Choosing a Thrombolytic Agent
October 1, 1997
Special Feature
Choosing a Thrombolytic Agent
By William E. Davis, MD
Myocardial infarction (mi) is the direct consequence of thrombotic occlusion of a coronary artery. Therapeutic strategies focus on the rapid identification of the patient suffering acute coronary artery thrombosis, optimal reperfusion of the occluded artery, and prevention of subsequent complications, including reinfarction, bleeding, stroke, arrhythmic death, and heart failure.
Nine large, placebo-controlled, randomized, clinical trials of more than 58,000 patients clearly demonstrated that intravenous fibrinolytic therapy confers a significant morbidity and mortality benefit in the treatment of patients with acute MI with ST elevation or bundle branch block.1 Despite an increased risk of hemorrhagic complications and stroke, this net benefit extended across all patient subgroups and was independent of all other outcome determinants. The clinical benefit was also more prominent the earlier treatment began. As a result, intravenous fibrinolytic therapy is the standard-of-care to which newer strategies are compared.
Subsequent studies have compared the effects of several available plasminogen activators, particularly reverse transcriptase plasminogen activator (rt-PA, t-PA, alteplase) and streptokinase (SK). The GUSTO-1 trial ushered in the current era of intravenous fibrinolytic therapy by demonstrating a significant mortality benefit of "accelerated" t-PA over SK.2 The recent introduction for clinical usage of recombinant plasminogen activator (reteplase, r-PA), a new "third generation" fibrinolytic agent, provides reason to reevaluate our choice of thrombolytic agents.
Determinants of Outcome in Acute MI
The primary determinants of outcome in acute MI are the baseline risk characteristics of the patient, the adequacy of flow in the reperfused artery, speed of reperfusion, the incidence of reocclusion of the infarct-related coronary artery, and the direct complications of the therapeutic intervention.
In a multivariate regression analysis of the data from the 41,021 patients in the GUSTO-1 trial, Lee and colleagues identified 16 baseline patient characteristics and their relative weights as independent predictors of 30-day mortality: age, systolic blood pressure, Killip class (degree of heart failure), heart rate, site of current infarction, prior infarction, the interaction of age with Killip class, height, time-to-treatment, diabetes, weight, smoking status, type of thrombolytic therapy, prior bypass surgery, hypertension, and prior cerebrovascular disease.3 Califf and associates then developed a model using a reduced set of these determinants that retained 90% of the predictive value of the original model.4 The most powerful variables predictive of 30-day mortality are listed in the Table.
Although the other factors such as time-to-treatment or prior cerebrovascular disease may affect the physiologic status of the patient, the independent contribution is relatively small. The impact of age is nearly two orders of magnitude greater than the choice of lytic agent.
The patency of the infarct-related artery is an important determinant of outcome. Infarct-artery patency is described using angiographic criteria from the early Thrombolysis in Myocardial Infarction (TIMI) trials. TIMI grade 3 flow is essentially normal flow. TIMI grade 2 flow is reduced flow but considered adequate to prevent immediate cell death. TIMI grades 0 and 1 flow reflect either no or inadequate perfusion, respectively.
The most powerful variables predictive of 30-day mortality
Variable Weight of Contribution (X2)
Age (years) 1390
Systolic blood pressure 533
Killip class 428
Heart rate 325
Site of infarctio 147
Prior myocardial infarctio 92
All thrombolytic treatments 15.5
A substudy in the GUSTO-1 trial randomized 2431 patients to evaluate the angiographic determinants of outcome.5 Left ventricular (LV) function was strongly correlated with the 90-minute infarct-related artery patency. The patients with TIMI-3 flow had better LV function and myocardial wall motion at 90 minutes and seven days. The 30-day mortality for patients with TIMI-3 flow in the infarct-related artery was 4.4%, while the mortality in the patients with TIMI-2 flow was 7.4%.
A pooled analysis of angiographic studies by Barbagelata and associates performed after thrombolysis confirmed the findings of the GUSTO angiographic investigators.6 TIMI-3 flow is associated with a substantially lower rate of congestive heart failure, lower rate of recurrent ischemia, better LV function, and 30-50% lower mortality compared to TIMI-2 flow, which is in turn better than TIMI-0 or -1 flow.
Linderink and colleagues, in a five-year follow-up of patients after t-PA therapy, noted that the predictors of long-term survival are enzymatic infarct size, LV function, the number of diseased vessels, and TIMI-3 perfusion at discharge.7
t-PA vs. SK
Mortality. Earlier large, randomized, controlled trials of thrombolytic therapy for acute MI failed to show any benefit of a three-hour infusion of t-PA over streptokinase.
The GUSTO-1 trial used a different approach to the administration of t-PA by "accelerating" the administration of the fibrinolytic (using a weight-adjusted dose) over 90 minutes instead of the "standard" 180-minute t-PA dosage regimen and by giving intravenous heparin immediately. A significant mortality benefit of "accelerated" t-PA over streptokinase regimens was evident throughout all treatment groups with the possible exception of those treated more than six hours after onset of symptoms, where there was no statistical difference. The analysis by Califf et al demonstrates that the absolute mortality benefit of t-PA vs. SK increases with increasing mortality risk.4 As a result, despite higher risks of treatment, the net mortality benefit of t-PA for the high-risk patient (e.g., elderly patient with anterior MI and CHF) was predictably greater than for the low-risk patient (e.g., young patient with inferior MI without heart failure). The higher the risk, the greater the absolute mortality benefit of t-PA vs. SK.
