Published online before print April 25, 2005, doi: 10.1161/01.CIR.0000163561.90680.1C
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2005;111:2233-2240.)
© 2005 American Heart Association, Inc.
Stroke |
Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Carotid Stenosis Evaluated Using Doppler Embolic Signal Detection
The Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial
From the Department of Clinical Neuroscience, St George’s Hospital Medical School, London, UK (H.S.M.); Service de Neurologie, Centre Hospitalier de Luxembourg, Luxembourg, Luxembourg (D.W.D.); Klinik und Poliklinik für Neurologie, Westfälische Wilhelms Universität, Münster, Germany (D.W.D., E.B.R.); Department of Neurology, Justus-Liebig Universitaet, Giessen, Germany (M.K.); Department of Neurology, University of Toulouse, Toulouse, France (V.L.); Acute Stroke Unit and Cerebrovascular Clinic, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary and University of Glasgow, Glasgow, UK (K.R.L.); and Klinik für Neurologie, Heinrich-Heine Universität, Düsseldorf, Germany (M.S.).
Correspondence to Dr Hugh Markus, Department of Clinical Neuroscience, St George’s Hospital Medical School, Cranmer Terrace, London, SW17 ORE, UK. E-mail h.markus{at}sghms.ac.uk
Received August 10, 2004; revision received January 13, 2005; accepted January 19, 2005.
Background— Evidence for efficacy of dual antiplatelet therapy in stroke is limited. Symptomatic carotid stenosis patients are at high risk of early recurrent stroke. In this group, asymptomatic microembolic signals (MES), detected by transcranial Doppler ultrasound (TCD), are markers of future stroke and transient ischemic attack (TIA) risk. They offer a surrogate marker to evaluate antiplatelet therapy, but no multicenter study has evaluated the feasibility of this approach.
Methods and Results— Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) is a randomized, double-blind study in subjects with recently symptomatic 
50% carotid stenosis. Patients were screened with TCD, and if MES were detected, they were randomized to clopidogrel and aspirin or aspirin monotherapy. Repeated TCD recordings were made on days 2 and 7. MES were detected in 110 of 230 patients by online analysis at baseline, of whom 107 were randomized. Intention-to-treat analysis revealed a significant reduction in the primary end point: 43.8% of dual-therapy patients were MES positive on day 7, as compared with 72.7% of monotherapy patients (relative risk reduction 39.8%; 95% CI, 13.8 to 58.0; P=0.0046). The secondary end point of MES frequency per hour was reduced (compared with baseline) by 61.4% (95% CI, 31.6 to 78.2; P=0.0013) in the dual-therapy group at day 7 and by 61.6% (95% CI, 34.9 to 77.4; P=0.0005) on day 2. There were 4 recurrent strokes and 7 TIAs in the monotherapy group versus no stroke and 4 TIAs in the dual-therapy group that were treatment emergent and ipsilateral to the qualifying carotid stenosis; 2 additional ipsilateral TIAs occurred before treatment started. MES frequency was greater in the 17 patients with recurrent ipsilateral events compared with the 90 without (mean±SD: 24.4±27.7 versus 8.9±11.5 per hour; P=0.0003).
Conclusions— In patients with recently symptomatic carotid stenosis, combination therapy with clopidogrel and aspirin is more effective than aspirin alone in reducing asymptomatic embolization. Doppler MES detection is a feasible method to evaluate the efficacy of antiplatelet therapy in multicenter studies.
Key Words: trials • embolism • stroke • ultrasonics • carotid arteries
Related Article:
Circulation 2005 111: 2151.
