Anaesthesia, 2005, 60, pages 11061114 doi:10.1111/j.1365-2044.2005.04405.x .....................................................................................................................................................................................................................

REVIEW ARTICLE

Statin therapy: a potentially useful peri-operative intervention in patients with cardiovascular disease
B. M. Biccard,1,4 J. W. Sear2 and P. Foex3
1 Clinical Research Fellow, 2 Professor of Anaesthetics, 3 Emeritus Nufeld Professor of Anaesthetics, Nufeld Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK, 4 Consultant Anaesthetist, Department of Anaesthetics, Nelson R Mandela School of Medicine, Private Bag 7, Congella, 4013, South Africa Summary

Statin cardiovascular protection is mediated by lipid lowering and pleiotropic effects. The efcacy of statins has been established in non-surgical patients with cardiovascular disease and also more recently in non-surgical patients who sustain an acute coronary event. Peri-operative statin administration has been shown to improve both short-term and long-term cardiac outcome following non-cardiac and coronary bypass graft surgery. This cardioprotection may be independent of peri-operative haemodynamics due to a positive effect on plaque stability. Recommendations for the peri-operative statin administration are suggested. These include indications for peri-operative statin therapy, timing of administration, therapeutic targets, duration of administration, the adverse implications of peri-operative statin withdrawal, safety and cost-effectiveness.
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Correspondence to: B. M. Biccard E-mail: bruce.biccard@nda.ox.ac.uk Accepted: 15 August 2005

Adverse peri-operative cardiac events are a signicant cause of hospital morbidity and mortality. In the United Kingdom, cardiovascular disease is consistently the most frequently reported comorbidity in peri-operative deaths (in excess of 60%) and the most common cause of perioperative death (36%) [1]. The estimated number of cardiac deaths is approximately 9000 patients per annum [2]. Peri-operative cardiac complications are far more frequent than deaths. Peri-operative cardiac events may be either coincidental in a high-risk surgical patient, or secondary to the peri-operative cardiovascular stress response. There have been many approaches to minimise these events in an attempt to improve peri-operative cardiac outcome. These include high dose opioid anaesthesia and regional anaesthesia (to minimise the stress response); pre-operative coronary artery revascularisation [3] and angioplasty [4] and peri-operative cardioprotective drugs [5]. The efcacy of all these interventions, including beta-blockers in the peri-operative period, is questionable [37]. This is partly due to the difculties of selecting appropriate patients, initiating treatment at the most appropriate time in the peri-operative period, and
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then considering the riskbenet analysis associated with specic interventions [37]. There is also recent interest in the role of statins as drugs for the prevention of coronary events. In this review we examine the evidence for the efcacy of these agents in the peri-operative period.
Sources and selection criteria

In order to evaluate the effect of statins on peri-operative outcome (assessed as their effects on all-cause mortality, cardiac death and major cardiovascular complications), we conducted a PubMed and Medline search (1994 to April 2005) for randomised controlled trials and systematic reviews examining the efcacy of statin administration following acute coronary syndromes in non-surgical patients and in the peri-operative period. The start date for our review was the date of publication of the rst nonsurgical study evaluating the role of statins on cardiovascular outcomes [8]. The reference lists of all subsequent eligible trials were also examined for further relevant trials, as well as the abstracts of the following scientic meetings:
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American Society of Anaesthesiologists; Anaesthetic Research Society; International Anaesthetic Research Society and American Heart Association. In addition, we have taken all studies and systematic reviews identied and also hand searched relevant articles from the reference lists. The effect of statins on acute coronary syndromes in non-surgical patients was considered important; should statins be efcacious in this scenario, this may be a useful pointer to future success in surgical patients. We identied 27 papers (randomised controlled trials or observational case series) examining the effects of early statin administration following acute coronary syndromes in non-surgical patients, or where statins had been given peri-operatively. There were 16 papers examining early statin administration following acute coronary syndromes which were appropriate for analysis. We excluded papers in which the study protocol included mandatory percutaneous coronary interventions, as access to percutaneous coronary interventions may not always be possible in the peri-operative period. There were also 11 peri-operative papers (randomised controlled trials or observational case series), of which 10 contained information on cardiac outcomes that could be analysed. One paper was excluded where statin therapy was initiated at hospital discharge and thus provides no evidence on the effect of statin administration on acute peri-operative outcome. We excluded publications not in the English language other than where an abstract in English was provided. Follow-up to authors was undertaken where outcome data were not clearly laid out in the publication. Data were analysed with regard to several endpoints in both the medical scenario and the peri-operative period, and are shown as the mean and 95% condence intervals for the relative risk reduction.
Possible mechanisms of statin cardiovascular protection

