Sep 2019;37(9):1768-1774. PMID: 30986788. 150. Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: A meta-analysis of randomized controlled trials. Clin Exp Hypertens. 2017;39(3):257-263. PMID: 28448185. 151. Wang C, Xiong B, Huang J. Efficacy and safety of spironolactone in patients with resistant hypertension: A meta-analysis of randomised controlled trials. Heart Lung Circ. Oct 2016;25(10):1021-1030. PMID: 27118266. 152. Makai P, IntHout J, Deinum J, Jenniskens K, Wilt GJV. A network meta-analysis of clinical management strategies for treatment-resistant hypertension: Making optimal use of the evidence. J Gen Intern Med. Aug 2017;32(8):921-930. PMID: 28275946. 153. Williams B, MacDonald TM, Morant SV, et al. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: The PATHWAY-2 mechanisms substudies. Lancet Diabetes Endocrinol. Jun 2018;6(6):464-475. PMID: 29655877. 154. Krieger EM, Drager LF, Giorgi DMA, et al. Spironolactone versus clonidine as a fourth-drug therapy for resistant hypertension: The ReHOT randomized study (Resistant Hypertension Optimal Treatment). Hypertension. Apr 2018;71(4):681-690. PMID: 29463627. 155. Rossignol P, Claggett BL, Liu J, et al. Spironolactone and resistant hypertension in heart failure with preserved ejection fraction. Am J Hypertens. Mar 10 2018;31(4):407-414. PMID: 29228101. 156. Agency for Health Research and Quality. The effective health care program stakeholder guide appendix d: Research questions & PICO(TS) 2011. https://www.ahrq.gov/research/findings/evidence-based- reports/stakeholderguide/appendixc.html. 157. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 2. Framing the question and deciding on important outcomes. J Clin Epidemiol. Apr 2011;64(4):395-400. PMID: 21194891. 158. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to recommendations: The significance and presentation of recommendations. J Clin Epidemiol. Jul 2013;66(7):719-725. PMID: 23312392. 159. National Heart Lung and Blood Institute. Your guide to lowering your blood pressure with DASH: DASH eating plan: Lower your blood pressure. Bethesda, Md. U.S. Dept.


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AHA Scientific Statement Nearly 400 000 coronary artery bypass graft surgery (CABG) procedures are performed annually in the A proven therapy for nearly 50 years, CABG is the most durable and complete treatment of ischemic heart disease. However, in the months and years that fol- low surgery, patients who have undergone CABG remain at risk for subsequent ischemic events as a result of native coronary artery disease (CAD) progression and the devel- opment of vein graft atherosclerosis. Secondary therapies therefore play a key role in the maintenance of native and graft vessel patency and in the prevention of adverse car- diovascular outcomes. Postoperative antiplatelet agents and lipid-lowering therapy continue to be the mainstay of secondary prevention after coronary surgical revasculariza- tion. Other opportunities for improving long-term clinical outcomes after CABG include the aggressive management of hypertension and diabetes mellitus, smoking cessation, weight loss, and cardiac rehabilitation (CR). Secondary pre- ventive therapies help maintain long-term graft patency and help patients obtain the highest level of physical health and quality of life after CABG. This scientific statement seeks to expand on two 2011 American Heart Association (AHA) and American College of Cardiology Foundation (ACCF) documents that provided a general overview of secondary prevention2 and briefly sum- marized the use of medical therapy after surgical coronary Since the writing of these 2 statements, important evidence from clinical and observational trials has emerged that further supports and broadens the merits of intensive risk-reduction therapies for CABG patients. The purpose of this scientific statement, specifically focused on the CABG population, is to thoroughly evaluate the current state of evidence on preventive therapies after surgery. In addition to providing revised and updated recommendations on the use of secondary preventive therapies after CABG, this statement highlights areas in need of prospectively collected clinical trial data.


In addition to providing revised and updated recommendations on the use of secondary preventive therapies after CABG, this statement highlights areas in need of prospectively collected clinical trial data. Comprehensive risk factor management reduces risk as assessed by a variety of outcomes, including improved sur- vival, reduced recurrent events, the need for revasculariza- tion procedures, and improved quality of life. It is important not only that the healthcare providers implement these rec- ommendations in appropriate CABG patients but also that healthcare systems support this implementation to maximize the benefit to the patient. In this scientific statement, clas- sifications of recommendations and levels of evidence are expressed in AHA/ACCF format, as detailed in the Table. Recommendations made herein are based largely on recent clinical and observational trials and major practice guide- lines previously published by the AHA/ACCF and the National Institutes of Health. Thus, the development of the present statement involved a process of partial adaptation of other guideline statements and reports and supplemental lit- erature searches. 2015 American Heart Association, Inc. Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0000000000000182 TheAmerican HeartAssociation makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on December 5, 2014. A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com.


A copy of the document is available at http://my.americanheart.org/statements by selecting either the By Topic link or the By Publication Date link. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@wolterskluwer.com. The American Heart Association requests that this document be cited as follows: Kulik A, Ruel M, Jneid H, Ferguson TB, Hiratzka LF, Ikonomidis JS, Lopez-Jimenez F, McNallan SM, Patel M, Roger VL, Sellke FW, Sica DA, Zimmerman L; on behalf of the American Heart Association Council on Cardiovascular Surgery and Anesthesia. Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association. Circulation. 2015;131:927 964. Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit http://my.americanheart.org/statements and select the Policies and Development link. Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright- Permission-Guidelines_UCM_300404_Article.jsp. A link to the Copyright Permissions Request Form appears on the right side of the page. Secondary Prevention After Coronary Artery Bypass Graft Surgery A Scientific Statement From the American Heart Association Alexander Kulik, MD, MPH, FAHA, Chair; Marc Ruel, MD, MPH, FAHA, Co-Chair; Hani Jneid, MD, FAHA; T. Bruce Ferguson, MD, FAHA; Loren F. Hiratzka, MD, FAHA; John S. Ikonomidis, MD, PhD, FAHA; Francisco Lopez-Jimenez, MD, MSc, FAHA; Sheila M. McNallan, MPH; Mahesh Patel, MD; V ronique L. Roger, MD, MPH, FAHA; Frank W. Sellke, MD, FAHA; Domenic A. Sica, MD, FAHA; Lani Zimmerman, PhD, RN; on behalf of the American Heart Association Council on Cardiovascular Surgery and Anesthesia The recommendations listed in this document are, when- ever possible, evidence based.


Secondary Prevention After Coronary Artery Bypass Graft Surgery A Scientific Statement From the American Heart Association Alexander Kulik, MD, MPH, FAHA, Chair; Marc Ruel, MD, MPH, FAHA, Co-Chair; Hani Jneid, MD, FAHA; T. Bruce Ferguson, MD, FAHA; Loren F. Hiratzka, MD, FAHA; John S. Ikonomidis, MD, PhD, FAHA; Francisco Lopez-Jimenez, MD, MSc, FAHA; Sheila M. McNallan, MPH; Mahesh Patel, MD; V ronique L. Roger, MD, MPH, FAHA; Frank W. Sellke, MD, FAHA; Domenic A. Sica, MD, FAHA; Lani Zimmerman, PhD, RN; on behalf of the American Heart Association Council on Cardiovascular Surgery and Anesthesia The recommendations listed in this document are, when- ever possible, evidence based. Writing group members per- formed these relevant supplemental literature searches with key search phrases, including but not limited to coronary artery bypass graft surgery; tobacco, smoking, and smoking cessation; blood pressure control and hypertension; choles- terol, hypercholesterolemia, lipids, lipoproteins, and dyslipid- emia; physical activity, exercise, and exercise training; weight management, overweight, and obesity; type 2 diabetes melli- tus management; antiplatelet agents and anticoagulants; renin, angiotensin, and aldosterone system blockers; -blockers; influenza vaccination; clinical depression and depression screening; and cardiac rehabilitation. These searches were limited to studies, reviews, and other evidence conducted in human subjects and published since 1979. In addition, writ- ing group members reviewed documents related to the subject matter previously published by the AHA, the ACCF, and the National Institutes of Health. Antiplatelet Therapy Aspirin First discovered in 1897, aspirin irreversibly inhibits platelet cyclooxygenase-1. By decreasing thromboxane A2 produc- tion, aspirin prevents platelet aggregation, reducing the risk of stroke, myocardial infarction (MI), and vascular death Table. Applying Classification of Recommendation and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak.


Applying Classification of Recommendation and Level of Evidence A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated. Kulik et al Secondary Prevention After CABG 929 in patients with ischemic heart disease.4,5 Over 30 years of experience has accrued with the use of aspirin after cardiac surgery, and essentially all patients undergoing CABG are candidates for long-term aspirin therapy.6 Aspirin inhibition of platelet function after CABG helps maintain graft patency and prevent major adverse cardiovascular events. Aspirin sig- nificantly improves vein graft patency rates, particularly dur- ing the first postoperative year. Preoperative aspirin use is safe and appears to reduce CABG operative morbidity and mortal- Therefore, aspirin should ideally be initiated before surgery at the time of hospital admission (with acute coronary syndrome or MI) or when CAD is first diagnosed.5,9,10 Considerable research has been performed to evaluate the impact of different dosing regimens and initiation times on post-CABG graft patency. The first randomized trials on the subject were conducted in the late 1970s, demonstrating that aspirin was safe for use in the postoperative period.


The first randomized trials on the subject were conducted in the late 1970s, demonstrating that aspirin was safe for use in the postoperative period. However, no benefit was seen in terms of graft patency in these early studies because of limited trial enrollment and late admin- istration, typically 3 days after surgery.11 13 In one of the first studies assessing aspirin administration within the early hours after surgery, Chesebro et al14 conducted a controlled trial comparing graft patency in 407 patients randomized to placebo or the combination of aspirin and dipyridamole beginning as early as 7 hours after surgery. Within 1 month of surgery, vein graft patency was significantly higher in patients treated with antiplatelet therapy (98% versus 90%, aspirin and dipyridamole versus placebo; P<0.0001). In a subsequent report, the authors noted an improvement in vein graft patency with antiplatelet therapy 1 year after surgery (89% versus 77%, aspirin and dipyridamole versus placebo; P<0.0001). Antiplatelet therapy was also shown to prevent the development of late vein graft occlusions in those patients whose grafts were documented as patent at the 1-month time point (6% versus 14% late occlusion rate, aspirin and dipyri- damole versus placebo; P=0.02).15 The largest placebo-controlled trial to date, the Veterans Administration Cooperative Study, randomized 772 CABG patients to several postoperative aspirin regimens admin- istered for 1 year. Within 60 days of surgery, 555 patients (1781 grafts) underwent angiographic graft assessment, revealing the following graft patency rates: aspirin 325 mg daily, 93.5%; aspirin 325 mg 3 times daily, 92.3%; and aspi- rin 325 mg and dipyridamole 75 mg 3 times daily, 91.9%.


