The Role of Revascularization in the Management of Patients with Chronic Coronary Syndrome: Focus on Percutaneous Coronary Intervention

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ACHAIKI IATRIKI | 2026; 45(1):39–50

Review

Michail I. Papafaklis1,2, Stamatis Kanellopoulos2, Kornilia Pepa2, Kassiani-Maria Nastouli2, Maria Bozika2, Grigorios Tsigkas1,2, Antonios Karanasos1,2, Rafail Koros2, Anastasios Papoutsoglou2, Virginia Mplani3, Athanasios Moulias2, Periklis Davlouros1,2

1Faculty of Medicine, School of Health Sciences, University of Patras, Rio, Greece
2Cardiology Division, University Hospital of Patras, Rio, Greece
3Intensive Care Unit, University Hospital of Patras, Rio, Patras, Greece

Received: 11 Apr 2025; Accepted: 16 Jun 2025

Corresponding author: Michail I. Papafaklis, MD, PhD, FESC, FACC, Cardiology Division, University Hospital of Patras, Rio 26504, Greece, Tel.: +30 2613603936, e-mail: mpapafaklis@upatras.gr

Keywords: Coronary artery disease, percutaneous coronary intervention, coronary artery bypass grafting, medical therapy, angina

 

Abstract

Coronary artery disease (CAD) remains a global health burden and presents in the form of acute and chronic coronary syndromes. The management of chronic coronary syndromes (CCS) aims to relieve symptoms, improve quality of life and reduce the occurrence of major adverse cardiac events including death, myocardial infarction and cardiac-related hospitalizations. Percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are the key revascularization strategies. Current European and American guidelines suggest revascularization in high-risk patients such as those with uncontrolled symptoms, multivessel disease, left main disease or reduced left ventricular function. PCI is favored in patients with high surgical risk while CABG is favored in complex cases. Several landmark trials have assessed the role of PCI in CCS during the last decades. While PCI improves angina symptoms and quality of life, its impact on event-free survival remains unclear. Recently, subgroup analyses and meta-analytic data suggest that PCI may reduce spontaneous myocardial infarction and cardiac mortality especially in high-risk patients. In contrast, CABG in complex coronary artery disease and left ventricular dysfunction, has been proven to confer long-term survival benefits. This review provides a concise summary of current evidence regarding the additive value of revascularization, in particular PCI, on top of optimal medical therapy.

INTRODUCTION

Chronic coronary syndrome (CCS), formerly known as stable coronary artery disease (CAD), is one of the principal manifestations of cardiovascular disease, and thus, a major health burden worldwide [1]. The term CCS was introduced by the European Society of Cardiology (ESC) in the 2019 guidelines for stable CAD to better describe the clinical demonstration of CAD symptoms in periods where the patient is stable or after an acute coronary  manifestation syndrome [2]; the American College of Cardiology (ACC) and the American Heart Association (AHA) used the respective term chronic coronary disease (CCD). Although patients classified with CCS may include different categories and presentations, the main category includes patients with angina or dyspnea, which may also be accompanied by reduced left ventricular ejection fraction (LVEF).

Treatment of CCS (medical therapy and coronary/myocardial revascularization) focuses on alleviating symptoms, improving quality of life and reducing the possibility of future major adverse cardiac events such as cardiac death and myocardial infarction [3]. Percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) constitute the two modalities of myocardial revascularization in specific populations. Landmark studies such as the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) [4], and recently, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) [5], have provided insights into the incremental value of myocardial revascularization in the clinical setting. However, it is not clear whether revascularization, in particular PCI, on top of medical therapy is associated with clinical benefit compared to optimal medical therapy alone. Several factors may influence the decision to proceed with revascularization, including the severity of ischemia, the complexity of coronary anatomy and the presence of comorbidities.

This review aims to present concise data regarding the value of coronary revascularization, in particular PCI, over medical therapy in patients with CCS, taking into account the current guidelines and recommendations, and exploring the potential benefit in specific patient populations according to available clinical data.

