|Year : 2008 | Volume
| Issue : 6 | Page : 756
Statins-More Than Just Plaque Stabilisation
Ashish K Khanna1, Satinder Gombar2
1 Senior Resident, Department of Anaesthesia & Intensive Care, Government Medical College and Hospital, Level V, Block D, GMCH, Chandigarh, India
2 Professor & Head, Department of Anaesthesia & Intensive Care, Government Medical College and Hospital, Level V, Block D, GMCH, Chandigarh, India
|Date of Acceptance||12-Nov-2008|
|Date of Web Publication||19-Mar-2010|
#1111, Sector 32 B, Government Medical College and Hospital Campus, Chandigarh,
Hydroxymethylglutaryl-CoA reductase inhibitors, better known as statins have come a long way in the recent years, not just in perioperative cardiac protection but also as potential agents for the critically ill patient in intensive care.
To review the large body of literature on the pleiotropic effects of statins and to highlight their role not just in the stabilisation of atherosclerotic plaques but also improved outcomes in sepsis. PubMed was searched using "perioperative", "cardiac", "critically ill", "statins" and combinations of these terms as keywords. The reference lists of relevant articles were further reviewed to identify additional citations.
Principal findings: The underlying pharmacology, cellular and metabolic responses to statin therapy are elucidated. The duration and timing of statin therapy in terms of perioperative practice is presented along with evidence regarding the utility and safety of peri-operative statin therapy. The indications for peri-operative statin therapy especially for vascular surgical patients and the need for continuation post operatively are highlighted. Potential roles in sepsis and septic shock though in their infancy as of now are reviewed and outcomes presented. Recommendations for peri-operative statin therapy are made with the need for more work before extrapolation to the clinical scenario.
Perioperative statin therapy seems to be associated with a survival benefit, with a variable effect on postoperative cardiovascular morbidity. The available evidence also suggests that, there may be a benefit from including statins in the therapy for treatment of sepsis. Larger prospective, randomized clinical trials are needed to confirm these observations and to determine the optimal timing and duration of statin therapy in the perioperative setting.
Keywords: Statins, Perioperative, Cardiac, Critically ill
|How to cite this article:|
Khanna AK, Gombar S. Statins-More Than Just Plaque Stabilisation. Indian J Anaesth 2008;52:756
| Introduction|| |
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most commonly prescribed agents for hypercholesterolemia and have revolutionized the management of hyperlipidemia and the area of cardiovascular risk reduction. However , more work into their molecular mechanisms of action and prospective studies have now suggested that their effects go well beyond the lipid lowering seen with long-term use and may include acute anti-inflammatory activity, anticoagulation, immunomodulation, as well as promotion of changes in smooth-muscle tone. These effects, also known as the pleiotropic effects of statins are the basis of research into the use of these agents in various critical care areas such as the early phases of bacteraemia, sepsis and septic shock.
Recent data also show promising results with regards to a decrease in cerebral vasospasm after subarachnoid haemorrhage and improved outcomes after ischemic strokes. More research is necessary to ascertain the true role of statins in the treatment of these various disorders. Nevertheless, the concept of a statin's role as being only a routine preventive therapy with benefits limited to patients undergoing treatment for hyperlipidemia is rapidly becoming inaccurate.
We conducted a search of the US National Library of Medicine database (PubMed) for articles published between 1991 and 2008 using the key words Perioperative, Cardiac, Critically ill, Statins and combination of these terms. Data which highlighted mechanisms of action of statins, perioperative outcome of statin therapy with special emphasis on cardiac morbidity and mortality in patients presenting for elective non cardiac surgery and role of statins in critical care areas, specially sepsis and septic shock was identified. Nearly 200 relevant publications were retrieved and their bibliographies were scanned for additional sources.
Accepted articles eventually included in the reference list of this review were identified by authors' consensus and generally included studies that reported original data on the outcomes of interest. Whenever needed, review articles were also quoted to supplement the discussion.
| Statins: An overview of clinical pharmacology|| |
The statins are a class of lipid-lowering drugs which competitively inhibit the enzyme 3-hydroxy-3methylglutaryl-coenzyme A (HMG-CoA) reductase ,the enzyme that catalyzes the rate limiting step in cholesterol biosynthesis i.e., the conversion of HMG CoA to mevalonate .They are an integral part of any treatment regime of hypercholesterolemia. In clinical studies, statins reduce total cholesterol, low-density lipid (LDL) cholesterol, apolipoprotein B, and triglyceride levels.
