Triple Vessel Coronary Artery Disease Needs a Consistent Definition for Management Guidelines

For


Introduction
Patients with stable ischemic heart disease (SIHD) and triple vessel disease (TVD) have been recommended coronary artery bypass grafting (CABG) with a view to derive a survival beneft compared to medical therapy [1].Initially, highrisk patient groups with stable angina were classifed as having more than 50% narrowing of the major coronary vessels including the main left, the left anterior descending, the circumfex or its marginal branch if it was the principal continuation, and the right coronary artery [2].Tis description was used in the early randomised controlled trials (RCTs) of CABG compared to medical therapy for defning subgroup analyses and survival differences.Te absence of a defnition of TVD in the international guidelines for revascularisation of coronary artery disease (CAD) and the interpretation of contemporary evidence upon which the guidelines have been based have created controversy in the management of the most common cardiac surgical condition in the Western world.Tis is a narrative review of the literature that will address the controversies related to the defnition of TVD in patients with SIHD undergoing revascularisation for survival beneft.
1.1.Te Defnition of TVD.In the three large early RCTs, TVD was defned as "a reduction of at least 50% in the three major arteries" (Veterans Administration Cooperative Study (VA study)) [3], "a 50% or more obstruction in three major arteries" (European Coronary Surgery Study (ECSS)) [4], and "a 70% or greater reduction in the internal diameter of the right, left anterior descending (LAD), and left circumfex coronary artery" (Coronary Artery Surgery Study (CASS)) [5].Although the ECSS trial did not state which arteries were major arteries, it is reasonable to assume that the intent and application were consistent with the earlier defnition which can be specifcally described as triple territory major vessel disease (TtmVD).
Te VA trial is the only RCT that has shown a survival beneft for CABG compared to medical therapy in patients with left main stenosis.Enrolment of such patients was low in the ECSS and patients with left main stenosis ≥70% were excluded in the CASS.Te ECSS included only patients with good LV function (ejection fraction ≥50%) and was the only RCT that showed a survival beneft for patients with TVD and good left ventricular (LV) function [4] (Table 1).Te CASS was the only RCT that used ≥70% coronary stenosis in the defnition and included only patients with Canadian Class symptoms ≤ 2 [5], and although it did not show a survival beneft in patients with good left ventricular function, there was a survival beneft in patients with TVD and moderately impaired function (ejection fraction 35-49%) [8].Te absence of a survival beneft from CABG in patients with TVD and good LV function in the CASS likely refects the protective efect of better coronary fow reserve in patients with low level symptoms.Notably, 20% of patients with TVD in the medical therapy arm in CASS crossed over to CABG within 14 months of randomisation and almost 40% did so by 5 years [5].Tis suggests that patients with TtmVD, good LV function, low level symptoms, and minimal ischemia on exercise testing can be observed on optimum medical therapy but that CABG should be recommended if there is any change in symptoms or observable ischemia.A subsequent analysis of patients, who were suitable for randomisation other than by the severity of their symptom class, with TVD and normal LV function in the CASS registry showed a survival advantage provided by CABG [6], consistent with the fndings of the ECSS.Tese RCTs demonstrated that CABG is efective in mitigating the risk of death due to CAD [9].A summary of the fndings of these three RCTs is presented in Table 1, being the only adequately powered RCTs in which survival has been reported in subgroup analyses.
Although there have been many subsequent RCTs assessing the benefts of intervention for TVD with a variety of defnitions, none have specifcally analysed the cohort of patients with TtmVD and good LV function to compare the survival from CABG and medical therapy [10,11].Assessment of the survival beneft provided by CABG in these patients should be based on the defnition used in the determination of the beneft.Te international guidelines have not provided defnitions of TVD, and although the term "multivessel disease" has implied involvement of more than one territory, this is frequently not stated.Terms such as quadruple vessel disease have added further confusion regarding the defnition of TVD and its applicability to prognostic signifcance.