Within 60 days of surgery, 555 patients (1781 grafts) underwent angiographic graft assessment, revealing the following graft patency rates: aspirin 325 mg daily, 93.5%; aspirin 325 mg 3 times daily, 92.3%; and aspi- rin 325 mg and dipyridamole 75 mg 3 times daily, 91.9%. Compared with the patency rate of placebo (85.2%), aspirin regimens significantly improved graft patency (P<0.05).16 In a subsequent report of 1-year graft patency assessed in 406 patients (1315 grafts), the graft occlusion rate was 15.8% in all of the aspirin groups combined compared with 22.6% for the placebo group (P=0.03). Thus, early postoperative aspirin administered for 1 year, regardless of dose, improved 60-day In addition to its graft patency benefits, several observa- tional studies have shown that aspirin use is associated with improved clinical outcomes after CABG. In 2002, Mangano evaluated the impact of aspirin administration within 48 hours after surgery. Among 5022 patients who survived the first 48 hours after surgery, aspirin (up to 650 mg daily) was administered to 59.7%. In their analysis, the authors reported that postoperative aspirin therapy within 48 hours of surgery was associated with a 68% reduction in the incidence of post- operative death (1.3% versus 4.0%, aspirin versus no aspirin; P<0.001). Aspirin was also associated with a 48% reduc- tion in the incidence of MI (2.8% versus 5.4%; P<0.001), a 50% reduction in the incidence of stroke (1.3% versus 2.6%; P=0.01), a 74% reduction in the incidence of renal failure (0.9% versus 3.4%; P<0.001), and a 62% reduction in the incidence of bowel infarction (0.3% versus 0.8%; P=0.01).


Aspirin was also associated with a 48% reduc- tion in the incidence of MI (2.8% versus 5.4%; P<0.001), a 50% reduction in the incidence of stroke (1.3% versus 2.6%; P=0.01), a 74% reduction in the incidence of renal failure (0.9% versus 3.4%; P<0.001), and a 62% reduction in the incidence of bowel infarction (0.3% versus 0.8%; P=0.01). Moreover, the authors reported that aspirin administration within 48 hours of surgery was safe, without an increase in the risk of hemorrhage, gastritis, infection, or impaired wound healing (odds ratio [OR] for adverse events, 0.63; 95% con- fidence interval [CI], 0.54 0.74).18 In a study assessing the impact of long-term postoperative aspirin therapy, Johnson found that CABG patients who consistently took aspi- rin over a 4-year period after surgery had significantly better long-term survival compared with those who did not (relative risk [RR] of death, 0.58; 95% CI, 0.47 0.70). Similar findings were noted in a long-term analysis of the CABG cohort of the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial, in which a lack of aspirin prescription at hospital discharge was identified as the strongest predictor of death at 4 years (hazard ratio [HR], With several trials featuring varied treatment protocols hav- ing been published in the literature, Fremes et al21 reviewed the impact of antiplatelet and anticoagulant therapy on vein graft patency in a meta-analysis of 17 randomized trials.


Similar findings were noted in a long-term analysis of the CABG cohort of the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial, in which a lack of aspirin prescription at hospital discharge was identified as the strongest predictor of death at 4 years (hazard ratio [HR], With several trials featuring varied treatment protocols hav- ing been published in the literature, Fremes et al21 reviewed the impact of antiplatelet and anticoagulant therapy on vein graft patency in a meta-analysis of 17 randomized trials. Summarizing the data, the authors reported that aspirin sig- nificantly reduced the odds of graft occlusion compared with placebo (aspirin with or without dipyridamole versus placebo: damole with aspirin provided no additional benefit compared with aspirin alone (aspirin plus dipyridamole versus aspirin further noted that a low (100 mg) to medium (325 mg) dose of daily aspirin was more effective and safer than a high dose (975 mg). Although preoperative administration provided no additional benefit, the ideal time for initiation of aspirin appeared to be within 6 hours after CABG. All together, the authors recommended indefinite aspirin use postoperatively in doses of 100 to 325 mg daily. Subsequently, Lim et al22 performed a meta-analysis of 5 randomized, controlled tri- als to compare the efficacy of low-dose (50 100 mg daily) and medium-dose (300 325 mg daily) aspirin therapy after CABG. Compared with low-dose aspirin, there was a trend toward an improvement in graft patency in favor of medium- statistical significance was not achieved, the authors advo- cated for the use of aspirin at a medium dose of 325 mg daily because of its excellent safety profile and minimal increase in cost.


Compared with low-dose aspirin, there was a trend toward an improvement in graft patency in favor of medium- statistical significance was not achieved, the authors advo- cated for the use of aspirin at a medium dose of 325 mg daily because of its excellent safety profile and minimal increase in cost. This finding is in agreement with the results of previous studies that demonstrated that lower doses of aspirin (100 200 mg) may be insufficient to effectively inhibit platelet function early after CABG as a result of resistance to the antiplatelet effect of aspirin in the postoperative period.23,24 A phenom- enon called aspirin resistance, this factor may adversely affect postoperative vein graft patency.23,25,26 Receptor Inhibitors Clopidogrel is a thienopyridine antiplatelet agent that irre- versibly inhibits the platelet P2Y12 adenosine diphosphate receptor. When exposed to clopidogrel, platelets are inhib- ited from aggregating for the remainder of their 7- to 10-day In contrast to ticlopidine, a thienopyridine that had been shown to improve graft patency,29,30 clopidogrel is 7-fold more potent and free of the unfavorable side effect profile of ticlopidine, which includes neutropenia and rash.28 Combining aspirin therapy with clopidogrel leads to potent synergistic antithrombotic effects,31 and substantial benefits have been demonstrated in several CAD trials studying the impact of dual antiplatelet therapy.32,33 The potential clinical benefits of clopidogrel administra- tion after CABG were first evaluated in subgroup analyses from the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO) multicenter trials. In the CURE study, 12562 patients presenting with acute coro- nary syndromes without ST-segment elevation were random- ized to aspirin alone or aspirin plus clopidogrel for 3 to 12 months.


In the CURE study, 12562 patients presenting with acute coro- nary syndromes without ST-segment elevation were random- ized to aspirin alone or aspirin plus clopidogrel for 3 to 12 months. The primary outcome (cardiovascular death, nonfatal MI, or stroke) occurred in 9.3% of patients treated with aspi- rin plus clopidogrel compared with 11.4% in patients treated with aspirin alone (P<0.001).32 In the subgroup of patients who ultimately underwent CABG after enrollment in the trial, there was a trend favoring aspirin plus clopidogrel with a reduction of the primary outcome (14.5% versus 16.2%, aspirin plus clopidogrel versus aspirin alone; RR, 0.89; 95% CI, 0.71 1.11). However, that benefit was entirely preopera- tive while the patients were awaiting surgery, and no benefit for clopidogrel was demonstrated for CURE patients after In response to a suggestion that dual antiplatelet therapy may be beneficial after CABG, Kim et al35 evaluated a large administrative database to compare the early clinical outcomes of 3268 patients who received both clopidogrel and aspirin early after CABG (with or without cardiopulmonary bypass) with those of 11799 patients who were treated with aspirin alone. Using propensity-score analysis, the authors found that compared with aspirin alone, dual antiplatelet therapy was associated with lower in-hospital mortality (1.0% ver- there was no difference in the rate of ischemic events (1.3% surprisingly, bleeding events were significantly lower in the group who received both aspirin and clopidogrel (4.2% versus cerns about selection bias. Similar findings were reported by S rensen et al,36 who evaluated the efficacy of clopidogrel after CABG using administrative data from 3545 patients in Denmark. Using multivariate analysis, the authors reported a lower risk of death (adjusted HR, 0.34; 95% CI, 0.20 0.61) in patients who received clopidogrel after surgery.


Using multivariate analysis, the authors reported a lower risk of death (adjusted HR, 0.34; 95% CI, 0.20 0.61) in patients who received clopidogrel after surgery. However, clopidogrel did not significantly reduce the incidence of recur- rent MI, cardiovascular death, or the need for repeat revascu- larization in this study. To date, 4 clinical trials have evaluated the impact of clopi- dogrel on the process of vein graft disease and graft occlusion after on-pump CABG, although most studies have enrolled a mix of both on-pump and off-pump patients. In the first study published in 2009, Gao and colleagues37 performed a nonran- domized trial involving 197 CABG patients, 37% of whom underwent off-pump surgery. Patients were assigned postop- eratively to either isolated clopidogrel 75 mg daily (n=102) or clopidogrel 75 mg plus aspirin 100 mg daily (n=95) on the basis of a weekly alternating treatment scheme. The trial was neither blinded nor placebo controlled. No significant dif- ference in graft patency was seen when isolated clopidogrel treatment was compared with dual antiplatelet therapy after CABG through the use of computed tomography angiography year: 93.5% versus 96.3%, P=0.25, clopidogrel versus clopi- dogrel plus aspirin). Although no differences were noted in this trial, other studies have suggested that clopidogrel on its own may be insufficient as a sole antiplatelet agent early after CABG. Unlike aspirin, clopidogrel does not apprecia- bly inhibit platelet aggregation during the first 5 postopera- tive days after coronary surgery,38 and it is not until days 9 to 28 after CABG that the antiplatelet effects of clopidogrel (at daily doses of 75 mg) become apparent.39 In a subsequent placebo-controlled trial, Sun et al40 used partial blinding to compare the combination of postoperative clopidogrel 75 mg and aspirin 81 mg daily with aspirin 81 mg alone among 100 patients undergoing on-pump CABG.


