Fibrinolytic drugs

Thrombolytic agents act by promoting the activity of circulating plasminogen.

There is a long history of use of one, streptokinase, whereas the other three, alteplase, reteplase and tenecteplase, are newer options.

Streptokinase is derived from streptococcal bacteria. Streptokinase is given by intravenous (IV) infusion.
Alteplase was introduced in the late 1980s. It is essentially the same as the naturally occurring activator of plasminogen in the human body, and is produced by recombinant DNA technology. It is given by IV infusion.
Reteplase and tenecteplase have been introduced more recently (1997 and 2001, respectively). They are new modified forms of plasminogen activator and can be given by rapid IV bolus injection, rather than infusion.

The timing of administration is a crucial factor determining the extent of benefit achieved by thrombolysis, and treatment should ideally be given as soon as possible (normally up to 12 hours) after the onset of AMI symptoms.

Complications

Bleeding complications are the main risks associated with thrombolysis. The most important bleeding complication is haemorrhagic stroke, which occurs in 0.5–1.0% of patients and is associated with high mortality and long-term disability in survivors. Bleeding may occur at the injection site, in the gastrointestinal tract or elsewhere.
Hypotension may also occur.
The risks and benefits of giving thrombolysis need to be considered in individual patients and settings.
The risk of haemorrhagic stroke following thrombolysis increases with age and blood pressure. Thrombolysis is contraindicated in individuals with bleeding disorders or a history of recent haemorrhage, trauma, surgery or acute cerebrovascular event. For full details of side effects and contraindications, see the Summary of Product Characteristics for the individual agents.


Administration of Heparin and Aspirin

Heparin (an anticoagulant) is given with all of the thrombolytic drugs except streptokinase. It is usually administered as an IV bolus injection before thrombolysis, followed by an IV infusion. When given with tenecteplase the heparin dose is weight adjusted.
Aspirin (an antiplatelet agent) is also usually given with any thrombolytic drug, because it delivers a mortality benefit in its own right.

Agents

Generic names	Streptokinase	Alteplase		Reteplase	Tenecteplase
Trade names	Streptase	Actilyse (rtPA)		Rapilysin	Metalyse
		Accelerated regimen	Standard regimen
Administration window	12 hours	6 hours	6 to 12 hours	12 hours	6 hours
	IV infusion over one hour	Initial IV bolus injection, then 2 IV infusions (1st over 30 mins, 2nd over 60 mins)	Initial bolus injection, then 5 infusions over 3 hours	Two IV boluses 30 mins apart	Single weight-adjusted IV bolus injection
Anti-streptococcal antibodies production	Yes	No
Costs	£80 to £90	£600		£716	£700 to £770
Complications	Haemorrhagic stroke Bleeding Hypotension Allergic reactions Anaphylaxis

Streptokinase (Streptase) is indicated up to 12 hours after onset of symptoms. It is administered as an IV infusion over 1 hour. It has been extensively studied and remains widely used. Streptokinase is associated with hypotension, infrequent allergic reactions and, rarely, anaphylaxis. Patients treated with streptokinase develop anti-streptococcal antibodies, which can inactivate the drug if subsequent treatment is needed. Consequently in current UK practice, patients are usually treated with streptokinase only once. It is estimated that around one-third of people with AMI have contraindications to streptokinase. A recent survey found that 82% of hospitals in England use streptokinase for eligible patients experiencing their first AMI; other data suggest that streptokinase represents between 53% and 65% of thrombolytic drug use. Streptokinase costs £80 to £90 per patient (excluding VAT) (British National Formulary 43, March 2002).

