In a retrospective analysis of smokers admitted with acute coronary syndromes, transdermal nicotine therapy was not associated with an increased risk of mortality.308 On the other hand, in a retrospective analysis of smokers hospital- ized during CABG, nicotine replacement therapy was asso- ciated with an increased mortality rate after adjustment for Both of these studies were limited by their observational design and specifically by the biases associated with the use of nicotine replacement therapy such as the degree of prior smoking. As a result, prospective studies are needed to determine the safety of using nicotine replace- ment therapy in patients with acute cardiovascular disease. At this time, judicious use and dosing of nicotine replacement therapy are recommended for patients admitted to hospital with an acute cardiovascular event. In addition to nicotine replacement medications, bupropion and varenicline can be effective adjuncts to smoking cessa- tion strategies, and their use has been supported by the US Public Health Service.305 Bupropion is generally well toler- ated and has been shown to be safe to use in the immediate period after MI.310,311 Among 629 patients with cardiovas- cular disease, a 7-week treatment with bupropion resulted in twice as many smokers quitting at 1 year compared with Varenicline has also been shown to be effective in reducing rates of smoking.313,314 In a randomized, placebo- controlled trial of 714 smokers with stable cardiovascular disease, varenicline was effective at reducing rates of smok- Based on data from this trial, however, the US Food and Drug Administration issued an advisory that varenicline may increase the risk of adverse cardiovascular events on the basis of statistically nonsignificant increases in the rates of nonfatal MI, coronary revascularization, and new peripheral vascular disease in this trial population.315 Although the car- diovascular risk profile of varenicline remains unsettled, the long-term benefits of smoking cessation far outweigh any potential adverse effects with varenicline. Therefore, it should still be carefully considered as a possible medication to assist in smoking cessation for patients with cardiovascular disease. During the process of smoking cessation, patients may face many potential obstacles to achieving their goal. They may struggle with high dependence on nicotine, severe withdrawal problems, low self-confidence, poor social support, weight gain, comorbid psychiatric illnesses, and suboptimal use of Addressing each of these issues as they arise is critical to achieving smoking cessation. In addition, criti- cal evaluation of the helpful and unhelpful aspects of prior attempts at smoking cessation can guide the development of revised and more effective treatment plans. Even among those smokers who have initial success, it is important to remain focused on these issues because most smokers try quitting several times before they finally achieve durable success.316 Ultimately, successful smoking cessation strategies require a long-term disease management approach to achieve perma- nent abstinence. Smoking Cessation Recommendations 1. Smoking cessation is critical, and counseling should be offered to all patients who smoke, during and after hospitalization for CABG, to help improve both short- and long-term clinical outcomes after surgery (Class I; Level of Evidence A). 2. It is reasonable to offer nicotine replacement therapy, bupropion, and varenicline as adjuncts to smoking cessation counseling for stable CABG patients after hospital discharge (Class IIa; Level of Evidence B). 3. Nicotine replacement therapy, bupropion, and var- enicline may be considered as adjuncts to smoking cessation counseling during CABG hospitalization, but their use should be carefully considered on an individualized basis (Class IIb; Level of Evidence B). Cardiac Rehabilitation Outpatient CR is a medically supervised, exercise-based pro- gram that is designed for patients with recent cardiovascular events to optimize overall health status and to minimize the risks for future adverse outcomes.317 325 In a meta-analysis of 48 trials involving CAD patients, CR was associated with a 26% risk reduction in the rate of cardiovascular mortality and a 20% risk reduction in overall mortality.321 Moreover, a strong, inverse dose-response relationship has been observed between the number of CR sessions attended and long-terms rates of MI and death.326 On the basis of this compelling evi- dence, CR has been strongly recommended for patients with several different cardiovascular diseases,327 including those recovering from recent CABG.3,317 The benefits of CR such as improved survival have been reported for all types of CAD patients, including younger and older patients, as well as men and women, independently of the nature of CAD diagnosis, the form of CR, and the dose of exercise intervention.317 325 The very first CR programs were launched in the 1960s, at a time when patients with cardiovascular disease were warned These initial CR programs, imple- mented for post-MI patients recovering in hospital, consisted of graded exercise programs. After a demonstration of their safety and success, these programs were later expanded into the outpatient setting.328 Over the years, CR programs have continued to adapt and to address the broad range of factors affecting cardiovascular outcomes, which has allowed them to evolve from purely supervised exercise programs to compre- hensive secondary prevention programs. The core components of contemporary CR programs include baseline patient assessments, nutritional counseling, risk factor management (lipids, BP, weight, diabetes mellitus, and smoking), psychosocial interventions, and physical activ- ity with counseling and exercise training.329 As a result of the broad effects of exercise training and the multiple components of these programs, CR has been shown to improve a wide range of health factors. Significant improvements have been demonstrated in CAD risk factors, functional capacity, vas- cular conditioning, and psychosocial well-being, all of which likely contribute to the robust effects of CR on overall clinical Among Medicare beneficiaries who have undergone CABG, patients are covered for up to 36 sessions of CR over the course of 1 year after the incident surgical hospitalization; other medical payers offer similar coverage plans. Despite the wealth of evidence and the presence of insurance coverage, CR use patterns remain poor nationwide.329 333 In an analysis of Medicare claims data, only 31% of CABG patients received at least 1 session of CR, and there was considerable geo- graphic heterogeneity in CR use patterns.333 One of the key barriers to CR use is the process of refer- ral to CR.327 Even among hospitals using the AHA Get With The Guidelines program, only 56% of eligible patients were referred to CR.332 Clearly, improving referral patterns to CR programs is a key area in need of greater focus.331 Recognizing Kulik et al Secondary Prevention After CABG 945 the importance of CR and the poor referral patterns to CR, the AHA and ACC, in collaboration with the American Association of Cardiac and Pulmonary Rehabilitation, have released performance measures for CR referral.327 Although CR referral rates are currently low, newly devel- oped referral strategies hold great promise to overcome this In a randomized trial of 2635 patients with CAD admitted to 11 different hospitals, a referral process that con- sisted of a combination of CR liaisons and an automated refer- ral system resulted in 85.8% of patients being referred to CR and 73.5% being