European and American Guidelines for Revascularization in CCS

According to the latest 2024 ESC guidelines for the management of patients with CCS, revascularization with either PCI or CABG is recommended for angina-related symptoms that are resistant to medical therapy (Class I Level A) [6-8]. In patient groups with left main disease or three-vessel disease, especially those with left ventricular dysfunction (EF ≤35%), randomized clinical trials (RCTs) and meta-analyses have shown superior outcomes for CABG compared with medical therapy alone (Class I Level B) [9-14]. In patients with high surgical risk, PCI may be considered as an alternative to CABG (Class IIb Level B), offering primarily symptom relief [15]. In patients with normal LV function, who have functionally significant left main stenosis (Class I Level A) [16,17], three-vessel disease (Class I Level A) or single-/two-vessel disease involving proximal LAD (Class I Level B) [18-23], revascularization has incremental value over medical therapy. CABG is considered to be superior to PCI in patients with multivessel disease, diabetes or higher complexity of CAD (Class I Level A) [24,25].

The AHA/ACC Joint Committee uses the term CCD instead of CCS as mentioned above. The AHA/ACC 2023 guidelines also emphasize the importance of revascularization in patients with symptomatic CCD who do not respond to guideline-directed medical therapy (Class 1 Level A) [8,26-28]. In those with CCD and LV dysfunction, who have left main disease or multivessel disease, CABG is better than medical therapy alone (Class 1 Level B-R) [10,14,29]. To reduce the possibility of major cardiovascular events, revascularization should be considered in patients with CCD and multivessel disease (Class 2a Level B-R) [18,19,23,30-32]. In patient groups with diabetes [33] or more complex coronary anatomy, CABG generally offers better outcomes compared to PCI (Class 1 Level A) [34], but PCI should be considered in those with high surgical risk (Class 2a Level B-NR).

According to the ESC (2024) and AHA/ACC (2023) guidelines, the use of revascularization is strongly supported in high-risk populations such as those with left main disease, multivessel disease, and left ventricular dysfunction, with a clear preference for CABG in more complex cases and PCI as a viable alternative in high-risk surgical candidates. Table 1 provides a comparative summary of the main recommendations in these guidelines regarding the role of revascularization in improving survival/prognosis.

Angina and Quality of Life

Angina, one of the most common symptoms in patients with CCS, elicits a significant impact on quality of life (QoL). Extensive studies and systematic analyses have demonstrated the pivotal role of revascularization in alleviating these symptoms and enhancing patient outcomes.

The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial evaluated 5,179 participants with chronic CAD and moderate or severe ischemia, comparing an initial invasive treatment strategy (catheterization ± revascularization) to an initial conservative strategy [5]. The ISCHEMIA research program included a 3-, 12-, 24- and 36-month follow-up QoL substudy which concluded that patients experiencing more frequent episodes of angina derived significant benefits from an invasive strategy. The average difference in the 19-item Seattle Angina Questionnaire (SAQ) summary score (an angina frequency score that measures health status related to CAD; scores range from 0 to 100 with higher scores indicating fewer symptoms and better health status) showed benefit in the invasive arm, with a mean increase of 1.4 points (95% CI: 0.2-2.5) across all follow-up periods. Among the 744 patients with more frequent angina at baseline (SAQ Angina Frequency score <80), those assigned to the invasive strategy achieved a mean 3.7-point higher score on the 19-item SAQ Summary compared to the conservative strategy group (95% CI: 1.6-5.8). Physical limitations (based on the Duke Activity Status Index score) increased by 3.2 points (95% CI: 0.2–6.1), angina frequency improved by 3.2 points (95% CI: 1.2-5.1), and QoL/Health Perceptions showed a gain of 5.3 points (95% CI: 2.8-7.8) in the invasive group compared to the conservative group. The invasive strategy was associated with marked improvements not only in angina-related symptoms but also in overall quality of life, encompassing enhanced physical functioning and psychological well-being [35].

The value of percutaneous revascularization in improving symptoms was further highlighted in the Objective Randomized Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina (ORBITA-2) trial [7]. In this trial, 301 patients with stable angina receiving minimal or no pharmacological therapy underwent revascularization treatment compared to another group that underwent a placebo intervention (i.e., no revascularization). At the 12-week follow-up, the PCI group had a mean angina symptom score of 2.9 compared to 5.6 in the placebo group, with an odds ratio of 2.21 (95% CI: 1.41-3.47, p<0.001). The outcomes of this trial demonstrated substantial benefits in terms of angina relief and quality of life improvement in these patients.

