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Assessing the Role of "Statin" Therapy and Perioperative Inflammatory Response in Patients Undergoing Major Orthopedic Surgery

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Michael Brown, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00656292
First received: April 4, 2008
Last updated: April 10, 2017
Last verified: April 2017
  Purpose

The purpose of the present study is to quantify the degree of modulation, if any, in the perioperative inflammatory response associated with statins use. Specifically, we hypothesize that:

In a population of patients undergoing elective orthopedic spine surgery, administration of a specific statin (Simvastatin, Zocor®, Merck Pharmaceuticals), will be associated with a decrease in perioperative inflammatory markers when compared to patients not taking statins


Condition Intervention Phase
Perioperative Inflammatory Response
Drug: Simvastatin
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Care Provider
Primary Purpose: Treatment
Official Title: Perioperative HMG-CoA-Reductase-Inhibitors: A Pilot Study Assessing the Role of "Statin" Therapy and Perioperative Inflammatory Response in Patients Undergoing Major Orthopedic Surgery

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Median Concentration of Aspartate Aminotransferase (AST) [ Time Frame: baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs ]
    Description: AST is an enzyme found in high amounts in liver, heart, and muscle cells. This test is mainly done along with other tests such as alkaline phosphatase and bilirubin to diagnose and monitor liver disease. This test evaluates hepatocyte integrity, as serum levels of this enzyme rise in response to a variety of forms of injury to hepatic cells. The normal range is 10 to 40 U/L.


Secondary Outcome Measures:
  • Median Concentration of Alanine Aminotransferase (ALT) [ Time Frame: baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs ]
    An enzyme normally present in liver and heart cells that is released into the bloodstream when the liver or heart is damaged. The blood ALT levels are elevated with liver damage (for example, from viral hepatitis) or with an insult to the heart (for example, from a heart attack). The normal range is 7 to 56 U/L.

  • Median Concentration of C-Reactive Protein (CRP) [ Time Frame: baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs ]
    C-reactive protein (CRP) is a substance produced by the liver in response to inflammation. Normal CRP levels are below 3.0 mg/L.

  • Median Concentration of Creatine Kinase (CK) [ Time Frame: baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs ]
    A creatine kinase test may be used to detect inflammation of muscles or muscle damage due to muscle disorders. A person may have muscle injury with few or nonspecific symptoms, such as weakness, fever, and nausea, that may also be seen with a variety of other conditions. A healthcare practitioner may use a CK test to help detect muscle damage in these cases, especially if someone is taking a drug such as a statin. Normal values at rest are usually between 60 and 174 IU/L.

  • Median Concentration of Interleukin-6 (IL-6) [ Time Frame: baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs ]
    Interleukin-6 (IL-6) may be used to help evaluate a person who has a condition associated with inflammation, such as lupus or rheumatoid arthritis, or with infection, such as sepsis. It may also be used in the evaluation of diabetes or cardiovascular disease. IL-6 is a cytokine, a protein produced by immune cells that acts on other cells to help regulate and/or promote an immune response. It also stimulates the production of acute phase reactants, proteins that increase in the blood with conditions that cause inflammation or tissue injury. Circulating IL-6 can be found in the blood of normal individuals in the 1 pg/mL range, with slight elevations during the menstrual cycle, modest elevations in certain cancers (melanoma) (10 pg/mL), and large elevations after surgery (30-430 pg/mL).

  • Median Concentration of Tumor Necrosis Factor-Alpha (TNF) [ Time Frame: baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs ]
    Tumor Necrosis Factor Alpha is a cell signaling protein (cytokine) involved in systemic inflammation and is one of the cytokines that make up the acute phase reaction. TNF is important to the body because it helps regulate the response of the immune system to a foreign object, especially to the present cancerous tumor. It promotes inflammation, produces other cells used in the inflammatory response, and can help cells heal. The normal range is 5 to 27.2 pg/ml.