enrolled in CR compared with 32.2% and 29.0%, respectively, in the control group.337 In addition, strat- egies such as educational interventions335 and early appoint- ments and start dates338 340 have been shown to improve CR referral and use patterns. However, as new referral strategies become adopted into clinical practice, it will be important for clinicians to remain active in the referral process because physician advocacy remains a strong factor in determining whether patients will enroll in CR programs.341 Beyond the challenges in the referral process, many patient and health system factors negatively affect CR use patterns. Referral to CR is particularly low among specific populations such as patients of low socioeconomic status, women, older adults, and ethnic minorities.323 In addition, CR program loca- tions and hours of operation prohibit the use of this service by some patients, and CR programs may not even be available in some rural or medically underserved areas. Finally, the finan- cial costs, related to copays, transportation, and time off from work, over the course of an entire CR program dissuade some patients from using this service. To address all these barriers to CR use, multiple strategies will need to be undertaken. First, greater attention will need to be paid in the referral process to identify and address an indi- vidual s unique barriers to CR use. This will require greater communication with patients and better coordination between the referring center (hospitals or office-based practices) and CR programs. Second, healthcare reform efforts will need to provide further incentives to patients and healthcare sys- tems to use CR programs. Third, new paradigms for deliv- ering comprehensive CR programs such as home-based CR programs will need to be further developed. Although these challenges are daunting, they are of central importance to improving clinical outcomes after CABG. CR Recommendations 1. CR is recommended for all patients after CABG, with the referral ideally performed early postopera- tively during the surgical hospital stay (Class I; Level of Evidence A). Self-Management of Cardiovascular Disease After CABG, CR programs help patients develop self-man- agement skills to facilitate lifestyle and behavior modifi- cation. Self-management is the process by which patients assume control of their health-related behaviors.342 Ultimately, patients decide what they will eat, if they will exercise, and what medication they will take. As healthcare experiences a paradigm shift from physician-centered to patient-centered care, CR programs play an integral role in education and transitioning patients to adopt health-related behaviors.342 CR personnel can act as health coaches, providing self-manage- ment support, collaborating with patients to establish goals, and developing problem-solving skills to foster risk factor modification. Successful CR programs stimulate patients to acquire the knowledge, skills, and confidence necessary to alter health-related behavior.342 346 The Reduction of Atherothrombosis for Continued Health (REACH) international registry reported that among patients who have undergone CABG, when secondary prevention goals are not met at 1 year, the incidence of adverse cardio- vascular events increases, regardless of the number of risk factors present at baseline. This highlights the importance of CR programs to help patients achieve their goals and to improve long-term outcomes.212 Multiple barriers exist to the adoption of preventive therapies, including knowledge defi- cit, ambivalence, comorbidities, preconceived beliefs, lack of support, employment, and readiness for change.347 349 For example, older patients with comorbidities who live alone are more likely after 1 year to remain sedentary and to have poor medication and diet compliance.350 Interventions for self-management of risk factors should be individualized to meet specific sex concerns. Women in par- ticular have difficulty with self-management of heart disease because of fatigue, anxiety, and depression, as well as feel- ings of guilt that home and family responsibilities are being Adherence to physical activity remains a challenging issue; 35% of women are no longer exercising 3 months after discharge from CR.353 In contrast, men experi- ence different barriers to secondary prevention compared with women. Some of the obstacles to compliance among men include comprehension of disease, dietary barriers (depen- dence on others for meals), and activity barriers (such as employment superseding CR).354 Participation in a hospital-based outpatient CR program compared with a home-based program helps improve exer- cise adherence for both men and women, increases knowledge about the condition for men, and improves stress control for Continuation of the secondary prevention education after discharge from CR can improve adherence to long-term self-management. Secondary prevention programs should be individualized, considering the patient s knowledge deficit. Self-efficacy and self-management skills can be developed by incorporating education and counseling techniques in either individualized or group sessions and focusing on motivational Applying technology through the use of the Internet and mobile phones can help provide education and trained peer support for CABG patients after surgery, even for those who are unable to access CR programs because of Finally, individual diaries have been shown to increase patient accountability for self-management of exercise activity after CR.360 Self-efficacy, along with an individualized plan for behavior change, is imperative to help optimize adherence to secondary prevention after CABG. Mental Health and Cognitive Impairment The negative impact of mental illness and cognitive impair- ment after CABG is well recognized, leading to greater risk of morbidity and mortality in the perioperative period and poor adherence to secondary preventative therapies in the long term. Screening for and preventing these neuropsychological conditions from developing may therefore improve outcomes after CABG. Depression is the most carefully studied mood disorder, having been reported in up to 33% of patients 1 year Depression is an important risk factor for the progression of CAD, and it is a more important predictor of CR success than many other variables.362 Both the presence of depressive symptoms before CABG and the worsening of these symptoms after surgery correlate with poorer physi- cal and psychosocial functioning and poorer quality of life Moreover, depression before or after surgery increases the risk of postoperative mortality and other adverse events such as heart failure hospitalization, MI, cardiac arrest, and the need for repeat revascularization.364,365 Finally, depres- sion after CABG is an important predictor for the recurrence of angina in the postoperative period.365 Interventions to help treat depression after CABG have been shown to be beneficial by improving depressive symptoms through cognitive behavioral therapy, telephone-delivered collaborative care, and supportive stress management.366,367 Participating in a CR program is another method that can help reduce postoperative depressive symptoms.368 In a random- ized, controlled trial, phone calls by nurses to patients after CABG improved depressive mood symptoms in the months Although interventions are frequently initiated postoperatively, cognitive behavioral therapy for preopera- tive depression and anxiety has also been shown to improve depressive symptoms and to reduce the length of stay in hospi- tal, justifying screening for depression even