Postoperative Myocardial Injury and Inflammation Is Not Blunted by a Trial of Atorvastatin in Orthopedic Surgery Patients

Abstract

Background

Orthopedic patients are at risk for adverse postoperative cardiovascular outcomes.

Questions/Purposes

This pilot randomized controlled trial (RCT) of atorvastatin vs. placebo in orthopedic surgery patients was performed in order to assess: (1) the prevalence of perioperative myocardial injury; (2) the effect of atorvastatin on perioperative inflammation; and (3) the feasibility of performing a large RCT of statin therapy in orthopedic patients.

Methods

Hip fracture (hip Fx) and total hip and knee replacement (THR and TKR) patients were randomized 1:1 to atorvastatin 40 mg daily vs. placebo, starting preoperatively and continuing until postoperative day (POD) 45. High-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hs-CRP), and interleukin-6 (IL-6) were measured preoperatively and on POD 2. Patients were monitored for adverse events until POD 90.

Results

Five hundred fifty-six patients were screened, 22 were recruited (4 hip Fx, 11 THR, 7 TKR), and 2 withdrew. Most (80%) had detectable hs-cTnI (> 1.1 pg/mL) preoperatively. Twenty percent had a perioperative rise in hs-cTnI (≥ 10 pg/mL), which was not blunted by atorvastatin. Hs-CRP rose in 19/20 patients, and IL-6 rose in all patients. However, atorvastatin did not blunt the rise in these inflammatory biomarkers. On POD 2, IL-6 and hs-cTnI levels correlated (ρ = 0.59, p = 0.02). Recruitment was limited by the high prevalence of statin use in the screened population and a high prevalence of exclusions among hip fracture patients.

Conclusion

Perioperative myocardial injury and inflammation are common in orthopedic patients and do not appear to be reduced in those randomized to atorvastatin.

Trial Registration

NCT02197065

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Albayati MA, Grover SP, Saha P, Lwaleed BA, Modarai B, Smith A. Postsurgical inflammation as a causative mechanism of venous thromboembolism. Semin Thromb Hemost. 2015;41:615–20.

  2. 2.

    Apple FS, Ler R, Murakami MM. Determination of 19 cardiac troponin I and T assay 99th percentile values from a common presumably healthy population. Clin Chem. 2012;58:1574–81.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Bass AR, Rodriguez T, Hyun G, Santiago FG, Kim JI, Woller SC, et al. Myocardial ischaemia after hip and knee arthroplasty: incidence and risk factors. Int Orthop. 2015;39:2011–6.

  4. 4.

    Beloosesky Y, Hendel D, Weiss A, Hershkovitz A, Grinblat J, Pirotsky A, et al. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. J Gerontol A Biol Sci Med Sci. 2007;62:420–6.

  5. 5.

    Bemenderfer TB, Rozario NL, Moore CG, Karunakar MA. Morbidity and mortality in elective total hip arthroplasty following surgical care improvement project guidelines. J Arthroplasty. 2017;32(8):2359–2362.

    Article  PubMed  Google Scholar 

  6. 6.

    Berwanger O, Le Manach Y, Suzumura EA, Biccard B, Srinathan SK, Szczeklik W, et al. Association between pre-operative statin use and major cardiovascular complications among patients undergoing non-cardiac surgery: the VISION study. Eur Heart J. 2016;37:177–85.

  7. 7.

    Bjornsson GL, Thorsteinsson L, Gudmundsson KO, Jonsson H,Jr, Gudmundsson S, Gudbjornsson B. Inflammatory cytokines in relation to adrenal response following total hip replacement. Scand J Immunol. 2007;65:99–105.

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Cavender MA, White WB, Jarolim P, Bakris GL, Cushman WC, Kupfer S, et al. Serial measurement of high sensitivity troponin I and cardiovascular outcomes in patients with type 2 diabetes mellitus in the EXAMINE Trial. Circulation. 2017;135(20):1911–1921.

  9. 9.

    Chloropoulou P, Iatrou C, Vogiatzaki T, Kotsianidis I, Trypsianis G, Tsigalou C, et al. Epidural anesthesia followed by epidural analgesia produces less inflammatory response than spinal anesthesia followed by intravenous morphine analgesia in patients with total knee arthroplasty. Med Sci Monit. 2013;19:73–80.

  10. 10.

    Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leao P, et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg. 2004;39:967,75; discussion 975-6.

  11. 11.

    Ekeloef S, Alamili M, Devereaux PJ, Gogenur I. Troponin elevations after non-cardiac, non-vascular surgery are predictive of major adverse cardiac events and mortality: a systematic review and meta-analysis. Br J Anaesth. 2016;117:559–68.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Fulton RJ, McDade RL, Smith PL, Kienker LJ, Kettman JR,Jr. Advanced multiplexed analysis with the FlowMetrix system. Clin Chem. 1997;43:1749–56.

    CAS  PubMed  Google Scholar 

  13. 13.

    Gaudilliere B, Fragiadakis GK, Bruggner RV, Nicolau M, Finck R, Tingle M, et al. Clinical recovery from surgery correlates with single-cell immune signatures. Sci Transl Med. 2014;6:255ra131.

  14. 14.

    Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto AM,Jr, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–61.

  15. 15.

    Hietala P, Strandberg M, Kiviniemi T, Strandberg N, Airaksinen KE. Usefulness of troponin T to predict short-term and long-term mortality in patients after hip fracture. Am J Cardiol. 2014;114:193–7.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Hijazi Z, Aulin J, Andersson U, Alexander JH, Gersh B, Granger CB, et al. Biomarkers of inflammation and risk of cardiovascular events in anticoagulated patients with atrial fibrillation. Heart. 2016;102:508–17.

  17. 17.

    Jameson SS, Kyle J, Baker PN, Mason J, Deehan DJ, McMurtry IA, et al. Patient and implant survival following 4323 total hip replacements for acute femoral neck fracture: a retrospective cohort study using National Joint Registry data. J Bone Joint Surg Br. 2012;94:1557–66.

  18. 18.

    Jones SA. Directing transition from innate to acquired immunity: defining a role for IL-6. J Immunol. 2005;175:3463–8.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    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;36:36–40.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Juliebo V, Krogseth M, Skovlund E, Engedal K, Wyller TB. Medical treatment predicts mortality after hip fracture. J Gerontol A Biol Sci Med Sci. 2010;65:442–9.

    Article  PubMed  Google Scholar 

  21. 21.

    Lalmohamed A, Vestergaard P, de Boer A, Leufkens HG, van Staa TP, de Vries F. Changes in mortality patterns following total hip or knee arthroplasty over the past two decades: a nationwide cohort study. Arthritis Rheumatol. 2014;66:311–8.

    Article  PubMed  Google Scholar 

  22. 22.

    Lalmohamed A, Vestergaard P, Klop C, Grove EL, de Boer A, Leufkens HG, et al. Timing of acute myocardial infarction in patients undergoing total hip or knee replacement: a nationwide cohort study. Arch Intern Med. 2012;172(16):1229–35.

  23. 23.

    Lapidus LJ, Ponzer S, Pettersson H, de Bri E. Symptomatic venous thromboembolism and mortality in orthopaedic surgery—an observational study of 45 968 consecutive procedures. BMC Musculoskelet Disord. 2013;14:177.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Le Manach Y, Collins G, Bhandari M, Bessissow A, Boddaert J, Khiami F, et al. Outcomes after hip fracture surgery compared with elective total hip replacement. JAMA. 2015;314:1159–66.

  25. 25.

    Lindahl B, Venge P, James S. The new high-sensitivity cardiac troponin T assay improves risk assessment in acute coronary syndromes. Am Heart J. 2010;160:224–9.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    London MJ, Schwartz GG, Hur K, Henderson WG. Association of perioperative statin use with mortality and morbidity after major noncardiac surgery. JAMA Intern Med. 2017;177:231–42.

    Article  PubMed  Google Scholar 

  27. 27.

    Lu N, Misra D, Neogi T, Choi HK, Zhang Y. Total joint arthroplasty and the risk of myocardial infarction: a general population, propensity score-matched cohort study. Arthritis Rheumatol. 2015;67:2771–9.

    Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Martins TB, Pasi BM, Litwin CM, Hill HR. Heterophile antibody interference in a multiplexed fluorescent microsphere immunoassay for quantitation of cytokines in human serum. Clin Diagn Lab Immunol. 2004;11:325–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Martins TB, Pasi BM, Pickering JW, Jaskowski TD, Litwin CM, Hill HR. Determination of cytokine responses using a multiplexed fluorescent microsphere immunoassay. Am J Clin Pathol. 2002;118:346–53.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Memtsoudis SG, Gonzalez Della Valle A, Besculides MC, Gaber L, Sculco TP. In-hospital complications and mortality of unilateral, bilateral, and revision TKA: based on an estimate of 4,159,661 discharges. Clin Orthop Relat Res. 2008;466:2617–27.

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Nagele P, Brown F, Gage BF, Gibson DW, Miller JP, Jaffe AS, et al. High-sensitivity cardiac troponin T in prediction and diagnosis of myocardial infarction and long-term mortality after noncardiac surgery. Am Heart J. 2013;166:325,332.e1.

  32. 32.

    NHFD. The national hip fracture database national report 2012 - Supplement. 2013. http://www.hqip.org.uk/assets/NCAPOP-Library/NCAPOP-2012-13/NHFD-National-Report-2012-Supplement.pdf.

  33. 33.

    Oberweis BS, Smilowitz NR, Nukala S, Rosenberg A, Xu J, Stuchin S, et al. Relation of perioperative elevation of troponin to long-term mortality after orthopedic surgery. Am J Cardiol. 2015;115:1643–8.

  34. 34.

    Pesic G, Jeremic J, Nikolic T, Zivkovic V, Srejovic I, Vranic A, et al. Interleukin-6 as possible early marker of stress response after femoral fracture. Mol Cell Biochem. 2017;430(1–2):191–199.

  35. 35.

    Peters SA, Palmer MK, Grobbee DE, Crouse JR, 3rd, O'Leary DH, Raichlen JS, et al. C-reactive protein lowering with rosuvastatin in the METEOR study. J Intern Med. 2010;268:155–61.

  36. 36.

    Poeran J, Rasul R, Suzuki S, Danninger T, Mazumdar M, Opperer M, et al. Tranexamic acid use and postoperative outcomes in patients undergoing total hip or knee arthroplasty in the United States: retrospective analysis of effectiveness and safety. BMJ. 2014;349:g4829.

  37. 37.

    Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM,Jr, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.

  38. 38.

    Rodriguez AL, Wojcik BM, Wrobleski SK, Myers DD, Jr, Wakefield TW, Diaz JA. Statins, inflammation and deep vein thrombosis: a systematic review. J Thromb Thrombolysis. 2012;33:371–82.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Sandoval Y, Smith SW, Apple FS. Present and future of cardiac troponin in clinical practice: a paradigm shift to high-sensitivity assays. Am J Med. 2016;129:354–65.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Scandinavian 4S. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383–9.

    Google Scholar 

  41. 41.

    Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813:878–88.

    Google Scholar 

  42. 42.

    Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR, et al. Dutch echocardiographic cardiac risk evaluation applying stress echocardiography study group. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009;361:980–9.

  43. 43.

    Shah K, Mohammed A, Patil S, McFadyen A, Meek RMD. Circulating cytokines after hip and knee arthroplasty: a preliminary study. Clin Orthop Relat Res. 2009;467:946–51.

    Article  PubMed  Google Scholar 

  44. 44.

    Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301–7.

  45. 45.

    Stoecklein VM, Osuka A, Lederer JA. Trauma equals danger—damage control by the immune system. J Leukoc Biol. 2012;92:539–51.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Sun T, Wang X, Liu Z, Chen X, Zhang J. Plasma concentrations of pro- and anti-inflammatory cytokines and outcome prediction in elderly hip fracture patients. Injury. 2011;42:707–13.

    Article  PubMed  Google Scholar 

  47. 47.

    Vallet H, Breining A, Le Manach Y, Cohen-Bittan J, Meziere A, Raux M, et al. Isolated cardiac troponin rise does not modify the prognosis in elderly patients with hip fracture. Medicine (Baltimore). 2017;96:e6169.

  48. 48.

