Nabil Fallouh, MD, MS

Accumulating evidence suggests that perioperative treatment with 3‐hydroxy‐3‐methylglutaryl coenzyme‐A (HMG‐CoA) reductase inhibitors (or, statins) reduces the incidence of cardiovascular events during noncardiac surgery.16 This evidence has lead the European Society of Cardiology (ESC) and American College of Cardiology Foundation/American Heart Association (ACCF/AHA) to endorse the use of perioperative statins in patients already on this treatment or those at high‐risk of cardiovascular events.7, 8

However, statins are available only in oral formulation. Consequently, prolonged bowel recovery or clinical instability may interfere with use during surgery. Furthermore, many clinicians may not recognize the imperative of postoperative statin resumption, viewing them principally as lipid‐lowering entities and not as agents of perioperative benefit. Failure to resume statins postoperatively can be catastrophic, as the ensuing inflammation and thrombosis frequently culminates in myocardial infarction (MI) or death.9, 10

In this article, we review the potent anti‐inflammatory properties of statins and their role in preventing perioperative cardiac events. We outline the biochemical basis for perioperative statin benefit, summarizing the basic, clinical, and experimental evidence regarding statin withdrawal. We conclude by presenting strategies to avert postoperative statin cessation and outline a research agenda dedicated to informing this practice.

METHODS

We performed a literature search using MEDLINE via Ovid (1946present), EMBASE (1946present), Biosis (1926present), and Cochrane CENTRAL (1960present). We used Boolean logic to search for key terms including statins, 3‐hydroxy‐3‐methylglutaryl CoA reductase inhibitors, death, MI, stroke, acute coronary syndrome (ACS), and statin withdrawal or cessation. All studies published in full‐text or abstract form were included. A total of 489 articles were retrieved by this search (last updated March 15, 2012). For this narrative review, we focused on studies that examined adverse outcomes associated with statin withdrawal.

BIOCHEMICAL BASIS OF STATIN PLEIOTROPICITY

The nonlipid‐lowering or pleiotropic properties of statins are especially valuable in the perioperative setting.16, 11 Perioperative cardiac complications occur due to oxygen supply:demand mismatch, vascular inflammation, or a combination of these states. A significant perisurgical catecholamine surge produces unopposed sympathetic effects,12 increasing the risk of rupture of vulnerable coronary plaques, thrombus formation, and adverse cardiac events.13, 14 Similarly, augmented inflammatory responses and increased circulating coagulation factors further predispose to a hazardous perioperative milieu.15 Statins attenuate this vascular inflammatory response by suppressing the synthesis of mevalonate by inhibiting HMG‐CoA reductase. Suppression of mevalonate synthesis reduces the bioavailability of 2 important isoprenoid molecules: farnesyl‐pyrophosphate and geranylgeranyl‐pyrophosphate.16 Diminution of these isoprenoid intermediaries leads to reductions in the active intracellular signaling molecules Ras, Rho, and Rac, which play critical roles in vascular reactivity, endothelial function, and coagulation and inflammatory pathways.1723 The cumulative effect of these cellular changes is diminished inflammation during periods of surgical stress (Figure 1).

Figure 1

While the perioperative pleiotropicity of statins is of inherent clinical value, several studies have shown that these effects are lost and even reversed when statins are withdrawn.2428 During statin treatment, absence of isoprenoid intermediaries induces cytosolic accumulation of nonactivated Rho and Rac proteins. Abrupt cessation of statins activates Rho/Rac‐kinase pathways, leading to unregulated inflammation, platelet hyper‐activation, and endothelial dysfunction.24, 25, 28, 29 For instance, statin withdrawal in mice‐models leads to an overshoot activation of Rho, resulting in down‐regulation of endothelial nitric oxide production,25 activation of nicotinamide adenine dinucleotide phosphate (NAD[P]H)‐oxidase, and increased superoxide production.29 In another mouse‐model, statin withdrawal was associated with up‐regulation of key pro‐thrombotic molecules including platelet factor 4 and beta‐thromboglobulin.24 In human studies, a platelet hyper‐activation state (manifested by increased platelet P‐selectin expression and enhanced platelet aggregation) occurs after statin discontinuation.27 Furthermore, withdrawal of statins in patients with hyperlipidemia increases inflammatory markers such as C‐reactive protein and interleukin‐6.26 In the perioperative context, absence of these important anti‐inflammatory properties increases the risk of cardiac events.9, 10

EVIDENCE SUGGESTING BENEFIT FROM PERIOPERATIVE STATIN TREATMENT

Retrospective studies first suggested clinical benefit from perioperative statin treatment. In a case‐control study involving 2816 patients undergoing vascular surgery at Erasmus Medical Center, statin use was associated with substantially decreased postoperative mortality (adjusted odd ratio [OR] 0.22, 95% confidence interval [CI] 0.100.47).5 In a subsequent retrospective cohort study of 780,591 patients who underwent major noncardiac surgery, the risk of postoperative mortality was considerably lower among statin users (unadjusted OR 0.68, 95% CI 0.640.72) compared to patients who did not receive, or received delayed treatment with statins.3 A third retrospective study of 1163 vascular surgery patients found that statins prevented perioperative cardiac complications including death, MI, congestive heart failure, and ventricular tachyarrhythmias (OR 0.52, 95% CI 0.350.76).4

The benefit from statin treatment found in retrospective studies prompted the first double‐blinded, randomized controlled trial (RCT) of perioperative statin use. In 2004, Durazzo and colleagues1 randomized 100 statin‐naive patients scheduled to undergo elective aortic, femoro‐popliteal, or carotid surgery to receive either 20 mg of atorvastatin or placebo for 45 days. Vascular surgery was performed, on average, 31 days after randomization. Atorvastatin therapy reduced the incidence of death from cardiac causes, nonfatal acute MI, ischemic stroke, and unstable angina (26% in the placebo group vs 8% in the atorvastatin group; P = 0.031).1 Although the small size of the trial rendered it underpowered to show a mortality benefit, this remains the first RCT to demonstrate a protective perioperative effect of statins.

In the 2009 Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE)‐III trial, Schouten and colleagues6 randomized 497 high‐risk, statin‐naive patients undergoing vascular surgery to receive, in addition to a beta‐blocker, either fluvastatin or placebo before surgery (median of 37 days). Postoperative myocardial ischemia (hazard ratio [HR] 0.55, 95% CI 0.340.88), and combined death from cardiovascular causes or nonfatal MI (HR 0.47, 95% CI 0.240.94), occurred less frequently in the treatment group.6 In 2009, the same group published DECREASE‐IV, a multicenter, prospective, open‐label, 2 2 factorial design trial of 1066 intermediate‐risk patients, scheduled to undergo elective, noncardiac surgery. Patients were assigned to bisoprolol, fluvastatin, combination treatment, or control therapy before surgery (median of 34 days). Although those randomized to fluvastatin demonstrated lower incidence of 30‐day cardiac death and MI than control (HR 0.65, 95% CI 0.351.10), these outcomes failed to reach statistical significance as the trial was principally powered to examine the effects of perioperative beta‐blockade.30

Using this pool of data, a meta‐analysis of 15 studies (223,010 patients) found a substantial 38% reduction in the risk of mortality after cardiac surgery (1.9% vs 3.1%; P = 0.0001) and an even greater 59% reduction in the risk of mortality following vascular surgery (1.7% vs 6.1%; P = 0.0001) with perioperative statin therapy. When including noncardiac surgery, a 44% reduction in mortality was observed (2.2% vs 3.2%; P < 0.01).2 We performed a similar meta‐analysis of 15 RCTs involving 2292 patients to determine whether perioperative statin treatment in statin‐naive patients, undergoing either cardiac or noncardiac surgery, improved clinical outcomes. Our analysis also found statistically significant reductions in the risk of MI associated with perioperative statin use in both cardiac and noncardiac surgery (risk reduction [RR] 0.53, 95% CI 0.380.74) and atrial fibrillation in statin‐naive patients undergoing cardiac surgery (RR 0.56, 95% CI 0.450.69).31 Taken together, a large volume of evidence supports the use of statins in surgical settings.

In view of this evidence, the ACCF/AHA perioperative guidelines for noncardiac surgery endorsed statins as an important risk‐reducing intervention in those undergoing noncardiac surgery, and recommended continued use in patients on chronic statin treatment scheduled for noncardiac surgery (Level of Evidence B, Class I; Benefits >>> Risk). Initiating statins in patients undergoing vascular surgery, with or without risk factors, was considered reasonable (Level of Evidence B, Class IIa; Benefits >> Risk).7 Current ESC perioperative guidelines in noncardiac surgery offer similar recommendations to those of ACCF/AHA, but differ by categorizing the recommendation to initiate statins in patients at high cardiovascular risk as a Class I recommendation.8

CLINICAL CONSEQUENCES OF STATIN WITHDRAWAL

Although statins provide important cardiac benefits, an important limitation to their perioperative use remains their oral‐only formulation. Thus, patients who are unable to resume oral intake may fail to resume treatment. Perioperative statin cessation has been hypothesized to lead to a statin withdrawal phenomenon. The evidence that supports the existence of this phenomenon comes from 3 distinct populations: ACS, ischemic stroke, and perioperative patients (Table 1).

CLINICAL INSIGHTS INTO FAILURE OF POSTOPERATIVE STATIN RESUMPTION

We hypothesize that failure to resume perioperative statins may occur for 4 cardinal reasons. First, resumption of an oral agent frequently proves clinically challenging when complications such as postoperative ileus, nausea, and vomiting peak. To date, no intravenous statin formulations are available, although phase‐I studies are currently underway.38 Second, it is not inconceivable that perioperative clinical instability may overshadow the resumption of statin treatment. Third, clinicians may also remain concerned regarding adverse effects of statins, a thought compounded by US Food and Drug Administration statin package inserts that specifically advocate for statins to be withheld during surgery. However, although the occurrence of elevated liver function tests and myopathy are theoretically important, the overwhelming majority of perioperative statin studies in noncardiac surgery have not found this to be a major occurrence.39 Nonetheless, a lack of uniform definitions and appropriate surveillance for adverse events are important limitations to this finding. In our recent systematic review, we were unable to provide refined estimates of these important side effects owing to differences in definition, variations in screening, and absence of standardized cutoffs used in studies.31 Finally, an important reason for failing to resume postoperative statins is that many physicians simply fail to recognize the perioperative importance of these agents.

STRATEGIES TO IMPROVE PERIOPERATIVE STATIN RESUMPTION

Using the existing evidence, we propose the following 4 clinical strategies to assist in avoiding a statin withdrawal state.

Preoperative Transition to Extended Release Statin Formulations

An innovative approach to minimizing statin withdrawal involves preoperative transition to an extended‐release statin formulation. This strategy may be of particular value in patients where prolonged bowel nonavailability is likely, such as those undergoing gastrointestinal surgery, or when prolonged postoperative dietary restriction (eg, NPO [nil per os]: nothing by mouth) status is expected (Figure 2).

Figure 2

CONCLUSIONS AND FUTURE DIRECTIONS

Sudden withdrawal of perioperative statins results in adverse clinical outcomes. Individuals engaged in the care of patients during surgery such as hospitalists, anesthesiologists, and surgeons must become more cognizant of a statin withdrawal state.

An important limitation associated with the study of perioperative statin withdrawal remains the ambiguity regarding the extent of the problem in the United States. Therefore, a logical first step could be the use of infrastructure within the National Surgical Quality Improvement Program (NSQIP) to understand the epidemiology of perioperative statin use and consequences associated with statin discontinuation.44 Mandating such quality reporting could easily be built into current NSQIP performance metrics. These data would help inform a research agenda targeting patients that experience statin withdrawal and strategies most likely to prevent it.

Accumulating evidence suggests that perioperative treatment with 3‐hydroxy‐3‐methylglutaryl coenzyme‐A (HMG‐CoA) reductase inhibitors (or, statins) reduces the incidence of cardiovascular events during noncardiac surgery.16 This evidence has lead the European Society of Cardiology (ESC) and American College of Cardiology Foundation/American Heart Association (ACCF/AHA) to endorse the use of perioperative statins in patients already on this treatment or those at high‐risk of cardiovascular events.7, 8

However, statins are available only in oral formulation. Consequently, prolonged bowel recovery or clinical instability may interfere with use during surgery. Furthermore, many clinicians may not recognize the imperative of postoperative statin resumption, viewing them principally as lipid‐lowering entities and not as agents of perioperative benefit. Failure to resume statins postoperatively can be catastrophic, as the ensuing inflammation and thrombosis frequently culminates in myocardial infarction (MI) or death.9, 10

In this article, we review the potent anti‐inflammatory properties of statins and their role in preventing perioperative cardiac events. We outline the biochemical basis for perioperative statin benefit, summarizing the basic, clinical, and experimental evidence regarding statin withdrawal. We conclude by presenting strategies to avert postoperative statin cessation and outline a research agenda dedicated to informing this practice.

