**8. Medical therapy**

In all patients with coronary heart disease aggressive risk factor reduction is recommended which includes aspirin, treatment for hypertension and serum lipids, avoidance of smoking, and controlling serum glucose in diabetic patients. The bypass angioplasty revascularization investigation (BARI) trial illustrated that intensive risk-factor modification and hypolipid medication use slows atherosclerosis progression within native coronary arteries of CABGtreated patients and may to a lesser extent improve long-term patency of surgical conduits. [89]

Atherosclerosis in arterial grafts can develop before coronary grafting when the graft is in the in situ native position, or after. The incidence of atherosclerosis in native arteries in the in situ position in the four major arterial grafts is low, especially in the IMA. [64] The incidence of atherosclerosis in bypass grafts is also low, in IMA grafts even as late 15 to 21 years after CABG. [67,82] However, the degree of stenosis in the native vessel is a major predictor of IMA graft patency. The observed association between non-significant stenosis of the native artery and high occlusion rate of the arterial bypass conduit raises concerns about the use of IMA in the treatment of native vessels with only mild or moderate stenosis. [83] In addition, the target vessel for the IEA must be one that is completely occluded or severely stenotic, with low coronary resistance, and in territories not totally infarcted to avoid "string sign" (conduit <1 mm diameter). Although the incidence of atherosclerosis is low in arterial grafts, 2 other morphologic changes may be present in arterial graft, fibrointimal proliferation and fibrosis representing organized thrombus. [84] The presence of fibrointimal proliferation is associated with long-term IMA graft narrowing and may be an important factor for late graft failure. Despite hypertension was associated with increased fibrointimal proliferation in SVG, this

Following graft revascularization, patients remain at very high risk for subsequent clinical events. In a large study from the Duke Cardiovascular Databank, patients who underwent catheterization 1 to 18 months after their first CABG were evaluated. [85] Patients were classified on the basis of their worst SVG stenosis as having no (<25%), noncritical (25% to 74%), critical (75% to 99%), or occlusive (100%) SVG disease and the primary outcome measure was the composite of death, MI or repeat revascularization. At 10-years, the corresponding adjusted composite event rates were 41.2%, 56.2%, 81.2%, and 67.1%, respectively (p<0.0001) and most events occurred immediately after catheterization in patients with critical and occlusive SVG disease. Multivariate analysis revealed critical, non-occlusive SVG disease as the strongest predictor of composite outcome (hazard ratio 2.36, 95% CI [2.00-2.79], p<0.0001). Many patients with recurrent stable angina following CABG can be treated medically for their symptoms and risk factor reduction. Evaluation for ischemia is as in other patients with stable angina without prior CABG. However, early diagnostic angiography is suggested as the different anatomic possibilities, i.e. graft stenosis or progression of native vessel disease in nonbypassed vessels can lead to recurrent ischemia. In patients with recurrent angina, ACS, change in exercise tolerance, positive exercise test after CABG, an increased risk for coronary

In all patients with coronary heart disease aggressive risk factor reduction is recommended which includes aspirin, treatment for hypertension and serum lipids, avoidance of smoking,

correlation could not be found in IMA grafts. [84]

200 Artery Bypass

events is observed. [86-88]

**8. Medical therapy**

**7. Treatment of coronary artery bypass graft failure**

*Antiplatelet therapy* - Antiplatelet therapy is recommended following CABG since it improves SVG patency and clinical outcomes. The 2008 EACTS guideline on antiplatelet and anticoa‐ gulation management in cardiac surgery [90] recommends that aspirin should be given postoperatively to all patients without contra-indications after CABG in order to improve the long-term patency of SVG. The recommended dose given is 150—325 mg. Several studies have shown a trend towards maximal benefit with 325 mg/day in the first year. [91-95] In contrast, there is no evidence that the use of aspirin after coronary artery bypass grafting improved the patency of arterial grafts. However, aspirin may be recommended on the basis of improved survival of patients in general who have atherosclerotic disease.

The optimal timing of the first dose of aspirin for patients after CABG was investigated in a meta-analysis of 12 studies and found that the benefit of aspirin was optimal if started at 6 h after surgery. [96] Although, the largest risk reduction was observed when aspirin was given at 1 h after operation, there was a non-significant increase in the rate of re-operation in this group. [91] In contrast, there was no benefit found in giving aspirin if starting more than 48 h postoperatively. [97] Practically, Aspirin should be commenced within 24 h of CABG.

