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Current status of data on cangrelor
JPT-06851; No of Pages 8 Pharmacology & Therapeutics xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera
Associate editor: Y.S. Chatzizisis
Current status of data on cangrelor Arman Qamar, Deepak L. Bhatt ⁎ Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, USA
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Keywords: Acute coronary syndrome Antiplatelet therapy Cangrelor Coronary artery disease P2Y12 receptor inhibition Percutaneous coronary intervention (PCI)
a b s t r a c t P2Y12 receptor inhibition in addition to aspirin is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Despite advances in contemporary antithrombotic therapy, periprocedural thrombotic complications such as myocardial infarction and stent thrombosis remain a major concern in patients treated with PCI. Current practice guidelines recommend treatment with a P2Y12 receptor inhibitor as early as possible in patients with ACS. Existing oral P2Y12 receptors inhibitors (clopidogrel, prasugrel, or ticagrelor) have several limitations such as delayed onset and offset of action, interindividual variation, and only oral availability. Cangrelor, an intravenous, fast-onset, direct-acting P2Y12 receptor inhibitor offers potent platelet inhibition that is rapidly reversible. In large randomized trials, cangrelor has shown substantial reduction in ischemic events with no increase in severe bleeding compared with clopidogrel among patients undergoing PCI. Cangrelor is approved as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary revascularization, and stent thrombosis in patients who have not been pretreated with a P2Y12 receptor inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor. This review aims at providing a comprehensive analysis of the current evidence pertaining to the role of cangrelor in contemporary practice. © 2016 Elsevier Inc. All rights reserved.
Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. CHAMPION PCI trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. CHAMPION PLATFORM trial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. CHAMPION PHOENIX trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. CHAMPION PHOENIX: Effect of Cangrelor on Intraprocedural Stent Thrombosis During PCI 6. CHAMPION PHOENIX: Outcomes on a background of bivalirudin . . . . . . . . . . . . 7. CHAMPION PHOENIX: Outcomes according to access site for PCI . . . . . . . . . . . . 8. CHAMPION PHOENIX: Outcomes in women . . . . . . . . . . . . . . . . . . . . . 9. CHAMPION PHOENIX: Outcomes in older patients . . . . . . . . . . . . . . . . . . 10. BRIDGE trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Transition from cangrelor to oral P2Y12 receptor inhibitors . . . . . . . . . . . . . . 12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. Source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: ACS, Acute Coronary Syndromes; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; ARC, Academic Research Consortium; ATP, Adenosine Triphosphate; CABG, Coronary Artery Bypass Graft; CAD, Coronary Artery Disease; EMA, European Medicines Agency; FDA, Food and Drug Administration; GUSTO, Global Use of Strategies to Open Occluded Arteries; IPST, Intraprocedural Stent Thrombosis; MI, Myocardial Infarction; NSTE-ACS, Non ST Segment Elevation ACS; PCI, Percutaneous Coronary Intervention; PRU, P2Y12 Reaction Units; STEMI, ST Segment Elevation Myocardial Infarction; TIMI, Thrombolysis in Myocardial Infarction. ⁎ Corresponding author at: Brigham and Women's Hospital Heart & Vascular Center, 75 Francis Street, Boston, MA 02115, USA. E-mail address: [email protected] (D.L. Bhatt).
http://dx.doi.org/10.1016/j.pharmthera.2016.01.004 0163-7258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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1. Introduction Dual antiplatelet therapy with a P2Y12 receptor inhibitor in addition to aspirin is the foundation of treatment in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) (Bhatt et al., 2014). PCI has been shown to reduce the risk of death and myocardial infarction (MI) in patients with ACS and to improve symptoms in patients with stable coronary artery disease (CAD). Despite advances in contemporary antithrombotic therapy, PCI may be complicated by periprocedural thrombotic events, thus, increasing death, MI or stent thrombosis during or after PCI. Current practice guidelines recommend prompt treatment with a P2Y12 receptor inhibitor and aspirin in all patients with ACS for at least 12 months (Hamm et al., 2011; Steg et al., 2012; O’Gara et al., 2013; Amsterdam et al., 2014). In patients with ACS, treatment with aspirin and clopidogrel compared with aspirin alone has been proven to reduce cardiovascular events (Yusuf et al., 2001). Pretreatment with clopidogrel before coronary angiography has shown uncertain efficacy in patients undergoing PCI; this has resulted in wide variation in the timing of clopidogrel loading (Mehta et al., 2001; Steinhubl et al., 2002; Widimsky et al., 2008; Rao et al., 2009; Bellemain-Appaix et al., 2012). Furthermore, clopidogrel has considerable limitations such as delayed onset and delayed offset of effect on platelet inhibition. Moreover, effect of clopidogrel is dependent on intestinal absorption and transformation to its active metabolite by cytochrome P450 enzymes, such as CYP2C19 (Bhatt, 2009). Consequently, genetic polymorphisms that affect CYP2C19 function result in variable effects for clopidogrel. For example, among patients treated with clopidogrel, those carrying loss-of-function CYP2C19 genetic variants have reduced inhibition of platelet aggregation and an increased risk of adverse cardiovascular events, including stent thrombosis, compared with non-carriers (Collet et al., 2009; Mega et al., 2009; Simon et al., 2009). Also, 10–15% of patients presenting with ACS have to undergo coronary artery bypass graft (CABG) surgery. Clopidogrel has a delayed offset of action related to irreversible inhibition of platelet P2Y12 receptors and is associated with an increased risk of perioperative bleeding in patients undergoing CABG (Fox et al., 2004). Therefore; patients need a delay of 5–7 days for platelet function to recover before CABG. As a result, many physicians refrain from administering clopidogrel until coronary angiography is performed. Compared with clopidogrel, prasugrel and ticagrelor, two more potent oral P2Y12 receptor inhibitors, have been associated with less interpatient variability and a significant reduction in ischemic events but at an increased risk of major bleeding (Wiviott et al., 2007; Wallentin et al., 2009). However, in the setting of ACS, particularly STsegment elevation myocardial infarction (STEMI), even these agents may take several hours to achieve maximal platelet inhibition (Agrawal and Bhatt, 2013). Additionally, in patients with ACS, the bioavailability of oral P2Y12 receptor inhibitors might be severely decreased in the presence of nausea, emesis, use of opiates, intubation,
impaired gut perfusion in cardiogenic shock, or therapeutic hypothermia (Heestermans et al., 2008; Souckova et al., 2013). As a result, these patients are at an increased risk of recurrent MI and stent thrombosis, particularly in the immediate peri-PCI period. Similar to clopidogrel, it takes 3–10 days for platelet inhibition to reverse fully in patients treated with ticagrelor or prasugrel. This is particularly problematic when the antiplatelet effect is no longer desirable, as in settings where emergent cardiac surgery is needed. Although antiplatelet therapy with an intravenous glycoprotein IIb/IIIa inhibitor is effective in reducing ischemic events, its effect lasts for several hours after stopping the infusion, and there is a higher bleeding risk (Bhatt and Topol, 2000). Due to the limitations for all oral antiplatelet agents, there has been an unmet clinical need for a potent, intravenous, rapidly acting, rapidly reversible P2Y12 receptor inhibitor (Table 1) (Franchi and Angiolillo, 2015; Rollini et al., 2016). Cangrelor is a novel, intravenous, nonthienopyridine adenosine triphosphate (ATP) analog that reversibly and directly inhibits the P2Y12 receptor (Storey et al., 2000; Angiolillo et al., 2012a, 2012b). When given as a bolus plus an infusion, it provides immediate, consistent, and profound platelet inhibition that is rapidly reversible. The plasma half life of cangrelor is 3–6 min, and platelet function normalizes within 60 min after discontinuation of the infusion. To date, several phase I and phase II studies with cangrelor have been conducted in diverse cohorts, including healthy volunteers and patients with renal impairment and CAD. All of these studies demonstrate fast onset and steady, potent, and rapidly reversible platelet inhibition without an increased risk of severe bleeding. Furthermore, cangrelor pharmacokinetics were not influenced by age, sex, genetic variations, or renal function. In a phase II open-label multicenter study of patients with ACS (n = 39), treatment with cangrelor in combination with aspirin and heparin produced robust, consistent platelet inhibition (N95%) and was well tolerated over an infusion period of up to 72 h (Storey et al., 2001). Among 199 patients undergoing elective PCI in a phase II randomized, openlabel trial, cangrelor was shown to cause rapid, dose-dependent and complete platelet inhibition similar to abciximab. In this study, there was less prolongation of bleeding time and more rapid return of platelet function to baseline with cangrelor than abciximab (Greenbaum et al., 2006). Three pivotal phase 3 trials, Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PCI (ClinicalTrials.gov Identifier, NCT00305162), CHAMPION PLATFORM (ClinicalTrials.gov Identifier, NCT00385138), and CHAMPION PHOENIX (ClinicalTrials.gov Identifier, NCT01156571), have explored the efficacy and safety of cangrelor in patients undergoing PCI (Bhatt et al., 2009, Harrington et al., 2009; Leonardi et al., 2012; Bhatt et al., 2013). The study designs and main features of the three trials are shown in Fig. 1 and Fig. 2, respectively (Steg et al., 2013). Based on these data, the US Food and Drug Administration (FDA) approved cangrelor as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary
Table 1 Pharmacological characteristics of P2Y12 receptor inhibitors (Franchi and Angiolillo, 2015; Rollini et al., 2016). ATP = adenosine triphosphate; ACS = acute coronary syndrome; PCI = percutaneous coronary intervention; CAD = coronary artery disease.
