EDITORIAL

Glycoprotein IIb/III Inhibition During Acute Percutaneous Coronary

Intervention: Tool or Talisman?

SEIF EL‐JACK, F.R.C.P., F.R.A.C.P., F.A.C.C., F.S.C.A.I.

From the CardioVascular Unit, North Shore Hospital, Auckland, New Zealand

(J Interven Cardiol 2013;26:340–342)

Glycoprotein IIb/IIIa receptor inhibitors (GPI) area class of antiplatelet agents variably used in thetreatment of acute coronary syndromes (ACS) and inhigh‐risk acute percutaneous coronary intervention(PCI). The three generic GPI (abciximab, eptafibatide,and tirofiban) have differing pharmacologic propertiesbut their efficacy has, largely, rightly or wrongly, beenconsidered a class effect.In this issue of JOIC, Song and co‐workers1 present

an open‐label randomized study of the upstreamadministration of high bolus tirofiban in acute STsegment elevation myocardial infarction (STEMI)patients scheduled for primary percutaneous interven-tion (PCI) versus a deferred strategy of its use in selectpatients with a large thrombus burden or slow flowduring PCI. They compare individual and compositetraditional end‐points of death, MI, stent thrombosis(ST), and target vessel revascularization (TVR) at7 days, 1 month, and 6 months. The safety end‐pointscomprised TIMI major and minor bleeding at 7 days.They also report left ventricular ejection fraction(LVEF) at 7 days.There was no significant difference in TIMI flow

before or after PCI between the 2 groups and nodifference in individual clinical outcome end‐points atthe prespecified times though the composite end‐pointwas less in the upstream tirofiban group at 7 days and1 month but not at 6 months (1.5% vs 4.2%, P¼ 0.037;3.3% vs 7.0%, P¼ 0.034; and 7.0% vs 10.3%, P¼NS,

respectively). There was a trend toward more TIMImajor and minor bleeding in the upstream group (4.5%vs 2.4%, P¼NS). In 89% of patients with echocardio-graphic assessment, LVEFwasmarginally higher in theupstream tirofiban group at 7 days, an increase of 3.5%versus 1.9% to baseline.There are several limitations in this study, some of

which are acknowledged by the authors. As per theirlocal hospital protocol at the time (2008–2010),patients were loaded with 300mg of clopidogrel ratherthan 600mg and those on tirofiban received a longerthan usual 24–36 hour infusion. All patients received anonconventional regimen of 86 IU/kg twice daily oflowmolecular weight heparin for 5 days post‐PCI. Thiswill limit extrapolation of their results into morestandard practice. Heparin dosing was adjusted for atarget ACT of 200–250 seconds for the upstreamtirofiban group and 250–350 seconds for the deferredcohort. This, together with the predominant use of theradial access (86% of procedures), may have contrib-uted to the low rate of bleeding in both groups,potentially with more reduction in the upstreamtirofiban group. The limited use of thrombus aspiration(25% of cases) may exaggerate the benefit of tirofiban.The lack of a difference in TIMI flow before and afterPCI in both groups together with the lack of differencein individual clinical end‐points (despite the positivetrends), makes the apparent difference in the compositeend‐point somewhat difficult to apply in clinicalpractice, particularly that this composite end‐pointdifference was only maintained at 1 month but not6 months. The 7‐day outcome measure is probably tooshort for these end‐points. Finally, an absolute 1.6%

Address for reprints: Seif El‐Jack, CardioVascular Unit, North ShoreHospital, Auckland, New Zealand. Fax: þ6494868963; e‐mail: seif.eljack@waitematadhb.govt.nz

© 2013, Wiley Periodicals, Inc.DOI: 10.1111/joic.12052

340 Journal of Interventional Cardiology Vol. 26, No. 4, 2013

difference in reported LVEF recovery between baselineechocardiography (some of which were acute bedsidestudies in the Emergency Room) compared to possiblymore concerted studies a week later is hardly a strongoutcome. This is particularly moreso if these areperformed by various operators leading to some inter‐observer variability.

