When is isosorbide mononitrate indicated for chronic stable angina patients who need long‑term prophylaxis and cannot tolerate or require additional therapy beyond beta‑blockers, calcium‑channel blockers, or ranolazine?

When to Give Isosorbide Mononitrate (ISMN)

Isosorbide mononitrate should be given as second-line therapy for chronic stable angina when beta-blockers are contraindicated or ineffective, or as add-on therapy when beta-blocker monotherapy fails to control symptoms. 1

Primary Indications

As Monotherapy (Second-Line)

• Use ISMN when beta-blockers are contraindicated (e.g., severe asthma, symptomatic bradycardia, high-degree heart block) 1
• Use ISMN when beta-blockers cause intolerable side effects that prevent adequate dosing 1
• ISMN is equally effective as calcium channel blockers in this setting, so choice depends on comorbidities and patient preference 1

As Combination Therapy (Add-On)

• Add ISMN to beta-blockers when beta-blocker monotherapy at full dose fails to control angina symptoms 1
• This combination is recommended as Class I evidence by multiple guidelines 1
• The beta-blocker must be titrated to maximum tolerated dose before adding ISMN 2

In Heart Failure Patients

• ISMN is recommended for angina relief in heart failure patients (NYHA Class II-IV) with reduced ejection fraction when beta-blockers alone are insufficient 1
• ISMN is safe in heart failure, unlike non-dihydropyridine calcium channel blockers (diltiazem, verapamil) which are contraindicated 1

Critical Dosing Requirements

Nitrate-Free Interval is Mandatory

• You must prescribe ISMN with a 10-14 hour nitrate-free interval daily to prevent tolerance 2, 3, 4
• For immediate-release ISMN: give 20 mg twice daily, 7 hours apart (e.g., 8 AM and 3 PM) 3, 4
• For extended-release ISMN: give 60-240 mg once daily in the morning 5, 4, 6
• Twice-daily dosing every 12 hours causes tolerance and should be avoided 4, 6

Formulation Selection

• Extended-release ISMN (60-240 mg once daily) is preferred over immediate-release because it maintains 12-hour efficacy without tolerance development 4, 6
• Immediate-release ISMN 20 mg twice daily (7 hours apart) is effective but requires strict timing adherence 3, 4
• ISMN is NOT for acute angina relief—it has insufficient rapid onset for aborting acute episodes 5

When NOT to Give ISMN

Contraindications

• Do not use ISMN for acute angina attacks—use sublingual nitroglycerin instead 3, 5
• Do not combine ISMN with nicorandil (both are nitrate-like agents with no additional efficacy) 1
• Avoid in patients taking phosphodiesterase-5 inhibitors (sildenafil, tadalafil) due to severe hypotension risk 1

Ineffective Scenarios

• ISMN has limited efficacy in microvascular angina because small arterioles are nitrate-resistant 1
• However, if vasospasm coexists with microvascular disease, ISMN provides benefit 1

Clinical Algorithm for ISMN Use

Step 1: Start beta-blocker and titrate to maximum tolerated dose 1

Step 2: If angina persists despite optimized beta-blocker:

• Add extended-release ISMN 60 mg once daily in the morning 3, 6
• OR add long-acting calcium channel blocker (amlodipine preferred) 1, 2

Step 3: If beta-blocker is contraindicated:

• Use ISMN as monotherapy (extended-release 60-120 mg once daily) 1
• OR use long-acting calcium channel blocker 1

Step 4: If two-drug combination fails:

• Refer for coronary revascularization rather than adding a third antianginal drug 2
• Three-drug regimens may be less effective than optimized two-drug therapy 2

Critical Pitfalls to Avoid

• Never prescribe ISMN twice daily at 12-hour intervals—this causes tolerance 4, 6
• Never use ISMN for acute symptom relief—it takes too long to work 5
• Never abruptly discontinue long-term ISMN—taper over several days to prevent rebound angina 6
• Never assume ISMN works in microvascular angina—it has minimal effect on small arterioles 1
• Always ensure aspirin and statin therapy are prescribed—these reduce mortality, unlike ISMN which only relieves symptoms 1, 2