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Featured Clinical Topic: Glycoprotein IIb/IIIa Inhibitors: Remaining Clinical Roles

09 Jun 2022 2:08 PM | Anonymous

Authors: Eric Johnston, Pharm.D. Candidate1, Justin Alberts, Pharm.D. Candidate1, Shane Austin, Pharm.D., BCPS2, Anastasia L. Armbruster, Pharm.D., FACC, BCPS, BCCP1
1St. Louis College of Pharmacy at the University of Health Sciences and Pharmacy
2Missouri Baptist Medical Center, St. Louis, MO 

Introduction 

Heart disease remained the leading cause of death in the United States in 2020 according to the Centers for Disease Control and Prevention.1 In the United States (U.S.), approximately every 40 seconds an individual experiences a heart attack.2 For the management of ST-segment-elevation myocardial infarction (STEMI) and non-ST-segment-elevation myocardial infarction (NSTEMI), the recent 2021 ACC/AHA/SCAI Guidelines for Coronary Artery Revascularization reaffirm the essential role of percutaneous coronary intervention (PCI) in improving clinical outcomes.3Additionally, an extensive array of clinical trials have evaluated antiplatelet therapy in concert with PCI over the past 25 years. Glycoprotein IIb/IIIa inhibitors (GPI) formerly served a critical role in augmenting platelet inhibition surrounding PCI, but in the current paradigm the role of GPIs has largely fallen out of favor. The purpose of this article is to clarify the remaining clinical utility of GPIs available in the U.S. (eptifibatide and tirofiban) through discussing GPI pharmacology and pharmacokinetics, reflecting on historical roles, and evaluating guideline recommendations. This article is intended for pharmacists who verify orders or are integrated into multidisciplinary teams that address patients with acute coronary syndromes (ACS).  

Pharmacology and Pharmacokinetics 

Two GPIs, eptifibatide (Integrilin®) and tirofiban (Aggrastat®), remain available for use in the U.S., since the last lot of abciximab (ReoPro®) expired in September 2019, and will no longer be manufactured.4 Eptifibatide and tirofiban are both small molecules that exert their pharmacodynamic effect of inhibiting platelet aggregation through reversible inhibition of the glycoprotein IIb/IIIa receptor on platelets5,6 but abciximab was a monoclonal antibody that was thought to utilize steric hindrance to block the glycoprotein IIb/IIIa receptor.7 Further information on the pharmacology of eptifibatide and tirofiban is provided in Table 1.  


Historical Guideline and Clinical Trial Considerations  

To help clarify the role of GPIs today, it is essential to understand the historical role of GPIs. The history of GPIs revolves around the general concept of platelet inhibition surrounding PCI for ACS. We constructed a timeline (Figure 1) to illustrate advancements in PCI technology, GPI trials, and dual antiplatelet therapy (DAPT) trials to represent the temporal reasoning for why GPIs have fallen out of favor. The origins of PCI are from 1977 when balloon angioplasty was first employed, and a decade passed until FDA approval was granted for the first bare-metal stent (BMS). PCI continued to advance with the utilization of drug-eluting stents (DES), beginning in 2002.8 

Landmark GPI trials are the next major element to consider. Specifically, the legacy of the GPIs in question for this article began in 1997 with the IMPACT II and RESTORE clinical trials for eptifibatide and tirofiban, respectively,9,10 and FDA approval followed shortly in May 1998 for both agents. A few more landmark trials for eptifibatide and tirofiban were published before the 2004 ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction and the two drugs received a class IIb recommendation for use in primary PCI whereas abciximab, benefitting from greater clinical trial experience, received a class IIa recommendation.11 However, a paradigm shift had already begun in 2001 with the results of the CURE trial, which set off a series of trials cementing the case for dual-antiplatelet therapy (DAPT) using aspirin combined with clopidogrel, prasugrel, or ticagrelor.12-14 Upon publication of the 2013 ACCF/AHA Guidelines for the Management of ST-Elevation Myocardial Infarction, the first set of guidelines following the completion of landmark clinical trials for each DAPT option, a Class 1 recommendation to use a loading dose of DAPT at the time of a primary PCI drove the standard for clinical practice firmly in favor of DAPT rather than GPIs. Furthermore, these guidelines narrowed the utility of GPIs to select patients: those with inadequate P2Y12 loading or with a large thrombus burden.15  

