By Christian Hamm
Other authors: Philippe Gabriel STEG, France; Deepak L Bhatt, USA; Gregg W. Stone, USA; C. Michael Gibson, USA; Kenneth W. Mahaffey, USA; Sergio Leonardi, USA; Tiepu Liu, USA; Simona Skerjanec, USA; Harvey D. White, USA; Robert A. Harrington, USA
Many of the periprocedural complications of percutaneous coronary intervention (PCI) are related to platelet activation. Cangrelor is a potent, rapidly acting and reversible intravenous platelet inhibitor which may help reduce PCI periprocedural thrombotic complications. Three recent large phase 3 randomized clinical trials have tested its efficacy and safety in PCI.
Material and methods:
This is a pre-specified patient level data meta-analysis of the three double-blind randomized trials (CHAMPION PCI, CHAMPION PLATFORM, and CHAMPION PHOENIX) comparing intravenous cangrelor with oral clopidogrel for the prevention of thrombotic complications after PCI. Trial participants were patients undergoing PCI for ST-segment elevation MI (STEMI) (11.6%), non-STE-ACS (57.4%) and stable coronary artery diseaseCAD (31.0%). The modified intention to treat (mITT) population of 24,910 patients, who received study drug and underwent PCI, was used to assess efficacy, focussing on the pre-specified primary efficacy composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours, a key secondary composite of stent thrombosis and a secondary composite endpoint of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Safety was assessed in the safety population of 25,107 randomized patients who received any study drug, with a primary safety outcome of non-CABG-related GUSTO severe/life-threatening bleeding.
At 48 hours, cangrelor reduced by approximately 19% both the primary composite quadruple outcome (3.8 vs 4.7% for cangrelor and clopidogrel respectively, OR 0.81 [95%CI 0.71-0.91], p=0.0007), and reduced the key secondary outcome of stent thrombosis by 41% (0.5 vs 0.8% for cangrelor and clopidogrel respectively, OR 0.59 [95% CI 0.43-0.80], p=0.0008). It reduced the secondary triple composite outcome of death/MI/IDR by 19% (3.6 vs 4.4% in the cangrelor and clopidogrel arms respectively, OR: 0.81 [95%CI: 0.71-0.92], p=0.0014). The efficacy outcomes were consistent across the three trials and across the main patient subsets. These benefits were maintained at 30 days. There was no increase in the primary safety outcome of non-CABG related GUSTO severe/life-threatening bleeding measured at 48 hours in the cangrelor group (0.2 vs 0.2% cangrelor and clopidogrel respectively), in TIMI major bleeding (0.3 vs 0.2%), or in transfusions (0.7 vs 0.6%). Cangrelor increased ACUITY major bleeding (4.2 vs 2.8%), mainly due to increased hematoma ≥ 5 cm. It also increased GUSTO mild and TIMI minor bleeding, with increases in ecchymosis, puncture site oozing and hematoma ≤ 5 cm.
Compared with clopidogrel, cangrelor may be useful as an adjunct to aspirin and anticoagulation for patients undergoing PCI in order to decrease periprocedural thrombotic complications, albeit at the expense of increased non-fatal bleeding.
Anti-thrombotic therapy is a pre requisite for successful treatment of patients undergoing percutaneous coronary intervention and in those with acute coronary syndromes in particular(1).
The potency, delay to onset of action, reversibility, delay to offset of action and the balance between safety and efficacy are important features for anti-thrombotic agents in order to reduce thrombotic complications and result in better short and long term clinical outcome(2).
Cangrelor which is an intravenous inhibitor of the platelet P2Y12 receptor possesses many of these properties and may be able to add clinical value to the armamentarium of agents available and approved for the use during PCI. Cangrelor has been evaluated in three major prospective randomized trials in patients undergoing PCI(3-5).
The investigators of the Champion study program are presenting the outcome of a meta-analysis with patient level data from nearly 25 000 patients(6). The study convincingly demonstrates that a strategy with cangrelor during PCI reduces peri-procedural complications and early post-procedural ischemic events compared with a strategy based on clopidogrel and suggests that the agent may fill an unmet need in the treatment of patients undergoing PCI across the spectrum of coronary disease.
While this well performed meta-analysis provides intriguing evidence that cangrelor may be clinically useful there are many questions that remain to be answered.
Does cangrelor provide any benefit if compared with pre-treatment with more potent and fast acting oral agent such as prasugrel or ticagrelor? In fact, cangrelor also increased minor peri-procedural bleeding events similar to these oral agents. Would cangrelor be superior to a bolus dose only or a short infusion of a GP IIb/IIIa-inhibitor during PCI? GP IIb/IIIa-inhibitor are fast acting and potent and the well described increase in bleeding risk is primarily associated with extended infusion of these agents. Would a universal use of bivalirudin in addition to oral P2Y12 inhibition result in a similar reduction of peri-procedural events but lower bleeding risk?
The results of the cangrelor meta-analysis open for new possible treatment strategies in the search for an optimal anti-platelet management of patients with acute coronary syndromes undergoing PCI. An anti-platelet strategy with early start of aspirin and cangrelor pre-PCI for the lowest possible peri-procedural ischemic risk, transition to potent oral treatment with ticagrelor in addition to aspirin during the hospital stay, dropping aspirin and continuing with long term therapy with ticagrelor alone would be an intriguing strategy as compared to standard of care for the next large scale randomized trial.
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