Lovastatin, pravastatin, and simvastatin are derived from fungal metabolites while atorvastatin, fluvastatin, pitavastatin and rosuvastatin are fully synthetic compounds. All these drugs are approved for clinical use. Cerivastatin sodium was withdrawn from the world market by the manufacturer in 2001 because of reports of fatal rhabdomyolysis. Only oral preparations are available with dose ranges from 10-80mg which should desirably be taken at bedtime because cholestrol synthesis has been found to occur maximally from midnight to around 2am [Table 1]. ,,
| What goes wrong in atherosclerosis and where do statins fit in?|| |
Elevated low-density lipoprotein cholesterol (LDL-C) plays a key role in initiating the development of atherosclerotic plaque. When LDL-C levels are high, there is an increased likelihood of LDL-C accumulation within the intima. Lipoprotein particles within the intima are subject to oxidation. The presence of modified lipoproteins within the intima may trigger leukocyte recruitment and accumulation.
Atherosclerosis, a well defined inflammatory process, is the end result of endothelial dysfunction due to various factors, including haemodynamic disturbances such as turbulence or shear stress, cardiovascular risk factors, changes in coagulation status and oxidation of low-density lipoprotein-cholesterol (LDLC). 
Lipid-laden foam cells are essentially macrophages that have scavenged lipids accumulated in the vascular intima. They further amplify the inflammatory process by secreting inflammatory cytokines and mediators, increasing leucocytes in the intima. This is an atherosclerotic lesion in its infancy , consisting of foam cells and activated T-lymphocyte cells and is known as a 'fatty streak'. Most teenage blood vessels of today have a fatty streak like lesion and are well on there way on the road to full blown atheroma formation. 
Plaque formation progresses with continued recruitment of inflammatory cells and lipid accumulation in the intima, which expands into the blood vessel lumen. Atherosclerosis is in part an inflammatory disease. The migration, proliferation, and apoptotic death of smooth muscle cells within the intima contribute to the remodeling of the vascular wall and the development of a lipid-rich core. Initially, remodeling of the vascular wall may not change the size of the vessel lumen, even in the presence of atherosclerosis with a large lipid-rich core. As plaque growth progresses, stable or unstable (vulnerable) plaques may form, leading to luminal narrowing or occlusion and serious complications . ,
A vulnerable plaque has a thin fibrous cap, with a large necrotic lipid pool, characterized by neovascularisation and many inflammatory cells. These pathological entities usually rupture with superimposed thrombosis, encroachment on the lumen and thus manifest as unstable coronary syndromes [Figure 1] . ,
In contrast, a stable plaque has a thick fibrous cap, with a small lipid pool and a preserved vascular lumen . These lesions may lead to significant stenosis and stable angina.
Factors associated with fibrous cap rupture may be intrinsic namely ,endothelial injury secondary to matrix metalloproteinases, which degrade the extracellular matrix, and interferon- γ, which induces smooth muscle cell apoptosis& decreases collagen synthesis. 
The extrinsic factors that may be associated with plaque rupture assume prime importance in the perioperative period and include haemodynamic shear stress, vasospasm, plaque fatigue, oxidation of LDLC and changes in coagulation status. 
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and thus decrease cholesterol synthesis. They also possess pleiotropic antiinflammatory, vasodilatory and antithrombogenic effects. These additional pharmacological properties are due to the inhibition of formation of intermediates that are necessary for post-translation modification of cellular signaling and intracellular trafficking protein. ,
| How long before surgery should statins be initiated?|| |
Various studies have shown that in patients with stable coronary artery disease (CAD) presenting for surgery in whom peri-operative statin therapy is considered desirable, at least 4-6 weeks of statin therapy would be required pre-operatively potentially to realise most of the beneficial cellular and metabolic effects of statin therapy. ,,
Hypercholesterolaemic patients may need a longer initial period of optimization, the suggested rationale being that oxidized lipoproteins are potent inducers of inflammation.  Importantly, response to statin therapy is faster following acute coronary syndromes in comparison with the time in patients with stable CAD as inflammation is the major culprit and consequently target for therapy in the former as compared to the latter. , Following withdrawal of statin therapy there is a rapid return to endothelial dysfunction and amplification of the inflammatory process, which may increase cardiovascular risk.