Defining a Survival Benefit from CABG
Ischemic heart disease remains the dominant cause of death in Western society.Patients with left main coronary disease or TtmVD have been shown to have a higher risk of death than those with lesser forms of coronary disease [9].One of the reasons for the higher risk of death in patients with left main and TtmVD is the large volume of myocardium in jeopardy of infarction [12].In addition to this, the severity of impaired coronary fow reserve also plays a role in predicting the risk of death.Lastly, it is understood that the extent of CAD is considered a good surrogate measurement of the volume of myocardium at risk and therefore is normally used to express the risk of death in patients with SIHD.
Myocardial infarction in one territory increases workload for the other territories of the heart.In patients with TtmVD, this creates a domino efect where the limited coronary fow reserve is unable to adequately meet the demands of increased workload.In 1979, the ECSS trial demonstrated a survival beneft at two years for CABG in patients with TVD and good LV function [13].Elective CABG for TVD was widely adopted with an immediate decline in the rate of death from coronary heart disease in Western nations such as England and Australia (Figure 1) [14][15][16].However, among patients who die from cardiogenic shock following acute myocardial infarction, the majority have TVD [17].Tis highlights a gap in patient care.Utilizing evidence from previous RCTs and the outcomes from the implementation of that evidence will help mitigate the risk of death if elective revascularisation is appropriately recommended by the guidelines.
Te patient population and extent of CAD studied in the early RCTs comparing CABG with optimal medical therapy was limited to young patients (<65 years) with discrete proximal coronary disease and TtmVD (involving the major coronary artery in each of the three coronary artery territories) mainly located in or before the proximal half of the artery in its course over the LV [9].A stenosis in the distal third of major arteries does not subtend a large myocardial volume, and so, its prognostic signifcance should be related to the myocardial volume at risk.
In contrast to the early RCTs, contemporary studies comparing CABG and percutaneous coronary intervention (PCI) did not stipulate involvement of "the major arteries" in their defnitions of TVD.Te Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) III trial defned three vessel disease as "≥50% diameter stenosis by visual estimation in each of the three major epicardial vessels or major side branches" [18] which did stipulate triple territory disease but technically permitted enrolment of patients with disease in a signifcant diagonal branch without involvement of the LAD.Tis is consistent with common practice where interventionalists who provide revascularisation to all three territories will count the number of territories rather than the number of the three 2 Journal of Cardiac Surgery major arteries revascularised, particularly if the LAD was included.In an analysis of 1,023 patients who underwent bilateral internal mammary artery composite Y grafting, 5.4% received an anastomosis to a secondary vessel in the circumfex territory in the presence of a patent larger artery in that territory.Te rates were 0.4% and 0.7% for the LAD and right coronary territories, respectively (unpublished data HSP).Tese data are consistent with the high rate (97%) of left internal mammary artery (LIMA) use in FAME III suggesting that a negligible number of patients without LAD disease were enrolled.Te number of patients with only one or two of the three major arteries revascularised is unlikely to be of little statistically signifcant unless subgroup analyses are performed.Te synergy between PCI with TAXus and  cardiac surgery (SYNTAX) trial used the defnition "at least 1 signifcant stenosis in all 3 major epicardial territories supplying viable myocardium" [19] with the requirement that the involved artery diameter be ≥1.5 mm.Although the expression "all three major epicardial territories" rather than all three major epicardial arteries was potentially confusing, the application of the defnition would have been similar to that in FAME III, particularly in those with high SYNTAX scores.However, the subgroup analyses with low SYNTAX scores might have included enough patients without TtmVD to afect the statistical signifcance of the outcomes.Unless specifcally stated, a major artery can be considered to be any artery large enough to be suitable for intervention, including secondary branches.However, where there is another artery of similar or greater size supplying the same territory, the volume of myocardium at risk is unlikely to be prognostically signifcant.Multivessel CAD is a poorly defned term, and if it is used where it does not involve the major artery in any territory, it should be termed as "minor or secondary vessel disease" for prognostic estimates, despite remaining suitable for intervention for symptomatic beneft.Considering this, TVD should be defned by a volume of myocardium at risk exceeding 50% of the myocardial volume in each of the three coronary territories in order to represent an extent of coronary disease for which CABG will provide a survival beneft based on the evidence from the early RCTs [9].

International Guidelines
Te 2011 ACCF/AHA guidelines [1] for coronary artery revascularisation in SIHD provided a Class 1 recommendation for CABG over medical therapy in patients with ">70% stenoses in 3 major arteries with or without proximal LAD disease" for a survival beneft.A modifying Class 2a "reasonable to choose CABG over PCI in patients with complex 3 vessel CAD" was added.Te 2021 ACC/AHA/ SCAI guidelines (AHA guidelines) [20] stratifed the recommendations for CABG for a survival beneft in patients with "multivessel CAD" according to LV function with Class 1 for severe LV impairment, Class 2a for mild to moderate impairment, and Class 2b (weak) for normal function.Te signifcant downgrades in recommendations occurred despite no change in the level of evidence B-R (one or more randomised clinical trials (RCTs)).Notably, the AHA guideline used three terms, "multivessel CAD," "3 major coronary arteries," and "triple vessel disease" apparently interchangeably and without specifc defnition [20].Te American Association of Toracic Surgeons and the Society of Toracic Surgeons have not endorsed these changes to the AHA guidelines [21], and representatives from numerous other international societies have questioned the reasoning [22].Tis highlights the need for a clear and prognostically signifcant defnition of TVD to inform clinical decisionmaking.Terms with poorly discriminatory defnitions allow a wide interpretation of TVD and likely refect popular usage but difer from the defnition used that showed a survival beneft from CABG in patients with TVD.
To provide a more precise representation of the survival beneft of CABG in patients with TtmVD and normal LV ejection fraction, it is necessary to incorporate additional criteria such as "Canadian symptom class ≤2 and mild or no regional ischemia on exercise tests or perfusion scans" to justify the class 2b recommendation in the AHA guidelines.Without these descriptors, the survival beneft should not be considered indeterminate.However, such a recommendation would be relevant for only a highly selected group of patients and not applicable across the spectrum of patients with TtmVD.On the other hand, an appropriate defnition of TVD that would support prognostic signifcance would be greater than 50% stenosis in or before the proximal half of the ventricular course of the major artery to each of the three coronary artery territories, where the severity of stenosis is at least 70% in two of those arteries, thus similar to the modifed Duke classifcation for severity of CAD [7,23].In cases where codominant arteries exist in one territory, >50% stenoses must exist in the two largest arteries.Logically, this would describe a myocardial volume at risk exceeding 55% of the total normal volume, as in the Bypass Angioplasty Revascularisation Investigation 2 Diabetes (BARI 2D) trial which showed an improved combined outcome (death, stroke, and MI) for CABG versus medical therapy in diabetic patients with >55% myocardium in jeopardy [12].
LV impairment increases the risk of death for all categories of CAD and is the most important modifer of the prognostic estimate provided by coronary disease extent in patients with SIHD, but the recommendations difer between the AHA and the ESC/EACTS [24] guidelines.For patients with TVD >50% stenoses, the AHA guideline recommendations vary from class 1 to class 2b according to LV function [20].Te ESC guidelines on myocardial revascularisation did not acknowledge the signifcance of moderate LV impairment and limited the recommendations for revascularisation purely for prognostic reasons to the following: (1) Tere is no better way to demonstrate this And with documented ischemia or physiologically signifcant stenoses or visual assessment of a major artery >90% (2) A large area of ischemia detected by functional testing (10% LV) and invasive FFR <0.75 Notably, TVD with good or moderately impaired LV function was excluded from the "for prognosis" list (unless two of the three major arteries were occluded) despite the requirement for documented evidence of ischemia.A proximal left anterior descending artery stenosis >50% (presumably including single vessel disease) was included on 4 Journal of Cardiac Surgery that conditional basis.No defnition of TVD was provided nor was it stated that there was a correlation between extent of vessel disease and extent of myocardial territory involvement, i.e., TVD equals triple territory myocardial risk.Both the AHA and ESC guidelines acknowledged diabetes as a prognostic modifer driving better outcomes from CABG compared to PCI.Te ESC guidelines provided a separate set of recommendations for either PCI or CABG when revascularisation was considered appropriate for survival or symptomatic beneft.As the symptomatic beneft is similar, it is presumed that the recommendations for CABG compared with PCI are based largely on survival beneft, but these were not included in the "for prognosis" recommendations.
In nondiabetic patients with three vessel disease and a low SYNTAX score, the ESC guidelines provided PCI and CABG class 1 recommendations.In those with intermediate and high SYNTAX scores, the recommendation for PCI was reduced to 2a and 3, respectively, while the recommendation for CABG remained class 1.In contrast to the ESC guidelines' recommendation for three vessel disease, the AHA guidelines disregarded the fndings of the SYNTAX trial, instead stratifying patients according to LV function regardless of severity of symptoms or objective evidence of ischemia.For patients with TVD and good LV function, the class 2b recommendation was provided for both CABG and PCI with "may be reasonable" for CABG and "usefulness. ..to improve survival is uncertain" for PCI.
A class 2a recommendation was provided "in selected patients with SIHD and multivessel CAD appropriate for CABG and mild-to-moderate left ventricular systolic dysfunction (ejection fraction 35%-50%), CABG (to include a left internal mammary artery (LIMA) graft to the LAD) is reasonable to improve survival."As it is generally accepted that almost all stenosed LADs should receive a LIMA graft, the recommendation for a LIMA graft is an unnecessary duplication and implies that multivessel CAD does not necessarily involve the LAD.However, multivessel disease with LAD involvement is not specifc enough to defne TtmVD.If the AHA guidelines had used a more specifc defnition of multivessel disease such as TtmVD according to the early RCTs, this recommendation would cover a substantially sized and high-risk population for whom it would be difcult to demonstrate an adequate mitigation of risk by guideline-directed medical therapy alone.[25] as new evidence contesting the fndings of the early RCTs relating to TVD and normal LV function.Te main limitations of the ISCHEMIA trial in determining the survival beneft provided by CABG have been presented elsewhere [21].Te hazard ratios for the outcomes were related to the severity and number of stenosed vessels and to the modifed Duke index of severity of CAD as assessed on the coronary computed tomography angiograms (CCTAs)