Class Reversibility Prodrug Administration route Onset of effect Duration of effect Half-life Frequency Influenced by genetic variation Approved settings a
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Thienopyridine Irreversible Yes Oral 2–8 h 5–7 days ~6 h Once daily Yes ACS (invasively or noninvasively treated) and PCI in stable CAD
Thienopyridine Irreversible Yes Oral 30 min to 4 h 7–10 days ~7 h Once daily No ACS undergoing PCI
Triazolopyrimidine Reversible No Oral 30 min to 4 h 3–5 days ~8 h Twice daily No ACS (invasively or noninvasively treated)
ATP analog Reversible No Intravenous Immediate 30–60 min 3–5 min Bolus plus infusion No a PCI in patients with ACS and stable CAD
Patients with ACS or stable CAD who have not been pretreated with a P2Y12 receptor inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor.
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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Fig. 1. CHAMPION study designs. Reprinted with permission (Steg et al., 2013). mITT = modified intention-to-treat; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; STEMI = ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention.
revascularization, and stent thrombosis in patients who have not been pretreated with a P2Y12 platelet inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor. Also, the European Medicines Agency (EMA) approved the use of cangrelor for reducing the risk of thrombotic cardiovascular events in patients with CAD undergoing PCI who did not receive an oral P2Y12 inhibitor before the PCI procedure, and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.
2. CHAMPION PCI trial The CHAMPION PCI trial was a randomized, double-blind, doubledummy, active control trial comparing cangrelor with clopidogrel in patients undergoing PCI. The study included 8887 patients undergoing PCI; 85% with ACS and 15% with stable CAD (Fig. 1; Fig. 2) (Harrington et al., 2009). Patients were randomly assigned in a 1:1 design to receive
Fig. 2. Comparison of design features of the CHAMPION studies. Reprinted with permission (Steg et al., 2013).
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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either cangrelor infusion (30 μg/kg bolus followed by a 4 μg/kg/min infusion) or 600 mg of clopidogrel within 30 min before PCI. Patients initially treated with cangrelor received 600 mg of clopidogrel upon discontinuation of the infusion. The primary efficacy endpoint was a composite of death, MI, or ischemia-driven revascularization. MI was defined by a new significant Q wave on an electrocardiogram or a post PCI elevation in CKMB level that was at least three times greater than the upper limit of normal, and when biomarkers were elevated before PCI, an additional 50% above baseline. At 48 h, the primary efficacy endpoint occurred in 7.5% of patients in the cangrelor group and 7.1% in the clopidogrel group [odds ratio (95% confidence interval): 1.05 (0.88– 1.24); P = 0.59]. Similarly, at 30 days, cangrelor was noninferior to clopidogrel with respect to the incidence of the primary composite endpoint. The risk of stent thrombosis at 48 h did not differ significantly between the two groups. In terms of safety, the investigators reported bleeding event rates according to various categories, including Global Use of Strategies to Open Occluded Arteries (GUSTO), Thrombolysis in Myocardial Infarction (TIMI), and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY). There was no significant difference in GUSTO severe or TIMI major bleeding or the need for blood transfusion with cangrelor compared with clopidogrel. However, according to the ACUITY criteria, cangrelor was associated with a trend toward a higher rate of major bleeding. 3. CHAMPION PLATFORM trial In this randomized, double-blind, placebo-controlled study, cangrelor was compared with clopidogrel in 5362 patients with nonST-segment elevation acute coronary syndrome (NSTE-ACS) or stable angina who were undergoing PCI (Fig. 1; Fig. 2) (Bhatt et al., 2009). Patients were randomly assigned in 1:1 ratio to receive either cangrelor (30 μg/kg bolus followed by a 4 μg/kg/min infusion for 2–4 h) or placebo for the duration of the PCI procedure. Patients in the cangrelor arm received 600 mg clopidogrel at the end of the cangrelor infusion, and those in the placebo arm received a 600 mg loading dose of clopidogrel at the completion of PCI. MI was adjudicated according to the criteria specified in the CHAMPION PCI trial. The incidence of the primary efficacy endpoint, a composite of death, MI, or ischemia-driven revascularization at 48 h did not differ significantly in the cangrelor group compared with the placebo group (7% versus 8%) [odds ratio (95% confidence interval): 0.87 (0.71–1.07); P = 0.17]. However, there was a significant reduction in the prespecified secondary endpoints, including stent thrombosis and death from any cause at 48 h with cangrelor. Analysis of the safety outcomes in this study showed no difference in GUSTO severe or moderate or TIMI major bleeding with cangrelor. Compared with placebo, an increased occurrence of ACUITY major bleeding due to an excess of groin hematomas was seen with cangrelor. Nevertheless, there was no significant increase in the frequency of blood transfusions with cangrelor compared with placebo. The CHAMPION PCI and CHAMPION PLATFORM trials were prematurely terminated for futility to meet their primary endpoint of death, MI, or ischemia-driven revascularization. The primary endpoints in both trials were driven by the frequency of the MI endpoint. The unexpectedly short times from hospital admission with ACS to PCI in both trials (~6–8 h) made it challenging to differentiate between MI occurring before or after randomization. Post hoc analysis of the CHAMPION PCI and CHAMPION PLATFORM data using the Universal Definition of MI instead of the trial definitions found a beneficial effect of cangrelor compared with clopidogrel in reducing rates of periprocedural ischemic events without an increase in severe bleeding. A pooled analysis of CHAMPION PCI and CHAMPION PLATFORM (n = 13,049) including reassessment of the MI endpoint using the Universal Definition of MI rather than the CHAMPION definition found a significant reduction in the primary composite endpoint of death, MI, or ischemia-driven revascularization with cangrelor compared with clopidogrel (3.1% versus 3.8%) [odds ratio (95% confidence interval): 0.82 (0.68–0.99); P =
