Effect of Low Dose Corticosteroids on Perioperative Markers of Thrombosis and Fibrinolysis in Total Knee Arthroplasty

NCT01815918 | Completed Phase 4 Results

• 1 other identifier: 2012-054
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

One postoperative complication following unilateral or bilateral total knee arthroplasty is thrombosis (blood clot formation). In this prospective, double-blinded randomized controlled clinical trial, researchers are investigating the effect of steroids on biochemical markers of thrombosis. Furthermore, elevated cellular markers of thrombosis (specifically IL-6) have been linked to postoperative depression following total knee arthroplasty surgery. Hence the investigators are also checking if use of hydrocortisone, a steroid, may help reduce the incidence of postoperative depression. Other studies have shown that surgery causes some reaction in the body that is consistent with inflammation. When the inflammation is extensive, it may affect different parts of the body. It may also lead to clotting disorders and result in blood clots. In a previous study by this principal investigator (see reference 22, "Use of low-dose steroids in decreasing cytokine release during bilateral total knee arthroplasty"), hydrocortisone was administered over 24 hours following surgery to patients who underwent bilateral total knee arthroplasty. The investigator found lower levels of cellular markers consistent with inflammation (specifically the protein, IL-6). Steroid use also showed additional benefits, such as decreased pain and better range of motion at the knee. In this study, investigators recruit patients undergoing total knee arthroplasty surgery. Patients are randomized to receive three 100 mg doses of hydrocortisone or three doses of a saline placebo. In addition to analyzing patients' blood samples for hydrocortisone's effect on clotting factors (i.e. IL-6), investigators record patients' pain scores and patients' oral analgesic use. To assess patients' well-being, patients are contacted one month and 3 months following their surgeries and administered the Patient Health Questionnaire (see reference 23, "The PHQ-9: validity of a brief depression severity measure.") arthroplasty.

Conditions

Total Knee Arthroplasty

Keywords

Orthopedic Procedures; Prostheses and Implants; Joint Prosthesis; Knee Prosthesis; Arthroplasty, Knee; Thromboembolism; Inflammation; B-Cell Differentiation Factor-2; Differentiation Factor-2, B-Cell; B-Cell Stimulatory Factor-2; BSF-2; IFN-beta 2; MGI-2; Interleukin-6 (IL-6); Steroids; Pregnenediones; Hydrocortisone; Physiological Effects of Drugs; Therapeutic Uses

Outcome Measures

Primary Outcomes (2)

• Prothrombin Fragment (PF1.2), a Marker of Thrombin Generation

  Study patients received 100 mg of intravenous hydrocortisone 2 h prior to surgery, and controls received normal saline. Blood samples, drawn pre-incision and at 4 h post tourniquet release, were assayed for PF1.2 and PAP

  Baseline and up to 4 hours following surgery

• Plasmin-alpha-2-antiplasmin Complex (PAP), a Marker of Fibrinolysis

  Study patients received 100 mg of intravenous hydrocortisone 2 h prior to surgery, and controls received normal saline. Blood samples, drawn pre-incision and at 4 h post tourniquet release, were assayed for PF1.2 and PAP

  Baseline and up to 4 hours following surgery

Secondary Outcomes (3)

• Hydrocortisone's Effect on Depression

  one month and up to 3 months following surgery

• Pain Scores and Opioid Consumption

  one month and up to 3 months following surgery

• Blinding Assessment

  one month and up to 3 months following surgery

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Patients receive a saline placebo before surgery, 8 hours after the first dose and 16 hours after the first dose.

Drug: Placebo

Treatment

ACTIVE COMPARATOR

Patients receive 3 100 mg of hydrocortisone: prior to surgery, 8 hours after the first dose and 16 hours after the first dose.

Drug: Hydrocortisone

Interventions

Hydrocortisone DRUG

Patients randomized to treatment arm will three doses of 100 mg of hydrocortisone at the following times: prior to surgery, 8 hours after the first dose and 16 hours after the first dose.

Also known as: Ala-Cort, Ala-Scalp HP, Anusol HC, Aquanil HC, Beta HC, Cetacort, Colocort, Corta-Cap

Treatment

Placebo DRUG

Patients receive placebo prior to surgery, 8 hours after the first dose and 16 hours after the first dose.

