CHAMPION: Negative Trials But Some Positive Angles for Cangrelor?

November 15, 2009

November 15, 2009 (Orlando, Florida) Full results of the CHAMPION-PCI and CHAMPION-PLATFORM trials, showing no clear benefit of the new intravenous P2Y12 platelet inhibitor cangrelor (the Medicines Company) over clopidogrel 600 mg in ACS patients scheduled for PCI, were presented today at the American Heart Association 2009 Scientific Sessions. They were also published online November 15, 2009 in the New England Journal of Medicine [1,2]

The two trials were stopped prematurely earlier this year, as reported by heartwire , after an interim analysis indicated that they would be unlikely to show benefit for the primary end point.

Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA), who was involved in both CHAMPION studies, told heartwire that while the primary end point was not significant in either trial, noninferiority of cangrelor to clopidogrel was shown, and cangrelor does have some practical advantages. "An IV agent would be useful in patients who have difficulty taking tablets, such as those who are intubated or those who are nauseous. Cangrelor also has the advantage of being reversible, which would be beneficial if the patient were subsequently taken to surgery," he said.

If we redid the trial with a better MI definition, I think we would have shown a better result.

Bhatt also noted that exploratory analyses of the two studies have suggested that the primary end point used may not have been the best to capture the advantages of cangrelor, with specific issues regarding biomarker-diagnosed periprocedural MIs. "We included these in the composite end point to increase event rates, but there has always been controversy about how to define them. I don't think we used the best definition of these MIs for our population, and as a result we saw a lot of confounding from patients with positive biomarkers at baseline. If we redid the trial with a better MI definition, I think we would have shown a better result."

Give Antiplatelet Before PCI

Bhatt also pointed out some "interesting messages" that could be gleaned from comparing the results of the two trials and their designs. These included the strong suggestion that it is beneficial to give antiplatelet therapy before PCI or at the time of PCI rather than waiting until the procedure is completed.

The two trials were similar in that they both included predominantly ACS patients for whom a strategy of deferred ADP-receptor blockade had been chosen (ie, the drugs were given after diagnostic angiography had established the indication for PCI). They differed, however, in the timing of clopidogrel administration.

In the CHAMPION-PCI trial, patients were randomized to cangrelor infusion (started within 30 minutes before PCI and continued for two hours) or clopidogrel 600 mg orally, again given within 30 minutes before PCI. After the infusion, patients in the cangrelor group were then given clopidogrel 600 mg, and patients who had already received clopidogrel were given placebo tablets.

In the CHAMPION-PLATFORM trial, the same two-hour cangrelor infusion was compared with a placebo infusion. All patients then received 600 mg of clopidogrel. In the cangrelor group, clopidogrel was given at the end of the infusion, and in the placebo group, clopidogrel was given at the end of the PCI procedure.

Bhatt commented to heartwire : "CHAMPION-PCI was testing cangrelor vs clopidogrel with both being given up front, whereas CHAMPION-PLATFORM was testing cangrelor up front vs delayed clopidogrel."

There were significant reductions in death and stent thrombosis in the cangrelor group . . . that I believe are real.

Although both trials failed to show a significant benefit of cangrelor on the primary end point (all-cause death/MI/ischemia-driven revascularization at 48 hours), Bhatt noted that there was a "more robust" effect of cangrelor on secondary end points in the CHAMPION-PLATFORM trial, where the new IV drug was being compared with placebo up front, than in the CHAMPION-PCI, where it was pitted against clopidogrel up front. "Although these observations must be thought of as hypothesis-generating, there were significant reductions in death and stent thrombosis in the cangrelor group vs the placebo group in CHAMPION-PLATFORM that I believe are real. This strongly supports the strategy of earlier antiplatelet therapy. It confirms that such therapy should be given before the procedure rather than after."

Asked if anyone was still actually waiting until after PCI to give antiplatelet agents, Bhatt said he believed some people were. "If you ask the experts, they will all tell you to give antiplatelet therapy up front before the PCI procedure. But if you look at what is actually going on, many interventionalists are giving clopidogrel after the procedure, even now in 2009, in ACS patients. This is probably just for practical reasons--the patient is flat on his back in the cath lab or may be sedated and groggy, so it is difficult to give pills at the beginning. But for me, the CHAMPION-PLATFORM trial reinforces that we need to get the antiplatelet therapy on board as soon as possible."