0.03] (Thygesen et al., 2012; White et al., 2012). In addition, there was more than a 50% reduction in stent thrombosis with cangrelor compared with clopidogrel in this analysis (0.2% versus 0.4%) [odds ratio (95% confidence interval): 0.44 (0.22–0.87); P = 0.01]. However, with the CHAMPION definition of MI, there was no significant effect of cangrelor on the primary endpoint in this analysis. A subsequent analysis using the Universal Definition of MI in the CHAMPION PLATFORM trial showed only a 4.3% incidence of PCIrelated MI compared with 6.5% identified using the CHAMPION definition (Leonardi et al., 2013). In this analysis, when the MI endpoint was reevaluated according to the Universal Definition of MI, the primary endpoint at 48 h, occurred in only 5.4% of patients, with 4.9% in the cangrelor arm and 6% in the placebo arm [odds ratio (95% confidence interval): 0.80 (0.63–1.02); P = 0.07] in contrast to 7.5% using the CHAMPION definition, with 7% in the cangrelor arm and 8% in the placebo arm [odds ratio (95% confidence interval): 0.87 (0.71–1.07); P = 0.17]. These hypothesis-generating findings in the post hoc analysis were further explored in the CHAMPION PHOENIX trial using the Universal Definition of MI. 4. CHAMPION PHOENIX trial In the CHAMPION PHOENIX trial, cangrelor was compared with clopidogrel in 11,145 patients presenting with stable angina, NSTEACS, or STEMI who required PCI (Bhatt et al., 2013). Patients were randomized after coronary angiography, 1:1 in a double-dummy, doubleblind fashion to receive either cangrelor (30 μg/kg bolus followed by a 4 μg/kg/min infusion for at least 2 h or the duration of procedure, whichever was longer) or a clopidogrel loading dose (300–600 mg) at the time of PCI. Patients who had received a P2Y12 inhibitor in the last 7 days were excluded from this trial. Glycoprotein IIb/IIIa inhibitors were only permitted as rescue therapy during PCI for certain angiographic complications. Aspirin (75 mg to 325 mg) was administered to all patients, and everyone received clopidogrel 75 mg during the first 48 h; subsequently, clopidogrel or an alternative P2Y12 inhibitor could be administered according to local guidelines. Cangrelor was shown to significantly reduce the risk of ischemic events, including stent thrombosis, at 48 h and 30 days, with no increase in the risk of severe bleeding across the spectrum of patients undergoing PCI. At 48 h, the primary composite efficacy endpoint of death, MI defined by universal definition for PCI-related MI, ischemia-driven revascularization, or stent thrombosis occurred in fewer patients in the cangrelor group than the clopidogrel group (4.7% versus 5.9%) [odds ratio (95% confidence interval): 0.78 (0.66–0.93); P = 0.005] (Fig. 3). The incidence of
Fig. 3. Kaplan–Meier curves for the primary efficacy endpoint in the CHAMPION PHOENIX trial. The primary efficacy endpoint was a composite of death from any cause, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. The inset shows the same data on an enlarged y axis. Reprinted with permission (Bhatt et al., 2013).
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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Fig. 4. Kaplan–Meier curves for the secondary endpoint in the CHAMPION PHOENIX trial. The secondary endpoint was stent thrombosis at 48 h after randomization. The inset shows the same data on an enlarged y axis. Reprinted with permission (Bhatt et al., 2013).
the secondary efficacy endpoint of stent thrombosis in the 48 h after randomization was also significantly lower in patients receiving cangrelor compared with those receiving clopidogrel (0.8% versus 1.4%) [odds ratio (95% confidence interval): 0.62 (0.43–0.90); P = 0.01] (Fig. 4). The rate of the primary safety endpoint, GUSTO-defined severe bleeding at 48 h, did not differ significantly between the two groups. Net clinical benefit, assessed as a combination of rates of primary efficacy endpoint and primary safety endpoint, favored cangrelor over clopidogrel (4.8% versus 6%) [odds ratio (95% confidence interval); 0.80 (0.68–0.94): P = 0.008]. Taken together, cangrelor demonstrated consistent benefit across all subgroups in CHAMPION PHOENIX. The substantial reduction in ischemic events with cangrelor was similar among patients presenting with stable angina, NSTE-ACS, and STEMI. The beneficial effect of cangrelor
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among patients in the United States and those in other countries were comparable. Likewise, there was no significant difference in the effect of cangrelor on the primary endpoint among patients treated with a 300 or 600 mg loading dose of clopidogrel. The effect of cangrelor was consistent irrespective of the timing of the loading dose of clopidogrel (within the context of loading in the catheterization laboratory); the benefit of cangrelor on the primary endpoint did not differ significantly between patients who received the loading dose of clopidogrel immediately before PCI or those who received it during or after the procedure. A prespecified, pooled analysis of the patient-level data of 24,910 patients from the three CHAMPION trials (PCI, PLATFORM and PHOENIX) compared cangrelor with clopidogrel (Steg et al., 2013). The primary efficacy endpoint was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis. MI was defined according to the universal definition used in CHAMPION PHOENIX. In this analysis, treatment with cangrelor was associated with ~20% reduction in the risk of the primary endpoint at 48 h compared with clopidogrel (3.8% versus 4.7%) [odds ratio (95% confidence interval); 0.81 (0.71–0.91): P = 0.0007] (Fig. 5). Compared with clopidogrel, cangrelor significantly reduced the incidence of stent thrombosis, MI, and Q-wave MI at 48 h. The reduction in the primary endpoint with cangrelor was consistent across all clinical subgroups and was maintained up to 30 days after PCI (Fig. 5). There was no increase in GUSTO severe or life-threatening bleeding or the need for blood transfusion with cangrelor. However, compared with clopidogrel, cangrelor was associated with an increase in the occurrence of GUSTO minor bleeding. 5. CHAMPION PHOENIX: Effect of Cangrelor on Intraprocedural Stent Thrombosis During PCI In the CHAMPION PHOENIX, stent thrombosis was defined as the occurrence of intraprocedural stent thrombosis (IPST) or Academic Research Consortium (ARC)-defined stent thrombosis occurring after the PCI procedure. In 10,939 patients from this trial, a blinded core
Fig. 5. Forest plot of the primary, key secondary, and secondary outcomes at 48 h, overall and in each of the three CHAMPION trials. Reprinted with permission (Steg et al., 2013). MI = myocardial infarction; IDR = ischemia-driven revascularization; ST = stent thrombosis; PCI = percutaneous coronary intervention.
