ST elevation myocardial infarction glycoprotein IIbIIIa inhibition

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Other Antiplatelet Agents Including Aspirin and Thienopyridines
There is clear data demonstrating the benefits of the antiplatelets apsirin and thienopyridenes in the management of patients with ST elevation MI treated with fibrinolytic administration. The benefits of clopidogrel vs placebo in patients undergoing primary angioplasty have not been established in randomized trials, although non-randomized registry data is consistent with a benefit of clopidogrel in this setting. The benefit of aspirin plus thienopyridine therapy versus aspirin monotherapy alone could be difficult to establish in randomized trials given that the majority of STEMI patients are treated with a stent which in turn obviates chronic thienopyridine treatment. Despite the required chronic thienopyridine therapy following stent placement, the slower onset of action of oral thienopyridines relative to that of parenteral antiplatelet agents such as glycoprotein IIbIIIa inhibitors raises important questions as to the acute / early benefits of glycoprotein IIbIIIa inhibitors versus thienopyridines. Furthermore, the optimal timing of thienopyridine therapy in primary PCI is not well established. In so far a few patients undergo coronary artery bypass grafting (CABG) surgery urgently in the setting of STEMI, the need to define the anatomy prior to theinopyridine administration may not be as compelling as it is in the setting of stable angina, unstable angina and non-ST elevation MI.

Current guidelines recommend pre-loading with 300 to 600 mg of clopidogrel in the primary PCI setting. Again, it should be emphasized that this is not based upon randomized trial data enrolling STEMI patients undergoing primary PCI, but rather from data originating from non-randomized subgroup analyses and registries. One registry demonstrated that pre-loading with clopidogrel in the setting of STEMI was associated with a 2.2 fold improvement in normal TIMI myocardial perfusion grade 3 (O.R. 1.2-3.9, p=0.01) was well as a reduced risk of recurrent MI (0% vs 3.2%, respectively, p= 0.04). In a subgroup of 2707 patients managed with primary PCI in the Acute Coronary Syndromes (ACOS) registry, 1 year mortality was significantly reduced among patients treated with aspirin plus clopidogrel versus aspirin alone (OR 0.38, 95% CI 0.23-0.62]. It should be noted that this data is limited by the fact that neither the loading dose nor timing of clopidogrel were reported . It should also be realized that in registries, clopidogrel administration is often a surrogate or a marker of the use of a stent, and it is not clear whether the benefit was mediated by the stent or by the clopidogrel. Finally, Gibson et al in a substudy from CLARITY have demonstrated that non-emergent PCI after fibrinolytic therapy was associated with improved mortality among patients randomized to clopidogrel (OR 0.34, 95% CI 0.13-0.92, P = .034) but not placebo (OR 1.41, 95% CI 0.63-3.19, P = .40, interaction P = .028).

Glycoprotein IIBIIIA Inhibition
Glycoprotein IIbIIIa inhibitors are a third class of antiplatelet agents that have, in contrast to aspirin and clopidogrel, been studied extensively in the setting of STEMI treated with primary PCI. Meta analyses of randomized trial data do support a clinical event reduction (including a strong trend toward a mortality reduction) among STEMI patients treated with GPIIbIIIa inhibitors. In contrast to primary PCI, there is no clinical benefit of GPIIbIIIa inhibition when added to the administration of a full dose of a fibrinolytic agent when co-administered at the time of presentation with STEMI. This combination is clearly associated with increased bleeeding, particularly in the elderly. The benefit of glycoprotein IIbIIIa administration in the cardiac catheterization laboratory several hours after fibrinloytic administration is supported by non-randomized observational data.