CHAMPION-PCI Results

The PLATFORM-PCI trial enrolled 8877 patients, 8716 of whom underwent PCI. Cangrelor was not superior to clopidogrel with respect to the primary end point. The rate of major bleeding (ACUITY definition) was higher with cangrelor, a difference that approached significance, but this was not the case for TIMI major bleeding or GUSTO severe or life-threatening bleeding. However, minor bleeding was increased with cangrelor.

CHAMPION-PCI: Major Results at 48 Hours

Outcome Cangrelor, n=3889 (%) Clopidogrel, n=3865 (%) Odds ratio (95% CI) p
Death/MI/ischemia-driven revascularization* 7.5 7.1 1.05 (0.88–1.24) 0.59
Major bleeding, ACUITY criteria 3.6 2.9 1.26 (0.99–1.60) 0.06
Major bleeding, TIMI criteria 0.4 0.3 1.36 (0.68–2.17) 0.39
Severe or life-threatening bleeding, GUSTO criteria 0.2 0.3 0.91 (0.39–2.14) 0.82
*Primary end point

The CHAMPION-PCI authors, led by Dr Robert Harrington (Duke University, Durham, NC), say the findings that cangrelor was not superior to clopidogrel were unexpected, especially since higher levels of periprocedural platelet inhibition were achieved with cangrelor. They say that these results raise questions about using biomarker-defined MI as an end point in this population, pointing out that an exploratory analysis on the composite end point of death/Q-wave MI/ischemia-driven revascularization showed an odds ratio of 0.66 in favor of cangrelor (although this was still not quite significant). They conclude that further clinical investigation of cangrelor may be worthwhile.

CHAMPION-PLATFORM results

The CHAMPION-PLATFORM trial enrolled 5362 patients. There was no significant difference in the primary end point between the cangrelor and placebo groups. However, two prespecified end points--stent thrombosis and death--were significantly reduced in the cangrelor group. There was no significant difference in transfusions between the two groups, but major bleeding was increased on one scale, which was accounted for by an increase in groin hematomas.

CHAMPION-PLATFORM: Major Results at 48 Hours

Outcome Cangrelor, n=2654 (%) Placebo, n=2641 Odds ratio (95% CI) p
Death/MI/ischemia-driven revascularization* 7.0 8.0 0.87 (0.71–1.07) 0.17
Death 0.2 0.7 0.33 (0.13–0.83) 0.02
Stent thrombosis 0.2 0.6 0.31 (0.11–0.85) 0.02
Major bleeding, ACUITY criteria 5.5 3.5 1.61 (1.23–2.10) <0.001
Major bleeding, TIMI criteria 0.2 0.3 0.44 (0.14–1.44) 0.17
Severe or life-threatening bleeding, GUSTO criteria 0.3 0.2 1.50 (0.53–4.21) 0.45
*Primary end point

The CHAMPION-PLATFORM authors, led by Bhatt, also raise the issue of periprocedural MIs not being the best end point in this population. Bhatt commented to heartwire : "With the benefit of hindsight, I don't think we used the best definition of periprocedural MI. When we analyzed the results according to troponin status, we saw a significant benefit on the primary end point in the troponin-negative patients, but not in the troponin-positive patients. This is the opposite of what we would expect, and we think we got these results because in the troponin-negative patients there was no issue of biomarker status confounding the diagnosis of periprocedural MI. So we believe cangrelor is reducing these MIs, but we just couldn't see it because it was being confounded by positive biomarkers at baseline."

Should Compare With Upstream Clopidogrel

In an accompanying editorial [3], Drs Adnan Kastrati and Gjin Ndrepepa (Deutsches Herzzentrum, Munich, Germany) point out that many operators now give clopidogrel upstream--before diagnostic angiography--and that a better design may have been to compare this strategy with IV cangrelor started after angiography. "Used in this way, cangrelor may eliminate the excess risk of bleeding associated with clopidogrel in the 30% to 40% of patients for whom PCI is deemed to be unsuitable, especially in those requiring urgent CABG, while providing rapid, potent platelet inhibition in those proceeding to PCI," they say.

They also suggest that a longer infusion duration of cangrelor, with a gradual reduction in the dose, may provide longer protection and a smoother transition to an oral agent. They conclude: "Cangrelor is a potent intravenous ADP-receptor antagonist, with a rapid onset and offset of action. These valuable qualities certainly warrant further study aimed at identifying more suitable niches for cangrelor and more appropriate approaches to its use."

The CHAMPION trials were sponsored by the Medicines Company. Bhatt has received grant support and travel expenses from the Medicines Company.

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