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Influence of Statins on Perioperative Outcomes
REVIEW ARTICLE Martin J. London, MD William C. Oliver, Jr, MD Gregory A. Nuttall, MD Section Editors
Influence of Statins on Perioperative Outcomes Katja Hindler, MD,* Holger K. Eltzschig, MD, PhD,† Amanda A. Fox, MD,‡ Simon C. Body, MBChB, MPH,‡ Stanton K. Shernan, MD,‡ and Charles D. Collard, MD*
T
HE ADMINISTRATION OF 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins,” to ambulatory patients is associated with a reduced incidence of adverse cardiovascular events, including death, myocardial infarction (MI), stroke, atrial fibrillation, and renal dysfunction.1-6 Moreover, the beneficial effects of statin therapy are not limited to patients with hypercholesterolemia. Multiple randomized clinical trials have shown that even in patients with normal total and low-density lipoprotein (LDL) cholesterol levels, long-term statin administration is associated with a reduced incidence of adverse cardiovascular outcomes and a decreased need for invasive procedures, such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery.3-6 Although there is little doubt that statin therapy is associated with a reduced long-term incidence of adverse cardiovascular events, recent evidence suggests that statins may also reduce the risk of acute adverse outcomes after invasive cardiovascular procedures.6-15 For example, statin therapy at the time of PTCA was recently shown to independently predict 30-day and 6-month survival.6 Additionally, growing evidence suggests that statins are associated with a reduced risk of perioperative morbidity and mortality in patients undergoing major cardiac or vascular surgery.7-15 Thus, HMG-CoA reductase inhibition may be one of the most important perioperative therapeutic regimens to reduce the risk of postoperative cardiovascular complications in high-risk surgical patients since the introduction of beta-blockers into the operative setting.16 The pharmacologic mechanisms and role of statins in the acute perioperative setting are reviewed. PHARMACOLOGIC MECHANISMS OF STATINS
Lipidemic Effects Cholesterol is a critical component of eukaryotic cell membranes, playing an important role in membrane fluidity and plasticity. Cholesterol is also a vital precursor of steroid hormone synthesis. Approximately 800 mg of cholesterol is synthesized in humans per day, primarily in the liver and the intestine.17 Statins inhibit cholesterol synthesis and lower LDL cholesterol. Specifically, statins inhibit the rate of conversion of acetate molecules into cholesterol by inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. Because cells require a certain amount of cholesterol, inhibition of cholesterol synthesis results in a cellular homeostatic response in which cells increase
the density of LDL receptors on their surface. This increases the clearance of LDL particles from the plasma, resulting in decreased circulating LDL levels. Clinically, this is associated with a reduction in atherosclerotic plaque formation and a stabilization of preexisting “vulnerable” atherosclerotic plaques at high risk for rupture.18,19 The “vulnerable plaque” responsible for most MIs consists of a highly thrombogenic lipid core that is densely infiltrated by active and apoptotic macrophages, and is covered by a thin fibrous cap (⬍65 m). Erosion or rupture of the fibrous cap covering the lipid-rich core results in thrombus formation and significantly increases the likelihood of subsequent MI. The probability of plaque erosion or rupture is inversely related to thickness of the fibrous cap.18 Plaque rupture is also strongly associated with the actions of matrix metalloproteinases (eg, MMP-3) derived from T-lymphocyte–stimulated macrophages that promote proteolysis of the thin fibrin cap. Postulated mechanisms of statinmediated stabilization of vulnerable plaques include a change in the plaque composition from a lipid-rich to a fibrotic/calcified environment, a reduction in macrophage proliferation, inhibition of matrix metalloproteinase activity, and decreased tissue factor expression.18-20 Nonlipidemic Effects Although statins are potent inhibitors of cholesterol biosynthesis, increasing evidence suggests that their beneficial effects are not limited to patients with hypercholesterolemia.21-29 For example, statin administration may reduce morbidity and mortality even
From the *Division of Cardiovascular Anesthesia, Texas Heart Institute at Saint Luke’s Episcopal Hospital, Houston, TX; †Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany; and ‡Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Charles D. Collard, MD, Division of Cardiovascular Anesthesiology, The Texas Heart Institute at St. Luke’s Episcopal Hospital, Baylor College of Medicine, 6720 Bertner Avenue, Room 0520, MC1-226, Houston, TX 77030. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2002-0025$32.00/0 doi:10.1053/j.jvca.2005.12.012 Key words: HMG-CoA reductase inhibitor, surgery, transplantation, prevention, cholesterol, inflammation
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Statins have also been shown to reduce tissue injury in models of ischemia and reperfusion in several organs, including the heart, lung, brain, kidney, and gut.25-28,37 For example, in an isolated, perfused rat heart model, simvastatin was found to be a potent and effective cardioprotective agent that inhibited leukocyte-endothelial cell interactions while preserving cardiac contractile function and coronary perfusion after myocardial ischemia and reperfusion.26 Furthermore, statins have been shown to attenuate vasoconstriction by increasing endothelial nitric oxide (NO) activity, a benefit seen within 6 weeks of the start of treatment.38 Endothelial type III NO synthase in thrombocytes is also upregulated by statins, leading to decreased platelet activation and vascular ischemia.39 Moreover, both in vitro and in vivo studies have shown that abrupt statin discontinuation results in decreased NO production, impaired endothelial and vascular function, and increased in-hospital morbidity (eg, 16.5% v 5.3% in patients whose statin therapy was discontinued after admission for acute MI).40-43 Statins thus exert pleiotropic effects, independent of cholesterol reduction, that have direct antiatherosclerotic, antithrombotic, and antiinflammatory impact.44,45 Statin Pharmacogenetics Fig 1. The HMG-CoA reductase pathway. (Color version of figure is available online.)
