The management of stable ischemic heart disease (SIHD) leading to ischemic cardiomyopathy (ICM) has been the focus of attention in the field of cardiology in more recent years, with numerous trials providing conflicting data regarding benefits of medical therapy versus revascularization, whether surgical or interventional. Herein we aim to review and analyze pivotal trials in management of SIHD in ICM, as well as explore the role of additional investigational testing such as viability studies as well as therapeutic modalities such as mechanical circulatory support in the management of this patient population.

Coronary artery disease, Ischemic cardiomyopathy, Percutaneous coronary intervention, Aortic stenosis,  Mitral regurgitation

Amir R, Roy S, Resar J, Rahman F (2024) Coronary Artery Disease Revascularization in Ischemic Cardiomyopathy. Ann Vasc Med Res 11(2): 1181.

Ischemic cardiomyopathy (ICMP) is a common type of cardiac pathophysiology driven by coronary artery disease (CAD) causing left ventricular dysfunction. Classical clinical manifestations of ICMP include symptoms of coronary ischemia such as angina (often presenting as chest pain or dyspnea) or symptoms of heart failure and low cardiac output. The management of stable CAD associated with ICMP is complex including decisions regarding revascularization through either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). The improvement in medical therapy in combination with newer studies has brought into question the traditional approaches to revascularization in patients with ICMP and stable coronary artery disease. In this review, we will discuss updates in the indications for revascularization in stable ischemic heart disease (SIHD) and outcomes of revascularization in patients with CAD.

Coronary Artery Disease and Ischemic Cardiomyopathy

SIHD describes a state of chronic CAD causing distal coronary ischemia due to poor oxygenation. The concept of SIHD has classically been attributed to CAD involving the epicardial arteries, though microvascular dysfunction has more recently been identified to either contribute or independently cause SIHD [1,2]. Of note, SIHD includes those with known ICMP with stable symptoms as well as those who are asymptomatic but have been diagnosed with CAD through non-invasive methods [3,4].

The consideration of revascularization relies on our understanding of how CAD causes cardiac dysfunction. Chronic ischemia can cause impairment in contractile function by necrosis and fibrosis replacing functional myocardium [5]. Alternatively, myocardium maybe viable, i.e. alive and not dead, but in a stunned or hibernating stage where contractile function is impaired but maybe able to return to normal function [6,7].

Myocardial hibernation refers to a state where the myocardium has adapted to chronic impairment in coronary perfusion by reducing its function and therefore its blood needs to prevent myocardial death [5], whereas stunned myocardium has suffered episode(s) of ischemia leading to a decrease in contractility [7]. In both these states, the hypothesis would be that restoration of myocardial flow by revascularization could improve cardiac function. Thus, ischemic cardiomyopathy may result from myocardial death, myocardial hibernation and/or myocardial stunning.

Despite our knowledge that coronary artery disease is a common cause of decreased LVEF, patients may not be completely evaluated for CAD. In a retrospective study of 67,161 patients with hospitalization for new diagnosis of heart failure, only 17.5% patients underwent ischemic evaluation during the index hospitalization, and only 27.4% of patients were evaluated at 90 days [8]. Furthermore, despite the knowledge of 80-85% sensitivity with stress testing for coronary artery disease and the risk of balanced ischemia resulting in a false negative, almost half of patients received stress test within 90 days as their evaluation for ischemia [8]. This finding brings into question, the results of All subsequent studies presented below including randomized trials, as the patients enrolled are likely a subset of patients with SIHD and ICMP.

Revascularization Strategies

Pivotal trials over the preceding decade have contributed to the evolving approach to revascularization in patients with SIHD. The Surgical Treatment for Ischemic Heart Failure (STICH) trial investigated whether revascularization via CABG together with guideline-directed medical therapy (GDMT) yielded superior outcomes compared to GDMT alone in patients with severe CAD and ICMP with LVEF ≤35% [9]. This multicenter randomized controlled trial of 1,212 patients excluding ACS or critical left main coronary disease initially showed no significant difference in the primary outcome of all-cause mortality at a mean follow- up of 4.7 years (36% in CABG and GDMT group vs 41% in GDMT alone group, P = 0.12), but the secondary outcome was lower (28% vs 33% in GDMT group, p = 0.05) in the CABG group [9]. Subsequent follow-up data at 10 years showed significant reduction in all-cause mortality with CABG and GDMT compared to GDMT alone (58.9% vs 66.1%, p = 0.02) [10]. Findings from the STICH trial have contributed to the Class 1 recommendation for CABG to improve survival in patients with SIHD, multivessel CAD, and LVEF <35% in the Guidelines [11].

