Current Role of Platelet Glycoprotein Iib/Iiia Inhibition in the Therapeutic Management of Acute Coronary Syndromes in the Stent Era

Journal of Cardiology & Current Research

Current Role of Platelet Glycoprotein IIb/IIIa Inhibition in the Therapeutic Management of Acute Coronary Syndromes in the Stent Era

Review Article Abstract The pathophysiology of acute coronary syndromes (ACS) is characterized by Volume 5 Issue 5 - 2016 disruption of atherosclerotic plaques, activation and aggregation of platelets,

and formation of an arterial thrombus. Thrombus formation can result in 1 either transient or persistent occlusion giving rise to the spectrum of ACS. This Department of Health Sciences’s Investigation, Sanatorio Metropolitano, Fernando de la Mora, Paraguay syndrome defines rapidly evolving symptoms of myocardial ischemia ranging 2Cardiology Division, First Department of Internal Medicine, from unstable angina pectoris to non-Q-wave myocardial infarction to Q-wave Clinic Hospital, Asunción National University, San Lorenzo, myocardial infarction. An early pharmacological strategy to reduce ischemic Paraguay complications of PCI was the use of parenteral glycoprotein (GP) IIb/IIIa inhibitors. *Corresponding author: Osmar Antonio Centurión, Professor of Medicine, Asuncion National University, The benefit of GP IIb/IIIa inhibitors in early studies was driven primarily by Department of Health Sciences’s Investigation, Sanatorio reductions in periprocedural myocardial infarction. Advances in both stent Metropolitano, Teniente Ettiene 215 c/ Ruta Mariscal design and adjunct pharmacology have led to improved outcomes in ACS and a Estigarribia,Fernando de la Mora, Paraguay, Tel: 595-21- diminished role for GP IIb/IIIa inhibitors as reflected in current PCI guidelines. 498200; Fax: 595-21-205630; Email: Current medical therapy with aspirin, clopidogrel, ticagrelol, prasugrel, and heparin provides important therapeutic benefits. The platelet GP IIb/IIIa receptor antagonists, by blocking the final common pathway of platelet aggregation, Received: March 07, 2016 | Published: May 03, 2016 are a breakthrough in the management of ACS. Several large multicenter trials have evaluated the platelet GP IIb/IIIa antagonists with and without heparin undergoing PCI or not. There was a significantly reduced incidence in the cardiac ischemic events. The clinically important benefit persisted at 3 years of follow- up. In addition to maintaining epicardial wall vessel patency, it was shown an improvement in microvascular perfusion and myocardial function as assessed by peak coronary flow velocity and regional wall motion. Despite the success of abciximab in preventing ischemic events after PCI, the use of intravenous, small-molecule GP IIb/IIIa antagonists, and the intention to broaden the clinical indication have produced varied results. Mechanisms contributing to these heterogeneous outcomes may include the possibility of pro- thrombotic events, as well as, normal variation in platelet or receptor number, differences in receptor activity, and interpatient variation in pharmacological dose response. Trials investigating the role of intravenous small-molecule GP IIb/IIIa antagonists underline the importance of adequate higher and effective dosing. These trials highlight the use of suboptimal dose as the cause for the poor outcome in some instances. Despite the heterogeneous outcome, these agents still have potential advantages in patients with high clinical risk but low bleeding risk. Adjunctive platelet GP IIb/IIIa receptor inhibition has proved beneficial effects in the setting of PCI, and still has a place as bailout therapy for periprocedural PCI complications in ACS patients, such as those patients with large thrombus, with stent thrombosis, and refractory no-reflow phenomenon following PCI.

Keywords: Platelet GP IIb/IIIa antagonists; Percutaneous coronary interventions; Acute coronary syndromes

Submit Manuscript | http://medcraveonline.com J Cardiol Curr Res 2016, 5(5): 00175 Current Role of Platelet Glycoprotein IIb/IIIa Inhibition in the Therapeutic Management Copyright: 2/14 of Acute Coronary Syndromes in the Stent Era ©2016 Centurión

Introduction in the platelet membrane [10]. The GP IIb/IIIa domains responsible Although there are major advances in the treatment and composed of a globular head and two flexible tails that are imbibed management of cardiovascular diseases, ischemic heart disease are characterized by their ability to recognize the peptide sequence continues to be the leading cause of mortality and morbidity RGD.for binding The RGD adhesive recognition proteins sequence have been was identified originally and described in general for worldwide. Ischemic heart disease affects nearly 16 million persons aged 20 years and older in the USA. More than 2 million Willebrand factor, vitronectin, and thrombospondin [11]. If two cases of unstable angina (UA), and nearly 4 million cases of acute activatedfibronectin platelets but is nowwith known functional to be GP present IIb/IIIa in fibrinogen,receptors each von myocardial infarction (AMI) occur annually in the world. These numbers will likely increase over the next decade due to aging between the two platelets. When these processes of aggregation population (1-5). The prevalence of patients who have survived arebind repeated the same thousands fibrinogen of molecule, times, a thrombus a fibrinogen is generated. bridge is createdIt is the an episode of AMI is estimated at 15 million, these patients are chief receptor responsible for platelet aggregation by its ability to at high risk to develop additional acute events. Although, the incidence of UA is lower than that of AMI, its prevalence is likely to leading ultimately to thrombus formation. However, this receptor be higher because patients are more likely to survive an episode bind soluble fibrinogen, which forms bridges between platelets of UA, and these patients are also at high risk for the occurrence of stimulated by agonists and undergoes a conformational change. additional acute coronary syndrome (ACS). Sinceremains GP unableIIb/IIIa toreceptors bind fibrinogen are unique unless to platelets, the platelet and are is firstthe Common antiplatelet agents such as aspirin and ticlopidine, clopidogrel, ticagrelol prasugrel, and antithrombin agents such these factors make these receptors an extremely favorable target as hirudin and heparin, act by inhibiting different pathways of forfinal therapeutic common pathwaypharmacologic for platelet blockade aggregation (Figure 1) by [12,13]. all agonists, platelet activation in a different manner. This may account for ABCIXIMAB (Murine monoclonal antibodies 7E3): More the limited ability of these agents to prevent platelet aggregation, than three decades ago, Coller [14] produced a mouse monoclonal since other avenues of activation are left undisturbed [1-3]. The antibody against the GP IIb/IIIa integrin receptor [14]. The Coller antibody, termed abciximab or 7E3, has a molecular weight of for all platelet aggregation suggests the possibility that agents designedcritical role to ofantagonize the GP IIb/IIIa this receptor receptor may as final be thecommon most pathwayeffective for the GP IIb/IIIa receptor, two properties that make 7E3 an type of agents for preventing platelet aggregation and, therefore, extremely47.6 kD and attractive exhibits therapeutic both a high-affinity agent for andthe blocking absolute of specificity adhesive thrombosis. Regardless of the stimulus for platelet activation, GP IIb/IIIa antagonists inhibit thrombosis by preventing GP IIb/IIIa receptor in either the active or inactive state with additionalproteins [15-18]. activity Abciximab against the shows vitronectin a high bindingreceptor affinity and possibly for the MAC-1 [19, 20]. The vitronectin receptor plays a role in cell thrombusfibrinogen fromformation binding [4-8]. to the Platelets platelet areGP IIb/IIIaknown receptor,to play thean adhesion, migration and proliferation. The vitronectin receptor importantfinal common role pathwayin the pathogenesis of platelet aggregation of ACS. However, and subsequent the high blockade can prevent smooth muscle cell hyperplasia, and MAC- levels of platelet inhibition attainable with GP IIb/IIIa antagonists 1 inhibition can prevent stimulated monocyte-induced smooth have failed to dramatically improve clinical outcomes outside of muscle cell apoptosis. Abciximab has almost no renal excretion, percutaneous coronary intervention (PCI). Therefore, this paper but is cleared rapidly from the plasma, however, it is detectable will concentrate and emphasize on the role of these anti-platelet bound to circulating platelets for at least 21 days [21, 22].

Small-Molecule Agents plateletagents in GP the IIb/IIIa setting studieswhere thewithout most PCIbenefit are isbeyond achieved, the that scope is, ofduring this report.PCI. Although, Thus, the some aim non-PCI of this manuscripttrials are briefly is to mentioned,review the a) Asp (KGD) amino acid sequence. It has a molecular weight of of ACS in the setting of PCI. 0.832Eptifibatide kD and is 50% a cyclic renal heptapeptide excretion [23]. based upon the Lys-Gly- current beneficial effects of GP IIb/IIIa inhibition in the treatment Platelet GP IIb/IIIa receptor inhibitors molecular weight of 0.495 kD and 40-70% renal excretion Platelet GP IIb/IIIa receptor is distributed widely on platelet b) [24].Tirofiban is tyrosine-derivative nonpeptide mimetic with surfaces. There are an estimated 40,000 to 80,000 GP IIb/IIIa receptors per platelet, making it the most numerous receptors on the platelet membrane surface [3]. Platelet aggregation is weight of 0.468 kD and 90% renal excretion [25]. mediated by the GP IIb/IIIa receptor, a member of the integrin c) Lamifiban is also nonpeptide mimetic with a molecular family of membrane-bound adhesion molecules. Integrins are Although there are several differences comparing Abciximab to the small-molecules agents (Table 1), a prospective, randomized betweendefined as cells subunit matrix. receptors The two composedsubunits of of GP a, IIb/IIIa α subunit are (GPencoded IIb), trial comparing the platelet effects of abciximab, tirofiban byand separate a β subunit gens (GP on IIIa) the capable long arm of mediated of chromosome adhesive 17. interactions Although platelet aggregation, similar reduction in the platelet- monocyte and eptifibatide, demonstrated similar levels of inhibition of each subunit is synthesized separately, the receptor heterodimer interaction and similar mean alpha-degranulation, as a measure must be assembled within the megakaryocyte for either subunit of antagonist-induced platelet activation [26]. Although, all of these agents reduce ischemic risk to a different level, there has served as a model for characterization of other integrin. It has does seem to be heterogeneity among the drugs with regard to beento be demonstratedexpressed [9]. byIt waselectron the first microscopy integrin tothat be the identified receptor and is the magnitude and durability of treatment effect, at least in the

Platelet GP IIb/IIIa antagonist are potent platelet inhibitors, be due to pharmacodynamics of receptor binding, with the slow dissociationsetting of PCI. of abciximabApparent variability contrasting among with the agents rapid in reversibility efficacy may of areand seenthus attheir the efficacy time of is the greatest iatrogenic in conditions arterial injury associated related with to of both the IIb/IIIa receptor and the alphaVbeta3 receptor may PCI.acute Attempts platelet-mediated to expand thrombosis. the therapeutic Consequently, indication major of GP benefits IIb/IIIa other agents. Additionally, the nonspecific blockade by abciximab antagonists to other conditions associated with platelet-mediated receptor blockade more completely suppresses platelet-mediated thrombosis outside PCI have been less fruitful than expected. thrombintheoretically generation provide thanan advantage do inhibition over of the either specific receptor agents. alone. Dual

Figure 1: Platelet activation pathway and site of action of antiplatelet agents. Platelets are activated via several different membrane receptors, resulting in platelet adhesion and aggregation. When endothelium is injured, the subendothelium exposes von Willebrand factor that binds to GP Ib, causing platelet adhesion. Thrombin, TXA2, and ADP bind to the thrombin receptor, TXA2 receptor, and P2Y12, respectively. This causes an increase in intracellular calcium (Ca2+) and a decrease in cAMP, leading to

platelet aggregation and thrombus formation. platelet contraction and GP IIb/IIIa activation. Activated GP IIb/IIIa on adjacent platelets bind to fibrinogen (final common pathway) leading to Abbreviations: AA: Arachidonic Acid; COX-2: Cyclo-Oxygenase-2; CAMP: Cyclic Adenosine Monophosphate; ADP: Adenosine Diphosphate; ASA:

Factor; TXA2R: Thromboxane A2 Receptor. Aspirin; UFH: Unfractionated Heparin; LMWH: Low Molecular Weight Heparin; TXA2: Thromboxane A2; GP: Glycoprotein; VWF: Von Willebrand

coronary stenting. Therap clin Risk Manag 2014; 10: 603-614. Reprinted with permission from Pasala T, Sattayaprasert P, Bhat PK, Athappan G, Gandhi S. Clinical and economic studies of eptifibatide in

Comparison of Abciximab to the Small-Molecule Agents

The small-molecule agents demonstrate exclusive specificity for GP IIb/IIIa receptor.

