Thrombolysis in myocardial infarction

Thrombolysis in myocardial infarction

Thrombolysis in myocardial infarction

Chronology of development of thrombolytic agents

First Generation:

Streptokinase
Anisoylated plasminogen streptokinase activator complex (APSAC)

Second Generation:

Alteplase  – Recombinant tissue plasminogen activator

Third Generation:

Reteplase
Lanoteplase
Tenecteplase – TNK tPA

Characteristics of an ideal thrombolytic agent

1. Long half-life
2. Single-bolus administration
3. High fibrin specificity/decreased bleeding and intracranial hemorrhage
4. Resistant to PAI-1
5. Rapid action
6. Reduction in 30 day mortality
7. No effect on blood pressure
8. No antigenicity
9. No re-occlusion
10. Compatible with other intravenous agents
An ideal thrombolytic agent is yet to be developed!

Streptokinase

Streptokinase was the first fibrinolytic to be extensively used in acute myocardial infarction. It is a bacterial protein from group C-ß streptococcus. Streptokinase complexes with plasminogen and converts plasminogen to plasmin. Two placebo-controlled trials, GISSI (1986; 11,712 patients) and ISIS-2 (1988; 17,187 patients) demonstrated the effectiveness of thrombolysis in acute myocardial infarction with streptokinase and documented the benefit in terms of mortality reduction.

Disadvantages/ limitations of streptokinase

Streptokinase requires 1 hour for administration and it is not a direct activator of plasmin. Neither is it fibrin specific. Hence there is a chance for increased systemic bleeding. Streptokinase is immunogenic and allergic reactions can occur rarely. Its effectiveness is decreased if given within 5 days to 12 months of prior use.

Alteplase (recombinant t-PA)

Alteplase (recombinant t-PA) is cloned from human t-PA. Unlike streptokinase, it is non-immunogenic. It has a short half life of 4-8 minutes. Hence it has to be administered over a period of 90 minutes. The 90-minute schedule is an accelerated infusion compared to the longer period of infusion which was used earlier. Alteplase has been shown to reduce mortality in GUSTO-I trial.

Disadvantages / limitations of alteplase

Since it has to be given as an intravenous infusion, pre-hospital use impractical or difficult. Even the “accelerated” schedule takes 90 minutes to administer. Alteplase is inhibited by PAI-1 (Plasminogen activator inhibitor).

Reteplase

Reteplase is the first genetically modified tPA. It is non-immunogenic like tPa. Reteplase has a longer half-life permitting usage as double bolus 30 minutes apart. Its efficacy in comparable to t-PA and has been documented by GUSTO-III trial.

Disadvantages/ limitations of reteplase

30 minutes are required for administration. It is less fibrin specific than alteplase. Reteplase is not resistant to PAI-I.

Lanoteplase

Lanoteplase is a mutant of wild-type t-PA. It is fibrin-selective and has a half-life of 37 minutes, permitting usage as a single bolus. But Lanoteplase causes an increased incidence of intracranial hemorrhage and hence its usage has been discontinued.

Tenecteplase

Tenecteplase is a genetically engineered variant of alteplase. It can be administered as single bolus and it is resistant to inactivation by PAI-1. Tenecteplase is fibrin specific. It is useful for pre-hospital thrombolysis.

Thrombolysis vs primary angioplasty in acute ST elevation myocardial infarction

Fibrinolysis is considered when:

Early presentation (≤3 hours AND delay to invasive strategy)

Invasive strategy is not an option as in
– Cath lab occupied / not available
– Vascular access difficulties
– Lack of access to a skilled PCI lab

Delay to invasive strategy
– Prolonged transport
– (Door-to-Balloon) – (Door-to-Needle) time > 1 hour
– Door-to-balloon time is > 90 min

Contraindications for thrombolysis: Absolute

Any prior intracranial hemorrhage
Known structural cerebral vascular lesion
Known malignant intracranial neoplasm
Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 4.5 hours
Suspected aortic dissection
Active bleeding or bleeding diathesis
Significant closed-head or facial trauma within 3 months

Contraindications for thrombolysis: Relative

Severe uncontrolled hypertension on presentation (> 180 / 110 mmHg)
H/o prior ischemic stroke > 3 months, dementia, or known intracranial pathology not covered in contraindications
Traumatic or prolonged (> 10 minutes) CPR or major surgery (< 3 weeks)
Recent (< 2 to 4 weeks) internal bleeding Noncompressible vascular punctures For streptokinase: prior exposure (>5 days ago) or prior allergic reaction to these agents
Pregnancy
Active peptic ulcer
Current use of anticoagulants: the higher the INR, the higher the risk of bleeding