Commentary

Glycoprotein Wars and PIECE Activists

Steven Goldberg, MD
Steven Goldberg, MD
After World War I, two independent companies named Bayer separately marketed the same compound with the trademarked name, Aspirin. This absurd scenario was well chronicled in the book, The Aspirin Wars, by Mann and Plummer.1 For the past decade, we have been witnessing a battle between other antithrombotic compounds used for coronary interventions, with marketing so intense it sometimes seems nearly as absurd as the Aspirin Wars. At the center of the Glycoprotein Wars is the role of these newer, more expensive agents in reducing cardiac events, first demonstrated by the oldest and most expensive of these agents, abciximab. Assumptions as to “class effects” have fueled speculation on more cost-effective alternatives to this best studied glycoprotein (GP) IIb/IIIa inhibitor agent. There have been several non-randomized, poorly-controlled trials (usually unpublished) seemingly with an agenda to demonstrate that cheaper GP IIb/IIIa agents could be used instead of abciximab and thereby save money, with the implication that these agents supply similar efficacy. At first blush, the study by Suleiman et al.2 in this issue seems to be an almost See Suleiman et al. on pages 319–323 absurd variation on this theme by distilling out the one feature which has been a mainstay of presumed benefit of GP IIb/IIIa inhibitor agents, the reduction in Post-Intervention Elevations in Cardiac Enzymes (PIECE). From EPISTENT to ESPRIT, the most consistent benefit shown by GP IIb/IIIa inhibitor agents has been a reduction in PIECE when compared to heparin alone, or when comparing the dominant agent abciximab to the “upstart challenger” tirofiban in the TARGET trial.3–5 Yet the non-randomized, retrospective study comparing abciximab to eptifibatide by Suleiman et al.2 completely ignores PIECE, since those operators do not check cardiac enzymes after their angioplasty procedures. Not surprisingly, they found no difference at the time of hospital discharge between the two agents in the combined or separate endpoints of death, target vessel revascularization or major bleeding episodes, given the expectedly low incidence of any of these events. They did find a difference in thrombocytopenia, a finding consistent with already known side effects of abciximab, and less so with eptifibatide.6 In fact, perhaps the most interesting conclusion from this study was the suggestion that despite the increased risk of thrombocytopenia, abciximab was not associated with increased bleeding risks, suggesting the thrombocytopenia was more of a nuisance than dangerous. Yet, before lambasting the authors of this manuscript for presenting a comparison study on the effect of different GP IIb/IIIa inhibitors while ignoring cardiac enzyme release as an outcome, perhaps it is appropriate to step back for a moment and ask if the reductionist analysis being presented is any more inappropriate than what we have become used to in focusing on PIECE as the primary endpoint comparing antithrombotic agents for coronary interventions. What do we hope to accomplish with the use of antithrombotic agents more advanced than heparin? Perhaps the operator performing the procedure is most interested in reducing visible thrombotic complications during the intervention, such as the development of thrombus inside the blood vessel, acute closure of the vessel or a side branch due to thrombus, and other angiographically identified complications. Do GP IIb/IIIa inhibitor agents accomplish this? In the PRISM-PLUS trial of patients with acute coronary syndromes, pretreatment with tirofiban and heparin for 48–96 hours before coronary angiography was associated with a slightly lower incidence of visible thrombus and slightly higher rates of TIMI 3 flow, compared with heparin alone.7 In the EPISTENT trial, the use of abciximab at the time of coronary intervention was associated with a lower incidence of side branch occlusions, transient coronary occlusion, or less than TIMI 3 flow at the end of the procedure, compared with unfractionated heparin alone.8 This would support a measurable, clinically relevant role for abciximab in patients undergoing intervention. However, the same investigators found no similar reduction in angiographic complications using eptifibitide in the ESPRIT trial, with the only effect of eptifibitide being a reduction in PIECE.9 Although the patient cohort in ESPRIT was likely at lower risk than the cohort in EPISTENT, this information supports a benefit with abxicimab which has not yet been demonstrated with eptifibatide. A second potential clinical benefit of antithrombotic agents is to reduce early and late-term clinical outcomes such as death or myocardial infarction. This is an area of confusion as many immediate post-procedural events are asymptomatic elevations in cardiac enzymes. Since they are asymptomatic, these become clinically relevant only if they are associated with late-term clinical problems, which might include future myocardial infarctions, arrhythmias, syndromes of diminished cardiac function, or death. In this manner, PIECE has been extensively used as a possible surrogate endpoint for late term events. Unfortunately, our ability to understand the implications of cardiac enzyme release after coronary intervention is confounded by the strong association of post-procedure cardiac enzyme release and more extensive vascular disease and other high risk characteristics.10 This makes it possible that cardiac enzyme release after an intervention is simply a marker for the high-risk patient. A medication which attenuates the cardiac enzyme release post-intervention will not have an impact on the high-risk features of the patient, and therefore may have little impact on distant cardiac complications. In other words, this may be an example of “true-true-unrelated:” True