They have less binding affinity, and shorter duration of biological effect beyond the administration period.

They predominantly undergo renal excretion.

Abciximab is derived from the monoclonal antibody 7E3, while the small molecule antagonists are modeled on the alpha-chain (RGD) and the

gamma-chain (KQADV) aminoacid recognition sequences in fibrinogen.

The inhibition of fibrinogen binding to GP IIb/IIIa receptors is competitive for the small molecule antagonists and non-competitive with abciximab due to its high affinity and slow dissociation rate.

Different agents interact with separate regions corresponding to, or located close to, the fibrinogen-binding sites on platelet GP IIb/IIIa receptor. Interaction with different sites may explain their differential ability to inhibit platelet mediated thrombin generation; abciximab is the most

potent, tirofiban intermediate, and eptifibatide is the weakest.

less so. The small molecules and abciximab differ in their binding specificity. Tirofiban and eptifibatide are highly specific for GP IIb/IIIa, abciximab is

Platelet GP IIb/IIIa inhibition in ACS during PCI patients undergoing PCI, wherein the timing of plaque injury and

The goals of any reperfusion strategy in ACS are fast restoration are up to 65 acute ischemic events prevented per 1000 patients treated.the role ofInhibition acute platelet of acute aggregation ischemic eventsare precisely is achieved defined. primarily There One possible mechanism by which GP IIb/IIIa antagonists exert of both epicardial blood flow and myocardial microcirculation. three year follow-up. However, important questions were raised micro-embolization downstream during mechanical reperfusion regardingin the first whether12 to 48 hssuch after a strategy revascularization should be and used maintained for all patients over their beneficial effects is by reducing platelet aggregation and and thereby preserving the microcirculation. The role of undergoing PCI, the timing of the revascularization procedure and periprocedural GP IIb/IIIa inhibition in the setting of PCI was the optimal duration of the post-procedural drug infusion. In this established by several randomized, placebo-controlled trials regard, the CAPTURE [30] trial reported a relative risk reduction enrolling over 30,000 patients. As adjunctive therapy for PCI, the primary objective of the randomized trials with intravenous GP it was far lesser than the relative risk reduction obtained with IIb/IIIa inhibitors was to reduce a 30-day ischemic composite theof only EPI-trials. 23% (p=0.012). This difference Although in the it resultswas a significantmay be related reduction, to the end point, namely, death, myocardial infarction (MI), urgent different duration of the post-procedural drug infusion. Although, revascularization.The most compelling support for platelet GP the CAPTURE trial had a long duration of the pre-procedural drug IIb/IIIa inhibition therapy comes from the abciximab trials. infusion (18 to 24 h), it had only a 1 h post-procedural infusion. In They have demonstrated a clinically important reduction in comparison, the EPI-trials employed a 12 h post-procedural drug infusion. Thus, the CAPTURE patient’s platelets were more likely to be under 80% inhibited, and also returned to normal function early ischemic events, sustained beneficial effects at long-term devices, lesion complexities and patient acuities. sooner after PCI. follow-up, and benefits that extends similarly to all interventional Pioneering Clinical Trials were obtained with the small-molecule agents. The IMPACT II Similar positive results with lesser statistical significance The EPIC [27], EPILOG [28], and EPISTENT [29] trials and RESTORE trials provided evidence that eptifibatide and higherdemonstrated reduction the in efficacy the 30-day of abciximab ischemic composite in reducing end complications point of 35% events, but the magnitude of treatment effect with this agents was tirofiban, respectively, also diminished periprocedural ischemic (p=0.008),among patients 56% at(p<0.001) high risk and during 51% PCI. (p<0.001) There was respectively. a significantly The less than in the abciximab trials and did not reach conventional greatest magnitude of clinical benefit with this agent is achieved in levels of statistical significance [31-33]. The same holds true for lamifiban which was studied in a randomized, placebo-controlled

