Section D: Clinical trial update: GP IIb/IIIa inhibition GP IIb/IIIa inhibition: Meta-analysis of 6 trials Content Points: Boersma et al conducted a meta-analysis of all large randomized trials of GP IIb/IIIa inhibition in patients with non–ST-elevation ACS and who were not routinely scheduled for early coronary revascularization.14 Study drugs included abciximab, eptifibatide, lamifiban, and tirofiban. As shown, GP IIb/IIIa inhibition produced a 9% reduction in risk of death or nonfatal MI at 30 days (odds ratio, 0.91; 95% CI, 0.85 to 0.98; P = 0.015). – The rate of combined outcome was 10.8% in the GP IIb/IIIa-inhibition group and 11.8% in controls Patients with positive troponins appeared to gain the most benefit (odds ratio, 0.85; 95% CI, 0.71 to 1.03; data not shown on slide). The study investigators concluded that GP IIb/IIIa inhibition reduces the occurrence of death or MI in patients with ACS who are not routinely scheduled for early revascularization. Event reduction was clinically most meaningful in selected high-risk patients. However, results were not consistent in all trials, as the next slide demonstrates.

GUSTO IV-ACS: Neutral effect of abciximab Content Points: Benefit has not been consistently shown in all clinical trials of GP IIb/IIIa inhibitors. GUSTO IV-ACS (Global Use of Strategies to Open Occluded Coronary Arteries Trial IV in Acute Coronary Syndromes) was conducted in 7800 patients with non–ST-elevation ACS.15 Study subjects were randomly assigned to receive abciximab (0.25-mg/kg bolus followed by a 24- or 48-hour 0.125 mg/kg/min infusion) or placebo. – All patients also received aspirin and heparins The primary outcome was death or nonfatal MI at 30 days. Neither of the active treatments showed benefit. These data suggest that GP IIb/IIIa inhibition with abciximab may not be appropriate in patients with non–ST-elevation ACS for whom an early invasive strategy is not planned.

IV GP IIb/IIIa inhibition: Treatment effects in 7 PCI trials Content Points: GP IIb/IIIa inhibition has shown most benefit in patients with ACS who are scheduled for PCI. Lincoff et al conducted a meta-analysis of all large randomized trials.16 Study drugs included abciximab, eptifibatide, and tirofiban. As shown, clinical benefit was consistently shown in all trials. A subsequent trial comparing abciximab and tirofiban in this setting is discussed in the next slide.

TARGET: Protection from early acute ischemic events: Tirofiban vs abciximab in PCI Content Points: TARGET (Do Tirofiban and ReoPro Give similar Efficacy Trial) compared the effects of two GP IIb/IIIa inhibitors (abciximab and tirofiban) in 4809 patients undergoing elective or urgent PCI.17 Patients with STEMI were excluded. The primary outcome was death, nonfatal MI, or urgent target vessel revascularization. As shown, the primary outcome occurred more frequently in the tirofiban group than in the abciximab group (7.6% vs 6.0%; hazard ratio, 1.26; 95% CI, 1.01 to 1.57; P = 0.038). Greater benefit with abciximab was consistently shown in each of the components of the primary outcome. The study investigators concluded that tirofiban offered less protection from ischemic events than abciximab. Two possible explanations for this difference were proposed: – Differing mechanisms of action: Tirofiban is highly specific for the GP IIb/IIIa receptor and has a relatively short half-life - Abciximab binds not only to the GP IIb/IIIa receptor but also to the aVb3 receptor (located on endothelial and smooth muscle cells) and the aMb2 receptor (found on white cells) - Theoretically, abciximab may influence platelet/endothelial cell and platelet/smooth muscle cell interactions –Underdosing: The tirofiban dosage may not have provided a comparable level of platelet-aggregation inhibition as abciximab

TARGET: Treatment effects of tirofiban and IV abciximab in stable/unstable CAD Content Points: Subgroup analysis of the TARGET data revealed differences in the effects of tirofiban and abciximab in patients with ACS or stable CAD.18 The 30-day results showed a significant difference in favor of abciximab with regard to occurrence of the primary outcome (death, nonfatal MI, or target vessel revascularization) in ACS patients. – However, there was no significant difference between the drugs in stable patients At 6 months, the primary outcome rate continued to be significantly lower in abciximab patients in the ACS group. – However, in stable patients the primary outcome rate was significantly lower in the tirofiban group This post hoc analysis suggests that efficacy with tirofiban may be comparable to abciximab in patients with stable CAD. Emerging data suggest that GP IIb/IIIa inhibitors may not be interchangeable and that clinicians should select the drug and dose that have been proven in clinical trials. There are no comparative data with eptifibatide against other GP IIb/IIIa inhibitors in the setting of PCI. – Thus, among GP IIb/IIIa inhibitors, the strongest evidence for use in this setting is with abciximab In contrast, however, when PCI is to be deferred, the evidence is in favor of tirofiban or eptifibatide.

