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Preoperative C-Reactive Protein Levels Predict Readmission Following Elective Vascular Surgery

CLI Journal Original Contribution – The Official Journal of CLI Global Society

Asrar Khan, MD1,2; Derrick L. Green, MD, MBA3; Steve Santilli, MD, PhD, MBA3; Debra K. Johnson, RN1,2;
Selma Carlson, MD1,2; Mackenzi Mbai, MD1,2; Rosemary F. Kelly, MD4;
Amy A. Gravely, MS5; Brad Bart, MD1,2; Selcuk Adabag, MD1,2; Santiago Garcia, MD6;
Qun Chen, PhD7,8; Ion S. Jovin, MD7,8; Edward Lesnefsky, MD7,8; Edward O. McFalls, MD, PhD1,2

Abstract

Background

C-reactive protein (CRP) levels may be reduced with long-term administration of ubiquinone (CoQ10) in patients with chronic ischemic heart disease, but the impact of a short-term period of administration in patients undergoing elective vascular surgery is uncertain.

Methods

A double-blind, randomized, controlled trial was implemented to determine whether preoperative administration of CoQ10 could reduce cardiac biomarker elevations. Patients were randomly assigned to CoQ10 (400 mg per day) versus placebo for 3 days prior to surgery. B-type natriuretic peptide (BNP), troponin, and CRP levels were obtained before and after surgery. The primary endpoint was peak biomarker elevations and secondary endpoints were length of stay and readmission.

Results

A total of 123 patients were randomly assigned to CoQ10 (n = 62) or placebo (n = 61) for 3 days before surgery. At 24 hours post-surgery, the group receiving CoQ10 had lower BNP levels, with no intergroup differences in CRP. Within 1 year post discharge, 36 patients (29%) were readmitted and preoperative risk for readmission included diabetes mellitus (hazard ratio [HR], 3.60; 95% confidence interval [CI], 1.46-8.91), active smoking (HR, 3.55; 95% CI, 1.43-8.78), and CRP (HR, 1.35; 95% CI, 1.04-1.76). C-index for all 3 variables predicting readmission was 0.727.

Conclusion

Short-term administration of CoQ10 reduced perioperative BNP, but not CRP levels. CRP, along with diabetes and active smoking, were independent predictors of readmission and might be suitable variables to modify as a means of reducing subsequent rehospitalizations following elective vascular procedures.

CLI Journal Original Contribution – The Official Journal of CLI Global Society: Read Full Article

Introduction

Among Medicare beneficiaries undergoing vascular surgery, nearly 1 in 4 patients are readmitted within 30 days of hospital discharge and as a diagnosis-related group (DRG), cause of readmission is second only to congestive heart failure.1 Although readmissions following vascular surgery are often unplanned,2,3 identifiable clinical risk factors can be recognized at the time of discharge and include age, socioeconomic factors, and select comorbidities.4-9 There is emerging interest in exploring the utility of perioperative biomarkers as a means of predicting those patients who have the highest risk of adverse postoperative outcomes, including unplanned readmissions.10 Preoperative N-terminal prohormone B-type natriuretic peptide (NT-proBNP) has been recommended as an optimal means of risk stratifying patients undergoing noncardiac operations11 and has value in patients undergoing vascular surgery.12 In support of those studies, we have shown that preoperative NT-proBNP levels predict postoperative risk of myocardial injury.13 C-reactive protein (CRP), a readily available biomarker, can also predict poor outcomes in patients with ischemic heart disease14,15 and together with BNP, may have value in predicting adverse events in patients with vascular disease.16,17

Ubiquinone (CoQ10) is an endogenous antioxidant that improves outcomes in patients with heart failure and ischemic heart disease.18 Reducing oxidant stress in the mitochondria within the myocyte may play a key role in attenuating inflammation within cardiac tissue. In fact, in a meta-analysis, CoQ10 administration significantly decreased plasma CRP levels.19 Interleukin-6 (IL-6) is a secondary messenger cytokine that induces hepatic CRP production20 and is also lowered by administration of CoQ10.21 To no surprise, the greatest effect on CRP reduction with CoQ10 administration is among those patients with elevated IL-6 levels.22 A plausible mechanism for CoQ10’s antioxidant effect on reduced inflammation is the inhibition of IL-6, which is upstream from the production of proinflammatory cytokines.23

In the present study, we assessed the utility of CRP levels in predicting risk of readmission to the hospital following hospital discharge. Because long-term administration of CoQ10 has been shown to reduce CRP levels in selected patients,24,25 testing the effects of a short-term period of administration on postoperative CRP levels is relevant.

