Antianginal pharmacotherapy has two distinct and separable goals.²·³ The first goal is symptom control (anti-ischemic): reduce the frequency, severity, and duration of anginal episodes; improve exercise tolerance; reduce sublingual nitroglycerin (SL-NTG) consumption; and improve quality of life. This is measured by Canadian Cardiovascular Society (CCS) class, anginal diary, exercise test results (time to ST depression, time to angina), and Seattle Angina Questionnaire (SAQ) scores.⁹ The second goal is prognostic benefit (cardioprotective): reduce the risk of MI, sudden cardiac death (SCD), and cardiovascular mortality. This is served by agents with proven mortality benefit: primarily beta-blockers (post-MI), antiplatelet therapy (aspirin), statins, ACE inhibitors/ARBs (post-MI or with LV dysfunction), and revascularization in appropriate candidates.²·³ A critical distinction must be maintained: nitrates, CCBs, ranolazine, ivabradine, nicorandil, and trimetazidine reduce symptoms but have NOT been shown to reduce mortality in stable angina (with the partial exception of nicorandil's IONA data and beta-blockers post-MI).²·³ Antianginal drug selection is primarily a symptom-control and quality-of-life decision. Every stable angina patient must receive optimized cardioprotective background therapy regardless of which antianginal agents are chosen for symptom control.²·³

Heart rate: resting target 55-60 bpm; exercise HR should not exceed 75% of age-predicted maximum during normal daily activity.²·³ Blood pressure: <130/80 mmHg in CAD per 2017 ACC/AHA guidelines; avoid systolic blood pressure (SBP) <110 mmHg (compromises coronary perfusion pressure).² Rate-pressure product: resting rate-pressure product (RPP) should be reduced by ≥15-20% from baseline with effective anti-ischemic therapy; the patient should no longer reach their anginal threshold RPP during maximal daily activity, as confirmed by serial exercise testing.⁵·⁹ Symptom metrics: CCS class reduction ≥1; reduction in weekly anginal episodes ≥50% from baseline; increased exercise duration before symptom onset or ≥1 mm ST depression on ETT.⁹

Safe and beneficial agents include:²·³ beta-blockers (carvedilol, metoprolol succinate ER, bisoprolol): address both HFrEF and angina; proven mortality benefit; first-line; initiate only when euvolemic and stable. Amlodipine: safe in HFrEF (PRAISE-1); effective anti-ischemic; does not worsen mortality;⁶ ivabradine: if sinus rhythm, HR ≥70 bpm despite maximally tolerated BB; addresses both HFrEF (SHIFT) and angina; preserves contractility;⁷ ranolazine: no adverse EF effect; can be added as anti-ischemic add-on;¹·² and long-acting nitrates: safe; preload reduction beneficial in HFrEF with congestion; manage tolerance carefully. Contraindicated or to be avoided:²·³·⁸ verapamil (significant negative inotropy; may precipitate acute HF decompensation); diltiazem (similar concerns; avoid EF <40%); and nifedipine IR (reflex tachycardia harmful). Practical stepwise approach for HFrEF + angina:²·³·⁶·⁷ Step 1: optimize HFrEF therapy first (BB + ACE inhibitor/ARB or angiotensin receptor-neprilysin inhibitor (ARNI) + mineralocorticoid receptor antagonist (MRA) + SGLT2i); Step 2: ensure BB at maximally tolerated dose (targets both conditions); Step 3: angina persists → amlodipine 5-10 mg; Step 4: HR still ≥70 bpm → ivabradine 5 mg BID; Step 5: still symptomatic → ranolazine; Step 6: long-acting nitrate if congestion is also present; manage tolerance carefully.

