Statins and Cardiovascular Risks Jae Woo Lee, MD Multiple clinical trials have demonstrated the beneﬁts of 3-hydroxy3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in reducing the risk of death and nonfatal ischemic cardiovascular events in both stable coronary heart diseases as well as following acute coronary syndromes (ACSs). Recently, statins have been shown to reduce cardiovascular events for patients undergoing major noncardiac surgery. This chapter reviews the cellular mechanism of myocardial infarction (MI), past clinical evidence supporting the use of statins for the primary and secondary prevention of coronary heart disease, and recent clinical trials that support the use of statins perioperatively. Cellular Mechanism of Acute Coronary Syndromes The pathophysiology leading to a fatal perioperative MI, speciﬁcally the disruption of an atherosclerotic plaque resulting in hemorrhage, thrombosis, and dynamic obstruction of a coronary vessel, is similar in nature to the underlying mechanism causing nonoperative MIs.1 Recently, knowledge of the underlying mechanism of an acute coronary event, particularly the role of inﬂammation, has increased substantially. Most ACSs result from a fracture in the ﬁbrous cap supporting a vulnerable plaque. A vulnerable plaque is an inﬂamed ﬁbroatheroma with a lipid-rich core containing cholesterol crystals and necrotic debris, a thin ﬁbrous cap with an inﬁltration of macrophages and lymphocytes, and low smooth muscle content. The ﬁbrous cap is a dynamic tissue that continuously undergoes remodeling of its interstitial collagen that gives it its tensile strength. Inﬂammatory mediators closely regulate the balance between the synthetic and degradative processes controlling the strength of the cap, speciﬁcally the synthesis of collagen. For example, lymphokine gamma interferon can inhibit the synthesis of interstitial collagen by smooth muscle cells, and proinﬂammatory cytokines can induce the 55 56 n Lee expression of matrix metalloproteinases such as collagenases and gelatinases, which degrade collagen ﬁbrils, weakening the plaque. Inﬂammatory cytokines can also trigger apoptosis of smooth muscle cells within the plaque. Smooth muscle cells are essential to maintaining the collagenous matrix, which supports the ﬁbrous cap. Rupture of the ﬁbrous cap leads to a thrombotic response through the release of tissue factor (TF) within the lipid-laden macrophages.2–4 Proinﬂammatory mediators are also involved in endothelial cell dysfunction. In the presence of inﬂammation, endothelial cells from atherosclerotic arteries show impaired vasodilator function as a result of a decrease in nitric oxide (NO) production. Inﬂammatory cytokines and oxidized lipoprotein also activate endothelial cells to produce proteases such as matrix metalloproteinase-2, a type IV collagenase, which can sever the tethers which bind endothelial cells to the underlying matrix causing a desquamative injury to the intima. Although most MIs are caused by a rupture of a vulnerable plaque, thrombosis from erosion of the endothelial surface can also trigger a cardiovascular event.2–4 Statins are potent inhibitors of HMG-CoA reductase which catalyzes the rate-limiting step of cholesterol biosynthesis in the liver, a 4-electron reductive deacylation of HMG-CoA to CoA and mevalonate. Statins also decrease bloodstream cholesterol levels through increased clearance of low-density lipoprotein-containing cholesterol (LDL-C) through increases in hepatic LDL-C receptor activity. Past studies have demonstrated an association between LDL-C and cardiovascular risk. However, in the Lipid Research Clinics Prevalence Study, Grover et al found that the LDL-C concentration was only 47% sensitive in predicting 10-year coronary artery disease (CAD) death rates.5 In addition, in clinical trials in the primary and secondary prevention of coronary heart disease, the overall beneﬁts of statins far exceeded the changes in lipid levels alone, suggesting effects beyond cholesterollowering. These ‘‘pleiotropic’’ effects of statins mitigate thrombotic complications of atherosclerosis through stabilization of unstable atherosclerotic plaques, improved endothelial function, reduction in inﬂammation, and reduction in thrombogenic response. The effects are believed to be caused by inhibition of isoprenoids that serve as lipid attachments for intracellular signaling molecules such as Rho, Ras, and Rac.6 In patients with signiﬁcant CAD, statin therapy was associated with a reduction in the progression of coronary atherosclerosis, an increased frequency of regression in atheroma size, and a reduction in cardiovascular end points as compared with placebos.7,8 In the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial, Nissen et al demonstrated that intensive lipid-lowering treatment with atorvastatin decreased the progression rate of coronary atheroma, measured by intravascular ultrasound, as compared with a moderate dose of pravastatin.9 The differences were attributed to a greater reduction in atherogenic Statins and Cardiovascular Risks n 57 lipoproteins (79 mg/dL in atorvastatin and 110 mg/dL in pravastatin) and C-reactive proteins (CRPs), a marker of inﬂammation and cardiovascular risk. In the ARBITER (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol) trial, Taylor et al found that intensive therapy with atorvastatin, reducing LDL-C <100 mg/dL, decreased carotid intima-media thickness as compared with a moderate dose of pravastatin.10 Corti et al also demonstrated that, in patients with asymptomatic hypercholesterolemia, long-term treatment with statins was not only associated with a signiﬁcant regression of established atherosclerotic lesions in both the aorta and carotid arteries, but also a modest increase in lumen area.11 An important characteristic of endothelial dysfunction associated with hypercholesterolemia is the impaired synthesis, release, and activity of endothelium-derived NO, which often occurs before angiographic evidence of disease. In the RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial, pravastatin therapy for 6 weeks improved endothelium-dependent relaxation but not endotheliumindependent relaxation in brachial arteries among patients with hyperlipidemia who experienced an acute MI or unstable angina.12 In several randomized trials such as the Lovastatin Restenosis trial, statin therapy improved the vasomotor response to intracoronary infusions of acetylcholine, an endothelium-dependent vasodilator, among patients with hyperlipidemia undergoing coronary angioplasty without a history of recent MI or unstable angina.13–15 The response to statin therapy was attributed to the upregulation of NO synthase, the prevention of NO downregulation caused by oxidized LDL,16 and inhibition of the release of endothelin-1, a potent vasoconstrictor.17 These ﬁndings suggested that qualitative changes in endothelial cells rather than a direct improvement in stenosis contributed to the beneﬁcial effect of statins. Aside from regression of coronary atheroma and improved endothelial cell function, statin therapy was shown to reduce the circulating levels and expression of proinﬂammatory cytokines and inﬂammatory markers that play a signiﬁcant role in coronary syndromes.18–21 In the CARE (Cholesterol and Recurrent Events) trial, Ridker et al found that in patients who experienced a prior MI but remained free of recurrent coronary events, pravastatin reduced the level of high-sensitivity CRP, a marker of inﬂammation and prospective cardiovascular risk, by 21.6% at 5 years.18,19 The reduction was not associated with any changes in lipid levels. Other clinical studies showed that statins decreased the levels of TNF-a, IL-6, and IL-1b,20,21 cytokines that are important to the synthesis of CRP. Statin therapy also reduced neointimal inﬂammation in models of unstable atherosclerotic plaques. Fukumoto et al, in Watanabe-heritable hyperlipidemic rabbits with LDL receptor deﬁciency, found that pravastatin decreased the expression of matrix metalloproteinase-1, -3, and -9 by macrophages within the intima of the atherosclerotic plaques. The 58 n Lee number of intimal smooth muscle cells as well as the expression of type I procollagen mRNA also increased as compared with the placebo.22 In the same model, Shiomi et al found that pravastatin decreased the lipid component (macrophages + extracellular lipids) in whole aortic plaques by 34% and in the ﬁbrous caps of coronary plaques by 55%. The authors concluded that plaque vulnerability, as expressed in the ratio of lipid component/ﬁbromuscular component (= smooth muscle cells + collagen