Beyond “stent-assisted angioplasty”, CABG also plays a crucial role in angina relief. It has been demonstrated that the relief of anginal symptoms and improvement in quality of life become evident early and remain significant over a four-year follow-up period. Zhang et al. assessed cardiac-specific health status using the SAQ at baseline and at 6- and 12-months post-revascularization in patients randomized to either stent-assisted PCI with 488 patients or CABG with 500 patients as part of the ‘Stent or Surgery’ trial [36]. Significant improvements in physical limitation, angina frequency, and quality of life scores were observed in both the PCI and CABG treatment groups. At 6 months, scores improved within a range of 13.6 to 34.7 points, and at 12 months, the range was 14.3 to 38.2 points, with all changes being statistically significant (p<0.001). Brorsson et al. conducted a prospective survey and reviewed medical records of 601 Swedish patients with stable angina and one- or two-vessel disease [37]. The cohort included 252 patients who underwent CABG and 349 who underwent PCI. At 6 months, patients who underwent bypass surgery showed greater improvements compared to those who had angioplasty in physical functioning (15.3 vs 10.5, p<0.05) and general health perception (16.5 vs 10.2, P<0.05). Additionally, at 21 months, patients in the CABG group experienced better pain relief (19.4 vs 14.6, p<0.05), improved quality of sleep (17.6 vs. 4.6, p<0.05), and enhanced general health perception (17.3 vs. 12.1, p<0.05). However, by the 48-month follow-up, these differences were no longer observed between the two groups.

Bangalore et al. conducted a systematic review and meta-analysis examining routine revascularization in patients with stable ischemic heart disease [8]. They concluded that the invasive strategy not only alleviates anginal symptoms (relative risk [RR]: 1.10, 95% CI: 1.05-1.15) but is also associated with a reduced risk of future episodes of unstable angina (RR 0.64, 95% CI: 0.45-0.92).

The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation-2 (FAME 2) trial compared PCI guided by fractional flow reserve (FFR) to optimal medical therapy alone in patients with stable CAD, aiming to evaluate both clinical outcomes and cost-effectiveness [31,38]. A three-year follow-up of the FAME 2 trial revealed that PCI in patients with stable CAD significantly improved angina relief and quality of life, with the PCI group consistently reporting less severe angina at all follow-up points over the three years. Additionally, while initial costs were significantly higher for the PCI group ($9,944 vs. $4,440; p<0.001), the total costs between the groups equalized by the three-year mark ($16,792 vs. $16,737; p=0.94). The incremental cost-effectiveness ratio for PCI compared to medical therapy was $17,300 per quality-adjusted life-year at 2 years, decreasing to $1,600 per QALY at 3 years, making PCI a more economically favorable strategy over time [39].

The second Randomized Intervention Treatment of Angina trial (RITA-2) compared initial strategies of PCI with continued medical therapy in patients with angina, enabling the evaluation of long-term health outcomes [40]. The three-year follow-up of the RITA-2 trial revealed that alleviation of cardiac symptoms, such as breathlessness and angina, in patients who underwent coronary angioplasty significantly improved their perceived quality of life compared to those receiving continued medical therapy. At one year, 9.7% of patients who underwent PCI and 4.8% of medically treated patients achieved the maximum physical functioning score of 100, indicating no limitations across all 10 items [41].

Impact of Revascularization on Survival and Myocardial Infarction in CCS

The fundamental principle of revascularization is that by restoring coronary blood flow, the extent of myocardial ischemia is reduced, leading to relief of angina symptoms and a decreased risk of cardiovascular events. CABG, as shown in a systematic overview of evidence from RCTs [10], has demonstrated survival benefits compared to medical therapy alone, particularly in patients with multivessel disease, diabetes, or reduced left ventricular function. The benefit of PCI (over medical therapy alone) for “hard” outcomes in CCS has been a long-standing issue of debate with mainly negative results in stand-alone trials.