Mandatory post-MI pharmacotherapy includes:²·³ aspirin + P2Y12 inhibitor (dual antiplatelet therapy for 12 months post-ACS); high-intensity statin; beta-blocker (indefinite; first-line anti-ischemic); ACE inhibitor or ARB (particularly if EF <40% or diabetes); and aldosterone antagonist (if EF ≤35% with HF symptoms or diabetes). For recurrent angina post-MI: optimize beta-blocker first, then add amlodipine if symptoms persist, then add ranolazine (MERLIN data in post-ACS population),³ then reassess for revascularization (in-stent restenosis, new lesion, incomplete revascularization).²·³

Use cardioselective agents (bisoprolol, metoprolol succinate, nebivolol). Beta-blockers mask tachycardia and tremor of hypoglycemia; sweating is preserved (sympathetic cholinergic, not blocked by beta-blockers). Counsel patients and increase frequency of glucose monitoring during initiation.²·³ Do NOT withhold if post-MI or in HFrEF; benefit clearly outweighs risk. Ranolazine is the PREFERRED ADD-ON in diabetes + angina:¹·² mild HbA1c reduction (~0.5% at 1000 mg BID); MERLIN-TIMI 36 showed reduced recurrent ischemia in the diabetic subgroup;³ no hypoglycemia risk. Amlodipine is metabolically neutral and safe in diabetes with or without CKD. sodium-glucose cotransporter 2 (SGLT2) inhibitors (not antianginals per se; empagliflozin, dapagliflozin) are cardioprotective in T2DM with established CVD, reducing HF hospitalization and CV death, and are now included in HFrEF guidelines regardless of diabetes status.

In COPD without significant reversibility, cardioselective agents (bisoprolol preferred) can be used at standard doses with acceptable safety.⁸ GOLD guidelines do not classify cardioselective beta-blockers as contraindicated in COPD.⁸ Monitor for worsening dyspnea and adjust if needed. Post-MI or HFrEF: benefits exceed risks in most COPD patients.⁸ In asthma with active bronchospasm, beta-blockers are relatively contraindicated; use DHP-CCB or ivabradine for HR control. When beta-blockers are contraindicated:²·³ ivabradine provides pure HR reduction with no bronchoconstrictive effect and is ideal when HR is elevated and BB cannot be used;⁶ DHP-CCB (amlodipine) is effective antianginal with no respiratory effects and is the first choice for anti-ischemic monotherapy; and non-dihydropyridine CCB is useful if HR control is also needed (check EF first; avoid in HFrEF). Short-acting beta-2 agonist inhalers (salbutamol/albuterol) cause tachycardia that worsens the anginal threshold; use minimal effective doses. Beta-blockers partially counteract bronchodilation if used concurrently; this is unavoidable in post-MI COPD; titrate carefully.

Start low, go slow: begin all agents at half the standard starting dose and uptitrate more slowly (4-week intervals rather than 2-week).²·³ Beta-blockers have reduced hepatic and renal clearance in the elderly, greater sensitivity to bradycardia and hypotension, and more symptomatic fatigue. Bisoprolol or nebivolol is preferred (once-daily; predictable kinetics).¹⁰·¹² Nitrates carry a higher orthostatic hypotension risk; ensure the patient is seated before SL-NTG; counsel family about syncope risk. Cognitive effects of hypotension in the elderly (falls, delirium) are clinically important. Amlodipine is well tolerated in the elderly but ankle edema is more prominent (compound venous insufficiency). Non-DHP CCBs carry a higher bradycardia and constipation risk; use with caution; avoid in impaired AV conduction. Ranolazine requires no dose adjustment in mild-moderate renal impairment but dizziness at initiation creates fall risk; start at 500 mg BID; it is a good option when hemodynamic agents cannot be further uptitrated.¹·² Polypharmacy requires systematic CYP3A4 interaction review for non-dihydropyridine CCBs and ranolazine at each visit. Annual deprescribing review is warranted: assess continuing need for each agent; nitrate tolerance is particularly relevant.

Chronic kidney disease alters the pharmacokinetics of multiple antianginal agents, eliminates certain agents entirely at advanced stages, and concentrates multiple interacting drugs in patients who are already on complex polypharmacy for their renal comorbidities. A systematic approach by drug class is required.²·³