METHODS

We performed a literature search using MEDLINE via Ovid (1946present), EMBASE (1946present), Biosis (1926present), and Cochrane CENTRAL (1960present). We used Boolean logic to search for key terms including statins, 3‐hydroxy‐3‐methylglutaryl CoA reductase inhibitors, death, MI, stroke, acute coronary syndrome (ACS), and statin withdrawal or cessation. All studies published in full‐text or abstract form were included. A total of 489 articles were retrieved by this search (last updated March 15, 2012). For this narrative review, we focused on studies that examined adverse outcomes associated with statin withdrawal.

BIOCHEMICAL BASIS OF STATIN PLEIOTROPICITY

The nonlipid‐lowering or pleiotropic properties of statins are especially valuable in the perioperative setting.16, 11 Perioperative cardiac complications occur due to oxygen supply:demand mismatch, vascular inflammation, or a combination of these states. A significant perisurgical catecholamine surge produces unopposed sympathetic effects,12 increasing the risk of rupture of vulnerable coronary plaques, thrombus formation, and adverse cardiac events.13, 14 Similarly, augmented inflammatory responses and increased circulating coagulation factors further predispose to a hazardous perioperative milieu.15 Statins attenuate this vascular inflammatory response by suppressing the synthesis of mevalonate by inhibiting HMG‐CoA reductase. Suppression of mevalonate synthesis reduces the bioavailability of 2 important isoprenoid molecules: farnesyl‐pyrophosphate and geranylgeranyl‐pyrophosphate.16 Diminution of these isoprenoid intermediaries leads to reductions in the active intracellular signaling molecules Ras, Rho, and Rac, which play critical roles in vascular reactivity, endothelial function, and coagulation and inflammatory pathways.1723 The cumulative effect of these cellular changes is diminished inflammation during periods of surgical stress (Figure 1).

Figure 1

While the perioperative pleiotropicity of statins is of inherent clinical value, several studies have shown that these effects are lost and even reversed when statins are withdrawn.2428 During statin treatment, absence of isoprenoid intermediaries induces cytosolic accumulation of nonactivated Rho and Rac proteins. Abrupt cessation of statins activates Rho/Rac‐kinase pathways, leading to unregulated inflammation, platelet hyper‐activation, and endothelial dysfunction.24, 25, 28, 29 For instance, statin withdrawal in mice‐models leads to an overshoot activation of Rho, resulting in down‐regulation of endothelial nitric oxide production,25 activation of nicotinamide adenine dinucleotide phosphate (NAD[P]H)‐oxidase, and increased superoxide production.29 In another mouse‐model, statin withdrawal was associated with up‐regulation of key pro‐thrombotic molecules including platelet factor 4 and beta‐thromboglobulin.24 In human studies, a platelet hyper‐activation state (manifested by increased platelet P‐selectin expression and enhanced platelet aggregation) occurs after statin discontinuation.27 Furthermore, withdrawal of statins in patients with hyperlipidemia increases inflammatory markers such as C‐reactive protein and interleukin‐6.26 In the perioperative context, absence of these important anti‐inflammatory properties increases the risk of cardiac events.9, 10

EVIDENCE SUGGESTING BENEFIT FROM PERIOPERATIVE STATIN TREATMENT

Retrospective studies first suggested clinical benefit from perioperative statin treatment. In a case‐control study involving 2816 patients undergoing vascular surgery at Erasmus Medical Center, statin use was associated with substantially decreased postoperative mortality (adjusted odd ratio [OR] 0.22, 95% confidence interval [CI] 0.100.47).5 In a subsequent retrospective cohort study of 780,591 patients who underwent major noncardiac surgery, the risk of postoperative mortality was considerably lower among statin users (unadjusted OR 0.68, 95% CI 0.640.72) compared to patients who did not receive, or received delayed treatment with statins.3 A third retrospective study of 1163 vascular surgery patients found that statins prevented perioperative cardiac complications including death, MI, congestive heart failure, and ventricular tachyarrhythmias (OR 0.52, 95% CI 0.350.76).4

The benefit from statin treatment found in retrospective studies prompted the first double‐blinded, randomized controlled trial (RCT) of perioperative statin use. In 2004, Durazzo and colleagues1 randomized 100 statin‐naive patients scheduled to undergo elective aortic, femoro‐popliteal, or carotid surgery to receive either 20 mg of atorvastatin or placebo for 45 days. Vascular surgery was performed, on average, 31 days after randomization. Atorvastatin therapy reduced the incidence of death from cardiac causes, nonfatal acute MI, ischemic stroke, and unstable angina (26% in the placebo group vs 8% in the atorvastatin group; P = 0.031).1 Although the small size of the trial rendered it underpowered to show a mortality benefit, this remains the first RCT to demonstrate a protective perioperative effect of statins.