The COURAGE trial, which included 2,287 patients [4], was a landmark study that evaluated the role of PCI plus optimal medical therapy (OMT) versus OMT alone in patients without left main disease and normal ejection fraction. There was no difference in all-cause mortality in the PCI group compared with the OMT group (19% vs 18.5% respectively; HR: 1.05, 95% CI: 0.87-1.27, p=0.62), nor in MI (13.2% vs 12.3%, respectively; HR: 1.13, 95% CI: 0.89-1.43, p=0.33), during a 4.6-year follow-up. However, there are some limitations of the trial, including the lack of high-risk patients, the use of bare-metal stents instead of drug-eluting stents (DES) in 97.3% of patients, the rather short follow-up (median of 4.6 years), the lack of ischemia-guided PCI and the high crossover rate; 33% of patients in the OMT group underwent eventually PCI [42].

Another significant trial in the same era was the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D), which compared the effectiveness of CABG versus PCI, with the goal of determining which method offered better long-term outcomes in patients with both diabetes and CAD [43]. Among 2,368 patients, only CABG was associated with a decrease in major cardiovascular events compared to medical therapy alone. BARI-2D shares similar limitations with the COURAGE trial (5-year follow up, DES in 34.7% of patients and 39% crossover rate).

The Future Revascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial investigated the outcomes of CABG versus PCI with drug-eluting stents in patients with diabetes and multivessel CAD [44]. The study demonstrated that CABG was superior to PCI in reducing the incidence of primary outcome (death, MI or stroke) at 5 years (18.7 vs 26.6%, p=0.005).

The FAME 2 trial studied patients with stable CAD and functionally significant stenosis, and demonstrated that FFR-guided PCI in addition to OMT reduced the need for urgent revascularization compared to OMT alone [31]. During a 5-year follow-up, there was a notable reduction in MI (overall and spontaneous [i.e. type 1]) among patients who underwent PCI, with a relative risk reduction of 34% (HR: 0.66, 95% CI: 0.43-1.00) and 38% (HR: 0.62, 95% CI: 0.39-0.99), respectively [45].

The ISCHEMIA trial was a major clinical study designed to compare the outcomes of an invasive approach (catheterization with a view to PCI or CABG) versus a conservative approach (medical therapy without catheterization) for patients with stable CAD and moderate to severe ischemia (patients with left main disease and low EF<35% were excluded) [5]. The median follow-up was 3.2 years and the primary outcome was a composite of death from cardiovascular causes, MI, hospitalization for unstable angina or heart failure or resuscitated cardiac arrest. At 6-month follow-up, the primary endpoint was 5.3% in the invasive group and 3.4% in the conservative strategy group (Δ=1.9, 95% CI: 0.8-3.0) and at 4 years was 13.3% and 15.5%, respectively (Δ= −2.2, 95% CI= −4.4 to 0.0; adjusted HR: 0.93, p=0.34) [5]. In this trial, type 1 MI (spontaneous MI), which increases the risk of cardiovascular death [46], was more frequent in the conservative group, while procedural MI rates were increased in patients who followed the invasive strategy [47].

Lately, the results of the ISCHEMIA-EXTEND were presented including the extended follow-up (median seven years) of the patients who participated in the ISCHEMIA trial [48]. There was a 22% lower hazard of cardiovascular mortality in patients with an initial invasive strategy compared with those receiving OMT only (6.4% vs 4.4%, 95% CI: 0.63-0.96) and a lower risk of cardiovascular mortality after revascularization in those with multivessel disease (≥70% stenosis on computed tomography coronary angiography; hazard ratio [HR]: 0.68, 95% CI: 0.63-0.96) [18].

Observational studies also show consistent lower mortality or MI with revascularization in the long-term (10 years) especially in those with severe disease. Bainey, et al. have shown that an invasive strategy in patients with CCS and high-risk coronary anatomy relates to improved outcomes [49]. Rozanski, et al. have related early revascularization with decreased mortality among patients with normal left ventricular function and severe inducible ischemia as well as in patients with low EF and moderate or severe ischemia [50].

A recent meta-analysis of 25 RCTs, which included 19,806 patients, showed that revascularization provided a significant benefit for “hard” outcomes during longer follow-up [19]. Cardiac mortality was significantly lower in those who underwent PCI (relative risk: 0.79, 95% confidence interval: 0.67-0.93, p<0.01) and the risk of cardiac death was decreased by 19% for each four-year follow-up. Spontaneous MIs were also reduced after revascularization (relative risk: 0.74, 95% CI: 0.64-0.86, p<0.01).

In conclusion, evaluating the effect of revascularization on survival and myocardial infarction which represent events with rather low frequency in CCS requires large population samples and extended follow-up periods in order to achieve statistical significance for observed differences.

