Drug Evaluation
Cangrelor for treatment of arterial thrombosis
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Joseph A Walsh III & Matthew J Price† 1.
Introduction
Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, CA, USA
2.
Overview of the market
3.
Cangrelor
4.
Conclusion
5.
Expert opinion
Introduction: Percutaneous coronary intervention (PCI) is a highly effective treatment for obstructive coronary artery disease. Oral platelet P2Y12 receptor antagonists reduce ischemic events in patients treated with PCI. However, there are several limitations to their use, including variable pharmacodynamics, a slow onset and offset, and in those patients who are pretreated but subsequently require cardiac surgery, increased bleeding. Cangrelor is an intravenous agent that provides rapid and intensive inhibition of the P2Y12 receptor that quickly dissipates after discontinuation. A recent, Phase III randomized clinical trial of PCI patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding. Areas covered: This review outlines the pharmacodynamics, pharmacokinetics, and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned PCI. Expert opinion: Cangrelor is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients, without increasing major bleeding or the need for transfusion. Cangrelor will have particular benefit in clopidogrel-naı¨ve patients with high anatomical complexity and/or increased clinical risk (where the absolute risk for thrombotic and ischemic complications of PCI is greatest). Keywords: ADP antagonist, P2Y12 receptor, percutaneous coronary intervention, platelet, platelet inhibitor Expert Opin. Pharmacother. (2014) 15(4):565-572
1.
Introduction
Coronary artery disease (CAD) is the most common cause of death worldwide with an estimated 7.3 million deaths per year [1]. Percutaneous coronary intervention (PCI) with coronary stent implantation is the primary treatment for acute coronary syndrome (ACS) and for refractory stable angina or ischemia. In the year 2010, there were approximately 1,145,000 unique hospitalizations for ACS and 954,000 PCIs performed in the United States [2]. Although PCI is a highly effective therapy, periprocedural complications can occur. Early and longer-term therapy with the oral platelet P2Y12 receptor antagonists clopidogrel, prasugrel and ticagrelor substantially reduce the risk of post-PCI ischemic events, including myocardial infarction (MI), stent thrombosis (ST), and in the case of ticagrelor, cardiovascular mortality [3-5]. Dual antiplatelet therapy with aspirin and an oral platelet P2Y12 receptor inhibitor is therefore the standard of care in the treatment of patients undergoing PCI [6-8]. However, these oral agents have several limitations, particularly in the acute setting. This manuscript will review the pharmacology of cangrelor, a novel intravenous P2Y12 receptor antagonist, and the clinical data supporting its safety and efficacy in the setting of PCI.
10.1517/14656566.2014.882319 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication
Cangrelor III Arterial thrombosis (but not yet FDA-approved) P2Y12 receptor inhibitor
Pharmacology description Route of Intravenous administration Chemical structure
S
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O O O P P HO P O O HO OH OH CI CI
N O HO
NH
N OH
N
N S
F F F
Pivotal trial(s)
2.
CHAMPION PCI, CHAMPION PLATFORM, CHAMPION PHOENIX
Overview of the market
Platelet activation and aggregation is a key driver of coronary thrombosis during ACS and plays a major role in thrombotic complications of PCI. Antiplatelet agents currently used before and during PCI include the oral P2Y12 receptor antagonists, clopidogrel, prasugrel and ticagrelor (Table 1), and the intravenous glycoprotein (GP) IIb/IIIa receptor antagonists, eptifibatide, tirofiban and abciximab. While the GP IIb/IIIa inhibitors significantly reduce ischemic events, they are associated with increased major bleeding and severe thrombocytopenia can occasionally occur, in particular with abciximab [9]. Large, randomized trials have demonstrated that the oral P2Y12 receptor antagonists reduce the composite endpoint of cardiovascular death, MI or stroke in patients with ACS treated with PCI [3,5,10]; clopidogrel also reduces ischemic events in patients undergoing nonurgent PCI [11]. However, these agents have several limitations that influence clinical outcomes and processes of care. First, clopidogrel and prasugrel are prodrugs that require biotransformation into an active metabolite to exert their antiplatelet effect [12,13]. The onset of platelet inhibition after a clopidogrel loading dose (LD) is slow, requiring pretreatment to establish a significant pharmacodynamic effect at the time of PCI. At least a 15-h pretreatment duration with a clopidogrel 300 mg LD may be required to detect a clinical effect (although there is limited data on the timing and relative benefit of clopidogrel preloading) [14]. While a clopidogrel 600 mg LD reaches steady-state inhibition more quickly [15], this larger dose did not reduce ischemic events in patients with ACS undergoing early invasive management [16]. Although some studies have suggested that pretreatment with clopidogrel is associated with a significantly lower incidence of periprocedural MI after 566
elective PCI, others have suggested no benefit to pretreatment compared with administration of the drug in the catheterization laboratory [17]. Pretreatment also has significant drawbacks if a patient subsequently requires coronary artery bypass grafting (CABG), since exposure to an oral P2Y12 receptor antagonist increases rates of major bleeding, blood transfusions, reoperation and lengths of stay, or results in surgical delay, with its attendant risks of recurrent ischemic events [8]. Second, there is substantial inter-individual variability in the pharmacodynamic effect of clopidogrel, which impacts clinical outcomes after PCI [18-20]. While prasugrel and ticagrelor have a more rapid and intensive antiplatelet effect than clopidogrel, there is a delayed onset of action in ST-elevation MI patients, which may be associated with worse outcomes [21,22]. In the ACCOAST trial, pretreatment with prasugrel in non--ST-elevation MI patients significantly increased bleeding without providing ischemic benefit [23]. Finally, ACS patients are often taken emergently to the cardiac catheterization laboratory, and logistical issues such as sedation and hemodynamic instability may limit the ability to successfully administer an oral drug in a timely fashion. These shortcomings provide the rationale for the development of an intravenous, P2Y12 inhibitor with rapid pharmacodynamic onset and offset to be used in the acute setting. 3.
