Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose (LOAD)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by Hospital do Coracao
Sponsor:
Information provided by (Responsible Party):
Instituto de Ensino e Pesquisa, Hospital do Coracao
ClinicalTrials.gov Identifier:
NCT01543555
First received: February 27, 2012
Last updated: August 22, 2014
Last verified: August 2014

February 27, 2012
August 22, 2014
November 2012
November 2017   (final data collection date for primary outcome measure)
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.
MACE [ Time Frame: 30 days ] [ Designated as safety issue: No ]
Cardiovascular mortality OR non-fatal myocardial infarction OR non-fatal stroke OR non-fatal cardiac arrest OR new-onset atrial fibrillation OR confirmed pulmonary embolism
Complete list of historical versions of study NCT01543555 on ClinicalTrials.gov Archive Site
  • 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
  • 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
  • Elevation of markers of myocardial necrosis [ Time Frame: 72hs ] [ Designated as safety issue: No ]
    Estimation of lesion to myocytes by: value of troponin T at 24hs, area under the curve (AUC) of troponin T over the first 72hs after surgery, peak value of troponin T during hospital stay
  • 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
  • Ultrasensitive PCR [ Time Frame: 72hs ] [ Designated as safety issue: No ]
    Substitute outcome for inflammation after surgery
  • 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 ]
    Myalgya as a substitute for rhabdomyolysis
  • Creatinine [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Substitute for renal dysfunction
  • Arrhythmia [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    New atrial fibrillation, new atrial flutter, new tachycardia requiring chemical or electrical cardioversion, new need for temporary or definitive pacemaker
  • PE/DVT [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    New pulmonary embolism or deep vein thrombosis diagnosed by the caring physician
  • Infection [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    New infection requiring antibiotics, as diagnosed by the caring physician
  • MI [ 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
Not Provided
Not Provided
 
Lowering the Risk of Operative Complications Using Atorvastatin Loading Dose
Multicenter Randomized Controlled Trial of Loading Dose Statins for the Prevention of Cardiovascular Complications in High-Risk Non-Cardiac Surgery

Patients undergoing some kinds of surgeries are at increased risk of developing a myocardial infarction and other serious cardiovascular complications during and after the procedure. Atorvastatin, a drug used to lower cholesterol levels, might reduce this risk. The objective of this study is to evaluate if starting atorvastatin as close as possible to surgery, but not longer than 18 hours ahead, and taking this drug for at least 7 days thereafter can reduce the risk of a composite end point of myocardial infarction, atrial fibrillation, stroke or death in the postoperative period.

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.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Myocardial Infarction
  • Peripheral Vascular Disease
  • Aortic Aneurism
  • Drug: Atorvastatin
    80mg atorvastatin before surgery, than 40mg atorvastatin 12hs after the loading dose, than 40mg atorvastatin every night for 7 days
    Other Names:
    • Liptor (R)
    • Kolevas (R)
  • Drug: Placebo
    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
  • 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.
    Intervention: Drug: Atorvastatin
  • 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.
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
2500
December 2017
November 2017   (final data collection date for primary outcome measure)

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:

  1. Major surgery;
  2. Emergency surgery;
  3. Previous history of heart failure;
  4. diabetes;
  5. Arterial hypertension;
  6. Smoking habit along the last two years;
  7. chronic kidney disease (creatinine greater than 2mg/dl);
  8. 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
Both
40 Years and older
No
Contact: Otávio DG Berwanger, MD, PhD +55 11 30536611 ext 8201 oberwanger@hcor.com.br
Contact: Dimas T Ikeoka, MD, PhD +55 11 30536611 ext 8239 dikeoka@hcor.com.br
Brazil
 
NCT01543555
02/15/2012
Yes
Instituto de Ensino e Pesquisa, Hospital do Coracao
Hospital do Coracao
Not Provided
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
Hospital do Coracao
August 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP