• Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase; they are primarily indicated for the treatment of hypercholesterolemia and reducing low-density lipoprotein-cholesterol (LDL-C).
• Statins have also been shown to possess several pleiotropic effects:
  • Improved vascular endothelial function
  • Immunomodulation
  • Stabilization of atheromatous plaques
  • Protection against thrombosis
• In future investigations, indications for perioperative statin use are likely to be expanded and further delineated.

• Pharmacology: Primary role is the reduction of cholesterol synthesis. Statins competitively inhibit HMG-CoA reductase in the liver. HMG-CoA reductase catalyzes the synthesis of mevalonate, the rate-limiting step in cholesterol biosynthesis.
• Decreases in hepatic intracellular cholesterol synthesis and release result in extrahepatic upregulation of LDL receptor expression on their cell surfaces, thereby increasing clearance of LDL and VLDL.
• Pleiotropic effects
  • Improved endothelial function; impairments are closely associated with adverse outcomes.
    • Hypercholesterolemia and atherosclerosis impair endothelium-dependent vasodilation and nitric oxide (NO) production.
    • NO has several anti-inflammatory and anti-thrombotic effects that protect against chemokine expression, left ventricular remodeling and dysfunction, and thrombogenesis.
  • Immunomodulation: Statins decrease systemic inflammation and stabilize atheromatous plaques by reducing:
    • LDL levels: Normal oxidative modification of LDL-C elicits an antigenic response by macrophages, strongly promoting inflammation.
    • Interleukins (IL): The inflammatory process in atherosclerotic plaques produce inflammatory mediators (e.g., interleukin-6 [IL-6])
    • Tumor necrosis factor (TNF): A pro-inflammatory cytokine produced from atherosclerotic plaque-related inflammatory processes.
    • C-reactive Protein (CRP): Produced by hepatocytes in response to IL-6 and TNF. CRP is a universal marker for inflammation, and is prognostic for coronary heart disease.
  • Protection against thrombosis: Statin therapy reduces platelet adhesion and inhibits thrombogenesis. Venous thrombosis increases the risk of MI and stroke.

• Adverse effects are rare and dose dependent.
  • Muscle damage: Rhabdomyolysis and myopathy (rare). More common when combined with fibrate therapy or used jointly with amiodarone or verapamil.
  • Mild transient proteinuria: There is no associated pattern of renal failure or injury.
  • Mild hepatotoxicity:
    • Hepatic transaminase levels are elevated in 0.5–2.0% of patients; this is a dose-dependent response (1) [A].
    • Abnormal liver function is typically clinically insignificant and progression to liver failure due to statin therapy is rare, if existent.
    • Despite this evidence, cholestasis and acute liver disease are contraindications to statin therapy.
  • Teratogenicity has been described and therefore statins should not be used during pregnancy.
  • Diabetes mellitus: Slightly increases the risk of development.
• Evidence of adverse effects due to perioperative statin exposure (muscle cramps or myalgias, jaundice, or hepatic tenderness) should be followed by testing for creatine kinase or liver function tests, and statins should be discontinued (2) [A].

