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29 March 2010
Intravenous cangrelor has failed to show a benefit on the primary end point of a composite of death, myocardial infarction (MI) or ischaemia-driven revascularisation 48 hours after percutaneous coronary intervention (PCI). In the CHAMPION PCI (n=8,877) study cangrelor was less effective than a loading dose of clopidogrel 600mg administered before PCI. In the CHAMPION PLATFORM (n=5,362) study cangrelor was less effective than placebo when 600mg of clopidogrel was given at the time of PCI. Assessment of bleeding risk was complicated by the use of more than one rating scale.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
Patients with acute coronary syndrome (ACS) undergoing PCI require careful risk assessment and current guidelines recommend the use of antiplatelet agents such as clopidogrel or prasugrel as appropriate. The results of the CHAMPION studies demonstrate that intravenous cangrelor failed to show any advantage over clopidogrel in patients with ACS in whom the administration of the antiplatelet agent was deferred until angiography had identified the need for PCI.
What is the background to this?
Options for patients who have undergone angiography because of ACS are PCI, medical management or coronary artery bypass grafting (CABG). Antiplatelet drugs that block adenosine diphosphate (ADP) are widely used in patients with ACS. The ideal ADP receptor antagonist would be fast-acting, potent and reversible. Cangrelor is a reversible inhibitor of P2Y12 on platelets and the first to be administered intravenously.
Both clopidogrel and prasugrel▼ are oral, irreversible inhibitors of P2Y12on platelets and take at least an hour to work. Clopidogrel in combination with aspirin is used for non-ST-segment elevation ACS, and recommended by NICE. Prasugrel is used with aspirin in ACS and ST-segment-elevation myocardial infarction (STEMI) for patients undergoing primary or delayed PCI. NICE recommends prasugrel as an option when immediate primary PCI is necessary, when stent thrombosis has occurred with clopidogrel or for patients with diabetes. Ticagrelor, a further oral agent, is not yet licensed. It does not require metabolic activation and its effects are rapidly reversible. The potential advantage of ticagrelor when a patient with ACS needs urgent CABG is discussed in our blog of the PLATO study.
What do these studies claim?
Enrolment into both studies was stopped early when interim analyses showed that the trials were unlikely to demonstrate superiority for the primary end point.
In the CHAMPION PCI study (n=8,877) the primary end point in the modified intention-to-treat (ITT) population was a composite of death from any cause, MI or ischaemia-driven revascularisation 48 hours after PCI. Cangrelor was not superior to clopidogrel when both were administered in the 30 minutes before PCI: 7.5% vs. 7.1%, odds ratio [OR] 1.05, 95% confidence interval [CI] 0.88 to 1.24, P=0.59.
Bleeding risk was assessed using criteria from three other trials: ACUITY, GUSTO and TIMI. A large quantity of data relating to these criteria was collected. Only a brief summary will be given in this blog.
In the CHAMPION PCI study, the rate of minor bleeding (ACUITY criteria) was higher with cangrelor: 17.6% vs. 15.2%, OR 1.19, 95%CI 1.06 to 1.33, P=0.003. Major bleeding was not statistically different from clopidogrel (3.6% vs. 2.9%, OR 1.26, 95%CI 0.99 to 1.60, P=0.06). But this was not the case for the GUSTO criteria where mild bleeding was significantly higher with cangrelor: 19.6% versus 16.9% for clopidogrel, OR 1.20 (95%CI 1.07 to 1.34), P=0.001.
The CHAMPION PLATFORM study (n=5,362) used the same primary outcome. Unlike in CHAMPION PCI, where the loading dose of clopidogrel was administered at the time of the cangrelor infusion, in CHAMPION PLATFORM the clopidogrel was given after the end of the cangrelor infusion. There was no significant difference in the rate of the primary end point between the cangrelor and placebo groups (7.0% and 8.0%, respectively, OR 0.87, 95%CI 0.71 to 1.07, P=0.17).
There were more minor/mild bleeding events in the cangrelor group, according to the ACUITY and GUSTO criteria. In relation to the ACUITY criteria, minor bleeding was seen in 12.0% of cangrelor patients vs. 9.3% of placebo ones (OR 1.34, 95%CI 1.12 to 1.59, P=0.001). The figures for major bleeding were 5.5% vs. 3.5%, respectively (OR 1.61, 95%CI 1.23 to 2.10, P<0.001). GUSTO mild bleeding events were seen in 16.0% vs. 11.7% of patients, respectively, (OR 1.44, 95%CI 1.23 to 1.69), P<0.001.
How do these relate to other studies?
No other phase III trials of cangrelor are shown on the trials register and no head-to-head studies with prasugrel or ticagrelor appear to be planned. Further information on the management of ACS can be found on the ACS section of NPC. A NICE clinical guideline on unstable angina and NSTEMI is due to be published shortly. A higher incidence of dyspnoea was seen in cangrelor patients in these trials. Dyspnoea was also reported in ticagrelor patients in the PLATO trial.
So what?
On the basis of these findings, cangrelor offers no advantages with respect to efficacy over clopidogrel. Although cangrelor was not associated with a significant effect on major bleeding complications, there may be an increased risk of minor bleeding.
