I. Causes of angina and pathophysiology of coronary flow

II. Diagnostic approach

A. Clinical features of typical angina

Typical angina is characterized by three features:

1. Retrosternal or epigastric discomfort; neck/jaw/arm pain.
   
2. Occurrence with exertion or emotional stress.
   
3. Quick relief by rest or nitroglycerin (within 30 s – 5 min). A prolonged pain (>20 min), or a delay to relief with rest or nitroglycerin (>5 min) usually implies one of two extremes: acute MI or non-cardiac pain.

Angina is precipitated by walking uphill, in the cold, or after a meal.^* Nausea or diaphoresis during pain increases the likelihood of angina. Postprandial angina is often a marker of severe, sometimes multivessel CAD. As opposed to biliary colic or peptic ulcer disease, angina occurs immediately after the meal and is exacerbated by postprandial physical activity. Nocturnal angina may imply severe CAD vs. vasospasm on top of fixed CAD; the increased venous return in the recumbent position increases O₂ demands and triggers ischemia in patients with critical, sometimes multivessel, CAD. Rest angina without an exertional component may be seen in patients with significant CAD whose angina is mainly triggered by a vasospastic reduction of O₂ supply (although many of the latter patients also have exertional angina). Dyspnea may be an angina equivalent and may indicate extensive CAD with secondary increase in LVEDP during ischemic spells; however, dyspnea is very non-specific compared to chest pain. “Warm-up” angina is angina that starts with the onset of activity and improves with further exertion (e.g., in the morning); it suggests a very severe stenosis, with collaterals that get recruited during exertion and a myocardium that adapts to ischemia (ischemic preconditioning).

B. Pre-test clinical probability of significant CAD

The presence of all three features defines typical (definite) angina, while two features define possible angina, and chest pain without any additional feature defines non-anginal chest pain. The combination of (1) angina features, (2) age and sex, and (3) risk factors establishes the probability of CAD (Diamond-Forrester and Duke classifications, combined in Figure 3.1).^11–13 Note that typical angina is defined by its relation to exertion, not by a description of “chest heaviness” or arm radiation.

In addition, primary ST-T changes or Q waves on the resting ECG imply a higher probability of CAD and a higher-risk CAD, even out- side unstable angina.¹³

Only 50% of women with classic angina have CAD (as opposed to ~90% of men). The WISE registry shows that ~40% of women undergoing coronary angiography for suspected myocardial ischemia have CAD; the remaining patients likely have macrovascular spasm or microvascular dysfunction without obstructive CAD. While fewer women have obstructive CAD than men, women without obstructive CAD who continue to have chest pain have a worrisome ~9% risk of death/MI at 4 years.¹⁴

C. Pre-test probability of high-risk CAD (multivessel, extensive CAD)

Hubbard et al. identified five clinical parameters that predict severe (three-vessel or left main) CAD, beside age: male sex, typical angina, diabetes, insulin dependency, prior MI by history or ECG.¹⁵ A 40-year-old patient with four or more of these parameters, or a 60-year-old patient with three or more of these parameters, has a probability of severe CAD of over 40% (e.g., a 60-year-old diabetic man with typical angina). Such symptomatic patients are appropriately referred directly to coronary angiography or CTA without stress testing, as it is highly unlikely that the latter will be normal and, if normal, it may represent a false negative test.¹⁶

Other clinical features are predictive of severe CAD and may justify direct referral to angiography (class I for severe angina):^13,17,18

• High-probability angina that is severe or frequent (e.g., ≥daily). A severe angina is likely to require revascularization for symptom control regardless of stress test results or extent of CAD, as standalone medical therapy is less effective than PCI for symptom control of class III or IV angina.
  
• HF that is likely ischemic (HF with angina, flash pulmonary edema, or older age/combination of risk factors).
  
• Q waves or primary ST-T abnormalities on the baseline ECG, or regional wall motion abnormalities on echo.

D. Testing modalities (diagnostic and prognostic purposes):

• High pre-test probability:
  
  
  
  • Coronary angiography is directly performed if typical exertional angina is severe and requires revascularization.
    