There are several clinical questions regarding GP IIbIIIa inhibition in the setting of STEMI that have not been definitively resolved in randomized trials:
 * 1) What is the optimal timing of GP IIbIIIa inhibitors in STEMI? Is it before cardiac catheterization which may improve patency on arrival to the cardiac catheterization laboratory or is at the time of percutaneous coronary intervention (PCI)?
 * 2) What is the optimal route of GP IIbIIIa inhibitors in STEMI? Is it via the intravenous route early, or via the intracoronary route once the anatomy has been defined.
 * 3) What is the optimal duration of GP IIbIIIa inhibition? Longer durations of infusion may be associated with greater efficacy but also with more bleeding.
 * 4) What is the role of GP IIbIIIa inhibitors in STEMI in the context of bivalirudin therapy?
 * 5) What is the role of GP IIbIIIa inhibitors in STEMI in the context of more potent antiplatelet agents that may become available.

Mechanism of Benefit of Glycoprotein IIBIIIA Inhibition
Glycoprotein IIbIIIa inhibition blocks the cross-linking of fibrin strands to the platelet at the glycoprotein IIbIIIa receptor. GPIIbIIIa inhibition blocks the formation of new thrombus in this fashion, but high levels of inhibition have been associated with disaggregation of pre-existing clot.

Among STEMI patients, Gibson et al have demonstrated that a greater number of glycoprotein IIbIIIa receptors occupied is associated with improved myocardial perfusion, ST segment resolution and coronary blood flow.

Among patients with ST elevation myocardial infarction, treatment with GPIIb/IIIa inhibitors has been associated with improved epicardial patency (TIMI 3 flow improves from approximately 15% to 30%) and improved myocardial perfusion on arrival to the cardiac catheterization laboratory. Despite these improved rates of flow and perfusion, the isolated use of a GP IIb/IIIa inhibitor does not restore TIMI 3 flow in a sufficient proportion of patients to make it a viable stand alone pharmacologic strategy in the absence of adjunctive PCI. To improve the rate of normal TIMI grade 3 flow on arrival to the cardiac catheterization laboratory, GP IIb/IIIa antagonists have been combined with fibrinolytic agents. Despite the improvement in epicardial vessel patency with the combination of these agents, clinical outcomes were not meaningfully improved, and the combination of these agents prior to cardiac catheterization for STEMI has largely fallen out of favor.

Facilitated PCI Using a Glycoprotein IIb/IIIa Inhibitor Alone in the Absence of Fibrinolytic Administration
The glycoprotein IIb/IIIa inhibitors such as the small molecules tirofiban, and eptifibatide as well as the large molecule abciximab have been associated with improved outcomes in Primary PCI trials. One issue is the optimal timing of the administration of these agents: should they be administered in the emergency room prior to cardiac catheterization (which may cause a delay in transferring the patient to the cardiac catheterization laboratory, or should they be administered in the cardiac catheterization laboratory which may miss the potential benefit of opening the vessel prior to arrival in the cardiac catheterization laboratory.

Comparisons of Glycoprotein IIb/IIIa Inhibitors
There are few randomized trials directly comparing agents in this class. The Multicentre Evaluation of Single High-Dose Bolus Tirofiban vs. Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent/ in Acute Myocardial Infarction (MULTISTRATEGY) trial compared the small molecule tirofiban with the large molecule abciximab in the management of primary PCI patients. While this was a randomized trial, it was not blinded. All 745 patients were treated with 300 mg of clopidogrel prior to cardiac catheterization. There was a 2 X 2 randomization in the trial. The first level of randomization was to high dose tirofiban (25 μg/kg bolus regimen) versus abciximab, both administered at the time of first medical contact with the patient. The second level of randomization was to either sirolimus-eluting (SES) or bare metal stenting (BMS). Given that only 745 patients were enrolled, a highly powered endpoint was chosen, which was ST segment resolution at 90 minutes following PCI. ST segment resolution associated with Tirofiban (85.3%) was statistically non-inferior to abciximab (83.6%)(RR, 1.020; 97.5% CI, 0.958-1.086; p<0 .001 for noninferiority). Consistent with these EKG findings of non-inferiority, there was likewise no difference in major adverse cardiac events (MACE) for tirofiban vs abciximab at either 30 days (4.0% vs. 4.3%, respectively; p=0.85)or 8 months (9.9% vs. 12.4% respectively; p=0.30. With respect to safety, there was a significant increase in the risk of thrombocytopenia associated with abciximab (0.5% for tirofiban versus 2.4% for abciximab: 2.4%; p=0.03). The increased risk of thrombocytopenia associated with abciximab has been consistently observed across multiple trials.