Cangrelor
Cangrelor is an intravenous, fast- and direct-acting platelet ADP P2Y12 receptor antagonist whose antiplatelet effect reverses rapidly. It is manufactured by The Medicines Co. (Parsippany, NJ, USA) and is currently under evaluation for approval by the United States FDA. In the setting of PCI, it is administered as a 30 µg/kg bolus followed by a 4 µg/kg/min infusion for the duration of the procedure or for 2 h, whichever is longer. Chemistry Cangrelor is a non-thienopyridine ATP analog with the chemical structure shown in Box 1. Alternative names include AR-C69931XX (cangrelor free acid), and AR-C69931MX (cangrelor tetrasodium salt). The chemical name is N6[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5´-adenylic acid, monoanhydride with (dichloromethylene) diphosphonic acid. 3.1
Pharmacodynamics Cangrelor directly, reversibly and competitively inhibits ADP binding to the P2Y12 receptor, which is broadly expressed on the surface of platelets. In healthy volunteers, a 30 µg/kg bolus followed by a 4 µg/kg/min infusion provided extensive inhibition of platelet aggregation by 2 min after the bolus dose, and 80% of subjects returned to near-baseline platelet activity within 60 min (Figure 1) [24]. In patients undergoing nonurgent or urgent PCI, a 4 µg/kg/min infusion without bolus provided nearly complete ADP-induced inhibition of 3.2
Expert Opin. Pharmacother. (2014) 15(4)
Cangrelor
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Table 1. Platelet P2Y12 inhibitors. Cangrelor
Ticagrelor
Clopidogrel
Prasugrel
Chemical class Interaction with the P2Y12 receptor
ATP analog Competitive, reversible
Thienopyridine Competitive, irreversible
Thienopyridine Competitive, irreversible
Prodrug Primary CYP enzyme for metabolism Onset of PD effect with loading dose Offset of effect
No None
CPTP Allosteric, noncompetitive, reversible No 3A4
Yes 2C19
Yes 3A4 and 2B6
Immediate
Rapid
Delayed
Rapid
~1 h
5 days
5 -- 7 days
7 -- 9 days
CPTP: Cyclopentyltriazolopyrimidine; CYP: Cytochrome P450; PD: Pharmacodynamics.
aggregation as measured by whole-blood impedance aggregometry [25,26]. The pharmacodynamics of low-dose cangrelor infusion were extensively studied in the BRIDGE (Maintenance of Platelet Inhibition With Cangrelor After DIscontinuation of Thienopyridines in Patients Undergoing Surgery) trial [27], which randomly assigned patients who had received a thienopyridine and were awaiting cardiac surgery to either placebo or 0.75 µg/kg/min infusion of cangrelor until surgery was performed. Patients treated with cangrelor had low levels of platelet reactivity throughout the treatment period (a median infusion duration of 2.8 days in the cangrelor arm). At the time of surgical incision (a median of 3.2 h after cangrelor discontinuation), platelet reactivity was not significantly different than patients treated with placebo.
of distribution (5.1 L), similar to that observed in healthy volunteers [25,34-38]. Cangrelor is rapidly dephosphorylated by ecto-endonucleatase to its major metabolite, ARC69412XX. The nucleoside AR-C69412XX, which is inactive, is further metabolized into several products, and is primarily eliminated in the urine (58%) and to a lesser degree in the feces (35%). In vitro studies demonstrated no significant inhibition of the cytochrome P450 system. Studies of patients with renal insufficiency have demonstrated that the plasma concentration--time profiles for cangrelor and its primary metabolite were comparable to those observed previously in healthy volunteers [25,34-38]. The pharmacokinetic/ pharmacodynamic relationships for the parent compound and metabolites are unchanged in renal impairment.
Interaction with thienoypyridines A pharmacodynamic interaction between cangrelor and the thienopyridines has been documented. Occupation of the P2Y12 receptor by cangrelor may prevent clopidogrel or prasugrel active metabolite from forming the necessary covalent bond with the receptor and to achieve antagonism but the exact mechanism of the interaction is not known [28]. Consistent with this possible interaction, the antiplatelet effect of clopidogrel was attenuated when administered at the start of cangrelor infusion in healthy volunteers, but no such effect was observed when clopidogrel was administered upon completion of the cangrelor infusion [29]. In the CHAMPION clinical trials, clopidogrel was administered to cangrelortreated patients after discontinuation of the infusion [30-32], not during the infusion, and there did not appear to be a significant pharmacodynamic interaction or effect on clinical events [33]. The effect of cangrelor infusion on the antiplatelet effect of ticagrelor has not been evaluated.
Clinical efficacy There have been three major Phase III clinical trials of cangrelor: CHAMPION (Cangrelor versus standard therapy to achieve optimal Management of Platelet Inhibition)-PCI, CHAMPION PLATFORM and CHAMPION PHOENIX (Table 2). All three trials evaluated the safety and efficacy of cangrelor during PCI in patients with stable angina/ischemia or ACS; they differed according to the timing of clopidogrel administration in the control group, and, in the case of PHOENIX, the definition of the ischemic endpoints that were assessed.
3.2.1
Pharmacokinetics and metabolism Cangrelor rapidly achieves steady-state concentration after bolus infusion and has an average half-life of 3 -- 6 min in healthy volunteers. Among patients with unstable angina or non-ST-elevation MI, there is rapid clearance of the parent compound from the plasma (44.3 L/h) and low initial volume 3.3
3.4
CHAMPION-PCI The CHAMPION-PCI trial randomly assigned 8716 patients with stable angina, unstable angina or non-ST-elevation myocardial infarction (NSTEMI) to receive a bolus and infusion of cangrelor (continued for 2 h or the duration of the PCI procedure, whichever was longer) followed by transition to clopidogrel or to receive clopidogrel 600 mg LD within 30 min of the start of PCI [31]. Cangrelor did not reduce the rate of the primary endpoint (composite of death, MI or ischemia-driven revascularization [IDR] at 48 h) compared with placebo (7.5 vs 7.1%, odds ratio [OR] 1.05, 95% CI 0.88 -- 1.24, p = 0.59), nor did it significantly increase the risk of GUSTO severe or TIMI major bleeding, although 3.4.1
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% of baseline impedance (Ohms)
160 Group A
Group B
140 120 100 80 60 40 20
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0 0
20
40
60
80
100
120
140
160
Time (min)
Figure 1. Effect of cangrelor on ADP-induced (20 mM) platelet aggregation by whole-blood electrical impedance in healthy volunteers. Group A, cangrelor 15 µg/kg bolus + 2 µg/kg/min infusion for 1 h; group B, cangrelor 30 µg/kg bolus + 4 µg/kg/min infusion for 1 h. Data are presented as mean ± SD. Adapted with permission from [24].
