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Cangrelor in percutaneous coronary intervention Expert Rev. Clin. Pharmacol. 2(2), 137–145 (2009)
Julie H Oestreich† and Steven R Steinhubl Author for correspondence 725 Rose Street, College of Pharmacy, University of Kentucky, Lexington, KY 40514, USA Tel.: +1 859 257 1998 Fax: +1 859 257 7564 [email protected] †
Cangrelor is a novel, intravenous P2Y12 receptor antagonist in development for use in percutaneous coronary intervention. Currently in Phase III testing, the reversible platelet inhibitor provides several inherent advantages over other P2Y12 receptor antagonists in this setting for the prevention of adverse cardiac events. Unlike the class of thienopyridines (ticlopidine, clopidogrel and potentially soon to be available, prasugrel), cangrelor has nearly immediate onset after a bolus dose and a short half-life, and achieves maximal inhibition of ADP-mediated platelet function. Cangrelor’s distinct mechanism of action allows for intravenous administration and avoids both hepatic and renal metabolism. These unique characteristics make cangrelor a promising agent for use in cardiovascular patients undergoing percutaneous coronary intervention. Keywords: acute coronary syndrome • cangrelor • clopidogrel • P2Y12 receptor • percutaneous coronary intervention • platelet inhibition
Market overview
Percutaneous coronary intervention (PCI) is a common procedure in the USA for patients presenting with acute coronary syndrome (ACS), which includes unstable angina and acute myocardial infarction (MI). The most recent American Heart Association statistics estimate that over 1.2 million PCI procedures are performed each year on diseased vessels, and the majority of patients leave the catheterization laboratory with at least one stent placement [101] . In addition to heparin, appropriate platelet inhibition with P2Y12 receptor antagonists and other antiplatelet agents is indicated to prevent adverse cardiovascular events during and after PCI. The importance of P2Y12 receptor antagonism is substantiated by the millions of patients worldwide who have been treated with clopidogrel in PCI and other settings. Moreover, its costliness and common utilization make clopidogrel one of the most profitable prescription drugs in the world for its manufacturers. The value of targeting the platelet P2Y12 receptor in PCI has been established by the clinical utility of the thienopyridines ticlopidine (Ticlid®, Roche, NJ, USA) and clopidogrel (Plavix®/Iscover®, Sanofi-Aventis, NJ, USA), the only P2Y12 receptor antagonists currently available on the market. Due to the increased incidence of bone marrow toxicity and blood dyscrasias with ticlopidine, clopidogrel is the www.expert-reviews.com
10.1586/17512433.2.2.137
preferred agent for prevention of acute and long-term adverse coronary events in ischemic patients and is marketed in numerous countries worldwide. Several large-scale clinical trials have established the benefit of clopidogrel in cardiovascular patients with and without additional platelet inhibition with aspirin [1–5] . For patients undergoing PCI, long-term clopidogrel therapy for 1 year in addition to aspirin reduces the combined primary outcome of death, MI and stroke by 26.9% (relative risk reduction) [2] . In addition, treatment with a loading dose of clopidogrel prior to PCI results in a 58.8% relative risk reduction of the combined end points of death, MI and urgent target vessel revascularization, albeit these results are based on a post hoc analysis and are dependent upon the dose and time of administration [2,6] . For a 300-mg loading dose, adequate pretreatment prior to a PCI of several hours (15–24 h) is required to achieve therapeutic benefit; however, a more rapid onset of action and maximal pharmacodynamic effect may be obtained with a 600-mg loading dose [2,6,7] . On the other hand, in a primarily non-invasively treated ACS population, a 300-mg loading dose of clopidogrel, compared with placebo, leads to a noticeable separation of event rates within several hours that is statistically significant by 24 h [8] . Standard (300 mg) and high-dose (600 mg) pretreatment with clopidogrel is currently being evaluated for the first time in the
© 2009 Expert Reviews Ltd
ISSN 1751-2433
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prospective, double-blinded Clopidogrel Optimal Loading Dose The newer thienopyridine, prasugrel (Effient ®, Eli Lilly Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy and Company, IN, USA, and Daiichi Sankyo, Inc., NJ, USA) for Interventions (CURRENT/OASIS7) trial (NCT00335452). has more consistent metabolism to an active metabolite and Clinical outcomes from this large-scale study should further reduced variability in platelet response compared with clopidogclarify the optimal loading dose for PCI. rel [25–28] . The pivotal clinical trial Trial to Assess Improvement Based on this evidence, recent consensus documents recom- in Therapeutic Outcomes by Optimizing Platelet Inhibition with mend the administration of a clopidogrel loading dose (gener- Prasugrel–Thrombolysis In Myocardial Infarction (TRITON ally at least 300 mg, but up to 600 mg) before or when PCI TIMI-38) established the superiority of prasugrel over clopidogrel is initiated, and maintenance treatment for various durations, at the dosing regimen investigated the prevention of the comdepending on the type of stent and ACS diagnosis [9] . In patients bined clinical end point of cardiovascular death, MI and stroke undergoing elective stenting without a high risk for bleeding, in ACS patients undergoing PCI; however, the higher extent the standard clopidogrel maintenance dose of 75 mg is advised of platelet inhibition was also associated with a statistically sigfor at least 1 month and preferably up to 12 months for bare- nificant increase in TIMI major bleeding events, including fatal metal stents, and a minimum 12 months of treatment is indi- bleeding [29] . Therefore, the role of prasugrel in this setting is still cated when drug-eluting stents are placed [9] . For patients with unclear. In an ideal world, analysis of platelet function would non-ST-segment elevation ACS and ST-segment elevation MI distinguish which patients would benefit from the more potent (STEMI), clopidogrel for 12 months is recommended irrespective thienopyridine and its associated risk. Unfortunately, there are of the acute treatment [10,11] . Combined, these recommendations currently not enough concrete data to recommend dose adjustsupport the usefulness of P2Y12 receptor inhibition in the setting ments based upon ex vivo platelet testing. The appropriate target of PCI. range for platelet inhibition that provides sufficient protection Despite the undisputed clinical benefit and widespread utili- from adverse cardiac events balanced with the lowest bleeding zation of clopidogrel in PCI, there are significant shortcomings risk is still unknown. Although more potent platelet inhibition associated with its use. As with all thienopyridines, clopidogrel is presumably advantageous for some patients, prasugrel is still is a prodrug that requires hepatic conversion by the cytochrome plagued by other characteristics of thienopyridines. Prasugrel, P450 system to attain pharmacological activity [7] . Consequently, similar to other thienopyridines, requires hepatic conversion to an clopidogrel has a delayed onset of action and its activity is suscep- active metabolite and irreversibly inhibits ADP-induced platelet tible to variations in metabolism. The short-lived active metabo- function for the life of the platelet [30] . These limitations have lite of the drug is believed to form a disulfide bridge with extra- spurred further development of new P2Y12 antagonists optimized cellular cysteines on the P2Y12 receptor to cause incomplete and for use in PCI. irreversible inhibition of ADP-mediated aggregation for the life of the platelet (7–10 days) [12–14] . There is no pharmacological Cangrelor antidote, and a small percentage of patients undergoing PCI Chemistry also require emergent coronary artery bypass graft (CABG) sur- The novel antiplatelet agent cangrelor (The Medicines Company, gery [15] . More importantly, in patients with an ACS, if whom NJ, USA) is a specific and potent antagonist of ADP-induced approximately 15% will require CABG for revascularization [16] , platelet activity currently in Phase III development [31] . early initiation of clopidogrel can lead to either prolonged hospi- Cangrelor (2-trifluoropropylthio, N-(2-(methylthio)-ethyl-β, talization while awaiting surgery or an increased risk of bleeding γ-dichloromethylene ATP)) is an ATP analogue (Figure 1) that if surgery is not delayed [1] . competitively inhibits platelet activation and aggregation by Furthermore, there is well-documented ex vivo variability in the reversibly binding the P2Y12 receptor. The structure of ATP, response to clopidogrel, as 4–30% of patients do not obtain the an endogenous antagonist to the target receptor, was altered expected degree of inhibition depending on the type of assay uti- to produce a compound with increased stability, affinity and lized and definition of nonresponsiveness employed [17,18] . Evidence potency [13,32] . to support the clinical relevance of this variability is limited, although nonresponders + 4Na have shown a higher risk for thrombotic S CH3 HN events [19–22] . The potential mechanisms of clopidogrel nonresponsiveness are N N diverse, yet several explanations relate to O O O CF3 the intrinsic pharmacokinetic properties O P O N S N P P O O of the drug, including drug–drug interacO O O Cl tions, bioavailability [23] and genetic variaCl OH tions in cytochrome P450 enzymes [24] . As HO with all medications, compliance is also an important factor that could contribute to Figure 1. Cangrelor, an ATP analogue and novel antiplatelet agent. variability in response. 138
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Drug Profile
Cangrelor in percutaneous coronary intervention
muscle cells) and, therefore, serves as a favorable therapeutic target [12,13] . The Gq-coupled P2Y1 receptor is ubiquitously expressed and mediates transient platelet shape change and increased intracellular calcium, whereas binding of ADP to the Gi-coupled P2Y12 receptor is required for complete and irreversible platelet activation [13,33,34] . P2Y12 receptor activation triggers several signaling pathways via both Gα and Gβγ subunits of the protein, ultimately causing platelet granule secretion of ADP and other mediators, thromboxane A2 generation and increased expression and activation of the αIIbβ3 (glycoprotein IIb/IIIa)
Pharmacology
ADP P2Y receptors are critical regulators of platelet function. Although ADP is considered a weak agonist, platelet activation by more potent agonists is dependent upon ADP secretion from platelet granules and subsequent binding to P2Y receptors. ADP is the endogenous ligand for both P2Y12 and P2Y1 receptors that stimulate platelet aggregation (Figure 2) , while ATP is a natural antagonist for both receptors [33] . Unlike the widely distributed P2Y1 receptor, the P2Y12 receptor has only been found on select cell types (including platelets, glioma cells and vascular smooth
ADP Cangrelor P2Y1 P2Y12 GIRK Giα AC
ATP
PP
Ca++
α
Gβγ
β γ
Gqα γ β
PDE
PI3K
PLCβ
α
Rac cAMP
IP3 DAG
Shape change
Granule release
PKC
PKA P-VASP
VASP
Akt
Ca++
PIP2
Rap1b
Ca++ release
ERK2
Membrane phospholipids
PLA2
PGG2
αIIbβ3/GPIIb–IIIa conformational change
PGH2 TxA2
AA
COX-1
TxAS
Expert Rev. Clin. Pharmacol. © Future Science Group (2009)
Figure 2. Effects of the ADP receptors P2Y1 and P2Y12 on platelet activation and aggregation. Cangrelor specifically and selectively inhibits the P2Y12 receptor, one of two G-protein-coupled platelet ADP receptors. Activation of the P2Y12 receptor by ADP leads to TxA2 generation, platelet granule release of ADP and other mediators of aggregation and coagulation, and increased expression and activation of the αIIbβ3 receptor (GP IIb/IIIa). The P2Y12 receptor causes irreversible and sustained platelet activation and aggregation through multiple signaling pathways via both Giα and Gβγ subunits. Conversely, the P2Y1 receptor has transient and reversible effects on platelet shape change and aggregation mediated by calcium release. AA: Arachidonic acid; AC: Adenylate cyclase; cAMP: Cyclic adenosine monophosphate; COX: Cyclooxygenase; DAG: Diacylglycerol; GP: Glycoprotein; IP3: Inositol 1,4,5-triphosphate; PDE: Phosphodiesterase; PG: Prostaglandin; PI3K: Phosphoinositide-3 kinase; PIP2: Phosphatidylinositol (4,5)-bisphosphate; PK: Protein kinase; PlA2: Phospholipase A2; PLCβ: Phospholipase C-β; P-VASP: Phosphorylated vasodilator-stimulated phosphoprotein; TxA2: Thromboxane A2; TxAS: Thromboxane A2 synthase; VASP: Vasodilator-stimulated phosphoprotein.
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two separate Phase II multicenter trials (one open-label and the other randomized, double-blinded and placebo-controlled), 130 combined unstable angina and non-ST-segment elevation MI (NSTEMI) patients were administered an infusion of cangrelor Pharmacokinetics & metabolism or placebo in addition to aspirin and heparin or low-molecularCangrelor is a rapid-acting and short-lived intravenous medica- weight heparin. Both preliminary studies demonstrate that cantion. Following a bolus dose and infusion regimen in healthy grelor infused up to 72 h is not accumulated nor associated with volunteers (15 µg/kg bolus plus 2 µg/kg/min or 30 µg/kg bolus an increase in serious adverse events [38,41] . Intravenous cangrelor plus 4 µg/kg/min), maximal and steady-state cangrelor concen- has also been studied as adjunct therapy to fibrinolysis for acute trations are obtained within minutes of administration [35] . The myocardial infarction in the Safety, Tolerability and Effect on drug displays linear, dose-dependent pharmacokinetics at the Patency in Acute Myocardial Infarction (STEP-AMI) trial [39] . studied range and has a limited volume of distribution (∼3.7 l) A total of 101 patients were randomized to receive one of three due to its polar nature and fast metabolism [35] . Cangrelor levels cangrelor doses in addition to alteplase 50 mg (tissue plasminogen return to baseline within 10 min after stopping the infusion activator), cangrelor alone or alteplase alone (100 mg). Although because the drug is rapidly dephosphorylated by an ecto-ADPase the trial was stopped early due to the sponsor at that time’s deciassociated with vascular endothelial cells [35,36] . This unique sion not to pursue clinical development, bleeding complications pathway allows cangrelor to avoid both hepatic and renal routes and major adverse clinical events were not different between of metabolism. In addition to the fast onset and reversible prop- combination therapy and standard-dose alteplase, and a potential erties of the drug, cangrelor’s extremely short half-life (2.6–3.6 clinical benefit could not be ruled out with the small number of min) is an attractive feature for patients undergoing PCI [35,37] . subjects tested [39] . A Phase II, multicenter, randomized, placebo and active Pharmacodynamics controlled trial also evaluated cangrelor in patients undergoing Similar to the pharmacokinetic data, the platelet pharmaco PCI [40] . Subjects in part 1 were randomized to placebo or a dynamic response to cangrelor is rapid-acting and quickly revers- cangrelor 1-, 2- or 4-µg/kg/min infusion initiated before PCI ible following drug discontinuation. Ex vivo platelet testing of in combination with aspirin and heparin. Part 2 compared the cangrelor-treated healthy volunteers demonstrates that platelet highest dose of cangrelor with abciximab. No statistically siginhibition is obtained within minutes of initiating therapy, as nificant differences were obtained between cangrelor and either demonstrated by ADP-activated whole-blood aggregometry and control group for major and minor bleeding or when comparing flow cytometric analysis of agonist-induced P-selectin expression. the 30‑day incidence of adverse cardiac events between cangrelor In total, 50% of platelet function is recovered within 10–30 min and abciximab [40] . Although both cangrelor and abciximab comafter stopping the infusion and a complete return to baseline pletely inhibited ADP-stimulated platelet aggregation, as measfunction is achieved within 60–90 min [35] . In preliminary stud- ured by electrical impedance aggregometry, subjects returned to ies, the short half-life of cangrelor is not associated with rebound baseline platelet function more quickly with cangrelor after the platelet activation following termination of the infusion [38–40] . infusion was discontinued. Two large-scale Phase III clinical trials are ongoing to assess Clinical efficacy the safety and efficacy of cangrelor in patients with coronary Cangrelor has been well tolerated in clinical trials alone and in atherosclerosis and ACS requiring PCI (Table 1) . Both prospeccombination with other agents, including aspirin and heparin. In tive, randomized, double-blinded and placebo-controlled studies are evaluating a composite primary Table 1. Ongoing clinical trials to assess the efficacy and safety end point of all-cause mortality, MI and of cangrelor. ischemia-driven revascularization assessed 48 h after randomization. The Cangrelor Cangrelor trials Phase Expected Primary Population enrollment end point versus Standard Therapy to Achieve (n) Optimal Management of Platelet Inhibition (CHAMPION)-PCI trial is expected to CHAMPIONIII 6400 Efficacy ACS with PCI enroll 9000 patients (a mix of stable angina, PLATFORM unstable angina, NSTEMI and STEMI) CHAMPION-PCI III 9000 Efficacy ACS with PCI to be managed with PCI following randQT/QTc I 66 Safety Healthy volunteers omization and administration of a clopiBRIDGE II 200 Platelet inhibition Patients discontinuing dogrel 600-mg loading dose or cangrelor clopidogrel 3–5 days 30-µg/kg intravenous bolus and 4-µg/kg/ prior to planned min infusion (NCT00305162). Patients CABG will receive study drug infusion (cangrelor ACS: Acute coronary sydrome; BRIDGE: Maintenance of Platelet Inhibition With Cangrelor; or placebo) for up to 2 h or the duration CABG: Coronary artery bypass graft; CHAMPION: Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition; PCI: Percutaneous coronary intervention. of PCI, whichever is longer. At the time receptors (Figure 2) . Through these processes, the P2Y12 receptor pathway potentiates platelet recruitment, aggregation and coagulation [34] .
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120
Light transmittance (%)
100
Clopidogrel at the end of cangrelor infusion Clopidogrel only Clopidogrel plus cangrelor
Drug Profile
7 days or presenting with STEMI within 48 h are not eligible. Enrollment is expected to reach 6400 subjects to assess the efficacy and tolerability of cangrelor added to standard treatment (NCT00385138). Completion of both CHAMPION trials is expected by early 2009.
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Safety & tolerability
The safety of cangrelor has been evaluated in healthy volunteers, patients with unstable angina and acute MI, and those undergoing PCI. Generally, the drug has 40 been well tolerated, and the most common adverse effect, as expected, is pro20 longation of bleeding time and bleeding events [38,40,41] . Initial studies suggest that bleeding and adverse events are similar 0 or better with cangrelor compared with 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 abciximab and alteplase [39,40] . In one Time (h) open-label study, 21% of patients treated with a cangrelor infusion for up to 72 h Figure 3. Clopidogrel inhibits ADP-induced platelet aggregation when experienced elevated ALT levels [41] ; howadministered immediately following a cangrelor infusion, but does not achieve ever, there were no associated clinical the expected level of inhibition when administered simultaneously with manifestations with the increase and this cangrelor. The effect of cangrelor and clopidogrel on ADP-induced (20 µM) platelet aggregation was evaluated by light transmittance aggregometry. Subjects finding was not reproduced in randomized randomized to treatment arm 1 (n = 10) were administered a cangrelor 30 µg/kg controlled studies [38] . A double-blind, intravenous bolus plus a 4 µg/kg/min infusion for 1 h immediately followed by oral placebo-controlled, positive-controlled, administration of clopidogrel 600 mg at the end of the cangrelor infusion (solid line). randomized, crossover Phase I safety trial Subjects in treatment arm 2 (n = 10) were first administered oral clopidogrel 600 mg (Table 1) is ongoing to assess the effect of followed by a 2-week washout period. After the washout period, subjects were therapeutic and supratherapeutic doses readministered oral clopidogrel 600 mg simultaneous with a cangrelor 30 µg/kg of cangrelor on the QT/QTc interval in intravenous bolus and a 4 µg/kg/min infusion for 2 h (dashed lines). Data are 66 healthy volunteers (NCT00699504). presented as mean ± SEM. Similar results were obtained with electrical impedance Additionally, there is an ongoing Phase II aggregometry and flow cytometry. Adapted from [42] . trial to assess the safety of a prolonged cangrelor infusion (up to 5 days) prior of completion of the study drug infusion, patients randomized to CABG surgery (NCT00767507). The Maintenance of to cangrelor will receive clopidogrel 600 mg, while the control Platelet Inhibition with Cangrelor after Discontinuation of arm will receive matching placebo. In a small pharmacodynamic Thienopyridines in Patients Undergoing Surgery (BRIDGE) substudy, approximately 300 patients will undergo serial platelet trial is designed primarily to identify the appropriate cangrelor function testing to determine if cangrelor influences clopidogrel’s infusion dose for longer durations that might be used in patients ability to inhibit platelet function. treated with an irreversible P2Y12 receptor antagonist requiring The CHAMPION-PLATFORM trial is investigating can- bridging therapy prior to an invasive procedure. The trial will grelor compared with usual care in PCI subjects. As in the evaluate platelet inhibition and bleeding and is expected to be CHAMPION-PCI trial, patients will be randomized to receive completed by late 2009 (Table 1). a cangrelor bolus and infusion or matching placebo prior to the initiation of PCI. Then, unlike the PCI trial, patients enrolled Drug interactions in the PLATFORM trial will not receive a 600-mg loading dose Interestingly, the only reported drug interaction with cangreof clopidogrel or matching placebo until the PCI procedure is lor to date is a pharmacodynamic interaction with clopidogcomplete. Again, similar to the PCI study, patients will receive rel [42] . Patients undergoing PCI, including those treated with oral drug of either clopidogrel 600 mg for those randomized cangrelor, will be expected to maintain long-term oral P2Y12 to cangrelor, or matching placebo for those in the control arm, inhibition to prevent adverse coronary events. A clinical trial following completion of the 2-h study drug infusion. Eligible assessing the transition of patients from cangrelor to clopidogrel patients are similar between PCI and PLATFORM; however, in identified a probable competitive and time-dependent inter PLATFORM, patients taking any thienopyridine in the previous action between the drugs as assessed by whole-blood electrical 60
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impedance aggregometry, light-transmittance aggregometry and flow cytometry. Healthy volunteers randomized to receive a 600-mg clopidogrel loading dose immediately following a cangrelor 30-µg/kg intravenous bolus and 1-h 4-µg/kg/min infusion obtained the expected degree of platelet inhibition for both antiplatelet agents [42] . Cangrelor inhibited 80% of lighttransmittance platelet aggregation induced by ADP 20 µM, and clopidogrel inhibited 50–60% of the platelet response following a predicted delay of onset. Those randomized to receive the loading dose of clopidogrel simultaneously with cangrelor did not achieve the expected inhibition with clopidogrel as post infusion pharmacodynamic measures returned and remained at baseline (Figure 3) [42] . Most probably, there is a competitive interaction when the short-lived active metabolite of clopidogrel is unable to compete for receptor occupancy in the presence of the reversible inhibitor cangrelor. Cangrelor’s high affinity for the P2Y12 receptor prevents clopidogrel’s active metabolite from irreversibly binding the target receptor. The half-life of clopidogrel’s unstable active metabolite is postulated to be very short, and evidence from this study suggests that no active metabolite remains 2 h after a 600-mg loading dose [42] . The clinical relevance of this interaction in PCI patients is unknown. Recently, a similar interaction was shown to occur with the active metabolite of prasugrel [43] . Other nonthienopyridine, orally available P2Y12 antagonists might avoid this potential interaction. Regulatory affairs
Cangrelor was purchased by The Medicines Company from AstraZeneca. The Medicines Company possesses the development, marketing and sales rights for cangrelor in all countries worldwide, except for Japan, Korea, China, Thailand and Taiwan [44] . Conclusion
Cangrelor is a novel antagonist of the P2Y12 receptor that directly, potently and reversibly inhibits ADP-induced platelet aggregation. Intravenously administered cangrelor has a fast onset of action and is quickly reversible once the infusion is stopped. These unique characteristics provide advantages over currently available antiplatelet medications, supporting cangrelor as a promising option for patients undergoing PCI.
Expert commentary & five-year view
Beyond the current standard of care with aspirin, clopidogrel and occasional glycoprotein (GP) IIb/IIIa antagonism, cangrelor has the potential to impact antiplatelet treatment in the cardiac catheterization laboratory. Its novel pharmacokinetic profile provides unparalleled intrinsic advantages over the currently available agents. The remaining questions for Phase III testing are critical and will decide if cangrelor is effective and if there are over-riding safety concerns that have not previously been identified. Although cangrelor is not the first intravenous antiplatelet therapy, it has several assumed advantages over the GP IIb/IIIa receptor antagonists. Cangrelor targets the upstream G-proteincoupled P2Y12 receptor and leaves the receptors for platelet-toplatelet aggregation intact. This may account for a preferential bleeding profile with cangrelor compared with GP IIb/IIIa antagonists, although this has yet to be proven. Although other receptors are certainly important for response, the dependency of all platelet pathways on ADP release for complete activity makes the P2Y12 receptor a good target in theory. Other novel targets for platelet inhibition are advanced in testing and may certainly prove useful; however, in the meantime, clopidogrel has established the P2Y12 receptor as a gold mine for drug effectiveness and certainly financial gain. For several years, there have been no feasible antiplatelet alternatives beyond combination therapy with aspirin and clopidogrel. The probable addition of prasugrel to the armamentarium of ADP antagonists allows, for the first time, a choice for more potent inhibition, even if the target level of inhibition is unclear. Research is ongoing and necessary to clarify individual differences in platelet function and drug response. The future of antiplatelet therapy is tailored, personalized treatments to an appropriate level of platelet inhibition. The role for cangrelor in that future setting and now is promising, particularly since its features allow for several safety advantages. Cangrelor is direct, fast-acting and reversible and, if proven safe and effective, will substantiate the flexibility for P2Y12 receptor inhibition in PCI. Furthermore, when the optimal level of platelet inhibition is determined, cangrelor would provide the luxury of titration to pharmacodynamic response in individual patients.
