All That Is Old Becomes New Again: New Roles for Old, Antiplatelets in STEMI

Along with prompt percutaneous coronary intervention (PCI), rapid inhibition of platelet aggregation is essential when managing acute ST-segment elevation myocardial infarction (STEMI). Prior to the age of oral P2Y12 agents (i.e. clopidogrel), the pharmacologic agent of choice for antiplatelet therapy peri-PCI in STEMI was a IIb/IIIa inhibitor (abciximab).

The field has since shifted toward oral antiplatelet agents as standard therapy for STEMI patients.¹ Newer agents like prasugrel and ticagrelor have significant advantages over clopidogrel, chiefly a more rapid onset and less variable antiplatelet effect. Both drugs outperformed clopidogrel in their respective landmark clinical trials, and as such they are currently the preferred antiplatelet agents for STEMI patients undergoing primary PCI.^2,3

Despite the superiority of prasugrel and ticagrelor over clopidogrel, emerging literature suggests that both new oral medications still have a delayed onset of antiplatelet effect in the setting of acute STEMI.⁴ This is particularly problematic, as this window of time without drug effect may expose patients to the risk of a peri-procedural complication (i.e. in-stent thrombosis or peri-PCI myocardial infarction). Thus, there may still be a complementary role for intravenous antiplatelet agents.

Cangrelor is a relatively new intravenous P2Y12 receptor antagonist that is FDA approved for use during PCI in place of an oral agent. Cangrelor’s place in the drug therapy armamentarium for STEMI patients has yet to be determined, as it has not been directly compared to either prasugrel or ticagrelor.⁵ Furthermore, it directly blunts the pharmacodynamic effects of clopidogrel and prasugrel, so I cannot see cangrelor emerging as a feasible option to “bridge” patients early after administration of an oral agent.

Re-enter tirofiban. This agent was first introduced as a treatment for non-ST elevation MI (NSTEMI) back in May of 1998. A recent pilot study named FABOLUS PRO randomized 100 STEMI patients to prasugrel 60 mg alone versus 25 mcg/kg tirofiban bolus with or without post-bolus 2-h infusion of tirofiban plus prasugrel.⁶ Patients randomly assigned to the prasugrel alone arm had significantly lower levels of platelet inhibition for the first 2 hours after administration. Those who received either tirofiban regimen had faster inhibition of platelets; further, this study found superior inhibition of platelets with combination therapy, and suggests that this combination may offer a synergistic “2-hit” approach through complementary pharmacology.

Glycoprotein IIb/IIIa inhibitors are currently recommended as a provisional or “bailout” option in STEMI patients, meaning that they are relegated to those with large thrombus burden visualized on angiography.¹ The results of FABOLUS PRO are intriguing, and suggest that the combination of tirofiban with a newer oral P2Y12 receptor antagonist may not only lead to faster response, but also more complete platelet inhibition. Obviously, this strategy mush be further vetted through larger studies with adequate power to assess bleeding and thrombotic endpoints before routine clinical use can be considered.

If confirmed, this combination regimen may not only yield improved outcomes, but also potentially cost savings, as alternative agents like cangrelor carry a much higher price tag than any of the oral P2Y12 agents or tirofiban.

While still preliminary, I commend the authors of FABOLUS PRO for their innovation. This scenario exemplifies how older medications, when re-evaluated in the proper clinical setting, can become new again. The irony behind the potential resurrection of tirofiban as a competitor to cangrelor cannot go unmentioned, as the latter drug was approved on the basis of a clinical trial named after the mythical bird symbolizing rebirth.

References

1. OGara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-elevation MI. Am Coll Cardiol. 2013;61:e78 —e140.

2.

Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs. clopidogrel in patients with acute coronary syndrome. N Engl J Med. 2007;357:2001-2015.

3. Wallentin L, Becker RC, Budaj A, et al.

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes.

N Engl J Med. 2009;361:1045-1057.

4. A

lexopoulos D, Xanthopoulou I, Gkizas V, et al.

Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST-segment-elevation myocardial infarction.

Circ Cardiovasc Interv. 2012;5:797-804.

5. Bhatt Bl, Stone GW, Mahaffey KW, et al.

Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events.

N Engl J Med. 2013;368:1303-1313.

6. Zeymer U, Mochmann HC, Mark B. Double-blind, randomized, prospective comparisoin of loading doses of 600 mg clopidogrel versus 60 mg prasugel in patients witha cute ST-segment elevation MI scheduled for primary PCI. Am Coll Cardiol Intv. 2012;5:268—277.