THROMBOLYTIC+AGENTS

Thrombolytic agents
 * History:** The use and study of thrombolytics for the treatment of thrombotic and/or thromboembolic disorders began following the discovery in 1933 of the fibrinolytic activities of beta-hemolytic streptococci isolates. Because of the bleeding risks and inadequate efficacy data at the time, however, the use of thrombolytics was limited.[285] The first documented use of thrombolytic therapy for the treatment of myocardial infarction occurred in 1958 by Fletcher using high-dose, prolonged streptokinase therapy.[286]

Interest in the clinical use of thrombolytic agents was limited until the late 1970s due to skepticism regarding the risk of hemorrhage associated with the use of thrombolytic therapy. In addition, until DeWood and colleagues demonstrated the prevalence of thrombotic occlusion in the first 24 hours of myocardial infarction and provided evidence of "spontaneous reperfusion" in the hours following infarction, the medical community remained reticent to accept the role of coronary thrombosis in the development of myocardial infarction.[287] Other investigators contributed landmark research during the early to middle 1980s that demonstrated the utility of thrombolytic therapy, which is now regarded as responsible for saving thousands of lives yearly.

After proving that thrombotic occlusion mediated the development of AMI, the feasibility of acute administration of intracoronary streptokinase was demonstrated and resulted in a beneficial effect for patients with respect to myocardial salvage.[288] An important concept was first introduced in the Western Washington Intracoronary SK Trial, which demonstrated the value of an open coronary artery; one-year mortality was over five times higher in patients with an occluded coronary vessel at the time of acute angiography compared with those with a patent coronary vessel at the same time point.[289]

The next phase to be evaluated in establishing the efficacy of thrombolytic therapy was the relationship of time of administration of the thrombolytic agent to infarction onset. The GISSI-1 trial demonstrated a reduction in mortality for patients treated with intravenous streptokinase and linked the observed reduction in mortality with time elapsed before treatment; 21-day mortality was reduced by nearly 50% in patients treated most rapidly after symptom onset.[290]

In the late 1980s, the ability to use biotechnology and recombinant DNA techniques to create more "clot-specific" thrombolytic agents occurred. Clearly, knowledge and expertise in using these agents exploded in a period of roughly 15 years and has significantly changed the management and prognosis of AMI. Proof of the efficacy of thrombolytic agents, particularly in the treatment of AMI, is exemplified by the more than 2000 scientific papers pertaining to thrombolytic therapy that had been published in the medical literature by 1992. Included were "megatrials" enrolling tens of thousands of patients. These trials provided great statistical and often clinical power that can be incorporated into ensuring continued improvement of care.


 * Background:** There are five thrombolytic agents approved for use in the United States: alteplase (t-PA), derived from recombinant DNA; streptokinase (SK), derived from beta-hemolytic streptococci; urokinase (UK), derived from human kidney cell extracts; anisoylated plasminogen streptokinase activator complex (APSAC); and tenecteplase, a modified form of human tissue plasminogen activator (tPA) that binds to fibrin and converts plasminogen to plasmin. Urokinase is indicated primarily for the treatment of deep vein thrombosis, pulmonary emboli, and catheter recanalization, while the other three agents are indicated in the treatment of AMI. As a direct result of the use of thrombolytic agents, mortality after AMI has been dramatically reduced, and knowledge of the appropriate use of various adjunctive medications has grown.[285]


 * Mechanism of Action:** The fibrinolytic system is an endogenous enzymatic system that results in dissolution of intravascular clots by plasmin, a nonspecific enzyme, which digests fibrin as well as several coagulation factors. Fibrinolytic activity is normally maintained in homeostatic balance by several circulating inhibitors. Administration of exogenous thrombolytics activates the normal fibrinolytic system via various pathways, all of which ultimately result in the conversion of plasminogen to plasmin, causing clot dissolution.[291]

Unlike alteplase, streptokinase is a nonspecific activator of plasminogen (circulating and bound); administration of streptokinase theoretically results in a systemic lytic state. A secondary and potentially undesirable effect of streptokinase administration is the induction of a procoagulant response via increased release of thrombin. Although the procoagulant response occurs with all thrombolytics, //in vitro// data suggest that it occurs to the greatest extent with streptokinase. Some believe this induced procoagulable state can slow the rapidity with which early thrombolysis occurs.[285]'[291]

Urokinase is also a direct activator of plasminogen and induces systemic effects similar to those observed with streptokinase. Because urokinase is derived from human sources, however, antigenicity does not occur.[291]

Altepase, or t-PA, has the theoretical advantage of being a "clot-specific" thrombolytic agent (i.e., it binds selectively to plasminogen bound to fibrin). As a result, plasmin is produced predominantly at the site of a pathological thrombus, avoiding a systemic lytic state. It is, however, important to keep in mind that this selectivity is relative, and at higher doses a systemic effect is observed.[291]

