| COMMENTARIES |
An Approach to the Use of Peri-Operative Statins to Decrease Cardiac Morbidity Associated with Non-Cardiac Surgery
B.M. Biccard, Nelson R Mandela School of Medicine, Private Bag 7, Congella, 4013, South Africa, and Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford, OX3 9DU, UK
Please address correspondence to:
B.M. Biccard
Department of Anaesthetics
Nelson R Mandela School of Medicine
Private Bag 7
Congella, 4013, South Africa.
Tel: +27 31 2401763
Email: bruce.biccard@nda.ox.ac.uk
In anesthesiology there remains one small randomized placebo-controlled trial of peri-operative statin therapy for noncardiac surgery [1]. Recent systematic reviews considering peri-operative statin therapy suggest that as the majority of the data is observational, further prospective studies are needed [2,3]. Adopting a standardized approach to peri-operative statin use based on an interpretation of the current medical and surgical data would therefore be desirable.
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thus decrease cholesterol synthesis. A second effect of HMG-CoA reductatse inhibition is decreased L-mevalonic acid synthesis which inhibits synthesis of isoprenoid intermediates such as farnesyl pyrophosphate and geranylgeranylpyrophosphate [4]. These intermediates are necessary for post-translation modification of various proteins essential for cellular signaling and intracellular trafficking [4]. These pleiotropic effects exhibit anti-inflammatory, vasodilatory and antithrombogenic effects [4].
Anesthesiologists are interested in the duration of statin therapy necessary to achieve these beneficial effects. This is crucial in determining when to initiate statin therapy prior to surgery. The following important trends are noted [5]. Firstly, the time to beneficial effects is generally longer in hypercholesterolemic than normocholesterolemic patients. Secondly, early immunomodulation is quicker following acute coronary syndromes (ACS) in comparison to patients with stable coronary artery disease (CAD) [6]. Withdrawal of statin therapy results in a rapid reversal of the beneficial pleiotropic effects [5].
Implications for anesthesiologists. In patients with stable CAD presenting for surgery, in whom peri-operative statin therapy is considered desirable, at least four to six weeks of statin therapy would be required pre-operatively to realize most of the beneficial cellular and metabolic effects of statin therapy. In hypercholesterolemic patients this run-in period should be longer. Patients who sustain an acute coronary event may have rapid reversal of inflammatory markers following initiation of statin therapy, although endothelial dysfunction is prolonged [5]. The clinical importance of this observation is discussed later. Finally, following withdrawal of statin therapy there is a rapid return to endothelial dysfunction and amplification of the inflammatory process, which may increase cardiovascular risk.
The cardioprotective mechanisms of statin-associated survival differ between ACS and stable CAD. An understanding of these mechanisms is essential for ensuring an appropriate peri-operative therapeutic strategy.
Stable coronary artery disease
LDL-C lowering is probably the most important mechanism by which statins improve long-term cardiovascular outcomes in patients with stable CAD [7]. A recent meta-analysis showed a proportional reduction of 12% in all-cause mortality per mmol.L-1 reduction in LDL-C [8]. In addition, a recent meta-regression analysis could not differentiate statin trials, from other modalities of LDL-C reduction (such as diet, bile acid sequestrents, and ileal bypass surgery) when the effect of the achieved LDL-C in the identified studies were compared to late coronary heart disease death and fatal and nonfatal stroke [9].
The duration of statin therapy is also important. While the majority of cellular and metabolic benefits of statins require one to two months of therapy in stable CAD [5], this only translates into a survival benefit after about a year of therapy [10].
The efficacy of high dose (intensive) statin therapy for patients with stable CAD is controversial. Atorvastatin 80mg daily with LDL-C of approximately 2mmol.L-1 possibly offers cardiovascular protection to patients with stable CAD [11,12], however it is associated with significantly increased incidence of raised aminotransferases (1-1.2% versus 0.1-0.2%) [11,12].
Importantly, withdrawal of statin therapy for up to six weeks in patients with stable CAD does not result in increased acute coronary events [13].
Implications for anesthesiologists. Although four to six weeks of pre-operative statin therapy is desirable based on cellular and metabolic responses, in patients with stable CAD it is possible that longer duration of therapy is necessary to realize survival benefits. In addition, LDL-C reduction should be considered an important therapeutic target prior to surgery in patients with stable CAD.
Acute coronary syndromes
ACS are fundamentally different from stable CAD. ACS are characterized by recurrent coronary events within the first six months following an ACS [7]. While death and recurrent myocardial infarction (MI) may exceed 12% following ACS, the same outcome may be less than 2% in patients with stable CAD [7]. Acute coronary syndromes are associated with vulnerable atherosclerotic plaques [14], and the plaque burden is predictive of ACS [15]. The marker of inflammation, C-reactive protein (CRP) has been associated with adverse cardiovascular outcomes [4]. Importantly, there is a correlation between systemic inflammation and local coronary inflammation in acute coronary syndromes [16]. Thus the pleiotropic effects associated with statins may be relatively more important following ACS [7] and assessment of the LDL-C in isolation would be inappropriate.
Analysis of the efficacy of statins following acute coronary events is essential if one is to identify appropriate management protocols for patients who sustain an acute coronary event following surgery. Analysis of the prospective studies of ACS [17-19] has identified the following therapeutic principles. Statin therapy should start early; it should be high dose (intensive) therapy, which is guided by inflammatory markers; it should not be withdrawn; and it should continue for the long term.
