Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD)
Peripheral Vascular Disease
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
|Official Title:||Multicenter Randomized Controlled Trial of Loading Dose Statins for the Prevention of Cardiovascular Complications in High-Risk Non-Cardiac Surgery|
- Major Adverse Cardiovascular Events (MACE) [ Time Frame: 30 days ] [ Designated as safety issue: No ]Proportion of patients with non-lethal myocardial infarction, atrial fibrilation, stroke or death during hospital stay up to 30 days.
- Cardiovascular mortality [ Time Frame: 30 days ] [ Designated as safety issue: No ]Mortality attributed to progression of cardiovascular diseases or sudden death in an otherwise healthy subject
- Stroke [ Time Frame: 30 days ] [ Designated as safety issue: No ]New neurologic symptom with compatible lesion on brain imaging and confirmation by a neurologist of the diagnosis of stroke
- Liver enzymes [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]Elevation of AST and ALT after randomization
- CPK [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]Elevation of CPK after randomization, as a substitute for rhabdomyolysis
- Myalgia [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]Myalgia as a substitute for rhabdomyolysis
- Myocardial infarction [ Time Frame: 30 days ] [ Designated as safety issue: No ]Rate of myocardial infarction as defined by any 2 of: typical chest pain OR typical ECG changes (ST-segment depression, ST-segment elevation, new Q waves, transitory T wave inversion) OR new rise in troponin levels (CK-MB levels if unavailable) OR new wall motion abnormality on echocardiogram. Pathological confirmation of myocardial necrosis on necropsy will also be accepted
- VTE - Venous Thromboembolism [ Time Frame: 30 days ] [ Designated as safety issue: No ]Any deep vein thrombosis or pulmonary embolism confirmed by adequate images on ultrasound, computed tomography or angiography
- Major bleeding [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]Any non-traumatic retro peritoneal, intraocular, intramedullary or intracranial bleeding in the first 48 hours after surgery or any need for re-operation for hemosthasis.
- Troponin levels [ Time Frame: 72hs ] [ Designated as safety issue: No ]Absolute values of troponin (I, T, hsI, hsT depending on the assay available in each center) once a day in the first 3 days after surgery. Surrogate for myocardial lesion.
- Clinically relevant atrial fibrillation [ Time Frame: 30 days ] [ Designated as safety issue: No ]A newly diagnosed atrial fibrillation that results in angina, heart failure, hypotension, or that requires treatment with an anti-arrhythmic drug or electric cardioversion
|Study Start Date:||November 2012|
|Estimated Study Completion Date:||December 2017|
|Estimated Primary Completion Date:||November 2017 (Final data collection date for primary outcome measure)|
Experimental: Atorvastatin active
Loading dose atorvastatin (80mg) given to the patient as close as possible to the procedure, but not longer than 18 hours before. A second dose (40mg) of atorvastatin at least 12 hours after the loading dose. Daily doses of atorvastatin (40mg) initiated in the next day after the second dose, and maintained for the following seven days.
80mg atorvastatin before surgery, than 40mg atorvastatin 12hs after the loading dose, than 40mg atorvastatin every night for 7 days
Placebo Comparator: Placebo
Loading dose of matching placebo given to the patient as close as possible to the procedure, but not longer than 18 hours before. A second dose of matching placebo at least 12 hours after the loading dose. Daily doses of matching placebo initiated in the next day after the second dose, and maintained for the following seven days.
80mg placebo capsule before surgery, 40mg placebo capsule 12hs after the loading dose, 40mg placebo capsule every night for 7 days
Other Name: Standard care
Cardiovascular complications, such as myocardial infarction (MI) and stroke are common in non-cardiac surgery, with mean incidences of 7% for high-risk patients. Despite a significant reduction of 30% in the rates of MI, beta-blockers have been associated with a prohibitive 117% increase in the risk of stroke in this situation. Since the evidence supporting the use of aspirin, calcium-channel blockers and clonidine is also weak, it is still unclear whether pharmacologic interventions are effective in this population.
Data from observational studies have shown that chronic users of statins have a 20%-30% lower incidence of periprocedural MI and 3 prospective randomized controlled trials (RCTs) have shown a 48% risk reduction for the initiation of statins 30 days before surgery. However, this intervention demands a 1-month delay in the procedure, which makes it unfeasible in many situations, such as emergency.
Experimental data show that statins have acute anti-inflammatory properties, which promote the stabilization of atherosclerotic lesions and, therefore, might reduce the risk of MI even after shorter use. A single loading dose of statins as early as 12hs before the procedure has been associated with a 44% reduction in the rate of MI in patients undergoing elective percutaneous coronary intervention (PCI), making it a promising intervention for patients undergoing non-cardiac surgery. This study was designed to test the effectiveness of atorvastatin started before a non-cardiac surgery on the reduction of perioperative cardiovascular events.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01543555
|Contact: Otávio DG Berwanger, MD, PhD||+55 11 30536611 ext firstname.lastname@example.org|
|Contact: Dimas T Ikeoka, MD, PhD||+55 11 30536611 ext email@example.com|
|Hospital do Coração||Recruiting|
|São Paulo, SP, Brazil, 04005-000|
|Contact: Otavio Berwanger, MD, PhD 3053-6611 ext 8237 firstname.lastname@example.org|
|Contact: Dimas T Ikeoka, MD, PhD 3053-6611 ext 8239 email@example.com|
|Principal Investigator: Otávio Berwanger, MD, PhD|
|Study Director:||Otávio Berwanger, MD, PhD||Hospital do Coração|
|Principal Investigator:||Diogo DG Bugano, MD||Hospital do Coração|
|Study Chair:||Rafael M Soares, MSc||Hospital do Coração|
|Study Director:||Renato D Lopes, MD Phd||Brazilian Clinical Research Institute|
|Principal Investigator:||Sabrina B Pereira, MD, MSc||Hospital do Coração, SP|
|Principal Investigator:||Dimas T Ikeoka, MD, Post-Doc||Hospital do Coração, SP|