What is the step-by-step approach for antianginal therapy?

Stepwise Antianginal Therapy Approach

Start all patients with short-acting sublingual nitroglycerin for immediate symptom relief, then initiate beta-blockers and/or calcium channel blockers as first-line therapy, optimizing doses before adding second-line agents like ranolazine, ivabradine, or long-acting nitrates. 1

Step 1: Immediate Relief for All Patients

• Prescribe sublingual nitroglycerin 0.4 mg for acute angina episodes, instructing patients to take up to 3 doses at 5-minute intervals 1, 2
• This is mandatory for every patient regardless of other therapy 3, 4
• If sublingual preparations are ineffective, consider buccal formulations 3

Step 2: First-Line Antianginal Therapy

Beta-blockers are the preferred initial agent for most patients with chronic coronary syndrome 1, 2

• Start with cardioselective beta-1 blockers: metoprolol 50-100 mg twice daily, atenolol 50-100 mg daily, or bisoprolol 10 mg once daily 2, 4
• Titrate to target heart rate of 55-60 beats per minute before adding other agents 3
• Optimize the dose fully before considering additional medications 1, 4
• Beta-blockers provide mortality benefit, particularly in post-MI patients (within 1 year) 1, 2
• Diabetes is NOT a contraindication—diabetic patients derive equal or greater benefit 2, 4

Calcium channel blockers (CCBs) are an alternative first-line option if beta-blockers are contraindicated or not tolerated 1, 3

• Dihydropyridines (amlodipine 5-10 mg daily, nifedipine long-acting) are particularly effective for vasospastic angina and can be combined with beta-blockers 3, 5
• Non-dihydropyridines (verapamil up to 480 mg/day, diltiazem up to 260 mg/day) should NOT be combined with beta-blockers in heart failure patients due to negative inotropic effects 1, 4
• Avoid immediate-release or short-acting dihydropyridines as they increase adverse cardiac events 2, 4

Step 3: Combination Therapy When Monotherapy Fails

If beta-blocker monotherapy provides insufficient symptom control, add a dihydropyridine CCB 1, 3

• This combination (beta-blocker + dihydropyridine CCB like amlodipine) is often required for adequate symptom control 3
• The combination is safe and provides additive antianginal effects 1

If CCB monotherapy is used and fails, consider adding or substituting with:

• Long-acting nitrates (with mandatory 10-12 hour nitrate-free interval to prevent tolerance) 3, 6
• Nicorandil (where available) 1, 3
• Ivabradine (if heart rate remains elevated and LVEF <40% with heart failure) 3

Step 4: Second-Line Add-On Therapy

When symptoms persist despite optimal doses of two first-line agents, add a metabolic or second-line agent 1, 3

Ranolazine is particularly useful for:

• Patients with low blood pressure or heart rate who cannot tolerate further dose increases of first-line agents 3, 7
• Microvascular angina and endothelial dysfunction 3, 7
• Can be safely combined with beta-blockers and/or CCBs 7

Trimetazidine (where available):

• Should only be used as add-on therapy after optimizing beta-blockers and/or CCBs 3
• Works through metabolic modulation without hemodynamic effects 3
• Particularly beneficial in microvascular angina and heart failure with reduced ejection fraction 3
• Do NOT use as monotherapy—it has no proven mortality benefit 3

Ivabradine:

• Consider only in patients with LVEF <40% and clinical heart failure 1
• NOT recommended as add-on therapy in patients with LVEF >40% and no heart failure 1
• Do NOT combine with non-dihydropyridine CCBs or strong CYP3A4 inhibitors 1, 4

Long-acting nitrates (isosorbide mononitrate):

• Reserve as third-line therapy due to tolerance development 1, 8
• Require a 10-12 hour nitrate-free interval to maintain efficacy 3, 6
• All long-acting nitrates appear equally effective 8

Step 5: Revascularization

Refer for coronary angiography when symptoms remain uncontrolled on optimal doses of two antianginal drugs 3, 4

• Invasive coronary angiography with FFR/iFR is recommended for high-risk patients to refine risk stratification and improve outcomes 1
• PCI is effective for anatomically suitable lesions when medical therapy fails 4
• CABG improves survival in left main disease, three-vessel disease, or two-vessel disease including proximal LAD 4, 8

Critical Pitfalls to Avoid

• Never abruptly discontinue beta-blockers in coronary artery disease—taper over 1-2 weeks to avoid severe angina exacerbation, MI, or ventricular arrhythmias 3
• Avoid combining verapamil or diltiazem with beta-blockers in heart failure patients 4
• Do NOT use three antianginal drugs simultaneously as initial therapy—this may provide less symptomatic protection than two drugs 1, 4
• Avoid nitrates in hypertrophic cardiomyopathy or with phosphodiesterase inhibitors 1
• Do NOT combine ivabradine with non-dihydropyridine CCBs 1, 4
• Optimize dosing of one drug before adding another—poor adherence is a common cause of treatment failure 1, 4
• Do NOT use immediate-release short-acting dihydropyridines 2, 4

Special Considerations by Pathophysiology

Vasospastic angina:

• High-dose CCBs are most effective (verapamil up to 480 mg/day, diltiazem up to 260 mg/day, nifedipine up to 120 mg/day) 1
• Nitrates are highly effective for acute vasospasm but less successful for prevention 1
• Smoking cessation is essential 1

Microvascular angina:

• Ranolazine is particularly beneficial 3, 7
• Trimetazidine shows specific benefit in this subgroup 3

Post-MI patients:

• Beta-blockers are mandatory (proven mortality benefit within 1 year post-MI) 1, 2, 4

Heart failure with reduced ejection fraction:

• Beta-blockers remain first-line 2
• Trimetazidine can be safely added without negative hemodynamic effects 3
• Ivabradine may be considered if LVEF <40% 3, 4
• Avoid non-dihydropyridine CCBs 4