Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee Meeting Regarding Cangrelor Thibault Lhermusier, MD, PhD, Nevin C. Baker, DO, and Ron Waksman, MD* Landmark clinical trials have established the benefit of P2Y12 inhibitors in the setting of acute coronary syndrome and percutaneous coronary intervention. On February 12, 2014, the Medicines Company (Sponsor) presented efficacy and safety data regarding cangrelor to the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee. The Sponsor sought approval for 2 indications: (1) in the setting of percutaneous coronary intervention for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with coronary artery disease and (2) in the setting of bridging therapy in patients with acute coronary syndrome or with stents who are at increased risk for thrombotic events (such as stent thrombosis) when oral P2Y12 therapy is interrupted because of surgery. The following is a summary of the data presented to the FDA by the Sponsor, the FDA’s clinical review of cangrelor. Ó 2015 Elsevier Inc. All rights reserved. (Am J Cardiol 2015;115:1154e1161) Landmark clinical trials have established the benefit of P2Y12 inhibitors in the setting of acute coronary syndrome (ACS) and percutaneous coronary intervention (PCI). Clopidogrel, ticagrelor, and prasugrel have thus become cornerstones in the current standard of care for antiplatelet therapy in the setting of ACS.1e3 Cangrelor is a novel P2Y12 receptor antagonist that blocks adenosine diphosphatee induced platelet activation and aggregation with unique pharmacodynamic and pharmacokinetic properties. This direct-acting intravenous drug is characterized by immediate onset.4 This effect is consistent and is not associated with interindividual variability as clopidogrel is because it does not require metabolic activation.5 Because of a short half-life (3 to 6 minutes) and a reversible binding to the P2Y12 receptor, this drug has a rapid offset that allows recovery of platelet function within 1 hour.6 Cangrelor was clinically investigated in 3 clinical trials gathered in the CHAMPION program.7e9 On February 12, 2014, the Medicines Company (Parsippany, New Jersey; Sponsor) therefore presented efficacy and safety data regarding cangrelor to the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee (CRDAC). The Sponsor sought approval for 2 indications: in the setting of PCI for the reduction of thrombotic cardiovascular events (including stent thrombosis [ST]) in patients with coronary artery disease (CAD) and in the setting of bridging therapy in patients with ACS or with stents who are at increased risk for thrombotic events (such as ST) when oral P2Y12 therapy is interrupted because of surgery. The following is a summary of the data
Department of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC. Manuscript received October 10, 2014; revised manuscript received and accepted January 9, 2015. See page 1160 for disclosure information. *Corresponding author: Tel: (202) 877-2812; fax: (202) 877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.551
presented to the FDA by the Sponsor, the FDA’s clinical review of cangrelor, and the recommendations made during the CRDAC meeting. Data to Support Cangrelor Approval Presented by the Sponsor The Sponsor used data from 3 randomized controlled trials (CHAMPION-PHOENIX, CHAMPION-PLATFORM, and CHAMPION-PCI) conducted in 25,107 patients with CAD to provide evidence on the safety of cangrelor. The trial designs are presented in Table 1. The Sponsor presented the results of the CHAMPION-PHOENIX as the pivotal study supporting the efficacy of cangrelor in the PCI setting and the BRIDGE trial as the pivotal study supporting its use as bridge therapy.7e10 Cangrelor efficacy and safety in the setting of PCI: the CHAMPION program: The design of each trial in the CHAMPION program was presented by the Sponsor and is outlined in Figure 1. Noted by the FDA review committee and a source of great debate among the clinical reviewers in the second part of the meeting was that although the cangrelor dose (30 mg/kg bolus and 4 mg/kg/min infusion) and duration (2 to 4 hours) were the same in the 3 studies, the comparator arm (clopidogrel) differed (Figure 1). In CHAMPION-PCI, clopidogrel 600 mg was given at the time of PCI; in CHAMPION-PLATFORM, clopidogrel 600 mg was given at the end of PCI; and in CHAMPIONPHOENIX, clopidogrel dose (either 300 or 600 mg) was left to the discretion of the individual sites and was to be administered either before or immediately after PCI. At the end of the infusion, patients in the cangrelor arm received 600 mg of clopidogrel in the 3 studies. CHAMPION-PCI and CHAMPION-PLATFORM were terminated early and failed to meet their respective primary end points. Incidence of the protocol-defined primary efficacy end point, a composite of all-cause death, myocardial infarction (MI), www.ajconline.org
Table 1 Pivotal trials to support cangrelor indications TRIAL Subject CHAMPION-PCI (TMC-CAN- 05-02)
CHAMPION-PHOENIX (TMC-CAN-10-01)
BRIDGE (TMC-CAN-08-02)
Prospective, randomized (1:1), double-blind, double-dummy, active-control, parallel-group Active control: clopidogrel 600 mg Prospective, randomized (1:1), double-blind, double-dummy, placebo-control, parallel-group over standard of care: including clopidogrel 600mg Prospective, randomized (1:1), double-blind, double-dummy, active-control, parallel-group Active control: clopidogrel 300 mg or 600 mg Stage 1: Prospective, open label, dose-finding, multi-center. Stage 2: Prospective, double-blind, placebocontrolled, randomized, multi-center.
ITT Sample Size
Description
Primary objective
Primary End Point
8,877 Cangrelor: 4,433 Clopidogrel: 4,444
UA/ NSTEACS/ STEMI patients amenable to PCI
Superiority of cangrelor efficacy over clopidogrel 600 mg in patients requiring PCI
Composite of allcause mortality, MI, and IDR at 48 hours
5,364 Cangrelor: 2,695 Placebo: 2,669
UA/NSTEACS patients amenable to PCI
Superiority of cangrelor (combined with usual care) efficacy over usual care, in patients; requiring PCI
Composite of allcause mortality, MI, and IDR at 48 hours
11,145 Cangrelor: 5,581 Clopidogrel: 5,564
UA/NSTEACS/STEMI patients amenable to PCI
Superiority of cangrelor efficacy over clopidogrel standard of care in patients; requiring PCI
Composite of allcause mortality, MI, IDR and ST at 48 hours (MI: as per UDMI, ST: as per ARC and IPST)
Stage 2: 207 (n¼106 cangrelor; n¼101 placebo)
Patients requiring bridging from oral thienopyridine Therapy prior to cardiac surgery
cangrelor ability to provide effective and consistent P2Y12 inhibition without increasing surgical bleeding compared to standard of care
Percentage of patients with PRU < 240 as determined by VerifyNow P2Y12 point of care assay measured during study drug infusion pre-surgery
Review/FDA Review of Cangrelor
CHAMPION-PLATFORM (TMC-CAN-05-03)
Study Design
ARC ¼ Academic Research Consortium; IDR ¼ ischemia-driven revascularization; IPST ¼ intra-procedural stent thrombosis; IV ¼ intravenous; MI ¼ myocardial infarction; NSTEACS ¼ non ST elevation acute coronary syndrome; PCI ¼ percutaneous coronary intervention; ST ¼ stent thrombosis; STEMI ¼ ST elevation myocardial infarction; UA ¼ unstable angina; UDMI ¼ universal definition of myocardial infarction.
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The American Journal of Cardiology (www.ajconline.org) Table 2 Logistic regression of the Sponsor’s primary end point at 48 hours in the clopidogrel arm of PHOENIX25
600-mg load Age Diabetes Angina Hours to PCI
Odds Ratio
95% CI
p
0.62 1.01 0.80 1.61 0.68
[0.47-0.82] [1.00-1.02] [0.61-1.05] [1.25-2.08] [0.50-0.93]
0.001 0.02 0.11 0 0.01
CI ¼ confidence interval; PCI ¼ percutaneous coronary intervention.
