Secondary Prevention Medications Post Coronary Artery Bypass Grafting Surgery

Abstract

Secondary prevention after coronary artery bypass graft (CABG) surgery is imperative in slowing the progression of atherosclerosis in both native and grafted vessels. Aspirin and statins remain the key medications for all patients without significant contraindications. The evidence for dual antiplatelet therapy with clopidogrel is less convincing, but there is hope for newer antiplatelet agents, such as ticagrelor. Meanwhile, β-blockers and angiotensin converting enzyme inhibitors might only offer benefits to specific sub-groups. Post-CABG patients appear to have different medication needs to the general cardiovascular patient and respond differently. In this review, we cover the drug regimens proposed by recent guidelines and the evidence behind their use. Assessing the evidence behind these recommendations, we find that there is an unmet need in some areas for robust population-specific evidence. We hope that future research will address this gap.

Keywords

CABG secondary prevention antiplatelets statins

Introduction

Myocardial revascularization by coronary artery bypass graft (CABG) remains the primary treatment for coronary artery disease (CAD) affecting 3 vessels or the left main coronary artery.¹ As surgical techniques improve, patients of increasingly greater risk are being considered for surgery.² It is becoming clear that CABG patients are a unique subpopulation and require different post-operative medical considerations compared to CAD patients.

Unfortunately, symptom relief from revascularization is impermanent. Venous grafts can occlude within a year³ from post-surgical thrombosis and the underlying atherosclerotic process. Therefore, medication is necessary to slow native disease and delay graft occlusion. This involves a combination of antiplatelets, statins, and sometimes β-blockers and renin-angiotensin-aldosterone system (RAAS) inhibitors.

Optimal use of secondary prevention remains unclear. These medications have good evidence in various other settings, e.g. after myocardial infarction (MI) or stable CAD. However, evidence for best practice after CABG is lacking and current data suggests that post-CABG patients respond differently to these medications. Many recommendations are made on extrapolated data from CAD patients and, where evidence is CABG-specific, it is often from retrospective studies, with few randomized trials with extended follow-up. This review summarizes the current guidelines and evaluates the data on the use of secondary prevention medications following CABG.

Literature Search

A comprehensive literature search was done through PubMed, SCOPUS, Embase, Cochrane and Ovid to identify relevant articles. Key words were “CABG,” “Secondary prevention,” “RAAS-inhibitor,” “renin-angiotensin-aldosterone,” “RAAS inhibitor,” “ARB,” “ACE,” “ACEi,” “ACE inhibitor,” “*pril,” “*olol,” “*statin,” “beta blocker,” “beta-blocker,” “anti-platelet,” “antiplatelet,” “dual antiplatelet,” “aspirin,” “atorvastatin,” “clopidogrel,” “ticagrelor,” and “prasugrel.” Filters limited the results to the English language, with no other limits. All relevant articles (and reference lists) were identified and screened by 3 authors.

Guidelines

We reviewed the clinical practice guidelines from the United States and Europe. Both sets of guidelines include assessments of the evidence and make recommendations for clinical practice. Individual recommendations are graded in 2 ways: by the balance of benefit and risks (Class of Recommendation, COR), and by the quality of its evidence base (Level of Evidence, LOE).⁴ These are summarized in Figure 1, while a comprehensive comparison is in Supplementary Table 1.

Figure 1.

Summary of guidelines for secondary prevention following CABG procedures. Recommendations in: bold: applicable to the entire post-CABG population; non-bold: defined sub-populations. Italics: gaps without specific recommendations. Underlined: recommendation applies to non-post-CABG patients. * A combination of aspirin and clopidogrel can be used if the patient is ineligible for ticagrelor and prasugrel. Abbreviations used in the figure: A = aspirin, ACEi = ACE inhibitor, ACS = acute coronary syndrome, ARB = angiotensin receptor blocker, C = clopidogrel, CABG = coronary artery bypass grafting, CAD = coronary artery disease, CKD = chronic kidney disease, CV RF = cardiovascular risk factors, DAPT = dual antiplatelet therapy, DM = diabetes mellitus, HTN = hypertension, IHD = ischemic heart disease, LVEF = left ventricular ejection fraction, MI = myocardial infarction, P = prasugrel, T = ticagrelor, _/12 = _ months.

