Perioperative statin therapy: current knowledge and future directions

Abstract

Perioperative statin therapy has come to represent a cornerstone of risk reduction for millions of patients who undergo cardiac and noncardiac surgeries. While large-scale, robust, randomized controlled studies support the use of statins in cardiac surgery, their role in noncardiac surgery has become ambiguous following concerns regarding scientific misconduct in many pivotal studies. In this edition of the Expert Opinion on Pharmacotherapy, Irwin et al. comprehensively summarize the evidence for perioperative statin treatment. The authors add to this review by providing expert opinions regarding the state of the science and future paths for research and enquiry.

Keywords::

• noncardiac surgery
• perioperative
• risk reduction
• statin

The use of statins as perioperative mediators of cardiovascular protection is a tale of progressive scientific enquiry. Curiosity regarding the use of statins around the time of surgery began at the turn of the century, when Christenson first reported a decrease in the risk of postoperative thrombocytosis in a study of 77 patients undergoing coronary artery bypass grafting (CABG) [1]. These investigators randomized patients to receive simvastatin based on the observation that hypercholesterolemia increased cholesterol content in the platelet membrane, leading to increased platelet aggregation, thrombocytosis and postoperative thromboses. A year later, Dotani et al. observed that preoperative statin therapy reduced the composite endpoint of death, myocardial infarction (MI), unstable angina, cerebrovascular accident, new arrhythmias and congestive heart failure (odds ratio [OR] = 0.26, 95% confidence interval [CI]: 0.145 – 0.451) in a retrospective cohort of 323 consecutive patients undergoing CABG [2]. While promising, early data were not all necessarily positive. Fears regarding use of these agents in patients undergoing surgical intervention were also prevalent, which was manifested by case reports and editorials reporting devastating side effects [3].

It was not until 2003 that more robust data specifically testing the hypothesis that statins reduced perioperative cardiac risk became available. Researchers at Erasmus Medical Center in the Netherlands were among the first to report a substantial decrease in perioperative mortality among statin users in a well designed, case-control study of 2,816 patients undergoing vascular surgery (OR = 0.22, 95% CI: 0.10 – 0.47) [4]. In a 2004 retrospective cohort study using a nationally representative claims database from the United States, Lindenauer et al. also found a decrease in mortality among 780,591 statin users undergoing noncardiac surgery (adjusted OR = 0.62, 95% CI: 0.58 – 0.67) [5]. Although encouraging, concerns regarding unmeasured, confounding, healthy user effects and selection and recall bias continued to plague this literature.

Durazzo et al. addressed this problem by performing the first double-blind, randomized, placebo-controlled trial of perioperative statin treatment. Following the randomization of 100 statin-naïve patients to statin treatment or placebo, these investigators found that atorvastatin significantly reduced death from cardiac causes, nonfatal acute MI, ischemic stroke and unstable angina (26 vs 8%; p = 0.031) in elective major vascular surgery [6]. The improvement in outcomes reported by this study set into cascade a series of investigations that ultimately changed the evidence-base and clinical care guidelines for the role of statins in cardiac and noncardiac vascular surgeries. For instance, in the ensuing DECREASE-III study, Schouten et al. found that postoperative myocardial ischemia and combined death from cardiovascular causes or nonfatal MI were less frequent in patients who received fluvastatin prior to vascular surgery (hazard ratio [HR] = 0.55, 95% CI: 0.34 – 0.88 and HR = 0.47, 95% CI: 0.24 – 0.94, respectively) [7]. Similarly, the subsequent DECREASE-IV trial found a reduction in the incidence of 30-day cardiac death and MI in patients who received fluvastatin prior to noncardiac surgeries (HR = 0.65, 95% CI: 0.35 – 1.10) [8]. These, and other studies [9], firmly entrenched statin treatment as a tool to reduce cardiovascular risk in patients destined to undergo cardiac and noncardiac surgeries.

However, this fairy tale was soon to meet with a dark twist, as allegations of scientific misconduct in several of the landmark studies led by Don Poldermans at Erasmus Medical Center emerged [10]. Indeed, when examining the body of evidence for the use of statins in noncardiac surgery, one realizes that the majority of the available evidence came from this prolific group. With uncertainty surrounding these crucial data, the evidence supporting the use of statins in noncardiac surgery has become ambiguous. In our published systematic review and meta-analysis that showed benefit of statin use in noncardiac surgery [11], 1,030 of the 1,236 eligible patients came from the DECREASE trials. Excluding these patients produces statistically nonsignificant and clinically attenuated effects in statin-naïve patients who receive perioperative treatment with these agents prior to noncardiac surgery.