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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laboratory performed an angiographic analysis for the presence of IPST (Gѐnѐreux et al., 2014). IPST occurred in 0.8% of the entire study population. The development of IPST was independently associated with an increased risk of adverse ischemic events, including death, MI, ischemia-driven revascularization, or stent thrombosis occurring at 48 hours and 30 days from randomization. Furthermore, treatment with cangrelor resulted in a 35% reduction in the rate of IPST compared with clopidogrel at 48 hours (0.6% versus 1%) [odds ratio (95% confidence interval): 0.65 (0.42–0.99); P = 0.04]. The effect of cangrelor in reducing IPST was evident in several subgroups, including patients with stable angina, NSTE-ACS, or STEMI. 6. CHAMPION PHOENIX: Outcomes on a background of bivalirudin A prespecified subgroup analysis in the CHAMPION PHOENIX examined the efficacy and safety of cangrelor compared with clopidogrel in patients who received bivalirudin during PCI (White et al., 2015). Bivalirudin was used in approximately 19% of the patients (n = 2,059) in CHAMPION PHOENIX. In patients who received bivalirudin, treatment with cangrelor resulted in a significant 32% reduction in the primary efficacy endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 h compared with clopidogrel (4.7% versus 6.7%) [odds ratio (95% confidence interval): 0.68 (0.47–0.99); P = 0.04]. Furthermore, in the patients treated with bivalirudin, there was a significant reduction in MI with cangrelor compared with clopidogrel. In addition, cangrelor reduced the rate of stent thrombosis by 50% at 48 h from randomization. This beneficial effect was apparent within 2 h from randomization. Moreover, there were no significant differences in the risk of major bleeding between cangrelor and clopidogrel in patients treated with bivalirudin. These results suggest that combining cangrelor with bivalirudin may mitigate the risk of early stent thrombosis seen with bivalirudin in some prior studies, particularly in primary PCI for STEMI. 7. CHAMPION PHOENIX: Outcomes according to access site for PCI Bleeding events after PCI are most commonly due to vascular access site complications and are associated with worse short- and long-term clinical outcomes (Rao et al., 2013). PCI via the radial approach has been shown to reduce bleeding, access site complications, and, in some analyses, death compared with femoral access (Valgimigli et al., 2015). In a prespecified secondary analysis of CHAMPION PHOENIX, the efficacy and safety of cangrelor was examined according to the access site (femoral versus radial) used for PCI (Gutierrez et al., 2015). Of the 11,145 study participants, 74% underwent PCI via the femoral artery and 26% by the radial approach. Compared with clopidogrel, cangrelor reduced the primary efficacy endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 h regardless of the PCI access site. There was no significant increase in the primary safety endpoint of GUSTO-defined severe bleeding or blood transfusions associated with cangrelor compared with clopidogrel for the femoral or radial groups. However, the absolute rate of bleeding, irrespective of the definition, was lower with the radial approach for PCI compared with femoral access in both treatment arms of the study. 8. CHAMPION PHOENIX: Outcomes in women Previous studies have shown heterogeneity in the risks and benefits of antiplatelet therapy in women versus men (Wang et al., 2012). A prespecified subgroup analysis of the CHAMPION PHOENIX trial explored the safety and efficacy of cangrelor in women undergoing PCI (O’Donoghue et al., 2016). Of the 11,145 patients in CHAMPION PHOENIX, 28% (n = 3,051) were women. At 48 h, treatment with cangrelor resulted in a significant 33% reduction in the primary endpoint in women compared with clopidogrel [odds ratio (95% confidence interval): 0.67(0.50–0.92); P = 0.01]. Consistent with the results in the trial as a whole, cangrelor was associated with ~60% reduction in the
risk of stent thrombosis in women at 48 h. Reassuringly, there was no significant difference in the incidence of GUSTO severe bleeding in women who received cangrelor versus clopidogrel. Overall, compared with clopidogrel, cangrelor was associated with superior net clinical benefit in women undergoing PCI. These findings provide reassurance regarding the use of cangrelor to optimize platelet inhibition safely and effectively in women undergoing PCI. 9. CHAMPION PHOENIX: Outcomes in older patients In contemporary practice, older patients comprise a major proportion of patients undergoing PCI. Older patients undergoing PCI are at increased risk of ischemic and bleeding complications compared with younger patients (Batchelor et al., 2000). However, older patients are underrepresented in most clinical studies, particularly those involving antithrombotic therapy. The paucity of data has led to the underutilization of guideline-directed antiplatelet therapy in this patient population (Dauerman et al., 2010). Many physicians may withhold antiplatelet therapy in older patients because of the concern for bleeding. Older patients (age ≥75 years) comprised 20% (n = 2010) of the PHOENIX cohort. In this prespecified subgroup, treatment with cangrelor showed a consistent benefit similar to younger patients (age b75 years) (Cavender et al., 2015). In older patients, cangrelor showed a consistent reduction in the primary efficacy endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis compared with clopidogrel with no increase in the incidence of GUSTO severe bleeding. Furthermore, compared with clopidogrel, cangrelor resulted in a similar net clinical benefit in older versus younger patients. These results validate a promising role of cangrelor for safe, potent platelet inhibition in older patients undergoing PCI. 10. BRIDGE trial Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor within five days of CABG is associated with an increased risk of perioperative bleeding. Premature interruption of dual antiplatelet therapy among patients treated medically or with PCI is associated with an increased risk of ischemic events (Ho et al., 2008). Regardless of elevated risk of thrombotic events, current guidelines recommend discontinuing P2Y12 receptor inhibitors at least 5–7 days before surgery to reduce bleeding. The BRIDGE trial was a prospective, randomized doubleblind, placebo controlled trial of 210 patients with ACS or those treated with coronary stents on a thienopyridine with planned CABG (Angiolillo et al., 2012a, 2012b). In this trial, thienopyridines were discontinued and patients were randomly assigned in 1:1 ratio to receive either cangrelor (infusion dose of 0.75 μg/kg/min without a bolus) or placebo for at least 48 h, with discontinuation 1–6 h prior to surgery. The primary efficacy endpoint defined as percentage of patients with platelet reactivity less than 240 P2Y12 Reaction Units (PRU) was assessed daily throughout the pre-operative period with the VerifyNow™ P2Y12 assay. The median duration of infusion was 2.8 days for cangrelor and 3.4 days for placebo. The median time from discontinuation of study drug infusion to surgical incision was 3.2 h for both cangrelor and placebo. The investigators found a consistent level of platelet inhibition resulting in a higher rate of the primary efficacy endpoint of percentage of patients with platelet reactivity less than 240 PRU throughout the infusion with cangrelor compared with placebo (98.8% versus 19%) [relative risk 5.2 (95% confidence interval): (3.3–8.1); P b 0.001]. In addition, bridging with cangrelor did not result in a significant increase in the primary safety endpoint of CABG-related bleeding. These findings support a theoretical role for cangrelor as a bridging strategy in patients waiting for CABG who require P2Y12 inhibition after thienopyridine discontinuation. However, this study was not powered to evaluate if platelet inhibition with cangrelor prior to CABG would decrease the risk of ischemic events compared with placebo. In part due to that fact, cangrelor is not currently approved for this indication. However, if a doctor elects to use
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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a bridging strategy, it probably makes more sense to use cangrelor than an intravenous glycoprotein IIb/IIIa inhibitor (Huang et al., 2012).
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Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. Dr. Arman Qamar declares no competing interests.
11. Transition from cangrelor to oral P2Y12 receptor inhibitors References Treatment with cangrelor requires transition to an oral P2Y12 receptor inhibitor. In patients transitioning to clopidogrel, as in CHAMPION PHOENIX, 600 mg immediately after discontinuation of the cangrelor infusion should be administered. Thus far, no randomized clinical trial has examined the efficacy and safety of cangrelor in patients receiving prasugrel or ticagrelor. Pharmacodynamic studies have explored the optimal transition strategy from cangrelor to prasugrel or ticagrelor in patients with stable CAD. A pharmacodynamic study examining the transition from cangrelor to prasugrel showed a transient recovery in platelet reactivity in the first hour after stopping cangrelor infusion (Schneider et al., 2015). However, the rebound recovery in platelet reactivity was attenuated when prasugrel was administered 30 min before discontinuing cangrelor. To maintain platelet inhibition after discontinuation of cangrelor, prasugrel 60 mg should be administered immediately after stopping the cangrelor infusion. A study evaluating the transition from cangrelor to ticagrelor observed no significant increase in platelet reactivity after cangrelor was stopped (Schneider et al., 2014). Therefore, ticagrelor 180 mg can be administered anytime during the cangrelor infusion or immediately after the cangrelor infusion ends. 12. Conclusion Intravenous P2Y12 receptor inhibition with cangrelor significantly reduces the rates of ischemic events without increasing severe bleeding or blood transfusions across a broad spectrum of patients undergoing PCI. Cangrelor's pharmacologic profile with intravenous availability, fast-onset, and fast-offset offers a promising approach to P2Y12 receptor inhibition in patients receiving PCI. The same attributes of cangrelor could be useful to maintain platelet inhibition in patients requiring premature discontinuation of an oral P2Y12 receptor inhibitor before surgery. Further study of cangrelor in other settings such as upstream therapy in STEMI, NSTEMI, or stroke could prove useful. 13. Source of funding None. 14. Conflict of interest statement Dr. Deepak L. Bhatt discloses the following relationships — Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company (including for his role as co-Chair of the CHAMPION trials); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude
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Contents lists available at ScienceDirect
Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera
Associate editor: Y.S. Chatzizisis
Current status of data on cangrelor Arman Qamar, Deepak L. Bhatt ⁎ Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, USA
a r t i c l e
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Keywords: Acute coronary syndrome Antiplatelet therapy Cangrelor Coronary artery disease P2Y12 receptor inhibition Percutaneous coronary intervention (PCI)
a b s t r a c t P2Y12 receptor inhibition in addition to aspirin is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI). Despite advances in contemporary antithrombotic therapy, periprocedural thrombotic complications such as myocardial infarction and stent thrombosis remain a major concern in patients treated with PCI. Current practice guidelines recommend treatment with a P2Y12 receptor inhibitor as early as possible in patients with ACS. Existing oral P2Y12 receptors inhibitors (clopidogrel, prasugrel, or ticagrelor) have several limitations such as delayed onset and offset of action, interindividual variation, and only oral availability. Cangrelor, an intravenous, fast-onset, direct-acting P2Y12 receptor inhibitor offers potent platelet inhibition that is rapidly reversible. In large randomized trials, cangrelor has shown substantial reduction in ischemic events with no increase in severe bleeding compared with clopidogrel among patients undergoing PCI. Cangrelor is approved as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary revascularization, and stent thrombosis in patients who have not been pretreated with a P2Y12 receptor inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor. This review aims at providing a comprehensive analysis of the current evidence pertaining to the role of cangrelor in contemporary practice. © 2016 Elsevier Inc. All rights reserved.