Unfortunately, guidelines often do not apply specifically to the post-CABG population. The key guideline from the American institutions, the 2011 ACC/AHA Guidelines Coronary Artery Bypass Graft Surgery report,⁵ was published almost a decade ago with the only update being the 2016 update on dual antiplatelet therapies.⁶ From Europe, recommendations are split across publications that focus on different populations. The 2008 Guideline on Antiplatelet and Anticoagulation Management⁷ and 2017 EACTS Guidelines on perioperative medication⁸ both make recommendations for treatment following all cardiac surgery. The 2014 ESC/EACTS Guidelines on myocardial revascularization⁹ encompass all forms of revascularization, while the 2019 ESC/EAS Guidelines for the management of dyslipidemias¹⁰ refer to all CAD patients.

Recommendations aimed at more general populations may overlook the nuance involved in secondary prevention following CABG. CABG patients typically have more extensive cardiovascular disease and restricted myocardial blood flow, while patients undergoing PCI are more likely to have significant co-morbidities, advanced age and frailty.¹¹

The lack of evidence focusing on post-CABG patients should be addressed with future research. A 2014 ESC expert position paper¹² was critical of the extension of recommendations on antiplatelet and DAPT to CABG patients, highlighting inconsistent evidence, and, in some places, a lack of direct evidence in post-CABG patients.

Key Differences

The European and American guidelines mostly align, but there are some notable differences (Supplementary Table 1). The first such difference is the advice on DAPT. Recent evidence was sufficiently ground-breaking to require both bodies to publish updates.^6,13 Both stressed only patients with stable disease should be prescribed DAPT. However, while the AHA/ACC recommends a 12-month treatment duration, the ESC stratifies patients by bleeding risk to either a 6-month or 12-month course. In low-risk groups, ESC provide the option to extend treatment up to 3 years.

Further, both guidelines recommend statin therapy to all CABG patients. However, there is disagreement on the target LDL-cholesterol level. In 2011, the ACC/AHA recommended reduction below 100 mg/dL or below 70 mg/dL in high-risk patients,⁵ while the 2019 ESC/EAS update on the management of dyslipidemias advised reduction below 55 mg/dL.¹⁰ Both ACC/AHA recommendations were graded as LOE “C” meaning that there was limited data to decide the thresholds. The ESC/EAS level is LOE “A,” meaning that the studies used are of a rigorous level, but these studies comprised large cohorts of patients with CAD, atherosclerosis, and/or acute coronary syndrome (ACS). As such, these more general groups may have reduced applicability to the post-CABG population. As discussed below, there is limited evidence in this cohort for the 70 mg/dL target, let alone a sub-55 mg/dL one. Further research is required to elucidate what benefit is gained from such intensive lipid reduction.

Finally, the recommendations for β-blockers are different. American guidelines recommend β-blockers for all CABG patients without contraindications.⁵ Meanwhile, the European committees suggest that long-term use of β-blockers is only suitable in patients with a recent history of MI or a low ejection fraction.⁸ There are arguments to follow either direction; the ESC/EACTS advice is based on a higher grade of evidence but one that applies to a more general population, while the AHA/ACC advice is based on expert opinion but specifically relates to the post-CABG patient group.

Secondary Prevention After Surgery

Atherosclerosis is chronic inflammatory process whereby lipid-rich plaques develop in coronary arteries and impede blood flow either by progressive vessel occlusion or with the acute development of thrombi. Bypass techniques bridge the affected section alleviating the ischemic symptoms, but vessels are still vulnerable to atherosclerosis and post-surgical thrombosis. Four main drug groups are used to address these risks to maintain graft patency and overall cardiovascular outcomes.

Antiplatelets

Clotting is the process behind thromboemboli, which cause acute ischemic crises to occlude CABG grafts. Antiplatelets inhibit the clotting cascade, a sequence mediated by activated platelets via several ligand-receptor positive feedback loops. Aspirin irreversibly inhibits cyclooxygenase-1, while thienopyridines, e.g. clopidogrel, inhibit the P2Y12 receptor activated by ADP to propagate thrombus formation.¹⁴ As they act on different targets, they have synergistic effects. Together, the antithrombotic effect is increased, but with higher bleeding risk.