there was a trend toward increased ACUITY major bleeding (3.6 vs 2.9%, OR 1.26, 95% CI 0.99 -- 1.60, p = 0.06). The median time from hospital admission to PCI was only 6.3 h, which may have reduced the specificity of postprocedure cardiac biomarkers to detect a true recurrent MI in patients who presented with an ACS; post hoc analysis suggested a possible benefit for the combined endpoint of death, Q-wave MI or IDR (OR 0.67, 95% CI 0.39 -- 1.14, p = 0.14). CHAMPION-PLATFORM The CHAMPION-PLATFORM trial randomly assigned 5362 patients with stable angina/ischemia, unstable angina or NSTEMI who had not been treated with a thienopyridine to receive a bolus and infusion of cangrelor within 30 min of PCI followed by transition to clopidogrel or to receive a clopidogrel 600 mg LD immediately after the procedure [30]. Cangrelor did not significantly reduce the rate of the primary endpoint of death, MI or IDR at 48 h compared with placebo (7.0 vs 8.0%, OR 0.87, 95% CI 0.71 -- 1.07, p = 0.17). However, cangrelor did reduce the prespecified secondary endpoints of ST (0.2 vs 0.6%, OR 0.31, 95% CI 0.11 -- 0.85, p = 0.02), death from any cause (0.2 vs 0.7%, OR 0.33, 95% CI 0.13 -- 0.83, p = 0.02), and the post hoc, exploratory endpoint of death, Q-wave MI and IDR [0.9 vs 1.6%, OR 0.55 95% CI 0.33 -- 0.93, p = 0.02). 3.4.2
Challenges in ascertaining periprocedural MI in the current era of PCI
3.4.3
The primary endpoints of the CHAMPION PCI and PLATFORM were driven by the occurrence of MI. When ACS patients present with elevated biomarkers and the time from presentation to PCI is short, it is difficult to ascertain a periprocedural MI, as increased levels of biomarkers may reflect 568
the initial thrombotic event rather than a result of the procedure. The median time from hospital admission to PCI was only 6.3 and 7.9 h, respectively, in PCI and PLATFORM. Although both trials were negative with respect to their primary endpoint, the exploratory and post hoc findings in CHAMPION PCI and PLATFORM suggested a reduction in endpoints not dependent on biomarkers (i.e., ST, and the composite of death, Q-wave MI and IDR). Together with the short interval between admission and PCI, this supports the hypothesis that the biomarker definition for MI used in these trials may have underestimated the clinical efficacy of cangrelor. The universal definition of MI states that if biomarkers are elevated before the procedure and not stable or decreasing in at least two samples 6 h apart, there are insufficient data to diagnose periprocedural MI [39]. When the universal definition of MI was applied to a post hoc pooled analysis of the CHAMPION-PCI and CHAMPIONPLATFORM trials, there was a significant reduction in the primary endpoint of death, MI and IDR with cangrelor (OR 0.82, 95% CI 0.68 -- 0.99, p = 0.037) [40]. This pooled analysis furthermore demonstrated a substantial reduction in ST (OR 0.44, 95% CI 0.22 -- 0.87, p = 0.018). These hypothesis-generating findings formed the basis of the design and conduct of the CHAMPION PHOENIX trial. CHAMPION-PHOENIX The CHAMPION-PHOENIX trial randomly assigned 11,145 patients with stable CAD or ACS to receive either a bolus and infusion of cangrelor followed by transition to clopidogrel or a clopidogrel 300 or 600 mg LD [32]. The primary endpoint was a composite of death, MI, IDR or ST at 48 h. In this case, the definition of periprocedural MI required a careful assessment of patients’ baseline biomarker status and, if abnormal, additional clinical evidence of 3.4.4
Expert Opin. Pharmacother. (2014) 15(4)
Cangrelor
Table 2. The Phase III clinical trials of cangrelor. Trial
CHAMPION PCI CHAMPION PLATFORM CHAMPION PHOENIX
Trial size
Prior exposure to thienopyridine
Comparator
N = 5362
Prior exposure allowed Naı¨ve patients only
N = 11145
Naı¨ve patients only
Clopidogrel 600 mg within 30 min prior to PCI Clopidogrel 600 mg at end of PCI Clopidogrel 300 or 600 mg, dose and timing per operator
N = 8877
Endpoint
Duration
Death, MI or IDR
48 h
Death, MI or IDR
48 h
Death, MI (universal definition), IDR or ST
48 h
Outcome
7.5 vs 7.1%, p = 0.59 7.0 vs 8.0%, p = 0.17 4.7 vs 5.9%, p = 0.005
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IDR: Ischemia-driven revascularization; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; ST: Stent thrombosis.
ischemia. Stent thrombosis included both intraprocedural stent thrombosis (IPST) and definite ST according to the Academic Research Consortium definition. An independent blinded clinical events committee adjudicated all primary efficacy endpoints, and an independent and blinded angiographic core laboratory evaluated all procedures to objectively determine any procedural complications. Inclusion of IPST in the primary endpoint is a unique aspect of the CHAMPION PHOENIX trial, and prior studies as well as a recent analysis from CHAMPION PHOENIX have shown that this procedural complication is associated with substantial morbidity and mortality [41,42]. In PHOENIX, cangrelor significantly reduced the primary efficacy endpoint (4.7 vs 5.9%, OR 0.78, 95% CI 0.66 -- 0.93, p = 0.005), driven by reductions in ST and MI. The treatment effect of cangrelor was consistent across the subgroups of stable CAD, NSTEMI and STEMI (interaction p = 0.98), and whether the patient received clopidogrel 300 mg LD or 600 mg LD (interaction p = 0.61). With regard to safety, the rates of the primary safety endpoint, GUSTO severe bleeding, were not significantly different between groups. Pooled analysis A patient-level, pooled meta-analysis [43] of all three Phase III trials found that cangrelor significantly reduced the rate of the composite outcome of death, MI according to the universal definition, IDR or ST at 48 h (3.8 vs 4.7%, p = 0.0007) and that these results were maintained at 30 days. These findings must be interpreted with the understanding that the universal definition of MI was applied retrospectively to the adjudicated events from the CHAMPION-PLATFORM and CHAMPION-PCI. Consistent with the individual trials, there was no significant increase in GUSTO-defined moderate-to-severe bleeding or the need for blood transfusion among patients randomly assigned to cangrelor. 3.4.5
BRIDGE After discontinuation of a clopidogrel and prasugrel, at least 5 and 7 days are required for platelet functional recovery, respectively [44,45]. This results in surgical delays in patients with ACS and also represents a clinical dilemma in patients 3.4.6
with drug-eluting stents who require surgery. BRIDGE was a Phase II trial that evaluated the use of cangrelor for bridging thienopyridine-treated patients to CABG. A total of 210 patients with ACS or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery were randomly assigned to receive either cangrelor infusion or placebo. The primary efficacy endpoint was platelet reactivity measured by the VerifyNow P2Y12 test (Accumetics, San Diego, CA, USA), and the main safety endpoint was excessive CABG-related bleeding. A greater proportion of patients treated with cangrelor had low levels of platelet reactivity consistent with the maintenance of P2Y12 inhibition throughout the treatment period (98.8 vs 19%, p < 0.001); there were no significant differences in major bleeding prior to CABG or excessive CABG-related bleeding [27]. This study was not powered to address ischemic outcomes. Safety and tolerability There is a large body of data regarding the safety and tolerability of cangrelor, as this agent has been studied in several Phase III studies involving in total > 25,000 patients. Pooled analysis of patient-level data from these trials demonstrated that cangrelor bolus and infusion during PCI did not increase indices of major bleeding (i.e., GUSTO severe or TIMI major) or the need for any blood transfusion. However, cangrelor was associated with a greater rate of less severe bleeding events (GUSTO mild and TIMI minor) and increased bleeding according to more sensitive indices such as ACUITY major bleeding (4.2 vs 2.8%, p < 0.0001). The incidence of ACUITY major bleeding excluding large hematomas >5 cm was significantly greater with cangrelor, but the absolute difference was relatively small (1.3 vs 1.0%, p = 0.007). The rates of serious treatment-emergent adverse events were similar between cangrelor and placebo, although cangrelor was associated with a higher rate of dyspnea compared with placebo (1.1 vs 0.4%, p < 0.0001), which led to drug cessation in 0.1% of cases. 3.5
Regulatory affairs Cangrelor has not been approved for use in the United States, Canada or the European Union. It is currently undergoing 3.6
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evaluation by health authorities in several countries, including the FDA.