in individuals with normal or only moderately elevated LDL levels.18,30-32 Although the exact mechanisms by which statins reduce the likelihood of cardiovascular events have yet to be fully elucidated, the metabolite of HMG-CoA reductase, mevalonic acid, is a precursor of the cholesterol and the isoprenoid intermediates farnesyl and geranylgeranyl pyrophosphate (Fig 1). These intermediates are essential for the posttranslational modification of intracellular G-proteins, such as Rho, Rac, and Ras, which regulate endothelial, platelet, and leukocyte function.22,24 Statins have also been shown to modulate vascular remodeling by inhibiting cellular matrix metalloproteinases and transcription factors, such as nuclear factor-B.22 In patients with acute coronary syndromes (ACS) or idiopathic dilated cardiomyopathy, statin therapy has been shown to reduce untoward inflammatory activity, including changes in C-reactive protein, serum amyloid A, tumor necrosis factor ␣, interleukin 6, and brain natriuretic peptide levels.22,23 Moreover, statins have been reported to decrease serum levels of the inflammatory marker C-reactive protein within 14 days of administration, suggesting an acute protective role for these drugs.33 The anti-inflammatory and immunomodulatory properties of statins have also been shown in patients with other complex inflammatory syndromes, such as sepsis and septic shock. In septic patients, statins have been shown to attenuate the release of acute-phase inflammatory proteins and to exert antiapoptotic effects, thereby inhibiting sepsis-induced endothelial activation and dysfunction.34 Statins also reduce cell-surface expression of toll-like receptors on monocytes, thereby decreasing monocyte activation by circulating endotoxins.35 Additionally, they inhibit expression of leukocyte function antigen-1, thus decreasing lymphocyte cell adhesion and T-cell activation in the early stages of sepsis.36
The individual response to statin therapy has been shown to be influenced by genetic variation within several genes, including apolipoprotein E (Apo E), LDL receptor, angiotensin-I converting enzyme, paraoxonase, and cytochrome P2C9.46-49 For example, several studies, including a meta-analysis of 625 patients, have shown that statin-mediated lowering of LDL cholesterol is significantly greater in individuals expressing the Apo E2 genotype when compared with individuals expressing the E4 allele (37% v 33%, p ⬍ 0.05).50 Additionally, the enhanced response to statin therapy in individuals expressing the Apo E2 allele may be gender specific. Plasma triglyceride lowering with atorvastatin was improved only in men carrying the E2 allele (⫺27%) when compared with E3 (⫺13%) or E4 (⫺22%) alleles.51 Nonetheless, statin therapy is still associated with a 2-fold reduction in mortality risk in MI survivors expressing the Apo E4 allele, suggesting these patients may especially benefit from statin therapy.52 STATIN USE IN MEDICAL PATIENTS
Statins are commonly prescribed for the primary or secondary prevention of cardiovascular events in patients with hypercholesterolemia who are at risk for or known to have coronary artery disease (CAD).1-3,5,53,54 A meta-analysis of the Scandinavian Simvastatin Survival Study, Cholesterol and Recurrent Events Trial, and Long-Term Intervention with Pravastatin Ischemic Disease Trial showed that statin therapy reduced the risk of MI by 30% in patients with preexisting CAD.4,5,55,56 Based on these observations, the American College of Cardiology/American Heart Association guidelines now recommend statin therapy for management of patients with unstable angina or MI.57 Moreover, recent data obtained from the Treating to New Targets Trial and the Heart Protection Study suggest that patients at high risk for CAD may especially benefit from aggressive lipid-lowering strategies.58,59 In the Heart Protection Study, statin therapy was independently associated with a sig-
INFLUENCE OF STATINS ON PERIOPERATIVE OUTCOMES
nificant reduction in the risk of all-cause mortality and incidence of adverse cardiovascular events (including major coronary events, stroke, and revascularization).59 Early implementation of statin therapy within 24 hours of admission for acute MI has also been shown to be beneficial, with 1 study showing an absolute reduction in mortality by approximately 10% when statin therapy was continued or introduced early upon admission.60 Furthermore, intensive lipid-lowering statin regimens have been shown to provide greater protection against death and major cardiovascular events in ACS patients than standard regimens. For example, the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Trial showed that intensive statin therapy (atorvastatin, 80 mg, v pravastatin, 40 mg) in ACS patients significantly reduced the composite endpoint of death, MI, or rehospitalization (3% v 4.2%, p ⫽ 0.04).61 Based on these findings, several investigators have advocated that optimal serum LDL cholesterol levels should be well below current recommended guidelines, in the range of 50 to 70 mg/dL.59 STATINS AND PERIOPERATIVE OUTCOMES
Major Noncardiac Surgery Cardiovascular complications after major noncardiac vascular surgery are a primary cause of perioperative morbidity and mortality. Perioperative mortality ranges as high as 5% to 6%, with nonfatal MI occurring in up to 34% of patients.62,63 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.8 Similarly, a recent retrospective cohort study, based on the hospital discharge and pharmacy records of 780,591 patients from 329 United States hospitals who underwent major noncardiac surgery, showed that preoperative lipidlowering therapy was associated with a reduced risk of postoperative mortality, even after controlling for patient demographics, perioperative risk factors, and propensity score (adjusted odds ratio ⫽ 0.62; 95% confidence interval, 0.580.67).64 Furthermore, only patients reinitiated on statin therapy early after surgery (before postoperative day 2) were included in the final analysis, suggesting that the observed survival benefit may be dependent on continuation of statin therapy throughout the perioperative period. Finally, long-term statin use has been associated with reduced risk of all-cause (2.5-fold) and cardiovascular (3-fold) mortality after abdominal aortic aneurysm repair.13 Two recent prospective trials investigating perioperative statin therapy in patients undergoing vascular surgery further underpin the statin-associated benefit seen in previous retrospective studies.11,65 Durazzo et al11 showed that adverse cardiac events after a 6-month follow-up period were 3 times more likely in patients receiving placebo compared with patients receiving atorvastatin (26% v 8%, p ⫽ 0.03). Both Durazzo et al11 and Schouten et al65 observed a lower incidence of postoperative nonfatal acute MI among statin users (6% v 16% and 6.6% v 10.7%, respectively). Furthermore, a recent pharmacoeconomic analysis by Biccard et al66 of these studies suggested that perioperative statin therapy for the prevention of compli-
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cations after vascular surgery is even more cost-effective than statin therapy for the primary and secondary prevention of CAD. Although the mechanisms by which statins reduce postoperative mortality have yet to be fully elucidated, statinmediated atherosclerotic plaque stabilization, along with statins’ antithrombotic and anti-inflammatory effects, may contribute to improved postoperative outcomes.8,13,22,32,45,64 Cardiac Surgery After CABG surgery, the lifespan of venous grafts is often limited by the development of accelerated postoperative atherosclerosis. Therefore, considerable attention has been directed to the role of statins in preventing early graft atherosclerosis and occlusion. For example, 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.67 The PostCABG Trial investigators found that, in addition to reductions in postoperative serum LDL levels, long-term statin administration was associated with a significant decrease in the progression of vein graft lesions and the incidence of graft occlusion.10 Furthermore, statin treatment was associated with a 30% reduction in the need for revascularization procedures.68 Similarly, Christenson69 showed that as little as 4 weeks of preoperative simvastatin administration minimized the incidence of CABG lesions (10% v 46%) and occlusions (2.5% v 60%) when compared with patients not receiving statins in the first year after surgery. In addition to preserving vein graft function, 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.70 Statins have also been shown to reduce the incidence of adverse clinical outcomes after CABG surgery.7,9,15,68,69,71 In a nonrandomized retrospective study, statins were shown to be associated with a reduced risk of the composite clinical outcome of death, MI, and arrhythmias (1% v 9%, p ⬍ 0.001) 60 days after CABG surgery.9 Additionally, statins were associated with a reduced risk of the composite outcome of death and MI (0% v 5%, p ⫽ 0.01) 1 year after CABG surgery.9 Similar beneficial effects of statins were also reported in a subgroup of 2,245 patients who underwent revascularization (PTCA, CABG surgery, or both) in the Cholesterol and Recurrent Events Trial. Statin use reduced the relative risk of the composite outcome of cardiac death and nonfatal MI by 36%, fatal or nonfatal MI by 39%, stroke by 39%, and the need for repeat revascularization by 18%.71 In a recent retrospective study of 1,663 patients undergoing CABG surgery, preoperative statin therapy was independently associated with a reduced risk of 30-day all-cause mortality (1.8% v 3.75%, p ⬍ 0.05).7 However, statins were not independently associated with a reduced risk of postoperative MI, arrhythmias, stroke, or renal dysfunction.7 Finally, preoperative statin therapy was shown to be associated with a significant reduction in the risk of acute cardiac death within the first 4 days of operation (0.3% v 1.4%, p ⬍ 0.03) after elective CABG surgery with cardiopulmonary bypass.15 In contrast to cardiac outcomes, a recent retrospective, observational study found that preoperative statin therapy
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Table 1. Randomized Clinical Trials Reporting Statin-Associated Adverse Effects Trial
Statin
Scandinavian Simvastatin Survival Study54
Simvastatin (20 mg/d)
Expanded Clinical Evaluation of Lovastatin103
Lovastatin (20-80 mg/d)
Cholesterol and Recurrent Events Trial5
Pravastatin (40 mg/d)
West of Scotland Prevention Study2
Pravastatin (40 mg/d)
Heart Protection Study59
Simvastatin (40 mg/d)
Air Force/Texas Coronary Athersclerosis Prevention Study3 Myocardial Ischemia Reduction with Acute Cholesterol Lowering Study22 Lipoprotein and Coronary Atherosclerosis Study104 Federal Drug and Safety Administration Reports
Safety Record
Number of Patients
Lovastatin (20-40 mg/d)
One case of rhabdomyolysis; no increased rate of hepatotoxicity and nephrotoxicity Myopathy over a 2-year followup period only at doses of 40-80 mg/d No increased rate of myotoxicity No increased rate of myalgia, muscle pain, or hepatotoxicity Similar incidence of myotoxicity (0.09%) and elevated liver enzymes (0.8%) No differences
6,605 men and women
Atorvastatin (80 mg/d)
Adverse event frequency ⬍1%
3,086 patients
Fluvastatin (20 mg/d)
Adverse events ⬍1%
429 patients
Cerivastatin (0.4-0.8 mg/d)
Increased incidence of rhabdomyolysis (53 deaths) Rhabdomyolysis ⬍0.01%
Rusovastatin (10-40 mg/d)
was not associated with a decrease in the incidence of cognitive dysfunction (34.5% v 37.2%) 6 weeks after CABG surgery.72 Furthermore, multivariate analysis revealed that patients receiving statin therapy at discharge showed a higher prevalence of cognitive deficit compared with nonstatin users (42% v 34.5%, p ⫽ 0.19).72 Several recent studies have suggested that statins may also reduce the progression of calcific aortic stenosis and bioprosthetic valve degeneration.14,73-75 Calcific aortic stenosis is the most common heart defect in adults and is associated with an increased risk of cardiac death.74 In an experimental animal model of aortic stenosis, statin administration inhibited the development of left ventricular hypertrophy and improved left ventricular function.75 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 (0.06 ⫾ 0.16 cm) compared with nonstatin users (0.11 ⫾ 0.18 cm, p ⫽ 0.03).76,77 Statin treatment was also an independent predictor of a reduced increase in the aortic peak gradient (p ⫽ 0.02).76 Moreover, statin administration has been shown to reduce the progression of bioprosthetic valve degeneration.14 This effect is independent of cholesterol levels, suggesting a role for the non–lipid-mediated, pleiotropic effects of statins.
4,444 patients
8,245 patients
3,244 patients 6,595 men
20,500 patients
such as cyclosporine and corticosteroids. Data supporting this hypothesis come from several randomized clinical trials in heart transplant recipients showing that statins lower cholesterol levels, decrease the incidence of transplant vasculopathy, and improve long-term survival.82-85 Statin-treated heart transplant recipients also show improved epicardial and microvascular endothelial function, along with decreased levels of the proinflammatory cytokines interleukin 6 and tumor necrosis factor ␣.86 Similar findings have been observed in lung, liver, and kidney transplant recipients.80,81,87-90 Statin administration after lung transplantation was recently shown to be associated with improved lung function, a reduced number of inflammatory cells after bronchoalveolar lavage, and improved long-term survival.81 Moreover, statins have been shown to acutely reduce posttransplant cholesterol levels. Liver transplant recipients’ total and LDL cholesterol levels are significantly reduced compared with those of control patients within 14 days of beginning treatment with atorvastatin.87 The National Kidney Foundation also recently released guidelines suggesting statins as first-line agents for the management of hyperlipidemia in renal transplant recipients.79 Interestingly, statin use was recently shown to be associated with improved blood pressures in renal transplant recipients, independent of changes in cholesterol.91
Organ Transplantation Solid-organ transplant recipients undergoing immunosuppressive therapy have a higher incidence of dyslipidemia and accelerated graft atherosclerosis than does the general population.78-81 Several investigators have therefore hypothesized that long-term statin administration to transplant recipients may offset the dyslipidemic effects of immunosuppressive drugs,
Statin Safety The issue of statin safety has received much attention, especially after the withdrawal of cerivastatin in August 2001.92,93 In general, statins are well tolerated but can produce a variety of side effects (Table 1), including gastrointestinal disturbances, dyspepsia, headache, myalgia, central nervous system
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disturbances, and sleep disorders.93 However, statin-related hepatotoxicity and myopathy, which in rare instances have been reported to progress into life-threatening rhabdomyolysis (including renal failure, cardiac arrest, and compartment syndrome), are probably the 2 most clinically worrisome adverse side effects. Statin side effects are dose related and inherent to all commercially available preparations. When used alone, the reported incidence of statin-associated myopathy and rhabdomyolysis is 0.1% to 0.5% and 0.04% to 0.2%, respectively.93 However, administration of concomitant medications, such as gemfibrozil, cyclosporin, niacin, or erythromycin, as well as certain physical conditions (eg, acute infection, hypotension, trauma, and severe metabolic, endocrine, or electrolyte disorders), may significantly increase the incidence of rhabdomyolysis.94 Indeed, the administration of pharmacologic agents metabolized via the same pathways as statins (ie, the cytochrome P-450 3A4 system) has been shown to increase serum statin levels and to increase the risk of myopathy and rhabdomyolysis by up to 10-fold.93 To date, few clinical data are available regarding the influence of preoperative statin therapy on the incidence of postoperative myopathy. One recent report speculated that preoperative pravastatin administration may have contributed to the occurrence of severe postoperative rhabdomyolysis after combined CABG/abdominal aortic replacement surgery.95 Additionally, it has been suggested that statin therapy be discontinued 4 to 7 days preoperatively in patients scheduled to undergo major surgery associated with a significant risk of direct muscle trauma.94 Despite these recommendations, a recent prospective clinical trial investigating the potential risk of statin-associated myopathy in patients undergoing major noncardiac surgery found that preoperative statin use was not associated with an increased risk of postoperative myopathy.65 Thus, further clinical data are needed to evaluate the risk/benefit ratio of discontinuing statins in the preoperative period. CONCLUSION
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. Despite careful use of regression models and propensity scores to adjust for potential confounders that may affect postoperative outcomes, confounding factors may still exist. Physician bias may have influenced patient selection, choice of statin type, and dosages. Indeed, randomized clinical trials of statin use in other settings, such as ACS (eg, the Myocardial
Ischemia Reduction with Acute Cholesterol Lowering trial), although encouraging, have not always confirmed the marked reduction in mortality seen in early observational studies.96,97 Thus, a need for prospective, randomized studies investigating the influence of statin therapy on adverse surgical outcomes still exists. Second, the influence of the duration of preoperative statin therapy on the risk of postoperative outcomes has not yet been adequately addressed. 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.6,21,22 However, the minimum length of preoperative statin administration necessary to protect against acute perioperative outcomes has yet to be determined. Similarly, a growing body of evidence suggests that genetic factors may significantly affect the response to statin therapy.98,99 Thus, there also remains a need for pharmacogenetic studies examining the impact of genotype on statin efficacy, metabolism, and side effects. 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 and colleagues100 showed that patients experiencing ACS who received statin therapy before the onset of symptoms had a reduced incidence of 30-day all-cause mortality and nonfatal MI compared with ACS patients not receiving statins. Furthermore, the cardiac event rate was significantly greater among patients in whom statin therapy was withdrawn than among patients who continued to receive statins. Statin therapy was also shown to be less effective in reducing the risk of death or nonfatal MI when initiated after the presentation of an ACS rather than before the onset of symptoms (14% v 51% relative risk reduction).100 These results suggest that postoperative discontinuation of statin therapy may increase the risk of adverse cardiovascular events. Nonetheless, although American College of Cardiology and American Heart Association guidelines recommend statins for CABG patients with LDL concentrations ⬎100 mg/dL,101 two thirds of eligible candidates may not be receiving statin therapy at discharge.102 Explanations for not reinitiating statin therapy after CABG surgery may include patients’ decreased tolerance of oral medications secondary to nausea and vomiting, transient renal dysfunction, concerns about hepatic toxicity or myositis, or forgetfulness on behalf of the responsible physician at the time of discharge. Educating physicians about the potential benefits of continuing statin therapy throughout the perioperative period may thus be warranted.
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coronary syndromes in the MIRACL study. Circulation 108:1560-1566, 2003 23. Brown WV: Benefits of statin therapy in patients with special risks: Coronary bypass surgery, stable coronary disease, and acute coronary syndromes. Clin Cardiol 26:III13-III18, 2003 24. Shishehbor MH, Brennan ML, Aviles RJ, et al: Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 108:426-431, 2003 25. Chen J, Nagasawa Y, Zhu BM, et al: Pravastatin prevents arrhythmias induced by coronary artery ischemia/reperfusion in anesthetized normocholesterolemic rats. J Pharmacol Sci 93:87-94, 2003 26. Lefer AM, Campbell B, Shin YK, et al: Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 100:178-184, 1999 27. Naidu BV, Woolley SM, Farivar AS, et al: Simvastatin ameliorates injury in an experimental model of lung ischemia-reperfusion. J Thorac Cardiovasc Surg 126:482-489, 2003 28. Wan MX, Schramm R, Klintman D, et al: A statin-based inhibitor of lymphocyte function antigen-1 protects against ischemia/reperfusion-induced leukocyte adhesion in the colon. Br J Pharmacol 140: 395-401, 2003 29. 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 30. Ridker PM, Cannon CP, Morrow D, et al: C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352:20-28, 2005 31. Effect of simvastatin on coronary atheroma: The Multicentre Anti-Atheroma Study (MAAS). Lancet 344:633--638, 1994 32. Vaughan CJ, Gotto AM Jr, Basson CT: The evolving role of statins in the management of atherosclerosis. J Am Coll Cardiol 35:110, 2000 33. Plenge JK, Hernandez TL, Weil KM, et al: Simvastatin lowers C-reactive protein within 14 days: An effect independent of lowdensity lipoprotein cholesterol reduction. Circulation 106:1447-1452, 2002 34. Hack CE, Zeerleder S: The endothelium in sepsis: Source of and a target for inflammation. Crit Care Med 29:S21-S27, 2001 35. 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 30:1212-1217, 1997 36. Weitz-Schmidt G, Welzenbach K, Brinkmann V, et al: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med 7:687-692, 2001 37. Lazar HL, Bao Y, Zhang Y, et al: Pretreatment with statins enhances myocardial protection during coronary revascularization. J Thorac Cardiovasc Surg 125:37-42, 2003 38. Dupuis J, Tardif JC, Cernacek P, et al: Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (reduction of cholesterol in ischemia and function of the endothelium) trial. Circulation 99:3227-3233, 1999 39. Laufs U, Gertz K, Huang P, et al: Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice. Stroke 31:2442-2449, 2000 40. Xing Y, Chen H, Hu DY: [Effects of withdrawal of statins on nitric oxide production in vascular endothelial cells]. Zhonghua Nei Ke Za Zhi 44:22-24, 2005 41. Gertz K, Laufs U, Lindauer U, et al: Withdrawal of statin treatment abrogates stroke protection in mice. Stroke 34:551-557, 2003 42. Thomas M, Mann J: Increased thrombotic vascular events after change of statin. Lancet 352:1830-1831, 1998
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43. Spencer FA, Allegrone J, Goldberg RJ, et al: Association of statin therapy with outcomes of acute coronary syndromes: The GRACE study. Ann Intern Med 140:857-866, 2004 44. Yildirir A, Muderrisoglu H: Non-lipid effects of statins: Emerging new indications. Curr Vasc Pharmacol 2:309-318, 2004 45. Willerson JT, Ridker PM: Inflammation as a cardiovascular risk factor. Circulation 109:II2-II10, 2004 46. Turban S, Fuentes F, Ferlic L, et al: A prospective study of paraoxonase gene Q/R192 polymorphism and severity, progression and regression of coronary atherosclerosis, plasma lipid levels, clinical events and response to fluvastatin. Atherosclerosis 154:633-640, 2001 47. Marian AJ, Safavi F, Ferlic L, et al: Interactions between angiotensin-I converting enzyme insertion/deletion polymorphism and response of plasma lipids and coronary atherosclerosis to treatment with fluvastatin: The lipoprotein and coronary atherosclerosis study. J Am Coll Cardiol 35:89-95, 2000 48. Vohl MC, Szots F, Lelievre M, et al: Influence of LDL receptor gene mutation and apo E polymorphism on lipoprotein response to simvastatin treatment among adolescents with heterozygous familial hypercholesterolemia. Atherosclerosis 160:361-368, 2002 49. Kirchheiner J, Kudlicz D, Meisel C, et al: Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (-)-3S,5R-fluvastatin and (⫹)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther 74:186-194, 2003 50. Ordovas JM, Lopez-Miranda J, Perez-Jimenez F, et al: Effect of apolipoprotein E and A-IV phenotypes on the low-density lipoprotein response to HMG CoA reductase inhibitor therapy. Atherosclerosis 113:157-166, 1995 51. Pedro-Botet J, Schaefer EJ, Bakker-Arkema RG, et al: Apolipoprotein E genotype affects plasma lipid response to atorvastatin in a gender-specific manner. Atherosclerosis 158:183-193, 2001 52. Gerdes LU, Gerdes C, Kervinen K, et al: The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction: A substudy of the Scandinavian simvastatin survival study. Circulation 101:1366-1371, 2000 53. Olin JW: Cholesterol lowering: Perspectives on the 4S and West of Scotland studies. Cleve Clin J Med 63:80-83, 1996 54. Manzato E: Scandinavian simvastatin study (4S). Lancet 344: 1767, 1994 55. Wright RA, Flapan AD: Scandinavian simvastatin study (4S). Lancet 344:1765, 1994 56. Ahmed M, Griffiths P: Statins and secondary prevention of coronary heart disease. Br J Community Nurs 9:160-165, 2004 57. Pepine CJ: Optimizing lipid management in patients with acute coronary syndromes. Am J Cardiol 91:30B-35B, 2003 58. Cleland JG, Coletta AP, Freemantle N, et al: Clinical trials update from the American College of Cardiology meeting: CARE-HF and the remission of heart failure, Women’s Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER. Eur J Heart Fail 7:931-936, 2005 59. Ballantyne CM: Current and future aims of lipid-lowering therapy: Changing paradigms and lessons from the Heart Protection Study on standards of efficacy and safety. Am J Cardiol 92:3K-9K, 2003 60. Fonarow GC, Wright RS, Spencer FA, et al: Effect of statin use within the first 24 hours of admission for acute myocardial infarction on early morbidity and mortality. Am J Cardiol 96:611-616, 2005 61. Cannon CP, Braunwald E, McCabe CH, et al: Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 350:1495-1504, 2004 62. Krupski WC, Layug EL, Reilly LM, et al: Comparison of cardiac morbidity between aortic and infrainguinal operations. Study of Perioperative Ischemia (SPI) Research Group. J Vasc Surg 15:354-365, 1992
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63. Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms. The United Kingdom Small Aneurysm Trial Participants. N Engl J Med 346:1445-1452, 2002 64. Lindenauer PK, Pekow P, Wang K, et al: Lipid-lowering therapy and in-hospital mortality following major noncardiac surgery. JAMA 291:2092-2099, 2004 65. Schouten O, Kertai MD, Bax JJ, et al: Safety of perioperative statin use in high-risk patients undergoing major vascular surgery. Am J Cardiol 95:658-660, 2005 66. Biccard BM, Sear JW, Foex P: The pharmacoeconomics of perioperative statin therapy. Anaesthesia 60:1059-1063, 2005 67. Porter KE, Turner NA: Statins for the prevention of vein graft stenosis: A role for inhibition of matrix metalloproteinase-9. Biochem Soc Trans 30:120-126, 2002 68. Knatterud GL, Rosenberg Y, Campeau L, et al: Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation in the post coronary artery bypass graft trial. Post CABG Investigators. Circulation 102:157-165, 2000 69. Christenson JT: Preoperative lipid control with simvastatin reduces the risk for graft failure 1 year after myocardial revascularization. Cardiovasc Surg 9:33-43, 2001 70. 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 71. Flaker GC, Warnica JW, Sacks FM, et al: Pravastatin prevents clinical events in revascularized patients with average cholesterol concentrations. Cholesterol and Recurrent Events CARE Investigators. J Am Coll Cardiol 34:106-112, 1999 72. Mathew JP, Grocott HP, McCurdy JR, et al: Preoperative statin therapy does not reduce cognitive dysfunction after cardiopulmonary bypass. J Cardiothorac Vasc Anesth 19:294-299, 2005 73. Rosenhek R, Rader F, Loho N, et al: Statins but not angiotensinconverting enzyme inhibitors delay progression of aortic stenosis. Circulation 110:1291-1295, 2004 74. Palta S, Pai AM, Gill KS, et al: New insights into the progression of aortic stenosis: Implications for secondary prevention. Circulation 101:2497-2502, 2000 75. Luo JD, Zhang WW, Zhang GP, et al: Effects of simvastatin on left ventricular hypertrophy and function in rats with aortic stenosis. Zhongguo Yao Li Xue Bao 20:345-348, 1999 76. Novaro GM, Tiong IY, Pearce GL, et al: Effect of hydroxymethylglutaryl coenzyme a reductase inhibitors on the progression of calcific aortic stenosis. Circulation 104:2205-2209, 2001 77. Shavelle DM, Takasu J, Budoff MJ, et al: HMG CoA reductase inhibitor (statin) and aortic valve calcium. Lancet 359:1125-1126, 2002 78. Wenke K: Management of hyperlipidaemia associated with heart transplantation. Drugs 64:1053-1068, 2004 79. Mathis AS, Dave N, Knipp GT, et al: Drug-related dyslipidemia after renal transplantation. Am J Health Syst Pharm 61:565-587, 2004 80. Imagawa DK, Dawson S 3rd, Holt CD, et al: Hyperlipidemia after liver transplantation: Natural history and treatment with the hydroxy-methylglutaryl-coenzyme: A reductase inhibitor pravastatin. Transplantation 62:934-942, 1996 81. Johnson BA, Iacono AT, Zeevi A, et al: Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 167:1271-1278, 2003 82. O’Rourke B, Barbir M, Mitchell AG, et al: Efficacy and safety of fluvastatin therapy for hypercholesterolemia after heart transplantation: Results of a randomised double-blind placebo-controlled study. Int J Cardiol 94:235-240, 2004
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83. Wenke K, Meiser B, Thiery J, Nagel D, et al: Simvastatin initiated early after heart transplantation: 8-year prospective experience. Circulation 107:93-97, 2003 84. See VY Jr, DeNofrio D, Goldberg L, et al: Effect of atorvastatin on postcardiac transplant increase in low-density lipoprotein cholesterol reduces development of intimal hyperplasia and progression of endothelial dysfunction. Am J Cardiol 92:11-15, 2003 85. Kato T, Tokoro T, Namii Y, et al: Early introduction of HMGCoA reductase inhibitors could prevent the incidence of transplant coronary artery disease. Transplant Proc 32:331-333, 2000 86. Weis M, Pehlivanli S, Meiser BM, et al: Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation. J Am Coll Cardiol 38:814-818, 2001 87. Taylor PJ, Kubler PA, Lynch SV, et al: Effect of atorvastatin on cyclosporine pharmacokinetics in liver transplant recipients. Ann Pharmacother 38:205-208, 2004 88. Fellstrom B: Impact and management of hyperlipidemia posttransplantation. Transplantation 70:SS51-SS57, 2000 89. Holdaas H, Fellstrom B, Jardine AG, et al: Effect of fluvastatin on cardiac outcomes in renal transplant recipients: A multicentre, randomised, placebo-controlled trial. Lancet 361:2024-2031, 2003 90. Cosio FG, Pesavento TE, Pelletier RP, et al: Patient survival after renal transplantation III: The effects of statins. Am J Kidney Dis 40:638-643, 2002 91. Prasad GV, Ahmed A, Nash MM, et al: Blood pressure reduction with HMG-CoA reductase inhibitors in renal transplant recipients. Kidney Int 63:360-364, 2003 92. Jamal SM, Eisenberg MJ, Christopoulos S: Rhabdomyolysis associated with hydroxymethylglutaryl-coenzyme A reductase inhibitors. Am Heart J 147:956-965, 2004 93. Omar MA, Wilson JP, Cox TS: Rhabdomyolysis and HMGCoA reductase inhibitors. Ann Pharmacother 35:1096-1107, 2001 94. Rosenberg AD, Neuwirth MG, Kagen LJ, et al: Intraoperative rhabdomyolysis in a patient receiving pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor. Anesth Analg 81:1089-1091, 1995 95. Wilhelmi M, Winterhalter M, Fischer S, et al: Massive postoperative rhabdomyolysis following combined CABG/abdominal aortic
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replacement: A possible association with HMG-CoA reductase inhibitors. Cardiovasc Drugs Ther 16:471-475, 2002 96. 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, 2002 97. Waters D, Schwartz GG, Olsson AG: The Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) trial: A new frontier for statins? Curr Control Trials Cardiovasc Med 2:111-114, 2001 98. Chasman DI, Posada D, Subrahmanyan L, et al: Pharmacogenetic study of statin therapy and cholesterol reduction. JAMA 291: 2821-2827, 2004 99. Kajinami K, Brousseau ME, Ordovas JM, et al: Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin. Atherosclerosis 175:287-293, 2004 100. Heeschen C, Hamm CW, Laufs U, et al: Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 105:1446-1452, 2002 101. Eagle KA, Guyton RA, Davidoff R, et al: ACC/AHA guidelines for coronary artery bypass graft surgery: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). American College of Cardiology/American Heart Association. J Am Coll Cardiol 34:1262-1347, 1999 102. Khanderia U, Faulkner TV, Townsend KA, et al: Lipid-lowering therapy at hospital discharge after coronary artery bypass grafting. Am J Health Syst Pharm 59:548-551, 2002 103. Bradford RH, Shear CL, Chremos AN, et al: Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia. Am J Med 91:18S-24S, 1991 104. Herd JA, Ballantyne CM, Farmer JA, et al: Effects of fluvastatin on coronary atherosclerosis in patients with mild-to-moderate cholesterol elevation (Lipoprotein and Coronary Atherosclerosis Study [LCAS]). Am J Cardiol 80:278-286, 1997
Influence of Statins on Perioperative Outcomes Katja Hindler, MD,* Holger K. Eltzschig, MD, PhD,† Amanda A. Fox, MD,‡ Simon C. Body, MBChB, MPH,‡ Stanton K. Shernan, MD,‡ and Charles D. Collard, MD*
T
HE ADMINISTRATION OF 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or “statins,” to ambulatory patients is associated with a reduced incidence of adverse cardiovascular events, including death, myocardial infarction (MI), stroke, atrial fibrillation, and renal dysfunction.1-6 Moreover, the beneficial effects of statin therapy are not limited to patients with hypercholesterolemia. Multiple randomized clinical trials have shown that even in patients with normal total and low-density lipoprotein (LDL) cholesterol levels, long-term statin administration is associated with a reduced incidence of adverse cardiovascular outcomes and a decreased need for invasive procedures, such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG) surgery.3-6 Although there is little doubt that statin therapy is associated with a reduced long-term incidence of adverse cardiovascular events, recent evidence suggests that statins may also reduce the risk of acute adverse outcomes after invasive cardiovascular procedures.6-15 For example, statin therapy at the time of PTCA was recently shown to independently predict 30-day and 6-month survival.6 Additionally, growing evidence suggests that statins are associated with a reduced risk of perioperative morbidity and mortality in patients undergoing major cardiac or vascular surgery.7-15 Thus, HMG-CoA reductase inhibition may be one of the most important perioperative therapeutic regimens to reduce the risk of postoperative cardiovascular complications in high-risk surgical patients since the introduction of beta-blockers into the operative setting.16 The pharmacologic mechanisms and role of statins in the acute perioperative setting are reviewed. PHARMACOLOGIC MECHANISMS OF STATINS
Lipidemic Effects Cholesterol is a critical component of eukaryotic cell membranes, playing an important role in membrane fluidity and plasticity. Cholesterol is also a vital precursor of steroid hormone synthesis. Approximately 800 mg of cholesterol is synthesized in humans per day, primarily in the liver and the intestine.17 Statins inhibit cholesterol synthesis and lower LDL cholesterol. Specifically, statins inhibit the rate of conversion of acetate molecules into cholesterol by inhibiting HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis. Because cells require a certain amount of cholesterol, inhibition of cholesterol synthesis results in a cellular homeostatic response in which cells increase
the density of LDL receptors on their surface. This increases the clearance of LDL particles from the plasma, resulting in decreased circulating LDL levels. Clinically, this is associated with a reduction in atherosclerotic plaque formation and a stabilization of preexisting “vulnerable” atherosclerotic plaques at high risk for rupture.18,19 The “vulnerable plaque” responsible for most MIs consists of a highly thrombogenic lipid core that is densely infiltrated by active and apoptotic macrophages, and is covered by a thin fibrous cap (⬍65 m). Erosion or rupture of the fibrous cap covering the lipid-rich core results in thrombus formation and significantly increases the likelihood of subsequent MI. The probability of plaque erosion or rupture is inversely related to thickness of the fibrous cap.18 Plaque rupture is also strongly associated with the actions of matrix metalloproteinases (eg, MMP-3) derived from T-lymphocyte–stimulated macrophages that promote proteolysis of the thin fibrin cap. Postulated mechanisms of statinmediated stabilization of vulnerable plaques include a change in the plaque composition from a lipid-rich to a fibrotic/calcified environment, a reduction in macrophage proliferation, inhibition of matrix metalloproteinase activity, and decreased tissue factor expression.18-20 Nonlipidemic Effects Although statins are potent inhibitors of cholesterol biosynthesis, increasing evidence suggests that their beneficial effects are not limited to patients with hypercholesterolemia.21-29 For example, statin administration may reduce morbidity and mortality even
From the *Division of Cardiovascular Anesthesia, Texas Heart Institute at Saint Luke’s Episcopal Hospital, Houston, TX; †Department of Anesthesiology and Intensive Care Medicine, University Hospital, Tübingen, Germany; and ‡Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. Address reprint requests to Charles D. Collard, MD, Division of Cardiovascular Anesthesiology, The Texas Heart Institute at St. Luke’s Episcopal Hospital, Baylor College of Medicine, 6720 Bertner Avenue, Room 0520, MC1-226, Houston, TX 77030. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2002-0025$32.00/0 doi:10.1053/j.jvca.2005.12.012 Key words: HMG-CoA reductase inhibitor, surgery, transplantation, prevention, cholesterol, inflammation
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Statins have also been shown to reduce tissue injury in models of ischemia and reperfusion in several organs, including the heart, lung, brain, kidney, and gut.25-28,37 For example, in an isolated, perfused rat heart model, simvastatin was found to be a potent and effective cardioprotective agent that inhibited leukocyte-endothelial cell interactions while preserving cardiac contractile function and coronary perfusion after myocardial ischemia and reperfusion.26 Furthermore, statins have been shown to attenuate vasoconstriction by increasing endothelial nitric oxide (NO) activity, a benefit seen within 6 weeks of the start of treatment.38 Endothelial type III NO synthase in thrombocytes is also upregulated by statins, leading to decreased platelet activation and vascular ischemia.39 Moreover, both in vitro and in vivo studies have shown that abrupt statin discontinuation results in decreased NO production, impaired endothelial and vascular function, and increased in-hospital morbidity (eg, 16.5% v 5.3% in patients whose statin therapy was discontinued after admission for acute MI).40-43 Statins thus exert pleiotropic effects, independent of cholesterol reduction, that have direct antiatherosclerotic, antithrombotic, and antiinflammatory impact.44,45 Statin Pharmacogenetics Fig 1. The HMG-CoA reductase pathway. (Color version of figure is available online.)
in individuals with normal or only moderately elevated LDL levels.18,30-32 Although the exact mechanisms by which statins reduce the likelihood of cardiovascular events have yet to be fully elucidated, the metabolite of HMG-CoA reductase, mevalonic acid, is a precursor of the cholesterol and the isoprenoid intermediates farnesyl and geranylgeranyl pyrophosphate (Fig 1). These intermediates are essential for the posttranslational modification of intracellular G-proteins, such as Rho, Rac, and Ras, which regulate endothelial, platelet, and leukocyte function.22,24 Statins have also been shown to modulate vascular remodeling by inhibiting cellular matrix metalloproteinases and transcription factors, such as nuclear factor-B.22 In patients with acute coronary syndromes (ACS) or idiopathic dilated cardiomyopathy, statin therapy has been shown to reduce untoward inflammatory activity, including changes in C-reactive protein, serum amyloid A, tumor necrosis factor ␣, interleukin 6, and brain natriuretic peptide levels.22,23 Moreover, statins have been reported to decrease serum levels of the inflammatory marker C-reactive protein within 14 days of administration, suggesting an acute protective role for these drugs.33 The anti-inflammatory and immunomodulatory properties of statins have also been shown in patients with other complex inflammatory syndromes, such as sepsis and septic shock. In septic patients, statins have been shown to attenuate the release of acute-phase inflammatory proteins and to exert antiapoptotic effects, thereby inhibiting sepsis-induced endothelial activation and dysfunction.34 Statins also reduce cell-surface expression of toll-like receptors on monocytes, thereby decreasing monocyte activation by circulating endotoxins.35 Additionally, they inhibit expression of leukocyte function antigen-1, thus decreasing lymphocyte cell adhesion and T-cell activation in the early stages of sepsis.36
The individual response to statin therapy has been shown to be influenced by genetic variation within several genes, including apolipoprotein E (Apo E), LDL receptor, angiotensin-I converting enzyme, paraoxonase, and cytochrome P2C9.46-49 For example, several studies, including a meta-analysis of 625 patients, have shown that statin-mediated lowering of LDL cholesterol is significantly greater in individuals expressing the Apo E2 genotype when compared with individuals expressing the E4 allele (37% v 33%, p ⬍ 0.05).50 Additionally, the enhanced response to statin therapy in individuals expressing the Apo E2 allele may be gender specific. Plasma triglyceride lowering with atorvastatin was improved only in men carrying the E2 allele (⫺27%) when compared with E3 (⫺13%) or E4 (⫺22%) alleles.51 Nonetheless, statin therapy is still associated with a 2-fold reduction in mortality risk in MI survivors expressing the Apo E4 allele, suggesting these patients may especially benefit from statin therapy.52 STATIN USE IN MEDICAL PATIENTS
Statins are commonly prescribed for the primary or secondary prevention of cardiovascular events in patients with hypercholesterolemia who are at risk for or known to have coronary artery disease (CAD).1-3,5,53,54 A meta-analysis of the Scandinavian Simvastatin Survival Study, Cholesterol and Recurrent Events Trial, and Long-Term Intervention with Pravastatin Ischemic Disease Trial showed that statin therapy reduced the risk of MI by 30% in patients with preexisting CAD.4,5,55,56 Based on these observations, the American College of Cardiology/American Heart Association guidelines now recommend statin therapy for management of patients with unstable angina or MI.57 Moreover, recent data obtained from the Treating to New Targets Trial and the Heart Protection Study suggest that patients at high risk for CAD may especially benefit from aggressive lipid-lowering strategies.58,59 In the Heart Protection Study, statin therapy was independently associated with a sig-
INFLUENCE OF STATINS ON PERIOPERATIVE OUTCOMES
nificant reduction in the risk of all-cause mortality and incidence of adverse cardiovascular events (including major coronary events, stroke, and revascularization).59 Early implementation of statin therapy within 24 hours of admission for acute MI has also been shown to be beneficial, with 1 study showing an absolute reduction in mortality by approximately 10% when statin therapy was continued or introduced early upon admission.60 Furthermore, intensive lipid-lowering statin regimens have been shown to provide greater protection against death and major cardiovascular events in ACS patients than standard regimens. For example, the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Trial showed that intensive statin therapy (atorvastatin, 80 mg, v pravastatin, 40 mg) in ACS patients significantly reduced the composite endpoint of death, MI, or rehospitalization (3% v 4.2%, p ⫽ 0.04).61 Based on these findings, several investigators have advocated that optimal serum LDL cholesterol levels should be well below current recommended guidelines, in the range of 50 to 70 mg/dL.59 STATINS AND PERIOPERATIVE OUTCOMES
Major Noncardiac Surgery Cardiovascular complications after major noncardiac vascular surgery are a primary cause of perioperative morbidity and mortality. Perioperative mortality ranges as high as 5% to 6%, with nonfatal MI occurring in up to 34% of patients.62,63 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.8 Similarly, a recent retrospective cohort study, based on the hospital discharge and pharmacy records of 780,591 patients from 329 United States hospitals who underwent major noncardiac surgery, showed that preoperative lipidlowering therapy was associated with a reduced risk of postoperative mortality, even after controlling for patient demographics, perioperative risk factors, and propensity score (adjusted odds ratio ⫽ 0.62; 95% confidence interval, 0.580.67).64 Furthermore, only patients reinitiated on statin therapy early after surgery (before postoperative day 2) were included in the final analysis, suggesting that the observed survival benefit may be dependent on continuation of statin therapy throughout the perioperative period. Finally, long-term statin use has been associated with reduced risk of all-cause (2.5-fold) and cardiovascular (3-fold) mortality after abdominal aortic aneurysm repair.13 Two recent prospective trials investigating perioperative statin therapy in patients undergoing vascular surgery further underpin the statin-associated benefit seen in previous retrospective studies.11,65 Durazzo et al11 showed that adverse cardiac events after a 6-month follow-up period were 3 times more likely in patients receiving placebo compared with patients receiving atorvastatin (26% v 8%, p ⫽ 0.03). Both Durazzo et al11 and Schouten et al65 observed a lower incidence of postoperative nonfatal acute MI among statin users (6% v 16% and 6.6% v 10.7%, respectively). Furthermore, a recent pharmacoeconomic analysis by Biccard et al66 of these studies suggested that perioperative statin therapy for the prevention of compli-
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cations after vascular surgery is even more cost-effective than statin therapy for the primary and secondary prevention of CAD. Although the mechanisms by which statins reduce postoperative mortality have yet to be fully elucidated, statinmediated atherosclerotic plaque stabilization, along with statins’ antithrombotic and anti-inflammatory effects, may contribute to improved postoperative outcomes.8,13,22,32,45,64 Cardiac Surgery After CABG surgery, the lifespan of venous grafts is often limited by the development of accelerated postoperative atherosclerosis. Therefore, considerable attention has been directed to the role of statins in preventing early graft atherosclerosis and occlusion. For example, 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.67 The PostCABG Trial investigators found that, in addition to reductions in postoperative serum LDL levels, long-term statin administration was associated with a significant decrease in the progression of vein graft lesions and the incidence of graft occlusion.10 Furthermore, statin treatment was associated with a 30% reduction in the need for revascularization procedures.68 Similarly, Christenson69 showed that as little as 4 weeks of preoperative simvastatin administration minimized the incidence of CABG lesions (10% v 46%) and occlusions (2.5% v 60%) when compared with patients not receiving statins in the first year after surgery. In addition to preserving vein graft function, 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.70 Statins have also been shown to reduce the incidence of adverse clinical outcomes after CABG surgery.7,9,15,68,69,71 In a nonrandomized retrospective study, statins were shown to be associated with a reduced risk of the composite clinical outcome of death, MI, and arrhythmias (1% v 9%, p ⬍ 0.001) 60 days after CABG surgery.9 Additionally, statins were associated with a reduced risk of the composite outcome of death and MI (0% v 5%, p ⫽ 0.01) 1 year after CABG surgery.9 Similar beneficial effects of statins were also reported in a subgroup of 2,245 patients who underwent revascularization (PTCA, CABG surgery, or both) in the Cholesterol and Recurrent Events Trial. Statin use reduced the relative risk of the composite outcome of cardiac death and nonfatal MI by 36%, fatal or nonfatal MI by 39%, stroke by 39%, and the need for repeat revascularization by 18%.71 In a recent retrospective study of 1,663 patients undergoing CABG surgery, preoperative statin therapy was independently associated with a reduced risk of 30-day all-cause mortality (1.8% v 3.75%, p ⬍ 0.05).7 However, statins were not independently associated with a reduced risk of postoperative MI, arrhythmias, stroke, or renal dysfunction.7 Finally, preoperative statin therapy was shown to be associated with a significant reduction in the risk of acute cardiac death within the first 4 days of operation (0.3% v 1.4%, p ⬍ 0.03) after elective CABG surgery with cardiopulmonary bypass.15 In contrast to cardiac outcomes, a recent retrospective, observational study found that preoperative statin therapy
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Table 1. Randomized Clinical Trials Reporting Statin-Associated Adverse Effects Trial
Statin
Scandinavian Simvastatin Survival Study54
Simvastatin (20 mg/d)
Expanded Clinical Evaluation of Lovastatin103
Lovastatin (20-80 mg/d)
Cholesterol and Recurrent Events Trial5
Pravastatin (40 mg/d)
West of Scotland Prevention Study2
Pravastatin (40 mg/d)
Heart Protection Study59
Simvastatin (40 mg/d)
Air Force/Texas Coronary Athersclerosis Prevention Study3 Myocardial Ischemia Reduction with Acute Cholesterol Lowering Study22 Lipoprotein and Coronary Atherosclerosis Study104 Federal Drug and Safety Administration Reports
Safety Record
Number of Patients
Lovastatin (20-40 mg/d)
One case of rhabdomyolysis; no increased rate of hepatotoxicity and nephrotoxicity Myopathy over a 2-year followup period only at doses of 40-80 mg/d No increased rate of myotoxicity No increased rate of myalgia, muscle pain, or hepatotoxicity Similar incidence of myotoxicity (0.09%) and elevated liver enzymes (0.8%) No differences
6,605 men and women
Atorvastatin (80 mg/d)
Adverse event frequency ⬍1%
3,086 patients
Fluvastatin (20 mg/d)
Adverse events ⬍1%
429 patients
Cerivastatin (0.4-0.8 mg/d)
Increased incidence of rhabdomyolysis (53 deaths) Rhabdomyolysis ⬍0.01%
Rusovastatin (10-40 mg/d)
was not associated with a decrease in the incidence of cognitive dysfunction (34.5% v 37.2%) 6 weeks after CABG surgery.72 Furthermore, multivariate analysis revealed that patients receiving statin therapy at discharge showed a higher prevalence of cognitive deficit compared with nonstatin users (42% v 34.5%, p ⫽ 0.19).72 Several recent studies have suggested that statins may also reduce the progression of calcific aortic stenosis and bioprosthetic valve degeneration.14,73-75 Calcific aortic stenosis is the most common heart defect in adults and is associated with an increased risk of cardiac death.74 In an experimental animal model of aortic stenosis, statin administration inhibited the development of left ventricular hypertrophy and improved left ventricular function.75 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 (0.06 ⫾ 0.16 cm) compared with nonstatin users (0.11 ⫾ 0.18 cm, p ⫽ 0.03).76,77 Statin treatment was also an independent predictor of a reduced increase in the aortic peak gradient (p ⫽ 0.02).76 Moreover, statin administration has been shown to reduce the progression of bioprosthetic valve degeneration.14 This effect is independent of cholesterol levels, suggesting a role for the non–lipid-mediated, pleiotropic effects of statins.
4,444 patients
8,245 patients
3,244 patients 6,595 men
20,500 patients
such as cyclosporine and corticosteroids. Data supporting this hypothesis come from several randomized clinical trials in heart transplant recipients showing that statins lower cholesterol levels, decrease the incidence of transplant vasculopathy, and improve long-term survival.82-85 Statin-treated heart transplant recipients also show improved epicardial and microvascular endothelial function, along with decreased levels of the proinflammatory cytokines interleukin 6 and tumor necrosis factor ␣.86 Similar findings have been observed in lung, liver, and kidney transplant recipients.80,81,87-90 Statin administration after lung transplantation was recently shown to be associated with improved lung function, a reduced number of inflammatory cells after bronchoalveolar lavage, and improved long-term survival.81 Moreover, statins have been shown to acutely reduce posttransplant cholesterol levels. Liver transplant recipients’ total and LDL cholesterol levels are significantly reduced compared with those of control patients within 14 days of beginning treatment with atorvastatin.87 The National Kidney Foundation also recently released guidelines suggesting statins as first-line agents for the management of hyperlipidemia in renal transplant recipients.79 Interestingly, statin use was recently shown to be associated with improved blood pressures in renal transplant recipients, independent of changes in cholesterol.91
Organ Transplantation Solid-organ transplant recipients undergoing immunosuppressive therapy have a higher incidence of dyslipidemia and accelerated graft atherosclerosis than does the general population.78-81 Several investigators have therefore hypothesized that long-term statin administration to transplant recipients may offset the dyslipidemic effects of immunosuppressive drugs,
Statin Safety The issue of statin safety has received much attention, especially after the withdrawal of cerivastatin in August 2001.92,93 In general, statins are well tolerated but can produce a variety of side effects (Table 1), including gastrointestinal disturbances, dyspepsia, headache, myalgia, central nervous system
INFLUENCE OF STATINS ON PERIOPERATIVE OUTCOMES
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disturbances, and sleep disorders.93 However, statin-related hepatotoxicity and myopathy, which in rare instances have been reported to progress into life-threatening rhabdomyolysis (including renal failure, cardiac arrest, and compartment syndrome), are probably the 2 most clinically worrisome adverse side effects. Statin side effects are dose related and inherent to all commercially available preparations. When used alone, the reported incidence of statin-associated myopathy and rhabdomyolysis is 0.1% to 0.5% and 0.04% to 0.2%, respectively.93 However, administration of concomitant medications, such as gemfibrozil, cyclosporin, niacin, or erythromycin, as well as certain physical conditions (eg, acute infection, hypotension, trauma, and severe metabolic, endocrine, or electrolyte disorders), may significantly increase the incidence of rhabdomyolysis.94 Indeed, the administration of pharmacologic agents metabolized via the same pathways as statins (ie, the cytochrome P-450 3A4 system) has been shown to increase serum statin levels and to increase the risk of myopathy and rhabdomyolysis by up to 10-fold.93 To date, few clinical data are available regarding the influence of preoperative statin therapy on the incidence of postoperative myopathy. One recent report speculated that preoperative pravastatin administration may have contributed to the occurrence of severe postoperative rhabdomyolysis after combined CABG/abdominal aortic replacement surgery.95 Additionally, it has been suggested that statin therapy be discontinued 4 to 7 days preoperatively in patients scheduled to undergo major surgery associated with a significant risk of direct muscle trauma.94 Despite these recommendations, a recent prospective clinical trial investigating the potential risk of statin-associated myopathy in patients undergoing major noncardiac surgery found that preoperative statin use was not associated with an increased risk of postoperative myopathy.65 Thus, further clinical data are needed to evaluate the risk/benefit ratio of discontinuing statins in the preoperative period. CONCLUSION
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. Despite careful use of regression models and propensity scores to adjust for potential confounders that may affect postoperative outcomes, confounding factors may still exist. Physician bias may have influenced patient selection, choice of statin type, and dosages. Indeed, randomized clinical trials of statin use in other settings, such as ACS (eg, the Myocardial
Ischemia Reduction with Acute Cholesterol Lowering trial), although encouraging, have not always confirmed the marked reduction in mortality seen in early observational studies.96,97 Thus, a need for prospective, randomized studies investigating the influence of statin therapy on adverse surgical outcomes still exists. Second, the influence of the duration of preoperative statin therapy on the risk of postoperative outcomes has not yet been adequately addressed. 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.6,21,22 However, the minimum length of preoperative statin administration necessary to protect against acute perioperative outcomes has yet to be determined. Similarly, a growing body of evidence suggests that genetic factors may significantly affect the response to statin therapy.98,99 Thus, there also remains a need for pharmacogenetic studies examining the impact of genotype on statin efficacy, metabolism, and side effects. 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 and colleagues100 showed that patients experiencing ACS who received statin therapy before the onset of symptoms had a reduced incidence of 30-day all-cause mortality and nonfatal MI compared with ACS patients not receiving statins. Furthermore, the cardiac event rate was significantly greater among patients in whom statin therapy was withdrawn than among patients who continued to receive statins. Statin therapy was also shown to be less effective in reducing the risk of death or nonfatal MI when initiated after the presentation of an ACS rather than before the onset of symptoms (14% v 51% relative risk reduction).100 These results suggest that postoperative discontinuation of statin therapy may increase the risk of adverse cardiovascular events. Nonetheless, although American College of Cardiology and American Heart Association guidelines recommend statins for CABG patients with LDL concentrations ⬎100 mg/dL,101 two thirds of eligible candidates may not be receiving statin therapy at discharge.102 Explanations for not reinitiating statin therapy after CABG surgery may include patients’ decreased tolerance of oral medications secondary to nausea and vomiting, transient renal dysfunction, concerns about hepatic toxicity or myositis, or forgetfulness on behalf of the responsible physician at the time of discharge. Educating physicians about the potential benefits of continuing statin therapy throughout the perioperative period may thus be warranted.
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