(CRP) [9, 12] and increasing decay-accelerating factor [9]. CRP levels are related linearly to the risk of recurrent myocardial infarction or coronary death [12]. Statins also improve endothelial function by increasing the expression of the vasodilator endothelial nitric oxide synthetase (eNOS) and decreasing the vasoconstrictor endothelin-1 [9, 10, 13]. Endothelial function and arterial ow improve within 24 h of the initiation of atorvastatin, before a decrease in CRP or cholesterol [13], suggesting that early improvement in ow is independent of inammation or cholesterol levels [13]. Vasomotor function continues to improve on statin therapy secondary to a decrease in serum cholesterol and LDL oxidation [9, 10, 13]. Statins decrease the thrombogenic response to plaque rupture by inhibiting platelet activation (by increasing eNOS, and decreasing thromboxane A2 production) [9] and promoting brinolysis (by increasing tissue plasminogen activator and decreasing plasminogen activator inhibitor-1) [9, 11]. These mechanisms are relevant to the peri-operative period as peri-operative myocardial infarction is secondary to plaque disruption [14] and the myocardial oxygen supply demand imbalance [15]. Statin therapy could therefore provide cardiovascular protection, independent of peri-operative haemodynamics.
Statins and their effects on outcome

It is difcult to differentiate the cardioprotective mechanisms of statins between lipid lowering and pleiotropic effects [9]. In addition, benecial effects are not necessarily universal across the group due to differences in drug structure, potency, and hydro- or lipophilicity [9]. Statins increase atherosclerotic plaque stability by decreasing the size of the lipid core [10], inhibition of neovascularisation [9, 10] and inammatory modulation [9, 10]. Statins decrease subendothelial basement membrane degradation [10] and smooth muscle apoptosis by decreasing macrophage inltration [9, 11], decreasing the release of matrix metalloproteinases [9, 11], decreasing interferon-c release and leucocyte adhesion [911]. Statins protect the endothelium by decreasing complement mediated injury by decreasing C-reactive protein
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Statins and cardiovascular protection in non-surgical patients Statin therapy has been shown to decrease the incidence of long-term cardiovascular events in patients with or at risk of coronary heart disease (CHD) [8, 1624]. Subgroup analysis has shown that benets can be derived by women [8, 1720], the elderly [8, 1622], various ethnic groups [19, 23], patients with impaired left ventricular function [17, 21], diabetics [1721] and patients without diagnosed CHD, but established peripheral vascular and cerebrovascular disease [20]. The benets of statin therapy increase in patients at higher absolute risk of a major coronary event [18]. In these randomised medical studies, the unadjusted relative risk (95% condence interval) associated with statin therapy of all-cause mortality is 0.93 (0.910.95) and of cardiovascular mortality 0.90 (0.870.93) [8, 1624]. Statins also improve both short- and long-term cardiovascular outcomes following acute coronary syndromes (ACS) (Table 1) [2539]. In the prospective ACS studies, the unadjusted relative risk associated with statin therapy of all-cause mortality is 0.88 (0.800.97) [26, 29, 34, 37, 38] and of cardiovascular mortality 0.85 (0.74 0.98) [26, 34, 37, 38].
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Table 1 Acute coronary syndrome studies in non-surgical patients (early statin therapy vs. standard therapy).
First author Retrospective studies Schiele [25] Stenestrand [27] Bybee [28] Aronow [30] Giugliano [31] Heeschen [32, 33] Spencer [36] Spencer [36] Newby [35] Saab [39] Prospective studies Arntz [26] Schwartz [29] Liem [34] Cannon [37] De Lemos [38] n Diagnosis Time of statin initiation Follow-up NNT all-cause mortality