Patency of the infarct-related artery. The mortality benefit of accelerated t-PA over SK is attributed to the higher rate of early infarct-related artery patency. The late patency is also an important angiographic determinant of improved outcome and operates by a different mechanism than early patency.
The angiographic substudy of GUSTO-1 revealed that accelerated t-PA produced a significantly higher rate of open vessels (TIMI 2 and 3 combined) of 81% and complete reperfusion (TIMI 3) of 54% at 90 minutes, compared to SK rates of 60% and 41%, respectively. The patency rates were not significantly different at 180 minutes between t- PA and SK. Most of the survival benefit of accelerated t-PA over SK in the GUSTO-1 trial appears to be largely due to this advantage of early patency.
The pooled analysis by Barbagelata et al6 of 5475 angiograms from 15 studies reported infarct-related artery patency rates for accelerated t-PA and SK as follows: the rates of TIMI-3 flow at 60 and 90 minutes for accelerated t-PA were 57% and 63%, respectively; and at 90 minutes for streptokinase was 31%. By 180 minutes, the patency rates with accelerated t-PA appear to fall to approximately the level of that for SK (~44%), and then increase again to approximately 70% by 24 hours. Streptokinase was associated with a stable TIMI-3 flow of approximately 55%.
New plasminogen activators
Urokinase and t-PA are the natural endogenous fibrinolytic agents produced in the body to regulate thrombosis. The "third generation" of plasminogen activators are molecular modifications of the wild-type t-PA molecule. Several third generation agents are currently undergoing clinical testing, and reteplase is now available for clinical use. The goal of these new agents is to provide faster and higher early patency rates with lower rates of reocclusion and hemorrhagic complications compared to accelerated t-PA.
Reteplase. Recombinant plasminogen activator (r-PA, reteplase) is a new fibrinolytic agent created as a nonglycosylated deletion mutant of the wild-type t-PA. The half-life of r-PA is prolonged to 13-16 minutes compared to 3-6 minutes for alteplase. The longer half-life will hopefully lead to a lower rate of reocclusion. The binding affinity to fibrin is reduced to approximately 30% of that of alteplase. This lower fibrin affinity may allow for better penetration of the clot. The in vitro fibrinolytic efficiency of reteplase and alteplase are essentially equal. Reteplase does not appear to be significantly antigenic in clinical trials to date. This is a significant advantage over streptokinase.
The randomized trials published thus far evaluating the safety and efficacy of reteplase suggest that reteplase may be clinically superior to t-PA, producing higher early coronary artery patency rates without an increased rate of bleeding complications.
The RAPID trial compared several dosage regimens of r-PA to standard t-PA.8 It also followed the incidence of adverse clinical outcomes including stroke, reinfarction, heart failure, angina, the need for angioplasty, coronary artery bypass surgery, and intracoronary thrombolysis. All groups received intravenous heparin and aspirin. Using a double bolus regimen of 10 MU initially, then 10 MU 30 minutes later, reteplase produced comparable overall patency rates and significantly higher TIMI-3 flow rates compared to standard alteplase. There was no increased incidence of bleeding complications or adverse clinical outcomes for r-PA compared to t-PA.
The RAPID 2 trial compared the 1O MU + 1O MU double bolus regimen of reteplase to accelerated alteplase.9 The results of the study were that, at 90 minutes, the incidence of TIMI-3 flow was significantly higher in the r-PA group than the alteplase group (60% vs 45%, P = 0.011).
Based on these higher early patency rates, the GUSTO-III trial was designed to evaluate the hypothesis that r-PA would reduce 30-day mortality compared to t-PA in the treatment of acute MI.10 After enrolling more than 15,000 patients, the study steering committee issued the preliminary report that no statistically significant differences were observed between the two plasminogen activators in efficacy or complication rates. However, "there is still some uncertainty as to whether these drugs can be regarded as equivalent."
Summary
Intravenous fibrinolytic therapy is the standard of care for acute MI with ST elevation or bundle branch block. Treatment with the weight-adjusted "accelerated" t-PA protocol of GUSTO-1 provides a net absolute mortality benefit in all treatment groups as compared to SK. The higher the baseline risk of the patient, the greater the mortality benefit observed. Reteplase, a recently marketed "third-generation" plasminogen activator, offers clinical results comparable to those of accelerated t-PA. The ease of administration of the double bolus r-PA regimen makes this an appealing alternative to t-PA. Despite the higher early patency rates for r-PA in initial human studies, there is no information demonstrating a clinical benefit clearly superior to that of accelerated t-PA.
References
1. Fibrinolytic Therapy Trialists' Collaborative Group. Lancet 1994;343:311-322.
2. The GUSTO Investigators. N Engl J Med 1993;329: 673-682.
3. Lee KL, et al. Circulation 1995;91:1659-1668.
4. Califf RM, et al. Am Heart J 1997;133:630-639.
5. The GUSTO Angiographic Investigators. N Engl J Med 1993;329:1615-1622.
6. Barbagelata NA, et al. Am Heart J 1997;133:273-282.
7. Lenderink T, et al. Circulation 1995;92:1110-1116.
8. Smalling RW, et al and the RAPID Investigators. Circulation 1995;91:2725-2732.
9. Bode C, et al. Circulation 1996;94:891-898.
10. Cody RJ. J Amer Coll Cardiol 1997;30:1-7.
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