Ticagrelor Gains FDA Approval for Use in ACS

After a series of delays over the past several years, the US Food and Drug Administration (FDA) officially approved ticagrelor, a direct-acting reversible P2Y12 receptor inhibitor, on July 20, 2011, for reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndromes (ACS).

Physicians interviewed by TCTMD expressed excitement about the new contender joining the crowded field of antiplatelet therapies.

Ticagrelor, which will be marketed as Brilinta (AstraZeneca; Wilmington, DE), may not be available in the immediate future, a company press release hints, but only after a 12-month roll-out period.

PLATO and Then Some

Ticagrelor’s FDA approval hinged on results from the PLATO (PLATelet inhibition and patient Outcomes) trial.

Published in the New England Journal of Medicine in September 2009, PLATO randomized more than 18,000 ACS patients in 43 countries worldwide to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). All patients also received aspirin.

At 12 months, the primary endpoint (CV death, MI, or stroke) was observed in 9.8% of ticagrelor patients compared with 11.7% of clopidogrel patients (HR 0.84; 95% CI 0.77-0.92; P < 0.001). But results from a prespecified subanalysis also revealed that ticagrelor had less effect in North American patients, who tended to receive higher aspirin doses than subjects enrolled elsewhere. Concerns about this disparity appeared to be at the heart of the debate over FDA approval.

In July 2010, an FDA advisory committee voted 7 to 1 in favor of ticagrelor’s approval, but the agency remained unconvinced and 5 months later asked for further analyses of the PLATO data.

The Black Box: Bleeding Risk, Aspirin Dose

With the FDA’s approval comes a “black box” warning highlighting 2 key areas: bleeding risk and the relationship between aspirin dose and efficacy.

In terms of bleeding, the label cautions that ticagrelor should not be used in patients with active pathological bleeding or a history of intracranial hemorrhage. It also is recommended that the drug not be started in those slated for CABG and ideally should be stopped at least 5 days prior to surgery. Clinicians should look for bleeding in patients who are hypotensive and have recently undergone angiography, PCI, CABG, or other surgical procedures. When possible, bleeding should be managed without discontinuing ticagrelor, in order to limit the risk of cardiovascular events.

With regard to aspirin, the label advises that maintenance doses above 100 mg reduce ticagrelor’s effectiveness and thus should be avoided. After any initial dose, 75 to 100 mg aspirin daily is appropriate.

New Option Greeted with Optimism

TCTMD gathered feedback from numerous physicians about ticagrelor’s long-awaited debut.

In an e-mail communication, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said the news was very exciting, in that now clinicians have another potential agent to treat ACS patients.

“Several unique attributes about the agent as well as the PLATO study design will render this drug more translatable to clinical practice, in my mind, than prasugrel,” he commented. “First, the fact that both clopidogrel and ticagrelor were given prior to angiography in the study makes PLATO more consistent with conventional clinical practice in ACS patients. Second, the more rapid offset of this agent will likely influence clinicians to feel more comfortable in giving this agent to a broader number of patients, even those who may have to undergo CABG.”

Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), similarly pointed out that that the pivotal trial for prasugrel, TRITON-TIMI 38, studied patients whose anatomy had already been deemed suitable for PCI. “So ticagrelor was studied in a broader patient group,” he noted in telephone interview.

Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), whose research group has designed and led 2 pharmacodynamic investigations of ticagrelor vs. clopidogrel—the ONSET-OFFSET and RESPOND studies—also was positive about the recent approval.

Widespread Use Expected

ONSET-OFFSET demonstrated that ticagrelor shows more rapid onset than 600 mg clopidogrel, offers greater platelet inhibition during maintenance, and has faster offset, he told TCTMD in an e-mail communication. “These effects provided a clear-cut mechanism to explain the superior outcomes observed with ticagrelor in PLATO,” Dr. Gurbel said, while RESPOND found that ticagrelor overcame clopidogrel non-responsiveness. And an analysis that pooled patients from both studies found no evidence of high on-treatment platelet reactivity during ticagrelor therapy, he added.

“Taken together, we believe that these pharmacodynamic effects in conjunction with the PLATO results should strongly influence the choice for ticagrelor in the ACS patient. The robust effect of ticagrelor across all groups should favor widespread implementation,” he concluded, adding that the decision is further backed by the drug’s mortality benefit.

In an e-mail communication, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), predicted that ticagrelor would be widely adopted in both STEMI and NSTEMI patients.

Asked how ticagrelor would compete with prasugrel, Dr. Stone outlined why 1 drug would be chosen over the other in different situations. Ticagrelor stands out for its effect on mortality in PLATO, he said, but ticagrelor and prasugrel work through different mechanisms that make them suitable for certain patient subgroups.

Ticagrelor can cause side effects such as dyspnea, “which while not physiologically important can be clinically worrisome,” he noted, and can cause ventricular pauses, so “must be used carefully, if at all, in patients with conduction system disease.” Prasugrel potentially comes out ahead by virtue of being given once rather than twice daily like ticagrelor, and it “has been particularly effective in suppressing stent thrombosis.”

But differences between TRITON-TIMI 38 and PLATO make it difficult to compare outcomes across trials, and much has been learned in the years since TRITON, Dr. Stone said, emphasizing that, “clearly there needs to be a head-to-head trial of these 2 agents so the appropriate therapeutic decisions can be made.”

Few Reservations

For his part, Dr. Gurbel said, “I have no reservations whatsoever about the approval of ticagrelor. It should have happened earlier.”

Dr. Kirtane, meanwhile, cautioned that it remains to be seen how possible side effects and the need for twice daily dosing with ticagrelor will play out in clinical practice. “Despite some wariness regarding the prolonged time to FDA approval and aspirin dosing issues, I would expect most clinicians to be quite pleased to have another option for their patients,” he concluded.

The key question, added Dr. Kleiman, is whether there will be less enthusiasm for ticagrelor if stent thrombosis rates, having decreased in the past few years, continue to drop.

“There’s going to be a lot more talk about clopidogrel resistance, which is a real thing, but how critical this is when we’re talking about stent thrombosis rates that are 0.4%, I’m not sure,” he noted.

In general, as new drugs become available, “[t]hey all come with a lot of promotion that gets people’s attention, but I really think people need to look at the data themselves and understand who they do and don’t want to be using the drug in,” Dr. Kleiman stressed. “When you talk about antithrombotic drugs, if you’re going to use them you’re obligated to know something about them. You need to be aggressive about getting information.”

 

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Source:
FDA approves new medicine Brilinta (ticagrelor) for use in the US [press release]. Wilmington, DE; AstraZeneca; June 20, 2011. http://www.astrazeneca.com/Media/Press-releases/Article/20110720-fda-approves-brilinta-us. Published July 20, 2011. Accessed July 22, 2011.

 

 

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• New PLATO Analysis: Aspirin Dose May Explain Discordant North American Outcomes
• FDA Ticagrelor Surprise: Further PLATO Analyses Required Before Approval
• FDA Advisory Panel Votes to Recommend Ticagrelor Approval