What is the treatment for ischemia due to non-obstructive coronary artery disease (NOCAD)?

Treatment of Ischemia with Non-Obstructive Coronary Artery Disease (INOCA)

All patients with INOCA should receive intensive medical management combining aggressive cardiovascular risk factor modification with mechanism-targeted antianginal therapy, guided by invasive coronary function testing when available, to improve symptoms and quality of life. 1, 2

Universal Foundation: Risk Factor Modification for All Patients

Every patient with INOCA requires aggressive cardiovascular risk factor management regardless of the underlying mechanism 1, 2:

• Statin therapy is mandatory, 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
• Aspirin 75-100 mg daily for secondary prevention in patients with previous MI or revascularization, though benefits in INOCA without prior events remain uncertain 2
• Lifestyle modifications including heart-healthy diet, regular exercise, stress management, weight control, and smoking cessation are essential 2, 3
• Blood pressure control targeting systolic BP 120-130 mmHg in general population, 130-140 mmHg if >65 years 3
• Diabetes optimization with HbA1c target <7% 3

Diagnostic Strategy: Identify the Mechanism

The 2024 ESC guidelines provide a Class I recommendation for invasive coronary function testing (CFT) availability at the time of initial coronary angiography when mechanisms are uncertain 1. This represents a paradigm shift from empirical treatment to mechanism-based therapy.

CFT should be pursued in symptomatic INOCA patients to identify underlying mechanisms including 1:

• Coronary microvascular dysfunction (CMD)
• Coronary artery spasm (epicardial or microvascular)
• Myocardial bridging
• Diffuse non-obstructive atherosclerosis

Mechanism-Targeted Pharmacotherapy

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

For Coronary Microvascular Dysfunction

• Beta-blockers are first-line therapy (Class IIa, Level B) 2
• ACE inhibitors for endothelial dysfunction-mediated symptoms (Class IIa, Level B) 2
• These medications target both symptom control and the underlying pathophysiology of CMD 4, 5

For Vasospastic Angina

• Calcium channel blockers are the strongest recommendation (Class I, Level A) 2
• Nitrates (Class IIa, Level B) as additional or alternative therapy 2
• Nicorandil is another option for vasospastic mechanisms 2

Clinical Practice Reality

Survey data reveals significant practice variation, with most US cardiologists prescribing statins (68%), aspirin (66%), calcium channel blockers (63%), and beta-blockers (55%), but nearly 70% never prescribe ACE inhibitors or ARBs despite guideline support 6. This highlights a knowledge-practice gap that clinicians should address.

Antianginal Therapy Goals

The goal is symptom resolution through tailored anti-ischemic and risk factor-modifying therapy in patients with demonstrable ischemia 1. Treatment is not angiography-based but rather symptom-based and mechanism-based 1.

For women with IHD symptoms and demonstrable ischemia in the setting of mild non-obstructive CAD (>0% but <50% stenosis), including those with significant coronary artery calcium (score ≥100), initiation of anti-ischemic regimens is reasonable 1.

Prognostic Considerations

INOCA is not a benign condition 1, 2:

• Patients face significantly elevated risks of major adverse cardiovascular events compared to reference populations without ischemic heart disease 2, 7
• INOCA is associated with recurrent chest pain presentations, impaired functional capacity, reduced quality of life, and high healthcare costs 4, 7
• Risk of developing flow-limiting CAD, myocardial infarction, heart failure with preserved ejection fraction, and death is increased 5, 7

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, 3
• Multidisciplinary involvement including cardiologists, general practitioners, nurses, dieticians, physiotherapists, psychologists, and pharmacists improves outcomes 2, 3
• Cardiac rehabilitation enrollment is recommended for all eligible patients, as it reduces all-cause and cardiovascular mortality while improving quality of life 3

Important Caveats

The 2024 ESC guidelines acknowledge that current treatments remain largely empirical despite the mechanism-based approach, and benefits of antithrombotic therapy in non-obstructive CAD remain uncertain 2. Adjunctive non-pharmacologic treatments including neuromodulation, therapeutic angiogenesis, and coronary sinus reducer therapy require further study 2.

Referral to invasive angiography with CFT capability should be considered for patients with persistent symptoms and poor quality of life despite medical therapy 1. The ISCHEMIA trial showed that early revascularization did not yield short-term survival benefit in stable CAD without left main disease or reduced LVEF, supporting initial conservative management with optimized medical therapy 1.