Contents 1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. CHAMPION PCI trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. CHAMPION PLATFORM trial. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. CHAMPION PHOENIX trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. CHAMPION PHOENIX: Effect of Cangrelor on Intraprocedural Stent Thrombosis During PCI 6. CHAMPION PHOENIX: Outcomes on a background of bivalirudin . . . . . . . . . . . . 7. CHAMPION PHOENIX: Outcomes according to access site for PCI . . . . . . . . . . . . 8. CHAMPION PHOENIX: Outcomes in women . . . . . . . . . . . . . . . . . . . . . 9. CHAMPION PHOENIX: Outcomes in older patients . . . . . . . . . . . . . . . . . . 10. BRIDGE trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Transition from cangrelor to oral P2Y12 receptor inhibitors . . . . . . . . . . . . . . 12. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13. Source of funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14. Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abbreviations: ACS, Acute Coronary Syndromes; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; ARC, Academic Research Consortium; ATP, Adenosine Triphosphate; CABG, Coronary Artery Bypass Graft; CAD, Coronary Artery Disease; EMA, European Medicines Agency; FDA, Food and Drug Administration; GUSTO, Global Use of Strategies to Open Occluded Arteries; IPST, Intraprocedural Stent Thrombosis; MI, Myocardial Infarction; NSTE-ACS, Non ST Segment Elevation ACS; PCI, Percutaneous Coronary Intervention; PRU, P2Y12 Reaction Units; STEMI, ST Segment Elevation Myocardial Infarction; TIMI, Thrombolysis in Myocardial Infarction. ⁎ Corresponding author at: Brigham and Women's Hospital Heart & Vascular Center, 75 Francis Street, Boston, MA 02115, USA. E-mail address: [email protected] (D.L. Bhatt).
http://dx.doi.org/10.1016/j.pharmthera.2016.01.004 0163-7258/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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1. Introduction Dual antiplatelet therapy with a P2Y12 receptor inhibitor in addition to aspirin is the foundation of treatment in patients with acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention (PCI) (Bhatt et al., 2014). PCI has been shown to reduce the risk of death and myocardial infarction (MI) in patients with ACS and to improve symptoms in patients with stable coronary artery disease (CAD). Despite advances in contemporary antithrombotic therapy, PCI may be complicated by periprocedural thrombotic events, thus, increasing death, MI or stent thrombosis during or after PCI. Current practice guidelines recommend prompt treatment with a P2Y12 receptor inhibitor and aspirin in all patients with ACS for at least 12 months (Hamm et al., 2011; Steg et al., 2012; O’Gara et al., 2013; Amsterdam et al., 2014). In patients with ACS, treatment with aspirin and clopidogrel compared with aspirin alone has been proven to reduce cardiovascular events (Yusuf et al., 2001). Pretreatment with clopidogrel before coronary angiography has shown uncertain efficacy in patients undergoing PCI; this has resulted in wide variation in the timing of clopidogrel loading (Mehta et al., 2001; Steinhubl et al., 2002; Widimsky et al., 2008; Rao et al., 2009; Bellemain-Appaix et al., 2012). Furthermore, clopidogrel has considerable limitations such as delayed onset and delayed offset of effect on platelet inhibition. Moreover, effect of clopidogrel is dependent on intestinal absorption and transformation to its active metabolite by cytochrome P450 enzymes, such as CYP2C19 (Bhatt, 2009). Consequently, genetic polymorphisms that affect CYP2C19 function result in variable effects for clopidogrel. For example, among patients treated with clopidogrel, those carrying loss-of-function CYP2C19 genetic variants have reduced inhibition of platelet aggregation and an increased risk of adverse cardiovascular events, including stent thrombosis, compared with non-carriers (Collet et al., 2009; Mega et al., 2009; Simon et al., 2009). Also, 10–15% of patients presenting with ACS have to undergo coronary artery bypass graft (CABG) surgery. Clopidogrel has a delayed offset of action related to irreversible inhibition of platelet P2Y12 receptors and is associated with an increased risk of perioperative bleeding in patients undergoing CABG (Fox et al., 2004). Therefore; patients need a delay of 5–7 days for platelet function to recover before CABG. As a result, many physicians refrain from administering clopidogrel until coronary angiography is performed. Compared with clopidogrel, prasugrel and ticagrelor, two more potent oral P2Y12 receptor inhibitors, have been associated with less interpatient variability and a significant reduction in ischemic events but at an increased risk of major bleeding (Wiviott et al., 2007; Wallentin et al., 2009). However, in the setting of ACS, particularly STsegment elevation myocardial infarction (STEMI), even these agents may take several hours to achieve maximal platelet inhibition (Agrawal and Bhatt, 2013). Additionally, in patients with ACS, the bioavailability of oral P2Y12 receptor inhibitors might be severely decreased in the presence of nausea, emesis, use of opiates, intubation,
impaired gut perfusion in cardiogenic shock, or therapeutic hypothermia (Heestermans et al., 2008; Souckova et al., 2013). As a result, these patients are at an increased risk of recurrent MI and stent thrombosis, particularly in the immediate peri-PCI period. Similar to clopidogrel, it takes 3–10 days for platelet inhibition to reverse fully in patients treated with ticagrelor or prasugrel. This is particularly problematic when the antiplatelet effect is no longer desirable, as in settings where emergent cardiac surgery is needed. Although antiplatelet therapy with an intravenous glycoprotein IIb/IIIa inhibitor is effective in reducing ischemic events, its effect lasts for several hours after stopping the infusion, and there is a higher bleeding risk (Bhatt and Topol, 2000). Due to the limitations for all oral antiplatelet agents, there has been an unmet clinical need for a potent, intravenous, rapidly acting, rapidly reversible P2Y12 receptor inhibitor (Table 1) (Franchi and Angiolillo, 2015; Rollini et al., 2016). Cangrelor is a novel, intravenous, nonthienopyridine adenosine triphosphate (ATP) analog that reversibly and directly inhibits the P2Y12 receptor (Storey et al., 2000; Angiolillo et al., 2012a, 2012b). When given as a bolus plus an infusion, it provides immediate, consistent, and profound platelet inhibition that is rapidly reversible. The plasma half life of cangrelor is 3–6 min, and platelet function normalizes within 60 min after discontinuation of the infusion. To date, several phase I and phase II studies with cangrelor have been conducted in diverse cohorts, including healthy volunteers and patients with renal impairment and CAD. All of these studies demonstrate fast onset and steady, potent, and rapidly reversible platelet inhibition without an increased risk of severe bleeding. Furthermore, cangrelor pharmacokinetics were not influenced by age, sex, genetic variations, or renal function. In a phase II open-label multicenter study of patients with ACS (n = 39), treatment with cangrelor in combination with aspirin and heparin produced robust, consistent platelet inhibition (N95%) and was well tolerated over an infusion period of up to 72 h (Storey et al., 2001). Among 199 patients undergoing elective PCI in a phase II randomized, openlabel trial, cangrelor was shown to cause rapid, dose-dependent and complete platelet inhibition similar to abciximab. In this study, there was less prolongation of bleeding time and more rapid return of platelet function to baseline with cangrelor than abciximab (Greenbaum et al., 2006). Three pivotal phase 3 trials, Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PCI (ClinicalTrials.gov Identifier, NCT00305162), CHAMPION PLATFORM (ClinicalTrials.gov Identifier, NCT00385138), and CHAMPION PHOENIX (ClinicalTrials.gov Identifier, NCT01156571), have explored the efficacy and safety of cangrelor in patients undergoing PCI (Bhatt et al., 2009, Harrington et al., 2009; Leonardi et al., 2012; Bhatt et al., 2013). The study designs and main features of the three trials are shown in Fig. 1 and Fig. 2, respectively (Steg et al., 2013). Based on these data, the US Food and Drug Administration (FDA) approved cangrelor as an adjunct to PCI to reduce the risk of periprocedural MI, repeat coronary
Table 1 Pharmacological characteristics of P2Y12 receptor inhibitors (Franchi and Angiolillo, 2015; Rollini et al., 2016). ATP = adenosine triphosphate; ACS = acute coronary syndrome; PCI = percutaneous coronary intervention; CAD = coronary artery disease.