Benefit in patient subgroups

Numerous studies have focused on specific subgroups of patients with CCS (Figure 1), yielding several noteworthy outcomes. Categories of interest that will be discussed include patients with complex CAD, such as multivessel or left main disease, and those with left ventricular dysfunction. Additionally, asymptomatic patients with significant CAD represent another population of interest in terms of management.

Figure 1. Management of patients with chronic coronary syndrome and the incremental value of revascularization.

Left panel: Overview of typical presentation and important subgroups of patients diagnosed with chronic coronary syndrome (CCS). Middle panel: This panel illustrates the available therapeutic options for CCS management, i.e. optimal medical therapy alone or optimal medical therapy in combination with coronary revascularization (either by percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]). Right panel: The additive clinical value of revascularization strategies (PCI or CABG) beyond optimal medical therapy is highlighted. Emphasis is placed on personalized medical care according to which revascularization decisions should be individualized based on patient symptoms, coronary anatomy complexity, surgical risk, and disease severity. Benefits of revascularization include symptom relief, enhanced quality of life, and potential reductions in major cardiovascular events, notably spontaneous myocardial infarction and cardiac death.

Complex CAD

The Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial evaluated the outcomes of PCI with drug-eluting stents (DES) compared to CABG in patients with three-vessel or left main disease [3]. The five-year follow-up of the SYNTAX trial highlighted that among a population of 1,800 patients, both CABG and DES-PCI provided significant and sustained quality-of-life improvements in patients with left main CAD over the study period. These improvements included a reduction in the number of angina episodes that occurred on a given day, and in the number of antianginal medications prescribed on that day. The analysis also revealed a significant interaction between angiographic complexity, as measured by the SYNTAX score, and angina relief. The mean difference in the SAQ score for CABG versus PCI was −0.9, 3.3, and 3.9 points for patients with low, intermediate, and high SYNTAX scores, respectively (p = 0.048 for interaction). This finding further supports the strong recommendation to prioritize CABG for patients with higher angiographic complexity [51]. Lastly, a 10-year follow-up of the SYNTAX trial revealed no significant difference in all-cause mortality between DES-PCI and CABG. At 10 years, 248 patients (28%) had died following PCI compared to 212 patients (24%) after CABG (hazard ratio [HR]: 1.19, 95% CI: 0.99–1.43, p=0.066). However, CABG demonstrated a clear survival benefit in patients with three-vessel disease (HR: 1.42, 95% CI: 1.11-1.81) but not in those with left main disease. In the subgroup of patients with left main disease, mortality rates were 27% for DES-PCI and 28% for CABG (HR: 0.92, 95% CI: 0.69–1.22 [52].

In a registry investigating angiographic disease, Bainey et al. demonstrated that revascularization in patients with stable ischemic heart disease and high-risk coronary anatomy, defined as 3-vessel disease with ≥70% stenosis in all three epicardial vessels or left main disease with ≥50% stenosis (isolated or in combination with other lesions), was associated with improved long-term outcomes compared to conservative therapy [49]. The study followed a cohort of 9,016 patients with stable CAD and high-risk coronary anatomy between April 2002 and March 2016, and compared the primary composite outcome of all-cause mortality or MI between patients treated with revascularization and those managed conservatively. Coronary revascularization resulted in better outcomes compared to conservative management (inverse probability weighted hazard ratio [IPW-HR]: 0.62, 95% CI: 0.58–0.66, p<0.001).

In a prespecified secondary analysis of the ISCHEMIA trial, among patients with severe CAD (i.e. Duke score=6 corresponding to 3-vessel severe stenosis [≥70%] or 2-vessel severe stenosis with proximal LAD, N=659) according to the modified Duke Prognostic Index which categorizes CAD according to extent, location, and stenosis severity, the composite of cardiovascular death or MI was reduced in the invasive compared to the conservative arm at 4 years (11.6 vs 17.9%; difference: −6.3 [95% CI: −12.4 to −0.2]); this benefit was mainly due to a reduction in the rate of spontaneous MI in the invasive arm (5.4 vs 10.2%; difference: −4.8 [95% CI: −9.3 to −0.3]) [23].

The above observations underscore the importance of considering the coronary anatomical profile when determining treatment strategies for patients with stable CAD.

