REVIEW DRUG EVALUATION REVIEW For reprint orders, please contact: [email protected]
Cangrelor for treatment during percutaneous coronary intervention Julie H Oestreich*,1 & Paul P Dobesh1
ABSTRACT: Dual antiplatelet therapy consisting of aspirin and a P2Y12-receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention (PCI). The current P2Y12-receptor antagonists are only available for oral administration and exhibit a delayed onset of action. Furthermore, several days are required for platelet function to return to normal following cessation of therapy. Cangrelor is an intravenous ATP analog that directly, selectively and reversibly inhibits P2Y12 receptors on platelets. A 30-μg/kg bolus dose followed by a 4-μg/kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration. Cangrelor also demonstrates a fast offset as normal platelet function is restored 1–2 h after cessation of the infusion. Three large, double-blind, randomized trials – CHAMPION PLATFORM, CHAMPION PCI and CHAMPION PHOENIX – assessed the efficacy and safety of cangrelor compared with clopidogrel (during or immediately after PCI) or placebo in the setting of PCI. In the most recent CHAMPION PHOENIX trial, cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding. Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset, cangrelor may provide benefit in certain patients undergoing PCI. Scope of acute coronary syndrome & its complications Cardiovascular disease remains the number one cause of death worldwide and is a major contributor to health expenditures, estimated at over $300 billion annually in the USA [1,2] . In the USA alone, over 1 million people are hospitalized each year for acute coronary syndrome (ACS), a subset of cardiovascular disease that includes unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI) [1] . The health and economic consequences of ACS extend beyond the acute event. However, with the use of evidencebased therapies and percutaneous coronary intervention (PCI), the rates of death, cardiogenic shock, heart failure and other complications can be reduced [1] . Approximately 1 million PCI procedures were performed in the USA in 2010, further strengthening the role of PCI for the treatment of ACS [1] . Appropriate assessment of the benefit-to-risk ratio is important as PCI can cause serious complications including stent thrombosis and death [3] .
KEYWORDS
• antiplatelet therapy • cangrelor • P2Y12-receptor antagonist • percutaneous
coronary intervention
Overview of P2Y12-receptor antagonists Pharmacologic targeting with antiplatelet therapy is an important component of PCI management, since platelets contribute to thrombus formation. ADP P2Y receptors are critical regulators of platelet function, and the P2Y12 receptor is required for complete and irreversible platelet activation [4–6] . University of Nebraska Medical Center, College of Pharmacy, Department of Pharmacy Practice, Omaha, NE, USA *Author for correspondence: Tel.: +1 402 559 2916; Fax: +1 402 559 5673; [email protected] 1
10.2217/FCA.13.108 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(2), 201–213
part of
ISSN 1479-6678
201
Drug Evaluation Oestreich & Dobesh 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, while ATP is a natural antagonist for both receptors [4] . In addition to aspirin, the class of purinergic P2Y12-receptor antagonists comprises the second component of dual antiplatelet therapy recommended for the treatment and secondary prevention of adverse cardiovascular events for patients with ACS or undergoing PCI [3,7] . The thienopyridine ticlopidine was the first selective P2Y12-receptor antagonist to be identified. Ticlopidine was followed by the approval of the second-generation thienopyridine clopidogrel, which demonstrated an improved safety profile including decreased neutropenia. In 2009, the European Commission and the US FDA approved the third-generation thienopyridine, prasugrel (Effient® [US]/Efient® [EU], Daiichi Sankyo/Eli Lilly), which achieves faster and more potent platelet inhibition compared with clopidogrel [8,9] . The thienopyridines are prodrugs and require conversion by the cytochrome P450 (CYP) enzyme system in the liver for activity. Therefore, ticlopidine, clopidogrel, and prasugrel are administered orally. Following CYPmediated metabolism in the liver, the opened thienopyridine ring exposes a thiol moiety in the formed active metabolite capable of forming an irreversible disulfide bond with the P2Y12 receptor (Figure 1) [10] . Thus, platelet inhibition by the active metabolite persists for the life of the platelet. Unlike the thienopyridines, the newest P2Y12receptor antagonist on the market is direct acting and does not require first-pass metabolism to generate an active metabolite. Ticagrelor (Brilinta® [US]/Brilique® [EU], AstraZeneca) is a cyclopentyl-triazolo-pyrimidine modified from the structure of cangrelor to produce a potent and selective P2Y12-receptor antagonist that is orally active (Figure 2) [12] . While the thienopyridines irreversibly bind the P2Y12 receptor to block ADP signaling, ticagrelor targets a separate binding site, and therefore demonstrates noncompetitive and reversible antagonism of the P2Y12 receptor [13] . Although patients treated with ticagrelor restore platelet function at a faster rate following drug discontinuation than patients treated with clopidogrel, the amount
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of time required for platelet recovery remains similar, due to more potent platelet inhibition at steady-state with ticagrelor (Table 1) [14] . Limitations of current antiplatelet therapy All of the available P2Y12-receptor antagonists are effective for preventing major adverse cardiovascular events in patients managed with PCI. However, major bleeding occurs in 1.8–4.5% of patients treated with dual antiplatelet therapy [20–22] . This bleeding risk significantly increases when more potent P2Y12-receptor inhibitors (i.e., prasugrel or ticagrelor) are used rather than clopidogrel [20–22] . Nonetheless, the bleeding risk is considered acceptable in most cases given the reduction in thrombotic events [3] . Although the currently available P2Y12 receptor antagonists provide additional benefit in PCI, areas for improvement remain. Clopidogrel, prasugrel and ticagrelor must be administered orally. While the expected number of affected patients is not large, this presents a challenge in patients undergoing PCI who are intubated or in cardiogenic shock, as well as in patients who present with nausea and vomiting. Furthermore, in the pressured setting of STEMI, there is little time available for early administration, and even the more potent P2Y12-receptor antagonists exhibit a delayed onset of action [23] . This delayed onset could leave patients at risk for stent thrombosis or other cardiovascular events in PCI, which occurs at the highest rate immediately after the procedure [24–27] . In the CREDO trial, only patients who received their clopidogrel loading dose before PCI demonstrated a reduction in cardiovascular events and no benefit was seen in patients receiving clopidogrel post-PCI [28] . Similarly, in the HORIZONS-AMI trial, acute stent thrombosis was higher in patients who did not have antiplatelet therapy beyond aspirin compared with those with a more aggressive antiplatelet regimen [26] . Another critical limitation of antiplatelet therapy during PCI is the extended time required for platelet recovery following cessation of the treatment. For both the irreversible thienopyridines and the reversible ticagrelor, platelet activity does not return to baseline for several days (Table 1) . Therefore, unless the net benefit of P2Y12-receptor inhibitor therapy outweighs the risk of excessive bleeding, current guidelines recommend withholding P2Y12-receptor antagonist therapy prior to planned coronary artery bypass grafting (CABG) surgery for at least 5 days in
future science group
Cangrelor for treatment during percutaneous coronary intervention
OCH3
O
Drug Evaluation
O O H3C
N
N O
S
Cl
S
F
Clopidogrel
Prasugrel
OCH3
O
HOOC
N
HS
O
HOOC
Cl
Clopidogrel active metabolite
N
HS
F Prasugrel active metabolite R-138727
Figure 1. Structures of the thienopyridine class of P2Y12-receptor antagonists. Clopidogrel and prasugrel are both prodrugs that require a multistep process for conversion to thiol-containing active metabolites [11]. The free thiol is capable of forming a disulfide bond with the P2Y12 receptor causing irreversible inhibition for the life of the platelet.
patients receiving clopidogrel and ticagrelor and for 7 days in patients receiving prasugrel [7] . In total, a direct-acting intravenous (iv.) medication with a fast onset and offset of action has the potential to mitigate these limitations and improve care for certain patients with ACS. Introduction to the compound & its chemistry Cangrelor (The Medicines Company) is an investigational and iv. antiplatelet agent in development for use in patients undergoing PCI. It directly, selectively, reversibly and competitively inhibits P2Y12 receptors on platelets [29] . The chemical structure of cangrelor (2-trif luoropropylthio, N-(2-(methylthio)-ethylβ,γ-dichloromethylene ATP)) was designed by altering the stability, affinity and potency of ATP, the endogenous antagonist for the P2Y12 receptor (Figure 2) [12,29,30] . Cangrelor and similar compounds were used to characterize the pharmacologic properties of P2Y12 receptors on platelets [5] . In preclinical studies, cangrelor improved outcomes in canine and rabbit models of arterial thrombosis [31–33] . In addition, ex vivo work demonstrated that cangrelor significantly reduced adhesion and shear-induced platelet aggregation
future science group
in blood obtained from healthy volunteers [34–36] . Since these early studies, three large, double-blind, randomized trials – CHAMPION PL ATFOR M, CH A MPION PCI and CHAMPION PHOENIX – assessed the efficacy and safety of cangrelor compared with clopidogrel or placebo in the setting of PCI. Cangrelor has also been compared with abciximab for PCI and as a bridging therapy prior to CABG surgery. ●●Pharmacokinetics
Consistent pharmacokinetic parameters for two separate dosage regimens, including the treatment dose used in the CHAMPION program, suggest that cangrelor demonstrates linear and dose-dependent pharmacokinetics [15] . Unlike the orally available P2Y12-receptor antagonists [23] , cangrelor avoids the delays associated with bioavailability and absorption because it is administered iv. The small apparent volume of distribution for cangrelor (estimated at 3.7 l in healthy volunteers and at 5.1 l in subjects with unstable angina or NSTEMI) indicates that the medication is rapidly circulated within the intravascular compartment in close proximity to platelets [15,37] . In fact, a 30-μg/kg bolus dose
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Drug Evaluation Oestreich & Dobesh
NH2 N
OH
O
P
P
P HO
N
N
O
O
O
N
O
O
O
OH
OH
ATP
OH
HO
F HN HO N
F
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N O
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HO
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Ticagrelor
OH
S HN
4Na+ O Cl O
O
N
O
O
O
O
P
P
P
N
O
O
N
N
CF3
S
O
Cl HO
OH
Cangrelor
Figure 2. Structures of the P2Y12-receptor antagonists that mimic ATP. The orally available (ticagrelor) and intravenous (cangrelor) drugs were designed and modified from ATP, the endogenous antagonist of the P2Y12 receptor. Chemically, ticagrelor is (1S,2S,3R,5S)-3-[7-{[(1R,2S)2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]5-(2-hydroxyethoxy)cyclopentane-1,2-diol (MW = 522.57). The chemical structure of cangrelor is 2-trifluoropropylthio, N-(2-(methylthio)-ethyl-β,γ-dichloromethylene ATP). The molecular weight of cangrelor tetrasodium is 864.29.
followed by a 4-μg/kg per min continuous infusion achieves maximum plasma concentrations (Cmax) within 2 min of administration in healthy volunteers [15] . In addition to its fast onset and rapid obtainment of steady-state concentrations, cangrelor
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possesses a fast offset. Following discontinuation, the average elimination half-life for cangrelor is approximately 3–5 min [15] , and 90% of patients with ACS displayed a half-life less than 9 min [37] . Cangrelor is promptly dephosphorylated and metabolized by ecto-enzymes associated
future science group
Cangrelor for treatment during percutaneous coronary intervention
Drug Evaluation
Table 1. Pharmacokinetic and pharmacodynamic properties of P2Y12-receptor antagonists. Properties
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Route of administration Availability of compound Receptor interaction Time to maximal platelet inhibition Time for platelet recovery following discontinuation
Oral Prodrug
Oral Prodrug
Oral Direct-acting
Intravenous Direct-acting
Irreversible 300 mg LD: ≥6 h 600 mg LD: 2–4 h ∼5 days
Irreversible 60 mg LD: 30–60 min ∼7 days
Reversible 180 mg LD: 2h 4–5 days
Reversible 30-μg/kg bolus dose: 2 min 60–90 min
LD: Loading dose. Data taken from [14–19].
with vascular endothelial cells and leukocytes [38–40] . Therefore, the clearance of cangrelor is rapid (41–44 l/h) [15,37,41] , and likely avoids the renal and hepatic routes of metabolism [29] . The pharmacokinetics of cangrelor are shown in Table 2.
more complicated setting of ACS, the majority (70%) of subjects recovered 60% of baseline function at 60 min [37] . The fast return to normal platelet function may provide safety advantages for cangrelor over other P2Y12 receptor antagonists in the context of bleeding or transition to CABG surgery [44] .
●●Pharmacodynamics ●●Drug interactions
Analogous to the pharmacokinetic f indings, cangrelor demonstrates potent, rapid and reversible inhibition of platelet activity. Extensive platelet inhibition is achieved within 2 min of bolus administration followed by continuous infusion in healthy volunteers [15] . In patients with ACS or undergoing PCI, platelet aggregation – as measured by whole blood impedance aggregometry – was inhibited by >80% in all subjects treated with a cangrelor infusion of 4 μg/kg per minute [37,42] . However, in the earlier Phase III trials in the setting of PCI (CHAMPION PLATFOR M and CHAMPION PCI), 11% of cangrelor-treated subjects demonstrated high on-treatment platelet reactivity, defined as P2Y12 reaction units (PRU) >235 measured by the VerifyNow assay (Accumetrics) [43] . Cangrelor also displays a faster return to normal platelet function compared with the oral P2Y12 -receptor antagonists and abciximab, a glycoprotein IIb/IIIa receptor antagonist [42] . Within 60 min after stopping the infusion, 80% of healthy volunteers returned to near-baseline platelet activity [15] . In the
Early studies with cangrelor indicated a potential drug–drug interaction with clopidogrel if the two medications were given simultaneously. An in vitro study showed that pre-incubation of collected whole blood with cangrelor reduced the ability of the active metabolites of clopidogrel and prasugrel to irreversibly inhibit platelet activity [45] . Similar results were obtained in healthy volunteers administered cangrelor concurrently with a 600-mg loading dose of clopidogrel. The sustained level of inhibition expected for clopidogrel was not achieved following cessation of the cangrelor infusion, likely due to the reversible inhibitor cangrelor directly preventing binding of the short-lived, but irreversible active metabolite of clopidogrel [46] . In this study, clopidogrel administered at the end of cangrelor infusion provided the anticipated amount of platelet inhibition [46] . Indeed, no interaction was identified in the pharmacodynamic substudy of primarily the CHAMPION PCI trial, in which subjects treated with cangrelor were also dosed with 600 mg of clopidogrel once the infusion was discontinued [43] .
Table 2. Pharmacokinetic properties of cangrelor. Volume of distribution Clearance Half-life
3.7–5.1 l 41–44 l/h 3–5 min
Data taken from [15,37].
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Drug Evaluation Oestreich & Dobesh Drug interactions based on renal or hepatic elimination are unlikely because cangrelor is primarily eliminated by ATPases in the blood. ●●Clinical efficacy
Phase II trials
Patients with an ACS event and those receiving stents typically require at least a year of dual antiplatelet therapy. It has been estimated that approximately 5% of these patients will require some type of surgery within a year of starting dual antiplatelet therapy [41] . Since there are millions of patients in the USA alone on dual antiplatelet therapy, this adds up to a significant number of times dual antiplatelet therapy needs to be interrupted for a procedure. During the time that the P2Y12 inhibitor is discontinued preceding surgery (typically 5–7 days), the patient is not receiving adequate antiplatelet therapy. It has been estimated that as many as 12.5% of patients will experience an adverse cardiovascular event during this window [47] . One solution has been to bridge patients with iv. glycoprotein IIb/IIIa inhibitors during this window. However, this approach has not been well studied, and even small-molecule agents need to be stopped at least 4–6 h before the time of surgery. Moreover, prolonged infusions of glycoprotein IIb/IIIa inhibitors can increase bleeding [48,49] . These issues led to the investigation of cangrelor in the BRIDGE trial [50] . The BRIDGE trial consisted of two stages. The purpose of the first stage was to determine the dose of cangrelor that provided greater than 60% platelet inhibition in 80% of samples as measured by the VerifyNow P2Y12 assay. A dose of 0.75 μg/kg per min was found to meet this criterion [50] . The second stage of the trial was done to determine if the 0.75 μg/kg per minute dose of cangrelor would maintain levels of platelet reactivity to less than 240 PRU. This cutoff was chosen because it is thought to be the level of platelet inhibition that would be maintained if the patient had remained on oral P2Y12 inhibitor therapy. The BRIDGE trial included patients already on oral P2Y 12 -receptor antagonists (96% clopidogrel and 4% prasugrel) who needed to undergo elective CABG surgery. Patients (n = 207) were randomized in a double-blinded fashion to cangrelor 0.75 μg/kg per min or placebo to be started after discontinuation of the P2Y12-receptor inhibitor. The duration of