Aspirin

Aspirin reduces thrombosis and graft occlusion in the early and late post-operative periods. The effect on graft patency is well established, with an early systematic review¹⁵ reporting that antiplatelet treatment, mainly aspirin monotherapy, results in reduced graft occlusion. It should be noted that this effect is in venous grafts, as internal mammary artery grafts remain largely unobstructed regardless of aspirin use.¹⁶

Aspirin use is also associated with improved clinical outcomes. In a prospective observational study with 5065 patients, Mangano et al (2002)¹⁷ demonstrated that post-operative aspirin therapy within 48 hours was associated with reduced mortality (68%), MI, and stroke without increasing bleeding events during hospitalization. Multiple observational studies^18
-20 have since shown an association between aspirin use and improved long-term survival.

With extensive evidence, aspirin is justifiably recommended after CABG for all patients by both American and European guidelines.^5,8 However, grafts still fail despite aspirin therapy and research has recently focused on whether better outcomes can be achieved by combining aspirin with a thienopyridine antiplatelet in dual antiplatelet therapy (DAPT). Most studies use clopidogrel, but prasugrel and ticagrelor have also garnered attention.

DAPT using clopidogrel

DAPT with clopidogrel has been studied extensively. While there are many studies that assess the effect on graft patency, there remains little consensus on whether there is an overall benefit. This is reflected in both American and European guidelines—both recommendations regarding the use of DAPT in CABG patients without a separate indication are graded as class “IIb” meaning they only provide some benefit.

Two recent network meta-analyses reported on whether patency is improved with clopidogrel DAPT.^21,22 Chakos et al (2018)²¹ found no difference, while Solo et al (2019)²² showed a benefit. This conflict may be due to a difference in their primary end-point; Chakos et al (2018)²¹ looked at overall graft patency, while Solo et al (2019)²² studied SVG failure defined as “patients with at least one occluded SVG.” Furthermore, Chakos et al (2018)²¹ had more restrictive inclusion criteria, restricting their analysis to RCTs with more than 50 patients and a follow-up beyond 3 months, which may have reduced the effect size.

Looking in closer detail at the larger studies on the topic, there remains little consensus. In the 4 largest RCTs,^23

-26 improved graft patency was seen at 3 months in Ge Gao et al (2010)²⁴ and at 12 months in Mannacio et al (2012),²⁵ but Abdi et al (2020)²⁶ and Gao et al (2009)²³ found no significant difference at 6 and 12 months respectively. The 2 largest observational trials, each including more than 2000 patients,^27,28 both reported insignificant differences in graft patency up to 5 years with DAPT compared to aspirin monotherapy. In the longest available trial for graft patency, Hage et al (2018)²⁹ reported no difference in venous graft patency after 7 years, but a “lower incidence of moderate to severe progression of native coronary artery disease.”

It is also unclear if there is any benefit on clinical outcomes. The most recent meta-analyses, Verma et al (2015)³⁰ and Solo et al (2019),²² both reported no difference in all-cause mortality between DAPT and aspirin monotherapy. This is in contrast to the previous influential report by Deo et al (2013),³¹ who found reduced 30-day mortality with DAPT. Deo et al (2013),³¹ however, included observational studies and did not find a significant difference when considering RCTs alone. Looking more closely, Mannacio et al (2012),²⁵ a large RCT who had found a benefit with clopidogrel on graft patency, did not see that translate to improved clinical outcomes. In 5 large observational studies with long-term follow-up beyond a year,^27,32
-34 DAPT was only shown to have a benefit by Sørensen et al (2011).³³ They demonstrated that clopidogrel-treated patients had a lower combined risk of death or recurrent MI after 466 days.

DAPT with newer antiplatelets

Ticagrelor and prasugrel provide alternatives to clopidogrel to use in DAPT regimens and several meta-analyses have demonstrated benefit. Agarwal et al (2018)³⁵ found DAPT with ticagrelor or prasugrel was associated with fewer major adverse cardiovascular events (MACE) and all-cause mortality. Cardoso et al (2018)³⁶ reported lower cardiovascular mortality. Both of these meta-analyses also showed that ticagrelor or prasugrel improved SVG occlusion. Finally, Verma et al (2015)³¹ who had found no benefit with clopidogrel, reported that ticagrelor or prasugrel used with aspirin showed significantly lower risk for all-cause mortality, although this was only based on 2 studies.

With prasugrel specifically, a post-hoc analysis from the TRITON-TIMI 38 Trial³⁷ found there was reduced all-cause mortality at 30 days with prasugrel DAPT compared to clopidogrel DAPT. However, they also reported increased blood loss and bleeding complications, and the study was restricted to ACS patients. Further studies are needed to confirm if benefits might outweigh bleeding risks and that they extend long-term.

Meanwhile, a post-hoc analysis from the PLATO trial found ticagrelor used with aspirin led to significant reduction in cardiovascular mortality compared to clopidogrel and aspirin.³⁸ Furthermore, Zhao et al (2018)³⁹ reported improved graft patency with ticagrelor and aspirin when compared to aspirin alone, however this was not accompanied with a statistically significant difference in MACE or MI. This contrasts the data from the POP-CABG trial⁴⁰ which found no difference in SVG occlusion rates in 499 patients after a year of DAPT with ticagrelor (compared to aspirin and placebo).

In a meta-analysis, Von Scheidt et al (2020)⁴¹ concluded that ticagrelor-based regimens are superior compared to clopidogrel-based regimens, especially in ACS patients. Approximately 4000 patients were included in total over 12 months. However, 2 of the 5 trials did not reach completion, while only one of the remaining 3 had mortality and cardiovascular events as a primary outcome.

Finally, results may be different in patients with arterial grafts due to lower occlusion rates.¹⁶ Chang et al (2019)⁴² found no difference in outcomes in patients with exclusively arterial grafts between ticagrelor DAPT and clopidogrel DAPT after an average of 1.8 years.

A summary of the above conclusions is presented in Table 1.

Table 1.

Summary of Findings for Antiplatelet Agents.

	Aspirin	Clopidogrel DAPT	Prasugrel DAPT	Ticagrelor DAPT
Advantages	Well-documented effect on patency and mortality	Possible benefit after OPCAB	Improved mortality	Improved mortality, especially after ACS
Disadvantages	Not completely effective in halting graft disease	No significant improvement to aspirin monotherapy	Single study available Increased bleeding risk	Unclear effect on patency Limited number of completed studies
Conclusions	Recommended for all patients	No benefit to general population, but may benefit OPCAB or recent ACS patients	Further study required	Likely recommended DAPT agent following further research (TARGET, TAACSI)

OPCAB = Off pump coronary artery bypass.

Statins

Cholesterol is the main component of stable atherosclerotic plaques. Statins lower cholesterol and are thought to be protective for cardiovascular disease.⁴³ Statins inhibit HMG-CoA reductase, the rate-limiting step in the mevalonate pathway which produces precursors for endogenous hepatic cholesterol generation. As intracellular cholesterol is decreased, LDL receptors are upregulated, and LDL is cleared from the bloodstream.

Statins also have non-lipid pleiotropic effects that independently improve cardiovascular mortality.⁴⁴ The mevalonate pathway inhibited by statins also produces intermediates and precursors involved in other signaling pathways, including those for growth, differentiation, and maturation of inflammatory and fibrotic cell lines. This is thought to explain why statins improve endothelial dysfunction, fibrotic processes, and myocardial hypertrophy.⁴⁴

In CABG patients, statins are associated with reduced plaque progression⁴⁵ and multiple observational studies^46

-50 have shown improved long-term clinical outcomes. Kulik et al (2008)⁴⁸ demonstrated that early statin initiation post-CABG was associated with a reduction in all-cause mortality and MACE. Although significant differences were only reached after 6 years of follow-up, this was shown elsewhere. Philip et al (2015)⁴⁹ saw a significant reduction in mortality and MACE at 30 days and long-term in 3637 patients. Most recently, Björklund et al (2019)⁵⁰ reported that statin therapy conferred a significant mortality benefit after adjusting for “time-updated use” of other medications in 28812 first-time CABG patients with a median follow-up of 4.9 years.