manner in the PARAGON B clinical trial [34,35]. Ischemic events

in-stentEPILOG restenosis and EPISTENT. in De Furthermore,novo native coronary the ERASER lesion trial,in patients using subsequentwere reduced 30 considerablydays. The composite by eptifibatide end point or of tirofiban death, MI, at 24or undergoingintravascular stent ultrasound implantation examination, with adjunctive did not find abciximab a reduction [44]. of to 48 hs, but attenuation of clinical benefit occurred over the However, the EPISTENT trial demonstrated that in a subgrup of patients with diabetes mellitus there was a 51% (p=0.002) (8.0%urgent vs revascularization 10.5%, p=0.052). at Higher 30 days dosing for regimens eptifibatide had comparedimproved restenosis reduction [45]. The processes of recoil and remodeling theto placebo clinical was outcome (9.9% withvs 11.4%, the small p=0.220), molecule and forantagonists. tirofiban wasThe are not operative with stents and neointimal hyperplasia is the interaction of platelet glycoprotein IIb/IIIa blockade and coronary predominant mechanism of luminal re-narrowing [46]. Thus, revascularization was not tested in a randomized fashion in the in the setting of stenting, abciximab may reduce restenosis in diabetic patients, who are known to be at high risk for this complication. ofPURSUIT patients and underwent PRISM PLUSPCI during trials study that utilized drug infusion, eptifibatide although and At the time when trials of GP IIb/IIIa inhibitors were selectiontirofiban, for respectively this procedure [36,37]. was However,a post-randomization a substantial event number and assessing balloon angioplasty and atherectomy, there was a substantial change in the approach of coronary stenotic lesions. The therapeutic practice turned into the direction of stenting. wasmay that have GP been IIb/IIIa influenced blockade by was the effective occurrence in stabilizing of ischemic patients end Two large randomized international trials demonstrated the beforepoints. the Nevertheless, performance the of consistent PCI and in finding reducing in theseischemic two events trials unquestionable superiority of stents over balloon angioplasty, after mechanical revascularization. In the PURSUIT trial, 1228 reduced necessity for repeat revascularization [47,48]. Stenting in these patients was associated with a reduction in the composite activatesmainly because expression of significantly of the GP IIb/IIIa less incidence receptor of on restenosis the platelet and endpatients point underwent of death orPCI MI within by 30 the days first (16.7%72 hs. Eptifibatide vs 11.6%, therapyp=0.01, surface and predisposes to coronary thrombus, which is partly the risk of MI before mechanical revascularization (5.5% vs 1.7%, absolute risk reduction of 5.1%), and a significant reduction in [49]. The use of a metal prosthetic device during the procedure mayreflected also leadby the to clinical mural thrombus syndrome inside known the as stent, subacute distal thrombosis emboli of in IMPACT II was almost certainly due to inadequate dosing. The p<0.001). The relatively modest treatment effect with eptifibatide atherosclerotic material or fragmented thrombus, and predispose to deeper arterial wall trauma and platelet activation because of ischemic complications is suggested by the substantial treatment effectpotential among for higher patients doses in PURSUIT of eptifibatide trial who to more underwent effectively early reduce PCI. more adequately and effectively controlled with the association of platelethigh pressure GP IIb/IIIa inflation. receptor These antagonists pathophysiological to stenting. triggers The GPmay IIb/ be of patients. The patients who underwent PCI appeared to derive In the PRISM PLUS trial, angioplasty was performed in only 30.5% IIIa receptors antagonists have shown that can maintain patency of the re-canalized vessel, besides avoiding emboli of platelet Though the analysis of patients who underwent PCI is not based particular benefit from pretreatment with tirofiban plus heparin. aggregates to the distal circulation [50]. reduction in cardiac ischemic events after PCI, including a 43% The EPISTENT trial showed that stenting associated to on a randomized cohort, patients treated with tirofiban had a 46% 43% (p=0.0017) reduction in the same end point at 48 hs was by GP IIb/IIIa antagonists is superior to stenting alone. If the reportedreduction in in the the ESPRIT composite trial endin which point 98% of death of the or enrolled MI. Likewise, patients a EPISTENTinhibition ofresults the final are applied common to pathway all PCI procedures of platelet aggregationworldwide, underwent PCI with a 96% rate of stent implantation [38]. A sub- the use of abciximab would be expected to prevent more than study of this trial has shown that in the modern era of PCI and in 2,500 deaths, 40,000 MI, and more than 6,500 emergency an extremely homogeneous population, the GP IIb/IIIa receptor shown that abciximab further improves early and late clinical ischemic complications similarly in women and in men [39]. The outcomesrevascularization in patients procedures treated [29]. with The stent CADILLAC implantation, trial has alsobut blockade with eptifibatide is an effective therapy to prevent especially in patients undergoing balloon PCI alone [51]. The reduction in the 30-day MACE rate with abciximab was more particularlyTACTICS-TIMI in 18patients trial (n=1,851) with a positive had confirmed troponin withthe benefit an absolute of an pronounced in patients assigned to balloon angioplasty (4.3% reductioninvasive approach in the primary in patients composite with ACSend point treated of withdeath, tirofiban, MI, and vs 8.1%, RR 47%, p=0.01) than in those assigned to stenting re-hospitalization for ACS at six month of 10%. Among patients with MI, those with troponin elevation before the initiation of reperfusion therapy are at high risk for death and heart failure. PCI,(4.2% which vs 5.3%, is more RR 21%,pronounced NS). Therefore, in patients these undergoing findings highlight balloon In this setting, the prognostic value of troponin and serum angioplasty,the beneficial probably effects of due platelet to the GP less IIb/IIIa internal receptor luminal blockade diameter in myoglobin is independent of baseline variables, time to initiation achieved with this procedure compared to stenting. A meta- therapy [40-42]. on stent placement in AMI with either adjunctive abciximab or of PCI, infarct location, and measures of the efficacy of reperfusion placeboanalysis was of 3 described randomized [52]. trials Adjunctive (ISAR II,use ADMIRAL, of abciximab CADILLAC) in stent In the EPIC trial, abciximab infusion was associated with treated patients resulted in an event rate of 12% vs 16.6% without a reduction in target vessel revascularization procedures at abciximab (OR 0.70; 95% CI 0.54-0.92, p<0.001). Thus, abciximab prevented 44 major events per 1000 patients treated. It was the speculation that this drug may reduce restenosis [43]. 6 months, from 22% to 16% (p=0.007), a finding that led to concluded that optimal mechanical reperfusion in AMI is provided by stent placement and GP IIb/IIIa use, with a 30% odd reduction revascularization was not observed in the subsequent trials of This significant decrease in the need for late target vessel in the composite end point. It was demonstrated that even in very

