The Antiplatelet Enigma

Clinical trials supporting the efficacy of new antiplatelet agents have not yet equated to their widespread acceptance.

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The introduction of new, highly effective antiplatelet agents for the treatment of ACS represents promising new alternatives to the current mainstay, clopidogrel. However, despite conclusive study findings — and the inclusion of these new agents in the latest clinical guidelines — clinicians have been relatively slow to incorporate these new drugs into their practices.

“The most recent data from the United States that I have seen, from August or September of 2012, suggest that most of the use of P2Y12 inhibitors is still with clopidogrel [Plavix, Sanofi-Aventis],” said Matthew T. Roe, MD, MHS, associate professor of medicine at Duke University, Durham, N.C. “The use of ticagrelor [Brilinta, AstraZeneca] and prasugrel [Effient, Eli Lilly/Daiichi Sankyo] is low.”

The disconnect between scientific validation and widespread acceptance can be attributed to a variety of factors, including concerns about bleeding risk in certain patient demographics. In addition, the recent introduction of generic clopidogrel may have given the older drug a distinct advantage with insurance payers (see Sidebar below).

However, among doctors who see the potential of the new agents, their slow adoption seems counterintuitive.

“In very large scientific trials that measure the clinical outcomes of patients with ACS, both prasugrel and ticagrelor have proven to be superior to clopidogrel,” said Marc Cohen, MD, chief of the division of cardiology, Newark Beth Israel Medical Center, New Jersey. “Despite the fact that these trials are very large and very clear-cut in terms of their conclusions, the uptake of these newer agents has been, to be honest, a little slow. So we’re not translating the results of the clinical trials into clinical practice quite as enthusiastically as one might have thought.”

As the benefits of the new drugs continue to be established, however, some clinicians believe the playing field will inevitably become more level.

“The introduction of the new drugs has provided an important tool for treating our patients with ACS,” said Matthew J. Price, MD, director of the cardiac catheterization laboratory at Scripps Clinic in La Jolla, Calif. “As time goes by, they will continue to be incorporated in a greater way.”

Prasugrel: Faster Conversion

Based largely on the strength of the TRITON-TIMI 38 trial, prasugrel was approved by the FDA in July 2009 for the reduction of thrombotic CV events in patients with ACS. Like clopidogrel, prasugrel is a thienopyridine and binds irreversibly to P2Y12 receptors on platelets.

“It irreversibly antagonizes the receptor for the life of the platelet by blocking adenosine diphosphate [ADP] binding,” Price said.

Prasugrel is a prodrug, like clopidogrel, but is converted in the liver more quickly than the older drug. Platelet inhibition with prasugrel can be seen after 15 to 30 minutes and at a considerably lower loading dose compared with clopidogrel (60 mg vs. 300 mg), which achieves platelet inhibition within 1 to 2 hours after a single loading dose.

“Clopidogrel has a two-step conversion that slows the generation of the active component,” said David P. Faxon, MD, vice chair of medicine for strategic planning at Brigham and Women’s Hospital, Boston. “And, in a significant number of patients, polymorphisms of the specific enzymes (CYP2C19) responsible for this conversion result in a lower effective inhibition of platelets.”

TRILOGY ACS: Neutral Results

In August, the phase 3 TRILOGY ACS trial was presented at the European Society of Cardiology Congress in Munich. Investigators compared prasugrel plus aspirin with clopidogrel plus aspirin in patients with unstable angina or non-STEMI who were managed medically without revascularization. The study did not show a significant between-group difference in the primary endpoint of death from CV causes, MI or stroke at the median follow-up of 17 months in patients younger than 75 years of age (prasugrel, 13.9% vs. clopidogrel, 16%; P=.21); similar results were also reported in the entire population.

Prasugrel is currently approved only for ACS patients undergoing PCI and is not recommended for those who are being medically managed without an artery-opening procedure. According to Roe, administration of prasugrel is recommended at the time of PCI with Class I recommendations in the guidelines.

