2026 Focused Update of the Saudi Heart Association Guidelines on Best Practices in the Management of Chronic Coronary Syndromes

Abstract

Background

Chronic coronary syndromes (CCS) continue to impose a substantial clinical and economic burden in Saudi Arabia. Since publication of the 2022 Saudi Heart Association (SHA) CCS guidelines, important advances have emerged in diagnosis, pharmacotherapy, cardiometabolic risk reduction, antiplatelet management, and revascularization. This 2026 focused update selectively revises and clarifies key recommendations to reflect these advances within the Saudi context.

Methods

A multidisciplinary SHA expert panel conducted a structured review of randomized trials, meta-analyses, and relevant international guidance published since 2022. Updates were restricted to areas with substantive new evidence or evolving clinical practice. Recommendations were formulated through expert consensus in accordance with SHA methodological standards. This document complements the 2022 guideline and does not replace it.

Results and conclusions

This focused update advances a more personalized, risk-driven approach to CCS management. Diagnostic algorithms now explicitly integrate pre-test probability, reinforce coronary computed tomography angiography as the preferred initial modality in low-to-intermediate probability, and refine the positioning of functional stress imaging. Residual risk assessment and preventive strategies are also strengthened. Importantly, this update introduces a dedicated diagnostic and management framework for angina and ischemia with non-obstructive coronary arteries (ANOCA/INOCA), emphasizing endotype-specific evaluation and targeted therapy for this historically under-recognized population. Anti-anginal therapy positions beta-blockers and calcium channel blockers as equivalent first-line agents, upgrades long-acting nitrates, and integrates ranolazine, ivabradine, and trimetazidine as evidence-based add-on options. Antiplatelet guidance emphasizes individualized dual antiplatelet therapy duration after percutaneous coronary intervention (PCI), early de-escalation strategies, and selective use of P2Y12 inhibitor monotherapy. Lipid management and cardiovascular risk reduction options are now expanded and revascularization recommendations are restructured. Collectively, these updates strengthen the delivery of contemporary, evidence-based, and patient-centered CCS care and provide a clear framework for implementation across diverse healthcare settings.

1. Introduction

A therosclerotic cardiovascular disease (ASCVD), including chronic coronary syndromes (CCS), remains a leading cause of morbidity and mortality worldwide and continue to impose a substantial clinical and economic burden in Saudi Arabia [1,2]. In recognition of this, the Saudi Heart Association (SHA) released its Guidelines on Best Practices in the Management of Chronic Coronary Syndromes in 2022 [3], providing comprehensive, evidence-based recommendations tailored to local practice patterns, resource availability, and population characteristics.

Since the publication of the 2022 guidelines, important advances have occurred across multiple domains relevant to the diagnosis and management of CCS. These include refinement of pathophysiological concepts underpinning CCS [4], maturation of evidence supporting contemporary diagnostic strategies, and the publication of several pivotal clinical trials informing pharmacological and interventional management. In parallel, evolving therapeutic landscapes, particularly in lipid lowering, antithrombotic therapy, cardiometabolic risk modification, and inflammation-targeted strategies, have necessitated reassessment of existing recommendations to ensure continued clinical relevance and scientific accuracy.

Accordingly, the SHA convened an expert panel to conduct a focused update of the CCS guidelines. The purpose of this update is not to replace the 2022 document, but rather to selectively revise, clarify, and expand key recommendations where new evidence has emerged or where updates were required to reflect current best practice, drug availability, and healthcare delivery considerations within Saudi Arabia. Areas without substantive new evidence remain unchanged, and readers are referred to the original 2022 guideline for detailed discussion of these recommendations [3].

2. Methods

2.1. Expert panel and scope of the focused update

A multidisciplinary expert panel was convened under the auspices of the SHA, comprising cardiologists with expertise in chronic coronary disease, interventional cardiology, non-invasive imaging, and cardiovascular prevention. Panel members were selected based on clinical experience, academic contributions, and familiarity with guideline development and regional practice patterns. This focused update was developed in accordance with the established methodology for SHA clinical practice guidelines and position statements, as previously described in the 2022 SHA Guidelines on the Management of Chronic Coronary Syndromes published in the Journal of the Saudi Heart Association [3].

The aim of this focused updated was to selectively revise and clarify recommendations from the 2022 SHA Guidelines on the Management of Chronic Coronary Syndromes [3]. This document represents a focused update rather than a de novo guideline. The update was therefore intentionally limited in scope and did not seek to comprehensively rewrite all sections of the original guideline. Instead, the expert panel systematically reviewed all sections and recommendations contained within the 2022 SHA CCS guideline and emphasis was placed on areas where new evidence had emerged, clinical practice had evolved, or additional clarification was required to enhance applicability within the Saudi healthcare setting. In some instances, topics that had received limited coverage in the original guideline, such as angina and ischemia with non-obstructive coronary arteries (ANOCA/INOCA), were expanded into dedicated sections to reflect their growing evidence base and increasing clinical relevance.

2.2. Evidence review and evidence synthesis

A structured, non-restrictive literature review was conducted to identify evidence relevant to the updated sections of the guideline. The review focused on publications informing the diagnosis, risk stratification, and management of CCS, including advances in diagnostic testing, pharmacological therapy, interventional strategies, and emerging concepts such as ANOCA/INOCA.

For recommendations identified as requiring reassessment, electronic searches were performed using PubMed as the primary database, supplemented by Embase, Scopus, and the Cochrane Library. Searches targeted randomized controlled trials, meta-analyses, systematic reviews, observational studies, and high-quality real-world evidence published since the release of the 2022 SHA CCS guidelines [3], while landmark earlier studies were also considered when necessary to provide clinical context. Relevant international (including ESC and ACC/AHA) and regional guidelines and consensus documents were reviewed to ensure recommendations are aligned with contemporary standards of care.

The evidence review followed an iterative, recommendation-based approach rather than a formal systematic review process. Evidence selection prioritized studies with clear clinical relevance, robust methodology, and applicability to routine practice. Evidence synthesis integrated published evidence with expert interpretation of its clinical significance and potential impact on existing recommendations. Particular attention was given to data relevant to local populations, Saudi healthcare system characteristics, drug availability, and implementation feasibility.

2.3. Consensus development and recommendation formulation

Draft revisions and proposed recommendations were developed through iterative expert review and discussion. The panel convened for five structured virtual meetings during which identified evidence was presented, critically appraised, contextualized, and discussed. The panel critically evaluated the strength and consistency of the available evidence, its anticipated clinical impact, and its applicability to Saudi clinical practice before considering revisions to the existing recommendations. Proposed modifications to the 2022 recommendations were deliberated by the full expert panel. Recommendations underwent iterative refinement throughout this process until consensus was achieved on their final wording. Consensus was obtained through open dialogue and moderated deliberation, with disagreements resolved through clarification of evidence and expert discussion rather than formal voting procedures.

Consistent with SHA methodological standards, recommendations were expressed using qualitative strength descriptors (recommended, should be considered, may be considered, or not recommended, as shown in Table 1). Formal grading of evidence levels was not applied. Where evidence was limited or evolving, recommendations were framed conservatively and supported by expert consensus. All studies informing recommendation updates are cited in the relevant sections.

Table 1.

Saudi Heart Association classes of recommendations.

Color	Class	Definition
	Recommended	The usefulness and efficacy of a particular treatment/procedure/action is supported by available evidence
	Should be considered	The usefulness and efficacy of a particular treatment/procedure/action is established by favorable expert opinion on conflicting evidence
	May be considered	The usefulness and efficacy of a particular treatment/procedure/action is not well established by evidence and expert opinion.
	Not recommended	A particular treatment/procedure/action is not useful nor effective and is potentially harmful based on available evidence and/or general agreement.

2.4. Review, validation, and finalization

Draft sections of the focused update were circulated to all panel members for detailed review. Feedback was incorporated to improve clarity, accuracy, and consistency with the 2022 SHA CCS guideline framework. Particular attention was paid to internal coherence, avoidance of redundancy, and clear delineation between unchanged recommendations and updated guidance.

Final approval of the focused update was obtained from all contributing experts prior to submission. This document should be read as a complement to the 2022 SHA CCS guidelines [3] and not as a standalone replacement.

3. Diagnosis

3.1. Initial evaluation

The initial evaluation of patients with suspected CCS remains largely unchanged from the SHA 2022 CCS guidelines [3] and continues to comprise basic laboratory investigations and non-invasive baseline testing, as summarized in Table 2. Readers are referred to the original guideline document for a detailed discussion of these established recommendations, which are not reiterated in this focused 2026 update.

Table 2.

Recommendations on the initial evaluation of patients with suspected CCS.

