Lack of concordance between angiographic core laboratory and CEC in the
assessment of stent thrombosis: Results from the TRACER angiographic substudy
C. Michael Gibson, MD, MS, MA;1 Christopher J. Popma, BS;1 Gerald Chi, MD;1 Pierluigi Tricoci, MD, MHS, PhD;2 Cassandra
1
1
2
2
3
2
Abueg, MPH; Kristin Feeney, MPH; Zhen Huang, MS; Meredith Smith; Edmond Chen, MD; Kenneth W. Mahaffey, MD
Beth Israel Deaconess Medical Center, Boston, MA, USA; Duke Clinical Research Institute, Durham, NC, USA; Merck, Whitehouse
Station, NJ, USA
Purpose
•Adjudication of stent thrombosis (ST) is commonly based on clinical event
committee (CEC) review of case report forms (CRFs) and source documentation.
•The assessment of stent thrombosis in clinical research studies is complex and
requires precise definitions.
•While thrombosis may be present in the vessel in which an intervention was
performed, it may not be due to stent thrombosis, and investigator reported cases
of stent thrombosis may not in fact meet rigorous criteria required to adjudicate
stent thrombosis.
•Stent thrombosis may be missed by the clinical site, and it is important to review
all cases of urgent revascularization to determine if stent thrombosis was in fact
the cause of the urgent revascularization.
•However, the degree to which the CEC adjudication is concordant with the
review of an independent angiographic core laboratory (ACL) has not been
established.
Methods
•We aimed to collect serial angiograms of NSTE ACS patients who underwent
PCI at study entry in the TRACER trial who had clinical suspicion of stent
thrombosis as determined by either of the following:
1. Had ST reported by local site on the CRF
2. OR, had a CEC-confirmed myocardial infarction or urgent
revascularization
•A total of 450 patients met these criteria. Of these, 347 were successfully
reviewed by the ACL, blinded to the presence or absence of ST.
•CEC adjudication was based upon the Academic Research Consortium (ARC)
definition of ST, using CRF data and source documents, including catheterization
laboratory reports.
•Baseline and all subsequent angiograms from interventions preceding the
purported stent thrombosis or urgent revascularization were reviewed to
determine exactly where the stent was placed because some stents may not be
sufficiently radio-opaque on follow-up angiography
•Cohen’s κ-coefficients were calculated for agreement between the CEC and
sites, CEC and ACL, and ACL and sites.
•All statistics were calculated were using only those cases that were assessed by
the CEC as definite ST by the ARC definition.
Figure 1 – Study Design
Results
•Of the 347 cases, sites reported a total of 192 cases of ST, the CEC adjudicated 72
cases as definite for ST, and the ACL found the presence of ST in 114 cases. See
Figure 2.
•Using the ACL as the golden standard, the CEC was able to identify 62 of 114
(54.4%) cases of ST, but misadjudicated 10 of the 233 (4.3%) cases confirmed by
the ACL to be absent of ST. The CEC and ACL disagreed in a total of 62 instances,
representing 17.9% of all cases in the analysis.
•The sites were able to correctly identify 84 of 114 (73.7%) cases of ST, but
misreported 108 of the 233 (46.4%) cases found by the ACL to be lacking ST. Of
these latter cases, 9 of the 233 (3.9%) were also misadjudicated as ST by the CEC
•All three groups agreed on the presence of ST in 56 of 114 (49.1%) cases and the
lack of ST in 124 of 233 (35.7%) cases.
•Poor to fair agreement was found between reports of ST by local sites and the ACL
(κ = 0.2327), poor to fair agreement between local sites and CEC defined definite
ST (κ = 0.2121), and moderate to good agreement between the ACL confirmed ST
and CEC defined definite ST (κ = 0.5530). See Table 1.
•Among subjects who received stenting during index hospitalization and based
upon the ACL assessment of ST, the rates of ST were 1.80% in the vorapaxar group
and 2.14% in the placebo group (HR 0.80; 95% CI, 0.55-1.16; p = 0.238)
•When assessed by the CEC adjudication of probable and definite ST, the event
rates were 1.7% in the vorapaxar group and 1.5% in the placebo group (HR 1.12;
95% CI. 0.78-1.62; p = 0.54).
Figure 3– ST events as assessed by Site-CRF, CEC, ACL compared to each
study arm.
Conclusion
The fair agreement between both the sites and the ACL and the sites and CEC
emphasizes the need to review all potential events. There is only moderate
concordance between a site CRF, a CEC using ARC, and an ACL using an
angiogram in the assessment of ST. Importantly, nearly half of ST cases detected
by ACL review of the angiogram were not detected by CEC, due to under reporting
of ST in source documents, including catheterization reports. This may lead to a
high level of disagreement between the CEC and ACL. Our results may have
implications with respect to the optimal strategy to identify ST in clinical trials.
This substudy was limited by incomplete angiographic collection.
The suboptimal agreement between ACL and CEC may have implication in the
assessment of treatment effects, as suggested by trend towards reduced risk for ST
determined with ACL with ACL with vorapaxar and a reverse tendency observed
when ST was assessed by the CEC.
References
1Tricoci
P, Huang Z, Held C, Moliterno DJ, Armstrong PW, Van de Werf F, White HD, Aylward PE, Wallentin L,
Chen E, Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian AM, Jennings LH, Ambrosio G, Bode C, Cequier A,
Cornel JH, Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukema JW, Lewis BS, Lincoff AM, Montalescot G,
Nicolau JC, Ogawa H, Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, Valgimigli M, Whellan DJ,
Widimsky P, Strony J, Harrington RA, Mahaffey KW. Thrombin-receptor antagonist vorapaxar in acute
coronary syndromes. N Engl J Med. 2012;366:20-33
Disclosure of Interest
Figure 2 – Venn Diagram showing overlap between stent thrombosis as report
on CRFs and by the CEC and ACL. Numbers in each region represent the
number of cases specific to that region.
Cohen’s κ-coefficient
[95% CI]
Site-CEC (N = 12,944) 0.2121 [0.1754, 0.2489]
Site-ACL (N = 347) 0.2327 [0.1418, 0.3235]
ACL-CEC (N = 347) 0.5530 [0.4583, 0.6477]
Interpretation
Poor - Fair
Poor - Fair
Moderate - Good
Table 2 – Agreement between Sites and CEC, Sites and ACL, and ACL and
CEC on the presence of stent thrombosis.
Present Research/Grant Funding: Angel Medical Corporation, Atrium Medical Systems, Bayer Corp., Ikaria,
Inc., Janssen Pharmaceuticals, Johnson & Johnson Corporation, ,Lantheus Medical Imaging, Merk & Co.,
Portola Pharmaceuticals, Roche Diagnostics, Sanofi-Aventis, Stealth Peptides, Inc., St. Jude Medical, Volcano
Corp., Walk Vascular. Peer-to-peer Communications: Daiichi Sankyo Company, Inc., Eli Lilly and Company,
The Medicines Company. Consultant: AstraZeneca, Atrium Medical Systems, Baxter Healthcare, Bristol
Myers Squibb Company, Cardiovascular Research Foundation, Consensus Medical Communications, CSL
Behring, Cytori Therapeutics, Daiichi Sankyo Company, Eli Lilly and Company, Exeter Group, Genentech,
Inc., GlaxoSmithKline, St. Jude Medical, the Medicines Company. Consultant with $0.00 Monies received:
Bayer Corp., Janssen Pharmaceuticals, Johnson & Johnson Corporation, Ortho McNeil. Past Research/Grant
Funding/Past Speakers Bureau/Past Consulting: Abbott, Angel Medical Systems, Archemix Corporation,
Astra Zeneca, Ascenta Therapeutics, Atrium Medical Corporation, Baxter Healthcare, Biogen IDEC, Boston
Scientific Corporation, Bristol Meyers Squibb Company, British Biotech, plc., Ciba Geigy Corporation, Eli
Lilly and Company, FibroGen, Inc., FoldRx, Genentech, Inc., GlaxoSmithKline, Heartscape Technologies,
Ischemix, Inc., Merck & Co., Inc., NIH, Novartis Corporation, Pfizer, Pocket Medicine, Point Biomedical
Corporation, Portola Pharmaceuticals, Inc., Regado Biosciences, Inc., Sanofi-Aventis Corporation, Schering
Plough Corporation, Smith Kline Beecham, St. Jude Medical, The Medicines Company, timi3 Systems, Inc.