Noteworthy Findings from TRILOGY ACS

Despite the neutrality of the TRILOGY ACS primary outcome, Roe said the study’s findings did raise interesting questions.

“The study didn’t show a significant reduction in the composite endpoint across a 30-month follow-up point, but what’s interesting is that the event curves separated after 1 year,” Roe said. “We really didn’t see much at all in the first year, and this could suggest that there may be a later-term treatment effect with prasugrel vs. clopidogrel in those who are medically managed. Other studies haven’t continued drugs long enough to even observe such a finding.”

He said the study also yielded interesting information about multiple recurrent ischemic events in the medically managed population.

“We looked at multiple ischemic events, not just the first event that happened in a patient, as is traditional,” he said. “And we saw an accentuation of benefit with prasugrel during the later timeframe, after a year, meaning that medically managed patients may be the ones who are more susceptible to repetitive ischemic events because they’re not undergoing revascularization. These results are intriguing, but should be considered hypothesis-generating.”

Cohen said this finding is especially relevant because roughly 30% of patients who present with ACS end up on medical therapy, rather than undergoing immediate PCI or CABG.

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“The TRILOGY ACS study is one of the few studies to ask how these patients behave, and lo and behold, it turns out that as a group, they have a lot of recurrent events similar to the patients who were treated invasively and with intervention,” he said. “So it was an eye-opener for us to really appreciate the fact that regardless of the treatment strategy, all of these patients have a significant event rate over the subsequent year.”

Roe added, however, that these findings are not likely to alter prasugrel’s status in the American Heart Association and American College of Cardiology guidelines.

“These are thought-provoking observations, but likely won’t change the pathway in terms of guideline recommendation or approval,” he said.

Cohen said another important finding from TRILOGY ACS pertained to the incidence of life-threatening or very severe bleeding in elderly or low body-weight patients receiving the 5-mg dosage of prasugrel.

“In other words, the caveats we took away from the original TRITON trial appeared to work,” he said. “If you follow the rules that emerged from the TRITON trial, then you can feel very confident that the safety profile of prasugrel will be good.”

Platelet Function Substudy

Recently released at the AHA Scientific Sessions 2012, the findings of the platelet function substudy of the TRILOGY ACS trial measured platelet reactivity in patients with ACS without STEMI, who were not treated with revascularization. The study found that, in these patients, prasugrel use was linked to lower platelet reactivity compared with clopidogrel use, regardless of age, weight and dose.

“Furthermore, we demonstrated a lower frequency of high on-treatment platelet reactivity [HPR] with prasugrel vs. clopidogrel using HPR cut-points derived from prior studies of PCI patients, but limited discrimination for defining a cut-point for HPR in this unique population,” Roe said.

The substudy also found a lack of association between platelet reactivity and ischemic outcomes. At 30 months, the difference in the primary efficacy endpoint for patients in this substudy was not statistically significant between the two groups (prasugrel, 17.2% vs. clopidogrel, 18.9%; P=.29). The researchers also found no significant differences in continuous distributions of 30-day P2Y12 reaction unit values with a primary endpoint event after 30 days (n=214) compared with patients with no event (n=1,794; P=.07).

Roe said these data call into question the value of platelet function testing in establishing a prognosis for patients treated with P2Y12 inhibitors.

“We believe that these findings, coupled with those from the concurrently presented and published ARCTIC study, challenge the utility of platelet function testing for determining the prognosis of patients treated with P2Y12 inhibitors, and for guiding the selection of antiplatelet therapies,” he said.

Price, who wrote the editorial that accompanied the platelet function substudy in the Journal of the American Medical Association, said the value of platelet function testing depends upon the population.

“The prognostic value and utility of platelet function testing is greatest in ACS patients undergoing PCI, and weakest in medically managed patients recovering from ACS,” he said.