Table 2. Comparison of current and emerging P2Y12 receptor antagonists. Drug
Approval status
Route of administration
Drug class
Bioavailability
Receptor interaction
Pharmacodynamic half-life
Ticlopidine
Approved
Oral
Thienopyridine (1st generation)
Prodrug
Irreversible
Life of platelet
Clopidogrel
Approved
Oral
Thienopyridine (2nd generation)
Prodrug
Irreversible
Life of platelet
Prasugrel
Phase III completed
Oral
Thienopyridine (3rd generation)
Prodrug
Irreversible
Life of platelet
Cangrelor
Phase III
IV
ATP analog
Direct-acting
Reversible
Minutes
Ticagrelor
Phase III
Oral
ATP analog
Direct-acting
Reversible
6-12 h
PRT060128
Phase II
Oral, IV
Direct-acting
Reversible
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Even if cangrelor reaches the market for use in the catheterization laboratory, long-term inhibition of the P2Y12 receptor will still be indicated. The clinical relevance of the influence of cangrelor on the onset of clopidogrel’s antiplatelet effects will be determined through the CHAMPION trials [42] . Fortunately, the horizon for new antiplatelet agents includes cangrelor’s sister compound ticagrelor (AZD6140, AstraZeneca, London, UK), an orally administered ATP analogue in Phase III testing (Table 2) [30,44] . Early speculation would propose no significant interaction between cangrelor and long-term therapy with ticagrelor. A standard scenario 5 years from now with cangrelor and ticagrelor for the prevention of adverse cardiac events during and following PCI in ACS patients is certainly possible and, quite possibly, an improvement to current therapy. In addition to these compounds, the pipeline also includes PRT060128 (Portola Pharmaceuticals, Inc., CA, USA), a P2Y12 antagonist available in both intravenous and oral formulations currently in Phase II development (Table 2) [31] . The future for P2Y12 inhibition in PCI looks optimistic, with many new and improved agents on the horizon, and cangrelor
Drug Profile
certainly adds to this promise. Its large-scale clinical efficacy trials are highly anticipated due to the superior pharmacokinetic profile of cangrelor compared with available treatments. Acknowledgements
Appreciation is extended to Tom Dolan at the University of Kentucky for his work on the platelet figure (Figure 2). Financial & competing interests disclosure
This work acknowledges the support of awards from the American Heart Association, the Pharmaceutical Research and Manufacturers of America Foundation, the American Foundation for Pharmaceutical Education and the Sigma Xi Scientific Society. Steven Steinhubl is an employee of The Geisinger Clinic, Danville, PA and The Medicines Company, Zurich, Switzerland. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Cangrelor is a novel P2Y12 receptor antagonist in Phase III development for use in acute coronary syndrome patients undergoing percutaneous coronary intervention. • Cangrelor potently and reversibly inhibits platelet function and has a fast onset and offset of action. • Cangrelor does not require conversion to a prodrug and is metabolized in the bloodstream without hepatic or renal involvement. • These unique pharmacokinetic advantages compared with the thienopyridines (ticlopidine, clopidogrel and prasugrel) make cangrelor a promising candidate for this setting. • Results from cangrelor’s large-scale clinical efficacy and safety trials are highly anticipated to determine its potential role for acute coronary syndrome patients undergoing percutaneous coronary intervention.
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Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345(7), 494–502 (2001). Steinhubl SR, Berger PB, Mann JT 3rd et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288(19), 2411–2420 (2002).
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Steinhubl SR, Berger PB, Brennan DM, Topol EJ. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J. Am. Coll. Cardiol. 47(5), 939–943 (2006).
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von Beckerath N, Taubert D, PogatsaMurray G, Schomig E, Kastrati A, Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation 112(19), 2946–2950 (2005).
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348(9038), 1329–1339 (1996).
4
Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366(9497), 1607–1621 (2005).
5
Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial
www.expert-reviews.com
Coronary Intervention: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 117(2), 261–295 (2008).
infarction with ST-segment elevation. N. Engl. J. Med. 352(12), 1179–1189 (2005).
References
8
Yusuf S, Mehta SR, Zhao F et al. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 107(7), 966–972 (2003).
9
King SB 3rd, Smith SC Jr, Hirshfeld JW Jr et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous
10
Bassand JP, Hamm CW, Ardissino D et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur. Heart J. 28(13), 1598–1660 (2007).
11
Van de Werf F, Bax J, Betriu A et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur. Heart J. 29(23), 2909–2945 (2008).
12
Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP. Inactivation of the human P2Y12 receptor by thiol reagents requires
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atherothrombotic events in patients with acute myocardial infarction. Circulation 109(25), 3171–3175 (2004).
interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101(10), 3908–3914 (2003). 13
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Kunapuli SP, Ding Z, Dorsam RT, Kim S, Murugappan S, Quinton TM. ADP receptors – targets for developing antithrombotic agents. Curr. Pharm. Des. 9(28), 2303–2316 (2003). Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J. Am. Coll. Cardiol. 49(14), 1505–1516 (2007). Yang EH, Gumina RJ, Lennon RJ, Holmes DR Jr, Rihal CS, Singh M. Emergency coronary artery bypass surgery for percutaneous coronary interventions: changes in the incidence, clinical characteristics, and indications from 1979 to 2003. J. Am. Coll. Cardiol. 46(11), 2004–2009 (2005). Mehta RH, Chen AY, Pollack CV Jr et al. Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-STsegment elevation acute coronary syndromes. Am. J. Cardiol. 98(5), 624–627 (2006).
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Wallentin L, Varenhorst C, James S et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur. Heart J. 29(1), 21–30 (2008). Brandt JT, Payne CD, Wiviott SD et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am. Heart J. 153(1), E66–E69 (2007).
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Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am. J. Cardiol. 93(4), 456–458 (2004).
27
Bonello L, Camoin-Jau L, Arques S et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J. Am. Coll. Cardiol. 51(14), 1404–1411 (2008).
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Barragan P, Bouvier JL, Roquebert PO et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilatorstimulated phosphoprotein phosphorylation. Catheter Cardiovasc. Interv. 59(3), 295–302 (2003). Matetzky S, Shenkman B, Guetta V et al. Clopidogrel resistance is associated with increased risk of recurrent
144
Gladding P, Webster M, Ormiston J, Olsen S, White H. Antiplatelet drug nonresponsiveness. Am. Heart J. 155(4), 591–599 (2008). Jakubowski JA, Payne CD, Li YG et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb. Haemost. 99(1), 215–222 (2008).
Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J. Am. Coll. Cardiol. 45(2), 246–251 (2005).
20
Heestermans AA, van Werkum JW, Taubert D et al. Impaired bioavailability of clopidogrel in patients with a ST‑segment elevation myocardial infarction. Thromb. Res. DOI: 10.1016/j. thromres.2008.01.021 (2008) (Epub ahead of print).
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19
Cuisset T, Frere C, Quilici J et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J. Thromb. Haemost. 4(3), 542–549 (2006).
Jernberg T, Payne CD, Winters KJ et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur. Heart J. 27(10), 1166–1173 (2006).
29
Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357(20), 2001–2015 (2007).
30
Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am. Heart J. 156(2 Suppl.), S10–S15 (2008).
31
van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin. Thromb. Hemost. 31(2), 195–204 (2005).
32
Ingall AH, Dixon J, Bailey A et al. Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J. Med. Chem. 42(2), 213–220 (1999).
33
Hollopeter G, Jantzen HM, Vincent D et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409(6817), 202–207 (2001).
34
Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J. Clin. Invest. 113(3), 340–345 (2004).
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Data on file with The Medicines Company.
36
Marcus AJ, Broekman MJ, Drosopoulos JH et al. Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases. J. Pharmacol. Exp. Ther. 305(1), 9–16 (2003).
37
Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. Ann. Pharmacother. 40(5), 925–930 (2006).
38
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. 24(5), 752–765 (2002).
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Greenbaum AB, Ohman EM, Gibson CM et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEPAMI) angiographic trial. Am. Heart J. 154(4), 702–709 (2007).
40
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 activecontrolled trial. Am. Heart J. 151(3), 689E1-689E10 (2006).
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Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb. Haemost. 85(3), 401–407 (2001).
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Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Charnigo R, Akers WS. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb. Res. 121(4), 527–534 (2008).
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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. 6(7), 1153–1159 (2008). Angiolillo DJ, Guzman LA. Clinical overview of promising nonthienopyridine antiplatelet agents. Am. Heart J. 156(Suppl. 2), S23–S28 (2008).
