Introduction

Coronary artery bypass graft surgery (CABG) is the most complete and durable treatment of ischemic heart disease and has been an established therapy for nearly 50 years. Nevertheless, in the years that follow surgery, CABG patients remain at risk for subsequent ischemic events as a result of native coronary artery disease (CAD) progression and the development of vein graft atherosclerosis. Secondary preventative therapies, therefore, play an essential role in the management of patients recovering from CABG to slow the disease process and prevent adverse cardiovascular outcomes both in the perioperative period and in the long term.¹ Secondary preventive therapies help maintain long-term graft patency and allow patients to obtain the highest level of physical health and quality of life following CABG.

As noted in recent guideline statements,^2,3 postoperative antiplatelet agents and lipid-lowering therapies continue to be mainstays of secondary prevention. Other opportunities that exist to improve the long-term clinical outcomes after CABG include the aggressive management of hypertension and diabetes mellitus, smoking cessation, weight loss, and cardiac rehabilitation. For healthcare professionals, administering secondary preventative therapies is a fundamental responsibility following CABG. However, patient adherence to prescribed medications remains just as important; several studies have noted higher event rates among patients with CAD who have poor long-term compliance to medical therapy.^4-6 The purpose of this analysis is to highlight recent developments in the field of secondary prevention after CABG.

Antiplatelet Therapy

In patients with CAD, aspirin reduces the risk of stroke, myocardial infarction, and vascular death. As such, all CABG patients are candidates for long-term aspirin therapy.¹ Aspirin is safe for use when administered prior to surgery,⁷ and a recent meta-analysis reported that preoperative aspirin significantly reduces the risk of vein graft occlusion.⁸ In the postoperative period, initiating aspirin therapy within 6 hours after CABG helps improve graft patency, prevents adverse cardiovascular events, and improves long-term survival.^1,2

Nevertheless, even with aspirin-mediated platelet inhibition, saphenous vein graft disease continues to be a clinical challenge in the current era. Therefore, several investigators have evaluated the role of other antiplatelet agents following surgery, including clopidogrel, to prevent graft occlusion and slow the progression of native CAD.⁹ Substantial benefits have been demonstrated with the combination of clopidogrel and aspirin in CAD trials. However, in the cardiac surgery literature, the results have been mixed. Some trials have noted a slight improvement in vein graft patency with the addition of clopidogrel after off-pump CABG,^1,10 but others have found no benefit with postoperative clopidogrel.¹¹ Summarizing the data on more than 25,000 patients from both randomized and observational studies, Deo et al. reported that the addition of clopidogrel to aspirin lowered the risk of vein graft occlusion by 41% (p = 0.02), but at the cost of significantly more major bleeding events, compared with aspirin alone.¹⁰ Importantly, this benefit for dual antiplatelet therapy appeared to be applicable only to patients undergoing off-pump CABG.¹⁰ For the majority of patients who undergo on-pump surgery in the current era, aspirin alone is currently recommended.^2-3

Given the limited benefits noted with postoperative clopidogrel, several trials have been initiated to evaluate ticagrelor and prasugrel after CABG. These newer P2Y12 receptor inhibitors have a more rapid onset of action and lead to greater platelet inhibition compared with clopidogrel.^1,2 Moreover, they have shown promising results in recent CAD prevention trials.^1,12 In the first prospective trial to evaluate the impact of ticagrelor after CABG, Saw et al. performed a placebo-controlled study, randomizing 70 patients to ticagrelor plus aspirin or aspirin alone for 3 months following surgery.¹³ Patency was assessed for 56 patients (a small sample size), and the authors noted a significant reduction in vein graft disease with the combination of ticagrelor and aspirin (graft occlusion or stenosis: 11.5% vs. 26.7% ticagrelor plus aspirin vs. aspirin alone, p = 0.007). However, a significantly higher risk of bleeding was seen in the dual antiplatelet arm of this study (minor bleeding requiring medical intervention: 31.4% vs. 2.9%, ticagrelor plus aspirin vs. aspirin alone, p = 0.003).¹³

Most recently, Zhao et al. published a clinical trial whereby 500 patients were randomized to ticagrelor plus aspirin, ticagrelor alone, or aspirin alone following surgery.¹⁴ One year after CABG, the authors reported that the combination of ticagrelor with aspirin significantly improved 1-year vein graft patency compared with aspirin alone (11.3% vs. 23.5%, ticagrelor plus aspirin versus aspirin alone, p < 0.001). Although the patency data were striking, the study should be interpreted with caution because there was no blinding or placebo control, and several major bleeding events occurred among subjects who received ticagrelor. Moreover, the majority of trial participants underwent off-pump CABG (76%), implying that the results may not be generalizable to those treated with standard on-pump CABG. Most importantly, the trial was limited by the use of low-dose aspirin (100 mg daily) in the control arm of the study. Current guidelines^2,3 recommend dual antiplatelet therapy for patients recovering from off-pump CABG, the primary technique used in this trial. By under-treating the patients in the aspirin arm of the trial, the results may be biased in favor of the combination of ticagrelor and aspirin.¹⁴