before the opera- Recently, a trial examining the efficacy of treating depression before surgery randomized 361 patients to escita- lopram 10 mg daily or placebo starting 2 to 3 weeks before elective CABG. Although the therapy had no effect on mor- bidity and mortality after CABG, depressed patients treated with escitalopram had a better quality of life and less pain Therefore, treating depression before CABG can lead to improved psychological outcomes after surgery. Alteration of cognitive function has been reported in up to 30% of patients after CABG.371 374 The exact frequency depends on the timing of the postoperative assessment and the criteria used to measure cognitive decline.375,376 Studies with appropriate comparison groups (including nonsurgical and healthy control subjects) have demonstrated that most patients do not suffer cognitive decline as a result of CABG.377,378 For those who do, the postoperative cognitive changes are usually mild and generally resolve within 3 months of surgery.379 Long- term cognitive decline after CABG has been reported,380,381 but studies have shown that similar late cognitive decline occurs even among patients with CAD who do not undergo surgery, supporting that the decline is not related to the operation or the use of cardiopulmonary bypass.382 Cognitive changes have also been reported after general anesthesia for noncardiac Several risk factors for short-term postoperative cognitive decline have been identified, including preoperative factors for cerebrovascular disease, central nervous system disease, and preexisting cognitive impairment.371,386,387 It had previously been suggested that cognitive decline might be less frequent after off-pump CABG compared with on-pump surgery.388 As summarized in a meta-analysis, however, taken collectively, most studies failed to show a benefit of off-pump CABG In particular, large, robust, randomized, clinical trials comparing late cognitive outcomes after on-pump and off-pump CABG surgery reported no difference.390,391 Current findings therefore do not support a recommendation for off- pump surgery as an approach to prevent cognitive decline. Mental Health and Cognitive Decline Recommendations 1. For patients after CABG, it is reasonable to screen for depression in collaboration with a primary care physician and a mental health specialist (Class IIa; Level of Evidence B). 2. Cognitive behavior therapy or collaborative care for patients with clinical depression after CABG can be beneficial to reduce depression (Class IIa; Level of Evidence B). Obesity and Metabolic Syndrome Obesity is a major risk factor for cardiovascular disease. Many epidemiological studies have shown a clear associa- tion between obesity and CAD.392 The association is mediated mostly through the effect of obesity-related cardiovascular risk factors such as hypertension, dyslipidemia, or diabetes melli- tus but also through a direct atherogenic effect by increased circulation of free fatty acids, by adrenergic stimulation, and through the effect of adipose tissue related hormones. Biologically, obesity is defined as increased body fat, but for simplicity purposes, the World Health Organization defines obesity on the basis of body weight in relation to height. The most widely accepted method to diagnose obesity is the body mass index (BMI), calculated by dividing the weight in kilo- grams by the height in meters squared. Recent studies have challenged the accuracy of BMI in detecting body adipos- ity, particularly in patients with established CAD.393,394 This new evidence suggests that the assessment of adiposity needs to go beyond total body adiposity and the measurement of With a focus on the distribution of adipose tissue, central obesity and greater amounts of visceral fat convey the highest mortality risk in patients with CAD.395 The assessment of body fat distribution can be performed in a simple manner by measuring the waist and hip circumference to calculate the waist-to-hip ratio. The metabolic syndrome is defined as the coexistence of several interrelated conditions, including central obesity, hyperglycemia, elevated systemic BP, hypertriglyceridemia, and decreased HDL. The presence of 3 of these abnormali- ties establishes the diagnosis of metabolic syndrome based on the Adult Treatment Panel III consensus.397 The metabolic syn- drome has been associated with numerous pathophysiological mechanisms that can lead to cardiovascular disease, includ- ing insulin resistance, increased oxidative stress, endothelial dysfunction, and atherogenic lipid patterns. The presence of metabolic syndrome increases the risk for cardiovascular events Kulik et al Secondary Prevention After CABG 947 from 2- to 4-fold independently of the presence of diabetes mel- litus. As a well-established cardiovascular risk factor, the meta- bolic syndrome is common among patients undergoing CABG, with some studies reporting the prevalence as high as 50%.398 The metabolic syndrome has been associated with increased in-hospital mortality in subjects undergoing CABG. In a study of 5304 consecutive CABG patients, those with metabolic syn- drome had a 2.7-times higher in-hospital mortality than those without metabolic syndrome, a risk that was independent of the presence of diabetes mellitus.399 Moreover, patients with metabolic syndrome also have an increased risk for long-term mortality. Angeloni et al398 noted that all-cause mortality was 50% higher in those patients with metabolic syndrome com- pared with those without in a long-term follow-up study of 1726 CABG patients. The metabolic syndrome also increased the long-term risk for cardiac arrhythmias, renal failure, and the composite outcome of major adverse cardiovascular events Patients with the meta- bolic syndrome are 2.3-times more likely to develop AF after This increased risk may be mediated by an elevated C-reactive protein level.401 Patients with metabolic syndrome are also at risk for decreased patency of saphenous vein grafts Given the multiple pathophysiological mechanisms link- ing obesity and cardiovascular disease, it is logical to expect favorable clinical outcomes after weight loss in patients with CAD. Unfortunately, there is minimal evidence proving any benefit associated with weight loss after CABG. Retrospective, observational studies assessing the association between weight loss and clinical outcomes after CABG have shown para- doxical results, with worse outcomes among patients losing weight after CABG.403 However, these studies could not dif- ferentiate between purposeful and unintentional weight loss. Unintentional weight loss could reflect comorbidities such as heart failure, cancer, and lung diseases or may reflect the sever- ity of other conditions associated with decreased survival. One of the few studies that showed improved outcomes after weight loss in patients with CAD was based in a CR setting, suggest- ing that purposeful weight loss in CAD patients may be benefi- Weight loss has an indisputable benefit for BP, diabetes mellitus, and lipid control and improves quality of life and functional capacity. Therefore, despite the limited scientific evidence, it is generally accepted that weight loss should be recommended for overweight or obese patients after CABG. Long-term, successful weight loss continues to represent a major clinical challenge. Most studies have noted that much of the weight lost in the first 6 months is regained at 1 year. The therapeutic options to achieve successful weight loss are limited because some of the medications that can promote weight loss are contraindicated in patients with CAD. To date, the only