Whether clopidogrel given in addition of aspirin to high-risk patients after CABG would reduce thrombotic complications was evaluated in several studies. Registry data showed that adding clopidogrel to aspirin was independently associated with a decrease in recur‐ rence of anginal complaints and adverse cardiac events following off-pump CABG. Nonetheless, clopidogrel use beyond 30 days did not show a significant effect on adverse cardiac events. [98] In the randomized CASCADE (Clopidogrel After Surgery for Coro‐ nary Artery Disease) study, aspirin monotherapy was compared with aspirin plus clopi‐ dogrel in 113 patients undergoing CABG and SVG intimal hyperplasia was determined by intravascular ultrasound at 1 year. [99] Compared with aspirin monotherapy, the combination of aspirin plus clopidogrel did not significantly reduce SVG intimal hyper‐ plasia 1 year after CABG. Although the study was not powered for clinical outcomes, there was no significant difference in SVG patency or cardiovascular events, neither was there a difference in the incidence of major bleeding between the 2 treatment groups at 1 year. Moreover, the superiority of clopidogrel over aspirin for optimising graft patency after CABG has not been established and thus aspirin should be regarded as the drug of first choice, however, clopidogrel is an acceptable alternative to aspirin. [90]

In patients whom underwent CABG for ACS subgroup analyses of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events) and CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study provides supportive evidence to prescribe clopi‐ dogrel for 9 to 12 months in addition to aspirin. [100,101] In patients undergoing coronary bypass surgery with a coronary stent in situ implanted within 1 year, clopidogrel should be continued if the stented vessel has not been grafted. Finally, in patients with SVG failure treated with PCI, prehospital use of antiplatelet therapy compared with patients not using antiplatelets was associated with lower occurrence of major adverse cardiac events after SVG intervention. [102] Also, DAPT did not improved outcomes when compared to single antiplatelet therapy.

The PREVENT IV trial, including almost 3,000 patients that underwent CABG, demonstrated that rates of use of secondary prevention medications in patients with ideal indications for these therapies are high for antiplatelet agents and lipid-lowering therapy, but suboptimal for beta-blockers and ACE inhibitors or ARBs. [115] The study demonstrated that the use of multiple secondary prevention medications after CABG was associated with significant improve in clinical outcome death or MI at 2 years (4.2% in patients taking all indicated medications versus 9.0% in patients taking half or fewer of the indicated medications). No association was found between the use of most individual medications and subsequent outcomes, thus underscoring the importance of ensuring appropriate secondary prevention

Treatment of Coronary Artery Bypass Graft Failure

http://dx.doi.org/10.5772/54928

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**9. Guidelines on revascularization in patients with prior CABG**

CABG or PCI should be decided by the Heart Team.

choice when performing redo CABG. [123]

In the European Society of Cardiology (ESC)/ European Association for Cardio-Thoracic Surgery (EACTS) guidelines on myocardial revascularization [116] published in 2010 states that in acute post-operative graft failure PCI may be an alternative to re-operation with acceptable results and fewer complications. [117] The target for PCI is the body of the coronary artery of the arterial graft while freshly occluded SVG or the anastomosis itself should be targeted due to the risk of embolization or perforation. When multiple grafts are occluded or the graft or native coronary artery appears unsuitable for PCI, surgery should be favoured. In asymptomatic patients, redo CABG or PCI should only be considered if the graft or coronary artery is of good size, severely narrowed and supplies a large territory of myocardium. Redo

Repeat revascularization in patients with late graft failure is indicated in the presence of severe anginal symptoms despite anti-anginal medication. In patients with mild or no symptoms repeat revascularization is dependent on risk stratification by non-invasive testing. [118,119] In patients with previous CABG, PCI has worse acute and long-term outcomes than in patients without prior CABG. Redo CABG has a two- to four-fold higher mortality than the first procedure which is mainly driven by comorbidity and less by the re-operation itself. [120,121] There is limited data comparing the efficacy of PCI with redo CABG in patients with previous CABG. In a propensity analysis of long-term survival after redo CABG or PCI in patients with multivessel disease and high-risk features, short-term outcome was very favourable, with nearly identical survival at 1 and 5 years. [118] However, in the AWESOME RCT and registry the overall in-hospital mortality was higher in the redo CABG group compared to the PCI group. [17,122] Because of the initial higher mortality of redo CABG and comparable longterm mortality, the guidelines state that PCI is the preferred revascularization strategy in patients with LIMA or amenable anatomy. Redo CABG is preferred in patients with more diseased or occluded grafts, reduced systolic function, total occlusions of native coronary arteries or in the absence of a patent arterial graft. [118] If possible, the IMA is the conduit of

In the 2012 appropriateness criteria for coronary revascularization focussed update of the American College of Cardiology Foundation Appropriateness Criteria Task Force (ACCF),

measures after CABG.