Enrollment: 61
Study Start Date: April 2008
Study Completion Date: March 2016
Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Simvastatin
Subjects randomized to this arm will receive statin therapy (simvastatin 40 mg) two days before surgery -- allowing three doses of simvastatin before incision -- and these will be continued until patients are either discharged from the hospital or have completed a 3-day postoperative course (6 days of simvastatin therapy), whichever occurs earlier. If patients are unable to take oral medications, the enteral route via nasogastric tube (at our institution, nasogastric tubes are routinely placed for both lumbar and thoracic instrumentation) will be used to deliver either placebo or the statin, as no parenteral form of this drug is currently available.
Drug: Simvastatin
40 mg po/nasogastric tube (NG) every day for 6 days
Other Name: Zocor
Experimental: Placebo
Subjects randomized to this arm will receive placebo two days before surgery -- allowing three doses of placebo before incision -- and these will be continued until patients are either discharged from the hospital or have completed a 3-day postoperative course (6 days of placebo), whichever occurs earlier. If patients are unable to take oral medications, the enteral route via nasogastric tube (at our institution, nasogastric tubes are routinely placed for both lumbar and thoracic instrumentation) will be used to deliver either placebo or the statin, as no parenteral form of this drug is currently available.
Drug: Placebo
1 pill po/NG every day x 6 days

Detailed Description:

Previous studies have reported activation of the body's immune system during the perioperative period.1 Typically, this "stress response" is limited and goes unnoticed by the patient and health care team. However, physiologic insults that occur during major surgery may elicit a more pronounced response known as the systemic inflammatory response syndrome (SIRS). Such a response is of great clinical consequence, as it is known to significantly worsen perioperative morbidity and mortality.1 HMG Co-A Reductase Inhibitors (hereafter identified by the common name, "the statins") are potent inhibitors of cholesterol synthesis, and their role in the treatment of atherosclerosis and prevention of coronary artery disease is well documented.2-5 Interestingly, data from animal studies have shown that statins have unique anti-inflammatory properties that are independent of their lipid lowering effects.6 Recently, statin therapy has been associated with a reduced incidence of perioperative cardiovascular and neurologic complications in major vascular and thoracic surgery patients as well as improved outcomes in patients experiencing acute coronary syndrome (ACS).7-13 In all ACS patient populations studied, improvement in outcome has been attributed to coronary plaque stabilization, presumably a result of statins mitigating the local inflammatory response at the level of the coronary plaque.

The purpose of this study is to quantify the magnitude of perioperative inflammation during major orthopedic spine surgery and determine whether statins alter this systemic physiologic response.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

1. Patients scheduled for elective major spine surgery (multilevel (2-6 level) open thoracic or lumbar spine surgery with instrumentation)

Exclusion Criteria:

  1. Pregnancy
  2. Lactating females
  3. Oral or parenteral corticosteroid use in the past 30 days
  4. Elevation of AST or ALT > 3x normal
  5. Elevation of creatinine kinase > 2x normal
  6. Previous adverse drug reaction to any medication in the statin class
  7. Current use of fibrates, niacin, itraconazole, ketoconazole, macrolide antibiotics, HIV protease inhibitors and/or nefazodone
  8. Active liver disease
  9. Current statin use
  10. Anti-inflammatory use of the following medications within the last 30 days:

    • Sulfasalazine
    • Mycophenolate
    • Cyclosporine
    • Cyclophosphamide
    • Azathioprine
    • Chlorambucil
    • Minocycline
    • Myochrysine
    • Penicillamine
    • Hydroxychloroquine
    • Leflunomide
  11. Any medications listed in 3 or 10 above in the post-operative period
  12. Use of Activated protein C at any time during the patients hospitalization
  13. Use of anti-inflammatory medications listed below within the last 30 days:

    • Leflunomide
    • Sulfasalazine
    • Mycophenolate
    • Cyclosporine
    • Cyclophosphamide
    • Azathioprine
    • Chlorambucil
    • Minocycline
    • Myochrysine
    • Penicillamine
    • Hydroxychloroquine
    • Methotrexate
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00656292

Locations
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Principal Investigator: Michael J. Brown, M.D. Mayo Clinic Department of Anesthesiology
Principal Investigator: Daryl Kor, M.D. Mayo Clinic Department of Anesthesiolgy
  More Information

Responsible Party: Michael Brown, MD, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00656292     History of Changes
Other Study ID Numbers: 06-002881
Study First Received: April 4, 2008
Results First Received: April 10, 2017
Last Updated: April 10, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by Mayo Clinic:
Plasma concentrations of inflammatory markers
C-Reactive Protein (CRP)
Interleukin-6 (IL-6)
Tumor Necrosis Factor-Alpha (TNF)
Aspartate Aminotransferase (AST)
Alanine Aminotransferase (ALT)
Creatine Kinase (CK)

Additional relevant MeSH terms:
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents

ClinicalTrials.gov processed this record on May 22, 2017