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* From the Departments of Anesthesia, Lower Bucks Hospital, Bristol, Pennsylvania; and
Cooper University Hospital, Camden, New Jersey, USA.
Address correspondence to: Dr. Nader Boushra, MD. Department of Anesthesia, Lower Bucks Hospital, 501 Bath Road, Bristol, PA 19007, USA. E-mail: nadboush{at}hotmail.com
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Abstract |
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 TOP Abstract Search strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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Source: MEDLINE search using "perioperative", "cardiac morbidity", "atherosclerosis", "vulnerable plaque", "statins" and combinations of these terms as keywords. The reference lists of relevant articles were further reviewed to identify additional citations.
Principal findings: The nonstenotic, yet rupture-prone VAP causes most myocardial infarctions (MIs) and other ACSs, both in the nonsurgical and surgical patients. Large clinical trials in both primary and secondary prevention and in patients with ACSs have demonstrated that statin therapy will reduce cardiovascular morbidity and mortality across a broad spectrum of patient subgroups. These trials also suggest, and laboratory investigations establish, that statins possess favourable vascular effects independent of cholesterol reduction. Statins appear to interfere specifically with the pathophysiologic mechanisms implicated in atherothrombotic disease. Statins reduce vascular inflammation, improve endothelial function, stabilize VAPs, and reduce platelet aggregability and thrombus formation. Recent studies have shown that PST is associated with a reduced incidence of perioperative and long-term cardiovascular complications in high-risk patients. Combined therapy with statins and ß-blockers is a conceptually valid strategy targeting critical steps in the pathogenesis of an ACS.
Conclusion: Emerging evidence for the efficacy and safety of PST is promising, especially when combined with ß-blocker therapy in patients at highest risk. Confirmation of this early evidence awaits the results of ongoing and future prospective randomized controlled trials.
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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Statins: a major breakthrough in cholesterol lowering therapy
Statins: beyond cholesterol lowering
Perioperative cardiac morbidity
Pharmacologic reduction of perioperative cardiac risk in NCS
Logistic considerations in perioperative use of statins
Conclusions
PERIOPERATIVE myocardial infarction (PMI) complicating non-cardiac surgery (NCS) accounts for considerable morbidity and mortality and consumes constrained economic resources. Patients with preexisting coronary artery disease (CAD) undergoing major vascular surgery are particularly at risk.1 However, while the incidence of perioperative cardiac complications is lower in patients undergoing other types of NCS, there are many more of these patients compared with the vascular surgery population and, thus, their impact on the population burden of disease may be greater.2 Of the approximately 26 million North Americans who undergo other NCS every year, at least 0.7% will suffer a major perioperative cardiac event. If the estimated increase in cost associated with perioperative myocardial ischemic injury is ~ $10,000 per patient,3 the economic burden of perioperative cardiac events in other NCS patients is ~ $1.8 billion a year, while the 500,000 patients who undergo major vascular surgery annually with perioperative cardiac events occurring in 17.8%3 will cost ~ $ 0.9 billion a year. Several independent lines of evidence suggest that acute disruption of a non-stenotic yet vulnerable atherosclerotic plaque (VAP) in the infarct-related coronary artery, similar to that observed in nonsurgical patients,4–6 may be common in PMIs. For example, preoperative risk assessment with methods that detect fixed intracoronary lesions such as preoperative dobutamine stress echocardiography have failed to reliably identify the anatomic location of fatal acute PMI.7 Also, experience with preoperative dipyridamole thallium scintigraphy done on consecutive patients has shown no association between thallium redistribution defects and adverse outcomes; the majority of MIs occurred in patients without redistribution defects.8 Furthermore, there is angiographic9,10 and histopathologic11,12 evidence that PMIs may indeed occur distal to non-critical stenosis because of a VAP rupture.
Statins have been shown to have favourable actions on atherosclerosis and vascular properties other than those attributed to cholesterol lowering. The focus of this report is to review the role of statin therapy in VAP stabilization, and to examine the available evidence on the clinical benefits of statin therapy in reducing the perioperative risk of acute cardiac events.
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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An overview of atherosclerosis and acute coronary syndromes (ACS) |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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). Alterations in blood flow at specific arterial sites coupled with increased oxidative stress upregulate endothelial gene expression of specific atherothrombogenic molecules. The expression of these molecules is under control of the immunomodulatory cell surface protein dyad CD40/CD40L and the intracellular nuclear transcription nuclear factor kappa B (NF
B). The endothelial dysfunction increases the adhesiveness of the endothelium with respect to leucocytes and platelets as well as its permeability. The dysfunctional endothelium also has a procoagulant instead of anti-coagulant properties and forms vasoactive molecules, cytokines and growth factors.
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), a potent inducer of apoptotic SMC death and inhibitor of collagen synthesis; and matrix metalloproteinases (MMPs) which degrade the extracellular matrix of the fibrous cap. The MMPs and their co-secreted inhibitors, tissue inhibitors of metalloproteinases (TIMPs), are critical for vascular remodelling. Eccentric outward expansion during plaque growth to minimize luminal encroachment despite large plaque size, known as positive remodelling, has been shown to be more common at culprit lesion sites in unstable angina, whereas inward or negative remodelling is more common in stable angina.14 A sudden surge of sympathetic activity with an increase in blood pressure, heart rate, force of cardiac contraction and coronary blood flow may fatigue and weaken the fibrous cap that ultimately may rupture within the coronary artery lumen. The tension created by the blood pressure in fibrous caps is given by Laplace’s law: the higher the blood pressure and the larger the luminal diameter, the more tension develops in the wall. Consequently, mildly or moderately stenotic plaques are generally stressed more than severely stenotic plaques and could therefore be more prone to rupture.5 Surges of elevated heart rate can increase stiffness of the fibrous cap and expose it to repetitive loading with resultant fatigue fracture near the junction of the cap with the more normal intima, where plaque fissuring often occurs.15 Conversely, reduction of blood pressure and heart rate by ß-blockers can favourably affect circumferential vessel wall stress and thus prevent plaque disruption, specifically in patients with relatively fast heart rates and left ventricular hypertrophy.16
Disruption of a VAP with a subsequent change in plaque geometry, shear-induced platelet activation and exposure of extremely thrombogenic plaque components (lipid core, collagen) resulting in thrombosis lead to a complicated lesion (Figure 2). The local thrombogenic response is activated by the damaged subendothelium (intrinsic coagulation pathway) and by the exposure of tissue factor (TF)-rich lipid core (extrinsic pathway), as well as by a systemic hypercoagulable state and defective fibrinolytic activity. These pathways result in the formation of fibrin, which consolidates thrombus formation. The rapid change in the VAP may result in stenosis with or without angina, or in acute occlusion with an ACS, i.e., unstable angina, MI or sudden coronary death (SCD) (Figure 2). As many as two thirds of patients who develop an ACS have acute progression of fairly small coronary lesions (as detected by angiography). Indeed, Yamagishi et al.,17 using intravascular ultrasound, confirmed that large eccentric plaques containing an echolucent zone (which represents the lipid core of plaques) and thin fibrous cap with preserved coronary lumen area at the time of initial study, have been associated with ACS in clinical settings.
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Statins: a major breakthrough in cholesterol lowering therapy |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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).They are used widely for the treatment of hypercholesterolemia. Lovastatin, pravastatin, and simvastatin are derived from fungal metabolites while atorvastatin, cerivastatin (withdrawn from clinical use in 2001), fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds. Pravastatin and rosuvastatin are relatively hydrophilic compared with other statins except for fluvastatin, which has intermediate physicochemical properties.
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).18–22 Interestingly, the improvement in cardiovascular endpoints was incompletely explained by the baseline or treated LDL-C level; reductions in CAD morbidity and mortality being similar regardless of the baseline or on-treatment LDL-C level.
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Statins in acute coronary syndromes
Several retrospective25–30 and prospective31–33 studies suggest a possible beneficial effect from concomitant or very early statin administration in patients with ACS. The results of these trials suggest that patients with ACSs should begin to receive statin therapy before leaving hospital,31,32 irrespective of baseline LDL-C levels, and that more intensive lipid lowering significantly increases clinical benefit.32 For example, the Myocardial Ischemia Reduction with Acute Cholesterol Lowering ( MIRACL ) trial31 which enrolled 3,086 patients demonstrated that intensive lowering of cholesterol with atorvastatin (80 mg·day–1) initiated 24 to 96 hr after an ACS, reduced the incidence of the composite endpoint of death, nonfatal MI, resuscitated cardiac arrest, and recurrent symptomatic myocardial ischemia from 17.4% in the placebo group to 14.8% in the atorvastatin group (P = 0.048) over a follow-up period of four months. However, the borderline statistical significance of the primary composite endpoint reduction and failure of atorvastatin therapy to significantly affect more concrete individual trial endpoints, e.g., death or recurrent MI, were disappointing. Whether this reflected a true lack of physiologic impact of early statin treatment or merely indicated that the study was underpowered to detect differences in these endpoints remains unclear.
More recently, Cannon et al. (PROVE IT trial)32 compared two statin regimens of different lipid-lowering intensities for the prevention of cardiovascular events among 4,162 patients who had recently been hospitalized for an ACS. The more intensive regimen (atorvastatin 80 mg·day–1) resulted in a lower risk of death from any cause or major cardiac events than did a more moderate degree of lipid lowering with the use of a standard statin dose (pravastatin 40 mg·day–1).
The data emerging from clinical outcome trials in both stable and unstable CAD, suggest that non-lipid or direct mechanisms contribute to the early beneficial cardiovascular event reduction observed in these trials. However, because of their excellent lipid lowering potential, statins always modify serum cholesterol levels and, thus, it is impossible to differentiate lipid-independent effects from those associated with lipid reduction, especially if these effects are complementary.
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Statins: beyond cholesterol lowering |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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). Initially, beneficial effects may be due to enhanced endothelial function and a favourable effect on blood coagulation and fibrinolysis. Later, effects on plaque composition and size may be operative.
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shows that inhibition of mevalonate synthesis by statins not only blocks the formation of cholesterol, but also isoprenoid intermediates, a diverse group of nonsteroidal compounds important in maintaining membrane fluidity, electron transport, and protein isoprenylation. Hence, control of eukaryotic cell growth, differentiation, proliferation, signalling and apoptosis is influenced secondarily. The isoprenoids are added during post-translational modification of a variety of proteins, including G-proteins and G-proteins subunits, Ras and Ras-like proteins such as Rho. Statins, by inhibiting G-protein-dependent signalling pathways, activate peroxisomal proliferator-activated receptors (PPARs) and/or suppress NFB expression. Peroxisomal proliferator-activated receptors and NFB are nuclear transcription factors which control the expression of specific inducible target genes, leading to the synthesis of anti- and pro-atherothrombogenic molecules, respectively.
Statins’ antiatherothrombotic actions: in vivo studies
The experimental data demonstrating antiatherothrombotic actions of statins, outlined in Table II, have been supported by several in vivo human studies.
ENDOTHELIAL FUNCTION
Endothelium-dependent vasomotor function reflects the functional integrity of vascular endothelium in vivo, and can serve as surrogate for the bioavailability of nitric oxide (NO). Improvement of endothelial vasomotor function occurs early after initiation of statin therapy and can be observed in conduit and resistance arteries in both the forearm and coronary circulation. Improvement in brachial endothelial function with statin therapy has been shown in patients with hypercholesterolemia,56 patients with CAD57 and patients with ACS.58 Studies in humans have also shown that cholesterol lowering with statins improves coronary endothelial function in patients with hypercholesterolemia, 59 or CAD.60 In statin-treated CAD patients, significantly lower levels of coagulation, systemic inflammation and soluble adhesion markers were also found.61 Moreover, Mostaza et al.62 demonstrated that a 16-week treatment of CAD patients with pravastatin improves myocardial perfusion during dipyridamole thallium single photon emission computed tomography testing.
PLAQUE STABILIZATION
Recent in vivo studies indicate that statins induce plaque stabilization in humans. For example, Corti et al.63 demonstrated using sequential high resolution magnetic resonance imaging of the aorta and carotid arteries, significant regression of atherosclerotic plaque size in asymptomatic hypercholesterolemic patients after 12 months of statin treatment. More interestingly, no change in the lumen dimension was registered after 12 months, suggesting that statin treatment initially induces vascular remodelling, as a possible consequence of radical changes of plaque composition. Similarly, a recent intravascular ultrasound study of coronary arteries with angiographically mild lesions demonstrated that 12 months of simvastatin treatment is associated with significant regression in plaque size without any concomitant change in lumen volume.64
Crisby et al.,42 confirmed in patients treated for three months with pravastatin, using endarterectomy specimens, significantly lower content in lipid, oxLDL, macrophages, T cells, MMPs, and greater content in TIMPs and collagen. Another study65 also showed that carotid plaques retrieved at carotid endarterectomy from patients taking a variety of statins for > six weeks before surgery revealed significantly lower concentration of MMPs and interleukin-6. Interestingly, this study also showed that patients on statins were less likely to have spontaneous cerebral embolization from their carotid plaque (as detected by transcranial Doppler before surgery), providing additional evidence of plaque stabilization in statin users.
THROMBOGENICITY AND FIBRINOLYSIS
In men with marked hypercholesterolemia, lowering serum cholesterol by a three-month simvastatin treatment is accompanied by a reduction of thrombin generation both at basal conditions and after activation of hemostasis by microvascular injury.66 Similar results are obtained in CAD patients and borderline high cholesterol levels studied by Undas et al.67 They assessed TF-initiated coagulation in blood samples collected from bleeding time wounds and demonstrated that three-month simvastatin treatment depresses clotting through a concerted influence on the clotting cascade. Furthermore, in hypercholesterolemic patients with CAD, treatment with simvastatin for 14 weeks significantly lowered plasma levels of TF and plasminogen activator inhibitor 1 (PAI-1), markers of plaque thrombogenicity.68 In all these studies66–68 the antithrombotic actions of simvastatin showed no relationship to its cholesterol lowering action. Finally, Cortellaro et al.69 evaluated the thrombogenicity of human carotid plaques before and after atorvastatin treatment, using endarterectomy specimens obtained at baseline and after treatment. They showed that TF and TFPI antigens and TF activity in plaques after atorvastatin treatment are lower than after placebo.
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Perioperative cardiac morbidity |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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PATHOLOGIC DATA
Evidence of unstable plaques with disruption was noted in two retrospective studies which specifically investigated the coronary pathology of fatal PMI.11,12 In a study by Dawood et al.,11 histopathological analysis of coronary arteries and myocardium was compared in 42 patients who died of PMI and 25 patients who died of non-PMI. Evidence of plaque disruption was noted in 55% of PMI patients. In more than half the patients, the site of MI could not have been predicted from the severity of the underlying stenosis. Similarly, Cohen and Aretz12 analyzed the coronary pathology of 26 patients who died from PMI and found evidence of plaque rupture in 12 patients (46%). Although the methodology of these two studies (i.e., retrospective review of small number of autopsy specimens) was inherently insensitive for detection of plaque rupture, they indicated that ~ 50% of patients who died of PMI had no evidence of plaque rupture. In these patients, who often have significantly stenotic and multivessel CAD, stress-induced prolonged perioperative myocardial ischemia may have been responsible for their PMI and death.70
SIGNIFICANCE OF PLAQUE BURDEN
Evidence from nonsurgical patients indicates that the occurrence of ACSs is determined by atherosclerotic plaque burden, as detected by high coronary calcium score on screening electron beam computed tomography (EBCT) imaging, rather than the presence of focal coronary luminal stenoses.76 Similarly, surgical patients who experienced PMIs had more angiographic evidence of extensive CAD when compared with a matched control group without PMI or death.9 Mahla et al.77 examined the impact of coronary atherosclerosis plaque burden, measured by EBCT-derived coronary calcium score, on the potential for perioperative myocardial cell injury, as detected by cardiac troponin T elevations, in patients undergoing elective vascular surgery. A high coronary calcium score > 1000 carried an increased risk for myocardial cell injury after vascular surgery.
INFLAMMATION AND MULTICENTRIC CORONARY INSTABILITY IN ACSS
In patients with ACS, there is emerging evidence for the presence of widespread coronary78 and myocardial79 inflammation affecting remote non-infarct related coronaries and myocardium. Furthermore, intravascular ultrasound,80 angioscopic81 and angiographic82 studies have identified additional lesions with characteristics associated with plaque vulnerability and rupture at sites other than the culprit lesion, implying an overall coronary instability in ACS patients. A similar observation was noted in PMI pathologic studies where 14% of the PMI patients had direct evidence of plaque disruption in more than one coronary artery.11 Plasma C-reactive protein (CRP) elevations in patients with CAD appear to reflect the burden of inflammation within atherosclerotic lesions, thus reflecting the grade of vulnerability and instability of the plaques. Indeed, a positive correlation between plasma CRP levels and complex angiographic morphology of the culprit lesion in patients with unstable angina has been described.83 Burke et al.84 have confirmed in pathologic studies of SCD patients that plasma CRP as measured by high sensitivity assay (hsCRP) is correlated with amounts of CRP in atheroma and with number of thin cap atheromas. Stable plaques were associated with modest elevation in hsCRP, erosive plaques greater elevation, and marked elevations were seen with ruptured plaques. The value of preoperative plasma CRP determination in predicting outcome after coronary artery bypass graft (CABG)85 and coronary angioplasty86 have recently been reported. Further studies are needed in order to assess their utility and reliability in patients undergoing NCS.
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Pharmacologic reduction of perioperative cardiac risk in NCS |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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Toward a new paradigm
However, not all patients are equally protected by ß-blocker therapy. The results of a recent large observational study91 indicated that ß-blockers may be harmful in low-risk patients, neutral in patients at intermediate risk, and only beneficial in high-risk patients. Moreover, patients identified by clinical risk factors and dobutamine stress echocardiography as being at high-risk often have a considerable cardiac complication rate despite the use of ß-blockers.90 Thus, additional treatment options are necessary to improve perioperative prognosis in high-risk patients undergoing high-risk NCS.
As in the nonoperative setting, perioperative plaque disruption may be prevented by stabilizing plaques against disruption and/or by avoiding or reducing potential trigger activities. Since successful plaque stabilization by statins eliminates the prerequisite for plaque disruption i.e., the VAP, it is tempting to speculate that the combination of ß-blockers (for trigger reduction) and statins (for VAP stabilization) would obtain maximum benefit to reduce ACSs and perioperative cardiac morbidity. According to this paradigm, statins may be viewed as antiatherothrombotic agents that will affect overall coronary heart disease risk even when the LDL-C level is not the most prominent problem within the risk profile.
Two long-term randomized placebo-controlled carotid ultrasound studies in humans provide strong evidence for the beneficial effect of ß-blocker-statin drug combination and suggest that ß-blockade may have antiatherosclerotic effects on its own. Evidence from the Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study (BCAPS)92 indicates that ß-blockers and statins appear to have an independent effect on both slowing of atherosclerotic plaque progression and reduction of cardiovascular events. Similarly, the Effects of Long-term treatment of metoprolol CR/XL on surrogate Variables for Atherosclerotic disease (ELVA) trial93 demonstrated that ß-blockers and statins affect different mechanisms in the atherosclerotic process and have additive beneficial effects.
Moreover, a recent retrospective analysis94 evaluated the effect of initiating statin or ß-blocker treatment early in the course of heart failure developed during acute MI compared with the effect of neither or both treatments in 5,031 patients followed for an average of 3.1 yr. While early initiation of statins or ß-blockers alone had a positive impact on endpoints of cardiovascular death, all-cause mortality, reinfarction and resuscitated cardiac arrest, the combination of the treatments had additive effects on these endpoints (Figure 4).
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Effect of perioperative statin therapy (PST) on outcomes |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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).95–102 Other favourable perioperative outcomes unique to vascular surgery have also been reported in association with statin use: a reduced infrarenal aortic aneurysm growth,103 preserved renal function after suprarenal aortic clamping, 104 decreased amputation rate,105 improved graft patency105,106 and shorter length of stay102 after infrainguinal bypass surgery, and better carotid endarterectomy outcomes as measured by improved carotid artery anatomic durability107 and reduction in mortality and stroke.108 Moreover, a favourable outcome has been demonstrated in most,109–112 but not all,113 studies of CAD patients undergoing interventional [i.e., percutaneous coronary intervention (PCI)]109,110 and surgical (i.e., CABG)111,112 coronary revascularization. Conceivably, myocardial damage in association with PCI or CABG can be caused by a variety of different mechanisms including direct trauma to coronary arteries or myocardium and/or focal embolic phenomena, and thus at least a portion of this damage may be unavoidable.
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and discussed below.
PERIOPERATIVE OUTCOME
The first study to suggest beneficial effect of statins in reducing cardiac risk after NCS did not appear until 2003.95 This retrospective case-controlled study on patients undergoing major vascular surgery indicated that the use of statins was significantly less in cases (i.e., patients who died during or after surgery) than in controls (8% vs 25%; P < 0.001). The risk of perioperative mortality was reduced 4.5 times among statin users compared with nonusers. Subsequent perioperative studies after NCS were generally consistent with the benefit of statins in reducing rates of perioperative cardiac events and lower mortality, with relative reductions in risk between 30%99–101 and 70%96,98,102 compared with patients not receiving statins. One study, however, failed to demonstrate better in-hospital cardiac outcomes in patients undergoing carotid endarterectomy.108
The first prospective randomized placebo-controlled PST study was reported by Durazzo et al.98 in which they randomly assigned 100 patients to treatment with either 20 mg atorvastatin or placebo for 45 days, irrespective of their serum cholesterol concentration. Of 100 patients, 90 (44 statin users and 46 nonusers) underwent elective vascular surgery (aortic, infrainguinal, carotid and amputation) performed on average 30 days after randomization, and these patients were prospectively followed over six months. Outcome measures included cardiac death, nonfatal MI, ischemic stroke, and unstable angina. Most of these primary endpoints were detected during the hospital stay. The incidence of combined endpoint of these cardiovascular events was more than three times higher with placebo (26%) compared with atorvastatin (8%, P = 0.031) i.e., a 68% reduction in the incidence of events in patients receiving atorvastatin. The study is, however, limited by the relatively small sample size (n = 100), and the borderline statistically significant result for a broad composite outcome. Indeed, none of the individual outcomes demonstrated a statistically significant difference.
The study by Lindenauer et al.100 also deserves special attention. In a retrospective study of 780,591 patients undergoing major NCS at 329 US hospitals, they compared patients given lipid-lowering therapy (primarily statins) in the first two days after admission with those who were not given lipid-lowering therapy or who received it after day two. The primary outcome measure was in-hospital mortality. Lipid-lowering therapy was associated with a lower crude mortality rate of 2.13%, compared with a mortality rate of 3.05% among those who did not receive the drugs (P < 0.001). The risk of mortality remained lower in the treated group even after adjustment for multiple variables. In total, 70,159 of these patients were identified as statin users. After correction for numerous baseline differences, statin use was associated with a 1.4-fold reduced risk of in-hospital mortality, i.e., a 28% relative risk reduction. This study also gave a number-needed-to-treat (NNT) to prevent in-hospital deaths according to Lee’s revised cardiac risk index (RCRI). The NNT varied with cardiac risk ranging from 168 in patients with no risk factors (RCRI = 0) to 30 in patients with RCRI 
4. Clearly, the cardioprotective effect of PST was more pronounced in high-risk patients (RCRI 3). The interpretation of this observational database was, however, limited by several factors including potential bias from misclassification of patients, the unreliability of postoperative cardiovascular complications rates obtained from administrative databases, and absent information concerning the duration of lipid lowering therapy before hospital admission, pertinent laboratory results such as serum cholesterol and CRP and certain risk factors such as smoking and left ventricular dysfunction.
LONG-TERM OUTCOME
Kertai et al.97 followed 510 patients who survived aortic aneurysm surgery for a median of 4.7 yr (range 2.7–7.3 yr) and the Kaplan-Meier method was used to assess the prognostic importance of long-term statin use after surgery with respect to event-free survival. Compared with nonusers, patients using statins had a 2.5-fold reduction in the risk of all-cause mortality and more than a three-fold reduction in the risk of cardiovascular mortality. This association remained unchanged after adjusting for other covariates (including clinical risk factors and ß-blocker use) and the propensity score. However, this observational study was limited by its nonrandomized design which can only explore associations but not causality. Also the retrospective nature of the study introduced the possibility of unmeasured confounders which may have affected the study results.
Similar results were reported by Ward et al.102 who followed up their infrainguinal vascular surgery patients over a mean of 5.5 yr. Unadjusted Kaplan-Meier survival curves indicated that preoperative statin therapy was associated with improved long-term survival [odds ratios (OR) 0.48, P < 0.003)] which persisted after adjusting for significant baseline characteristics (OR 0.52, P < 0.004). Also, in Durazzo et al.’s study,98 where patients were followed for six months following their vascular surgery, Kaplan-Meier analysis was used to compare risk for event occurrence between atorvastatin users and nonusers. The rate of event-free survival after surgery at six months was 91.4% in the atorvastatin group and 73.5% in the placebo group (P = 0.018) i.e., a threefold reduction in the incidence of cardiovascular events in statin users compared with nonusers.
However, other studies105,106,114 which investigated long-term outcomes in vascular surgery patients, but with a primary focus on different predictors or different outcome measures, have yielded mixed results. For example, in a retrospective study designed to examine the efficacy of noninvasive testing and subsequent coronary revascularization on long-term outcome, Landesberg et al.114 followed up 502 patients who underwent 578 major vascular surgery for a period of 55.3 ± 32.3 (range 18 to 138) months. It was found that patients who were receiving hypolipidemic medications had improved long-term survival by univariate analysis (OR 0.49, P = 0.04). However, multivariate analysis did not show significance (OR 0.54, P = 0.08), indicating only a tendency for better event-free survival rates in statin users. Also, two small retrospective studies,105,106 primarily focused on the influence of statins on graft patency after infrainguinal bypass surgery, did not show significant beneficial effects of statins on mortality at 17 months105 and two years.106 These studies, however, were limited by their retrospective design, the relatively small number of patients, and the low mortality rates.
COMBINED PERIOPERATIVE STATIN AND ß-BLOCKER THERAPY
The interaction of PST with perioperative ß-blockers has not well been characterized. Statins seem to inhibit the farnesylation-dependent process of up-regulation of ß adrenoreceptor density induced by ß-blockade.115 This statin-induced inhibition of ß-adrenergic receptor up-regulation is beneficial in the setting of both chronic heart failure116 and myocardial ischemia.87 However, the PST outcome studies which also reported on the impact of concomitant ß-blocker therapy in patients undergoing NCS were inconsistent. Thus, in some of these studies perioperative ß-blocker therapy was not protective against perioperative cardiac complications nor was it associated with improved longterm survival.102,105,114 In Poldermans et al.’s study,95 although cardioprotective effects of ß-blockers were found, there was no significant interaction between the use of statins and ß-blockers with regard to perioperative mortality, implying that both agents have an additive effect. In contrast, studies by Kertai et al., indicated that patients who were using ß-blockers have a twofold lower risk of the perioperative composite endpoint compared with nonusers,96 and a 1.5-fold reduction in all-cause and cardiovascular mortality when followed for a median of 4.7 yr97 after abdominal aortic aneurysm surgery. Furthermore, among 103 patients receiving a combination of ß-blockers and statins, only two (1.9%) perioperative events occurred compared to 13 (8.5%) perioperative events in 153 patients using only ß-blockers (OR = 0.21, 95% confidence interval = 0.05–0.96). Patients using combination of statins and ß-blockers appeared to be at lower risk for the composite endpoint of perioperative mortality and MI, particularly in patients with three or more risk factors (RCRI 3, Figure 5). These authors hypothesized that because statins and ß-blockers affect different mechanisms in the prevention of myocardial ischemia (ß-blockers particularly influence supply and demand mismatch, whereas statins affect coronary plaque stabilization), these medications seem to have an independent positive effect, and their combination could result in synergistic activity.117 Clearly, more adequately powered perioperative studies are needed to clarify the nature and significance of ß-blocker-statin drug interaction.
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Logistic considerations in perioperative use of statins |
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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Targeting perioperative statin therapy
Potential candidates for PST would include surgical patients with symptomatic atherosclerosis i.e., patients with a history of ischemic manifestations in coronary,23 cerebral119 or femoral120,121 vessels, especially if the proposed surgery is itself associated with an elevated risk as is the case for vascular, thoracic and major abdominal procedures. All hypercholesterolemic patients and patients with the metabolic syndrome122 should also be evaluated as candidates for statin treatment. Patients with features of the metabolic syndrome have a higher rate of recurrent plaque rupture predisposing to sudden death123 and statins have been shown to cause significant cardiovascular disease risk reduction in these patients.122 Biccard et al. have suggested that the acute initiation of PST should be guided by points scored on Lee’s RCRI,124 as the efficacy of PST is greater in higher risk patients (RCRI 3).100 Moreover, any patient who develops a perioperative ACS and is not on statin therapy should be initiated on such therapy as soon as possible.25–33 Measurement of coronary calcium score (by EBCT) and/or plasma hs-CRP levels may further improve targeting, and perhaps dosing, of statin therapy. However, data on use of CRP and calcium score estimation perioperatively are incomplete77,85,125 and merit further evaluation.
Perioperative statin therapy target endpoint
Perioperative titration of a statin agent to a specific therapeutic target is not yet defined. Initiation of a statin in high-risk patients when baseline serum LDL-C is < 100 mg·dl–1, e.g., to reduce LDL-C to < 70 mg·day–1, is a reasonable therapeutic decision only on the basis of clinical judgment that the patient is still at very high absolute risk for future ACS.126 This therapeutic strategy is supported by the results of HPS23 and PROVE IT,32 and has been suggested to be the therapeutic target for PST.124 However, the efficacy of statin therapy may be related to the underlying level of vascular inflammation as detected by hs-CRP. As statins lower CRP in a manner largely independent of LDL-C reduction, measuring and monitoring of hs-CRP following initiation of statin therapy may be a useful target endpoint.127 Moreover, as both cholesterol lowering and pleiotropic effects of statins contribute to plaque stability and the reduction in clinical events, LDL-C is not necessarily the most appropriate index of the future risk of ACS, nor indeed the best measure of response to statin therapy. Reduced circulating isoprenoids may mediate cholesterol-independent effects of statins. However, despite the many critical functions of isoprenoids, only limited data exist with regard to feasibility and methods of their assay in biological systems.
Lipophilic vs hydrophilic statins
Both the hydrophilic pravastatin19–21 and rosuvastatin128 and the more lipophilic compounds18,22–24 have demonstrated similar benefit in large clinical trials. Inhibition of vascular SMC proliferation and the pro-apoptotic effect on SMCs induced by several lipophilic statins in vitro45 might theoretically favour destabilization of established plaques. However, the in vitro effects of lipophilic statins on vascular SMC proliferation and apoptosis were observed using statin concentrations far higher than those achieved with therapeutic doses in clinical situation. Indeed, that no harm resulted from aggressive treatment strategy in ACSs31–33 should allay theoretical concern that statin-mediated reductions in vascular SMC proliferation and/or induction of SMC apoptosis might destabilize the healing plaques.
Intensive high-dose vs conventional statin regimen
As intensive statin regimen provides greater protection against death or major cardiovascular events than does a standard regimen,32 the intensive high dose statin regimen will more likely be the dose regimen to be used for high-risk patients not already on statin therapy at the initial preoperative risk-evaluation visit. Nonetheless, the possibility of a beneficial effect after a standard statin regimen, as the one used in Durazzo et al. study,98 could not be excluded. The high dose statin regimen carries with it a higher risk of dose-dependent adverse effects, vis-à-vis liver and muscle injury. Further prospective randomized controlled trials are needed to define the optimal perioperative statin dosage, timing and duration in surgical patients with different cardiovascular risk profiles.
Statin pharmacokinetics and perioperative drug interactions
With the exception of pravastatin, which is transformed nonenzymatically in the liver cytosol, all statins undergo extensive microsomal metabolism by cytochrome P450 (CYP) isoenzyme systems. The CYP 3A4 isoenzyme is responsible for the metabolism of lovastatin, simvastatin and atorvastatin; while fluvastatin and to a lesser extent rosuvastatin are metabolized by CYP 2C9. As CYP 3A4 handles about half of all drugs currently available in clinical practice, particular attention should be given to drug interactions when employing CYP 3A4-dependent statins in patients receiving multiple medications and presenting for anesthesia and surgery. Atorvastatin inhibits CYP 3A4 activity in vitro and its concurrent administration with these drugs could result in alteration in their pharmacokinetics. However, available limited information indicates that while chronically administered atorvastatin decreases the clearance of iv midazolam,129 it does not alter the pharmacokinetics of alfentanil130 in patients undergoing elective surgery. On the other hand, increased bioavailability of statins resulting in myopathy and rhabdomyolysis has been reported after concurrent use of statins and several different classes of drugs e.g., macrolides, azole antifungals, calcium antagonists and cyclosporin. A recent case report131 described the development of rhabdomyolysis in a post-CABG patient probably secondary to an interaction between simvastatin and amiodarone, a potent inhibitor of CYP 3A4 isoenzyme.
Time course of action of statins
The beneficial action of statins on endothelial function and aberrant components of the coagulation cascade occur rapidly and may yield early clinically important anti-ischemic effects. For example, atorvastatin 20 mg·day–1 can rapidly improve endothelial function and NO availability in forearm vasculature almost completely after three days of therapy in hypercholesterolemic patients.132 More interestingly, Wassmann et al.133 have shown that treatment with a single oral 40 mg dose of pravastatin significantly improves endothelium-dependent coronary vasomotion within 24 hr in the absence of significant cholesterol reduction. Preoperative endothelial dysfunction is a known independent predictor of postoperative cardiovascular events in patients undergoing vascular surgery.134 Thus, it is possible that statins, even when started in the immediate preoperative period, could have favourable effects on postoperative cardiovascular outcome after NCS. Similarly, it has been shown that four-day pretreatment with high dose (80 mg·day–1) simvastatin produces early suppression of inflammatory response and associated procoagulant response to endotoxin in humans.135 Inferring from statin trials in ACS patients,25–33 statins administered from the day of surgery should still provide cardiovascular protection in case of acute coronary events occurring postoperatively.
Pharmaco-economics of perioperative statin therapy
Biccard et al.136 conducted a pharmaco-economic analysis of the prospective PST studies98,101 in patients undergoing vascular surgery. The NNT to prevent an adverse perioperative event or death with PST was 15, offsetting the total additional cost of atorvastatin therapy. Indeed, this analysis suggested that PST may represent the most cost-effective use of statin therapy yet described. Further pharmaco-economic analyses are warranted.
Adverse effects of perioperative statin therapy
In general, statins are well tolerated and serious adverse effects are rare. The most serious adverse effect associated with statin therapy is myopathy which may progress to fatal or nonfatal rhabdomyolysis. The withdrawal of cerivastatin from clinical use in 2001 heightened scrutiny of these effects, although all available data indicate that the increased incidence of rhabdomyolysis reported for cerivastatin appears to be specific to this agent. Perioperatively, two reports described statin-related postoperative rhabdomyolysis with subsequent acute renal failure.137,138 It is note-worthy that the current American Heart Association Clinical Advisory Statement on Statins Safety139 suggests the discontinuation of statin treatment during major surgery or critical illness. While this appears to be safe in patients with stable CAD,140 the degree of risk associated with abrupt statin discontinuation in patients with ACS is still unresolved.28
The potential for a greater likelihood of statin-induced rhabdomyolysis in patients with pre-existing muscle disease is not known. Nevertheless, malignant hyperthermia susceptibility has been recently revealed by myalgia and/or rhabdomyolysis during statin treatment in three patients.141,142
Safety of perioperative statin therapy
Schouten et al.101 studied the safety of PST in 885 patients undergoing major vascular surgery. Although PST was not associated with an increased risk of myopathy or rhabdomyolysis, the incidence of perioperative creatine phosphokinase > ten times upper limit of normal was 8% in statin users, a 40-fold more than that reported in the large trials of medical patients.18–22 The perioperative incidence of statin-induced myotoxicity is likely to be more frequent than that reported in medical patients because of the unique risk factors related to the surgery itself and because common risk factors for adverse perioperative cardiac events such as raised creatinine or heart failure have often been exclusion criteria in medical patients. Therefore, definitive determination of PST safety requires pooling of the data of future large randomized perioperative trials which includes patients with risk factors previously excluded from the large medical trials.
Contraindications to perioperative statin therapy
As in the nonoperative setting, statins should not be initiated in patients with chronic liver disease, inflammatory muscle disease, severe renal disease, on concurrent treatment with cyclosporin, fibrates, or high dose niacin, or in females with child bearing potential.
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TOPAbstractSearch strategySearch strategyAn overview of atherosclerosis...Statins: a major breakthrough...Statins: beyond cholesterol...Perioperative cardiac morbidityPharmacologic reduction of...Effect of perioperative statin...Logistic considerations in...ConclusionsReferences |
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= tumour necrosis factor-alpha; tPA = tissue plasminogen activator; VAP = vulnerable atherosclerotic plaque; VCAM = vascular cell adhesion molecule.