Class Reversibility Prodrug Administration route Onset of effect Duration of effect Half-life Frequency Influenced by genetic variation Approved settings a
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
Thienopyridine Irreversible Yes Oral 2–8 h 5–7 days ~6 h Once daily Yes ACS (invasively or noninvasively treated) and PCI in stable CAD
Thienopyridine Irreversible Yes Oral 30 min to 4 h 7–10 days ~7 h Once daily No ACS undergoing PCI
Triazolopyrimidine Reversible No Oral 30 min to 4 h 3–5 days ~8 h Twice daily No ACS (invasively or noninvasively treated)
ATP analog Reversible No Intravenous Immediate 30–60 min 3–5 min Bolus plus infusion No a PCI in patients with ACS and stable CAD
Patients with ACS or stable CAD who have not been pretreated with a P2Y12 receptor inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor.
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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Fig. 1. CHAMPION study designs. Reprinted with permission (Steg et al., 2013). mITT = modified intention-to-treat; NSTE-ACS = non-ST-segment elevation acute coronary syndrome; STEMI = ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention.
revascularization, and stent thrombosis in patients who have not been pretreated with a P2Y12 platelet inhibitor and are not receiving a glycoprotein IIb/IIIa inhibitor. Also, the European Medicines Agency (EMA) approved the use of cangrelor for reducing the risk of thrombotic cardiovascular events in patients with CAD undergoing PCI who did not receive an oral P2Y12 inhibitor before the PCI procedure, and in whom oral therapy with P2Y12 inhibitors is not feasible or desirable.
2. CHAMPION PCI trial The CHAMPION PCI trial was a randomized, double-blind, doubledummy, active control trial comparing cangrelor with clopidogrel in patients undergoing PCI. The study included 8887 patients undergoing PCI; 85% with ACS and 15% with stable CAD (Fig. 1; Fig. 2) (Harrington et al., 2009). Patients were randomly assigned in a 1:1 design to receive
Fig. 2. Comparison of design features of the CHAMPION studies. Reprinted with permission (Steg et al., 2013).
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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either cangrelor infusion (30 μg/kg bolus followed by a 4 μg/kg/min infusion) or 600 mg of clopidogrel within 30 min before PCI. Patients initially treated with cangrelor received 600 mg of clopidogrel upon discontinuation of the infusion. The primary efficacy endpoint was a composite of death, MI, or ischemia-driven revascularization. MI was defined by a new significant Q wave on an electrocardiogram or a post PCI elevation in CKMB level that was at least three times greater than the upper limit of normal, and when biomarkers were elevated before PCI, an additional 50% above baseline. At 48 h, the primary efficacy endpoint occurred in 7.5% of patients in the cangrelor group and 7.1% in the clopidogrel group [odds ratio (95% confidence interval): 1.05 (0.88– 1.24); P = 0.59]. Similarly, at 30 days, cangrelor was noninferior to clopidogrel with respect to the incidence of the primary composite endpoint. The risk of stent thrombosis at 48 h did not differ significantly between the two groups. In terms of safety, the investigators reported bleeding event rates according to various categories, including Global Use of Strategies to Open Occluded Arteries (GUSTO), Thrombolysis in Myocardial Infarction (TIMI), and Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY). There was no significant difference in GUSTO severe or TIMI major bleeding or the need for blood transfusion with cangrelor compared with clopidogrel. However, according to the ACUITY criteria, cangrelor was associated with a trend toward a higher rate of major bleeding. 3. CHAMPION PLATFORM trial In this randomized, double-blind, placebo-controlled study, cangrelor was compared with clopidogrel in 5362 patients with nonST-segment elevation acute coronary syndrome (NSTE-ACS) or stable angina who were undergoing PCI (Fig. 1; Fig. 2) (Bhatt et al., 2009). Patients were randomly assigned in 1:1 ratio to receive either cangrelor (30 μg/kg bolus followed by a 4 μg/kg/min infusion for 2–4 h) or placebo for the duration of the PCI procedure. Patients in the cangrelor arm received 600 mg clopidogrel at the end of the cangrelor infusion, and those in the placebo arm received a 600 mg loading dose of clopidogrel at the completion of PCI. MI was adjudicated according to the criteria specified in the CHAMPION PCI trial. The incidence of the primary efficacy endpoint, a composite of death, MI, or ischemia-driven revascularization at 48 h did not differ significantly in the cangrelor group compared with the placebo group (7% versus 8%) [odds ratio (95% confidence interval): 0.87 (0.71–1.07); P = 0.17]. However, there was a significant reduction in the prespecified secondary endpoints, including stent thrombosis and death from any cause at 48 h with cangrelor. Analysis of the safety outcomes in this study showed no difference in GUSTO severe or moderate or TIMI major bleeding with cangrelor. Compared with placebo, an increased occurrence of ACUITY major bleeding due to an excess of groin hematomas was seen with cangrelor. Nevertheless, there was no significant increase in the frequency of blood transfusions with cangrelor compared with placebo. The CHAMPION PCI and CHAMPION PLATFORM trials were prematurely terminated for futility to meet their primary endpoint of death, MI, or ischemia-driven revascularization. The primary endpoints in both trials were driven by the frequency of the MI endpoint. The unexpectedly short times from hospital admission with ACS to PCI in both trials (~6–8 h) made it challenging to differentiate between MI occurring before or after randomization. Post hoc analysis of the CHAMPION PCI and CHAMPION PLATFORM data using the Universal Definition of MI instead of the trial definitions found a beneficial effect of cangrelor compared with clopidogrel in reducing rates of periprocedural ischemic events without an increase in severe bleeding. A pooled analysis of CHAMPION PCI and CHAMPION PLATFORM (n = 13,049) including reassessment of the MI endpoint using the Universal Definition of MI rather than the CHAMPION definition found a significant reduction in the primary composite endpoint of death, MI, or ischemia-driven revascularization with cangrelor compared with clopidogrel (3.1% versus 3.8%) [odds ratio (95% confidence interval): 0.82 (0.68–0.99); P =