Disclosures

The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

1Division of Cardiology, Minneapolis VA Medical Center, Minneapolis, Minnesota;
2Division of Cardiology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota;
3Division of Vascular Surgery, Minneapolis VA Medical Center, Minneapolis, Minnesota;
4Division of Cardiothoracic Surgery, University of Minnesota, Minneapolis, Minnesota;
5Department of Research Statistical Center, Minneapolis VA Medical Center, Minneapolis, Minnesota;
6Minneapolis Heart Institute, Minneapolis, Minnesota;
7Department of Medicine, Virginia Commonwealth University, Richmond, Virginia; and the
8Division of Cardiology, McGuire VA Medical Center, Richmond, Virginia.

Clinicaltrials.gov Identifier: NCT03956017

Manuscript accepted May 4, 2022.

Address for correspondence: Edward McFalls, MD, Richmond VAMC, Hunter Holmes McGuire VA Medical Center, 1201 Broad Rock Boulevard, Richmond, VA 23249. Email: mcfal001@umn.edu

References

1. Jencks SF, Williams MV, Coleman EA. Rehospitalizations among patients in the Medicare fee-for-service program. N Engl J Med. 2009;360(14):1418-1428. doi:10.1056/NEJMsa0803563

2. Jackson BM, Nathan DP, Doctor L, Wang GJ, Woo EY, Fairman RM. Low rehospitalization rate for vascular surgery patients. J Vasc Surg. 2011;54(3):767-772. Epub 2011 Jul 1. doi:10.1016/j.jvs.2011.03.255

3. Kansagara D, Englander H, Salanitro A, et al. Risk prediction models for hospital readmission: a systematic review. JAMA. 2011;306(15):1688-1698. doi:10.1001/jama.2011.1515

4. Giles KA, Landon BE, Cotterill P, O’Malley AJ, Pomposelli FB, Schermerhorn ML. Thirty-day mortality and late survival with reinterventions and readmissions after open and endovascular aortic aneurysm repair in Medicare beneficiaries. J Vasc Surg. 2011;53(1):6-12,3.e1. Epub 2010 Oct 27. doi:10.1016/j.jvs.2010.08.051

5. Durham CA, Mohr MC, Parker FM, Bogey WM, Powell CS, Stoner MC. The impact of socioeconomic factors on outcome and hospital costs associated with femoropopliteal revascularization. J Vasc Surg. 2010;52(3):600-606; discussion 606-607. Epub 2010 Jul 3. doi:10.1016/j.jvs.2010.04.011

6. Bodewes TCF, Pothof AB, Darling JD, et al. Preoperative anemia associated with adverse outcomes after infrainguinal bypass surgery in patients with chronic limb-threatening ischemia. J Vasc Surg. 2017;66(6):1775-1785.e2. Epub 2017 Aug 16. doi:10.1016/j.jvs.2017.05.103

7. Bluemn EG, Flahive JM, Farber A, et al. Analysis of thirty-day readmission after infrainguinal bypass. Ann Vasc Surg. 2019;61:34-47. Epub 2019 Jul 23. doi:10.1016/j.avsg.2019.04.029

8. Kolte D, Kennedy KF, Shishehbor MH, et al. Thirty-day readmissions after endovascular or surgical therapy for critical limb ischemia: analysis of the 2013 to 2014 Nationwide Readmissions Databases. Circulation. 2017;136(2):167-176. Epub 2017 May 2. doi:10.1161/CIRCULATIONAHA.117.027625

9. Fry DE, Nedza SM, Pine M, Reband AM, Huang CJ, Pine G. Medicare risk-adjusted outcomes in elective major vascular surgery. Surgery. 2018;164(4):831-838. Epub 2018 Jun 22. doi:10.1016/j.surg.2018.03.025