8335 19599 264 20809 14124 1520 13159 15481 12365 1639 135 3086 540 4162 4497

AMI AMI AMI ACS AMI ACS ACS ACS ACS ACS ACS ACS AMI ACS ACS

3 days Before discharge Chronic medication and <24 h Before discharge Before discharge Chronic medication Chronic medication In hospital 7 days <24 h or >24 h 6 5 days 2496 h 14 days Intensive vs. standard 3.7 days (mean) vs. 4 months

In hospital 1 year In hospital 30 days 1 year 30 days In hospital In hospital 90 days In hospital 2 years 112 days 1 year 2 years 721 days (median)

Data not available 19 14 200 67 91 13 13 111 161 47 435 71 100 83

NS, not signicant. ACS, acute coronary syndrome. AMI, acute myocardial infarction. NNT, number-needed-to-treat.

Table 2 Statins and peri-operative outcome in surgical patients.

No. of operations All-cause mortality (OR or NNT)

First author

Study design

Surgery

Follow-up

Major non-cardiac surgery Poldermans [40] Retrospective Landesberg [41] Kertai [42] Durazzo [43] Kertai [44] Retrospective Retrospective Prospective, randomised Retrospective, CCS Retrospective Retrospective Prospective

Major vascular Major vascular AAA Vascular AAA Major non-cardiac surgery Vascular surgery Major vascular CABG CABG

160 cases 320 controls 502 510 90 570 204 885 1163 981 323 1663

30 days 18138 months >30 days up to 4.7 years (median) 6 months 30 days >2 days until hospital discharge Day of surgery until discharge Until discharge 1 year First 30 days

0.22 (0.100.47) 0.49 (0.250.96) NNT 3 NNT 32

Lindenauer [45] ONeil-Callahan [46] Schouten [47] Coronary artery bypass Dotani [48] Retrospective Pan [49] Retrospective

NNT 103 [278]* NNT 56 NNT 27 NNT 51

AAA, abdominal aortic aneurysmectomy. CABG, coronary artery bypass grafting. CCS, case-control study. NNT, number-needed-to-treat. *[number-needed-to-harm].

There is therefore good reason to suggest that statin therapy may provide cardiovascular protection to the highrisk patient during the peri-operative period [4049]. Statins and peri-operative outcome Studies of peri-operative statin administration in patients undergoing major non-cardiac surgery or coronary artery bypass grafting (CABG) are listed in Table 2. The majority of the studies show statins to be benecial in the surgical patient, especially with regards to all-cause mortality, cardiovascular mortality and myocardial infarction. However, with the exception of the study by Kertai
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et al. [42], the numbers needed-to-treat are large (> 10) and may indicate the presence of other confounding variables, including the time of initiation and duration of statin therapy, different outcome measures and follow-up periods. Timing of statin therapy With the exception of a single study [45], patients were either on long-term statin therapy prior to surgery [40 42, 44, 4649] or received acute pre-operative statin therapy [43, 47]. In one study patients received statins within 2 days of surgery [45].
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Table 3 The NNT to prevent an

in-hospital death with statin therapy based on points scored on Lees Revised Cardiac Risk Index [45, 50].
NNT (95% CI)

Points 0 186 (168214) 1 103 (93119) 2 60 (5469) 3 39 (3545) 4 30 (2735)

Score one point for: high-risk surgery (which includes intraperitoneal, intrathoracic and suprainguinal vascular procedures), pre-operative insulin therapy, ischaemic heart disease, congestive cardiac failure, stroke and creatinine > 180 mmol.l)1 [50]. NNT, number-needed-to-treat.

