Contemporary Management of Stable Coronary Artery Disease　― Implications of the ISCHEMIA Trial ―

Abstract

Coronary artery disease (CAD) remains a leading cause of mortality and morbidity in developed countries. Although urgent revascularization is the cornerstone of management of acute coronary syndrome (ACS), for patients with stable CAD recent large-scale clinical trials indicate that a mechanical ‘fix’ of a narrowed artery is not obviously beneficial; ACS and stable CAD are increasingly recognized as different clinical entities. We review the perspectives on (1) modifying the diagnostic pathway of stable CAD with the incorporation of modern estimates of pretest probability, (2) non-imaging evaluations based on their availability, (3) the optimal timing of invasive coronary angiography and revascularization, and (4) the implementation of medical therapy during the work-up.

Coronary artery disease (CAD) remains a leading cause of mortality and morbidity in developed countries. After more than 2 decades of research, major randomized controlled trials (RCTs), including the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial, have provided no clear consensus regarding whether revascularization should be offered to patients with stable CAD.¹ However, more than 100,000 percutaneous coronary intervention (PCIs) are performed in stable patients annually in Japan, with approximately one-third of the patients apparently asymptomatic.² To address these concerns, the Japanese Circulation Society (JCS) Guidelines Committee began updating their clinical practice guidelines in April 2021. Within this comprehensive review, we aimed to provide (1) constructive suggestions for modifying the diagnostic pathway of stable CAD with the incorporation of modern estimates of pretest probability (PTP), (2) non-imaging evaluations based on their availability, (3) the optimal timing of invasive coronary angiography (ICA) and revascularization, (4) the implementation of contemporary medical therapy during the work-up, and (5) considerations for high-risk populations.

Estimation of Pretest Probability

PTP Assessment

The most common clinical manifestation of stable CAD is angina pectoris, which is defined frequently as chest discomfort consistent with that of myocardial ischemia, but without the prolonged duration and severity seen in typical acute myocardial infarction (MI). However, this clinical definition of stable CAD is rather arbitrary. More contemporary guidelines and reviews recommend estimation of the PTP to (or not to) select downstream diagnostic tests (patients with ‘low’ PTP [<5%] can be excluded from further diagnostic testing, as a rare rule-in opportunity exists^3,4). The Diamond-Forrester (DF) approach, which considers age, sex, and the type of symptoms (i.e., typical angina, atypical angina, or non-anginal chest pain) have been the mainstay in the estimation of PTP, although more contemporary large-scale studies have revealed that the DF approach results in lower diagnostic accuracy.^5,6 In more than 4,000 suspected CAD patients who were included in the Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial, the proportion of patients with obstructive CAD was only 13.9% in those classified as ‘intermediate risk’ (PTP 15–85%) based on DF.⁷ Given these findings, the most recent European Society of Cardiology (ESC) guidelines recommend incorporating the updated PTP table in the diagnostic algorithm for stable CAD.^8,9 In the aforementioned PROMISE trial, more than 50% of patients previously defined as having an intermediate likelihood were reclassified as having a PTP <15% according to the updated PTP.¹⁰

The ESC guidelines also highlight the use of clinical likelihood (CL) measures in the risk stratification of stable CAD. The CL is based on traditional risk factors (e.g., hypertension) and fundamental test results (e.g., chest X-ray, resting ECG, and laboratory tests, with emphasis on global left ventricular (LV) function and chronic kidney disease (CKD) assessment) as its modifiers.¹¹ The CL can be feasibly calculated in current practice^12,13 and can function as a “coefficient” to determine if individual patients are actually afflicted with obstructive CAD. For example, when assessing a patient with a PTP of 15%, a lower CL (e.g., a CL ratio of 0.1) can rule out a CAD diagnosis. Conversely, a high CL (e.g., a CL ratio of 10) corresponds with approximately 50% of the positive test value, possibly resulting in a relatively high possibility of false positives.

An optimal plot of the PTP-based diagnostic algorithm for CAD is provided in Figure 1. Sequential PTP and CL assessments can determine the optimal ranges of the clinical possibility for each testing tool, facilitating the reclassification of patients from intermediate to either low or high post-test probability of CAD.¹⁴

Figure 1.