In his editorial, Price wrote that the TRILOGY ACS platelet function substudy sets an important precedent for future trials.

“Systematic blood sample collection should be considered in randomized clinical trials designed to evaluate novel therapeutics or expand product labeling,” he wrote. “This might permit pharmacodynamics analyses by independent groups that might be useful in identifying individuals who may safely derive the greatest treatment benefit.”

Ticagrelor: Reversible Interaction

The newest P2Y12 receptor antagonist on the market, ticagrelor binds differently to the P2Y12 receptor than prasugrel or clopidogrel, Price said.

“Rather than blocking the receptor at the ADP-binding site, it binds at a separate site, and it prevents activation of the receptor by ADP,” he said. “Unlike the thienopyridines, it also interacts reversibly with the receptor. It comes on and off the receptor, rather than binding irreversibly. There are certain patients who might benefit particularly from this.”

The FDA approved ticagrelor in July 2011, and since that time, it has been recommended for certain patients in the most recent revisions of the AHA and ACC guidelines.

Roe said the guidelines include broader recommendations for ticagrelor than for prasugrel.

“Ticagrelor is recommended for all types of ACS patients, and is given upstream and then continued during PCI, and it’s given a Class I recommendation across all those indications,” he said.

The largest study of ticagrelor to date was the PLATO study. PLATO was a randomized, double blind, parallel-group trial comparing ticagrelor and clopidogrel for the prevention of CV events in 18,624 patients. The patients in the study had been admitted to the hospital within 24 hours of ACS symptoms, including unstable angina, non-STEMI and STEMI. The patients were treated for at least 6 months and up to a year, and ticagrelor and clopidogrel were evaluated with aspirin and other standard treatments.

Researchers found that among these patients, treatment with ticagrelor compared with clopidogrel significantly decreased mortality from vascular causes, MI or stroke.

Although there was no significant difference between the two medications and the rates of major bleeding (ticagrelor, 11.6% vs. clopidogrel, 11.2%; P=.43), ticagrelor was linked to a higher rate of major bleeding not related to CABG. This included more instances of fatal intracranial bleeding, and fewer of fatal bleeding of other types.

In addition, ticagrelor comes with a boxed warning that aspirin doses of 100 mg or higher decrease the effectiveness of the drug.

Faxon said he has begun incorporating ticagrelor into his practice where appropriate.

“At our institution, ticagrelor is the agent of choice in patients with STEMI undergoing primary PCI,” he said. “However, in stable patients, clopidogrel is still preferred. Both agents increase bleeding, and I use them cautiously in patients with increased risk of bleeding, and I avoid them in patients with prior central nervous system bleeding or stroke.”

Consulting the Guidelines

Now that prasugrel and ticagrelor have both been incorporated into the AHA and ACC clinical guidelines, cardiologists may feel more confident in prescribing these newer agents where indicated.

“I would say this gives more clarity for the practicing physician,” said Dominick J. Angiolillo, MD, PhD, associate professor and director of cardiovascular research at the University of Florida, Jacksonville. “Physicians can now feel comfortable implementing these drugs in their clinical practice, if they believe there is indication to use them.”

Price said although it is useful to have guideline recommendations to back these options, he feels the guidelines do not establish a clear frontrunner among them.

“Practicing physicians always like to see treatment options in the guidelines, because it provides support for their practice. However, as the guidelines currently stand, they do not show a preference for one drug over another, and since there is no ticagrelor vs. prasugrel trial, we need guidance regarding which drugs should be used for which patients,” he said.

The lack of studies directly comparing prasugrel and ticagrelor may also make it difficult for practitioners to choose between the two newer agents, Angiolillo said.

“We can’t say which of these two drugs is better, because we have no head-to-head comparisons,” he said. “That’s why it’s important to understand the risks and benefits of each drug.”

With that in mind, Angiolillo said he likes to offer the newer drugs to his patients when it is feasible. – by Jennifer Byrne