  • CTA is preferred if typical angina is not severe. It excludes left main disease and allows conservative CAD management, as per ISCHEMIA trial.¹⁹
    
  • As an alternative to CTA in typical angina that is not severe, stress testing may be performed, especially in CKD. Here, stress testing is less useful for diagnostic purposes, as the likelihood of CAD remains high even with a negative test. It is, however, useful for risk stratification: a low-risk result allows conservative management.²⁰
  
  
• Intermediate pre-test probability: stress testing or CTA is performed for diagnosis and prognosis. CTA is also indicated after a high- or intermediate-risk stress test or a negative stress test yet persistent symptoms. SCOT-Heart trial showed that routine CTA on top of functional testing reduces the 5-year MI risk in patients with chest pain, typical or atypical, compared to functional testing alone, not via more revascularizations but via assessing plaque burden and dictating aggressive risk factor control.²¹
  
• Low pre-test probability (young patient with atypical angina): stress testing may not need to be performed. Even if the stress test is positive, the probability of CAD increases from <10% up to 20%, i.e., the stress test is likely falsely positive. However, if judged necessary, ECG or echo stress testing may be performed (class IIa). Avoid nuclear stress testing in low-probability patients, as it has a high false-positive rate in this population and a radiation hazard.

Treadmill stress imaging (nuclear or echo) >Treadmill stress ECG Baseline ST depression >1 mma High pre-test probability of CAD Prior coronary revascularization (stress imaging allows localization of ischemia and has a higher sensitivity in detecting single-vessel ischemia) Prior stress ECG with intermediate result Pharmacological stress imaging (nuclear or echo) Unable to walk Able to walk but baseline ECG has LBBB or ventricular paced rhythm (classically, pharmacological nuclear imaging is performed)b

^a LVH without ST depression is appropriately tested with stress ECG.

^b Exercise and dobutamine may exaggerate the septal motion abnormality and septal defect present in LBBB, falsely suggesting ischemia, but have shown an appropriate yield when the apical motion or perfusion is analyzed, rather than the septum.²⁵

High risk: yearly cardiac mortality >3%, yearly cardiac events >5% DTS ≤–11a Reversible, large or severe perfusion defect (summed stress score >+8, corresponding to ischemia involving >10% of the myocardium) Fixed, large or severe perfusion defect with LV dilatation/low EF Rest- or stress-induced LV dysfunction with EF ≤35%, even if the defect is mild or moderate On stress echo: ischemia of ≥3 segments (out of 17), or >one coronary distribution, especially if it occurs at a low rate <120 bpm or a low dose of dobutamine (≤10 mcg/kg/min) Intermediate risk: yearly cardiac mortality 1–3%, cardiac events 1–5% DTS –10 to +4 Summed stress score 4–8 Low risk: yearly cardiac mortality and cardiac events <1% (~0.5% with stress imaging) DTS ≥+5 (≥ +8 is very low risk) No perfusion defect or small perfusion defect with a summed stress score <4

^a Duke Treadmill Score (DTS) = prognostic score for treadmill stress testing

= Exercise time on Bruce protocol – 5 × (the deepest ST depression on ECG) – 4 × (angina score) (Angina score: 0 = no angina, 1 = non-limiting angina, 2 = exercise-limiting angina)

F. Putting it together: diagnostic approach and management of chronic chest pain (Figure 3.2)

III. Silent myocardial ischemia. Is there a role for screening asymptomatic patients and post-PCI patients?

A totally silent severe myocardial ischemia is uncommon (10- 15% of CAD). The more common form of silent myocardial ischemia consists of silent ischemia interspersed with symptomatic ischemia, such as angina or prior MI. Even if asymptomatic, ischemia is a strong predictor of cardiac events and mortality and may have the same prognostic significance as symptomatic ischemia.²⁹

However, revascularization does not modify this prognosis, and screening asymptomatic patients based solely on risk factors is not indicated, nor is screening of post-PCI patients indicated. In the DIAD study, asymptomatic diabetic patients, who constitute a relatively

high-risk population, were screened for CAD with nuclear stress imaging. These asymptomatic patients actually had a low risk of cardiac events (0.6% per year), and while this risk was higher in the small subgroup of patients with moderate or severe ischemia (2.5% per year), 70% of events eventually occurred in patients with normal testing. In fact, a 0.6% event rate in 90% of the population leads to more total events than a 2.5% event rate in 10% of the population. Even if revascularization reduces the risk of late MI in this small subgroup, the benefit is nullified by the periprocedural risk of MI and by the risk of unnecessary diagnostic angiograms in patients with false positive stress tests. This explains why the event rate was similar in the screened and non-screened diabetic populations. Thus, stress testing is not generally useful in asymptomatic patients, even those at seemingly high risk, particularly if risk factors and hemoglobin A1c are well controlled (as in the DIAD study).³⁰ These findings were corroborated by another study, wherein asymptomatic diabetic patients were randomized to coronary CTA screening vs. routine care. Coronary CTA found significant CAD (>70% stenosis) in 11% of patients and resulted in a 6% revascularization rate, which did not translate into any reduction of death, MI, or unstable angina (FACTOR-64 study).³¹ Moreover, the following 3 ideas argue against testing and stenting asymptomatic patients:

• ~75% of MIs arise from a plaque that was not obstructive (<50%) on a recent CT or coronary angiography (within the last couple of years).³² This is particularly true if the patient is asymptomatic, even more so if asymptomatic despite being active.
  
• Atherosclerotic burden, as assessed by CT calcium scoring, is at least as good a predictor of coronary events as the presence of obstructive CAD. Stenting does not modify this major driver of outcomes, i.e., plaque burden.³³
  
• Occlusion of a stenosis>70% is far less likely to cause a large MI than occlusion of mild disease (30% vs. 75% likelihood), and far more likely to be preceded by angina as first presentation (70%). This is because chronic collaterals reduce infarct size in the former. Thus, seeking stenoses >70% is seeking the less deadly disease.³⁴

The only valuable test in asymptomatic patients is CT calcium scoring, a powerful risk stratifier that dictates more aggressive risk factor modification, not revascularization. If stress testing is done in asymptomatic patients, the detection of severe ischemia would lead to revascularization only in extensive CAD, mainly left main disease.

Silent ischemia 6 months after PCI, even if severe, is not clearly associated with increased death or MI. In-stent restenosis is asymptomatic ~50% of the time, in which case the prognosis is very good; routine angiographic follow-up and PCI of asymptomatic in-stent restenosis does not improve outcomes compared to angina-driven PCI.³⁵

IV. Medical therapy: antiplatelet therapy

While the combination of aspirin and clopidogrel is beneficial for up to 1 year after MI or stent placement, this combination has not shown superiority to aspirin monotherapy in stable CAD and peripheral vascular disease (CHARISMA trial). However, in a substudy of CHARISMA, patients with prior MI appeared to derive a benefit from prolonged combination therapy for up to 28 months, especially if they had disease in multiple vascular locations (e.g., MI and PAD).³⁶ In monotherapy, clopidogrel is an alternative to aspirin and may be slightly superior in reducing coronary and cerebrovascular events with a slightly lower risk of GI bleed.³⁷

Patients with CAD who also have an indication for anticoagulation (AF or a history of DVT) are best treated with standalone anticoagulation beyond 1 year of MI or coronary stenting (warfarin or NOAC). Anticoagulation, per se, effectively reduces coronary events, as in the modern AFIRE trial using rivaroxaban;³⁸ in older trials, warfarin monotherapy or warfarin–aspirin combination was more effective than aspirin in preventing coronary events, at the cost of a higher bleeding risk.³⁹

V. Medical therapy: antianginal therapy and risk factor control

Myocardial oxygen demands are related to the following four factors: inotropism, chronotropism, afterload, and preload. Each antianginal agent targets some of these factors. Nitrates and vasodilatory calcium channel blockers reduce ischemia by reducing preload and afterload, and, except in vasospastic angina, the coronary vasodilatory effect is a less important effect.

VI. Indications for revascularization

The first step is to determine if the patient requires coronary angiography (Figure 3.2). The second step is to determine if the patient requires revascularization. The third step is to determine whether CABG or PCI is appropriate. The need for coronary angiography does not imply a need for revascularization once CAD is found. In fact, medical therapy is frequently appropriate in a patient with significant, even multivessel CAD (with no left main disease). Coronary angiography serves as a risk stratification tool that helps determine whether medical therapy alone is appropriate. Based on ISCHEMIA trial, coronary CTA may replace coronary angiography and may be used to exclude left main disease and proceed with conservative management even in patients with multivessel disease.

In order to benefit from revascularization, one of the following 2 features excluded from ISCHEMIA trial must be present: (1) severe refractory angina, or (2) severe left main disease, regardless of angina.^19,20 Extensive 3-vessel CAD or 2-vessel CAD with proximal LAD may also benefit from CABG, but less strongly. Refractory angina is defined as frequent angina (multiple times weekly) that persists despite the use of at least two antianginal medications (or less in case of intolerance or a baseline low BP and heart rate).