Several other novel antiplatelet trials are ongoing in the cardiac surgery community, including a Veteran Affairs study that is examining the combination of prasugrel plus aspirin versus aspirin alone on the prevalence of graft thrombus 1 year after CABG (ClinicalTrials.gov Identifier: NCT01560780). Other trials are exploring the impact of combining aspirin with ticagrelor to reduce postoperative graft occlusion rates (ClinicalTrials.gov Identifier: NCT02352402) and ticagrelor's role in reducing postoperative clinical events (ClinicalTrials.gov Identifier: NCT01755520). Approximately 2 years ago, we launched the Ticagrelor Antiplatelet Therapy to Reduce Graft Events and Thrombosis (TARGET) trial (ClinicalTrials.gov Identifier: NCT02053909) to evaluate the potential benefits of ticagrelor 90 mg twice daily, compared with aspirin 81 mg twice daily, on 1- and 2-year graft patency after CABG.¹⁵ Given the greater risks of bleeding associated with dual antiplatelet therapy, ticagrelor monotherapy may offer the best balance of safety and benefit, with a lower bleeding complication rate compared with dual antiplatelet therapy and an anticipated improved efficacy over aspirin alone.¹⁵

Lipid Management

Extensive evidence exists supporting the use of statins to treat hyperlipidemia and improve long-term survival for patients with CAD, particularly for those who have had CABG. Statins have been shown to reduce the progression of native artery atherosclerosis, slow the process of vein graft disease, and reduce adverse cardiovascular events following surgical revascularization.^1,2,16 For many years, statins were administered after CABG to reduce low-density lipoprotein levels to <100 mg/dL. However, recent attention has turned toward the use of high-intensity statin therapy to achieve even further low-density lipoprotein reduction to 70 mg/dL or less.^2,16 Multiple studies have demonstrated significantly improved outcomes for patients with CAD who were treated with high-dose statin therapy compared with usual medium or lower statin doses.^2,16 As such, recent guideline statements have recommended high-intensity statin therapy (i.e., atorvastatin 80 mg or rosuvastatin 20-40 mg) for nearly all patients who have undergone CABG.^2,3,16 For patients who cannot tolerate high-dose statins and those with contraindications, ezetimibe may be considered because it recently was shown to improve cardiovascular outcomes when added to simvastatin 40 mg in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).¹⁷ Encouraging data continue to accumulate regarding the use of PCSK9 inhibitors,¹⁸ but to date, limited clinical information is available to recommend their use after CABG.

Notwithstanding the guideline recommendations, it remains unclear whether high-intensity statins early after CABG improve graft patency or postoperative outcomes. Two randomized controlled trials raised doubts regarding the benefits of initiating high-dose statin therapy in the perioperative period. No improvements were noted with high-dose statins in terms of reducing the risk of perioperative atrial fibrillation, myocardial damage, or kidney injury early after CABG.^19,20 Regarding graft patency, the ACTIVE (Aggressive Cholesterol Therapy to Inhibit Vein Graft Events After CABG) trial was recently published, whereby 173 CABG patients were randomized to receive early postoperative atorvastatin 10 mg or 80 mg daily for the duration of 1 year.^21,22 The primary outcome of the study, vein graft occlusion at 1 year, did not significantly differ between the 2 groups (12.9% vs. 11.4%, atorvastatin 10 mg vs. atorvastatin 80 mg, p = 0.85) (Figure 1). However, the authors noted a trend toward fewer patients developing vein graft disease (either occlusion or stenosis) in the atorvastatin 80 mg group (29.2% vs. 19.2%, atorvastatin 10 mg vs. atorvastatin 80 mg, p = 0.18). Future studies from this group will help determine whether early high-intensity statin therapy has an impact on the development of vein graft disease in the years that follow surgery.^21,22

Figure 1: Incidence of Vein Graft Stenosis or Occlusion at 1 Year Among Patients Randomized to Atorvastatin 10 mg or Atorvastatin 80 mg Early After CABG

Hypertension Management

Hypertension is a frequent condition among patients undergoing CABG, with the majority prescribed beta-blockers and angiotensin-converting enzyme (ACE) inhibitors for the medications' "cardio-protective" features.^1,2 Beta-blockers have particular benefits for patients with a history of previous myocardial infarction, heart failure, or left ventricular dysfunction.^1,2 In a recent observational study evaluating the impact of beta-blocker adherence, Zhang et al. noted that consistent postoperative beta-blocker use significantly improved outcomes among CABG patients who had previously suffered a myocardial infarction.⁶ Moreover, prophylactic beta-blocker therapy reduces the risk of new-onset atrial fibrillation in the postoperative period by 50%, justifying their administration to nearly all patients undergoing CABG.²³ Regarding ACE inhibitor use, their routine administration to all patients after CABG may lead to more harm than benefit. Instead, they should be used selectively for those with a history of previous myocardial infarction, heart failure, left ventricular dysfunction, diabetes mellitus, or chronic kidney disease.¹ In those patients who remain hypertensive despite a suitably titrated regimen including a beta-blocker and, if appropriate, an ACE inhibitor, a calcium channel blocker or a diuretic can be considered as a next therapy choice.

