Tirofiban vs. Abciximab During PCI

Abstract & Commentary

The do tirofiban and reopro give similar efficacy? (target) Trial, was the first (and thus far, the only) trial to directly compare 2 glycoprotein IIb/IIIa inhibitors in a "head-to-head" fashion.1 The study was designed to include a broad range of patients undergoing percutaneous coronary intervention (PCI). Any patient at a participating institution without ST-elevation myocardial infarction (MI), or cardiogenic shock, and a > 70% coronary lesion with morphology amenable to stent implantation could be considered for enrollment. In this study, 4809 patients undergoing coronary stent implantation were randomized to receive either abciximab (ReoPro) or tirofiban (Aggrastat). The primary end point of TARGET was a composite of death, nonfatal MI, or urgent target vessel revascularization (TVR) at 30 days. The study was designed and statistically powered to demonstrate "noninferiority" of tirofiban when compared with abciximab. However, the primary end point occurred more frequently in the tirofiban group than in the abciximab group (7.6% vs 6.0%; P = 0.038), resulting in a 1.6% absolute risk reduction and a 20% relative risk reduction with abciximab therapy. The difference in the primary end point was driven largely by higher rates of MI in the tirofiban group (6.9% vs 5.4%). Therefore, the TARGET investigators concluded that tirofiban offered less protection from major ischemic events than did abciximab for patients undergoing PCI.

The latest report from the TARGET investigators was presented at this year’s ACC meeting and is currently available as a "rapid track" electronic publication on the Circulation web site (www.circulationaha.org). It will be published in an upcoming print issue of the journal. In this report, Stone and colleagues provide information about outcomes beyond the 30-day primary end point extending to 6 months of follow-up. In addition, they evaluate outcomes when patients are stratified with respect to the acuity of the clinical syndrome at entry into the study. Of the 4809 patients randomized, 3025 presented with an acute coronary syndrome (ACS), defined as recent Q-wave MI, recent non-Q-wave MI, or unstable angina, the remaining 1784 patients presented with non-ACS, including stable angina, silent ischemia, or "other" clinical syndromes.

As would be expected, the ACS patients constituted an overall higher-risk group, with a higher percentage of females, smokers, left ventricular dysfunction, and prior MI included in the group. When compared with the stable subgroup, patients with ACS in this study had higher rates of death or MI at 30 days and 6 months, and higher rates of TVR at 6 months as well. The presence of ACS was an independent predictor of adverse outcomes at 6 months.

Of the ACS patients, 1511 received abciximab and 1514 received tirofiban. The demographic, clinical and anatomic characteristics, and procedural success rates were similar between the 2 groups, though the ACS patients receiving abciximab were slightly older and more likely to have left anterior descending coronary artery disease with PCI. Patients with ACS treated with abciximab had lower rates of the composite primary end point (death, MI, or urgent TVR) at 30 days when compared to those receiving tirofiban (6.3% vs 9.3%; P = 0.002). The difference in outcomes for ACS patients was again almost entirely attributable to lower rates of MI in patients receiving abciximab (5.8% vs 8.5%; P = 0.004), as there were no significant differences in rates of death or TVR between the 2 groups at 30 days. Of the stable, non-ACS patients, 900 received abciximab and 884 received tirofiban. In contrast, the non-ACS patients did not demonstrate improved outcomes with abciximab when compared to tirofiban therapy, either in terms of the composite primary end point (5.6% vs 4.5%; P = 0.32) or in any individual component of the composite end point.

At 6-months follow-up, there was no statistically significant reduction in the composite end point attributable to abciximab therapy in either the ACS (15.5% vs 18.0%; P = 0.056, with a strong trend favoring abciximab) or the non-ACS (13.4% vs 10.3%; P = 0.056, with a strong trend favoring tirofiban). Of interest, the MI rates at 6 months remained lower only in the ACS patients who received abciximab (7.2% vs 9.8%; P = 0.013). Conversely, TVR rates at 6 months were somewhat higher in the non-ACS patients who received abciximab when compared to those receiving tirofiban (8.4% vs 5.8%; P = 0.04). However, it is interesting to note that neither of these differences translated into a reduction in mortality at 6 months, which was equivalent for abciximab or tirofiban therapy for the ACS, as well as the non-ACS patients. For the ACS and non-ACS groups alike, abciximab resulted in significantly higher rates of thrombocytopenia and higher rates of minor bleeding. However, no differences in major bleeding or transfusion were noted with abciximab administration in either group. (Stone GW, et al. Circulation. 2002; 105:r87-r94.)

