Glycoprotein IIb/IIIa Inhibitors in Percutaneous Coronary Intervention



Glycoprotein IIb/IIIa Inhibitors in Percutaneous Coronary Intervention


Deepak P. Vivekananthan

Deepak L. Bhatt

Eric J. Topol



Platelet activation and aggregation play an important role in promoting ischemic complications during and after percutaneous coronary intervention (PCI) (1). The routine use of aspirin pretreatment, by itself, has been demonstrated to reduce the incidence of large Q-wave myocardial infarction (MI) after PCI by over 75% (2). However, aspirin is a relatively weak agent whose antiplatelet activity is limited to inhibition of the cyclooxygenase pathway; thus, patients are not fully protected from thrombotic complications. The development and use of antagonists to the platelet glycoprotein IIb/IIIa receptor complex (3) has dramatically improved ischemic complications associated with PCI and now has made it possible for interventional cardiologists to approach more complex lesion subsets with salutary short- and long-term outcomes. The goal of this chapter is to review the pharmacology and efficacy of the three clinically available intravenously administered GP IIb/IIIa antagonists (Table 49.1), review patient characteristics and lesion subsets most likely to benefit from these agents, and make recommendations regarding the most optimal strategy to implement the use of these agents in clinical practice in the era of direct thrombin inhibition and drug-eluting stents.


PROOF OF CLINICAL EFFICACY

The clinical trials that established the efficacy and safety of glycoprotein IIb/IIIa inhibitors during PCI are listed in Table 49.2. In summary, the landmark trials of abciximab found on average a 28% to 55% reduction in ischemic endpoints in high-risk patients undergoing balloon angioplasty (BA) in the c7E3 for the Prevention of Ischemic Complications (EPIC) trial (4), in combination with a reduced heparin dose in the Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) trial (5), as an adjunct to coronary stenting in the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) study (6), and in medically refractory unstable angina in c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) (7). Whereas the use of standard high-dose unfractionated heparin (100 U/kg) in EPIC resulted in a doubling in the rate of thrombolysis in myocardial infarction (TIMI) major bleeding in the abciximab arm, the reduction in heparin dose (70 U/kg) in the EPILOG and EPISTENT trials resulted in comparable rates of major bleeding. These trials demonstrated that the significant reduction in early periprocedural ischemic
events translated into a survival advantage in higher-risk patients at long-term follow-up (8).








TABLE 49.1. PHARMACOLOGY OF CLINICALLY AVAILABLE GLYCOPROTEIN IIB/IIIA INHIBITORS

























Agent

Biochemistry

Pharmakinetics

Dose


Abciximab (ReoproTM, Eli Lilly, Indianapolis, IN)

Chimeric, murine-derived monoclonal Fab antibody fragment of 7E3 IgG against GP IIb/IIIa receptor; binds with similar affinity to vitronectin (avB3 receptor)

Plasma half-life: 10 minutes; drug may remain plateletbound for two weeks (70)

PCI: 0.25 mg/kg bolus, then 0.125 mg/kg/min × 12h after PCI.
No dose adjustment needed in renal failure


Eptifibatide (IntegrilinTM, Millennium Pharmaceuticals, Cambridge, MA)

Cyclic, peptidomimetic inhibitor containing amino acid sequence of lysine-glycineaspartic acid (KGD) important for reversible binding to GP IIb/IIIa receptor

Rapid onset of action (1 hour) Plasma half-life: 2.5 hours 75% of drug cleared by kidney

ACS: 180 μg/kg bolus, 2 μg/kg/min
PCI: 180 μg/kg double bolus, 10 minutes apart, 2 μg/kg/min × 18h after PCI; reduce drip rate to 1 μg/kg/min in patients with severe renal impairment (Cr. Cl. <50 cc/min)


Tirofiban (AggrastatTM, Guilford Pharmaceuticals, Baltimore, MD)

Tyrosine-derived non-peptide analog which mimics the geometry of the arginineglycine-aspartic acid (RGD) sequence important for reversible GP IIb/IIIa blockade

Plasma half-life: 2 hours Renal clearance is primary mechanism for elimination

Approved for use in ACS only; not yet approved for elective PCI
Dose: 0.4 μg/kg/min × 30 min, then 0.1 μg/kg/min
Reduce maintenance dose by 50% in patients with Cr. Cl <30 cc/min


ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; Cr. Cl, creatinine clearance; kg, kilogram; min, minute.


