved similar results with paediatric patients.²⁰
  • Blocked or thrombosed arteriovenous shunts
  • Wound desloughing (topical streptokinase)

Fibrinolytics can cause bleeding: avoid them where patients are at high-risk of bleeding or where the consequences of a bleed would be devastating. However, most contra-indications are not absolute since the benefits may outweigh the risk in the particular circumstance (given the high mortality associated with MI).
Always consult local protocols and be aware that contra-indications change - for example, menstruation and proliferative diabetic retinopathy are no longer considered absolute contra-indications.²¹ Recognise that pressure to give the drug quickly should not be at the expense of a proper assessment of the patient and risks.

Include:

• Bleeding is usually limited to the site of injection but intracerebral or distant site bleeding may occur. The risk of haemorrhagic stroke is increased (an additional 4 events per 1000 patients treated) and other haemorrhage (an additional 7 major non-cerebral bleeds per 1000 patients treated) when fibrinolytics are used in MI.⁶ Intracranial bleeding when it occurs is associated with high mortality and long-term disability in survivors.
• Hypotension is commonly seen with streptokinase used in acute MI.
• Back pain.
• Allergy including rash, flushing and uveitis. Anaphylaxis is rare but again more common with streptokinase.
• Nausea and vomiting are common side-effects.

• Standard emergency management of ST elevation-ACS²³:
  • Sit patient up.
  • Give oxygen by face mask.
  • Aspirin 300 mg orally, if not already given pre-hospital or contra-indication.
  • With ischaemic ECG changes or elevation of cardiac enzymes, also give clopidogrel 300mg orally.
  • Cardiac monitoring and 12 lead ECG.
  • IV access and bloods (FBC, U&E, glucose, cardiac enzymes).
  • IV opioid analgesia and anti-emetic (metoclopramide or cyclizine).
  • Beta-blockers, nitrates and other standard anti-anginal drugs as appropriate.
  • GP IIb/IIa receptor antagonists are not routinely used in patients with ST elevation receiving thrombolytic treatment as there appears no overall benefit.
  • All patients should also receive anticoagulation, normally with low molecular weight (LMW) heparin at full treatment dose. This should last for more than 48 hours, and in practice is continued for 8 days post-event or until discharge or coronary revascularisation.
  • An insulin infusion should be used to normalize blood glucose.
• Check reperfusion is indicated:
  • Any patient with history of chest pain/discomfort of <12 hours
  • Associated with ECG changes:
    • Persistent ST elevation of more than 1 mm in 2 adjacent limb leads
    • ST elevation of 2 mm or more in 2 or more contiguous chest leads
    • New onset bundle branch block (the original study²⁴ did not differentiate between Left and right bundle branch block, many guidelines specify only acute LBBB and whilst acute RBBB is usually accompanied by ST elevation in the context of an MI, it is unknown whether thrombolysis for RBBB alone is helpful.)
• Check for contra-indications to thrombolysis.
• Explain the procedure and possible risks: ensure that the patient understands and consents.
• Always ask the patient if they have been treated with streptokinase in the past - if they have, use an alternative drug.
• Which thrombolytic agent is the most appropriate? NICE guidance⁵ recommends that the choice of thrombolytic drug for treating acute myocardial infarction should take account of the likely balance of benefit and harm to individual patients. There are no clear differences on statistical comparison between the drugs in terms of their clinical efficacy,²⁵ streptokinase is the safest drug as far as the risk of haemorrhagic stroke but carries a greater risk of allergy, heart failure and possibly major bleeds requiring transfusion.⁵ Streptokinase is also the most cost-effective drug.²⁵ Follow local protocols.
• Administer thrombolysis (door-to-needle target is now 20 minutes⁷) and monitor carefully for hypotension or reperfusion arrhythmias. Make sure a defibrillator is close by. If hypotension occurs with streptokinase, tilt the bed head down and elevate the patient's legs and slow/stop the infusion until BP recovers and try restarting at a lower rate.

• Where allergic reactions occur with streptokinase (characterised by rash and flushing), stop the infusion and restart at a lower rate.
• Bleeding at injection site may be controlled by pressure, but serious bleeding calls for stopping the thrombolytic, use of coagulation factors and even antifibrinolytic drugs (such as tranexamic acid)
• Where patients continue to have severe symptoms, ongoing evidence of myocardial dysfunction or widespread ST elevation, thrombolysis is unlikely to have achieved reperfusion. Seek help from the cardiologists, further 'rescue' thrombolysis or emergency PCI may be required. Rescue thrombolysis more than doubles the risk of bleeding complications²¹ and PCI is the usual preferred option under these circumstances.²⁶

Pre-hospital thrombolysis reduces the risk of dying in hospital from any cause compared to thrombolysis after arrival²⁷ so is gradually being implemented in the NHS where population geography or the accessibility of acute hospital facilities makes it otherwise difficult to give the drugs within the necessary time frame. It remains uncommon in the UK - only about 5% of all thrombolysis is currently given by trained paramedics.⁵Different models of pre-hospital delivery exist including:

• Community hospital administration (by nurse specialist or GP)
• GP administration (at the point of contact)
• Mobile coronary care units²⁸
• Telemetry-supported paramedic administration
• Autonomous paramedic administration²⁹

However it is delivered, there needs to be high quality training for all staff involved, clear clinical protocols and robust clinical governance for monitoring its use and outcomes.⁷

There are practical problems associated with giving controlled-rate infusions in pre-hospital settings and, for streptokinase, concerns about monitoring and managing allergic reactions and hypotension in a community setting. Given these considerations, NICE recommends the use of bolus drugs (reteplase or tenecteplase) in the pre-hospital setting.⁵