Outcome The main outcome measures in the peri-operative period are cardiac death and major cardiac complications (which include myocardial infarction, unstable angina, lifethreatening arrhythmias and acute left ventricular failure). All these studies showed an improved postoperative cardiovascular outcome [4049]. Effect on peri-operative mortality within 30 days of major surgery. Most studies have been conducted in, or observational data analysed from, patients undergoing vascular surgery, or patients with a known history or at risk of coronary artery disease. Most studies have shown a reduction in early mortality (both all-cause and cardiovascular) [40, 44, 45, 47, 49], with the exception of the recent study by ONeil-Callahan et al. (which still decreased adverse cardiac events) [46] in non-cardiac vascular surgical patients. Statins were equally efcacious irrespective of age, gender, body mass, type of vascular surgery, ventricular function or diabetes [46]. The cardioprotective effect of peri-operative statin therapy on early peri-operative mortality in non-elective surgery is difcult to assess due to small sample size trials, with few outcome events and hence results with wide condence intervals [46]. In a retrospective cohort study of 329 hospitals in the United States [45], patients undergoing major noncardiac surgery who received statins within the rst two days of admission to hospital had increased survival compared with patients who did not receive statins or received statins after the second day of hospital admission. This study is important as it also gives a number-neededto-treat (NNT) to prevent in-hospital deaths according to Lees Revised Cardiac Risk Index (Table 3) [50]. Clearly, the efcacy of statin therapy is greater in higher-risk patients (three or more points) [45]. Analysis of the patients who died within two days of vascular surgery suggested that early statin use decreases mortality [46]. This may be due to the improved outcome of patients on statin therapy following an ACS [28, 32, 33, 36, 39], combined with the increased risk of patients who have statins withdrawn at the time of an acute coronary event (Table 4) [32, 33, 36, 51]. The benet of long-term statin administration on ACS is lost by statin
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Table 4 Effect of statin withdrawal and all-cause mortality in

non-surgical patients with acute coronary syndrome [32, 33, 36, 51; Heeschen, personal communication].
Long-term statin withdrawal All-cause mortality Survivors 619 4627 No statins 1509 13 896

Relative risk ratio (95% CI) 1.16 (1.081.25).