The trials evaluating the efficacy of small-molecule agents in PCI have yielded positive although less impressive results. For example, the modest 22% reduction in 30-day ischemic events in a post hoc analysis from the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) trial was attributed to suboptimal (˜50%) platelet inhibition (9) at the time of PCI. Further dose-finding studies (10) found a novel double-bolus regimen, followed by a higher maintenance infusion rate of eptifibatide (180 μg/kg double bolus, 2 μg/kg per min) resulted in >80% platelet inhibition. Utilizing this new dosing regimen in its treatment arm, the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial (11) found patients treated with eptifibatide had a significant reduction in the primary endpoint of death, MI, urgent target-vessel revascularization (TVR), or bailout with a GP IIb/IIIa inhibitor at 48 hours (6.6% versus 10.5%, p = 0.0015) and a 35% reduction in ischemic events at 30 days. Although enrolling a lower-risk population than EPISTENT, ESPRIT demonstrated that the benefits achieved with abciximab during PCI could be approached with an appropriately dosed small-molecule GP IIb/IIIa blocker. On the other hand, the ideal bolus dose of tirofiban for PCI use has not yet been determined, although studies are ongoing (12). The Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis (RESTORE) dose (13) was derived from preclinical testing using 5uM ADP, a rather weak agonist of platelet aggregation (14). Inadequate platelet inhibition (15,16) at the time of PCI may have been responsible for the superiority of abciximab compared with tirofiban in the Do Tirofiban and Reopro Give Similar Efficacy Outcomes (TARGET) trial (17). For example, patients presenting with acute coronary syndromes (ACS) treated with abciximab had a marked reduction in the composite endpoint at 30 days (5.8% versus 8.5%, p = 0.004) and 6 months (7.2% versus 9.8%, p = 0.013) (18) compared with tirofiban. In contrast, patients presenting with stable angina had no difference in short- and long-term outcomes between the two therapies. Considering that patients with unstable angina have heightened platelet activation (19), maximal platelet inhibition achievable with abciximab at the time of balloon inflation is vital to attenuate the ischemic sequelae of ACS during PCI. The similar outcomes between the two agents in stable angina imply that a lower threshold of platelet inhibition achievable with tirofiban is sufficient in these patients. Considering the suboptimal performance of tirofiban in TARGET, the efficacy of a novel, higher bolus dose of tirofiban during PCI will be tested in the phase III Tirofiban Evaluation of Novel Dosing versus Abciximab with Clopidogrel and Inhibition of Thrombin Study (TENACITY).









TABLE 49.2. TRIALS OF GLYCOPROTEIN IIB/IIIA INHIBITOR USE IN ELECTIVE/URGENT PCI































































Abciximab Trials

Patient Population

Heparin Regimen/Goal ACT

Efficacy (30-day) (composite endpoint)

TIMI Major Bleeding


EPIC (Nov. 1991-Nov. 1992) N = 2,099

“High-risk” patients: evolving MI, ACS, diabetes, advanced age; Class B1, B2, or C lesions

Not weight-adjusted 10,000-12,000 U bolus
Goal ACT: 300-350 sec

D/MI/urgent TVR
Placebo: 12.8%
Bolus alone: 11.4%
Bolus + drip: 8.3%
(p = 0.008 versus placebo)

Placebo: 7%
Abciximab: 14%


EPILOG (Feb. 1995-Dec. 1995) N = 2,792

Elective PCI; excluded ACS within 24 hours; excluded planned stent implantation

Placebo: 100 U/kg
Abx. low dose: 70 U/kg
Abx. high dose: 100 U/kg

D/MI/urgent TVR
Placebo: 11.7%
Abx. low dose: 5.2%
Abx. high dose: 5.4%
(p <.001)

Placebo: 3.1%
Abx. low dose: 2.0%
Abx. high dose: 3.5%
(p = 0.7)


EPISTENT (July 1996-Sept. 1997) N = 2,399

Elective or urgent PCI if lesion amenable to POBA or stent; enrolling relatively high-risk patients