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4.
Conclusion
Cangrelor is a novel, intravenous, ATP analog that provides rapid and nearly complete inhibition of the platelet P2Y12 receptor and restoration of platelet function within approximately 60 min after discontinuation. This agent has been evaluated in several Phase III studies involving in total > 25,000 patients undergoing PCI for stable CAD or ACS. The drug is well tolerated, although transient dyspnea may rarely occur. Cangrelor reduces ischemic events compared to conventional clopidogrel therapy in thienopyridine-naı¨ve patients undergoing PCI, driven by reductions in MI according to the universal definition and in ST, with similar rates to placebo of major bleeding and blood transfusions but at the cost of more minor bleeding events. 5.
Expert opinion
Several observations from the CHAMPION trial program will impact the adoption of cangrelor into clinical practice. First, efficacy was demonstrated in thienopyridine-naı¨ve patients, that is, those not pretreated prior to angiography. Since pretreatment has not been routinely adopted in the United States, the PHOENIX trial design is consistent with, and the trial results applicable to, current practice for many US operators. Second, the magnitude of benefit must be interpreted in the context of the potential cost of the agent and the definition of the endpoints used in the landmark trials. In PHOENIX, the absolute risk reduction for periprocedural MI was 0.9%, providing a number needed to treat Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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(NNT) of 111; for overall ST, 0.6% (NNT = 167); and for IPST, 0.4% (NNT = 250). Although the consequences of ST may be severe, the relatively large NNT means that the magnitude of cangrelor adoption will likely be strongly influenced by the cost, particularly in the current era of health-care cost containment. The cost:benefit ratio will likely be more favorable in patients in whom the risk of procedural complications or significant periprocedural MI is the greatest -- that is, those with anatomical complexity (e.g., high SYNTAX scores) and/or increased clinical risk (e.g., high GRACE scores). Third, the safety and incremental efficacy of cangrelor has not been examined with ticagrelor or prasugrel, which are superior to clopidogrel in patients with ACS [3,5]. Cangrelor appears to have pharmacodynamic advantages over these agents, particularly in the setting of primary PCI for STEMI [21,22], but whether these translate into clinical benefit requires further evaluation. Despite these potential limitations, cangrelor represents an important addition to the pharmacological armamentarium of the interventional cardiologist for the acute care of patients undergoing PCI, as it does not require oral administration and reduces periprocedural MI and early ST without increasing major bleeding or the need for transfusion.
Declaration of interest MJ Price has received consulting honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly & Co., Accumetrics Inc, The Medicines Co., Medicure, St. Jude and Boston Scientific, equity interest in Iverson Genetics, and received speaking honoraria from AstraZeneca and Daiichi Sankyo/Eli Lilly & Co. J Walsh reports no conflicts of interest.
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Akers WS, Oh JJ, Oestreich JH, et al. Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. J Clin Pharmacol 2010;50:27-35
25.
Greenbaum AB, Grines CL, Bittl JA, et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial. Am Heart J 2006;151:689; e1-89, e10
26.
Wallentin L. P2Y(12) inhibitors: differences in properties and mechanisms Expert Opin. Pharmacother. (2014) 15(4)
27.
.
Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery. JAMA 2012;307:265-74 This phase II trial demonstrated that among thienopyridine-treated patients requiring CABG, a continuous infusion of cangrelor maintained consistent platelet inhibition which was rapidly reversed after discontinuation without associated excess CABG-related bleeding.
28.
Dovlatova NL, Jakubowski JA, Sugidachi A, Heptinstall S. The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost 2008;6:1153-9
29.
Steinhubl SR, Oh JJ, Oestreich JH, et al. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb Res 2008;121:527-34
30.
Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med 2009;361:2330-41
31.
Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med 2009;361:2318-29
32.
Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med 2013;368:1303-13 This is the landmark CHAMPION PHOENIX trials that established Cangrelor as superior to clopidogrel in reducing the rate of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis in patients undergoing PCI for stable angina/ischemia and acute coronary syndromes.
..
33.
Angiolillo DJ, Schneider DJ, Bhatt DL, et al. Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. J Thromb Thrombolysis 2012;34:44-55
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34.
Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. Ann Pharmacother 2006;40:925-30
35.
Wang K, Zhou X, Zhou Z, et al. Blockade of the platelet P2Y12 receptor by AR-C69931MX sustains coronary artery recanalization and improves the myocardial tissue perfusion in a canine thrombosis model. Arterioscler Thromb Vasc Biol 2003;23:357-62
.
universal definition of myocardial infarction. Am Heart J 2012;163:182-90; e4 This hypothesis-generating, post-hoc analysis of the CHAMPION PLATFORM and PCI trials formed the basis of the study design and management of CHAMPION PHOENIX.
41.
Brener SJ, Cristea E, Kirtane AJ, et al. Intra-procedural stent thrombosis: a new risk factor for adverse outcomes in patients undergoing percutaneous coronary intervention for acute coronary syndromes. JACC Cardiovasc Interv 2013;6:36-43 Genereux P, Stone GW, Harrington RA, et al. Impact of intra-procedural stent thrombosis during percutaneous coronary intervention: insights from the CHAMPION PHOENIX trial. J Am Coll Cardiol 2013.[Epub ahead of print]
36.
Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and ARC69931MX in patients with ischaemic heart disease. Platelets 2002;13:407-13
37.