Unlike aspirin, clopidogrel does not apprecia- bly inhibit platelet aggregation during the first 5 postopera- tive days after coronary surgery,38 and it is not until days 9 to 28 after CABG that the antiplatelet effects of clopidogrel (at daily doses of 75 mg) become apparent.39 In a subsequent placebo-controlled trial, Sun et al40 used partial blinding to compare the combination of postoperative clopidogrel 75 mg and aspirin 81 mg daily with aspirin 81 mg alone among 100 patients undergoing on-pump CABG. Graft patency was assessed with computed tomography angi- ography, which was performed for 79 patients at 1 month. No difference was seen in terms of graft patency between the 2 groups, either among all grafts (92.9% versus 95%, aspirin versus aspirin and clopidogrel; P=0.43) or vein grafts alone (93.2% versus 93.5%, aspirin versus aspirin and clopidogrel; P=0.92). In the first trial to demonstrate a statistical impact of clopi- dogrel on graft patency, Gao et al41 randomized 249 patients undergoing CABG (58% off-pump) to receive either clopi- dogrel 75 mg plus aspirin 100 mg daily or aspirin 100 mg alone starting within 48 hours of surgery. No blinding or pla- cebo control was used in this trial. At 3 months, graft patency was assessed in 90% of patients with computed tomography angiography. Overall graft patency was not significantly dif- ferent between the 2 groups (89.7% versus 93.5%, aspirin versus aspirin and clopidogrel; P=0.07). However, vein graft patency was significantly improved in the combined treatment group compared with the isolated aspirin treatment group (85.7% versus 91.6%, aspirin versus aspirin and clopidogrel; P=0.04).


However, vein graft patency was significantly improved in the combined treatment group compared with the isolated aspirin treatment group (85.7% versus 91.6%, aspirin versus aspirin and clopidogrel; P=0.04). Although dual antiplatelet therapy improved vein graft patency in this study, providing low-dose aspirin (100 mg) to the control subjects may have resulted in undertreat- ment of these patients, biasing the results in favor of those who received combination therapy. Using a higher dose of aspirin, the Clopidogrel After Surgery For Coronary Artery Disease (CASCADE) trial was a randomized, double-blind, placebo-controlled trial of 113 patients comparing aspirin 162 mg daily with aspirin 162 mg plus clopidogrel 75 mg daily. The majority of patients (96%) underwent on-pump CABG in this study. Patients underwent conventional coronary angiography 1 year after surgery, and each patient underwent intravascular ultrasound assessment of Kulik et al Secondary Prevention After CABG 931 1 randomly selected vein graft to evaluate the extent of graft intimal hyperplasia. The combination of aspirin plus clopido- grel did not significantly reduce the development of vein graft intimal hyperplasia as indicated by intravascular ultrasound 1 year after CABG compared with aspirin. Overall graft patency (95.2% versus 95.5%, aspirin and clopidogrel versus aspirin; P=0.90) and vein graft patency (94.3% versus 93.2%, aspi- rin and clopidogrel versus aspirin; P=0.69) were not different between the groups at 1 year.42 Most recently, investigators from the Randomized On/ Off Bypass (ROOBY) on-pump and off-pump CABG trial performed an observational study to evaluate the impact of clopidogrel use on graft patency 1 year after surgery. The authors noted similar graft patency between patients who received clopidogrel after surgery (86.5%) and those who To summarize the published data, 3 meta-analyses have assessed the potential benefits of dual antiplatelet therapy after CABG, presenting mixed results.


The authors noted similar graft patency between patients who received clopidogrel after surgery (86.5%) and those who To summarize the published data, 3 meta-analyses have assessed the potential benefits of dual antiplatelet therapy after CABG, presenting mixed results. In the largest meta-analysis on the subject involving 5 ran- domized trials and 6 observational studies including >25000 patients, dual antiplatelet therapy was found to reduce vein On the other hand, another review came to the opposite con- clusion, stating that combination antiplatelet therapy has not been demonstrated to improve graft patency.45 Although there is some suggestion that adding clopidogrel to aspirin may improve postoperative vein graft patency, that effect appears to be most pronounced after off-pump CABG.44 46 Dual anti- platelet therapy was also found to significantly increase the risk of major bleeding after surgery.44 Whereas controversy remains concerning clopidogrel use after CABG, 2 new agents have recently been introduced, increasing the number of therapeutic options available for postoperative platelet inhibition. Like clopidogrel, both prasu- grel and ticagrelor inhibit the platelet P2Y12 adenosine diphos- phate receptor, but they have a more rapid onset of action and more consistent and pronounced platelet inhibition than clopi- Prasugrel was first evaluated in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) study, in which 13608 patients presenting with acute coronary syndromes were ran- domized to receive aspirin plus clopidogrel 75 mg daily or aspirin plus prasugrel 10 mg daily for 6 to 15 months.


Like clopidogrel, both prasu- grel and ticagrelor inhibit the platelet P2Y12 adenosine diphos- phate receptor, but they have a more rapid onset of action and more consistent and pronounced platelet inhibition than clopi- Prasugrel was first evaluated in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) study, in which 13608 patients presenting with acute coronary syndromes were ran- domized to receive aspirin plus clopidogrel 75 mg daily or aspirin plus prasugrel 10 mg daily for 6 to 15 months. The pri- mary outcome (cardiovascular death, nonfatal MI, or stroke) was significantly reduced for patients who received prasugrel although major bleeding complications were observed more frequently with prasugrel (2.4% versus 1.8%, prasugrel versus In a post hoc analysis of the 346 ran- domized patients in the TRITON-TIMI 38 study who under- went CABG, prasugrel was associated with a lower rate of death after CABG compared with clopidogrel (adjusted OR, 0.26; P=0.025). However, prasugrel led to more blood loss after surgery (P=0.05).50 The use of ticagrelor for the treatment of acute coronary syndrome was assessed in the Platelet Inhibition and Patient Outcomes (PLATO) study, a randomized trial comparing 1-year treatment with aspirin plus ticagrelor 90 mg twice daily with aspirin plus clopidogrel 75 mg daily in 18624 patients. The primary end point of the study (cardiovascular death, MI, or stroke) was significantly reduced by ticagrelor (9.8% versus 11.7%, ticagrelor versus clopidogrel; P<0.001), but ticagrelor was associated with a higher rate of major bleeding (4.5% versus 3.8%, ticagrelor versus clopidogrel; P=0.03). The trial investigators thereafter performed a post hoc analysis of the 1261 patients who underwent CABG within 7 days of receiv- ing study drug treatment in PLATO.


The trial investigators thereafter performed a post hoc analysis of the 1261 patients who underwent CABG within 7 days of receiv- ing study drug treatment in PLATO. In this CABG subgroup, ticagrelor led to a nonsignificant reduction in the primary end point at 1 year (10.6% versus 13.1%, ticagrelor versus clopi- dogrel; P=0.29) and a significant reduction in cardiovascular mortality (4.1% versus 7.9%, ticagrelor versus clopidogrel; P<0.01). There was no significant difference in CABG-related major bleeding between the randomized treatments.49 On fur- ther review of the causes of death in the CABG subgroup, the mortality reduction with ticagrelor appeared to be related to fewer deaths as a result of cardiovascular, bleeding, and infec- tion complications compared with clopidogrel.51 Although the post hoc analyses of prasugrel and ticagre- lor after surgery are provocative, no prospective, randomized data have yet to become available on their use specifically in the CABG population. This area remains the subject of active research, with ongoing antiplatelet trials evaluating graft patency and clinical events compared with standard isolated aspirin therapy. Off-Pump CABG By avoiding cardiopulmonary bypass, off-pump surgery (off- pump coronary artery bypass [OPCAB]) reduces the systemic inflammatory response after CABG and improves hemostasis by averting the activation and consumption of clotting factors and platelets associated with bypass. However, the clotting disorders and platelet dysfunction induced by cardiopulmo- nary bypass may actually have desirable effects by protecting anastomosis patency and preventing graft thrombosis.


However, the clotting disorders and platelet dysfunction induced by cardiopulmo- nary bypass may actually have desirable effects by protecting anastomosis patency and preventing graft thrombosis. Several reports have documented the existence of a relative hyperco- agulable state after off-pump surgery, associated with higher levels of postoperative platelet activity and a decrease in plate- let sensitivity to aspirin after OPCAB.52 60 Moreover, in some early studies of graft patency after OPCAB, vein graft occlu- sion was noticeably higher both early and late after OPCAB compared with conventional CABG.53,61 Questions were therefore raised about whether antiplatelet therapy with aspi- rin alone would be sufficient for patients after OPCAB, and as early as 2003, leading off-pump centers instituted policy changes to treat all OPCAB patients with both clopidogrel and aspirin after surgery for a duration of 3 months.62 Although dual antiplatelet therapy developed into the stan- dard of care after OPCAB, data confirming the merits of com- bined aspirin and clopidogrel after off-pump surgery have been fairly limited. Some benefits were noted in terms of improved and clinical outcomes64 in single-center obser- vational studies. In a small, randomized trial comparing the combination of clopidogrel 75 mg and aspirin 150 mg daily with aspirin 150 mg alone, Nielsen et al65 noted that patients who received dual antiplatelet therapy achieved greater plate- let inhibition as determined by thromboelastography studies 30 days after OPCAB. Most recently, Mannacio et al66 performed a single-center, prospective, randomized trial to evaluate the impact of clopidogrel on graft patency after off-pump surgery. Three hundred OPCAB patients without a history of diabetes mellitus were randomized to receive either aspirin 100 mg plus clopidogrel 75 mg daily or aspirin 100 mg daily for 1 year after surgery.