Left ventricular dysfunction

While revascularization has demonstrated clear benefits in CCS patients with complex disease, the outcomes in studies focusing on patients with left ventricular dysfunction have been inconsistent.

A secondary analysis from the ISCHEMIA trial, focusing on patients with heart failure or left ventricular dysfunction (i.e. EF 35-45% considering that EF<35% was an exclusion criterion for the trial), demonstrated that those randomized to the invasive strategy had a lower rate of the primary outcome (i.e., the composite of death from cardiovascular causes, MI, hospitalization for unstable angina or heart failure or resuscitated cardiac arrest) compared to the conservative strategy (17.2% vs. 29.3% at 4 years; difference: −12.1%, 95% CI: −22.6% to −1.6%), whereas no such benefit was observed in participants without heart failure/left ventricular dysfunction (13.0% vs. 14.6%; 4-year event rate difference: −1.6%, 95% CI: −3.8% to 0.7%). According to these outcomes, in the small, high-risk subgroup with heart failure or moderately reduced left ventricular EF, an initial invasive approach was associated with improved event-free survival [53].

Rozanski et al. prospectively studied a population of 43,443 patients to evaluate the association between stress-induced myocardial ischemia assessed by single-photon emission computed tomography (SPECT), revascularization (including PCI or CABG) within 90 days after SPECT, and all-cause mortality according to left ventricular EF. Among 3,560 patients with reduced EF (<45%), revascularization conferred no mortality advantage in cases of no or mild ischemia but demonstrated a significant mortality reduction when there was moderate (10-14%; HR: 0.67, 95% CI: 0.49–0.91) and severe (>15%; HR: 0.55, 95% CI: 0.38-0.80) ischemia. The overall findings indicated that early myocardial revascularization significantly reduced mortality in patients with severe inducible ischemia and normal left ventricular EF, as well as in those with low LVEF and moderate or severe inducible ischemia [50].

The Surgical Treatment for Ischemic Heart Failure (STICH) trial was designed to evaluate whether the combination of CABG and guideline-directed medical therapy for CAD, heart failure, and severe left ventricular dysfunction (EF<35%) would provide a survival benefit compared to medical therapy alone, and randomized 1,212 patients [29]. Although there was no significant difference in survival at a median follow-up of approximately five years (death from any cause: 36% in the CABG group versus 41% in the medical therapy group, HR 0.86, 95% CI: 0.72-1.04, p=0.12) [29], the extended ten-year follow-up showed benefit with CABG (all-cause mortality: 58.9% in the CABG group versus 66.1% in the medical-therapy group; HR 0.84, 95% CI: 0.73-0.97, p=0.02) [54]. Cardiovascular mortality (40.5% vs. 49.3%; HR 0.79, 95% CI: 0.66–0.93, p=0.006) and the composite of all-cause mortality or cardiovascular hospitalization (76.6% vs. 87.0%; HR 0.72; 95% CI: 0.64–0.82; p<0.001) were also reduced with CABG. These findings support the conclusion that, in patients with ischemic cardiomyopathy, CABG combined with medical therapy is associated with significantly lower 10-year rates of all-cause mortality, cardiovascular mortality, and the composite of all-cause mortality or cardiovascular hospitalization compared to medical therapy alone.

Lately, the REVIVED-BCIS2 trial randomized 700 patients with severe ischemic left ventricular systolic dysfunction and extensive CAD to medical therapy alone or revascularization by PCI [15]. In this trial, ischemic left ventricular dysfunction was defined as EF≤35%, extensive CAD was assessed with a British Cardiovascular Intervention Society jeopardy score of ≥6 (on a scale from 0 to 12, with higher scores indicating greater extent of disease), and demonstrable viability was required in at least four dysfunctional myocardial segments amenable to revascularization with PCI. Patients were also excluded if they had experienced an acute MI within four weeks prior to randomization, or if they had acute decompensated heart failure or sustained ventricular arrhythmias within 72 hours before randomization. At a medium-term follow-up of about 3.5 years, the primary endpoint of death from any cause or hospitalization for heart failure occurred in 129 patients (37.2%) in the PCI group and 134 patients (38.0%) in the optimal-medical-therapy group, with a hazard ratio of 0.99 (95% CI: 0.78-1.27, p=0.96). However, the Kansas City Cardiomyopathy Questionnaire overall summary score (range 0 to 100, with higher scores indicating better quality of life) appeared to favor the PCI group at both 6 and 12 months, with mean differences of 6.5 points (95% CI, 3.5 to 9.5) and 4.5 points (95% CI, 1.4 to 7.7), respectively.