Jacobsson F, Swahn E, Wallentin L, Ellborg M. Safety profile and tolerability of intravenous AR-C69931MX, a new antiplatelet drug, in unstable angina pectoris and non-Q-wave myocardial infarction. Clin Ther 2002;24:752-65
42.
38.
Chattaraj SC. Cangrelor AstraZeneca. Curr Opin Investig Drugs 2001;2:250-5
43.
39.
Thygesen K, Alpert JS, White HD, et al. Universal definition of myocardial infarction. Circulation 2007;116:2634-53
Steg PG, Bhatt DL, Hamm CW, et al. Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data. Lancet 2013;382:1981-92
40.
White HD, Chew DP, Dauerman HL, et al. Reduced immediate ischemic events with cangrelor in PCI: a pooled analysis of the CHAMPION trials using the
44.
Price MJ, Walder JS, Baker BA, et al. Recovery of platelet function after discontinuation of prasugrel or
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clopidogrel maintenance dosing in aspirin-treated patients with stable coronary disease: the recovery trial. J Am Coll Cardiol 2012;59:2338-43 45.
.
Price MJ, Teirstein PS. Dynamics of platelet functional recovery following a clopidogrel loading dose in healthy volunteers. Am J Cardiol 2008;102:790-5 This study demonstrated that the antiplatelet effect of a clopidogrel loading dose has a slow onset and varies substantially among individuals, highlighting the limitations of this agent and emphasizing the unmet clinical need for a rapid onset agent that provides a consistent and substantial effect in patients who require PCI.
Affiliation Joseph A Walsh III MD MS & Matthew J Price† MD † Author for correspondence Division of Cardiovascular Diseases, Scripps Clinic, 10666 North Torrey Pines Road, Maildrop S1056, La Jolla, CA 92037, USA Tel: +1 858 554 5032; Fax: +1 858 554 6883; E-mail: [email protected]
Cangrelor for treatment of arterial thrombosis
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Joseph A Walsh III & Matthew J Price† 1.
Introduction
Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, CA, USA
2.
Overview of the market
3.
Cangrelor
4.
Conclusion
5.
Expert opinion
Introduction: Percutaneous coronary intervention (PCI) is a highly effective treatment for obstructive coronary artery disease. Oral platelet P2Y12 receptor antagonists reduce ischemic events in patients treated with PCI. However, there are several limitations to their use, including variable pharmacodynamics, a slow onset and offset, and in those patients who are pretreated but subsequently require cardiac surgery, increased bleeding. Cangrelor is an intravenous agent that provides rapid and intensive inhibition of the P2Y12 receptor that quickly dissipates after discontinuation. A recent, Phase III randomized clinical trial of PCI patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding. Areas covered: This review outlines the pharmacodynamics, pharmacokinetics, and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned PCI. Expert opinion: Cangrelor is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients, without increasing major bleeding or the need for transfusion. Cangrelor will have particular benefit in clopidogrel-naı¨ve patients with high anatomical complexity and/or increased clinical risk (where the absolute risk for thrombotic and ischemic complications of PCI is greatest). Keywords: ADP antagonist, P2Y12 receptor, percutaneous coronary intervention, platelet, platelet inhibitor Expert Opin. Pharmacother. (2014) 15(4):565-572
1.
Introduction
Coronary artery disease (CAD) is the most common cause of death worldwide with an estimated 7.3 million deaths per year [1]. Percutaneous coronary intervention (PCI) with coronary stent implantation is the primary treatment for acute coronary syndrome (ACS) and for refractory stable angina or ischemia. In the year 2010, there were approximately 1,145,000 unique hospitalizations for ACS and 954,000 PCIs performed in the United States [2]. Although PCI is a highly effective therapy, periprocedural complications can occur. Early and longer-term therapy with the oral platelet P2Y12 receptor antagonists clopidogrel, prasugrel and ticagrelor substantially reduce the risk of post-PCI ischemic events, including myocardial infarction (MI), stent thrombosis (ST), and in the case of ticagrelor, cardiovascular mortality [3-5]. Dual antiplatelet therapy with aspirin and an oral platelet P2Y12 receptor inhibitor is therefore the standard of care in the treatment of patients undergoing PCI [6-8]. However, these oral agents have several limitations, particularly in the acute setting. This manuscript will review the pharmacology of cangrelor, a novel intravenous P2Y12 receptor antagonist, and the clinical data supporting its safety and efficacy in the setting of PCI.
10.1517/14656566.2014.882319 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary. Drug name Phase Indication
Cangrelor III Arterial thrombosis (but not yet FDA-approved) P2Y12 receptor inhibitor
Pharmacology description Route of Intravenous administration Chemical structure
S
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O O O P P HO P O O HO OH OH CI CI
N O HO
NH
N OH
N
N S
F F F
Pivotal trial(s)
2.
CHAMPION PCI, CHAMPION PLATFORM, CHAMPION PHOENIX
Overview of the market
Platelet activation and aggregation is a key driver of coronary thrombosis during ACS and plays a major role in thrombotic complications of PCI. Antiplatelet agents currently used before and during PCI include the oral P2Y12 receptor antagonists, clopidogrel, prasugrel and ticagrelor (Table 1), and the intravenous glycoprotein (GP) IIb/IIIa receptor antagonists, eptifibatide, tirofiban and abciximab. While the GP IIb/IIIa inhibitors significantly reduce ischemic events, they are associated with increased major bleeding and severe thrombocytopenia can occasionally occur, in particular with abciximab [9]. Large, randomized trials have demonstrated that the oral P2Y12 receptor antagonists reduce the composite endpoint of cardiovascular death, MI or stroke in patients with ACS treated with PCI [3,5,10]; clopidogrel also reduces ischemic events in patients undergoing nonurgent PCI [11]. However, these agents have several limitations that influence clinical outcomes and processes of care. First, clopidogrel and prasugrel are prodrugs that require biotransformation into an active metabolite to exert their antiplatelet effect [12,13]. The onset of platelet inhibition after a clopidogrel loading dose (LD) is slow, requiring pretreatment to establish a significant pharmacodynamic effect at the time of PCI. At least a 15-h pretreatment duration with a clopidogrel 300 mg LD may be required to detect a clinical effect (although there is limited data on the timing and relative benefit of clopidogrel preloading) [14]. While a clopidogrel 600 mg LD reaches steady-state inhibition more quickly [15], this larger dose did not reduce ischemic events in patients with ACS undergoing early invasive management [16]. Although some studies have suggested that pretreatment with clopidogrel is associated with a significantly lower incidence of periprocedural MI after 566
elective PCI, others have suggested no benefit to pretreatment compared with administration of the drug in the catheterization laboratory [17]. Pretreatment also has significant drawbacks if a patient subsequently requires coronary artery bypass grafting (CABG), since exposure to an oral P2Y12 receptor antagonist increases rates of major bleeding, blood transfusions, reoperation and lengths of stay, or results in surgical delay, with its attendant risks of recurrent ischemic events [8]. Second, there is substantial inter-individual variability in the pharmacodynamic effect of clopidogrel, which impacts clinical outcomes after PCI [18-20]. While prasugrel and ticagrelor have a more rapid and intensive antiplatelet effect than clopidogrel, there is a delayed onset of action in ST-elevation MI patients, which may be associated with worse outcomes [21,22]. In the ACCOAST trial, pretreatment with prasugrel in non--ST-elevation MI patients significantly increased bleeding without providing ischemic benefit [23]. Finally, ACS patients are often taken emergently to the cardiac catheterization laboratory, and logistical issues such as sedation and hemodynamic instability may limit the ability to successfully administer an oral drug in a timely fashion. These shortcomings provide the rationale for the development of an intravenous, P2Y12 inhibitor with rapid pharmacodynamic onset and offset to be used in the acute setting. 3.
