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12.11.2000

Prof. Ivan Scheerder

Cardiology, University Hospitals Leuven, Belgien

Results on two Studies with Tirofiban: 1. Results of the TACTICS-TIMI 18 Study: Direct Comparison of Two Different Treatment Strategies - One Aggressive and One Conservative - in Patients with Acute Coronary Syndromes (ACS) Receiving Tirofiban 2. Results of the TARGET Study: Direct Comparison of Tirofiban and Abciximab in Percutaneous Intervention (PCI)

Keywords: Acute coronary syndrome, PCI, PTCA, GP llb/llla Receptor antagonists, Troponin, Abciximab, Tirofiban

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Take Home Messages

  • TACTICS-TIMI 18 is the first prospective trial to demonstrate that GPIIb/IIIa therapy with Tirofiban administered prior to and in conjunction with an aggressive invasive strategy (angioplasty plus stent) provides incremental benefits over early administration combined with a conservative medical approach, a finding consistent with ESC and AHA/ACC guidelines.
  • In TACTICS, immediate treatment with Tirofiban followed by PCI resulted in a combined risk reduction from 19,4% to 15,9% in death, MI and rehospitalization at 6 months (significant relative risk reduction of 22%).
  • Inclusion of the GPIIb/IIIa drug Tirofiban in the pre-treatment phase of treatment through the invasive procedure itself was the key difference between TACTICS-TIMI 18 and earlier trials, which did not show any difference in outcomes between patients treated with invasive versus conservative strategies or which showed patients treated with invasive procedures had worse outcomes.
  • In the experimental setting of TARGET, Tirofiban has not proven equivalent efficacy to Abciximab.
  • In TARGET, a non specified subgroup analysis in non-ACS patients showed comparable efficacy between Tirofiban and Abciximab.

Thrombosis, platelet aggregation, and GP llb/llla inhibitors

Thrombosis plays a major role in unstable angina pectoris, MI (myocardial infarction) and in high-risk coronary intervention. Aggregation of thrombocytes (platelets) within a blood vessel can cause vascular obstruction and distal embolisation. A new class of potent drugs called platelet glycoprotein receptor antagonists (GP llb/llla) has emerged. The GP llb/llla inhibitors block the key receptor in platelet aggregation, thereby reducing the risk of thrombosis during percutaneous coronary intervention techniques (PCI).
Two different types of GP llb/llla inhibitors are presently available for use in clinical practice: non-competitive (monoclonal antibodies, e.g., abciximab) and competitive (non-peptide: tirofiban, peptide: eptifibatide) (1). Both eptifibatide and tirofiban are relatively short-acting, with return of more than 50% of platelet function within 4 hours of cessation of the infusion (2). Abciximab, however, has a measurable antiplatelet effect that lasts for several days because of irreversible binding to although the plasma half-life is extremely short - less than 10 minutes. However, the avid binding of abciximab to platelets gives it a prolonged biological effect.

Clinical success with GP llb/llla inhibitors in percutaneous coronary intervention: Differences in efficacy or trial design?


Illustration 1: A variety of differently designed clinical trials have all independently shown good clinical success when GP llb/llla inhibitors were used in percutaneous coronary intervention (PCI).

GP llb/llla receptors have been evaluated both in the clinical settings of unstable angina pectoris (PRISM, PRISM Plus, GUSTO IV, TACTICS) and PCI (EPIC, EPILOG, EPISTENT). As illustration 1 summarizes a variety of differently designed clinical trials, all showing independently good clinical success when GP llb/llla inhibitors were used in percutaneous coronary intervention (PCI). Here, all GP llb/llla inhibitors compared to control were successful in reducing the incidence of the primary composite endpoint.

TACTICS-TIMI 18 study design and results


Illustration 2: Previous trials comparing invasive and conservative strategies.

This six-month study was performed in patients with acute coronary syndromes (unstable angina and non-ST elevation MI) receiving early treatment with tirofiban (Illustration 2). Treatment strategies were either invasive, i.e., an early interventional treatment strategy, (routine catheterization and revascularization) or con-servative which was defined as not performing procedures until a patient's medical condition worsened.