Pretest probability estimation to guide downstream noninvasive testing for stable coronary artery disease. Contemporary pretest probability estimates incorporate dyspnea, cardiovascular risk factors, and basic testing results, in addition to the factors used in previous modeling, including age, sex, and angina symptoms. ECG, electrocardiography; LV, left ventricular.

Choice of Noninvasive Imaging Tests Based on Availability

Noninvasive Imaging

After the assessment of individual PTP, noninvasive cardiac imaging methods are used for further risk stratification in stable CAD patients. The availability of imaging modalities (e.g., coronary computed tomography angiography [CCTA] or myocardial perfusion imaging [MPI]) may vary among treatment centers (Supplementary Table).

MPI is one of the most commonly used functional imaging techniques, and numerous studies have confirmed its diagnostic accuracy and validated its role in long-term risk prediction. MPI uses various stress protocols as the functional testing modality.¹⁵ Patients with normal perfusion are known to exhibit a good prognosis (<1% per year for adverse cardiac events) regardless of their PTP.¹⁶

CCTA has recently emerged as a premier modality for noninvasively assessing coronary arterial status, as it provides excellent negative predictive value and is suitable for ruling out stable CAD in daily clinical practice. The Coronary Computed Tomographic Angiography and Risk of All-Cause Mortality (CONFIRM) registry has reported that the absence of CAD was associated with significantly improved prognosis.¹⁷ Moreover, the ability to assess the extent of coronary plaque deposition is an important advantage of CCTA, and the relationship between plaque morphology and future ACS has been demonstrated.^18–21 Recently, the Scottish Computed Tomography of the HEART (SCOT-HEART) trial demonstrated that CT-guided management was associated with improved patient outcomes compared with the traditional approach; this positive finding was driven by the higher implementation of optimized medical therapy in the CT arm.²² Several other studies have also reported that the low-attenuation plaque detected by CCTA could be a therapeutic target to facilitate preventive medicine.^23–25 Thus, the ESC guidelines have highlighted the use of CCTA as a primary imaging modality for patients with stable CAD.⁸ On the other hand, the positive predictive value for obstructive CAD is moderate at best due to the overestimation of stenosis in calcified lesions.²⁶ To further improve the diagnostic accuracy of CCTA, functional estimation using computational fluid dynamics has merged (FFR-CT). RCTs have shown that FFR-CT has high reproducibility and predictability compared with invasive FFR.^27–29

Considering the accumulating evidence and recent development of technologies that require less radiation exposure, there is a growing demand for a high-quality CT-based approach to imaging and diagnosis of stable CAD patients exhibiting low-to-intermediate risk.^8,30 CCTA is also useful for visualizing the severity of atherosclerotic plaque burden, facilitating the use of aggressive preventive therapy.²² The study protocol for the ISCHEMIA trial required the use of CCTA prior to randomization to exclude patients with left main trunk (LMT) CAD and nonobstructive CAD.¹ However, as described previously, substantial overestimation of organic stenosis may increase the use of ICA.²⁵ The Myocardial Perfusion CMR vs. Angiography and FFR to Guide the Management of Patients with Stable Coronary Artery Disease (MR-INFORM) study reported that cardiac magnetic resonance (CMR)-based stress assessments were comparable to FFR in terms of prognostic utility, and, importantly, CMR-guided management strategies significantly reduced the need for ICA or revascularization.³¹ Thus, the detection of hemodynamic flow-limiting disease via functional imaging is necessary, especially for intermediate-to-moderate risk patients.

The flow of the proposed diagnostic pathway based on the availability of noninvasive testing is presented in Figure 2. According to the latest ESC guidelines, high-risk anatomical features are defined as LMT disease, 3-vessel disease with proximal stenoses, or proximal left anterior descending artery (LAD) disease, although the results of the ISCHEMIA trial suggest that initial conservative management is feasible in the latter 2 scenarios. If a CT scanner is the only imaging device available at an institution, we propose that nonobstructive disease should first be ruled out by CCTA; subsequent invasive procedures should be considered only if high-risk anatomical features, refractory angina (under optimal medical therapy [OMT]) are present or in near-ACS status.