Class	Recommendation
Laboratory tests
	CBC, creatinine, estimation of glomerular filtration rate and lipid profile are recommended in all patients with suspected CCS.
	Screening for diabetes is recommended in all patients with suspected or established CCS (including HbA1c, fasting plasma glucose). In the event that findings are inconclusive (HbA1c, fasting plasma glucose), glucose tolerance test is recommended.
	Thyroid function test is recommended in case of suspicion of thyroid dysfunction.
	hs-CRP, fibrinogen and/or Lp(a) levels may be considered for patients with suspected CCS.
Non-invasive baseline tests
	A resting 12 leads ECG is recommended in all patients with chest pain or equivalent.
	A resting transthoracic echocardiogram is recommended for all patients to: (1) eliminate other causes of chest pain; (2) detect regional wall motion abnormalities suggestive of CCS; (3) assess LVEF for risk stratification; and (4) assess diastolic function.
	Chest X-ray may be considered to assess signs of HF, rule out pulmonary diseases, and other non-cardiac causes for chest pain.

Abbreviations: CBC: Complete blood count; CCS: chronic coronary syndrome; ECG: electrocardiogram; HbA1c: glycated hemoglobin; HF: heart failure; hs-CRP: high-sensitivity C-reactive protein; Lp(a): Lipoprotein(a); LVEF: left ventricular ejection fraction.

Notably, the 2026 CCS guidelines acknowledge an evolving role for biomarkers in the initial assessment of CCS. High-sensitivity C-reactive protein (hs-CRP) has been consistently shown to be a robust predictor of cardiovascular risk in patients with CCS, independent of statin therapy [5–10]. In statin-treated populations, its prognostic value for future cardiovascular events and all-cause mortality may exceed that of conventional lipid parameters, including low-density lipoprotein cholesterol (LDL-C) [11,12].

Additional inflammatory biomarkers, such as fibrinogen and lipoprotein(a) [Lp(a)], have also been independently associated with an increased risk of cardiovascular events [5,8,13–20]. Although their prognostic relevance is less well established than that of hs-CRP, measurement of fibrinogen and Lp(a) may be considered during the initial evaluation of patients with suspected CCS, where available.

Elevated inflammatory biomarkers, particularly hs-CRP, likely reflect residual inflammatory risk in patients receiving lipid-lowering therapy [11,21,22]. Identification of such risk has potential implications for downstream management, including consideration of strategies aimed at modulating residual inflammation.

3.2. Diagnostic testing (functional/anatomical)

Revised recommendations for the diagnosis of CCS using functional and anatomical testing are summarized in Table 3. The overall diagnostic approach continues to be guided by the pre-test probability (PTP) of obstructive coronary artery disease (CAD), together with relevant clinical variables, as outlined in the SHA 2022 CCS guidelines [3]. Detailed descriptions of individual diagnostic modalities, including test characteristics, indications, and limitations, are provided in the original 2022 guideline document and are not reiterated in this focused 2026 update. A summary of the performance characteristics and practical considerations of each modality is provided in Table 4.

Table 3.

Recommendations on diagnostic testing (functional/anatomical) for patients with suspected CCS.

Class	Recommendation
	It is recommended that the choice of initial diagnostic test be founded on the PTP of obstructive CAD and other patient characteristics, with consideration of test performance (contraindications), local expertise, cost, test accessibility, in addition to patient expectations and preferences.
Non-invasive anatomical assessment
	In symptomatic patients with suspected CCS and low or intermediate PTP of obstructive CAD, CCTA is recommended as an initial diagnostic test.
	In cases where diagnosis could not be established based on CCTA, or CCTA reflected CAD of uncertain functional significance, further functional and/or anatomical evaluation is recommended for confirmation of CCS diagnosis, including CT-FFR to assess lesion-specific ischemia, where available.
	CCTA is not recommended when adequate image quality cannot be ensured (e.g., extensive coronary calcification, irregular heart rate, significant obesity, inability to cooperate with breath-hold commands).
	Coronary calcium detection by CT is not an alternative to CCTA and is not recommended to diagnose obstructive CAD.
Non-invasive functional/anatomical assessment
	In symptomatic patients with suspected CCS and low PTP of obstructive CAD, exercise ECG is recommended as an initial diagnostic test in selected patients (interpretable resting assessment and able to exercise).
	Exercise ECG is not recommended for the intent of diagnosis in patients with ≥0.1 mV ST-segment depression on resting ECG or in patients receiving treatment with digitalis.
	In symptomatic patients with suspected CCS and intermediate or high PTP of obstructive CAD, non-invasive functional imaging for the assessment of myocardial ischemia (stress echocardiography, stress SPECT/PET (MPI), stress CMR) is recommended as an initial and/or follow-up diagnostic test.
Invasive functional/anatomical assessment
	Invasive coronary angiography is recommended as an initial diagnostic test for CAD in the following cases - High PTP. - Severe symptoms uncontrolled by pharmacologic therapy. - Typical angina at a low level of exercise. - High event risk* based on clinical evaluation.
	Invasive functional assessment with FFR/IFR/IMR/CFR during invasive coronary angiography should be accessible and should be used to assess intermediate coronary stenoses (40–70% stenosis) before revascularization when clinical significance of lesion is in doubt.
	CCTA may be considered as an alternative to invasive angiography if inconclusive or non-diagnostic results were obtained from another non-invasive test.

^*Survived sudden cardiac death or potentially life-threatening ventricular arrhythmias or developed symptoms and signs of heart failure.

Abbreviations: CAD: coronary artery disease; CCS: chronic coronary syndrome; CCTA: coronary computed tomography angiography; CFR: coronary flow reserve; CMR: Cardiac magnetic resonance; CT: computed tomography; ECG: electrocardiogram; FFR: Fractional flow reserve; iFR: Instantaneous wave-free ratio; IMR: index of microcirculatory resistance; MPI: myocardial perfusion imaging; PET: Positron emission tomography; PTP: pre-test probability; SPECT: Single-photon emission computed tomography.

Table 4.

Overview of non-invasive imaging modalities for the diagnosis of CCS.

Modality	Typical use	Advantages	Limitations	High-risk features
CCTA	Preferred initial test for low or intermediate PTP Assessment of obstructive and non-obstructive atherosclerosis. Graft evaluation post-CABG patients Performed with iodinated contrast, radiation and premedication for heart rate control and adequate vasodilation	High accuracy for exclusion and visualization of obstructive CAD. Allows atherosclerotic plaque visualization. Rapid test	Limited functional assessment Image artifacts (“bloom artifact”) with severe coronary calcium Poor image quality in high heart rate and irregular rhythm Exposure to radiation Not suitable for patients with contraindication to iodinated contrast (severe renal impairment)	Left main stenosis ≥50% 3 vessel disease 2 vessel disease including proximal LAD
Stress echocardiography	Assessment of LVEF and volumes, wall motion abnormalities, myocardial perfusion, and/or coronary velocity flow reserve. Performed with exercise or pharmacologic stress (dobutamine, vasodilators)	High diagnostic accuracy and prognostic value Rapid test Widely available Low cost No exposure to radiation	Poor image quality (echo windows) in case of large body habitus and significant pulmonary disease Operator-dependent Not suitable for patients with contraindication to stressor	Post-stress new regional wall abnormalities Post-stress global LV impairment Diastolic dysfunction Post-stress LV cavity dilatation Mitral regurgitation
Stress SPECT (MPI)	Assessment of ischemia, LVEF and volumes, and viability Performed with radioactive tracer and exercise or pharmacologic stress (vasodilator)	Comparable performance between exercise and pharmacologic stress Widely available	Image quality affected by soft tissue attenuation and motion artifacts Possible underestimation of ischemia (reliance on relative vs absolute perfusion) Exposure to radiation Not suitable for patients with contraindication to stressor	Large reversible perfusion defect Multiple perfusion defects SSS>13 SDS ≥6 Post-stress transient ischemic dilation Post-stress right ventricle uptake Post-stress lung uptake Abnormal post-stress LVEF
Stress PET (MPI)	Assessment of ischemia, LVEF, blood flow and viability Performed with radioactive tracer and pharmacologic stress (vasodilator)	High diagnostic accuracy Superior to SPECT, particularly for significant stenosis (>50%), multivessel disease, and patients with large BMI. Allows measurement of coronary calcium and global myocardial blood flow reserve (Global MBFR).	Exposure to radiation Not suitable for patients with contraindication to stressor Limited availability Cost
Stress CMR	Assessment of LVEF and volumes, ischemia, blood flow, wall motion abnormalities, and myocardial infarction Performed with pharmacologic stress (vasodilator or dobutamine)	High diagnostic accuracy High spatial resolution No exposure to radiation	Not suitable for patients with non- CMR-compatible metal devices, claustrophobia or very large body habitus Limited availability Cost	SDS ≥7 Presence of late gadolinium enhancement Reversible perfusion defects

Abbreviations: CAD: coronary artery disease; CCS: chronic coronary syndrome; CCTA: coronary computed tomography angiography; CMR: Cardiac magnetic resonance; ECG: electrocardiogram; FFR: Fractional flow reserve; iFR: Instantaneous wave-free ratio; LV: left ventricle; LVAD: Left ventricular assist device; LVEF: Left ventricular ejection fraction; MPI: myocardial perfusion imaging; PET: Positron emission tomography; PTP: pre-test probability; SDS: Summed Difference Score; SPECT: Single-photon emission computed tomography; SSS: Summed Stress Score.