Old retrospective analyses suggested that revascularization in the setting of extensive ischemia involving ≥10% of the LV was associated with a reduction of mortality; this suggested a role for ischemia assessment in guiding revascularization.⁶¹ However, the large randomized trial ISCHEMIA disproved this hypothesis. Analyses from both ISCHEMIA and COURAGE suggest that the anatomic burden of disease is a far superior predictor of death and cardiac outcomes than ischemia, even though neither one predicts a benefit from revascularization. ^62,63 Ruling out left main disease via CTA or angiography appears more important than functional ischemia evaluation.

VII. CABG and CABG vs. medical therapy

CABG is the only revascularization modality shown to improve survival in the high-risk subsets of stable CAD. In a meta-analysis that included the three classic trials of CABG vs. medical therapy, the Coronary Artery Surgery Study (CASS), the European Coronary Surgery Study (ECSS), and the VA study, CABG reduced mortality by 40–50% in the following groups:⁶⁸

• Left main disease (mortality reduction of ~75%).
  
• Three-vessel CAD, or one- or two-vessel CAD involving the proximal LAD. CABG is beneficial in these patients irrespective of LV function, but more so in the case of mild LV dysfunction with EF 35–50% or evidence of moderate/severe ischemia on stress testing (i.e., make sure CAD is functionally significant).

CABG was beneficial in the classic trials despite a 25% crossover to CABG in the medical therapy arm at 5 years, implying that the absolute CABG benefit is even higher. This CABG benefit was seen irrespective of symptom status and extended to asymptomatic patients. Note that the survival benefit in stable CAD does not emerge until 2 years after CABG, partly because of the early surgical hazard; thus, CABG is an appropriate therapy in patients who are otherwise likely to have a good longevity. CABG is expected to be beneficial sooner in patients with unstable CAD. Those trials were done in the 1970s, at a time when CABG technique was suboptimal (LIMA was not routinely used, which explains why the survival advantage of CABG gradually narrowed beyond 10 years). But in those trials medical therapy was also suboptimal (mainly consisting of β-blockers, with very limited use of aspirin and no statin). In fact, in the CABG stratum of the modern BARI 2D trial, initial CABG did not reduce the mortality of diabetic patients with multivessel, non-left main disease (vs. initial medical therapy). Same results were replicated in ISCHEMIA trial. Thus, the only absolute indication for CABG in the stable CAD setting is left main disease, not 3-vessel or proximal LAD disease.

The above trials excluded patients with severe LV dysfunction (EF <35%). In patients with severe ischemic LV dysfunction (EF <35%), no or mild angina, and no severe HF, CABG improved death and cardiovascular hospitalizations at 10 years in the STICH trial.^69,70The benefit was, however, not dramatic (~20% reduction of cardiovascular death). Once again, the benefit did not emerge until 2 years after CABG. This benefit was irrespective of viability testing.

CABG may also be performed for single- or two-vessel CAD not involving the LAD, if PCI is not technically feasible and the patient has refractory, severe angina. The value of a single- or two-vessel CABG to a non-LAD vessel is mainly symptomatic.

The well-known benefit of CABG in diabetic patients is seen in CABG vs. PCI trials, rather than in the above trials of CABG vs. medical therapy.

VIII. PCI and PCI vs medical therapy

General PCI indications and pitfalls- Consider the following three settings:

• PCI is a first-line consideration for one- or two-vessel CAD, along with severe angina.
  
• PCI is an alternative to CABG in three-vessel CAD, or two-vessel CAD involving the proximal LAD, with an angiographic SYNTAX score ≤22 and no diabetes.
  
• In three-vessel CAD, or complex two-vessel disease involving the LAD (especially proximal LAD), with either diabetes or SYNTAX score >22, CABG significantly improves survival in comparison with PCI (SYNTAX and FREEDOM trials).

PCI is flawed by a risk of restenosis of 20% with BMS, which is reduced to <10% with DES. At the 5-year follow-up of PCI populations without extensive CAD, 20-25% of patients had recurrent events, mainly recurrent symptoms with a need for revascularization. Approximately 50% of these events occur in the target vessel, mainly the target stented lesion, while 50% occur in remote vessels (non-culprit disease progression).^67,71 Those events would be more common in patients with diffuse and complex CAD, who not only have a higher risk of restenosis but also a higher risk of progression of non-target lesions/vessels, as PCI only addresses the focal disease.