The STICH and REVIVED trials exhibited several key differences that are worth highlighting [55]. Firstly, the available follow-up duration in REVIVED-BCIS2 was significantly shorter (3.5 years) compared to the ten-year extended follow-up in STICHES. Moreover, the available optimal medical therapy during the REVIVED trial period (2013–2020) was notably superior to that of the STICH recruitment period (2002-2007) since several important pharmacologic agents—such as angiotensin-receptor blockers (±neprilysin inhibitors), mineralocorticoid receptor antagonists and sodium-glucose co-transporter-2 inhibitors—were incorporated into standard care well after 2010. Lastly, the use of implantable cardio-defibrillators and devices for cardiac resynchronization therapy, which are a critical part of current patient management in order to improve outcomes, was limited during the STICH trial period. Therefore, overall conservative patient management without revascularization was certainly further improved/optimized during the REVIVED period, thereby leading to superior outcomes compared to previous periods; this makes it harder to identify any incremental value of PCI on top of medical therapy. These differences may partly explain the discrepancies in the outcomes observed between the two studies.

Gaudino, M. et al. conducted a network meta-analysis that included all randomized controlled trials and observational studies comparing PCI, CABG, and medical therapy in patients with ischemic left ventricular systolic dysfunction [56]. The primary outcome assessed was mortality at the longest available follow-up; the analysis included 23 studies, with 23,633 patients, and 4 of the studies were randomized controlled trials. Compared to CABG, PCI was associated with higher mortality (IRR 1.32, 95% CI: 1.13–1.53), cardiac mortality (IRR 1.65, 95% CI: 1.18-2.33), MI rate (IRR 2.18, 95% CI: 1.70-2.80) and repeat revascularization rate (IRR 3.75, 95% CI: 2.89-4.85). Medical therapy also showed worse outcomes than CABG, with higher mortality (IRR 1.52, 95% CI: 1.26-1.84), cardiac mortality (IRR 3.83, 95% CI: 2.12-6.91), MI rate (IRR 3.22, 95% CI: 1.52-6.79), and revascularization rate (IRR 3.37, 95% CI: 1.67-6.79). Of note, PCI reduced cardiac death compared to medical therapy (IRR 0.43, 95% CI: 0.24-0.78), while CABG was the best strategy for reducing mortality, cardiac death, MI, and repeat revascularization. The authors concluded that CABG appears to represent the most effective therapeutic strategy for CAD with left ventricular dysfunction. However, this conclusion is predominantly derived from observational data. Rigorous randomized controlled trials comparing CABG and PCI in this patient population are warranted to provide definitive evidence.

Asymptomatic patients

Asymptomatic, i.e. “silent”, ischemia is regarded as a marker of poor prognosis, particularly following MI [57]. However, in patients with stable CAD, the prognostic significance of asymptomatic ischemia and the benefits of revascularization remain less well established.

The Swiss Interventional Study on Silent Ischemia Type II (SWISSI II) was a randomized, unblinded, controlled trial conducted in the 1990s at public hospitals in Switzerland. The study included 201 patients with recent MI (within the last three months) who had silent myocardial ischemia (ECG ischemic changes at exercise test) confirmed by stress imaging, and one or two vessel disease [58]. Over a mean follow-up of 10.2 years, the PCI group (without stenting during that era) had 27 major adverse cardiac events (defined as cardiac death, nonfatal MI, or symptom-driven revascularization) compared to 67 in the drug therapy group (adjusted HR: 0.33, 95% CI: 0.20–0.55; p<0.001), with an absolute event reduction of 6.3% per year (95% CI: 3.7%-8.9%; p<0.001). Ischemia rates (defined by ischemia on repeat exercise ECG) were lower in the PCI group at follow-up (11.6% vs. 28.9%; p=0.03), and EF remained stable (53.9% to 55.6%), while significantly declining in the medical therapy group (59.7% to 48.8%; p<0.001) during follow-up. The study concluded that among patients with a recent MI, silent myocardial ischemia confirmed through stress imaging, and one or two vessel disease, PCI was associated with a significant reduction in the long-term risk of major cardiac events compared to anti-ischemic drug therapy [58].