TACTICS–TIMI 18: Evaluation of invasive and conservative strategies in UA/NSTEMI Content Points: The TACTICS–TIMI 18 trial (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18) included 2220 patients with UA or NSTEMI. All patients received aspirin, heparin, and GP IIb/IIIa inhibition with tirofiban.19 Study subjects were then randomized to one of the following two groups: – Catheterization and subsequent PCI/coronary artery bypass graft surgery (CABG) within 4 to 48 hours – Conservative strategy with catheterization performed only if there was objective evidence of recurrent ischemia or a positive exercise stress test The primary outcome was death, MI, and rehospitalization for ACS.

TACTICS–TIMI 18: Primary outcome (death, nonfatal MI, rehospitalization for ACS) Content Points: At 6 months, the primary outcome occurred in 15.9% of the invasive-strategy group and 19.4% of the conservative-strategy group (odds ratio, 0.78; 95% CI, 0.62 to 0.97; P = 0.025)19 Rate of death or nonfatal MI was also significantly lower in the invasive-strategy group at 6 months (7.3% vs 9.5%; odds ratio, 0.74; 95% CI, 0.54 to 1.00; P < 0.05; data not shown on slide).

TACTICS–TIMI 18: Greater benefit among high-risk subgroups Content Points: Subgroup analysis, according to the TIMI risk score, indicated that patients with baseline markers of high risk derived greater benefit from the invasive strategy than patients who did not exhibit these markers. These markers included ST-segment changes, CK-MB levels >5 ng/mL, TnT levels >0.1 ng/mL, and TIMI risk score. In particular, intermediate-risk and high-risk patients (according to TIMI risk score of 3 to 7; 75% of the trial population) derived significant benefit from early PCI, whereas low-risk patients (risk score, 0 to 2) had similar outcomes with either strategy.19

ADMIRAL: IV GP IIb/IIIa inhibition in primary PCI for STEMI Content Points: ADMIRAL (Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up) was an evaluation of GP IIb/IIIa inhibition plus PCI in management of STEMI.20 The investigators administered aspirin, and then randomly assigned patients to stenting plus abciximab (n = 149) or stenting plus placebo (n = 151). Study drug was administered immediately on randomization, prior to the interventional procedure. The primary outcome was combined death, reinfarction, or urgent target vessel revascularization. As shown, at 30 days the primary outcome had occurred in 6.0% of patients receiving abciximab and 14.6% of patients receiving placebo (P = 0.01). At 6 months, the primary outcome had occurred in 7.4% of abciximab patients and 15.9% of placebo patients (P = 0.02). The ADMIRAL investigators concluded that GP IIb/IIIa inhibition with abciximab given early in STEMI improves coronary patency before stenting, left ventricular function, and clinical outcomes.

CADILLAC: Evaluation of stenting and PTCA ± IV GP IIb/IIIa inhibition Content Points: The CADILLAC trial (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) was similar to ADMIRAL. CADILLAC used a 2x2 factorial design to assign 2082 patients with STEMI to one of the following21: – Percutaneous transluminal coronary angioplasty (PTCA) alone (n = 518) – PTCA plus abciximab (n = 528) – Stenting alone (n = 512) – Stenting plus abciximab (n = 524) Prior to the interventional procedure, all patients received aspirin (324 mg po in North American Centers or 250 mg IV in European centers), ticlopidine 500 mg or clopidogrel 300 mg, UFH 5000-U bolus, and IV b-blockade. The primary outcome was combined death, reinfarction, repeat revascularization, or disabling stroke.

CADILLAC: Treatment effects on primary outcome Content Points: As shown, at 30 days the primary outcome had occurred in 8.3% of PTCA-alone patients, 4.8% of PTCA plus abciximab patients, 5.7% of stenting-alone patients, and 4.4% of stenting plus abciximab patients.21 – The difference was significant for PTCA alone versus PTCA plus abciximab (P < 0.02) and for PTCA alone versus stenting plus abciximab (P = 0.08) At 6 months, the primary outcome had occurred in 20% of PTCA-alone patients, 16.5% of PTCA plus abciximab patients, 11.5% for stenting alone patients, and 10.2% for stenting plus abciximab patients. – The difference was significant for PTCA alone versus stenting plus abciximab (P < 0.001) and for PTCA plus abciximab versus stenting plus abciximab (P = 0.03) Between-group differences at 30 days and 6 months were driven by lower rates of repeat revascularization in the group treated with stenting compared with the group treated with PTCA (data not shown on slide). The investigators concluded that in patients with STEMI, stenting alone is superior to PTCA alone and is not inferior to PTCA plus GP IIb/IIIa inhibition with abciximab.