“A perfection of means, and confusion of aims,seems to be our main problem”

—Albert Einstein

One of the conundrums of understanding the role ofGPI in primary PCI is how to apply the trial evidence toindividual patients in different clinical scenarios.Studies have compared GPI versus active or non‐active alternatives, different dosing regimens, differenttiming of administration, combinations with otherantiplatelets, anticoagulants or fibrinolytics and indeedcoupled with the use, or not, of thrombectomy devices,not to mention different indications in ACS, NSTEMI,and STEMI. Abxciximab is the most widely researchedagent in primary PCI and may reduce 30‐day mortalityand reinfarction rates.2,3 Some limited evidence wouldsuggest similar efficacy using the smaller moleculestirofiban and eptafibatide. The MULTISTRATEGYstudy is one of the larger reports showing non‐inferiority of tirofiban compared to abciximab inprimary PCI.4 This was also suggested in a recentstatistical extrapolation of the TENACITY trial.5

Despite this apparent equivalence, 2 meta‐analyses ofabciximab and tirofiban trials were conflicting in theirconclusions as to the efficacy of these agents.6,7 In thehigh‐dose P2Y12 inhibitors pretreatment era, trials ofGPI similarly resulted in differing outcome benefits,ON‐TIME 28 favoring pretreatment with tirofiban withno benefit from upstream abciximab in BRAVE‐3.9

This becomes more ambiguous when bivalirudinpretreatment is suggested to be superior to heparin‐GPI combination in STEMI patients10 or if GPI areused in complex designs including a fibrinolysis armsuch as FINESSE.11 A meta‐regression of GPI use inSTEMI (excluding bivalirudin treatment) more recent-ly suggested selective benefit, regardless of P2Y12

inhibitors pretreatment.12 To compound this confusion,tirofiban can be administered in 2 fashions: high‐bolusdosing as in this study (25mg/kg bolus followed by aninfusion of 0.15mg/kg/min for 18–24 hours), or theUS‐approved dosing of 0.4mg/kg/min for 30minutesfollowed by a 0.1mg/kg/min infusion. There may be

some temporal benefit from early platelet inhibitionwith the high dosing. Furthermore, tirofiban needs tobe reduced by 50% if the creatinine clearance is<30ml/min. This may further limit direct comparisonsbetween tirofiban trials.

“There are known unknowns; that is to say, thereare things that we now know we don’t know”

—United States Secretary of Defense, DonaldRumsfeld�

Unfortunately, the present study does not helpfurther my understanding beyond what we alreadyknow about GPI use in primary PCI. Their efficacy withthe advent of potent thienopyridine (and other) P2Y12

platelet inhibitors and the preferred use of directthrombin inhibition has become even less clear. Otherfactors beyond platelet inhibition, such as the continuedimprovement in early access to primary PCI13 or betteroutcomes through the routine use of thrombusaspiration,14–16 may further attenuate any perceivedbenefit from GPI. Conversely, the increased worldwideuptake of the radial access for PCI may mitigate someof the bleeding risk associated with their use. Thecurrent AHA/ACC Guidelines 2009 Update17 stillgives GPI use in STEMI a “reasonable” IIa indication atthe time of primary PCI in select patients (level ofevidence [LOE] A for abciximab and B for tirofiban oreptafibatide). Their routine use prior to angiographyremains uncertain (IIb, LOE‐B). This is almostidentical to the European Society of Cardiology 2012STEMI Guidelines.18 As such they probably should bereserved as a bailout strategy in patients with a largethrombus burden at angiography or with impairedTIMI flow, or in select high‐risk patients wherebivalirudin is not used. One could be sure, though,that, as in many aspects of science, there will remain 1or 2 “unknown unknowns—the things we do not knowwe don’t know.” �

References

1. Jia Z, Guo M, Zhang YQ, et al. Short‐term effect of upstreamadministration in comparison to deferred injection of tirofiban onpatients with acute ST‐segment elevation myocardial infarctionundergoing primary percutaneous coronary intervention. J IntervCardiol 2013;26:332–339.

2. De Luca G, Suryapranata H, Stone GW, et al. Abciximab asadjunctive therapy to reperfusion in acute ST‐segment elevationmyocardial infarction: A meta‐analysis of randomized trials.JAMA 2005;293:1759–1765.

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3. Montalescot G, Antoniucci D, Kastrati A, et al. Abciximabin primary coronary stenting of ST‐elevation myocardialinfarction: A European meta‐analysis on individual patients’data with long‐term follow up. Eur Heart J 2007;28:443–449.

