Fibrinolytics

Fibrinolytic agents act on the acute coronary thrombosis directly or indirectly as plasminogen activators. Plasminogen, an inactive proteolytic enzyme, binds directly to fibrin during thrombus formation, forming a plasminogen-fibrin complex. This plasminogen-fibrin complex is more susceptible to activation than plasma plasminogen, and this promotes fibrin proteolysis.

Randomized controlled clinical trials comparing streptokinase to placebo for treatment of acute myocardial infarction demonstrated that fibrinolytic therapy improved left ventricular function and short-term and long-term mortality rate.1,2 and3 A meta-analysis of all nine clinical trials that randomized more than 1000 patients to fibrinolytic therapy or control treatments found that the net benefit of treatment in the first 3 h was more than 30 lives saved per thousand patients. The loss of benefit per hour delay in thrombolytic administration was 1.6 lives per 1000 patients per hour.

Fibrinolytic therapy is indicated for patients with symptoms compatible with acute myocardial infarction, a time to treatment of less than 6 to 12 h, and an electrocardiogram that has at least 1-mm ST-segment elevation in two or more contiguous leads.4 Therapy is most beneficial if given early and is more beneficial for larger infarctions and anterior infarctions than it is for smaller or inferior wall infarctions.

In the elderly, the overall risk of mortality from acute myocardial infarction (AMI) is high with and without therapy. The proportionate reduction in mortality rate appears to be less in patients older than age 75, but the absolute number of patients who may be saved is still large.

Contraindications to thrombolytic therapy are those that increase the risk of hemorrhage ( Ta.b!e,...4.?.:2). The most catastrophic complication is intracranial bleeding. Clinical variables that can be assessed in the emergency department and predict an increased risk of intracranial hemorrhage are age (older than 65 years, odds ratio of 2.2), low body weight (less than 70 kg, odds ratio 2.1), and hypertension on presentation (odds ratio, 2.0). 4 Intracranial hemorrhage is also more common with tissue plasminogen activator (tPA) than with streptokinase (odds ratio, 1.6). Patients with relative contraindications may still receive fibrinolytic therapy when the benefits of therapy outweigh the risks of the complications, but institutions with direct percutaneous intervention availability might consider direct angioplasty over fibrinolytic therapy in the presence of relative contraindications. Reperfusion therapy with fibrinolysis is the standard of care for patients with ST-segment elevation AMI. However, this treatment has limitations. First, even the most potent fibrinolytic agents do not achieve early and complete restoration of coronary blood flow in 40

to 50 percent of patients. Fibrinolytics are plasminogen activators. When fibrin is lysed, thrombin is exposed. The exposed thrombin is one of the most potent biologic platelet activators known. As a result, the more fibrin that is lysed, the more thrombin is exposed and more prothrombotic substrate is engendered. The second limitation of fibrinolytic therapy is that approximately 1 percent of patients have intracranial hemorrhage, which usually results in death or disabling stroke.

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