Use of Contemporary
[7] (Table 2, Figure 2).Te modifed Duke coronary disease classifcation used >70% stenosis in each of the three major arteries or ≥70% stenosis in two vessels including the proximal left anterior descending (LAD) artery to defne the highest risk category [7,23].Based on the CCTA fndings, greater severity of CAD was associated with increased risks of all-cause death, cardiovascular death, myocardial infarction, and the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) [7] (Table 2).In the CAD-stratifed cohorts, the only outcomes for which the invasive strategy provided a signifcant reduction in the risk compared to the conservative strategy during the four-year period of follow-up were for myocardial infarction in the two-vessel >70% stenosis cohort and for the combination of myocardial infarction and cardiac death in the modifed Duke 6 cohort [7].Although the invasive strategy achieved a reduction in some of the risks relative to the conservative strategy, it did not remove the risks associated with CAD severity and extent that would normally be associated with a survival beneft provided by CABG (Table 2).CAD severity is a very weak predictor of outcomes following CABG.Te outcomes associated with the dominance of allocation of patients with extensive CAD to PCI (Table 1, Figure 2) are consistent with the AHA guidelines which state that "there are no RCTs that have demonstrated a survival advantage of PCI over medical therapy in patients with SIHD."However, this allocation was a violation of the study protocol which recommended "guidelines from professional societies and appropriateness criteria should be incorporated into the decision process" for allocation of patients to PCI or CABG (AHA 2011 guideline [1]: CABG class 1, PCI class 2b; ESC 2014 guideline [26]: CABG class 1 and PCI class 3 for SYNTAX score >22).Despite this, the authors appear to argue that the higher mortality in patients with extensive CAD was a disease efect immune to an interventional treatment efect.Essentially, those patients are stuck with their higher mortality risk with the implication that no treatment strategy will provide better risk mitigation than medical therapy alone; "we cannot defnitively conclude that those with the most extensive CAD beneft from an invasive strategy" [7].However, as CABG was provided to a minority of patients to whom it should have been allocated, it is logical to conclude that the multiple violations of the study protocol resulted in avoidable deaths in the invasive arm.Te extent and impact of the protocol violations based on the fndings of direct coronary angiography in the invasive arm have not been reported, without which the signifcance of the trial fndings may be considered indeterminate.Te need to blind clinicians to the results of the CCTAs in the conservative arm to ensure protocol adherence seems to have been validated by the extent of violations in the invasive arm which might have been predicted but not monitored.Future RCTs involving patients with TtmVD must have a defnitive CABG arm to allow monitoring of the safety of randomisation of patients to the alternate strategy arm.Although this might have been the intention of the ISCHEMIA protocol, it was not the application.
