Ticagrelor/Prasugrel: Poor Platelet Effect in STEMI

PATRAS, Greece — Neither ticagrelor (Brilinta, AstraZeneca) nor prasugrel (Effient, Lilly/Daiichi-Sanyo) brought about adequate platelet inhibition at the time of primary PCI in patients with STEMI in a new study [1].

Both agents showed a delayed onset of action compared with what would be predicted based on assessments in stable patients, and there was no difference in platelet inhibition between the two drugs in the first 24 hours of STEMI. However, at day five ticagrelor appeared more effective than prasugrel at lowering platelet reactivity.

The study, published online on November 20, 2012 in Circulation Cardiovascular Interventions, was led by Dr Dimitrios Alexopoulos (Patras University Hospital, Greece).

Surprised

Alexopoulos told heartwire that he was surprised by the results. "We expected ticagrelor to have a faster onset of antiplatelet effect than prasugrel because it is a direct-acting agent; it does not need activation in the liver. But this was not the case in our study. Both drugs were similar, but neither produced effective reductions in platelet reactivity in the first two hours. A high percentage of patents in both groups had high platelet reactivity at the time of PCI."

Commenting on the paper for heartwire , Dr Paul Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD) said: "This is the first randomized pharmacodynamic evaluation of these new agents in STEMI, and is important because the onset of the effect of both agents has been primarily studied in stable, non-PCI patients. The results need to be validated by others, but if confirmed, they highlight a delayed pharmacodynamic effect of these oral P2Y12 inhibitors in the setting of STEMI. This delayed effect may affect ischemic event occurrence and warrant the use of parenteral antiplatelet therapy to achieve an early desirable antiplatelet effect. Also, the mechanisms behind the delayed onset need further study."

Alexopoulos explained that in STEMI patients there is an urgency to supply fast antiplatelet action as these patients normally get immediate PCI. "Time is very important. At present we load with antiplatelet agents often only 20–30 minutes before the procedure. But our study suggests that this is not sufficient."

He said that this seems to be a particular problem for STEMI patients, as studies in healthy volunteers and stable patients, as well as non-STEMI ACS patients, all suggest good antiplatelet action with these drugs in about 30 minutes.

He speculated that STEMI patients are different in some way. "They may not absorb the drugs as well as other patients. They are also often in pain, which leads to sympathetic activation, which causes vasoconstriction and can affect the motility of the intestine. Pharmacokinetic studies where the active metabolite is measured would be useful to confirm this."

Other Approaches Needed

Alexopoulos stressed that other ways are needed to cover the gap in platelet inhibition, perhaps by using a GP IV IIb/IIIa inhibitor or higher doses of ticagrelor/prasugrel. Studies are now underway to evaluate such approaches. Another study, ATLANTIC, is investigating prehospital administration of ticagrelor in STEMI patients. "Until we have the results of all these studies, I would advise trying to get loading doses of ticagrelor or prasugrel into patients as early as possible--in the ambulance or emergency room," he said.

He pointed out that the ticagrelor results differ from those seen in a small Platelet Inhibition and Patient Outcomes (PLATO) substudy, which suggested effective platelet inhibition in four out of five STEMI patients on ticagrelor. But he noted that having only five STEMI patients in the substudy was far too small to draw any conclusions.

Although he acknowledged recent studies that have shown no correlation between platelet function measurement and clinical outcomes, Alexopoulos argued that he still believes platelet function information is important in the setting of acute STEMI. "Of course platelet function testing has lost credibility with these negative results, but these studies have been done at later stages. STEMI patients in the acute setting at the time of primary PCI are very high risk. Good platelet inhibition is of utmost importance here, and platelet function testing should still give us useful information in this situation."

In the study, 55 STEMI patients undergoing PCI were randomized to ticagrelor 180 mg loading followed by 90 mg twice daily or prasugrel 60 mg loading followed by 10 mg daily for five days. Platelet reactivity was assessed using the VerifyNow test and Multiplate analyzer at zero, one, two, six, and 24 hours, and five days after randomization. The primary end point, platelet reactivity measure using the VerifyNow test at one hour, did not significantly differ between ticagrelor and prasugrel. There was also no difference at two, six, and 24 hours, although at five days platelet reactivity was lower with ticagrelor than prasugrel.

Platelet Reactivity With Ticagrelor or Prasugrel at Various Time Points

Time	Ticagrelor, PRU (n=27)	Prasugrel, PRU (n=27)	p value
1 h	257.3	231.3	0.2
2 h	196.1	153.6	0.2
6 h	75.2	69.4	0.8
24 h	46.7	40.8	0.7
5 days	25.6	50.3	0.01

Researchers note that the clinical significance of the observed antiplatelet superiority of ticagrelor at five days is unknown; that is, whether it translates into to less ischemia and more bleeding episodes or has no measurable clinical effect at all.

At two hours, high on-treatment platelet reactivity (cutoff 208 PRU) was seen in 46.2% of ticagrelor patients and 34.6% of prasugrel patients. These percentages significantly decreased after this time point in both groups, but did not differ between groups at any time point.

Alexopoulos reports receipt of speaker fees from Sanofi-Aventis, Pharmaserve/Eli Lilly and Co, AstraZeneca, and Boehringer Ingelheim