The Use of Embolic Signal Detection in Multicenter Trials to Evaluate Antiplatelet Efficacy Signal Analysis and Quality Control Mechanisms in the CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) Trial Ralf Dittrich, MD; Martin A. Ritter, MD; Manfred Kaps, MD; Mario Siebler, MD; Kennedy Lees, FRCP; Vincent Larrue, MD; Darius G. Nabavi, MD; E. Bernd Ringelstein, MD; Hugh S. Markus, FRCP; Dirk W. Droste, MD Background and Purpose—The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial proved the effectiveness of the combination of clopidogrel and aspirin compared with aspirin alone in reducing presence and number of microembolic signals (MES) in patients with recently symptomatic carotid stenosis. The present study aimed at installing primary and secondary quality control measures in CARESS because MES evaluation relies on subjective judgment by human experts. Methods—As primary quality control, centers participating in CARESS evaluated a reference digital audio tape (DAT) before the study containing both MES and artifacts. Interobserver agreement of classifying signals as MES was expressed as proportions of specific agreement of positive ratings (psvalues). For all DATs included in CARESS (n=300), online number of MES and off-line number of MES read by the central reader were compared using correlation coefficients. As secondary control, a sample of 16 of 300 DATs was cross-validated by another independent reader (post-trial validator). Results—For the reference tape, the cumulative psvalue was 0.894 based on 12 of 14 observers. Two observers with very different results improved after a training procedure. Agreement between post-trial validator and central reader was ps+=0.805, indicating very good agreement. Correlation between online evaluation and off-line evaluation of DATs was very good overall (cumulative =0.84; P0.001). Conclusion—Multicenter studies using MES as outcome parameter are feasible. However, primary and secondary quality control procedures are important. (Stroke. 2006;37:1065-1069.) Key Words: antiplatelet agents  carotid stenosis  stroke  ultrasonography, Doppler, transcranial C linically silent cerebral microembolic signals (MES) can frequently be detected by transcranial Doppler (TCD) sonography in patients with symptomatic carotid stenosis. 1–5 Several small studies have shown that MES predict recurrent stroke or transient ischemic attack (TIA) and stroke alone in patients with symptomatic carotid stenosis. 5–8 MES-positive patients with symptomatic carotid stenosis therefore define a subset of high-risk patients for stroke recurrence. In this group, MES offer an attractive surrogate marker to evaluate antiplatelet efficacy. The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial demonstrated a superior efficacy of clopidogrel plus aspirin compared with aspirin alone in reducing the presence and the number of MES after 1 week of treatment. 9 Interob- server agreement in the identification of MES has been shown to be high within centers and between very experi- enced centers. However, disagreement can occur, particularly for MES with small intensity increases. 10,11 The standard of evaluation of MES is still the off-line evaluation of a recorded investigation by a human expert. 12 Although there have been efforts to develop intelligent software capable of automati- cally classifying events as MES or artifacts, it is still felt that the technique is premature. 12–14 For this reason, as for most multicenter trials involving human experts’ judgment (eg, neu- Received August 30, 2005; final revision received November 28, 2005; accepted December 14, 2005. From the Department of Neurology (R.D., M.A.R., D.G.N., E.B.R., D.W.D.), University Hospital of Mu ¨nster, Germany; Department of Neurology (M.K.), University Hospital of Giessen, Germany; Department of Neurology (M.S.), University Hospital of Du ¨sseldorf, Germany; Division of Cardiovascular and Medical Sciences (K.L.), University of Glasgow, United Kingdom; Department of Neurology (V.L.), University of Toulouse, France; Centre for Clinical Neuroscience (H.S.M.), St. George’s University of London, United Kingdom; and Department of Neurology (D.W.D.), Centre Hospitalier de Luxembourg. The first 2 authors contributed equally to this study. Correspondence to Martin A. Ritter, MD, Department of Neurology, University of Mu ¨nster, Albert-Schweitzer-Straße 33, 48129 Mu ¨nster, Germany. E-mail ritterm@uni-muenster.de © 2006 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000209331.39894.3d 1065 by guest on November 17, 2015 http://stroke.ahajournals.org/ Downloaded from