Beta-blockers in chronic kidney disease: metoprolol succinate and bisoprolol are the preferred agents. Metoprolol is predominantly hepatically cleared via CYP2D6 (cytochrome P450 2D6), and its inactive metabolites that are renally excreted have no pharmacological effect; no dose adjustment is required in any stage of chronic kidney disease.²·³ Bisoprolol has a 50% hepatic and 50% renal elimination split; at eGFR below 20 mL/min/1.73m², maximum dosing should be reduced to 10 mg daily and titration slowed.²·³ Carvedilol is essentially entirely hepatically metabolized and requires no dose adjustment for renal impairment alone, though the increased baseline sympathetic activity of advanced chronic kidney disease may make it less well tolerated hemodynamically.²·³ Atenolol is substantially renally excreted (85-100% unchanged) and must be dose-adjusted at eGFR below 35 mL/min/1.73m² and avoided or dose-halved at eGFR below 15 mL/min/1.73m²; it should be discontinued and replaced by metoprolol or bisoprolol in advanced chronic kidney disease.²·³ Nebivolol requires dose reduction at eGFR below 30 mL/min/1.73m² (initiate at 2.5 mg once daily).²·³

Calcium channel blockers in chronic kidney disease: amlodipine is entirely hepatically metabolized via CYP3A4 to inactive metabolites and requires no dose adjustment in any stage of chronic kidney disease, making it the first-choice calcium channel blocker for angina in this population.²·³ It also provides the additional benefit of modest proteinuria reduction, relevant in diabetic nephropathy. Verapamil and diltiazem are also hepatically metabolized via CYP3A4 and do not require dose reduction for renal impairment per se; however, their active metabolites (norverapamil for verapamil) have reduced renal clearance in severe chronic kidney disease and may accumulate, contributing to additional HR and conduction effects; use with monitoring in eGFR below 20 mL/min/1.73m².²·³ Non-dihydropyridine calcium channel blockers also carry the additional interaction risk of raising digoxin levels, which is particularly hazardous in chronic kidney disease where digoxin itself already accumulates due to reduced renal clearance.²·³ If a patient with chronic kidney disease requires both digoxin (for rate control in atrial fibrillation or for heart failure) and a non-dihydropyridine CCB for angina, digoxin toxicity monitoring becomes mandatory.

Nitrates in chronic kidney disease: organic nitrates do not undergo significant renal elimination and require no dose adjustment in any stage of chronic kidney disease.²·³ They are safe and effective antianginals across the full spectrum of renal function, and are frequently among the first agents added to regimens where beta-blocker or calcium channel blocker titration is limited by hemodynamic concerns. The mandatory nitrate-free interval must be preserved regardless of renal status.²·³

Ranolazine in chronic kidney disease: ranolazine itself undergoes predominantly hepatic metabolism, and no dose adjustment is required for mild to moderate chronic kidney disease (eGFR 30-60 mL/min/1.73m²).¹·² However, ranolazine's metabolites, several of which retain pharmacological activity, are renally excreted and accumulate in severe chronic kidney disease (eGFR below 30 mL/min/1.73m²).¹·² The clinical consequence of metabolite accumulation is uncertain but requires caution; if ranolazine is used in severe chronic kidney disease, it should be initiated at 500 mg twice daily and QTc monitored at baseline and after four weeks. Ranolazine is generally avoided in patients on dialysis due to the unknown clearance of active metabolites by dialysis membranes.¹·²

Ivabradine in chronic kidney disease: ivabradine and its active metabolite S18982 undergo predominantly hepatic metabolism; at eGFR below 30 mL/min/1.73m², the manufacturer recommends initiating at the lowest available dose (2.5 mg twice daily) and titrating carefully, though clinical experience in severe chronic kidney disease is limited.⁶ In patients with chronic kidney disease who also have atrial fibrillation, a common combination; ivabradine is contraindicated regardless of renal function, as it has no AV nodal effect and cannot control ventricular rate in atrial fibrillation.⁶

Drug interaction priorities specific to the chronic kidney disease patient with angina: the patient with advanced chronic kidney disease and angina is frequently prescribed an ACE inhibitor or angiotensin receptor blocker (renoprotective and cardioprotective), a statin (cardiovascular risk reduction), an antiplatelet agent, and one or more antianginal drugs. The combination of verapamil or diltiazem with a statin in this patient requires particular attention: CYP3A4 (cytochrome P450 3A4) inhibition by either non-dihydropyridine CCB substantially raises simvastatin and atorvastatin plasma concentrations, and chronic kidney disease itself is an independent risk factor for statin-induced myopathy.¹¹ Rosuvastatin (not CYP3A4-dependent) or pravastatin (also not CYP3A4-dependent) are preferred statins in patients receiving non-dihydropyridine CCBs. Additionally, ranolazine inhibits P-glycoprotein and can raise digoxin levels; in a chronic kidney disease patient where digoxin is already being used at reduced doses for rate control, the addition of ranolazine requires digoxin level monitoring within two weeks.¹·²

