Statin Neuroprotection and Carotid Endarterectomy: Safety, Feasibility and Outcomes

NCT ID: NCT02850081

Last Updated: 2022-11-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-01
• Study Completion Date: 2022-02-23

Brief Summary

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.

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.

Conditions

Carotid Artery Stenosis; Strokes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: NO_INTERVENTION

No interventions assigned to this group

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.

Group Type: EXPERIMENTAL

Statin

Intervention Type: DRUG

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)

Placebo

Intervention Type: OTHER

A placebo pill will be used for patients that are to maintain their current dose of statins prior to their CEA.

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

Group Type: EXPERIMENTAL

Atorvastatin

Intervention Type: DRUG

A lipid-lowering agent and for prevention of events associated with cardiovascular disease.

10 mg or 80 mg capsules

Interventions

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)

Intervention Type: DRUG

Atorvastatin

A lipid-lowering agent and for prevention of events associated with cardiovascular disease.

10 mg or 80 mg capsules

Intervention Type: DRUG

Placebo

A placebo pill will be used for patients that are to maintain their current dose of statins prior to their CEA.

Intervention Type: OTHER

Other Intervention Names

Pre-existing statin regimen; Lipitor; Sugar pill

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Columbia University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Edward S Connolly, MD, FACS

Role: PRINCIPAL_INVESTIGATOR

Columbia University Medical Center/New York Presbyterian

Eric Heyer, MD, Ph.D.

Role: STUDY_DIRECTOR

Columbia University

Locations

Valley Hospital

Ridgewood, New Jersey, United States

Albany Medical College/The Vascular Group at Albany

Albany, New York, United States

State University of New York at Buffalo

Buffalo, New York, United States

New York University School of Medicine

New York, New York, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

Cornell University Medical College (Weill)

New York, New York, United States

Countries

United States

Other Identifiers

AAAM2407

Identifier Type: -

Identifier Source: org_study_id