Figure 2.

Diagnostic flow for downstream noninvasive imaging based on availability. The diagnostic strategy for stable CAD is, in fact, restricted by institutional availability of noninvasive testing modalities. A combination of anatomical and functional imaging can maximize appropriate diagnostic throughput. *CCTA should be avoided when the image quality can be non-diagnostic. ^†CCTA and stress perfusion MRI are not recommended for advanced CKD patients. CAD, coronary artery disease; CCTA, coronary computed tomography angiography; ExECG, exercise treadmill electrocardiography; FFR, fractional flow reserve; ICA, invasive coronary angiography; LMT, left main trunk; MRI, magnetic resonance imaging; OMT, optimal medical therapy; Sx, symptoms.

Exercise Treadmill ECG Testing

Exercise ECG (ExECG) testing, mainly using a treadmill, has been recommended for the diagnosis of stable CAD in the JCS guidelines and the American College of Cardiology (ACC)/American Heart Association (AHA) 2002 guidelines for patients with an intermediate PTP of CAD who are able to exercise and who have an interpretable resting ECG, taking cost-effectiveness into account,^32,33 whereas in the ESC guidelines, ExECG was recommended as an ‘alternative approach’, given its limited sensitivity and specificity in diagnosing obstructive CAD.⁸ The performance of ExECG is known to be adequate when the PTP is high (≥80%) or low (≤19%).¹⁴

However, it should be noted that exercise capacity itself is a potent predictor of clinical risk, even in the setting of nonischemic (normal) functional imaging.³⁴ Hence, ExECG is recommended for the assessment of exercise tolerance, cardiac symptoms, arrhythmias, and blood pressure responses, and for determining event risks in selected patients.⁸ In the present era, the primary aim of using ExECG is to confirm manageable exercise capacity in the absence of an unfavorable hemodynamic response.

Invasive Coronary Angiography and Revascularization

Risks and Benefits of Revascularization

As mentioned above, recent studies have emphasized that the occurrence of adverse cardiovascular events are largely attributed to plaque rupture or the erosion of a lesion with any degree of stenosis (so-called “vulnerable plaque”), rather than to anatomically significant stenosis. The difficulty in identifying an individual “vulnerable plaque”³⁵ led us to search for a more comprehensive approach to reducing adverse cardiovascular outcomes, and question the actual benefits of revascularization treatment, because numerous RCTs, including the Clinical Outcomes Using Revascularization and Aggressive Drug Evaluation (COURAGE),³⁶ and the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial demonstrated no significant clinical benefit with early revascularization.³⁷ The Fractional Flow Reserve Versus Angiography for Multivessel Evaluation-2 (FAME-2) was conducted in patients with significant ischemia (defined as an FFR of ≤0.8) and demonstrated a significant reduction in the composite scores for death, MI, or urgent revascularization in the PCI group,³⁸ although the difference was driven mainly by urgent revascularization, and there were no significant differences in the incidence of death or MI.

Directionally similar findings have been reported for coronary artery bypass grafting (CABG).^39–41 A meta-analysis of these trials revealed a lower mortality rate in the CABG group,⁴² although there were difficulties in eliciting any reliable conclusion from the results, as the majority of the clinical trials were conducted before the establishment of current OMT protocols and the study included subjects with LMT disease. In the BARI-2D trial, there was also a significant reduction in the composite score for death, MI, or stroke in the CABG stratum;³⁷ however, the difference was mainly driven by the lower incidence of MI in patients undergoing CABG.

Considering the adequate generalizability of these and the ISCHEMIA trial,⁴³ we believe that ICA should not be performed routinely and should be restricted for indicated patients undergoing sufficient OMT; also, patients with LMT stenosis should be excluded. For a patient with high-risk coronary anatomical features other than LMT stenosis (e.g., non-LMT multivessel disease or proximal LAD stenosis), revascularization may be considered if the patient has uncontrolled angina or LV ventricular dysfunction (LV ejection fraction [LVEF] <35%). For a patient with single-vessel disease other than the proximal LAD, revascularization can be performed if symptoms remain uncontrolled; otherwise, it is rarely indicated (Figure 3).