Three hundred OPCAB patients without a history of diabetes mellitus were randomized to receive either aspirin 100 mg plus clopidogrel 75 mg daily or aspirin 100 mg daily for 1 year after surgery. The authors noted that combined therapy with aspirin and clopidogrel was associated with a significant reduc- tion in the rate of vein graft occlusion as assessed by computed tomography angiography at 1 year (7.4% versus 13.1%, aspirin and clopidogrel versus aspirin alone; P=0.04). Similar findings were reported in a meta-analysis evaluating the role of dual antiplatelet therapy after CABG surgery in which the benefit of combined clopidogrel and aspirin treatment was most pro- nounced after off-pump CABG, reducing vein graft occlusion by 55% compared with aspirin alone.44 Antiplatelet Therapy Recommendations 1. Aspirin should be administered preoperatively and within 6 hours after CABG in doses of 81 to 325 mg daily. It should then be continued indefinitely to reduce graft occlusion and adverse cardiac events (Class I; Level of Evidence A). 2. After off-pump CABG, dual antiplatelet should be administered for 1 year with combined aspirin (81 162 mg daily) and clopidogrel 75 mg daily to reduce graft occlusion (Class I; Level of Evidence A). 3. Clopidogrel 75 mg daily is a reasonable alterna- tive after CABG for patients who are intolerant of or allergic to aspirin. It is reasonable to continue it indefinitely (Class IIa; Level of Evidence C). 4. In patients who present with acute coronary syn- drome, it is reasonable to administer combination antiplatelet therapy after CABG with aspirin and either prasugrel or ticagrelor (preferred over clopi- dogrel), although prospective clinical trial data from CABG populations are not yet available (Class IIa; Level of Evidence B). 5.


In patients who present with acute coronary syn- drome, it is reasonable to administer combination antiplatelet therapy after CABG with aspirin and either prasugrel or ticagrelor (preferred over clopi- dogrel), although prospective clinical trial data from CABG populations are not yet available (Class IIa; Level of Evidence B). 5. As sole antiplatelet therapy after CABG, it is rea- sonable to consider a higher aspirin dose (325 mg daily) rather than a lower aspirin dose (81 mg daily), presumably to prevent aspirin resistance, but the benefits are not well established (Class IIa; Level of Evidence A). 6. Combination therapy with both aspirin and clopi- dogrel for 1 year after on-pump CABG may be con- sidered in patients without recent acute coronary syndrome, but the benefits are not well established (Class IIb; Level of Evidence Level A). Antithrombotic Therapy In the early years of coronary bypass graft surgery, before the introduction of routine aspirin use in the 1980s, a need was recognized for adjunctive pharmacotherapy to improve patency and to prevent thrombosis of bypass grafts after CABG. With the hypothesis that anticoagulation could reduce the likelihood of graft occlusion, several trials were performed to evaluate the role of anticoagulation with warfarin, a vitamin K antagonist. In 1979, in one of the first trials on the subject, Pantely et al11 found no improvement in graft patency among CABG patients treated with warfarin. Two subsequent stud- ies suggested some benefit associated with warfarin treatment, but aspirin treatment had yet to be incorporated into everyday practice at that time.12,67 In the largest trial in the field, the Post-Coronary Artery Bypass Graft (Post-CABG) trial ran- domized 1351 patients to low-dose warfarin anticoagulation (mean international normalized ratio, 1.4) or placebo, with all patients receiving aspirin 81 mg daily.


Two subsequent stud- ies suggested some benefit associated with warfarin treatment, but aspirin treatment had yet to be incorporated into everyday practice at that time.12,67 In the largest trial in the field, the Post-Coronary Artery Bypass Graft (Post-CABG) trial ran- domized 1351 patients to low-dose warfarin anticoagulation (mean international normalized ratio, 1.4) or placebo, with all patients receiving aspirin 81 mg daily. The authors noted no significant differences in angiographic outcome between the patients who were randomized to warfarin or placebo, and warfarin did not slow the process of vein graft disease.68 With inconsistent results reported from clinical trials and increased bleeding risks associated with warfarin, Fremes et summarized the literature with a meta-analysis of 17 tri- als on antithrombotic and antiplatelet therapy after CABG. This analysis illustrated that both aspirin (OR, 0.60; 95% CI, 0.33 0.93; P=0.025) reduced the odds of graft occlusion com- pared with placebo. However, anticoagulation did not improve graft patency compared with aspirin alone (OR, 0.95; 95% CI, 0.62 1.44; P=0.87). Overall, the data do not support the use of warfarin anti- thrombotic therapy to prevent graft occlusion after CABG or to slow the process of vein graft disease. Outside the scope of this statement and covered in detail elsewhere, postopera- tive antithrombotic therapy should continue to be reserved for patients recovering from CABG who have other indications for warfarin, including those with atrial fibrillation (AF),69 patients with a history of venous thromboembolism,70 and those who undergo concurrent valve replacement at the time When warfarin is prescribed after CABG, aspirin is typically administered at lower doses (75 162 mg daily) to reduce the risk of bleeding complications.69 71 Although newer antithrombotic agents (dabigatran, apixaban, rivaroxaban) have recently become available, their efficacy in the CABG population has yet to be prospectively evaluated.


Outside the scope of this statement and covered in detail elsewhere, postopera- tive antithrombotic therapy should continue to be reserved for patients recovering from CABG who have other indications for warfarin, including those with atrial fibrillation (AF),69 patients with a history of venous thromboembolism,70 and those who undergo concurrent valve replacement at the time When warfarin is prescribed after CABG, aspirin is typically administered at lower doses (75 162 mg daily) to reduce the risk of bleeding complications.69 71 Although newer antithrombotic agents (dabigatran, apixaban, rivaroxaban) have recently become available, their efficacy in the CABG population has yet to be prospectively evaluated. Moreover, safety concerns have been raised about their use early after surgery and in those with mechanical prosthetic valves.72 74 Antithrombotic Therapy Recommendations 1. Warfarin should not be routinely prescribed after CABG for graft patency unless patients have other indications for long-term antithrombotic therapy (such as AF, venous thromboembolism, or a mechani- cal prosthetic valve) (Class III; Level of Evidence A). 2. Antithrombotic alternatives to warfarin (dabiga- tran, apixaban, rivaroxaban) should not be routinely administered early after CABG until additional safety data have accrued (Class III; Level of Evidence C). Lipid Management Statins and Low-Density Lipoprotein Management Elevated low-density lipoprotein (LDL) cholesterol levels strongly influence the process of saphenous vein graft disease after CABG, including the development of intimal hyperplasia Kulik et al Secondary Prevention After CABG 933 and atheromatous plaques.75,76 Through lifestyle changes and medications, the treatment of hyperlipidemia reduces adverse cardiovascular events in patients with CAD, and among CABG patients in particular.68,77 79 Statins, the most com- monly prescribed agents for hyperlipidemia, have been shown to improve survival and to reduce the risks of adverse car- diovascular events across a wide range of cholesterol levels.


Lipid Management Statins and Low-Density Lipoprotein Management Elevated low-density lipoprotein (LDL) cholesterol levels strongly influence the process of saphenous vein graft disease after CABG, including the development of intimal hyperplasia Kulik et al Secondary Prevention After CABG 933 and atheromatous plaques.75,76 Through lifestyle changes and medications, the treatment of hyperlipidemia reduces adverse cardiovascular events in patients with CAD, and among CABG patients in particular.68,77 79 Statins, the most com- monly prescribed agents for hyperlipidemia, have been shown to improve survival and to reduce the risks of adverse car- diovascular events across a wide range of cholesterol levels. Statins also reduce the progression of native artery atheroscle- Of importance to the CABG population, statins have been demonstrated to inhibit the development of saphe- nous vein graft disease68,83 by reducing neointimal formation and smooth muscle proliferation.84 86 A number of studies have investigated the role of statins for postoperative cholesterol reduction after CABG. In the land- mark Post-CABG Trial, 1351 patients who had previously undergone CABG 1 to 11 years earlier and who had LDL lev- els between 130 and 175 mg/dL were randomized to aggres- sive cholesterol reduction with lovastatin 40 to 80 mg daily or moderate cholesterol reduction with lovastatin 2.5 to 5 mg daily. As measured annually during the study period, mean LDL levels of patients who received aggressive treatment ranged from 93 to 97 mg/dL compared with 132 to 136 mg/ dL for patients who received moderate treatment (P<0.001).


As measured annually during the study period, mean LDL levels of patients who received aggressive treatment ranged from 93 to 97 mg/dL compared with 132 to 136 mg/ dL for patients who received moderate treatment (P<0.001). Angiography 4 years after study initiation demonstrated that aggressive cholesterol reduction lowered the incidence of new vein graft occlusions (10% versus 21%, aggressive reduction versus moderate reduction; P<0.0001) and the number of grafts with progression of atherosclerosis (27% versus 39%, aggressive reduction versus moderate reduction; P<0.001).68 In a follow-up study of trial participants 3 years later, the aggressive treatment approach was associated with a 30% reduction in the need for repeat revascularization and a 24% reduction in adverse cardiovascular events (both P=0.001).87 Overall, the Post-CABG trial noted that aggressive lowering of LDL to <100 mg/dL reduced both cardiovascular events and the progression of atherosclerosis in native coronary arter- ies and saphenous vein grafts.68,87 The importance of postoperative LDL reduction with statins has been confirmed in several other randomized and observational studies in the cardiac surgery literature.


