POST-OP Pilot: Pilot Study of Atorvastatin for Orthopedic Surgery Patients

• Sponsor: Hospital for Special Surgery, New York (Other)
• Overall Status: Completed
• CT.gov ID: NCT02197065
• Collaborator: Weill Medical College of Cornell University (Other), Washington University School of Medicine (Other), University of Utah (Other)
• Enrollment: 20
• Locations: 2
• Arms: 2
• Actual Duration (Months): 28
• Patients Per Site: 10
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Up to 35% of hip fracture patients have been shown to experience heart injury after surgery, and as many as 10% have a heart attack or die in the three months after surgery. Hip and knee arthroplasty patients are also at risk of cardiovascular complications. Patients who have these complications have higher levels of inflammation postoperatively. Statins (such as atorvastatin/Lipitor) lower cholesterol and also lessen inflammation. Both of these effects are important in preventing heart attacks. Statins have been shown to reduce the risk of heart attacks in non-surgical patients, and to protect from heart attacks in patients having heart surgery. Whether statins can prevent heart attacks in orthopedic patients is not known.

In this pilot study the investigators will treat 30 orthopedic surgery patients (hip fracture, hip or knee arthroplasty) with either atorvastatin or placebo (a capsule with no study drug). Patients will start the study drug prior to surgery and take it for 45 days after surgery. Neither the doctors nor the patients will know whether they are taking atorvastatin or placebo. The investigators will look for evidence of inflammation and heart injury after surgery. The investigators hypothesize that atorvastatin will lessen the degree of postoperative inflammation found in these patients. In this study, the investigators will use a very sensitive test of heart injury that can detect problems even when patients have no symptoms. The investigators hypothesize that this test will demonstrate silent heart injury in over 50% of the hip fracture patients and over 30% of arthroplasty patients in our study.

The results of this trial will help us to develop a larger study in 1000 hip fracture and joint replacement patients to determine whether atorvastatin protects orthopedic surgery patients from heart injury and other complications of surgery.

Condition or Disease	Intervention/Treatment	Phase
Hip Fracture; Myocardial Ischemia; Inflammation	Drug: Atorvastatin; Drug: Placebo	Phase 2

Detailed Description

• Thirty statin-naïve patients ≥ 65 years of age admitted to New York Presbyterian Hospital or Hospital for Special Surgery with an acute hip fracture, or for elective hip or knee arthroplasty will be randomized in a 1:1 ratio to atorvastatin 40 mg daily or matching placebo.

• Atorvastatin will be initiated at least 4 hours prior to hip fracture surgery, or 4 days prior to arthroplasty, and will be continued until postoperative day (POD) 45.

• Patients will be assessed daily in the hospital for adverse events.

• Patients will be contacted by telephone weekly for four weeks after surgery and again on POD 45 and POD 90.

• Patients will mail back study medication bottles on POD 45 for pill counts to assess compliance.

• High sensitivity cardiac troponin I (hs-cTnI) will be measured pre-operatively (prior to atorvastatin therapy) and on POD 2.

• High sensitivity C-reactive protein (hs-CRP), and a panel of cytokines (IL-1β, IL-2, IL-2r, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-17, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and soluble (s)CD-40L) will be measured preoperatively and on POD 2.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: The Post-Operative Statin for Thromboprophylaxis & Cardiovascular Outcomes Protection (POST-OP) Pilot Trial
• Actual Study Start Date: Sep 1, 2014
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atorvastatin Atorvastatin 40mg daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45.	Drug: Atorvastatin; Atorvastatin or placebo will be started at least 4 hours prior to surgery, and continued nightly until postoperative day 45; Other Names: Lipitor
Placebo Comparator: Sugar pill Sugar pill (placebo) daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Percentage of All Enrolled Patients With a Peri-operative Rise in High-sensitivity Cardiac Troponin I [change from preoperative to postoperative day 2]

   The percentage of orthopedic patients with a ≥ 10 pg/mL rise in high-sensitivity cardiac troponin I (hs-cTnI) from baseline pre-operatively to post-operative day (POD)2

2. Peri-operative Rise in High Sensitivity C-reactive Protein (Hs-CRP) [Change from preoperative to post-operative day 2]

   The change in the level of hs-CRP from baseline to POD2 in 20 orthopedic patients randomized (1:1) to atorvastatin 40mg versus placebo.