Figure 3.

Indication of revascularization based on the results of invasive coronary angiography. Indication for revascularization is based on subjective symptoms, as well as objective anatomical and/or ischemic features. ACS, acute coronary syndrome; FFR, fractional flow reserve; HF, heart failure; iFR, instantaneous wave-free ratio; LAD, left anterior descending artery; LMT, left main trunk; LV, left ventricular; OMT, optimal medical therapy; PRO, patient-reported outcomes; SAQ, Seattle Angina Questionnaire; Sx, symptoms.

Implementation of Optimized Medical Therapy

Together with the diagnostic and risk stratification process described in the previous section, secondary prevention combining lifestyle and intensive pharmacological interventions (i.e., symptom control and event prevention), often referred to as OMT (Table 1), should be introduced simultaneously for all patients with suspected stable CAD (Figure 4).

Table 1. Implementation of Optimized Medical Therapy

	AHA clinical practice guideline recemmendations*1		ESC clinical practice guideline recemmendations*3
		Class		Class
Behavioral
Smoking	Smoking cessation	I	Smoking cessation	I
Physical activity	30–60 min of moderate-intensity aerobic activity at least 5 days and preferably 7 days per week	I	30–60 min moderate physical activity most days	I
Meals	Intake high in fresh fruits, whole grains, vegetables; restricted intake of saturated fats (<7% of total calories), trans fatty acids (<1% of total calories), and cholesterol (<200 mg/day); and reduced sodium intake	I	Intake high in vegetables, fruit, and wholegrains; limit saturated fat to <10% of total intake calories	I
Physiological
Blood pressure	No target BP (start antihypertensive agents when BP >140/90 mmHg)	I	Systolic BP: 120–130 mmHg as office BP	I
LDL-C	<70 mg/dL for very high risk patients*2	IIa	50% ≥LDL-C reduction from baseline and LDL <55 mg/dL*4	IIa
BMI	BMI 18.5–24.9	I	BMI <25	I
Diabetes	HbA1c <7% in selected patients (shorter duration of DM, long-life expectancy) or HbA1c 7–9% (selected according to age, hypoglycemia, complication, coexisting medical conditions)	IIa	Use SGLT2i or GLP-1RA. Mainly patients HbA1c <7%, selected patients (elderly) were <8% or <9%*5	I
Pharmacological agents
Aspirin (acetylsalicyclic acid)	75–162 mg for all patients without contraindications	I	Aspirin 75–100 mg is recommended in patients with a previous MI or revascularization	I
P2Y12 inhibitor	Use for patients with contraindication to aspirin; In combination with aspirin for participants who receive PCI (duration depends on BMS vs. DES); post-MI/ACS for 1 year	I	Use for patients with contraindication to aspirin; In combination with aspirin for participants who receive PCI (duration depends on BMS vs. DES); post-MI/ACS for 1 year	I
Statin	Maximum tolerated dose of high-intensity statin	I	Maximum tolerated dose of high-intensity statin	I
Ezetimib	Use for very high risk patients who are unable to reach LDL-C goal on maximally tolerated statin dose*2	IIa	Use for very high risk patients who are unable to reach LDL-C goal on maximally tolerated statin dose	IIa
Evolocumab (PCSK9 inhibitor)	Use for very high risk patients who are unable to reach LDL-C goal on maximally tolerated statin dose and ezetimibe*2	IIa	Use for very high risk patients who are unable to reach LDL-C goal on maximally tolerated statin dose	IIa
RAASi	Use for hypertension, diabetes, eGFR <60 or LVEF <40%	I	Use for hypertension, diabetes, eGFR <60 or LVEF <40%	I
BB	Use for history of MI or LVEF <40%	I	Use for history of MI or LVEF <40%	I

