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Statins and noncardiac surgery: Current evidence and practical considerations

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ABSTRACT

Vascular surgery is associated with a high risk of peri­operative morbidity and mortality that is partly attributable to inflammatory stress induced by the surgical procedure. Preoperative initiation of a long-acting statin is a strategy intended to reduce the inflammatory stress response and the excess risk associated with vascular surgery. The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III demonstrated significant reductions in perioperative myocardial ischemia and the composite end point of myocardial infarction or cardiovascular death with extended-release fluvastatin (relative to placebo) initiated 30 days prior to vascular surgery. These benefits were achieved with no increase in liver dysfunction, evidence of myopathy, or other side effects. Observational data suggest that perioperative statin use is associated with improved recovery from acute kidney injury after high-risk vascular surgery and with improved long-term survival in patients undergoing such surgery.

KEY POINTS

  • The inflammatory and oxidative stress induced by vascular surgery can be blunted by statin therapy.
  • Statin therapy started preoperatively can reduce the incidence of myocardial ischemia and the level of inflammatory markers in patients undergoing high-risk vascular surgery.
  • The purpose of perioperative statin use should be reduction of the inflammatory stress response to surgery, with the long-term goal being achievement of target lipid levels.
  • A long-acting statin is preferred preoperatively to best extend the anti-inflammatory effects into the postoperative period. Statin therapy should be continued postoperatively, if possible, to avoid deleterious acute withdrawal effects.


 

References

Current uncertainty over the best approach for preventing fatal perioperative myocardial infarction (MI) lies in our inability, despite sophisticated testing methods, to detect unstable coronary plaque prior to surgery. Unstable plaque can be present in patients with coronary lumina that appear normal on coronary angiography. Therefore, reliance on medical therapy to blunt inflammation is currently the best practice for minimizing the risk that unstable plaque poses.

Perioperative use of statins is a cornerstone of such therapy. This article briefly reviews the rationale for perioperative statin use in the setting of noncardiac surgery, presents the latest evidence on the clinical effects of perioperative statin use, and considers the potential role for statins in promoting recovery from acute kidney injury after vascular surgery.

FATAL MI: ORIGINS AND APPROACHES TO RISK REDUCTION

Fatal perioperative MI has two potential origins.1,2 One is a culprit coronary plaque that fissures and ruptures, causing a cascade of thrombogenic events (hemorrhage and thrombosis) inside the vessel wall, culminating in an MI. Less often, fatal perioperative MI results from long-lasting myocardial ischemia (a demand/supply mismatch of oxygen), typically as a consequence of a fixed coronary stenosis.

In nearly half of patients with fatal MI, coronary inflammation is a key contributor. In the perioperative setting, surgical stress induces the release of inflammatory cytokines that disrupt smooth muscle cells in the endothelium and contribute to disruption of a non­obstructing coronary plaque, predisposing to acute thrombus formation.

Risk reduction depends on pathophysiology

Strategies for minimizing the risk of perioperative MI depend on the pathophysiology involved. In the case of oxygen demand/supply mismatch as a result of flow-limiting stenosis, a beta-blocker and coronary revascularization, if possible, may be useful.

In the more common case of unstable plaque, a multifactorial strategy appears optimal, involving the following:

  • Statin therapy to reduce coronary inflammation
  • Aspirin to blunt the prothrombotic milieu postoperatively
  • Chronic low-dose beta-blockade to decrease myocardial oxygen demand or inhibit plaque rupture.

A particular role for statins

Ridker et al found that patients with an acute coronary syndrome who experience a decline in high-sensitivity C-reactive protein (hsCRP) level after treatment with a statin have improved clinical outcomes compared with those whose hsCRP level remains high, regardless of their resultant low-density lipoprotein (LDL) cholesterol level.3

Among surgical patients, those most at risk for poor cardiovascular outcomes are those who undergo vascular surgery. In Europe, the cardiovascular death rate in such patients is approximately 2%.4

Retrospective cohort data and data from randomized clinical trials have demonstrated reductions in perioperative cardiac complications with statin use in patients undergoing various types of noncardiac vascular surgery.5–9 In light of these data, my colleagues and I recently undertook a prospective study to examine the effect of perioperative statin use on cardiovascular complications in patients undergoing vascular surgery.10 Key details and findings are surveyed in the following section.

DECREASE III: PROSPECTIVE EVIDENCE FOR ISCHEMIC BENEFIT FROM PERIOPERATIVE STATINS

The Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo III (DECREASE III) was conducted at a single center (Erasmus Medical Center, Rotterdam, the Netherlands) in a randomized, double-blind, placebo-controlled manner.10

Patients and study design

The study population included 497 statin-naïve patients who were scheduled for one of four noncardiac vascular surgical procedures (repair or revascularization for abdominal aortic aneurysm, abdominal aortic stenosis, lower limb arterial stenosis, or carotid artery stenosis). Patients with unstable coronary artery disease or left main disease were excluded.

Patients were randomized to placebo or extended-release fluvastatin (80 mg/day) starting on the day of randomization, which was a median of 37 days before surgery. Treatment was continued until 30 days after surgery.

Extended-release fluvastatin was chosen because its long half-life permits a bridge to the early postoperative period, during which oral medications are not permitted in patients undergoing high-risk vascular surgery.

The primary end point was the occurrence of myocardial ischemia as assessed by three methods:

  • Holter monitoring during the first 72 postoperative hours
  • Measurement of troponin T on days 1, 3, 7, and 30
  • Additional electrocardiographic recordings on days 7 and 30.

The secondary end point was a composite of cardio­vascular death and nonfatal MI during the first 30 postoperative days.

Baseline characteristics were similar between the two randomized groups, with a median age approaching 66 years. About three-fourths of the patients were male, one-fourth had a history of MI, one-fourth had angina pectoris, one-fifth had diabetes mellitus, and nearly 30% had a history of cerebrovascular accident or transient ischemic attack.

All patients were being treated with a beta-blocker, about 60% with antiplatelet therapy, more than one-fourth with anticoagulant therapy, nearly half with either an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and more than one-fourth with diuretics. There were no significant differences between the groups in the proportion of patients on each of these therapies.

Results: Reductions in inflammatory markers

Baseline levels of hsCRP and interleukin-6 (IL-6) were comparable between the groups. In patients randomized to placebo, the hsCRP level increased by 3%, from a median of 5.80 mg/L at randomization to 6.00 mg/L immediately prior to surgery. In contrast, the hsCRP level in patients randomized to extended-release fluvastatin decreased by 21%, from a median of 5.93 mg/L to 4.66 mg/L. The between-group difference in the change in hsCRP level was statistically significant (P < .001). There was also a significantly greater reduction from baseline in median level of IL-6 among fluvastatin recipients compared with placebo recipients (–33% vs –4%; P < .001).

The specificity of hsCRP for cardiac inflammation is not yet known, but measures of hsCRP and IL-6 can provide a fingerprint of inflammatory activity prior to surgery. Other inflammatory and noninflammatory markers are being investigated to better identify (prior to surgery) those high-risk patients most likely to benefit from perioperative statin use.

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