Placebo

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All patients undergoing unilateral or bilateral total knee replacement
• Age 50-90

You may not qualify if:

• All patients on steroid therapy regardless of dose or duration of treatment or those requiring stress-dose steroids preoperatively
• Patients who are smokers
• Patients under 50 years of age
• Patients over 90 years of age
• Patients with diabetes
• Patients with a prior history of corticosteroid intolerance
• Patients with previous complications of steroid use

Sponsors & Collaborators

• Hospital for Special Surgery, New York: lead

Study Sites (1)

Hospital for Special Surgery

New York, New York, 10021, United States

Location

Related Publications (24)

• Boermeester MA, van Leeuwen PA, Coyle SM, Wolbink GJ, Hack CE, Lowry SF. Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis. Arch Surg. 1995 Jul;130(7):739-48. doi: 10.1001/archsurg.1995.01430070061012.

  PMID: 7611862 BACKGROUND

• Busso N, Belin D, Failly-Crepin C, Vassalli JD. Plasminogen activators and their inhibitors in a human mammary cell line (HBL-100). Modulation by glucocorticoids. J Biol Chem. 1986 Jul 15;261(20):9309-15.

  PMID: 3087993 BACKGROUND

• Collen D, Hoylaerts MF. Relationship between inflammation and venous thromboembolism as studied by microparticle assessment in plasma. J Am Coll Cardiol. 2005 May 3;45(9):1472-3. doi: 10.1016/j.jacc.2005.02.029. No abstract available.

  PMID: 15862421 BACKGROUND

• Cremeans-Smith JK, Soehlen S, Greene K, Alexander T, Delahanty DL. In-hospital levels of C-reactive protein and IL-6 predict post-operative depressive symptoms among patients undergoing total knee replacement surgery. Brain Behav Immun. 2009 Nov;23(8):1096-103. doi: 10.1016/j.bbi.2009.06.148. Epub 2009 Jun 24.

  PMID: 19559081 BACKGROUND

• Fox EA, Kahn SR. The relationship between inflammation and venous thrombosis. A systematic review of clinical studies. Thromb Haemost. 2005 Aug;94(2):362-5. doi: 10.1160/TH05-04-0266.

  PMID: 16113826 BACKGROUND

• Hogevold HE, Hoiseth A, Reikeras O. Effect of high-dose corticosteroids on the incidence of deep vein thrombosis after total hip replacement. Arch Orthop Trauma Surg. 1991;111(1):29-31. doi: 10.1007/BF00390189.

  PMID: 1722989 BACKGROUND

• Jansen NJ, van Oeveren W, van den Broek L, Oudemans-van Straaten HM, Stoutenbeek CP, Joen MC, Roozendaal KJ, Eysman L, Wildevuur CR. Inhibition by dexamethasone of the reperfusion phenomena in cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1991 Oct;102(4):515-25.

  PMID: 1656149 BACKGROUND

• Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, Buller HR. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999 Dec 4;354(9194):1940-7. doi: 10.1016/S0140-6736(99)01264-7.

  PMID: 10622296 BACKGROUND

• Levi M, van der Poll T. Two-way interactions between inflammation and coagulation. Trends Cardiovasc Med. 2005 Oct;15(7):254-9. doi: 10.1016/j.tcm.2005.07.004.

  PMID: 16226680 BACKGROUND

• Medcalf RL, Van den Berg E, Schleuning WD. Glucocorticoid-modulated gene expression of tissue- and urinary-type plasminogen activator and plasminogen activator inhibitor 1 and 2. J Cell Biol. 1988 Mar;106(3):971-8. doi: 10.1083/jcb.106.3.971.

  PMID: 3126194 BACKGROUND

• Medcalf RL, Kruithof EK, Schleuning WD. Plasminogen activator inhibitor 1 and 2 are tumor necrosis factor/cachectin-responsive genes. J Exp Med. 1988 Aug 1;168(2):751-9. doi: 10.1084/jem.168.2.751.

  PMID: 3137305 BACKGROUND

• Nilsson T, Carlsson J, Sundqvist G. Inactivation of key factors of the plasma proteinase cascade systems by Bacteroides gingivalis. Infect Immun. 1985 Nov;50(2):467-71. doi: 10.1128/iai.50.2.467-471.1985.