Death was reduced by 57% with abciximab compared to patients associated with an increased risk of non–life-threatening bleeding withhigh riskplacebo patients [53]. in Two cardiogenic observational, shock there non-randomized is a beneficial studies effect. andafter need angiography for transfusion. (Figure The 3). Theduration early of use the of infusion eptifibatide time was have shown that treatment with platelet GP IIb/IIIa inhibitor also investigated in the BRIEF PCI trial [59]. The investigators abciximab during angioplasty resulted in improved outcome of patients with shock complicating AMI [54,55]. Similar results can be abbreviated safely to less than 2 h. It is not inferior to the standarddemonstrated 18-h thatinfusion after inuncomplicated preventing ischemic PCI, eptifibatide outcome, infusion and it patients. Although, only 25% of the shock-patients underwent may be associated with less major bleeding. PCI,were a obtainedretrospective with sub-study eptifibatide of the in PURSUIT this subgroup trial demonstrated of high risk Several trials demonstrated that adding Platelet GP IIb/IIIa adjusted odds of 30-day death from shock (OR=0.51, 95% CI 0.28- effects [63]. It was demonstrated that 1) has both short-and 0.94;that patientsp=0.03), treatedsuggesting with a eptifibatidepossible salutary seemed effect to haveof platelet reduced GP long-termreceptor inhibition reduction therapy in ischemic to PCI resultedcomplications, in several 2) beneficialimproves microcirculatory function and recovery of myocardial function, 3) prevents the development of restenosis in diabetic patients designedII/b/IIIa blockadestudies. during shock [56]. Since this finding is derived from a post hoc analysis, it should also be verified in specifically and 4) reduces long-term mortality. Proposed mechanisms to patients undergoing coronary stenting (57-59). In the TARGET reduced platelet-mediated thrombin generation, reduced release trial,Several patients trials were compared randomized the relative in a efficacydouble-blind of two fashion agents toin fromexplain platelets this benefit of vasoactive include inhibitionagents, reduced of platelet platelet-mediated aggregation, clot retraction and reduced intimal hyperplasia in response to aspirin, heparin and clopidogrel [57]. The primary end point vascular injury [64-68]. In a well done experimental study of wastirofiban 30-day (n=2,398) death, MI, orand abciximab urgent revascularization, (n=2414) in and addition the trial to stenting and abciximab, it was demonstrated that abciximab treatment reduced platelet thrombus formation area by 89%, but did not prevent the deposition of a discontinuous monolayer of reductionwas powered in the to primary demonstrate end point the non-inferiorityof 1.54% (6.01% of vs tirofiban. 7.55%, platelet, demonstrating that abciximab blocks platelet to platelet Abciximab, compared to tirofiban, produced an absolute interactions, but not platelet adhesion [69]. The authors of this within 12 hs of the bolus. The authors concluded that, although experimental study proposed that stent insertion leads to a p=0.037). The benefit of abciximab appeared early, reducing MI the trial was intended to assess the noninferiority of tirofiban networkreduction that in bloodcan trap flow the immediately nearby layer adjacentof stagnant to blood.the wall, The which most didas comparedabciximab with(Figure abciximab, 2). Similar the conclusions findings demonstrated can be obtained that plausiblefavors thrombin explanation generation for abciximab’s and the effect development is that it of decreases a fibrin tirofiban offered less protection from major ischemic events than platelet thrombus formation at the sites where the stent struts degree of inhibition after an abciximab bolus and 12 h infusion to contact the vessel wall and thus decreases thrombin generation ischemicfrom the outcomeAU-Assessing in patients Ultegra undergoing (GOLD) study, PCI [60]. which However, related itthe is very important to emphasize that in the absence of intervention, thrombi at the site of stent insertion which explains the protective effectand fibrin of abciximab formation. on There the microcirculation were also significantly [69]. A smallerstudy designed platelet as seen in the GUSTO IV trial, it may be reversed or associated to assess endothelium-dependent vasomotion after coronary withthe benefit paradoxical is of lesser harm magnitude [61]. There and was for abciximaba stepwise in increase particular, in stenting plus abciximab demonstrated that abciximab preserves events from 8.0% in the placebo group to 9.1% in the 48 h treated group. This represents a 14% increase in death or MI primary end point for the long-infusion abciximab strategy. This may be wasthe coronary impaired blood after flowstenting, response however to acetylcholine when it was after associated coronary to due to paradoxical platelet activation when there is less than stenting. Acetylcholine-mediated increase in coronary blood flow 80% platelet inhibition. Platelet inhibition of >80% is required stent alone group. The preservation of microvascular endothelial abciximab there was a significantly superior response than in the inhibition is associated with lack of protection from acute events. IIIa receptor antagonists in patients undergoing PCI [70]. for maximum efficacy. Failure to achieve these high levels of function may help explain the beneficial clinical effects of GP IIb/ associated with a paradoxical increase in ischemic complications the platelet GP IIb/IIIa inhibitors. The reduction of bleeding dueModerate to the levels unmasking of platelet antagonist-induced inhibition not only pro-thrombotic lack efficacy but and are complicationsThere are severalin the factorsPCI plus to considerGP IIb/IIIa in the antagonists safety profile trials of demonstrates that reduction of concomitant heparin doses, as well more than 25% of patients are less than 80% inhibited increasing as early vascular sheath removal ameliorate excess hemorrhagic thepro-inflammatory possibility of effectsimportant [62]. thrombotic, During an abciximabcounter regulatory infusion, risk in this setting. Thrombocytopenia occurs infrequently with GP events. Thus, abciximab should not be used in unstable coronary IIb/IIIa inhibition but may be precipitous and profound (platelet count of<50,000 mm3). It occurred in 7% of patients randomized syndromes in the absence of PCI. The TARGET trial confirms the in the PURSUIT trial and it was an independent predictor of 30 day superiorityOn the other of abciximab hand, depending over tirofiban on the in timethe setting of initiation of PCI of[57]. the death and MI. Therefore, platelet count should be measured early pharmacological agent, the outcome may vary accordingly. The followed for the duration of therapy. Pseudo-thrombocytopenia is different periods of time during the course of the ACS [58]. The the(within cause the of firstmore 2 thanto 4 onehs) afterthird administering(36%) of low plateletthese agents counts and in authorsEARLY ACS observed trial investigated in patients the who same had drugACS administeredwithout ST-segment in two patients undergoing PCI who are treated with abciximab. Pseudo- thrombocytopenia is a benign laboratory condition that does not increase the risk of bleeding, stroke, transfusion requirements elevation, that the use of eptifibatide 12 h or more before angiography was not superior to the provisional use of eptifibatide