Using the advances in biotechnology that produced alteplase, APSAC was developed in an attempt to avoid the rapid development of a systemic lytic state after administration of streptokinase. APSAC is simply a streptokinase molecule modified using biotechnology techniques to create a plasminogen streptokinase complex that would be slowly deacylated to streptokinase at a rate that would not induce a lytic state. Unfortunately, the dose of APSAC required to produce effective thrombolysis is enough that a systemic lytic state still develops.[291]

Tenecteplase is a fibrin-specific, recombinant TNK-tissue type plasminogen activator, which exerts its thrombolytic action on the endogenous fibrinolytic system to convert plasminogen to plasmin. Unlike streptokinase or urokinase, most of the activity of alteplase or tenecteplase is dependent on the presence of fibrin. Minimal amounts of plasminogen are converted to plasmin in the absence of fibrin. Tenecteplase has increased fibrin-specificity versus alteplase; however, the clinical significance of fibrin-specificity has not been determined.


 * Distinguishing Features:** Urokinase and streptokinase are similar drugs, but urokinase is significantly more expensive, so streptokinase is usually the primary nonspecific agent used for the treatment of AMI. Urokinase is used to treat pulmonary embolism, deep venous thrombosis, and, most commonly, for local thrombus dissolution (i.e., IV catheter thrombi).

As multiple thrombolytic preparations became available, studies were designed to determine if a particular product would demonstrate superior efficacy. The Thrombolysis in Myocardial Infarction (TIMI) trial, phase I, was one of the first such studies. This trial documented early recanalization (within 90 minutes) in patients treated with rt-PA compared with patients treated with streptokinase. The study demonstrated that rt-PA was significantly better at opening the infarct-related artery within 90 minutes, with no difference in side effects.[292] The investigators completed a six- and twelve-month follow-up of the phase I TIMI trial and found that in early and/or sustained infarct-related artery patency, there was a trend (NS) toward improved mortality in the patients treated with rt-PA.[293]

By the end of the 1980s, the medical community had studied many thousands of patients. The GUSTO trial was designed to remove the confounding variables that had complicated interpretation of some of the previous comparative studies and to attempt to determine if one thrombolytic agent was indeed superior. The recently completed trial demonstrated that 90-minute patency of the infarct-related artery was greater in the t-PA group compared with the combined streptokinase groups, although later patency rates of infarct-related arteries were shown to be equal in the two groups. A benefit to survival was seen at some, but not all, time points of lytic administration for the patients treated with t-PA. Although mortality was improved with t-PA, a small increase in bleeding complications (fatal and nonfatal stroke) were observed in the t-PA group compared with the streptokinase aggregate group.[294]

The major advantage of tenecteplase (TNK-t-PA) over t-PA and alteplase is its simple and rapid bolus administration over 5 seconds, which may increase the potential for early treatment of acute myocardial infarction.


 * Adverse Reactions:** Bleeding is the most serious complication of thrombolytic therapy. Bleeding associated with thrombolytic therapy can manifest as minor bleeding or major internal bleeding. Less serious spontaneous bleeding includes superficial hematoma, hematuria, gingival bleeding, and hemoptysis. Severe spontaneous bleeding includes cerebral, retroperitoneal, genitourinary, and GI hemorrhage. Bleeding occurs most commonly at access sites such as catheter insertion sites or venipuncture sites. Patients with preexisting coagulopathies are at the highest risk for developing bleeding complications during thrombolytic therapy. The incidence of bruising or hematoma formation is high, particularly following IM administration. Hemorrhage can result from concomitant therapy with heparin or other platelet-aggregation inhibitors. If severe bleeding occurs during therapy, the drug should be promptly discontinued.

Rapid coronary lysis can result in the development of arrhythmias; however, they are generally transient in nature. Arrhythmias that have been observed include sinus bradycardia, accelerated idioventricular rhythm, ventricular premature depolarizations, and ventricular tachycardia.

Nausea, vomiting, hypotension, and fever have been reported, although it is uncertain whether these adverse reactions are associated with the myocardial infarction or are attributable to thrombolytic therapy. Fever has occurred in as many as 21% of patients during streptokinase therapy, and it rarely requires discontinuation of therapy. Symptomatic management with an antipyretic other than aspirin (acetaminophen) is advised. Hypotension, sometimes severe, has occurred in 1—10% of patients receiving SK or APSAC. This reaction is rarely, if ever, anaphylactic in nature or due to excessive bleeding. The cause is usually related to the rate of infusion or, more likely, an immunological reaction to the drug because it is derived from bacterial sources.

Close monitoring of hemodynamics and vital signs is generally considered standard with thrombolytic therapy, particularly during the initial 24—48 hours.