A meta-analysis of the prospective randomized trials that started statins within 14 days of an acute coronary event showed no improvement in short-term composite outcome of death, nonfatal myocardial infarction, and nonfatal stroke at both 1 and 4 months [20]. A further meta-analysis shows that survival and cardiovascular events only begin to separate at 4 months and achieve statistical significance for a composite of any cardiovascular event at 6 months [21]. Even an analysis of the studies which randomized all patients within a mean of the first three days following an ACS still shows no significant improvement in 30-day outcome [5]. The time to a significant improvement in cardiac outcome following ACS, interestingly tracks the time to improvement of endothelial function following initiation of statin therapy after ACS, which is 4 months [22]. Retrospective data suggests that statin therapy initiated within 24 hours of admission for an acute coronary event may be beneficial in decreasing in-hospital death [23,24].
Intensive statin therapy however, may result in earlier cardioprotection (before 4 months) following ACS. In the PROVE-IT study 80mg atorvastatin daily decreased the composite end-point of death, MI and recurrent ACS significantly by 30 days [7,18], despite a median time to randomization of 7 days after the acute coronary event. In addition, intensive therapy continues to provide superior cardioprotection at 4 months [19] and 6 months [18]. Importantly, as inflammatory modification is necessary following ACS, intensive therapy should be initiated irrespective of LDL-C level [18]. Importantly, both the CRP and LDL-C have been shown to be independent predictors of an adverse outcome [25]. An elevated CRP at the time of hospital admission for unstable angina is associated with a poorer outcome [6]. Intensive statin therapy results in lower CRP levels following ACS [26-28]. While LDL-C is probably more important for long-term outcome, CRP reduction is probably more important for earlier outcomes [27]. CRP also has a positive correlation with multiple plaque rupture following myocardial infarction [29]. The therapeutic target associated with the most significant decrease in cardiac death and recurrent MI following an acute coronary syndrome was a combined target of LDL-C < 70mg.dL-1 (1.8mmol.L-1) and an hsCRP < 2mg.L-1 [28].
Surprisingly, there appear to be no studies comparing the cardioprotective efficacy of chronic statin therapy versus acute statin administration following acute coronary syndromes. Although, data is available in two retrospective studies, it is unadjusted for covariates [29,30], and therefore inappropriate to draw conclusions on the relative beneficial effect of chronic statin therapy compared to acute statin therapy following acute coronary syndromes [5].
Implications for anesthesiologists. It is probable that early cardioprotection following ACS will only be realized if statins are started before or very early (within 24 hours) of an acute coronary event. Thus it is probably more important for anesthesiologists to correctly identify patients at risk of peri-operative coronary events and institute statins pre-operatively in these patients, as opposed to initiation of statin therapy after an established coronary event. Intensive statin therapy is essential should a patient have an acute coronary event. C-reactive protein reduction is an appropriate therapeutic target in all patients who have had an acute coronary event.
Possible Mechanisms of Peri-Operative Cardiovascular Protection Afforded by Statin Therapy
There are theoretically three potential pathways of peri-operative cardioprotection associated with statin therapy. Firstly, if the run-in period is adequate, then decreasing LDL-C [1] will decrease the inflammation associated with oxidized lipoprotein. Secondly, statins may stabilize vulnerable plaque via pleiotropic effects. Carotid endarterectomy studies show that patients on statin therapy are less likely to present with symptomatic carotid artery disease [31,32]. Finally, statins may further decrease the inflammatory response associated with major surgery, which may result in less plaque disruption. It is unknown whether the systemic inflammatory response associated with surgery results in conversion of stable to vulnerable coronary plaques. However, it is possible that this does happen, as in surgical patients, an elevated CRP has been shown to be an independent predictor of postoperative myocardial infarction over a year [33] and an independent predictor of cardiovascular and graft related events over a mean duration of 342 days [34] in patients with peripheral arterial disease.
Which patients should receive peri-operative statin therapy?
Based on the inconclusive peri-operative evidence [2,3], it would be appropriate to consider routine statin use only in patients who have medical indications for statin therapy independent of the surgery [2]. For example, the National Institute for Health and Clinical Excellence (NICE) recommends statin therapy for secondary prevention in all patients with clinical evidence of cardiovascular disease [35]. Cardiovascular disease is defined as coronary heart disease, stroke, transient ischemic attack (TIA), or peripheral arterial disease (PAD) [35]. The majority of vascular surgical patients would have at least one of these indications. However, only about 50% of major vascular patients receive statin therapy pre-operatively [36].
Do vascular patients require intensive statin therapy?
CRP has been shown to be a marker of the severity of peripheral arterial disease and to be associated with an adverse late cardiovascular outcomes [34,37]. Thus it is not surprising, that higher statin doses are associated with significantly less all-cause mortality and cardiac death over a mean follow-up of 6.4 ± 3.6 years in patients with peripheral arterial disease [38]. Higher doses of statin therapy have also been associated with improved cardiac outcomes at 30 days and less myocardial ischemia following vascular surgery [39]. Although this study [39] would suggest that high dose statin therapy is necessary, there were unfortunately no CRP levels in this study. It is therefore impossible to examine the relationship between inflammation and statin dosage in this study.
Is peri-operative withdrawal of statin therapy detrimental?
Withdrawal of statin therapy may be potentially hazardous following acute coronary syndromes [23], but not necessarily so in medical patients with stable coronary artery disease [13]. As high-risk surgical patients may have vulnerable coronary plaques, it would appear that withdrawal of statin therapy for a period postoperatively may be detrimental. Withdrawal of more than four days of statin therapy postoperatively was an independent predictor of cardiac myonecrosis (defined as an elevated troponin I level) following infrarenal aortic vascular surgery [40]. Therefore statin withdrawal in the postoperative period should not exceed four days.
Conclusion
Based on these observations, a standardized approach to peri-operative statin therapy has been suggested for both clinical and peri-operative statin trials (See Table 1) [41]. It is hoped that by adopting a standardized peri-operative statin regimen based on the current medical and surgical literature, more meaningful meta-analyses would be possible in the future.
References