Secondary Outcome Measures

1. Peri-operative Rise in Interleukin-6 (IL-6) Levels [Change from preoperative to postoperative day 2]

   The change in the level of IL-6 from baseline to POD2 in 16 arthroplasty patients randomized (1:1) to atorvastatin 40mg versus placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hip fracture or elective hip or knee arthroplasty

• Age 65 years or older

• Life expectancy > 3 months

Exclusion Criteria:

• Pathological hip fracture due to cancer

• Currently taking a statin, or took a statin within the last 30 days

• Previous statin intolerance

• Acute myocardial infarction or unstable angina

• History of myocardial infarction, acute coronary syndrome, angina, coronary/arterial re-vascularization

• Hip fracture patients with peripheral arterial disease

• Hip fracture patients with history of stroke or transient ischemic attack.

• Muscle disorder

• Serious liver disease or alanine aminotransferase > 3x upper limit of normal

• Serious renal disease (creatinine clearance <30cc/min)

• Treatment with HIV protease inhibitor or Hepatitis C protease inhibitor

• Treatment with erythromycin, clarithromycin, niacin or azole antifungal agent

• Pregnant, planning to become pregnant, or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital for Special Surgery	New York	New York	United States	10021
2	New York Presbyterian Hospital (Cornell)	New York	New York	United States	10065

Sponsors and Collaborators

• Hospital for Special Surgery, New York
• Weill Medical College of Cornell University
• Washington University School of Medicine
• University of Utah

Investigators

• Principal Investigator: Anne R Bass, MD, Hospital for Special Surgery, New York

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hospital for Special Surgery, New York
• ClinicalTrials.gov Identifier: NCT02197065
• Other Study ID Numbers: EPAR4398; UL1TR000457-06
• First Posted: Jul 22, 2014
• Last Update Posted: Jul 2, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Hospital for Special Surgery, New York: hip fracture; myocardial ischemia; statin; surgery; troponin; complication; arthroplasty; hip; knee; orthopedic; atorvastatin; cardiovascular
• Additional relevant MeSH terms: Myocardial Ischemia; Coronary Artery Disease; Inflammation; Ischemia; Hip Fractures; Atorvastatin

Study Results

Participant Flow

Arm/Group Title	Atorvastatin	Sugar Pill
Arm/Group Description	Atorvastatin 40mg daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Atorvastatin: Atorvastatin or placebo will be started at least 4 hours prior to surgery, and continued nightly until postoperative day 45	Sugar pill (placebo) daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Placebo
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Atorvastatin	Sugar Pill	Total
Arm/Group Description	Atorvastatin 40mg daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Atorvastatin: Atorvastatin or placebo will be started at least 4 hours prior to surgery, and continued nightly until postoperative day 45	Sugar pill (placebo) daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Placebo	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	71	75	73
Sex: Female, Male (Count of Participants)
Female	8 80%	6 60%	14 70%
Male	2 20%	4 40%	6 30%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	10 100%	20 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 10%	0 0%	1 5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 10%	1 5%
White	9 90%	9 90%	18 90%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	10 100%	20 100%
Orthopedic procedure (Count of Participants)
Knee arthroplasty	2 20%	4 40%	6 30%
Hip arthroplasty	6 60%	4 40%	10 50%
Hip fracture repair	2 20%	2 20%	4 20%

Outcome Measures

1. Primary Outcome

Title	Percentage of All Enrolled Patients With a Peri-operative Rise in High-sensitivity Cardiac Troponin I
Description	The percentage of orthopedic patients with a ≥ 10 pg/mL rise in high-sensitivity cardiac troponin I (hs-cTnI) from baseline pre-operatively to post-operative day (POD)2
Time Frame	change from preoperative to postoperative day 2

Outcome Measure Data

Analysis Population Description

20 orthopedic surgery patients.