GP IIb/IIIa inhibitor agents reduce PIECE, true PIECE is a marker for late-term events, but these facts are not necessarily related. This is a situation which has plagued the medical community in other conditions relying upon seemingly important surrogates, such as the favorable impact of hormones on lipids but without reducing cardiovascular events.11 Furthermore, although it is true that PIECE is a predictor for late-term outcomes,10 there is evidence that cardiac enzyme release is in fact a relatively poor predictor (with the notable exception of large elevations in cardiac enzyme release12). In a meta-analysis of trials comparing abciximab to unfractionated heparin, Anderson et al. demonstrated a possible mortality benefit of abciximab as well as a reduction in PIECE, yet found that most late-term deaths occurred in individuals without cardiac enzyme release at the time of the intervention.13 Furthermore, this analysis suggested abciximab had a benefit in mortality reduction independent of its effect on reducing cardiac enzyme release. Similarly, preliminary data have suggested that beta-blockers after coronary intervention reduce both PIECE as well as follow-up mortality — but not in the same patients.14 Therefore, studies which emphasize reductions in PIECE may be failing to identify the true clinical benefits (or lack thereof) of these antithrombotic agents. This extends not only to GP IIb/IIIa agents, but also to other antithrombotic regimens, such as bivalirudin. The recent REPLACE II trial did not demonstrate a significant difference in the triple endpoint at 30 days of death, myocardial infarction or urgent target vessel revascularization, but it is unclear if this is an appropriate surrogate endpoint, since it is driven by PIECE.15 As suggested by the study of Anderson et al., if late term, poorly understood, mortality benefits exist for abciximab, these benefits would not be recognized in the 30-day outcomes which have been presented in the REPLACE II trial. The operators of the study by Suleiman et al.,2 who do not check cardiac enzymes after coronary interventions, have perhaps challenged us to stop trying to pick up the PIECEs. Should we end the search for PIECE, and abandon checking cardiac enzymes after coronary interventions, given the lack of therapeutic choices whether or not PIECE is discovered? Should we be relying upon PIECE to select our medical therapy before, during and after coronary interventions? Should we challenge those marketing these agents, and designing studies, that questions remain about the value of PIECE as a surrogate endpoint? Alas, regardless of any of our stances on these important questions, and even though the combatants may change, it is highly likely the Glycoprotein Wars are going to continue.
References
1. Mann CC, Plummer ML. The Aspirin Wars: Money, Medicine, and 100 years of Rampant Competition. New York: Knopf; 1991. 2. Suleiman M, Gruberg L, Hammerman H, et al. Comparison of two platelet glycoprotein IIB/IIIA inhibitors, eptifibitide and abciximab: Outcomes, complications and thrombocytopenia during percutaneous coronary intervention. J Invas Cardiol 2003;15:319–323. 3. The EPISTENT Investigators. Randomized placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with the use of platelet glycoprotein IIb/IIIa blockade: Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1998;352:87–92. 4. The ESPRIT Investigators. Novel dosing regimen of eptifibitide in planned coronary stent implantation (ESPRIT): A randomized, placebo-controlled trial. Lancet 2000;356:2037–2044. 5. Topol EJ, Moliterno DJ, Herrmann HC, et al. for the TARGET Investigators. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001;344:1888–1894. 6. Dasgupta H, Blankenship JC, Wood GC, et al. Thrombocytopenia complicating treatment with intravenous glycoprotein IIb/IIIa receptor inhibitors: a pooled analysis. Am Heart J 2000;140:206–211. 7. Zhao X, Theroux P, Snapinn SM, Sax FL, for the PRISM-PLUS Investigators. Intracoronary thrombus and platelet glycoprotein IIb/IIIa receptor blockade with tirofiban in unstable angina or non-Q-wave myocardial infarction. Angiographic results from the PRISM-PLUS Trial (Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms). Circulation 1999;100:1609–1605. 8. Islam MA, Blankenship JC, Balog C, et al., for the EPISTENT Investigators. Effect of abciximab on angiographic complications during percutaneous coronary stenting in the evaluation of platelet IIb/IIIa inhibition in stenting trial (EPISTENT). Am J Cardiol 2002;90:916–921. 9. Blankenship JC, Tasissa G, O'Shea JC, et al., for the ESPRIT Investigators. Effect of glycoprotein IIb/IIIa receptor inhibition on angiographic complications during percutaneous coronary intervention in the ESPRIT Trial. J Am Coll Cardiol 2001;38:653–658. 10. Ellis SG, Chew D, Chan A, et al. Death following creatine kinase-MB elevation after coronary intervention. Identification of an early risk period: Importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy. Circulation 2002;106:1205–1210. 11. D'Agostino Jr. RB. Debate: The slippery slope of surrogate outcomes. Curr Control Trials Cardiovasc Med 2000;1:76–78. 12. Stone GW, Mehran R, Dangas G, et al. Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: A device specific analysis of 7,147 patients. Circulation 2001;104:642–647. 13. Anderson KM, Califf RM, Stone GW, et al. Long-term mortality benefit with abciximab in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2001;37:2059–2065. 14. Sharma SK, Kini A, Marmur JD, Fuster V. Cardioprotective effect of prior B-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention. Benefit is extended to improvement in intermediate-term survival. Circulation 2000;102. 15. Lincoff AM, Bittl JA, Harrington RA, et al., for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 Randomized Trial. JAMA 2003;289:853–863.