Angiography 4 years after study initiation demonstrated that aggressive cholesterol reduction lowered the incidence of new vein graft occlusions (10% versus 21%, aggressive reduction versus moderate reduction; P<0.0001) and the number of grafts with progression of atherosclerosis (27% versus 39%, aggressive reduction versus moderate reduction; P<0.001).68 In a follow-up study of trial participants 3 years later, the aggressive treatment approach was associated with a 30% reduction in the need for repeat revascularization and a 24% reduction in adverse cardiovascular events (both P=0.001).87 Overall, the Post-CABG trial noted that aggressive lowering of LDL to <100 mg/dL reduced both cardiovascular events and the progression of atherosclerosis in native coronary arter- ies and saphenous vein grafts.68,87 The importance of postoperative LDL reduction with statins has been confirmed in several other randomized and observational studies in the cardiac surgery literature. A small, controlled trial published in 1999 noted that statin treatment started 4 weeks preoperatively and continued for 1 year after CABG reduced the risk of MI both in the perioperative period (0% versus 14%, preoperative statin versus regular care; and during the first year after CABG (0% ver- sus 19%, preoperative statin versus regular care; P=0.03).89 In a cohort study of 7503 patients, statin treatment within 1 month of CABG was independently associated with a reduc- tion in the risk of all-cause mortality (adjusted HR, 0.82; 95% CI, 0.72 0.94; P=0.004) and major adverse cardiovascular Nearly identical findings were reported in 2 observational studies that followed, with significant associa- tions demonstrated between postoperative statin therapy and lower all-cause mortality and cardiac events long term after Of interest, the survival benefits associated with statins after CABG appear to be similar in magnitude to that associated with the use of 2 internal mammary artery grafts compared with the use of only 1 graft.92 In addition to their lipid-lowering effects, statins appear have important non lipid-related actions that may contribute to their beneficial effect.93,94 These cholesterol-independent or pleiotropic properties include improvements in endothelial function, nitric oxide levels, and antioxidant activity, as well as the inhibition of inflammatory responses, vasoconstric- tion, thrombosis, and platelet aggregation.94 98 Administering statins before surgery has been shown to diminish the systemic inflammatory response associated with the use of cardiopul- monary bypass during CABG.99 102 Through antisympathetic activity and the stabilization of ion channels,103 both random- ized and observational studies have illustrated that statin treat- ment significantly reduces the risk of AF after CABG both in the perioperative period and long term after surgery.104 110 Although selection bias cannot be excluded, several nonran- domized, retrospective studies have noted significant asso- ciations between perioperative statin use and a lower risk of postoperative renal dysfunction,111,112 even among patients without elevated lipid profiles before surgery.119 Some investigators have sug- gested that preoperative statin treatment may reduce the risk of mortality late after surgery,117,120 122 but it is also possible that preoperative statin administration simply predicts those who will receive statins after surgery,123 ultimately leading to improved long-term outcomes.78 Recently, attention in the cardiology community has turned toward the use of high-intensity statin therapy to achieve an LDL reduction to 70 mg/dL to further improve cardiovas- cular outcomes in patients with CAD.77,82,124 In the Treating to New Targets (TNT) Trial, 10001 patients with CAD were ran- domized to receive either atorvastatin 80 mg/d or atorvastatin In a subgroup analysis that focused on the 4654 patients with a history of previous CABG, atorvastatin 80 mg was associated with a significantly lower risk for adverse car- and a lower need for repeat revascularization (HR, 0.70; 95% CI, 0.60 0.82; P<0.0001) during follow-up compared with Similar findings, albeit nonsignificant, were also reported in the comparison of intensive statin therapy with standard statin therapy among patients with a history of previous CABG in the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction (PROVE-IT TIMI 22) and the Aggrastat to Zocor (A to Z) tri- Although a potential benefit with high-intensity statin therapy was suggested, these subgroup analyses were limited by the lack of graft patency data and the lengthy time span between surgery and study recruitment.


More recently, several studies have evaluated the impact of intensive lipid reduction early after CABG. In a cohort study of 418 CABG patients, Ouattara et al128 noted a significant reduction in the incidence of perioperative cardiovascular events (heart failure, malignant arrhythmia, or cardiac death) in patients who received high-dose statin therapy before sur- gery compared with those who were treated with low-dose intracoronary angioscopy 12 to 16 months after CABG, Hata noted yellow plaque and thrombus in the vein grafts of all 11 studied patients who had LDL levels >100 mg/dL (mean, 130 mg/dL). In contrast, in the 10 patients who had LDL levels <80 mg/dL (mean, 64 mg/dL), no yellow plaque or thrombus was seen, suggesting that aggressive lipid-low- ering therapy after CABG may prevent the development of saphenous vein graft disease. In a recent post hoc analysis of the CASCADE trial, 1-year graft patency was notably higher for patients with LDL levels <100 mg/dL (96.5%) compared with those with LDL levels >100 mg/dL (83.3%; P=0.03). However, no improvement in graft patency was noted with further LDL reduction to <70 mg/dL (P=1.00).83 Extensive evidence exists supporting the use of high-inten- sitystatintherapyforsecondarypreventionamongpatientswith clinical atherosclerotic cardiovascular disease.82 Although the data are sparse in the CABG literature, the recent ACC/AHA cholesterol guideline statement recommended high-intensity statin therapy for the majority of patients who have clinical atherosclerotic cardiovascular disease, which would include nearly all patients who have previously undergone CABG.82 The only exception to this recommendation relates to patients >75 years of age, given the potential for drug-drug interactions in this population and because few patients of this age were included in the high-intensity statin trials.82 Notwithstanding the new recommendations, little experience has accrued with the use of high-intensity statin therapy early after CABG as it relates to patient compliance and side effects.


However, no improvement in graft patency was noted with further LDL reduction to <70 mg/dL (P=1.00).83 Extensive evidence exists supporting the use of high-inten- sitystatintherapyforsecondarypreventionamongpatientswith clinical atherosclerotic cardiovascular disease.82 Although the data are sparse in the CABG literature, the recent ACC/AHA cholesterol guideline statement recommended high-intensity statin therapy for the majority of patients who have clinical atherosclerotic cardiovascular disease, which would include nearly all patients who have previously undergone CABG.82 The only exception to this recommendation relates to patients >75 years of age, given the potential for drug-drug interactions in this population and because few patients of this age were included in the high-intensity statin trials.82 Notwithstanding the new recommendations, little experience has accrued with the use of high-intensity statin therapy early after CABG as it relates to patient compliance and side effects. Moreover, it remains unclear whether high-intensity statin therapy early after CABG will improve graft patency or slow the process of vein graft disease compared with usual moderate statin doses, highlighting the need for further research on the subject.


Moreover, it remains unclear whether high-intensity statin therapy early after CABG will improve graft patency or slow the process of vein graft disease compared with usual moderate statin doses, highlighting the need for further research on the subject. Statins are generally well tolerated and appear to be one of the safest classes of drugs ever developed.130,131 Although concerns had previously been raised about the safety of statins early after CABG,132 more recently, it has become clear that the perioperative risks associated with statin use are mark- edly less than originally anticipated.133,134 Furthermore, delay- ing statin reinitiation early after surgery may lead to greater Postoperative statin withdrawal may worsen endo- thelial function and result in a greater risk of postoperative Several studies in the cardiac and vascular surgery literature have reported a significantly greater risk of postoperative morbidity and mortality among patients whose statins are discontinued after surgery.122,136,137 Despite their benefits and low risk profile,134 statins remain underused after CABG,123,138 and long-term patient adherence to these medications remains a challenge.139 To maximize the benefits associated with their use and to potentially improve perioperative outcomes, statins should be administered pre- operatively when CAD is first documented and restarted early after CABG surgery. Postoperatively, statin use should be resumed when the patient is able to take oral medications and should be continued indefinitely. There is no evidence to support the use of one statin over another, either before or after CABG, although the administration of generic statins is appealing from a cost point of view because this may improve patient compliance.140 Essentially all patients under- going CABG are candidates for long-term statin therapy in the absence of contraindications such as liver disease.


There is no evidence to support the use of one statin over another, either before or after CABG, although the administration of generic statins is appealing from a cost point of view because this may improve patient compliance.140 Essentially all patients under- going CABG are candidates for long-term statin therapy in the absence of contraindications such as liver disease. For the occasional subject who cannot take statins, alternative lipid treatments such as bile acid sequestrants, niacin, and fibrates should be considered, as described elsewhere.82,141 High-Density Lipoprotein Management Many patients remain at high risk for adverse cardiovascu- lar events even when their LDL levels have been aggressively reduced by statins.142 Thus, increasing attention has recently been directed to the evaluation of therapies to raise high-den- sity lipoprotein (HDL) levels to further improve cardiovascu- Frequently seen in patients with CAD, a low HDL level has been well described as an independent risk factor for adverse cardiovascular outcomes in several stud- Some of the earliest data on the subject became available from the Framingham Heart Study, in which low HDL was found to be a more potent CAD risk factor than high Recent studies from the current era have shown that HDL levels are inversely related to cardiovascular events, even among patients receiving statin therapy152 and those with LDL levels aggressively treated to <70 mg/dL.151 In addition, mod- erate increases in HDL appear to be associated with regression of coronary atherosclerosis in statin-treated patients.153 Smoking cessation, weight loss, exercise, and moderate alcohol intake all modestly increase HDL. Fibrate therapy can raise HDL levels by 5% to 10%, and niacin increases HDL by 15% to 25%. Statins, on the other hand, have little effect on HDL.


Statins, on the other hand, have little effect on HDL. Given the risk for adverse cardiovascular events that remains despite statin treatment,142,151 several research groups have focused their attention on the evaluation of therapies to increase HDL and to possibly improve clinical outcomes in patents already treated with preventative medications.143 147 Many clinical trials have confirmed that HDL levels can be increased through pharmacological intervention, including the use of niacin,143,144,154,155 fenofi- Although some studies have demonstrated modest biological effects such as the reduction of either carotid artery intimal thickness144,154 or angiographic the majority of the studies in the field have produced negative clinical results.143,145,155,159,160 Focusing on non-CABG populations, 2 large, placebo- controlled, clinical trials have evaluated the use of fenofi- brate therapy for the prevention of cardiac events in patients with diabetes mellitus. Fenofibrate, with or without concur- rent statin therapy, led to significant increases in HDL levels in both studies but failed to significantly reduce the primary clinical end points of fatal or nonfatal MI in either trial.159,160 Most recently, 2 large clinical trials received much atten- tion by evaluating the impact of niacin treatment to reduce vascular events among statin-treated patients with well- controlled LDL levels. In Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH), 3414 patients with a history of cardiovascular disease were ran- domized to receive high-dose extended-release niacin or placebo. Niacin increased HDL levels by 20% but failed to reduce the rate of cardiovascular events over the 5-year trial duration (5.8% versus 5.6%, niacin versus placebo; P=NS).


Niacin increased HDL levels by 20% but failed to reduce the rate of cardiovascular events over the 5-year trial duration (5.8% versus 5.6%, niacin versus placebo; P=NS). The trial was halted prematurely because of the absence of clinical benefit, and a small increase in ischemic stroke was noted in the niacin group.143 Presented in 2013, the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial yielded similarly disappoint- ing results for niacin. In this trial, 25 673 patients with Kulik et al Secondary Prevention After CABG 935 well-controlled LDL levels were randomized to extended- release niacin plus an antiflushing agent (laropiprant) or placebo. Niacin increased HDL by 14% but failed to reduce the primary clinical end point (fatal or nonfatal MI, stroke, or coronary revascularization; 14.5% versus 15.0%, niacin versus placebo; P=NS). Moreover, niacin increased the risk of myopathy in this trial.155 Although it increases HDL lev- els, adding niacin to statin therapy does not improve choles- terol efflux or the antioxidant functions of HDL, which may explain the lack of clinical effect in clinical trials.161 Casting doubt on the HDL theory, no therapy to date has been shown to increase HDL levels and to improve outcomes in a clinical trial enrolling CAD patients already treated with Therapies to increase HDL appear to be ineffective in terms of reducing adverse cardiovascular events, and no evidence exists to support the premise that raising HDL cholesterol leads to clinical benefit in CAD (and specifi- cally non-CABG) patient populations.


