Use of GP IIb/IIIa Inhibitors in Percutaneous Coronary

Intervention-CURRENT STATUS

A short review

Clinical Trials of GP IIb/IIIa

Clinical Trials of GP IIb/IIIa• GP IIb/IIIa inhibitors have been studied intensively over

the last 2 decades with tens of thousands of patients enrolled in randomized, double-blinded, placebo-controlled clinical trials.

• All patients included in GP IIb/IIIa inhibitor trials were treated with aspirin and heparin and the early trials were conducted in the era of percutaneous transluminal coronary (balloon) angioplasty (PTCA).

• The primary endpoint for most of the studies was a composite of death, MI and urgent revascularization, whereas bleeding was considered a secondary outcome.

Outcomes of patients receiving GPIIB/IIIA inhibitors

Major Studies Addressing GPI Use in Patients Undergoing PCI (Elective Indication or ACS) BEFORE the Era of Routine Stenting and Appropriate Thienopyridine Pre-Loading

Major Studies Addressing GPI Use in Patients With ACS, a Proportion of Whom Underwent PCI, BEFORE the Era of Routine Stenting and Appropriate Thienopyridine Pre-Loading

Things changed in the era of ROUTINE STENTING AND

ADEQUATE THENOPYRIDINE LOADING

Major Studies Addressing GPI Use in Patients Undergoing Primary PCI for STEMI

Use in STEMI ACC AHA SCAI RECOMMENDATIONS

Use in UA/NSTEMI ACC AHA SCAI RECOMMENDATIONS

Use in SIHD ACC AHA SCAI RECOMMENDATIONS

ESC GUIDELINES 2014 -STEMI

ESC GUIDELINES 2014 –UA/NSTEMI

ESC GUIDELINES 2014 -SIHD

Anti-ischemic value of GPI seems currently limited to 4 subgroups of patients:

1. Patients with NSTEMI undergoing PCI, particularly if they are not receiving

bivalirudin, or if they are receiving bivalirudin but are not adequately preloaded with a thienopyridine, as recommended by the American College of Cardiology guidelines

2. Patients having thrombotic complications or large side branch closure during any PCI performed for stable or unstable CAD, whether bivalirudin is used or not (GPI were used for bailout in 7% and 9% of patients randomized to bivalirudin in the REPLACE-2 and ACUITY trials, respectively);

3. Select patients with STEMI, particularly those not pre-loaded with a thienopyridine in the emergency department or those with a large thrombus burden;

4. Patients undergoing ad hoc PCI for stable or unstable CAD and not adequately pre-loaded with a thienopyridine .

USE IN SIDE BRANCH COMPROMISE????

HOW MUCH EVIDENCE BASED????

EPISTENT TRIAL 2002

Am J Cardiol 2002;90:916–921

CAPTURE TRIAL 1997 ABCIXIMAB

TEXTBOOK PERSPECTIVE

TOPOL TEXTBOOK OF INTERVENTIONAL CARDIOLOGY 6TH EDITION

INDIAN DATA WITH TIROFIBAN

FINAL STATEMENT

• GOOD ENOUGH EVIDENCE• BUT ERA HAS CHANGED• ADVENT OF NEW AND POTENT

THENOPYRIDINES• NEED TRIALS TO JUSTIFY ITS USE IN BAIL OUT

SITUATIONS esp SIDE BRANCH OCCLUSION

ASSOCIATED BLEEDING??

PREDICTORS OF HIGH BLEEDING RISK

• Age >75 years, • Female sex, • Chronic kidney disease stage 3 or worse, • Baseline anemia, • History of prior bleeding,• Cardiogenic shock, • Class IV heart failure.

Measures that reduce bleeding associated with GPI

SUMMARY• Early studies have shown a reduction of ischemic events with GPI, yet more

recent studies performed in the era of routine thienopyridine therapy show an increase in bleeding risk and a less consistent net clinical benefit of GPI administration.

• In Post procedure side branch occlusion/pinching= GPI may be considered• To use GPI safely, one should:

Target high-risk patients, particularly NSTEMI patients or patients undergoing PCI without adequate clopidogrel pre-loading.

Avoid the routine upstream use of GPI in ACS, particularly if thienopyridines are used early on.

Appropriately adjust dose for patients with renal failure. Reduce or eliminate the infusion. Use radial approach, particularly in patients with NSTEMI who otherwise have an

indication to receive GPI. Select lower bleeding risk patients, which is challenging because ACS patients who

are likely to benefit from GPI have a higher bleeding risk than stable patients

IMPORTANT ISSUES• SANTISS directly compared high-dose bolus tirofiban with double

bolus eptifibatide and the superiority of tirofiban was shown

• TENACITY AND TARGET TRIALS HAVE CLEARLY SHOWN SUPERIORITY OF ABCIXIMAB OVER TIROFIBAN

• EASY AND BRIEF PCI TRIALS DEMONSTRATE THAT SHORT INFUSION (BRIEF PCI TRIAL <2 HRS) AND BOLUS DOSE ONLY (EASY TRIAL) DEMONSTRATE EQUAL EFFICACY IN COMPARISON TO LONGER INFUSIONS OF GPI IN CURRENT ERA WITH CLOPIDOGREL LOADING

• Intracoronary—as compared with intravenous—administration of GP IIb/IIIa inhibitors has been tested in several small studies and was associated with some benefits, which have not been confirmed in larger trials

Tirofiban • Tirofiban , a tyrosine derivative with a molecular weight of 495 kd, is a

nonpeptide inhibitor (peptidomimetic) of the platelet GPIIb/IIIa receptor.

• Administer intravenously 25 mcg/kg over 3 minutes and then 0.15

mcg/kg/min for up to 18 hours.

• In patients with creatinine clearance ≤60 mL/min, give 25 mcg/kg

over 3 minutes and then 0.075 mcg/kg/min.

tirofuse• It is currently not FDA approved for PCI, although it is both

approved and widely used throughout Europe for this indication (bolus 10 mcg/kg followed by infusion 0.15 mcg/kg/min for 18–24 hours). Several studies have documented that this approved bolus and infusion regimen for tirofiban achieves suboptimal levels of platelet inhibition for up to 4 to 6 hours that likely accounted for inferior clinical results in the PCI setting. For this reason, a high-dose bolus regimen (25 mcg/kg over 3 min) achieving more optimal platelet inhibition has been suggested.

• Half life is 2 hrs, but platelet inhibition continues for upto 4 hrs after discontinuation

Intracoronary

Intracoronary drug delivery.

• Though this approach has been used empirically in the past and still

continues to be used in cardiac catheterization laboratories around the

world, it has never been evaluated in a large-scale randomized study.

• The rationale for this approach is the ability to achieve a very high

concentration of the drugs at the site of the thrombus without

significantly increasing the risk of bleeding.

Why favouring intracoronary

Improves microvascular function and clinical outcomes.

Concentration after IC administration depends on coronary blood flow. It has

been estimated that the concentration may be as much as 280-fold greater

when compared to IV delivery, depending on inflow and washout of blood.

Facilitate the diffusion of the drug into the acute thrombus, with the potential of

promoting clot dissolution in the epicardial and microvessels.

Moreover, a high local concentration leads to increased receptor occupancy in

the case of GP IIb/IIIa inhibitors.

Decreases the greater risk of bleeding.

In conclusion, compared to IV administration , IC administration of GPIs has favorable effects on TIMI flow, TVR, and short-term mortality after PCI, with no difference in rates of bleeding.

CICERO TRIAL 534 PATIENTS

• CICERO trial is the largest clinical trial to date to determine the effect of intracoronary vs

intravenous administration of abciximab in STEMI patients undergoing primary PCI.

• Did not improve myocardial reperfusion as assessed by ST-segment resolution but did

improve myocardial reperfusion as assessed by myocardial blush grade and a smaller

enzymatic infarct size in STEMI patients undergoing primary PCI 

AIDA STEMI TRIAL - negative

• 2065 pts with STEMI <12 hrs rand to Pri PCI with IC vs IV bolus abciximab.

• Intracoronary versus intravenous abciximab bolus (0·25 mg/kg bodyweight) during

percutaneous coronary intervention with a subsequent 12 h intravenous infusion 0·125 μg/kg

per min (maximum 10 μg/min).

• The IC bolus delivered directly through the guiding catheter as well as the IV bolus were

followed by an IV infusion of abciximab for 12 h.

• Thrombectomy was used in about 20% of patients almost equally in both groups, particularly

in lesions with high thrombus burden.

• Intracoronary abciximab does not reduce rates of death or

myocardial infarction (MI) compared to standard intravenous (IV)

administration of the glycoprotein IIb/IIIa inhibitor in patients

with ST-segment elevation myocardial infarction (STEMI)

undergoing primary percutaneous coronary intervention (PCI).

• IC decreases CHF.

Final statement

• USE IT IN TROP POSITIVE PATIENTS SPECIALLY IF NOT GIVEN BIVALIRUDIN AND ADEQUATE THENOPYRIDINE PRELOAD

• USE HIGH BOLUS DOSE TIROFIBAN• KEEP INFUSION TIME SHORT (2-4 HOURS)• REMOVE SHEATH EARLY (4-6 HOURS)

THANKYOU

Espirit trial 1999

ABCIXIMAB• Abciximab is the Fab fragment of the chimeric human-

murine monoclonal antibody 7E3. With intravenous bolus, plasma concentrations decrease rapidly with an initial half-life of less than 10 minutes and second-phase half-life of 30 minutes, likely related to rapid binding to the platelet glycoprotein receptor.

• At highest dose, 80% of platelet glycoprotein receptors are occupied in 2 hours, and platelet aggregation is completely inhibited.

• On cessation, free plasma concentrations rapidly decrease over the first 6 hours and thereafter at a slower rate.

• When initially studied in ACS, the patients invariably underwent angioplasty without stenting and thienopyridine therapy was not used.

• Several randomized trials were performed, and in a subsequent meta-analysis including more than 5400 patients from the EPIC, EPILOG, RAPPORT, EPISTENT, and CAPTURE studies who received percutaneous transluminal coronary angioplasty (PTCA), abciximab significantly reduced 30-day mortality and reinfarction (hazard ratio [HR] 0.52, 95% confidence interval [CI] 0.41–0.65).