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infusion had to be at least 48 h and a maximum of 7 days, and the infusion was stopped 1–6 h before surgical incision. The median duration of the infusion was 2.8 days, with the infusion being discontinued a median of 3.2 h before surgical incision [50] . While the mean PRU was similar in the cangrelor and placebo groups at the time of stopping oral therapy (211 vs 214; p = 0.82), the investigated dose of cangrelor maintained adequate platelet inhibition (PRU
Cangrelor for treatment during percutaneous coronary intervention Julie H Oestreich*,1 & Paul P Dobesh1
ABSTRACT: Dual antiplatelet therapy consisting of aspirin and a P2Y12-receptor antagonist is important for preventing major adverse cardiovascular events in patients managed with percutaneous coronary intervention (PCI). The current P2Y12-receptor antagonists are only available for oral administration and exhibit a delayed onset of action. Furthermore, several days are required for platelet function to return to normal following cessation of therapy. Cangrelor is an intravenous ATP analog that directly, selectively and reversibly inhibits P2Y12 receptors on platelets. A 30-μg/kg bolus dose followed by a 4-μg/kg per minute continuous infusion of cangrelor achieves peak concentration and maximal platelet inhibition within minutes of administration. Cangrelor also demonstrates a fast offset as normal platelet function is restored 1–2 h after cessation of the infusion. Three large, double-blind, randomized trials – CHAMPION PLATFORM, CHAMPION PCI and CHAMPION PHOENIX – assessed the efficacy and safety of cangrelor compared with clopidogrel (during or immediately after PCI) or placebo in the setting of PCI. In the most recent CHAMPION PHOENIX trial, cangrelor was superior to clopidogrel for preventing adverse cardiovascular events with no significant increase in major bleeding. Based on the clinical trial results combined with unique properties such as intravenous administration and fast onset and offset, cangrelor may provide benefit in certain patients undergoing PCI. Scope of acute coronary syndrome & its complications Cardiovascular disease remains the number one cause of death worldwide and is a major contributor to health expenditures, estimated at over $300 billion annually in the USA [1,2] . In the USA alone, over 1 million people are hospitalized each year for acute coronary syndrome (ACS), a subset of cardiovascular disease that includes unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI) [1] . The health and economic consequences of ACS extend beyond the acute event. However, with the use of evidencebased therapies and percutaneous coronary intervention (PCI), the rates of death, cardiogenic shock, heart failure and other complications can be reduced [1] . Approximately 1 million PCI procedures were performed in the USA in 2010, further strengthening the role of PCI for the treatment of ACS [1] . Appropriate assessment of the benefit-to-risk ratio is important as PCI can cause serious complications including stent thrombosis and death [3] .
KEYWORDS
• antiplatelet therapy • cangrelor • P2Y12-receptor antagonist • percutaneous
coronary intervention
Overview of P2Y12-receptor antagonists Pharmacologic targeting with antiplatelet therapy is an important component of PCI management, since platelets contribute to thrombus formation. ADP P2Y receptors are critical regulators of platelet function, and the P2Y12 receptor is required for complete and irreversible platelet activation [4–6] . University of Nebraska Medical Center, College of Pharmacy, Department of Pharmacy Practice, Omaha, NE, USA *Author for correspondence: Tel.: +1 402 559 2916; Fax: +1 402 559 5673; [email protected] 1
10.2217/FCA.13.108 © 2014 Future Medicine Ltd
Future Cardiol. (2014) 10(2), 201–213
part of
ISSN 1479-6678
201
Drug Evaluation Oestreich & Dobesh 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, while ATP is a natural antagonist for both receptors [4] . In addition to aspirin, the class of purinergic P2Y12-receptor antagonists comprises the second component of dual antiplatelet therapy recommended for the treatment and secondary prevention of adverse cardiovascular events for patients with ACS or undergoing PCI [3,7] . The thienopyridine ticlopidine was the first selective P2Y12-receptor antagonist to be identified. Ticlopidine was followed by the approval of the second-generation thienopyridine clopidogrel, which demonstrated an improved safety profile including decreased neutropenia. In 2009, the European Commission