In a smaller earlier trial called STRATEGY (Single High Dose Bolus Tirofiban and Sirolimus Eluting Stent vs Abciximab and Bare Metal Stent in Myocardial Infarction [STRATEGY]), the same investigators compared the outcomes among STEMI patients treated with high-dose tirofiban plus a sirolimus-eluting stent (n = 87) versus abciximab plus a bare-metal stent (n = 88). The hypothesis was that administration of tirofiban instead of abciximab would allow the expanded use of drug eluting stents by nullifying the cost differential between sirolimus-eluting vs bare-metal stents. The primary endpoint of death, nonfatal myocardial infarction, stroke, or binary restenosis at 8 months occurred in 19% of tirofiban patients versus 50% of abciximab patients (p<0.001).

A meta-analysis that incorporated randomized trial data from 6 trials involving 2,197 patients through Cotober 2008 indicates that there is no difference in outcomes between primary PCI patients treated with abciximab versus either high dose tirofiban (5 trials) versus eptifibatide (1 trial) Abciximab was not associated with an improvement in either the rate of TIMI flow grade 3 post PCI (89.8% vs. 89.1%, p = 0.72) or ST-segment resolution following PCI (67.8% vs. 68.2%, p = 0.66). Likewise, abciximab was not associated with a reduction in either 30-day mortality (2.2% vs. 2.0%, p = 0.66) or reinfarction (1.2% vs. 1.2%, p = 0.88). No difference in bleeding was observed.

Facilitated PCI trials using tirofiban
Early upstream administration of tirofiban has been associated with better pre-PCI angiographic outcomes, but these studies were not sufficiently powered to demonstrate significant clinical benefit. The benefit of early administration of tirofiban compared to upstream administration was assessed in the TIGER-PA trial (TIrofiban Given in the Emergency Room before Primary Angioplasty). This study consisted of 100 patients who received tirofiban either in the ER or in the cath lab. There was a significant improvement in the initial angiographic parameters such as TIMI flow grade (TFG), corrected TIMI frame count (CTFC) and TIMI myocardial perfusion grade (TMPG). This study was not powered to demonstrate a significant clinical benefit.

Likewise, the investigators from the On-TIME trial (Ongoing Tirofiban in myocardial infarction Evaluation) evaluated a similar strategy of administration of tirofiban approximately one hour before PCI compared to administration of tirofiban in the cath lab. The primary endpoint of TIMI grade 3 flow pre-PCI was not increased with the use of early tirofiban (19% vs. 15%, p=0.22), but TIMI grade 2 and 3 flow combined, thrombus burden and myocardial perfusion were improved. This study also was not powered to demonstrate a clinical benefit.

In contrast to the above two studies, another small trial (RAPIER) demonstrated that the upstream use of tirofiban in the ER was not associated with a significant improvement in the rate of TIMI grade 2 or 3 flow compared with the delayed administration of tirofiban in the cardiac catheterization laboratory (39% vs. 27% p >0.2). There was, however, a trend towards improved ST segment resolution in the ER group (69% vs.77%, p=0.07).

