Statin Neuroprotection and Carotid Endarterectomy: Safety, Feasibility and Outcomes "STANCE"

Recruiting

Phase 3 Results N/A

Update History

7 Jun '17
Trial acronym was updated.
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STANCE
Trial name was updated.
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Statin Neuroprotection and Carotid Endarterectomy: Safety, Feasibility and Outcomes
The Summary of Purpose was updated.
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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.
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The investigators hypothesizes 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 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.
The description was updated.
New
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.
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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 (2 weeks) before CEA, and 2) clearly establish the neuroprotective outcome of an acute alternation 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.
The gender criteria for eligibility was updated to "All."
The eligibility criteria were updated.
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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).
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Inclusion Criteria: - asymptomatic for neurologic events (stroke and transient ischemic attack) Exclusion Criteria: - medically unstable defined as unstable angina - myocardial infarction within 3 months - unable to provide informed consent
A location was updated in Ridgewood.
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The overall status was updated to "Not yet recruiting" at Valley Hospital.
A location was updated in Buffalo.
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The overall status was updated to "Not yet recruiting" at State University of New York at Buffalo.
A location was updated in New York.
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The overall status was updated to "Not yet recruiting" at Cornell University Medical College (Weill).
3 Aug '16
The Summary of Purpose was updated.
New
The investigators hypothesizes 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 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.
Old
The investigator hypothesizes 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 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. We 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.
The description was updated.
New
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 (2 weeks) before CEA, and 2) clearly establish the neuroprotective outcome of an acute alternation 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.
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CEA reduces the risk of future stroke in this patient population by 55-65%, but its effectiveness is dependent on very low peri-operative morbidity, especially in patients presenting with asymptomatic disease. Recent improvements in the medical management of patients with asymptomatic stenosis have improved the outcome for un-operated patients to such a degree that some have even questioned whether the benefits of asymptomatic CEA still justify its risks. The rate of peri-operative stroke has fallen precipitously over the same period to less than 1.5%. It is critical that peri-operative management continue to evolve if the neuroprotective effects of CEA are to be realized for all CEA patients. Given that post-CEA stroke is so rare, investigators have increasingly looked to subtler, although more common, forms of cerebral injury to inform treatment decisions and improve procedural safety. eCD affects ~25% of patients undergoing CEA and ~15% of undergoing asymptomatic CEA. It is associated with marked elevations in tissue markers of cerebral injury (S100B) and is associated with earlier post-CEA mortality (1-3). 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. We now have data that pre-operative statin use is not only associated with a reduction in peri-operative clinical stroke, but a 50% reduction in eCD(4). While no patient taking statins actually suffered a stroke, the rate of eCD varied dramatically among both statin type and dose. In fact, in looking at the incidence of eCD in those taking the two most commonly prescribed agents (80% of patients), simvastatin use was associated with significantly less eCD than atorvastatin(5).This difference was observed at all doses with the exception of high dose atorvastatin (80mg), which provided similar neuroprotection as high dose simvastatin (40mg). We also observed that statin use was associated with less risk of early mortality that appears to be completely related to its effect on eCD, supporting the contention that statins not only protect against injury, but may be involved in injury repair as has been shown previously in animals(6,7). As >50% of patients are on a lower dose statin regimen, it is imperative that we 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 that we: 1) explore the safety and feasibility of altering statin regimen acutely (2 weeks) before CEA, and 2) clearly establish the neuroprotective outcome of an acute alternation in statin regimen.If we can do this, we will be well on our way to achieving our ultimate goal of better understanding statin neuroprotection in humans and determining the statin treatment that affords the most neuroprotection in patients undergoing one of the most commonly performed procedures in the US.Further support for our study purpose, based on IRB inquiry: In our previous work, we have evaluated a cohort of asymptomatic CEA patients and regardless of statin dose or type, we found that ~20% of patients' not on statins had cognitive dysfunction compared to 11% of patients on statins. This statistic alone leads us to believe that while a higher dose may be "more neuroprotective", any statin therapy at all will be beneficial to a patient undergoing CEA, and should become standard of care. Although we have evidence to demonstrate the efficacy of statin neuroprotection in CEA, the aim of this study is to reconfirm this and indicate that statin use should be a standard of care preoperatively. We do not have a dose response curve and are guessing that a high dose is most beneficial. The purpose of this study is to show that. In addition, patients in the first arm of the study who are already on the high dose will be maintained, so no discrepancies there. Patients in the second arm of the study, having already been started on statins, will just maintain the original regimen deemed appropriate by their prescribing physician or a high dose, which we hope to demonstrate will reduce the incidence of cognitive dysfunction. Regardless of the randomization, they will be on a dose considered to be suitable for them and we believe they will experience sufficient neuroprotection perioperatively. As for the third arm of this study, while we would have liked to randomize patients not already on a statin, to placebo or high dose atorvastatin, we think that providing a low dose may be sufficient. There is no evidence of the most effective dose of atorvastatin or any statin to provide increased benefit. These patients not already on statin therapy to begin in the 2 week pre-operative period will afford significantly greater protection than going into CEA without statin therapy. As no patients in this study will be entirely without statin therapy, we feel the benefit of a statin in general (versus no statin) greatly outweighs the issue of optimal (versus sub-optimal) dose.