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

• ClinicalTrials.gov Identifier: NCT01543555
• Recruitment Status: Completed
• First Posted: March 5, 2012
• Last Update Posted: December 31, 2015
• Sponsor: Hospital do Coracao
• Information provided by (Responsible Party): Instituto de Ensino e Pesquisa, Hospital do Coracao

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Myocardial Infarction; Peripheral Vascular Disease; Aortic Aneurism	Drug: Atorvastatin; Drug: Placebo	Phase 3

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 648 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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
• Study Start Date: November 2012
• Actual Primary Completion Date: June 2015
• Actual Study Completion Date: June 2015

Arms and Interventions

Arm	Intervention/treatment
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.	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)
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.	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

Outcome Measures

Primary Outcome Measures :

1. Composite outcome [ Time Frame: 30 days ]
   Composite of all-cause mortality, nonfatal myocardial injury after noncardiac surgery and stroke at 30 days.

Secondary Outcome Measures :

1. All-cause mortality [ Time Frame: 30 days ]
   Death from any cause.
2. Myocardial injury after noncardiac surgery (MINS) [ Time Frame: 30 days ]
   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).
3. Stroke [ Time Frame: 30 days ]
   New neurologic symptom with compatible lesion on brain imaging and confirmation by a neurologist of the diagnosis of stroke.
4. Myocardial infarction [ Time Frame: 30 days ]
   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
5. Cardiovascular death [ Time Frame: 30 days ]
   Evidence of death primarily caused by one of the following: acute myocardial infarction, stroke, pulmonary embolism, heart failure or ventricular arrhythmias.
6. Pulmonary embolism [ Time Frame: 30 days ]
   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.
7. Deep venous thrombosis [ Time Frame: 30 days ]
   Any signs or symptoms of deep vein thrombosis confirmed by adequate images on ultrasound, computed tomography or angiography
8. Clinically relevant atrial fibrillation [ Time Frame: 30 days ]
   A newly diagnosed atrial fibrillation that results in angina, heart failure, hypotension, or that requires treatment with an anti-arrhythmic drug or electric cardioversion
9. Rhabdomyolysis [ Time Frame: 30 days ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Brazil

Hospital do Coração

São Paulo, SP, Brazil, 04005-000

Sponsors and Collaborators

Hospital do Coracao

Investigators

• Study Chair: Otávio Berwanger, MD, PhD; Hospital do Coração
• Study Chair: Renato D Lopes, MD Phd; Brazilian Clinical Research Institute

More Information

Publications:

POISE Study Group, Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Málaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008 May 31;371(9627):1839-47. doi: 10.1016/S0140-6736(08)60601-7. Epub 2008 May 12.

Kapoor AS, Kanji H, Buckingham J, Devereaux PJ, McAlister FA. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ. 2006 Dec 2;333(7579):1149. Epub 2006 Nov 6. Review.

Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leão P, Caramelli B. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg. 2004 May;39(5):967-75; discussion 975-6.

Dunkelgrun M, Boersma E, Schouten O, Koopman-van Gemert AW, van Poorten F, Bax JJ, Thomson IR, Poldermans D; Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV). Ann Surg. 2009 Jun;249(6):921-6. doi: 10.1097/SLA.0b013e3181a77d00.

Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR, Verhagen HJ, Khan NA, Dunkelgrun M, Bax JJ, Poldermans D; Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009 Sep 3;361(10):980-9. doi: 10.1056/NEJMoa0808207.

Patti G, Cannon CP, Murphy SA, Mega S, Pasceri V, Briguori C, Colombo A, Yun KH, Jeong MH, Kim JS, Choi D, Bozbas H, Kinoshita M, Fukuda K, Jia XW, Hara H, Cay S, Di Sciascio G. Clinical benefit of statin pretreatment in patients undergoing percutaneous coronary intervention: a collaborative patient-level meta-analysis of 13 randomized studies. Circulation. 2011 Apr 19;123(15):1622-32. doi: 10.1161/CIRCULATIONAHA.110.002451. Epub 2011 Apr 4.

• Responsible Party: Instituto de Ensino e Pesquisa, Research Institute HCor, Hospital do Coracao
• ClinicalTrials.gov Identifier: NCT01543555
• Other Study ID Numbers: 02/15/2012
• First Posted: March 5, 2012
• Last Update Posted: December 31, 2015
• Last Verified: December 2015

Keywords provided by Instituto de Ensino e Pesquisa, Hospital do Coracao:

myocardial infarction; statin; perioperative care; peripheral vascular diseases; anesthesiology

Additional relevant MeSH terms:

Myocardial Infarction; Aneurysm; Aortic Aneurysm; Vascular Diseases; Peripheral Vascular Diseases; Peripheral Arterial Disease; Infarction; Ischemia; Pathologic Processes; Necrosis; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Aortic Diseases; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases; Atorvastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors