Does the use of statins improve outcomes in coronary artery bypass graft surgery?

Abstract

Statins (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) are one of the most frequently prescribed medications throughout the world with beneficial effects that extend beyond their lipid-lowering activity. It has been suggested that statins may offer a simple and cost-effective strategy to reduce some of the complications that occur in association with coronary artery bypass graft (CABG) surgery. Limited existing randomized trial evidence in the setting of cardiac surgery suggests that statins may reduce the incidence of postoperative atrial fibrillation. However, any effect of statins on other outcomes is less clear. The clinical significance of specific statin agent and dose, acute statin withdrawal and the potential benefits associated with statin reloading remain important yet currently unresolved issues. Despite limited high-quality evidence, class I recommendations have been made that all patients undergoing coronary artery bypass graft surgery should receive statin therapy unless contraindicated.

KEYWORDS:

• anesthesia
• cardiovascular
• evidence
• outcome
• surgery

Coronary artery bypass graft (CABG) surgery remains a common surgical procedure, performed in almost 400,000 patients per year in the United States alone. (http://www.cdc.gov/nchs/fastats/inpatient-surgery.htm). Operative mortality after CABG and other cardiac surgery is approximately 2–5%, and less than 1% in low-risk elective cases.[1] However, other complications occur more frequently and are associated with significant disability and increased cost, including atrial fibrillation (AF), myocardial infarction (MI), acute kidney injury (AKI), delirium and stroke.[2–5] Simple and cost-effective strategies to reduce this postoperative burden are urgently required but remain elusive.

The rationale for statins

The 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (“statins”) are one of the most frequently prescribed medications throughout the world.[6] Large studies in the community setting confirm their effectiveness at reducing elevated total cholesterol levels through a reduction in the low-density lipoprotein (LDL) fraction as well as a long-term reduction in mortality and other adverse cardiovascular outcomes.[7–10] Although full lipid-lowering effects may take 4–6 weeks to occur, most of the effect is apparent within 2 weeks of commencing therapy.[11]

Interestingly, the beneficial effects of statins extend beyond their long-term lipid lowering activity.[12] Lipid-independent (pleiotropic) effects may occur within hours of initiation of statins and are thought to include reduced oxidative stress and inflammation, vasodilation, improved endothelial function, enhanced stability of atherosclerotic plaques through modulation of macrophage activation and inhibition of thrombogenesis, as well as effects on the immune system and CNS.[11]

Randomized trial evidence supports a reduction in periprocedural MI with statin administration even when commenced 24 h before percutaneous coronary intervention.[13] However, extrapolating findings from nonsurgical studies to the operative setting may not be appropriate, [14,15] and although statins are generally well tolerated and safe, they do have well-documented adverse effects that may be amplified in elderly patients receiving multiple medications.[16] This highlights the importance of evaluating the evidence for statin therapy within the context of cardiac surgery rather than relying on indirect evidence or hypothetical benefits to guide practice.

The evidence for statins

Since the first study evaluating the effects of statin therapy before CABG surgery was published in 1999, at least 12 further randomized trials, many more observational studies, meta-analyses and a Cochrane systematic review have been conducted in an attempt to clarify the effect of statins in the cardiac surgery setting.

A large meta-analysis combining observational studies and randomized trials of statin therapy in more than 30,000 patients undergoing cardiac surgery noted reduced all-cause mortality (odds ratio (OR): 0.57; 95% CI: 0.49–0.67; p < 0.0001), postoperative AF (OR: 0.67; 95% CI: 0.51–0.88; p = 0.004) and stroke (OR: 0.74; 95% CI: 0.60–0.91; p = 0.004) among patients receiving preoperative statin therapy, but no change in risk of MI or renal failure.[17]

A subsequent Cochrane review that included 11 randomized trials in 984 participants undergoing (predominantly) CABG surgery[3] found that statins reduced the incidence of AF (OR: 0.40; 95% CI: 0.29–0.55) and led to a shorter intensive care unit (weighted mean difference, −3.39 [95% CI: −5.77 to −1.01] h) and hospital (weighted mean difference, −0.48 [95% CI: −0.85 to −0.11] days) stay, but no difference in mortality, MI, stroke or renal failure.

More recently, a pooled analysis of 54 studies including more than 90,000 patients undergoing any type of cardiac surgery found a 31% reduction in odds for short-term mortality (OR: 0.69; 95% CI: 0.59–0.81; p < 0.0001) in patients receiving preoperative statins.[18] However, this effect was lost when the analysis was restricted to randomized trials only (OR: 0.98; 95% CI: 0.14–7.10).

Other outcomes

Brunelli et al. examined the relationship between preoperative statin exposure and postoperative AKI in a retrospective analysis of more than 98,000 patients from two institutions undergoing major vascular, abdominal, thoracic and cardiac surgical procedures over a 10-year period.[19] While they found a 20–26% reduction in renal injury that remained consistent across AKI definitions, baseline renal function and diabetic status, any benefit appeared markedly attenuated in patients undergoing cardiac surgery.

