乌鸦传媒

BARCELONA -- In a head-to-head trial with clopidogrel (Plavix) -- currently the standard treatment for acute coronary syndrome -- an investigational oral, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 was associated with fewer strokes, heart attacks, and cardiovascular deaths, researchers here said.

Some 9.8% of patients randomized to the new antiplatelet drug ticagrelor (Brilinta) reached the composite endpoint of cardiovascular death, stroke, or myocardial infarction versus 11.7% of those randomized to clopidogrel. That was a relative reduction of 16% (P<0.001), according to Lars Wallentin, MD, PhD, of Uppsala Clinical Research Center in Uppsala, Sweden.

Wallentin reported results of the PLATO study (Study of Platelet Inhibition and Patient Outcomes) today at the European Society of Cardiology meeting here. The findings were simultaneously published online by the New England Journal of Medicine.

In terms of the combined endpoint, for every 1,000 patients admitted to the hospital because of an ACS event, 12 months of therapy with ticagrelor instead of clopidogrel was associated with 14 fewer deaths, or 11 fewer MI's, or eight fewer cases of stent thrombosis, without an increase in major bleeds, Wallentin said at an ESC press conference today.

"This is the first antiplatelet to achieve a benefit in cardiovascular mortality compared with clopidogrel," he added.

Moreover, with ticagrelor "the reduction in risk of cardiovascular events appears early and the benefit over clopidogrel grows with time," he said.

"The mortality benefit is rock solid, and that's the big one," said Christopher Cannon, MD, of Brigham and Women's Hospital in Boston, who is a PLATO investigator.

There were no significant differences in the overall rate of major bleeding between ticagrelor and clopidogrel. However, ticagrelor was associated with a higher rate of intracranial bleeding and other major bleeding events not related to coronary artery bypass graft surgery (4.5% versus 3.8%, P=0.03).

The multicenter, double-blind study randomized 18,624 ACS patients to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300 to 600 mg loading dose, 75 mg thereafter). Patients were followed for 12 months.

If ticagrelor wins FDA approval, it will be the third P2Y12-inhibitor to enter the market. The absence of an overall increase in bleeding risk compared with clopidogrel could make the drug especially attractive, said Clyde Yancy, MD, President of the American Heart Association.

Yancy noted that prasugrel (Effient), which won FDA approval last month, reduced death, MI, and stroke by 19% compared with clopidogrel in the pivotal TRITON-TIMI 38 trial. But major bleeding events occurred in 2.4% of prasugrel patients, compared with 1.8% of those in the clopidogrel arm. (See FDA Approves New Antiplatelet for Angioplasty Patients)

Elliott M. Antman, MD, of Brigham and Women's Hospital in Boston and lead investigator of the 13,608-patient TRITON-TIMI 38 trial, said he was pleased that another trial had demonstrated that use of a more potent antiplatelet was associated with a better outcome just as was the case with prasugrel.

Antman said that ticagrelor, if approved by the FDA, was likely to become one of three options rather than the standard of care.

Moreover, Antman said "cost is likely to play into this -- prasugrel costs $5 a pill, clopidogrel costs $3 a pill, but you need eight pills." He said he didn't know how much ticagrelor would cost, but "they have to recoup the cost of development." The figure being batted about the ESC hallways was $5 to $7 a pill or $10 to $14 a day.

In an editorial also published online by NEJM, Albert Schornig, MD, of Deutsches Herzzentrum in Munich, wrote that unlike prasugrel, ticagrelor demonstrated a reduction of 22% in overall mortality risk compared with clopidogrel (4.5% versus 5.9%, P<0.001).

Ticagrelor may also have an edge over clopidogrel and prasugrel because its antiplatelet action can be switched on and off relatively quickly.

If approved, Yancy said, ticagrelor may be the drug of choice for patients who require dual antiplatelet therapy for ACS but who also need surgery for another indication. "One could conceivably put such a patient on a fast-acting P2Y12 inhibitor like ticagrelor," he said.

He said that ticagrelor also "almost totally bypasses the liver," but patients randomized to ticagrelor were also more likely to experience slight increases in creatinine and uric acid than controls. And dyspnea was more common among patients in the ticagrelor group.

W. Douglas Weaver, MD, immediate past president of the American College of Cardiology, predicted that the drug -- if approved -- could challenge clopidogrel's dominant position.

Weaver, who is head of cardiovascular medicine and director of the Henry Ford Cardiovascular Institute at the Henry Ford Health System in Detroit, was not involved in the study.