This article has been cited by other articles:
 |
|
 |
|
  A. King and H. S. Markus Doppler Embolic Signals in Cerebrovascular Disease and Prediction of Stroke Risk: A Systematic Review and Meta-Analysis * Supplemental Online References Stroke, December 1, 2009; 40(12): 3711 - 3717. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Chandratheva, Z. Mehta, O. C. Geraghty, L. Marquardt, P. M. Rothwell, and On behalf of the Oxford Vascular Study Population-based study of risk and predictors of stroke in the first few hours after a TIA Neurology, June 2, 2009; 72(22): 1941 - 1947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Easton, J. L. Saver, G. W. Albers, M. J. Alberts, S. Chaturvedi, E. Feldmann, T. S. Hatsukami, R. T. Higashida, S. C. Johnston, C. S. Kidwell, et al. Definition and Evaluation of Transient Ischemic Attack: A Scientific Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease: The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists. Stroke, June 1, 2009; 40(6): 2276 - 2293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tousoulis, A. Briasoulis, S. S Dhamrait, C. Antoniades, and C. Stefanadis Effective platelet inhibition by aspirin and clopidogrel: where are we now? Heart, May 1, 2009; 95(10): 850 - 858. [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr Secondary Prevention of Atherothrombotic Events After Ischemic Stroke Mayo Clin. Proc., January 1, 2009; 84(1): 43 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Leung, S. C.H. Yu, W. W.M. Lam, L. K.S. Wong, O. O. Zaidat, and M. Chimowitz THE NIH REGISTRY ON USE OF THE WINGSPAN STENT FOR SYMPTOMATIC 70-99% INTRACRANIAL ARTERIAL STENOSIS Neurology, September 30, 2008; 71(14): 1124 - 1125. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Sullivan and N. Amarshi Dual antiplatelet therapy with clopidogrel and aspirin Am. J. Health Syst. Pharm., June 15, 2008; 65(12): 1134 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Sudlow Preventing further vascular events after a stroke or transient ischaemic attack: an update on medical management Practical Neurology, June 1, 2008; 8(3): 141 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Y. Gasparyan, T. Watson, and G. Y.H. Lip The Role of Aspirin in Cardiovascular Prevention: Implications of Aspirin Resistance J. Am. Coll. Cardiol., May 13, 2008; 51(19): 1829 - 1843. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Thijs, R. Lemmens, and S. Fieuws Network meta-analysis: simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke Eur. Heart J., May 1, 2008; 29(9): 1086 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y Iguchi, K Kimura, K Kobayashi, Y Ueno, K Shibazaki, and T Inoue Microembolic signals at 48 hours after stroke onset contribute to new ischaemia within a week J. Neurol. Neurosurg. Psychiatry, March 1, 2008; 79(3): 253 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. T. Engelter, T. Brandt, S. Debette, V. Caso, C. Lichy, A. Pezzini, S. Abboud, A. Bersano, R. Dittrich, C. Grond-Ginsbach, et al. Antiplatelets Versus Anticoagulation in Cervical Artery Dissection Stroke, September 1, 2007; 38(9): 2605 - 2611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M Rothwell Transient ischaemic attacks: time to wake up Heart, August 1, 2007; 93(8): 893 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. E. Kikano and M. T. Brown Antiplatelet Therapy for Atherothrombotic Disease: An Update for the Primary Care Physician Mayo Clin. Proc., May 1, 2007; 82(5): 583 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Bonvini, M. Righini, M. Hamon, J. W. Riddell, A. O. Maree, K. A. Rosenfield, J.-L. Mas, G. Chatellier, and the EVA-3S Investigators Endarterectomy versus Stenting for Carotid Stenosis N. Engl. J. Med., January 18, 2007; 356(3): 305 - 307. [Full Text] [PDF]
|
|
|
|
|
|