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Drug Profile
Affiliations •
Julie H Oestreich, PharmD 725 Rose Street, College of Pharmacy, University of Kentucky, Lexington, KY 40514, USA Tel.: +1 859 257 1998 Fax: +1 859 257 7564 [email protected]
•
Steven R Steinhubl, MD The Geisinger Clinic, Danville, PA and The Medicines Company, Zurich, Switzerland
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Cangrelor in percutaneous coronary intervention Expert Rev. Clin. Pharmacol. 2(2), 137–145 (2009)
Julie H Oestreich† and Steven R Steinhubl Author for correspondence 725 Rose Street, College of Pharmacy, University of Kentucky, Lexington, KY 40514, USA Tel.: +1 859 257 1998 Fax: +1 859 257 7564 [email protected] †
Cangrelor is a novel, intravenous P2Y12 receptor antagonist in development for use in percutaneous coronary intervention. Currently in Phase III testing, the reversible platelet inhibitor provides several inherent advantages over other P2Y12 receptor antagonists in this setting for the prevention of adverse cardiac events. Unlike the class of thienopyridines (ticlopidine, clopidogrel and potentially soon to be available, prasugrel), cangrelor has nearly immediate onset after a bolus dose and a short half-life, and achieves maximal inhibition of ADP-mediated platelet function. Cangrelor’s distinct mechanism of action allows for intravenous administration and avoids both hepatic and renal metabolism. These unique characteristics make cangrelor a promising agent for use in cardiovascular patients undergoing percutaneous coronary intervention. Keywords: acute coronary syndrome • cangrelor • clopidogrel • P2Y12 receptor • percutaneous coronary intervention • platelet inhibition
Market overview
Percutaneous coronary intervention (PCI) is a common procedure in the USA for patients presenting with acute coronary syndrome (ACS), which includes unstable angina and acute myocardial infarction (MI). The most recent American Heart Association statistics estimate that over 1.2 million PCI procedures are performed each year on diseased vessels, and the majority of patients leave the catheterization laboratory with at least one stent placement [101] . In addition to heparin, appropriate platelet inhibition with P2Y12 receptor antagonists and other antiplatelet agents is indicated to prevent adverse cardiovascular events during and after PCI. The importance of P2Y12 receptor antagonism is substantiated by the millions of patients worldwide who have been treated with clopidogrel in PCI and other settings. Moreover, its costliness and common utilization make clopidogrel one of the most profitable prescription drugs in the world for its manufacturers. The value of targeting the platelet P2Y12 receptor in PCI has been established by the clinical utility of the thienopyridines ticlopidine (Ticlid®, Roche, NJ, USA) and clopidogrel (Plavix®/Iscover®, Sanofi-Aventis, NJ, USA), the only P2Y12 receptor antagonists currently available on the market. Due to the increased incidence of bone marrow toxicity and blood dyscrasias with ticlopidine, clopidogrel is the www.expert-reviews.com
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preferred agent for prevention of acute and long-term adverse coronary events in ischemic patients and is marketed in numerous countries worldwide. Several large-scale clinical trials have established the benefit of clopidogrel in cardiovascular patients with and without additional platelet inhibition with aspirin [1–5] . For patients undergoing PCI, long-term clopidogrel therapy for 1 year in addition to aspirin reduces the combined primary outcome of death, MI and stroke by 26.9% (relative risk reduction) [2] . In addition, treatment with a loading dose of clopidogrel prior to PCI results in a 58.8% relative risk reduction of the combined end points of death, MI and urgent target vessel revascularization, albeit these results are based on a post hoc analysis and are dependent upon the dose and time of administration [2,6] . For a 300-mg loading dose, adequate pretreatment prior to a PCI of several hours (15–24 h) is required to achieve therapeutic benefit; however, a more rapid onset of action and maximal pharmacodynamic effect may be obtained with a 600-mg loading dose [2,6,7] . On the other hand, in a primarily non-invasively treated ACS population, a 300-mg loading dose of clopidogrel, compared with placebo, leads to a noticeable separation of event rates within several hours that is statistically significant by 24 h [8] . Standard (300 mg) and high-dose (600 mg) pretreatment with clopidogrel is currently being evaluated for the first time in the
© 2009 Expert Reviews Ltd
ISSN 1751-2433
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prospective, double-blinded Clopidogrel Optimal Loading Dose The newer thienopyridine, prasugrel (Effient ®, Eli Lilly Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy and Company, IN, USA, and Daiichi Sankyo, Inc., NJ, USA) for Interventions (CURRENT/OASIS7) trial (NCT00335452). has more consistent metabolism to an active metabolite and Clinical outcomes from this large-scale study should further reduced variability in platelet response compared with clopidogclarify the optimal loading dose for PCI. rel [25–28] . The pivotal clinical trial Trial to Assess Improvement Based on this evidence, recent consensus documents recom- in Therapeutic Outcomes by Optimizing Platelet Inhibition with mend the administration of a clopidogrel loading dose (gener- Prasugrel–Thrombolysis In Myocardial Infarction (TRITON ally at least 300 mg, but up to 600 mg) before or when PCI TIMI-38) established the superiority of prasugrel over clopidogrel is initiated, and maintenance treatment for various durations, at the dosing regimen investigated the prevention of the comdepending on the type of stent and ACS diagnosis [9] . In patients bined clinical end point of cardiovascular death, MI and stroke undergoing elective stenting without a high risk for bleeding, in ACS patients undergoing PCI; however, the higher extent the standard clopidogrel maintenance dose of 75 mg is advised of platelet inhibition was also associated with a statistically sigfor at least 1 month and preferably up to 12 months for bare- nificant increase in TIMI major bleeding events, including fatal metal stents, and a minimum 12 months of treatment is indi- bleeding [29] . Therefore, the role of prasugrel in this setting is still cated when drug-eluting stents are placed [9] . For patients with unclear. In an ideal world, analysis of platelet function would non-ST-segment elevation ACS and ST-segment elevation MI distinguish which patients would benefit from the more potent (STEMI), clopidogrel for 12 months is recommended irrespective thienopyridine and its associated risk. Unfortunately, there are of the acute treatment [10,11] . Combined, these recommendations currently not enough concrete data to recommend dose adjustsupport the usefulness of P2Y12 receptor inhibition in the setting ments based upon ex vivo platelet testing. The appropriate target of PCI. range for platelet inhibition that provides sufficient protection Despite the undisputed clinical benefit and widespread utili- from adverse cardiac events balanced with the lowest bleeding zation of clopidogrel in PCI, there are significant shortcomings risk is still unknown. Although more potent platelet inhibition associated with its use. As with all thienopyridines, clopidogrel is presumably advantageous for some patients, prasugrel is still is a prodrug that requires hepatic conversion by the cytochrome plagued by other characteristics of thienopyridines. Prasugrel, P450 system to attain pharmacological activity [7] . Consequently, similar to other thienopyridines, requires hepatic conversion to an clopidogrel has a delayed onset of action and its activity is suscep- active metabolite and irreversibly inhibits ADP-induced platelet tible to variations in metabolism. The short-lived active metabo- function for the life of the platelet [30] . These limitations have lite of the drug is believed to form a disulfide bridge with extra- spurred further development of new P2Y12 antagonists optimized cellular cysteines on the P2Y12 receptor to cause incomplete and for use in PCI. irreversible inhibition of ADP-mediated aggregation for the life of the platelet (7–10 days) [12–14] . There is no pharmacological Cangrelor antidote, and a small percentage of patients undergoing PCI Chemistry also require emergent coronary artery bypass graft (CABG) sur- The novel antiplatelet agent cangrelor (The Medicines Company, gery [15] . More importantly, in patients with an ACS, if whom NJ, USA) is a specific and potent antagonist of ADP-induced approximately 15% will require CABG for revascularization [16] , platelet activity currently in Phase III development [31] . early initiation of clopidogrel can lead to either prolonged hospi- Cangrelor (2-trifluoropropylthio, N-(2-(methylthio)-ethyl-β, talization while awaiting surgery or an increased risk of bleeding γ-dichloromethylene ATP)) is an ATP analogue (Figure 1) that if surgery is not delayed [1] . competitively inhibits platelet activation and aggregation by Furthermore, there is well-documented ex vivo variability in the reversibly binding the P2Y12 receptor. The structure of ATP, response to clopidogrel, as 4–30% of patients do not obtain the an endogenous antagonist to the target receptor, was altered expected degree of inhibition depending on the type of assay uti- to produce a compound with increased stability, affinity and lized and definition of nonresponsiveness employed [17,18] . Evidence potency [13,32] . to support the clinical relevance of this variability is limited, although nonresponders + 4Na have shown a higher risk for thrombotic S CH3 HN events [19–22] . The potential mechanisms of clopidogrel nonresponsiveness are N N diverse, yet several explanations relate to O O O CF3 the intrinsic pharmacokinetic properties O P O N S N P P O O of the drug, including drug–drug interacO O O Cl tions, bioavailability [23] and genetic variaCl OH tions in cytochrome P450 enzymes [24] . As HO with all medications, compliance is also an important factor that could contribute to Figure 1. Cangrelor, an ATP analogue and novel antiplatelet agent. variability in response. 138
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Drug Profile
Cangrelor in percutaneous coronary intervention
muscle cells) and, therefore, serves as a favorable therapeutic target [12,13] . The Gq-coupled P2Y1 receptor is ubiquitously expressed and mediates transient platelet shape change and increased intracellular calcium, whereas binding of ADP to the Gi-coupled P2Y12 receptor is required for complete and irreversible platelet activation [13,33,34] . P2Y12 receptor activation triggers several signaling pathways via both Gα and Gβγ subunits of the protein, ultimately causing platelet granule secretion of ADP and other mediators, thromboxane A2 generation and increased expression and activation of the αIIbβ3 (glycoprotein IIb/IIIa)
Pharmacology
ADP P2Y receptors are critical regulators of platelet function. Although ADP is considered a weak agonist, platelet activation by more potent agonists is dependent upon ADP secretion from platelet granules and subsequent binding to P2Y receptors. ADP is the endogenous ligand for both P2Y12 and P2Y1 receptors that stimulate platelet aggregation (Figure 2) , while ATP is a natural antagonist for both receptors [33] . Unlike the widely distributed P2Y1 receptor, the P2Y12 receptor has only been found on select cell types (including platelets, glioma cells and vascular smooth
ADP Cangrelor P2Y1 P2Y12 GIRK Giα AC
ATP
PP
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Expert Rev. Clin. Pharmacol. © Future Science Group (2009)
Figure 2. Effects of the ADP receptors P2Y1 and P2Y12 on platelet activation and aggregation. Cangrelor specifically and selectively inhibits the P2Y12 receptor, one of two G-protein-coupled platelet ADP receptors. Activation of the P2Y12 receptor by ADP leads to TxA2 generation, platelet granule release of ADP and other mediators of aggregation and coagulation, and increased expression and activation of the αIIbβ3 receptor (GP IIb/IIIa). The P2Y12 receptor causes irreversible and sustained platelet activation and aggregation through multiple signaling pathways via both Giα and Gβγ subunits. Conversely, the P2Y1 receptor has transient and reversible effects on platelet shape change and aggregation mediated by calcium release. AA: Arachidonic acid; AC: Adenylate cyclase; cAMP: Cyclic adenosine monophosphate; COX: Cyclooxygenase; DAG: Diacylglycerol; GP: Glycoprotein; IP3: Inositol 1,4,5-triphosphate; PDE: Phosphodiesterase; PG: Prostaglandin; PI3K: Phosphoinositide-3 kinase; PIP2: Phosphatidylinositol (4,5)-bisphosphate; PK: Protein kinase; PlA2: Phospholipase A2; PLCβ: Phospholipase C-β; P-VASP: Phosphorylated vasodilator-stimulated phosphoprotein; TxA2: Thromboxane A2; TxAS: Thromboxane A2 synthase; VASP: Vasodilator-stimulated phosphoprotein.
