IIb or not IIb: That is the question, but what is the TARGET?

Original Citation

Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, Cohen EA, Bertrand M, Neumann F, Stone GW, DiBattiste PM, Demopoulos L, for the TARGET investigators. A comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization.

Overall Study Question

The TARGET (Do Tirofiban and Reopro Give Similar Efficacy Outcomes Trial) trial was designed to compare the efficacy and safety of two glycoprotein IIb/IIIa antagonists, tirofiban and abciximab, in patients scheduled to undergo urgent or elective coronary stenting who possessed new or restenotic atherosclerotic lesions and either native or bypass grafts.  Previous studies involving the individual glycoprotein IIb/IIIa antagonists have demonstrated the clinical benefit of these individual agents for use in percutaneous coronary interventions, however, no study has compared whether clinical differences between agents exist for this indication.

The primary hypothesis in this study was that tirofiban would not be inferior to abciximab in regards to the primary endpoint. The primary endpoint of this study was a composite of death, non-fatal infarction, or urgent target vessel revascularization within 30 days after the procedure.  Secondary outcomes were each component of the primary endpoint and the effect of the medications on the following subgroups: presence or absence of diabetes, sex, age (< 65 years or >=65 years), country (US versus other), and whether or not clopidogrel was administered prior to the procedure.

Are the Results of the Study Valid?

Was assignment of patients randomized?

Yes. Immediately prior to the procedure, patients were randomized to tirofiban or abciximab. Tirofiban was administered as a bolus of 10 ug/kg, followed by an infusion of 0.15 ug/kg/min for 18-24 hours. Abciximab was administered as a 0.25 mg/kg bolus, followed by a 0.125 ug/kg/min infusion for 12 hours. All patients received heparin at least 4 hours prior to the procedure, and at a maximum dose of 70 u/kg to achieve a target activated clotting time of 250 seconds. It was recommended that heparin be discontinued immediately after the procedure. Additionally, all patients received 250 mg to 500 mg of aspirin and a 300 mg load of clopidogrel two to six hours prior to the procedure. Both agents (75 mg-325 mg for aspirin and 75 mg for clopidogrel) were continued for 30 days after the procedure.

Were all patients who entered the trial properly accounted for and attributed at its conclusion?

There were 5,308 patients enrolled (2647 randomized to tirofiban and 2661 to abciximab). The protocol specified that patients would be excluded from the analysis if they did not actually receive a study drug.  Two hundred and forty-nine (9%) patients randomized to receive tirofiban and 250 (9%) patients randomized to receive abciximab were excluded for this reason.  There were 4,809 patients (2,398 in the tirofiban group and 2,411 in the abciximab group) ultimately evaluated for the primary endpoint.

Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes.  Treatment was assigned and administered in a double-blinded, double-dummy manner.  An independent committee of cardiologists who were unaware of the patients’ treatment assignment were responsible for evaluating the endpoints.  Endpoints were confirmed after two cardiologists evaluated the data and came to a consensus.  In the event that the two physicians did not agree, a third cardiologist was asked to make the final decision.
Were the groups similar at the start of the trial?
Yes. The baseline characteristics for both groups were similar in regards to age, sex, risk factors for heart disease, and past medical history.  Ninety-five percent of patients underwent stenting and 95% of the lesions involved native coronary vessels.

Aside from the experimental intervention, were the groups treated equally?

There were no obvious treatment differences between groups reported in the study.   The mean dose of heparin was 6,327 U in the tirofiban group and 6,372 U in the abciximab group.

What were the Results?

How large was the treatment effect? 

The study was designed to be an equivalence trial, with a pre-set primary hypothesis that tirofiban would not be inferior to abciximab.  The results rejected the primary hypothesis. The authors then went on to determine whether or not tirofiban was superior to abciximab.

The 30-day primary endpoint was met in 7.6% of patients in the tirofiban group and 6% in the abciximab group, p=0.038.  This translates into a 27% relative risk reduction in the abciximab group or a number needed to treat (NNT) of 63 patients treated with abciximab, infused for 12 hours, and aspirin and clopidogrel administered for 30 days. The difference was primarily due to a reduction in nonfatal myocardial infarctions, especially larger infarctions.  These events occurred in 6.9% of patients in the tirofiban group=, and 5.4% of patients in the abciximab (p=0.04).