Figure 1 presents a risk assessment framework for patients with suspected CCS based on PTP and clinical probability modifiers. In addition to clinical factors, the choice of diagnostic testing should take into account test performance, cost, and local availability, as each modality has a distinct role and inherent advantages and limitations in the evaluation of CCS (Table 4). Patient preferences and expectations should also be considered, in keeping with the principles of shared decision-making.

Fig. 1.

Risk assessment strategy for patients with suspected CCS based on pre-test probability and clinical probability modifiers. Abbreviations: CAC: Coronary artery calcium; CAD: coronary artery disease; CCS: chronic coronary syndrome; CT: computed tomography; CVD: Cardiovascular disease; ECG: electrocardiogram; LV: left ventricle.

In this 2026 focused update, PTP of CAD is more explicitly integrated into the diagnostic pathway to optimize the use of both non-invasive and invasive testing for diagnostic confirmation in patients with suspected CCS, as illustrated in Fig. 2. Coronary computed tomography angiography (CCTA) remains the preferred initial diagnostic modality for patients with suspected CCS and a low to intermediate PTP of CAD. Evidence from established and emerging studies supports diagnostic performance comparable to invasive coronary angiography (ICA), with fewer procedure-related complications, better tolerability, and favorable effects on clinical outcomes [23–27]. In cases where diagnosis could not be established based on CCTA, or CCTA reflected CAD of uncertain functional significance, further evaluation becomes necessary. Recent evidence supports the incremental role of computed tomography-derived fractional flow reserve (CT-FFR) in this setting, providing lesion-specific physiological assessment that improves diagnostic accuracy and specificity compared with CCTA alone, with close agreement to invasive fractional flow reserve (FFR) [28–32].

Fig. 2.

Diagnostic algorithm for patients with suspected CCS. *CBC, renal function, lipid profile, diabetes screening. † Applicable in case resting assessment is interpretable and patient is able to exercise, particularly when diagnostic or therapeutic strategy will be affected. ‡ Stress echocardiography, Stress SPECT/PET (MPI), or Stress CMR. Abbreviations: CAD: coronary artery disease; CBC: complete blood count; CCS: chronic coronary syndrome; CCTA: coronary computed tomography angiography; CMR: Cardiac magnetic resonance; ECG: electrocardiogram; hs-CRP: high-sensitivity C-reactive protein; Lp(a): Lipoprotein(a); MPI: myocardial perfusion imaging; PET: Positron emission tomography; SPECT: Single-photon emission computed tomography.

For selected patients with a low PTP of CAD who have an interpretable resting electrocardiography (ECG) and are able to exercise adequately, exercise ECG may be considered as an initial diagnostic test, consistent with the 2022 CCS guidelines [3]. However, exercise ECG is no longer recommended as an alternative to non-invasive imaging when the latter is unavailable or for the assessment of ischemia or symptom control in patients receiving anti-anginal therapy, owing to its lower diagnostic accuracy, limited prognostic value and higher risk of adverse events compared to CCTA [23,33–36].

Non-invasive functional stress imaging modalities, including stress echocardiography, stress single-photon emission computed tomography (SPECT) or positron emission tomography (PET) myocardial perfusion imaging, and stress cardiovascular magnetic resonance (CMR), demonstrate satisfactory diagnostic accuracy and clinical outcomes comparable to CCTA. These modalities are therefore recommended for the assessment of myocardial ischemia in symptomatic patients with suspected CCS and an intermediate to high PTP of obstructive CAD [36–55]. However, it is important to note that certain modalities, particularly PET, have limited availability across the Kingdom and may be associated with substantial costs, potentially restricting their widespread use in routine clinical practice. Accordingly, the selection of a functional imaging modality should be individualized, taking into account local availability, cost considerations, and the specific clinical scenario to ensure optimal diagnostic yield and efficient resource utilization.

ICA is reserved for patients with a high PTP of obstructive CAD or for those with additional indications for invasive assessment. These include severe or refractory symptoms despite optimal medical therapy, typical angina at a low level of exertion, or a high estimated event risk based on clinical evaluation [56–59]. When ICA is performed, invasive functional assessment using FFR, instantaneous wave-free ratio (iFR), index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) should be available and considered. These techniques improve diagnostic precision and inform risk stratification and clinical outcomes [60–68]. Routine use of FFR for all lesions has not been shown to improve outcomes compared with angiography-guided management alone, but it remains particularly valuable for the assessment of angiographically intermediate coronary stenoses [69,70].

Figure 3 presents a diagnostic algorithm for patients with established CCS presenting with chest pain. This approach is largely aligned with the diagnostic principles applied to patients with suspected CCS.

Fig. 3.

Diagnostic algorithm for patients with established CCS presenting with chest pain. * High risk features or previous revascularization. † Exercise ECG is associated with a higher false-negative rate and lower diagnostic accuracy (sensitivity and specificity) relative to imaging modalities, limiting its reliability. Abbreviations: CCS: chronic coronary syndrome; CCTA: coronary computed tomography angiography; CMR: Cardiac magnetic resonance; ECG: electrocardiogram; GDMT: guideline-directed medical therapy; MPI: myocardial perfusion imaging; PET: Positron emission tomography; SPECT: Single-photon emission computed tomography.

3.3. ANOCA/INOCA

Multiple studies have shown that the majority of unselected patients and approximately 40% of patients referred for angina assessment based on suspected symptoms do not have obstructive CAD, a condition referred to as angina with non-obstructive coronary arteries (ANOCA) [24,71,72]. This condition occurs more frequently in females, accounting for approximately 50–70% of cases, compared with 30–50% in males [72–74].

Recognizing the clinical relevance of angina and ischemia in the absence of obstructive CAD, the expert panel emphasized the need for improved identification and management of ANOCA and ischemia with non-obstructive coronary arteries (INOCA). Accordingly, the limited reference to this condition in the 2022 CCS guideline diagnostic section has been expanded into a dedicated section in this focused update, incorporating updated recommendations (Table 5) and a structured diagnostic and therapeutic algorithm (Fig. 4).

Table 5.

Recommendations on diagnosis and management of ANOCA/INOCA.

Class	Recommendation
Diagnosis
	Invasive coronary function testing is recommended for patients with suspected ANOCA/INOCA (coronary microvascular dysfunction/vasospastic angina with no apparent or non-obstructive CAD) to determine pathophysiological endotypes and guide the choice of antianginal therapy to relieve symptoms and improve quality of life.
	Non-invasive imaging (PET, CMR, stress echocardiography, perfusion CCTA) with myocardial blood flow reserve measurement (where applicable) should be considered for patients with suspected ANOCA/INOCA (coronary microvascular dysfunction/vasospastic angina with no apparent or non-obstructive CAD) to determine pathophysiological endotypes and guide the choice of antianginal therapy to relieve symptoms and improve quality of life.
Management
	Lifestyle management and risk factor modification is recommended for patients with suspected or confirmed ANOCA/INOCA.
	Initiation of endotype-based anti-anginal/anti-ischemic therapy is recommended for patients with confirmed ANOCA/INOCA to relieve symptoms and improve quality of life.

Abbreviations: ANOCA: Angina with non-obstructive coronary arteries; CAD: coronary artery disease; CCTA: Cardiac computed tomography angiography; CMR: cardiac magnetic resonance; INOCA: ischemia with non-obstructive coronary arteries; PET: positron emission tomography.

Fig. 4.

Algorithm for the diagnosis and management of ANOCA/INOCA. Abbreviations: ACE: angiotensin-converting enzyme; ACH, acetylcholine; ANOCA, angina with no obstructive coronary artery disease; CAD, coronary artery disease; CCS, chronic coronary syndrome; CCTA, coronary computed tomography angiography; CMR, cardiac magnetic resonance; FCA, fractional flow reserve coronary angiography; INOCA, ischemia with no obstructive coronary artery disease; PET, positron emission tomography.

3.3.1. Diagnosis

As defined in the 2022 CCS guideline, ANOCA refers to patients with angina and normal or near-normal coronary arteries, while INOCA describes objective myocardial ischemia attributable to coronary vascular dysfunction in the absence of obstructive CAD [3]. ANOCA/INOCA encompasses two principal pathophysiological endotypes: 1) Microvascular angina, caused by coronary microvascular dysfunction; and 2) Epicardial vasospastic angina, resulting from dynamic epicardial coronary obstruction due to vasomotor abnormalities [75]. The coexistence of microvascular dysfunction and epicardial vasospasm is increasingly recognized and constitutes a third, mixed endotype that includes both structural and functional microvascular abnormalities [75].

