CHAMPION PHOENIX

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Bhatt DL, et al. "Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events". The New England Journal of Medicine. 2013. 368(14):1303-1313.
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Clinical Question

Among patients undergoing urgent or elective PCI, does cangrelor reduce the risk of ischemic events, as compared to clopidogrel?

Bottom Line

Among patients undergoing urgent or elective PCI, cangrelor reduces the risk of ischemic events, as compared to clopidogrel.

Major Points

The effectiveness of P2Y12-receptor antagonist (eg, clopidogrel, prasugrel, ticagrelor) in ACS has been demonstrated in multiple trials including the CURE, COMMIT, TRITON-TIMI 38, and PLATO. Periprocedural administration of these oral agents can be challenging if there is significant nausea, dysphagia, or altered mental status. Cangrelor is an intravenous, fast-acting (half-life 2.9-5.5 minutes) antiplatelet medication that has rapidly reversible inhibition of the P2Y12 receptor.[1] Its efficacy in PCI was unknown.

Published 2013, the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized patients undergoing urgent or elective PCI to receive cangrelor (n=5472) or clopidogrel (n=5470). All patients also received aspirin. The primary outcome was a composite of all-cause mortality, MI, ischemia-driven revascularization, or stent thrombosis. Cangrelor significantly reduced the risk of the primary outcome (4.7% vs. 5.9%; OR 0.78; 95% CI 0.66-0.93; P=0.005; NNT=83

). There was no significant increase in the risk of severe bleeding. However, cangrelor treatment was associated with a higher risk of dyspnea. This complication was seen in the PLATO and EUCLID (Ticagrelor) trials investigating the similar reversible mediatedking, P2Y12 antagonist ticagrelor.

Despite the findings of this single trial, a meta-analysis including the CHAMPION PHOENIX trial and the phase 3 trials CHAMPION PCI and CHAMPION PLATFORM reported no difference in the risk of the primary outcome between patients treated with cangrelor or clopidogrel.[2] It is also unclear how cangrelor compares to the more potent P2Y12 inhibitors, prasugrel and ticagrelor.[3]

Guidelines

As of June 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, randomized trial
  • N=11,145
    • Cangrelor (n=5472)
    • Clopidogrel (n=5470)
  • Setting: 153 centers in multiple countries
  • Enrollment: 2010-2012
  • Follow-up: 48 hours
  • Analysis: Modified intention-to-treat
  • Primary outcome: All-cause mortality, MI, ischemia-driven revascularization, or stent thrombosis within 48 hours post-randomization

Population

Inclusion Criteria

  • Age ≥18 years
  • PCI indicated for 1 of these reasons:
    • Stable angina with diagnostic coronary angiogram <90 days prior to randomization
    • NSTE-ACS with diagnostic coronary angiogram <72 hours prior to randomization
    • STEMI

Exclusion Criteria

Details are presented elsewhere.[4][5]

  • Treatment with P2Y12 receptor antagonist, or abciximab within 7 days prior to randomization
  • Treatment with eptifibatide, tirofiban, or fibrinolytic therapy within 12 hours prior to randomization
  • Hypertension (systolic BP >180 mm Hg or diastolic BP >110 mm Hg) inadequately controlled by antihypertensive therapy
  • Impaired hemostasis, coagulopathy, or thrombocytopenia
  • Planned admission for <12 hours post-PCI
  • Planned PCI where the second stage will occur ≤30 d after the initial intervention
  • Allergy or contraindication to aspirin, clopidogrel, cangrelor, mannitol, sorbitol, or microcrystalline cellulose
  • Pregnancy or lactation, other investigational drug/device use, prior enrollment in this protocol

Baseline Characteristics

From the cangrelor group

  • Demographics: Age 64 years, 28% female, 94% white race; 37% from United States
  • Weight: 84 kg
  • Diagnosis: Stable angina 57%; NSTE-ACS 25%, STEMI 18%; normal cardiac-biomarker (64.4%)
  • PMH: DM 28%, active smoker 28%, HTN 80%, HLD 69%, stroke or TIA 5%, PAD 8%, previous MI 20%, HF 10%
  • PSH: PTCA or PCI 23%, CABG 11%
  • Periprocedural medications: clopidogrel (300 mg loading dose 26%; 600 mg loading dose 74%), bivalirudin 23%, unfractionated heparin 78%, LMWH 13%, fondaparinux 3%, ASA 94%
  • PCI specifics: Duration 18 min, DES 56%, BMS 42%, balloon angioplasty 5%

Interventions

  • Patients were randomized, in a double-blind manner to a group:
    • Cangrelor - IV cangrelor bolus of 30 μg/kg followed by an infusion of 4 μg/kg/min for ≥2 hours or the duration of the procedure (whichever is longer) and placebo capsules
    • Clopidogrel - Placebo infusion then clopidogrel loading dose 600 mg or 300 mg
  • Both groups received the following:
    • Aspirin 75-325 mg and clopidogrel 75 mg, during the first 48 hours
  • The investigator selects the periprocedural anticoagulant of choice
  • Glycoprotein IIb/IIIa inhibitors were used only as rescue therapy during PCI

Outcomes

Comparisons are cangrelor vs. clopidogrel. The main outcome were adjusted for baseline status and clopidogrel loading dose.

Primary Outcomes

All-cause mortality, MI, ischemia-driven revascularization, or stent thrombosis
4.7% vs. 5.9% (OR 0.78; 95% CI 0.66-0.93; P=0.005; NNT=83)

Secondary Outcomes

Stent thrombosis
0.8% vs. 1.4%; OR 0.62; 95% CI 0.43-0.90; P=0.01
"Definite" stent thrombosis
0.2% vs. 0.4%; OR 0.54; 95% CI 0.27-1.10; P=0.09

Other Outcomes

MI
3.8% vs. 4.7% (OR 0.80; 95% CI 0.67-0.97; P=0.02)
Q-wave MI: 0.2% vs. 0.3% (OR 0.61; 95% CI 0.29-1.29; P=0.19)
Ischemia-driven revascularization: 0.5% vs. 0.7% (OR 0.74; 95% CI 0.45-1.20; P=0.22)
All-cause mortality
0.3% vs. 0.3% (OR 1; 95% CI 0.52-1.92; P>0.999)
CV mortality
0.3% vs. 0.3% (OR 1; 95% CI 0.52-1.92; P>0.999)
Mortality or stent thrombosis
1.1% vs. 1.6% (OR 0.67; 95% CI 0.48-0.94; P=0.02)
Mortality, Q-wave MI, or ischemia-driven revascularization
0.9% vs. 1.2% (OR 0.76; 95% CI 0.53-1.11; P=0.16)

Subgroup Analysis

For the primary outcome

PAD
Yes: 4.5% vs. 11.4% (OR 0.36; 95% CI 0.21–0.63)
No: 4.7% vs. 5.5% (OR 0.86; 95% CI 0.72–1.03)
P-value for interaction 0.003

No significant interactions for age, gender, race, region, presenting diagnosis, weight, biomarker status, diabetes, previous MI, TIA or stroke, history of heart failure, dose of aspirin or clopidogrel, periprocedural anticoagulant, specifics of PCI (eg, arterial access, number of vessels, stent type) and timing of clopidogrel loading dose.

Adverse Events

Note: The modified intention-to-treat (mITT) population for safety outcomes was not the same as the mITT population for the efficacy outcomes above. Safety outcomes appear to have excluded only those who did not receive the study drug while the efficacy outcomes excluded those who did not undergo PCI or those who did not receive the study drug. There were 91 and 83 more participants in the safety mITT population. It is unclear to the WJC editors if these extra participants who received the study drug but did not undergo PCI had different bleeding rates by treatment assignment. See figure S2 in the supplementary appendix for details.[6]

GUSTO-defined bleeding[7]
Severe: 0.16% vs. 0.11% (OR 1.50; 95% CI 0.53-4.22; P=0.44)
Moderate: 0.4% vs. 0.2% (OR 1.69; 95% CI 0.85-3.37; P=0.13)
Severe or moderate: 0.6% vs. 0.3% (OR 1.63; 95% CI 0.92-2.9; P=0.09)
TIMI-defined bleeding[8]
Major: 0.1% vs. 0.1% (OR 1.00; 95% CI 0.29-3.45; P>0.999)
Minor: 0.2% vs. 0.1% (OR 3.00; 95% CI 0.81-11.10; P=0.08)
Major or minor: 0.3% vs. 0.1% (OR 1.75; 95% CI 0.73-4.18; P=0.20)
Blood transfusion
0.5% vs. 0.3% (OR 1.56; 95% CI 0.83-2.93; P=0.16)
Dyspnea
1.2% vs. 0.3% (P<0.001)

Additional Analyses

Mortality, MI, ischemia-driven revascularization, stent thrombosis, or GUSTO-defined severe bleeding
4.8% vs. 6% (HR 0.80; 95% CI 0.68-0.94; P=0.008)

Criticisms

  • It may be difficult to differentiate MI which occurs prior to or after randomization.[9]
  • Although stent thrombosis was reported to be lower, the incidence of definite stent thrombosis did not differ significantly between the treatment groups.[9]
  • It is unclear how stent thrombosis was diagnosed.[9]
  • Clopidogrel 300 mg was the loading dose in ~25% of the participants. This is thought to be a less effective loading dose which may lead to inadequate platelet inhibition and greater likelihood of ischemic events. Further, clopidogrel is inferior to ticagrelor and prasugrel in reducing PCI complications. It is not clear how cangrelor compares to these other agents.[9]
  • The extent of myocardial damage was not evaluated when patients were treated with urgent PCI.[10]
  • Little racial diversity

Funding

The Medicines Company, the manufacturer or Kengreal (the brand name of cangrelor).

Further Reading

  1. Storey RF et al. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 2002. 13:407-13.
  2. Pandit A et al. Cangrelor versus clopidogrel in percutaneous coronary intervention: a systematic review and meta-analysis. EuroIntervention 2014. 9:1350-8.
  3. Gurm HS. Cangrelor and glycoprotein IIb/IIIa inhibitors. ACC.org. Published 2017-01-10.]
  4. Leonardi S et al. Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial. Am. Heart J. 2012. 163:768-776.e2.
  5. CHAMPION PHOENIX protocol.
  6. Supplementary appendix.
  7. Mehran R et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011. 123:2736-47.
  8. Rao SV, O’Grady K, Pieper KS, et al. A Comparison of the Clinical Impact of Bleeding Measured by Two Different Classifications Among Patients With Acute Coronary Syndromes. J Am Coll Cardiol. 2006;47(4):809-816. doi:10.1016/j.jacc.2005.09.060.
  9. 9.0 9.1 9.2 9.3 Lange RA & Hillis LD The duel between dual antiplatelet therapies. N. Engl. J. Med. 2013. 368:1356-7.
  10. Riezebos RK & Verheugt FW ACP Journal Club. Cangrelor reduced ischemic PCI complications more than clopidogrel without increasing severe bleeding. Ann. Intern. Med. 2013. 158:JC5.