Prasugrel, Ticagrelor Show Delayed Action in STEMI Patients

Both ticagrelor and prasugrel show evidence of a delay in the onset of antiplatelet action in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). The findings, published online November 20, 2012, ahead of print in Circulation: Cardiovascular Interventions, suggest that STEMI patients exhibit impaired drug absorption that inhibits rapid platelet response

Investigators led by Dimitrios Alexopoulos, MD, of Patras University Hospital (Patras, Greece), examined platelet reactivity in 55 STEMI patients undergoing PCI at their center who were randomized to either ticagrelor (180 mg loading dose followed by 90 mg twice daily) or prasugrel (60 mg loading dose followed by 10 mg daily) for 5 days. Assessment of platelet reactivity with the VerifyNow assay (Accumetrics, San Diego, CA) was performed at time of randomization, at 1, 2, 6, and 24 hours after randomization, and 5 days later.

Few Early Differences Seen

Platelet reactivity at 1 hour (the primary endpoint) did not differ between patients randomized to ticagrelor or prasugrel. Platelet reactivity at 2, 6, and 24 hours also did not differ between the 2 groups, but at day 5 platelet reactivity was lower in the ticagrelor group (table 1).

Table 1. Platelet Reactivity After PCI

Importantly, the rate of onset of the antiplatelet effect curve from hour 0 to 2 with VerifyNow was similar between ticagrelor and prasugrel (-23.9 PRU/hr vs. -44.6 PRU/hr; P = 0.1). The area under the curve from hour 0 to 6 was 1,017.0 PRU×hr for ticagrelor and 876.2 PRU×hr for prasugrel.

High on-treatment platelet reactivity at hour 1 ranged from 52.2% to 74.1% and 45% to 66.7% for ticagrelor and prasugrel, respectively. It was not until the 2 hour mark that these rates started to fall, ranging from 31.8% to 46.2% with ticagrelor and 20% to 34.6% with prasurel, respectively. High on-treatment platelet reactivity rates were effectively decreased by both agents thereafter. No major bleeding occurred in either treatment arm.

Impaired Drug Absorption Likely

The study authors say their findings are in line with other reports showing a suboptimal degree of early platelet inhibition in the first 2 hours or by the time primary PCI is performed following a 60-mg loading dose of prasugrel. Since ticagrelor is an active drug and has a simpler metabolism leading to the formation of an active metabolite, it would be expected to have a faster onset of antiplatelet action than prasugrel, a finding not borne out by the study, they add.

A possible explanation may lie with absorption problems relative to STEMI. According to the authors, “a disturbed clopidogrel absorption possibly leading to impairment in its pharmacokinetics and pharmacodynamics has been described in STEMI patients.”

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), agreed with Dr. Alexopoulos and colleagues that impaired absorption is a likely culprit.

“What this shows essentially is that the absorption of drugs in sick patients, particularly those with STEMI, is very different than all the data that have been accrued in healthy or stable patients,” Dr. Brener said. “I think many of these patients are hemodynamically compromised, although in this study they did exclude such patients. But some of them still had altered absorption.”

Dr. Brener also was in agreement with the study authors that use of other agents such as glycoprotein IIb/IIIa inhibitors or the investigational P2Y12 inhibitor cangrelor could potentially be used as a “bridge” to cover the initial activation gaps with prasugrel and ticagrelor.

Another possible avenue for study involves testing whether a higher loading dose of either drug “could theoretically achieve a faster platelet inhibition,” the study authors write. Finally, yet another means of overcoming the delay could be pre-hospital administration of antiplatelet agents, a strategy currently being tested in the ongoing 30 Day Study to Evaluate Efficacy and Safety of Pre-hospital vs. In-hospital Initiation of Ticagrelor Therapy in STEMI Patients Planned for Percutaneous Coronary Intervention (ATLANTIC) study.

Findings Do Not Affect Clinical Decision Making

As for the clinical significance of the observed antiplatelet superiority of ticagrelor at day 5, the study authors say it is unclear whether this translates to less ischemic and more bleeding episodes.

Dr. Brener stressed that the demonstrated delay in the onset of action of prasugrel and ticagrelor does not detract from their superiority over clopidogrel or suggest that they should not be used in STEMI patients. “We know from TRITON-TIMI 38 as well as PLATO that the STEMI cohort did much better with either of these 2 drugs compared with clopidogrel,” he said, adding that the study raises interesting questions about ticagrelor that will only be answered by trial data directly comparing the drugs in STEMI patients.

Study Details

All patients received aspirin (325 mg) and unfractionated heparin intravenously (70 U/kg) at first medical contact, with additional heparin or bivalirudin at the time of PCI per operator discretion. After PCI, all patients received aspi­rin (100 mg/d) indefinitely.

 

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Source:
Alexopoulos D, Xanthopoulou I, Gkizas V, et al. Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with ST elevation myocardial infarction. Circ Cardiovasc Interv. 2012;Epub ahead of print.

 

 

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