CHAMPION Pooled: Cangrelor Cuts Thrombotic Events During PCI

Shelley Wood

September 06, 2013

AMSTERDAM, THE NETHERLANDS — A pooled analysis of three pivotal CHAMPION trials suggests that cangrelor (the Medicines Company) can reduce the risk of periprocedural thrombotic complications during PCI compared with placebo or clopidogrel, at the expense of some mild bleeding[1].

Results of the patient-level analysis were presented earlier this week at the European Society of Cardiology (ESC) 2013 Congress and published concurrently September 3, 2013 in the Lancet. The study combines data from CHAMPION-PCI , CHAMPION-PLATFORM , and CHAMPION-PHOENIX and therefore represented the "totality of evidence regarding clinical outcomes after use of cangrelor for PCI," the authors, led by Dr Gabriel Steg (Hôpital Bichat, Paris, France), note.

The FDA accepted the manufacturer's new drug application (NDA) for cangrelor in July 2013.

The plan of pooling these three trials was prespecified before the third trial, CHAMPION PHOENIX, was started. As previously reported, two of the three studies (CHAMPION-PCI and CHAMPION-PLATFORM) were negative trials. Of note, the "universal definition of MI,' " published in 2007, was used in PHOENIX but retrospectively applied to the two previous trials for the purposes of the pooled analysis.

Pooled and Positive

Combined, the three trials included patients with STEMI, non-STEMI, and stable coronary disease randomized to either cangrelor or control (either clopidogrel or placebo). The primary outcome, a combination of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours, was significantly lower in the cangrelor-treated patients compared with clopidogrel or placebo--an absolute difference of 1.9% and a relative risk reduction of 19%. Stent thrombosis was also reduced in the cangrelor-treated group--an absolute difference of 0.3% and a relative risk reduction of 41%. And while the primary safety outcome--non-CABG-related GUSTO moderate bleeding or transfusions--was not significant between the groups, the rate of GUSTO mild bleeding was higher in the cangrelor-treated patients.

End point Cangrelor, n=12 475 (%) Clopidogrel, n=12 435 (%) Odds ratio p
Primary end point* 3.8 4.7 0.81 0.0007
Stent thrombosis 0.5 0.8 0.59 0.0008
Severe/life threatening GUSTO bleeding 0.2 0.2 1.22 NS
Moderate GUSTO bleeding 0.6 0.4 1.36 NS
Mild GUSTO bleeding 16.8 13 1.39 <0.0001

*Death/MI/ischemia-driven revascularization/stent thrombosis at 48 hours

Asked just how "mild" these bleeds were, senior author Dr Bob Harrington (Stanford University, CA) told heartwire : "The trade-off was in the range of what is accepted in other areas of acute-care cardiology and [would have a] worthwhile public-health impact given the large number of PCIs performed."

Using the TIMI bleeding definitions, investigators saw a similar pattern, but with ACUITY bleeding definitions, both major and minor bleeds were significantly higher in the cangrelor group.

Both the benefits and risks of the therapy were consistent across different subgroups, the authors note.

Cost data, Harrington added, "still need analysis."

A Circuitous Course

In an accompanying editorial, Dr Shamir Mehta (McMaster University, Hamilton, CA) pointed out that cangrelor "has taken a circuitous course" in the direction of market approval, particularly since two of the three pivotal trials that make up the key data set for the NDA filing showed no significant reductions in periprocedural ischemic events, yet the sponsor pressed on[2]. Combined, concedes Mehta, the results that "show that cangrelor is indeed an effective antiplatelet drug that reduces periprocedural ischemic events . . . including stent thrombosis and myocardial infarction."

Unlike clopidogrel, cangrelor produces "almost-immediate" platelet inhibition, Mehta notes, and unlike the other, newer antiplatelets, ticagrelor (Brilinta, AstraZeneca) and prasugrel (Effient, Lilly/Daiichi-Sanyo), as well as clopidogrel, cangrelor is intravenously administered and has a very short biological half-life of three to six minutes, "with normalization of platelet function within one hour."

Like ticagrelor, he notes, cangrelor is reversible.

At issue, however, is whether this new analysis, while positive for cangrelor, is enough to convince 'physicians and regulators that the drug will measure up against currently approved agents used in PCI. There are no studies comparing cangrelor against the newer drugs, ticagrelor and prasugrel, or against clopidogrel when a 600-mg preloading dose is used (only a minority of patients received this in the CHAMPION trials).

That said, Mehta continues, he doesn't rule out the possibility of "several clinical situations where cangrelor could have a major role." Among them: in high-risk STEMI, in patients with nausea/vomiting, in intubated patients, and in patients in cardiogenic shock.

Other potential scenarios include high-risk non-STEMI, where early intervention is warranted; centers where clopidogrel pretreatment is not routine, and patients with high-risk anatomic or clinical features "undergoing same-sitting or ad hoc elective PCI" for stable CAD.

"Somewhat surprisingly, neither ticagrelor nor prasugrel has been formally studied in this large group of patients," Mehta notes.

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