weight-loss strategy with effective long-term results is bariatric surgery. Observational studies have shown signifi- cant improvements in cardiometabolic parameters, quality of life, and cardiac mechanics following major weight loss after Many patients after CABG with a BMI of would qualify for bariatric surgery, and this thera- peutic modality may be considered for long-lasting weight Bariatric surgery has been shown to be safe in stable patients with CAD who have not had a recent MI.407 The cornerstone of the management of metabolic syndrome is lifestyle modification with increased exercise, improved diet, and weight loss. Lifestyle changes can improve all of the metabolic syndrome components. Diets low in carbohydrates can effectively improve hypertriglyceridemia. High protein intake, along with a high consumption of fruits, vegetables, and nonfat dairy products, can improve BP.408 Commonly, pharmacological treatment is needed for hypertension, diabe- tes mellitus, and dyslipidemia despite lifestyle changes. For patients with advanced degrees of obesity, bariatric surgery has been shown to significantly reduce the prevalence of meta- Obesity and Metabolic Syndrome Recommendations 1. The assessment of central distribution of fat is rea- sonable in CABG patients by measuring waist and hip circumference and calculating waist-to-hip ratio, even if the BMI is within normal limits (Class IIa; Level of Evidence C). 2. Bariatric surgery may be considered for CABG patients with a BMI >35 kg/m2 if lifestyle interven- tions have already been attempted without meaning- ful weight loss (Class IIb; Level of Evidence C). Nutrition The nutritional status of patients plays an important role in the results after CABG. Approximately 20% of patients have been identified as having poor preoperative nutritional sta- tus before undergoing cardiac surgery.410 Several nutritional screening tools exist, including the Malnutrition Universal Screening Tool. When the Malnutrition Universal Screening Tool score is added to the EuroSCORE in a multivariable model evaluating perioperative risk, the prediction of the model for both postoperative complications and mortal- ity is significantly improved compared with the use of the Preoperative malnutrition, whether defined on the basis of a nutritional screening tool or serum albumin level, has been shown to predict adverse postopera- tive events such as reoperation for bleeding, postoperative renal failure, prolonged ventilatory support, vasopressor treatment for >11 days, antibiotic treatment for >21 days, intensive care unit stay, total length of stay, increased inflam- matory response, infection, positive blood cultures, and It is well established that BMI decreases after major surgery such as CABG. DiMaria-Ghalili413 assessed 91 patients under- going CABG and observed a 5% change between the preop- erative BMI level and the level measured 4 to 6 weeks after surgery. This finding corresponded to a 13.8% decrease in self-reported physical health during the same time period. At a mean follow-up of 19 months, this same investigator observed that older patients undergoing elective CABG usually did not regain the weight they lost between the preoperative period and after hospital discharge. Furthermore, patients who lost more weight in the postoperative period were more likely to require subsequent hospital readmission.414 In an observational study of 100 consecutive patients under- going cardiac surgery, van Venrooij et al415 noted that low pre- operative protein intake ( 0.98 g kg 1 ) did not result in more complications or a longer hospital stay compared with a high preoperative protein intake (>0.98 g kg 1 ). On the other hand, a high-energy preoperative diet (>22 kcal kg 1 ) resulted in more postoperative complications. Racca and evaluated nutrition biomarkers in 50 nondiabetic patients on admission to a rehabilitation facility after cardiac surgery and 16 days later. Patients received a standard car- diac diet with controlled caloric support (30 kcal kg 1 ) providing 15% to 20% dietary protein, 30% fat, and 50% to 55% carbohydrates rich in fruits and vegetables. After 16 days on this standard dietary regimen, low plasma albumin levels increased, anemia improved, and markers of inflammation declined. From the above data, it would appear that controlled, com- prehensive dietary intake is effective in restoring the nutri- tional insults brought about by major surgery such as CABG but that oversupplementation may be detrimental. Although it seems justified to modulate nutritional intake to promote a quicker recovery from CABG, to date, there are no prospec- tive, randomized trials documenting a benefit associated with perioperative nutritional modification. Vitamins and Supplements The use of vitamin supplementation is a widespread prac- tice in the general population that amounts to tremendous expenditure. Many benefits have been attributed to the use of vitamin supplements, particularly those touted to have protective effects against cardiovascular disease and stroke. Observational studies have suggested that some vitamin supplements can reduce adverse cardiovascular events. For example, in the prospective Nurses Health Study of >80000 participants, women who voluntarily reported taking vitamin C and vitamin E supplements were noted to have a lower risk of developing CAD over more than a decade of follow-up.417,418 However, large, randomized, controlled studies of vitamins have not demonstrated such benefits in a variety of general and high-risk populations. The Physicians Health Study II was a randomized, double-blind, placebo-controlled trial of vitamin C and vitamin E supplementation that enrolled 14641 US male physicians 50 years of age. In this study, neither vitamin C nor vitamin E supplements reduced the risk of major cardiovascular events, even after more than a decade of treatment and follow-up.419,420 Among 12064 MI survivors, a placebo-controlled trial demonstrated that supplementation with folic acid and vitamin B12 also did not have beneficial effects on cardiovascular outcomes.421 This was confirmed in a meta-analysis of >37000 participants that demonstrated that high-dose B vitamins and folic acid are not effective as a secondary prevention measure for cardiovascular disease.422 Finally, a meta-analysis of 50 randomized, controlled trials with nearly 300000 participants showed no benefit of vitamin and antioxidant supplementation in reducing the risk of major cardiovascular events, including subgroup meta-analyses examining the effects of individual vitamins.423 Undergoing cardiac surgery leads to considerable stress on the body, which plays a key factor in determining outcome. Along with weight loss and protein catabolism, cardiac sur- gery is often associated with numerous derangements in stored vitamin and other metabolite levels. CABG is accompanied by a significant acute phase and inflammatory response, lead- ing to oxidative stress, free radical production, and antioxi- Louw and coworkers427 observed that this early acute-phase reaction was associated with decreases in the levels of both vitamin A and vitamin C, which are impor- tant antioxidants that aid in wound healing. Interestingly, both vitamin levels returned to normal after surgery without specific therapeutic intervention. Schindler and colleagues428 studied serial plasma samples before, during, and up to 48 hours after surgery, demonstrating significant decreases in levels of both vitamin A and vitamin E, with persistently low vitamin E levels 48 hours postoperatively. Similarly, in the early perioperative period after CABG, reductions have