The FAME 2 trial enrolled 888 patients with at least one hemodynamically significant stenosis (FFR <0.80) in a major epicardial artery who were randomized to receive either optimal medical therapy alone or PCI in addition to medical therapy (PCI group) [31,38,45]. Of these, 98 patients were asymptomatic with 53 assigned to PCI plus medical therapy and 45 to medical therapy alone. Patients randomized to PCI had a significantly lower rate of death/MI (9.4% vs. 31.1%, HR: 0.24, 95% CI: 0.08-0.66, p=0.006). This post hoc analysis highlights that PCI is associated with superior outcomes compared to medical therapy alone in stable patients with silent ischemia [59].

DISCUSSION

The perfect balance between optimal medical therapy alone or adjunctive revascularization (either with PCI or CABG) in the management of CCS remains intricate. The objective of the revascularization strategies is not only to alleviate symptoms but also to improve quality of life and long-term cardiovascular outcomes (Figure 1).

CABG, especially in patients with complex anatomy, such as multivessel disease, presents durable benefits in alleviating symptoms. The ISCHEMIA and the FAME-2 follow-up data demonstrated that in patients with symptoms, revascularization with PCI enhances quality of life and diminishes angina symptoms in patients with moderate to severe ischemia according to SAQ scores [5,39]. The ORBITA-2 study provided further insights into the role of PCI in stable angina. The outcomes demonstrated that PCI resulted in significantly lower angina symptom scores at 12 weeks compared to placebo [7]. PCI provides meaningful improvement in symptom relief and health status, particularly in patients presenting ischemia symptoms that do not receive medical treatment.

CABG has been proven to provide a long-term survival benefit in patients with complex disease or reduced LVEF, as shown by landmark studies such as SYNTAX and STICH [3,60]. It is the preferred strategy for decreasing mortality and MACEs in these high-risk cohorts. The STICH trial and its long-term follow-up also underlines the importance of CABG in reducing hospitalizations in patients with ischemic cardiomyopathy.

The added benefit of PCI regarding cardiovascular mortality and myocardial infarction remains unclear although meta-analytic data including very large patient numbers and very long follow-up indicate potential advantages with percutaneous revascularization. It becomes evident that the prognosis of CCS, especially with the increasing number of medications with highly positive outcomes during the last two decades, is rather benign with low event rates for hard outcomes. Thus, it is even harder to demonstrate an additional gain by PCI; this requires population sizes which are infrequently included in single randomized trials. Furthermore, sub-analyses focusing on cardiac outcomes, i.e. cardiac mortality and spontaneous type 1 MI, instead of broad unfocused endpoints such as all-cause mortality, support the value of PCI. Lastly, PCI seems to be particularly beneficial in certain patient populations with more severe disease, and it is also a good alternative for patients with high surgical risk, thereby highlighting the importance of individualized patient care and appropriate patient selection.

CONCLUSION

CCS is a lifelong disease with high prevalence worldwide. Optimal medical therapy is the foundation of treatment in all patients with CAD and physicians should strictly adhere to the guidelines for best management practices. Revascularization is not the first choice for all patients, but it offers significant benefits. CABG has been associated with improved long-term survival. Although the benefit of percutaneous revascularization for the management of CCS has been questioned during the last two decades, there is now a large amount of clinical evidence to make strong inferences for the value of PCI in preventing cardiac-specific events. The final decision for patient management should be based on the operator’s expertise, the patient profile and the patient’s choice. Future research should focus on the long-term outcomes of revascularization and the development of a more personalized treatment strategy to provide optimal care in CCS patients.

Conflict of Interest

None to declare.

Declaration of funding sources

This work was supported by the program “MEDICUS” of the University of Patras.

Author Contribution

Conception and design, M.I.P., P.D.; analysis and interpretation of the data, M.I.P., S.K., K.P., K-M.N., R.K., A.P.; drafting of the article, S.K., K.P., K-M.N., M.B., R.K., A.P.; critical revision of the article for important intellectual content, M.I.P, G.T., A.K., V.M., A.M., P.D.; final approval of the article, all authors.

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