Cangrelor vs. Ticagrelor for Early Platelet Inhibition in STEMI

This randomized, controlled trial compares the anti-thrombotic effect of cangrelor and ticagrelor on platelet activity in patients with acute ST-elevation myocardial infarction.

Patients will receive either prehospital ticagrelor (180 mg - crushed) or in-hospital cangrelor (bolus 30 μg/kg within 1 minute followed by infusion (4 μg/kg/minute) for two hours) followed by 180 mg ticagrelor.

The primary study end-point is platelet reactivity at sheath insertion, at the end of the PCI procedure (before sheath removal) and two hours after PCI is initiated. The secondary end-point is the proportion of patients with inappropriate or harmful P2Y12 administration.

In patients with ST-elevation myocardial infarction (STEMI) early restoration of blood flow in the culprit coronary artery is essential to reduce infarct size and thereby mortality and morbidity. The recommended method for achieving reperfusion is primary percutaneous coronary intervention (PPCI) (1,2). Early initiation of adjunctive antithrombotic therapy is important to prevent further thrombus formation and to facilitate PPCI.

International guidelines currently recommend immediate oral or intravenous administration of aspirin and intravenous administration of heparin in patients with suspected STEMI (1,2).

A second platelet inhibitor (of the P2Y12 family) is often added already in the ambulance. This enhances the antiplatelet effect, but also increases bleeding risk.

A recently introduced antithrombotic agent, that can be administered intravenously, can potentially achieve the same antithrombotic effect at the same time of the oral agent, with the added benefit, that administration can await coronary angiography. This would reduce the risk of administrating powerful antithrombotic medicine to patients with diagnosis other than STEMI.

In the ATLANTIC trial (3) prehospital administration was compared to in-hospital (catheterization laboratory) administration of ticagrelor. The trial indicated that ticagrelor could safely be administered in the ambulance, although there was no apparent effect on Thrombolysis in Myocardial Infarction (TIMI) flow in the culprit coronary artery and no effect on ST-segment resolution in the ECG. However, the median time difference between ticagrelor administration in the two groups was only 31 minutes. This might not leave enough time for adequate platelet inhibition in the prehospital group.

In patients with NSTEMI (Non-ST-elevation myocardial infarction), pretreatment with prasugrel has been shown to be associated with increased bleeding risk and confers no benefit on ischemic outcomes (4). Thus, there are indications that the addition of oral P2Y12 inhibitor can await the coronary angiography, thereby minimizing the risk of excessive platelet inhibition in patients with a high bleeding risk or a potentially lethal differential diagnosis such as aortic dissection (5). Previous studies document that approximately 15% of patients with suspected STEMI have a final diagnosis other than an acute coronary syndrome (6). There is a fine balance between the benefit and possible deleterious effects of early, aggressive oral platelet inhibition in patients with suspected STEMI.

Recently a novel, intravenous P2Y12 inhibitor - cangrelor - has been released. Cangrelor enables immediate inhibition of the platelet P2Y12 inhibitor. The drug has a short half-life, is reversible and is only effective during administration (7). This contrasts with the available oral P2Y12 inhibitors, which all induce inhibition of the platelets for several days. Although ticagrelor is reversible, the platelet inhibition induced by this widely used, potent drug lasts for at least 3 days (8). The effects of cangrelor on platelet inhibition and clinical outcome have been documented in three, large clinical randomized trials (9-11).

Currently it is unknown whether platelet inhibition achieved by cangrelor administered in the catheterization laboratory is more effective compared to ticagrelor administered in the ambulance in patients with suspected STEMI.

The objective of this trial is to compare the effect of oral ticagrelor vs. intravenous cangrelor on platelet inhibition in ST-elevation myocardial infarction.

Patients will be included in the ambulance and randomized to one of two treatment groups; either to receive oral ticagrelor or intravenous cangrelor.

The study randomization will not be blinded to either investigator or patient (Open label, randomized, controlled clinical trial).

The hypothesis is that platelet inhibition with cangrelor administered intravenously in the catheterization laboratory after coronary angiography, but before PPCI is as effective as platelet inhibition achieved by ticagrelor administered orally in the ambulance in patients with suspected STEMI.

It is also assumed that administration of a P2Y12 inhibitor after coronary angiography reduces the proportion of inappropriate administration due to a final diagnosis other than STEMI.

Eligibility Criteria:
Inclusion Criteria:

1. Patients triaged for PPCI due to suspicion of STEMI.
2. Symptom duration \< 12 hours

Exclusion Criteria:

1. Previous inclusion in the study
2. Already in treatment with ticagrelor, prasugrel or clopidogrel
3. Treatment with oral anticoagulants (warfarin, coumarins, rivaroxaban, apixaban, dabigatran)
4. Adjunctive use of glycoprotein IIb/IIIa inhibitor during PCI
5. Active bleeding
6. Known, severe kidney failure (GFR \< 30 ml/min) and/or liver disease
7. Women of child bearing ability who are not using contraceptive medication
8. Severe mental or psychiatric disease, altered mental state (including unconsciousness) making it impossible to achieve informed consent