The only contrasting evidence comes from Goyal et al (2007),⁵¹ who found lipid-lowering treatments were not associated with improved outcomes (death or MI) at 2 years. They, however, had a shorter follow-up and acknowledge that they might not have sufficient power to detect an association between individual medications and clinical outcomes.

Current guidance recommends all patients without contraindications are on statins,^5,10 although most patients are on statins pre-surgery. Statins should be continued post-operatively and, according to guidelines, be targeted to patient’s LDL levels. The exact LDL target level, however, is up for debate. Recent guidelines have encouraged a more intensive LDL target of 55 mg/dL,¹⁰ but there is no evidence showing statin monotherapy provides benefits below 100 mg/dL.

In the Post-CABG trial,⁶⁰ patients on aggressive therapy (40-80 mg lovastatin supplemented with cholestyramine) had reduced disease progression compared to patients on lower doses (2.5-5 mg lovastatin); the mean LDL levels were 93-97 mg/dL and 132-136 mg/dL respectively. Shah et al (2008)⁴⁷ also reported reduced cardiac events with higher dose atorvastatin (80 mg vs 10 mg); the patients on the intensive regimen reached LDL levels of 79 mg/dL (vs. 101 mg/dL). Additionally, Philip et al (2015)⁴⁹ reported patients with LDL levels < 100 mg/dL had lower mortality compared to patients over 130 mg/dL.

Meanwhile, studies using LDL levels below 100 mg/dL have not found significant results. In the ACTIVE trial,⁶¹ no significant difference was seen in occlusion or freedom from MACE in patients on 80 mg atorvastatin with mean LDL level of 58.5 mg/dL compared to 10 mg atorvastatin with mean LDL levels of 79.2 mg/dL. Further, a post-hoc analysis of the CASCADE trial found that while LDL levels <100 mg/dL were associated with improved 12 month graft patency, no improvements were noted with further reductions.⁶²

In summary, statin therapy should be targeted to LDL levels, as there is clear evidence that more aggressive intervention improves outcomes, but further evidence in this patient population is required to determine if further reduction is justified.

Beta Blockers

Beta blockers are used to reduce both blood pressure and cardiac ischemia. Hypertension, a modifiable CAD risk factor, contributes to atherosclerosis by increasing endothelial damage and pathological remodeling. Blocking the cardiac-specific β₁-adrenoceptors intercepts the sympathetic drive of cardiac inotropy and chronotropy. This blockade allows for longer diastole, increasing coronary artery filling, and decreases oxygen demand, thus decreasing myocardial ischemia. Decreased cardiac drive also decreases cardiac output and arterial pressure. Beta blockers also act by inhibiting the renin-angiotensin-aldosterone system (RAAS), potentially further lowering blood pressure.

This theoretical benefit translates less clearly to clinical benefit post-operatively. There is a paucity of robust trial evidence of long-term protection from graft disease, future cardiovascular events and mortality, with most data coming from observational cohort studies. These are often complicated by the fact that CABG patients often take β-blockers for indications separate to secondary prevention of CAD.

These studies can be placed into 3 categories: studies that show an association,^{19,49,52,54
-56} studies that only show an effect in some patient sub-groups,^57,58 and studies that show no effect^50,51,59 (Table 2). The Björklund et al (2019)⁵⁰ paper is the newest and largest study on the topic, and so their results raise significant questions. In a cohort of 28 812 patients, they found that antiplatelets, RAAS-inhibitors and statins, but not β-blockers, were individually associated with lower mortality.

Table 2.

Summary of the Observational Studies Regarding the Use of β-Blockers for Secondary Prevention After CABG.