In the 2009 Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE)‐III trial, Schouten and colleagues6 randomized 497 high‐risk, statin‐naive patients undergoing vascular surgery to receive, in addition to a beta‐blocker, either fluvastatin or placebo before surgery (median of 37 days). Postoperative myocardial ischemia (hazard ratio [HR] 0.55, 95% CI 0.340.88), and combined death from cardiovascular causes or nonfatal MI (HR 0.47, 95% CI 0.240.94), occurred less frequently in the treatment group.6 In 2009, the same group published DECREASE‐IV, a multicenter, prospective, open‐label, 2 2 factorial design trial of 1066 intermediate‐risk patients, scheduled to undergo elective, noncardiac surgery. Patients were assigned to bisoprolol, fluvastatin, combination treatment, or control therapy before surgery (median of 34 days). Although those randomized to fluvastatin demonstrated lower incidence of 30‐day cardiac death and MI than control (HR 0.65, 95% CI 0.351.10), these outcomes failed to reach statistical significance as the trial was principally powered to examine the effects of perioperative beta‐blockade.30

Using this pool of data, a meta‐analysis of 15 studies (223,010 patients) found a substantial 38% reduction in the risk of mortality after cardiac surgery (1.9% vs 3.1%; P = 0.0001) and an even greater 59% reduction in the risk of mortality following vascular surgery (1.7% vs 6.1%; P = 0.0001) with perioperative statin therapy. When including noncardiac surgery, a 44% reduction in mortality was observed (2.2% vs 3.2%; P < 0.01).2 We performed a similar meta‐analysis of 15 RCTs involving 2292 patients to determine whether perioperative statin treatment in statin‐naive patients, undergoing either cardiac or noncardiac surgery, improved clinical outcomes. Our analysis also found statistically significant reductions in the risk of MI associated with perioperative statin use in both cardiac and noncardiac surgery (risk reduction [RR] 0.53, 95% CI 0.380.74) and atrial fibrillation in statin‐naive patients undergoing cardiac surgery (RR 0.56, 95% CI 0.450.69).31 Taken together, a large volume of evidence supports the use of statins in surgical settings.

In view of this evidence, the ACCF/AHA perioperative guidelines for noncardiac surgery endorsed statins as an important risk‐reducing intervention in those undergoing noncardiac surgery, and recommended continued use in patients on chronic statin treatment scheduled for noncardiac surgery (Level of Evidence B, Class I; Benefits >>> Risk). Initiating statins in patients undergoing vascular surgery, with or without risk factors, was considered reasonable (Level of Evidence B, Class IIa; Benefits >> Risk).7 Current ESC perioperative guidelines in noncardiac surgery offer similar recommendations to those of ACCF/AHA, but differ by categorizing the recommendation to initiate statins in patients at high cardiovascular risk as a Class I recommendation.8

CLINICAL CONSEQUENCES OF STATIN WITHDRAWAL

Although statins provide important cardiac benefits, an important limitation to their perioperative use remains their oral‐only formulation. Thus, patients who are unable to resume oral intake may fail to resume treatment. Perioperative statin cessation has been hypothesized to lead to a statin withdrawal phenomenon. The evidence that supports the existence of this phenomenon comes from 3 distinct populations: ACS, ischemic stroke, and perioperative patients (Table 1).

CLINICAL INSIGHTS INTO FAILURE OF POSTOPERATIVE STATIN RESUMPTION

We hypothesize that failure to resume perioperative statins may occur for 4 cardinal reasons. First, resumption of an oral agent frequently proves clinically challenging when complications such as postoperative ileus, nausea, and vomiting peak. To date, no intravenous statin formulations are available, although phase‐I studies are currently underway.38 Second, it is not inconceivable that perioperative clinical instability may overshadow the resumption of statin treatment. Third, clinicians may also remain concerned regarding adverse effects of statins, a thought compounded by US Food and Drug Administration statin package inserts that specifically advocate for statins to be withheld during surgery. However, although the occurrence of elevated liver function tests and myopathy are theoretically important, the overwhelming majority of perioperative statin studies in noncardiac surgery have not found this to be a major occurrence.39 Nonetheless, a lack of uniform definitions and appropriate surveillance for adverse events are important limitations to this finding. In our recent systematic review, we were unable to provide refined estimates of these important side effects owing to differences in definition, variations in screening, and absence of standardized cutoffs used in studies.31 Finally, an important reason for failing to resume postoperative statins is that many physicians simply fail to recognize the perioperative importance of these agents.