| Clinical Scenarios|| |
A. Cardiovascular disease
Stable coronary artery disease
Various studies have investigated the molecular mechanisms of benefits of statin therapy. The majority of results show that LDL-C lowering is probably the most important mechanism by which statins improve long-term cardiovascular outcomes, implications of which being that the pleiotropic effects of statins offer little or no additional late cardiovascular protection over and above the degree of LDL-C reduction. ,, In stable CAD patients actual survival benefit from statin therapy has only been seen nearly after a year of therapy.  Controversial results have been seen when evaluating high dose (intensive) that is atorvastatin 80 mg daily. Such high doses do offer cardiovascular protection (a composite of cardiac death, non-fatal myocardial infarction, non-fatal cardiovascular accident (CVA) and non-fatal cardiac arrest) to patients with stable CAD however this comes at the cost of a significantly increased incidence of raised aminotransferases . ,
Thus for patients with stable CAD, a longer duration of therapy (> 4-6 weeks) may be necessary to truly achieve survival benefits. One very important biochemical parameter which we need to look at preoperatively is LDL-C reduction, as it is this response to statin therapy that is associated with improved survival in patients with stable CAD.
Acute coronary syndromes (ACS)
It has been seen that an ACS is associated with an increased number of life threatening recurrent coronary events in the 6 months after the initial acute event.  C-Reactive Protein (CRP), and systemic inflammation, have been associated with adverse cardiovascular outcomes in these patients. , Thus LDL-C ,which is the sole target of therapy in stable CAD would now be an inappropriate consideration in isolation and the pleiotropic effects associated with statins may be relatively more important following ACS. 
Assessment of the analysis of the efficacy of statins following acute coronary syndrome has shown surprising results in that the efficacy of statin therapy following ACS is poor when compared to the efficacy shown in long-term trials of stable CAD patients. ,,
Correct identification of a patient with a recent acute coronary event and risk assessment using the AHA/ACC guidelines is extremely important. The early institution of statins pre-operatively in these patients, will be more beneficial as opposed to delayed initiation of therapy after an established coronary event. ,
Creactive protein has been shown to be associated with major adverse cardiovascular events after an ACS and if possible should be monitored in these patients  .Standard dose statin therapy should be the norm unless the patient has a documented ACS, where intensive therapy is cost effective and does decrease all cause mortality. 
Early withdrawal of statins following an ACS may be potentially hazardous with an increasing trend towards cardiac morbidity and mortality. ,,,
Studies have shown significantly decreased markers of myocardial damage (creatine kinase-MB, troponin I and myoglobin) along with a significantly decreased myocardial infarction in the statin group when they were used prior to a percutaneous coronary intervention. , These findings further underscore the value of these drugs as prophylactic cardioprotective agents.
Thus, in an ACS situation statin therapy should be initiated as early as possible, should be high-dose (intensive) therapy, guided by inflammatory markers (CRP) and should continue long term into the post operative period . ,,
B. Perioperative myocardial protection
Peri-operative cardiovascular protection associated with statin therapy has been understood at the molecular level. The potential mechanisms are decreased low-density lipoprotein-cholesterol (LDL-C) and decreased inflammation associated with oxidized lipoprotein, stabilization of vulnerable plaques via pleiotropic effects and decreased inflammatory response to major surgery, which may result in less plaque disruption . 
Addition of beta blockers, the perioperative myocardial protection of whom has been proven now beyond doubt may further decrease the risk of a cardiac event. Vulnerable plaques are more likely to rupture with an increased heart rate and in patients with hypertension and left ventricular hypertrophy.  Beta blockers, by decreasing the perioperative stress response and catecholamine release decrease the shear stress on a vulnerable plaque. Beta-blocker and statin therapy when used together have been found to be independently protective in patients undergoing abdominal aortic aneurysm surgery . 
Statin withdrawal in medical patients with stable coronary artery disease may not significantly alter cardiovascular morbidity and mortality, whereas patients with an ACS have an increased cardiac risk after early statin withdrawal. , Which of these two categories does the high risk surgical patient receiving preoperative statins fit into? It has been shown in patients who underwent infrarenal aortic vascular surgery that up to 4 days of statin withdrawal postoperatively was tolerated adequately, after which there was a rise in markers of cardiac myonecrosis (Troponin I).  At the present moment of time this arbitrary limit can be accepted, but the need to restart statins as early as possible in the post operative period has to be kept as a very high priority indeed.
Outcome analysis: What does Evidence Based Medicine say?
Two large meta analyses have looked at short term outcomes in terms of cardiovascular mortality after cardiac as well as non cardiac surgery in patients on perioperative statins. These studies concluded that it is reasonable to advocate that statins should be started preoperatively in eligible patients who would warrant statin therapy for medical reasons independent of the proposed operation-for example, patients with coronary disease, patients with multiple cardiac risk factors, or those with elevated low density lipoprotein cholesterol levels. Though there is a significant reduction in mortality, the data are based on retrospective studies and hence cannot be used as template for recommending routine preoperative statins to every high risk patient . ,
Statins have also been shown in retrospective studies to improve graft patency following peripheral vascular surgery, to improve survival with intensive therapy in patients with peripheral vascular disease and to improve long term outcomes after aortic surgery. These are the patients most likely to sustain acute coronary events and similar to the non-surgical patient with an acute coronary syndrome where early intensive statin therapy may be important so it may be a similar case here also. Though there is evidence to suggest that intensive statin therapy may improve long term survival in vascular disease however there is no literature on the use of intensive statin therapy on early postoperative cardiac outcomes in such patients presenting for surgery . ,,
With regards to timing of initiation prior to surgery, in a meta analysis it has been seen that though maximum patients in studies showing improved outcomes were on long-term statin therapy (4-6 weeks) prior to surgery, even acute pre-operative statin therapy within 2 days of surgery was beneficial. 
Therapeutic goals and recommendations from guidelines
The 2004 update of the National Heart, Lung, and Blood Institute's Adult Treatment Panel (ATP) III report defined optional lower target cholesterol levels for very high-risk coronary heart disease (CHD) patients, especially those with acute coronary syndromes, and expanded indications for drug treatment. Additional trials afterwards demonstrated cardiovascular benefit for lipid lowering significantly below these levels for those with chronic CHD.
These trials proved that low-density lipoprotein cholesterol (LDL-C) should be <100 mg/dL for all patients with CHD and other clinical forms of atherosclerotic disease. In addition, intensive statin therapy with goals to treat to LDL-C <70 mg/dL in such patients was found to be superior in the reduction of morbidity and mortality associated with an ACS. When the <70mg/dL target is chosen, it may be prudent to increase statin therapy in a graded fashion to determine a patient's response and tolerance. Furthermore, if it is not possible to attain LDL-C <70 mg/dL because of a high baseline LDL-C, it is generally possible to achieve LDLC reductions of >50% with either statins or LDL-C- lowering drug combinations.
For patients without atherosclerotic disease who have diabetes or multiple risk factors and a 10-year risk level for CHD >20% the recommended LDL-C goal is that of <100 mg/dL. Cholesterol levels of <70 mg/dL do not apply to other types of lower-risk individuals who do not have CHD or other forms of atherosclerotic disease; in such cases, recommendations contained in the 2004 ATP III update still pertain [Table 2]. ,,
In addition the National Institute for Health and Clinical Excellence (NICE) guidelines recommend statin therapy for all vascular surgical patients, though there are no randomized controlled trials to substantiate this suggestion. 
| Statins and Intensive Care: The new frontier|| |
It has been estimated that sepsis occurs in more than 750,000 individuals in the United States annually. Of these, about half require intensive care and almost one third do not survive. The average length of stay is nearly 20 days and results in a cost of more than $20,000/case .
