1. بسم الله الرحمن الرحيم

2. Should all patients receive statins before major noncardiac and cardiac surgeries?!! By Amr Abdelmonem,MD Assistant professor of anesthesia, faculty of medicine,Cairo university

3. Thus we should beware of clinging to vulgar opinions, and judge things by reason‘s way,not by popular say. MONTAIGNE(1533-1592)

4. The world of statins

5. The lipidemic effects of statins The lipidemic effects of statins

6. What is cholesterol ? Pearly –colored,waxy, solid alcohol that is soapy to touch Where does cholesterol come from? 80 % comes from the body itself, every cell in the body is capable of making its own cholesterol, most don’t and rely instead on that made in the liver and skin. Cholesterol and triglycerides are insoluble in blood Lipoproteins are envelops that enclose cholesterol and triglycerides Making them soluble in blood,so that they can be transported to tissues

7. The cholesterol factory Stryer L:Biochemistry.New york,W.H.Freeman Co.,1988 3- hydroxy-3 methyl-glutaryl-coenzyme A reductase HMG-CoA Reductase The rate limiting step The LDL cholesterol from the blood Fall in LDL cholesterol

8. Ashen DM,blumenthal SR.low HDL levels.N Engl Med.2005;353:1252 Ginsberg NH,Zhanng LYet al.metabolic syndrome:focus on dyslipidemia.Obes Res ;2006:14s

9. Are the beneficial effects of statins limited to patients of hypercholesterolemia ? No Albert MA, Danielson E, Rifai N, et al: Effect of statin therapy on C-reactive protein levels: The pravastatin inflammation/CRP evaluation (PRINCE): A randomized trial and cohort study. JAMA 286: 64-70, 2001 Cipollone F, Fazia M, Iezzi A, et al: Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans. Circulation 107:1479-1485, 2003 Harris MB, Blackstone MA, Sood SG, et al. Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol 2004; 287: H560–6

10. Pleiotropic effects of statins Modulate the immune properties of cells by regulation of endothelial, platlet, and leukocyte function Kinlay S, Schwartz GG, Olsson AG, et al: High-dose atorvastatin enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003; 108:1560- 1566, Shishehbor MH, Brennan ML, Aviles RJ, et al: Statins promote potent systemic antioxidant effects through specific inflammatory pathways.Circulatio 2003; 108:426-431, Attenuate the release of acute phase proteins thus reducing the inflammation Hack CE, Zeerleder S: The endothelium in sepsis: Source of and a target for inflammation. Crit Care Med 2001; 29:S21-S27, Inhibit monocyte activation by certain endotoxins and reducing cytokine release and adhesion molecule expression Weber C, Erl W, Weber KS, et al: HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 1997; 30:1212-1217,

11. Pleiotropic effects of statins (cont.) Thmbosis is suppressed and fibrinolysis is enhanced by reducing platlet aggregation and adhesion and thromboxane formation enhancing tissue plasminogen activator synthesis and reducing plasminogen activator inhibitor Schwarts GC,Olsson AG. The case for intensive statin therapy after acute coronary syndromes.Am J Cardiol.2005;96:45-53F Modulate microvascular remodeling and attenuate vasoconstriction by increased expression of endothelial nitric oxide synthase (eNOS), in conjunction with down-regulation of inducible nitric oxide synthase and inhibiting the release of angiotensin II and endothelin McGrown C and Brookes Z.Beneficial effects of statins on the microcirculation during sepsis.Br J Aneaesth 2007 ;98:163-75

12. Unfortunately, statins don’t work their magic without side effects or without expense

13. ACC/AHA/NHLBI clinical advisory on monitoring the side effects and follow up schedule for statins Follow up scheduleMonitoring parameter Evaluate symptoms initially,6- 8 weeks after starting Evaluate muscle symptoms and ck before starting, muscle symptoms 6-12 weeks after starting and obtain CK when syptoms occure Evaluate initially, 12 weeks after starting and then annually or more frequently when indicated Headache,dyspepsia Muscle soreness,tenderness or pain ALT/AST