ﬁbers), was reduced by 28% in aortic plaques and 61% in coronary plaques23 in pravastatin-treated animals. The incidence of plaque vulnerability decreased by 74% among coronary plaques in the pravastatin group. In patients with symptomatic carotid artery stenosis who underwent scheduled carotid endarterectomy (CEA), Crisby et al found that pretreatment with pravastatin for 3 months before the CEA reduced the lipid content, the oxidized LDL content, macrophage and T cell number, matrix metalloproteinase-2 level, and the number of cell deaths in the carotid plaques versus controls. The patients treated with pravastatin also had increased collagen content and tissue inhibitor of metalloproteinase-1 immunoreactivity within the plaques.24 Lastly, the antiatherothrombotic effects of statin agents were also derived from its effect on TF, TF inhibitor, and platelets.25 Lipophilic statins suppressed TF and its corresponding mRNA, often found in macrophages from human atherosclerotic plaques,26 through inhibition of a geranylgeranylated protein involved in its synthesis. Lipophilic statins also increased the production of tissue factor pathway inhibitor (TFPI).27,28 Consequently, statins appeared to suppress the initiation of the extrinsic coagulation pathway. In addition, Alfon et al found in cholesterol-fed swine that atorvastatin signiﬁcantly diminished platelet deposition on mildly damaged vessel walls at high shear rates, representative of atherosclerosisinduced stenotic vessels, but did not have an effect on severely injured vessel walls. Atorvastatin also did not have an effect on platelet aggregation induced by ADP or collagen (glycoprotein IIb/IIIa), vWF level, or glycoprotein Ib receptor. Regardless, in this model, atorvastatin reduced the development of atherosclerotic lesions in the coronary arteries through inhibition of platelet thrombus formation. The modulation of platelet activity was possibly caused by alterations in the cholesterol/phospholipid composition of platelets.29 Statins in Stable Coronary Heart Disease and Acute Coronary Syndromes Multiple trials have demonstrated an association between LDL-C and cardiovascular risk and the beneﬁts of statin therapy in the primary and secondary prevention of CAD.30–40 Statins and Cardiovascular Risks n 59 Among 4444 patients with CAD and hypercholesterolemia in the Scandinavian Simvastatin Survival Study (4S), patients who received simvastatin had reduced rates of all cause deaths, coronary events, and myocardial revascularizations at 5.4 years median follow up.30 In pooled data from 4 atherosclerosis regression trials (Pravastatin Atherosclerosis Intervention Program) of 1891 patients with atherosclerosis and mildly to moderately elevated lipid levels, pravastatin therapy to LDL-C level of 123 mg/dL reduced the combined outcome of nonfatal or fatal MI by 62% at 2.3 years average follow up. Similar to the 4S trial, the beneﬁt of statin therapy appeared after only 1 year of treatment.31 In patients with CAD but average cholesterol levels, the CARE investigators found that patients randomized to pravastatin treatment to LDL-C of 97 to 98 mg/dL among 4159 patients had reduced rates of fatal coronary event or nonfatal MI by 24%, stroke by 31%, and revascularization procedures by 27% at 5 years. However, there was no signiﬁcant difference in overall morality rates.32 Similar beneﬁts of statin therapy on stroke and cardiovascular events were also found among 19,343 hypertensive patients with low or average cholesterol levels at 3.3 years median follow up (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm33). Again, the beneﬁt of statin therapy was seen at 1 year. Among 9014 patients with a history of MI or unstable angina with a broad range of cholesterol levels, patients randomized to pravastatin with a 25% reduction in the LDL-C level from the placebo group had reduced rates of death from cardiovascular disease or all cause (LIPID trial34). In the LIPID trial, the authors estimated that over a period of 6.1 years, 30 deaths, 28 nonfatal MIs, and 9 nonfatal strokes in 48 patients were prevented for every 1000 patients randomly assigned to treatment with pravastatin. In addition, 23 coronary artery bypass grafts (CABGs), 20 coronary angioplasties, and 82 hospital admissions for unstable angina were also estimated to be avoided.34 Among 6595 men with moderate hypercholesterolemia without a history of MI, Shepherd et al found that patients randomized to pravastatin had reduced rates of MI and cardiovascular related death (West of Scotland Coronary Prevention Study Group35). Lastly, among 2838 patients without a history of CAD or high LDL-C levels but with type II diabetes, patients randomized to atorvastatin with roughly 40% reduction in LDL-C levels as compared with the placebo had reduced rates of acute coronary events by 36%, stroke by 48%, revascularizations by 31%, and death by 27% at 3.9 years median follow up.36 Using the clinical trials, the National Cholesterol Education Program (NCEP) expert panel published the third report on the detection, evaluation, and treatment of cholesterol in adults (ATP III). For patients with coronary heart disease, the goal of therapy in secondary prevention was to lower LDL-C <100 mg/dL.37 However, in a retrospective review of young patients without CAD or diabetes hospitalized with an acute MI with mean lipid levels within the normal range, Akosah et al found that only 25% of men and 18% of women qualiﬁed for pharmacotherapy by the 60 n Lee NCEP guidelines. The ATP III underappreciated the risk of disease for young people.38 The beneﬁts of statins were also found to extend to patients who survived ACS39,40; patients with ACS were at the highest risk of death or recurrent ischemic events. In previous trials such as the 4S,30 CARE,32 and LIPID,34 patients were enrolled at least 3 months after the qualifying event. In the MIRACL trial, Schwartz et al found that among 3086 patients who experienced unstable angina or non-Q-wave MI who received atorvastatin between 24 hours and 96 hours after the event had a 16% reduction in recurrent ischemic episodes within the subsequent 16 weeks, predominantly in ischemic events requiring hospitalization. However, there was no significant difference in risk of death, nonfatal MI, or cardiac arrest.40 Previously, high-sensitivity CRP, a marker for systemic inﬂammation, was shown to be associated with future cardiovascular events in patients with underlying CAD. In the MIRACL trial, statin therapy was associated with a signiﬁcant reduction in inﬂammatory markers, CRP and serum amyloid A,41 and in the risk of recurrent cardiovascular events associated with high levels of the proinﬂammatory, prothrombic cytokine CD40 ligand.42 Correia et al also found the acute rise in CRP found in patients after non-ST-elevation ACS was abolished by the short-term use of atorvastatin.43 Long-term trials such as the 4S44 and CARE45 demonstrated the beneﬁts of statins in reducing the combined end point of stroke and transient ischemic events or stroke, respectively, in patients with or at risk for CAD. In the MIRACL trial, Waters et al also found that intensive cholesterollowering with atorvastatin in patients with ACS reduced the overall stroke rate by 50% and did not cause hemorrhagic strokes46 within a 16-week period. However, a meta-analysis of 45 prospective cohorts, which included 450,000 patients and 13,000 strokes, showed no association between total cholesterol levels and stroke.47,48 In contrast, in the MRFIT (Multiple Risk Factor Intervention Trial), the risk of death from nonhemorrhagic stroke increased with increasing serum cholesterol. There was also a negative association between hemorrhagic strokes and low cholesterol levels, particularly in men with hypertension.47,49 Additional studies in patients representative of the typical stroke population will be needed to determine whether stroke reduction by statins resulted from a reduction in cardiac events such as a systemic thromboembolism or from a direct effect on the cerebral arteries. In the MIRACL trial, the reduction in ischemic events by atorvastatin did not depend on baseline lipid levels or percentage changes in the LDL-C levels. However, the authors used intensive statin therapy or high-dose atorvastatin reducing LDL-C levels to, on average, 72 mg/dL. Most of the trials using statins reduced LDL-C levels by 25% to 35% with a target of <100 mg/dL (2.59 mmol/L) for patients with established CAD or diabetes. To determine if high or standard statin therapy affected clinical outcomes, Cannon et al, in the PROVE IT-TIMI 22 trial, randomized 