been noted in levels of homocysteine and folic acid, which are part of the body s antioxidant first line of defense.429 Other studies of CABG patients have documented decreases in B complex vitamins such as B6 , and thiamine, which are essential for mitochondrial function.416,427,430 Vitamin D levels have been shown to be important predictors of outcome after cardiac surgery. In a study of 4418 patients recovering from cardiac surgery, Zittermann et al431 noted that 38.0% had deficient 25(OH)D values (<30 nmol/L). In multivariable- adjusted models, a low 25(OH)D value was independently associated with a greater risk of major adverse cardiac events, longer duration of mechanical ventilatory support and inten- sive care unit stay, and higher 6- and 12-month mortality. Intuitively, from these data, vitamin supplementation should promote a faster recovery from CABG. However, very little is currently known about the value of vitamin supplementation after cardiac surgery, and studies examining the use of vita- min supplementation in CABG patients either with or with- out specific deficiencies are lacking. Only in the perioperative period as a means of preventing postoperative AF has the role of vitamin supplementation received some attention. Given the suggestion that oxidative stress may potentiate AF, several investigators have evaluated the prophylactic administration of omega-3 fatty acids and antioxidant vitamins to reduce its incidence after CABG. Meta-analyses on this subject have presented conflicting data, suggesting a potential for vitamins and omega-3 fatty acids to reduce the risk of perioperative AF, but the results are inconsistent, with a lack of high-quality data in the literature.432 434 Therefore, the available evidence to date remains insufficient, and additional large-scale, adequately powered clinical studies are warranted before routine admin- istration of antioxidant vitamins can be recommended for the reduction of AF after CABG. Vitamins and Supplements Recommendations 1. Vitamin supplementation in patients with specific vitamin deficiencies may be considered for patients undergoing CABG, but the effectiveness is not well established (Class IIb; Level of Evidence C). 2. Supplementation with omega-3 fatty acids and anti- oxidant vitamins may be considered to prevent post- operative AF after CABG, but additional clinical Kulik et al Secondary Prevention After CABG 949 studies are warranted before routine use of antioxi- dant vitamins can be recommended (Class IIb; Level of Evidence A). Vaccination Influenza is one of the most common, contagious, and mor- bid respiratory infections, with a seasonal pattern of affliction during winter climate.435 Among nontraditional risk factors, a growing interest has developed in the evaluation of influenza infection as a potential cause for subsequent cardiovascular Previous studies have suggested that seasonal influenza-like illnesses may explain the timing of acute throm- botic events in patients with CAD,438 and several epidemio- logical studies have identified an inverse relationship between influenza vaccination and the risk of fatal and nonfatal cardio- Although the mechanism underlying that risk of influenza is not clear, it may relate to triggering the rupture of a vulnerable atherosclerotic plaque, fluid overload, and heart failure or to the susceptibility of a frail and vulner- Randomized, controlled trials have since been performed to explicitly test whether influenza vaccination can reduce the risk of cardiovascular events. In one of the first trials on the subject, Gurfinkel et al443,444 randomized 200 patients with MI and 101 patients undergoing elective percutaneous coronary intervention to either multivalent influenza vaccine or pla- cebo. At 1 year of follow-up, the risk of MI and cardiovascu- lar death was significantly lower among patients who received the vaccine. These results were subsequently confirmed in other inpatient and outpatient CAD populations.445,446 In a ran- domized trial of 439 patients admitted with acute coronary syndrome, influenza vaccine significantly lowered the com- posite end point of death or hospitalization for CAD, heart failure, or stroke (vaccine versus placebo, 9.5% versus 19.3%; Most recently, a meta-analysis of 6 randomized trials involving 6735 patients at high risk for cardiovascu- lar disease demonstrated that influenza vaccine significantly lowered the risk of cardiovascular events (RR, 0.64; 95% CI, 0.48 0.86; P=0.003), with the greatest treatment benefit seen among the highest-risk patients with more active CAD.435 These findings provide support for the current recommenda- tions for influenza vaccination of all patients admitted with acute coronary syndrome.2,447 Within the general population, the Centers for Disease Control and Prevention currently recommends routine annual influenza vaccination for all people >6 months of age unless specific contraindications are For patients undergoing CABG, there is justification based on the evidence in the cardiology literature to provide influ- enza vaccination for those in whom no contraindication exists. Hospitalization for cardiac surgery provides an opportunity to vaccinate those people who are not immunized and to potentially lower the risk of subsequent adverse cardiovascu- lar events. However, no studies exist regarding the safety or effectiveness of influenza vaccination in reducing periopera- tive morbidity or mortality after CABG. Furthermore, peri- operative immunological alterations may reduce a patient s ability to respond to and to develop immunity after a vaccina- Thus, the optimal timing of perioperative influenza vaccination in patients undergoing cardiac surgery remains unclear. Whether patients should receive the influenza vaccine preoperatively or in the days or weeks after CABG should be the subject of future research. Vaccination Recommendations 1. Annual influenza vaccination should be offered to all CABG patients, unless contraindications exist (Class I; Level of Evidence B). Disclosures Writing Group Disclosures Writing Group Member Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/Advisory Board Other Alexander Kulik Boca Raton Regional Hospital AHA None None None None None AstraZeneca ticagrelor research study* Marc Ruel University of Ottawa Heart Institute None None None None None None None T. Bruce Ferguson East Carolina Heart Institute at ECU None None None None None None None Loren F. Hiratzka TriHealth Heart Institute at Bethesda North and Good Samaritan Hospitals None None None None None None None John S. Ikonomidis Medical University of South Carolina None None None None None None None Hani Jneid Baylor College of Medicine None None None None None None None Francisco Lopez-Jimenez Mayo Clinic None None None None None None None Sheila M. McNallan Mayo Clinic None None None None None None None Mahesh Patel Duke University None None None None None None None V ronique L. Roger Mayo Clinic None None None None None None None Frank W. Sellke Rhode Island Hospital/Brown Medical School None None None None None Boehringer Ingelheim, DSMB for clinical trial*; CSL Behring, adjudication committee for trial*; Stryker, advisory committee (pending)* None Domenic A. Sica Virginia Commonwealth University Health System None None None None None None None Lani Zimmerman University of Nebraska Medical Center None None None None None None None This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Significant. Reviewer Disclosures Reviewer Employment Research Grant Other Research Support Speakers Bureau/ Honoraria Expert Witness Ownership Interest Consultant/ Advisory Board Other