As outlined in the diagnostic algorithm (Fig. 4), patients with suspected ANOCA/INOCA should undergo a systematic diagnostic evaluation (preferably in expert centers) to confirm the diagnosis and define the underlying endotype, which subsequently guides targeted therapy (see Section 3.3.2). This approach is particularly important given the heterogeneity of clinical presentation. Although symptoms may resemble those of obstructive CAD, patients with ANOCA/INOCA more frequently present with non-classical or atypical manifestations, leading to underdiagnosis and delayed treatment. Sex-specific and age-related differences are well documented, with women and younger patients more likely to exhibit atypical angina or ischemic symptoms [71,76–78].

Invasive coronary function testing is recommended for patients with suspected ANOCA/INOCA, particularly those with persistent angina or ischemia in the absence of obstructive CAD. This comprehensive assessment enables evaluation of coronary physiology through measurements of intracoronary pressure and flow, microvascular resistance, and vasomotor function at both epicardial and microvascular levels. Provocative testing allows assessment of endothelial-dependent and -independent vasodilation, as well as the identification of epicardial and microvascular spasm.

Invasive diagnostic modalities, which include coronary angiography combined with functional coronary assessment (FCA) using guidewire-based measurements, adenosine testing, and acetylcholine (ACh) provocation, have been shown to be safe and effective for stratifying patients into distinct endotypes. Importantly, this approach has been associated with improved clinical outcomes through the implementation of tailored, endotype-specific therapies [79–82].

Overall, Invasive coronary function testing remains the gold standard for comprehensive ANOCA/INOCA assessment, as non-invasive functional tests may fail to detect coronary microvascular abnormalities [83,84]. Nevertheless, non-invasive imaging modalities, including PET, CMR, stress echocardiography, and perfusion CCTA, can provide valuable information on coronary flow and microvascular function and may support diagnosis when invasive testing is unavailable or contraindicated [85–95].

3.3.2. Treatment

Management of ANOCA/INOCA requires a patient-centered, multifaceted approach. As with other chronic coronary syndromes, lifestyle modification and aggressive cardiovascular risk factor management are recommended for all patients with suspected or confirmed ANOCA/INOCA (see section 4) [96,97].

Once the diagnosis is established, targeted treatment of the identified endotype is strongly recommended. The CorMicA trial demonstrated that stratified medical therapy based on invasive coronary function testing significantly improves angina-related health status in patients with nonobstructive CAD [82]. Endotype-specific therapeutic options are summarized in Fig. 4.

Although randomized trial data remain limited, available evidence supports tailored pharmacological strategies. Calcium channel blockers are the first-line therapy for vasospastic angina and may also be beneficial in microvascular angina, with multiple randomized studies demonstrating reductions in angina frequency and improvements in prognosis [98–103]. Long-acting nitrates may be added in patients with vasospastic angina to further reduce angina burden [100,104,105].

Nicorandil and ranolazine, represent alternative antianginal therapies than can be considered in both microvascular and vasospastic endotypes [106–108]. Beta-blockers are effective in improving symptoms and functional status in patients with microvascular angina [98,109–111], as are ivabradine [112] and trimetazidine [113]. However, beta-blockers and ivabradine should be avoided in vasospastic angina owing to the risk of exacerbating coronary spasm or lack of demonstrated efficacy. The ongoing EXAMINE–CAD trial (NCT05294887) is expected to provide further evidence on the comparative efficacy of beta-blockers and calcium channel blockers in ANOCA.

Angiotensin-converting enzyme (ACE) inhibitors may improve symptoms and endothelial function in patients with microvascular angina [114–116] and may confer additional benefit when combined with statin therapy [117,118]. However, the recent WARRIOR trial did not demonstrate a reduction in 5-year major adverse cardiovascular outcomes with intensive medical therapy (high-dose statins plus ACE inhibitor/angiotensin II receptor blockers [ARB]) compared with usual care in patients with non-obstructive coronary arteries [119].

Novel approaches continue to be explored. The PRIZE trial evaluated the endothelin A receptor antagonist zibotentan in microvascular angina but failed to demonstrate clinical benefit with short-term therapy and was associated with a high incidence of adverse effects [120]. Novel device- and cell-based therapies targeting the underlying pathology of ANOCA/INOCA are also under investigation. The coronary sinus reducer, designed to improve subendocardial perfusion via coronary sinus flow modulation, has demonstrated symptomatic benefit and improved quality of life in patients with refractory angina [121–123]. Similarly, CD34⁺ cell therapy has been associated with improvements in angina burden and functional capacity in refractory angina populations [124,125].

Evidence supporting the use of these therapies specifically in patients with ANOCA/INOCA remains limited. Early mechanistic and interventional studies suggest potential benefit in coronary microvascular dysfunction, including improvements in coronary flow reserve, microvascular/endothelial dysfunction, and symptoms with CD34⁺ cell therapy [126,127], and coronary sinus reducer [128,129]. However, data are derived from small, highly selected cohorts and current evidence is insufficient to support routine use. As a result, these approaches should be considered investigational pending results from larger, adequately powered trials.

In conclusion, there remains a paucity of disease-specific therapies supported by large randomized trials despite growing recognition of ANOCA/INOCA. Future research should focus on mechanistic, endotype-driven interventions, longer-term outcome studies, and sex-specific treatment strategies to address this substantial unmet clinical need.

4. CCS management: non-pharmacological therapy

Non-pharmacological management in the 2026 focused update remain largely aligned with the SHA 2022 CCS guidelines, which provide a detailed discussion of the recommended approach [3]. Recommendations continue to emphasize smoking cessation, adoption of a healthy diet, regular physical activity, maintenance of a healthy body weight, and psychosocial assessment for patients with CCS (Table 6).

Table 6.

Recommendations on non-pharmacological therapy for CCS.

Class	Recommendation
	Referral to smoking cessation clinic is recommended.
	It is recommended to advise patients to follow the Mediterranean diet and ensure high intake of fruits and legumes.
	Reduction in sedentary periods and sustained aerobic physical activity (≥150–300 minutes per week of moderate intensity or ≥75–150 minutes per week of vigorous intensity) is recommended.
	It is recommended to advise patients to achieve and/or maintain healthy weight, defined as body mass index of 18.5 to 24.9 kg/m2, and waist circumference less than 102 cm (40 inches) in men and less than 88 cm (35 inches) in women.
	Psychosocial assessment is recommended to direct psychological interventions.
	Annual influenza vaccination is recommended.

For physical activity, the 2026 update adds greater specificity regarding the recommended duration and intensity of exercise, in order to improve clarity and facilitate implementation in clinical practice [130–138]. The recommendation for annual influenza vaccination has been upgraded to better reflect robust clinical evidence demonstrating a reduction in major cardiovascular events and cardiovascular-related hospitalizations [139–141]. This update highlights influenza vaccination as an important adjunctive strategy for secondary prevention in patients with CCS.

5. CCS management: pharmacological therapy

The 2026 focused update provides updated recommendations on pharmacological therapy for symptom control and event prevention, as summarized in Tables 7 and 8. Key changes and new evidence are discussed in the sections below.

Table 7.

Recommendations on anti-anginal therapy for symptom control.

Class	Recommendation
	Beta-blockers and/or CCBs are indicated to control symptoms.
	Combination of a beta-blocker with a dihydropyridine-CCB should be considered if angina symptoms are uncontrolled
	Long-acting nitrates should be considered when initial therapy with a beta-blocker and/or a CCB is contraindicated, is not well tolerated, or not sufficient to control angina symptoms. Consider a nitrate-free or nitrate-low interval of ~10–14 h to avoid tolerance.
	Ranolazine should be considered when initial therapy with a beta-blocker and/or a CCB is contraindicated, is not well tolerated, or not sufficient to control angina symptoms.
	Short-acting nitrates are recommended for immediate alleviation of angina.
	Ivabradine may be considered as add-on to antianginal therapy in select patients with elevated heart rate (≥70 bpm) and inadequate symptom control on maximally-tolerated dose of a beta blocker.
	Trimetazidine may be considered as add-on therapy in patients with inadequate symptom control with maximally-tolerated dose of a beta-blocker and/or a CCB.

Abbreviations: CCB: Calcium channel blocker.

Table 8.

Recommendations on pharmacological therapies for event prevention in CCS.