4162 Statins and Cardiovascular Risks n 61 patients who were hospitalized for an ACS within the previous 10 days to 80 mg atorvastatin (high dose), reducing LDL-C <70 mg/dL, or 40 mg of pravastatin (standard therapy), reducing LDL-C <100 mg/dL. The authors found that, in Kaplan-Meier estimates of the rates of primary end points (death, MI, unstable angina requiring hospitalization, revascularization, and stroke), high-dose therapy reduced the hazard ratio of primary end points by 16% at 2 years.50 In addition, Nissen et al, for the REVERSAL investigators, found that intensive therapy with atorvastatin reduced progression of coronary atherosclerosis further than standard therapy with pravastatin.9 In contrast, de Lemos et al, in Phase Z of the A to Z trial, found that in 4500 patients with ACS randomized to high-dose statin therapy; the regimen showed no statistically signiﬁcant beneﬁt in reducing the primary composite end points (cardiovascular death, MI, readmission for ACS, or stroke) and had high rates of myopathy within the ﬁrst 4 months. However, post hoc analysis of the A to Z trial did show a statistically signiﬁcant reduction of cardiovascular end points from 4 months to the end of the study.51 The different results between the MIRACL and PROVE-IT-TIMI 22 trials and the Phase Z of the A to Z trial may have derived from the effect of statins on inﬂammation. In the MIRACL and PROVE-IT trial, CRP decreased by 34% and 38%, respectively, whereas, in the A to Z trial, CRP decreased by only 17%. The early beneﬁt from statin therapy may be largely derived from the antiinﬂammatory effects of the drug, the ‘‘pleiotropic’’ effects, whereas the delayed beneﬁts were lipid-modulated. The beneﬁt from high-dose statin therapy was apparent within 6 months for the MIRACL and PROVE-IT trials, whereas the beneﬁts were only apparent after 4 months for the A to Z trial.52 The large clinical trials demonstrating the beneﬁts of statin therapy on the primary and secondary prevention of CAD have largely dispelled any further concerns about the safety and tolerability of the drug. The most important adverse effects of the drug, myopathy and asymptomatic increase in hepatic transaminases, are infrequent. The incidence of elevation of hepatic transaminases, approximately 1%, is dose-related and comparable among the different statins. The reaction generally occurs within the ﬁrst 3 months. The incidence of myopathy, approximately 0.1% to 0.2%, describes a broad clinical spectrum of disorders from mild muscle aches with elevation of creatine kinase levels to fatal rhabdomyolysis with onset from a few weeks to more than 2 years from initiation of therapy. With the exception of cerivastatin (discontinued), fatal rhabdomyolysis has been reported at rates of <1 per million prescriptions for all statins. The underlying mechanism through which statins produce muscle injury is unknown. However, with the exception of pravastatin, which is enzymatically transformed in the liver cytosol, most statins undergo metabolism by the cytochrome P450 (CYP) isoenzyme, speciﬁcally CYP3A4.53 In an extensive review of U.S. Food and Drug Administration-reported episodes of statin-associated rhabdomyolysis from January 1990 to March 2002, 58% 62 n Lee of 3339 reported cases were associated with concomitant medications, which affected statin metabolism.53,54 In the Phase Z trial, the myopathy rate, creatine kinase >10 times the upper limit of normal, occurred in 0.4% of the patients receiving simvastatin 80 mg/d, which was higher than average but consistent with the reported rate for the higher dose.51,52 The beneﬁt of statins also applied to patients after percutaneous coronary interventions (PCI). Lee et al, in the LIPS trial, found that treatment with ﬂuvastatin produced signiﬁcant reduction in major adverse cardiac events and coronary atherosclerotic events in patients after percutaneous transluminal coronary angioplasty for unstable or stable angina with average cholesterol levels at 3.9 years median follow up.55 In a prospective review of 5052 patients without a history of acute MI, recent MI, and cardiogenic shock who underwent a PCI, Chan et al found that patients on statin therapy had a reduced mortality rate at 30 days and at 6 months. After adjusting for the propensity to receive statin therapy and other confounders, statin therapy remained an independent predictor of survival at 6 months.56 Clinical Trials of Perioperative Statin Use In the United States, over 25 million operations are performed each year of which approximately 1 million are complicated by a perioperative cardiovascular event.57 Among patients undergoing major noncardiac surgery, the overall perioperative MI rate is 2% to 3%, rising up to 34% in highrisk groups such as vascular surgery patients.58 Although statin use has clearly been shown to be beneﬁcial in primary and secondary cardiovascular prevention, its perioperative use has been limited. Currently, the use of statin perioperatively is not the standard of care. However, several recent trials have suggested the beneﬁts of statin therapy for cardiovascular protection. Lindenauer et al found, in a retrospective cohort study based on hospital discharge and pharmacy records of 780,591 patients who underwent major noncardiac surgery throughout the country, that despite signiﬁcant preoperative cardiovascular risk, only 9.9% of patients received lipid-lowering agents perioperatively. In these hospitals, which were predominantly Southern, medium size, nonteaching, and urban, 55% of patients had a revised cardiac risk index of 1 or more,58 and 30% of the procedures were labeled high-risk. The use of lipid-lowering agents during the early perioperative period was associated with a 1% absolute reduction of hospital mortality and a 38% reduction in the odds of inhospital mortality among patients undergoing major noncardiac surgery who were matched for likelihood of treatment. For patients with a revised cardiac risk index of 4 or more, the number needed to treat with lipid-lowering agents to prevent a postoperative death was only 30.59 Unfortunately, the actual Statins and Cardiovascular Risks n 63 duration of statin treatment perioperatively was unknown; by pharmacy record, patients who received statin therapy on postoperative day 1 or 2 were categorized as having received statin perioperatively. In addition, the postoperative cardiovascular complication rate and the presence of laboratory markers of inﬂammation such as CRP were unavailable from the database. Perhaps more signiﬁcantly, only patients who survived beyond the second hospital day were included in the study. Another relevant question unanswered from the trial was the rate at which statins were discontinued perioperatively whether the result of ignorance, drug complication, or the severity of the patient’s illness. In a subgroup analysis of the PRISM (Platelet Receptor Inhibition in Ischemic Syndrome Management) trial, Heeschen et al found that patients with a history of CAD who were pretreated for at least 6 months with a statin before admission for chest pain at rest or accelerating chest pain within the last 24 hours had a reduction in death and nonfatal MI at 30 days follow up as compared with patients not on statin therapy. Although not statistically signiﬁcant, patients who were on statins preadmission and had it discontinued irrespective of the risk proﬁle had a higher rate of death and nonfatal MI as compared with patients who continued to receive statins or even compared with patients who never received statin therapy. This was associated with an increased event rate during the ﬁrst week after onset of symptoms and was not associated with cholesterol levels.60,61 In a retrospective case-controlled study of 2816 patients undergoing major vascular surgery, Poldermans et al found that the risk of perioperative mortality among statin users was reduced 4.5 times compared with nonusers. The results were consistent among the patients irrespective of the type of surgery, cardiac risk factors, and the use of aspirin or bblockers.62 For patients undergoing abdominal aortic aneurysm (AAA) repair, Kertai et al found, in a retrospective study, that perioperative 30-day mortality and MI were signiﬁcantly lower in patients who took statins (3.7% vs. 11.0%); the signiﬁcant decrease remained after correcting for other covariates. For patients with a revised cardiac risk index greater than 3 already on a b-blocker, the addition of statin therapy further reduced perioperative MI and death independent of the effect of the b-blocker.63 Kertai et al also found that statin