Illustration 3: Randomization into the invasive and conservative treatment strategy of TACTICS-TIMI 18.

The first hypothesis to be proven was that an invasive strategy is superior compared to a conservative strategy in ACS patients pretreated with Tirofiban. The primary endpoint in the study was death, MI and rehospitalization for acute coronary syndrome at 6 months. 2'220 patients were included into the study who received heparin, aspirin and tirofiban (i.v. loading infusion 0.4 mg/kg) followed by a 48- to 108-hour infusion (0.1 mg/kg). The drugs were administered immediately upon diagnosis. Patients were randomized within 24 hours of the last episode of chest pain to either an early invasive or an early conservative treatment strategy. For patients in the early invasive arm (1'114 patients), cardiac catheterization (usually with coronary intervention) was performed within 4 to 48 hours after randomization. Patients in the early conservative arm (1'106 patients) were treated medically and did not undergo cardiac catheterization unless they experienced one or more pre-specified clinical criteria for medical therapy failure (illustration 3).


Illustration 4: The primary endpoint was significantly different between the early invasive arm (15.9%) and the early conservative arm at 6 months (19.4%).

The results of the study showed that an early invasive strategy significantly reduced the chance of major cardiac events (death, MI or rehospitalization of worsening chest pain) in patients with acute coronary syndromes, as compared to a conservative, medical strategy (illustrations 4 and 5). The primary endpoint was statistically significant between both treatment arms: 15.9% of patients in the early invasive arm experienced a cardiac event versus 19.4% of patients in the early conservative arm at 6 months (p = 0.025). The results demonstrate that for patients pre-treated with tirofiban, the strategy of continuation of the drug through an early procedure was superior to the strategy of 'waiting and watching'.


Illustration 5: The cardiac events at 6 months.

TARGET study design and results


Illustration 6: The study design of TARGET.

Previous trials showed that GP llb/llla inhibitors are effective in PCI (illustration 1), especially when combined with stent deployment. The efficacy of these substances has never been compared head to head in the same clinical trial. While abciximab appears to be more effective based on previous data tirofiban is cheaper, is easier to handle and may have an advantage because of it's shorter half-life in terms of bleeding complications.

The study design shown in illustration 6 is based upon the hypothesis that tirofiban will have comparable efficacy to abciximab in reducing the incidence of 30 days adverse cardiac ischemic events (death, MI, urgent target vessel revascularization) in patients after intracoronary stent placement.


Illustration 7:. Endpoints of TARGET.

Patients were pretreated with ASA (aspirin) and clopidogrel. Immediately prior to the initiation of the PCI procedure, tirofiban (bolus + 18-24 hr infusion) or abciximab (bolus + 12 hr infusion) were given with heparin in a low-dose (70 U/kg) regimen. After PCI patients were followed for the occurrence of composite endpoints (Illustration 7).

TARGET included 4'812 patients. The rate of events for the primary composite endpoint at 30 days was 7.55% for tirofiban versus 6.01% with abciximab (p = 0.037) (illustration 8). In a non-pre-specified subgroup analysis the benefit of abciximab appeared limited to patients undergoing PCI for acute coronary syndrome.


Illustration 8:. Results of the primary endpoints.

A non specified subgroup analysis in non-ACS patients showed comparable efficacy between Tirofiban and Abciximab (illustration 9). Both tirofiban and abciximab were generally well tolerated and there was no statistical significant difference in the incidence of TIMI-major bleedings (1.2% versus 1.0%, n.s.; illustration 10). However, the rate of TIMI-minor bleeding was significantly lower in the tirofiban group (3.5% versus 5.6%, p<0.001) as was the rate of thrombocytopenia (0.5% versus 2.4%, p<0.001).

A GPIIb/IIIa blocker, like Tirofiban, is essential in the treatment of patients presenting to the hospital with acute coronary syndrome, including patients who subsequently go on to have a angioplasty procedure. The benefits of tirofiban in improving outcomes in these patients were firmly established in the PRISM-Plus Study.


Illustration 9: Subgroup Analysis


Illustration 10: Less bleeding complications with Tirofiban

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