Figure 1. CHAMPION studies designs. NSTEACS ¼ noneST-elevation acute coronary syndrome; UA ¼ unstable angina.
and ischemic driven revascularization, was not significantly reduced in cangrelor-treated patients (CHAMPIONPLATFORM: 7.0% cangrelor- vs 8.0% clopidogrel-treated patients; odds ratio [OR] 0.87, 95% confidence interval [CI] 0.71 to 1.07, p ¼ 0.1746; CHAMPION-PCI: 7.5% vs 7.1%; OR 1.05, 95% CI 0.88 to 1.24, p ¼ 0.5929). According to the Sponsor, post hoc analysis of the PLATFORM and PCI trials suggested signs of cangrelor efficacy, including reductions in the incidence of thrombotic events, such as ST, Q-wave MI, and ischemia-driven revascularization (IDR) but not of the end point of periprocedural MI. Results using the 2007 universal definition of myocardial infarction (UDMI)11 demonstrated that cangrelor reduced (18% significant reduction, OR 0.82, 95% CI 0.68 to 0.99, p ¼ 0.0374) the composite of death, UDMI, and IDR at 48 hours compared to clopidogrel 600 mg in a pooled analysis of both trials.12 The CHAMPION-PHOENIX trial was therefore designed to avoid confounding periprocedural MI with evolving preprocedural MI in patients with elevated biomarkers using the UDMI.13 In PHOENIX, ST definition was also modified to measure events occurring during and after the procedure. Intraprocedural ST (IPST) was included in addition to Academic Research Consortium (ARC)edefined ST and was defined as any procedural new or worsened thrombus related to the stent.14,15 The results of CHAMPION-PHOENIX demonstrated that cangrelor compared to clopidogrel standard of care is effective when administered to patients undergoing PCI. At 48 hours, the CHAMPION-PHOENIX trial demonstrated that, compared to clopidogrel, cangrelor provided a significant reduction in the primary efficacy end point of all-cause mortality, MI, IDR, and ST (4.7% vs 5.9%, respectively; OR 0.79, 95% CI 0.66 to 0.93, p ¼ 0.005), which was maintained at 30 days (6.0% vs 7.0%, respectively; OR 0.85, 95% CI 0.73 to 0.99, p ¼ 0.035). In addition, a significant reduction in protocoldefined ST (0.8% vs 1.4%, respectively; OR 0.62, 95% CI 0.43 to 0.90, p ¼ 0.010), and MI (3.8% vs 4.7%, respectively; OR 0.80, 95% CI 0.67 to 0.97, p ¼ 0.022) were also observed but without a reduction in all-cause mortality (0.3% vs 0.3%, respectively; OR 1.00, 95% CI 0.52 to 1.92, p >0.999).9 In the pooled CHAMPION program, there was
no significant increase in the primary safety outcome of Global Use of Strategies to Open Occluded Arteries (GUSTO) severe or life-threatening bleeding (OR 1.22, 95% CI 0.70 to 2.11, p ¼ 0.48) or GUSTO moderate bleeding (OR 1.36, 95% CI 0.96 to 1.92, p ¼ 0.08). Cangrelor was associated with an increase in GUSTO mild bleedings (OR 1.35, 95% CI 1.26 to 1.45, p
Department of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC. Manuscript received October 10, 2014; revised manuscript received and accepted January 9, 2015. See page 1160 for disclosure information. *Corresponding author: Tel: (202) 877-2812; fax: (202) 877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/15/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2015.01.551