Cangrelor
Cangrelor is an intravenous, fast- and direct-acting platelet ADP P2Y12 receptor antagonist whose antiplatelet effect reverses rapidly. It is manufactured by The Medicines Co. (Parsippany, NJ, USA) and is currently under evaluation for approval by the United States FDA. In the setting of PCI, it is administered as a 30 µg/kg bolus followed by a 4 µg/kg/min infusion for the duration of the procedure or for 2 h, whichever is longer. Chemistry Cangrelor is a non-thienopyridine ATP analog with the chemical structure shown in Box 1. Alternative names include AR-C69931XX (cangrelor free acid), and AR-C69931MX (cangrelor tetrasodium salt). The chemical name is N6[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5´-adenylic acid, monoanhydride with (dichloromethylene) diphosphonic acid. 3.1
Pharmacodynamics Cangrelor directly, reversibly and competitively inhibits ADP binding to the P2Y12 receptor, which is broadly expressed on the surface of platelets. In healthy volunteers, a 30 µg/kg bolus followed by a 4 µg/kg/min infusion provided extensive inhibition of platelet aggregation by 2 min after the bolus dose, and 80% of subjects returned to near-baseline platelet activity within 60 min (Figure 1) [24]. In patients undergoing nonurgent or urgent PCI, a 4 µg/kg/min infusion without bolus provided nearly complete ADP-induced inhibition of 3.2
Expert Opin. Pharmacother. (2014) 15(4)
Cangrelor
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Table 1. Platelet P2Y12 inhibitors. Cangrelor
Ticagrelor
Clopidogrel
Prasugrel
Chemical class Interaction with the P2Y12 receptor
ATP analog Competitive, reversible
Thienopyridine Competitive, irreversible
Thienopyridine Competitive, irreversible
Prodrug Primary CYP enzyme for metabolism Onset of PD effect with loading dose Offset of effect
No None
CPTP Allosteric, noncompetitive, reversible No 3A4
Yes 2C19
Yes 3A4 and 2B6
Immediate
Rapid
Delayed
Rapid
~1 h
5 days
5 -- 7 days
7 -- 9 days
CPTP: Cyclopentyltriazolopyrimidine; CYP: Cytochrome P450; PD: Pharmacodynamics.
aggregation as measured by whole-blood impedance aggregometry [25,26]. The pharmacodynamics of low-dose cangrelor infusion were extensively studied in the BRIDGE (Maintenance of Platelet Inhibition With Cangrelor After DIscontinuation of Thienopyridines in Patients Undergoing Surgery) trial [27], which randomly assigned patients who had received a thienopyridine and were awaiting cardiac surgery to either placebo or 0.75 µg/kg/min infusion of cangrelor until surgery was performed. Patients treated with cangrelor had low levels of platelet reactivity throughout the treatment period (a median infusion duration of 2.8 days in the cangrelor arm). At the time of surgical incision (a median of 3.2 h after cangrelor discontinuation), platelet reactivity was not significantly different than patients treated with placebo.
of distribution (5.1 L), similar to that observed in healthy volunteers [25,34-38]. Cangrelor is rapidly dephosphorylated by ecto-endonucleatase to its major metabolite, ARC69412XX. The nucleoside AR-C69412XX, which is inactive, is further metabolized into several products, and is primarily eliminated in the urine (58%) and to a lesser degree in the feces (35%). In vitro studies demonstrated no significant inhibition of the cytochrome P450 system. Studies of patients with renal insufficiency have demonstrated that the plasma concentration--time profiles for cangrelor and its primary metabolite were comparable to those observed previously in healthy volunteers [25,34-38]. The pharmacokinetic/ pharmacodynamic relationships for the parent compound and metabolites are unchanged in renal impairment.
Interaction with thienoypyridines A pharmacodynamic interaction between cangrelor and the thienopyridines has been documented. Occupation of the P2Y12 receptor by cangrelor may prevent clopidogrel or prasugrel active metabolite from forming the necessary covalent bond with the receptor and to achieve antagonism but the exact mechanism of the interaction is not known [28]. Consistent with this possible interaction, the antiplatelet effect of clopidogrel was attenuated when administered at the start of cangrelor infusion in healthy volunteers, but no such effect was observed when clopidogrel was administered upon completion of the cangrelor infusion [29]. In the CHAMPION clinical trials, clopidogrel was administered to cangrelortreated patients after discontinuation of the infusion [30-32], not during the infusion, and there did not appear to be a significant pharmacodynamic interaction or effect on clinical events [33]. The effect of cangrelor infusion on the antiplatelet effect of ticagrelor has not been evaluated.
Clinical efficacy There have been three major Phase III clinical trials of cangrelor: CHAMPION (Cangrelor versus standard therapy to achieve optimal Management of Platelet Inhibition)-PCI, CHAMPION PLATFORM and CHAMPION PHOENIX (Table 2). All three trials evaluated the safety and efficacy of cangrelor during PCI in patients with stable angina/ischemia or ACS; they differed according to the timing of clopidogrel administration in the control group, and, in the case of PHOENIX, the definition of the ischemic endpoints that were assessed.