Facilitated PCI trials using abciximab
The use of abciximab in the emergency room (ER) has likewise been compared to delayed administration in the cardiac catheterization laboratory. The RELax-AMI study (Randomized Early versus Late abciximab in Acute Myocardial Infarction treated with primary coronary intervention) included 210 patients with acute ST segment elevation myocardial infarction. Of these 105 patients received abciximab in the ER and the remaining 105 received abciximab in the cardiac catheterization laboratory. This study demonstrated significant improvements in the pre-PCI angiographic parameters including TIMI grade 3 flow (24% vs. 10%, p=0.01), corrected TIMI frame count (78±30 vs. 92±21, p=0.001) and myocardial blush grade (MBG 2/3) [15% vs. 6%, p=0.02] in the early abciximab group compared to the upstream group. The post-PCI ST segment resolution (>70%) was greater in the early abciximab group (50% vs. 35%, p=0.03) and the myocardial blush grade following PCI was also improved (MBG 2/3 79% vs. 58%, p=0.001). The one month ejection fraction was significantly better in the early group.

Similarly, the ERAMI trial (Early Reopro Administration in Myocardial Infarction) demonstrated significant improvements in the post PCI CTFC and increased rate of normal TIMI Myocardial Perfusion Grade 3 among patients who received abciximab in the ER compared to those who received it in the cath lab despite an absence of any difference in pre-PCI angiographic parameters.

Multiple other studies have demonstrated similar improvements in angiographic outcomes associated with early administration. Zorman et al demonstrated that ER administration of abciximab resulted in increased patency rates, improved ST segment resolution, and better survival compared to administration of abciximab in the cath lab. Bellandi et al demonstrated not only an increase in the rate of TIMI grade 3 flow and improved TIMI Frame Count / Myocardial Blush Grade but also left ventricular function recovery compared to delayed abciximab administration in the cardiac catheterization laboratory. Finally, the ReoPro- BRIDGING study also demonstrated that early administration of abciximab was associated with increased patency of infarct arteries and improved myocardial perfusion.

Facilitated PCI trials using eptifibatide
Comparable to studies using tirofiban and abciximab, in the INTAMI study (INTegrilin in Acute Myocardial Infarction), Zeymer et al demonstrated that administration of eptifibatide in the ER was associated increased TFG 3 pre PCI compared to administration in the cath lab (34% vs. 10%, p=0.01). But there was no difference in the TFG 3 post-PCI, death, reinfarction, stroke and major bleed up to 30 days.

The TITAN TIMI-34 (Time to Integrilin Therapy in Acute Myocardial Infarction) was a larger trial than the INTAMI trial consisting of a total of 343 STEMI patients of which 180 received eptifibatide in the ER compared to 163 who received the drug in the cath lab. The primary endpoint, pre PCI corrected TIMI frame count was significantly better in the ER group compared to the cath lab group (77.5±32.2 vs. 84.3±30.7, p=0.049). The pre PCI TMPG 3 was more frequently seen in the ER group (24% vs. 14%, p=0.026). However there was no difference in the bleeding events and clinical outcomes between the two groups.

Facilitated PCI trials combining low dose fibrinolytic agent and glycoprotein IIb/IIIa inhibitor
Given the discrepancies in the outcomes in facilitated PCI using fibrinolytic alone and glycoprotein IIb/IIIa inhibitor alone, a strategy of combined therapy using low dose fibrinolytic and full dose glycoprotein IIb/IIIa inhibitor was examined. The Strategies for Patency Enhancement in the Emergency Department (SPEED-GUSTO-4 Pilot trial) examined the benefit of administration of fibrinolytic with or without abciximab among patients undergoing early PCI following an acute MI. This non randomized study demonstrated that administration of a half-dose reteplase and abciximab was safe and effective. This strategy was associated with TIMI flow grade 3 in 86% of cases at 90 minutes and the composite end point of death, reinfarction and urgent revascularization occurred in 5.6% of cases in the PCI group compared to 16% in those who did not undergo PCI.