presented to the FDA by the Sponsor, the FDA’s clinical review of cangrelor, and the recommendations made during the CRDAC meeting. Data to Support Cangrelor Approval Presented by the Sponsor The Sponsor used data from 3 randomized controlled trials (CHAMPION-PHOENIX, CHAMPION-PLATFORM, and CHAMPION-PCI) conducted in 25,107 patients with CAD to provide evidence on the safety of cangrelor. The trial designs are presented in Table 1. The Sponsor presented the results of the CHAMPION-PHOENIX as the pivotal study supporting the efficacy of cangrelor in the PCI setting and the BRIDGE trial as the pivotal study supporting its use as bridge therapy.7e10 Cangrelor efficacy and safety in the setting of PCI: the CHAMPION program: The design of each trial in the CHAMPION program was presented by the Sponsor and is outlined in Figure 1. Noted by the FDA review committee and a source of great debate among the clinical reviewers in the second part of the meeting was that although the cangrelor dose (30 mg/kg bolus and 4 mg/kg/min infusion) and duration (2 to 4 hours) were the same in the 3 studies, the comparator arm (clopidogrel) differed (Figure 1). In CHAMPION-PCI, clopidogrel 600 mg was given at the time of PCI; in CHAMPION-PLATFORM, clopidogrel 600 mg was given at the end of PCI; and in CHAMPIONPHOENIX, clopidogrel dose (either 300 or 600 mg) was left to the discretion of the individual sites and was to be administered either before or immediately after PCI. At the end of the infusion, patients in the cangrelor arm received 600 mg of clopidogrel in the 3 studies. CHAMPION-PCI and CHAMPION-PLATFORM were terminated early and failed to meet their respective primary end points. Incidence of the protocol-defined primary efficacy end point, a composite of all-cause death, myocardial infarction (MI), www.ajconline.org
Table 1 Pivotal trials to support cangrelor indications TRIAL Subject CHAMPION-PCI (TMC-CAN- 05-02)
CHAMPION-PHOENIX (TMC-CAN-10-01)
BRIDGE (TMC-CAN-08-02)
Prospective, randomized (1:1), double-blind, double-dummy, active-control, parallel-group Active control: clopidogrel 600 mg Prospective, randomized (1:1), double-blind, double-dummy, placebo-control, parallel-group over standard of care: including clopidogrel 600mg Prospective, randomized (1:1), double-blind, double-dummy, active-control, parallel-group Active control: clopidogrel 300 mg or 600 mg Stage 1: Prospective, open label, dose-finding, multi-center. Stage 2: Prospective, double-blind, placebocontrolled, randomized, multi-center.
ITT Sample Size
Description
Primary objective
Primary End Point
8,877 Cangrelor: 4,433 Clopidogrel: 4,444
UA/ NSTEACS/ STEMI patients amenable to PCI
Superiority of cangrelor efficacy over clopidogrel 600 mg in patients requiring PCI
Composite of allcause mortality, MI, and IDR at 48 hours
5,364 Cangrelor: 2,695 Placebo: 2,669
UA/NSTEACS patients amenable to PCI
Superiority of cangrelor (combined with usual care) efficacy over usual care, in patients; requiring PCI
Composite of allcause mortality, MI, and IDR at 48 hours
11,145 Cangrelor: 5,581 Clopidogrel: 5,564
UA/NSTEACS/STEMI patients amenable to PCI
Superiority of cangrelor efficacy over clopidogrel standard of care in patients; requiring PCI
Composite of allcause mortality, MI, IDR and ST at 48 hours (MI: as per UDMI, ST: as per ARC and IPST)
Stage 2: 207 (n¼106 cangrelor; n¼101 placebo)
Patients requiring bridging from oral thienopyridine Therapy prior to cardiac surgery
cangrelor ability to provide effective and consistent P2Y12 inhibition without increasing surgical bleeding compared to standard of care
Percentage of patients with PRU < 240 as determined by VerifyNow P2Y12 point of care assay measured during study drug infusion pre-surgery
Review/FDA Review of Cangrelor
CHAMPION-PLATFORM (TMC-CAN-05-03)
Study Design
ARC ¼ Academic Research Consortium; IDR ¼ ischemia-driven revascularization; IPST ¼ intra-procedural stent thrombosis; IV ¼ intravenous; MI ¼ myocardial infarction; NSTEACS ¼ non ST elevation acute coronary syndrome; PCI ¼ percutaneous coronary intervention; ST ¼ stent thrombosis; STEMI ¼ ST elevation myocardial infarction; UA ¼ unstable angina; UDMI ¼ universal definition of myocardial infarction.