Study	Sample	Mean follow-up	Results
Positive effect
Chan et al (2010)⁵²	3102 cardiac surgery patients (2547 CABG) from 1 center	75.2 ± 20.2 months	0.65 (0.49-0.87 95% CI) HR for mortality. Similar results in CABG patients
Kalavrouziotis et al (2011)⁵³	3163 patients 65 years and over undergoing isolated CABG at single institution.	3.1 years (median)	0.83 (0.74-0.93 95%CI) HR for event-free survival.
O’Neal et al (2014)⁵⁴	4430 first-time isolated CABG patients at single institution. 88% of sample on β-blockers.	4.3 years median	0.33 (0.23-0.46 95%CI) HR for mortality in black patients 0.48 (0.39-0.58 95%CI) HR for mortality in white patients
Zhang et al (2015)⁵⁵	5926 CABG patients from 1 center.	12 months	1.42 (1.01-2.00 95% CI) HR for mortality with never using β-blockers. 1.29 (1.10-1.50 95% CI) HR for composite MACCE* with never using β-blockers. Effect seen in patients with and without recent MI. Relationship between more consistent use and all-cause mortality/composite outcomes.
Philip et al (2015)⁴⁹	3637 patients undergoing single isolated CABG at 1 center.	11 years (median)	0.731 (0.624-0.857 95%CI) HR for mortality
Iqbal et al (2015)¹⁹	897 CABG patients in the SYNTAX trial.	5 years	0.46 (0.30-0.70 95%CI) HR for mortality
Park et al (2020)⁵⁶	5382 CABG patients	4 years	0.40 (0.19-0.81 95%CI) HR for all-cause mortality in the first 12 months, but not significant thereafter. Difference driven by non-cardiac causes.
Restricted sample
Chen et al (2000)⁵⁷	8482 CABG patients. All patients are >65yo with confirmed MI.	1 year	0.70 (0.55-0.89 95%CI) HR for mortality.
Angeloni et al (2013)⁵⁸	388 patients with COPD	30.8 ± 8.5 months	0.38 HR on Kaplan-Myer analysis without exacerbating COPD
No effect
Goyal et al (2007)⁵¹	2970 first-time CABG patients from PREVENT IV trial (multicenter study)	2 years	0.53 (0.24, 1.17 95%CI) HR for death or MI in ideal patients (any history of MI or reduced EF < 45% with NYHA class II or III) reported as trend.
Booij et al (2015)⁵⁹	2233 CABG patients from the IMAGINE trial. Patients were hemodynamically stable and had EF > 40%.	3 years	0.97 (0.74-1.27 95%CI) HR for cardiovascular events. No difference in subgroups.
Björklund et al (2019)⁵⁰	28812 isolated first-time CABG patients from SWEDEHEART registry alive 6 months after discharge.	4.9 years median	0.97 (0.90-1.06 95%CI) HR for mortality when adjusted for other secondary preventative drugs.

MACCE = major adverse cardiac and cerebrovascular events.

It is unclear why there are such conflicting conclusions. Most studies have large sample sizes, adequate follow-up, and similar rates of heart failure, hypertension, and prior MI. One possibility is confounding interactions with other secondary prevention medications.^49,51,52,63 Some authors suggest that surgical techniques have outpaced the usefulness of β-blockers, but there are studies in favor of their use published very recently—taking into account these surgical advances.

A new RCT is needed to update the only one from 1995,⁶⁴ which found no benefit to metoprolol over placebo in 967 patients. A newer RCT would account for 25 years of surgical advancements, medication regimens, and more complete revascularization.

The slight majority of studies suggest β-blockers provide a long-term mortality benefit. A recent large study raised questions about their effect, and it remains unclear if only certain sub-groups of patients benefit from treatment. A meta-analysis of current data may provide further clarity.

RAAS Inhibitors

RAAS inhibitors are key in hypertension management by regulating circulatory volume and, therefore, blood pressure.⁶⁵ Low arterial pressure, hyponatremia, or sympathetic drive stimulate renin production in the kidney, which promotes the production of angiotensin II (ATII). ATII increases vascular tone and stimulates aldosterone release from the adrenal cortex; aldosterone drives sodium reuptake in the distal nephron, encouraging water retention.⁶⁵ Overall, circulatory volume and vascular tone is increased, raising peripheral blood pressure.