STRATEGIES TO IMPROVE PERIOPERATIVE STATIN RESUMPTION

Using the existing evidence, we propose the following 4 clinical strategies to assist in avoiding a statin withdrawal state.

Preoperative Transition to Extended Release Statin Formulations

An innovative approach to minimizing statin withdrawal involves preoperative transition to an extended‐release statin formulation. This strategy may be of particular value in patients where prolonged bowel nonavailability is likely, such as those undergoing gastrointestinal surgery, or when prolonged postoperative dietary restriction (eg, NPO [nil per os]: nothing by mouth) status is expected (Figure 2).

Figure 2

CONCLUSIONS AND FUTURE DIRECTIONS

Sudden withdrawal of perioperative statins results in adverse clinical outcomes. Individuals engaged in the care of patients during surgery such as hospitalists, anesthesiologists, and surgeons must become more cognizant of a statin withdrawal state.

An important limitation associated with the study of perioperative statin withdrawal remains the ambiguity regarding the extent of the problem in the United States. Therefore, a logical first step could be the use of infrastructure within the National Surgical Quality Improvement Program (NSQIP) to understand the epidemiology of perioperative statin use and consequences associated with statin discontinuation.44 Mandating such quality reporting could easily be built into current NSQIP performance metrics. These data would help inform a research agenda targeting patients that experience statin withdrawal and strategies most likely to prevent it.

Accumulating evidence suggests that perioperative treatment with 3‐hydroxy‐3‐methylglutaryl coenzyme‐A (HMG‐CoA) reductase inhibitors (or, statins) reduces the incidence of cardiovascular events during noncardiac surgery.16 This evidence has lead the European Society of Cardiology (ESC) and American College of Cardiology Foundation/American Heart Association (ACCF/AHA) to endorse the use of perioperative statins in patients already on this treatment or those at high‐risk of cardiovascular events.7, 8

However, statins are available only in oral formulation. Consequently, prolonged bowel recovery or clinical instability may interfere with use during surgery. Furthermore, many clinicians may not recognize the imperative of postoperative statin resumption, viewing them principally as lipid‐lowering entities and not as agents of perioperative benefit. Failure to resume statins postoperatively can be catastrophic, as the ensuing inflammation and thrombosis frequently culminates in myocardial infarction (MI) or death.9, 10

In this article, we review the potent anti‐inflammatory properties of statins and their role in preventing perioperative cardiac events. We outline the biochemical basis for perioperative statin benefit, summarizing the basic, clinical, and experimental evidence regarding statin withdrawal. We conclude by presenting strategies to avert postoperative statin cessation and outline a research agenda dedicated to informing this practice.

METHODS

We performed a literature search using MEDLINE via Ovid (1946present), EMBASE (1946present), Biosis (1926present), and Cochrane CENTRAL (1960present). We used Boolean logic to search for key terms including statins, 3‐hydroxy‐3‐methylglutaryl CoA reductase inhibitors, death, MI, stroke, acute coronary syndrome (ACS), and statin withdrawal or cessation. All studies published in full‐text or abstract form were included. A total of 489 articles were retrieved by this search (last updated March 15, 2012). For this narrative review, we focused on studies that examined adverse outcomes associated with statin withdrawal.

BIOCHEMICAL BASIS OF STATIN PLEIOTROPICITY

The nonlipid‐lowering or pleiotropic properties of statins are especially valuable in the perioperative setting.16, 11 Perioperative cardiac complications occur due to oxygen supply:demand mismatch, vascular inflammation, or a combination of these states. A significant perisurgical catecholamine surge produces unopposed sympathetic effects,12 increasing the risk of rupture of vulnerable coronary plaques, thrombus formation, and adverse cardiac events.13, 14 Similarly, augmented inflammatory responses and increased circulating coagulation factors further predispose to a hazardous perioperative milieu.15 Statins attenuate this vascular inflammatory response by suppressing the synthesis of mevalonate by inhibiting HMG‐CoA reductase. Suppression of mevalonate synthesis reduces the bioavailability of 2 important isoprenoid molecules: farnesyl‐pyrophosphate and geranylgeranyl‐pyrophosphate.16 Diminution of these isoprenoid intermediaries leads to reductions in the active intracellular signaling molecules Ras, Rho, and Rac, which play critical roles in vascular reactivity, endothelial function, and coagulation and inflammatory pathways.1723 The cumulative effect of these cellular changes is diminished inflammation during periods of surgical stress (Figure 1).