High-intensity statin defined as atorvastatin 40–80 mg or rosuvastatin 20–40 mg. Very high risk defined as a history of multiple major atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event and multiple high-risk conditions such as elderly, diabetes, hypertension. *¹2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease. *²2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. *³2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. *⁴2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). *⁵2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. ACS, acute coronary syndrome; BP, blood pressure; BMI, body mass index; eGFR, estimated glomerular filtration rate; GLP-1RA, glucagon like peptide-1 receptor antagonist; HbA1c, hemoglobin A1c; LVEF, left ventricular ejection fraction; MI, myocardial infarction; LDL-C, low-density lipoprotein cholesterol; PCI, percutaneous coronary intervention; SGLT2i, sodium/glucose cotransporter-2.

Figure 4.

Initiation of medical therapy during the diagnostic process for stable coronary artery disease. Secondary prevention with lifestyle and intensive pharmacological interventions should be introduced for all patients with stable CAD, including those currently in the diagnostic process. *Caution required in bradycardic patients or other contraindications. ^†Bleeding risk assessment required. CAD, coronary artery disease; PRO, patient-reported outcomes; SAQ, Seattle Angina Questionnaire.

Lifestyle Interventions

Patients with stable CAD benefit from regular exercise, a healthy diet with restricted intake of saturated fats, abstinence from tobacco or excessive alcohol use, and the control of hypertension and serum lipid and blood glucose levels.⁸ These lifestyle modifications should be encouraged during the work-up for stable CAD, with an emphasis on risk stratification. Importantly, regular exercise is not contraindicated for these patients.⁴⁴

Pharmacological Interventions

Antianginal Drugs Initial drug therapy for CAD usually consists of 1 or 2 antianginal drugs, as necessary, with β-blockers (BBs) or non-dihydropyridine (non-DHP) calcium-channel blockers (CCBs) being recommended as the first-line treatment; a combination of these drugs should be considered if angina symptoms are not sufficiently controlled. Long-acting nitrates should be considered as a second-line treatment option when initial therapy with a BB or a non-DHP CCB is contraindicated, poorly tolerated, or inadequate to control angina symptoms.⁸

CCBs are widely used in Japan.^45,46 However, it should be noted that BBs have been shown to decrease the incidence of major adverse cardiovascular events (predominantly in patients with a history of MI or a reduced LVEF),⁴⁷ whereas there is no proof that CCBs are beneficial in any group of CAD patients.⁴⁸ Thus, physicians should evaluate each patient’s symptoms carefully to diagnose vasospastic angina and, more importantly, to select anti-ischemic drugs based on each individual’s clinical characteristics.

Antiplatelet Agents For all stable CAD patients with sinus rhythm, low-dose acetylsalicylic acid (ASA) is strongly recommended; for those with an intolerance to ASA, P2Y12 inhibitors are recommended. Dual antiplatelet therapy (DAPT) or low-dose rivaroxaban plus low-dose ASA is beneficial in selected high-risk patients, such as those recovering from ACS or those who have undergone PCI. In a meta-analysis, stable CAD patients or those with a similar risk profile who had undergone PCI experienced a 22% risk reduction in MI following DAPT.⁴⁹

Lipid-Lowering Therapy The 2018 ACC/AHA Cholesterol Guideline for patients with clinical atherosclerotic cardiovascular disease recommends treatment with a maximally tolerated dose of a statin (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) to achieve ≥50% reduction in low-density lipoprotein cholesterol (LDL-C) levels. The guideline further recommends the use of ezetimibe as an adjuvant with a high-intensity statin for patients with known CAD and an LDL level persistently ≥70 mg/dL.⁵⁰ In Japan, only 20 mg atorvastatin and 20 mg rosuvastatin formulations are available as the maximum dose.⁵¹ Regardless, given the recent Randomized Evaluation of Aggressive or Moderate Limit Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) trial in Japan, physicians should consider prescribing the maximum dose of high-intensity statins.⁵²

High-Risk Populations

Although known high-risk features such as aging, frailty, advanced CKD, and heart failure (HF) predispose patients to a high prevalence of CAD and increased risk of cardiovascular events, such patients have been under-represented in clinical trials (Table 2). Diagnostic and therapeutic recommendations are scarce for these patients, making evidence-based strategies extremely challenging.

