Which thrombolytics are currently available for treating acute myocardial infarction? Who should receive which one? What newer agents are there?

Thrombolysis
Natural thrombolysis occurs via the action of plasmin on fibrin thrombi. Plasmin is formed from plasminogen by cleavage of a single peptide bond. Plasmin is a non-specific protease and dissolves coagulation factors as well as fibrin clots. Three thrombolytic agents are currently available. Streptokinase (SK) forms a non-covalent link with plasminogen. The resultant conformational change exposes the active site on plasminogen to induce the formation of plasmin. Tissue plasminogen activator (tPA) is a serine protease and binds directly to fibrin via a lysine site, activating fibrin-bound plasminogen. The theoretical advantages of tPA are its increased specificity and potency because of its direct effect on fibrin-bound plasminogen. Being the product of recombinant DNA technology, there should be no allergic reaction to tPA. Unlike SK which should be used only once, tPA can be used repeatedly. Some, but not all, of these theoretical advantages translate into definite clinical benefit. Recently reteplase, a variation of tPA, has become available.

The Fibrinolytic Therapy Trialists Collaborative Group1 summarised results from thrombolytic trials encompassing more than 100,000 patients. The overall relative risk reduction in 35 day mortality with treatment was 18% (p < 0.00001). The mortality at this time was ~13%, reduced to 8–9% with treatment. However, in real life where the population is older than in the trials the true mortality is about 18–20%. Administration of a thrombolytic saves about 30 lives in a 1000 in those presenting within 6 hours of symptom onset but only 20 lives in a 1000 when patients receive treatment between 6 and 12 hours after symptom onset. Aspirin has an independent beneficial effect on mortality and can be chewed.2 The LATE Trial showed no benefit 12 hours after onset of symptoms. Judging the onset of symptoms can be difficult and may be influenced by collateral flow from another artery. If a patient presents with stuttering symptoms over 24 hours or so but has had severe pain over a few hours and has an appropriately abnormal ECG, thrombolytic treatment should be seriously considered. Prehospital thrombolysis has been shown to reduce cardiac mortality compared to in-hospital thrombolysis by 17% (p = 0.03), by reducing the mean time to treatment by about one hour.4 Despite this, prehospital thrombolysis has in general not been taken up for logistical reasons.

Is one thrombolytic better than another?
Although angiographic studies show higher early patency rates with tPA compared with SK (~70% vs ~35%), neither the GISSI- 2 study5 nor the ISIS-3 study found any difference in 30 day mortality rate (8.5% SK vs 8.9% tPA) and (10.6% for SK and 10.3% for tPA) respectively. In the GUSTO trial a more aggressive regimen was used, so called front-loaded tPA, producing a small but significant benefit favouring tPA (6.3% vs 7.3% p > 0.04). There were, however, an excess of strokes (0.72% for tPA vs
0.54% for SK). Combining deaths and strokes there was still a benefit favouring front-loaded tPA (6.9 % vs 7.8%).

Currently, in many countries streptokinase remains the first line treatment for AMI. This is because the advantage for tPA is modest and tPA is expensive ((£470) compared to SK (£80) per patient). Since streptokinase neutralising antibodies are formed from about day 4 onwards, tPA will need to be administered should the patient reinfarct after this time.

The lack of any large difference in clinical outcome between tPA and SK despite the difference in early angiographic patency needs to be explained. TPA is locally effective, with little systemic thrombolytic effect (for example on circulating plasminogen). It is, however, very specific, which is the cause for the excess in strokes. It has a short half life compared to SK. It has been clearly shown in animal models of arterial thrombotic occlusion that opening of the vessel by administration of tPA may be followed by early reocclusion, perhaps within minutes. The 90 minute angiogram cannot reflect the consequent reocclusion of the artery, which will happen less with SK which has a longer half life. Thus the increased patency with tPA may not translate into a decrease in mortality. The short half life of tPA means that heparin should be coadministered
and continued for 24 hours although true benefit has never actually been proven.

What to give
Currently, the choice of thrombolytic varies by country and depends especially on the type of health care system and funding in place. In many countries, in the absence of previous administration the first line thrombolytic is SK (1.5 million units in 100 mls 5% dextrose/0.9% NaCl over 30–60 minutes). Alternatively, tPA is given as a 15mg bolus followed by 50mg over 60 minutes, then 35mg over a further 30 minutes. Based on the GUSTO study a case can be made for tPA in those presenting very early (<4 hours with large anterior infarcts). New plasminogen activators such as recombinant plasminogen activator (r- PA) and prourokinase are currently the subject of a number of
clinical studies. Reteplase (rPA), is a nonglycosylated deletion mutant of wild type tPA. It is the first member of the third generation thrombolytics, has a longer half life and is given as a double bolus (10IU + 10IU). Equivalence trials comparing tPA and reteplase have demonstrated no difference in outcome and currently these two drugs are interchangeable, with decisions about use being based on availability and price.6 Lanoteplase has been withdrawn prior to launch because of patent issues and TNK-tPA is being trialled against tPA (ASSENT 2).7 Bleeding with this new agent was between 2.8% and 7.4% dependent on dose (ASSENT 1).8 Data suggest that there may be a role for “rescue” angioplasty in patients who fail to show electrocardiographic evidence of reperfusion.9 However, results of randomised trials addressing this issue are awaited.