Moreover, niacin increased the risk of myopathy in this trial.155 Although it increases HDL lev- els, adding niacin to statin therapy does not improve choles- terol efflux or the antioxidant functions of HDL, which may explain the lack of clinical effect in clinical trials.161 Casting doubt on the HDL theory, no therapy to date has been shown to increase HDL levels and to improve outcomes in a clinical trial enrolling CAD patients already treated with Therapies to increase HDL appear to be ineffective in terms of reducing adverse cardiovascular events, and no evidence exists to support the premise that raising HDL cholesterol leads to clinical benefit in CAD (and specifi- cally non-CABG) patient populations. Less is known about the relevance of HDL after CABG,162 although data from the prestatin era suggested that a rela- tionship exists between lower HDL levels and higher risk of atherosclerosis progression and adverse events after sur- Through reverse cholesterol transport, HDL prevents the development of foam cells in a vessel wall.142,144 Moreover, independently of its involvement in cholesterol metabolism, HDL has properties that reduce vascular inflammation and thrombosis, improve endothelial function, and promote endothelial repair.142 Ultimately, higher levels of HDL particles may help slow the process of saphenous vein graft disease and decrease the risk of adverse outcome Previous observational studies have dem- onstrated associations between lower HDL and both worse long-term survival and higher risk of cardiovascular events In the only HDL clinical trial involving CABG patients, the Lopid Coronary Angiography Trial (LOCAT) enrolled 395 men with HDL levels <42.5 mg/dL who had undergone CABG on average 2 years earlier. From an era before the rou- tine use of statins after CABG, patients were randomized to receive either slow-release gemfibrozil 1200 mg/d or match- ing placebo.


From an era before the rou- tine use of statins after CABG, patients were randomized to receive either slow-release gemfibrozil 1200 mg/d or match- ing placebo. Coronary angiography was performed at baseline and after a mean of 32 months of therapy. Gemfibrozil ther- apy led to significant increases in HDL levels (P<0.001) and slowed the progression of native CAD (P=0.009). Moreover, gemfibrozil significantly reduced the risk of developing new lesions in bypass grafts on follow-up angiography (2% ver- sus 14%, gemfibrozil versus placebo; P<0.001).156 Despite the notable results of LOCAT, gemfibrozil never became incorpo- rated into the routine care of CABG patients. This was likely a reflection of the impressive data published that same year promoting the use of statins after CABG,68 as well as the high risk of side effects associated with gemfibrozil, particularly when combined with statin therapy.167,168 Lower HDL levels are associated with worse long-term sur- vival and higher risk of cardiovascular events after CABG.163,164 Although there is strong evidence supporting the use of statins after CABG, adding gemfibrozil to a patient s medication regimen can increase the risk of side effects such as myopa- thy and rhabdomyolysis. Theoretically, HDL modulation may help slow the process of saphenous vein graft disease, but this concept must be tempered by the absence of data on the administration of fenofibrate or niacin therapy after CABG. Moreover, in the non-CABG population, the administration of these agents on top of statins has proven to be futile in recent Future research may help further explore this possible strategy of administering second-line agents such as fenofibrate to elevate low levels of HDL after surgery, with a view toward improving post-CABG vein graft patency.


Moreover, in the non-CABG population, the administration of these agents on top of statins has proven to be futile in recent Future research may help further explore this possible strategy of administering second-line agents such as fenofibrate to elevate low levels of HDL after surgery, with a view toward improving post-CABG vein graft patency. Triglyceride Management Although LDL remains the primary therapeutic target for hyperlipidemia, high triglyceride levels are also associated with an elevated risk of developing CAD.169,170 Elevated tri- glyceride levels are a marker of atherogenic remnant lipopro- teins, which are more easily oxidized, leading to increased Triglyceride levels >150 mg/dL tend to be associated with a greater burden of small and dense LDL, making the calculation of the LDL level with the Friedewald formula inaccurate. Therefore, using the non- HDL cholesterol level, defined as the difference between total cholesterol and HDL levels, has been suggested as a more accurate tool for risk and treatment assessment in the presence of high triglyceride levels. Non-HDL cholesterol includes all cholesterol present in lipoprotein particles con- sidered to be atherogenic, including LDL, lipoprotein(a), intermediate-density lipoprotein, and very-low-density lipo- In patients with hypertriglyceridemia, first-line thera- pies usually include diet modification, exercise, and weight loss, with a focus on restriction of refined carbohydrates and reduced alcohol intake, in association with increased intake of omega-3 fatty acids. Statins may be of benefit in lowering non-HDL cholesterol levels in patients with high triglycer- In an era before the routine use of statins, 2 placebo-controlled trials reported that gemfibrozil treatment caused marked reductions in triglyceride levels and increased HDL levels, leading to significant reduction in car- Because of the dangers associated with gemfibrozil,167,168 fenofibrate therapy has been the focus of more recent studies as a treatment option for dyslipidemia and elevated triglycer- ide levels.


Statins may be of benefit in lowering non-HDL cholesterol levels in patients with high triglycer- In an era before the routine use of statins, 2 placebo-controlled trials reported that gemfibrozil treatment caused marked reductions in triglyceride levels and increased HDL levels, leading to significant reduction in car- Because of the dangers associated with gemfibrozil,167,168 fenofibrate therapy has been the focus of more recent studies as a treatment option for dyslipidemia and elevated triglycer- ide levels. Fenofibrate is a fibric acid derivative that activates the peroxisome proliferator activated receptor- , leading to lower triglyceride levels and increased HDL levels. Compared with statin monotherapy, fenofibrate monotherapy tends to improve triglyceride and HDL cholesterol levels to a greater extent, whereas statins improve LDL and total cholesterol lev- els to a larger degree.175 In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9797 patients with diabetes mellitus who were not taking statins were ran- domized to micronized fenofibrate 200 mg daily or matching placebo for 5 years. Treatment with fenofibrate did not sig- nificantly reduce the risk of the primary outcome of cardio- vascular death or nonfatal MI (HR, 0.89; 95% CI, 0.75 1.05; P=0.16), but it was associated with a reduction in the second- ary end point of total cardiovascular events (including nonfa- tal MI and coronary revascularization).160 Published more recently, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was a double-factor, randomized, clinical trial that studied inten- sive glucose and blood pressure (BP) control and the addition of fenofibrate therapy to statin treatment. In the lipid arm of ACCORD, 5518 participants who were treated with open- label simvastatin to achieve LDL levels <80 mg/dL were ran- domized to receive either fenofibrate or placebo.


In the lipid arm of ACCORD, 5518 participants who were treated with open- label simvastatin to achieve LDL levels <80 mg/dL were ran- domized to receive either fenofibrate or placebo. Treatment with fenofibrate therapy led to significant decreases in triglyc- eride levels and increases in HDL levels, but no difference was seen between groups in the primary composite outcome of a major fatal or nonfatal cardiovascular event (HR, 0.92; 95% Subsequent subgroup analyses of the FIELD and ACCORD Lipid trials confirmed the safety of fenofibrate when used alone or in combination with a statin. Moreover, potential benefits with fenofibrate therapy were suggested in terms of decreasing cardiovascular risk among patients with the most pronounced dyslipidemia, including those with the highest levels of triglycerides and lowest levels After CABG, elevated triglyceride levels may increase the risk of postoperative adverse outcomes. In an observational study of >25000 patients who underwent primary isolated CABG between 1971 and 1998, investigators noted that a higher baseline triglyceride level at the time of surgery was significantly associated with a higher risk of repeat coronary revascularization (stent or reoperation) during long-term Similarly, Sprecher et al177 reported that higher triglyceride levels at the time of surgery were asso- ciated with significantly greater risk of mortality and worse event-free survival in a prospective study of 6602 CABG patients. Of interest, after CABG, women with high triglyc- eride levels have far worse long-term survival (HR, 1.5; 95% CI, 1.1 2.1) compared with men with high triglyceride levels (HR, 1.1; 95% CI, 0.9 1.3).


Of interest, after CABG, women with high triglyc- eride levels have far worse long-term survival (HR, 1.5; 95% CI, 1.1 2.1) compared with men with high triglyceride levels (HR, 1.1; 95% CI, 0.9 1.3). Other studies also have demon- strated that elevated triglyceride values after surgery predict vein graft occlusion,178 recurrent angina and MI,179 181 and the need for redo CABG.182,183 In a secondary analysis of the Post- CABG Trial, the study investigators demonstrated that a high triglyceride level was a significant prognostic factor for vein graft atherosclerosis progression.165 Although the mechanism by which elevated triglyceride levels increase cardiovascu- lar risk is not entirely clear, triglyceride-rich lipoproteins in the vessel wall may lead to fatty streaks, which are noted in saphenous vein grafts as early as 18 months after CABG.184,185 High triglyceride levels have been shown to be a marker of worse outcomes after CABG. However, very few data are available to support the use of medical therapy to lower tri- glyceride levels after CABG. Before the advent of routine statin therapy, Barbir et al186 performed a small pilot trial of combination therapy with colestipol 10 mg and bezafibrate 400 mg/d for 2 months after CABG, noting a reduction in total cholesterol of 17%, in LDL cholesterol of 23%, and in triglyc- eride levels of 19%. In the previously described LOCAT study in which gemfibrozil reduced the development of new bypass graft lesions, gemfibrozil increased HDL levels and led to a 36% reduction in triglyceride levels (P<0.001).156 To date, no trial has investigated the use of fenofibrate ther- apy to reduce triglyceride levels and to potentially improve outcomes after CABG, highlighting the need for more research on the subject.


