Perioperative Statin Therapy: Are Formal Guidelines and Physician Education Needed?

Abstract

In this issue of Anesthesia & Analgesia, Le Manach et al. add to the growing evidence that perioperative statin therapy reduces surgical morbidity and mortality (1–6). Moreover, data from these same authors and others suggest that postoperative discontinuation of statin therapy is associated with worsened cardiac outcomes after major cardiovascular surgery (1,2). Thus, administration of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or “statins,” may be one of the most important perioperative therapeutic regimens to reduce the risk of postoperative cardiovascular complications in high-risk surgical patients since the introduction of β-blockers into the operative setting (6). However, unlike the situation with perioperative β-blocker therapy, the American College of Cardiology/American Heart Association Task Force on Practice Guidelines have yet to publish a consensus statement regarding perioperative statin therapy. Current National Cholesterol Education Program Adult Treatment Panel guidelines recommend decreasing LDL levels to <100 mg/dL in patients with known coronary disease, and more aggressive statin therapy to decrease LDL levels to <70 mg/dL in patients with coronary disease and high risk factors such as diabetes, hypertension, obesity, smoking, the metabolic syndrome, and acute coronary syndromes (ACS) (7). Thus, on the basis of these guidelines, most patients undergoing major cardiovascular surgery would qualify for statin therapy. Yet, despite these guidelines, it is estimated that up to two-thirds of eligible candidates may not be receiving statin therapy at hospital discharge (8). Explanations for not starting or reinitiating statin therapy after cardiovascular surgery may include patients’ decreased tolerance of oral medications secondary to nausea and vomiting, transient renal dysfunction, concerns pertaining to hepatic toxicity or myositis, or failure of the responsible physician to reimplement preoperative medications. The most serious potential statin side effect is rhabdomyolysis. Cerivastatin, which is no longer on the market, carried the greatest risk of this complication (3.16 per million prescriptions). In contrast, the risk of statin-induced rhabdomyolysis ranges only from 0 to 0.19 per million prescriptions for the other commonly used statins (9). Furthermore, the risk for rhabdomyolysis is associated with factors that increase serum statin concentrations, such as small body size, advanced age, renal or hepatic dysfunction, diabetes, hypothyroidism, and drugs that interfere with statin metabolism, such as cyclosporin, antifungal drugs, calcium-channel blockers, and amiodarone (9). When this small risk is compared with the incidence and socioeconomic cost of cardiac perioperative morbidity and mortality after major cardiovascular surgery, the benefits of statin therapy seem to largely outweigh any potential risks in the vast majority of patients. Moreover, in a recent study by Schouten et al., perioperative statin use in a large group of patients was not associated with an increased risk of perioperative myopathy or increased creatine phosphokinase levels after major vascular surgery (10). Indeed, after correcting for cardiac risk factors and clinical risk factors for myopathy, length of surgery remained the only independent predictor for myopathy (10). No case of rhabdomyolysis was observed, and there was no difference in creatine phosphokinase levels between patients on long-term statin therapy and patients who started statin therapy shortly before surgery (10). Although statins are potent inhibitors of cholesterol biosynthesis and have been shown to stabilize preexisting “vulnerable” atherosclerotic plaques at high risk for rupture, increasing evidence suggests that their beneficial effects are not limited to patients with hypercholesterolemia. For example, statin administration may reduce morbidity and mortality even in individuals with normal or only moderately elevated LDL levels (11). Although the exact mechanisms by which statins reduce the likelihood of cardiovascular events have yet to be fully elucidated, the metabolite of 3-hydroxy-3-methylglutaryl coenzyme A reductase, mevalonic acid, is a precursor of the cholesterol and the isoprenoid intermediates farnesyl and geranylgeranyl pyrophosphate. These intermediates are essential for the posttranslational modification of intracellular G-proteins, such as Rho, Rac, and Ras, that