Statin Neuroprotection and Carotid Endarterectomy: Safety, Feasibility and Outcomes (STANCE)

The investigators hypothesize that pre-operative statin use is neuroprotective at maximal doses. The goals are to determine the safety, feasibility, and efficacy of maximizing statin doses for two weeks (12-18 days) prior to CEA using change in performance on a battery neuropsychometric tests as outcome measure. Study will recruit patients based on their preexisting statin regimen.

The investigators hypothesize that in asymptomatic CEA patients: 1) Pre-operative statin use is neuroprotective against early cognitive dysfunction (eCD) and lowers the risk of early mortality. 2) Maximal doses may be essential in achieving optimal neuroprotection against eCD.

Study Overview

• Status: Completed
• Conditions: Carotid Artery Stenosis; Strokes
• Intervention / Treatment: Drug: Statin; Other: Placebo; Drug: Atorvastatin

Detailed Description

Carotid endarterectomy (CEA) is a common surgery performed to reduce the risk of stroke in patients with carotid artery narrowing. Statins, a class of drugs usually used to lower blood cholesterol, may protect the brain after surgery. Specific statins have been shown to protect the brain after surgery when compared to others. eCD affects about 25% of patients undergoing CEA and about 15% of undergoing asymptomatic CEA. It is associated with marked elevations in tissue markers of cerebral injury and is associated with earlier post-CEA mortality. This clinically significant, but subtle, cerebral injury is 10 times more common than stroke and its mechanism appears to be similarly related to regional hypoperfusion and ischemia. It is imperative to determine in a prospective randomized trial whether alteration/increase of preoperative statin regimens leads to improved neurologic outcome and an even lower incidence of stroke and possibly greater survival.

In order to optimally design and conduct such a trial it is critical to: 1) explore the safety and feasibility of altering statin regimen acutely (approximately 2 weeks) before CEA, and 2) clearly establish the neuroprotective outcome of an acute alteration in statin regimen. This would promote a better understanding of statin neuroprotection in humans and determine the statin treatment that affords the most neuroprotection in patients undergoing one of the most commonly performed procedures in the US.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Ridgewood, New Jersey, United States, 07450
      • Valley Hospital
  • New York
    • Albany, New York, United States, 12208-3479
      • Albany Medical College/The Vascular Group at Albany
    • Buffalo, New York, United States, 14260-7016
      • State University of New York at Buffalo
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016-6402
      • New York University School of Medicine
    • New York, New York, United States, 10065-4805
      • Cornell University Medical College (Weill)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 18 years of age.
2. Patient is currently on atorvastatin or simvastatin or rosuvastatin or statin naïve (no statins in the last 30 days).

3. The patient has unilateral or bilateral carotid artery stenosis that is considered severe (carotid artery diameter reduction ≥ 70%) as defined by:

   1. Peak systolic velocity of at least 230 cm/s plus at least one of these:
   2. End diastolic velocity ≥ 100 cm/s OR
   3. CTA showing ≥ 70% stenosis OR
   4. MRA showing ≥ 70% stenosis
4. This stenosis has not caused any stroke, transient cerebral ischemia, or other relevant neurological symptoms in the past.
5. The patient's attending doctor(s) (PMD, cardiologist, vascular/neurosurgeon) AND the patient have decided to proceed with a CEA to treat the patient's severe carotid stenosis.
6. The patient has no known circumstance or condition likely to preclude 1 year follow-up or adherence to the study protocol.
7. The patient is independent in their Activities of Daily Living at baseline.
8. Patient has the ability to provide informed consent.

Exclusion Criteria:

1. Patient has underlying disease other than atherosclerosis (i.e. autoimmune disease, known active malignancy).
2. Patient has documented dementia or screens out based on abnormal Baseline MoCA (≤25) and AD8 (≥2).
3. Patient's life expectancy is < 12 months.
4. Patient has advanced renal failure (serum creatinine > 2.5 mg/dL)
5. Patient has evidence of severe congestive heart failure or has history of end-stage cardiovascular disease (e.g. CHF NYHA Class III or IV or unstable angina).
6. Patient has history of intolerance or allergic reaction to any statins (myotoxicity, hepatic dysfunction, rash, etc.)
7. Patient has received an investigational drug within 30 days.
8. Patient is pregnant or lactating.