Table 2. Proportion of High-Risk Conditions in Major Studies of Stable CAD

Study (published year, total no. of patients)	Major inclusion criteria	Comparison	Age		Kidney function			LVEF		Comment on eligibility criteria
			Mean age, years	>80 years (%)	Mean eGFR (mL/min/ 1.73 m2)	Moderate to severe CKD* (%)	On HD (%)	Mean (or median) LVEF (%)	Low LVEF (%)
COURAGE36 (2007, n=2,287)	(1) ≥70% proximal s tenosis+ischemia OR (2) ≥80% stenosis+symptoms	PCI vs. OMT	61.6	≈3.2†	77.5‡ 64	2.3 65	0	60.8	0§	LVEF <30% excluded HD excluded
BARI-2D37 (2009, n=2,368)	(1) T2DM AND (2a) ≥50% stenosis+ischemia (2b) ≥70% stenosis+symptom	CABG or PCI vs. OMT	62.4	≈3.7†	76.3	0# 66	ND¶	57.2	≈0–1†	Cr >2.0 mg/dL excluded
STICH62 (2011, n=1,212)	(1) LVEF ≤35% AND (2) CAD amenable to CABG	CABG vs. OMT	59.5	ND	74.1** 67	7.8†† 67	ND	27.5	100	LVEF >35% excluded
FAME238 (2012, n=888)	(1) ≥50% stenosis AND (2) FFR ≤0.8	PCI vs. OMT	63.7	≈4.3†	ND	ND	0	ND	0§	LVEF <30% excluded
ORBITA68 (2018, n=200)	≥70% stenosis+symptoms	PCI vs. OMT	66.0	≈5.9†	76.9**	ND	ND	≈58.7‡‡	0§	LVEF <30% excluded
ISCHEMIA1 (2020, n=5,179)	≥Moderate ischemia (stress imaging/ Echo/ECG)	PCI vs. OMT	64	ND	ND	0	0	60.0	0§§	LVEF <35% excluded eGFR <30 mL/ min/1.73 m2 excluded
ISCHEMIA- CKD56 (2020, n=777)	(1) ≥Moderate ischemia (stress imaging/Echo/ECG) (2) CKD (eGFR <30 mL/min/1.73 m2)	PCI vs. OMT	63	ND	23.0	100	53.4	58.0	0§§	LVEF <35% excluded eGFR >30 mL/ min/1.73 m2 excluded

*Moderate CKD defined as eGFR <45 mL/min/1.73 m² and severe CKD as eGFR <30 mL/min/1.73 m².^† Proportions were calculated from a standard normal distribution table using the mean and standard deviation.^‡ Value estimated only from the OMT group.^§ Low EF defined as <30%.^# Proportion of Pts with creatinine ≥1.5 mg/dL.^¶ Probably no Pts on hemodialysis because patients with creatinine levels >2 mg/dL were excluded. **eGFR calculated by the Modification of Diet in Renal Disease Study equation.^†† Proportion of Pts with creatinine ≥1.5 mg/dL.^‡‡ Assuming a normal EF is 60%, mild impairment of 50%, and moderate impairment of 37.5%, LVEF was calculated from each proportion.^§§ Low EF defined as <35%. CA, coronary artery; CABG, coronary artery bypass graft; CAD, coronary artery disease; Cr, creatinine; Echo, echocardiography; eGFR, estimated glomerular filtration rate; HD, hemodialysis; LVEF, left ventricular ejection fraction; ND, no description; PCI, percutaneous coronary intervention; Pts, patients; OMT, optimal medical therapy; T2DM, type 2 diabetes mellitus.

Elderly Patients

Elderly patients frequently present with atypical symptoms, and the application of the PTP could be limited. In addition, the incidence of cardiac troponin elevation, likely reflecting subclinical cardiomyocyte injury, is higher in older than in younger adults; thus, the upper limit of normal for troponin levels used to define MI is typically set to a higher value in the elderly. Although assessing exercise capacity can provide incremental information for respective risk stratification, it is frequently impractical due to decreased muscle strength and cognitive ability in older patients.