4. Valgimigli M, Campo G, Percoco G, et al. Comparison ofangioplasty with infusion of tirofiban or abciximab and withimplantation of sirolimus‐eluting or uncoated stents for acutemyocardial infarction: The MULTISTRATEGY randomizedtrial. JAMA 2008;299:1788–1799.

5. Berger PB, Williams JB, Hasselblad V, et al. Would tirofibanhave been shown non‐inferior to abciximab had the TENACITYtrial not been terminated for financial reasons? J Interv Cardiol2013;26:123–130.

6. Jeremias A, Vasu S, Gruberg L, et al. Impact of abciximab onmortality and reinfarction in patients with acute ST‐segmentelevation myocardial infarction treated with primary stenting.Catheter Cardiovasc Interv 2010;75:895–902.

7. Sethi A, Bahekar A, Doshi H, et al. Tirofiban use withclopidogrel and aspirin decreases adverse cardiovascular eventsafter percutaneous coronary intervention for ST‐elevationmyocardial infarction: A meta‐analysis of randomized trials.Can J Cardiol 2011;27:548–554.

8. ten Berg JM, van ’t Hof AW, Dill T, et al. Effect of early, pre‐hospital initiation of high bolus dose tirofiban in patients withST‐segment elevation myocardial infarction on short‐ and long‐term clinical outcome. J Am Coll Cardiol 2010;55(22):2446–2455.

9. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients withacute ST‐segment‐elevation myocardial infarction undergoingprimary percutaneous coronary intervention after clopidogrelloading: A randomized double‐blind trial. Bavarian ReperfusionAlternatives Evaluation‐3 (BRAVE‐3) Study Investigators.Circulation 2009;119:1933–1940.

10. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudinduring primary PCI in acute myocardial infarction. TheHORIZONS‐AMI (Harmonizing Outcomes With Revasculari-zation and Stents in Acute Myocardial Infarction) Trial. N Engl JMed 2008;358:2218–2230.

11. Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI inpatients with ST‐elevation myocardial infarction (FINESSE). NEngl J Med 2008;358:2205–2217.

12. Sethi A, Bajaj A, Bahekar A, et al. Glycoprotein IIb/IIIainhibitors with or without thienopyridine pretreatment improveoutcomes after primary percutaneous coronary intervention inhigh‐risk patients with ST elevation myocardial infarction—ameta‐regression of randomized controlled trial. Catheter Car-diovasc Interv 2012; Sep 7 [Epub ahead of print].

13. RoeMT,MessengerMC,WeintraubWS, et al. Treatments, trends,and outcomes of acute myocardial infarction and percutaneouscoronary intervention. J Am Coll Cardiol 2010; 56:254–263.

14. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death andreinfarction after 1 year in the thrombus aspiration duringpercutaneous coronary intervention in acute myocardial infarc-tion study (TAPAS): A 1‐year follow‐up study. Lancet 2008;371:1915–1920.

15. Bavry AA, Kumbhani DJ, Bhatt DL. Role of adjunctivethrombectomy and embolic protection devices in acute myo-cardial infarction: A comprehensive meta‐analysis of random-ized trials. Eur Heart J 2008;29:2989–3001.

16. Burzotta F, De Vita M, Gu YL, et al. Clinical impact ofthrombectomy in acute ST‐elevation myocardial infarction: Anindividual patient‐data pooled analysis of 11 trials. Eur Heart J2009;30:2193–2203.

17. Kushner FG, HandM, Smith SC Jr, et al. 2009 FocusedUpdates:ACC/AHA Guidelines for the management of patients with ST‐elevationmyocardial infarction (updating the 2004 guideline and2007 focused update) and ACC/AHA/SCAI Guidelines onpercutaneous coronary intervention (updating the 2005 guidelineand 2007 focused update). A report of the American College ofCardiology Foundation/American Heart Association Task Forceon practice Guidelines. J Am Coll Cardiol 2009;54:2205–2241.

18. Steg PG, James SK, Atar D, et al. ESC Guidelines for themanagement of acute myocardial infarction in patients present-ing with ST‐segment elevation. The task force on themanagement of ST‐segment elevation acute myocardial infarc-tion of the European Society of Cardiology (ESC). Eur Heart J2012;33:2569–2619.

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