• Cardiac protection
  • Perioperative MI
    • Type I MI (coronary plaque rupture): Statin therapy has been shown to decrease the incidence by stabilizing coronary plaques and protect against rupture, thus reducing coronary thrombosis (2) [A].
    • Type II MI (due to oxygen supply/demand mismatch): Not affected by statin therapy.
  • Arrhythmias: Decreased incidence, likely via an anti-inflammatory process. Statin therapy has been shown to consistently and significantly protect against atrial fibrillation. However, there is inconclusive evidence indicating protection against ventricular fibrillation.
  • Valvular effects: Active inflammatory processes can lead to valvulitis and calcification.
    • Inhibition of inflammation and stabilization of valvular endothelium is thought to inhibit progression of stenosis.
    • Statin therapy is associated with a reduced incidence of both rheumatic aortic and mitral valve stenosis.
    • There is conflicting evidence as to whether statin exposure influences postoperative morbidity and mortality (as measured by EuroSCORE risk of mortality and long-term survival rates) after valvular heart surgery (2).
  • All-cause mortality following cardiac surgery: Significantly decreased with both long-term treatment and immediate preoperative statin exposure.
• Vascular protection
  • Thrombosis/venous adverse events are decreased.
  • Atherosclerosis
    • Therapy with rosuvastatin or atorvastatin reduced LDL 40%, the amount necessary to achieve atherosclerosis regression.
    • Reasonable target LDL-C levels in high-risk patients are <70 mg/dL (2) [A].
  • Abdominal aortic aneurysm (AAA): A meta-analysis correlates statin exposure with reduced expansion rates of small AAA, as well as improved outcomes in surgical and endovascular AAA repair. Likely due to immunomodulatory effects.
  • Carotid artery disease: Statins may slow progression or cause regression of intima-media thickness and decrease the rate of microemboli. Outcome studies have shown a reduction in stroke risk and cardiovascular events (1).
  • Peripheral artery disease: Statins have been shown to decrease the incidence of cardiac events, perioperative mortality, and renal dysfunction.
• Renal protection
  • Percutaneous coronary interventions: Statin preloading has been shown to decrease contrast-induced nephropathy (CIN).
  • Major vascular surgery: Chronic use has been associated with decreased renal insufficiency and improved recovery rates from renal injury (2) [A]. The role of preloading is unclear.
• Neuroprotection
  • Stroke: Observational studies demonstrate reduced frequency of stroke following major vascular surgery (3). When combined with beta-blockers, statin exposure reduced the incidence of stroke during CABG.
  • Encephalopathy: Evidence is currently inconclusive.
• Other effects
  • Sepsis: Statins appear to play an adjuvant role via suppression of inflammation (reduced IL-6 and TNF levels) and antithrombotic effects. Meta-analyses correlate therapy with reduced infection and improved mortality rates during sepsis. Randomized trials are needed to develop applicable recommendations for use in sepsis.
  • Reactive airway disease: Statin exposure is linked with reduced bronchial hyperreactivity.
• Perioperative strategy of beginning statin therapy: While there is evidence suggesting the beneficial effects of statin therapy in perioperative outcome, further evidence from randomized clinical trials is needed to develop a comprehensive strategy. At this time, dose, type, and duration of therapy need to be determined as well as differentiating between indications for high-risk and average-risk patients.
  • Indications: Currently only for treatment of high-risk cardiac patients. Should be combined with aspirin and titrated with a beta-blocker regimen in patients with ischemic heart disease (4) [A].
  • Type:
    • A meta-analysis of literature determined rosuvastatin or atorvastatin20 mg/dL (potency: Rosuvastatin > atorvastatin > pravastatin > simvastatin) to be optimal (achieved target LDL-C levels) (1) [A].
    • Rosuvastatin has a similar risk-benefit profile as other statins, but its increased potency is advantageous due to the dose-dependent nature of adverse effects.
    • Fluvastatin is less potent than rosuvastatin or atorvastatin. However, its longer half-life and extended release may make it preferable in patients unable to receive oral medications in the immediate postoperative period. It is not hepatically metabolized, so it may be preferred in cases of hepatic injury (2) [A],(1) [B].
  • Duration of therapy:
    • Short-term therapy (7 days) initiated preoperatively in cardiac and vascular surgical patients is associated with a reduced incidence of adverse events.
    • If possible, it has been suggested to administer the day of or the night before surgery to maximize potential benefits.
    • A high loading dose immediately prior to percutaneous coronary intervention was also shown to reduce myocardial injury and major cardiac adverse events (1) [A].
• Discontinuation of statin therapy
  • Statin therapy should not be discontinued prior to open or endovascular procedures and should be resumed postoperatively as soon as possible.
  • Discontinuation after major vascular surgery has been shown to significantly increase incidence risk for cardiac death or recurrent MI (5).
  • A delay of >4 days in restarting therapy increased the risk of cardiac myonecrosis (related to duration of hospitalization and death) in treatment of infrarenal aneurysms (5) [B].
  • Effects of statin withdrawal are related to severity of coronary artery disease.

Pediatric Considerations

• Coronary Artery Disease
• Liver Function Tests
• Peripheral Vascular Disease
• Aortic Valve Repair
• Abdominal Aortic Aneurysm
• Septic Shock
• Chronic Angina

N. Matthew Decker , BS

Nina Singh-Radcliff , MD