Journal of Cardiac Surgery 4.2.Meta-Analyses of RCTs.Te AHA guideline also cited one network meta-analysis [10] and four meta-analyses of RCTs comparing CABG, PCI, and medical therapy for patients with SIHD [11,27,28] as additional justifcation for the downgrading of the recommendation for CABG.Only one of the analyses analysed outcomes according to the percent of patients with multivessel disease [11].No analyses were performed on TVD subgroups.Te network metaanalysis of 100 RCTs provided three-way comparisons of CABG, PCI, and medical therapy and showed a survival beneft provided by CABG over medical therapy [10].Te four meta-analyses combined CABG and PCI into a single revascularisation group for comparison with medical therapy, and none showed an overall survival beneft for revascularisation compared to medical therapy.One of the four meta-analyses included the early trials of the 70s, and this was the only meta-analysis to show a reduction in cardiac death in the revascularisation group [11].All fve analyses included the only two RCTs of CABG versus medical therapy for patients with multivessel CAD and good LV function undertaken since the early trials of the 70s [12,29].Te Medicine, Angioplasty, or Surgery Study (MASS) II required multivessel CAD >70% stenosis and randomised 406 patients (mean LVEF 67.5% and TVD 58.5%) to CABG or medical therapy [29].Te outcomes for patients with TVD were not reported separately.Tere was a nonsignifcant reduction in all-cause mortality in the CABG group at 5 and 10 years but a signifcant reduction in cardiac death at 10 years.In the Bypass Angioplasty Revascularisation Investigation 2 Diabetes (BARI 2D) study, 763 diabetic patients with symptoms or evidence of myocardial ischemia that would prompt revascularisation and with multivessel CAD >50% stenosis were enrolled and randomised to either CABG or medical therapy [11].In the subgroup of patients with three vessel disease (CABG n � 165 and medical therapy n � 156), there was a statistically signifcant beneft for CABG in reducing the primary combined outcome of death, myocardial infarction, and stroke (p � 0.0084), but death was not reported independently.Tere was also a similar beneft provided by CABG in the subgroup of patients with a high myocardial jeopardy score (>55% of total myocardial volume) (p � 0.0038).Te outcomes of patients with three vessel disease and good LV function were not reported separately.
Te only other RCT to compare CABG and medical therapy in patients with CAD "amenable to CABG" included only those with severe LV impairment (ejection fraction <35%) and showed a survival beneft from CABG at 10 years [30].

Summary
TVD a surrogate measurement of a high myocardial volume at risk of infarction and is the most commonly used parameter to estimate the risk of death in patients with SIHD.However, impaired LV function (estimated by reduced ejection fraction), impaired coronary fow reserve (tightness of coronary stenoses, physiological testing, and myocardial perfusion scans), and severity of symptoms or ease of onset of ischemia (Canadian Class, early symptoms on exercise test) all reduce the survival of patients with SIHD and should be included in the estimate of risk that can be mitigated by CABG.TVD should be defned according to the defnition used in the RCTs that have shown a survival beneft for CABG.Te international guidelines should be amended to incorporate these factors in their recommendations for revascularisation of CAD.

Table 1 :
Trials of patients with triple vessel disease and good LV function.

Literature in 2021 AHA Guidelines
Figure 2: ISCHEMIA trial fow chart of distribution of patients from randomisation.Patients who did not undergo revascularisation in the Duke index categories can be calculated by subtracting the PCI and CABG numbers from the totals.Te PCI and CABG totals above the Duke index categories include patients who did not have CCTA analyses.

Table 2 :
[7]come risks for the total patient population in the ISCHEMIA trial[7]associated with coronary artery disease severity according to the modifed Duke prognostic index and number of stenosed arteries.