Controversy continues to surround the choice of fibrinolytic agent. There have been three large trials comparing streptokinase to tPA and one large trial comparing reteplase to alteplase.
STREPTOKINASE Streptokinase is a polypeptide derived from b-hemolytic Streptococcus cultures. It binds 1:1 to plasminogen, causing a conformational change that activates the plasminogen-streptokinase complex. This complex cleaves peptide bonds on other plasminogen molecules to activate them. This activated complex does not have fibrin specificity.
Initial trials demonstrated a reduction in mortality rate and improvement in left ventricular function with streptokinase relative to placebo. 12 and 3 Other fibrinolytic agents have not been evaluated in large randomized placebo-controlled clinical trials.
Antibodies may develop after treatment, so retreatment should be avoided. Streptokinase allergy can be seen in approximately 5 percent of patients treated for the first time, especially those with a recent Streptococcus infection. Self-limited allergic reactions usually respond to antihistamines. Fewer than 0.2 percent of patients experience a serious anaphylactic reaction. During intravenous administration, approximately 15 percent of patients will experience hypotension, which usually responds to decreasing the rate of infusion and volume expansion. The 1998 recommended dose of streptokinase is 1.5 million units over 60 min, which produces a fibrinolytic state for up to 24 h. Streptokinase is less costly than other fibrinolytic agents.
TISSUE PLASMINOGEN ACTIVATOR tPA is a naturally occurring enzyme produced by the vascular endothelium and other tissues. It has a binding site for fibrin that allows it to attach to a formed thrombus and trigger fibrinolysis (fibrin specificity). Small trials (28 to 144 patients) compared infarct-related patency rates of tPA to placebo and found that tPA achieved higher patency rates than was seen with placebo or in trials of streptokinase. Three large randomized controlled clinical trials have compared streptokinase to tPA. Using the composite end point of stroke or death at 30 to 35 days, GISSI-2 (more than 20,000 patients) found that tPA resulted in an increased rate of stroke/death of 5 per 1000 patients relative to streptokinase. 5 ISIS-3 (27,000 patients) found a 1 per 1000 patient benefit in favor of tPA.6 GUSTO-1 found a 5.4 per 1000 patient benefit in favor of tPA, which increased to 9 patients per 1000 when the accelerated tPA regimen was given. 7 As a result, most cardiologists recommend the use of the accelerated tPA regimen.
When these trials are taken together, these three megatrials found no statistical difference between streptokinase and tPA with respect to the composite end point of stroke and death. A meta-analysis of the data from these three trials found that tPA offered a nonstatistical benefit of 1.6 ± 1.9 per 1000 patients ( p = 0.4). Using only death as the end point, tPA rather than streptokinase use results in a nonstatistical difference of 2.0 ± 1.9 lives saved per thousand patients ( p > 0.1). Based on this analysis, the choice of which thrombolytic agent to use is probably less relevant than the speed of thrombolytic administration (which results in saving an additional 1.6 per 1000 lives per hour earlier that treatment is provided). In addition, it is probably better to choose streptokinase over tPA when the risk for intracranial hemorrhage is highest (elderly, etc.) since tPA has an increased likelihood of resulting in hemorrhagic stroke. 4
The mechanism of improved benefit of tPA in the GUSTO angiographic substudy is early patency of the infarct-related vessel. 8 For tPA, streptokinase-subcutaneous heparin, streptokinase-intravenous heparin, and streptokinase-tPA, the patency rates at 90 min were 81, 56, 61, and 73 percent, respectively. 8 These patency rates were predictive of survival outcomes.
The accelerated regimen of tPA, as used in the GUSTO trial, is an initial bolus of 15 mg, followed by 0.75 mg/kg (up to 50 mg) in the first 30 min and 0.5 mg/kg (up to 35 mg) in the next hour.7
RETEPLASE rPA is a genetically engineered modification of tPA with a prolonged half-life (18 min vs 3 min) and reduced fibrin binding. GUSTO-3 compared rPA to tPA in 15,000 patients and found similar mortality and stroke rates between the two agents.9 Smaller studies suggest that reteplase has a faster time to reperfusion. Reteplase can be given as a double bolus, 10 mg each, 30 min apart.
Other genetically engineered molecules are currently in the developmental stages, and results of clinical trials are not yet available. TNK-tPA is another tPA mutant with prolonged half-life, that is resistant to endogenous plasminogen activator inhibitor-1 (PIA-1) inactivation, and has high fibrin specificity and binding. In animal models, it produces more active and complete fibrinolysis with less risk of intracranial bleeding. Results of clinical trials are pending. n-PA is a deletion and point mutant of tPA that has a more extended half-life (30 to 45 min) with improved lytic activity in animal models and reduced fibrin affinity.
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