In patients with acute coronary syndromes (ACS) scheduled to undergo an invasive management strategy, the reversible P2Y₁₂ receptor inhibitor ticagrelor is superior to clopidogrel, reducing cardiovascular and all-cause mortality without increasing bleeding risk, according to findings from a substudy of the randomized PLATO trial published online January 13, 2010, ahead of print in the Lancet.

Initial results from the PLATO (PLATelet inhibition and patient Outcomes) subanalysis were first presented Friday, September 25, 2009, at the annual Transcatheter Cardiovascular Therapeutics symposium in San Francisco, CA.

For the study, investigators led by Christopher P. Cannon, MD, of Brigham and Women’s Hospital (Boston, MA), randomized 13,408 ACS patients for whom an invasive strategy was planned to antithrombotic therapy with ticagrelor (180-mg loading dose followed by 90 mg twice daily; n = 6,732) plus placebo or clopidogrel (300-mg loading dose followed by 75 mg daily; n = 6,676) plus placebo for 6 to 12 months. All patients also received 75 to 100 mg of aspirin daily.

The primary efficacy endpoint, a composite of cardiovascular death, MI, or stroke, was reduced by 16% in the ticagrelor group vs. the clopidogrel group. Moreover, all-cause mortality was 20% lower among those receiving ticagrelor. There was no difference between the 2 groups with respect to the primary safety endpoint of total major bleeding or GUSTO-defined severe bleeding (table 1).

Table 1. One-Year Outcomes in ACS Patients with Planned Intervention: Ticagrelor vs. Clopidogrel

^a Composite of cardiovascular death, MI, or stroke.
Abbreviation: ACS, acute coronary syndromes.

In addition, at 360 days the risk of definite stent thrombosis was lower with ticagrelor compared with clopidogrel (1.3% vs. 2.0%; P = 0.005). A similar advantage for ticagrelor was found even when compared with patients who received a ≥ 600-mg loading dose of clopidogrel.

Episodes of dyspnea were more common among the ticagrelor group than the clopidogrel group (13.9% vs. 8.0%; P < 0.0001), although less than 1% of patients discontinued the study drug because of this adverse effect.

A New Standard Emerges

“The mortality reduction is a key step forward,” Dr. Cannon told TCTMD in an e-mail correspondence. “Even compared with what many people think is the optimal loading dose of clopidogrel [600 mg], all the benefits were seen [with ticagrelor]. There was [also] no increase in bleeding overall . . . . This could become potentially the new standard of care.”

Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), agreed. “These compelling results support ticagrelor as a new standard of care in acute coronary syndromes,” he writes in an accompanying comment. “However, a personalized approach to drug selection should be used wherein each patient’s individualized risk of ischemia versus bleeding is considered. Clopidogrel might still be appropriate for selected patients who are at relatively low risk of myocardial infarction or stent thrombosis and/or high risk of major bleeding, and/or for whom non-compliance with ticagrelor because of cost or other considerations (eg, twice daily dosing) is a concern.”

Study Details

Of the total cohort, 49.1% had STEMI and 50.9% had non-STEMI, unstable angina, or other ACS. The 2 groups were well matched for baseline characteristics.

Patients started the study drug at a median 8.9 hours after the onset of chest pain. Those who had received a loading dose of clopidogrel before randomization or who had been taking either drug 5 days or more before randomization may not have received the loading dose of clopidogrel.

Patients undergoing PCI more than 24 hours after randomization were additionally given 90 mg of ticagrelor (or a placebo if they were in the clopidogrel group). Those undergoing PCI at any time could be given, at the discretion of the investigator, an additional loading dose of 300 mg of clopidogrel (or placebo if they were in the tricagrelor group).

Note: Dr. Stone is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

2. Stone GW. Ticagrelor in ACS: Redefining a new standard of care? Lancet. 2010;Epub ahead of print.

Disclosures:

• The PLATO trial was supported by AstraZeneca.
• Dr. Cannon reports receiving research or grant support from Accumetrics, AstraZeneca, Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Merck, Intekrin Therapeutics, Novartis, and Takeda, and owning equity in Automedics Medical Systems.
• Dr. Stone reports receiving honoraria from BMS-Sanofi and AstraZeneca and serving on advisory boards for Boston Scientific and Abbott Vascular.

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