withdrawal. This may occur as early as 72 h following statin withdrawal [32, 33]. Effect of statins on long-term outcome following major noncardiac surgery. As well as an effect on peri-operative mortality within 30 days of surgery, there is evidence that long-term patient survival is also improved [41, 42]. Patients who survived more than 30 days post abdominal aortic aneurysm surgery had a 2.5-fold reduction in allcause mortality and a threefold reduction in cardiovascular mortality over 4.7 years [42]. The high cardiovascular mortality of the control group (34%), suggests that statin therapy would currently be considered appropriate in a number of these patients [52]. It is suggested that all vascular surgical patients should now be on statin therapy [53], due to the ndings of the Heart Protection Study [20]. Statin therapy appeared to be equally efcacious in the following subgroups: patients on beta-blockers, aspirin, older patients, patients with a history of myocardial infarction, stroke, renal dysfunction or pulmonary disease [42]. However, further large studies are probably needed to conrm these ndings. Drug interactions Statins may not be the only cardioprotective drug that high-risk surgical patients receive. In the peri-operative period it is suggested that the protective effects of statin therapy are additive to those of beta-blockade, as statins may improve plaque stability and beta-blockers the myocardial oxygen supply demand balance [40, 42, 44]. Indeed, the peri-operative protective effect of statins was
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shown to be independent of beta-blockade in the perioperative period [40, 4244, 46], as seen in medical patients [20]. However, the protective effect of beta-blockade on peri-operative outcome was unclear; benecial effects were reported in three studies [40, 42, 44] but not in three other studies [41, 43, 46]. Prospective peri-operative trials There are only two prospective peri-operative statin trials examining the efcacy and safety of statins in patients undergoing non-cardiac surgery [43, 47]. In a randomised placebo controlled study [43], statins started on average of 31 days prior to vascular surgery resulted in a signicant reduction of a combined end-point of cardiac death, myocardial infarction, unstable angina or stroke at 6 months from 28.3% to 9.1% (p = 0.022). Despite a month of pre-operative statin administration, three of the four postoperative cardiac events occurred within the rst 10 days of surgery [43]. At the present, the optimal duration of the statin run-in time is unknown. It is possible that the longer the run-in time, the better the peri-operative cardiovascular outcome [40]. Clearly, this is an area for future evaluation and study. Does the extent of cholesterol reduction affect outcome? The LDL-cholesterol levels were similar between the groups, with a baseline mean of over 3.4 mmol.l)1. Post therapy there was a signicant difference between the groups, with the statin group reaching a mean of 2.3 ( 0.8) mmol.l)1 [43]. The PROVE-IT study [37] suggests that more aggressive LDL-cholesterol reduction may further improve early peri-operative outcome. The study protocol allowed for atorvastatin administration for 45 days [43]. It is likely that continued statin administration would have improved outcome further, as in patients who experience ACS, the outcome continues to improve with prolonged statin administration [30], and vascular patients probably benet from long-term statin therapy [20, 53]. Although 96% of the patients randomised to statin therapy were advised to continue the statins after the study, only 13.8% were, in fact, still taking the drugs at 6 months [43]. In the second study by Schouten et al. [47], the statin group included a composite of patients on long-term therapy and patients with elevated total serum cholesterol who were administered statins pre-operatively for an average of 40 days prior to vascular surgery. The composite end-point of peri-operative death and myocardial infarction was signicantly reduced in the statin group with a NNT of 17 [47]. In this study, statins were temporarily discontinued postoperatively in 59% of the patients because of difculty with oral intake for a median of one day (range 14 days). Importantly, there was no
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relationship between stopping statins and postoperative myocardial infarction [47], despite the concerns of statin withdrawal (Table 4) [32, 33, 36, 51] at a time of increased cardiovascular risk [15]. Effect of statins on outcome following CABG surgery Long-term statin therapy in two retrospective cohort studies improved short-term (30- or 60-day) [48, 49] and long-term (one-year) outcomes following CABG [48]. Safety of statins in the peri-operative period No increased incidence of adverse effects has been reported in the peri-operative statin patients [4049]. There was no statistical difference between postoperative creatine kinase levels between statin users and non-users [47].
Peri-operative recommendations and conclusions

The considerations of peri-operative statin administration are highlighted in Table 5. Patients who require longterm statin therapy [52] should be identied pre-operatively. It is possible that the majority of vascular patients may require long-term statin administration [20, 53]. Surgeons should be alerted to the importance of early identication of these patients and initiation of statins, as the run-in time may affect peri-operative cardiovascular outcome [40, 43]. The advantage of pre-operative administration of statins in patients at high risk of an acute coronary event is that they are started prior to a potential ACS. The appropriateness of acute peri-operative statin administration may be determined by a cost-effectiveness analysis based on Lees Revised Cardiac Risk Index [50] and the associated NNT derived by Lindenauer et al. (Table 3) [45]. Peri-operative clinical trials based on this approach are needed. If statins are administered peri-operatively to improve the outcome of a potential ACS, the LDL-cholesterol level should be monitored and a low range targeted (< 1.8 mmol.l)1) [37, 52]. Postoperatively, all patients in whom long-term statin therapy is indicated should continue their therapy [52]. Any patient who has an acute coronary event postoperatively and is not on statin therapy should be considered for statin therapy, which should be initiated as soon as possible [29, 36, 39]. The appropriate time to withdraw acute peri-operative statin therapy (where long-term therapy is not indicated) is unknown. It would be reasonable to continue statins for at least 72 h postoperatively as this is the time period most likely to be associated with an acute coronary event [15].
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Table 5 Peri-operative statin therapy

considerations.