The authors of the studies note that the results raise questions about choosing appropriate end points. The composite end point of the studies included MI and the short time between admission and PCI made it difficult for assessors to distinguish MIs occurring before or after randomisation. In addition, the assessment time of 48 hours post-PCI may have been too short to fully determine the effectiveness of this agent. The use of multiple measures of bleeding has complicated the assessment of bleeding risk.
Study details: CHAMPION PCI
Harrington RA, Stone GW, McNulty S et al. Platelet inhibition with cangrelor in patients undergoing PCI. New Eng J Med 2009; 361:2318-29
Design: Randomised, double-blind, double-dummy, phase III trial. Allocation was concealed.
Patients: Patients with stable angina, unstable angina, or non-ST-segment-elevation myocardial infarction (NSTEMI) with obstructive coronary artery disease and who were scheduled to undergo PCI were included. An additional 1,000 patients with STEMI for whom primary PCI was planned were also eligible. Fibrinolytic agents or glycoprotein IIb/IIIa inhibitors within the previous 12 hours or clopidogrel (if more than 75mg per day) in the previous 5 days were not allowed.
Patients were mainly men, median age 62 years. Hypertension or hyperlipidaemia were present in the majority of patients and 30.5% of the patients had diabetes.
Intervention and comparison: Patients received cangrelor 30 microgram/kg as an intravenous bolus followed by an infusion of 4 microgram/kg/min (n=4,367), or a placebo bolus and infusion (n=4,355). The infusion began in the 30 minutes before PCI and continued for at least 2 hours or until the conclusion of the procedure. Patients received 600mg of clopidogrel or placebo at the time of the infusion. At the end of the infusion the transition from intravenous cangrelor to oral clopidogrel was facilitated by those in the cangrelor group receiving 600mg clopidogrel and those in the clopidogrel group receiving placebo capsules. All patients received 75 to 325mg of aspirin.
Outcomes and results: Planned recruitment was 9,000 patients, but enrolment was stopped early because interim analysis concluded that the trial would be unlikely to show superiority for the primary end point. 98% of the 8,877 patients enrolled underwent PCI. The primary efficacy analysis (a composite of death from any cause, MI or ischaemia-driven revascularisation 48 hours after PCI) was measured in the modified ITT population (randomised patients who received at least one dose of study medication and underwent PCI, but excluded the STEMI cohort). At 48 hours cangrelor (n=3,889) was not superior to clopidogrel (n=3,865) for the primary outcome: 7.5% vs. 7.1%, OR 1.05, 95%CI 0.88 to 1.24, P=0.59.
Adverse events were reported in 26.4% of patients in the cangrelor group and 25.7% of the clopidogrel patients. Bleeding events at 48 hours were recorded on 3 different scales by the investigators. The rate of minor bleeding (ACUITY criteria) was higher with cangrelor: 17.6% vs. 15.2%, OR 1.19, 95%CI 1.06 to 1.33, P=0.003. ACUITY major bleeding was seen in 3.6% vs. 2.9% of patients, respectively, OR 1.26, 95%CI 0.99 to 1.60, P=0.06). The reported rate of mild bleeding was higher with cangrelor with the GUSTO criteria (19.6% vs. 16.9%, OR 1.20, 95%CI 1.07 to 1.34, P=0.001). Dyspnoea was reported by 1.0% of the cangrelor patients and 0.4% of clopidogrel patients, P=0.001.
Sponsorship: The Medicines Company
Study details: CHAMPION PLATFORM
Bhatt DL, Lincoff AM, Gibson CM et al for the CHAMPION PLATFORM investigators. Intravenous platelet blockade with cangrelor during PCI. New Eng J Med 2009; 361:2330-41
Design: Randomised, double-blind, double-dummy, placebo-controlled, phase III study.
Patients: Patients with NSTEMI or unstable angina with at least one atherosclerotic lesion amenable to PCI. Patients were included if they had diabetes or were aged 65 years or older or both. Patients at high risk of bleeding were excluded. Patients enrolled were mainly men with a median age of 63.0 years.
Intervention and comparison: Patients received either cangrelor 30microgram/kg bolus and then 4microgram/kg/min infusion (n=2,656) or placebo bolus and infusion (n=2,645) at the time of PCI. Patients in the cangrelor group received 600mg clopidogrel after the end of the cangrelor infusion, and those in the placebo group received 600mg clopidogrel at the end of the procedure.
Outcomes and results: The primary end point was a composite of death, MI, or ischaemia-driven revascularisation at 48 hours after PCI in the modified ITT population (all randomised patients who received at least one dose of study medication and underwent PCI). Enrolment was stopped early when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.
There was no significant difference in the rate of the primary outcome between the cangrelor (n=2,654) and placebo (n=2,641) groups (7.0% vs. 8.0%, OR 0.87, 95%CI 0.71 to 1.07, P=0.17). There were more minor bleeding events in the cangrelor group, according to the ACUITY and GUSTO criteria. Major bleeding (ACUITY criteria) was seen in 5.5% of cangrelor patients vs. 3.5% of placebo patients, OR 1.61,95% CI 1.23 to 2.10, P<0.001. Dyspnoea occurred in 1.4% of cangrelor patients vs. 0.5% in those receiving placebo, P=0.002.
Sponsorship: The Medicines Company
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