Perioperative Statin Therapy Research Articles

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

Charles D. Collard, MD 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 -blockers into the operative setting (6). However, unlike the situation with perioperative -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, calciumchannel 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 From the Division of Cardiovascular Anesthesiology, Baylor College of Medicine, Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston, Texas. Accepted for publication March 6, 2007. Address correspondence to Charles D. Collard, MD, Baylor College of Medicine, Texas Heart Institute, St. Luke’s Episcopal Hospital, 6720 Bertner Ave., Houston, TX 77030. Address e-mail to ccollard@heart.thi. tmc.edu. Copyright © 2007 International Anesthesia Research Society

Statins and perioperative myocardial infarction

The growing prevalence of atherosclerosis means that perioperative myocardial infarction (PMI) is of significant concern to anesthesiologists. Perioperative revascularization (if indicated medically), beta blockade (in high risk patients) and statin therapy are therapeutic modalities that are currently employed to reduce PMI. Statins not only lower low density lipoprotein levels but, via their actions on the isoprene pathway, exhibit pleiotropic effects. Statins stabilize vulnerable plaque, predominantly via their anti-inflammatory effects, and improve the functioning of the endothelium in atherosclerosis. These effects appear to reduce the perioperative complications of atherosclerotic lesions. It is important to have an understanding of newer developments in the pathophysiology of atherosclerosis to be able to appreciate the mechanisms of action of statins. The focus has changed from identification of stenotic coronary lesions to the identification of vulnerable plaque. This review is divided into 2 parts. The first part focuses on the pathophysiology of atherosclerosis. The second part will be published in a later issue and will discuss the pharmacology of statins and the mechanisms whereby they may reduce the incidence of PMI.

Non-antiarrhythmic agents for prevention of postoperative atrial fibrillation: role of statins

Atrial fibrillation is the most common arrhythmia following cardiac surgery, having both serious medical and socioeconomic consequences. Although there are established antiarrhythmic agents for preventing and treating postoperative atrial fibrillation, these therapies are neither 100% reliable, nor without risks and limitations. Thus, there remains a strong need for non-antiarrhythmic, adjunctive therapies for the prevention of postoperative atrial fibrillation. Long-term statin administration in ambulatory patients is associated with a reduced risk of adverse cardiovascular events, including death, myocardial infarction, stroke, renal dysfunction and atrial fibrillation. Recent evidence suggests, however, that statins may also reduce the risk of acute adverse outcomes following invasive procedures, including postoperative atrial fibrillation. Although the exact mechanisms by which statins may reduce postoperative atrial fibrillation are unclear, accumulating evidence suggests that statins exert multiple effects independent of their effect on LDL cholesterol. For example, in patients with acute coronary syndromes, statin therapy has been shown to modulate remodeling of the cardiac extracellular matrix and to reduce markers of inflammation, including C-reactive protein, serum amyloid A, tumor necrosis factor-alpha, and IL-6. Perioperative statin therapy may represent an important non-antiarrhythmic, adjunctive therapeutic strategy for the prevention of postoperative atrial fibrillation.

Le rôle des statines dans la réduction du risque cardiaque périopératoire : perspectives physiologiques et cliniques

To review the pathobiology and clinical implications of coronary vulnerable atherosclerotic plaques (VAPs), to discuss the role of statin therapy in VAP stabilization, and the potential benefits of perioperative statin therapy (PST) in reducing perioperative risk of acute coronary syndromes (ACSs). MEDLINE search using "perioperative", "cardiac morbidity", "atherosclerosis", "vulnerable plaque", "statins" and combinations of these terms as keywords. The reference lists of relevant articles were further reviewed to identify additional citations. The nonstenotic, yet rupture-prone VAP causes most myocardial infarctions (MIs) and other ACSs, both in the nonsurgical and surgical patients. Large clinical trials in both primary and secondary prevention and in patients with ACSs have demonstrated that statin therapy will reduce cardiovascular morbidity and mortality across a broad spectrum of patient subgroups. These trials also suggest, and laboratory investigations establish, that statins possess favourable vascular effects independent of cholesterol reduction. Statins appear to interfere specifically with the pathophysiologic mechanisms implicated in atherothrombotic disease. Statins reduce vascular inflammation, improve endothelial function, stabilize VAPs, and reduce platelet aggregability and thrombus formation. Recent studies have shown that PST is associated with a reduced incidence of perioperative and long-term cardiovascular complications in high-risk patients. Combined therapy with statins and ss-blockers is a conceptually valid strategy targeting critical steps in the pathogenesis of an ACS. Emerging evidence for the efficacy and safety of PST is promising, especially when combined with ss-blocker therapy in patients at highest risk. Confirmation of this early evidence awaits the results of ongoing and future prospective randomized controlled trials.

The pharmaco-economics of peri-operative beta-blocker and statin therapy in South Africa.

We conducted a pharmaco-economic analysis of the prospective peri-operative studies of beta-blocker and statin administration for major elective non-cardiac surgery, using the Discovery Health claims costs for 2004. This analysis shows that acute peri-operative beta-blockade and statin therapy could result in a cost saving through a reduction in major perioperative cardiovascular complications in patients with an expected peri-operative major cardiovascular complication rate exceeding 10% following elective major non-cardiac surgery. The validity of these findings is dependent on whether the incidence of cardiovascular complications following major noncardiac surgery reported in the international literature is found to be similar in South Africa.