3.2.1
Pharmacokinetics and metabolism Cangrelor rapidly achieves steady-state concentration after bolus infusion and has an average half-life of 3 -- 6 min in healthy volunteers. Among patients with unstable angina or non-ST-elevation MI, there is rapid clearance of the parent compound from the plasma (44.3 L/h) and low initial volume 3.3
3.4
CHAMPION-PCI The CHAMPION-PCI trial randomly assigned 8716 patients with stable angina, unstable angina or non-ST-elevation myocardial infarction (NSTEMI) to receive a bolus and infusion of cangrelor (continued for 2 h or the duration of the PCI procedure, whichever was longer) followed by transition to clopidogrel or to receive clopidogrel 600 mg LD within 30 min of the start of PCI [31]. Cangrelor did not reduce the rate of the primary endpoint (composite of death, MI or ischemia-driven revascularization [IDR] at 48 h) compared with placebo (7.5 vs 7.1%, odds ratio [OR] 1.05, 95% CI 0.88 -- 1.24, p = 0.59), nor did it significantly increase the risk of GUSTO severe or TIMI major bleeding, although 3.4.1
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% of baseline impedance (Ohms)
160 Group A
Group B
140 120 100 80 60 40 20
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0 0
20
40
60
80
100
120
140
160
Time (min)
Figure 1. Effect of cangrelor on ADP-induced (20 mM) platelet aggregation by whole-blood electrical impedance in healthy volunteers. Group A, cangrelor 15 µg/kg bolus + 2 µg/kg/min infusion for 1 h; group B, cangrelor 30 µg/kg bolus + 4 µg/kg/min infusion for 1 h. Data are presented as mean ± SD. Adapted with permission from [24].
there was a trend toward increased ACUITY major bleeding (3.6 vs 2.9%, OR 1.26, 95% CI 0.99 -- 1.60, p = 0.06). The median time from hospital admission to PCI was only 6.3 h, which may have reduced the specificity of postprocedure cardiac biomarkers to detect a true recurrent MI in patients who presented with an ACS; post hoc analysis suggested a possible benefit for the combined endpoint of death, Q-wave MI or IDR (OR 0.67, 95% CI 0.39 -- 1.14, p = 0.14). CHAMPION-PLATFORM The CHAMPION-PLATFORM trial randomly assigned 5362 patients with stable angina/ischemia, unstable angina or NSTEMI who had not been treated with a thienopyridine to receive a bolus and infusion of cangrelor within 30 min of PCI followed by transition to clopidogrel or to receive a clopidogrel 600 mg LD immediately after the procedure [30]. Cangrelor did not significantly reduce the rate of the primary endpoint of death, MI or IDR at 48 h compared with placebo (7.0 vs 8.0%, OR 0.87, 95% CI 0.71 -- 1.07, p = 0.17). However, cangrelor did reduce the prespecified secondary endpoints of ST (0.2 vs 0.6%, OR 0.31, 95% CI 0.11 -- 0.85, p = 0.02), death from any cause (0.2 vs 0.7%, OR 0.33, 95% CI 0.13 -- 0.83, p = 0.02), and the post hoc, exploratory endpoint of death, Q-wave MI and IDR [0.9 vs 1.6%, OR 0.55 95% CI 0.33 -- 0.93, p = 0.02). 3.4.2
Challenges in ascertaining periprocedural MI in the current era of PCI
3.4.3
The primary endpoints of the CHAMPION PCI and PLATFORM were driven by the occurrence of MI. When ACS patients present with elevated biomarkers and the time from presentation to PCI is short, it is difficult to ascertain a periprocedural MI, as increased levels of biomarkers may reflect 568
the initial thrombotic event rather than a result of the procedure. The median time from hospital admission to PCI was only 6.3 and 7.9 h, respectively, in PCI and PLATFORM. Although both trials were negative with respect to their primary endpoint, the exploratory and post hoc findings in CHAMPION PCI and PLATFORM suggested a reduction in endpoints not dependent on biomarkers (i.e., ST, and the composite of death, Q-wave MI and IDR). Together with the short interval between admission and PCI, this supports the hypothesis that the biomarker definition for MI used in these trials may have underestimated the clinical efficacy of cangrelor. The universal definition of MI states that if biomarkers are elevated before the procedure and not stable or decreasing in at least two samples 6 h apart, there are insufficient data to diagnose periprocedural MI [39]. When the universal definition of MI was applied to a post hoc pooled analysis of the CHAMPION-PCI and CHAMPIONPLATFORM trials, there was a significant reduction in the primary endpoint of death, MI and IDR with cangrelor (OR 0.82, 95% CI 0.68 -- 0.99, p = 0.037) [40]. This pooled analysis furthermore demonstrated a substantial reduction in ST (OR 0.44, 95% CI 0.22 -- 0.87, p = 0.018). These hypothesis-generating findings formed the basis of the design and conduct of the CHAMPION PHOENIX trial. CHAMPION-PHOENIX The CHAMPION-PHOENIX trial randomly assigned 11,145 patients with stable CAD or ACS to receive either a bolus and infusion of cangrelor followed by transition to clopidogrel or a clopidogrel 300 or 600 mg LD [32]. The primary endpoint was a composite of death, MI, IDR or ST at 48 h. In this case, the definition of periprocedural MI required a careful assessment of patients’ baseline biomarker status and, if abnormal, additional clinical evidence of 3.4.4
Expert Opin. Pharmacother. (2014) 15(4)
Cangrelor
Table 2. The Phase III clinical trials of cangrelor. Trial
CHAMPION PCI CHAMPION PLATFORM CHAMPION PHOENIX
Trial size
Prior exposure to thienopyridine
Comparator
N = 5362
Prior exposure allowed Naı¨ve patients only
N = 11145
Naı¨ve patients only
Clopidogrel 600 mg within 30 min prior to PCI Clopidogrel 600 mg at end of PCI Clopidogrel 300 or 600 mg, dose and timing per operator
N = 8877
Endpoint
Duration
Death, MI or IDR
48 h
Death, MI or IDR
48 h
Death, MI (universal definition), IDR or ST
48 h
Outcome
7.5 vs 7.1%, p = 0.59 7.0 vs 8.0%, p = 0.17 4.7 vs 5.9%, p = 0.005
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IDR: Ischemia-driven revascularization; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; ST: Stent thrombosis.