Citation: Centurión OA (2016) Current Role of Platelet Glycoprotein IIb/IIIa Inhibition in the Therapeutic Management of Acute Coronary Syndromes in the Stent Era. J Cardiol Curr Res 5(5): 00175. DOI: 10.15406/jccr.2016.05.00175 Current Role of Platelet Glycoprotein IIb/IIIa Inhibition in the Therapeutic Management Copyright: 7/14 of Acute Coronary Syndromes in the Stent Era ©2016 Centurión or the need for repeat revascularization. Besides, it does not Abciximab re-administration in this situation is safe and does not result in an allergic response or any increase in adverse events, although, increased levels of thrombocytopenia are seen. The lostrequire by premature specific therapy. termination Therefore, of therapy it is important[71]. Due to to its recognize murine presence or absence of a positive HACA titer was not predictive of origin,this condition abciximab so thatelicits the an beneficial immune effectsresponse of abciximabin the form are of IgGnot a lack of clinical effectiveness, development of thrombocytopenia, antibody production, termed the human anti-chimeric antibody or other sequelae in patients undergoing re-administration. Thus, overall side effects are similar with the different agents and therapy. This does not occur with the small molecule antagonists. usually not a major clinical problem. (HACA), in 7% of patients within the first month after initiation of

Figure 2: Incidence of the Primary End Point in the Target trial. Incidence of the Primary End Point, a Composite of Death, Nonfatal Myocardial Infarction, or Urgent Target-Vessel Revascularization, in the First

30 Days after Enrollment. After 30 days, the incidence of the primary end point was 7.6 percent in the tirofiban group and 6.0 percent in the abciximabReprinted groupwith permission (hazard ratio, from 1.26; Topol 95 percentEJ, Moliterno confidence DJ, Hermann interval, 1.01HC, etto 1.57;al. For P=0.038). the TARGET Trial investigators. Comparison of two platelet

Engl J Med 2001; 344: 1888-1894. glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for thr prevention of ischemic events with percutaneous coronary revascularization. N

Figure 3:

Major Efficacy and Safety. Results in the EARLY ACS Trial. Rates of the primary efficacy composite end point (death, myocardial infarction, recurrent ischemia leading to urgent revascularization, or thrombotic bailout) at 96 h, key secondary efficacy composite (death or myocardial infarction) at 30 days, and the primary safety end point (TIMI major bleeding) are shown for a delayed, provisional use of eptifibatide just prior to percutaneous coronary intervention (blue) versus the routine earlyReprinted administration with permission of eptifibatide from Giugliano (red). OR: RP, odds Braunwald ratio. E. The year in non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol 2009; 54(16): 1544-1555.

Lessons from meta-analysis and recent studies all four prerequisites of the open vasculature hypothesis. It would therefore be logical to offer the best of the two complimentary Boersma E et al. [72] found that treatment with GP IIb/IIIa strategies by combining the speed of patency and improved inhibitors led to a 9% reduction in the RR of death or MI with microvascular function provided by a pharmacologic strategy a concurrent 1% absolute increase in major bleeding in a meta- analysis of more than 30,000 patients with ACS. However, only intervention. It is possible that early PCI after pharmacologic 24% of these patients underwent PCI. More recently, Sethi A et reperfusionwith the speed therapy of flowhas the following potential more to fuse definitive the best mechanical aspects al. [73] performed a meta-analysis of randomized trials of GP IIb/ IIIa inhibitors use in patients undergoing primary PCI. In this Combination therapy also allows the use of lower doses of study of more than 7,000 patients, GP IIb/IIIa inhibitors use was thrombolyticof fibrinolysis, agents, antiplatelet which may drugs in turn and potentially mechanical reduce reperfusion. the risk associated with a 25% reduction in mortality. Meta-regression of intracranial hemorrhage; and it combats the pro-thrombotic state induced by thrombolytic agents. Thus, Platelet GP IIb/IIIa receptor antagonists may be well suited as an adjunct to both analysis suggested that the benefits of GP IIb/IIIa inhibitors use Winchester DE et al. [74] performed a meta-analysis of GP IIb/ thrombolytic and mechanical interventions in AMI. Another were confined to patients at highest risk of mortality. Moreover, IIIa inhibitors use in ACS and PCI on the basis of trials performed advantage of facilitated early PCI relates to patient stability in in the contemporary era of stents and dual antiplatelet therapy. the catheterization laboratory. Patients arriving in the laboratory Among ACS patients, GP IIb/IIIa inhibitors use was associated with patent infarct-related artery due to earlier reperfusion with reduced-dose thrombolytic and GP IIb/IIIa antagonists are minor bleeding but no differences in mortality or major bleeding. less likely to be in cardiogenic shock [77]. These are plausible with a significant reduction in nonfatal MI and an increase in Thus, although there are numerous differences in patient theoretical assumptions that were not fully demonstrated. populations, timing of drug administration, and concomitant medical therapy, most studies have tended to demonstrate that Early trials of rescue PCI did not include, for the most part, the use of either stents or adjunctive GP IIb/IIIa inhibitors. In the PACT in terms of ischemic complications with a concomitant increase in trial, for example, stents and abciximab were used in 26% and 5% bleeding,GP IIb/IIIa particularly inhibitors usein the in ACShighest and risk PCI patients.leads to modest benefits of patients, respectively. Several other studies have investigated the role of GP IIb/IIIa antagonists in rescue PCI after failed