Several parts of the axis can be targeted, but ACE inhibitors are most commonly used because of their efficacy and safety. These are thought to have cardiovascular protective functions independent of blood pressure reduction.⁶⁶ The inhibition of ACE shifts the balance toward the breakdown of ATI and ATII to Ang-(1-7) and Ang-(1-9).⁶⁵ These breakdown molecules are hypothesized to impact progression of nephropathy and cardiac fibrosis, among other effects.⁶⁵

RAAS inhibitors are not routinely prescribed post-CABG, but are selectively given to those with co-morbidities such as hypertension, diabetes, and heart failure (HF).^5,8 ARBs are recommended as an alternative to ACEi, and were recently shown to be as effective up to 48 months.⁶⁷

ACE inhibitors have shown some benefit in limited studies. Oosterga et al (2001)⁶⁸ randomized 149 ACE-naive patients to either quinapril or placebo. Over 91% had NYHA class II or III HF, but left ventricular ejection fraction (LVEF) was not reported. At 1 year, they saw no difference in ischemia during exercise testing, but the quinapril group had significantly fewer clinical ischemic events. Kjøller-Hansen et al (2003)⁶⁹ reported similar data in 130 post-CABG patients with low LVEF, but without a clinical diagnosis of HF. Patients were randomized to ramipril or placebo and followed up for a median 33 months. Ramipril was significantly associated with a reduction in the composite endpoint (cardiac death, MI, and development of clinical HF). Ramipril was also associated with a beneficial effect on end-systolic volume. This benefit may stem from secondary cardioprotective effects, rather than directly improving atherosclerosis.

It is unlikely that low-risk patients, without HF, benefit from long-term RAAS inhibition. The IMAGINE trial (2008)⁷⁰ randomized 2553 CABG patients with EF > 40% to receive either quinapril or placebo. Analysis after 3 months showed increased morbidity and mortality with quinapril, although there was no significant difference at the end-point (median 2.95 years). Goyal et al (2007)⁵¹ also found that ACE inhibitors may have harmful effects on mortality when prescribed to non-ideal patients.

Some observational studies also reported contradictory results, as 4 studies^19,49,51,53 found no benefit, while the most recent two did^50,71 (Table 3). These conflicting conclusions may be due to different proportions of patients with significant heart failure in the samples. On balance, ACE inhibitors offer a benefit to patients with HF, but they should not be prescribed as secondary prevention to all patients following CABG.

Table 3.

Summary of the Studies Regarding the Use of ACE Inhibitors for Secondary Prevention After CABG.

Study	Sample	HF classification	Follow up	Results
Goyal et al (2007)⁵¹	2970 first-time CABG patients from PREVENT IV trial (multicenter study)	9%-10.5% with history of CHF depending on group. Median LVEF 50%-55%, with 75% of patients over 40%. 60.3% of patients NYHA	2 years	0.87 (0.52-1.45 95%CI) HR for death or MI in ideal patients (any history of MI or reduced EF < 45% with NYHA class II or III). 1.64 (1.00-2.68 95%CI) HR for non-ideal.
Kalavrouziotis et al (2011)⁵³	3163 patients 65 years and over undergoing isolated CABG at single institution.	16.3% with clinical CHF and 26.3% of patients with LVEF < 50%.	3.1 years (median)	1.12 (0.96-1.30 95%CI) HR for mortality and CV rehospitalization.
Philip et al (2015)⁴⁹	3637 patients undergoing single isolated CABG at Cleveland Clinic.	Mean EF 45% ± 9% and mean NYHA class 2.5 ± 1.	11 years (median)	0.936 (0.78-1.109 95%CI) HR for mortality
Iqbal et al (2015)¹⁹	897 patients undergoing CABG in the SYNTAX trial	5.3% with clinical CHF. 2.5% with LVEF < 30%.	5 years	0.78 (0.56-1.09 95%CI) HR for composite of death/MI/cerebrovascular incident
Ding et al (2019)⁷¹	8581 patients with CABG and/or valve surgery, of which 2831 were prescribed RAAS inhibitors at discharge.	31.3% in the RAAS group and 30.7% in the non-treatment group after adjustment with diagnosed CHF.	4.43 years mean	0.86 (0.73-0.99 95%CI) RR at 2 years and 0.84 (0.72-0.96 95%CI) RR at 6 years after adjustment for mortality.
Björklund et al (2019)⁵⁰	28 812 isolated first-time CABG patients from SWEDEHEART registry alive 6 months after discharge.	20.9% of patients with diagnosed CHF and 30% with LVEF < 50%.	4.9 years median	0.78 (0.73-0.84 95%CI) HR for mortality when adjusted for other secondary preventative drugs.

