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

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 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: November 27, 2013
Last verified: November 2013

February 27, 2012
November 27, 2013
November 2012
November 2014   (final data collection date for primary outcome measure)
Major Adverse Cardiovascular Events (MACE) [ Time Frame: 7 days ] [ Designated as safety issue: No ]
Proportion of patients with non-lethal myocardial infarction or cardiovascular death during hospital stay up to 7 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: 7 days ] [ Designated as safety issue: Yes ]
    Elevation of AST and ALT after randomization
  • CPK [ Time Frame: 7 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
  • 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
  • VTE - Venous Thromboembolism [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Any deep vein thrombosis or pulmonary embolism confirmed by adequate images on ultrassound, computed tomography or angiography
  • Major bleeding [ Time Frame: 7 days ] [ Designated as safety issue: Yes ]
    Any non-traumatic retroperitoneal, intra-ocular, intra-medullary or intra-cranial bleeding in the first 48hs after surgery or any need for reoperation for hemosthasis.
  • Troponin levels [ Time Frame: 72hs ] [ Designated as safety issue: No ]
    Absolute values of troponin (I, T, hsI, hsT depending on the essay available in each center) once a day in the first 3 days after surgery. Surrogate for myocardial lesion.
  • 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 surgery 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 a few hours before surgery and taking this drug for at least another 7 days reduces the risk of suffering a myocardial infarction during surgery.

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. The primary objective of this study will be to test if introducing atorvastatin as a loading dose 3hs before surgery and maintaining it for another 7 days reduces the rates of myocardial infarction and cardiovascular death during hospital stay and up to 30 days after the procedure.

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 3-6h 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 3-6hs 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
    Intervention: Drug: Atorvastatin
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
7000
December 2014
November 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

Patients older than 45 years-old undergoing non-cardiac surgery with an expected hospital stay of at least 24hs and any one of the following criteria:

  1. Major vascular surgery
  2. All types of surgery in patients with overt atherosclerosis (any significant or symptomatic coronary, cerebral or peripheral artery disease)
  3. Intra-thoracic, intra-peritoneal or major orthopedic surgery and at least 2 additional risk factors for cardiovascular complications: emergency surgery, heart failure, diabetes, chronic kidney disease (creatinine greater than 2mg/dl), hypertension, age older than 70 y/o.

Exclusion Criteria:

  • Primary coronary intervention (PCI) or coronary artery bypass graft surgery in the last 5 or less years AND NO angina or NO ischemia on stress test (effort ECG, stress echocardiogram, stress scintigraphy)
  • Instability demanding immediate surgery, in which it is impossible to conduct the study intervention in a timely manner.
  • Previous intolerance to statins
  • Current rhabdomyolysis
  • Current use of statins
  • Severe Liver Failure (CHILD-PUGH SCORE C)
  • Breast-feeding or pregnancy
Both
45 Years and older
No
Contact: Otávio DG Berwanger, MD, PhD +55 11 30536611 ext 8201 oberwanger@hcor.com.br
Contact: Diogo DG Bugano, MD +55 11 30536611 ext 8237 dbugano@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
November 2013

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