HMG-CoA reductase inhibitors have now been shown to do more than just lowering lipids and may have a major role in sepsis protection& therapy. The mechanism by which statins modulate the immune response is complex, but is often regarded as lipid independent as they are not related to lowering LDL cholesterol. Their pleiotropic actions which involve inhibition of production of potentially harmful intermediates and control of signal processing in the lipid cycle are the most strongly hypothesized mechanisms underlying these. Additionally, they modulate leucocyte biology, alter leucocyte response, modulate cytokines which initiate sepsis, favourably affect the coagulation cascade and endothelial cell function along with antigen presenting cell function. ,
A randomized controlled trial by Macin et al demonstrated that patients with ACS treated with atorvastatin 40 mg day -1 had a rapid reduction in CRP compared with placebo suggesting anti-inflammatory effects of statins in vivo in humans.  Statins improve platelet function and diminish procoagulant activity by a reduction in platelet aggregation, TF activity, reduced conversion of prothrombin to thrombin with resultant reduced thrombin activity, and a decline in fibrinogen levels.
A close analysis of literature reveals the following areas where statins have been found to be useful in sepsis:
- Reduction in superimposed infections (bacterial pneumonia) in patients at risk of sepsis(uncontrolled diabetics)
- Reduction in the risk of development of severe sepsis (acute organ system dysfunction with sepsis)
- Reduction of mortality in sepsis
These results are however solely based on retrospective data and observational studies. ,
The ASEPSIS trial, is amongst the few dozen trials all over the globe currently under way which are investigating the emerging role of statins in sepsis. Importantly though, they are not multicentric and do not have mortality as the primary outcome variable which may prove to be a problem when it comes to the application of their results in clinical practice. ,
Cerebral vasospasm constitutes one of the major complications associated with subarachnoid haemorrhage and is a significant contributor to the delayed morbidity and mortality associated with the event. Proposed mechanisms include involvement of inflammatory processes and the increased production of superoxide anions and iron ions after haemolysis, which leads not only to elevated levels of reactive oxygen species but also to increased binding of nitric oxide ,,
Literature shows mixed results with most studies showing a favourable outcome though there is one study in which the incidence of vasospasm actually increased following statin use. ,,,,
C. Ischemic Stroke
Investigations into the potential benefits of statins in the setting of acute stroke have been based on potential fibrinolytic effects seen beyond their lipid lowering activity. The mechanism has been a proposed upregulation of endothelial nitric oxide synthase (eNOS), leading to improved cerebral blood flow.
A correlation has been found in a retrospective study, between statin therapy in the setting of stroke with a decreased mortality rate.  Patients who reported a history of statin use one month before admission were compared with nonusers. However, there is a lack of data regarding the type and dosage of the statins used to produce this effect, as well as the duration and compliance with this therapy before admission. The differences in baseline characteristics reported, as well as the omission of reporting other concomitant drugs such as aspirin, antiplatelet therapies, and warfarin for stroke protection along with absence of data regarding functional outcome in these patients also impairs credibility of this study.
As with perioperative use, the use of these agents in critical care units has not come up with answers to the optimal duration of therapy for adequate efficacy, to withdrawal of treatment and rebound effects and to the interagent variations seen with the statin salts in current day use.
| Safety profile - Still a grey area?|| |
The most commonly reported adverse effects of statin use include a reversible, proximal myopathy which can progress to myoglobinuria and renal failure. This condition is seen particularly with the concomittant use of drugs metabolized by the cytochrome enzyme system (CYP3A4) - erythromycin, azole antifungals, cyclosporine, antidepressants& protease inhibitors. The other important side effect is a dose dependent hepatotoxicity and an elevation of transaminases. In this regard it is advisable to discontinue therapy at >3 times the normal levels.
Amongst the less common side effects the important ones are:
- G.I disturbances
- Prothrombin time increased in warfarin treated patients
- Lupus like syndrome
- Peripheral neuropathy
The American College of Cardiology/American Heart Association/National Heart, Lung, and Blood Institute has issued a clinical advisory on the use and safety of statins. Regular liver function tests and serum creatine kinase levels need to be regularly followed up in patients on chronic therapy. 