*Warfarin* – Conflicting evidence is reported whether warfarin in addition to aspirin is beneficial in patients post CABG. In an extended follow-up of 7.5 years of the post CABG trial, low-dose anticoagulation compared with placebo reduced the rate of death by 35%, deaths or myocardial infarction (MI) by 31%, and the composite clinical endpoint of death, MI, stroke, CABG, or angioplasty by 17%. [103] However, in a smaller randomized trial, moderate-intensity oral anticoagulation alone or combined with low-dose aspirin was not superior to low-dose aspirin in the prevention of recurrent ischemic events in patients with non-ST-elevation ACS and previous CABG. [104] Currently, the American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines recommended that oral anticoagulation in addition to aspirin can be considered only when it is indicated for other reasons. [105]

*Lipid lowering therapy* – Clinical trials have shown that lipid lowering therapy (in particular statins) is beneficial in patients who have undergone CABG. [103,106-110] Besides the lipid lowering effect, statins also exert a number of pleiotropic effects on the vascular wall which may effect SVG in a similar way. In SVG, statins have shown to reduce vascular oxidative stress, improve NO bioavailability and reduce vascular inflammation, all critical components of SVG failure. [111] Subsequently, statins have systemic antithrombotic and anti-inflamma‐ tory effects and their administration may prevent acute SVG failure post CABG. [112] Ag‐ gressive lipid lowering therapy may be beneficial for long-term patency of grafts. In the randomized Post CABG trial, patients who had undergone bypass surgery 1 to 11 years before base line with elevated serum LDL-cholesterol concentrations (130 to 175 mg/dL / 3.4 to 4.5 mmol/L) were assigned to receive either aggressive lipid lowering therapy with lovastatin and, if needed, cholestyramine (target LDL-cholesterol <100 mg/dL / 2.6 mmol/L) or to moderate therapy (target LDL-cholesterol of approximately 134 mg/dL / 3.5 mmol/L). [106] Compared to a moderate strategy, aggressive lipid lowering therapy was associated with a delay in the progression of graft disease at an average of 4.3 years as assessed by angiography. Moreover, after clinical follow-up of 7.5 years, a 30% reduction in revascularization procedures and a 24% reduction in the composite endpoint of cardiovascular death, MI, stroke, CABG, or angioplasty were seen. [103] Similar findings were observed in a post hoc analysis from the TNT trial. In patients with previous CABG, simvastatine 80 mg compared to simvastatine 10 mg, was significantly more effective in reducing the rate of a combined cardiovascular endpoint at a median follow-up of 4.9 years (9.7% versus 13.0%). [110] Repeat revascularization with either CABG or PCI was also significantly reduced in patients assigned to the higher dose (11.3% versus 15.9%).

Antiplatelet agents and statin therapy are the only modalities with proven efficacy for the prevention of SVG stenosis. The routine use of beta blockers, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, or nitrates post CABG is not supported by data, however, many of these patients require beta blockers and ACE inhibitors for preexistent heart failure or MI according to the ACC/AHA guideline recommendations. [113,114]

The PREVENT IV trial, including almost 3,000 patients that underwent CABG, demonstrated that rates of use of secondary prevention medications in patients with ideal indications for these therapies are high for antiplatelet agents and lipid-lowering therapy, but suboptimal for beta-blockers and ACE inhibitors or ARBs. [115] The study demonstrated that the use of multiple secondary prevention medications after CABG was associated with significant improve in clinical outcome death or MI at 2 years (4.2% in patients taking all indicated medications versus 9.0% in patients taking half or fewer of the indicated medications). No association was found between the use of most individual medications and subsequent outcomes, thus underscoring the importance of ensuring appropriate secondary prevention measures after CABG.
