The routine use of more potent antiplatelet and antithrombotic therapies led to substantial improvements in outcomes after percutaneous coronary intervention (PCI) and has contributed to the interventionist’s ability to treat more complex lesions in ever more challenging patient populations. In the setting of acute ST-elevation myocardial infarction (STEMI), primary PCI reliably restores epicardial blood flow into the affected myocardium, but frequently fails to achieve reperfusion at the myocardial level, which has been associated with an increase in long-term mortality.1,2 The proposed mechanisms of inadequate myocardial reperfusion include spontaneous or device-induced embolization of platelet and platelet-leukocyte aggregates into the microcirculation, effectively obstructing flow at the microcirculatory level.3 The addition of platelet glycoprotein (GP) IIb/IIIa receptor inhibitors blocking the final common pathway of platelet aggregation may improve myocardial perfusion4 and have been shown to benefit patients undergoing PCI for STEMI5 and non-STEMI (NSTEMI).6 However, the magnitude of benefit from GP IIb/IIIa inhibition in most of these studies was less than expected when compared with its theoretical appeal, requiring accumulation of multiple studies in form of meta-analyses to demonstrate a reduction in the incidence of death and recurrent myocardial infarction (MI).7
An important downside to the use of GP IIb/IIIa inhibitors is a significant increase in major bleeding complications, occurring almost uniformly across all trials in which these agents were studied.8 A strategy of routine use of GP IIb/IIIa inhibitor in conjunction with unfractionated heparin (UFH) versus the direct thrombin inhibitor bivalirudin was compared in a series of trials in patients with stable angina9 and unstable angina, including NSTEMI10 and STEMI.11 These studies have consistently demonstrated that ischemic endpoints are similar with both therapies, leading to nonsignificant differences in major adverse cardiac events (MACE). However, there was a significant reduction in net adverse clinical events, consisting of a combination of MACE and major bleeding, in favor of bivalirudin. The importance of bleeding complications in the setting of PCI is increasingly recognized and, as demonstrated in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, may translate into a significant increase in all-cause as well as cardiac mortality at 30 days11 and 1 year. The competing risks of post-procedural MI and major bleeding on 1-year mortality were recently compared using data from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial.12 While both events are associated with a similar relative mortality risk (hazard ratio of 3.1 for mortality and 3.5 for bleeding), the mortality risk for MI is highest in the first few days after the event and then rapidly declines. Conversely, the risk associated with major bleeding remains consistent over the course of the 1-year follow up, indicating that the mortality hazard associated with bleeding is multifactorial in nature.
Based on these data, the routine use of GP IIb/IIIa inhibitors has dramatically decreased in the United States in favor of bivalirudin. Bivalirudin is an irreversible thrombin inhibitor with a halflife of 25 minutes, making it an ideal agent for periprocedural use. Inhibiting thrombin formation not only blocks the coagulation cascade, but has the added benefit of suppressing platelet activation via the protease-activated receptor 1 and certain integrins on the platelet surface that promote aggregation.13 This is in contrast to UFH14 and, paradoxically, even GP IIb/IIIa inhibitors15 that have been shown to activate platelet function and thus promote thrombus formation. Currently, GP IIb/IIIa inhibitors are mainly utilized in a provisional or “bailout” manner during PCI if an unforeseen complication occurs or if dual antiplatelet therapy with aspirin and a thienopyridine cannot be instituted in a timely fashion.
In this edition of the Journal, Feldman et al report on their institutional experience with provisional GP IIb/IIIa inhibitor use in patients undergoing elective or urgent PCI with periprocedural bivalirudin monotherapy. The majority of patients presented with unstable angina or NSTEMI, and dual antiplatelet therapy was administered either prior to or immediately after PCI. In this patient population, provisional GP IIb/IIIa inhibitor use was 11.6%, and presentation with NSTEMI was independently associated with the need for provisional GP IIb/IIIa inhibition. Interestingly, the in-hospital as well as 1-year outcomes were similar between the two groups after adjustment for baseline characteristics. As expected, there were significantly fewer hemorrhagic complications with bivalirudin monotherapy.
