Inhibitors of the platelet P2Y12 receptor reduce the risk of subsequent cardiovascular events in patients with acute coronary syndromes (ACS) and they reduce both periprocedural and subsequent cardiovascular events in patients treated with a percutaneous coronary intervention (PCI). Vessel injury that is associated with the rupture of atherosclerotic plaques, a frequent cause of ACS, and with PCI is a powerful stimulus to activate platelets. The platelet P2Y12 receptor plays a central role in amplifying the activation of platelets in response to the initial stimulus of activation 1. Accordingly, inhibition of the platelet P2Y12 receptor attenuates the activation of platelets in response to diverse stimuli.
The addition of clopidogrel to aspirin reduced the incidence of cardiovascular events in patients with ACS 2. More powerful antiplatelet agents, ticagrelor and prasugrel, have been shown to be more effective than clopidogrel in reducing the incidence of cardiovascular events 3,4. Accordingly, the inhibition of the platelet P2Y12 receptor is mechanistically an important target of inhibition of platelet activation that has been validated by large clinical trials showing that inhibition of this target reduces the risk of cardiovascular events.
Cangrelor is a direct-acting antagonist of the platelet P2Y12 receptor that has an onset of antiplatelet effect observed within minutes and offset of effect in ∼1 h. The rapid onset of effect allows clinicians to use this agent to reduce the risk of periprocedural cardiovascular complications during PCI. The impact on outcomes will be greatest in patients who are not adequately treated with antiplatelet therapy at the time of PCI. The rapid offset of effect has the theoretical advantage of allowing return of platelet function that would be expected to reduce the risk of bleeding complications. Because the recovery of platelet function may pose a risk of acute stent thrombosis, an effective transition strategy to oral long-term inhibition of the platelet P2Y12 receptor is necessary. This review will focus on the results available to guide effective transition from cangrelor to oral platelet P2Y12 receptor antagonists.
The CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) trials
Two large trials (CHAMPION-PCI and CHAMPION-Platform) tested whether cangrelor would reduce the incidence of cardiac ischemic events during PCI 5,6. Although cangrelor was not associated with a significant reduction in the primary efficacy end point in either of these trials, it was associated with reductions in secondary end points, including the incidence of stent thrombosis. One factor that contributed toward the lack of efficacy was the inclusion of patients early in the course of an evolving myocardial infarction. In this setting, the definition of periprocedural myocardial infarction is severely limited. On the basis of lessons learned from these trials, the CHAMPION PHOENIX trial was designed to prospectively evaluate whether cangrelor reduced ischemic complications of PCI 7. In this trial, treatment with cangrelor significantly reduced the rate of periprocedural complications of PCI. A 22% reduction in the incidence of periprocedural myocardial infarction was observed. Treatment with cangrelor did not significantly increase the risk of the primary safety end point, severe bleeding as defined by the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) criteria. The CHAMPION PHOENIX trial enrolled a broad range of coronary syndromes including 56.1% with stable angina, 25.7% with non-ST-elevation ACS, and 18.2% with ST-elevation myocardial infarction (STEMI). Subgroup analysis showed a consistent benefit irrespective of the presenting diagnosis. The CHAMPION trials used only clopidogrel as the oral antagonist of the platelet P2Y12 receptor.
Pharmacologic characteristics of P2Y12 antagonists
Available antagonists of the platelet P2Y12 receptor can be divided into two categories: thienopyridines and direct-acting agents (Table 1). Thienopyridines, ticlopidine, clopidogrel, and prasugrel are oral agents that require metabolism of the parent compound to form an active metabolite that binds irreversibly to the platelet P2Y12 receptor. Clopidogrel, which is the most widely used agent in the thienopyridine category, exerts a widely variable antiplatelet effect in large part because multiple factors influence the extent of absorption and metabolism of the parent compound 8. The active metabolites of the thienopryidines are present in blood for a relatively short interval 9,10. As noted, binding of the active metabolite to the platelet P2Y12 receptor is irreversible and so antiplatelet effects persist for the life span of the platelet. If the platelet P2Y12 receptor is uniformly and completely occupied while the active metabolite of thienopyridines is present in blood, antiplatelet effects of the thienopyridine will presumably not be evident until the next dose of the thienopyridine is ingested. Accordingly, the short circulating duration of the active metabolite of thienopyridines has important implications for the transition from cangrelor to these agents.
Cangrelor is a parenteral direct-acting antagonist of the platelet P2Y12 receptor. Cangrelor is an analogue of adenosine triphosphate that binds reversibly to the platelet P2Y12 receptor and prevents signaling and activation of platelets by ADP 11. As expected, this parenteral agent has a very rapid onset of effect. In healthy volunteers, antiplatelet effects were apparent within 2 min 12. After discontinuation of cangrelor, platelet function returned to baseline in ∼1 h 11. The rapid return of platelet function reflects the reversible binding of cangrelor and its rapid deactivation in blood by dephosphorylation. Because dephosphorylation is the primary mechanism by which antiplatelet effects are eliminated, dose adjustment for age or impairment of kidney and liver function is not necessary.