10. Cacko A, Kondracka A, Gawalko M, et al. Novel biochemical predictors of unfavorable prognosis for stable coronary disease. Medicine (Baltimore). 2018;97(37):e12372. doi:10.1097/MD.0000000000012372

11. Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular Society guidelines on perioperative cardiac risk assessment and management for patients who undergo noncardiac surgery. Can J Cardiol. 2017;33(1):17-32. Epub 2016 Oct 4. doi:10.1016/j.cjca.2016.09.008

12. Duceppe E, Patel A, Chan MTV, et al. Preoperative N-terminal pro-B-type natriuretic peptide and cardiovascular events after noncardiac surgery: a cohort study. Ann Intern Med. 2020;172(2):96-104. Epub 2019 Dec 24. doi:10.7326/M19-2501

13. Khan A, Johnson DK, Carlson S, et al. NT-Pro BNP predicts myocardial injury post-vascular surgery and is reduced with CoQ10: a randomized double-blind trial. Ann Vasc Surg. 2020;64:292-302. Epub 2019 Oct 17. doi:10.1016/j.avsg.2019.09.017

14. Lawler PR, Bhatt DL, Godoy LC, et al. Targeting cardiovascular inflammation: next steps in clinical translation. Eur Heart J. 2021;42(1):113-131. doi:10.1093/eurheartj/ehaa099

15. Jia RF, Li L, Li H, et al. Meta-analysis of C-reactive protein and risk of angina pectoris. Am J Cardiol. 2020;125(7):1039-1045. Epub 2020 Jan 8. doi:10.1016/j.amjcard.2020.01.005

16. Budzynski J, Tojek K, Czerniak B, Banaszkiewicz Z. Scores of nutritional risk and parameters of nutritional status assessment as predictors of in-hospital mortality and readmissions in the general hospital population. Clin Nutr. 2016;35(6):1464-1471. Epub 2016 Apr 4. doi:10.1016/j.clnu.2016.03.025

17. Stone PA, Schlarb H, Campbell JE, et al. C-reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization. J Vasc Surg. 2014;60(3):652-660 Epub 2014 Apr 29. doi:10.1016/j.jvs.2014.03.254

18. Raizner AE, Quiñones MA. Coenzyme Q(10) for patients with cardiovascular disease: JACC focus seminar. J Am Coll Cardiol. 2021;77(5):609-619. doi:10.1016/j.jacc.2020.12.009

19. Mazidi M, Kengne AP, Banach M. The Lipid and Blood Pressure Meta-analysis Collaboration Group. Effects of coenzyme Q10 supplementation on plasma C-reactive protein concentrations: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2018;128:130-136. Epub 2017 Aug 25. doi:10.1016/j.phrs.2017.08.011

20. Heinrich PC, Castell JV, Andus TJBj. Interleukin-6 and the acute phase response. Biochem J. 1990;265(3):621-636. doi:10.1042/bj2650621

21. Nagib MM, Tadros MG, Al-khalek HAA, et al. Molecular mechanisms of neuroprotective effect of adjuvant therapy with phenytoin in pentylenetetrazole-induced seizures: impact on Sirt1/NRF2 signaling pathways. Neurotoxicology. 2018;68:47-65. Epub 2018 Jul 11. doi:10.1016/j.neuro.2018.07.006

22. Fan L, Feng Y, Chen G-C, Qin L-Q, Fu C-l, Chen L-H. Effects of coenzyme Q10 supplementation on inflammatory markers: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res. 2017;119:128-136. Epub 2017 Feb 5. doi:10.1016/j.phrs.2017.01.032

23. Schmelzer C, Lorenz G, Rimbach G, Doring F. In vitro effects of the reduced form of coenzyme Q(10) on secretion levels of TNF-alpha and chemokines in response to LPS in the human monocytic cell line THP-1. J Clin Biochem Nutrition. 2009;44(1):62-66. Epub 2008 Dec 27. doi:10.3164/jcbn.08-182