The beneficial effects of abciximab were consistent for all patient subgroups.  Significant decreases in the primary endpoint occurred in the sub-group of patients who were < 65 years of age, female, or being treated in centers outside the United States.

There were no significant differences in the major bleeding rates between the two groups.  Minor bleeding rates were significantly lower in the tirofiban group (2.8%) compared to the abciximab group (4.3%), p=0.001.  Furthermore, thrombocytopenia occurred significantly more often with abciximab than with tirofiban.  There were no differences between groups in the need for red-cell or platelet transfusions.

How precise was the estimate of the treatment effect?

The 95% confidence interval for the primary endpoint was 1.01 to 1.57 (p=0.038).  The 95% confidence interval for the secondary outcomes of nonfatal myocardial infarction, treatment in patients < 65 years, female, and patients treated at medical centers outside the United States did not cross zero, indicating statistically significant differences.

Will the Results Help Me in Caring for My Patients?

Can the results be applied to my patient care?

This study indicates that treatment of patients undergoing elective or urgent percutaneous interventions with stenting derive greater benefit from treatment with abciximab than from tirofiban.

Were all clinically important outcomes considered?

The investigators evaluated the important clinical outcomes of death, nonfatal myocardial infarction, and the need for target vessel revascularization at 30 days and found a significant decrease in patients treated with abciximab.  Whether these results would be similar beyond 30 days is unclear.

It should be noted that although the entry criteria for the study included patients requiring stenting of bypass grafts, the majority (95%) of patients entered into the study underwent stenting of a native vessel.  Whether the results would have been different had more patients with bypass grafts been enrolled requires further study.

This study evaluated the incidence of adverse events between the two agents. The higher incidence of minor bleeding and thrombocytopenia with abciximab was consistent with previous abciximab studies.

Are the likely treatment benefits worth the potential harms and costs?

This trial addressed important clinical outcomes in patients undergoing elective or urgent percutaneous interventions. Although the cost of abciximab is higher than that of tirofiban (approximately $1277 for a bolus and 12-hour infusion of abciximab vs. $399 for a bolus and 24-hour infusion of tirofiban, for a 70-kg person), this study suggests that abciximab is a more efficacious than is tirofiban for use in percutaneous interventions.  Formal cost-effective analysis comparing these two agents and their outcomes are necessary.

Commentary

The development of percutaneous coronary interventions, such as angioplasty (PTCA) alone or with stent placement, has revolutionized the management of patients with ischemia by reducing symptoms, improving clinical outcomes and enhancing  patients’ quality of life.  Nevertheless, the use of these procedures can result in acute vessel closure in approximately 4-9% of cases, resulting in increased mortality. The use of glycoprotein IIb/IIIa receptor antagonists prior to and during PTCA have been shown to reduce death, nonfatal myocardial infarctions and the need for repeat percutaneous coronary interventions, although to date no study has evaluated the impact of these agents on all-cause mortality. The use of these agents are now routine during percutaneous coronary interventions.

The TARGET trial is the first published study designed to directly compare the efficacy and safety of two glycoprotein IIb/IIIa receptor antagonists, abciximab and tirofiban.  The results of the TARGET trial indicate that the use of abciximab is superior to that of tirofiban in preventing death, nonfatal myocardial infarctions, or urgent target-vessel revascularization within 30 days after the procedure.  It should be noted that the infusion duration for tirofiban used in this study was shorter than that used in the original study that demonstrated the clinical benefit of using tirofiban in percutaneous interventions. The choice in therapy duration for the study was chosen based upon the results of a sub-group analyses from a study evaluating tirofiban for patients with unstable angina or non-Q-wave myocardial infarctions. Whether this difference had an impact on the results of the current trial remains unknown.

Further investigations into whether differences between the other IIb/IIIa antagonists exist are warranted, not only in the setting of coronary interventions but also in the setting of acute coronary syndromes.

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