Comment by Sarah M. Vernon, MD

There is an extensive body of clinical trial data demonstrating the efficacy of glycoprotein IIb-IIIa inhibitors in the reduction of ischemic complications in patients with ACS and in patients undergoing PCI. Taken in total, these trials demonstrate that these drugs, as a class, are particularly useful is improving outcomes in the highest-risk populations of patients they are applied to, namely those with acute MI, with ACS (particularly in the presence of elevated biomarkers or ST depression), and in diabetics. Consequently, the use of glycoprotein IIb-IIIa inhibitors in coronary care units and cardiac catheterization laboratories is widespread, but particularly in the United States where it has been estimated they are used in 80-90% of PCI procedures. With contemporary dosing and adjuvant anticoagulation regimens, these drugs have proven to be safe, but for any individual patient the risk of complications, such as bleeding or thrombocytopenia, is real. In addition, these drugs, as a class, are extremely expensive to administer. Therefore, a strategy for their cost-effective use, including patient selection, choice of agent, dosing and duration, and adjuvant therapy is worthy of ongoing refinement in light of new data as it becomes available.

Despite the results of the initial study demonstrating superiority of abciximab at 30 days, the latest analysis of data from TARGET suggests that, for patients without ACS, there is no clear advantage to abciximab, and that at 6 months, tirofiban may provide equivalent, if not improved outcomes for these patients. There may be a role for tirofiban in the treatment of patients undergoing PCI after all, namely those patients presenting with a stable coronary syndrome. Stone et al acknowledge the limitations of the present study and state that these data should be interpreted with caution. This is a post-hoc analysis, as syndrome acuity was neither predefined nor prespecified for subgroup analysis, and probably not adequately powered to definitively evaluate the ACS and non-ACS populations separately. Nonetheless, these results are intriguing and suggest that there may be a relationship between syndrome acuity and response to individual glycoprotein IIb-IIIa inhibitors that could have "important implications for cost-effective medical practice."

There are significant theoretical differences between the drugs in terms of their pharmacology. For example, the monoclonal antibody derived agent, abciximab, binds the MAC-1 and vitronectin receptors of the vascular endothelium, while the small molecule agents, tirofiban and eptifibatide, specifically bind the platelet glycoprotein IIb-IIIa receptor only. Whether this feature of abciximab translates into clinically meaningful differences in its effectiveness remains open to speculation. In addition, many questions remain about optimal dosing for all of these agents to potentially enhance their efficacy and minimize risk. "Point-of-care" measurement of the actual degree of inhibition of platelet aggregation will likely lead to a better understanding of how each of these agents should be administered in a given patient. Direct comparison between the available agents has essentially been limited to TARGET, with the remainder of clinical trial data being placebo controlled or open label. Comparisons between clinical trials can provide some information, but understanding the details of patient selection, dose, duration, and specific definitions of outcomes needs to be taken into account. It is also important to remember that we have little data suggesting that these drugs, as a class, offer significant benefit to low-risk patients with stable syndromes. With these limitations, in clinical practice the selection of the most appropriate and most cost-effective agent for a given patient in many cases becomes a leap of faith. For example, tirofiban has become "dead in the water" for many interventional operators, who may opt for eptifibatide when selecting a small molecule GP IIb-IIIa agent, on the basis of data from the original TARGET trial combination with ESPRIT2 (a placebo-controlled trial of showing the benefit of eptifibatide in PCI). This has become common practice in many laboratories despite the fact these 2 studies hardly provide a direct comparison between the small molecule agents. The most recent results from the TARGET trial shed no further light on this specific issue. We still don’t know which is the superior glycoprotein IIb-IIIa inhibitor (if any) in a clinically stable patient, but perhaps if we ask the right questions it will eventually become clear.

Dr. Vernon is Assistant Professor of Medicine, Director, VMAC Cardiac University of New Mexico Health Sciences Center, Albuquerque, NM.

References

1. Topol EJ, et al. N Engl J Med. 2001;344:1888-1894.

2. The ESPRIT Investigators. Lancet. 2000;356: 2037-2044.