ischemia. Stent thrombosis included both intraprocedural stent thrombosis (IPST) and definite ST according to the Academic Research Consortium definition. An independent blinded clinical events committee adjudicated all primary efficacy endpoints, and an independent and blinded angiographic core laboratory evaluated all procedures to objectively determine any procedural complications. Inclusion of IPST in the primary endpoint is a unique aspect of the CHAMPION PHOENIX trial, and prior studies as well as a recent analysis from CHAMPION PHOENIX have shown that this procedural complication is associated with substantial morbidity and mortality [41,42]. In PHOENIX, cangrelor significantly reduced the primary efficacy endpoint (4.7 vs 5.9%, OR 0.78, 95% CI 0.66 -- 0.93, p = 0.005), driven by reductions in ST and MI. The treatment effect of cangrelor was consistent across the subgroups of stable CAD, NSTEMI and STEMI (interaction p = 0.98), and whether the patient received clopidogrel 300 mg LD or 600 mg LD (interaction p = 0.61). With regard to safety, the rates of the primary safety endpoint, GUSTO severe bleeding, were not significantly different between groups. Pooled analysis A patient-level, pooled meta-analysis [43] of all three Phase III trials found that cangrelor significantly reduced the rate of the composite outcome of death, MI according to the universal definition, IDR or ST at 48 h (3.8 vs 4.7%, p = 0.0007) and that these results were maintained at 30 days. These findings must be interpreted with the understanding that the universal definition of MI was applied retrospectively to the adjudicated events from the CHAMPION-PLATFORM and CHAMPION-PCI. Consistent with the individual trials, there was no significant increase in GUSTO-defined moderate-to-severe bleeding or the need for blood transfusion among patients randomly assigned to cangrelor. 3.4.5
BRIDGE After discontinuation of a clopidogrel and prasugrel, at least 5 and 7 days are required for platelet functional recovery, respectively [44,45]. This results in surgical delays in patients with ACS and also represents a clinical dilemma in patients 3.4.6
with drug-eluting stents who require surgery. BRIDGE was a Phase II trial that evaluated the use of cangrelor for bridging thienopyridine-treated patients to CABG. A total of 210 patients with ACS or treated with a coronary stent and receiving a thienopyridine awaiting CABG surgery were randomly assigned to receive either cangrelor infusion or placebo. The primary efficacy endpoint was platelet reactivity measured by the VerifyNow P2Y12 test (Accumetics, San Diego, CA, USA), and the main safety endpoint was excessive CABG-related bleeding. A greater proportion of patients treated with cangrelor had low levels of platelet reactivity consistent with the maintenance of P2Y12 inhibition throughout the treatment period (98.8 vs 19%, p < 0.001); there were no significant differences in major bleeding prior to CABG or excessive CABG-related bleeding [27]. This study was not powered to address ischemic outcomes. Safety and tolerability There is a large body of data regarding the safety and tolerability of cangrelor, as this agent has been studied in several Phase III studies involving in total > 25,000 patients. Pooled analysis of patient-level data from these trials demonstrated that cangrelor bolus and infusion during PCI did not increase indices of major bleeding (i.e., GUSTO severe or TIMI major) or the need for any blood transfusion. However, cangrelor was associated with a greater rate of less severe bleeding events (GUSTO mild and TIMI minor) and increased bleeding according to more sensitive indices such as ACUITY major bleeding (4.2 vs 2.8%, p < 0.0001). The incidence of ACUITY major bleeding excluding large hematomas >5 cm was significantly greater with cangrelor, but the absolute difference was relatively small (1.3 vs 1.0%, p = 0.007). The rates of serious treatment-emergent adverse events were similar between cangrelor and placebo, although cangrelor was associated with a higher rate of dyspnea compared with placebo (1.1 vs 0.4%, p < 0.0001), which led to drug cessation in 0.1% of cases. 3.5
Regulatory affairs Cangrelor has not been approved for use in the United States, Canada or the European Union. It is currently undergoing 3.6
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evaluation by health authorities in several countries, including the FDA.
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4.
Conclusion
Cangrelor is a novel, intravenous, ATP analog that provides rapid and nearly complete inhibition of the platelet P2Y12 receptor and restoration of platelet function within approximately 60 min after discontinuation. This agent has been evaluated in several Phase III studies involving in total > 25,000 patients undergoing PCI for stable CAD or ACS. The drug is well tolerated, although transient dyspnea may rarely occur. Cangrelor reduces ischemic events compared to conventional clopidogrel therapy in thienopyridine-naı¨ve patients undergoing PCI, driven by reductions in MI according to the universal definition and in ST, with similar rates to placebo of major bleeding and blood transfusions but at the cost of more minor bleeding events. 5.
Expert opinion
Several observations from the CHAMPION trial program will impact the adoption of cangrelor into clinical practice. First, efficacy was demonstrated in thienopyridine-naı¨ve patients, that is, those not pretreated prior to angiography. Since pretreatment has not been routinely adopted in the United States, the PHOENIX trial design is consistent with, and the trial results applicable to, current practice for many US operators. Second, the magnitude of benefit must be interpreted in the context of the potential cost of the agent and the definition of the endpoints used in the landmark trials. In PHOENIX, the absolute risk reduction for periprocedural MI was 0.9%, providing a number needed to treat Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
2.
3.
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(NNT) of 111; for overall ST, 0.6% (NNT = 167); and for IPST, 0.4% (NNT = 250). Although the consequences of ST may be severe, the relatively large NNT means that the magnitude of cangrelor adoption will likely be strongly influenced by the cost, particularly in the current era of health-care cost containment. The cost:benefit ratio will likely be more favorable in patients in whom the risk of procedural complications or significant periprocedural MI is the greatest -- that is, those with anatomical complexity (e.g., high SYNTAX scores) and/or increased clinical risk (e.g., high GRACE scores). Third, the safety and incremental efficacy of cangrelor has not been examined with ticagrelor or prasugrel, which are superior to clopidogrel in patients with ACS [3,5]. Cangrelor appears to have pharmacodynamic advantages over these agents, particularly in the setting of primary PCI for STEMI [21,22], but whether these translate into clinical benefit requires further evaluation. Despite these potential limitations, cangrelor represents an important addition to the pharmacological armamentarium of the interventional cardiologist for the acute care of patients undergoing PCI, as it does not require oral administration and reduces periprocedural MI and early ST without increasing major bleeding or the need for transfusion.
Declaration of interest MJ Price has received consulting honoraria from AstraZeneca, Daiichi Sankyo, Eli Lilly & Co., Accumetrics Inc, The Medicines Co., Medicure, St. Jude and Boston Scientific, equity interest in Iverson Genetics, and received speaking honoraria from AstraZeneca and Daiichi Sankyo/Eli Lilly & Co. J Walsh reports no conflicts of interest.
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Price MJ, Teirstein PS. Dynamics of platelet functional recovery following a clopidogrel loading dose in healthy volunteers. Am J Cardiol 2008;102:790-5 This study demonstrated that the antiplatelet effect of a clopidogrel loading dose has a slow onset and varies substantially among individuals, highlighting the limitations of this agent and emphasizing the unmet clinical need for a rapid onset agent that provides a consistent and substantial effect in patients who require PCI.
Affiliation Joseph A Walsh III MD MS & Matthew J Price† MD † Author for correspondence Division of Cardiovascular Diseases, Scripps Clinic, 10666 North Torrey Pines Road, Maildrop S1056, La Jolla, CA 92037, USA Tel: +1 858 554 5032; Fax: +1 858 554 6883; E-mail: [email protected]
