Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose

Study Overview
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Brief Summary
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Patients submitted to noncardiac surgeries are at increased risk of serious cardiovascular complications. Statins have shown to lower cholesterol levels and reduce cardiovascular events in other scenarios. The objective of this study is to explore the effects of atorvastatin, as compared with placebo, on the 30-day risk of a composite of death, nonfatal Myocardial Injury after Noncardiac Surgery (MINS), or stroke among patients who undergo noncardiac surgery.

Detailed Description
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Cardiovascular complications, such as myocardial infarction (MI) and stroke are common in the perioperative period of noncardiac surgeries. To the moment there are no safe and effective interventions to reduce vascular events in this scenario. Data from observational studies and small-sized randomized controlled trials (RCTs) have shown promising results in terms of risk reduction. In addition, experimental data have indicated that statins have acute anti-inflammatory properties, which promote the stabilization of atherosclerotic lesions and, therefore, might reduce the risk of MI, even in the short term. This study was designed to explore the effects of atorvastatin, as compared with placebo, on the 30-day risk of a composite of death, nonfatal Myocardial Injury after Noncardiac Surgery (MINS), or stroke among patients who undergo noncardiac surgery. The study was conducted in accordance with the prespecified protocol and reached successful enrollment rates when, by the end of 2014 the steering committee was invited to join an international initiative and participate in a much larger clinical trial to investigate this relevant question. Due to this outstanding possibility, the steering committee decided to redesign the study which is now formatted as an exploratory trial. As described, the study was completed with the inclusion of 648 participants in June, 2015.

Official Title
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Multicenter Randomized Controlled Trial of Loading Dose Statins for the Prevention of Cardiovascular Complications in High-Risk Non-Cardiac Surgery

Conditions
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Myocardial Infarction, Peripheral Vascular Disease, Aortic Aneurism

Intervention / Treatment
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* Drug: Atorvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients older than 40 years-old undergoing non-cardiac surgery with an expected hospital stay of at least 24hs and that fulfills any one of the following criteria: A) Established vascular disease: i) Major vascular surgery ii) All types of surgery in patients with overt atherosclerosis (any significant or symptomatic coronary, cerebral or peripheral artery disease) B) Without established vascular disease: At least 3 risk factors for cardiovascular complications: Major surgery; Emergency surgery; Previous history of heart failure; diabetes; Arterial hypertension; Smoking habit along the last two years; chronic kidney disease (creatinine greater than 2mg/dl); Patients older than 70 years. Exclusion Criteria: Previous intolerance to statins Current rhabdomyolysis Current use of statins Severe Liver Failure (CHILD-PUGH SCORE C) Breast-feeding or pregnancy Low-risk surgeries

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atorvastatin active<br>Atorvastatin 80mg anytime within 18 hours before surgery. A postoperative 40mg atorvastatin dose administered at least 12 hours after the 80mg loading dose. Subsequently, 40mg atorvastatin daily for the next seven days. | Drug: Atorvastatin<br>* Atorvastatin 80mg anytime within 18 hours before surgery. A postoperative 40mg atorvastatin dose administered at least 12 hours after the 80mg loading dose. Subsequently, 40mg atorvastatin daily for the next seven days.<br>* Other names: Kolevas (R);|
| Placebo Comparator: Placebo<br>Matching placebo 80mg anytime within 18 hours before surgery. A postoperative 40mg placebo dose administered at least 12 hours after the 80mg loading dose. Subsequently, 40mg placebo daily for the next seven days. | Drug: Placebo<br>* Matching placebo 80mg anytime within 18 hours before surgery. A postoperative 40mg matching placebo dose administered at least 12 hours after the 80mg loading dose. Subsequently, 40mg placebo daily for the next seven days.<br>* Other names: Standard care;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome | Composite of all-cause mortality, nonfatal myocardial injury after noncardiac surgery and stroke at 30 days. | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality | Death from any cause. | 30 days | 
| Myocardial injury after noncardiac surgery (MINS) | An elevated cardiac troponin measurement judged due to cardiac ischemia (i.e., there was no evidence of a non-ischemic etiology like sepsis or pulmonary embolism). | 30 days | 
| Stroke | New neurologic symptom with compatible lesion on brain imaging and confirmation by a neurologist of the diagnosis of stroke. | 30 days | 
| Myocardial infarction | 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 | 30 days | 
| Cardiovascular death | Evidence of death primarily caused by one of the following: acute myocardial infarction, stroke, pulmonary embolism, heart failure or ventricular arrhythmias. | 30 days | 
| Pulmonary embolism | Clinical signs accompanied by high-probability ventilation-perfusion lung scan or a filling defect of the pulmonary artery or its branches in a conventional arteriography or multi-slice spiral tomography. | 30 days | 
| Deep venous thrombosis | Any signs or symptoms of deep vein thrombosis confirmed by adequate images on ultrasound, computed tomography or angiography | 30 days | 
| Clinically relevant atrial fibrillation | A newly diagnosed atrial fibrillation that results in angina, heart failure, hypotension, or that requires treatment with an anti-arrhythmic drug or electric cardioversion | 30 days | 
| Rhabdomyolysis | elevation of CPK levels higher than 5 times the normal upper limit and myalgia or any CPK elevation higher than 10 times the upper limit, regardless of symptoms. | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myocardial infarction, statin, perioperative care, peripheral vascular diseases, anesthesiology