PCI vs medical therapy–The COURAGE trial evaluated patients with stable, rather mild angina, normal EF, and a good functional status (mean stress test exercise time = 7 min).⁷² It included a large population of patients with multivessel CAD (~70%, including 30% three-vessel CAD) and patients with proximal LAD disease (~35%). Initial PCI did not improve death or MI outcomes as compared to initial medical therapy ± delayed PCI (PCI was eventually performed in 31% of patients in the medical therapy arm). COURAGE results, however, do not dismiss the value of PCI in highly symptomatic patients with frequent anginal episodes (i.e., daily), those with severely limiting angina, or those with persistent angina despite medical therapy, patients in whom PCI has strong effects on quality of life and functional status, according to the COURAGE quality-of-life substudy.⁷³

Similar results were replicated in the BARI 2D trial.⁷⁴ In diabetic patients with mild angina, initial revascularization did not reduce death or MI in comparison to initial medical therapy, although 40% of patients eventually crossed over from medical therapy to revascularization over 5 years. More specifically, in patients with one- or two-vessel CAD, initial revascularization with PCI did not reduce death or MI in comparison with medical therapy (PCI stratum). In patients with extensive CAD randomized to initial CABG vs. medical therapy (CABG stratum), initial CABG reduced MI (14.6% vs. 7.4% at 5 years) but not death in comparison with medical therapy.

The FAME 2 trial randomized patients who mainly had one- or two-vessel CAD (65% proximal/mid-LAD) to FFR-guided PCI vs. medical therapy. FAME-2 trial differs from the COURAGE trial mainly in the use of FFR guidance. PCI strikingly reduced the risk of urgent revascularization at 8 months and 5 years (6% vs 21%), as well as all future revascularizations (13% vs 51%), more so in lesions with FFR≤0.65.⁶⁶ Yet PCI failed to show any mortality or MI reduction even at 5 years.²⁸ While PCI significantly reduced the risk of late spontaneous MI, which occurred in 10% of medically managed patients vs. 6.5% of PCI patients at 5 years, it was associated with a risk of periprocedural MI (2%) and stent thrombosis (1%) which, beside non-target lesion progression, negated the overall MI benefit. Moreover, late STEMI was not reduced by PCI and was similarly low in both arms (1.6% at 5 years). It was speculated that long-term mortality rates might diverge in favor of PCI, as spontaneous MI has a larger impact on long-term mortality than periprocedural MI,⁷⁵ but this was not seen at 5 years (not even a trend).

The ISCHEMIA trial selected stable patients with moderate or severe ischemia on stress testing (≥10% of the LV). Those patients were subjected to coronary CTA to confirm CAD diagnosis (≥50% in a major epicardial vessel) and to rule out left main disease; ~5% of screened patients had left main disease and were excluded. Patients with CAD were randomized to medical therapy vs. cardiac catheterization followed by revascularization; patients in the medical therapy arm only received CTA at baseline, not cardiac catheterization.¹⁸ Unlike COURAGE and BARI 2D, this trial randomized patients before any catheterization was done. In a way, this study did not just question the value of revascularization, but also the value of invasive coronary angiography after a severely abnormal stress test. At baseline, in both groups, 45% of patients had 3-vessel CAD on CTA, 31% had 2-vessel CAD, 47% had proximal LAD disease, and 42% had diabetes. In the invasive arm, only 13% did not have significant CAD on catheterization, and thus most patients underwent revascularization, of whom 76% received PCI and 24% received CABG. At 4 years of follow-up, invasive strategy and revascularization did not affect mortality (~6.5% in both arms), MI, or the combined endpoint of MI/mortality (11.7% for invasive vs 13.9% for conservative). Invasive strategy increased MI by ~2% in the first 6 months (large periprocedural MI) and reduced it by 4% between 6 months and 5 years (spontaneous MI), with a nearly neutral overall effect. This lack of benefit was consistent across all subgroups, including 3-vessel CAD, proximal LAD, and diabetic subgroups; and was not affected by ischemia or anatomic severity.⁶³ Of note, only EF>35% was included, and EF was mostly normal (median 60%). The biggest pitfall is that >95% of patients had CCS 0-II angina and most patients had infrequent angina, monthly or less.

