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

Treatment of INOCA (Ischemia with Non-Obstructive Coronary Arteries)

All patients with INOCA require invasive coronary function testing (CFT) to identify the specific mechanism causing their symptoms, followed by mechanism-targeted antianginal therapy combined with aggressive cardiovascular risk factor modification to improve symptoms and quality of life. 1

Step 1: Establish Diagnosis and Identify Mechanism

Invasive coronary function testing is the cornerstone of INOCA management and should be performed in all persistently symptomatic patients despite medical treatment who have poor quality of life. 1 This is a Class I, Level B recommendation from the 2024 ESC guidelines. 1

• CFT should be available at the time of initial coronary angiography when mechanisms of chest pain are uncertain after non-invasive testing. 1
• The testing identifies specific treatable endotypes: coronary microvascular dysfunction (CMD), vasospastic angina, myocardial bridging, diffuse atherosclerosis, or combinations thereof. 1
• For suspected vasospastic angina specifically, obtain a resting 12-lead ECG during angina episodes (Class I, Level C). 1
• If repetitive rest angina occurs with ST-segment changes that resolve with nitrates and/or calcium antagonists, invasive functional angiography is mandatory to confirm vasospasm and determine atherosclerotic disease severity (Class I, Level C). 1

Step 2: Universal Foundation Therapy for ALL Patients

Every INOCA patient requires intensive cardiovascular risk factor modification regardless of the underlying mechanism identified. 2

Lipid Management

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

Antiplatelet Therapy

• Aspirin 75-100 mg daily is recommended for patients with previous MI or revascularization. 2
• Note: Benefits in INOCA without prior cardiovascular events remain uncertain. 2

Blood Pressure Control

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

Diabetes Management

• Optimize glycemic control targeting HbA1c <7%. 2

Lifestyle Modifications

• Implement heart-healthy diet (Mediterranean, DASH, or AHA pattern). 3
• Prescribe supervised exercise-based cardiac rehabilitation programs (reduces all-cause and cardiovascular mortality). 2, 3
• Mandate smoking cessation. 2
• Achieve weight control and stress management. 2

Step 3: Mechanism-Targeted Antianginal Therapy

Treatment must be tailored based on CFT results to address the specific pathophysiologic mechanism. 1

For Coronary Microvascular Dysfunction (CMD)

• Beta-blockers are first-line therapy (Class IIa, Level B). 2
• ACE inhibitors are recommended for endothelial dysfunction-mediated symptoms (Class IIa, Level B). 2, 4, 5
• Combination of high-intensity statin PLUS maximally tolerated ACE inhibitor improves angina, stress testing, myocardial perfusion, and coronary vascular function. 5
• Ranolazine improves quality of life with moderate-quality evidence. 2, 4
• Nicorandil is an additional option for microvascular mechanisms. 2

For Vasospastic Angina

• Calcium channel blockers are the strongest recommendation (Class I, Level A) to control symptoms and prevent ischemia and potentially fatal complications. 1, 2
• Nitrates as additional or alternative therapy (Class IIa, Level B). 2
• Important caveat: Traditional nitrates did NOT significantly improve outcomes in general INOCA populations in systematic reviews, so reserve primarily for vasospastic phenotype. 4

For Mixed or Uncertain Mechanisms

• Consider combination therapy with beta-blockers, ACE inhibitors, and calcium channel blockers based on symptom response. 2
• Ranolazine provides benefit across multiple INOCA endotypes. 4

Step 4: Ongoing Monitoring and Reassessment

Periodic cardiovascular healthcare visits (e.g., annual) are mandatory to evaluate cardiovascular risk factor control and assess changes in risk status, disease status, and comorbidities. 1, 2

• Reassess symptoms, functional status, and quality of life at each visit. 2
• Monitor adherence to lifestyle modifications and medication targets. 2
• Evaluate for development of new comorbidities requiring intervention. 1

When to Escalate Care

If symptoms persist despite optimized medical therapy and poor quality of life continues, refer back for repeat invasive CFT to reassess mechanisms and refine treatment strategy (Class I, Level B). 1, 2

Critical Clinical Pitfalls to Avoid

Do Not Falsely Reassure Patients

INOCA is NOT a benign condition. Patients face significantly elevated risks of major adverse cardiovascular events, myocardial infarction, heart failure with preserved ejection fraction, and angina hospitalizations compared to reference populations without ischemic heart disease. 2, 6, 7, 8

Do Not Treat Empirically Without Mechanism Identification

The 2024 ESC guidelines represent a paradigm shift emphasizing mechanism-based treatment guided by CFT rather than empiric antianginal therapy. 1 Variable response to traditional antianginals occurs when mechanisms are not identified. 4

Do Not Undertreat Women

Women are more likely to have INOCA than men, experience more severe angina, have lower quality of life, yet are often undertreated due to false reassurance from non-obstructive angiography. 6, 7, 4

Do Not Forget Multidisciplinary Support

Involvement of cardiologists, general practitioners, nurses, dieticians, physiotherapists, psychologists, and pharmacists improves outcomes. 2 Behavioral interventions and mobile health tools improve adherence (Class I, Level A). 1

Do Not Overlook Comorbidities

In patients with deteriorating LV systolic function that cannot be attributed to reversible causes, reassess CAD status as INOCA can progress. 1 INOCA frequently coexists with heart failure with preserved ejection fraction. 6