regulate endothelial, platelet, and leukocyte function (12). Statins have also been shown to modulate vascular remodeling by inhibiting cellular matrix metalloproteinases and transcription factors, such as nuclear factor-κB (12). In patients with ACS or idiopathic dilated cardiomyopathy, statin therapy has been shown to reduce untoward inflammatory activity, including changes in C-reactive protein, serum amyloid A, tumor necrosis factor-α, interleukin-6, and brain natriuretic peptide levels (13). Furthermore, statins attenuate vasoconstriction by increasing endothelial nitric oxide activity, a benefit seen within 6 wk of the start of treatment (14). Statins thus exert pleiotropic effects, independent of cholesterol reduction, which have direct antiatherosclerotic, antithrombotic, and antiinflammatory impact (12). However, a number of important questions remain regarding perioperative statin therapy. For example, when should preoperative statins be started and at what dose? Additionally, should statins be used in conjunction with perioperative β-blocker therapy? The answer to these questions might be found in the results of the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo-IV (DECREASE-IV) Trial, a 4-yr, prospective, randomized study scheduled for completion in 2008 (6,15). The general objective of the DECREASE-IV Trial is to assess the clinical efficacy of β-blocker, statin, and combination therapy in patients undergoing major noncardiac surgery. To be included in this trial, patients have to: 1) be ≥40 years old (2); 2) be scheduled for elective noncardiac surgery (3) and 3) have an estimated risk for cardiovascular death of more than 1%. Importantly, patients who have previously used statins or β-blockers are excluded from the study. After enrollment, subjects are started on the study medication (i.e., statin, β-blocker, both, or placebo) within 0-30 days b surgery, and continued until 30 days after surgery. Hopefully, the results of the DECREASE-IV trial should further clarify the role of perioperative statin and β-blocker therapy in patients undergoing major, elective noncardiac surgery. What about patients with ACS who require urgent or emergent surgery and in whom statin therapy can only be initiated <24 h before surgical intervention? Although data are limited, a recent meta-analysis of 300,823 patients hospitalized for an acute myocardial infarction (MI) showed that initiation of statin therapy within 24 h of the infarction was associated with significantly lower mortality (15.4% vs 4.0%) (16). Additionally, there was a lower incidence of cardiogenic shock, arrhythmias, cardiac arrest, and rupture (16). Moreover, acute discontinuation of statins in ambulatory patients with ACS has been shown to increase the risk of adverse cardiovascular outcomes. Heeschen et al. demonstrated, in ambulatory patients experiencing ACS, that administration of statin therapy prior to the onset of symptoms was associated with a reduced incidence of 30-day all-cause mortality and nonfatal MI compared to patients not receiving statins (adjusted OR 0.49, 95%; CI 0.21-0.86; P = 0.004) (17). Moreover, the incidence of 30-day all-cause mortality and nonfatal MI was significantly increased when statin therapy was withdrawn compared to patients who continued to receive statins (adjusted OR 2.93, 95%; CI 1.64-6.27; P = 0.005). Statin therapy was also shown to be less effective in reducing the risk of death or nonfatal MI when initiated after the presentation of an ACS, compared with pretreatment prior to the onset of symptoms (14% vs 51% relative risk reduction). Together, these data are consistent with the surgical results of Le Manach et al. and others suggesting that postoperative discontinuation of statin therapy is associated with an increased risk of cardiac morbidity (1,2). In summary, there is a growing body of evidence that supports the use of perioperative statin therapy in patients with known coronary disease undergoing major cardiovascular surgery. Despite the current National Cholesterol Education Program Adult Treatment Panel guidelines recommending statin therapy in patients with known coronary disease, many patients presenting for surgery are not started on statins, or have their statin therapy discontinued in the postoperative period. Thus, there remains a strong need for formal practice guidelines regarding perioperative statin therapy, and continuing physician education about the potential benefits of continuing statin therapy throughout the perioperative period.