FDA Panel Backs Cangrelor for Use in PCI

Cangrelor, a novel P2Y12 inhibitor given intravenously, has been endorsed by an FDA advisory committee for use in PCI—specifically for patients in whom an oral P2Y12 inhibitor was not used before the procedure and is not feasible or desirable during PCI. The decision, on April 15, 2015, comes after the drug was rejected by the same panel in February 2014 and later failed to gain the agency’s approval.

Members of the Cardiovascular and Renal Drugs Advisory Committee voted 9 to 2 in favor, with 1 abstention.

Comments from some panel members who sided in favor of cangrelor, however, belied the apparent overwhelming support indicated by the vote. Their primary concern centered on the relatively small advantage for cangrelor when weighing the benefits and risks.Take Home: Some panel members express concern about small benefit-to-risk margin

Panelist James A. de Lemos, MD, of the University of Texas Southwestern Medical Center (Dallas, TX), who switched his vote from no last year to yes this time around, said during the meeting that the benefits “barely” outweigh the risks. Although it is likely there are subgroups of patients who would derive a greater benefit from cangrelor, he said, “if it is used broadly and indiscriminately, it will not only be expensive but will expose low-risk patients to unnecessary bleeding, some of which, as we’ve seen, can be quite substantial.”

Thus, if cangrelor is ultimately approved, “the onus is going to be on picking individuals at high enough risk for periprocedural complications that the benefit outweighs the bleeding risk,” Dr. de Lemos told TCTMD in a telephone interview. “I would hope that physicians use this drug judiciously and in situations where it really is the best option. This should be a niche drug and not a widely used drug, in my opinion.”

Additional Analyses Clarify Cangrelor’s Effects

The Medicines Company, which is developing cangrelor, put forth the 10,942-patient CHAMPION PHOENIX trial to support the application for approval. The results showed a lower rate of a composite of all-cause death, MI, ischemia-driven revascularization, or stent thrombosis (including intraprocedural events) at 48 hours with cangrelor vs clopidogrel.

During the first advisory committee meeting to consider cangrelor, panelists raised several issues related to the trial’s design and its differences from 2 prior studies of cangrelor—CHAMPION PLATFORM and CHAMPION PCI—that were stopped early after failing to show benefit from the drug. Those trials each had a composite primary endpoint that did not include stent thrombosis and had lower proportions of patients with stable angina (5% and 15% vs 58%). In addition, PHOENIX allowed use of either 300-mg or 600-mg doses of clopidogrel—whereas the others only used 600 mg—and only PHOENIX included a protocol restriction on glycoprotein IIb/IIIa inhibitors.

Panelists at the first meeting—who voted against recommending approval by a vote of 7 to 2—expressed concerns about how to interpret the positive PHOENIX results in the context of the previous failed trials. They cited issues such as the adequacy of antiplatelet therapy in the control group; the clinical relevance of intraprocedural stent thrombosis and the biomarker elevations used to define periprocedural MIs; and whether the reduction in thrombotic events outweighed the bleeding risk.

The FDA later declined to approve cangrelor for similar reasons and asked the company to perform further sensitivity analyses using a more clinically relevant definition of MI found in a 2013 consensus statement from the Society for Cardiovascular Angiography and Interventions (SCAI) and excluding intraprocedural stent thrombosis. Those new analyses continued to show a reduction in events with cangrelor (table 1).

 Table 1. Sensitivity Analyses of Primary Endpoint at 48 Hours

That information, combined with bleeding data, led the FDA reviewers to conclude that “the benefit of cangrelor compared to clopidogrel is small, but the risk is smaller,” according to briefing documents released before the meeting. The reviewers indicated that their other concerns were addressed, as well, and they recommended approval.

Panel Sides With Cangrelor, With Caveats

The panel appeared to agree with the FDA’s assessment, with only 2 votes against recommending approval. Dr. de Lemos said the new analyses addressed his main concern, which was the clinical relevance of the periprocedural MIs and intraprocedural stent thrombosis events that drove the benefit of cangrelor in the primary analysis.

“It’s still a very narrow benefit-to-risk margin. It was still not an easy decision at all,” he said, adding, however, that he feels the company established that cangrelor has clinically meaningful—albeit modest—effects.

Stuart Rich, MD, of the University of Chicago Pritzker School of Medicine (Chicago, IL), also voted in favor of cangrelor but with “great reluctance,” he said during the meeting.

“I would have loved to see new data rather than the same data repackaged again and cherry-picked out. I certainly don’t feel that this is a vote of confidence,” he commented, adding that he thinks the drug will help some patients nonetheless.

Another yes vote came from Jennifer S. Li, MD, MHS, of Duke University Medical Center (Durham, NC), who said she feels the additional analyses were more compelling in demonstrating that the benefits of cangrelor outweigh the risks. “It would be of utility to have an IV drug that has a fast onset and offset available in the cath lab armamentarium,” she said after the vote.

Other panelists were not convinced, however. Scott Emerson, MD, PhD, of the University of Washington (Seattle, WA), who voted against cangrelor at both advisory committee meetings, said he was not sure that CHAMPION PHOENIX could be considered a pivotal trial and expressed concerns about the endpoints and the appropriateness of the control group.

The other no vote came from Julia B. Lewis, MD, of Vanderbilt University Medical Center (Nashville, TN), who said the variety of concerns discussed during the meeting made her unwilling to accept a single trial as support for approval.

Thomas Fleming, PhD, of the University of Washington (Seattle, WA), who abstained, also questioned the appropriateness of the control group and said he could not ignore the failure of the 2 prior trials.

A ‘Breakthrough’ for Some

Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), supported the panel’s decision, telling TCTMD in an email, “US patients will greatly benefit from cangrelor in many scenarios in which ADP antagonists have not been given prior to PCI, which represents a large proportion of current use.

“Previously, not a single trial of oral [adenosine diphosphate (ADP)] antagonist preloading has been positive; 3 to 4 earlier studies showed increased bleeding without clear efficacy,” continued Dr. Stone, who was on the executive steering committee for the CHAMPION trials. “Conversely, in 3 large trials… rapid potent P2Y12 receptor inhibition with cangrelor minutes before PCI in clopidogrel-naive patients reduced stent thrombosis and large MI within 48 hours after PCI, with only a modest increase in bleeding, representing a favorable net clinical benefit for patients. This was true in stable CAD, NSTE-ACS, and recent STEMI.”

He concluded, “These outcomes shouldn’t be extrapolated to patients chronically taking or effectively preloaded with an oral ADP antagonist, and I don’t think they will be. For other patients, though, this represents a real breakthrough.”

 


Source:
US Food and Drug Administration. FDA briefing document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC). http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
CardiovascularandRenalDrugsAdvisoryCommittee/UCM442199.pdf
. Accessed April 15, 2015.

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Disclosures
  • Drs. de Lemos and Stone report no relevant conflicts of interest.

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