Strategies of Clopidogrel Load and Atorvastatin Reload - ARMYDA-9 CAROTID


A 600 mg load of clopidogrel has been shown to be superior to 300 mg in patients undergoing percutaneous coronary intervention (PCI). Similarly, periprocedural loading with high-dose statin has been shown to be beneficial in patients undergoing PCI, despite being on background statin therapy. The current trial sought to study the efficacy of 600 mg clopidogrel and high-dose statin in neuroprotection in patients undergoing carotid stenting.


A loading dose of 600 mg clopidogrel would be superior to 300 mg clopidogrel, and a periprocedural loading dose of 80 mg atorvastatin would be superior to no loading, in improving neurological outcomes in patients undergoing carotid stenting.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Factorial

Patient Populations:

  • Chronic statin therapy (>30 days)
  • >50% stenosis of the internal carotid artery detected by ultrasound or computed tomography scan in symptomatic patients or >60% stenosis in asymptomatic patients

    Number of enrollees: 156
    Duration of follow-up: 30 days
    Mean patient age: 72 years
    Percentage female: 24%


  • Previous disabling stroke (modified Rankin scale score ≥3 points)
  • Acute/subacute ischemic cerebral lesions at baseline MRI
  • Nonatherosclerotic carotid disease
  • Percutaneous intervention or surgery <30 days
  • Need for oral anticoagulant therapy
  • High risk of bleeding or contraindications to antiplatelet therapy (including platelet count <70 x 109/L)
  • Assumption of clopidogrel <10 days from randomization
  • Renal failure with serum creatinine >3 mg/dl or liver/muscle disease
  • Previous pacemaker implantation or claustrophobia

Primary Endpoints:

  • Thirty-day cumulative incidence of TIA/stroke or new ischemic lesions at cerebral DW-MRI performed 24-48 hours after carotid stenting

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 (hematoma >10 cm, pseudoaneurysm or arteriovenous fistula)

Drug/Procedures Used:

Clopidogrel-naïve patients on chronic statin therapy who were undergoing carotid stenting were randomized in a 2 x 2 factorial design to: 1) Loading with 300 mg or 600 mg of clopidogrel , and 2) Atorvastatin reload (80 mg 12 hours before intervention with further 40 mg dose 2 hours before) versus no statin reload. All procedures were performed via the femoral approach following a standard technique. The protocol recommended that a cerebral protection device should be mandatory. The type of protection device, the type of stent, and the strategies of intervention were left to the discretion of the operators.

Concomitant Medications:

  • Beta-blockers (45%)
  • Procedure: All patients were on long-term aspirin therapy (100 mg/day) and received intravenous 5000 IU of unfractionated heparin before the intervention.
  • Post-procedure: Atorvastatin 40 mg daily, aspirin 100 mg daily (indefinitely), clopidogrel 75 mg/day x 4 weeks

Principal Findings:

A total of 156 patients were randomized, 78 each to clopidogrel 600 mg versus 300 mg, and 76 to atorvastatin reload, and 80 to no reload. Baseline characteristics were fairly similar between the two arms. About 52% had diabetes mellitus, 24% had peripheral arterial disease, 43% had undergoce prior PCI, and 12% prior coronary artery bypass grafting. The majority of patients (86%) had asymptomatic carotid stenosis. Approximately 60% of the patients were on atorvastatin therapy at baseline. Median stenosis severity was 80%, and a thrombotic plaque was noted in 14% of the patients. A distal embolic protection device was utilized in 98% of the patients. The median stent diameter was 7.5 mm.

600 mg vs. 300 mg loading dose of clopidogrel: Thirty-day cumulative incidence of transient ischemic attack (TIA)/stroke or new ischemic lesions on cerebral diffusion-weighted magnetic resonance imaging (DW-MRI) was significantly lower in the 600 mg arm compared with the 300 mg arm (18% vs. 35.9%, p = 0.019). This was due to a reduction in both new TIA/stroke (0% vs. 9%, p = 0.02) and new ischemic lesions on MRI (18.0% vs. 33.3%, p = 0.044). The 30-day incidence of death/myocardial infarction/stroke was also numerically lower in the 600 mg clopidogrel arm (0% vs. 6.4%, p = 0.07). The incidence of vascular/bleeding complications was similar (6.4% vs. 10.3%, p = 0.56).

Loading vs. no loading dose of high-dose atorvastatin: Thirty-day cumulative incidence of TIA/stroke or new ischemic lesions on cerebral DW-MRI was significantly lower in the loading arm compared with the no loading arm (18.4% vs. 35.0%, p = 0.031). This was driven mostly due to a reduction in new ischemic lesions on MRI (17.1% vs. 33.8%, p = 0.028); 30-day incidence of TIA/stroke was similar (1.3% vs. 7.5%, p = 0.14). The incidence of vascular/bleeding complications was similar (7.9% vs. 8.8%, p = 0.92).

Although the formal test for interaction for the factorial design was negative, the lowest incidence of the primary endpoint was in patients who had received both 600 mg clopidogrel and high-dose atorvastatin prior to the procedure, and highest in those who received 300 mg clopidogrel and no loading dose of atorvastatin (18.9% vs. 53.9%, p = 0.004).


The results of the ARMYDA-9 CAROTID trial indicate that loading with 600 mg clopidogrel and high-dose atorvastatin in patients undergoing carotid stenting independently result in improved neurological outcomes; a strategy incorporating both medications seems to have the lowest incidence of adverse outcomes. The benefit of high-dose statin therapy was noted on a background of chronic statin therapy. These are very interesting results, and as such, easy and likely cost-effective, to adopt in routine practice.

One caveat is that the stroke incidences noted in the control arms of this trial were significantly higher than those noted in other contemporary trials on carotid stenting (2-3%). This may have thus biased the results towards a greater benefit in the active therapy arm. Confirmatory studies, as well as studies to elucidate exact mechanisms, are awaited.


Patti G, Tomai F, Melfi R, et al. Strategies of clopidogrel load and atorvastatin reload to prevent ischemic cerebral events in patients undergoing protected carotid stenting: results of the randomized ARMYDA-9 CAROTID study. J Am Coll Cardiol 2013;Mar 9:[Epub ahead of print].

Presented by Dr. Giuseppe Patti at ACC.13, San Francisco, March 9, 2013.

Clinical Topics: Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and Imaging, Interventions and Vascular Medicine, Magnetic Resonance Imaging

Keywords: Myocardial Infarction, Stroke, Ischemic Attack, Transient, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Arterial Disease, Ticlopidine, Heptanoic Acids, Constriction, Pathologic, Magnetic Resonance Imaging, Carotid Artery, Internal, Purinergic P2Y Receptor Antagonists, Stents, Percutaneous Coronary Intervention, Pyrroles, Embolic Protection Devices, Carotid Stenosis, Coronary Artery Bypass, Diabetes Mellitus

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