Despite improvements in drug therapy and an increase in the number of percutaneous coronary interventions (PCI), surgical treatment of coronary artery disease (CAD) remains one of the most important medical advances of the 20th century and plays a leading role in cardiovascular surgery in developed countries worldwide. In 2010, nearly 400,000 coronary artery bypass grafts were performed in the U.S. Although overall patient age and comorbidities have increased, in-hospital mortality associated with CABG has decreased significantly in both men and women [2].
In symptomatic patients, PCI or CABG revascularization may relieve symptoms and improve their quality of life compared to pharmacological treatment [3,4]. Therefore, the importance of CABG for CAD has been established in most cases, and guidelines based on strong evidence-based medical evidence recommend CABG to improve outcomes in patients with left main stem lesions, 3-branch vascular lesions, and severe stenotic lesions in the proximal left anterior descending branch [9-12]. However, in cases of left ventricular insufficiency (left
ventricular dysfunction (LVD), especially in patients with severe LVD, the impact of CABG on survival remains controversial and uncertain.
A large number of early studies comparing CABG with pharmacological treatment of patients with LVD consistently concluded that CABG improved patient survival, with a range of 10% to 50% improvement in survival compared with pharmacological treatment [13-17]. However, these non-randomized studies were mainly retrospective and the use of modern evidence-based medications for LVD had not been initiated at the time of study completion, nor was the use of intrathoracic arterial grafts widely available.
In addition, early randomized trials comparing CABG with drug therapy in such patient cases did not provide definitive conclusions, probably in part because these trials were completed at a time when modern drugs (e.g., beta-adrenergic receptor blockers, angiotensin-converting enzyme inhibitors, and statins) were not yet being used to treat LVD. in addition, severe left ventricular ejection fraction ( ejectionfraction, EF) decreased was excluded from the randomized trials. Although 26% of patients in the US Veterans Administration Collaborative Study [18] had EF <45%, they were not considered to have severe LVD. patients with EF <50% were excluded from the EuropeanSurgery Study (ESS) [19]. The Coronary Artery Surgery Study (CASS) excluded patients with EF <35% and New York Heart Association cardiac function class III-IV [20]. 160 patients with mild to moderate LVD (EF: 35%-49%) were included in the CASS study only. This study found that survival with surgical treatment was superior to drug treatment in patients with 3-vessel lesions and a similar degree of LVD, a result based on data from only 78 patients [21].The Meta-analysis of the CABG Collaborative Study included 7 clinical studies of CABG surgery compared with drug treatment [3], but included only 178 patients with EF < 40% (of the total 7%).
Some recent randomized clinical trials of intensive drug therapy for CAD versus myocardial revascularization therapy [4,22,23] have almost always excluded patients with severe LVD. In addition, prospective clinical trials comparing CABG with PCI have included mainly patients with normal LV function, without a specific focus on patients with decreased EF [5,6,24].
Surgical treatment of ischemic heart failure
The Surgical Treatment of Ischemic Heart Failure trial [25] is the first and currently the only prospective randomized trial designed to assess the impact of CABG in combination with evidence-based modern drug therapy in patients with CAD with EF ≤35%. the STICH trial was based on two hypotheses: in patients with ischemic heart failure, CABG in combination with evidence-based drug therapy compared with drug therapy alone In patients with ischemic heart failure, CABG in combination with evidence-based medication has better survival rates than medication alone (hemodynamic reconstruction hypothesis); in patients with EF ≤35% who undergo hemodynamic reconstruction and whose anterior left ventricular wall is predominantly dyskinetic or paradoxically mobile, CABG in combination with surgicalventricular
reconstruction (SVR) has a better survival rate than CABG alone (SVR hypothesis). In patients with left main stenosis or significant angina (Canadian Heart Association cardiac class III-IV), the SVR hypothesis is used instead of the hemodynamic reconstruction hypothesis.
