Further information: Percutaneous Coronary Intervention for Acute Myocardial Infarction (see p1021) from Cardiovascular Medicine, 3rd Edn*

The same group of investigators conducted two large, phase 3, randomized clinical trials that compared cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist with clopidogrel, both P2Y12 antagonists. In one trial, “Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PCI),” [1] the drugs were administered to patients before percutaneous coronary intervention (PCI), and in a second trial, CHAMPION PLATFORM [2], the drugs were administered at the beginning and before the end of the procedure.

Trials conducted to find the most efficacious P2Y12 antagonist are important to patients with acute coronary syndromes (ACS) who need PCI. Current guidelines recommend an oral loading dose of 300–600 mg clopidogrel, preferably administered prior to PCI, and followed by 75 mg daily. Clopidogrel requires approximately an hour to achieve platelet inhibition, is irreversible, and platelets are slow to normalize after cessation of the drug, creating difficulty for patients who must undergo CABG instead of PCI. In addition, the effect of clopidogrel may be adversely influenced by genetic polymorphisms that create clopidogrel nonresponders. Conversely, cangrelor is administered intravenously, is rapid, predictable, and reversible.

CHAMPION PCI was a randomized, double-blind, double-dummy, active-control trial that enrolled 8877 patients and compared cangrelor with 600 mg clopidogrel in patients undergoing PCI. The drugs were administered at least 30 min before PCI and continued for at least 2 h or until the conclusion of the procedure. Patients were randomly assigned to either cangrelor or clopidogrel in a 1:1 double-blind, double-dummy design. The primary efficacy end-point of the study was composite of death from any cause, myocardial infarction (MI), or ischemia-driven revascularization at 48 h. The secondary end-points included death or MI at 48 h and at 30 days, or ischemia-driven revascularization.

Results showed that at 48 h, the primary end-point occurred in 7.5% of the cangrelor patients and 7.1% of patients in the clopidogrel group, and thus, cangrelor was not superior to clopidogrel. Results also showed that cangrelor was not significant at 30 days. Assessment of bleeding was based on three criteria: GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries), TIMI (Thrombolysis in Myocardial Infarction) and ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy). Statistics for the rate of major bleeding differed with each tests, and results are reported in the article. For secondary end points, a trend toward cangrelor was shown, but it was not statistically significant (0.6% vs. 0.9%; odds ratio [OR], 0.67; 95% confidence interval [CI], 0.39–1.14; P=0.14). Investigators concluded that cangrelor, administered 30 min before PCI and continued for 2 h, was not superior to an oral loading dose of 600 mg clopidogrel that was administered 30 min before PCI in reducing the composite end-points of death, MI, or ischemia-driven revascularization in 48 h.

The major difference between the two trials was the timing of the administration of the study drugs, cangrelor vs. clopidogrel. In the first trial, both drugs were administered within 30 min prior to the start of PCI. In the second trial, cangrelor was administered at the beginning of PCI, and clopidogrel was administered at the end of the procedure. CHAMPION PLATFORM was a double-blind, placebo-controlled study in which a total of 5362 patients from 18 countries were enrolled from October 2006 to May 2009. Patients were assigned to receive either cangrelor (2654 patients) or placebo (2641 patients) at the time of PCI, followed later by 600 mg clopidogrel. The primary end-point was a composite of death, MI, or ischemia-driven revascularization 48 h post PCI, while the secondary end-points included individual rates of death, MI, new Q-wave MI, ischemia-driven revascularization, abrupt vessel closure, or stroke at 48 h.

Of the 2654 patients who received cangrelor, the primary end point occurred in 185 (7.0%) and of the 2641 patients who received placebo, it occurred in 210 (8.0%). An interim analysis was conducted that concluded the trial would be unlikely to show significant superiority for the primary end point. However, in the cangrelor group, two secondary end points were significantly reduced at 48 h. The rate of stent thrombosis was reduced from 0.6% to 0.2% (OR, 0.31; 95% CI, 0.11–0.85; P=0.02). The rate of death from any cause was reduced from 0.7% to 0.2% (OR 0.33; 95% CI, 0.13–0.83; P=0.02). There was no significant difference in the rate of blood transfusion. The rates of major bleeding did not differ significantly between the two groups according to the TIMI or GUSTO criteria, but according to the criteria for minor bleeding, ACUITY and GUSTO, the rates of minor bleeding were significantly higher in the cangrelor group because of the number of groin hematomas. The investigators concluded that additional study of cangrelor should be considered.

The writers of an accompanying editorial [3] recognized that cangrelor had negative results on the basis of the findings in both CHAMPION PCI and CHAMPION PLATFORM. The question raised in the editorial is whether or not the study design of the CHAMPION trials gave the drug an optimal chance to show better results that might be possible with cangrelor considering its advantages of intravenous administration and rapid onset and offset of action. The authors of the editorial believe that a drug with such assets warrants further study.

[1] Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI (CHAMPION PCI). N Engl J Med 2009;361:2318-2329

[2] Bhatt DL, Lincoff MA, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI (CHAMPION PLATFORM ). N Engl J Med 2009;361:2330-2341

[3] Kastrati AK, Ndrepepa G. Cangrelor—a champion lost in translation? N Engl J Med 2009;361:2382-2384

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