0.03] (Thygesen et al., 2012; White et al., 2012). In addition, there was more than a 50% reduction in stent thrombosis with cangrelor compared with clopidogrel in this analysis (0.2% versus 0.4%) [odds ratio (95% confidence interval): 0.44 (0.22–0.87); P = 0.01]. However, with the CHAMPION definition of MI, there was no significant effect of cangrelor on the primary endpoint in this analysis. A subsequent analysis using the Universal Definition of MI in the CHAMPION PLATFORM trial showed only a 4.3% incidence of PCIrelated MI compared with 6.5% identified using the CHAMPION definition (Leonardi et al., 2013). In this analysis, when the MI endpoint was reevaluated according to the Universal Definition of MI, the primary endpoint at 48 h, occurred in only 5.4% of patients, with 4.9% in the cangrelor arm and 6% in the placebo arm [odds ratio (95% confidence interval): 0.80 (0.63–1.02); P = 0.07] in contrast to 7.5% using the CHAMPION definition, with 7% in the cangrelor arm and 8% in the placebo arm [odds ratio (95% confidence interval): 0.87 (0.71–1.07); P = 0.17]. These hypothesis-generating findings in the post hoc analysis were further explored in the CHAMPION PHOENIX trial using the Universal Definition of MI. 4. CHAMPION PHOENIX trial In the CHAMPION PHOENIX trial, cangrelor was compared with clopidogrel in 11,145 patients presenting with stable angina, NSTEACS, or STEMI who required PCI (Bhatt et al., 2013). Patients were randomized after coronary angiography, 1:1 in a double-dummy, doubleblind fashion to receive either cangrelor (30 μg/kg bolus followed by a 4 μg/kg/min infusion for at least 2 h or the duration of procedure, whichever was longer) or a clopidogrel loading dose (300–600 mg) at the time of PCI. Patients who had received a P2Y12 inhibitor in the last 7 days were excluded from this trial. Glycoprotein IIb/IIIa inhibitors were only permitted as rescue therapy during PCI for certain angiographic complications. Aspirin (75 mg to 325 mg) was administered to all patients, and everyone received clopidogrel 75 mg during the first 48 h; subsequently, clopidogrel or an alternative P2Y12 inhibitor could be administered according to local guidelines. Cangrelor was shown to significantly reduce the risk of ischemic events, including stent thrombosis, at 48 h and 30 days, with no increase in the risk of severe bleeding across the spectrum of patients undergoing PCI. At 48 h, the primary composite efficacy endpoint of death, MI defined by universal definition for PCI-related MI, ischemia-driven revascularization, or stent thrombosis occurred in fewer patients in the cangrelor group than the clopidogrel group (4.7% versus 5.9%) [odds ratio (95% confidence interval): 0.78 (0.66–0.93); P = 0.005] (Fig. 3). The incidence of
Fig. 3. Kaplan–Meier curves for the primary efficacy endpoint in the CHAMPION PHOENIX trial. The primary efficacy endpoint was a composite of death from any cause, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. The inset shows the same data on an enlarged y axis. Reprinted with permission (Bhatt et al., 2013).
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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Fig. 4. Kaplan–Meier curves for the secondary endpoint in the CHAMPION PHOENIX trial. The secondary endpoint was stent thrombosis at 48 h after randomization. The inset shows the same data on an enlarged y axis. Reprinted with permission (Bhatt et al., 2013).
the secondary efficacy endpoint of stent thrombosis in the 48 h after randomization was also significantly lower in patients receiving cangrelor compared with those receiving clopidogrel (0.8% versus 1.4%) [odds ratio (95% confidence interval): 0.62 (0.43–0.90); P = 0.01] (Fig. 4). The rate of the primary safety endpoint, GUSTO-defined severe bleeding at 48 h, did not differ significantly between the two groups. Net clinical benefit, assessed as a combination of rates of primary efficacy endpoint and primary safety endpoint, favored cangrelor over clopidogrel (4.8% versus 6%) [odds ratio (95% confidence interval); 0.80 (0.68–0.94): P = 0.008]. Taken together, cangrelor demonstrated consistent benefit across all subgroups in CHAMPION PHOENIX. The substantial reduction in ischemic events with cangrelor was similar among patients presenting with stable angina, NSTE-ACS, and STEMI. The beneficial effect of cangrelor
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among patients in the United States and those in other countries were comparable. Likewise, there was no significant difference in the effect of cangrelor on the primary endpoint among patients treated with a 300 or 600 mg loading dose of clopidogrel. The effect of cangrelor was consistent irrespective of the timing of the loading dose of clopidogrel (within the context of loading in the catheterization laboratory); the benefit of cangrelor on the primary endpoint did not differ significantly between patients who received the loading dose of clopidogrel immediately before PCI or those who received it during or after the procedure. A prespecified, pooled analysis of the patient-level data of 24,910 patients from the three CHAMPION trials (PCI, PLATFORM and PHOENIX) compared cangrelor with clopidogrel (Steg et al., 2013). The primary efficacy endpoint was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis. MI was defined according to the universal definition used in CHAMPION PHOENIX. In this analysis, treatment with cangrelor was associated with ~20% reduction in the risk of the primary endpoint at 48 h compared with clopidogrel (3.8% versus 4.7%) [odds ratio (95% confidence interval); 0.81 (0.71–0.91): P = 0.0007] (Fig. 5). Compared with clopidogrel, cangrelor significantly reduced the incidence of stent thrombosis, MI, and Q-wave MI at 48 h. The reduction in the primary endpoint with cangrelor was consistent across all clinical subgroups and was maintained up to 30 days after PCI (Fig. 5). There was no increase in GUSTO severe or life-threatening bleeding or the need for blood transfusion with cangrelor. However, compared with clopidogrel, cangrelor was associated with an increase in the occurrence of GUSTO minor bleeding. 5. CHAMPION PHOENIX: Effect of Cangrelor on Intraprocedural Stent Thrombosis During PCI In the CHAMPION PHOENIX, stent thrombosis was defined as the occurrence of intraprocedural stent thrombosis (IPST) or Academic Research Consortium (ARC)-defined stent thrombosis occurring after the PCI procedure. In 10,939 patients from this trial, a blinded core
Fig. 5. Forest plot of the primary, key secondary, and secondary outcomes at 48 h, overall and in each of the three CHAMPION trials. Reprinted with permission (Steg et al., 2013). MI = myocardial infarction; IDR = ischemia-driven revascularization; ST = stent thrombosis; PCI = percutaneous coronary intervention.