IX. PCI vs. CABG in multivessel and left main disease

CABG outcome is less dependent on the complexity and diffuseness of lesions than PCI, and when a graft is placed, the whole proximal 6–8 cm of the coronary artery is protected from MI induced by plaque rupture (Table 3.3). Keep in mind that plaque ruptures and acute coronary occlusions occur overwhelmingly in the proximal third of the coronary arteries, a segment protected by CABG (80-90% of acute LAD and LCX plaque ruptures are in the proximal 5 cm).⁷⁸ Hence, CABG is consistently associated with a lower risk of MI and angina recurrence than PCI. Even when MI occurs after CABG, it is less likely to be fatal and more likely a small MI, as compared with patients receiving medical therapy or PCI (CASS registry, BARI trial, and SYNTAX trial).⁷⁹

BARI and ARTS trials – In the balloon angioplasty era, the BARI trial randomized very select patients with focal multivessel CAD to CABG vs. PCI. In comparison with PCI, CABG dramatically reduced mortality in diabetic patients by an absolute 16% at 5 years, and dramatically reduced repeat revascularizations in all patients.⁸⁰ The benefit on repeat revascularizations was shown in the BMS era as well (ARTS trial).⁸¹ The superiority of CABG was seen despite the very careful selection of patients with non-extensive CAD amenable to PCI (<10% of screened patients were randomized to CABG vs. PCI).

Isolated proximal LAD disease – A meta-analysis of randomized trials of CABG vs. PCI for isolated proximal LAD disease suggests the lack of mortality difference, although repeat revascularizations were much lower with CABG (pre-DES era).⁸²

SYNTAX trial – In the DES era, the SYNTAX trial randomized patients with three-vessel and/or left main disease to CABG vs. PCI with DES. This trial included patients with extensive, complex CAD, and graded the angiographic severity of CAD using the SYNTAX score. In the overall trial, at 5 years of follow-up, CABG was associated with a significant reduction in MI (~10% vs. 4%), a marked reduction in the need for repeat revascularizations (26% vs. 14%), but no mortality difference (13.9% vs. 11.4%). CABG significantly reduced mortality by an absolute 8% in the high SYNTAX scores (>32).^83,84 Conversely, patients with a low SYNTAX score (≤22) had comparable death, MI and even repeat revascularization rates with CABG and PCI, whether they had three-vessel or left main disease. Regarding 5- and 10-year mortality, CABG and PCI were equipoise for the left main subset (=left main +1, 2 or 3-vessel CAD), but CABG reduced mortality in 3-vessel CAD without left main. Interestingly, CABG outcomes were not affected by SYNTAX score, i.e., CABG success and post-CABG survival were not affected by angiographic complexity, in contradistinction with PCI. The only pitfall of CABG was the higher early risk of stroke (2.2% vs. 0.6% at 1 year).

The SYNTAX score assigns a number for the location of each stenosis (e.g., left main 5, proximal LAD 3.5, proximal LCx 1.5, OM 1, RCA 1), and multiplies this number by 2 in case of a 50–99% stenosis, and 5 in case of a CTO. Additional points are added at every lesion for tri- or bifurcation, long disease, calcium, and CTO complexity. Overall, the score emphasizes proximal stenoses (especially LAD) and angiographic complexity, especially CTO.

FREEDOM trial – Diabetic patients with two- or three-vessel CAD involving the LAD were randomized to CABG vs. PCI with DES.⁸⁵ At 5 years of follow-up, CABG significantly reduced mortality vs. PCI, almost as much as in the high SYNTAX group of SYNTAX trial (16.3% vs. 10.9%). It reduced MI (~14% vs. 6%) at the price of an increase in postoperative stroke and a higher early postoperative mortality. The benefit in these diabetic patients was consistent across all SYNTAX score groups, including the low SYNTAX group.

EXCEL and NOBLE trials of left main disease- Both EXCEL and NOBLE trials specifically randomized patients with left main disease and mainly low or intermediate SYNTAX score (≤32) to CABG vs. PCI; 81% of patients had distal left main disease, and 15-29% had diabetes. In both trials, CABG was slightly superior to PCI at 5 years of follow-up.^86,87 In EXCEL, the 5-year composite death/MI/stroke was not different, but CABG slightly yet significantly reduced mortality (13 vs. 9.9%), nonprocedural MI (6.8 vs. 3.5%), and repeat revascularizations (target and non-target, 16.9 vs 10%). In the CABG group, the composite outcome was increased in the first 30 days but reduced beyond 30 days (survival curves crossed at 1 year). In NOBLE, CABG significantly reduced the primary outcome, which included repeat revascularizations (28.9% vs 19%), and reduced nonprocedural MI, but did not reduce mortality.