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two separate Phase II multicenter trials (one open-label and the other randomized, double-blinded and placebo-controlled), 130 combined unstable angina and non-ST-segment elevation MI (NSTEMI) patients were administered an infusion of cangrelor Pharmacokinetics & metabolism or placebo in addition to aspirin and heparin or low-molecularCangrelor is a rapid-acting and short-lived intravenous medica- weight heparin. Both preliminary studies demonstrate that cantion. Following a bolus dose and infusion regimen in healthy grelor infused up to 72 h is not accumulated nor associated with volunteers (15 µg/kg bolus plus 2 µg/kg/min or 30 µg/kg bolus an increase in serious adverse events [38,41] . Intravenous cangrelor plus 4 µg/kg/min), maximal and steady-state cangrelor concen- has also been studied as adjunct therapy to fibrinolysis for acute trations are obtained within minutes of administration [35] . The myocardial infarction in the Safety, Tolerability and Effect on drug displays linear, dose-dependent pharmacokinetics at the Patency in Acute Myocardial Infarction (STEP-AMI) trial [39] . studied range and has a limited volume of distribution (∼3.7 l) A total of 101 patients were randomized to receive one of three due to its polar nature and fast metabolism [35] . Cangrelor levels cangrelor doses in addition to alteplase 50 mg (tissue plasminogen return to baseline within 10 min after stopping the infusion activator), cangrelor alone or alteplase alone (100 mg). Although because the drug is rapidly dephosphorylated by an ecto-ADPase the trial was stopped early due to the sponsor at that time’s deciassociated with vascular endothelial cells [35,36] . This unique sion not to pursue clinical development, bleeding complications pathway allows cangrelor to avoid both hepatic and renal routes and major adverse clinical events were not different between of metabolism. In addition to the fast onset and reversible prop- combination therapy and standard-dose alteplase, and a potential erties of the drug, cangrelor’s extremely short half-life (2.6–3.6 clinical benefit could not be ruled out with the small number of min) is an attractive feature for patients undergoing PCI [35,37] . subjects tested [39] . A Phase II, multicenter, randomized, placebo and active Pharmacodynamics controlled trial also evaluated cangrelor in patients undergoing Similar to the pharmacokinetic data, the platelet pharmaco PCI [40] . Subjects in part 1 were randomized to placebo or a dynamic response to cangrelor is rapid-acting and quickly revers- cangrelor 1-, 2- or 4-µg/kg/min infusion initiated before PCI ible following drug discontinuation. Ex vivo platelet testing of in combination with aspirin and heparin. Part 2 compared the cangrelor-treated healthy volunteers demonstrates that platelet highest dose of cangrelor with abciximab. No statistically siginhibition is obtained within minutes of initiating therapy, as nificant differences were obtained between cangrelor and either demonstrated by ADP-activated whole-blood aggregometry and control group for major and minor bleeding or when comparing flow cytometric analysis of agonist-induced P-selectin expression. the 30‑day incidence of adverse cardiac events between cangrelor In total, 50% of platelet function is recovered within 10–30 min and abciximab [40] . Although both cangrelor and abciximab comafter stopping the infusion and a complete return to baseline pletely inhibited ADP-stimulated platelet aggregation, as measfunction is achieved within 60–90 min [35] . In preliminary stud- ured by electrical impedance aggregometry, subjects returned to ies, the short half-life of cangrelor is not associated with rebound baseline platelet function more quickly with cangrelor after the platelet activation following termination of the infusion [38–40] . infusion was discontinued. Two large-scale Phase III clinical trials are ongoing to assess Clinical efficacy the safety and efficacy of cangrelor in patients with coronary Cangrelor has been well tolerated in clinical trials alone and in atherosclerosis and ACS requiring PCI (Table 1) . Both prospeccombination with other agents, including aspirin and heparin. In tive, randomized, double-blinded and placebo-controlled studies are evaluating a composite primary Table 1. Ongoing clinical trials to assess the efficacy and safety end point of all-cause mortality, MI and of cangrelor. ischemia-driven revascularization assessed 48 h after randomization. The Cangrelor Cangrelor trials Phase Expected Primary Population enrollment end point versus Standard Therapy to Achieve (n) Optimal Management of Platelet Inhibition (CHAMPION)-PCI trial is expected to CHAMPIONIII 6400 Efficacy ACS with PCI enroll 9000 patients (a mix of stable angina, PLATFORM unstable angina, NSTEMI and STEMI) CHAMPION-PCI III 9000 Efficacy ACS with PCI to be managed with PCI following randQT/QTc I 66 Safety Healthy volunteers omization and administration of a clopiBRIDGE II 200 Platelet inhibition Patients discontinuing dogrel 600-mg loading dose or cangrelor clopidogrel 3–5 days 30-µg/kg intravenous bolus and 4-µg/kg/ prior to planned min infusion (NCT00305162). Patients CABG will receive study drug infusion (cangrelor ACS: Acute coronary sydrome; BRIDGE: Maintenance of Platelet Inhibition With Cangrelor; or placebo) for up to 2 h or the duration CABG: Coronary artery bypass graft; CHAMPION: Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition; PCI: Percutaneous coronary intervention. of PCI, whichever is longer. At the time receptors (Figure 2) . Through these processes, the P2Y12 receptor pathway potentiates platelet recruitment, aggregation and coagulation [34] .
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Drug Profile
7 days or presenting with STEMI within 48 h are not eligible. Enrollment is expected to reach 6400 subjects to assess the efficacy and tolerability of cangrelor added to standard treatment (NCT00385138). Completion of both CHAMPION trials is expected by early 2009.