J. Kramer, J. Abraham, C. M. Teven, and P. A. Jones Role of Antiplatelets in Carotid Artery Stenting Stroke, January 1, 2007; 38(1): 14 - 14. [Full Text] [PDF]
|
|
|
|
|
|
A. Kastrup, U. Ernemann, T. Nagele, and K. Groschel Risk Factors for Early Recurrent Cerebral Ischemia Before Treatment of Symptomatic Carotid Stenosis Stroke, December 1, 2006; 37(12): 3032 - 3034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Tsivgoulis, K. Spengos, P. Manta, N. Karandreas, T. Zambelis, N. Zakopoulos, and D. Vassilopoulos Validation of the ABCD Score in Identifying Individuals at High Early Risk of Stroke After a Transient Ischemic Attack: A Hospital-Based Case Series Study Stroke, December 1, 2006; 37(12): 2892 - 2897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-C. Diener Update on clopidogrel and dual anti-platelet therapy: neurology Eur. Heart J. Suppl., October 1, 2006; 8(suppl_G): G15 - G19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hamon, S. Gomes, C. Oppenheim, R. Morello, R. Sabatier, T. Lognone, G. Grollier, P. Courtheoux, and M. Hamon Cerebral Microembolism During Cardiac Catheterization and Risk of Acute Brain Injury: A Prospective Diffusion-Weighted Magnetic Resonance Imaging Study Stroke, August 1, 2006; 37(8): 2035 - 2038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Poppert, S. Sadikovic, K. Sander, O. Wolf, and D. Sander Embolic Signals in Unselected Stroke Patients: Prevalence and Diagnostic Benefit Stroke, August 1, 2006; 37(8): 2039 - 2043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chaturvedi and J. S. Yadav The Role of Antiplatelet Therapy in Carotid Stenting for Ischemic Stroke Prevention Stroke, June 1, 2006; 37(6): 1572 - 1577. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. F. Giles, E. Flossman, and P. M. Rothwell Patient Behavior Immediately After Transient Ischemic Attack According to Clinical Characteristics, Perception of the Event, and Predicted Risk of Stroke Stroke, May 1, 2006; 37(5): 1254 - 1260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Dittrich, M. A. Ritter, M. Kaps, M. Siebler, K. Lees, V. Larrue, D. G. Nabavi, E. B. Ringelstein, H. S. Markus, and D. W. Droste 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 Stroke, April 1, 2006; 37(4): 1065 - 1069. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Alexandrov and N. M. Bornstein Advances in Neurosonology 2005 Stroke, February 1, 2006; 37(2): 299 - 300. [Full Text] [PDF]
|
|
|
|
 |
|
 Microembolic Signal Detection to Evaluate Antiplatelet Therapy Effects Journal Watch Neurology, December 8, 2005; 2005(1208): 4 - 4. [Full Text]
|
|
|
|
|
|
N. Nighoghossian, L. Derex, and P. Douek The Vulnerable Carotid Artery Plaque: Current Imaging Methods and New Perspectives Stroke, December 1, 2005; 36(12): 2764 - 2772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. H.E. Imray, D. J. Higman, C. Marshall, S. N. Cohen, H. S. Markus, D. W. Droste, D. W. Droste, E. B. Ringelstein, M. Kaps, V. Larrue, et al. Letter Regarding Article by Markus et al, "Dual Antiplatelet Therapy With Clopidogrel and Aspirin in Symptomatic Cardiac Stenosis Evaluated Using Doppler Embolic Signal Detection: The Clopidogrel and Aspirin for Reducton of Emboli in Symptomatic Carotid Stenosis (CARESS) Trial" * Response Circulation, November 15, 2005; 112(20): e325 - e326. [Full Text] [PDF]
|
|
|
|
|
|
K. T.S. Pattinson, C. H.E. Imray, H. S. Markus, and A. MacKinnon Transcranial Doppler and Carotid Artery Disease Strokes: More Than Just Risk Stratification * Response: Stroke, November 1, 2005; 36(11): 2340 - 2341. [Full Text] [PDF]
|
|
|
|
|
|
H. D. Aronow, M. Shishehbor, D. A. Davis, I. L. Katzan, D. L. Bhatt, C. T. Bajzer, A. Abou-Chebl, K. W. Derk, P. L. Whitlow, and J. S. Yadav Leukocyte Count Predicts Microembolic Doppler Signals During Carotid Stenting: A Link Between Inflammation and Embolization Stroke, September 1, 2005; 36(9): 1910 - 1914. [Abstract] [Full Text] [PDF]
|
|