Finally, there are two time domains which are important to consider: timing of GPI administration and timing of PCI. Timing of GPIs has been a source of debate as to whether any greater benefit could be derived by administering GPIs before proceeding with cardiac catheterization, but evidence strongly suggests that earlier administration of GPIs is not beneficial.16Time to PCI, such as “door-to-balloon” timing, has been another evolution in revascularization from the early 2000’s which significantly reduces in-hospital mortality,15 and may also contribute to the blunted clinical benefit of GPIs.

 

Current Clinical Roles for GPIs 

The appropriateness of GPIs in the present era depends on “large thrombus burden, no-reflow, or slow flow” according to the 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization (Class 2a recommendation).3 This is due to the preeminence of oral DAPT loading strategies as the mainstay of antiplatelet therapy in PCI to reduce mortality and other major clinical outcomes, such as recurrent MI. On the other hand, GPIs seem to only offer benefit in improving procedural success, rather than the aforementioned clinical outcomes.3,17 As described in Table 1, GPIs possess rapid and potent platelet inhibiting properties, hence their utility in complicated or burdensome thromboses of vessels receiving stenting. An important caveat of GPI use is that this is limited to patients presenting with ACS, since stable ischemic heart disease populations do not derive any clinical benefit of GPI therapy for PCI (Class 3 recommendation, no benefit).3,17 Furthermore, patient safety is promoted through discontinuation of GPIs prior to CABG in order to reduce bleeding complications. The optimal timing to discontinue eptifibatide or tirofiban is 4 hours prior to coronary artery bypass graft (CABG) (Class 1 recommendation). Finally, patients who do not have adequate P2Y12 inhibition should most likely be treated with cangrelor (Kengreal), an intravenous P2Y12 inhibitor, rather than a GPI (Class 2b recommendation).3 

Conclusion 

In summary, the appropriateness of GPIs in the present era should follow four primary traits: only for ACS patients receiving PCI, only be given once coronary anatomy is known (i.e. large thrombus burden), to improve procedural success, and must be discontinued 4 hours before CABG.  

 

References 

  1. Murphy SL, Kochanek KD, Xu JQ, Arias E. Mortality in the United States, 2020. NCHS Data Brief, no 427. Hyattsville, MD: National Center for Health Statistics. 2021.  
  2. Benjamin EJ, Muntner P, Alonso A, et al. Heart Disease and Stroke Statistics-2019 Update: A Report from the American Heart Association. Circulation. 2019;139(10):e56-e528.  
  3. Lawton JS, Tamis-Holland JE, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(3):e18-e114.  
  4. Wheeler M. Drug Shortage Detail: Abciximab Injection. Ashp.org. Published April 29, 2019. Accessed April 8, 2022.  
  5. Integrilin® (eptifibatide). Package insert. Merck & Co., Inc.; 1998. March 2013.  
  6. Aggrastat® (tirofiban). Package insert. Merck & Co., Inc.; 1998. April 2015.  
  7. ReoPro® (abciximab). Package insert. Eli Lilly and Co.; 1994. November 2013.  
  8. Canfield J, Totary-Jain H. 40 Years of Percutaneous Coronary Intervention: History and Future Directions. J Pers Med. 2018;8(4):33.  
  9. The IMPACT-II Investigators.  Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Lancet. 1997;349:1422-1428.  
  10. The RESTORE Investigators. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation.1997;96:1445-1453.  
  11. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2004;110(9):e82-e292.  
  12. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.  
  13. Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.  
  14. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.  
  15. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127(4):e362-e425.  
  16. Van't Hof AW, Ten Berg J, Heestermans T, et al. Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial. Lancet. 2008;372(9638):537-546.  
  17. O'Shea JC, Hafley GE, Greenberg S, et al. Platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention: the ESPRIT trial: a randomized controlled trial. JAMA. 2001;285(19):2468-2473.  

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