Douglas Jennings, PharmD, FCCP, FAHA, FACC, currently practices as the clinical pharmacy manager in heart transplant and mechanical circulatory support at New York Presbyterian Columbia University Medical Center. He is a past chair of the American College of Clinical Pharmacy (ACCP) Cardiology PRN, and he is a fellow of ACCP, the American Heart Association, and the American College of Cardiology.

Douglas Jennings, PharmD, FCCP, FAHA

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.

 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.

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.

 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.

  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.

 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.

 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. 

1.       OGara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA Guideline for the Management of ST-elevation MI. 

Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs. clopidogrel in patients with acute coronary syndrome. 

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

Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. 

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

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

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

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

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. 

Articles

This article discusses the potential role of tirofiban as a complementary agent to the newer oral P2Y12 receptor blockers in STEMI patients.  

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

Patients with both atrial fibrillation (AF) and recent coronary artery stenting present health care providers with a consternating clinical conundrum.

Dual antiplatelet therapy (DAPT) with aspirin (ASA) and a P2Y12 receptor antagonist is required to maintain stent patency; however, this regimen is inferior to warfarin monotherapy for preventing stroke in AF. Likewise, oral anticoagulation with warfarin and aspirin is insufficient to protect against stent thrombosis. Hence patients with both AF and newly-placed coronary artery stents often end up on a regimen of triple therapy (ASA, warfarin, and a P2Y12 receptor antagonist), which markedly increases bleeding risk. The direct acting oral anticoagulants (DOACs), like rivaroxaban and dabigatran, have emerged as safe and effective alternatives to warfarin for stroke prevention in AF patients. To date, the potential role of the DOACs as part of a triple therapy regimen has not been studied. 

The PIONEER AF-PCI trial randomly assigned 2124 patients with both AF and recent percutaneous coronary intervention (PCI) to one of 3 regimens:

		Group 1: Rivaroxaban 15 mg (10 mg if creatinine clearance 30-50 cc/min) daily plus P2Y12 inhibitor monotherapy for 12 months (n = 709).

		Group 2: Rivaroxaban 2.5 mg twice daily plus DAPT for 1, 6, or 12 months (n = 709). After completion of the 1 or 6 months of DAPT, patients received rivaroxaban 15 mg daily plus low-dose aspirin monotherapy.

		Group 3: Warfarin plus DAPT for 1, 6, or 12 months (n = 706). After completion of 1 or 6 months of DAPT, patients received warfarin plus low-dose aspirin monotherapy.

There are some other key points regarding this study that are worth mentioning:

		Most of these were stable patients. ST-segment elevation myocardial infarction (STEMI) only accounted for 12% of the enrolled patients, while non-STEMI was 19%, and unstable angina was 21%. 

		Most patients were on clopidogrel (93%) as the P2Y12 receptor antagonist. 

		Most received a drug-eluting stent (DES) 65%;  only 33% received a bare-metal stent (BMS). 

The primary outcome, incidence of clinically significant bleeding, occurred in 16.8% of group 1 vs. 18.0% of group 2 vs. 26.7% of group 3 (hazard ratio [HR] 0.59, 

In a separate post hoc analysis of the trial published in 

, combined all-cause mortality or hospitalization was reduced in the rivaroxaban groups compared to the warfarin control (group 3), with an advantage  in both group 1 (34.9% versus 41.9%, HR 0.79, 95% CI 0.66-0.94, number needed to treat=15) and group 2 (31.9% versus 41.9%, HR 0.75, 95% CI 0.62-0.90, number needed to treat=10).

The trial was limited in several ways. The duration of DAPT was nonrandomized and determined by provider discretion. For example, in the 1-month stratum, 67% received a BMS, while in the 12-month stratum, 72% received a DES.

The trial was also underpowered to detect a difference in key efficacy endpoints, like ischemic stroke and stent thrombosis. This is a critical limitation given that the doses of rivaroxaban used in both groups are lower than those approved in the US to prevent stroke in AF. The rivaroxaban 2.5 mg twice daily combined with DAPT was taken from the ATLAS TIMI 51 trial, which established the efficacy of this regimen against DAPT in ACS patients (not AF patients). However, this trial was fraught with issues related to data integrity, and as such the FDA has not approved this dose for secondary prevention in ACS patients. 

In light of these limitations, I find it hard to translate anything meaningful from this trial to my own clinical practice.  As the rivaroxaban arms were both underdosed, I’m not surprised by the decrease in major bleeding events. Likewise, given the lack of power to evaluate key efficacy endpoints, I fear the using a regimen of lower dose rivaroxaban with either DAPT or antiplatelet monotherapy may expose patients to excessive risk of harm from either ischemic stroke or stent thrombosis (or both). 

I will hence not be shifting my patients who require triple therapy to a regimen studied in PIONEER AF-PCI. For these patients, I would continue to advocate warfarin-based anticoagulation with the shortest possible duration of DAPT according to the type of stent placed. 

		Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. 

		Gibson CM, Pinto DS, Chi G, et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stenting treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy.  

 2016; DOI: 10.1161/CIRCULATIONAHA.116.025783.

		Krantz MJ, Kaul S. The ATLAS ACS 2—TIMI 51 Trial and the Burden of Missing Data.  

A recently-published study explores the outcomes associated with the combination of DOACs and dual anti platelet therapy.