Stephen E. Fremes Sunnybrook and Women s College Health Sciences Centre None None None None None None None Amit Khera UT Southwestern Medical Center None None None None None None None Peter Mason University of Wisconsin None None None None Medtronic* None None Todd Rosengart Baylor College of Medicine None None None None None None None This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be significant if (a) the person receives $10000 or more during any 12-month period, or 5% or more of the person s gross income; or (b) the person owns 5% or more of the voting stock or share of the entity, or owns $10000 or more of the fair market value of the entity. A relationship is considered to be modest if it is less than significant under the preceding definition. *Modest. Kulik et al Secondary Prevention After CABG 951 References 1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ, Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Mussolino ME, Neumar RW, Nichol G, Pandey DK, Paynter NP, Reeves MJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Wong ND, Woo D, Turner MB; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics 2014 update: a report from the American Heart Association. Circulation. 2014;129:e28 e292. doi: 10.1161/01.cir.0000441139.02102.80. 2. Smith SC Jr, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, Gibbons RJ, Grundy SM, Hiratzka LF, Jones DW, Lloyd-Jones DM, Minissian M, Mosca L, Peterson ED, Sacco RL, Spertus J, Stein JH,Taubert KA; World Heart Federation and the Preventive Cardiovascular Nurses Association. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124:2458 2473. doi: 10.1161/CIR.0b013e318235eb4d. 3. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, Cigarroa JE, Disesa VJ, Hiratzka LF, Hutter AM Jr, Jessen ME, Keeley EC, Lahey SJ, Lange RA, London MJ, Mack MJ, Patel MR, Puskas JD, Sabik JF, Selnes O, Shahian DM, Trost JC, Winniford MD. 2011 ACCF/ AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124:e652 e735. doi: 10.1161/CIR.0b013e31823c074e. 4. Fuster V, Dyken ML, Vokonas PS, Hennekens C. Aspirin as a therapeu- tic agent in cardiovascular disease: Special Writing Group. Circulation. 1993;87:659 675. 5. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocar- dial infarction, and stroke in high risk patients. BMJ. 2002;324:71 86. 6. Kulik A, Chan V, Ruel M. Antiplatelet therapy and coronary artery bypass graft surgery: perioperative safety and efficacy. Expert Opin Drug Saf. 2009;8:169 182. doi: 10.1517/14740330902797081. 7. Dacey LJ, Munoz JJ, Johnson ER, Leavitt BJ, Maloney CT, Morton JR, Olmstead EM, Birkmeyer JD, O Connor GT; Northern New England Cardiovascular Disease Study Group. Effect of preoperative aspirin use on mortality in coronary artery bypass grafting patients. Ann Thorac Surg. 2000;70:1986 1990. 8. Bybee KA, Powell BD, Valeti U, Rosales AG, Kopecky SL, Mullany C, Wright RS. Preoperative aspirin therapy is associated with improved postoperative outcomes in patients undergoing coronary artery bypass grafting. Circulation. 2005;112(suppl):I286 I292. doi: 10.1161/ CIRCULATIONAHA.104.522805. 9. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2012;126:875 910. 10. O Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobs AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kushner FG, Ohman EM, Stevenson WG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362 e425. doi: 10.1161/ CIR.0b013e3182742cf6. 11. Pantely GA, Goodnight SH Jr, Rahimtoola SH, Harlan BJ, DeMots H, Calvin L, R sch J. Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass: a controlled, randomized study. N Engl J Med. 1979;301:962 966. doi: 10.1056/ NEJM197911013011803. 12. McEnany MT, Salzman EW, Mundth ED, DeSanctis RW, Harthorne JW, Weintraub RM, Gates S, Austen WG. The effect of antithrombotic therapy on patency rates of saphenous vein coronary artery bypass grafts. J Thorac Cardiovasc Surg. 1982;83:81 89. 13. Sharma GV, Khuri SF, Josa M, Folland ED, Parisi AF. The effect of anti- platelet therapy on saphenous vein coronary artery bypass graft patency. Circulation. 1983;68(pt 2):II218 II221. 14. Chesebro JH, Clements IP, Fuster V, Elveback LR, Smith HC, Bardsley WT, Frye RL, Holmes DR Jr, Vlietstra RE, Pluth JR, Wallace RB, Puga FJ, Orszulak TA, Piehler JM, Schaff HV, Danielson GK. A platelet- inhibitor-drug trial in coronary-artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postopera- tive vein-graft patency. N Engl J Med. 1982;307:73 78. doi: 10.1056/ NEJM198207083070201. 15. Chesebro JH, Fuster V, Elveback LR, Clements IP, Smith HC, Holmes DR Jr, Bardsley WT, Pluth JR, Wallace RB, Puga FJ, Orszulak TA, Piehler JM, Danielson GK, Schaff HV, Frye RL. Effect of dipyridamole and aspirin on late vein-graft patency after coronary bypass operations. N Engl J Med. 1984;310:209 214. doi: 10.1056/NEJM198401263100401. 16. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty J, Read R, Chesler E, Sako Y, Lancaster L, Emery R, Sharma GVRK, Josa M, Pacold I, Montoya A, Parikh D, Sethi G, Holt J, Kirklin J, Shabetai R, Moores W, Aldridge J, Masud Z, DeMots H, Floten S, Haakenson C, Harker LA. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation. 1988;77:1324 1332. 17. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty J, Read R, Chesler E, Sako Y, Lancaster L, Emery R, Sharma GVRK, Josa M, Pacold I, Montoya A, Parikh D, Sethi G, Holt J, Kirklin J, Shabetai R, Moores W, Aldridge J, Masud Z, DeMots H, Floten S, Haakenson C, Harker LA. Saphenous vein graft patency 1 year after coronary artery bypass surgery and effects of antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation. 1989;80:1190 1197. 18. Mangano DT; Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med. 2002;347:1309 1317. doi: 10.1056/NEJMoa020798. 19. Johnson WD, Kayser KL, Hartz AJ, Saedi SF. Aspirin use and survival after coronary bypass surgery. Am Heart J. 1992;123:603 608. 20. Farooq V, Serruys PW, Bourantas C, Vranckx P, Diletti R, Garcia Garcia HM, Holmes DR, Kappetein AP, Mack M, Feldman T, Morice MC, Colombo A, Morel MA, de Vries T, van Es GA, Steyerberg EW, Dawkins KD, Mohr FW, James S, St hle E. Incidence and multivariable corre- lates of long-term mortality in patients treated with surgical or percuta- neous revascularization in the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial. Eur Heart J. 2012;33:3105 3113. doi: 10.1093/eurheartj/ehs367. 21. Fremes SE, Levinton C, Naylor CD, Chen E, Christakis GT, Goldman BS. Optimal antithrombotic therapy following aortocoronary bypass: a meta- analysis. Eur J Cardiothorac Surg. 1993;7:169 180. 22. Lim E, Ali Z, Ali A, Routledge T, Edmonds L, Altman DG, Large S. Indirect comparison meta-analysis of aspirin therapy after coronary sur- gery. BMJ. 2003;327:1309. doi: 10.1136/bmj.327.7427.1309. 23. Zimmermann N, Kienzle P, Weber AA, Winter J, Gams E, Schr r K, Hohlfeld T. Aspirin resistance after coronary artery bypass graft- ing. J Thorac Cardiovasc Surg. 2001;121:982 984. doi: 10.1067/ mtc.2001.111416. 24. Bednar F, Tencer T, Plasil P, Paluch Z, Sadilkova L, Prucha M, Kopa M. Evaluation of aspirin s effect on platelet function early after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2012;26:575 580. doi: 10.1053/j.jvca.2011.12.004. 25. Buchanan MR, Brister SJ. Individual variation in the effects of ASA on platelet function: implications for the use of ASA clinically. Can J Cardiol. 1995;11:221 227. 26. Yilmaz MB, Balbay Y, Caldir V, Ayaz S, Guray Y, Guray U, Korkmaz S. Late saphenous vein graft occlusion in patients with coronary bypass: possible role of aspirin resistance. Thromb Res. 2005;115:25 29. doi: 10.1016/j.thromres.2004.07.004. 27. Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409:202 207. doi: 10.1038/35051599. 28. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation. 1999;100:1667 1672. 29. Chevign M, David JL, Rigo P, Limet R. Effect of ticlopidine on saphe- nous vein bypass patency rates: a double-blind study. Ann Thorac Surg. 1984;37:371 378. 30. Limet R, David JL, Magotteaux P, Larock MP, Rigo P. Prevention of aorta- coronary bypass graft occlusion: beneficial effect of ticlopidine on early and late patency rates of venous coronary bypass grafts: a double-blind study. J Thorac Cardiovasc Surg. 1987;94:773 783. 31. Cadroy Y, Bossavy JP, Thalamas C, Sagnard L, Sakariassen K, Boneu B. Early potent antithrombotic effect with combined aspirin and a loading dose of clopidogrel on experimental arterial thrombogenesis in humans. Circulation. 2000;101:2823 2828. 32. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494 502. doi: 10.1056/NEJMoa010746. 33. Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators, Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy fol- lowing percutaneous coronary intervention: a randomized controlled trial. JAMA. 2002;288:2411 2420. 34. Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S; Clopidogrel in Unstable angina to prevent Recurrent ischemic Events Trial. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation. 2004;110:1202 1208. doi: 10.1161/01.CIR.0000140675.85342.1B. 35. Kim DH, Daskalakis C, Silvestry SC, Sheth MP, Lee AN, Adams S, Hohmann S, Medvedev S, Whellan DJ. Aspirin and clopidogrel use in the early postoperative period following on-pump and off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2009;138:1377 1384. doi: 10.1016/j.jtcvs.2009.07.027. 36. S rensen R, Abildstr m SZ, Hansen PR, Hvelplund A, Andersson C, Charlot M, Fosb l EL, K ber L, Madsen JK, Gislason GH, Torp-Pedersen C. Efficacy of post-operative clopidogrel treatment in patients revascular- ized with coronary artery bypass grafting after myocardial infarction. J Am Coll Cardiol. 2011;57:1202 1209. doi: 10.1016/j.jacc.2010.09.069. 37. Gao C, Ren C, Li D, Li L. Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting. Ann Thorac Surg. 2009;88:59 62. doi: 10.1016/j.athoracsur.2009.04.024. H, Khan O, Masood I, Large S. Clopidogrel did not inhibit platelet function early after coronary bypass surgery: a prospective randomized trial. J Thorac Cardiovasc Surg. 2004;128:432 435. doi: 10.1016/j.jtcvs.2004.03.007. 39. David JL, Limet R. Antiplatelet activity of clopidogrel in coronary artery bypass graft surgery patients. Thromb Haemost. 1999;82:1417 1421. 40. Sun JC, Teoh KH, Lamy A, Sheth T, Ellins ML, Jung H, Yusuf S, Anand S, Connolly S, Whitlock RP, Eikelboom JW. Randomized trial of aspi- rin and clopidogrel versus aspirin alone for the prevention of coronary artery bypass graft occlusion: the Preoperative Aspirin and Postoperative Antiplatelets in Coronary Artery Bypass Grafting study. Am Heart J. 2010;160:1178 1184. doi: 10.1016/j.ahj.2010.07.035. 41. Gao G, Zheng Z, Pi Y, Lu B, Lu J, Hu S. Aspirin plus clopidogrel ther- apy increases early venous graft patency after coronary artery bypass surgery a single-center, randomized, controlled trial. J Am Coll Cardiol. 2010;56:1639 1643. doi: 10.1016/j.jacc.2010.03.104. 42. Kulik A, Le May MR, Voisine P, Tardif JC, Delarochelliere R, Naidoo S, Wells GA, Mesana TG, Ruel M. Aspirin plus clopidogrel versus aspi- rin alone after coronary artery bypass grafting: the Clopidogrel After Surgery For Coronary Artery Disease (CASCADE) Trial. Circulation. 2010;122:2680 2687. doi: 10.1161/CIRCULATIONAHA.110.978007. 43. Ebrahimi R, Bakaeen FG, Uberoi A, Ardehali A, Baltz JH, Hattler B, Almassi GH, Wagner TH, Collins JF, Grover FL, Shroyer AL. Effect of clopidogrel use post coronary artery bypass surgery on graft patency. Ann Thorac Surg. 2014;97:15 21. doi: 10.1016/j.athoracsur.2013.08.058. 44. Deo SV, Dunlay SM, Shah IK, Altarabsheh SE, Erwin PJ, Boilson BA, Park SJ, Joyce LD. Dual anti-platelet therapy after coronary artery bypass grafting: is there any benefit? A systematic review and meta-analysis. J Card Surg. 2013;28:109 116. doi: 10.1111/jocs.12074. 45. de Leon N, Jackevicius CA. Use of aspirin and clopidogrel after coronary artery bypass graft surgery. Ann Pharmacother. 2012;46:678 687. doi: 10.1345/aph.1Q692. 46. Nocerino AG, Achenbach S, Taylor AJ. Meta-analysis of effect of single versus dual antiplatelet therapy on early patency of bypass conduits after coronary artery bypass grafting. Am J Cardiol. 2013;112:1576 1579. doi: 10.1016/j.amjcard.2013.07.017. 47. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001 2015. doi: 10.1056/ NEJMoa0706482. 48. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO Investigators, Freij A, Thors n M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045 1057. doi: 10.1056/ NEJMoa0904327. 49. Held C, Asenblad N, Bassand JP, Becker RC, Cannon CP, Claeys MJ, Harrington RA, Horrow J, Husted S, James SK, Mahaffey KW, Nicolau JC, Scirica BM, Storey RF, Vintila M, Ycas J, Wallentin L. Ticagrelor versus clopidogrel in patients with acute coronary syndromes undergo- ing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2011;57:672 684. doi: 10.1016/j.jacc.2010.10.029. 50. Smith PK, Goodnough LT, Levy JH, Poston RS, Short MA, Weerakkody GJ, Lenarz LA. Mortality benefit with prasugrel in the TRITON-TIMI 38 coronary artery bypass grafting cohort: risk-adjusted retrospec- tive data analysis. J Am Coll Cardiol. 2012;60:388 396. doi: 10.1016/j. jacc.2012.03.030. 51. Varenhorst C, Alstr m U, Scirica BM, Hogue CW, senblad N, Storey RF, Steg PG, Horrow J, Mahaffey KW, Becker RC, James S, Cannon CP, Brandrup-Wognsen G, Wallentin L, Held C. Factors contribut- ing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol. 2012;60:1623 1630. doi: 10.1016/j.jacc.2012.07.021. 52. Mariani MA, Gu YJ, Boonstra PW, Grandjean JG, van Oeveren W, Ebels T. Procoagulant activity after off-pump coronary operation: is the current anticoagulation adequate? Ann Thorac Surg. 1999;67:1370 1375. 53. Kim KB, Lim C, Lee C, Chae IH, Oh BH, Lee MM, Park YB. Off-pump coronary artery bypass may decrease the patency of saphenous vein grafts. Ann Thorac Surg. 2001;72:S1033 S1037. 54. Casati V, Gerli C, Franco A, Della Valle P, Benussi S, Alfieri O, Torri G, D Angelo A. Activation of coagulation and fibrinolysis during coro- nary surgery: on-pump versus off-pump techniques. Anesthesiology. 2001;95:1103 1109. 55. Kurlansky PA. Is there a hypercoagulable state after off-pump coronary artery bypass surgery? What do we know and what can we do? J Thorac Cardiovasc Surg. 2003;126:7 10. 56. Bidstrup BP, Scarrott H, Luque M. Platelet function after off pump coro- nary surgery. Heart Surg Forum. 2003;6:286 287. 57. Quigley RL, Fried DW, Pym J, Highbloom RY. Off-pump coronary artery bypass surgery may produce a hypercoagulable patient. Heart Surg Forum. 2003;6:94 98. 58. Poston R, Gu J, Manchio J, Lee A, Brown J, Gammie J, White C, Griffith BP. Platelet function tests predict bleeding and thrombotic events after off- pump coronary bypass grafting. Eur J Cardiothorac Surg. 2005;27:584 591. doi: 10.1016/j.ejcts.2004.12.061. 59. Bednar F, Osmancik P, Vanek T, Mocikova H, Jares M, Straka Z, Widimsky P. Platelet activity and aspirin efficacy after off-pump compared with on-pump coronary artery bypass surgery: results from the prospective randomized trial PRAGUE 11-Coronary Artery Bypass and REactivity of Thrombocytes (CABARET). J Thorac Cardiovasc Surg. 2008;136:1054 1060. doi: 10.1016/j.jtcvs.2008.03.052. 60. Wang Z, Gao F, Men J, Ren J, Modi P, Wei M. Aspirin resistance in off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg. 2012;41:108 112. doi: 10.1016/j.ejcts.2011.04.021. 