and the US FDA approved the third-generation thienopyridine, prasugrel (Effient® [US]/Efient® [EU], Daiichi Sankyo/Eli Lilly), which achieves faster and more potent platelet inhibition compared with clopidogrel [8,9] . The thienopyridines are prodrugs and require conversion by the cytochrome P450 (CYP) enzyme system in the liver for activity. Therefore, ticlopidine, clopidogrel, and prasugrel are administered orally. Following CYPmediated metabolism in the liver, the opened thienopyridine ring exposes a thiol moiety in the formed active metabolite capable of forming an irreversible disulfide bond with the P2Y12 receptor (Figure 1) [10] . Thus, platelet inhibition by the active metabolite persists for the life of the platelet. Unlike the thienopyridines, the newest P2Y12receptor antagonist on the market is direct acting and does not require first-pass metabolism to generate an active metabolite. Ticagrelor (Brilinta® [US]/Brilique® [EU], AstraZeneca) is a cyclopentyl-triazolo-pyrimidine modified from the structure of cangrelor to produce a potent and selective P2Y12-receptor antagonist that is orally active (Figure 2) [12] . While the thienopyridines irreversibly bind the P2Y12 receptor to block ADP signaling, ticagrelor targets a separate binding site, and therefore demonstrates noncompetitive and reversible antagonism of the P2Y12 receptor [13] . Although patients treated with ticagrelor restore platelet function at a faster rate following drug discontinuation than patients treated with clopidogrel, the amount
202
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of time required for platelet recovery remains similar, due to more potent platelet inhibition at steady-state with ticagrelor (Table 1) [14] . Limitations of current antiplatelet therapy All of the available P2Y12-receptor antagonists are effective for preventing major adverse cardiovascular events in patients managed with PCI. However, major bleeding occurs in 1.8–4.5% of patients treated with dual antiplatelet therapy [20–22] . This bleeding risk significantly increases when more potent P2Y12-receptor inhibitors (i.e., prasugrel or ticagrelor) are used rather than clopidogrel [20–22] . Nonetheless, the bleeding risk is considered acceptable in most cases given the reduction in thrombotic events [3] . Although the currently available P2Y12 receptor antagonists provide additional benefit in PCI, areas for improvement remain. Clopidogrel, prasugrel and ticagrelor must be administered orally. While the expected number of affected patients is not large, this presents a challenge in patients undergoing PCI who are intubated or in cardiogenic shock, as well as in patients who present with nausea and vomiting. Furthermore, in the pressured setting of STEMI, there is little time available for early administration, and even the more potent P2Y12-receptor antagonists exhibit a delayed onset of action [23] . This delayed onset could leave patients at risk for stent thrombosis or other cardiovascular events in PCI, which occurs at the highest rate immediately after the procedure [24–27] . In the CREDO trial, only patients who received their clopidogrel loading dose before PCI demonstrated a reduction in cardiovascular events and no benefit was seen in patients receiving clopidogrel post-PCI [28] . Similarly, in the HORIZONS-AMI trial, acute stent thrombosis was higher in patients who did not have antiplatelet therapy beyond aspirin compared with those with a more aggressive antiplatelet regimen [26] . Another critical limitation of antiplatelet therapy during PCI is the extended time required for platelet recovery following cessation of the treatment. For both the irreversible thienopyridines and the reversible ticagrelor, platelet activity does not return to baseline for several days (Table 1) . Therefore, unless the net benefit of P2Y12-receptor inhibitor therapy outweighs the risk of excessive bleeding, current guidelines recommend withholding P2Y12-receptor antagonist therapy prior to planned coronary artery bypass grafting (CABG) surgery for at least 5 days in
future science group
Cangrelor for treatment during percutaneous coronary intervention
OCH3
O
Drug Evaluation
O O H3C
N
N O
S
Cl
S
F
Clopidogrel
Prasugrel
OCH3
O
HOOC
N
HS
O
HOOC
Cl
Clopidogrel active metabolite
N
HS
F Prasugrel active metabolite R-138727
Figure 1. Structures of the thienopyridine class of P2Y12-receptor antagonists. Clopidogrel and prasugrel are both prodrugs that require a multistep process for conversion to thiol-containing active metabolites [11]. The free thiol is capable of forming a disulfide bond with the P2Y12 receptor causing irreversible inhibition for the life of the platelet.