Beneficial effects of statins on perioperative cardiovascular outcome

This review evaluates clinical and experimental articles that have recently been published on the cardioprotective effect of perioperative statin therapy. Perioperative statin therapy improves short and long-term cardiac outcome following noncardiac surgery. This cardiovascular protection has been attributed to the so-called pleiotropic effects, which have a positive effect on plaque stability. With no clinical studies reporting an increased incidence of adverse effects of perioperative statin use, it appears to be a safe and helpful therapeutic option. Perioperative statin therapy may stabilize coronary plaques due to pleiotropic effects and results in a reduction of perioperative cardiovascular complications.

Statins in the intensive care unit

Statins are effective lipid-lowering agents used extensively in medical practice. This review summarizes the evidence for statin treatment of cardiovascular patients in the intensive care unit and briefly discusses the role of statins in prevention and treatment of sepsis as a potential future application of statins in critical care. Recent studies have extended the use of statin therapy to the acute manifestations of cardiovascular disease and have suggested cholesterol-independent therapeutic benefits, termed pleiotropic effects, which have added a wide scope of potential targets for statin therapy. Statin therapy should be continued in intensive-care patients in whom statin therapy is warranted due to underlying cardiovascular disease or significant risk thereof. In acute coronary syndromes, statin therapy should be initiated within 24-96 h regardless of pretreatment cholesterol levels. Patients undergoing vascular surgery should receive peri-operative statin therapy. Placebo-controlled clinical trials are required to consolidate the experimental and observational evidence for prevention and treatment of sepsis.

The diabetic surgical patient

This review summarizes the current progress in disease classification, pathophysiology and management of diabetes mellitus with a special focus on treatment modalities and recommendations for the practicing anesthesiologist. The revised classification of diabetes mellitus emphasizes disease cause and eliminates any reference to age-of-onset and insulin therapy. Hyperglycemia has emerged as an important marker of outcome in the operating room. Intensive insulin therapy promises to reduce health risk in the surgical and critical care setting. Perioperative beta-blocker and statin therapy are likely to reduce cardiac morbidity and mortality in diabetic patients. Promotility therapy (with metoclopromide) intended to reduce the aspiration risk of diabetic gastroparesis is likely over-utilized and may only be indicated for diabetics with poor glucose control and high hemoglobin A1c levels. According to World Health Organization projections, anesthesiologists can expect to care for more diabetic patients than ever before. Diabetes and its associated complications present unique challenges to the perioperative physician. As biomedical research continues to unravel the genetic, cellular and molecular mechanisms of this complex metabolic disease, our specialty must be prominently involved in the design and testing of innovative treatments to protect the diabetic patient from the risks of surgery and anesthesia.

The pharmacoeconomics of peri‐operative beta‐blocker therapy

It is widely recommended that beta-blockade be used peri-operatively as it may reduce the incidence of postoperative cardiovascular complications including death. However, there are few data concerning the cost-effectiveness of such strategies. We have analysed the pharmacoeconomics of acute beta-blockade using data from eight prospective peri-operative studies in which patients underwent elective non-cardiac surgery, and in which the incidence of adverse side-effects of treatment, as well as clinical outcomes, have been reported. The costs of treatment were based on the NHS reference costs for 2004. From these data, the number-needed-to-treat (NNT) to prevent a major cardiovascular complication (including cardiovascular death) in high-risk patients was 18.5. This is comparable to the NNT for peri-operative statin therapy. The incremental cost of peri-operative beta-blockade (costs of drug acquisition and of treating associated adverse drug events) was 67.80 pounds sterling per patient. This results in a total cost of 1254.30 pounds sterling per peri-operative cardiovascular complication prevented. However, there is evidence that in patients at lower cardiovascular risk, beta-blockers may be potentially harmful, since their adverse effects (hypotension, bradycardia) may outweigh their potential cardioprotective effects.

The pharmaco‐economics of peri‐operative statin therapy

We analysed the pharmaco-economics of the prospective peri-operative studies of statin administration for major elective vascular surgery, using the NHS reference costs for 2004. This analysis suggests that peri-operative statin therapy for patients undergoing vascular surgery may present the most cost-effective use of statin therapy yet described, with a number-needed-to-treat of 15 and almost 60% of the total cost of atorvastatin therapy recovered through a reduction in peri-operative adverse events.

Statin therapy: a potentially useful peri‐operative intervention in patients with cardiovascular disease

Statin cardiovascular protection is mediated by lipid lowering and pleiotropic effects. The efficacy of statins has been established in non-surgical patients with cardiovascular disease and also more recently in non-surgical patients who sustain an acute coronary event. Peri-operative statin administration has been shown to improve both short-term and long-term cardiac outcome following non-cardiac and coronary bypass graft surgery. This cardioprotection may be independent of peri-operative haemodynamics due to a positive effect on plaque stability. Recommendations for the peri-operative statin administration are suggested. These include indications for peri-operative statin therapy, timing of administration, therapeutic targets, duration of administration, the adverse implications of peri-operative statin withdrawal, safety and cost-effectiveness.

Stopping Statins

Stopping Statins