Statin considerations Is a statin indicated?

Management considerations

a. Long-term indications [52] b. Acute peri-operative administration (Table 3) [45, 52] Time of administration Preferably as long before surgery as possible [40, 43] Therapeutic targets LDL-cholesterol < 1.8 mmol l)1 [37, 52] Postoperative statin administration a. Continuation with long-term indications [52] b. Initiate statins after an acute coronary event [29, 36, 39] c. Timing of withdrawal of acute statin therapy [15] Withdrawal of long-term statin Preferably never (Table 4) [32, 33, 36, 51] therapy Safety Further peri-operative investigation required Cost-effectiveness If the NNT* to prevent an adverse cardiac event 15 [54] *NNT, number-needed-to-treat.

Table 6 Adverse events associated with long-term-statin therapy [8, 1624].

Relative risk ratio (95% CI) 0.93 1.02 1.00 1.20 0.93 1.23 1.07 1.02 0.98 (0.971.01) (0.991.05) (0.981.02) (1.021.42) (0.621.38) (0.801.89) (1.011.16) (0.951.10) (0.931.03)

Adverse event Non-cardiovascular deaths [8, 1624] All cancers [8, 1620, 2224] Myalgia, muscle aches [16, 1922] Creatine kinase > 10 ULN [8, 16, 17, 19, 20, 22] Myopathy: CK >10 ULN and muscle symptoms [1721] Rhabdomyolysis [8, 1922, 24] AST and or ALT >3 ULN [8, 1622] Neuropsychiatric [8, 1720, 23] Non neoplastic respiratory admissions [20]

Statin 1542 39 718 3057 38 918 3542 20 566 54 24 068 13 20 966 8 24 653 346 29 380 358 24 055 765 10 269

Standard therapy 1591 39 699 2948 38 899 3572 20 574 36 24 075 15 20 948 5 24 641 297 29 377 352 24 055 800 10 267

ULN, upper limit of normal of laboratory reference values. CK, creatine kinase. AST, aspartate transaminase. ALT, alanine transaminase. Neuropsychiatric effects include violence, suicides, accidents and associated deaths.

In patients on long-term statin therapy and at risk of an acute coronary event [50], it is vital that therapy is not unintentionally withdrawn in the peri-operative period (Table 4) [32, 33, 36, 51]. Temporarily discontinuing therapy for a day appears to be safe [47], but high-risk patients are probably at increased risk after three days [32, 33]. This may necessitate other strategies in patients unable to take enteral medications. The small but known risk of adverse effects of statins may be increased in the peri-operative period. Although statins appear safe in the large randomised clinical trials of medical patients (Table 6) [8, 1624], a number of the exclusion criteria in these studies (such as a raised creatinine or heart failure), are peri-operative risk factors for an acute coronary event [50]. In the study by Durazzo et al. [43] patients with a raised creatinine were excluded and in the study by Schouten et al. [47] only 4% of the statin users had a creatinine > 180 mmol.l)1. The peri-operative incidence of creatinine kinase was > 10 times the upper limit of normal
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and was similar between statin (8%) and non-statin users (10%) in this study. No patient developed rhabdomyolysis [47]. However, this incidence is substantially more than that reported in the large trials of medical patients (0.2%) (Table 6) [8, 1624]. Thus, although the majority of vascular patients should receive statin therapy [53], determining the safety of these drugs in the peri-operative period requires the pooling of the data of large randomised peri-operative trials, which include patients with risk factors previously excluded from the large medical trials [8, 1624]. Finally, one should consider the other potential benets of starting statin therapy in vascular patients, which include a delay in the progression of ischaemic vascular complications, possibly improved patency of arterial grafts and an attenuation of the progression of aneurysmal disease [11]. Peri-operative statin therapy is a costeffective intervention in elective major vascular surgery, where the number-needed-to-treat to prevent an adverse cardiac event is 15 [54].
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