patients receiving clopidogrel and ticagrelor and for 7 days in patients receiving prasugrel [7] . In total, a direct-acting intravenous (iv.) medication with a fast onset and offset of action has the potential to mitigate these limitations and improve care for certain patients with ACS. Introduction to the compound & its chemistry Cangrelor (The Medicines Company) is an investigational and iv. antiplatelet agent in development for use in patients undergoing PCI. It directly, selectively, reversibly and competitively inhibits P2Y12 receptors on platelets [29] . The chemical structure of cangrelor (2-trif luoropropylthio, N-(2-(methylthio)-ethylβ,γ-dichloromethylene ATP)) was designed by altering the stability, affinity and potency of ATP, the endogenous antagonist for the P2Y12 receptor (Figure 2) [12,29,30] . Cangrelor and similar compounds were used to characterize the pharmacologic properties of P2Y12 receptors on platelets [5] . In preclinical studies, cangrelor improved outcomes in canine and rabbit models of arterial thrombosis [31–33] . In addition, ex vivo work demonstrated that cangrelor significantly reduced adhesion and shear-induced platelet aggregation
future science group
in blood obtained from healthy volunteers [34–36] . Since these early studies, three large, double-blind, randomized trials – CHAMPION PL ATFOR M, CH A MPION PCI and CHAMPION PHOENIX – assessed the efficacy and safety of cangrelor compared with clopidogrel or placebo in the setting of PCI. Cangrelor has also been compared with abciximab for PCI and as a bridging therapy prior to CABG surgery. ●●Pharmacokinetics
Consistent pharmacokinetic parameters for two separate dosage regimens, including the treatment dose used in the CHAMPION program, suggest that cangrelor demonstrates linear and dose-dependent pharmacokinetics [15] . Unlike the orally available P2Y12-receptor antagonists [23] , cangrelor avoids the delays associated with bioavailability and absorption because it is administered iv. The small apparent volume of distribution for cangrelor (estimated at 3.7 l in healthy volunteers and at 5.1 l in subjects with unstable angina or NSTEMI) indicates that the medication is rapidly circulated within the intravascular compartment in close proximity to platelets [15,37] . In fact, a 30-μg/kg bolus dose
www.futuremedicine.com
203
Drug Evaluation Oestreich & Dobesh
NH2 N
OH
O
P
P
P HO
N
N
O
O
O
N
O
O
O
OH
OH
ATP
OH
HO
F HN HO N
F
N
N O
N
HO
N
S
Ticagrelor
OH
S HN
4Na+ O Cl O
O
N
O
O
O
O
P
P
P
N
O
O
N
N
CF3
S
O
Cl HO
OH
Cangrelor
Figure 2. Structures of the P2Y12-receptor antagonists that mimic ATP. The orally available (ticagrelor) and intravenous (cangrelor) drugs were designed and modified from ATP, the endogenous antagonist of the P2Y12 receptor. Chemically, ticagrelor is (1S,2S,3R,5S)-3-[7-{[(1R,2S)2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]5-(2-hydroxyethoxy)cyclopentane-1,2-diol (MW = 522.57). The chemical structure of cangrelor is 2-trifluoropropylthio, N-(2-(methylthio)-ethyl-β,γ-dichloromethylene ATP). The molecular weight of cangrelor tetrasodium is 864.29.
followed by a 4-μg/kg per min continuous infusion achieves maximum plasma concentrations (Cmax) within 2 min of administration in healthy volunteers [15] . In addition to its fast onset and rapid obtainment of steady-state concentrations, cangrelor
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possesses a fast offset. Following discontinuation, the average elimination half-life for cangrelor is approximately 3–5 min [15] , and 90% of patients with ACS displayed a half-life less than 9 min [37] . Cangrelor is promptly dephosphorylated and metabolized by ecto-enzymes associated
future science group
Cangrelor for treatment during percutaneous coronary intervention
Drug Evaluation
Table 1. Pharmacokinetic and pharmacodynamic properties of P2Y12-receptor antagonists. Properties
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Route of administration Availability of compound Receptor interaction Time to maximal platelet inhibition Time for platelet recovery following discontinuation
Oral Prodrug
Oral Prodrug
Oral Direct-acting
Intravenous Direct-acting
Irreversible 300 mg LD: ≥6 h 600 mg LD: 2–4 h ∼5 days
Irreversible 60 mg LD: 30–60 min ∼7 days
Reversible 180 mg LD: 2h 4–5 days
Reversible 30-μg/kg bolus dose: 2 min 60–90 min
LD: Loading dose. Data taken from [14–19].
with vascular endothelial cells and leukocytes [38–40] . Therefore, the clearance of cangrelor is rapid (41–44 l/h) [15,37,41] , and likely avoids the renal and hepatic routes of metabolism [29] . The pharmacokinetics of cangrelor are shown in Table 2.
more complicated setting of ACS, the majority (70%) of subjects recovered 60% of baseline function at 60 min [37] . The fast return to normal platelet function may provide safety advantages for cangrelor over other P2Y12 receptor antagonists in the context of bleeding or transition to CABG surgery [44] .
