In a patient with chronic coronary syndrome on the maximum tolerated dose of a β‑blocker whose resting heart rate is about 70 bpm, which medication should be added?

Adding Ivabradine to Beta-Blocker Therapy in CCS

In a patient with chronic coronary syndrome on maximum-dose beta-blocker with a resting heart rate of 70 bpm, ivabradine should be added as the next antianginal agent. 1

Guideline-Based Recommendation

The 2024 ESC guidelines explicitly recommend ivabradine as add-on antianginal therapy in patients with left ventricular systolic dysfunction (LVEF <40%) and inadequate symptom control, or as part of initial treatment in properly selected patients (Class IIa, Level B). 1 However, ivabradine is NOT recommended as add-on therapy in patients with CCS, LVEF >40%, and no clinical heart failure (Class III, Level B). 1

Critical Decision Point: Left Ventricular Function

Your next step depends entirely on the patient's LVEF:

If LVEF ≤35-40% with Heart Failure Symptoms:

• Add ivabradine at 5 mg twice daily, titrating to 7.5 mg twice daily as tolerated 1
• The European Medicines Agency specifically endorses ivabradine for patients in sinus rhythm with heart rate ≥70 bpm whose symptoms are inadequately controlled with beta-blockers 1
• Ivabradine provides synergistic benefit when combined with beta-blockers, and adding ivabradine is more efficient than further uptitration of beta-blockers 1
• In heart failure patients, ivabradine reduces HF hospitalization (though not cardiovascular death) 1

If LVEF >40% without Heart Failure:

• Do NOT add ivabradine – it is contraindicated by 2024 ESC guidelines 1
• Instead, add one of the following second-line agents:

Option 1: Add a Dihydropyridine Calcium Channel Blocker (DHP-CCB)

• Combination of beta-blocker + DHP-CCB (e.g., amlodipine) is the preferred dual therapy for most patients (Class IIa, Level B) 1
• This combination is hemodynamically complementary and well-tolerated 1

Option 2: Add Ranolazine

• Ranolazine 500 mg twice daily, titrating to 1000 mg twice daily as needed (Class IIa, Level B) 1, 2
• Particularly useful if the patient has:
  • Diabetes (reduces HbA1c levels) 2
  • Bradycardia or hypotension (neutral hemodynamic profile) 1, 2
  • Microvascular angina 2
• Does not affect heart rate or blood pressure 1, 2
• Contraindicated in liver cirrhosis 2

Option 3: Add Long-Acting Nitrates

• Isosorbide mononitrate or isosorbide dinitrate (Class IIa, Level B) 1
• Avoid if:
  • Systolic BP <90 mmHg 3
  • Patient uses phosphodiesterase-5 inhibitors (sildenafil, tadalafil) – absolute contraindication 3

Option 4: Add Trimetazidine

• Modified-release trimetazidine 35 mg twice daily (Class IIa, Level B) 1, 4
• Particularly useful if the patient has:
  • Low heart rate or blood pressure (no hemodynamic effects) 4, 3
  • Diabetes (though ranolazine is preferred) 3
• Contraindicated in:
  • Parkinson's disease or movement disorders 4, 3
  • Severe renal impairment (CrCl <30 mL/min) 4, 3

Common Pitfalls to Avoid

1. Do not add ivabradine in preserved LVEF patients – the SIGNIFY trial showed potential harm in the chronic stable angina subgroup without heart failure 1

2. Do not combine ivabradine with non-dihydropyridine CCBs (verapamil or diltiazem) or strong CYP3A4 inhibitors – this is contraindicated 1

3. Ensure beta-blocker is truly at maximum tolerated dose before adding second-line therapy – only 25% of patients in ivabradine trials were on optimal beta-blocker doses 1

4. Do not use three hemodynamically active drugs simultaneously – if combining beta-blocker + CCB + third agent, choose a metabolically active drug (ranolazine or trimetazidine) rather than nitrates 4

5. Remember that antianginal drugs improve symptoms but do not reduce mortality in stable CCS – continue guideline-directed medical therapy (aspirin, statin, ACE inhibitor) for event prevention 1, 4

Practical Algorithm

Patient on max-dose beta-blocker, HR 70 bpm, persistent angina
↓
Check LVEF
↓
├─ LVEF ≤35-40% + HF symptoms → Add IVABRADINE 5 mg BID [1]
│
└─ LVEF >40% or no HF → Choose based on patient factors:
   ├─ Normal HR/BP → Add DHP-CCB (amlodipine) [1]
   ├─ Low HR/BP → Add ranolazine or trimetazidine [2,4]
   ├─ Diabetes → Add ranolazine (preferred) [2]
   └─ Microvascular angina → Add ranolazine [2]