Controversy continues to exist regarding the ideal blood pressure (BP) for patients with CAD and those recovering from CABG. Recent guideline statements have recommended BP target ranges of <140/85² or <140/90²⁴ based on several trials that identified these goals to be safe and beneficial for patients with a history of hypertension, diabetes, and cardiovascular risk factors. Admittedly, however, no clinical trials have specifically assessed BP targets following CABG and their impact on clinical outcomes. Most recently, the results of SPRINT (Systolic Blood Pressure Intervention Trial) were published, noting significantly lower event rates and improved survival for patients with cardiovascular risk factors who were randomized to intensive BP reduction with a target systolic pressure <120 mmHg, compared with a standard systolic BP <140 mmHg.²⁵ Many medical conditions that are common in the CABG population were key exclusion criteria for the trial, such as a history of diabetes, previous stroke, heart failure, and chronic kidney disease. As such, it may be difficult to extrapolate the results of SPRINT to the post-CABG setting. Nevertheless, lower BP goals will likely be recommended in upcoming guideline statements based on the impressive results of this trial.

Conclusions

Despite successful revascularization, CABG remains a palliative operation because patients remain at risk for future cardiovascular events. Therefore, initiating secondary prevention in the perioperative period is essential to optimize graft patency and allow patients to achieve the highest level of physical health and quality of life following CABG. Elements important to secondary prevention after CABG include antiplatelet and lipid-lowering medications and the aggressive management of hypertension.

References

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2. Kulik A, Ruel M, Jneid H, et al. Secondary prevention after coronary artery bypass graft surgery: a scientific statement from the American Heart Association. Circulation 2015;131:927-64.
3. Sousa-Uva M, Head SJ, Milojevic M, et al. 2017 EACTS Guidelines on perioperative medication in adult cardiac surgery. Eur J Cardiothorac Surg 2018;53:5-33.
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11. Ebrahimi R, Bakaeen FG, Uberoi A, et al. Effect of clopidogrel use post coronary artery bypass surgery on graft patency. Ann Thorac Surg 2014;97:15-21.
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13. Saw J, Wong GC, Mayo J, et al. Ticagrelor and aspirin for the prevention of cardiovascular events after coronary artery bypass graft surgery. Heart 2016;102:763-9.
14. Zhao Q, Zhu Y, Xu Z, et al. Effect of Ticagrelor Plus Aspirin, Ticagrelor Alone, or Aspirin Alone on Saphenous Vein Graft Patency 1 Year After Coronary Artery Bypass Grafting: A Randomized Clinical Trial. JAMA 2018;319:1677-86.
15. Kulik A, Abreu AM, Boronat V, Kouchoukos NT, Ruel M. Impact of ticagrelor versus aspirin on graft patency after CABG: Rationale and design of the TARGET (ticagrelor antiplatelet therapy to reduce graft events and thrombosis) randomized controlled trial (NCT02053909). Contemp Clin Trials 2018;68:45-51.
16. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S1-45.
17. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387-97.
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21. Kulik A, Abreu AM, Boronat V, Ruel M. Intensive versus moderate atorvastatin therapy and one-year graft patency after CABG: Rationale and design of the ACTIVE (Aggressive Cholesterol Therapy to Inhibit Vein Graft Events) randomized controlled trial (NCT01528709). Contemp Clin Trials 2017;59:98-104.
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Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Lipid Metabolism, Nonstatins, Statins, Acute Heart Failure, Interventions and Coronary Artery Disease, Chronic Angina

Keywords: Angiotensin-Converting Enzyme Inhibitors, Atherosclerosis, Aspirin, Arteries, Adenosine, Atrial Fibrillation, Blood Platelets, Blood Pressure, Calcium Channel Blockers, Cardiac Rehabilitation, Cardiovascular Diseases, Cholesterol, Constriction, Pathologic, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Diuretics, Heart Failure, Hyperlipidemias, Lipoproteins, LDL, Lipids, Myocardial Infarction, Peptidyl-Dipeptidase A, Perioperative Period, Platelet Aggregation Inhibitors, Prevalence, Prospective Studies, Quality of Life, Renal Insufficiency, Chronic, Research Personnel, Risk Factors, Saphenous Vein, Secondary Prevention, Simvastatin, Smoking Cessation, Stroke, Thrombosis, Ticlopidine, Ventricular Dysfunction, Left, Weight Loss, Angina, Stable

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