From a therapeutic perspective, specific considerations are required for both medical and invasive therapies. The side effects of drugs, along with drug intolerance and overdosing, are frequent occurrences in the elderly.⁸ Similarly, antithrombotic therapy for the elderly should only be administered following the evaluation of bleeding and thrombosis risks. Although lipid-lowering drugs, including statins, are generally recommended for patients with CAD, the expected benefit of lipid-lowering therapy remains undetermined, as most large RCTs evaluating the effect of statins on prognosis have only included patients aged 45–75 years.⁵³ The treatment of chronic CAD in the elderly is also complicated by their increased vulnerability to complications with invasive strategies, and revascularization decisions should be highly personalized based on multifactorial modifiers such as life expectancy.

Patients With CKD

As the GFR declines below ∼60–75 mL/min/1.73 m², the probability of developing CAD increases in a linear fashion.⁵⁴ Risk stratification for predicting cardiovascular events in patients with CKD could be improved by using albuminemia assessments in combination with conventional GFR-based models, as the presence of and amount of albuminemia can help predict cardiovascular events.⁵⁵ In the ISCHEMIA-CKD trial, the use of an initial invasive strategy failed to reduce the risk of death or nonfatal MI, instead increasing the incidence of stroke compared with that on the initial conservative strategy.⁵⁶

Although exercise testing and pharmacological perfusion imaging are less accurate for detecting CAD in CKD patients, functional stress testing and noninvasive imaging have been widely used in patients with advanced CKD.^57–60 The risks of acute kidney injury and nephrogenic systemic fibrosis must be considered when CCTA and enhanced CMR are used (in the ISCHEMIA-CKD trial, CCTA was not mandated as part of the work-up of stable CAD patients with at least moderate ischemia).⁶¹ There is also a therapeutic challenge in the implementation of OMT in CKD patients. The prognostic benefit of statin-based treatment decreases as the eGFR declines, with no evidence of beneficial outcomes among patients receiving dialysis.

Based on the current evidence, the use of CCTA should be restricted in such patients due to the risk of deterioration of kidney function (except for those receiving hemodialysis) and the potential of excessive coronary calcification, leading to low image quality. Statin-based lipid-lowering therapy should be prioritized only in CKD patients prior to initiating hemodialysis, and conservative treatment strategies should be considered due to the low therapeutic value and high risk of revascularization.

Patients With HF

The benefits of revascularization for patients with a low LVEF (≤35%) were not evaluated in the ISCHEMIA trial, as these patients were excluded. In the STICH trial, however, which included patients with a LVEF ≤35%, there was no benefit of revascularization via CABG during the approximately 5-year observation period,⁶² although a subanalysis of the trial revealed that patients with an LVEF ≤27% benefited from revascularization. In a study with an extended observation period of 10 years, the addition of CABG was associated with lower all-cause mortality and cardiovascular hospitalization rates compared with those of medical therapy alone.⁶³ In a subanalysis of the ISCHEMIA trial, there was a trend toward low event-free survival in patients with moderately reduced LVEF (35–45%) in the invasive treatment group compared with that of the conservative treatment group.

Conclusions

In this review, we have described practical recommendations to modify the diagnostic and treatment work-up for patients meeting certain criteria that place them in a gray-zone in terms of risk for CAD based on previous methods of calculating the PTP. We also described the optimal approach to diagnosis and treatment based on the availability of imaging modalities within an institution. At the present time, the priority in stable CAD management is to prevent adverse events, lifestyle modifications and evidence-based medications, and these measures should be offered during the work-up process. Revascularization should be received only by patients with high-risk anatomical/ischemic features or refractory symptoms after OMT.

Disclosures

S.K. has received investigator-initiated grants from Daiichi-Sankyo and Bristol-Myers Squibb (BMS) and has been a speaker for BMS/Pfizer. Other authors have no disclosures.

IRB Information / Data Availability

Not applicable.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0345

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