Treatment with tirofiban, a glycoprotein IIb/IIIa receptor blocker that inhibits platelet aggregation, by paramedics led to a lower rate of major adverse cardiac events (death, recurrent MI, or urgent target vessel revascularization) and a strong trend toward reduced mortality at 30 days and at 1 year, compared to no tirofiban or placebo.
The results are from a pre-specified pooled analysis of the On-TIME 2 trial, by Dr. Jurrien M. ten Berg from St. Antonius Hospital, Nieuwegein, the Netherlands, and colleagues. On-TIME 2 had two parts, both randomized: an open-label phase of tirofiban vs no tirofiban (n = 414), and a double-blind, placebo-controlled phase (n = 984).
In 2008, the research team reported that in phase 2, routine prehospital initiation of tirofiban improved ST-segment resolution and clinical outcome after percutaneous coronary intervention. (See Reuters Health story, “Prehospital tirofiban improves post-angioplasty outcomes in MI patients,” dated Aug 14, 2008.)
According to the current report, published June 1st in the Journal of the American College of Cardiology, a total of 709 patients received tirofiban and 698 received placebo or no study drug at all. In 96% of cases, randomization was done in the ambulance; the remaining 4% were randomized at the hospital.
Patients received a 25 mcg/kg bolus of tirofiban and a 0.15-mcg/kg/min maintenance infusion. They also received unfractionated heparin 5000 IU, aspirin 500 mg by IV, and a 600 mg oral loading dose of clopidogrel, either in the ambulance or at the hospital.
The 30-day rate of major adverse cardiac events was 5.8% in the treatment group vs 8.6% in controls (p = 0.043). There were 15 deaths (2.2%) in the tirofiban group and 27 (4.1%) in the placebo/no tirofiban group (p = 0.051). Corresponding rates of urgent percutaneous target vessel revascularization were 3.0% and 4.7% (p = 0.098).
Patients who received early tirofiban treatment also had a lower rate of stroke within 30 days (0.3% vs 1.4%, p = 0.031).
Rates of major and minor bleeding did not differ significantly between groups.
One-year mortality, which was available for nearly 95% of patients, showed a trend toward reduced mortality with tirofiban (3.7% vs 5.8%, p = 0.08). The difference was more pronounced in patients treated within 75 minutes after symptom onset (1.8% vs 4.3%, p = 0.059).
In fact, the authors estimated that for early presenters, treating 26 patients would prevent a major adverse cardiac event, whereas among patients treated more than 75 minutes after onset, the number needed to treat would be 113. They ascribe the difference to the lytic effects of glycoprotein IIb/IIIa inhibitors on fresh thrombi.
“The results emphasize the importance of pre-hospital infarct diagnosis in the ambulance and subsequent initiation of potent antithrombotic therapy very early after the onset of symptoms,” the researchers say.
But in an editorial, Dr. Ron Waksman says the results “should be viewed only as hypothesis generating” because the two trial phases differed in design and were not well powered, even in combination.
Dr. Waksman, from Washington Hospital Center in Washington, DC, notes that tirofiban pretreatment did not produce significantly higher rates of Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 or less distal remobilization. Furthermore, the On-TIME 2 data differ from those of similar trials, he says.
Dr. Waksman believes the added value of glycoprotein IIb/IIIa inhibitors “remains in question in the era of the new, rapid-onset, potent antiplatelet agents and should be subjected to well-powered, prospective, randomized clinical trials.
The study was funded in part by Merck & Co and Iroko Pharmaceuticals.
J Am Coll Cardiol 2010;55:2446-2455,2456-2458.