What is the initial treatment approach for patients with Ischemia with No Obstructive Coronary Artery (INOCA) disease?

Initial Treatment Approach for INOCA

All patients with INOCA require a dual-pronged approach: universal aggressive cardiovascular risk factor modification combined with mechanism-targeted antianginal therapy guided by invasive coronary function testing. 1, 2

Universal Foundation: Risk Factor Modification (For ALL Patients)

Every INOCA patient must receive intensive risk factor management regardless of the underlying mechanism 2, 3:

Lipid Management

• Initiate high-intensity statin therapy immediately targeting LDL-C reduction ≥50% from baseline AND/OR achieving LDL-C <55 mg/dL (<1.4 mmol/L) 2, 3
• Add ezetimibe if LDL targets are not achieved after 4-6 weeks of maximally tolerated statin therapy 2, 3

Antiplatelet Therapy

• Aspirin 75-100 mg daily is recommended for secondary prevention in patients with previous MI or revascularization 2, 3
• Benefits in INOCA without prior events remain uncertain 2

Blood Pressure Control

• Target systolic BP 120-130 mmHg in general population 2
• Target 130-140 mmHg if age >65 years 2

Diabetes Management

• Optimize glycemic control targeting HbA1c <7% 2

Lifestyle Modifications

• Heart-healthy diet, regular exercise, stress management, weight control, and smoking cessation are essential 1, 2, 3

Diagnostic Strategy: Identify the Mechanism FIRST

Before initiating mechanism-specific therapy, pursue invasive coronary function testing (CFT) to identify the underlying pathophysiology 1, 2:

• Class I recommendation (Level B) for invasive coronary angiography with availability of invasive functional assessment at the same time in individuals with uncertain diagnosis after non-invasive testing 1
• CFT includes assessment of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and provocative testing for coronary artery spasm 1
• Alert the performing invasive cardiologist to the need for CFT at the time of referral to ensure the patient receives a specific diagnosis 1

Mechanism-Targeted Pharmacotherapy Algorithm

Once the mechanism is identified through CFT, tailor antianginal therapy as follows 1, 2:

For Coronary Microvascular Dysfunction (CMD with reduced CFR and/or elevated IMR)

First-line therapy: Beta-blockers (Class IIa, Level B) 1, 2, 3

Additional options include:

• Calcium channel blockers 1
• Ranolazine 1, 4
• Trimetazidine 1
• Ivabradine 1

Important caveat: The combination of ivabradine with diltiazem or verapamil is NOT recommended 1

For Endothelial Dysfunction

Primary recommendation: ACE inhibitors (Class IIa, Level B) 1, 2, 3

ACE inhibitors improve symptoms in patients with ANOCA due to CMD with reduced CFR 1, 4

For Vasospastic Angina

Strongest recommendation: Calcium channel blockers (Class I, Level A) 1, 2, 3

• Combination therapy may be necessary: A dihydropyridine AND non-dihydropyridine calcium channel blocker may be required for symptom control 1
• Unusually high doses may be needed: Up to 400-960 mg per day of diltiazem may be necessary for symptom relief 1

Additional options:

• Nitrates (Class IIa, Level B) 1, 2, 3
• Nicorandil 1, 2, 3

Goals: Symptom control, prevention of ischemia, and potentially fatal complications 1

For Combination Mechanisms

Consider combination medical therapy approach (Class IIb, Level B) when multiple mechanisms coexist 1

Refer to ESC guideline Figure 9 for preferred and non-preferred combinations of antianginal drugs 1

When Initial Therapy Fails

For patients with persistent symptoms and poor quality of life despite medical therapy, pursue invasive CFT (Class I, Level B) after considering patient preferences 1, 2

Alternative non-invasive options (Class IIb, Level B) include:

• Stress PET (preferred non-invasive modality) 1
• Stress cardiac magnetic resonance imaging 1
• Transthoracic Doppler of LAD during stress echocardiography 1

Ongoing Monitoring and Multidisciplinary Care

• Periodic cardiovascular healthcare visits are necessary to reassess risk status, lifestyle modifications, adherence to targets, and development of comorbidities 2
• Enroll all eligible patients in cardiac rehabilitation, as it reduces all-cause and cardiovascular mortality while improving quality of life 2
• Multidisciplinary team involvement including cardiologists, general practitioners, nurses, dieticians, physiotherapists, psychologists, and pharmacists improves outcomes 2

Critical Pitfalls to Avoid

Do not assume INOCA is benign: Patients face significantly elevated risks of major adverse cardiovascular events compared to reference populations without ischemic heart disease 2, 3, 5

Do not rely on ambulatory ECG alone for vasospastic angina: Few patients with coronary artery spasm confirmed by provocative testing have ST elevation on ambulatory monitoring or 12-lead ECG during chest pain 1

Do not use empiric therapy without mechanism identification: Current treatments remain largely empirical when not guided by CFT, and benefits of antithrombotic therapy in INOCA remain uncertain 1, 3

Nitrates have limited evidence: Notably, nitrates did not significantly improve any outcome in systematic reviews of INOCA treatment 4