What happens in sepsis can further impair the detoxification abilities of the liver and additionally result in elevated liver enzymes. How and to what degree does sepsis impair the liver's ability to deal with statin metabolism and does it synergistically add to statin toxicity, rhabdomyolysis and incidence of renal shutdown does deserve further investigation. As statins are highly protein bound, it is particularly important to define the influence of hypoalbuminaemia on statin bioavailability and toxicology.
Also another issue is the bioavailability of these drugs which are only available as an oral preparation. Gut mucosal ischemia in the setting of sepsis has been a known fact for some time now .The lack of an intravenous formulation or of a clear pharmacokinetic profile for statins in patients with sepsis would need to be addressed before their use could become widespread. 
| Statins, Surgery, Sepsis and the Anaesthesiologist: Do we have all the answers yet?|| |
Cardiovascular complications after major noncardiac surgery are the major source of perioperative morbidity and mortality. The pathophysiology leading to a fatal perioperative myocardial infarction, specifically the disruption of an atherosclerotic plaque causing thrombosis and obstruction of a coronary vessel, is believed to be similar in nature to the underlying mechanism causing nonperioperative myocardial infacrtions. Recently, several trials have shown the benefit of statin therapy on perioperative morbidity and mortality in patients undergoing major noncardiac surgery as well as cardiac surgery . 
Lately, intensive statin therapy, decreasing LDLC to <70 mg/dL, has been shown to be superior to moderate-dose therapy, decreasing LDL-C <100 mg/ dL, in the reduction of morbidity and mortality associated with ACS. However, the effect of statin therapy far exceeds the decrease in LDL-C alone. These pleiotropic effects of statins mitigate thrombotic complications of atherosclerosis through improved endothelial function, reduction in inflammation, stabilization of atherosclerotic plaques, and reduction in the thrombotic response. 
Anaesthetists as the perioperative physicians of today need to be in a position to correctly identify and initiate statins in patients who are candidates for therapy. Started even on the day prior to surgery there is enough evidence to believe that these drugs will potentially benefit the high risk cardiac patient. Concurrent usage with beta blockers is also another approach to decrease the risk of a perioperative cardiac event. Vascular surgical patients have clear cut long term benefits when on statins and they are a subgroup which needs to be on chronic therapy as a rule. Given the low toxicity associated with statins and the high cardiovascular risk of certain patient populations and surgeries, it is imperative to expand on the limited clinical trials to better elucidate the effect of statins on perioperative cardiovascular risk.
Intensivists need to be aware, that given their pleiotropic effects related to many pathophysiological determinants of sepsis, statins are on the verge of breaking through as an important adjuvant in the management of septicemia and septic shock. The weight of evidence is strongly on their side while we still await the results of the many ongoing RCTS in this regard. In addition they may be considered drugs of the future in the prevention of vasospasm in a subarachnoid bleed and in the betterment of outcome of ischemic stroke victims.
| Statins - Implications for the perioperative physician|| |
- At least 4-6 weeks of statin therapy, pre-operatively in patients with stable coronary disease (CAD) , guided by LDL-C levels.
- In an ACS, statin therapy should be, high-dose (intensive) therapy, guided by inflammatory markers (CRP) and should continue long term into the post operative period.
- Perioperative protection with these agents should be initiated atleast 4-6 weeks prior and subsequently restarted as early as possible in the post operative period.
- Acute pre-operative statin therapy has been shown to be beneficial.
- Routine preoperative statins to every high risk patient cannot be recommended as the data for improved outcomes are based solely on retrospective studies
- There is an increasing evidence for the use of statins in reduction of mortality and morbidity in sepsis, cerebral vasospasm and ischemic stroke.
- More work needs to be done on the efficacy of statins in critically ill patients and the safety profile of these agents in such scenarios.
The challenge is the determination of the appropriate time to initiate statin therapy, while balancing the need for peri-operative cardioprotection with the risk of drug-associated adverse events. Statins have emerged hand in hand with beta blockers in providing a safer and more stable myocardium to the anaesthetist. The next move is to the ICU, where adjuvant therapy for sepsis may be on the verge of a promising change.
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[Table 1], [Table 2]