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  1. Strategies of Clopidogrel Load and Atorvastatin Reload to Prevent Ischemic Cerebral Events in Patients Undergoing Protected Carotid Stenting.Results from the Randomized ARMYDA-9 CAROTID StudyGiuseppe Patti, MD, FACCCampus Bio-Medico University of RomeNo conflit of interest related to this presentation to disclose

  2. Background • A 600 mg clopidogrel load significantly reduced peri-procedural myocardial infarction vs the conventional 300 mg dose (ARMYDA-2 study) in the setting of PCI, but it is unknown whether this higher dose may similarly provide neuroprotection also in patients undergoing carotid stenting • The ARMYDA-RECAPTURE study showed that a short-term reload with high-dose atorvastatin prevents from peri-procedural myocardial infarction in patients undergoing coronary stenting even in the background of chronic statin therapy. It is unknown whether this strategy of atorvastatin reload may decrease ischemic cerebral events also in patients receiving carotid stenting

  3. ARMYDA-9 CAROTID study Prospective, multicenter, randomized, open-label study investigating efficacy of 600 mg vs 300 mg clopidogrel load and of atorvastatin reload in clopidogrel-naïve patients on chronic statin therapy undergoing carotid stenting Institutions: Campus Bio-Medico University of Rome; European Hospital of Rome Co-Chairman: Germano Di Sciascio Co-Chairman and Principal Investigator:Giuseppe Patti Investigators:Fabrizio Tomai,Rosetta Melfi, Elisabetta Ricottini, Michele Macrì, Pietro Sedati, Arianna Giardina, Cristina Aurigemma, Mario Leporace, Andrea D’Ambrosio

  4. ARMYDA-9 CAROTID: Study design N=156 clopidogrel-naive patients on chronic statin therapy undergoing carotid stenting Randomized to receive (2 x 2 factorial): ● CLOPIDOGREL: 600 mg vs 300 mg load ● STATIN: Atorvastatin reload (80 mg 12 hrs before intervention with further 40 mg dose 2 hrs before) vs no statin reload Carotid stenting Primary end-point:30-day incidence of TIA/stroke or new ischemic lesions at cerebral DW-MRI

  5. ARMYDA-9 CAROTID: Enrolment criteria • Inclusion criteria • Chronic statin therapy (>30 days) • >50% stenosis of the internal carotid artery detected by ultrasound or CT scan in symptomatic* patients or >60% stenosis in asymptomatic patients * Symptomatic patients: hemispheric or retinal transient ischemic attack (TIA) or a non-disabling stroke (or retinal infarct) <6 months before enrolment • Exclusion criteria • Previous disabling stroke (modified Rankin scale score ≥3 points) • Acute/subacute ischemic cerebral lesions at baseline MRI • Non-atherosclerotic carotid disease • Percutaneous intervention or surgery <30 days • Need for oral anticoagulant therapy • High risk of bleeding or contra-indications to antiplatelet therapy (including platelet count <70x109/L) • Assumption of clopidogrel <10 days from randomization • Renal failure with serum creatinine >3 mg/dl or liver/muscle disease • Previous pace-maker implantation or claustrophobia

  6. ARMYDA-9 CAROTID: Study endpoints • Primary endpoint • 30-day cumulative incidence of TIA*/stroke** or new ischemic lesions at cerebral DW-MRI performed 24 to 48 hours after carotid stenting(both for clopidogrel comparison and statin comparison) • * TIA: any new, rapidly developing, neurological deficit (either cerebral or ocular) consistent with focal cerebral ischemia that resolved within 24 hours • ** Stroke: any the above neurological deficit persisting >24 hours. Stroke was considered major in presence of modified Rankin scale score ≥3 • Secondary endpoints • Individual components of the composite primary endpoint • Number of new lesions and occurrence of >5 mm new lesions at DW-MRI • Incidence of TIA/stroke at 30 days • Vascular/bleeding complications: a) major or minor bleeding, according to the TIMI criteria, or b) entry-site complications (haematoma >10 cm, pseudoaneurysm or arterio-venous fistula)

  7. ARMYDA-9 CAROTID: Sample size calculation • Hypothesizing a 30-day incidence of TIA/stroke or new cerebral lesions of 40% and a 50% risk reduction of the primary endpoint in the active treatment arm for both comparisons (clopidogrel and statin), a study population of at least 156 patients would be needed to detect such reduction with alpha of 0.05 (two-tailed) and beta of 0.8

  8. ARMYDA-9 CAROTID: Demographic/clinical features

  9. ARMYDA-9 CAROTID: Procedural features

  10. ARMYDA-9 CAROTID: Results (clopidogrel) Primary end-point 30-day incidence of TIA/stroke or new cerebral lesions % P=0.019 35.9 18

  11. ARMYDA-9 CAROTID: Results (clopidogrel)

  12. ARMYDA-9 CAROTID: Results (statin) Primary end-point 30-day incidence of TIA/stroke or new cerebral lesions % P=0.031 35 18.4

  13. ARMYDA-9 CAROTID: Results (statin)

  14. ARMYDA-9 CAROTID: MV analysis

  15. ARMYDA-9 CAROTID Event rates in the four groups according to clopidogrel/statin randomization P=0.004 30-day TIA/stroke or new cerebral lesions (%) 53.9 18 18.9 17.1 There was no interaction for the primary end-point between the clopidogrel dose and statin groups according to the factorial design (P=0.28)

  16. Conclusions • ARMYDA-9 CAROTID indicates that use of 600 mg clopidogrel loading dose reduces peri-procedural ischemic cerebral events and TIA/stroke rates at 30 days in patients with carotid disease undergoing stent implantation (58% RRR; NNT= 5.5) • The faster and more intense platelet suppression at the time of intervention provided by high dose clopidogrel load may prevent from distal embolization, protect microvascular bed and counterbalance the post-procedural pro-coagulant status • A short-term reload with high-dose atorvastatin significantly decreased cerebral events even in the background of chronic statin therapy (77% RRR; NNT=6) • Rapid, LDL-independent neuro-protective effects may be responsible of this atorvastatin benefit, by limiting peri-procedural micro-embolization and procedural injury • Drug therapy recommended in the Guidelines of carotid stenting procedures is mainly derived from interventional coronary pharmacology, whereas our study supplies evidence directly obtained in the specific setting of carotid intervention; results of ARMYDA-9 CAROTID may contribute to guide pharmacological management of carotid stenting

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