Guidelines Elevate Ticagrelor to First-line Antiplatelet Status in Unstable Angina

Updated guidelines issued by the American College of Cardiology/American Heart Association (ACC/AHA) rank the P2Y12 inhibitor ticagrelor alongside the 2 other currently approved antiplatelet agents, prasugrel and clopidogrel, as acceptable therapeutic options in addition to aspirin for patients with unstable angina/non-ST-elevation myocardial infarction (NSTEMI). The “focused update” appears online July 16, 2012, ahead of print in Circulation and the Journal of the American College of Cardiology.

A writing group led by Hani Jneid, MD, of the Baylor College of Medicine (Houston, TX), looked at trials and key data released since the last update, released in 2011. During the interim, ticagrelor received approval from the US Food and Drug Administration.

The new guidelines add ticagrelor as an accepted option with the other 2 antiplatelets in several clinical situations for unstable angina/NSTEMI patients:

• As a loading dose followed by daily maintenance therapy in those unable to take aspirin
• In addition to aspirin at presentation in patients at medium or high risk who are undergoing an invasive strategy (both before and at the time of PCI)
• As a loading and maintenance dose (up to 12 months) in patients managed noninvasively
• As a loading dose before planned PCI

Prasugrel, approved in 2009, also is recommended as a loading dose prior to revascularization in those unable to take aspirin. The agent was already recommended in other clinical scenarios based on the 2011 guideline update.

‘Major Impact on Daily Practice’

“I expect these guidelines will have a major impact on daily practice for clinical and interventional cardiologists,” Dr. Jneid commented in an e-mail communication with TCTMD. He noted that the update also addresses modified recommendations on aspirin use and recommendations pertinent to timing of glycoprotein IIb/IIIa inhibitor use. The new guidelines also call for platelet function testing only if the results will alter management and recommend CYP2C19 genotyping on the same basis as a second-line option.

“I expect that clinicians will reconsider their antiplatelet therapies carefully, and have more options to choose from,” Dr. Jneid said. “Compared with many years earlier, we now have 2 novel P2Y12 receptor inhibitors that are fast acting, very potent, and have [performed well] in robust randomized clinical trials in various clinical settings. Clinicians need to weigh the risks, benefits and alternatives for each antiplatelet therapy and the clinical setting in which each agent was shown to have improved clinical outcome.”

The writing committee stressed that data supporting the 2 newer agents come solely from the TRITON-TIMI 38 trial (for prasugrel) and the PLATO trial (for ticagrelor). Each trial compared clopidogrel with 1 of the newer antiplatelet drugs in ACS patients, demonstrating a reduction in clinical events but also the potential for increased bleeding with prasugrel and ticagrelor, respectively.

According to Deepak L. Bhatt, MD, MPH, of Brigham and Women's Hospital (Boston, MA), the guideline update will have an effect on practicing clinicians, but to what extent will vary depending on the individual. “Clearly there are clinicians who have already been using ticagrelor since its approval,” he told TCTMD in a telephone interview. “But there are definitely clinicians who want to see things in the guidelines before they do them. Certainly for someone who might have wanted to use ticagrelor but was a little hesitant, [the update] provides the imprimatur to use it, and in that respect I think it will be very useful.”

Split from Euro Guidelines

Dr. Bhatt noted an interesting divergence from the European NSTE ACS guidelines, which recommend ticagrelor and prasugrel preferentially in some circumstances over clopidogrel on the basis of the TRITON-TIMI 38 and PLATO trials.

“Trials have clearly shown that for ACS in the case of ticagrelor and ACS [patients] undergoing PCI, for prasugrel, that those respective agents are superior to clopidogrel. And if something is superior for a particular population, you should use it,” he said. “So from a pure trialist’s perspective, the way the European guidelines position things makes perfect sense.”

However, Dr. Bhatt was quick to point out that other practical issues such as cost and bleeding complications play into antiplatelet therapy decisions. “I don’t think it’s an unreasonable approach the American guidelines have taken leaving it to the physicians to choose realizing that yes, clinical trial data do and should guide decision making, but there are other factors, as well,” he said.

“I believe the US guidelines are more evidence-based and more scientifically robust,” Dr. Jneid commented. “We realize that the cost effectiveness of these agents (compared with clopidogrel) and their performance in the real world, especially with respect to bleeding, are not well known. This is why we, unlike our European colleagues, gave equal footing for the choice of any of the 3 P2Y12 receptor inhibitors as a second oral agent after an acute coronary syndrome.”

How to Choose?

Dr. Jneid stressed that the decision between the 3 antiplatelet agents “should be individualized according to the risks, benefits and alternatives available to the patient.” For instance, he noted that in the case of a high-risk ACS patient undergoing PCI who has not been preloaded with a P2Y12 receptor inhibitor, “the choice of a fast acting and potent agent (prasugrel or ticagrelor) may be reasonable. If, however, the patient is older (> 75 years of age), underweight, or had prior TIA/stroke, then prasugrel should not be utilized.”

Dr. Bhatt added that how the cost issue will play out is uncertain, especially now that clopidogrel is off-patent (as of May 2012), allowing for less costly generic versions. “Once there are multiple generics that have been out for a while, the cost will really go down, and it will depend on what insurers will pay for, what tier the drugs will end up on, how big the copays are for patients,” he said. “We’ll have to give some careful thought, even more so than now, to figuring out which agent to use for which patient. There’s going to be a lot of individualized therapy based not only on the patient’s phenotype but perhaps also based on their insurance situation.”

For instance, the higher cost of prasugrel and ticagrelor, if borne by patients, could affect compliance, Dr. Bhatt observed.

Source:

Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (Updating the 2007 guideline and replacing the 2011 focused update). Circulation. J Am Coll Cardiol. 2012;Epub ahead of print.

Disclosures:

• Dr. Jneid reports no relevant conflicts of interest.
• Dr. Bhatt reports receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, and The Medicines Company, and serving on committees for the TRILOGY (prasugrel vs. clopidogrel) and PEGASUS (ticagrelor) trials.

Related Stories:

• Ticagrelor Provides More Potent Platelet Inhibition Than Prasugrel
• PLATO Substudy Shows Greater Platelet Inhibition with Ticagrelor vs. Clopidogrel
• Ticagrelor, Prasugrel Overcome Platelet Reactivity Better than Clopidogrel