March 17, 2010 (Atlanta, Georgia) — ACS patients in the PLATO trial who received the investigational antiplatelet agent ticagrelor (AstraZeneca) and then underwent CABG were 50% less likely to die that those who received clopidogrel. But this difference in mortality was not explained by bleeding events, which were similar between the two drug arms, so the findings are somewhat mystifying, researchers said at American College of Cardiology 2010 Scientific Sessions today.

Dr Claes Held (Uppsala Clinical Research Center, Sweden) presented the new results during a late-breaking clinical-trials session. During a discussion afterward, Dr Gregg Stone (Columbia University Medical Center, New York) said: "I'm on record as being very impressed with the overall results of PLATO, and while I'm not bothered by these results, I don't understand them. We didn't see a major difference in bleeding, we didn't see a major difference in reinfarction, but we saw a difference in survival--help me understand this."

And in the press conference on the late-breaking trials, moderator Dr David Holmes (Mayo Clinic, Rochester, MN) had similar concerns: "There wasn't any difference in major bleeding and yet the results were better in terms of a reduction in mortality [with ticagrelor]."

Held admitted he was as flummoxed as everyone else, telling heartwire : "We are a bit puzzled, because there is a substantial reduction in death [with ticagrelor], and yet we don't see any effect on the bleeding, so we are trying to understand the mechanism. We don't have the answers. So we are reanalyzing the causes of death in more detail, by vascular and nonvascular categories, to see what these patients died from."

New Analysis Is Retrospective and Nonrandomized

In the overall PLATO trial, first reported at European Society of Cardiology Conference last year, 18 624 patients with ACS, with or without ST-segment elevation, were randomized to receive either ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg thereafter) for one year. Patients also received aspirin, at a dose of 75 mg to 100 mg day, unless they could not tolerate the drug. At 12 months, the primary end point--a composite of death from vascular causes, MI, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those taking clopidogrel (hazard ratio 0.84; p<0.001). Predefined secondary end points were also significantly reduced with ticagrelor as compared with clopidogrel, such as MI and death from vascular causes.

The new PLATO analysis, which was predefined, was intended to evaluate the efficacy and safety of ticagrelor in comparison with clopidogrel after CABG, in patients with last intake of study drug within seven days of surgery. Held explained that recovery of platelet function only occurs five to seven days after the cessation of clopidogrel and aspirin, but the clinical reality is that patients often require surgery sooner than this, which can increase the risk of complications such as bleeding. But the reversible inhibition and rapid offset of action provided by ticagrelor could shorten this interval to two to three days.

Although this was by nature "a retrospective, nonrandomized comparison," Held said the baseline characteristics of the two groups were similar.

Nevertheless, in this new analysis, there was no difference in the composite primary end point between the two study arms or in the rates of MI or stroke. But death was mysteriously reduced by 50%, despite the absence of any difference in bleeding between the clopidogrel and ticagrelor arms.

Post CABG Primary and Secondary End Points in CABG PLATO*

Outcome Ticagrelor, n=631 (%) Clopidogrel, n=629 (%) Hazard ratio p
Primary end point        
CV death, MI, and stroke 10.5 12.6 0.84 0.29
Secondary end points        
MI 5.9 5.6 1.06 0.82
CV death 4.0 7.5 0.52 0.009
Stroke 2.1 1.7 1.17 0.70
All-cause mortality 4.6 9.2 0.49 0.002
Non-CV death 0.6 1.7 0.35 0.07

* Patients could have had more than one end point

Are There Pleiotropic Effects of Ticagrelor?

In PLATO overall, ticagrelor was in fact associated with a 25% higher rate of major bleeding not related to CABG than clopidogrel (4.5% vs 3.8%; p=0.03). Commentators at the time said it was reassuring that overall bleeding was not increased but wondered why there was an increase in non–procedure-related bleeding. They were also curious as to why a reversible agent like ticagrelor did not actually lower bleeding in CABG surgery.

But lead investigator of PLATO, Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), said then: "One way of looking at it is that patients [on ticagrelor] tolerated a more intense platelet inhibition without an increase in bleeding."

Stone wondered whether, in the new CABG analysis, Held et al had looked at bleeding "as a function of when the drug was discontinued before surgery." Held replied that there did seem to be "somewhat of an association between the last intake of study drug and the difference in mortality--although it was not significant--so some of the difference might depend on when you stop the study drug, but we don't quite understand the mechanisms here."

Holmes said: "Are there other effects? Ticagrelor is a more potent agent, and a more potent agent should give you more bleeding, but this didn't--are there pleiotropic effects of this specific medication?"

He added: "It is too early to say that, but it's certainly very intriguing."

The PLATO trial was funded by AstraZeneca. Held discloses research grants/support from AstraZeneca, GlaxoSmithKline, Schering-Plough, Sanofi-Aventis, Pfizer, and Bristol-Myers Squibb.


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