Cangrelor Cuts Complications at PCI vs Clopidogrel in CHAMPION-PHOENIX; Bleeding a Caution

March 10, 2013

SAN FRANCISCO, California — It was a battle between two ADP-receptor blockers as well as between IV and oral antiplatelet therapy at coronary interventions: a >11 000-patient randomized trial found that intravenous cangrelor (the Medicines Company) cut the risk of periprocedural complications at all kinds of PCI compared with taking a pill of clopidogrel, long a mainstay of such procedures [1].

The newer agent's benefit of a 22% drop in a composite efficacy end point was driven by reductions in MI and stent thrombosis and was not associated with an increase in bleeding complications as they were prospectively defined.

There were cautions, however, when bleeding complications were defined using other accepted criteria: some kinds of bleeding were more common with cangrelor.

Dr Robert Harrington

"And that to us seemed to strike a nice balance," Dr Robert Harrington (Stanford University, CA), co–principal investigator for the CHAMPION-PHOENIX trial. "You see a bleeding effect suggesting that the drug is in fact a more potent antithrombotic than the comparator, but yet you're not seeing the kind of bad bleeding that would be worrisome when adding another drug into the medical regimen," he said to heartwire .

Dr Deepak L Bhatt

"Intravenous cangrelor when compared with oral clopidogrel appears to be a better strategy for ADP blockade at the time of PCI," he said. "Whether or not it is better than [other ADP-receptor blockers] like prasugrel [Effient, Lilly/Daiichi-Sanyo] or ticagrelor [Brilinta, AstraZeneca] and how it will fit into a strategy where those drugs are increasingly used need more study, for sure."

CHAMPION-PHOENIX is published online today in the New England Journal of Medicine, with first author Dr Deepak L Bhatt (VA Boston Healthcare System and Brigham and Women's Hospital, MA), to coincide with co–principal investigator Bhatt's presentation of the trial here at the American College of Cardiology 2013 Scientific Sessions .

The trial's primary result had been disclosed by the Medicines Company in January in a cursory announcement aimed at investors and was reported by heartwire at the time. According to Bhatt et al, CHAMPION-PHOENIX was launched after the earlier phase 3 CHAMPION PCI and CHAMPION PLATFORM trials, led by many of the same investigators, saw no benefits from the agent vs clopidogrel in their primary efficacy end points but did show advantages for some important secondary end points, such as stent thrombosis, without raising the bleeding risk.

The antiplatelet effects of IV cangrelor are fast acting and rapidly reversible on withdrawal; the drug has a plasma half-life of three to five minutes, Bhatt et al observe in their report.

Observing that the trial was in part a comparison of two treatment strategies, Harrington said, "There's no question that intravenous administration of cangrelor provides a more predictable level of platelet inhibition than you see with the oral administration of clopidogrel."

"Clear-Cut Superiority"

At a briefing on the trial for the media, Bhatt said CHAMPION-PHOENIX "demonstrates clear-cut superiority and consistency of benefit in all the major subgroups that a doctor might worry about." But beyond that, he said, cangrelor's short-acting nature affords flexibility to initiate and rapidly stop ADP inhibition, in case, for example, the patient requires surgery or develops bleeding complications.

In contrast, after withdrawal of clopidogrel, a patient might have to wait days in the hospital before surgery while ADP inhibition tapers off. "Potentially, with the use of cangrelor, that uncomfortable situation disappears," Bhatt said.

Accompanying Bhatt at the press briefing were several well-known interventional cardiologists who spoke in glowing terms about changes to their practice should cangrelor be approved in the US.

Dr Cindy L Grines

"The great thing about this study is that it incorporated patients with STEMI and with unstable angina, as well as elective cases. Now, we don't have very many antiplatelet studies in elective cases," said Dr Cindy L Grines (Detroit Medical Center, MI).

And "it shows us that we do not necessarily have to pretreat these patients [with an ADP blocker]. But once they get in the lab, we can give them a very rapidly acting medication with rapid onset of action." That's likely to reduce the risk of stent thrombosis and intraprocedural MI.

In the event of bleeding complications, she added, "we might want to turn the infusion off and have [ADP inhibition] go away within a few minutes. There's no other agent out there that will allow us to do that."

And Dr Martin Leon (Columbia University, New York, NY) said, "I think it's an incredible study. I think that it has global implications in terms of how we treat patients with PCI. The generalizability to the full spectrum of PCI patients is most striking to me. The idea of not having to pretreat patients is extremely appealing. And the rapid on-and-off sequence, I think, deals with a lot of clinical scenarios that we face all the time. It gives us better control over potential bleeding complications in patients, and it opens new flexibility in terms of leaving these patients open to rapid surgery. So I think it’s a strikingly important study."