Microvascular angina (MVA) diagnosis requires:⁹ symptoms and signs of myocardial ischemia; objective evidence of ischemia (positive stress test, stress imaging, or coronary physiological assessment); non-obstructive coronary arteries on angiography (<50% stenosis in all epicardial vessels); and demonstration of coronary microvascular dysfunction (coronary flow reserve (CFR) <2.0 on adenosine-augmented PET, CMR, or index of microcirculatory resistance >25).

MVA first-line options (ESC 2019 Class IIa):³·⁹ beta-blocker: reduces myocardial oxygen consumption (MVO2); effective for effort-triggered MVA; metoprolol or bisoprolol preferred; particularly useful when exertional pattern is dominant. CCB (amlodipine 5-10 mg): improves microvascular tone in approximately 40-50% of patients; amlodipine has the most consistent evidence; symptom improvement may not correlate with CFR improvement on functional testing.³·⁹ SL-NTG is less reliably effective in MVA than in obstructive or vasospastic angina; limited microvascular vasodilation; possible microvascular steal phenomenon; some patients report worsening with SL-NTG; warn patients.³·⁹ ACE inhibitors (ESC 2019 Class IIb):³·⁹ improve endothelial function and microvascular NO bioavailability; ramipril is most studied in MVA; particularly relevant in MVA with hypertension, diabetes, or post-menopausal women. Ranolazine (ESC 2019 Class IIb):¹·²·³ the RWISE trial of ranolazine 1000 mg BID vs. placebo in women with INOCA did not significantly reduce angina SAQ scores, though improved myocardial perfusion in subgroup analysis; reasonable add-on when BB + CCB is insufficient; improved diastolic function may contribute. Additional approaches include:³·⁹ imipramine at low tricyclic dose (reduces cardiac pain perception via neural sensitization mechanism; it is not anti-ischemic; specialist use only; QTc monitoring required); SGLT2 inhibitors (emerging data on coronary microvascular function improvement); cognitive behavioral therapy (addresses amplified pain perception in refractory cases); and estrogen therapy in post-menopausal women with MVA (individual risk-benefit assessment required; not a general recommendation).

Initial therapy commencement: review at 4-6 weeks (resting HR, BP, symptoms, anginal diary, adverse effects). After each dose change or new agent: review at 2-4 weeks. Stable on optimized therapy: 6-monthly clinic review; annual exercise testing (or imaging stress test) to objectively assess ischemic burden.²·³

All patients: resting HR (every visit); BP; 12-lead ECG (annually or with new symptoms); lipid profile, HbA1c, and renal function (annually).²·³ Beta-blockers: HR, BP, fatigue/exercise intolerance; ECG if symptomatic bradycardia or palpitations; glucose in diabetics at dose changes; never abruptly discontinue in CAD. Non-DHP CCBs (diltiazem, verapamil): HR, PR interval (ECG), signs of AV block; constipation (verapamil); digoxin level if co-prescribed; CYP3A4 drug interactions. DHP-CCBs: ankle edema at each visit; BP (orthostatic); HR (assess for reflex tachycardia); gingival hyperplasia. Nitrates: assess adherence to NFI at every visit; ask specifically about nitrate timing; omitted NFI is the most common management error; headache as a proxy for adequate absorption; document SL-NTG frequency as an angina severity marker. Ranolazine: QTc at initiation and after dose increase to 1000 mg BID; annually thereafter; CYP3A4 drug interaction review at each prescription renewal; renal and hepatic function annually; metoprolol levels/bradycardia if co-prescribed.¹·² Ivabradine: sinus rhythm confirmation at every visit (ECG if irregular pulse suspected); resting HR; phosphenes (counsel before initiation; reassure if present; reduce dose if bothersome); AF development.⁶