    Vascular Events In Noncardiac Surgery Patients Cohort Evaluation (VISION) Study Investigators, Devereaux PJ, Chan MT, Alonso-Coello P, Walsh M, Berwanger O, Villar JC, Wang CY, Garutti RI, Jacka MJ, Sigamani A, Srinathan S, Biccard BM, Chow CK, Abraham V, Tiboni M, Pettit S, Szczeklik W, Lurati Buse G, Botto F, Guyatt G, Heels-Ansdell D, Sessler DI, Thorlund K, Garg AX, Mrkobrada M, Thomas S, Rodseth RN, Pearse RM, Thabane L, McQueen MJ, VanHelder T, Bhandari M, Bosch J, Kurz A, Polanczyk C, Malaga G, Nagele P, Le Manach Y, Leuwer M, Yusuf S. Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. JAMA. 2012;307:2295–304.

    Article  Google Scholar 

  49. 49.

    Wadia SK, Belkin M, Chow KS, Nattiv J, Appis A, Feinstein SB, et al. In-hospital statin underutilization among high-risk patients: delayed uptake of the 2013 cholesterol guidelines in a U.S. cohort. Hosp Pract (1995). 2017;45:16–20.

  50. 50.

    Winchester DE, Wen X, Xie L, Bavry AA. Evidence of pre-procedural statin therapy a meta-analysis of randomized trials. J Am Coll Cardiol. 2010;56:1099–109.

    Article  PubMed  Google Scholar 

  51. 51.

    Wu AH, Shea E, Lu QT, Minyard J, Bui K, Hsu JC, et al. Short- and long-term cardiac troponin I analyte stability in plasma and serum from healthy volunteers by use of an ultrasensitive, single-molecule counting assay. Clin Chem. 2009;55:2057–9.

Download references

Funding

This trial was funded by the Weill Cornell Clinical and Translational Science Center (UL1TR000457-06). Pfizer provided study drug and matching placebo for a subset of patients (the remainder was compounded locally), but had no involvement in the design of the trial, analysis of the results, or manuscript preparation. Abbott provided reagents for hs-cTnI testing.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Anne R. Bass MD.

Ethics declarations

Conflict of Interest

Jaclyn D. Szymonifka, MA; Matthew T. Rondina, MD, MS; Margaret Bogardus, BA; Scott C. Woller, MD; Scott M. Stevens, MD; Kerri Merritt; Gerard Moskowitz, PhD; Alejandro Gonzalez Della Valle, MD; and Eva Flores, MD, have declared that they have no conflict of interest. Mitchell G. Scott, PhD, reports a grant from Abbott Diagnostics during the conduct of the study. He also reports grants from Instrumentation Laboratory and Siemens Healthcare; other from Becton, Dickinson and Roche Diagnostics, outside the work. Anne R. Bass, MD, reports grants from Weill Cornell Clinical and Translational Science Center (UL1TR000457-06) and other from Pfizer and Abbott Labs during the conduct of the study. Charles Eby, MD, reports grants from Siemens Healthcare Diagnostics and personal fess from Boehringer Ingelheim and Bayer Pharmaceuticals, outside the work. Brian F. Gage, MD, MSc, reports ownership of stock in at least 1 pharmaceutical company that markets or manufactures statins.

Human/Animal Rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed Consent

Informed consent was obtained from all patients for being included in the study.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Additional information

Level of evidence: double-blind, randomized controlled trial, level II

The work was performed at Hospital for Special Surgery, New York Presbyterian Hospital, University of Utah (cytokine assays) and Washington University in St. Louis (hs-troponin and hs-CRP assays).

Electronic supplementary material

ESM 1

(PDF 56 kb)

ESM 2

(PDF 4971 kb)

Appendix

Appendix

Table 3 Adverse events
Fig. 5
figure5figure5

Cytokines levels at baseline and on postoperative day 2.

Table 4 Atorvastatin effect on perioperative cytokine levels. This data demonstrates that the preoperative levels of the cytokines predicted the postoperative levels, and that atorvastatin did not significantly affect the change in cytokine levels, with the possible exception of IL­5 (P = 0.043). The negative intercept for IL-4 indicates a significant decline after surgery, while positive intercepts for IL-5 and especially IL-6 indicates significant rises after surgery.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bass, A.R., Szymonifka, J.D., Rondina, M.T. et al. Postoperative Myocardial Injury and Inflammation Is Not Blunted by a Trial of Atorvastatin in Orthopedic Surgery Patients. HSS Jrnl 14, 67–76 (2018). https://doi.org/10.1007/s11420-017-9577-1

Download citation

Keywords

  • troponin
  • orthopedics
  • inflammation
  • interleukin-6
  • C-reactive protein
  • myocardial ischemia