Optimizing the Use of Cangrelor in the Real World

Arman Qamar; Deepak L. Bhatt

Disclosures

Am J Cardiovasc Drugs. 2017;17(1):5-16. 

In This Article

CHAMPION PHOENIX Trial

In this double-blind, placebo-controlled trial, cangrelor was compared with clopidogrel in 11,145 patients who were undergoing either elective or urgent PCI.[43,44] The indication for PCI was stable angina in 56 % of the patients, non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in 26 %, and STEMI in 18 %. Overall, the median time from hospital admission to PCI was approximately 4 h. Patients were randomized to receive either cangrelor (30-μg/kg bolus followed by a 4-μg/kg/min infusion for at least 2 h or the duration of the procedure, whichever was longer) or to receive a loading dose of 600 or 300 mg of clopidogrel before PCI. The investigators excluded patients who had received a P2Y12 receptor inhibitor or abciximab at any time in the 7 days before randomization and those who received other glycoprotein IIb/IIIa inhibitors or fibrinolytic therapy in the 12 h before randomization. All patients were treated with aspirin (75–325 mg) and clopidogrel 75 mg during the first 48 h; thereafter, patients received either clopidogrel or another P2Y12 receptor inhibitor at the discretion of the investigator. Three-fourths of the trial patients were anticoagulated with unfractionated heparin, and in the remainder, operators chose to use bivalirudin, low-molecular weight heparin, or fondaparinux.

The rate of the primary composite efficacy end point of death from any cause, MI defined according to the universal definition, IDR, or stent thrombosis at 48 h after randomization was significantly lower in patients receiving cangrelor compared with those receiving clopidogrel (4.7 vs. 5.9 %) [odds ratio 0.78; 95 % confidence interval (CI) 0.66–0.93; P = 0.005] (Fig. 1). The beneficial effect of cangrelor in reducing the primary efficacy end point was not influenced by the clopidogrel loading dose (600 vs. 300 mg) or the timing of administration of the loading dose (immediately before PCI vs. during or after the procedure). Moreover, there was no heterogeneity in the favorable effect of cangrelor between patients presenting with stable angina, NSTE-ACS, and STEMI. At 48 h, the rate of the key secondary efficacy end point of stent thrombosis occurred in fewer patients in the cangrelor group than in the clopidogrel group (0.8 vs. 1.4 %) (odds ratio 0.62; 95 % CI 0.43–0.90; P = 0.01) (Fig. 2). Similarly, at 30 days, the frequency of the primary composite efficacy end point and the rate of stent thrombosis remained significantly lower in the cangrelor group than in the clopidogrel group. Glycoprotein IIb/IIIa inhibitors were only used as rescue therapy during PCI to treat new or persistent thrombus formation, slow or no reflow, side branch compromise, dissection, or distal embolization. The need for rescue therapy during PCI was significantly lower with cangrelor than with clopidogrel.

Figure 1.

Kaplan–Meier curves for the primary efficacy end point in the CHAMPION PHOENIX trial. The primary efficacy end point was a composite of death from any cause, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. The inset shows the same data on an enlarged y-axis. Reprinted with permission from Bhatt et al. [44]. CHAMPION Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition

Figure 2.

Kaplan–Meier curves for the secondary end point in the CHAMPION PHOENIX trial. The secondary end point was stent thrombosis at 48 h after randomization. The inset shows the same data on an enlarged y-axis. Reprinted with permission from Bhatt et al. [44]. CHAMPION Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition

The primary safety end point, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) severe bleeding, did not significantly differ in the cangrelor and clopidogrel groups (0.16 vs. 0.11 %) (odds ratio 1.50; 95 % CI 0.53–4.22; P = 0.44). A composite end point termed net adverse clinical events, comprising the primary efficacy and the primary safety end points, occurred in 4.8 % patients in the cangrelor group and 6.0 % of patients in the clopidogrel group (odds ratio 0.80; 95 % CI 0.68–0.94; P = 0.008). The rate of adverse events related to treatment was similar in both the groups, though there was a higher incidence of transient dyspnea with cangrelor compared with clopidogrel (1.2 vs. 0.3 %; P<0.001). However, most dyspnea events in the cangrelor group were mild in severity, and only four patients discontinued therapy due to dyspnea. Overall, intravenous platelet inhibition with cangrelor in the CHAMPION PHOENIX trial reduced ischemic events without a significant increase in severe bleeding or in transfusions across entire spectrum of CAD patients undergoing PCI, with consistent benefit across all major patient subsets.

A pooled analysis of the data from the three CHAMPION trials (PCI, PLATFORM, and PHOENIX) explored the efficacy and safety of cangrelor compared with clopidogrel in reducing periprocedural thrombotic events in 24,910 patients undergoing PCI.[46] The prespecified primary efficacy end point of death from any cause, MI defined by universal definition of PCI-related MI, IDR, or stent thrombosis at 48 h occurred in 3.8 % of patients receiving cangrelor and 4.7 % of patients receiving clopidogrel (odds ratio 0.81; 95 % CI 0.71–0.91; P = 0.007) (Fig. 3). Furthermore, the rate of the secondary outcome of stent thrombosis at 48 h was also lower in the cangrelor group than in the clopidogrel group (0.5 vs. 0.8 %) (odds ratio 0.59; 95 % CI 0.43–0.81; P = 0.0008). These benefits were also significant at 30 days after randomization. The reduction in the primary efficacy end point with cangrelor was consistent across all major subgroups, defined according to the indication for PCI (STEMI, NSTE-ACS, or stable angina), patient characteristics (for example, age, sex, history of diabetes, or MI), and the loading dose or timing of administration of clopidogrel. At 48 h, the rate of the primary safety end point of non-CABG-related GUSTO severe or life threatening bleeding, or thrombolysis in myocardial infarction (TIMI) major bleeding, or the need for transfusions did not differ significantly between the two groups. However, cangrelor compared with clopidogrel significantly increased the incidence of less severe bleeding events and transient dyspnea.

Figure 3.

Forest plot of the primary, key secondary, and secondary outcomes at 48 h, overall and in each of the three CHAMPION trials. Reprinted with permission from Steg et al. [46]. CHAMPION Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition, CI confidence interval, IDR ischemia-driven revascularization, MI myocardial infarction, OR odds ratio, PCI percutaneous coronary intervention, ST stent thrombosis

The CHAMPION PHOENIX trial provided the primary evidence of efficacy for cangrelor that resulted in its regulatory approval for clinical use. In June 2015, the US Food and Drug Administration (FDA) approved the use of cangrelor as an adjunct to PCI for reducing periprocedural thrombotic events in patients who have not been treated with a P2Y12 receptor inhibitor or are not receiving a glycoprotein IIb/IIIa inhibitor. Similarly, the European Medicines Agency (EMA) approved the use of cangrelor in patients undergoing PCI who have not been preloaded with an oral P2Y12 receptor inhibitor before PCI, and in clinical settings were treatment with oral P2Y12 inhibitors is not feasible or desirable. Since the publication of the original trial results, several prespecified subgroup analyses in CHAMPION PHOENIX have confirmed the beneficial effect of cangrelor in reducing ischemic events in patients undergoing PCI.

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