Patients With LV Dysfunction

There is little deviation in the recommended medical management of patients with LV dysfunction following CABG from guidance for the general HF population. There is sparse data on this population and most of the evidence cited comes from patients with HF regardless of surgical status.

Evidence for ACEi has been discussed previously and little data exists for β-blockers. In 2010, Lin et al⁷² reported improvements in mortality both in-hospital and at 30 days in 1369 post-CABG patients with EF < 40%. However, Ferguson et al (2002)⁶³ reported a trend toward increased 30-day mortality in patients with EF < 30%. Thus, while patients may benefit from β-blockers, patients with severe dysfunction may need to be considered on a more individual basis.

Limited studies also show a synergistic effect between RAAS inhibitors and β-blockers. Gandhi et al (2007)⁷³ showed that patients randomized to combination therapy had greater improvements in LVEF and end-systolic diameter after 6 months compared to patients taking ACE inhibitors alone. Maruyama et al (2008)⁷⁴ suggest that this is because ACE inhibitors affect end-diastolic volume, while β-blockers affect end-systolic volume and EF.

Two studies have shown that optimal medical HF therapy also improves outcomes for HF patients after CABG. In a post-hoc analysis of the STICH trial, Wolfe et al (2020)⁷⁵ reported that CABG and guideline-directed medical therapy were both independently associated with improved mortality, suggesting that medication offers incremental risk reduction. This was corroborated by Wurm et al (2017),⁷⁶ who found that medication improved survival at 5 years.

HF therapy should still be used alongside optimal CABG therapy. Statins in particular have been shown to equalize the difference in mortality caused by a reduced EF.⁴⁹ Further, sub-group analysis from Björklund et al (2019)⁵⁰ show that patients with reduced EF still derive benefit from statins and antiplatelets.

Future Research

Further improvement in clinical outcomes will depend on progress in medication regimens and surgical techniques. Randomized trials, in particular, are needed to study the effect of these medications in this specific population and direct future guidelines. These may also address how different sub-groups within the CABG population respond to medications, e.g. whether DAPT is more beneficial after off-pump coronary artery bypass (OPCAB).

New medications also offer new opportunities. New research into ticagrelor, either as a monotherapy or in conjunction with aspirin, is due to be published in the coming years. Similarly, PCSK9 inhibitors may offer an additional option to help hyperlipidemic patients achieve their LDL targets.

Intra-operative SVG harvesting technique, SVG length, and sequential grafting has been linked with graft patency.⁷⁷ Equally, arterial grafts have a lower failure rate than venous grafts, but also derive less benefit from medication.^16,42,78 Arterial grafts may offer improved benefits to patients, leading to reduced need for medical therapy and pharmacological burden on patients, and these differences need to be considered in future research.

Conclusion

Secondary prevention is imperative post-CABG, but these patients often have different requirements than CAD patients prior to surgical revascularization. Aspirin and statins are the mainstay of secondary prevention, but there is ongoing controversy over the additional benefit other medications offer.

Supplemental Material

Supplemental Material, sj-docx-1-cpt-10.1177_1074248420987445 - Secondary Prevention Medications Post Coronary Artery Bypass Grafting Surgery—A Literature Review

Supplemental Material, sj-docx-1-cpt-10.1177_1074248420987445 for Secondary Prevention Medications Post Coronary Artery Bypass Grafting Surgery—A Literature Review by Stavros Dimitriadis, Evelyn Qian, Amy Irvine and Amer Harky in Journal of Cardiovascular Pharmacology and Therapeutics

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Author Contributions

All authors have read and approved the content of the manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Stavros Dimitriadis

Amer Harky

Supplemental Material

Supplemental material for this article is available online.

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