In the past decade, patient outcomes after PCI have improved considerably with the advent of the oral P2Y12 receptor antagonists clopidogrel, prasugrel and ticagrelor.
Depending on the scenario, the variable platelet inhibition and delayed onset of these drugs may lead to increased ischemic events, and the associated prolonged duration of action and reversibility may be problematic for bleeding (see Table). If an agent had the best of both worlds, it would have a quick onset, allowing delayed administration until the coronary anatomy is known, decreasing ischemic events during PCI, as well as a quick offset, decreasing the risk for bleeding in the event of CABG surgery. A potentially ideal agent is cangrelor (The Medicines Company), an investigational, IV P2Y12 receptor antagonist that possesses the aforementioned characteristics.
Available data on cangrelor
Cangrelor has been studied in two clinical scenarios. First, the CHAMPION series (PCI, PLATFORM and PHOENIX) studied clopidogrel compared with cangrelor in the PCI setting. In CHAMPION-PCI, stable angina and non-ST elevation ACS patients received a 30 mcg/kg bolus followed by 4 mcg/kg/min of cangrelor or 600 mg clopidogrel after the coronary anatomy was defined. Patients in the cangrelor arm received clopidogrel 600 mg after the end of the infusion. CHAMPION-PLATFORM was similar, except clopidogrel was started after PCI in both arms. The primary outcome was a composite of death, MI, ischemia-driven revascularization or stent thrombosis at 48 hours. Both studies were stopped early because interim analyses showed no difference in the primary efficacy endpoints between cangrelor and clopidogrel.
Despite the negative results of the two previous studies, CHAMPION-PHOENIX was conducted due to controversial MI definitions. The purpose of CHAMPION-PHOENIX was to discriminate index MIs from periprocedural MIs by modifying the periprocedural MI definition. This definition required baseline cardiac biomarkers in all patients and used more stringent criteria for periprocedural biomarker, electrocardiographic and symptomatic changes. Otherwise, the design of CHAMPION-PHOENIX was nearly identical to CHAMPION-PCI and, in addition, included STEMI patients. The primary efficacy outcome at 48 hours occurred less frequently in the cangrelor group (4.7% vs. 5.9%; risk ratio=0.78; P=.005). Both GUSTO-defined and TIMI-defined major bleeding were not significantly different between groups. Dyspnea, also observed with ticagrelor (Brilinta, AstraZeneca), was more frequent with cangrelor.
One concern with the study designs, especially in CHAMPION-PLATFORM, was a delay in clopidogrel administration in the clopidogrel arm. The delay to clopidogrel administration in cangrelor-treated patients may be warranted due to a potential drug interaction if overlapped. A small pharmacokinetic study showed clopidogrel administration before or during cangrelor infusion may prevent its full antiplatelet effects and therefore requires separation of the two agents. For those patients who only received clopidogrel, however, delayed administration may lead to increased risk for ischemic complications. In CHAMPION-PHOENIX, the use of clopidogrel 300 mg vs. 600 mg in a large portion of patients randomly assigned clopidogrel may also pose similar concerns. Finally, there are no data that compare cangrelor with the new P2Y12 agents, prasugrel (Effient, Daiichi Sankyo/Eli Lilly) and ticagrelor, in the setting of PCI, making it unknown whether cangrelor has any advantage over these agents.
The longer duration of the existing P2Y12 receptor antagonists is not ideal for patients requiring surgery. BRIDGE was a prospective, randomized, controlled trial in 210 patients designed to assess the efficacy and safety of cangrelor in patients undergoing non-emergent CABG surgery. Patients were randomly assigned to cangrelor or placebo within 2 to 7 days before CABG. The study drug infusion was started a median of 29 hours after discontinuation of oral P2Y12 receptor antagonists and was discontinued a median of 3 hours before incision. The primary outcome was the proportion of patients with low platelet reactivity using the VerifyNow assay. A lower platelet reactivity unit (PRU) corresponds to increased platelet inhibition. Although an exact cutoff for adequate platelet inhibition has not been established in the literature, the BRIDGE researchers targeted a PRU <240. Secondary endpoints included bleeding outcomes and the combined incidence of death, MI, stroke or need for urgent revascularization within 30 days.
The BRIDGE trial showed a significantly higher proportion of patients with PRU values <240 as compared with placebo (98.8% vs. 19%; relative risk=5.2; 95% CI, 3.3-8.1). There were no differences in any secondary outcomes, including study-defined bleeding.
Although cangrelor performed statistically better than placebo, platelet reactivity may not correlate with clinical outcomes and conclusions from such surrogate markers must be interpreted with caution. In the BRIDGE trial, 97% of patients were maintained on aspirin therapy perioperatively. Cangrelor use in non-CABG surgeries has not been investigated, nor has it been studied when both P2Y12 receptor antagonists and aspirin are interrupted. Additionally, although cangrelor may potentially reduce cardiac events preoperatively, there are data that describe increased risks intraoperatively and postoperatively when dual antiplatelet therapy is discontinued. The rapid offset of cangrelor at discontinuation provides no additional protection during the time of highest risk.
Future use, future research
Despite the potentially ideal pharmacokinetic properties of cangrelor, evidence from studies does not support its use currently. On Feb. 12, FDA advisers voted against approval of cangrelor for use during PCI and as a bridge to surgery in patients on P2Y12 receptor antagonists. Some concerns raised by the FDA were the delay in clopidogrel administration, questionable clinical relevance of the biomarker defined endpoint of MI, and prohibition of ticagrelor, prasugrel and glycoprotein IIb/IIIa inhibitors.
Given the necessity to discontinue cangrelor before starting clopidogrel, it is unlikely large-scale cangrelor PCI trials will be repeated. Future large, clinical, outcome-based studies may be warranted to elucidate a role for cangrelor as a bridge to cardiac and noncardiac surgeries.
Bhatt DL. N Engl J Med. 2009;361:2330-2341.
Harrington RA. N Engl J Med. 2009;361:2318-2329.
Bhatt DL. N Engl J Med. 2013;368:1303-1313.
Angiolillo DJ. JAMA. 2012;307:265-274.
Steinhubl SR. Thromb Res. 2008;121:527-534.
Sara Varnado, PharmD, and Hasan Kazmi, PharmD, are PGy2 cardiology pharmacy residents and Danielle Blais, PharmD, BCPS, is a cardiology specialty pharmacist, all at The Ohio State University Wexner Medical Center. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at University of the Sciences in Philadelphia, Pa. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104; email: email@example.com.
Disclosure: The authors report no relevant financial disclosures.