14. What is the Strength of evidence for routine perioperative use of statins to reduce cardiovascular risk 18 studies –two randomised trials,15 cohort studies and one case control studies – assessed whether statins provide perioperative cardiovascular protection. Statins were not randomly allocated, results in retrospective studies were larger than those in prospective cohort studies, and dose,duration and safety of statin use was not reported

15. Conclusion The evidence base for routine adminstration of statins to reduce perioperative cardiovascular risk for patients without established coronary artery disease is inadequate Kapoor S,Kanji H,McAlister F. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ 2006;333:1149

16. It is not recommended by evidence that patients with RCRI less than 2 recieve routine statins to reduce perioperative cardiac risk Beattie W, Elliott R. Evidence – based perioperative risk reduction. Canadian Journal of Anesthesia 2005 ;52:R5 Beattie W, Elliott R. Evidence – based perioperative risk reduction. Canadian Journal of Anesthesia 2005 ;52:R5

17. What about the patients with coronary artery disease independent for the proposed operation

18. Major noncardiac surgery In a case-control study of 2,816 patients undergoing major noncardiac vascular surgery, patients who received statins preoperatively had an approximately 4.5-fold reduction in the risk of postoperative mortality compared with patients who did not receive statins Poldermans D, Bax JJ, Kertai MD, et al: Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003;107:1848-1851, Both Durazzo et al and Schouten et al observed a lower incidence of postoperative nonfatal acute MI among statin users (6% v 16% and 6.6% v 10.7%, respectively). Schouten O, Kertai MD, Bax JJ, et al: Safety of perioperativestatin use in high-risk patients undergoing major vascular surger Am J Cardiol 95:658-660, 2005

19. Recommendations Kapoor S,Kanji H,McAlister F. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies. BMJ 2006;333:1149 Beattie W, Elliott R. Evidence – based perioperative risk reduction. Canadian Journal of Anesthesia 2005 ;52:R5 Wright RS, Murphy JG, Bybee KA, et al: Statin lipid-lowering therapy for acute myocardial infarction and unstable angina: Efficacy and mechanism of benefit. Mayo Clin Proc 77:1085-1092 Waters D, Schwartz GG, Olsson AG. The Myocardial IschemiaReduct2002 ;ion with Acute Cholesterol Lowering (MIRACL) trial: A newfrontier for statins? Curr Control Trials Cardiovasc Med2001; 2:111-114, Statins shoud be started preoperatively in eligible patients who would warrant statin therapy for medical reasons : Patients with coronary artery disease Patients with multiple cardiac risk factors Patients with LDL >100 mg/dl

20. Questions about timing The minimum length of preoperative statin adminstration necessary to protect against acute perioperative outcomes has yet to be determined Hindler K, Collard C.influence of statins on perioperative outcomes.journal of cardiothoracic and vascular anesthesia 2006;20:251-258 Previous studies have shown that statin therapy improves endothelial function and lowers serum inflammatory markers as early as 6 to 16 weeks after beginning administration Chan AW, Bhatt DL, Chew DP, et al: Early and sustained survival benefit associated with statin therapy at the time of percutaneou coronary intervention. Circulation 2002;105:691-696, Kinlay S, Schwartz GG, Olsson AG, et al: High-dose atorvastati enhances the decline in inflammatory markers in patients with acute coronary syndromes in the MIRACL study. Circulation 2003; 108:1560-1566

21. If you started statins preoperatively, you should continue it in the perioperative period Durazzo AE, Machado FS, Ikeoka DT, et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg 2004; 39:967–975 Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003; 107:1848–1851..