Figure 1

While the perioperative pleiotropicity of statins is of inherent clinical value, several studies have shown that these effects are lost and even reversed when statins are withdrawn.2428 During statin treatment, absence of isoprenoid intermediaries induces cytosolic accumulation of nonactivated Rho and Rac proteins. Abrupt cessation of statins activates Rho/Rac‐kinase pathways, leading to unregulated inflammation, platelet hyper‐activation, and endothelial dysfunction.24, 25, 28, 29 For instance, statin withdrawal in mice‐models leads to an overshoot activation of Rho, resulting in down‐regulation of endothelial nitric oxide production,25 activation of nicotinamide adenine dinucleotide phosphate (NAD[P]H)‐oxidase, and increased superoxide production.29 In another mouse‐model, statin withdrawal was associated with up‐regulation of key pro‐thrombotic molecules including platelet factor 4 and beta‐thromboglobulin.24 In human studies, a platelet hyper‐activation state (manifested by increased platelet P‐selectin expression and enhanced platelet aggregation) occurs after statin discontinuation.27 Furthermore, withdrawal of statins in patients with hyperlipidemia increases inflammatory markers such as C‐reactive protein and interleukin‐6.26 In the perioperative context, absence of these important anti‐inflammatory properties increases the risk of cardiac events.9, 10

EVIDENCE SUGGESTING BENEFIT FROM PERIOPERATIVE STATIN TREATMENT

Retrospective studies first suggested clinical benefit from perioperative statin treatment. In a case‐control study involving 2816 patients undergoing vascular surgery at Erasmus Medical Center, statin use was associated with substantially decreased postoperative mortality (adjusted odd ratio [OR] 0.22, 95% confidence interval [CI] 0.100.47).5 In a subsequent retrospective cohort study of 780,591 patients who underwent major noncardiac surgery, the risk of postoperative mortality was considerably lower among statin users (unadjusted OR 0.68, 95% CI 0.640.72) compared to patients who did not receive, or received delayed treatment with statins.3 A third retrospective study of 1163 vascular surgery patients found that statins prevented perioperative cardiac complications including death, MI, congestive heart failure, and ventricular tachyarrhythmias (OR 0.52, 95% CI 0.350.76).4

The benefit from statin treatment found in retrospective studies prompted the first double‐blinded, randomized controlled trial (RCT) of perioperative statin use. In 2004, Durazzo and colleagues1 randomized 100 statin‐naive patients scheduled to undergo elective aortic, femoro‐popliteal, or carotid surgery to receive either 20 mg of atorvastatin or placebo for 45 days. Vascular surgery was performed, on average, 31 days after randomization. Atorvastatin therapy reduced the incidence of death from cardiac causes, nonfatal acute MI, ischemic stroke, and unstable angina (26% in the placebo group vs 8% in the atorvastatin group; P = 0.031).1 Although the small size of the trial rendered it underpowered to show a mortality benefit, this remains the first RCT to demonstrate a protective perioperative effect of statins.

In the 2009 Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE)‐III trial, Schouten and colleagues6 randomized 497 high‐risk, statin‐naive patients undergoing vascular surgery to receive, in addition to a beta‐blocker, either fluvastatin or placebo before surgery (median of 37 days). Postoperative myocardial ischemia (hazard ratio [HR] 0.55, 95% CI 0.340.88), and combined death from cardiovascular causes or nonfatal MI (HR 0.47, 95% CI 0.240.94), occurred less frequently in the treatment group.6 In 2009, the same group published DECREASE‐IV, a multicenter, prospective, open‐label, 2 2 factorial design trial of 1066 intermediate‐risk patients, scheduled to undergo elective, noncardiac surgery. Patients were assigned to bisoprolol, fluvastatin, combination treatment, or control therapy before surgery (median of 34 days). Although those randomized to fluvastatin demonstrated lower incidence of 30‐day cardiac death and MI than control (HR 0.65, 95% CI 0.351.10), these outcomes failed to reach statistical significance as the trial was principally powered to examine the effects of perioperative beta‐blockade.30