  PMID: 3902645 BACKGROUND

• Parvizi J, Mui A, Purtill JJ, Sharkey PF, Hozack WJ, Rothman RH. Total joint arthroplasty: When do fatal or near-fatal complications occur? J Bone Joint Surg Am. 2007 Jan;89(1):27-32. doi: 10.2106/JBJS.E.01443.

  PMID: 17200306 BACKGROUND

• Pulido L, Ghanem E, Joshi A, Purtill JJ, Parvizi J. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res. 2008 Jul;466(7):1710-5. doi: 10.1007/s11999-008-0209-4. Epub 2008 Apr 18.

  PMID: 18421542 BACKGROUND

• Reikeras O, Clementsen T. Thrombosis markers in hip versus knee arthroplasty: a pilot study. J Orthop Surg (Hong Kong). 2009 Dec;17(3):291-5. doi: 10.1177/230949900901700309.

  PMID: 20065366 BACKGROUND

• Sharrock NE, Go G, Sculco TP, Salvati EA, Westrich GH, Harpel PC. Dose response of intravenous heparin on markers of thrombosis during primary total hip replacement. Anesthesiology. 1999 Apr;90(4):981-7. doi: 10.1097/00000542-199904000-00009.

  PMID: 10201667 BACKGROUND

• van der Poll T, Levi M, Hack CE, ten Cate H, van Deventer SJ, Eerenberg AJ, de Groot ER, Jansen J, Gallati H, Buller HR, et al. Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees. J Exp Med. 1994 Apr 1;179(4):1253-9. doi: 10.1084/jem.179.4.1253.

  PMID: 8145042 BACKGROUND

• van Deventer SJ, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990 Dec 15;76(12):2520-6.

  PMID: 2124934 BACKGROUND

• van Giezen JJ, Chung-A-Hing JE, Vegter CB, Bouma BN, Jansen JW. Fibrinolytic activity in blood is distributed over a cellular and the plasma fraction which can be modulated separately. Thromb Haemost. 1994 Dec;72(6):887-92.

  PMID: 7740459 BACKGROUND

• Voshaar RC, Banerjee S, Horan M, Baldwin R, Pendleton N, Proctor R, Tarrier N, Woodward Y, Burns A. Predictors of incident depression after hip fracture surgery. Am J Geriatr Psychiatry. 2007 Sep;15(9):807-14. doi: 10.1097/JGP.0b013e318098610c. Epub 2007 Aug 13.

  PMID: 17698601 BACKGROUND

• Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol. 2003 Dec;23(12):2131-7. doi: 10.1161/01.ATV.0000095974.95122.EC. Epub 2003 Sep 18.

  PMID: 14500287 BACKGROUND

• Jules-Elysee KM, Lipnitsky JY, Patel N, Anastasian G, Wilfred SE, Urban MK, Sculco TP. Use of low-dose steroids in decreasing cytokine release during bilateral total knee replacement. Reg Anesth Pain Med. 2011 Jan-Feb;36(1):36-40. doi: 10.1097/AAP.0b013e31820306c5.

  PMID: 21455087 BACKGROUND

• Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001 Sep;16(9):606-13. doi: 10.1046/j.1525-1497.2001.016009606.x.

  PMID: 11556941 BACKGROUND

• McLawhorn AS, Poultsides LA, Sakellariou VI, Kunze KN, Fields KG, Jules-Elysee K, Sculco TP. Low-Dose Perioperative Corticosteroids Can Be Administered Without Additional Morbidity in Patients Undergoing Bilateral Total Knee Replacement: A Retrospective Follow-up Study of a Randomized Controlled Trial. HSS J. 2022 Feb;18(1):48-56. doi: 10.1177/15563316211006098. Epub 2021 Apr 9.

  PMID: 35087332 DERIVED

Related Links

• This is a link to the Hospital for Special Surgery home page.

MeSH Terms

Conditions

Thromboembolism; Inflammation

Interventions

Hydrocortisone

Condition Hierarchy (Ancestors)

Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; 17-Hydroxycorticosteroids

Results Point of Contact

• Title: Kethy Jules-Elysee, MD
• Organization: Hospital for Special Surgery

JulesElyseeK@HSS.EDU

212-606-1206

Study Officials

• Kethy Jules-Elysée, M.D.

  Hospital for Special Surgery, New York

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2013
• First Posted: March 21, 2013
• Study Start: February 1, 2011
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: April 14, 2022
• Results First Posted: June 14, 2017

Record last verified: 2022-04

Locations

US (1)