What is the recommended management for a patient with heart failure and ischemia with non‑obstructive coronary arteries (INOCA)?

Management of Heart Failure with INOCA

For patients with heart failure and ischemia with non-obstructive coronary arteries (HF-INOCA), you should pursue invasive coronary functional testing to identify the specific endotype, then implement mechanism-based pharmacotherapy tailored to the underlying pathophysiology while simultaneously optimizing guideline-directed heart failure therapy. 1

Diagnostic Approach

Initial Assessment Based on LVEF

• If LVEF >35%: In patients with HFpEF presenting with angina or equivalent symptoms and normal/non-obstructive epicardial coronaries, PET or CMR perfusion imaging or invasive functional coronary testing should be considered (Class IIa, Level B) to detect or rule out coronary microvascular dysfunction 1

• If LVEF ≤35%: Invasive coronary angiography is recommended to evaluate for obstructive CAD amenable to revascularization for prognostic benefit 1

Invasive Coronary Functional Testing

In persistently symptomatic patients despite medical treatment with poor quality of life, invasive coronary functional testing is recommended (Class I, Level B) to identify potentially treatable endotypes 1. This represents the cornerstone of modern INOCA management and allows you to move from empirical to targeted therapy.

The testing should include:

• Guidewire-based coronary flow reserve (CFR) and/or microcirculatory resistance measurements (IMR)
• Intracoronary acetylcholine testing with ECG monitoring to assess for microvascular vasospasm 1

Mechanism-Based Pharmacotherapy

Medical therapy should be chosen based on results of invasive coronary function testing (Class IIa, Level A) 2. This is the key paradigm shift—treatment is no longer empirical but targeted to the specific endotype identified.

For All INOCA Patients (Foundational Therapy)

• Cardiovascular risk factor management: hypertension, dyslipidemia, diabetes
• Lifestyle modifications: healthy diet, exercise, stress management, weight management, smoking cessation
• Statins are recommended in all patients with chronic coronary syndrome 1

Endotype-Specific Treatment

1. Coronary Microvascular Dysfunction (CMD) with reduced CFR (≤2.5) and/or elevated IMR (≥25):

• Beta-blockers (Class IIa, Level B) 2
• Calcium channel blockers
• Ranolazine
• Trimetazidine
• Ivabradine
• ACE inhibitors are also recommended by guideline authors for CMD with reduced CFR 2

2. Endothelial Dysfunction:

• ACE inhibitors (Class IIa, Level B) for symptom control 2, 1

3. Vasospastic Angina:

• Calcium channel blockers (Class I, Level A) to control symptoms and prevent ischemia and potentially fatal complications 2, 1
• Nitrates (Class IIa, Level B) to prevent recurrent episodes
• Nicorandil
• Important caveat: Unusually high CCB doses may be needed—up to 400-960 mg/day of diltiazem for symptom relief 2. Combination of dihydropyridine and non-dihydropyridine CCB may be necessary 2

4. Overlapping Endotypes:

• Combination therapy with nitrates, calcium channel blockers, and other vasodilators may be considered (Class IIb, Level B) 1

Critical Drug Interaction Warning

Avoid combining ivabradine with diltiazem or verapamil 2—this combination is not recommended due to excessive heart rate reduction.

Heart Failure-Specific Management

All CCS patients with heart failure should be enrolled in a multidisciplinary heart failure management program (Class I, Level A) to reduce heart failure hospitalization and improve survival 1.

For HFrEF (LVEF ≤40%):

• Sacubitril/valsartan is recommended as replacement for ACE-I or ARB (Class I, Level B) to reduce heart failure hospitalization and death 1
• SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended (Class I, Level A) 1
• Diuretics are recommended for congestion (Class I, Level B) 1
• ICD is recommended if symptomatic (NYHA II-III), LVEF ≤35% despite ≥3 months optimized GDMT, and expected survival >1 year with good functional status (Class I, Level A) 1
• CRT is recommended if sinus rhythm, LVEF ≤35%, QRS ≥150 ms with LBBB morphology (Class I, Level A) 1

For HFmrEF/HFpEF:

• SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended (Class I, Level A) to reduce heart failure hospitalization or cardiovascular death 1

Clinical Algorithm

1. Confirm INOCA diagnosis: Angina/ischemia with non-obstructive coronaries on angiography
2. Assess LVEF and heart failure status
3. Pursue invasive coronary functional testing if persistently symptomatic despite initial medical therapy
4. Identify specific endotype(s): CMD, endothelial dysfunction, vasospasm, or combination
5. Initiate mechanism-targeted therapy based on functional testing results
6. Optimize guideline-directed heart failure therapy based on LVEF
7. Enroll in multidisciplinary heart failure program
8. Reassess symptoms and quality of life using validated tools (Seattle Angina Questionnaire)

Important Caveats

• Antithrombotic therapy benefits in INOCA remain uncertain 2—this is a recognized knowledge gap
• Current treatments remain largely empirical despite guideline recommendations 2, highlighting the need for invasive functional testing to guide therapy
• Non-pharmacologic treatments (neuromodulation, therapeutic angiogenesis, coronary sinus reducer) require further study 2
• The 2024 ESC guidelines represent a paradigm shift toward mechanism-based rather than empirical treatment 2

The evidence strongly supports that stratified medical therapy based on invasive coronary functional testing improves symptoms and quality of life 2, making this the preferred approach over empirical treatment in persistently symptomatic patients.