• A meta-analysis looking at STEMI patients who underwent PCI with stenting with abciximab or placebo included the RAPPORT, ADMIRAL, ISAR-2, CADILLAC, and ACE20 studies.

• Abciximab showed a significant reduction in mortality at 30 days (2.4% vs 3.4% with placebo) and at 6 to 12 months (4.4% vs 6.2%), with no increased bleeding seen in these patients

• In terms of patients with stable coronary heart disease undergoing PCI, 2 trials evaluated outcomes comparing abciximab with placebo in predominantly stable patients, and came to differing conclusions.

• EPISTENT randomized 2399 patients undergoing elective (approximately 40%) or emergent PCI to stenting alone, stenting with abciximab, or PTCA with abciximab.

• All patients who received a stent were given aspirin and ticlopidine. Adverse events (death, myocardial infarction [MI], and urgent revascularization) at 30 days (10.8%, 5.3%, and 6.9%) and 6 months (11.4%, 5.6%, and 7.8%) were significantly lower in the abciximab groups, with the difference largely driven by reduced death and NSTEMI.

• The ISAR-REACT study consisted of 2159 patients with stable coronary artery disease undergoing PCI with stenting and treated with aspirin and thienopyridine, who were randomized to abciximab or placebo.

• The 30-day rates of major adverse cardiac events (MACE) between abciximab and placebo were the same (both 4%), and major bleeding complications were comparable.

• In the ISAR-REACT 2 trial, abciximab administration, among high-risk NSTEMI patients receiving clopidogrel with a 600 mg loading dose, was associated with a lower incidence of death, MI, or urgent revascularization (8.9% vs 11.9%, P 5 .03; relative risk [RR] 0.75, 95% CI 0.58–0.97), but the benefit was confined to those who with elevated troponin (13.1% vs 18.3%, P 5 .02; RR 0.71, 95% CI 0.54–0.95) compared with those who had a normal troponin level (4.6% vs 4.6%, P 5 .98; RR 0.99, 95% CI 0.56–1.76).

TIROFIBAN• Stable patients undergoing PCI were evaluated in the ADVANCE trial,

which aimed to assess the potential benefit of using a higher dose of tirofiban than had been used in trials assessing the drug in the setting of ACS (RESTORE, PRISM, and PRISM-PLUS trials).

• A total of 202 patients, pretreated with thienopyridines, were randomized to high-dose bolus tirofiban (25 mg/kg/3 min, and infusion of 0.15 mg/kg/min for 24–48 hours) or to placebo.

• At 6 months, adverse events (death, MI, target vessel revascularization [TVR], or bailout GPI) were significantly less frequent with tirofiban (20% vs 35%, P 5 .01; HR 0.51, 95% CI 0.29– 0.88), a difference driven by the incidence of MI and bailout GPI in the placebo group.

• In subgroup analysis, the benefit of tirofiban was significant among patients with ACS but not among those with stable angina.

• A small study of 96 patients, the TOPSTAR (The Effect of Additional Temporary Glycoprotein IIb/ IIIa Receptor Inhibition on Troponin Release in Elective Percutaneous Coronary Interventions after Pretreatment with Aspirin and Clopidogrel) trial, was a randomized, double-blind, placebo controlled study, and the first to observe that additional inhibition of platelet aggregation by tirofiban with aspirin and clopidogrel reduced periprocedural troponin release and the composite end point (death, MI, and TVR) after 9 months (2.3% with tirofiban vs 13.0% with placebo, P<.05)

EPTIFIBATIDE

• Eptifibatide is a heptapeptide of the glycoprotein IIb/IIIa receptor that inhibits platelet aggregation.

• The plasma half-life is 10 to 15 minutes, and it ispredominantly renally excreted (75%) with the remainder via hepatic pathways (25%)

• More than 4000 patients were enrolled in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis—II) study (59% with stable coronary disease), which randomized patients to either placebo or 1 of 2 doses of eptifibatide.

• At 30 days, there was no significant difference in MACE between the groups, and eptifibatide did not increase rates of major bleeding or transfusion.

• By a treatment-received analysis, the lower dose regimen produced a significant reduction in the composite end point (11.6% vs 9.1%, P < .035), with reduced rates of abrupt closure and ischemic events at 30 days, but the higher dose produced a less substantial reduction (11.6% vs 10.0%, P < .18).

• The investigators believed that the doses studied appeared to be at the lower end of the efficacy-response curve, and that further investigation was needed

• The ESPRIT trial randomly assigned 2064 patients to placebo or eptifibatide immediately before elective PCI.

• The trial was terminated prematurely because eptifibatide reduced the primary end point (48-hour death, MI, urgent revascularization, or bailout GPI) by 37% (6.6% vs 10.5%,P < .0015)

ANY PREDICTORS???

AGE>75 yrsDIABETESELEVATED CARDIAC MARKERSSTEMI IN LAST 7 DAYSUSA IN LAST 48 HRS