In the previously described LOCAT study in which gemfibrozil reduced the development of new bypass graft lesions, gemfibrozil increased HDL levels and led to a 36% reduction in triglyceride levels (P<0.001).156 To date, no trial has investigated the use of fenofibrate ther- apy to reduce triglyceride levels and to potentially improve outcomes after CABG, highlighting the need for more research on the subject. For CABG patients with severely elevated tri- glyceride levels >500 mg/dL, fenofibrate therapy should be administered in addition to statin therapy to help prevent The use of combination fenofibrate-statin therapy may also be considered in diabetic patients recover- ing from CABG who have high triglyceride levels and low HDL cholesterol levels that persist despite statin therapy,141 as indicated by post hoc subgroup analyses from the FIELD and Lipid Management Recommendations 1. Unless contraindicated, all CABG patients should receive statin therapy, starting in the preoperative period and restarting early after surgery (Class I; Level of Evidence A). 2. High-intensity statin therapy (atorvastatin 40 80 mg, rosuvastatin 20 40 mg) should be administered after surgery to all CABG patients <75 years of age (Class I; Level of Evidence A). 3. Moderate-intensity statin therapy should be adminis- tered after CABG for those patients who are intoler- ant of high-intensity statin therapy and for those at greater risk for drug-drug interactions (ie, patients >75 years of age) (Class I; Level of Evidence A). 4. Discontinuation of statin therapy is not recommended before or after CABG unless patients have adverse reactions to therapy (Class III; Level of Evidence B). -Blocker Therapy Activation of the adrenergic nervous system to excessive lev- els contributes to the pathophysiology and symptoms of many cardiovascular diseases. -Blockers are competitive antago- nists at the -adrenergic receptors, thus modulating activities in this pathway.


-Blockers are competitive antago- nists at the -adrenergic receptors, thus modulating activities in this pathway. Although most of the pharmacological effects are attributed to this receptor blockade, some -blockers are relatively selective for the 1 -adrenergic receptor, others are nonselective, and still others have intrinsic sympathomimetic activity, -adrenergic receptor blockade, and direct vasodilat- Data to support the use of -blocker therapy in ischemic heart disease date back to the early 1980s, when randomized trial data were first generated evaluating the use of -blocker therapy in patients with acute MI.188 At that time, it was not uncommon for CABG operations to be postponed if patients were treated with -blocker therapy (ie, propranolol) because of the presumption of increased risk of surgical mortality. This sentiment undoubtedly contributed to the lower use of -blocker therapy at discharge among MI patients undergo- ing CABG compared with those treated with medical ther- Subsequently, Chen et al189 noted in a cohort study that -blocker therapy was just as effective in reducing 1-year mortality for patients undergoing revascularization as it was for patients not undergoing revascularization. In the Chen et al189 study, 33.1% of patients undergo- ing CABG in 1994 to 1995 were not prescribed -blocker therapy at discharge. Thereafter, in 2002, Ferguson and col- raised awareness of the importance of -blocker Kulik et al Secondary Prevention After CABG 937 therapy among CABG patients by documenting an association between preoperative -blocker therapy and improved 30-day mortality. Evaluating the outcomes of >600000 CABG patients in the Society of Thoracic Surgeons Database from 1996 to 1999, these authors noted that patients who received -blockers before surgery had significantly lower 30-day mor- tality rates compared with those who did not (adjusted OR, 0.94; 95% CI, 0.91 0.97).


Evaluating the outcomes of >600000 CABG patients in the Society of Thoracic Surgeons Database from 1996 to 1999, these authors noted that patients who received -blockers before surgery had significantly lower 30-day mor- tality rates compared with those who did not (adjusted OR, 0.94; 95% CI, 0.91 0.97). However, it remained for a number of quality-improvement projects that emerged in the early-to-mid-2000s to link sec- ondary prevention and -blockade therapy in CABG. These studies created the environment for attention to and adoption of -blocker therapy after CABG. Foody et al191 documented in a national database that only 61.5% of CABG patients received -blocker therapy after presenting with MI between 1998 and 1999, which was lower than the non-CABG patient population. This study laid the foundation for establishing baseline secondary prevention benchmarks for aspirin, angio- tensin-converting enzyme (ACE) inhibitors, and lipid-lower- ing medications. With this study as a call to action, a number of regional and national quality-improvement efforts using a variety of techniques established increases in postdischarge -blocker therapy. The Alabama CABG project demonstrated an increase in -blocker therapy at discharge from 65% to 78% Similarly, Williams et al193 reported a significant increase in adherence for all secondary preven- tion medications, including -blocker therapy, in a national quality-improvement program. Single centers during the same time frame were able to achieve even more impressive results, with the University of Kentucky improving its -blocker use after CABG from 95% to 100% by implementing an intensive Finally, in a study exploring the Get With The Guidelines database, investigators noted that 90.8% of patients were discharged on -blocker therapy after Interestingly, this was less than comparable patients discharged after percutaneous coronary intervention.


Single centers during the same time frame were able to achieve even more impressive results, with the University of Kentucky improving its -blocker use after CABG from 95% to 100% by implementing an intensive Finally, in a study exploring the Get With The Guidelines database, investigators noted that 90.8% of patients were discharged on -blocker therapy after Interestingly, this was less than comparable patients discharged after percutaneous coronary intervention. All of these studies were limited by their observational nature, and only 1 randomized trial of -blocker therapy after CABG has been performed. In 1995, Sjoland et al196 conducted a double-blind, placebo-controlled, randomized, controlled trial of 967 patients undergoing CABG. In this study, patients were randomized 4 to 21 days after CABG to 50 mg meto- prolol twice a day for 2 weeks and 100 mg metoprolol twice a day thereafter versus placebo for 2 years. The authors found no difference between the 2 arms of the trial with respect to the risk of death or the development of cardiac events, and there was no improvement in exercise capacity among the 618 patients who received an exercise test at follow-up. However, patients treated with placebo were found to have a higher (worse) chest pain score compared with patients treated with Contraindications to -blocker therapy can be particu- larly relevant in the post-CABG population because of the prevalence of reactive airway and pulmonary disease in these patients. However, the management of this comorbid condi- tion in the perioperative setting has improved substantially, and the specificity of 1 - and 2 -blockers has minimized the cross-reactivity between the cardiac and pulmonary effects of -blockade.


However, the management of this comorbid condi- tion in the perioperative setting has improved substantially, and the specificity of 1 - and 2 -blockers has minimized the cross-reactivity between the cardiac and pulmonary effects of -blockade. Even more recently, the pharmacogenetics of -adrenergic receptor antagonists have become clear, with certain genes being identified that influence the pharmacody- namic and pharmacokinetic effects of -blocker compounds.187 To clearly establish the benefit of -blocker therapy and secondary prevention after CABG, a link to improved mortal- ity is needed. An important study by Goyal et al198 assessed both the use and clinical impact of secondary preven- tion medications after CABG. The use of aspirin, -blockers, ACE inhibitors or angiotensin receptor blockers (ARBs), and lipid therapy was measured in patients enrolled in the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT IV) trial of 3014 patients. In ideal candidates for these therapies, -blocker rates at discharge (88.8%) and 1 year (76.9%) were suboptimal, but in this trial context, the rates of use were substantially higher than in contemporane- ous observational studies. The authors noted a stepwise asso- ciation between medication use at discharge and a lower risk of adverse patient outcomes (death or MI).198 Most recently, a study by Bangalore et al199 evaluated the use of -blocker therapy in stable patients with risk factors for CAD or a history of CAD or MI. This longitudinal, obser- vational registry study demonstrated that the use of -blocker therapy was not associated with a lower risk of cardiovascular events, including cardiovascular death, nonfatal MI, or non- fatal stroke, whether patients had risk factors only, a known prior MI, or known CAD without MI.199 Many patients under- going CABG would likely fall into one of these categories.


This longitudinal, obser- vational registry study demonstrated that the use of -blocker therapy was not associated with a lower risk of cardiovascular events, including cardiovascular death, nonfatal MI, or non- fatal stroke, whether patients had risk factors only, a known prior MI, or known CAD without MI.199 Many patients under- going CABG would likely fall into one of these categories. However, it is not yet clear how this information should be directly applied to the postoperative patient because many CABG patients have additional clinical conditions that war- rant -blocker therapy after surgery, including hypertension and AF. Because AF continues to occur at a high rate after -blocker therapy remains the mainstay of both AF prevention and rate control through its 1 -adrenergic A meta-analysis of contemporary clinical trials illustrated a 50% reduction in the risk of postoperative AF with prophylactic -blocker therapy.202 Moreover, many patients on preoperative -blocker therapy have rebound tachycardia if -blocker therapy is not resumed early in the postoperative period. The role of -blocker therapy in the perioperative period remains controversial. A substantial percentage of patients undergoing CABG receive preoperative -blocker therapy because it has been demonstrated to convey a mortality ben- Consequently, preoperative -blocker therapy was determined to be a quality metric for cardiac surgery by the National Quality Forum and was included in the Society of Thoracic Surgeons Composite Score for CABG Quality pro- However, other more recent studies have questioned whether preoperative -blocker therapy actually affects mor- It is possible that the outcomes from surgical revas- cularization have improved to the point where a benefit from preoperative -blocker therapy can no longer meet the thresh- old of statistical significance.204 Nevertheless, continuation of preoperative -blockade therapy into the postoperative period remains an important consideration.


A substantial percentage of patients undergoing CABG receive preoperative -blocker therapy because it has been demonstrated to convey a mortality ben- Consequently, preoperative -blocker therapy was determined to be a quality metric for cardiac surgery by the National Quality Forum and was included in the Society of Thoracic Surgeons Composite Score for CABG Quality pro- However, other more recent studies have questioned whether preoperative -blocker therapy actually affects mor- It is possible that the outcomes from surgical revas- cularization have improved to the point where a benefit from preoperative -blocker therapy can no longer meet the thresh- old of statistical significance.204 Nevertheless, continuation of preoperative -blockade therapy into the postoperative period remains an important consideration. The use of -blocker therapy for the treatment of hyperten- sion remains a controversial subject. In a critical review of the literature, Bangalore et al205 documented that -blockade was not as effective long-term compared to other antihypertensive thera- pies (eg, diuretic therapy). In addition, -blockers are often asso- ciated with side effects such as weight gain, fatigue, and sexual dysfunction, reducing rates of adherence. Thus, for long-term secondary prevention therapy, the use of -blockers for hyperten- sion is influenced by the presence or absence of other cardiovas- cular conditions (such as previous MI and heart failure). The most compelling data on -blocker therapy exist after an acute MI, and this circumstance pertains to most post- CABG patients. Several studies from the 1980s and 1990s demonstrated the benefits associated with -blockade dur- ing and after MI.188,206 In a meta-analysis of >54000 patients, Freemantle et al207 reported a 23% reduction in the odds of death with -blocker therapy for long-term secondary preven- tion after MI. These studies and others laid the foundation for routine -blocker therapy after MI.