9. Patient is currently taking any of the following which have been shown to interact with atorvastatin and/or simvastatin and/or rosuvastatin (as per current drug package inserts):

   • Cyclosporine;
   • HIV Protease Inhibitors/Antivirals (e.g. rotanavir or plus rotanavir, tipranavir, lopinavir, boceprevir, saquinovir, darunavir, fosamprenavir, nelfinavir, efavirenz/tenofobir, atazanavir, simeprevir);
   • Hep C Protease Inhibitor/Antivirals (e.g. telapravir);
   • Antibiotics (i.e. cobicistat-containing products like Tybost, rifampin/rifampicin, clarithromycin, telithromycin, erythromycin);
   • Anti-fungals (i.e. itraconazole, ketoconazole, posaconazole, voriconazole, fluconazole); *Gemfibrozil; Other Fenofibrates (e.g. Tricor, fibric acid);
   • Niacin > 1g/day or statins in combination with niacin (e.g. Vytorin, Simcor);
   • Colchicine;
   • Danazol;
   • Calcium Channel Blockers: Diltiazem, Varapamil;
   • Dronedarone;
   • Amiodarone;
   • Digoxin;
   • Ranolazine;
   • Nefazodone;
   • Warfarin/Coumadin;
   • Lomitapide;
   • Grapefruit juice > 1.2 liters/day (40.5 ounces/day).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Observational - Maximal Dose - ARM 1; Patients on a pre-existing maximal dose of either Simvastatin (40mg) with/without currently taking amlodipine (Norvasc) and those on Simvastatin 20mg while currently on amlodipine; Atorvastatin (80mg), or Rosuvastatin (20mg) regimen will be observed for ~2 weeks before their CEA.
Experimental: Less Than Maximal Dose - ARM 2; Patients on a pre-existing statin regimen at a lower dose (less than maximal) of Simvastatin <40mg without amlodipine and <20mg with amlodipine; Atorvastatin (<80mg) or Rosuvastatin (<20mg) will be randomized to maintain their current dose plus placebo or be increased to the maximal dose of their current statin for ~2 weeks before their CEA.	Drug: Statin; Standard of care treatment (one of four): Simvastatin (to 40mg without amlodipine); Simvastatin (to 20 mg if currently on amlodipine); Atorvastatin (to 80mg); Rosuvastatin (to 20mg); Other Names: Pre-existing statin regimen; Other: Placebo; A placebo pill will be used for patients that are to maintain their current dose of statins prior to their CEA.; Other Names: Sugar pill
Experimental: Statin Naive - ARM 3; Patients on no pre-existing statin regimen will be randomized to Atorvastatin 10 mg or Atorvastatin 80 mg for ~2 weeks before their CEA	Drug: Atorvastatin; A lipid-lowering agent and for prevention of events associated with cardiovascular disease. 10 mg or 80 mg capsules; Other Names: Lipitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of eCD	Neurocognitive assessments ≥2SD worse than reference group in two or more cognitive domains or (b) ≥1.5SD worse than the reference group in all cognitive domains.	30 Days: 1) Pre-op vs. Post-CEA Day 1 (12-25 hrs post-op) and 2) Pre-op vs. Post-CEA Day 30

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of early mortality	Data will be collected by follow up phone call	1 year

Collaborators and Investigators

• Sponsor: Columbia University
• Investigators: Principal Investigator: Edward S Connolly, MD, FACS, Columbia University Medical Center/New York Presbyterian; Study Director: Eric Heyer, MD, Ph.D., Columbia University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2017
• Primary Completion (Actual): February 23, 2022
• Study Completion (Actual): February 23, 2022

Study Registration Dates

• First Submitted: July 27, 2016
• First Submitted That Met QC Criteria: July 27, 2016
• First Posted (Estimate): July 29, 2016

Study Record Updates

• Last Update Posted (Actual): November 4, 2022
• Last Update Submitted That Met QC Criteria: November 1, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: stroke; Carotid endarterectomy; CEA; asymptomatic stenosis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Arterial Occlusive Diseases; Carotid Artery Diseases; Carotid Stenosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Other Study ID Numbers: AAAM2407

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No