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

This study has been completed.
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: December 30, 2015
Last verified: December 2015

February 27, 2012
December 30, 2015
November 2012
June 2015   (final data collection date for primary outcome measure)
Composite outcome [ Time Frame: 30 days ] [ Designated as safety issue: No ]
Composite of all-cause mortality, nonfatal myocardial injury after noncardiac surgery and stroke at 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
  • All-cause mortality [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Death from any cause.
  • Myocardial injury after noncardiac surgery (MINS) [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    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).
  • Stroke [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    New neurologic symptom with compatible lesion on brain imaging and confirmation by a neurologist of the diagnosis of stroke.
  • Myocardial infarction [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    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
  • Cardiovascular death [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    Evidence of death primarily caused by one of the following: acute myocardial infarction, stroke, pulmonary embolism, heart failure or ventricular arrhythmias.
  • Pulmonary embolism [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    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.
  • Deep venous thrombosis [ Time Frame: 30 days ] [ Designated as safety issue: No ]
    Any signs or symptoms of deep vein thrombosis confirmed by adequate images on ultrasound, computed tomography or angiography
  • 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
  • Rhabdomyolysis [ Time Frame: 30 days ] [ Designated as safety issue: Yes ]
    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.
  • 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
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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 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.

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.

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
    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.
    Other Names:
    • Liptor (R)
    • Kolevas (R)
  • Drug: Placebo
    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.
    Other Name: Standard care
  • Experimental: Atorvastatin active
    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.
    Intervention: Drug: Atorvastatin
  • Placebo Comparator: Placebo
    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.
    Intervention: Drug: Placebo

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
648
June 2015
June 2015   (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 information is only displayed when the study is recruiting subjects
Brazil
 
NCT01543555
02/15/2012
Yes
Not Provided
Not Provided
Instituto de Ensino e Pesquisa, Hospital do Coracao
Hospital do Coracao
Not Provided
Study Chair: Otávio Berwanger, MD, PhD Hospital do Coração
Study Chair: Renato D Lopes, MD Phd Brazilian Clinical Research Institute
Hospital do Coracao
December 2015

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