Abx. arms: 70 U/kg Goal ACT: ≥200 sec
Stent/placebo: 100 U/kg Goal ACT: ≥300 sec

D/MI/urgent TVR
Stent/abx: 5.3%
POBA/abx: 6.9%
Stent/placebo: 10.8%
(p <0.01)

Stent/placebo: 2.2%
Abx. arms: 1.4%-1.5%


CAPTURE (May 1993-Dec. 1995) N = 1,265

Refractory unstable angina; cath demonstrating culprit lesion; PCI planned in 18-24h

Weight-adjusted:
Max dose: 100 U/kg
Goal ACT: 300 sec

D/MI/urgent TVR
Placebo: 15.9%
Abciximab: 11.3% (p = 0.012)

Placebo: 1.9%
Abciximab: 3.8%


Eptifibatide Trials


IMPACT II (Nov. 1993-Nov. 1994) N = 4,010

Elective, urgent, or emergent PCI; trial encompassed full spectrum of PCI patients

Weight-adjusted:
Dose: 100 U/kg
Goal ACT: 300-350 sec

D/MI/urgent TVR/stent
Placebo: 11.4%
Eptifibatide (130/0.5): 9.2%
Eptifibatide (130/0.75): 9.9%

Placebo: 4.8%
Eptifibatide: 5.1%-5.2%


ESPRIT (June 1999-Feb. 2000) N = 2,064

Elective PCI with planned stent implantation Exclusions: MI <24h, urgent PCI

60 U/kg (max: 6,000 U)
Goal ACT: 200-300 sec

D/MI/uTVR/IIb-IIIa bailout
Placebo: 10.5%
Eptifibatide: 6.6%
(p = 0.0015)

Placebo: 0.4%
Eptifibatide: 1%


Tirofiban Trials


RESTORE (Jan. 1995-Dec. 1995) N = 2,141

Unstable angina/acute MI within 72 hours prior to PCI

Weight-adjusted:
150 U/kg max: (10,000 U)
Goal ACT: 300-400 sec

D/MI/CABG/TVR/stent
Placebo: 12.2%
Tirofiban: 10.3% (p = 0.16)

Placebo: 2.1%
Tirofiban: 2.4%


TARGET (Dec. 1999-Aug. 2000) N = 4,809

Elective or urgent PCI with stent implantation; excluded STEMI

Weight-adjusted:
Max dose: 70 U/kg
Goal ACT: 250 sec

D/MI/urgent TVR
Tirofiban: 7.6%
Abciximab: 6.0%
(p = 0.038)

Tirofiban: 0.9%
Abciximab: 0.7%


MI, myocardial infarction; ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; POBA, balloon angioplasty;
ACT, activated clotting time; Abx., abciximab; D, death; TVR, target-vessel revascularization; CABG, coronary artery bypass grafting.



GP IIB/IIIA INHIBITORS AND AN EARLY INVASIVE STRATEGY IN ACS

Prior to the glycoprotein IIb/IIIa era, no overall benefit to an early invasive strategy was found, because the potential benefits of early revascularization were counterbalanced by the increased risk of periprocedural MI (20). With these considerations in mind, intravenous GP IIb/IIIa inhibitors have been studied as an adjunct to standard medical and reperfusion therapy for treatment of ACS. These randomized trials (21) varied according to the agent used, duration of GP IIb/IIIa inhibitor therapy, risk profile of patient population studied, and timing of PCI. Promising retrospective analyses from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM-PLUS) study using tirofiban and the Platelet Glycoprotein IIb/IIIa in Unstable
Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial found a 30% to 42% reduction in early ischemic endpoints in patients treated with early PCI as opposed to more modest benefits in patients treated medically alone. However, the use of early PCI was left up to the discretion of the treating physician, thus any analyses regarding the benefits of PCI in these studies were inherently confounded by selection bias and needed testing in a prospective fashion.