Using this pool of data, a meta‐analysis of 15 studies (223,010 patients) found a substantial 38% reduction in the risk of mortality after cardiac surgery (1.9% vs 3.1%; P = 0.0001) and an even greater 59% reduction in the risk of mortality following vascular surgery (1.7% vs 6.1%; P = 0.0001) with perioperative statin therapy. When including noncardiac surgery, a 44% reduction in mortality was observed (2.2% vs 3.2%; P < 0.01).2 We performed a similar meta‐analysis of 15 RCTs involving 2292 patients to determine whether perioperative statin treatment in statin‐naive patients, undergoing either cardiac or noncardiac surgery, improved clinical outcomes. Our analysis also found statistically significant reductions in the risk of MI associated with perioperative statin use in both cardiac and noncardiac surgery (risk reduction [RR] 0.53, 95% CI 0.380.74) and atrial fibrillation in statin‐naive patients undergoing cardiac surgery (RR 0.56, 95% CI 0.450.69).31 Taken together, a large volume of evidence supports the use of statins in surgical settings.

In view of this evidence, the ACCF/AHA perioperative guidelines for noncardiac surgery endorsed statins as an important risk‐reducing intervention in those undergoing noncardiac surgery, and recommended continued use in patients on chronic statin treatment scheduled for noncardiac surgery (Level of Evidence B, Class I; Benefits >>> Risk). Initiating statins in patients undergoing vascular surgery, with or without risk factors, was considered reasonable (Level of Evidence B, Class IIa; Benefits >> Risk).7 Current ESC perioperative guidelines in noncardiac surgery offer similar recommendations to those of ACCF/AHA, but differ by categorizing the recommendation to initiate statins in patients at high cardiovascular risk as a Class I recommendation.8

CLINICAL CONSEQUENCES OF STATIN WITHDRAWAL

Although statins provide important cardiac benefits, an important limitation to their perioperative use remains their oral‐only formulation. Thus, patients who are unable to resume oral intake may fail to resume treatment. Perioperative statin cessation has been hypothesized to lead to a statin withdrawal phenomenon. The evidence that supports the existence of this phenomenon comes from 3 distinct populations: ACS, ischemic stroke, and perioperative patients (Table 1).

CLINICAL INSIGHTS INTO FAILURE OF POSTOPERATIVE STATIN RESUMPTION

We hypothesize that failure to resume perioperative statins may occur for 4 cardinal reasons. First, resumption of an oral agent frequently proves clinically challenging when complications such as postoperative ileus, nausea, and vomiting peak. To date, no intravenous statin formulations are available, although phase‐I studies are currently underway.38 Second, it is not inconceivable that perioperative clinical instability may overshadow the resumption of statin treatment. Third, clinicians may also remain concerned regarding adverse effects of statins, a thought compounded by US Food and Drug Administration statin package inserts that specifically advocate for statins to be withheld during surgery. However, although the occurrence of elevated liver function tests and myopathy are theoretically important, the overwhelming majority of perioperative statin studies in noncardiac surgery have not found this to be a major occurrence.39 Nonetheless, a lack of uniform definitions and appropriate surveillance for adverse events are important limitations to this finding. In our recent systematic review, we were unable to provide refined estimates of these important side effects owing to differences in definition, variations in screening, and absence of standardized cutoffs used in studies.31 Finally, an important reason for failing to resume postoperative statins is that many physicians simply fail to recognize the perioperative importance of these agents.

STRATEGIES TO IMPROVE PERIOPERATIVE STATIN RESUMPTION

Using the existing evidence, we propose the following 4 clinical strategies to assist in avoiding a statin withdrawal state.

Preoperative Transition to Extended Release Statin Formulations

An innovative approach to minimizing statin withdrawal involves preoperative transition to an extended‐release statin formulation. This strategy may be of particular value in patients where prolonged bowel nonavailability is likely, such as those undergoing gastrointestinal surgery, or when prolonged postoperative dietary restriction (eg, NPO [nil per os]: nothing by mouth) status is expected (Figure 2).

Figure 2

CONCLUSIONS AND FUTURE DIRECTIONS

Sudden withdrawal of perioperative statins results in adverse clinical outcomes. Individuals engaged in the care of patients during surgery such as hospitalists, anesthesiologists, and surgeons must become more cognizant of a statin withdrawal state.

An important limitation associated with the study of perioperative statin withdrawal remains the ambiguity regarding the extent of the problem in the United States. Therefore, a logical first step could be the use of infrastructure within the National Surgical Quality Improvement Program (NSQIP) to understand the epidemiology of perioperative statin use and consequences associated with statin discontinuation.44 Mandating such quality reporting could easily be built into current NSQIP performance metrics. These data would help inform a research agenda targeting patients that experience statin withdrawal and strategies most likely to prevent it.