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

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ClinicalTrials.gov Identifier: NCT00656292
Recruitment Status : Completed
First Posted : April 11, 2008
Results First Posted : May 19, 2017
Last Update Posted : May 19, 2017
Sponsor:
Information provided by (Responsible Party):
Michael Brown, Mayo Clinic

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Care Provider);   Primary Purpose: Treatment
Condition Perioperative Inflammatory Response
Interventions Drug: Simvastatin
Drug: Placebo
Enrollment 61
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 32 29
Completed 29 24
Not Completed 3 5
Reason Not Completed
Withdrawal by Subject             2             3
Screen failure             1             2
Arm/Group Title Simvastatin Placebo Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 32 29 61
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 32 participants 29 participants 61 participants
54.9  (16.2) 56.3  (15.6) 55.6  (15.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 32 participants 29 participants 61 participants
Female
22
  68.8%
16
  55.2%
38
  62.3%
Male
10
  31.3%
13
  44.8%
23
  37.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 32 participants 29 participants 61 participants
32 29 61
1.Primary Outcome
Title Median Concentration of Aspartate Aminotransferase (AST)
Hide Description 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.
Time Frame baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 24
Median (Inter-Quartile Range)
Unit of Measure: U/L
baseline
24.5
(18.8 to 31.0)
24.5
(21.0 to 27.8)
time 0 hours
21.0
(18.0 to 24.0)
20.0
(17.0 to 24.0)
time 8 hours
29.0
(21.0 to 33.0)
25.0
(19.3 to 31.5)
time 24 hours
41.5
(28.0 to 84.8)
30.5
(22.5 to 72.5)
time 48 hours
53.0
(26.5 to 118.0)
35.0
(25.8 to 80.8)
time 72 hours
56.5
(29.3 to 100.3)
44.0
(28.0 to 97.5)
2.Secondary Outcome
Title Median Concentration of Alanine Aminotransferase (ALT)
Hide Description 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.
Time Frame baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 24
Median (Inter-Quartile Range)
Unit of Measure: U/L
baseline
23
(18.5 to 28.0)
22.0
(17.5 to 28.5)
time 0 hours
16.5
(14.0 to 25.0)
16.0
(14.0 to 24.0)
time 8 hours
18.0
(13.0 to 23.0)
16.5
(12.3 to 21.0)
time 24 hours
20.5
(17.0 to 29.5)
17.0
(12.7 to 23.5)
time 48 hours
23.0
(16.5 to 42.0)
18.0
(14.80 to 25.0)
time 72 hours
24.0
(18.5 to 45.5)
25.0
(16.0 to 39.0)
3.Secondary Outcome
Title Median Concentration of C-Reactive Protein (CRP)
Hide Description C-reactive protein (CRP) is a substance produced by the liver in response to inflammation. Normal CRP levels are below 3.0 mg/L.
Time Frame baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 24
Median (Inter-Quartile Range)
Unit of Measure: mg/L
baseline
3.0
(3.0 to 3.5)
3.0
(3.0 to 4.2)
time 0 hours
3.0
(3.0 to 3.2)
3.0
(3.0 to 5.1)
time 8 hours
3.0
(3.0 to 5.2)
4.1
(3.0 to 8.0)
time 24 hours
47.5
(22.8 to 70.6)
52.5
(26.9 to 86.9)
time 48 hours
139.7
(112.7 to 199.2)
157.8
(96.0 to 258.2)
time 72 hours
122.4
(100.3 to 173.1)
197.2
(120.5 to 235.3)
4.Secondary Outcome
Title Median Concentration of Creatine Kinase (CK)
Hide Description 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.
Time Frame baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 24
Median (Inter-Quartile Range)
Unit of Measure: U/L
baseline
89.5
(58.5 to 112.5)
111.0
(86.0 to 154.2)
time 0 hours
71.0
(51.0 to 134.8)
103.0
(66.0 to 147.0)
time 8 hours
527.0
(213.0 to 754.0)
257.0
(206.8 to 558.0)
time 24 hours
1345.0
(434.5 to 2621.2)
647.0
(273.0 to 1688.0)
time 48 hours
973.0
(446.0 to 2724.0)
685.0
(272.0 to 1357.0)
time 72 hours
597.0
(355.0 to 1839.0)
886.0
(253.0 to 1565.0)
5.Secondary Outcome
Title Median Concentration of Interleukin-6 (IL-6)
Hide Description 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).
Time Frame baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 24
Median (Inter-Quartile Range)
Unit of Measure: ng/ml
baseline
1.5
(0.1 to 2.8)
2.4
(0.7 to 3.8)
time 0 hours
1.2
(0.1 to 2.3)
1.8
(0.5 to 3.4)
time 8 hours
50.0
(24.6 to 135.7)
56.7
(27.8 to 135.7)
time 24 hours
64.2
(41.5 to 182.4)
70.2
(51.9 to 172.7)
time 48 hours
89.2
(46.6 to 155.9)
87.0
(39.3 to 175.7)
time 72 hours
37.7
(16.3 to 55.5)
45.2
(22.0 to 92.4)
6.Secondary Outcome
Title Median Concentration of Tumor Necrosis Factor-Alpha (TNF)
Hide Description 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.
Time Frame baseline, at the start of the surgical procedure (0 hrs), 8 hrs, 24 hrs, 48 hrs, 72 hrs
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 29 24
Median (Inter-Quartile Range)
Unit of Measure: pg/ml
baseline
1.0
(0.7 to 1.2)
0.85
(0.6 to 1.3)
time 0 hours
0.95
(0.60 to 1.21)
0.96
(0.71 to 1.30)
time 8 hours
0.94
(0.64 to 1.34)
0.86
(0.54 to 1.06)
time 24 hours
1.25
(0.89 to 1.53)
1.00
(0.67 to 1.26)
time 48 hours
1.57
(1.05 to 1.70)
1.37
(0.89 to 1.63)
time 72 hours
1.58
(1.14 to 1.85)
1.36
(0.99 to 1.69)
Time Frame 72 hours after spine surgery
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Simvastatin Placebo
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Simvastatin Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/29 (0.00%)      0/24 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Simvastatin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/29 (3.45%)      3/24 (12.50%)    
Cardiac disorders     
Arrhythmia   0/29 (0.00%)  0 1/24 (4.17%)  1
Pulmonary embolism   0/29 (0.00%)  0 1/24 (4.17%)  1
Respiratory, thoracic and mediastinal disorders     
Non-invasive ventilation required > 24 hrs post-op   1/29 (3.45%)  1 1/24 (4.17%)  1
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Simvastatin Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/29 (0.00%)      1/24 (4.17%)    
Gastrointestinal disorders     
Post-op Ileus   0/29 (0.00%)  0 1/24 (4.17%)  1
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Michael J. Brown, M.D.
Organization: Mayo Clinic
Phone: 507-284-6317
Responsible Party: Michael Brown, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00656292     History of Changes
Other Study ID Numbers: 06-002881
First Submitted: April 4, 2008
First Posted: April 11, 2008
Results First Submitted: April 10, 2017
Results First Posted: May 19, 2017
Last Update Posted: May 19, 2017