In the May edition of the Expert Opinion on Pharmacotherapy, Irwin et al. [12] presented a comprehensive narrative review of the literature delineating the myriad of benefits conferred by statins in patients undergoing cardiac and noncardiac surgeries. While the authors were meticulous in describing the studies and outcomes associated with statin use in many domains, they did not address the proverbial elephant in the room: how do we interpret the existing evidence of statin use in noncardiac surgery given concerns of scientific misconduct? Many of us in the field have deferred judgment on this issue, waiting for the final results of the scientific enquiry committee investigating these concerns [13]. However, it is plausible that we will remain enamored with the statin paradigm, irrespective of the results of this enquiry. As articulated by the authors, the clinical and economic benefits afforded by perioperative statin therapy are compelling reasons for their ongoing use. How may clinicians proceed with management of their patients in this time of uncertainty? We propose three recommendations:

1. First, we must accept the fact that statin treatment in patients undergoing major cardiac and noncardiac vascular surgeries indubitably improves perioperative outcomes [2,6,9,14-16]. The use of statins in this setting is, therefore, not in question. Regardless of cholesterol levels, statin-naïve patients undergoing CABG or high-risk vascular surgery will benefit from high-dose statin treatment. A recent Cochrane review by Liakopoulos et al. involving 984 cardiac surgery patients affirmed this finding, noting that preoperative statins reduced the incidence of postoperative atrial fibrillation (AF) (OR = 0.40, 95% CI: 0.29 – 0.55), intensive care and hospital stay. While the risk of MI was also reduced, this outcome failed to reach statistical significance due to a paucity of events in the eligible studies (OR = 0.52, 95% CI: 0.14 – 1.12) [16].

2. Second, when it comes to the use of statins in noncardiac surgery in general, we advocate a Bayesian perspective when interpreting the available data. Prior and ongoing researches continue to suggest that statins improve perioperative outcomes in noncardiac surgery. In a recent retrospective cohort of 370,447 patients who underwent major noncardiac surgery, statin users had lower rates of postoperative AF following adjustment for patient risk factors and surgery type (OR = 0.79, 95% CI: 0.71 – 0.87) [17]. The benefits conferred by statins, as described by Irwin et al., may also extend beyond cardiovascular risk reduction. In addition to the association with reduced renal injury and AF, statins may also play a role in reducing neurological injury and postoperative infections [14,18]. For these reasons, we recommend continued, cautious use of these agents in high-risk patients undergoing noncardiac surgery until further data are available.

3. Third, we must strive to advance the field by not asking whether statins improve perioperative outcomes but by asking how they may biologically moderate such effects. While the pleiotropic effects of statins on G-protein and non-lipid pathways have long been postulated as being anti-inflammatory and causal to their benefit in this setting, the recently concluded STAR-Vas randomized trial found no incremental effect of statins on perioperative inflammatory markers, thus challenging this assertion [19]. In another recent study, Hinz et al. found that statin treatment also did not produce hemodynamically tangible effects in those undergoing cardiac surgery [20]. Without a proven biological mechanism for its effect, perioperative statin treatment will always be viewed with a skeptical eye, a view we must refocus in the years ahead. Understanding which dose, duration, formulation and dosing strategy are most associated with these outcomes is but a natural part of this enquiry.

Expert opinion

Although some studies have suggested an association between lower lipid levels in critically ill surgical patients and higher mortality rates [21], the benefits of perioperative statin treatment, regardless of baseline lipid levels, have been well documented in the literature. Based on available evidence, we recommend that statin treatment be continued in patients undergoing cardiac surgery or major noncardiac vascular surgery. In noncardiac surgery, in general, use of statins in patients who are deemed to be at high risk of cardiac complications, or those already on statins, appears reasonable despite limitations of the available literature. For all other scenarios, many questions must be answered before evidence-based recommendations can be made. Questions such as how statins improve perioperative outcomes; is there truly a benefit in noncardiac surgery given that a significant proportion of the evidence is enshrouded by allegations of misconduct and whether or not moderate risk, statin-naïve patients should receive statin treatment prior to noncardiac surgery represent but a few of these conundrums. Answers to these questions represent the next frontier of enquiry for this domain. In particular, we believe that investigations specifically examining the effects of statins on patient outcomes and cardiac biomarkers may provide answers to these and other questions [22]. The use of C-reactive protein (or other markers such as B-type natriuretic peptide and members of the interleukin family) to identify patients who might benefit from perioperative statin therapy paired with surgical risk and outcome data offers both a patient- and procedure-oriented approach to statin therapy that can be algorithmically tested and implemented [23]. In our opinion, linkages between molecular biology, pharmacotherapy, risk-prediction and clinical outcomes represent the path that investigations into perioperative statin treatment must take.

Article highlights.

• Statin therapy improves perioperative outcomes in cardiac and noncardiac surgeries.

• Some of the evidence in noncardiac surgery remains in doubt owing to concerns of scientific misconduct.

• Understanding not whether, but how, statins improve outcomes in those undergoing surgery should represent the next frontier in this field.

• Future research in incorporating biomarker and clinical markers may unlock the secrets of perioperative statin treatment.

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.

Notes

This box summarizes key points contained in the article.