Alteplase (Actilyse, recombinant human tissue plasminogen activator, rtPA) can be delivered in a standard or accelerated regimen. The accelerated regimen, which is much more commonly used, is indicated up to 6 hours after symptom onset and is delivered by an initial IV bolus injection, followed by two IV infusions, the first given over 30 minutes and the second over 60 minutes. The standard regimen is indicated between 6 and 12 hours after symptom onset and requires a bolus injection followed by five infusions over 3 hours. Like the other newer drugs, alteplase does not stimulate the production of antibodies, so it can be used repeatedly. It is estimated that alteplase represents between 23% and 32% of thrombolytic drug use in the UK. Alteplase costs £600 per patient (excluding VAT) (British National Formulary 43, March 2002).


Reteplase (Rapilysin) is indicated up to 12 hours after symptom onset. It is given as two IV bolus injections 30 minutes apart. It is estimated that reteplase represents between 12% and 15% of thrombolytic drug use in the UK. Reteplase costs £716 per patient (excluding VAT) (British National Formulary 43, March 2002).


Tenecteplase (Metalyse) is indicated up to 6 hours after symptom onset. It is administered as a single (weight-adjusted) IV bolus injection. It is estimated that tenecteplase currently accounts for around 1% of thrombolytic drug use in the UK, the manufacturer indicates that the proportion is increasing. Tenecteplase costs £700 to £770 per patient (excluding VAT) (British National Formulary 43, March 2002).

Delivering thrombolytic drugs

The National Service Framework (NSF) for coronary heart disease (CHD) in England and Tackling CHD in Wales specify that eligible patients with AMI should be given thrombolysis within 60 minutes of calling for professional help (‘call-to-needle’ time) and should receive thrombolysis within 20 minutes of arriving at hospital (‘door-to-needle’ time). It is also suggested that it may be appropriate to provide pre-hospital thrombolysis where local ‘call-to-hospital’ times are likely to be over 30 minutes. The NHS Plan in England gave a commitment to train and equip ambulance paramedics to provide thrombolysis.

Direct admission to a coronary care unit (CCU) is often not possible, and accident and emergency (A&E) departments are being encouraged to administer thrombolysis to reduce delays in door-to-needle times.

Currently, streptokinase is the only thrombolytic that paramedics are authorised to administer under the Prescription Only Medicines (Human Use) Order 1997.


In-hospital thrombolysis models include:

• assessment and treatment in A&E
• rapid assessment in A&E and transfer to CCU
• direct admission to CCU.

Pre-hospital models include:

• community hospital administration (nurse or general practitioner)
• general practitioner administration (at the point of contact)
• telemetry-supported paramedic administration
• autonomous paramedic administration.

Evidence: In hospital thrombolysis 

Accelerated alteplase = Tenecteplase = Reteplase

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Standard alteplase = streptokinase

In summary, given the evidence on clinical effectiveness, it can be concluded that, in the hospital setting, in terms of mortality:

• standard alteplase is as effective as streptokinase
• reteplase is at least as effective as streptokinase, and
• tenecteplase is as effective as accelerated alteplase.

If accelerated alteplase is believed to be superior to streptokinase, then indirectly tenecteplase would also be considered to be superior to streptokinase.

Conclusions regarding the equivalence of reteplase compared with accelerated alteplase depend on the interpretation of GUSTO-III.

Furthermore, if reteplase is considered to be equivalent to accelerated alteplase, then this indirectly implies that reteplase is as effective as tenecteplase.

Important differences in major adverse events between the thrombolytic agents are also apparent. The newer drugs are associated with a higher risk of haemorrhagic stroke compared with streptokinase, but there are no apparent differences in the frequency of haemorrhagic stroke between accelerated alteplase and reteplase (GUSTO-III), or between accelerated alteplase and tenecteplase (ASSENT-2).

However, compared with streptokinase, the newer drugs may also be associated with a lower incidence of congestive heart failure.

In addition, allergic reactions are more common with streptokinase than with the other drugs, and major bleeds (leading to transfusions) may also be more common with streptokinase, although the evidence on this is not consistent across the trials. There is also some evidence that tenecteplase may be associated with lower rates of major bleeds and heart failure than accelerated alteplase.

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