In cases where CABG is selected as the revascularization option, there is a Class I recommendation to calculate a Society of Thoracic Surgeons (STS) risk score to help stratify patient risk [11-13], although cirrhosis, frailty, and malnutrition are not risk factors assessed in this score. In addition, identification of appropriate conduits is paramount to successful outcomes. The LIMA to LAD graft is very well established as offering mortality benefit to patients undergoing CABG [11,14-17]. In addition, a class I recommendation has been included for use of radial artery in preference to a saphenous vein conduit to graft the second most important vessel to improve long-term cardiac outcomes[11]. This is based on observational studies, and systematic reviews and meta-analyses collectively suggesting a survival benefit, improved mid- and long-term patency rates [18-22].

The role of PCI has been more controversial. The recently published, Revascularization for Ischemic Ventricular Dysfunction (REVIVED-BCIS2) trial studied whether patients with SIHD, severely reduced LVEF (<35%), extensive CAD amenable to PCI, and myocardial viability could have improved outcomes if revascularized by PCI compared to GDMT alone [23]. This multicenter randomized controlled trial of 700 patients found no difference in its primary outcome of all-cause mortality or hospitalization for heart failure (37.2% in PCI and GDMT group vs 38.0% in GDMT group, p = 0.96)[23]. There was also no difference in secondary outcomes of change in LVEF at 12 months between the groups, and neither group saw a meaningful change in LVEF at 12 months (2% in the PCI group and 1.1% at 12 months). However, the main criticisms of this trial have been short duration of follow-up, and the inclusion of mainly patients with minimal or no symptoms (77% with NYHA Class I or II symptoms, and 66% with no angina).

The findings of the REVIVED study were in contrast to the multicenter observational study, RESTORE EF. In this study, 406 patients with ICMP underwent high-risk PCI with hemodynamic support using a percutaneous ventricular assist device [24]. Results showed that baseline LVEF significantly improved with paired assessment at 90 days post-PCI, with LVEF improving from 35 ± 15% to 45 ± 14% (29% relative improvement, P < 0.0001), and there was significantly greater improvement in patients with complete revascularization, as characterized by a residual SYNTAX score of 0 [24]. Compared with REVIVED, in RESTORE EF 62% of patients had NYHA Class III or IV symptoms and 72% had CCS III or IV angina at baseline improving to 15% and 2%, respectively after PCI on follow-up [24]. These findings are similar to the PROTECT-II trial which was evaluating outcomes in patients undergoing high-risk PCI randomized to either intra- aortic balloon pump or percutaneous left ventricular assist device. Both groups demonstrated an 22% improvement in LVEF from baseline and with only 26% at NYHA Class III/IV at 90-days compared to baseline of 62%. Unfortunately, these studies were not comparing patients with a medical therapy arm and thus the improvement with only medical therapy would be unclear. However, the findings do suggest that patients with significant symptomatic ICMP who undergo revascularization often demonstrate an improvement in LVEF and symptoms on short- term follow-up [25]. These findings are in contrast to the results seen in the REVIVED trial which did not report any significant improvement in LVEF, and given the majority of patients had minimal symptoms at baseline, this remained the case at 6 and 12 month follow-ups. Taken together, in our opinion the data would suggest patients with depressed LVEF with significant symptoms may benefit from high-risk PCI for revascularization whereas patients with minimal symptoms may be managed medically if not considered a CABG candidate.

Viability and Cardiovascular Revascularization in Cardiomyopathy

Viability has been a particularly controversial consideration as more data has become available. Viability uses the concept discussed earlier that myocardium that is hibernating or stunned could have a return in functionality with improvement in blood flow as opposed to dead myocardium. The main methods of myocardial viability assessment are nuclear testing methods with SPECT or PET, dobutamine echocardiography and cardiac magnetic resonance. However, these assess different features of cardiomyocytes and have added to the confusion and the usefulness of viability in revascularization. For example, dobutamine echocardiography requires the demonstration that contractility can be improved by the administration of an inotropic agent. In comparison, in cardiac MRI, late gadolinium enhancement is used to identify myocardial cells with membrane integrity versus areas of scar [26].

The concept of viability was introduced early in the 1980s, and soon after, utilization of this new asset to identify patients with CAD who may benefit from revascularization was initiated. Iskandrian et al., was one of the first to report benefit of 

thallium scintigrams in predicting improvement in EF with revascularization. In his study of 16 patients with normal resting images or evidence of reversible ischemia and 10 patients with fixed perfusion defects at rest, improvement in EF was observed in 86% of patients in the first group versus only 22% of patients in the latter group (p < 0.01) [27]. These findings were supported by several other similarly small studies [28-31]. Although this data was suggestive of the ability of PET to predict improvement in cardiac function with revascularization, the value and effect of PET utilization on mortality was unclear. In 2002, a meta-analysis of 3088 patients with CAD and an average LVEF of 32 +/- 8% who were followed for 25 +/- 10 months noted that in patients with viability, there was a 79.6% reduction in annual mortality with revascularization compared to medical therapy alone ( p < 0.0001) [32]. Despite this encouraging data, it is important to note some key limitations which limited the influence these studies had on guidelines and day to day practice. Most of the reported studies took place years before optimization of medical therapies, specifically antiplatelet therapies and guideline directed medical therapy for ICMP, which is key in functional recovery and survival. Additionally, most studies are of very small cohorts, making it difficult to extrapolate data to apply to the general population, and increasing the likelihood of selection bias. Another key limitation is that this data is derived primarily from retrospective or observational studies, as opposed to true randomized controlled trials (RCTs), opening the door to a myriad of additional potential biases.