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The American Journal of Cardiology (www.ajconline.org) Table 2 Logistic regression of the Sponsor’s primary end point at 48 hours in the clopidogrel arm of PHOENIX25
600-mg load Age Diabetes Angina Hours to PCI
Odds Ratio
95% CI
p
0.62 1.01 0.80 1.61 0.68
[0.47-0.82] [1.00-1.02] [0.61-1.05] [1.25-2.08] [0.50-0.93]
0.001 0.02 0.11 0 0.01
CI ¼ confidence interval; PCI ¼ percutaneous coronary intervention.
Figure 1. CHAMPION studies designs. NSTEACS ¼ noneST-elevation acute coronary syndrome; UA ¼ unstable angina.
and ischemic driven revascularization, was not significantly reduced in cangrelor-treated patients (CHAMPIONPLATFORM: 7.0% cangrelor- vs 8.0% clopidogrel-treated patients; odds ratio [OR] 0.87, 95% confidence interval [CI] 0.71 to 1.07, p ¼ 0.1746; CHAMPION-PCI: 7.5% vs 7.1%; OR 1.05, 95% CI 0.88 to 1.24, p ¼ 0.5929). According to the Sponsor, post hoc analysis of the PLATFORM and PCI trials suggested signs of cangrelor efficacy, including reductions in the incidence of thrombotic events, such as ST, Q-wave MI, and ischemia-driven revascularization (IDR) but not of the end point of periprocedural MI. Results using the 2007 universal definition of myocardial infarction (UDMI)11 demonstrated that cangrelor reduced (18% significant reduction, OR 0.82, 95% CI 0.68 to 0.99, p ¼ 0.0374) the composite of death, UDMI, and IDR at 48 hours compared to clopidogrel 600 mg in a pooled analysis of both trials.12 The CHAMPION-PHOENIX trial was therefore designed to avoid confounding periprocedural MI with evolving preprocedural MI in patients with elevated biomarkers using the UDMI.13 In PHOENIX, ST definition was also modified to measure events occurring during and after the procedure. Intraprocedural ST (IPST) was included in addition to Academic Research Consortium (ARC)edefined ST and was defined as any procedural new or worsened thrombus related to the stent.14,15 The results of CHAMPION-PHOENIX demonstrated that cangrelor compared to clopidogrel standard of care is effective when administered to patients undergoing PCI. At 48 hours, the CHAMPION-PHOENIX trial demonstrated that, compared to clopidogrel, cangrelor provided a significant reduction in the primary efficacy end point of all-cause mortality, MI, IDR, and ST (4.7% vs 5.9%, respectively; OR 0.79, 95% CI 0.66 to 0.93, p ¼ 0.005), which was maintained at 30 days (6.0% vs 7.0%, respectively; OR 0.85, 95% CI 0.73 to 0.99, p ¼ 0.035). In addition, a significant reduction in protocoldefined ST (0.8% vs 1.4%, respectively; OR 0.62, 95% CI 0.43 to 0.90, p ¼ 0.010), and MI (3.8% vs 4.7%, respectively; OR 0.80, 95% CI 0.67 to 0.97, p ¼ 0.022) were also observed but without a reduction in all-cause mortality (0.3% vs 0.3%, respectively; OR 1.00, 95% CI 0.52 to 1.92, p >0.999).9 In the pooled CHAMPION program, there was
no significant increase in the primary safety outcome of Global Use of Strategies to Open Occluded Arteries (GUSTO) severe or life-threatening bleeding (OR 1.22, 95% CI 0.70 to 2.11, p ¼ 0.48) or GUSTO moderate bleeding (OR 1.36, 95% CI 0.96 to 1.92, p ¼ 0.08). Cangrelor was associated with an increase in GUSTO mild bleedings (OR 1.35, 95% CI 1.26 to 1.45, p
