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1. Use of GP IIb/IIIa Inhibitors in
Percutaneous Coronary Intervention-
CURRENT STATUS
A short review

2. Clinical Trials of GP IIb/IIIa

3. 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.

4. Outcomes of patients receiving
GPIIB/IIIA inhibitors

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

6. 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

9. Things changed in the era of
ROUTINE STENTING AND
ADEQUATE THENOPYRIDINE
LOADING

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

12. Use in STEMI
ACC AHA SCAI RECOMMENDATIONS

13. Use in UA/NSTEMI
ACC AHA SCAI RECOMMENDATIONS

14. Use in SIHD
ACC AHA SCAI RECOMMENDATIONS

15. ESC GUIDELINES 2014 -STEMI

16. ESC GUIDELINES 2014 –UA/NSTEMI

17. ESC GUIDELINES 2014 -SIHD

18. 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 .

19. USE IN SIDE BRANCH
COMPROMISE????
HOW MUCH EVIDENCE BASED????

20. EPISTENT TRIAL 2002
Am J Cardiol 2002;90:916–921

21. CAPTURE TRIAL 1997 ABCIXIMAB

22. TEXTBOOK PERSPECTIVE
TOPOL TEXTBOOK OF INTERVENTIONAL CARDIOLOGY 6TH EDITION

23. INDIAN DATA WITH TIROFIBAN

24. 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

25. ASSOCIATED BLEEDING??

26. 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.

27. Measures that reduce bleeding
associated with GPI

28. 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

29. 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

30. 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.

31. 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

32. Intracoronary

33. 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.

34. 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.

35. 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.

36. 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

37. 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.

38. • 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.

39. 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)

40. THANKYOU

43. Espirit trial 1999

44. 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.

45. • 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

46. • 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.

47. • 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).

48. 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.

49. • 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)

50. 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%)

51. • 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

52. • 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)

53. ANY PREDICTORS???

54. AGE>75 yrs
DIABETES
ELEVATED CARDIAC MARKERS
STEMI IN LAST 7 DAYS
USA IN LAST 48 HRS