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Heart Online First, published on February 23, 2013 as 10.1136/heartjnl-2012-303103 Cardiovascular pharmacology
ORIGINAL ARTICLE
A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial Sergio Leonardi,1,2 Adriano A M Truffa,1 Megan L Neely,1 Pierluigi Tricoci,1 Harvey D White,3 C Michael Gibson,4 Matthew Wilson,1 Gregg W Stone,5 Robert A Harrington,6 Deepak L Bhatt,7 Kenneth W Mahaffey1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ heartjnl-2012-303103). 1
Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina, USA 2 Department of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy 3 Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand 4 Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA 5 Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York, USA 6 Stanford University, Stanford, California, USA 7 VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts, USA Correspondence to Dr Sergio Leonardi, Duke Clinical Research Institute, 2400 Pratt Street, Room 0311 Terrace Level, Durham, NC 27705, USA;
[email protected] Received 2 October 2012 Revised 23 January 2013 Accepted 25 January 2013
ABSTRACT Objective To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). Design We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. Setting The CHAMPION PLATFORM trial. Patients Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). Interventions Cangrelor versus placebo. Main outcome measures The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committeeadjudicated (CEC PCI-MI) results was investigated. Results Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference ( p3×ULN in patients with normal baseline biomarkers and a re-elevation of at least 20% between peak and nadir with a peak >3×ULN in patients with abnormal but stable/falling biomarkers. According to the universal MI definition, type 4a MI cannot be assessed when biomarkers are rising or unknown at the time of PCI.
Original CHAMPION MI definition (CEC PCI-related MI) The definition of PCI-related MI used by the original CHAMPION PLATFORM clinical events committee (CEC) is shown in the online supplementary appendix. This definition, which is similar to definitions used prior to the publication of the universal MI definition, relied on clinical judgement rather than a strict assessment of baseline biomarker status to assess relationships between the timing of cardiac ischaemia-related symptoms, biomarker trends and PCI. Thus, stable or falling biomarkers at the time of PCI were not required to assess PCI-related MI. In addition, the relative increase required with the original CEC PCI-related MI definition was at least 50%, while it is at least 20% in the universal MI definition. The definition of spontaneous (non-procedural) MI in CHAMPION PLATFORM required clinical manifestations of myocardial ischaemia based on signs, symptoms and/or electrocardiographic changes plus an elevation of at least 2×ULN of CK-MB, which was favoured over troponin.
Statistical analyses
Figure 1 A typical plot in a patient with abnormal biomarkers at time of percutaneous coronary intervention. ULN, upper limit of normal. 2
Patients adjudicated as having normal or stable/falling biomarker status defined the primary cohort. If the biomarker status was unknown, typically due to insufficient or no biomarker data before PCI, the patient was classified by convention as rising and excluded from the primary cohort. After the reconciliation between reviewers was finalised, the statistician linked the peak and nadir identification to the actual CK-MB value and calculated the relative increase. If the peak was >20% higher than Leonardi S, et al. Heart 2013;0:1–6. doi:10.1136/heartjnl-2012-303103
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Cardiovascular pharmacology the nadir and >3×ULN, a type 4a MI was assigned. Inter-observer agreement rate was calculated with κ statistics. Only CK-MB (re-)elevations in patients in the primary cohort were included in the final analysis. Categorical data are presented as proportions and continuous data are presented as medians (25th, 75th percentiles). Baseline differences between the primary and non-primary cohort patients and between rates of type 4a MI and CEC-adjudicated PCI-MI were compared using the χ2 test or the Mann–Whitney test, as appropriate. The universal MI definition encourages a full reporting of biomarker elevations after PCI and specifically thresholds of 5 and 10×ULN.11 Thus, additional type 4a MI EPs were defined using these thresholds for the CK-MB peak. Differences in the incidence of type 4a MI between cangrelor and placebo were evaluated by fitting a logistic regression model with type 4a MI as outcome and randomised treatment as predictor. Similar analyses were performed with type 4a MI defined by thresholds of 5 and 10×ULN. We then used type 4a MI definitions in lieu of the original CEC PCI-related MI definition and explored randomised treatment effect on the primary composite EP of death, MI and IDR at 48 h. For the latter analysis, the MI component (total MI) included the newly defined PCI-related MI (type 4a MI) instead of the original PCI-related MI definition (CEC PCI-related MI), while MI unrelated to PCI was left as originally defined by the CEC. Q-wave MIs (related or unrelated to PCI) were also included.10 According to the original primary analysis in PLATFORM, all analyses were performed in the modified intention-to-treat population, defined as randomised patients who received at least one dose of study drug and underwent the index PCI.
Table 1 Baseline characteristics of primary and non-primary cohort patients
Age (years) Male sex (%) History (%) Congestive HF Hypertension Family history of CAD Hyperlipidaemia Previous stroke PAD Previous PCI Time from admission to angiography (h) Creatinine, median (25th, 75th) (mg/dl) Systolic BP at admission (mm Hg) Heart rate at admission (bpm) Aspirin use (%) Use of any GP IIb/IIIa inhibitors (%)
Non-primary cohort (N=1889)
Primary cohort* (N=3406)
p Value
63.0 (54.0, 71.0) 70.6
62.0 (54.0, 71.0) 71.5
0.139 0.463
7.0 72.8 30.3 44.9 5.9 5.2 12.9 4.7 (1.9, 17.3)
7.7 75.0 35.8 53.1 6.0 4.8 15.8 8.5 (2.5, 23.6)
0.160 0.183