●●Pharmacodynamics ●●Drug interactions
Analogous to the pharmacokinetic f indings, cangrelor demonstrates potent, rapid and reversible inhibition of platelet activity. Extensive platelet inhibition is achieved within 2 min of bolus administration followed by continuous infusion in healthy volunteers [15] . In patients with ACS or undergoing PCI, platelet aggregation – as measured by whole blood impedance aggregometry – was inhibited by >80% in all subjects treated with a cangrelor infusion of 4 μg/kg per minute [37,42] . However, in the earlier Phase III trials in the setting of PCI (CHAMPION PLATFOR M and CHAMPION PCI), 11% of cangrelor-treated subjects demonstrated high on-treatment platelet reactivity, defined as P2Y12 reaction units (PRU) >235 measured by the VerifyNow assay (Accumetrics) [43] . Cangrelor also displays a faster return to normal platelet function compared with the oral P2Y12 -receptor antagonists and abciximab, a glycoprotein IIb/IIIa receptor antagonist [42] . Within 60 min after stopping the infusion, 80% of healthy volunteers returned to near-baseline platelet activity [15] . In the
Early studies with cangrelor indicated a potential drug–drug interaction with clopidogrel if the two medications were given simultaneously. An in vitro study showed that pre-incubation of collected whole blood with cangrelor reduced the ability of the active metabolites of clopidogrel and prasugrel to irreversibly inhibit platelet activity [45] . Similar results were obtained in healthy volunteers administered cangrelor concurrently with a 600-mg loading dose of clopidogrel. The sustained level of inhibition expected for clopidogrel was not achieved following cessation of the cangrelor infusion, likely due to the reversible inhibitor cangrelor directly preventing binding of the short-lived, but irreversible active metabolite of clopidogrel [46] . In this study, clopidogrel administered at the end of cangrelor infusion provided the anticipated amount of platelet inhibition [46] . Indeed, no interaction was identified in the pharmacodynamic substudy of primarily the CHAMPION PCI trial, in which subjects treated with cangrelor were also dosed with 600 mg of clopidogrel once the infusion was discontinued [43] .
Table 2. Pharmacokinetic properties of cangrelor. Volume of distribution Clearance Half-life
3.7–5.1 l 41–44 l/h 3–5 min
Data taken from [15,37].
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Drug Evaluation Oestreich & Dobesh Drug interactions based on renal or hepatic elimination are unlikely because cangrelor is primarily eliminated by ATPases in the blood. ●●Clinical efficacy
Phase II trials
Patients with an ACS event and those receiving stents typically require at least a year of dual antiplatelet therapy. It has been estimated that approximately 5% of these patients will require some type of surgery within a year of starting dual antiplatelet therapy [41] . Since there are millions of patients in the USA alone on dual antiplatelet therapy, this adds up to a significant number of times dual antiplatelet therapy needs to be interrupted for a procedure. During the time that the P2Y12 inhibitor is discontinued preceding surgery (typically 5–7 days), the patient is not receiving adequate antiplatelet therapy. It has been estimated that as many as 12.5% of patients will experience an adverse cardiovascular event during this window [47] . One solution has been to bridge patients with iv. glycoprotein IIb/IIIa inhibitors during this window. However, this approach has not been well studied, and even small-molecule agents need to be stopped at least 4–6 h before the time of surgery. Moreover, prolonged infusions of glycoprotein IIb/IIIa inhibitors can increase bleeding [48,49] . These issues led to the investigation of cangrelor in the BRIDGE trial [50] . The BRIDGE trial consisted of two stages. The purpose of the first stage was to determine the dose of cangrelor that provided greater than 60% platelet inhibition in 80% of samples as measured by the VerifyNow P2Y12 assay. A dose of 0.75 μg/kg per min was found to meet this criterion [50] . The second stage of the trial was done to determine if the 0.75 μg/kg per minute dose of cangrelor would maintain levels of platelet reactivity to less than 240 PRU. This cutoff was chosen because it is thought to be the level of platelet inhibition that would be maintained if the patient had remained on oral P2Y12 inhibitor therapy. The BRIDGE trial included patients already on oral P2Y 12 -receptor antagonists (96% clopidogrel and 4% prasugrel) who needed to undergo elective CABG surgery. Patients (n = 207) were randomized in a double-blinded fashion to cangrelor 0.75 μg/kg per min or placebo to be started after discontinuation of the P2Y12-receptor inhibitor. The duration of
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infusion had to be at least 48 h and a maximum of 7 days, and the infusion was stopped 1–6 h before surgical incision. The median duration of the infusion was 2.8 days, with the infusion being discontinued a median of 3.2 h before surgical incision [50] . While the mean PRU was similar in the cangrelor and placebo groups at the time of stopping oral therapy (211 vs 214; p = 0.82), the investigated dose of cangrelor maintained adequate platelet inhibition (PRU