These studies and others laid the foundation for routine -blocker therapy after MI. The use of -blockade in chronic heart failure has also evolved over the years, from a relative contraindication in the past to a mainstay of therapy now, leading to a consistent 30% reduction in mortality, improved well-being, and an improvement in symptoms.205 -Blockers likely protect the heart from the chronic upregulation of adrenergic receptors on the myocardium from epinephrine and norepinephrine, thus reducing remodeling and fibrosis in congestive heart failure. Three -blockers have been shown to be effective in reducing the risk of death in patients with chronic heart and sustained-released metoprolol both of which selectively block 1 -receptors, which blocks 1 -, and 2 -receptors. Many CABG patients with left ventricular (LV) dysfunction have significant heart failure both before and after surgical revascularization, and -blocker therapy can be adminis- tered safely and effectively to the majority. As a rule, LV dysfunction alone is not a contraindication to -blocker therapy after CABG. In summary, -blocker therapy is a mainstay of secondary prevention strategies after surgical revascularization for isch- emic heart disease. -Blocker Therapy Recommendations 1. All CABG patients should be prescribed periopera- tive -blocker therapy to prevent postoperative AF, ideally starting before surgery, unless contraindi- cated (ie, bradycardia, severe reactive airway dis- ease) (Class I; Level of Evidence A). 2. CABG patients with a history of MI should be pre- scribed -blocker therapy unless contraindicated (Class I; Level of Evidence A). 3. CABG patients with LV dysfunction should be pre- scribed -blocker therapy (bisoprolol, sustained- release metoprolol succinate, or carvedilol), unless contraindicated (Class I; Level of Evidence B). 4.


CABG patients with LV dysfunction should be pre- scribed -blocker therapy (bisoprolol, sustained- release metoprolol succinate, or carvedilol), unless contraindicated (Class I; Level of Evidence B). 4. Chronic -blocker therapy for hypertension treat- ment after CABG (in the absence of prior MI or LV dysfunction) may be considered, but other antihy- pertensive therapies may be more effective and more easily tolerated (Class IIb; Level of Evidence B). Hypertension Management Hypertension is a common antecedent condition before CABG, occurring in as many as 80% of patients.212 The preop- erative antihypertensive regimens used in patients undergoing CABG can be quite varied but generally include a -blocker or an ACE inhibitor, in part because of their cardioprotective Despite the routine use of these drug classes, however, pre-CABG and post-CABG BP control remains Previous AHA guidelines recommended a BP goal of <130/80 mmHg for patients with CAD.216 More recent guideline statements have proposed less aggressive BP target mmHg) for patients with CAD risk factors such as diabetes mellitus and chronic kid- ney disease. This is a controversial subject. Inconsistent ben- efits have been noted in clinical trials comparing intensive BP reduction (systolic <130 mmHg) and standard BP treatment goals (systolic <140 mmHg) for patients with previous coro- nary events and a history of hypertension and diabetes mel- litus, therefore justifying the currently recommended systolic target value of <140 mmHg.220 225 With regard to diastolic BP goals, targeting a value of <85 mmHg appears to be safe and has been shown in 3 randomized trials to improve the clinical outcomes of patients with a history of hypertension, diabe- tes mellitus, or multiple cardiovascular risk factors compared with higher diastolic values.226 228 Admittedly, no clinical trials to date have specifically assessed BP targets after CABG with respect to clinical outcomes.


Inconsistent ben- efits have been noted in clinical trials comparing intensive BP reduction (systolic <130 mmHg) and standard BP treatment goals (systolic <140 mmHg) for patients with previous coro- nary events and a history of hypertension and diabetes mel- litus, therefore justifying the currently recommended systolic target value of <140 mmHg.220 225 With regard to diastolic BP goals, targeting a value of <85 mmHg appears to be safe and has been shown in 3 randomized trials to improve the clinical outcomes of patients with a history of hypertension, diabe- tes mellitus, or multiple cardiovascular risk factors compared with higher diastolic values.226 228 Admittedly, no clinical trials to date have specifically assessed BP targets after CABG with respect to clinical outcomes. However, given the high inci- dence of diabetes mellitus and other cardiovascular risk fac- tors in the CABG population, a BP goal of <140/85 mmHg217 appears reasonable and broadly applicable to all patients who have undergone CABG. Achieving the BP goal for secondary prevention in the patient having undergone CABG requires an understanding of the effectiveness of pre-CABG antihypertensive therapies and the temporary reduction in BP that occurs during recovery from postoperative surgical circumstances such as anemia and reduced myocardial function. With an emphasis on BP con- trol in the broad context of secondary prevention measures, antihypertensive medication regimens and BP goals should be adapted to the individualized circumstances of each patient.198 BP patterns and the response to treatment can be best assessed with the use of home BP monitoring.229 Lifestyle measures such as exercise, reducing weight, and limiting sodium intake are useful adjunct measures in the post-CABG patient with hypertension.


With an emphasis on BP con- trol in the broad context of secondary prevention measures, antihypertensive medication regimens and BP goals should be adapted to the individualized circumstances of each patient.198 BP patterns and the response to treatment can be best assessed with the use of home BP monitoring.229 Lifestyle measures such as exercise, reducing weight, and limiting sodium intake are useful adjunct measures in the post-CABG patient with hypertension. In addition, identifying comorbid risk factors for hypertension such as the BP change seen with post-CABG cognitive disorders, anxiety, depression, and sleep abnormalities and providing the indicated therapies can improve the overall effectiveness of the chosen antihyperten- sive therapies. No studies have prospectively evaluated the rapidity with which BP should be reduced in the post-CABG patient with hypertension. In addition, it is not known whether the J-curve relationship for morbidity and mortality occurs at a higher BP level in the post-CABG patient than in the patient without CAD. In the post-CABG patient with hypertension, the choice of antihypertensive agents and the order of their introduc- tion have not been methodically studied. Two major therapy groups, -blockers and ACE inhibitors, are routinely given Kulik et al Secondary Prevention After CABG 939 for their established cardioprotective features, as much as they are used for BP reduction.213,214 -Blockers should be administered as soon as possible after CABG in those patients without contraindications to reduce the risk of AF201,202 and to improve outcomes in those patients with congestive heart failure and LV dysfunction.205 However, their effect on BP has not been systematically explored. In the only randomized trial to date, Sjoland et al196 found no clinical benefit asso- ciated with a 2-year treatment with metoprolol after CABG.


In the only randomized trial to date, Sjoland et al196 found no clinical benefit asso- ciated with a 2-year treatment with metoprolol after CABG. Compared with placebo, metoprolol did not reduce the inci- dence of repeat revascularization, unstable angina, nonfatal MI, or death.197 ACE inhibitors should also be considered for CABG patients after surgery, particularly for those with recent MI, LV dysfunction, diabetes mellitus, and chronic kidney dis- ease. The BP-lowering effect of ACE inhibitors is dependent on a patient s volume state, thus the basis for their frequent administration together with a diuretic.230 ACE inhibitor use can be associated with a syndrome of functional renal insuf- ficiency or hyperkalemia. This form of acute kidney injury develops shortly after the initiation of ACE inhibitor therapy but can be observed after months or years of therapy, even in the absence of prior ill effects. It may relate to the drug dose or level of hydration, as well as to the degree of small and large renal artery obstructive disease.231 An ARB may be considered as an alternative in an ACE inhibitor intolerant patient. Two randomized, controlled trials have studied the use of ACE inhibitors after CABG. In a 149-patient trial evaluating the use of quinapril after surgery, investigators noted a reduc- tion in the composite outcome of angina, death, MI, repeat revascularization, stroke, or transient ischemic attacks in patients who received quinapril for 1 year compared with pla- cebo (3.5% versus 15%, quinapril versus placebo; P=0.02).232 However, these findings were not confirmed in the larger, mul- ticenter Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme (IMAGINE) trial of 2253 stable CABG patients.


In a 149-patient trial evaluating the use of quinapril after surgery, investigators noted a reduc- tion in the composite outcome of angina, death, MI, repeat revascularization, stroke, or transient ischemic attacks in patients who received quinapril for 1 year compared with pla- cebo (3.5% versus 15%, quinapril versus placebo; P=0.02).232 However, these findings were not confirmed in the larger, mul- ticenter Ischemia Management With Accupril Post-Bypass Graft via Inhibition of the Converting Enzyme (IMAGINE) trial of 2253 stable CABG patients. In this study, patients were excluded from randomization if they already had indications for ACE inhibitor therapy such as LV dysfunction, insulin- dependent diabetes mellitus, or renal dysfunction. Quinapril (40 mg daily) had no benefit compared with placebo when initiated within 7 days after surgery, with a 13.7% incidence of the primary composite end point (cardiovascular death, car- diac arrest, nonfatal MI, unstable angina or heart failure requir- ing hospitalization, and stroke) among quinapril patients and 12.2% in the placebo group (HR, 1.15; 95% CI, 0.92 1.42; P=0.21) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (P=0.04), and adverse events (such as hypotension) were also increased in the quinapril group, particularly during the first 3 postop- Thus, in this select trial population, routine ACE inhibitor therapy led to more harm than benefit when initiated early after CABG. In those patients who remain above the BP goal despite a suitably titrated regimen including a -blocker and, if appro- priate, an ACE inhibitor, then a calcium channel blocker or a diuretic can be considered as a next therapy choice.A long-act- ing dihydropyridine calcium channel blocker can effectively reduce BP and prevent graft spasm (radial artery conduit) and may offer an antianginal effect.