بسم الله الرحمن بسم الله الرحمن الرحيمالرحيم

Should all patients receive statins before major noncardiac and cardiac

surgeries!!?

By Amr Abdelmonem,MD

Assistant professor of anesthesia , faculty of medicine ,Cairo university

Thus we should beware of clinging to vulgar opinions , and judge things by reason‘s way ,not by popular say.

MONTAIGNE(1533-1592)

The world of statinsThe world of statins

The lipidemic effects of The lipidemic effects of statinsstatins

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

The cholesterol factoryStryer L:Biochemistry.New york,W.H.Freeman Co.,1988

3- hydroxy-3 methyl-glutaryl-coenzyme A reductaseHMG-CoA Reductase

The rate limiting step

The LDL cholesterol from the blood

Fall in LDL cholesterol

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

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 ,2001Cipollone F, Fazia M, Iezzi A, et al: Suppression of the functionallycoupled cyclooxygenase-2/prostaglandin E synthase as a basisof simvastatin-dependent plaque stabilization in humans. Circulation

107:1479-1485 ,2003Harris MB, Blackstone MA, Sood SG, et al. Acute activation andphosphorylation of endothelial nitric oxide synthase byHMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol

2004 ;287 :H560–6

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

inflammationHack 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 ,

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;96:45-53FModulate 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

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

without expense

ACC/AHA/NHLBI clinical advisory on monitoring the side effects and follow

up schedule for statinsMonitoring parameter

Follow up schedule

Headache ,dyspepsia

Muscle soreness ,tenderness or pain

ALT/AST

Evaluate symptoms initially ,6-8 weeks after startingEvaluate 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

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

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

   

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

What about the patients with coronary artery disease independent for the

proposed operation

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 statinsPoldermans 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

RecommendationsKapoor 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

Questions about timing

The minimum length of preoperative statin The minimum length of preoperative statin adminstration necessary to protect against acute adminstration necessary to protect against acute

perioperative outcomes has yet to be determinedperioperative outcomes has yet to be determined Hindler K, Collard C.influence of statins on perioperative outcomes.journal of cardiothoracic and vascular anesthesia 2006;20:251-258Hindler 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

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..

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; 30:120-126Statins 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 vasodilatationNakamura 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

Dosages , types of statin and safety issues

8080 mg of atorvastatin is the most common high mg of atorvastatin is the most common high intensity statin used and has been associated intensity statin used and has been associated with better outcomes in patients compared with with better outcomes in patients compared with moderate doses with other statins and the moderate doses with other statins and the benefits of this high dose appear to outweigh any benefits of this high dose appear to outweigh any potential riskspotential risksLazar 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

Statins and valve surgery Several recent studies have suggested that statins may alsoreduce the progression of calcific aortic stenosis and bioprostheticvalve 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 UsersNovaro 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,

Summary

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

Although an accumulating body of evidence suggests thatpreoperative statin therapy may reduce the risk of adversepostoperative outcomes, many of the studies performed to datehave important limitations First, administration of preoperative statin therapy was neither prospective nor randomized in many studies

Second, the influence of the duration of preoperative statintherapy on the risk of postoperative outcomes has not yet beenadequately addressed Third, further study is needed to evaluate the effect ofdiscontinuing statins in the postoperative period because acutediscontinuation may increase postoperative risk in patients withsevere, 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

ACC/AHA recommendations

Patients undergoing CABG should Patients undergoing CABG should receive statins to achieve LDL levels receive statins to achieve LDL levels of less than 100 mg /dlof less than 100 mg /dl

Or less than 70mg /dl for patients with Or less than 70mg /dl for patients with hihgest risk factors ( diabetes , hihgest risk factors ( diabetes , hypertension, obesity , hypertension, obesity , smoking ,metabolic syndrome and smoking ,metabolic syndrome and acute coronary syndromes)acute coronary syndromes)

Statins should be continued Statins should be continued thropughout the perioperative periodthropughout the perioperative period