Soon, the checklist for internists seeing patients about to undergo surgery may include prescribing one of the lipid-lowering hydroxymethylglutaryl-CoA reductase inhibitors, also called statins.
Statins? Not long ago, we were debating whether patients who take statins should stop taking them before surgery, based on the manufacturers’ recommendations.1 The discussion, however, has changed to whether patients who have never received a statin should be started on one before surgery to provide immediate prophylaxis against cardiac morbidity, and how much harm long-term statin users face if these drugs are withheld perioperatively.
The evidence is still very preliminary and based mostly on studies in animals and retrospective studies in people. However, an expanding body of indirect evidence suggests that these drugs are beneficial in this situation.
In this review, we discuss the mechanisms by which statins may protect the heart in the short term, drawing on data from animal and human studies of acute myocardial infarction, and we review the current (albeit limited) data from the perioperative setting.
FEW INTERVENTIONS DECREASE RISK
Each year, approximately 50,000 patients suffer a perioperative cardiovascular event; the incidence of myocardial infarction during or after noncardiac surgery is 2% to 3%.2 The primary goal of preoperative cardiovascular risk assessment is to predict and avert these events.
But short of canceling surgery, few interventions have been found to reduce a patient’s risk. For example, a landmark study in 2004 cast doubt on the efficacy of preoperative coronary revascularization.3 Similarly, although early studies of beta-blockers were promising4,5 and although most internists prescribe these drugs before surgery, more recent studies have cast doubt on their efficacy, particularly in patients at low risk undergoing intermediate-risk (rather than vascular) surgery.6–8
This changing clinical landscape has prompted a search for new strategies for perioperative risk-reduction. Several recent studies have placed statins in the spotlight.
POTENTIAL MECHANISMS OF SHORT-TERM BENEFIT
Statins have been proven to save lives when used long-term, but how could this class of drugs, designed to prevent the accumulation of arterial plaques by lowering low-density lipoprotein cholesterol (LDL-C) levels, have any short-term impact on operative outcomes? Although LDL-C reduction is the principal mechanism of action of statins, not all of the benefit can be ascribed to this mechanism.9 The answer may lie in their “pleiotropic” effects—ie, actions other than LDL-C reduction.
The more immediate pleiotropic effects of statins in the proinflammatory and prothrombotic environment of the perioperative period are thought to include improved endothelial function (both antithrombotic function and vasomotor function in response to ischemic stress), enhanced stability of atherosclerotic plaques, decreased oxidative stress, and decreased vascular inflammation.10–12
EVIDENCE FROM ANIMAL STUDIES
Experiments in animals suggest that statins, given shortly before or after a cardiovascular event, confer benefit before any changes in LDL-C are measurable.
Lefer et al13 found that simvastatin (Zocor), given 18 hours before an ischemic episode in rats, blunted the inflammatory response in cardiac reperfusion injury. Not only was reperfusion injury significantly less in the hearts of the rats that received simvastatin than in the saline control group, but the simvastatin-treated hearts also expressed fewer neutrophil adhesion molecules such as P-selectin, and they had more basal release of nitric oxide, the potent endothelial-derived vasodilator with antithrombotic, anti-inflammatory, and antiproliferative effects.14 These results suggest that statins may improve endothelial function acutely, particularly during ischemic stress.
Osborne et al15 fed rabbits a cholesterol-rich diet plus either lovastatin (Mevacor) or placebo. After 2 weeks, the rabbits underwent either surgery to induce a myocardial infarction or a sham procedure. Regardless of the pretreatment, biopsies of the aorta did not reveal any atherosclerosis; yet the lovastatin-treated rabbits sustained less myocardial ischemic damage and they had more endothelium-mediated vasodilatation.
Statin therapy also may improve cerebral ischemia outcomes in animal models.14,16
Sironi et al16 induced strokes in rats by occluding the middle cerebral artery. The rats received either simvastatin or vehicle for 3 days before the stroke or immediately afterwards. Even though simvastatin did not have enough time to affect the total cholesterol level, rats treated with simvastatin had smaller infarcts (as measured by magnetic resonance imaging) and produced more nitric oxide.
Comment. Taken together, these studies offer tantalizing evidence that statins have short-term, beneficial nonlipid effects and may reduce not only the likelihood of an ischemic event, but—should one occur—the degree of tissue damage that ensues.