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 were as follows:
Table
The most powerful variables predictive of 30-day mortality
Variable Weight of
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
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 impor-tant 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.
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 by Barbagelata and associates of angiographic studies 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 + 1OMU 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. Indications for fibrinolytic therapy in suspected acute myocardial infarction: Collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet 1994;343:311-322.
2. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993; 329:673-682.
3. Lee KL, et al. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. Circulation 1995;91:1659-1668.
4. Califf RM, et al. Selection of thrombolytic therapy for individual patients: Development of a clinical model. Am Heart J 1997;133:630-639.
5. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 1993;329:1615-1622.
6. Barbagelata NA, et al. TIMI grade 3 flow and reocclusion after intravenous thrombolytic therapy: A pooled analysis. Am Heart J 1997;133:273-282.
7. Lenderink T, et al. Benefit of thrombolytic therapy is sustained thoughout five years and is related to TIMI perfusion grade 3 but not grade 2 flow at discharge. Circulation 1995;92:1110-1116.
8. Smalling RW, et al and the RAPID Investigators. More rapid, complete, and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation 1995;91:2725-2732.
9. Bode C, et al. Randomized comparison of coronary thrombolysis achieved with double bolus reteplase (r-PA) and front-loaded "accelerated" alteplase (rt-PA) in patients with acute myocardial infarction. Circulation 1996;94:891-898.
10. Cody RJ. Results from late breaking clinical trials sessions at ACC 1997. J Amer Coll Cardiol 1997;30:1-7.
Clinical Scenario: The ECG shown in the Figure was obtained from a patient with known atrial fibrillation who was being treated for this condition. What is the most likely explanation for development of this "almost regular" rhythm in this patient with atrial fibrillation?
Interpretation: Despite the fact that the rhythm in the Figure becomes quite regular after the third beat, the patient is probably still in atrial fibrillation. Fine undulations are seen in the baseline. However, there is no consistent atrial activity in this lead II monitoring lead. The lack of upright P waves in a lead II rhythm strip essentially rules out a sinus mechanism for the rhythm. Normal QRS duration suggests a supraventricular etiology. Considering that the patient was known to be in atrial fibrillationand is currently "receiving treatment"the most likely explanation is that the rhythm in the Figure represents "regularization" of the atrial fibrillation as a manifestation of digitalis toxicity. The mechanism responsible for this phenomenon is complete AV block (from excess digitalis) in the presence of persistent atrial fibrillationwith resultant escape of a regular and slightly accelerated junctional pacemaker (at a rate of about 75 beats/min in this example).
Among the arrhythmias that are highly characteristic of digitalis toxicity are the AV blocks and accelerated junctional rhythms. Patients with atrial fibrillation who are being treated with digoxin should always have a 12-lead ECG repeated whenever the examiner hears "regularization" of the rhythm during cardiac auscultation. Only in this manner will it be possible to determine if there has been spontaneous conversion to normal sinus rhythm or development of digitalis toxicity with regularization of atrial fibrillation.
A final point worthy of mention regarding this tracing related to the shape of the ST segments. Use of digitalis may produce "dig effect"recognized clinically by either ST segment "scooping" (as shown here)and/or production of a sagging ST segment that closely resembles ST-T wave repolarization abnormalities of "strain." It is good to remember that at least one-third of patients who regularly take digoxin do not develop ECG evidence of "dig effect"and that ST-T wave changes produced by the drug are only poorly correlated with the serum digoxin level. A patient may, therefore, have severe clinical manifestations from digitalis toxicity, but little or no ST-T wave abnormality on their ECG.
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