Hemodynamic reconstruction versus drug therapy
The STICH trial of the hemodynamic reconstruction hypothesis included 1212 patients from 99 international study centers, 602 randomized to pharmacological treatment and 610 to CABG and pharmacological treatment [26]. For patients receiving surgical treatment, the goal was to achieve complete hemodialysis and to use the internal thoracic artery whenever possible (91% of patients used the internal thoracic artery). Evidence-based medications were used at high levels in both groups, with medications including beta-blockers (used in 91% of patients in year 1), angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists (91%), statins (91%), and aspirin (88%). Aspirin or warfarin was used in 93% of patients.
The primary outcome indicator was all-cause mortality. It was found [26] that after a mean follow-up of 56 months, the all-cause mortality rates were 41% and 36% for medication and CABG, respectively, with no significant difference between the two groups (p
=0.12). Therefore, the study was negative based on a prespecified intention-to-treat analysis.
However, several factors suggested better outcomes for patients treated with CABG. First, secondary endpoints such as cardiovascular mortality and the composite endpoint of all-cause death and hospitalization for cardiovascular events were significantly lower with CABG than with drug therapy (P = 0.05 and P < 0.001). Second, a small crossover population with significant impact emerged: 55 patients randomly assigned to the CABG group never received CABG; 65 patients randomly assigned to the drug treatment group received CABG earlier. both the actual treatment analysis and the compliance with the protocol analysis (excluding the crossover population) suggested that patients receiving CABG had significantly lower mortality than patients receiving drug treatment ( P<0.001 and P = 0.005) [26,27]. Finally, patients randomized to the CABG group showed significant improvements in symptoms and quality of life throughout the follow-up period [28].
The STICH trial on the effect of CABG on survival in patients with ischemic LVD can be interpreted as negative or positive because the views of clinical trialists (intention-to-treat analysis) differ from those of patients, clinicians, and surgeons (actual treatment analysis). Based on the fact that patients undergoing CABG face a higher risk of perioperative death in both intention-to-treat analyses and analyses correcting for crossover populations, physicians should explain the risks of the procedure to their patients preoperatively and weigh the long-term benefits of hemodynamic reconstructive surgery.
Subgroup Analysis of CABG and Drug Therapy
Several ancillary analyses of the STICH trial explored the subgroups of LVD patients most likely to benefit from CABG. A prospective subgroup study of the STICH trial explored myocardial viability and its extent, with 601 of 1212 patients undergoing single-photon emission tomography or low-dose dobutamine testing to determine the extent of surviving myocardium [29]. Patients with significantly surviving myocardium had a lower mortality rate than patients without significantly surviving myocardium according to a predefined definition of the range of myocardial survival: 37% and 51% for a median follow-up time of more than 5.1 years, respectively. However, there was no significant interaction between presence or absence of surviving myocardium, treatment allocation (CABG or drug therapy), and survival. Similarly, other prespecified secondary analyses based on median surviving myocardial score or continuous surviving myocardium versus risk models did not find significant interactions.
These findings run counter to the prevailing view.The Meta-analysis on myocardial viability completed by Allman et al [30], based primarily on a large number of earlier imaging studies assessing survival (CABG over drug therapy), suggested that patients with surviving myocardium were most likely to benefit from CABG. However, the main shortcomings of these previous studies, in addition to the retrospective study design and the heterogeneous definition of myocardial survival, are the apparent underuse of pharmacotherapy based on today’s criteria. For example, Allman et al [30] reported several studies completed in the 1980s and 1990s, when few, if any, patients were on beta-blockers and the annual mortality rate of patients with surviving myocardium on drug therapy was as high as 16%. In contrast, the annual mortality rate for patients with surviving myocardium on drug therapy in the STICH trial was only 7.1%, despite a more severe LVD (mean EF of 26.7% in the STICH trial and 32.9% in the Meta-analysis). Although the myocardial survival data from the STICH trial cannot be considered conclusive, a small randomized trial of CABG versus drug therapy in patients with ischemic LVD and evidence of myocardial survival also supports that CABG did not improve patient survival [31].