Arm/Group Title	All Patients
Arm/Group Description	All patients in the study
Measure Participants	20
Number [percentage of patients]	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Patients
	Comments	This was a pilot feasibility study and we were only powered to determine the frequency of troponin elevation in the entire study population, not to compare the frequency of a rise in troponin in the two study arms. Thus Aim 1 applies to the entire study cohort.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0.2
	Confidence Interval	(1-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Peri-operative Rise in High Sensitivity C-reactive Protein (Hs-CRP)
Description	The change in the level of hs-CRP from baseline to POD2 in 20 orthopedic patients randomized (1:1) to atorvastatin 40mg versus placebo.
Time Frame	Change from preoperative to post-operative day 2

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atorvastatin	Sugar Pill
Arm/Group Description	Atorvastatin 40mg daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Atorvastatin: Atorvastatin or placebo will be started at least 4 hours prior to surgery, and continued nightly until postoperative day 45	Sugar pill (placebo) daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Placebo
Measure Participants	10	10
Median (Inter-Quartile Range) [mg/L]	98.95	85.95

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Patients, Sugar Pill
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	13
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Peri-operative Rise in Interleukin-6 (IL-6) Levels
Description	The change in the level of IL-6 from baseline to POD2 in 16 arthroplasty patients randomized (1:1) to atorvastatin 40mg versus placebo.
Time Frame	Change from preoperative to postoperative day 2

Outcome Measure Data

Analysis Population Description

16 arthroplasty patients

Arm/Group Title	Atorvastatin	Sugar Pill
Arm/Group Description	Atorvastatin 40mg daily starting 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45.	Sugar pill (placebo) daily starting 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45.
Measure Participants	8	8
Median (Inter-Quartile Range) [pg/mL]	1.28	0.98

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Patients, Sugar Pill
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	90 days
Arm/Group Title	Atorvastatin		Sugar Pill
Arm/Group Description	Atorvastatin 40mg daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Atorvastatin: Atorvastatin or placebo will be started at least 4 hours prior to surgery, and continued nightly until postoperative day 45		Sugar pill (placebo) daily starting at least 4 hours prior to hip fracture surgery, or 4 days prior to hip or knee arthroplasty, and continued until postoperative day 45. Placebo
All Cause Mortality
	Atorvastatin		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Atorvastatin		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		2/10 (20%)
Cardiac disorders
Hypertension	1/10 (10%)	1	0/10 (0%)	0
fluid overload	0/10 (0%)	0	1/10 (10%)	1
Infections and infestations
bacteremia	0/10 (0%)	0	1/10 (10%)	1
Metabolism and nutrition disorders
alcohol withdrawal	0/10 (0%)	0	1/10 (10%)	1
Nervous system disorders
delirium	0/10 (0%)	0	1/10 (10%)	1
Vascular disorders
deep vein thrombosis	1/10 (10%)	1	0/10 (0%)	0
Other (Not Including Serious) Adverse Events
	Atorvastatin		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		5/10 (50%)
Cardiac disorders
Hypertension	1/10 (10%)	1	1/10 (10%)	1
Bradycardia	1/10 (10%)	1	0/10 (0%)	0
Infections and infestations
Infection	3/10 (30%)	4	2/10 (20%)	2
Nervous system disorders
delirium	2/10 (20%)	2	2/10 (20%)	2
neuropathy	0/10 (0%)	0	1/10 (10%)	1
Skin and subcutaneous tissue disorders
pruritis	0/10 (0%)	0	1/10 (10%)	1

Limitations/Caveats

Small sample size: recruitment was made difficult by comorbidities in hip fracture patients that limited participation, the reluctance of arthroplasty patients to enroll in an interventional trial, and statin use in 40% of the target population.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.