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

Phase 4

Completed

• Conditions: Perioperative Inflammatory Response
• Interventions: Drug: Placebo; Drug: Simvastatin

• Registration Number: NCT00656292
• Lead Sponsor: Mayo Clinic

Brief Summary

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

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.

Study Timeline

• Study Start: 2008-04
• Study First Submitted: 2008-04-04
• Study First Submitted QC: 2008-04-10
• Study First Posted: 2008-04-11
• Primary Completion: 2016-03
• Study Completion: 2016-03
• Status Verified: 2017-04
• Results First Submitted: 2017-04-10
• Results First Submitted QC: 2017-04-10
• Last Update Submitted: 2017-04-10
• Results First Posted: 2017-05-19
• Last Update Posted: 2017-05-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 61

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	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.
Simvastatin	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.

Primary Outcome Measures

Name	Time	Method
Median Concentration of Aspartate Aminotransferase (AST)	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

Name	Time	Method
Median Concentration of Creatine Kinase (CK)	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 Alanine Aminotransferase (ALT)	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)	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 Interleukin-6 (IL-6)	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)	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.

Trial Locations

Locations (1)

Mayo Clinic; 🇺🇸 Rochester, Minnesota, United States