The CARESS trial: Dual antiplatelet therapy superior to monotherapy in symptomatic carotid stenosis [Classics Series]

Classics Series, Landmark Trials in Medicine

1. Dual antiplatelet therapy with clopidogrel and aspirin was associated with a significant reduction in microembolic events in patients with symptomatic carotid stenosis compared to aspirin alone

2. There was no significant difference between the two groups in the risk of bleeding

Original Date of Publication: May 3, 2005 

Study Rundown: The CARESS trial assessed how combination antiplatelet therapy with clopidogrel and aspirin compared to aspirin alone when used to prevent embolic events in patients with symptomatic carotid stenosis. The study used microembolic signals (MES) detected by transcranial Doppler (TCD) ultrasound as a surrogate marker for antiplatelet efficacy and risk of TIA or stroke.

In summary, dual antiplatelet therapy was associated with a 39.8% relative risk reduction in the proportion of patients who were positive for MES after one week of treatment (95%CI 13.8-58.0; P=0.0046). Further, the frequency of MES was significantly reduced in the dual therapy group compared to the monotherapy group and there was no increased risk of bleeding associated with combination therapy. Although the trial did not assess a clinical end point, it demonstrated that MES detected by TCD is a feasible outcome measure that does not require the large sample size necessary to assess the end point of stroke.

Click to read the study in Circulation

In-Depth [randomized controlled trial]: This randomized, double-blind, multicentre study involved 11 centres located in France, Germany, Switzerland, and the United Kingdom. Eligible patients were >18 years old, had ≥50% stenosis, and had TIA or stoke in the past 3 months. These patients were evaluated for MES using TCD ultrasound. Exclusion criteria include having clinical/imaging evidence of hemorrhagic transformation, carotid endarterectomy scheduled within the next 2 weeks, acoustic window that did not allow TCD recording, atrial fibrillation or other major cardiac source of embolism, thrombolysis within the last 2 weeks, and anticoagulation within the past 3 days, amongst other factors.

Patients in whom MES were detected were randomized to receive clopidogrel plus aspirin or aspirin monotherapy. Those in the dual therapy group received a loading dose of 300 mg of clopidogrel on day 1, followed by 75 mg once daily up to day 7. Both groups received 75 mg of aspirin once daily for the duration of the study. The primary end point was the proportion of patients who were MES positive on day 7. Secondary end points included the proportion of patients who were MES positive on day 2 and the rate of embolization (in number of MES per hour) on days 2 and 7.

After screening for MES with TCD, 107 patients were randomized to receive either dual therapy or monotherapy. On intention-to-treat analysis, dual therapy was associated with a significant reduction in the proportion of patients who were MES positive on day 7 (RRR 39.8%; 95% CI 13.8-58.0; P=0.0046). MES frequency per hour was reduced in the dual therapy group compared to the monotherapy group at both day 7 (embolization rate reduction 61.4%; 95% CI 31.6-78.2; P=0.001) and day 2 (embolization rate reduction 61.6%; 95% CI 34.9-77.4; P<0.001). There was no significant difference in bleeding between the two treatment groups.

Image: PD

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