Carotid Artery Stenosis, Strokes
Conditions
Keywords
Carotid endarterectomy, CEA, stroke, asymptomatic stenosis
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.
Interventions
DRUGStatin
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)
DRUGAtorvastatin
A lipid-lowering agent and for prevention of events associated with cardiovascular disease. 10 mg or 80 mg capsules
OTHERPlacebo
A placebo pill will be used for patients that are to maintain their current dose of statins prior to their CEA.
Sponsors
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of eCD | 30 Days: 1) Pre-op vs. Post-CEA Day 1 (12-25 hrs post-op) and 2) Pre-op vs. Post-CEA Day 30 | 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. Due to early study termination and limited sample size, the study was not adequately powered to support inferential statistical comparisons. Therefore, outcome data are presented descriptively without formal statistical testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Prevalence of Early Mortality | 1 year | Data will be collected by follow up phone call. Due to early study termination and limited sample size, the study was not adequately powered to support inferential statistical comparisons. Therefore, outcome data are presented descriptively without formal statistical testing. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATOREdward S Connolly, MD, FACS
Columbia University Medical Center/New York Presbyterian
STUDY_DIRECTOREric Heyer, MD, Ph.D.
Columbia University
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 0 - 7 years old | 0 Participants |
| Age, Customized 18 - 65 years old | 7 Participants |
| Age, Customized > 65 years old | 24 Participants |
| Age, Customized 8 - 17 years old | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 6 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 0 / 12 | 0 / 6 | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 12 | 0 / 6 | 0 / 2 | 0 / 2 |
Outcome results
None listed