In contrast to the current study, a post-hoc analysis of the REPLACE-2 trial evaluating the outcomes of patients requiring bailout therapy found a significantly higher rate of the composite endpoint of death, MI or repeat revascularization at 30 days and 6 months among the bailout patients.16 Interestingly, because of the double-blind trial design, 5.2% of patients in the UFH/GP IIb/IIIa inhibitor group received bailout therapy (with placebo) compared with 7.2% of patients in the bivalirudin group. While this difference is statistically significant (p = 0.001), it represents only a minor clinical difference, indicating that GP IIb/IIIa inhibitors may not actually prevent the very complication that they are used for in a provisional fashion after its occurrence. Whether the addition of a GP IIb/IIIa inhibitor is beneficial is likely dependent on the type of procedural complication or occurrence, as well as the underlying patient population.17 Reasons for provisional GP IIb/IIIa inhibitor use include decreased thrombolysis in myocardial infarction (TIMI) flow, new or suspected thrombus and distal embolization.16 The use of GP IIb/IIIa inhibitors in these clinical settings is consistent with our pathophysiological understanding of the mechanism of action of these agents. However, bailout therapy was also used for unplanned or suboptimal stenting, persistent residual stenosis, dissection, side-branch closure and prolonged ischemia.16 These conditions are related to mechanical complications and are unlikely to improve with the use of a GP IIb/IIIa inhibitor. On the other hand, the “downside of bailout” is an increase in major and minor bleeding, in particular among more vulnerable populations of elderly and underweight patients, which is associated with a significant increase in long-term adverse events (i.e., mortality). Thus, the addition of a GP IIb/IIIa inhibitor during PCI in a patient treated with bivalirudin and dual antiplatelet therapy needs to be carefully evaluated and the decision based on the type of periprocedural complication (thrombotic versus mechanical) and the perceived bleeding risk of the patient. While the data presented in this issue of the Journal appear reassuring with respect to short- and long-term outcomes with the use of provisional GP IIb/IIIa inhibitors, this therapy should be limited to clinical situations in which GP IIb/IIIa inhibitors may be of benefit and to patients with a low bleeding risk.
__________________________
From the Department of Medicine (Cardiovascular Medicine), Stony Brook University Medical Center, Stony Brook, New York.
The authors report no conflicts of interest regarding the content herein.
Address for correspondence: Allen Jeremias, MD, MSc, Division of Cardiovascular Medicine, Stony Brook University Health Sciences Center T 16-080, Stony Brook, NY 11794-8171. E-mail: allen.jeremias@stonybrook.edu
1. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002;105:1909–1913.
2. Stone GW, Peterson MA, Lansky AJ, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol 2002;39:591–597.
3. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002;23:1112–1117.
4. de Lemos JA, Antman EM, Gibson CM, et al. Abciximab improves both epicardial flow and myocardial reperfusion in ST-elevation myocardial infarction. Observations from the TIMI 14 trial. Circulation 2000;101:239–243.
5. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol 2003;42:1879–1885.
6. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: The CAPTURE Study. Lancet 1997;349:1429–1435.
7. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: A meta-analysis of randomized trials. JAMA 2005;293:1759–1765.
8. Pannu R, Andraws R. Effects of glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention after pretreatment with clopidogrel: A meta-analysis of randomized trials. Crit Pathw Cardiol 2008;7:5–10.
9. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863.
10. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–2216.
11. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–2230.
12. Mehran R, Pocock SJ, Stone GW, et al. Associations of major bleeding and myocardial infarction with the incidence and timing of mortality in patients presenting with non-ST-elevation acute coronary syndromes: A risk model from the ACUITY trial. Eur Heart J April 7, 2009 [Epub ahead of print].
13. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258–264.
14. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 1998;97:251–256.
15. Bassler N, Loeffler C, Mangin P, et al. A mechanistic model for paradoxical platelet activation by ligand-mimetic alpha IIb beta 3 (GP IIb/IIIa) antagonists. Arterioscler Thromb Vasc Biol 2007;27:e9–e15.
16. Exaire JE, Butman SM, Ebrahimi R, et al. Provisional glycoprotein IIb/IIIa blockade in a randomized investigation of bivalirudin versus heparin plus planned glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention: Predictors and outcome in the Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial. Am Heart J 2006;152:157–163.
17. Jeremias A, Baim DS, Ho KK, et al. Differential mortality risk of postprocedural creatine kinase-MB elevation following successful versus unsuccessful stent procedures. J Am Coll Cardiol 2004;44:1210–1214.