22. Statin therapy in patients undergoing CABG Statins have been shown to prevent neointimal formation in saphenous vein grafts by inhibiting cellular matrix metalloproteinase activity and the proliferation and migration of smooth muscle cells Porter KE, Turner NA: Statins for the prevention of vein graft stenosis: A role for inhibition of matrix metalloproteinase-9. Biochem Soc Trans 2002; 30:120-126 Statins have been shown to protect arterial bypass grafts. Treatment of radial and left internal thoracic artery specimens With cerivastatin in vitro was recently found to preserve endothelium- dependent vasodilatation Nakamura K, Al-Ruzzeh S, Chester AH, et al: Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries. Ann Thorac Surg 73:1860-1865, 2002 Statin pretreatment before CABG imparts a beneficial effect with regard to reduced rates of acute morbidity and mortality Clark L, Ikonomidis J, Crawford F,et al.preoperative statin treatment is associated with reduced postoperative mortality and morbidity in patients undergoing cardiac surgery :8 -year retrospective cohort study.J thorac cardiovasc SURG 2006;131:679-85

23. Dosages, types of statin and safety issues 80 mg of atorvastatin is the most common high intensity statin used and has been associated with better outcomes in patients compared with moderate doses with other statins and the benefits of this high dose appear to outweigh any potential risks 80 mg of atorvastatin is the most common high intensity statin used and has been associated with better outcomes in patients compared with moderate doses with other statins and the benefits of this high dose appear to outweigh any potential risks Lazar H.should all patients receive statins before cardiac surgery :are more data necessary ?. J Lazar H.should all patients receive statins before cardiac surgery :are more data necessary ?. J thorac cardiovasc surg 2006;131:520-2

24. Statins and valve surgery Several recent studies have suggested that statins may also reduce the progression of calcific aortic stenosis and bioprosthetic valve degeneration Rosenhek R, Rader F, Loho N, et al: Statins but not angiotensinconverting enzyme inhibitors delay progression of aortic stenosis. Circulation 2004; 110:1291-1295, Luo JD, Zhang WW, Zhang GP, et al: Effects of simvastatin onleft ventricular hypertrophy and function in rats with aortic stenosis.Zhongguo Yao Li Xue Bao 20:345-348, 1999 In an experimental animal model of aortic stenosis, statin administration inhibited the development of left ventricular hypertrophy and improved left ventricular function Luo JD, Zhang WW, Zhang GP, et al: Effects of simvastatin onleft ventricular hypertrophy and function in rats with aortic stenosis.Zhongguo Yao Li Xue Bao 1999 20:345-348, Statin administration in humans has also been associated with a reduction in the progression of aortic stenosis, including a decrease in the aortic valve area in patients receiving statins compared with nonstatin Users Novaro GM, Tiong IY, Pearce GL, et al: Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression o calcific aortic stenosis. Circulation 2001; 104:2205-2209, Shavelle DM, Takasu J, Budoff MJ, et al: HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 2002; 359:1125-1126,

25. Summary

26. Statins can be classified into lipophilic HMG-CoA reductase inhibitors (atorvastatin, simvastatin, cervastatin, fluvastatin, and lovastatin) and hydrophilic HMG-CoA reductase inhibitors (pravastatin and rosuvastatin). Statins or hydroxy methyl glutaryl-CoA (HMG-CoA) reductase inhibitors are widely used clinically as cholesterol-lowering agents because of their ability to block hepatic conversion of HMG-CoA to L-mevalonate under low and normal cholesterol conditions, statins exert antiinflammatory actions independent of their lipid-lowering effects

27. Although an accumulating body of evidence suggests that preoperative statin therapy may reduce the risk of adverse postoperative outcomes, many of the studies performed to date have important limitations First, administration of preoperative statin therapy was neither prospective nor randomized in many studies Second, the influence of the duration of preoperative statin therapy on the risk of postoperative outcomes has not yet been adequately addressed Third, further study is needed to evaluate the effect of discontinuing statins in the postoperative period because acute discontinuation may increase postoperative risk in patients with severe, unstable CAD. Heeschen C, Hamm CW, Laufs U, et al: Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 2002; 105:1446-1452

28. ACC/AHA recommendations Patients undergoing CABG should receive statins to achieve LDL levels of less than 100 mg /dl Or less than 70mg /dl for patients with hihgest risk factors ( diabetes, hypertension, obesity, smoking,metabolic syndrome and acute coronary syndromes) Statins should be continued thropughout the perioperative period