The updated 2014 edition of the European guidelines for myocardial revascularization [12] still recommends CABG treatment in patients with LVD who show surviving myocardium, but only cites the Meta-analysis by Allman et al [30] to support this recommendation. As mentioned previously, none of the trials included in this Meta-analysis provided available, aggressive, evidence-based therapy (especially beta-blockers) for the “medication” group of patients. The European Heart Failure Treatment Guidelines [32] do not recommend (Class III) CABG procedures for patients with LVD without angina pectoris and surviving myocardium. In contrast, the 2013 edition of the US Heart Failure Treatment Guidelines [33] state that CABG may be considered in patients with moderate LVD (EF: 35% to 50%) with CAD or proximal left anterior descending lesions with multiple lesions, when there is evidence of surviving myocardium. however, in patients with severe LVD (EF: <35%), CABG is considered to improve survival rate. These recommendations are consistent with the results of the STICH trial.
Further analysis of the STICH trial confirmed that the effect of CABG on patient survival was independent of the degree of myocardial ischemia [34] and the level of circulating biomarkers [35] (e.g., brain natriuretic peptide and soluble tumor necrosis factor-α receptor-1). However, the improvement in survival by CABG seems to be predictable if based on preserved cardiac functional status. The latter can be assessed by: the Kansas City Cardiomyopathy Questionnaire or the 6-minute walk test [36] and the angiographic severity of CAD, the severity of left ventricular systolic dysfunction and the extent of left ventricular remodeling [37]. Thus, survival after CABG is more related to the patient’s functional status, the severity of CAD, the severity of LV remodeling, and less to objective markers of surviving myocardium or ischemia. patients with more severe CAD and more rapid LVD progression benefit more from CABG, but these patients are also at high risk.
Surgical left ventricular reconstruction (SVR)
Regardless of whether SVR in combination with CABG is justified or not, there has been great controversy and discussion about this surgical option that intends to restore LV size and morphology to enhance LV reverse remodeling, not limited to that achieved by hemodynamic reconstruction and aggressive pharmacological therapy. Although the procedure has a large number of proponents and encouraging clinical trial results [38,39], previous studies have been observational and unblinded in nature. There are no prospective clinical trials comparing SVR with CABG alone, especially in the context of evidence-based intensive pharmacotherapy.The SVR hypothesis of the STICH trial [40] was intended to address this issue by including 1000 patients with LVD with CAD suitable for CABG and with anterior wall dyskinesia or paradoxical motion suitable for SVR. Of these, 499 were randomized to the CABG-only group and 501 to the CABG+SVR group.
As expected, after a median follow-up of 4 years, there was no significant difference in the primary composite endpoint (all-cause mortality plus cardiovascular event hospitalization rate), which was 59% and 58% in the CABG and CABG+SVR groups, respectively, despite the fact that SVR significantly reduced left ventricular volume. In addition, secondary endpoints such as all-cause mortality, hospitalization, myocardial infarction, and stroke incidence did not differ significantly between the two groups. Quality of life also did not differ between the two groups, but SVR used more medical resources [41]. Patients with smaller and less remodeled left ventricles were most likely to benefit from SVR compared to CABG alone [42], while the extent and degree of anterior wall myocardial survival was not an important determinant of SVR outcome [43].
Conclusions
With the increasing burden of heart failure worldwide, it is important to recognize CAD as the primary cause of LV systolic insufficiency, both in developed and many developing countries.CAD as a predisposing cause of LV systolic insufficiency progresses faster and has a higher mortality rate than non-ischemic causes [44], especially in patients with the most severe LVD (EF <35%) [45]. Although evidence-based pharmacotherapy remains the basic treatment for all patients with LVD, CABG can provide a potential survival benefit, especially in high-risk patients with multiple vascular lesions and severe ventricular remodeling. The results of the prospective STICH trial [26] support those of earlier non-randomized studies [13-17] that CABG improves long-term survival compared with drug therapy alone and may offset the short-term risk of perioperative death with CABG. However, CABG in the highest-risk population needs to be performed with caution and should be subject to increased discussion and coordination among the multidisciplinary heart team.