New clinical guidelines on the management of unstable angina/non–ST-elevation myocardial infarction recommend the antiplatelet therapy ticagrelor as an alternative to prasugrel and clopidogrel.
Ticagrelor (Brilinta), which like prasugrel and clopidogrel works by inhibiting the P2Y12 receptor, was approved by the Food and Drug Administration in July 2011 following the results of a large, randomized, placebo-controlled trial that showed it significantly reduced the rate of rate of death from vascular causes, myocardial infarction, or stroke compared with clopidogrel, although ticagrelor was associated with a higher risk of bleeding (N. Engl. J. Med. 2009;361:1045-57).
Similarly, prasugrel had been shown in an earlier randomized controlled trial to be superior to clopidogrel in reducing rates of ischemic events, but was associated with a higher bleeding risk (N. Engl. J. Med. 2007;357:2001-15).
Clopidogrel has been associated with variability in patient response, and the newer agents are considered to be more potent. Current European guidelines for unstable angina/non–ST-elevation myocardial infarction (UA/NSTEMI) explicitly recommend ticagrelor as the agent of choice, followed by prasugrel (in patients proceeding to percutaneous coronary intervention [PCI]) and clopidogrel (in patients who cannot receive the newer agents).
However, the ACCF/AHA (American College of Cardiology Foundation/American Heart Association) guidelines’ authors, led by Dr. Hani Jneid of the Baylor College of Medicine and Michael E. DeBakey VA Medical Center, both in Houston, emphasized that they were not endorsing any of the three recommended P2Y12 receptor inhibitors over the other for the treatment of UA/NSTEMI. Dr. Jneid and his colleagues cautioned that despite their being given equal footing in the ACCF/AHA guidelines, the agents were not interchangeable, and that their use in clinical practice "should carefully follow how they were tested."
Dr. Eric M. Bates, a cardiologist at the University of Michigan in Ann Arbor, said in an interview that the newer agents "are both more powerful than clopidogrel, and should both probably be avoided in patients with a history of [transient ischemic attack] or stroke. In patients over 75 in general you might want to go with the gentler clopidogrel. You may have a price to pay for more potent antiplatelet therapy."
As in previous guidelines issued by the AHA and ACCF, aspirin is recommended for all UA/NSTEMI patients immediately upon hospitalization, continuing as long as it is tolerated. Patients selected to undergo invasive procedures should receive dual therapy with aspirin and clopidogrel, ticagrelor, eptifibatide, or tirofiban before the procedure; prasugrel may be administered upon PCI. Ticagrelor and clopidogrel are appropriate both for patients receiving medical therapy alone and for those undergoing PCI. Patients who cannot tolerate aspirin may receive monotherapy with clopidogrel, prasugrel (in PCI-treated patients), or ticagrelor.
The new guidelines recommend that patients undergoing medical treatment continue receiving aspirin immediately and clopidogrel or ticagrelor as soon as possible after hospitalization, continuing for up to 12 months, while aspirin should be continued indefinitely. The 2011 guidelines had recommended that the antiplatelet therapy be continued for at least a year.
Another change from previous guidelines concerned patients on warfarin: "Targeting oral anticoagulant therapy to a lower INR (e.g., 2.0 to 2.5) might be reasonable in patients with UA/NSTEMI managed with aspirin and a P2Y12 inhibitor," the investigators wrote.
In a comment on the new guidelines published by the AHA, Dr. Elliott Antman of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, praised their detailed dosing recommendations for both anticoagulant and antiplatelet therapy, and called the committee’s unwillingness to recommend one agent over another as "quite reasonable, since prasugrel and ticagrelor have only been compared to clopidogrel and not to each other and were studied in different populations."
However, Dr. Antman also referred to a May 2012 editorial cautioning that there was "no safe ground" to treat patients with a previous stroke or transient ischemic attack with the newer agents (Circulation 2012;125:2821-23). "Clinicians should also note that the secondary prevention guidelines for management of patients with stroke recommend against prescribing the combination of aspirin with clopidogrel unless there are compelling cardiovascular indications," Dr. Antman wrote.
Dr. Jneid declared no conflicts of interest related to the guidelines; however, 7 of the 15 members of the guidelines writing committee disclosed relationships with pharmaceutical companies including AstraZeneca, Eli Lilly, and Bristol-Myers Squibb/Sanofi, the manufacturers, respectively, of ticagrelor, prasugrel, and clopidogrel. Dr. Bates disclosed having served as an adviser to all three companies, and Dr. Antman disclosed having received support from these companies.