61. Gundry SR, Romano MA, Shattuck OH, Razzouk AJ, Bailey LL. Seven-year follow-up of coronary artery bypasses performed with and without cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1998;115: 1273 1277. 62. Puskas JD, Williams WH, Mahoney EM, Huber PR, Block PC, Duke PG, Staples JR, Glas KE, Marshall JJ, Leimbach ME, McCall SA, Petersen RJ, Bailey DE, Weintraub WS, Guyton RA. Off-pump vs conventional coronary artery bypass grafting: early and 1-year graft patency, cost, and quality-of-life outcomes: a randomized trial. JAMA. 2004;291:1841 1849. doi: 10.1001/jama.291.15.1841. Kulik et al Secondary Prevention After CABG 953 63. Ibrahim K, Tjomsland O, Halvorsen D, Wiseth R, Wahba A, Karevold A, Haaverstad R. Effect of clopidogrel on midterm graft patency fol- lowing off-pump coronary revascularization surgery. Heart Surg Forum. 2006;9:E581 E856. doi: 10.1532/HSF98.20061034. 64. Gurbuz AT, Zia AA, Vuran AC, Cui H, Aytac A. Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass graft surgery: a prospective study. Eur J Cardiothorac Surg. 2006;29:190 195. doi: 10.1016/j.ejcts.2005.11.033. 65. Nielsen AB, Bochsen L, Steinbr chel DA. Hypercoagulability and platelet inhibition after OPCAB: randomized intervention with clopidogrel. Scand Cardiovasc J. 2007;41:325 330. doi: 10.1080/14017430701383763. 66. Mannacio VA, Di Tommaso L, Antignan A, De Amicis V, Vosa C. Aspirin plus clopidogrel for optimal platelet inhibition following off-pump coronary artery bypass surgery: results from the CRYSSA (prevention of Coronary arteRY bypaSS occlusion After off-pump procedures) randomised study. Heart. 2012;98:1710 1715. doi: 10.1136/heartjnl-2012-302449. 67. Gohlke H, Gohlke-B rwolf C, St rzenhofecker P, G rnandt L, Ritter B, Reichelt M, Buchwalsky R, Schmuziger M, Roskamm H. Improved graft patency with anticoagulant therapy after aortocoronary bypass surgery: a prospective, randomized study. Circulation. 1981;64(pt 2):II22 II27. 68. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low- dose anticoagulation on obstructive changes in saphenous-vein coronary- artery bypass grafts. N Engl J Med. 1997;336:153 162. 69. Wann LS, Curtis AB, January CT, Ellenbogen KA, Lowe JE, Estes NA 3rd, Page RL, Ezekowitz MD, Slotwiner DJ, Jackman WM, Stevenson WG, Tracy CM, Fuster V, Ryd n LE, Cannom DS, Le Heuzey JY, Crijns HJ, Lowe JE, Curtis AB, Olsson S, Ellenbogen KA, Prystowsky EN, Halperin JL, Tamargo JL, Kay GN, Wann L, Jacobs AK, Anderson JL, Albert N, Hochman JS, Buller CE, Kushner FG, Creager MA, Ohman EM, Ettinger SM, Stevenson WG, Guyton RA, Tarkington LG, Halperin JL, Yancy CW; ACCF/AHA Task Force Members. 2011 ACCF/AHA/ HRS focused update on the management of patients with atrial fibril- lation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123:104 123. doi: 10.1161/ CIR.0b013e3181fa3cf4. 70. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuunemann HJ; American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl):7S 47S. 71. Bonow RO, Carabello BA, Chatterjee K, de Leon AC Jr, Faxon DP, Freed MD, Gaasch WH, Lytle BW, Nishimura RA, O Gara PT, O Rourke RA, Otto CM, Shah PM, Shanewise JS; 2006 Writing Committee Members; American College of Cardiology/American Heart Association Task Force. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart dis- ease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease). Circulation. 2008;118:e523 e661. doi: 10.1161/ CIRCULATIONAHA.108.190748. 72. Kulik A, Saltzman MB, Morris JJ. Dabigatran after cardiac surgery: cau- tion advised. J Thorac Cardiovasc Surg. 2011;142:1288. doi: 10.1016/j. jtcvs.2011.05.029. 73. Price J, Hynes M, Labinaz M, Ruel M, Boodhwani M. Mechanical valve thrombosis with dabigatran. J Am Coll Cardiol. 2012;60:1710 1711. doi: 10.1016/j.jacc.2012.06.039. 74. Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369:1206 1214. doi: 10.1056/NEJMoa1300615. 75. Daida H, Yokoi H, Miyano H, Mokuno H, Satoh H, Kottke TE, Hosoda Y, Yamaguchi H. Relation of saphenous vein graft obstruction to serum cholesterol levels. J Am Coll Cardiol. 1995;25:193 197. 76. Campeau L, Enjalbert M, Lesp rance J, Bourassa MG, Kwiterovich P Jr, Wacholder S, Sniderman A. The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation: a study 10 years after aortocoronary bypass surgery. N Engl J Med. 1984;311:1329 1332. doi: 10.1056/ NEJM198411223112101. 77. Cholesterol Treatment Trialists (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 par- ticipants in 26 randomised trials. Lancet. 2010;376:1670 1681. 78. Kulik A, Brookhart MA, Levin R, Ruel M, Solomon DH, Choudhry NK. Impact of statin use on outcomes after coronary artery bypass graft surgery. Circulation. 2008;118:1785 1792. doi: 10.1161/ CIRCULATIONAHA.108.799445. 79. Thielmann M, Neuh user M, Marr A, Jaeger BR, Wendt D, Schuetze B, Kamler M, Massoudy P, Erbel R, Jakob H. Lipid-lowering effect of preoperative statin therapy on postoperative major adverse cardiac events after coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2007;134:1143 1149. doi: 10.1016/j.jtcvs.2007.07.029. 80. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of cholesterol-lower- ing treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267 1278. doi: 10.1016/S0140-6736(05)67394-1. 81. Rossouw JE. Lipid-lowering interventions in angiographic trials. Am J Cardiol. 1995;76:86C 92C. 82. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, GoldbergAC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PWF. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce athero- sclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1 S45. doi: 10.1161/01. cir.0000437738.63853.7a. 83. Kulik A, Voisine P, Mathieu P, Masters RG, Mesana TG, Le May MR, Ruel M. Statin therapy and saphenous vein graft disease after coronary bypass surgery: analysis from the CASCADE randomized trial. Ann Thorac Surg. 2011;92:12841290. doi: 10.1016/j.athoracsur.2011.04.107. 84. Yang Z, Kozai T, van der Loo B, Viswambharan H, Lachat M, Turina MI, Malinski T, L scher TF. HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins. J Am Coll Cardiol. 2000;36:1691 1697. 85. Indolfi C, Cioppa A, Stabile E, Di Lorenzo E, Esposito G, Pisani A, Leccia A, Cavuto L, Stingone AM, Chieffo A, Capozzolo C, Chiariello M. Effects of hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin on smooth muscle cell proliferation in vitro and neointimal formation in vivo after vascular injury. J Am Coll Cardiol. 2000;35:214 221. 86. Porter KE, Naik J, Turner NA, Dickinson T, Thompson MM, London NJ. Simvastatin inhibits human saphenous vein neointima formation via inhibition of smooth muscle cell proliferation and migration. J Vasc Surg. 2002;36:150 157. 87. Knatterud GL, Rosenberg Y, Campeau L, Geller NL, Hunninghake DB, Forman SA, Forrester JS, Gobel FL, Herd JA, Hickey A, Hoogwerf BJ, Terrin ML, White C. Long-term effects on clinical outcomes of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anti- coagulation in the Post Coronary Artery Bypass Graft Trial: Post CABG Investigators. Circulation. 2000;102:157 165. 88. Christenson JT. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications fol- lowing CABG. Eur J Cardiothorac Surg. 1999;15:394 399. 89. Christenson JT. Preoperative lipid control with simvastatin protects coro- nary artery bypass grafts from obstructive graft disease. Am J Cardiol. 2001;88:896 899, A8. 90. Aihara K, Miyauchi K, Kasai T, Kubota N, Kajimoto K, Tamura H, Kojima T,Yokoyama K, Kurata T, Amano A, Daida H. Long-term efficacy of pravastatin therapy in diabetic patients undergoing complete coronary revascularization. J Atheroscler Thromb. 2010;17:350 355. 