Ticagrelor, like cangrelor, is a derivative of adenosine triphosphate in which the purine was replaced by a triazolopyrimidine heterocycle 13. This oral agent binds reversibly to the platelet P2Y12 receptor. Ticagrelor is rapidly absorbed and does not require metabolism to inhibit the platelet P2Y12 receptor. Ticagrelor and its active metabolite circulate in the plasma component of blood and are extensively bound to proteins. The elimination half-life of ticagrelor and its active metabolite ranges from 7 to 12 h. Thus, despite reversible binding to the platelet P2Y12 receptor, consistent antiplatelet effects are achieved with twice-daily dosing. After discontinuation of ticagrelor, 4–5 days are required for platelet function to return to baseline. On the basis of the characteristic of reversible binding, cangrelor would not be expected to interfere with the antiplatelet effects of ticagrelor.
Both in-vitro and in-vivo pharmacodynamics studies have evaluated the potential interaction between cangrelor and the available oral antagonists of the platelet P2Y12 receptor. Two in-vitro studies have shown conclusively that the active metabolite of clopidogrel and prasugrel cannot bind to the platelet P2Y12 receptor when cangrelor occupies the receptor 14,15. Accordingly, administration of clopidogrel and prasugrel should be timed so that cangrelor is not occupying the platelet P2Y12 receptor when the active metabolite is present in blood.
A series of small pharmacodynamic studies has been carried out to guide the timing of administration of oral antagonists of the platelet P2Y12 receptor. In these studies, patients were administered a cangrelor infusion and oral antagonists of the platelet P2Y12 receptor were administered at selected times during and after the infusion. Platelet function was assessed using multiple different assays to identify the pharmacodynamic interaction between cangrelor and oral platelet P2Y12 antagonists. For prasugrel and ticagrelor, patients who had been taking those agents were subsequently administered a cangrelor infusion. These studies showed that previous treatment with an oral platelet P2Y12 antagonist does not interfere with the antiplatelet effects of cangrelor.
When clopidogrel and an infusion of cangrelor were initiated simultaneously, the antiplatelet effects of clopidogrel were blocked, an effect not observed when clopidogrel was administered immediately after the cangrelor infusion was stopped 16. Recent results indicated that administration of clopidogrel 30 min or 1 h before the end of the cangrelor infusion does not attenuate the recovery of platelet function after cangrelor is discontinued 17. Taken together, these small mechanistic studies support a strategy in which clopidogrel is administered when the cangrelor infusion is stopped.
Another small mechanistic study was carried out to evaluate transition strategies with prasugrel 18. As noted, this study found that prasugrel did not alter the antiplatelet effects of cangrelor. Recovery of platelet reactivity was limited to a greater extent when prasugrel was administered 30 min before the end of the cangrelor infusion. These results suggest that the active metabolite of prasugrel persists in blood sufficiently to allow this overlap of therapy. Accordingly, this mechanistic study supports a strategy of initiating prasugrel either 30 min before discontinuation of cangrelor or at the end of the cangrelor infusion. The antiplatelet effects of prasugrel were apparent 4 h after the cangrelor was stopped when prasugrel was administered up to 1 h before cangrelor was discontinued as well as when prasugrel was administered 30 min after cangrelor was stopped 18.
Unlike the thienopyridines, ticagrelor binds reversibly to the platelet P2Y12 receptor. This mechanism suggests that although ticagrelor and cangrelor would be expected to compete for the receptor, their effect should be additive rather than competitive with respect to their pharmacodynamic properties. Additive effects would not be apparent when all platelet P2Y12 receptors are occupied. A small mechanistic study confirmed these findings. Ticagrelor can be administered before or during infusion of cangrelor without a marked effect on the antiplatelet properties of either agent 19. These results support a strategy in which ticagrelor is administered before or during the cangrelor infusion to limit recovery of platelet function during the transition to oral therapy.
The mechanistic studies support strategies designed to limit recovery of platelet function because such recovery poses a theoretical risk of acute stent thrombosis. Because these studies were small and carried out in healthy individuals or patients with stable coronary artery disease, the pharmacodynamic effects identified cannot necessarily be extrapolated to the acute setting. The most commonly used oral platelet P2Y12 antagonist is clopidogrel. The antiplatelet effects of clopidogrel are variable 20. The strategies identified with the mechanistic studies suggest that platelet reactivity during the transition period is likely to be less than that observed when patients are treated with clopidogrel at the time of PCI (Fig. 1). Accordingly, the results of the mechanistic pharmacodynamic studies show that cangrelor can be expected to extensively inhibit platelet reactivity during the PCI and that the recovery of platelet reactivity during transition should be less than that observed when the oral platelet P2Y12 antagonist is started at or shortly after the procedure.
