Abciximab plus Thrombolysis
Abciximab plus Thrombolysis
Abstract & commentary
Synopsis: Abciximab increases the achievement of 90-minute TIMI-3 flow without significantly increasing major hemorrhage or mortality in AMI patients.
Source: Antman EM, et al. Circulation 1999;99: 2720-2732.
Thrombolysis for acute myocardial infarction (AMI) provides an important survival advantage over conservative therapy if begun early in the course of AMI. However, initial culprit artery patency is not always achieved and reocclusion of successfully opened arteries remains a problem. Thus, Antman and colleagues tested the hypothesis that the platelet glycoprotein 11b/111a receptor blocker abciximab, in addition to reduced dose alteplase, aspirin, and two low-dose heparin regimes, would improve the achievement of TIM1-3 flow at 90 minutes after thrombolytic therapy as compared to full dose accelerated alteplase, standard weight adjusted heparin, and aspirin. During an initial dose-finding phase, 14 different reperfusion regimes were tested to maximize efficiency and minimize bleeding complications. Full dose accelerated alteplase was a bolus of 15 mg, up to 50 mg infusion over 30 minutes, and 35 mg over 60 minutes (100 mg total). Reduced dose alteplase omitted the middle infusion (50 mg total). Abciximab was given as 0.25 mg/kg bolus, followed by an infusion of 0.125 mg/kg/min over 12 hours. Full-dose heparin (given with alteplase above) was a 70 U/kg bolus followed by 15 U/kg/hr; low-dose heparin was either 60/7 or 30/4. The results are as shown in the table.
| Table-Percent of Patients Achieving TIMI-3 Flow at 90 Minutes, Major Hemorrhage, and Deaths | |||
| TIMI-3 | MH | Death | |
| Alteplase 100, full heparin | 62% | 6% | 3% |
| Alteplase 50, low heparin, abciximab | 77% | 7% | 5% |
| Alteplase 50, extremely low heparin, abciximab | 69% | 1% | 0 |
Antman et al conclude that abciximab increases the achievement of 90-minute TIMI-3 flow without significantly increasing major hemorrhage or mortality in AMI patients and extremely low dose heparin reduces bleeding episodes.
Comment by Michael H. Crawford, MD
To say that this study was complicated and the paper difficult to read is the understatement of the month. There were five different total doses of alteplase given by one to four different bolus-infusion combinations, three heparin doses, two bolus-infusion combinations of the one dose of abciximab, and four doses of streptokinase for a total of 14 combinations tested out of many more possibilities in the dose-finding phase of the trial. Based on angiographic efficiency and complication rates, the three regimes described in the table were chosen for the dose confirmation phase of the study. Streptokinase was discarded because the dosage that produced high TIMI-3 flow frequencies with abciximab caused unacceptably high major bleeding ranges even if heparin was withheld.
The theory behind this study is compelling. Arterial thrombi have variable combinations of fibrin, platelets, and thrombin. Thrombolysis attacks the fibrin mesh of the clot, but it also increases platelet activation and generates more thrombin, which produces more fibrin and also increases platelet activation. The latter procoagulant effects of thrombolysis are referred to as the "dark side." Thus, aspirin and heparin must be given to maximize the results of thrombolysis because they oppose these dark side effects on platelets and thrombin, respectively. However, aspirin is a relatively weak antiplatelet drug, which may explain why flow augmentation in the culprit artery is often suboptimal and why reocclusion can occur. Hence, the hypothesis tested in this study—that a more powerful platelet inhibitor would improve the results of thrombolysis, but with reduced doses of thrombolytics and heparin to guard against increases in major bleeding. The study proved this hypothesis suggesting that further platelet inhibition can augment the achievement of TIMI-3 flow, even with reduced doses of thrombolytics and heparin, without increasing major bleeding. Higher frequencies of TIMI-3 flow at 90 minutes post-therapy in AMI patients should translate into increased survival and higher left ventricular ejection fraction based upon other studies, but this remains to be proven in a larger trial.
TIMI-3 flow at 90 minutes post-treatment for AMI is most frequent with:
a. alteplase 100 mg, plus full-dose heparin.
b. alteplase 50 mg, reduced-dose heparin, and abciximab.
c. alteplase 50 mg, extremely low heparin, and abciximab.
d. streptokinase and abciximab.
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