The Alteplase and Tirofiban in Acute Myocardial Infarction (ATAMI), a small single centre study demonstrated that there was significantly high rates of TIMI grade 2/3 flow among STEMI patients randomized to combination therapy with 50mg alteplase and tirofiban prior to planned PCI compared to upstream administration of tirofiban in the catheter laboratory (87% vs. 42%, p<0.0001). These groups were compared with a matched control patients who underwent PCI with provisional abciximab in the cath lab (29% of patients had TIMI flow grade 2/3). The 30-day mortality was significantly lower in the combination therapy group compared to upstream tirofiban group and the control group (0.7% vs. 5.5%, p<0.02 vs. 6.3%). There were no differences in the incidence of bleeding events between the three groups. This study has its limitations given the fact that this was a single center study with relatively small number of patients and a lower dose of tirofiban was used (10μg/kg).

Contrary to the SPEED and the ATAMI studies, the BRAVE (Bavarian Reperfusion Alternatives Evaluation) study by Kastrati and coworkers was an open label, randomized multicenter study in which the beneficial effect of the use of half dose reteplase and abciximab on the infarct size using single photon emission tomography (SPECT) was examined. The investigators did not demonstrate any improvement in the final infarct size using the combination therapy (n=125) compared to abciximab alone (n=128) among STEMI patients referred for PCI (mean difference in the infarct size was 1.3% between the two groups). There was no difference in the secondary endpoints such as death, reinfarction or stroke. A similar strategy was examined in APAMIT (Asia Pacific Myocardial Infarction Trial) where all STEMI patients received abciximab and were randomized to either immediate PCI or to PCI sixty minutes later following the administration of alteplase. Like all previous studies this study demonstrated that facilitation with a lytic in addition to abciximab was associated with an increase TFG 3 pre PCI but no difference in the clinical outcomes.

Given the small sample size in the above studies, another randomized study, the ADVANCE-MI (ADressing the Value of facilitated Angioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction) study was designed to answer similar questions whether a strategy of combination fibrinolytic and a different glycoprotein IIb/IIIa inhibitor (eptifibatide) compared to eptifibatide + placebo prior to PCI would improve clinical outcomes. Although this study originally planned to recruit 5640 patients, it was prematurely terminated because of slow recruitment. An analysis of a total of 148 patients suggested that combination therapy (reduced dose tenecteplase and eptifibatide) was associated with improved epicardial flow and myocardial tissue perfusion on pre-PCI angiography. This strategy however resulted in a trend towards an increase in adverse outcomes (death, new/worsening heart failure or bleeding) compared to eptifibatide + placebo group.

The FINESSE trial (the largest trial on combination therapy) results were presented in the European Society of Cardiology meetings in 2007 (www.escardio.org). The Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) study is a 3000-patient, prospective, multicenter, randomized, double-blind, placebo-controlled trial. The study was designed to compare the efficacy and safety of early administration of reduced-dose reteplase and abciximab combination therapy or abciximab alone followed by PCI with abciximab alone administered just before PCI for acute STEMI. Patients were randomized to one of the two facilitated PCI treatments or primary PCI in a 1:1:1 fashion. At 90 days, there were no differences between treatment arms for the primary composite end points of the trial: all-cause mortality, readmission for heart failure, ventricular fibrillation, or cardiogenic shock [10.7% (PCI only group, n=806) vs. 10.5% (abciximab facilitated group, n=818) vs. 9.8% (reteplase and abciximab group, n=828)]. There were also no differences in all-cause mortality (4.5% vs. 5.5% vs. 5.2% respectively), complications of MI (8.9% vs. 7.5% vs. 7.4%), or any of the independent components of the primary composite end point. For safety end points, rates of TIMI major bleeding and minor bleeding were significantly higher for the abciximab/lytic facilitated PCI strategy as compared with primary PCI (14.5% vs. 6.9%, p<0.001). There was also a strong trend toward increased intracranial hemorrhage through discharge or day seven in the combined abciximab/lytic facilitation approach.

More recently, although not truly a facilitated PCI study, the CARESS-in-AMI (Combined Abciximab Reteplase Stent Study in Acute Myocardial Infarction) study determined whether early transfer for PCI following pharmacotherapy administration improves outcomes compared to a conservative watchful waiting approach among patients with STEMI with anticipated delay in primary PCI due to their presentation to a non-PCI center. Six hundred patients in this study were pretreated with aspirin, heparin, half dose reteplase and abciximab. Subsequently patients were randomized to either immediate transfer for PCI or transfer only in case of failed reperfusion or clinical deterioration. The investigators demonstrated that there was significant benefit in terms of reduction in 30-day mortality with the immediate transfer strategy (4.4% vs. 10.7%, p=0.004) without any differences in the bleeding events. It is important to note that the CARESS-in-AMI study determines whether early PCI improves pharmacotherapy outcomes. This is in contrast to the facilitated PCI strategy where pharmacotherapy is administered to improve PCI outcomes.

Use of Glycoprotein IIBIIIA Inhibitors in Rescue PCI Following Failed Fibrinolysis
In contrast to primary PCI, there is no clinical benefit of GPIIbIIIa inhibition when added to the administration of a full dose of a fibrinolytic agent when co-administered at the time of presentation with STEMI. This combination is clearly associated with increased bleeeding, particularly in the elderly. The benefit of glycoprotein IIbIIIa administration in the cardiac catheterization laboratory several hours after fibrinloytic administration is supported by non-randomized observational data. In a small non-randomized study of 59 consecutive patients at a single institution, death, reinfarction and urgent target vessel revascularization was significantly lower among patients treated with GP IIb/IIIa inhibition as compared with patients who were not treated (3.4% vs. 26.7%; p = 0.01).

Thrombocytopenia
Abciximab has consistently been associated with the development of thrombocytopenia. In one meta-analysis, abciximab but not small molecule GP IIBIIIA inhibitors was associated with an increased risk of mild thrombocytopenia when compared to placebo (4.2% vs 2.0%; P <.001; odds ratio 2.14) as well as severe thrombocytopenia as compared with placebo (1.0% vs 0.4%; P =.01; odds ratio 2.48). Thrombocytipenia has been in turn associated with an increase risk of major bleeding, transfusion, recurrent MI, stroke and both in-hosptial and 30 day mortality

==ACC / AHA Guidelines- Glycoprotein IIb/IIIa Inhibitors (DO NOT EDIT) ==

Class IIa
1. It is reasonable to start treatment with glycoprotein IIb/IIIa receptor antagonists (abciximab [Level of Evidence: A], tirofiban [Level of Evidence: B] or eptifibatide [Level of Evidence: B]) at the time of primary PCI (with or without stenting) in selected patients with STEMI.

Class IIb
1. The usefulness of glycoprotein IIb/IIIa receptor antagonists (as part of a preparatory pharmacological strategy for patients with STEMI before their arrival in the cardiac catheterization laboratory for angiography and PCI) is uncertain. (Level of Evidence: B)

==ACC / AHA Guidelines- Combination Therapy With Glycoprotein IIb/IIIa Inhibitors (DO NOT EDIT) ==

Class IIb
1. Combination pharmacological reperfusion with abciximab and half-dose reteplase or tenecteplase may be considered for prevention of reinfarction (Level of Evidence: A) and other complications of STEMI in selected patients: anterior location of MI, age less than 75 years, and no risk factors for bleeding. In two clinical trials of combination reperfusion, the prevention of reinfarction did not translate into a survival benefit at either 30 days or 1 year. (Level of Evidence: B)

2. Combination pharmacological reperfusion with abciximab and half-dose reteplase or tenecteplase may be considered for prevention of reinfarction and other complications of STEMI in selected patients: anterior location of MI, age less than 75 years, and no risk factors for bleeding in whom an early referral for angiography and PCI (i.e., facilitated PCI) is planned. (Level of Evidence: C)

Class III
1. Combination pharmacological reperfusion with abciximab and half-dose reteplase or tenecteplase should not be given to patients aged greater than 75 years because of an increased risk of ICH. (Level of Evidence: B)