A Pilot Study of The Effects of a Single High Dose Bolus Tirofiban in Diabetic Patients Undergoing Elective Percutaneous Coronary Intervention

Introduction Diabetes is a major risk factor for coronary artery disease and diabetic patients are considered CAD equivalent in the absence of CAD1. The presence of CAD and diabetes makes the patient at a much higher risk for future morbidity and mortality. Moreover, percutaneous coronary intervention (PCI) in diabetics is associated with a higher risk of major adverse cardiac events (MACE). Several studies have also suggested that the release of cardiac biomarkers during PCI procedures have an independent predictability of a worse prognosis in terms of both morbidity and death. Furthermore, previous investigations suggested that glycoprotein IIb/IIIa inhibitors (GPI) should be used routinely in all diabetics undergoing PCI due to their higher propensity of developing a hyper aggregatory status during such procedures that puts them at a higher risk of developing myocardial injury and subsequent cardiac biomarkers release. However, recent investigation suggested that high dose clopidogrel (600 mg given at least 4 hours prior to intervention) is as protective as Abciximab in low risk patients undergoing elective PCI 2. Thus, high dose clopidogrel preloading without GPI has become the standard for low risk patients undergoing elective PCI. There is limited data in the literature to suggest that routine administration of GPI prior to PCI in diabetic patients with a high dose preloading with clopidogrel is actually beneficial. That is why this trial is being undertaken.

Experience with the high dosage of tirofiban Several studies performed following the completion of TARGET strongly suggested that the 10 µg/kg bolus dose of tirofiban is inadequate3. The TARGET dosing regimen of tirofiban inhibited 20 uMADP-mediated platelet aggregation only by 60-66% from 15-60 minutes after onset of treatment when tested with PPACK as a sample anticoagulant, and as a result of rapid tissue redistribution yielded a tirofiban plasma level of 35-40 ng/mL4. Abciximab, as it was dosed in the TARGET trial, produced a 90-95% inhibition of platelet aggregation in this same time period. This difference in extent of platelet aggregation inhibition was proposed as the reason why more procedure-related ischemic events occurred among subjects receiving tirofiban in the TARGET trial.

To date, several published trials have been described using the single high-dose bolus (SHDB) of tirofiban in various clinical settings. Taken together, more than 600 patients received the SHDB of tirofiban in these clinical trials without evidence of a greater than expected increase in the frequency of bleeding events or thrombocytopenia. A variety of clinical, angiographic, and echocardiographic endpoints all consistently demonstrate that the SHDB of tirofiban is superior to placebo and appears to be comparable to abciximab.

Two trials up to now demonstrated that in the same dosing paradigm SHDB of tirofiban achieves comparable levels of platelet inhibition as does abciximab for patients undergoing PCI4, 5.

The largest experience published by Danzi and colleagues was a 554- patient observational study comparing the safety and efficacy of SHDB tirofiban in PCI patients to a cohort of PCI patients who received abciximab6. Patients were enrolled sequentially: the first 280 received abciximab and the subsequent 274 received HDB tirofiban. The incidence of major bleeding events or access site bleeding complications for patients treated with SHDB tirofiban was less than that seen with abciximab. Moreover, the point estimate of the incidence of in-hospital and 30-day major adverse cardiovascular events (MACE) in the SHDB tirofiban group was actually below that in the abciximab group (5.6% vs. 7.1%; P=0.65). This clinical experience suggests that SHDB tirofiban, administered at the time of PCI, is safe and can produce results similar to abciximab.