FDA Panel Rejects Cangrelor for Both PCI, Bridging Indications

After reviewing data from several pivotal trials studying the effects of the novel antiplatelet agent cangrelor, a US Food and Drug Administration (FDA) advisory panel has recommended against approval of the drug for 2 indications.

The Cardiovascular and Renal Drugs Advisory Committee voted 7-2 against approval of cangrelor (The Medicines Company, Parsippany, NY), a rapid acting intravenous P2Y12 inhibitor, for the reduction of thrombotic events including stent thrombosis in patients undergoing PCI. Additionally, the panel voted unanimously against use of the drug for bridging purposes or for maintenance of antiplatelet therapy in high-risk ACS patients awaiting surgery.

The panel heard presentations from the drug’s manufacturer, as well as investigators from the major cangrelor trials over the past several years.

Bleeding the Concern for PCI

Outcomes compared with clopidogrel in PCI patients have primarily been positive for cangrelor, although with certain caveats. Most recently, CHAMPION-PHOENIX, published in April 2013 in the New England Journal of Medicine, showed that cangrelor substantially reduces ischemic events across the entire spectrum of PCI patients.

In the study, almost 11,000 patients undergoing elective or urgent PCI were randomized to either a bolus and infusion of cangrelor or a loading dose of 600 mg or 300 mg of clopidogrel. CHAMPION-PHOENIX met both its primary (all-cause death, MI, ischemia-driven revascularization, or stent thrombosis) and secondary efficacy endpoints (stent thrombosis) at 48 hours, with the results maintained at 30 days. The rate of GUSTO severe bleeding (primary safety endpoint) was slightly higher in the cangrelor group compared with the clopidogrel group, but the difference was not significant.

Additionally, a meta-analysis presented in September 2013 at the European Society of Cardiology Congress in Amsterdam, the Netherlands and simultaneously published in the Lancet, confirmed the reduction in periprocedural events with cangrelor vs clopidogrel, but highlighted the bleeding disadvantage slightly more. The study included all 3 of the CHAMPION trials, including the aforementioned PHOENIX, as well as PCI and PLATFORM, for a total of about 25,000 patients.

At 48 hours, cangrelor reduced the combined risk of death, MI, ischemia-driven revascularization, or stent thrombosis (primary efficacy outcome) by 19% compared with clopidogrel, and this finding was maintained at 30 days. Individually, death only trended lower with cangrelor. There was no difference in GUSTO severe bleeding (primary safety outcome), which was 0.2% in both groups or in blood transfusion rates, but cangrelor was associated with increased GUSTO mild bleeding compared with clopidogrel (16.8% vs 13.0%; P < 0.0001).

Initial Bridging Data Positive

As for the second indication—use of cangrelor for bridging purposes—it has been 2 years since the publication of the BRIDGE trial in the Journal of the American Medical Association in January 2012, which showed that cangrelor can maintain levels of platelet inhibition associated with a low risk of thrombotic events without increasing CABG-related bleeding in patients who need to stop antiplatelet therapy in anticipation of surgery.

For the trial, 210 patients with ACS or treated with a coronary stent (BMS or DES) who discontinued thienopyridine therapy before CABG were randomized to cangrelor or placebo for between 48 hours and 7 days. Bridging therapy was discontinued 1 to 6 hours prior to surgery.

A greater proportion of patients treated with cangrelor met the primary efficacy endpoint of a PRU level < 240, as measured by VerifyNow (Accumetrics, San Diego, CA), throughout the treatment period compared with those treated with placebo (98.8% vs 19.0%; adjusted RR 5.2; 95% CI 3.3-8.0; P < 0.001). These reactivity levels were achieved regardless of prior thienopyridine dose and time of discontinuation.

Unmet Need for Interventionalists

Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), who attended the FDA panel meeting and presented data in support of cangrelor, told TCTMD in an e-mail that “the drug clearly has a favorable efficacy-to-safety profile, and would fill a major unmet need for patients undergoing PCI.”

The lack of even 1 interventional cardiologist on the advisory panel was “unfortunate,” he added, “making it difficult for them to appreciate the implications and importance of preventing major periprocedural events such as stent thrombosis.”

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/UCM385234.pdf. Accessed February 13, 2014.

 Related Stories

• CHAMPION: Cangrelor Bests Clopidogrel in PCI Patients in Large Meta-analysis
• Cangrelor Consistently Comes Out Ahead of Clopidogrel in All PCI Patients
• BRIDGE Published: Cangrelor Promising Option as Bridging Therapy