CADILLAC: Treatment effects on primary outcome by age and sex Content Points: The clinical benefits for stenting versus PTCA are consistently observed across all age groups studied, and in men and women.21

CADILLAC: Treatment effects on primary outcome Content Points: Clinical benefit for stenting versus PTCA was also consistently observed across baseline conditions and infarct-related vessels.21 The CADILLAC investigators concluded that the clinical benefits of stenting versus PTCA alone are independent of GP IIb/IIIa-inhibition use and can be attributed primarily to lower rates of early and late restenosis and reocclusion of the infarct-related artery. Boden et al hypothesized that one explanation for the difference between the CADILLAC and ADMIRAL trials with regard to their finding with abciximab may be that in ADMIRAL, GP IIb/IIIa inhibition was given prior to the interventional procedure.22

GUSTO V: Evaluation of combined fibrinolytic and IV GP IIb/IIIa inhibition Content Points: GUSTO V was an evaluation of GP IIb/IIIa inhibition as adjunct therapy to pharmacologic reperfusion in 16,588 patients with STEMI.23 Study subjects were randomly assigned within 6 hours of the evolving infarction to receive standard-dose reteplase (two 10-U boluses, 30 minutes apart) (n = 8260) or half-dose reteplase (two 5 U-boluses) plus abciximab (n = 8328). The primary outcome was all-cause mortality at 30 days.

GUSTO V: Treatment effects on mortality Content Points: As shown, at 30 days the mortality rate was 5.9% in the full-dose reteplase group and 5.6% in the reteplase plus abciximab group (P = 0.45).23 – The relative risk for all-cause mortality in the reteplase plus abciximab group was 0.95 (95% CI, 0.84 to 1.08) The combination therapy was associated with a lower 30-day rate of reinfarction and associated complications.23 However, this difference did not translate into long-term clinical benefit. At one year, there was an identical mortality rate in both groups (8.4%).24

GUSTO V: Bleeding complications and stroke at 30 days Content Points: Both groups had similar rates of intracranial hemorrhage and stroke.23 However, the reteplase plus abciximab group had significantly more non-intracranial bleeding complications. The investigators noted that the absolute rates were low. The GUSTO V investigators concluded that the reteplase plus abciximab regimen was associated with similar mortality as standard fibrinolytic therapy with reteplase alone. These data suggest that addition of GP IIb/IIIa inhibition to a standard pharmacologic reperfusion regimen does not result in any incremental benefit.

Increased mortality with oral GP IIb/IIIa inhibition Content Points: In contrast with IV GP IIb/IIIa inhibition, clinical trials of oral GP IIb/IIIa inhibition failed to demonstrate benefit. This slide shows the results—including odds ratios and combined data—of a meta-analysis of four large-scale, randomized, placebo-controlled trials (representing 33,326 evaluable patients).25 – EXCITE (Evaluation of Xemilofiban in Controlling Thrombotic Events) provided data on 7232 patients undergoing elective PCI26 - Active treatment was xemilofiban 10 or 20 mg tid for 6 months – OPUS (Orbofiban in Patients with Unstable Angina) reported data on 10,288 patients presenting with ACS27 - Active treatment was either orbofiban 50 mg bid for 30 days followed by 30 mg bid, or orbofiban 50 mg bid for 30 days, followed by 50 mg bid - Treatment for one year was planned; 10-month data were used in the meta-analysis – SYMPHONY (Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events post-acute cOroNary syndromes) reported data on 9169 patients presenting with ACS28 - Active treatment was sibrafiban 3 mg, 4.5 mg, or 6 mg bid, based on weight and serum creatinine to achieve a target antiplatelet effect - Treatment was for 90 days – The Second SYMPHONY trial reported data on 6637 patients presenting with ACS29 - Dosing was the same as in the first SYMPHONY trial - Treatment for 12 to 18 months was planned, but this trial was terminated early; results at 90-day drug exposure and 95-day follow-up were used in the meta-analysis Each trial showed a consistent increase in mortality with active treatment. – Overall, these agents were associated with 31% increased mortality versus placebo (odds ratio, 1.31; 95% CI, 1.12 to 1.53; P = 0.0001) The reason for these negative results has not been identified.