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Safety & tolerability
The safety of cangrelor has been evaluated in healthy volunteers, patients with unstable angina and acute MI, and those undergoing PCI. Generally, the drug has 40 been well tolerated, and the most common adverse effect, as expected, is pro20 longation of bleeding time and bleeding events [38,40,41] . Initial studies suggest that bleeding and adverse events are similar 0 or better with cangrelor compared with 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 abciximab and alteplase [39,40] . In one Time (h) open-label study, 21% of patients treated with a cangrelor infusion for up to 72 h Figure 3. Clopidogrel inhibits ADP-induced platelet aggregation when experienced elevated ALT levels [41] ; howadministered immediately following a cangrelor infusion, but does not achieve ever, there were no associated clinical the expected level of inhibition when administered simultaneously with manifestations with the increase and this cangrelor. The effect of cangrelor and clopidogrel on ADP-induced (20 µM) platelet aggregation was evaluated by light transmittance aggregometry. Subjects finding was not reproduced in randomized randomized to treatment arm 1 (n = 10) were administered a cangrelor 30 µg/kg controlled studies [38] . A double-blind, intravenous bolus plus a 4 µg/kg/min infusion for 1 h immediately followed by oral placebo-controlled, positive-controlled, administration of clopidogrel 600 mg at the end of the cangrelor infusion (solid line). randomized, crossover Phase I safety trial Subjects in treatment arm 2 (n = 10) were first administered oral clopidogrel 600 mg (Table 1) is ongoing to assess the effect of followed by a 2-week washout period. After the washout period, subjects were therapeutic and supratherapeutic doses readministered oral clopidogrel 600 mg simultaneous with a cangrelor 30 µg/kg of cangrelor on the QT/QTc interval in intravenous bolus and a 4 µg/kg/min infusion for 2 h (dashed lines). Data are 66 healthy volunteers (NCT00699504). presented as mean ± SEM. Similar results were obtained with electrical impedance Additionally, there is an ongoing Phase II aggregometry and flow cytometry. Adapted from [42] . trial to assess the safety of a prolonged cangrelor infusion (up to 5 days) prior of completion of the study drug infusion, patients randomized to CABG surgery (NCT00767507). The Maintenance of to cangrelor will receive clopidogrel 600 mg, while the control Platelet Inhibition with Cangrelor after Discontinuation of arm will receive matching placebo. In a small pharmacodynamic Thienopyridines in Patients Undergoing Surgery (BRIDGE) substudy, approximately 300 patients will undergo serial platelet trial is designed primarily to identify the appropriate cangrelor function testing to determine if cangrelor influences clopidogrel’s infusion dose for longer durations that might be used in patients ability to inhibit platelet function. treated with an irreversible P2Y12 receptor antagonist requiring The CHAMPION-PLATFORM trial is investigating can- bridging therapy prior to an invasive procedure. The trial will grelor compared with usual care in PCI subjects. As in the evaluate platelet inhibition and bleeding and is expected to be CHAMPION-PCI trial, patients will be randomized to receive completed by late 2009 (Table 1). a cangrelor bolus and infusion or matching placebo prior to the initiation of PCI. Then, unlike the PCI trial, patients enrolled Drug interactions in the PLATFORM trial will not receive a 600-mg loading dose Interestingly, the only reported drug interaction with cangreof clopidogrel or matching placebo until the PCI procedure is lor to date is a pharmacodynamic interaction with clopidogcomplete. Again, similar to the PCI study, patients will receive rel [42] . Patients undergoing PCI, including those treated with oral drug of either clopidogrel 600 mg for those randomized cangrelor, will be expected to maintain long-term oral P2Y12 to cangrelor, or matching placebo for those in the control arm, inhibition to prevent adverse coronary events. A clinical trial following completion of the 2-h study drug infusion. Eligible assessing the transition of patients from cangrelor to clopidogrel patients are similar between PCI and PLATFORM; however, in identified a probable competitive and time-dependent inter PLATFORM, patients taking any thienopyridine in the previous action between the drugs as assessed by whole-blood electrical 60
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impedance aggregometry, light-transmittance aggregometry and flow cytometry. Healthy volunteers randomized to receive a 600-mg clopidogrel loading dose immediately following a cangrelor 30-µg/kg intravenous bolus and 1-h 4-µg/kg/min infusion obtained the expected degree of platelet inhibition for both antiplatelet agents [42] . Cangrelor inhibited 80% of lighttransmittance platelet aggregation induced by ADP 20 µM, and clopidogrel inhibited 50–60% of the platelet response following a predicted delay of onset. Those randomized to receive the loading dose of clopidogrel simultaneously with cangrelor did not achieve the expected inhibition with clopidogrel as post infusion pharmacodynamic measures returned and remained at baseline (Figure 3) [42] . Most probably, there is a competitive interaction when the short-lived active metabolite of clopidogrel is unable to compete for receptor occupancy in the presence of the reversible inhibitor cangrelor. Cangrelor’s high affinity for the P2Y12 receptor prevents clopidogrel’s active metabolite from irreversibly binding the target receptor. The half-life of clopidogrel’s unstable active metabolite is postulated to be very short, and evidence from this study suggests that no active metabolite remains 2 h after a 600-mg loading dose [42] . The clinical relevance of this interaction in PCI patients is unknown. Recently, a similar interaction was shown to occur with the active metabolite of prasugrel [43] . Other nonthienopyridine, orally available P2Y12 antagonists might avoid this potential interaction. Regulatory affairs
Cangrelor was purchased by The Medicines Company from AstraZeneca. The Medicines Company possesses the development, marketing and sales rights for cangrelor in all countries worldwide, except for Japan, Korea, China, Thailand and Taiwan [44] . Conclusion
Cangrelor is a novel antagonist of the P2Y12 receptor that directly, potently and reversibly inhibits ADP-induced platelet aggregation. Intravenously administered cangrelor has a fast onset of action and is quickly reversible once the infusion is stopped. These unique characteristics provide advantages over currently available antiplatelet medications, supporting cangrelor as a promising option for patients undergoing PCI.
Expert commentary & five-year view
Beyond the current standard of care with aspirin, clopidogrel and occasional glycoprotein (GP) IIb/IIIa antagonism, cangrelor has the potential to impact antiplatelet treatment in the cardiac catheterization laboratory. Its novel pharmacokinetic profile provides unparalleled intrinsic advantages over the currently available agents. The remaining questions for Phase III testing are critical and will decide if cangrelor is effective and if there are over-riding safety concerns that have not previously been identified. Although cangrelor is not the first intravenous antiplatelet therapy, it has several assumed advantages over the GP IIb/IIIa receptor antagonists. Cangrelor targets the upstream G-proteincoupled P2Y12 receptor and leaves the receptors for platelet-toplatelet aggregation intact. This may account for a preferential bleeding profile with cangrelor compared with GP IIb/IIIa antagonists, although this has yet to be proven. Although other receptors are certainly important for response, the dependency of all platelet pathways on ADP release for complete activity makes the P2Y12 receptor a good target in theory. Other novel targets for platelet inhibition are advanced in testing and may certainly prove useful; however, in the meantime, clopidogrel has established the P2Y12 receptor as a gold mine for drug effectiveness and certainly financial gain. For several years, there have been no feasible antiplatelet alternatives beyond combination therapy with aspirin and clopidogrel. The probable addition of prasugrel to the armamentarium of ADP antagonists allows, for the first time, a choice for more potent inhibition, even if the target level of inhibition is unclear. Research is ongoing and necessary to clarify individual differences in platelet function and drug response. The future of antiplatelet therapy is tailored, personalized treatments to an appropriate level of platelet inhibition. The role for cangrelor in that future setting and now is promising, particularly since its features allow for several safety advantages. Cangrelor is direct, fast-acting and reversible and, if proven safe and effective, will substantiate the flexibility for P2Y12 receptor inhibition in PCI. Furthermore, when the optimal level of platelet inhibition is determined, cangrelor would provide the luxury of titration to pharmacodynamic response in individual patients.
Table 2. Comparison of current and emerging P2Y12 receptor antagonists. Drug
Approval status
Route of administration
Drug class
Bioavailability
Receptor interaction
Pharmacodynamic half-life
Ticlopidine
Approved
Oral
Thienopyridine (1st generation)
Prodrug
Irreversible
Life of platelet
Clopidogrel
Approved
Oral
Thienopyridine (2nd generation)
Prodrug
Irreversible
Life of platelet
Prasugrel
Phase III completed
Oral
Thienopyridine (3rd generation)
Prodrug
Irreversible
Life of platelet
Cangrelor
Phase III
IV
ATP analog
Direct-acting
Reversible
Minutes
Ticagrelor
Phase III
Oral
ATP analog
Direct-acting
Reversible
6-12 h
PRT060128
Phase II
Oral, IV
Direct-acting
Reversible
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Cangrelor in percutaneous coronary intervention
Even if cangrelor reaches the market for use in the catheterization laboratory, long-term inhibition of the P2Y12 receptor will still be indicated. The clinical relevance of the influence of cangrelor on the onset of clopidogrel’s antiplatelet effects will be determined through the CHAMPION trials [42] . Fortunately, the horizon for new antiplatelet agents includes cangrelor’s sister compound ticagrelor (AZD6140, AstraZeneca, London, UK), an orally administered ATP analogue in Phase III testing (Table 2) [30,44] . Early speculation would propose no significant interaction between cangrelor and long-term therapy with ticagrelor. A standard scenario 5 years from now with cangrelor and ticagrelor for the prevention of adverse cardiac events during and following PCI in ACS patients is certainly possible and, quite possibly, an improvement to current therapy. In addition to these compounds, the pipeline also includes PRT060128 (Portola Pharmaceuticals, Inc., CA, USA), a P2Y12 antagonist available in both intravenous and oral formulations currently in Phase II development (Table 2) [31] . The future for P2Y12 inhibition in PCI looks optimistic, with many new and improved agents on the horizon, and cangrelor
Drug Profile
certainly adds to this promise. Its large-scale clinical efficacy trials are highly anticipated due to the superior pharmacokinetic profile of cangrelor compared with available treatments. Acknowledgements
Appreciation is extended to Tom Dolan at the University of Kentucky for his work on the platelet figure (Figure 2). Financial & competing interests disclosure
This work acknowledges the support of awards from the American Heart Association, the Pharmaceutical Research and Manufacturers of America Foundation, the American Foundation for Pharmaceutical Education and the Sigma Xi Scientific Society. Steven Steinhubl is an employee of The Geisinger Clinic, Danville, PA and The Medicines Company, Zurich, Switzerland. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues • Cangrelor is a novel P2Y12 receptor antagonist in Phase III development for use in acute coronary syndrome patients undergoing percutaneous coronary intervention. • Cangrelor potently and reversibly inhibits platelet function and has a fast onset and offset of action. • Cangrelor does not require conversion to a prodrug and is metabolized in the bloodstream without hepatic or renal involvement. • These unique pharmacokinetic advantages compared with the thienopyridines (ticlopidine, clopidogrel and prasugrel) make cangrelor a promising candidate for this setting. • Results from cangrelor’s large-scale clinical efficacy and safety trials are highly anticipated to determine its potential role for acute coronary syndrome patients undergoing percutaneous coronary intervention.
