Streptokinase clinical trials

Several clinical trials have been conducted with streptokinase adrninistered either intravenously or by direct infusion into a catheterized coronary artery. The results from 33 randomized trials conducted between 1959 and 1984 have been examined (75), and show a significant decrease in mortaUty rate (15.4%) in enzyme-treated patients vs matched controls (19.2%). These results correlate well with an ItaUan study encompassing 11,806 patients (76), in which the overall reduction in mortaUty was 19% in the streptokinase-treated group, ie, 1.5 million units adrninistered intravenously, compared with placebo-treated controls. The trial also shows that a delay in the initiation of treatment over six hours after the onset of symptoms nullifies any benefit from this type of thrombolytic therapy. Conversely, patients treated within one hour from the onset of symptoms had a remarkable decrease in mortaUty (47%). The benefits of streptokinase therapy, especially in the latter group of patients, was stiU evident in a one-year foUow-up (77). In addition to reducing mortahty rate, there was an improvement in left ventricular function and a reduction in the size of infarction. Thus early treatment with streptokinase is essential. 

An exogenous plasminogen activator that has been used in clinical trials as a fibrinolytic agent is the 53-kDa single-chain polypeptide called streptokinase (SK). It forms a complex with plasminogen on an equimolar basis. The resulting 156-kDa streptokinase-plasminogen complex (plg-SK) converts Glu-plasmino-gen to Glu-plasmin (41). 

Concomitant use with thrombolytic therapy Clinical trials in HIT patients have provided only limited information on the combined use of lepirudin and thrombolytic agents. The following dosage regimen of lepirudin was used in 9 HIT patients in the studies who presented with TECs at baseline and were started on both lepirudin and thrombolytic therapy (alteplase, urokinase, or streptokinase). 

Recombinant t-PA has also been approved for use in acute ischemic stroke within 3 hours of symptom onset. In patients without hemorrhagic infarct or other contraindications, this therapy has been demonstrated to provide better outcomes in several randomized clinical trials. The recommended dose is 0.9 mg/kg, not to exceed 90 mg, with 10% given as a bolus and the remainder during a 1 hour infusion. Streptokinase has been associated with increased bleeding risk in acute ischemic stroke when given at a dose of 1.5 million units, and its use is not recommended in this setting. 

Clinical trials One of the trials (ISIS-3) showed that streptokinase plus aspirin performed as well as recombinant tissue-type plasminogen activator (rt-PA) or complex formulations of streptokinase such as anistreplase (APSAC). The GUSTO trial showed a small advantage for the much more expensive t-PA over streptokinase, but with a significantly higher risk of hemorrhagic stroke. Nine clinical trials—each containing over 1000 patients with suspected acute myocardial infarction—... 

Heparin-like anticoagulants such as nadroparin have been found to be useful in some clinical trials in stroke patients as have streptokinase-like drugs which dissolve the fibrin matrix of blood clots. 

Several large clinical trials have compared alteplase and anistreplase with streptokinase. No clear-cut differences in severe or life-threatening bleeding were observed in these studies. 

When it is suspected that there may only be small differences between active treatments, and when placebo controls are unavailable for clinical or ethical reasons, then it is often necessary to resort to large-scale studies ( mega-trials ). A good, famous example was the clinical trial known by the acronym GUSTO, where streptokinase and recombinant tissue plasminogen activator (t-PA) were compared for acute coronary thrombosis (for a commentary, see Hampton, 1996). 

Kohner EM, Pettit JE, Hamilton AM, Bulpitt CJ, Dollery CT. Streptokinase in central retinal vein occlusion a controlled clinical trial. Br Med J 1976 1 550-553. 

Controlled clinical trials have shown that alteplase improves the clinical outcome in patients with ischemic stroke if given within 3 hours after the onset of symptoms. Similar trials of streptokinase resulted in unacceptably high rates of bleeding. Glycoprotein Ilb/EIa receptor inhibitors like abciximab have not been tested in ischemic stroke. Vitamin K and factor Vni may actually worsen the patient s outcome. The answer is (B). 

O Neill W, Timmis GC, Bourdillon PD, Lai P, Ganghadarhan V, Walton J Jr, Ramos R, Laufer N, Gordon S, Schork MA, et al. A prospective randomized clinical trial of intracoronary streptokinase versus coronary angioplasty for acute myocardial infarction. N Engl J Med 1986 314 812-818. 

Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation. 1987 76 142-154. 

TPA is also under clinical trials for the treatment of unstable angina, ischaemic stroke, acute stroke and pulmonary embolism. A major competitor of TPA is streptokinase, which is a bacterial enzyme. Hiis compound is cheaper and may be more effective than TPA in some respects although there is a higher risk of allergenic response. 

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