Class	Recommendation
Antiplatelet therapy for CCS patients with no indication for OAC
	Aspirin 75–100 mg o.d. is recommended in patients with documented CCS.
	Clopidogrel 75 mg o.d. is recommended as an alternative to aspirin.
	Ticagrelor 90mg b.i.d. may be considered as an alternative to clopidogrel monotherapy or DAPT.
	Ticagrelor 60 mg b.i.d. should be considered in combination with aspirin for patients with prior myocardial infarction who have completed the standard duration of dual antiplatelet therapy and remain at high thrombotic risk without a high bleeding risk profile.
Antiplatelet therapy for CCS patients undergoing PCI with no indication for OAC
	For patients with CCS undergoing PCI with no indication for OAC, the duration and choice of antiplatelet therapy should be made based on bleeding risk and clinical variables.
	For patients with CCS undergoing PCI with no indication for OAC without high bleeding risk or high ischemic risk, the default recommended approach is initiation of DAPT (aspirin + clopidogrel 75 mg) for up to 6 months, followed by de-escalation to lifelong single antiplatelet therapy with a P2Y12 inhibitor (clopidogrel 75 mg o.d., ticagrelor 90mg b.i.d. or prasugrel 10mg o.d.).
	For patients with CCS undergoing PCI with no indication for OAC and high ischemic risk, DAPT (aspirin + clopidogrel 75 mg or alternative P2Y12 inhibitor*) duration is recommended for up to 12 months, followed by de-escalation to lifelong single antiplatelet therapy with a P2Y12 inhibitor (clopidogrel 75 mg o.d., ticagrelor 90mg b.i.d. or prasugrel 10mg o.d.).
	For patients with CCS undergoing PCI with no indication for OAC and high bleeding risk, DAPT (aspirin + clopidogrel 75 mg or alternative P2Y12 inhibitor*) duration is recommended for up to 3 months, followed by de-escalation to lifelong single antiplatelet therapy with a P2Y12 inhibitor (clopidogrel 75 mg o.d., ticagrelor 90mg b.i.d. or prasugrel 10mg o.d.).
	Lifelong P2Y12 inhibitor monotherapy (clopidogrel 75 mg o.d., ticagrelor 90mg b.i.d. or prasugrel 10mg o.d.) may be considered as an alternative to long-term aspirin in patients with prior MI or remote PCI.
Antiplatelet therapy for CCS patients with indication for OAC
	DOAC is recommended in preference to a Vitamin K antagonist in eligible patients with atrial fibrillation.
	The DOAC rivaroxaban 2.5mg twice daily may be considered in patients with CCS and polyvascular disease
Proton pump inhibitors
	Concomitant use of a proton pump inhibitor is recommended in patients with high risk of bleeding receiving aspirin monotherapy, DAPT, or oral anticoagulant monotherapy.
	Administration of a proton pump inhibitor is generally not recommended in the absence of gastrointestinal indications.
Lipid-lowering therapy
	Statins are recommended in all patients with CCS.
	Combination of statin with ezetimibe is recommended if treatment goal is not achieved with statins.
	Combination of statin with a PCSK9-targeted therapy* (±ezetimibe) is recommended in high-risk population who do not achieve LDL-C treatment goals.
	The addition of icosapent ethyl should be considered for statin-treated CCS patients with persistently elevated triglycerides (135–499 mg/dL) and controlled LDL-C (< 100 mg/dl) to reduce residual cardiovascular risk.
	The addition of EPA+DHA may be considered for statin-treated CCS patients with persistently elevated triglycerides (135–499 mg/dL) and controlled LDL-C (< 100 mg/dl) to reduce residual cardiovascular risk.
	The addition of a fibrate may be considered in combination with statins in CCS patients with persistently elevated triglycerides (>200 mg/dL) and controlled LDL-C (< 100 mg/dl) to reduce residual cardiovascular risk.
Renin-Angiotensin-Aldosterone Blocker Therapy
	ACE inhibitors (or ARBs) are recommended if a patient has LV systolic dysfunction, hypertension, diabetes, or chronic kidney disease.
SGLT 2 inhibitors and GLP-1 receptor agonists
	In patients with CCS and type 2 diabetes, SGLT2 inhibitors and GLP-1 receptor agonists with proven cardiovascular benefit are recommended for event prevention.
	In patients with CCS without type 2 diabetes who are overweight or obese, the GLP-1 receptor agonist semaglutide should be considered for event prevention.
Hormone replacement therapy
	Hormone replacement therapy is not recommended.

^*PCSK9-targeted therapy includes both PCSK9 inhibitors evolocumab and alirocumab, as well as siRNA inclisiran.

Abbreviations: ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CCS: chronic coronary syndrome; DAPT: dual antiplatelet therapy; DOAC: direct oral anticoagulant; GLP-1: glucagon-like peptide-1; LDL-C: low-density lipid cholesterol; LV: left ventricle; MI: myocardial infarction; OAC: oral anticoagulation; PCI: percutaneous coronary intervention; PCSK9: Proprotein convertase subtilisin/kexin type 9; SGLT2: Sodium—glucose cotransporter 2.

No changes have been introduced regarding the use of proton pump inhibitors, renin–angiotensin– aldosterone system blockade, or hormone replacement therapy. Readers are referred to the original 2022 SHA CCS guidelines for detailed discussion of these and all other unchanged recommendations [3].

5.1. Symptom control - anti-anginal therapy

Patients with CCS may require anti-anginal therapy for symptom relief. Beta-blockers and calcium channel blockers (CCBs) remain recommended as first-line therapy for the management of angina and may be used either as monotherapy or in combination (Table 7). For patients with persistent symptoms despite maximally tolerated doses of a beta-blocker and/or a CCB, second-line antianginal therapies include long-acting nitrates, ranolazine, ivabradine, and trimetazidine.

In the 2026 focused update, the recommendation for long-acting nitrates has been upgraded as it has become available for use as an add-on antianginal medication in Saudi Arabia. A new recommendation has also been added for ranolazine, supported by evidence demonstrating improvement in angina symptoms and exercise tolerance [3], and also reflecting its current registration with the Saudi Food and Drug Authority and availability in Saudi Arabia.

Additional recommendations have been introduced to provide guidance on the appropriate use of ivabradine and trimetazidine in selected patients. All anti-anginal therapy recommendations in the 2026 focused update are based on the evidence previously reviewed in the SHA 2022 CCS guidelines [3].

5.2. Event prevention – antiplatelet therapy

• Changes introduced in the 2026 Focused Update:

  1. Updated recommendations on antiplatelet therapy based on latest evidence.

5.2.1. CCS patients without an indication for OAC

As recommended in the 2022 SHA CCS guidelines, patients with CCS and no indication for oral anticoagulation (OAC) should receive aspirin as first-line antiplatelet therapy, with clopidogrel as an alternative in cases of aspirin intolerance (Table 8).

Emerging evidence from randomized clinical trials and meta-analyses suggests that ticagrelor monotherapy (90 mg twice daily) may be considered as an alternative to clopidogrel monotherapy or dual antiplatelet therapy (DAPT) in selected CCS patients, based on demonstrated non-inferiority (but not superiority) compared with conventional strategies [142–149]. Otherwise, the 2026 focused update maintains the previous SHA recommendation for ticagrelor 60 mg twice daily in combination with aspirin in selected patients following myocardial infarction.

5.2.2. CCS patients undergoing percutaneous coronary intervention (PCI) without an indication for OAC

For patients with CCS undergoing PCI and no indication for OAC, the choice and duration of antiplatelet therapy should be individualized according to bleeding risk, ischemic risk, and other relevant clinical variables. Several landmark trials published or presented since the 2022 guidelines have informed a shift toward more personalized DAPT strategies.

The TAILORED-CHIP trial compared a tailored antiplatelet approach consisting of early escalation with DAPT (low-dose ticagrelor 60 mg twice daily plus aspirin) followed by late de-escalation at 6 months to clopidogrel monotherapy with conventional 12-month DAPT. Among high-risk patients undergoing complex PCI, the tailored strategy did not significantly reduce the incidence of net adverse clinical events at 12 months and was associated with a higher rate of clinically relevant bleeding [150]. Similarly, the PARTHENOPE trial demonstrated that personalization of DAPT duration based on individual clinical risk improved outcomes compared with a uniform 12-month DAPT strategy [151].

A meta-analysis of randomized controlled trials including 34,774 patients showed that ultra-short DAPT (≤1 month) followed by P2Y12 inhibitor monotherapy reduced adverse clinical events in patients undergoing PCI, while achieving comparable ischemic outcomes to standard-duration DAPT of at least 6 months [152]. These findings were consistent regardless of the choice of P2Y12 inhibitor (ticagrelor or clopidogrel).

The HOST-EXAM trial further demonstrated that clopidogrel monotherapy was superior to aspirin monotherapy as long-term maintenance therapy after PCI, with a lower incidence of major bleeding and a comparable risk of ischemic events [153]. This benefit was consistent across subgroups defined by bleeding risk and PCI complexity [154]. These findings align with evidence from multiple trials and meta-analyses showing that P2Y12 inhibitor monotherapy provides superior safety and at least comparable efficacy to aspirin for long-term secondary prevention [147,155,156].