The F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease (PARR- 2) trial was one of the first RCTs to assess benefit of PET-assisted management in patients with CAD and severely reduced LVEF, with no demonstrated reduction in cardiac events with PET- assisted management versus standard of care [33]. In a substudy analysis of STICH cohort where 601 of 1212 patients underwent viability testing, 298 were randomized to the CABG and medical therapy group, while 303 were receiving medical therapy alone. Although higher survival was seen in patients with viable myocardium, but identifying viability did not help differentiate patients who may benefit from CABG versus medical therapy in terms of improving survival [34]. So the true role of viability testing in determining outcomes with revascularization remains unclear, with more recent literature suggesting limited utility.

Guidelines for CAD Revascularization

Recently, revised guidelines discussing coronary artery revascularization were jointly published by the American College of Cardiology, the American Heart Association, and the Society for Cardiovascular Angiography and Interventions (henceforth referred to as the “Guidelines”) [11]. Here, we will briefly summarize recommendations for revascularization in patients with SIHD before subsequently discussing the evidence that contributed to the Guidelines, focusing primarily on patients with SIHD.

Revascularization in patients with SIHD, whether through PCI or CABG, is generally pursued to improve survival and/ or symptoms. Due to mortality benefit, CABG is preferred over PCI in patients with SIHD and severe left main CAD, complex CAD, or multivessel CAD with severe ICMP, defined as having a left ventricular ejection fraction (LVEF) of <35% [10,11,35-37]. CABG is also favored in similar patients and with mild-moderate ICMP, defined as an LVEF ranging 35-50%, though the strength of recommendation is weaker in this subset of patients [11]. Patients with diabetes and SIHD, particularly with multivessel CAD involving the LAD also have a strong recommendation to proceed with CABG for revascularization, provided they are good candidates for left internal mammary artery (LIMA) grafting to the left anterior descending (LAD) coronary artery [11]. In addition, complex or multivessel CAD (SYNTAX score>33) is generally better treated with CABG. CABG is still typically pursued in patients with SIHD and preserved LVEF when there is severe triple vessel CAD, whether or not the proximal LAD is involved, though these recommendations are weaker [11].

In the context of symptom relief, revascularization of SIHD is indicated for refractory angina that significantly impacts quality of life despite guideline-directed anti-anginal and CAD medical therapy [11,38,39]. PCI is preferred over CABG when pursuing revascularization for symptom relief if the anatomy is appropriate, given the relatively less-invasive nature of PCI and the associated shorter recovery time.

The discussion of revascularization in acute coronary syndrome (ACS) is beyond the scope of this report, but it is worth noting that due to data findings of increased risk of major adverse cardiovascular events without revascularization, revascularization is strongly recommended in cases of non-ST segment elevation myocardial infarction (NSTEMI), particularly in cases of elevated risk scores (TIMI, GRACE, etc.) [40-42]. In patients presenting with ST-segment elevation myocardial infarction (STEMI), given the critical nature of these cases, revascularization via PCI is pursued emergently [42,43]. It is assumed that the lack of revascularization in these patients would increase the risk of irreversible ICMP.

The Guidelines highlight that decision-making regarding coronary revascularization in patients with CAD should be based entirely on clinical indication, regardless of sex, race, or ethnicity (Class I recommendation) [11]. Additionally, in complex cases of CAD where the optimal approach to revascularization may be unclear, a Class I recommendation exists to incorporate a multidisciplinary Heart Team approach that includes interventional cardiology, cardiac surgery, and clinical cardiology representation, while ultimately focusing on patient-centered shared-decision making [11].

The management of CAD in ICMP continues to evolve. In general, CABG is preferred for patients with ICMP and CAD and consistent with current guidelines. Among patients who are not a candidate for CABG, then PCI is likely beneficial for patients with significant symptoms (NYHA Class III/IV) but medical therapy maybe considered for patients with no or minimal symptoms (NYHA Class I/II). All patients need to be on guideline recommend medical therapy which has consistently shown to improve morbidity and mortality. A multidisciplinary Heart Team approach should be incorporated in the shared-decision making approach to complex cases of CAD in ICMP.

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