A larger pharmacodynamic substudy of CHAMPION-PCI showed that platelet reactivity was suppressed to a greater extent during infusion of cangrelor compared with placebo infusion 21. Further, platelet reactivity was similar in the two treatment arms (placebo and cangrelor infusion) up to 24 h after the infusion was stopped. These results indicate that the effect of clopidogrel was not altered by a previous infusion of cangrelor and confirms that the strategy of administering clopidogrel immediately after the cangrelor infusion is stopped enables the active metabolite of clopidogrel to bind to the platelet P2Y12 receptor.
Clinical trial results
The results of pharmacodynamic studies have utility to the extent that they predict clinical results. Although high platelet reactivity has been associated with a greater risk of cardiovascular events, a specific threshold that defines a greater risk has not been identified. The pharmacodynamic studies completed show that when cangrelor occupies the platelet P2Y12 receptor, the active metabolite of clopidogrel and prasugrel cannot bind to the receptor. Further, these pharmacodynamic studies are useful to identify dosing strategies that should limit this interaction. They are not sufficient, however, to determine whether the recovery of platelet function that occurs during the transition increases the risk of cardiovascular events, particularly acute stent thrombosis. Clinical trial results are necessary to draw these conclusions.
On the basis of the results of the small pharmacodynamics studies consistent with the established pharmacodynamic effects of the oral platelet P2Y12 antagonists, the recovery of platelet function should be greatest when cangrelor is transitioned to clopidogrel. Fortunately, the large clinical trial results have used clopidogrel. Accordingly, demonstration that the transition from cangrelor to clopidogrel is not associated with a greater risk of cardiovascular events during the transition interval supports the transition strategies proposed for ticagrelor and prasugrel.
The CHAMPION trials did not show evidence of a significantly increased incidence of early myocardial infarction or stent thrombosis in patients treated with cangrelor 5–7. Assessment of the incidence of a subset of important cardiovascular events as a function of time in patients enrolled in the CHAMPION PHOENIX trial shows a reduction in events during the infusion of cangrelor and a small, nonsignificant numerical increase in the incidence of events during the transition interval (Fig. 2). The CHAMPION PHOENIX trial enrolled 11 145 patients 7. Accordingly, the absence of a significant increase in the incidence of cardiovascular events during the transition period strongly supports the transition strategy defined for clopidogrel. Because the recovery of platelet function should be less when cangrelor is transitioned to prasugrel and ticagrelor, these results also support these strategies.
Cangrelor should be used as an adjunct for PCI when the patient has not been pretreated adequately with antiplatelet therapy at the time of the procedure. Because ad-hoc PCI is commonly performed, this situation may arise in patients who have not been treated before the procedure with oral platelet P2Y12 antagonists. Significant antiplatelet effects and hence adequate pretreatment will not be evident in patients who are treated with oral platelet P2Y12 antagonists at the time of or shortly before PCI. One such group is patients with STEMI who have been found to show poor oral absorption of oral antiplatelet therapy 24. For these patients, cangrelor should reduce their risk of periprocedural cardiovascular events.
The combination of the pharmacologic characteristics of the platelet P2Y12 antagonists, pharmacodynamic studies, and clinical trial results supports the following transition strategies: when the oral platelet P2Y12 antagonist is clopidogrel, clopidogrel should be administered when cangrelor is stopped. When the oral platelet P2Y12 antagonist is prasugrel, prasugrel should be administered up to 30 min before stopping cangrelor or at the end of the infusion. When the oral platelet P2Y12 antagonist is ticagrelor, ticagrelor can be administered before or during the infusion of cangrelor because of a lack of interaction between ticagrelor and cangrelor with respect to antiplatelet effects. Earlier administration of ticagrelor, particularly in STEMI patients, should limit recovery of platelet function to the greatest extent and reduce the risk of early thrombotic complications in this high-risk group of patients. As has been noted previously, clinical trial results provide the most compelling evidence and show an absence of a significant increase in the incidence of cardiovascular events during the transition from cangrelor to clopidogrel, indicating the efficacy of the transition strategy defined for clopidogrel. Because the recovery of platelet function should be less when cangrelor is transitioned to prasugrel and ticagrelor, these results also support the strategies defined for those agents.
Conflicts of interest
D.J.S. reports receiving honorarium (>$10 000) from The Medicine Company and honorarium (<$10 000) from Astra Zeneca.
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