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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laboratory performed an angiographic analysis for the presence of IPST (Gѐnѐreux et al., 2014). IPST occurred in 0.8% of the entire study population. The development of IPST was independently associated with an increased risk of adverse ischemic events, including death, MI, ischemia-driven revascularization, or stent thrombosis occurring at 48 hours and 30 days from randomization. Furthermore, treatment with cangrelor resulted in a 35% reduction in the rate of IPST compared with clopidogrel at 48 hours (0.6% versus 1%) [odds ratio (95% confidence interval): 0.65 (0.42–0.99); P = 0.04]. The effect of cangrelor in reducing IPST was evident in several subgroups, including patients with stable angina, NSTE-ACS, or STEMI. 6. CHAMPION PHOENIX: Outcomes on a background of bivalirudin A prespecified subgroup analysis in the CHAMPION PHOENIX examined the efficacy and safety of cangrelor compared with clopidogrel in patients who received bivalirudin during PCI (White et al., 2015). Bivalirudin was used in approximately 19% of the patients (n = 2,059) in CHAMPION PHOENIX. In patients who received bivalirudin, treatment with cangrelor resulted in a significant 32% reduction in the primary efficacy endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 h compared with clopidogrel (4.7% versus 6.7%) [odds ratio (95% confidence interval): 0.68 (0.47–0.99); P = 0.04]. Furthermore, in the patients treated with bivalirudin, there was a significant reduction in MI with cangrelor compared with clopidogrel. In addition, cangrelor reduced the rate of stent thrombosis by 50% at 48 h from randomization. This beneficial effect was apparent within 2 h from randomization. Moreover, there were no significant differences in the risk of major bleeding between cangrelor and clopidogrel in patients treated with bivalirudin. These results suggest that combining cangrelor with bivalirudin may mitigate the risk of early stent thrombosis seen with bivalirudin in some prior studies, particularly in primary PCI for STEMI. 7. CHAMPION PHOENIX: Outcomes according to access site for PCI Bleeding events after PCI are most commonly due to vascular access site complications and are associated with worse short- and long-term clinical outcomes (Rao et al., 2013). PCI via the radial approach has been shown to reduce bleeding, access site complications, and, in some analyses, death compared with femoral access (Valgimigli et al., 2015). In a prespecified secondary analysis of CHAMPION PHOENIX, the efficacy and safety of cangrelor was examined according to the access site (femoral versus radial) used for PCI (Gutierrez et al., 2015). Of the 11,145 study participants, 74% underwent PCI via the femoral artery and 26% by the radial approach. Compared with clopidogrel, cangrelor reduced the primary efficacy endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 h regardless of the PCI access site. There was no significant increase in the primary safety endpoint of GUSTO-defined severe bleeding or blood transfusions associated with cangrelor compared with clopidogrel for the femoral or radial groups. However, the absolute rate of bleeding, irrespective of the definition, was lower with the radial approach for PCI compared with femoral access in both treatment arms of the study. 8. CHAMPION PHOENIX: Outcomes in women Previous studies have shown heterogeneity in the risks and benefits of antiplatelet therapy in women versus men (Wang et al., 2012). A prespecified subgroup analysis of the CHAMPION PHOENIX trial explored the safety and efficacy of cangrelor in women undergoing PCI (O’Donoghue et al., 2016). Of the 11,145 patients in CHAMPION PHOENIX, 28% (n = 3,051) were women. At 48 h, treatment with cangrelor resulted in a significant 33% reduction in the primary endpoint in women compared with clopidogrel [odds ratio (95% confidence interval): 0.67(0.50–0.92); P = 0.01]. Consistent with the results in the trial as a whole, cangrelor was associated with ~60% reduction in the
risk of stent thrombosis in women at 48 h. Reassuringly, there was no significant difference in the incidence of GUSTO severe bleeding in women who received cangrelor versus clopidogrel. Overall, compared with clopidogrel, cangrelor was associated with superior net clinical benefit in women undergoing PCI. These findings provide reassurance regarding the use of cangrelor to optimize platelet inhibition safely and effectively in women undergoing PCI. 9. CHAMPION PHOENIX: Outcomes in older patients In contemporary practice, older patients comprise a major proportion of patients undergoing PCI. Older patients undergoing PCI are at increased risk of ischemic and bleeding complications compared with younger patients (Batchelor et al., 2000). However, older patients are underrepresented in most clinical studies, particularly those involving antithrombotic therapy. The paucity of data has led to the underutilization of guideline-directed antiplatelet therapy in this patient population (Dauerman et al., 2010). Many physicians may withhold antiplatelet therapy in older patients because of the concern for bleeding. Older patients (age ≥75 years) comprised 20% (n = 2010) of the PHOENIX cohort. In this prespecified subgroup, treatment with cangrelor showed a consistent benefit similar to younger patients (age b75 years) (Cavender et al., 2015). In older patients, cangrelor showed a consistent reduction in the primary efficacy endpoint of death, MI, ischemia-driven revascularization, or stent thrombosis compared with clopidogrel with no increase in the incidence of GUSTO severe bleeding. Furthermore, compared with clopidogrel, cangrelor resulted in a similar net clinical benefit in older versus younger patients. These results validate a promising role of cangrelor for safe, potent platelet inhibition in older patients undergoing PCI. 10. BRIDGE trial Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor within five days of CABG is associated with an increased risk of perioperative bleeding. Premature interruption of dual antiplatelet therapy among patients treated medically or with PCI is associated with an increased risk of ischemic events (Ho et al., 2008). Regardless of elevated risk of thrombotic events, current guidelines recommend discontinuing P2Y12 receptor inhibitors at least 5–7 days before surgery to reduce bleeding. The BRIDGE trial was a prospective, randomized doubleblind, placebo controlled trial of 210 patients with ACS or those treated with coronary stents on a thienopyridine with planned CABG (Angiolillo et al., 2012a, 2012b). In this trial, thienopyridines were discontinued and patients were randomly assigned in 1:1 ratio to receive either cangrelor (infusion dose of 0.75 μg/kg/min without a bolus) or placebo for at least 48 h, with discontinuation 1–6 h prior to surgery. The primary efficacy endpoint defined as percentage of patients with platelet reactivity less than 240 P2Y12 Reaction Units (PRU) was assessed daily throughout the pre-operative period with the VerifyNow™ P2Y12 assay. The median duration of infusion was 2.8 days for cangrelor and 3.4 days for placebo. The median time from discontinuation of study drug infusion to surgical incision was 3.2 h for both cangrelor and placebo. The investigators found a consistent level of platelet inhibition resulting in a higher rate of the primary efficacy endpoint of percentage of patients with platelet reactivity less than 240 PRU throughout the infusion with cangrelor compared with placebo (98.8% versus 19%) [relative risk 5.2 (95% confidence interval): (3.3–8.1); P b 0.001]. In addition, bridging with cangrelor did not result in a significant increase in the primary safety endpoint of CABG-related bleeding. These findings support a theoretical role for cangrelor as a bridging strategy in patients waiting for CABG who require P2Y12 inhibition after thienopyridine discontinuation. However, this study was not powered to evaluate if platelet inhibition with cangrelor prior to CABG would decrease the risk of ischemic events compared with placebo. In part due to that fact, cangrelor is not currently approved for this indication. However, if a doctor elects to use
Please cite this article as: Qamar, A., & Bhatt, D.L., Current status of data on cangrelor, Pharmacology & Therapeutics (2016), http://dx.doi.org/ 10.1016/j.pharmthera.2016.01.004
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a bridging strategy, it probably makes more sense to use cangrelor than an intravenous glycoprotein IIb/IIIa inhibitor (Huang et al., 2012).
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Medical; Trustee: American College of Cardiology; Unfunded Research: FlowCo, PLx Pharma, Takeda. Dr. Arman Qamar declares no competing interests.
11. Transition from cangrelor to oral P2Y12 receptor inhibitors References Treatment with cangrelor requires transition to an oral P2Y12 receptor inhibitor. In patients transitioning to clopidogrel, as in CHAMPION PHOENIX, 600 mg immediately after discontinuation of the cangrelor infusion should be administered. Thus far, no randomized clinical trial has examined the efficacy and safety of cangrelor in patients receiving prasugrel or ticagrelor. Pharmacodynamic studies have explored the optimal transition strategy from cangrelor to prasugrel or ticagrelor in patients with stable CAD. A pharmacodynamic study examining the transition from cangrelor to prasugrel showed a transient recovery in platelet reactivity in the first hour after stopping cangrelor infusion (Schneider et al., 2015). However, the rebound recovery in platelet reactivity was attenuated when prasugrel was administered 30 min before discontinuing cangrelor. To maintain platelet inhibition after discontinuation of cangrelor, prasugrel 60 mg should be administered immediately after stopping the cangrelor infusion. A study evaluating the transition from cangrelor to ticagrelor observed no significant increase in platelet reactivity after cangrelor was stopped (Schneider et al., 2014). Therefore, ticagrelor 180 mg can be administered anytime during the cangrelor infusion or immediately after the cangrelor infusion ends. 12. Conclusion Intravenous P2Y12 receptor inhibition with cangrelor significantly reduces the rates of ischemic events without increasing severe bleeding or blood transfusions across a broad spectrum of patients undergoing PCI. Cangrelor's pharmacologic profile with intravenous availability, fast-onset, and fast-offset offers a promising approach to P2Y12 receptor inhibition in patients receiving PCI. The same attributes of cangrelor could be useful to maintain platelet inhibition in patients requiring premature discontinuation of an oral P2Y12 receptor inhibitor before surgery. Further study of cangrelor in other settings such as upstream therapy in STEMI, NSTEMI, or stroke could prove useful. 13. Source of funding None. 14. Conflict of interest statement Dr. Deepak L. Bhatt discloses the following relationships — Advisory Board: Cardax, Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute, Harvard Clinical Research Institute, Mayo Clinic, Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor); Research Funding: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi Aventis, The Medicines Company (including for his role as co-Chair of the CHAMPION trials); Site Co-Investigator: Biotronik, Boston Scientific, St. Jude
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