It has been speculated that the pleiotropic properties of statins may provide a neuroprotective effect for patients undergoing cardiac surgery.[20] However, a small observational study failed to show any cognitive-sparing effect of statins nor any reduction in neuroinflammatory biomarkers.[21] Additional observational studies are conflicting regarding an association between statins and postoperative delirium, with one study reporting a 46% reduction in postoperative delirium after cardiac surgery [20]while a large observational study of patients undergoing a mix of cardiac and noncardiac surgery found preoperative statin therapy associated with an increased risk for postoperative delirium. Systematic reviews in the nonsurgical setting do not support a significant effect of statins on cognitive function.[22,23]

A protective association between statin therapy and infectious complications has been suggested by some observational studies, but not others. A meta-analysis [24] of six cohort studies of patients undergoing cardiac surgery failed to confirm such an association (OR: 0.81; 95% CI: 0.64–1.01).

A large randomized trial of rosuvastatin, 20 mg or placebo, administered to apparently healthy men and women found statins reduced the risk of venous thromboembolic disease by 43% (hazard ratio: 0.57; 95% CI: 0.37–0.86; p = 0.007) over a median follow-up of 1.9 years.[25] Subsequent meta-analyses addressing this question have produced conflicting results.[26,27] However, included studies appear largely based in the nonsurgical or outpatient setting and there are no studies specifically addressing this outcome in the context of cardiac surgery.

Statins appear to be generally safe when used in a critical care population.[28]

The effect of statin withdrawal

The absence of any parenteral formulation of statin therapy creates perioperative challenges for continued administration in the setting of major surgery. Acute statin withdrawal at the time of surgery, with or without a failure to recommence statin therapy postoperatively, may contribute to the observed risk–benefit profile reported with perioperative statin therapy.[29,30] However, confounding by indication, where patients experiencing a good postoperative recovery are able to recommence oral intake earlier than those patients with a more complicated postoperative course, cannot be ruled out. Nevertheless, preoperative statins with extended release formulations may be useful to minimize the period where a statin effect is absent.

Specific statin, dose and duration

Subgroup effects likely exist for both duration and type of statin therapy used.[31] Stratifying statins as either high-potency (atorvastatin and rosuvastatin) or low-potency (fluvastatin, pravastatin and simvastatin) according to their effectiveness in reducing LDL-cholesterol (LDL-C) levels suggests reduced mortality and MI with low-potency statins and reduced AF and hospital length of stay with high-potency statins.

A meta-regression analysis of randomized trials of preoperative statin therapy in cardiac surgery [32] found an increasing effect size for the reduction of AF with earlier preoperative exposure to statins (3% increase per day; p = 0.008) but no association between statin dose and risk of AF. Similarly, a single-center observational study of more than 2100 patients undergoing cardiac surgery failed to find a difference in effect between high-dose and low-dose statin therapy on postoperative AKI.[33]

Contrasting this, emerging data have recently highlighted the concept of statin-reloading in chronic statin users. In a rat model, statin-mediated cardioprotection may wane when statins are initiated more than a week prior to infarct, but can be recaptured by an acute high-dose reloading with atorvastatin 3–4 h prior to injury.[34] Such a phenomenon is supported by the ARMYDA-RECAPTURE study [35] in which 383 patients undergoing percutaneous coronary intervention for stable angina or non-ST segment elevation acute coronary syndromes and receiving chronic statin therapy were randomized to receive an atorvastatin reload (80 mg 12 h prior to intervention and a further 40 mg preprocedural dose) or placebo. Atorvastatin reloading was associated with a marked reduction (adjusted OR: 0.50; 95% CI: 0.20–0.80; p = 0.039) in 30-day incidence of major adverse cardiac events. However, such a concept has not been evaluated in the context of cardiac surgery.

Limitations, uncertainties, current recommendations and practice

Statin therapy prior to CABG surgery appears to reduce the incidence of postoperative AF. However, other outcome benefits are less clear. To date, randomized trial data are limited to approximately 1000 patients in total, adding to the uncertainty. Despite limited high-quality evidence for the role of statins in patients undergoing cardiac surgery, the current American College of Cardiology Foundation/American Heart Association Practice Guideline for CABG surgery provides a class I recommendation that all patients undergoing CABG surgery should receive statin therapy unless contraindicated, targeting an LDL level less than 100 mg/dl and at least 30% reduction in LDL-C level, with reintroduction of therapy postoperatively.[36] However, recent estimates suggest that less than 65% of patients undergoing isolated primary CABG surgery in the United States receive statin therapy preoperatively.[37] The equivalent European guideline makes no specific recommendation on the perioperative use of statins. Although perioperative statin therapy appears safe in most circumstances, complete adverse event reporting is unlikely to have occurred in most of the aforementioned studies.

The future

High-quality evidence to guide many aspects of perioperative statin therapy in patients undergoing CABG surgery is lacking. Intensive research efforts should be directed toward high-quality large randomized trials designed to resolve issues of efficacy, risk and cost–benefit, as well as addressing the role of statin reloading and preoperative dose and duration to obtain maximal benefit.

Financial and competing interests disclosure

D. McIlroy has received grant funding from the Australia & New Zealand College of Anaesthetists and the Society of Cardiovascular Anesthesiologists/International Anesthesia Research Society for projects unrelated to the current manuscript. P. Myles is funded by an Australian National Health and Medical Research Council (NH & MRC) Practitioner Fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Notes on contributors

David R. McIlroy

Paul S. Myles