Registry, CathPCI Registry data to investigate the association to abciximab alone, reteplase alone, and various combination of Safley DM et al. [75] utilized the National Cardiovascular Data between GP IIb/IIIa inhibitors use and PCI outcomes for ACS. reduce-dosefibrinolysis [78]. reteplase The SPEED with abciximab trial randomized and PCI was528 performedAMI patients in The primary outcome was all-cause in-hospital mortality. The most patients. Early PCI was encouraged, and 323 patients (61%) secondary outcome was major bleeding. In their study of nearly underwent PCI at a median of 63 min after reperfusion therapy one million patients undergoing PCI for ACS, they found that was started. Overall clinical success at 30 days (freedom from GP IIb/IIIa inhibitors use was associated with lower mortality death, re-infarction, urgent revascularization, major bleeding, but higher rates of major bleeding. These results were similar and transfusion) was achieved in 85% of patients undergoing regardless of the analytic approach used to adjust for potential early PCI. There were trends toward a lower composite end differences between those patients who did and did not receive point of death, re-infarction and urgent revascularization in the these agents. Subgroup analysis demonstrated that the mortality combination group (reduce-dose reteplase with abciximab), without an increase in intracerebral hemorrhage. Patients patients with ST-segment elevation MI and those treated with undergoing early PCI had fewer ischemic events and bleeding benefit of GP IIb/IIIa inhibitors in this setting was restricted to heparin anticoagulation. There was no evidence of differential complications (15% vs 30%, p=0.001) [79]. These results contrast with previous studies of angioplasty performed shortly Since the patients who received GP IIb/IIIa inhibitors tended to after full-dose thrombolysis [80-82]. Angioplasty techniques benefit or harm according to the radial or femoral access site. be sicker and more complex, their use was associated with higher have advanced substantially since these trials, however, and mortality in unadjusted analysis. However, in adjusted analyses they include the current widespread use of stents and potent the use of GP IIb/IIIa inhibitors was associated with reduced antiplatelet therapy. In this regard, several trials have shown mortality [75]. that abciximab can improve the results of primary angioplasty Facilitated PCI in AMI [83-86]. In the RAPPORT trial, 483 patients with AMI were randomized to abciximab or placebo before PCI [87]. The The term facilitated PCI refers to early, planned PCI after the rates of death, or MI, and death, MI, or urgent revascularization administration of a pharmacological regimen intended to open were reduced from 11.2% to 8.7% and from 17.8% to 11.8% the infarct-related artery. Gibson CM described four components respectively. A similar 47% reduction in a combined end point to the time-dependent “open vasculature” hypothesis. The implantation [88]. The GUSTO III trial included a prospectively designedwas observed subgroup in the analysis ADMIRAL to examine trial, which the effects also allowedof abciximab stent improvedachievement clinical of 1)outcomes early flow, in AMI 2) (76). full microvascularThe platelet GP flow, IIb/IIIa 3) in 392 patients with AMI who underwent rescue PCI within 24 receptorfull epicardial blockade flow, and and reduced-dose 4) sustained thrombolytics flow, are all may related more to lower in patients who received abciximab compare with those vessels and the microvasculature. On the other hand, mechanical whohs of didfibrinolytic not (3.6% infusion. vs 9.7%, The p=0.042). adjusted 30-dayHowever, mortality there were rate alsowas interventionsfully satisfy the may first better two satisfy criteria. the They latter rapidly two criteria, open epicardial offering a trend toward higher rates of major bleeding in the abciximab full and sustained reperfusion. Clinical outcomes are related not agent used may play a role in the improved outcome achieved. group (3.6% vs 1.0%, p=0.08) [89]. The specific fibrinolytic merely to the attainment of one, but rather to the fulfillment of

Reteplase has been shown to produce greater early TIMI grade other combination regimes and with data from larger studies of primary angioplasty. trial showed no difference in mortality rates of patients with MI What about the concomitant use of two platelets GP IIb/IIIa treated3 flow comparedwith reteplase with versus alteplase alteplase [90]. [91], Although patients the undergoing GUSTO III rescue PCI wih abciximab had improved outcomes when they had been randomized to reteplase compared to alteplase [89]. receptor antagonists in ACS? Following the PRISM PLUS and The STOPAMI 2 trial randomized 162 MI patients to stenting plus clinicalPURSUIT course. trials, thereSome hasof thesebeen anpatients increasing later usagerequire of tirofibanPCI and abciximab and to alteplase plus abciximab to compared clinical and eptifibatide to treat ACS patients in the early phase of their outcomes and myocardial salvage [92]. The combined incidence of death and recurrent MI was 7.4% in the stent and 17.3% in the demonstratedmay benefit from that the administration long-term improvement of abciximab in outcomes immediately that alteplase group, relative risk 0.40(95% CI 0.16-1.01), p=0.053. had been documented with abciximab. In this regard, Lev et al function in a safety manner [97]. Therefore, the conformational 0.60, 25th, 75th percentiles: 0.37, 0.82) than in the alteplase group changesafter tirofiban that the or smalleptifibatide molecule therapy drugs effectively induce in inhibits the platelet platelet GP (medianSalvage index 0.41, was0.13, significantly 0.58), p=0.001. greater In patients in the stent with group AMI, (medianstenting IIb/IIIa complex does not interfere with subsequent binding of plus abciximab increases the chances of a favorable clinical abciximab to the GP IIb/IIIa receptor. Thus, the presence of a small molecule GP IIb/IIIa inhibitor would not impede the inhibitory degree of myocardial salvage is the mechanism of the clinical outcome as compared to alteplase plus abciximab. The significant effect of abciximab on platelet function in patients undergoing subsequent PCI. Future randomized, controlled trials would shed further light on this manner. reperfusionbenefit yielding and by salvage, stenting assessed plus abciximab by myocardial [92]. Abciximab blush grade, was afteralso shown PCI for to acute significantly ST-elevation improve MI [93]. myocardial microcirculation A planned strategy of all 3 treatments produces patency rates The INTRO-AMI trial with 649 patients demonstrated that PCIseen may with further primary improve and rescue outcomes angioplasty by speeding without the sacrificing time to vessel the patency.critical early In this time endeavor, benefits the of FINESSEpharmacologic trial randomized therapy. Facilitated patients andeptifibatide-mediated even more importantly, inhibition speeds of the platelet process aggregationof reperfusion, in with AMI to facilitated PCI (reduced-dose reteplase, abciximab, suchconjunction that most with of half-dose the effect t-PA is already enhances observed the TIMI by flow60 min grade [94]. 3, and planned immediate PCI) or primary PCI with the use of abciximab at the time of intervention. They tested the hypothesis that facilitated PCI as a strategy for the management of myocardial minimumEptifibatide 1,600 was ng/ml administered plasma inconcentration a double-bolus which manner results (10 in infarction will be superior to primary PCI in higher risk patients. themin desired apart). levelThe single-bolusof receptor occupancyregimen of and 180 inhibition μg/kg achieves of platelet the However, Ellis SG et al. [98] observed that the FINESSE Trial failed aggregation of at least 80% of baseline. However, it is frequently to prove this hypothesis. They concluded that neither, facilitation accompanied by a transient decrease in drug concentration (below of PCI with reteplase plus abciximab nor facilitation with 1,600 ng/ml at 30 to 60 min) following the initial bolus [95,96]. There were 346 patients whom underwent PCI in the INTRO-AMI compared with abciximab given at the time of PCI, in patients with ST-segmentabciximab alone elevation significantly myocardial improved infarction the (Figureclinical 4)outcomes, [98]. as trial. The TIMI flow grade 3 observed compares favorably with