Extrapolation of these findings to the Saudi population should be undertaken with caution. Higher rates of clopidogrel resistance related to prevalent CYP2C19 polymorphisms among Arab and Saudi populations may influence treatment effectiveness [157–159] In addition, the high prevalence of diabetes mellitus and younger age at presentation in Saudi patients may modify both bleeding and ischemic risk profiles. Accordingly, antiplatelet therapy should be individualized based on patient characteristics, genetic considerations where available, cost, and local accessibility.

Based on the totality of evidence and consistent with the 2022 SHA CCS guidelines [3], patients with CCS undergoing PCI, without an indication for OAC and without high bleeding or ischemic risk, should receive DAPT with aspirin plus clopidogrel (75 mg once daily) for up to 6 months, followed by de-escalation to lifelong single antiplatelet therapy with a P2Y12 inhibitor (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily). In patients at high bleeding risk, DAPT duration should not exceed 3 months. Conversely, in patients at high ischemic risk, prolonged DAPT of up to 12 months may be considered.

5.2.3. CCS patients with an indication for OAC

No major changes have been introduced compared with the 2022 SHA CCS guidelines for CCS patients with an indication for OAC, except for a new caution against the long-term use of aspirin in patients with stable CCS and high thrombotic risk following prior stenting. This recommendation is informed by the paradigm-shifting results of the AQUATIC trial, which demonstrated that, compared with OAC monotherapy, the addition of aspirin conferred no clinical benefit and was associated with a significantly increased risk of cardiovascular events, major bleeding, and death [160].

5.3. Event prevention – lipid-lowering therapy

Since the publication of the 2022 SHA CCS guidelines [3], the small interfering RNA (siRNA) inclisiran has been approved as adjunct to diet and statins for the treatment of patients with clinical ASCVD requiring additional LDL-C lowering. This is supported by the positive results of its landmark clinical trials, which demonstrated reduction in LDL-C levels by up to 60% with inclisiran [161–166]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated significant cardiovascular risk reductions [167–169], while ongoing cardiovascular outcome trials are projected to confirm similar benefits for inclisiran [170–172]. As both monoclonal antibody PCSK9 inhibitors (evolocumab, alirocumab) and siRNA-based inclisiran provide comparable, clinically meaningful reductions in LDL-C levels [172,173], PCSK9-targeted therapies are equally recommended in this focused update (Table 8). Additional details and management recommendations are provided in the SHA’s position statement on PCSK9-targeted therapies for primary and secondary prevention of cardiovascular disease (to add reference once published).

The addition of omega 3 fatty acids (docosahexaenoic acid [DHA] and/or eicosapentaenoic acid [EPA]) to conventional lipid-lowering therapy, predominately statins, has been shown to result in significant improvements across lipid parameters in patients with residual hypertriglyceridemia despite maximally tolerated statin therapy [174–180]. However, clinical outcome data on their cardiovascular benefits have been heterogenous. Earlier meta-analyses of randomized data suggested cardiovascular and mortality benefits with omega-3 therapy that extend beyond their reduction of cholesterol and triglyceride levels [179,181]. Although these findings were corroborated by more recent meta-analyses supporting significant reductions in cardiovascular mortality, revascularization, and major cardiovascular events among patients with established cardiovascular disease or those at high cardiovascular risk [182,183], more recent large randomized trials evaluating EPA + DHA formulations (including STRENGTH, ORIGIN, ASCEND, and VITAL) failed to demonstrate significant reductions in major adverse cardiovascular events despite triglyceride lowering [184–187]. Overall, current evidence indicates that EPA monotherapy is more likely to lead to meaningful reductions in cardiovascular risk or improvement of clinical outcomes than with combined EPA plus DHA formulations [181].

Icosapent ethyl is a highly purified and stable EPA ethyl ester that leads primarily to significant reductions in triglyceride levels in statin-treated patients with hypertriglyceridemia [188–190]. In the REDUCE-IT trial, statin-treated patients with controlled LDL-C (<100 mg/dL) and elevated triglycerides (typically 130–499 mg/dL) who received icosapent ethyl at a dose of 2 g twice daily experienced a 25% relative risk reduction in MACE, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or urgent hospitalization for unstable angina [188]. This benefit corresponded to a number needed to treat of 21 over a median follow-up of approximately five years to prevent one MACE, underscoring the clinically meaningful impact of icosapent ethyl in reducing residual cardiovascular risk among appropriately selected patients. A meta-analysis confirms that the reduction of triglyceride levels by icosapent ethyl translates into significant dose-dependent reductions in the risk of major cardiovascular events [191].

Accordingly, icosapent ethyl should be considered as an add-on therapy in appropriately selected, statin-treated patients with controlled LDL-C but persistent hypertriglyceridemia to further reduce residual cardiovascular risk. Combined EPA + DHA formulations may also be used, as they have not been associated with harm, although cardiovascular benefit appears unlikely.

Fibrates represent an additional class of non-statin lipid-modifying therapies that may be considered in cardiovascular risk management. Available fibrates consistently produce moderate reductions in triglyceride levels, while their effects on LDL-C lowering are modest and variable [192–194]. To date, individual randomized controlled trials evaluating fenofibrate, gemfibrozil, and pemafibrate have not demonstrated a statistically significant reduction in ASCVD outcomes [192–199]. A recent meta-analysis of 12 randomized controlled trials including 25,781 participants reported a reduction in MACE with fibrate therapy (clofibrate, gemfibrozil, bezafibrate, and pemafibrate). However, the observed benefit appeared to be driven predominantly by LDL-C reduction rather than triglyceride lowering [200]. In light of the limited and heterogeneous evidence for cardiovascular benefit, fibrates may be considered as adjunctive therapy in selected patients with adequately controlled LDL-C who have persistent hypertriglyceridemia, particularly where triglyceride reduction is a therapeutic priority.

5.4. Event prevention – SGLT 2 inhibitors and GLP-1 receptor agonists

Sodium–glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists are established glucose-lowering therapies whose clinical utility now extends well beyond glycemic control into comprehensive cardiovascular risk reduction. Robust evidence from large cardiovascular outcomes trials demonstrates that SGLT-2 inhibitors consistently reduce MACE, hospitalization for heart failure, and progression of chronic kidney disease across a broad spectrum of patients, including those with type 2 diabetes at high cardiovascular risk, established ASCVD, heart failure, and chronic kidney disease, with benefits that appear partially independent of baseline glycemic status [201,202]. Notably, reductions in heart failure–related outcomes and renal endpoints have been observed even in patients without diabetes, supporting a class effect that is not solely mediated by glucose lowering.

GLP-1 receptor agonists have similarly demonstrated cardiovascular benefit, primarily through reductions in atherosclerotic events. Multiple agents, including liraglutide, semaglutide, albiglutide, dulaglutide, and efpeglenatide, have been shown to significantly reduce MACE in patients with type 2 diabetes and either established ASCVD or multiple cardiovascular risk factors [203–209]. These benefits are thought to be mediated through a combination of weight reduction, improvements in blood pressure and lipid parameters, anti-inflammatory effects, and favorable modulation of endothelial function, rather than glycemic control alone. Importantly, the SELECT trial extended the cardiovascular benefits of GLP-1 receptor agonists beyond the diabetic population. In patients with overweight or obesity and established cardiovascular disease but without diabetes, once-weekly semaglutide resulted in significant and sustained weight loss and a meaningful reduction in major cardiovascular events compared with placebo, establishing GLP-1 receptor agonism as an effective cardiovascular risk-reduction strategy independent of diabetes status [210].

Collectively, these data support the integration of SGLT-2 inhibitors and GLP-1 receptor agonists into the management of patients with CCS as part of a comprehensive secondary prevention strategy. Treatment selection should be individualized and phenotype-driven. In patients with CCS and concomitant type 2 diabetes, heart failure, chronic kidney disease, or obesity, these agents provide incremental cardiovascular risk reduction beyond optimal medical therapy, including antiplatelet, lipid-lowering, and blood pressure–lowering treatments. In selected patients with CCS without diabetes but with overweight or obesity, GLP-1 receptor agonist therapy, particularly semaglutide, should be considered to reduce recurrent cardiovascular events.

5.5. Event prevention – anti-inflammatory therapy

Chronic inflammation is a central driver of atherosclerosis and subsequent cardiovascular events [211,212], and many patients with cardiovascular disease continue to exhibit residual inflammatory risk despite optimal lipid-lowering and antithrombotic therapy [213–216]. Several randomized controlled trials (RCTs) have demonstrated that direct targeting of inflammatory pathways can result in meaningful reductions in ASCVD events, independent of lipid lowering [11,217,218]. Although meta-analyses of randomized trials further support the clinical benefit of anti-inflammatory therapies [219,220], clinical outcomes have varied according to the inflammatory pathway targeted and the patient population studied [217,221,222], underscoring the complexity of inflammatory signaling in atherosclerosis.