Cangrelor will likely cost more, probably a lot more, than clopidogrel, so Leon was circumspect about a universal recommendation to use the IV agent routinely in the lab. "I think this can be globally applied, but the cost implications may need to be considered, in certain healthcare systems, for more selective use."

Cangrelor in All PCI Comers

CHAMPION-PHOENIX randomized 11 145 patients undergoing urgent or elective PCI in double-blind fashion to receive cangrelor in a bolus plus infusion or a 600-mg or 300-mg loading dose of clopidogrel. Patients had been slated for PCI for stable CAD, ST-segment-elevation MI (STEMI), or non-STEMI (NSTEMI). Cangrelor was given as 30 µg/kg followed by an infusion of 4 µg/kg/min for at least two hours.

Efficacy Outcomes at 48 Hours After Randomization, Cangrelor vs Clopidogrel

End points HR (95% CI) p
Primary efficacy end point* 0.78 (0.66–0.93) 0.005
Stent thrombosis 0.62 (0.43–0.90) 0.01
MI 0.80 (0.67–0.97) 0.02

*All-cause mortality, MI, ischemia-driven revascularization, stent thrombosis

A subgroup analysis found few significant differences in efficacy outcomes compared with the primary analysis. "There was consistency across the multiple subgroups, which to me strengthens and supports the overall result," Harrington said. "You like to see consistency in these big trials, and I think we see that here."

Whether cangrelor has an effect on bleeding risk depends on how bleeding is defined, he said. Defined according to the GUSTO criteria used for the primary safety end point, bleeding didn't differ significantly between the two treatment arms. "But when you go with more sensitive measures of bleeding, like ACUITY [criteria], there was more bleeding with cangrelor than with clopidogrel," Harrington said.

Bleeding Complications by Different Bleeding Criteria, Cangrelor vs Clopidogrel

Bleeding complication HR (95% CI) p
GUSTO criteria*    
Severe non-CABG bleeding 1.50 (0.53–4.22) 0.44
Severe or moderate bleeding 1.63 (0.92–2.90) 0.09
TIMI criteria    
Major bleeding 1.00 (0.29–3.45) >0.999
Minor bleeding 3.00 (0.81–11.10) 0.08
ACUITY criteria    
Major bleeding 1.72 (1.39–2.13) <0.001
Minor bleeding 1.42 (1.26–1.61) <0.001

*Primary safety end point

The antiplatelet effects of IV cangrelor are fast acting and rapidly reversible on withdrawal; the drug has a plasma half-life of three to five minutes, Bhatt et al observe in their report. That can allow a level of control not generally possible with a slower-acting oral agent.

Observing that the trial was in part a comparison of two treatment strategies, Harrington said, "There's no question that intravenous administration of cangrelor provides a more predictable level of platelet inhibition than you see with the oral administration of clopidogrel."

In an accompanying editorial that strikes a more conservative tone about the contemporary relevance of cangrelor to PCI than offered by the press briefing[2], Drs Richard A Lange and L David Hillis (University of Texas Health Sciences Center at San Antonio) ask, "Where does cangrelor fit in the armamentarium of dual antiplatelet therapy? Unfortunately, the study by Bhatt et al does not answer this question definitively."

Among the reasons: cangrelor's full antiplatelet effects were "operative before and during PCI. This was not true in the case of the patients treated with clopidogrel," 37% of whom received the drug "during or after PCI." Also, many patients received clopidogrel at 300 mg, "which is inferior to a dose of 600 mg in achieving platelet inhibition and preventing periprocedural ischemic events."

While some patients going to PCI would benefit from an IV ADP-receptor blocker such as cangrelor, write Lange and Hillis, "the routine use of this therapy for all patients undergoing PCI is not yet justified."

CHAMPION-PHOENIX was supported by the Medicines Company. Harrington discloses receiving grants for his institution, travel expenses, and fees for participation in review activities from the Medicines Company; having grants or grants pending for his institution from Eli Lilly, Sanofi, Daiichi Sankyo, GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, Johnson & Johnson, Portola, and Merck; and receiving consulting fees from Eli Lilly, Sanofi, Daiichi Sankyo, Bristol-Myers Squibb, Merck, Johnson & Johnson, Portola, Gilead, and WebMD. Bhatt discloses receiving honoraria from the American College of Cardiology, Duke Clinical Research Institute, Slack Publications, and WebMD; receiving research grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi, and the Medicines Company. Disclosures for the other authors are provided by the journal at www.nejm.org .

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