Figure 4:

The composite Kaplan−Meier end point Estimates in the FINESSE of the Proportion trial included of Patients death withfrom the all Compositecauses and End complications Point. of myocardial infarction from randomization through day 90. Data are shown for all patients randomly assigned to a treatment group. P= 0.55 for the comparison of primary percutaneous coronary intervention (PCI) with reteplase-plus-abciximab–facilitated (combination-facilitated) PCI. P= 0.86 for the comparison of primary PCI with abciximab-facilitated PCI. P= 0.68 for the comparison of abciximab-facilitated PCI with combination-facilitated PCI. Reprinted with permission from Ellis SG, Tendera M, de Belder MA, et al. For the FINESSE investigators. A clinical trial of facilitated PCI in ST elevation myocardial infarction. N Engl J Med 2008; 358: 2205-2217.

As Gibson CM stated, there is a growing body of AMI literature 5. supporting a “union in reperfusion”: the use of pharmacologic Changes in glycoprotein IIb/IIIa inhibitor excess dosing with site- agents to quickly open both the artery and the microvasculature Mudrick DW, Chen AY, Roe MT, Newby LK, Gibler WB, et al. (2010) Unstable angina patients Suppress ADverse outcomes with Early implementationspecific safety feedbackof the ACC/AHA in the Canguidelines Rapid (CRUSADE) risk stratification initiative. of and keep arteries open [99]. Furthermore, with the addition Am Heart J 160(6): 1072-1078. and the use of adjunctive interventions to further improve flow pharmacological approach [100-105], plaque debris could be 6. retrievedof using anreducing emboli the protection incidence filter of deviceembolization plus a to multifaceted the distal receptors in cardiovascular medicine. N Engl J Med 332(23): 1553- Lefkovits J, Plow EF, Topol EJ (1995) Platelet glycoprotein IIb/IIIa circulation [106-110]. These measures are particularly interesting 1559. in saphenous vein grafts PCI, which are known to be associated 7. with worse outcome compared to intervention of native coronary arteries [111-113], a setting where abciximab has shown no Richardson PD, Davies MJ, Born GV (1989) Influence of plaque configuration and stress distribution of fissuring of coronary 8. atheroscleroticHirsh J, Salzman plaques. EW, Marder Lancet VJ,2(8669): Colman 941-944. RW (1994) Overview of the thrombotic process and its therapy. In: Colman RW, Hirsh J, et benefit [114,115]. It is always nice and rewarding to see that there al. [Eds.), Hemostasis and thrombosis: basic principles and clinical someis so much light on work yet unanswereddone on this questions.field, but even nicer to know that there is still a long way to go with further investigations to find 9. practice. JB Lippincot, Philadelphia, USA, pp. 1151-1163. Conclusion A Intravenous platelet GP IIb/IIIa receptor antagonists cation-dependentLoftus JC, O´Toole conformation.TE, Plow EF, Glass Science A, Frelinger 249(4971): III AL, 915-918. et al. (1990) β3 integrin mutation abolishes ligand binding and alters divalent 10. Phillips DR, Charo IF, Scarborough RM (1991) GP IIb/IIIa: the cardiology and have proven to be an important, clinically effective responsive integrin. Cell 65(3): 359-362. represent a significant advance in the practice of interventional 11. Charo IF, Kieffer N, Phillips DR (1994) Platelet membrane are most apparent in those patients with ACS with evidence of glycoproteins. In: Colman RW, Hirsh J, et al. (Eds.), Hemostasis and myocardialadjunct therapy damage during or who PCI. are The undergoing additional early beneficial PCI [116-118]. effects These agents have been a useful addition to the therapeutic Philadelphia, USA, pp. 489-507. thrombosis: basic principles and clinical practice. JB Lippincott, therapy should certainly be provided to patients at elevated risk 12. Coller BS (1990) Platelets and thrombolytic therapy. N Engl J Med 322(1): 33-42. forarmamentarium procedural complications in this setting [120]. [119-123]. Adding ThePlatelet benefits GP IIb/IIIa of this receptor inhibition therapy to coronary stenting implantation has 13. demonstrated to have short and long-term reduction in ischemic effect of a monoclonal antibody to the platelet glycoprotein IIb/IIIa complications, improved microcirculatory function and recovery receptorColler BS, in Foltsan experimental JD, Scudder animal LE, Smith model. SR Blood (1986) 68(3): Antithrombotic 783-786. of myocardial function, and better prevention of the development 14. Coller BS (1985) A new murine monoclonal antibody reports of restenosis in diabetic patients and reduced long-term mortality. an activation dependent change in the conformation and/or microenvironment of the glycoprotein IIb/IIIa complex. J Clin Invest Suboptimal levels of GP IIb/IIIa receptor antagonists are not 76(1): 101-108. only non-protective and pro-thrombotic, but they also promote 15. Faulds D, Sorkin EM (1994) Abciximab (c7E3 Fab): a review of its adequate dosage, intravenous GP IIb/IIIa inhibitors will continue pharmacology and therapeutic potential in ischemic heart disease. Drugs 48(4): 583-598. toinflammation. play an important However, role inin thethe management right clinical of indications ACS, especially with in the setting of PCI. 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