The benefits of an early invasive strategy in the modern era of GP IIb/IIIa blockade were formally validated in the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction (TACTICS-TIMI 18) trial (22) and in the Intracoronary Stenting with Antithrombotic Regimen Cooling-Off (ISAR-COOL) (23). TACTICS-TIMI 18 found patients randomized to an early invasive strategy (median time to coronary angiography of 22 hours) had a significantly lower incidence of the composite endpoint of death, MI, or rehospitalization for ACS at 6-month follow-up (15.9% versus 19.4%; OR 0.78; p = 0.025). Notably, death or MI was also significantly lower at 6 months in patients treated with the invasive strategy (7.3% versus 9.5%, p <0.05). Moreover, the use of an early invasive strategy was most efficacious in patients with baseline positive troponin values (troponin T >0.01 ng/mL) in whom a significant 39% reduction (14.8 versus 24.2, p <0.0001) in the composite endpoint was found, whereas in patients with normal baseline troponin, no benefit was found (16.7% versus 14.8%, p = 0.46). Similarly, the smaller ISAR-COOL (23) trial extended the results of TACTICS-TIMI 18 by comparing an early invasive strategy to a delayed invasive strategy after aggressive antiplatelet and antithrombotic therapy. Patients randomized to the early invasive arm (median time to coronary angiography of 2.4 hours) had a significantly lower incidence of the composite endpoint of death or large MI (5.9% versus 11.6%; p = 0.04). Thus, even with aggressive triple antiplatelet therapy, a hazard does seem apparent in delaying cardiac catheterization for 3 to 5 days. These results amalgamated with the results of TACTICS-TIMI 18 and the lack of benefit of abciximab when used to manage patients conservatively in GUSTO IV ACS (24) suggest that the routine use of early coronary angiography and aggressive antiplatelet therapy with GP IIb/IIIa inhibition in moderate- to high-risk patients with ACS is the optimal strategy to reduce major adverse cardiac events (MACE). However, the optimal timing of administration of GP IIb/IIIa blockade in the setting of an early invasive strategy has not been well studied. The Early Glycoprotein IIb/IIIa Inhibition in Non-ST-segment Elevation Acute Coronary Syndrome (EARLY ACS) trial will compare the efficacy of upstream initiation of eptifibatide versus in-laboratory initiation of eptifibatide at the time of PCI in high-risk ACS patients.


GP IIB/IIIA EFFICACY AND RISK PROFILE

Despite the evidence from large analyses (21) suggesting a modest, but significant treatment effect of GP IIb/IIIa inhibitors in ACS patients, the relatively high expense of these agents has limited their widespread use. To improve cost-effectiveness (25,26), these agents should be targeted to those patients most likely to benefit from their use. Specifically, patients with elevated troponin in the setting of ACS have a risk of death that is two- to threefold higher at 30 days compared with troponin-negative patients (27,28). Post hoc analyses from trials of abciximab and the small-molecule agents suggest a differential benefit from GP IIb/IIIa inhibitors based on troponin status. For example, in an analysis from the CAPTURE study, Hamm et al. (29) found a 68% reduction in death or MI in troponin-positive patients; no benefit of abciximab was observed in troponin-negative patients. Similarly, treatment with the small-molecule GP IIb/IIIa inhibitors lamifiban (30) and tirofiban (31) have found 48% to 75% reductions in MACE in troponin-positive patients and little or no benefit in patients with negative biomarkers.

Diabetic patients have a strikingly high risk of death in ACS (32) and adverse events after PCI. The increased baseline platelet activation (33) may be partly responsible for the increased tendency for thrombotic complications in diabetics and thus may serve as a target for potent antiplatelet therapy. In a pooled analysis limited to ACS trials, Roffi et al. (34) found a marked mortality benefit at 30 days in ACS patients treated with GP IIb/IIIa inhibitors (4.6% versus 6.2%, p = 0.007), and this difference was most pronounced in those diabetics who underwent PCI (1.2% versus 4.0%, p = 0.002) (Fig. 49.1). Of note, non-diabetic patients treated with GP IIb/IIIa inhibitors did not have a survival benefit at 30 days (3.0% versus 3.0%, p = NS).
Moreover, a pooled analysis including EPIC, EPILOG, and EPISTENT found that the use of abciximab in diabetic patients undergoing PCI was associated with a marked reduction in death at 1 year (2.5% versus 4.5%, p = 0.031) (35). Due to the long-term mortality benefit conferred by GP IIb/IIIa inhibitors in these analyses, these agents should be strongly considered for use in diabetic patients undergoing PCI.

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Sep 23, 2016 | Posted by in CARDIOLOGY | Comments Off on Glycoprotein IIb/IIIa Inhibitors in Percutaneous Coronary Intervention

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