ON-TIME 2 Pooled Analysis Published: Is Prehospital Tirofiban Worthwhile in STEMI?

May 26, 2010

May 26, 2010 (Nieuwegein, the Netherlands) — The pooled analysis of the Ongoing Tirofiban in Myocardial Infarction Evaluation 2 (ON-TIME 2) study, suggesting that prehospital administration of high-bolus-dose tirofiban (Aggrastat, Medicure Pharma/Iroko Pharmaceuticals) to patients with STEMI improves clinical outcomes after primary PCI, is published in the June 1, 2010 issue of the Journal of the American College of Cardiology [1].

But an accompanying editorial [2] by Dr Ron Waksman (Washington Hospital Center, Washington, DC) concludes that "the study's results are by no means conclusive, and . . . the added value of GP IIb/IIIa inhibitors prehospital and/or in the catheterization laboratory 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."

Asked by heartwire under what circumstances he might recommend prehospital IIb/IIIa blockers, Waksman replied they would best be used in patients with long transfer times to the lab and for those who are not pretreated with clopidogrel or prasugrel. "It's better to have antiplatelet in the vascular system than in the stomach," he added.

It's better to have antiplatelet in the vascular system than in the stomach.

In the paper, the authors, led by Dr Jurriën M ten Berg (St Antonius Hospital, Nieuwegein, the Netherlands), explain that the ON-TIME 2 trial consisted of two phases: a randomized, open-label phase (phase 1) and a placebo-controlled, randomized, double-blind phase (phase 2), both evaluating early administration of tirofiban in the ambulance in patients with STEMI destined to undergo primary PCI. All patients also received aspirin, heparin, and high-dose clopidogrel.

Results of the double-blind phase showed the tirofiban group had improved ST-segment resolution, but the effect on clinical outcome was unclear. The protocol prespecified a pooled analysis of the two study phases to assess the incidence of major adverse cardiac events at the 30-day follow-up and on total mortality at the one-year follow-up.

The two phases involved a total of 1398 patients (414 in the open-label phase and 984 patients in the double-blind phase). The combined analysis shows a significant reduction in major adverse cardiac events at 30 days and a strong trend toward a decrease in mortality in patients who received tirofiban pretreatment. And the mortality reduction appeared to be maintained during the one-year follow-up. No clinically relevant difference in bleeding was observed between the two groups.

ON-TIME 2: 30-Day Results

Outcome

Placebo/no tirofiban (%)

Tirofiban (%)

p

Death/re-MI/urgent TVR

8.6

5.8

0.043

Death

4.1

2.2

0.051

Re-MI

2.3

1.9

0.659

Urgent TVR

4.7

3.0

0.098

Major bleeding

2.9

3.4

0.580

Minor bleeding

4.4

5.9

0.206

Stroke

1.4

0.3

0.031

Net clinical outcome*

11.6

8.0

0.024

*The combined incidence of death, re-MI, urgent TVR, stroke, or major bleeding

TVR=target vessel revascularization

ON-TIME 2: Mortality Results at One Year

Outcome

Placebo/no tirofiban

Tirofiban

p

All–cause death

5.8

3.7

0.078

Cardiac death

4.4

2.5

0.061

Noncardiac death

1.4

1.2

0.773

The researchers point out that the beneficial effects of tirofiban were stronger for patients with a brief (<75 min) duration of symptoms before diagnosis compared with later presenters, suggesting that "every effort should be made to administer the medication as soon as possible in the ambulance at the first contact with the patient."

They conclude: "The results emphasize the importance of prehospital infarct diagnosis in the ambulance and subsequent initiation of potent antithrombotic therapy very early after the onset of symptoms."

Waksman: Caution

In his editorial, Waksman urges caution when interpreting these results. He lists several deficiencies in the analysis, specifically the different designs of the two phases and suboptimal power of even the pooled analysis for clinical outcomes. He says the results should therefore be viewed only as hypothesis generating.

Waksman also points out that the ON-TIME 2 results conflict with other studies such as AGIR-2 and FINESSE, which showed no benefit of prehospital tirofiban or abciximab in STEMI patients. He suggests that the better clinical outcome in the ON-TIME 2 trial may be due to the shorter time interval from symptom onset to drug administration and the fact that the control was placebo and not an active comparator. He adds that the low bleeding rates in ON-TIME 2 can be explained by the use of low-dose heparin and/or an increase in the use of closure devices.

These results are not sufficient to change guidelines.

He says: "Perhaps the most reassuring finding from ON-TIME 2 was that even with a 600-mg clopidogrel loading dose, the GP IIb/IIIa inhibitor showed a potential benefit without a significant increase in bleeding; however, given the deficiencies of the study and the lack of clear clinical benefit, these results are not sufficient to change guidelines or routine practice." He adds that the next question to answer will be whether new antiplatelet agents with faster onsets of action (ie, ticagrelor) will substitute the need for upstream GP IIb/IIIa inhibitor use.

The ON-TIME 2 study was partly funded by Merck and Iroko. Coauthor Dr Arnoud WJ van't Hof (Isala Klinieken, Zwolle, the Netherlands) has received speaker fees from Merck, Sanofi-Aventis, and Schering-Plough. Coauthor Dr Jochem W van Werkum (St Antonius Hospital) has received speaker fees from Siemens and Accumetrics and is a consultant for the Medicines Company. Senior author Dr Christian Hamm (Kerckhoff-Klinik, Bad Nauheim, Germany) has received advisory board/speaker fees from Merck, Iroko, Lilly, GlaxoSmithKline, Sanofi-Aventis, the Medicines Company, Roche, and Abbott. Waksman has received a research grant from Schering-Plough and is on the speakers' bureau of the Medicines Company.

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