Among available agents, colchicine has emerged as the most extensively studied anti-inflammatory therapy in CVD. In patients with stable coronary artery disease and in the post–myocardial infarction setting, the LoDoCo2 and COLCOT trials demonstrated that low-dose colchicine (0.5 mg once daily) significantly reduced the incidence of MACE when added to standard medical therapy [218,223]. However, these favorable findings have not been consistently replicated in more acute clinical settings. Recent trials conducted in patients with acute ischemic stroke or transient ischemic attack, including CONVINCE, CHANCE-3, and CLEAR SYNERGY, did not demonstrate comparable cardiovascular benefit [224–226]. [162]Despite the potential benefit of low-dose colchicine suggested by a meta-analysis of available evidence [227], the expert panel acknowledged the heterogeneity of trial populations, the limited data specifically in patients with CCS, and the predominance of neutral or negative results in recent acute-care trials. Consequently, colchicine is recognized as a safe, inexpensive, and potentially effective strategy for addressing residual inflammatory risk, but the panel refrained from issuing a formal recommendation for its routine use in CCS at this time due to the lack of a meaningful clinical benefit. Other targeted anti-inflammatory agents, including interleukin-1β inhibitors, interleukin-6 pathway inhibitors, and NLRP3 inflammasome modulators, are currently under investigation in ongoing clinical trials, with the aim of achieving more selective and potent suppression of vascular inflammation while minimizing off-target effects. The role of anti-inflammatory therapies in cardiovascular prevention and management is discussed in greater detail in the forthcoming SHA scientific statement [reference to be added upon publication].

5.6. Revascularization

The general principles of revascularization in CCS remain largely unchanged from the 2022 guideline; however, the section has been revised and restructured to improve clarity and coherence and is now consolidated under “General Principles of Revascularization in CCS.” Several overlapping recommendations, particularly those addressing patients with coronary anatomy suitable for either PCI or coronary artery bypass graft (CABG) and acceptable surgical risk, were removed and integrated into more specific sections to streamline the document and reduce ambiguity.

Expert review of the previous version identified substantial overlap and conceptual complexity, prompting a revision informed by available and emerging evidence (Fig. 5). Meta-analyses of randomized controlled trials confirm that CCS patients may derive some benefit compared with medical therapy alone, particularly in long-term outcomes [228,229]. However, data supporting these benefits were neither robust nor substantial, highlighting the role of medical therapy and the importance of careful patient selection to harness the full potential of revascularization.

Fig. 5.

Randomized Trial Evidence for Coronary Revascularization in Chronic Coronary Syndromes. Summary of select major randomized trials evaluating coronary revascularization versus optimal medical therapy (OMT) in patients with chronic coronary syndromes (CCS), stratified by the presence or absence of left ventricular (LV) dysfunction. The figure highlights study populations, treatment strategies, follow-up duration, and key outcomes. Although revascularization did not consistently reduce mortality compared with OMT alone, it was associated with improved clinical outcomes over long-term follow-up, particularly a reduction in spontaneous myocardial infarction. * composite of death, myocardial infarction, or urgent revascularization. † composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. ‡ composite of death from any cause or hospitalization for heart failure. Abbreviations: CABG: coronary artery bypass grafting; CCS: chronic coronary syndromes; CI: confidence interval; HR: hazard ratio; LV: left ventricular; MI: myocardial infarction; OMT: optimal medical therapy; PCI: percutaneous coronary intervention.

The updated framework provides clearer guidance for three clinically relevant patient populations beyond the general principles of revascularization: patients with three-vessel disease, revascularization as an approach to improve survival compared with medical therapy, and revascularization in the setting of left ventricular dysfunction (LVEF <35%) (Table 9).

Table 9.

Recommendations on revascularization for patients with CCS.

Class	Recommendation
General Principles of Revascularization in CCS
	Patient clinical and anatomical profile, heart team discussions and informed patient preference are all important qualifiers in the decision-making process for mode of revascularization strategy.
	Revascularization is recommended to improve symptoms in patients with significant coronary artery stenosis amenable to revascularization with the presence of limiting angina or angina equivalent on optimal medical therapy
	It is recommended to calculate the SYNTAX score (http://syntaxscore.org/) to assess the anatomical complexity of CAD.
	It is recommended to consider the feasibility of achieving complete revascularization when selecting between CABG and PCI.
	In patients undergoing PCI, intracoronary imaging (intravascular ultrasound or optical coherence tomography) should be considered to optimize stent sizing, deployment, and expansion, particularly in complex lesions (left main disease, true bifurcation lesions, long diffuse disease requiring long or overlapping stents, and heavily calcified lesions requiring lesion modification).
Revascularization in Patients with Three-Vessel Disease
	In patients with three-vessel disease and diabetes mellitus, CABG with optimal medical therapy is recommended over either PCI or optimal medical therapy alone.
	In patients with three-vessel disease, CABG is recommended over optimal medical therapy alone to improve survival, relieve symptoms, and reduce major cardiovascular events.
	In patients with three-vessel disease and low SYNTAX score, CABG or PCI are recommended.
	In patients with three-vessel disease and intermediate SYNTAX score, CABG is recommended but PCI can be considered only if it achieves similar completeness of revascularization as CABG.
	In patients with three-vessel disease and high SYNTAX score already on optimal medical therapy, CABG is recommended to improve survival, relieve symptoms, and reduce major cardiovascular events compared with either optimal medical therapy alone or PCI, irrespective of LVEF.
	Ad hoc PCI should be avoided in patients with three-vessel disease or left main disease.
Revascularization as an Approach to Improve Survival Compared with Medical Therapy
	Revascularization should be considered to improve survival in patients with CCS and concomitant: significant left main stenosis. multivessel CAD appropriate for CABG with severe left ventricular systolic dysfunction (left ventricular ejection fraction <35%). proximal LAD stenosis >50% with documented ischemia or a hemodynamically relevant lesion defined by FFR ≤0.80 or iwFR ≤0.89 or >90% stenosis by visual estimation. large areas of ischemia detected by functional testing (>10% of LV).
	Revascularization by CABG should be considered to improve survival in patients with CCS and concomitant mild to moderate left ventricular dysfunction (LVEF 35% – 50%) and multivessel CAD.
	Revascularization should be considered to improve survival in patients with CCS and multivessel CAD appropriate for either CABG or PCI, by lowering the risk of cardiovascular events such as spontaneous myocardial infarction, unplanned urgent revascularizations, or cardiac death.
Revascularization in Left Ventricular Dysfunction (EF <35%)
	In patients with LV dysfunction (EF <35%) and multivessel disease, CABG may be considered as the first revascularization strategy choice in the case of viable myocardium and acceptable surgical risk.
	In patients with LV dysfunction (EF <35%) and multivessel disease, PCI may be considered as an alternative for CABG in the case of high surgical risk.

Abbreviations: CABG: coronary artery bypass graft; CAD: coronary artery disease; CCS: chronic coronary syndrome; EF: ejection fraction; FFR: fractional flow reserve; iwFR; instantaneous wave-free ratio; LAD: left anterior descending artery; LV: left ventricle; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention; SYNTAX: Synergy Between PCI With Taxus and Cardiac Surgery score.

In parallel, intracoronary imaging–guided PCI (through intravascular ultrasound [IVUS] or optical coherence tomography [OCT]) has been extensively evaluated in randomized trials and meta-analyses, demonstrating overall improvements in procedural optimization and, in several analyses, reductions in target lesion failure and major adverse cardiovascular events. A recent network meta-analysis supported consistent procedural benefit across lesion subsets, particularly in complex PCI populations [230].

However, more recent randomized evidence has shown heterogeneous results depending on study design, population, and implementation strategy and were not included in this meta-analysis. The ILUMIEN IV trial (OCT-guided PCI) did not demonstrate a significant reduction in target vessel failure compared with angiography-guided PCI [231]. Similarly, the OPTIMAL trial and IVUS-CHIP trial reported neutral outcomes with IVUS-guided PCI in complex high-risk coronary lesions compared with angiography-guided strategies in Western populations [232,233]. In contrast, the DKCRUSH-VIII trial demonstrated improved outcomes with IVUS-guided optimization in complex bifurcation PCI in an East Asian population when a structured, protocol-driven two-stent strategy was applied [234].

Important methodological considerations have been raised regarding these trials. In several negative or neutral studies, intracoronary imaging was not consistently integrated into pre-PCI planning, and optimal imaging-derived stent optimization criteria were achieved in only approximately half of treated lesions. Procedural workflow variability, including prolonged procedural time and incomplete adherence to imaging-guided optimization protocols also potentially attenuates the expected benefit of imaging guidance. In addition, differences in lesion complexity, operator experience, and regional PCI practices may partly explain the observed heterogeneity in outcomes between Western and East Asian populations.