therapy was associated with a lower allcause and cardiovascular mortality during follow up of patients who survived AAA repair at a median of 4.7 years.64 In a prospective, randomized, placebo-controlled, double-blind clinical trial, Durazzo et al found that among 100 patients undergoing vascular surgery who were randomized to receive atorvastatin or a placebo irrespective of their serum cholesterol levels for 45 days, the atorvastatin group experienced a signiﬁcant reduction in cardiovascular events such as death, nonfatal MI, unstable angina, or stroke (8.0% vs. 26.0%) within 6 months after surgery.65 The duration of statin therapy was short-term, and the surgery was performed on average 30 days after randomization. The 64 n Lee data again suggested the beneﬁt of statin therapy, which was not accounted for by cholesterol levels alone. The beneﬁts of perioperative statin therapy appeared to apply to patients undergoing cardiac surgery as well. In a retrospective cohort study of 1663 patients, Pan et al found that preoperative statin use in patients undergoing CABG with cardiopulmonary bypass was independently associated with a signiﬁcant 50% reduction in the risk of 30-day all-cause mortality, although not independently associated with a reduced risk of postoperative MI, cardiac arrhythmias, stroke, or renal dysfunction.66 The study seemed to substantiate earlier retrospective reviews by Dotani et al67 and Christenson et al,68 who both found preoperative statin use was associated with decreased cardiovascular morbidity and mortality. In a subgroup analysis of patients in the CARE,69 LIPID,34 and PostCABG70 trials, patients who previously underwent CABG who were placed on statins postoperatively were associated with a signiﬁcant reduction in cardiovascular events and death as compared with patients not treated with statins. One major question unanswered from the trials was the association between the timing of statin therapy and the cardiovascular protection; approximately 15% to 25% graft occlusions occur within the ﬁrst postoperative year.71 Conclusions Multiple clinical trials have demonstrated the beneﬁts of HMG-CoA reductase inhibitors in reducing the rate of MI, stroke, and death in studies of both primary and secondary prevention of CAD. Recently, intensive statin therapy, decreasing LDL-C <70 mg/dL, has been shown to be superior to moderate-dose therapy, decreasing LDL-C <100 mg/dL, in the reduction of morbidity and mortality associated with ACS. However, the effect of statin therapy far exceeds the decrease in LDL-C alone. Early beneﬁts of statin appear to be derived largely from ‘‘pleiotropic’’ effects, whereas the delayed beneﬁts are predominantly lipid-modulated. These ‘‘pleiotropic’’ effects of statin mitigate thrombotic complications of atherosclerosis through improved endothelial function, reduction in inﬂammation, stabilization of atherosclerotic plaques, and reduction in the thrombotic response. Cardiovascular complications after major noncardiac surgery are the major source of perioperative morbidity and mortality. The pathophysiology leading to a fatal perioperative MI, speciﬁcally the disruption of an atherosclerotic plaque causing thrombosis and obstruction of a coronary vessel, is believed to be similar in nature to the underlying mechanism causing nonoperative MIs. Recently, several trials have shown the beneﬁt of statin therapy on perioperative morbidity and mortality in patients undergoing major noncardiac surgery as well as CABGs. Given the low Statins and Cardiovascular Risks n 65 toxicity associated with statins and the high cardiovascular risk of certain patient populations and surgeries, it is imperative to expand on the limited clinical trials to better elucidate the effect of statins on perioperative cardiovascular risk. References 1. Dawood MM, Gutpa DK, Southern J, et al. Pathology of fatal perioperative myocardial infarction: implications regarding pathophysiology and prevention. Int J Cardiol. 1996; 57:37–44. 2. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001;104:365–372. 3. Stone PH. Triggering myocardial infarction. N Engl J Med. 2004;351:1716–1718. 4. Rosenson RS, Brown AS. Statin use in acute coronary syndromes: cellular mechanisms and clinical evidence. 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