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In patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) and experience high platelet reactivity after treatment with clopidogrel, switching to ticagrelor reduces reactivity more than the alternative antiplatelet agent prasugrel. However, both of the newer P2Y12 inhibitors are potent enough to provide protection against recurrent ischemic events, according to pharmacodynamic data published in the July 17, 2012, issue of the Journal of the American College of Cardiology.

For the prospective, single-center study, investigators led by Dimitrios Alexopoulos, MD, of Patras University Hospital (Patras, Greece), randomized 44 ACS patients with high on-clopidogrel platelet reactivity within 24 hours of stent implantation to ticagrelor (90 mg twice daily) or prasugrel (10 mg once daily) for 15 days. At that point, the groups swapped regimens and continued on antiplatelet therapy for another 15 days.

Platelet reactivity was assessed at baseline and the end of each treatment period using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA). High on-treatment reactivity was defined as a value of at least 235 P2Y12 reaction units (PRU).

Ticagrelor Shows More Antiplatelet Muscle

The primary endpoint of platelet reactivity was estimated to be about one-third lower in patients receiving ticagrelor compared with those receiving prasugrel at the end of each treatment period as well as in the overall cohort (table 1). No period or carryover effect was seen.

Table 1. Estimated PRU Values According to Study Drug

 
Importantly, over the entire treatment period, no patient on ticagrelor and only 1 patient on prasugrel failed to achieve reactivity below the cutpoint of 235 PRU, chosen based on data linking it with reduced post-PCI ischemic risk. However, only 2 of 11 patients (18.2%) remained in the upper quartile of baseline platelet reactivity levels following ticagrelor treatment compared with 6 of 11 patients (50%) after prasugrel therapy.

Two patients developed allergic reactions to ticagrelor, 1 of which led to discontinuation of the drug during the first 15 days. No patient experienced a major adverse cardiovascular or bleeding event on either regimen. Two instances of minor bleeding occurred in patients on prasugrel and 2 in patients on ticagrelor. In addition, 2 cases of dyspepsia and 4 cases of dyspnea were seen, all in patients receiving ticagrelor.

Possible Explanation for Ticagrelor’s Potency

Although pharmacodynamic substudies from the pivotal TRITON-TIMI 38 trial of prasugrel and the PLATO trial of ticagrelor (both vs. clopidogrel) suggested a greater potency for ticagrelor, the paper reports, this is the first direct comparison of the 2 antiplatelet agents in the ACS setting.

The investigators suggest a possible explanation for ticagrelor’s greater suppression of platelet reactivity: Prasugrel metabolism may be unaffected by the genetic alleles that tend to undermine clopidogrel efficacy but still be susceptible to other genetic polymorphisms or hepatic abnormalities that reduce the level of its active metabolite. Ticagrelor, on the other hand, does not require hepatic activation.

Dr. Alexopoulos and colleagues observe that an earlier indirect clinical comparison of prasugrel and ticagrelor based on a meta-analysis of TRITON TIMI-38 and PLATO found no differences between the agents for the endpoints of death, MI, and stroke or their composite.

Nonetheless, the authors say, high-risk groups such as those with renal failure, STEMI, or stent thrombosis might be appropriate candidates for the stronger antiplatelet agent. In fact, a post-hoc analysis of the GRAVITAS trial found that a PRU level below 208 yielded reduced rates of death, MI, and stent thrombosis, suggesting that when it comes to platelet reactivity, “lower is better.” However, on the low end of the reactivity spectrum, PRU thresholds for avoiding increased bleeding have not been firmly established.

Looking for a PRU ‘Sweet Spot’

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), emphasized that the clinical usefulness of pharmacodynamic results remains to be seen. “I think the accepted clinical model right now is that there is a kind of ‘sweet spot’—somewhere between 80 and 150 or so [PRU]—where you get enough inhibition to prevent ischemic events but not so much that you cause bleeding,” he said. “That’s why I think that the 33 PRU [produced by ticagrelor] is a little concerning.”

On the other hand, Dr. Brener noted, the 235 PRU cutoff for protection against ischemic events used in the study is probably outdated in light of the clinical improvement shown by the lower 208 PRU threshold in the secondary analysis of GRAVITAS.

Although a head-to-head clinical comparison of ticagrelor and prasugrel would be helpful, Dr. Brener continued, such a trial is unlikely. Not only does ticagrelor “already have a leg up” on account of its proven mortality benefit in PLATO, he said, but given the efficacy of both drugs, a very large number of patients would be required to show a clinically meaningful difference between them.

Dr. Brener also expressed caution about too-quick acceptance of the pharmacodynamic findings. “The difference [in potency] between ticagrelor and prasugrel in this study is quite impressive—more than in previous studies,” he commented. “But I would be careful about assuming that the levels [of inhibition by ticagrelor] in the study are reproducible in a larger number of patients.”

One possible explanation for the very low platelet reactivity observed here, Dr. Brener said, may be that although ACS patients’ platelets are “red hot” shortly after PCI, they cool down over time. So measurements at 15 days may reflect the impact of the drug on top of natural platelet passivation, he suggested.

Study Details

At the time of PCI, clopidogrel-naive patients and those on a maintenance dose of the drug for fewer than 7 days without an initial loading dose received a 600-mg loading dose of clopidogrel. Those on maintenance clopidogrel for fewer than 7 days but with a 300-mg loading dose or those on clopidogrel for more than 7 days did not receive additional loading. All patients received 70 IU/kg heparin before PCI and 100 mg aspirin daily indefinitely afterward.

Related Stories:

•  PLATO Substudy Shows Greater Platelet Inhibition with Ticagrelor vs. Clopidogrel
• Ticagrelor, Prasugrel Overcome Platelet Reactivity Better than Clopidogrel
• Prasugrel Bests Double Clopidogrel Dose for STEMI Patients with High Residual Platelet Reactivity

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