Against this background, intracoronary imaging is increasingly recognized as an adjunctive tool that should be considered for PCI optimization where appropriate, particularly in anatomically complex coronary disease. Complex coronary anatomy is generally considered to include left main disease, true bifurcation lesions, long diffuse disease requiring long or overlapping stents, and heavily calcified lesions requiring lesion modification techniques.

5.6.1. Three-vessel disease

Evidence supporting the role of revascularization in patients with three-vessel disease remains robust. The STICH trial demonstrated that CABG significantly reduced cardiovascular mortality compared with medical therapy alone in patients with extensive coronary artery disease and severe left ventricular systolic dysfunction (LVEF ≤35%) [235]. No new evidence has emerged to challenge this finding. Accordingly, CABG continues to be recommended to improve outcomes in CCS patients with three-vessel disease.

In patients with diabetes, long-term evidence consistently favors CABG over PCI. The FREEDOM trial and its follow-on analyses confirmed superior long-term survival with CABG compared with PCI when both strategies are combined with optimal medical therapy, irrespective of angiographic disease complexity [236–241].

Data from the SYNTAX Extended Survival study further emphasize the importance of revascularization completeness. PCI was associated with higher rates of incomplete revascularization, which translated into significantly increased all-cause mortality at 10 years. In contrast, patients achieving complete revascularization with PCI demonstrated survival outcomes comparable to those undergoing CABG [242]. Consistent with this concept, the FAME 3 trial showed that in patients with three-vessel disease, FFR-guided PCI resulted in clinical outcomes non-inferior to CABG at one year with respect to death, myocardial infarction, stroke, and repeat revascularization [243]. This non-inferiority in the composite primary outcome was confirmed at the 3- and 5-year follow-up, although myocardial infarction and repeat revascularization were significantly more common after PCI [244,245].

Collectively, these data support the consideration of PCI as an alternative to CABG in carefully selected patients with three-vessel disease and low-to-intermediate anatomical complexity, provided that a similar degree of complete revascularization can be achieved. This principle is aligned with broader evidence demonstrating comparable survival between PCI and CABG in patients with left main disease at lower SYNTAX scores, with PCI offering a less invasive option [246–248]. Optimal outcomes in three-vessel disease require careful patient selection through structured Heart Team discussion, and ad-hoc PCI in this setting is strongly discouraged.

5.6.2. Revascularization as an approach to improve survival compared with medical therapy

Since the SHA 2022 CCS guideline, new evidence has refined the role of revascularization in stable coronary artery disease. The ISCHEMIA trial showed that routine invasive therapy, whether PCI or CABG, did not significantly reduce major adverse ischemic events compared with optimal medical therapy alone in patients with moderate or severe ischemia [249]. Early revascularization carries a higher risk of procedural complications [250], but may improve long-term outcomes, particularly by reducing spontaneous myocardial infarction [249]. Notably, the greatest benefit observed in patients with high angina burden or left ventricular dysfunction [251,252].

The PREVENT trial further demonstrated that in patients with non-flow-limiting but vulnerable plaques, adding PCI to optimal medical therapy significantly reduced target vessel failure, with sustained benefit at seven years [253]. However, the absolute event reduction was modest, with a high number of procedures required per event prevented. Accordingly, revascularization, including PCI, can be considered as a strategy to improve outcomes in carefully selected patients, emphasizing the importance of individualized decision-making based on ischemic burden, ventricular function, and lesion characteristics as outlined in Table 9.

5.6.3. Revascularization in left ventricular dysfunction (EF <35%)

The initial results of the STICH trial demonstrated that CABG was not associated with a significant survival advantage over optimal medical therapy at approximately 4 years of follow-up [254]. However, extended follow-up at 10 years showed that CABG was associated with improved long-term outcomes, including reductions in all-cause and cardiovascular mortality [235,255], supporting its role as a potential first revascularization strategy in selected patients with left ventricular dysfunction (EF<35%). In light of these findings, and acknowledging the delayed emergence of benefit and patient selection considerations, the strength of the recommendation for CABG was downgraded compared with the 2022 CCS guideline version.

The REVIVED-BCIS2 trial did not demonstrate a benefit of PCI compared with optimal medical therapy alone, in improving survival, reducing heart-failure hospitalizations, improving left ventricular ejection fraction, or enhancing health-related quality of life in patients with severe left ventricular dysfunction and extensive coronary artery disease [256,257]. Importantly, the absence of benefit was observed irrespective of myocardial viability extent (259).

More recent evidence further questions the role of procedural intensification in this setting. The CHIP–BCIS3 trial evaluated routine prophylactic left ventricular unloading during high-risk PCI in patients with severe left ventricular dysfunction and complex coronary disease and did not demonstrate an improvement in major clinical outcomes, with signals toward increased adverse events in the intervention arm (260). Although not a direct comparison of PCI versus medical therapy, these findings suggest that even optimized or device-supported PCI does not necessarily translate into improved clinical outcomes in this high-risk population.

Based on these findings, the recommendation for PCI as an alternative for CABG in this patient population was downgraded.

6. Conclusion

This 2026 focused update of the Saudi Heart Association Guidelines on the Management of Chronic Coronary Syndromes provides a targeted revision of selected recommendations in response to evolving evidence and clinical practice. While the overarching principles of CCS management remain consistent with the 2022 guidelines, several important refinements have been introduced to enhance diagnostic accuracy, optimize therapeutic strategies, and support individualized, risk-based decision- making.

Key updates include greater integration of PTP into diagnostic pathways, acknowledgment of the emerging role of inflammatory and lipid-related biomarkers, and updated recommendations for non-invasive and invasive diagnostic modalities. In the management of CCS, the update reinforces the central role of lifestyle and preventive strategies, while incorporating new evidence supporting contemporary pharmacological and interventional therapies. Antithrombotic strategies have been refined to reflect growing evidence favoring personalized approaches that balance ischemic and bleeding risk, particularly following percutaneous coronary intervention. This focused update also substantially expands guidance on ANOCA and INOCA, introducing a dedicated diagnostic and management framework that emphasizes endotype-specific evaluation and tailored therapy for a patient population that has historically been underrecognized and undertreated.

These updated recommendations are intended to support clinicians across Saudi Arabia in delivering high-quality, evidence-based care for patients with CCS. Ongoing research and future trial results will undoubtedly continue to shape the management of chronic coronary disease, and periodic updates will remain essential to ensure that clinical practice evolves in step with emerging evidence.

Abbreviations list:

ACE

Angiotensin-Converting Enzyme

Ach

Acetylcholine

ANOCA

Angina With Non-Obstructive Coronary Arteries

ARB

Angiotensin II Receptor Blockers

ASCVD

Atherosclerotic Cardiovascular Disease

CABG

Coronary Artery Bypass Graft

CAD

Coronary Artery Disease

CCB

Calcium Channel Blockers

CCS

Chronic Coronary Syndromes

CCTA

Coronary Computed Tomography Angiography

CFR

Coronary Flow Reserve

CMR

Cardiovascular Magnetic Resonance

CT-FFR

Computed Tomography-Derived Fractional Flow Reserve

DAPT

Dual Antiplatelet Therapy

DHA

Docosahexaenoic Acid

ECG

Electrocardiography

EPA

Eicosapentaenoic Acid

FCA

Functional Coronary Assessment

FFR

Fractional Flow Reserve

GLP-1

Glucagon-Like Peptide-1

hs-CRP

High-Sensitivity C-Reactive Protein

ICA

Invasive Coronary Angiography

iFR

Instantaneous Wave-Free Ratio

IMR

Index Of Microcirculatory Resistance

INOCA

Ischemia With Non-Obstructive Coronary Arteries

IVUS

Intravascular Ultrasound

LDL-C

Low-Density Lipoprotein Cholesterol

Lp(a)

Lipoprotein(A)

OAC

Oral Anticoagulation

OCT

Optical Coherence Tomography

PCSK9

Proprotein Convertase Subtilisin/Kexin Type 9

PET

Positron Emission Tomography

PTP

Pre-Test Probability

RCT

Randomized Controlled Trial

SGLT2

Sodium—Glucose Cotransporter-2

SHA

Saudi Heart Association

siRNA

Small Interfering RNA

SPECT

Single-Photon Emission Computed Tomography

Appendix

https://www.j-saudi-heart.com/cgi/editor.cgi?article=1516_window=additional_files_context=jsha.

Funding Statement

The authors also thank Konoz Retaj, Saudi Arabia and Nancy Al Akkary MSc, for providing editorial and medical writing assistance for the preparation of this manuscript. This medical writing fee was funded by MENARINI Middle East & Africa FZ L.L.C., Abbott Saudi Arabia Trading LLC, and Novo Nordisk Saudi Arabia. No AI or LLM tool has been used in drafting this manuscript