24. Lee B, Huang Y, Chen S, Lin P. Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with coronary artery disease. Nutrition. 2012;28(3):250-255. Epub 2011 Oct 12. doi:10.1016/j.nut.2011.06.004

25. Zahed NS, Ghassami M, Nikbakht H. Effects of coenzyme Q10 supplementation on C-reactive protein and homocysteine as the inflammatory markers in hemodialysis patients; a randomized clinical trial. J Nephropathol. 2016;5(1):38-43. Epub 2015 Nov 7. doi:10.15171/jnp.2016.07

26. Bhagavan HN, Chopra RK. Coenzyme Q10: absorption, tissue uptake, metabolism and pharmacokinetics. Free Radic Res. 2006;40(5):445-453. doi:10.1080/10715760600617843

27. Nguyen JT, Vakil K, Adabag S, et al. Hospital readmission rates following ami: potential interventions to improve efficiency. South Med J. 2018;111(2):93-97. doi:10.14423/SMJ.0000000000000768

28. Wada H, Dohi T, Miyauchi K, et al. Preprocedural high-sensitivity C-reactive protein predicts long-term outcome of percutaneous coronary intervention. Circ J. 2016;81(1):90-95. Epub 2016 Nov 19. doi:10.1253/circj.CJ-16-0790

29. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. Epub 2017 Aug 27. doi:10.1056/NEJMoa1707914

30. Ridker PM. From C-reactive protein to interleukin-6 to interleukin-1: moving upstream to identify novel targets for atheroprotection. Circ Res. 2016;118(1):145-156. doi:10.1161/CIRCRESAHA.115.306656

31. van Straten AH, Soliman Hamad MA, van Zundert AJ, Martens EJ, Schönberger JP, de Wolf AM. Preoperative C-reactive protein levels to predict early and late mortalities after coronary artery bypass surgery: eight years of follow-up. J Thorac Cardiovasc Surg. 2009;138(4):954-958. Epub 2009 Jun 23. doi:10.1016/j.jtcvs.2009.03.050

32. Kangasniemi OP, Biancari F, Luukkonen J, et al. Preoperative C-reactive protein is predictive of long-term outcome after coronary artery bypass surgery. Eur J Cardiothorac Surg. 2006;29(6):983-985. Epub 2006 May 8. doi:10.1016/j.ejcts.2006.02.022

33. D’Agostino D, Cappabianca G, Rotunno C, et al. The preoperative inflammatory status affects the clinical outcome in cardiac surgery. Antibiotics (Basel). 2019;8(4):176. doi:10.3390/antibiotics8040176

34. Owens CD, Ridker PM, Belkin M, et al. Elevated C-reactive protein levels are associated with postoperative events in patients undergoing lower extremity vein bypass surgery. J Vasc Surg. 2007;45(1):2-9; discussion 9. Epub 2006 Nov 21. doi:10.1016/j.jvs.2006.08.048

35. Singh TP, Morris DR, Smith S, Moxon JV, Golledge J. Systematic review and meta-analysis of the association between C-reactive protein and major cardiovascular events in patients with peripheral artery disease. Eur J Vasc Endovasc Surg. 2017;54(2):220-233. Epub 2017 Jun 27. doi:10.1016/j.ejvs.2017.05.009

36. Padayachee L, Rodseth RN, Biccard BM. A meta-analysis of the utility of C-reactive protein in predicting early, intermediate-term and long term mortality and major adverse cardiac events in vascular surgical patients. Anaesthesia. 2009;64(4):416-424. doi:10.1111/j.1365-2044.2008.05786.x

37. Scrutinio D, Guido G, Guida P, et al. Combined use of high-sensitivity C-reactive protein and N-terminal pro-B-type natriuretic peptide for risk stratification of vascular surgery patients. Ann Vasc Surg. 2014;28(6):1522-1529. Epub 2014 Feb 11. doi:10.1016/j.avsg.2014.01.012

38. Straatman J, Harmsen AM, Cuesta MA, Berkhof J, Jansma EP, van der Peet DL. Predictive value of C-reactive protein for major complications after major abdominal surgery: a systematic review and pooled-analysis. PLoS One. 2015;10(7):e0132995. eCollection 2015. doi:10.1371/journal.pone.0132995