1
2
3
Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345(7), 494–502 (2001). Steinhubl SR, Berger PB, Mann JT 3rd et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288(19), 2411–2420 (2002).
6
Steinhubl SR, Berger PB, Brennan DM, Topol EJ. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J. Am. Coll. Cardiol. 47(5), 939–943 (2006).
7
von Beckerath N, Taubert D, PogatsaMurray G, Schomig E, Kastrati A, Schomig A. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation 112(19), 2946–2950 (2005).
A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348(9038), 1329–1339 (1996).
4
Chen ZM, Jiang LX, Chen YP et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 366(9497), 1607–1621 (2005).
5
Sabatine MS, Cannon CP, Gibson CM et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial
www.expert-reviews.com
Coronary Intervention: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines: 2007 Writing Group to Review New Evidence and Update the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention, Writing on Behalf of the 2005 Writing Committee. Circulation 117(2), 261–295 (2008).
infarction with ST-segment elevation. N. Engl. J. Med. 352(12), 1179–1189 (2005).
References
8
Yusuf S, Mehta SR, Zhao F et al. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation 107(7), 966–972 (2003).
9
King SB 3rd, Smith SC Jr, Hirshfeld JW Jr et al. 2007 Focused Update of the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous
10
Bassand JP, Hamm CW, Ardissino D et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur. Heart J. 28(13), 1598–1660 (2007).
11
Van de Werf F, Bax J, Betriu A et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology. Eur. Heart J. 29(23), 2909–2945 (2008).
12
Ding Z, Kim S, Dorsam RT, Jin J, Kunapuli SP. Inactivation of the human P2Y12 receptor by thiol reagents requires
143
Drug Profile
Oestreich & Steinhubl
atherothrombotic events in patients with acute myocardial infarction. Circulation 109(25), 3171–3175 (2004).
interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 101(10), 3908–3914 (2003). 13
14
15
16
Kunapuli SP, Ding Z, Dorsam RT, Kim S, Murugappan S, Quinton TM. ADP receptors – targets for developing antithrombotic agents. Curr. Pharm. Des. 9(28), 2303–2316 (2003). Angiolillo DJ, Fernandez-Ortiz A, Bernardo E et al. Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J. Am. Coll. Cardiol. 49(14), 1505–1516 (2007). Yang EH, Gumina RJ, Lennon RJ, Holmes DR Jr, Rihal CS, Singh M. Emergency coronary artery bypass surgery for percutaneous coronary interventions: changes in the incidence, clinical characteristics, and indications from 1979 to 2003. J. Am. Coll. Cardiol. 46(11), 2004–2009 (2005). Mehta RH, Chen AY, Pollack CV Jr et al. Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-STsegment elevation acute coronary syndromes. Am. J. Cardiol. 98(5), 624–627 (2006).
22
23
24
26
Wallentin L, Varenhorst C, James S et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur. Heart J. 29(1), 21–30 (2008). Brandt JT, Payne CD, Wiviott SD et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am. Heart J. 153(1), E66–E69 (2007).
18
Mobley JE, Bresee SJ, Wortham DC, Craft RM, Snider CC, Carroll RC. Frequency of nonresponse antiplatelet activity of clopidogrel during pretreatment for cardiac catheterization. Am. J. Cardiol. 93(4), 456–458 (2004).
27
Bonello L, Camoin-Jau L, Arques S et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J. Am. Coll. Cardiol. 51(14), 1404–1411 (2008).
28
21
Barragan P, Bouvier JL, Roquebert PO et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilatorstimulated phosphoprotein phosphorylation. Catheter Cardiovasc. Interv. 59(3), 295–302 (2003). Matetzky S, Shenkman B, Guetta V et al. Clopidogrel resistance is associated with increased risk of recurrent
144
Gladding P, Webster M, Ormiston J, Olsen S, White H. Antiplatelet drug nonresponsiveness. Am. Heart J. 155(4), 591–599 (2008). Jakubowski JA, Payne CD, Li YG et al. A comparison of the antiplatelet effects of prasugrel and high-dose clopidogrel as assessed by VASP-phosphorylation and light transmission aggregometry. Thromb. Haemost. 99(1), 215–222 (2008).
Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Bhatt DL, Topol EJ. Variability in platelet responsiveness to clopidogrel among 544 individuals. J. Am. Coll. Cardiol. 45(2), 246–251 (2005).
20
Heestermans AA, van Werkum JW, Taubert D et al. Impaired bioavailability of clopidogrel in patients with a ST‑segment elevation myocardial infarction. Thromb. Res. DOI: 10.1016/j. thromres.2008.01.021 (2008) (Epub ahead of print).
25
17
19
Cuisset T, Frere C, Quilici J et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J. Thromb. Haemost. 4(3), 542–549 (2006).
Jernberg T, Payne CD, Winters KJ et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur. Heart J. 27(10), 1166–1173 (2006).
29
Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357(20), 2001–2015 (2007).
30
Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am. Heart J. 156(2 Suppl.), S10–S15 (2008).
31
van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible direct P2Y12 antagonists. Semin. Thromb. Hemost. 31(2), 195–204 (2005).
32
Ingall AH, Dixon J, Bailey A et al. Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J. Med. Chem. 42(2), 213–220 (1999).
33
Hollopeter G, Jantzen HM, Vincent D et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409(6817), 202–207 (2001).
34
Dorsam RT, Kunapuli SP. Central role of the P2Y12 receptor in platelet activation. J. Clin. Invest. 113(3), 340–345 (2004).
35
Data on file with The Medicines Company.
36
Marcus AJ, Broekman MJ, Drosopoulos JH et al. Metabolic control of excessive extracellular nucleotide accumulation by CD39/ecto-nucleotidase-1: implications for ischemic vascular diseases. J. Pharmacol. Exp. Ther. 305(1), 9–16 (2003).
37
Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. Ann. Pharmacother. 40(5), 925–930 (2006).
38
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. 24(5), 752–765 (2002).
39
Greenbaum AB, Ohman EM, Gibson CM et al. Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEPAMI) angiographic trial. Am. Heart J. 154(4), 702–709 (2007).
40
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 activecontrolled trial. Am. Heart J. 151(3), 689E1-689E10 (2006).
41
Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb. Haemost. 85(3), 401–407 (2001).
42
Steinhubl SR, Oh JJ, Oestreich JH, Ferraris S, Charnigo R, Akers WS. Transitioning patients from cangrelor to clopidogrel: pharmacodynamic evidence of a competitive effect. Thromb. Res. 121(4), 527–534 (2008).
Expert Rev. Clin. Pharmacol. 2(2), (2009)
Cangrelor in percutaneous coronary intervention
43
44
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. 6(7), 1153–1159 (2008). Angiolillo DJ, Guzman LA. Clinical overview of promising nonthienopyridine antiplatelet agents. Am. Heart J. 156(Suppl. 2), S23–S28 (2008).
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Websites 101
The Medicines Company www.themedicinescompany.com/ products_cangrelor.shtml
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American Heart Association Heart Disease and Stroke Statistics – 2008 Update www.americanheart.org/statistics
Drug Profile
Affiliations •
Julie H Oestreich, PharmD 725 Rose Street, College of Pharmacy, University of Kentucky, Lexington, KY 40514, USA Tel.: +1 859 257 1998 Fax: +1 859 257 7564 [email protected]
•
Steven R Steinhubl, MD The Geisinger Clinic, Danville, PA and The Medicines Company, Zurich, Switzerland
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