Definition and therapeutic objectives
Antianginal therapy in chronic coronary syndrome (CCS) is directed primarily at reducing myocardial ischaemia and relieving anginal symptoms, while maintaining tolerability and adherence. Selection should be individualized according to blood pressure, heart rate, left ventricular function, comorbidities, concomitant medications, potential drug interactions, the presumed mechanism of ischaemia, patient preferences, local availability, and cost.
The pathophysiological substrate of angina may differ between patients. Myocardial ischaemia may result predominantly from obstructive epicardial coronary disease, coronary vasospasm, microvascular dysfunction, or combinations of these mechanisms. Drug selection can therefore be tailored to the suspected mechanism. No antianginal class has demonstrated consistent superiority for symptom relief in direct comparative studies, and combinations are frequently required.
The central therapeutic aim is symptom control rather than modification of long-term cardiovascular outcomes. With the important exception of beta-blockers in selected patients after acute myocardial infarction (MI), antianginal drugs have not been shown to improve long-term cardiovascular outcomes in CCS.
General strategy
For most patients, initial therapy consists of a beta-blocker and/or a calcium channel blocker (CCB). If symptoms remain inadequately controlled, treatment should be reassessed and adapted. Escalation from monotherapy to combination therapy is reasonable, although the optimal initial combination strategy remains uncertain.
A beta-blocker combined with a dihydropyridine CCB is appropriate for many patients. Long-acting nitrates or ranolazine may be added when symptoms persist or when heart rate, blood pressure, left ventricular dysfunction, contraindications, or intolerance limit escalation of beta-blocker or CCB therapy. Nicorandil and trimetazidine are additional options in selected patients.
Treatment choices should be integrated with management of precipitating factors such as anaemia, uncontrolled hypertension, thyrotoxicosis, tachyarrhythmia, uncontrolled heart failure, and concomitant valvular disease. Risk-factor modification, physical activity, dietary and lifestyle measures, high-intensity statin therapy, and appropriate antithrombotic treatment form the broader management framework.
Response to treatment should be reviewed after initiation and after each adjustment. Persistent symptoms despite appropriately titrated medical therapy should prompt consideration of coronary angiography and possible revascularization. Revascularization may be selected for symptom relief after shared decision-making, particularly when the anginal burden is high or occurs at low workloads; its role in improving death or MI outcomes is more limited and depends on the coronary anatomy and clinical setting.
Beta-blockers
Mechanism and clinical role
Beta-blockers reduce myocardial oxygen demand and provide symptomatic relief by lowering heart rate and limiting adrenergic stimulation. When prescribed for antianginal purposes in CCS, the target resting heart rate is generally 55–60 beats per minute.
Beta-blockers also have prognostic value in selected populations. Their benefit is well supported in patients with heart failure with reduced ejection fraction (HFrEF) and coronary artery disease (CAD), and after acute coronary syndromes in patients with reduced left ventricular ejection fraction (LVEF). They are also recommended in patients within one year of MI and in those with LVEF ≤50% in the cited North American guideline discussion.
By contrast, the benefit of beta-blockers in patients with CAD without previous MI and with normal LVEF is uncertain. Similarly, evidence for routine long-term beta-blocker therapy after uncomplicated acute coronary syndrome when LVEF is >40% is not definitive. Observational studies have yielded conflicting results, and the appropriate duration of therapy in patients with previous MI and preserved LVEF remains unsettled.
Practical selection
Beta-blockers may be particularly suitable when angina coexists with:
Tachycardia
Hypertension
Hyperadrenergic features
Previous MI
HFrEF
Certain tachyarrhythmias
They may be less suitable in patients with:
Low heart rate
Low blood pressure
Sick sinus syndrome
Atrioventricular conduction disease
Peripheral arterial disease, where caution is advised
Chronic obstructive pulmonary disease, particularly with non-cardioselective agents
Bronchospasm or severe reactive airway disease
Diabetes, where caution is required
In patients with diabetes, beta-blockers with vasodilatory properties, such as carvedilol, nebivolol, or labetalol, may be preferred because of their neutral or favourable metabolic effects.
Beta-blockers should not be used in the presence of sick sinus syndrome or atrioventricular conduction disorders. Combination with verapamil or diltiazem requires particular caution because of the potential for excessive bradycardia, conduction impairment, and negative inotropy.
Heart failure with reduced ejection fraction
Beta-blockers are a mainstay of treatment in patients with HFrEF and CAD because of their prognostic benefit. In HFrEF, beta-blockers are part of cornerstone disease-modifying therapy alongside an ACE inhibitor or angiotensin receptor-neprilysin inhibitor and a mineralocorticoid receptor antagonist. These therapies should be titrated toward doses used in clinical trials or the maximally tolerated doses when target doses cannot be achieved.
When beta-blockers are contraindicated in a patient with HFrEF and sinus rhythm, ivabradine may be considered, particularly when the heart rate is >70 beats per minute. Other antianginal drugs can be used for persistent symptoms, but their effects on heart-failure and coronary outcomes are neutral or insufficiently established.
Calcium channel blockers
Clinical role
CCBs are effective antianginal agents and are suitable alternatives to beta-blockers for initial therapy. They may also be used in combination with beta-blockers, especially when a dihydropyridine CCB is selected.
CCBs are broadly useful when angina coexists with hypertension, vasospasm, or conditions in which beta-blockers are poorly tolerated or contraindicated. In coronary vasospasm, CCBs are specifically considered therapeutic options. In patients with chronic obstructive pulmonary disease with bronchospasm or asthma, nifedipine, amlodipine, verapamil, or diltiazem are listed as possible choices. For Raynaud syndrome, nifedipine or amlodipine may be preferred.
Dihydropyridine calcium channel blockers
A beta-blocker combined with a dihydropyridine CCB is considered an appropriate combination for many patients. This combination can be particularly useful when hypertension accompanies angina. Amlodipine combined with carvedilol is identified as potentially effective in patients with severe hypertension and angina.
Dihydropyridine CCBs should be used cautiously in patients with low blood pressure. They may be preferable to non-dihydropyridine agents when beta-blocker therapy is required, particularly because verapamil and diltiazem produce greater heart-rate slowing and negative inotropy.
Non-dihydropyridine calcium channel blockers
Verapamil and diltiazem slow the heart rate and may be useful when beta-blockers are contraindicated or when symptoms persist despite nitrate and beta-blocker therapy. They are also considered in vasospastic angina.
However, verapamil and diltiazem are contraindicated in HFrEF because they increase heart-failure-related events. CCBs in general require caution in HFrEF, and non-dihydropyridine CCBs should be avoided in patients with moderate or severe left ventricular dysfunction, sinus bradycardia, or atrioventricular conduction disturbances unless there is a compelling and carefully monitored indication.
Short-acting nifedipine should be avoided in the acute coronary syndrome setting.
Nitrates
Short-acting nitrates
Short-acting nitrates are recommended for immediate relief of angina and may also be used prophylactically when symptoms are anticipated. Sublingual nitroglycerin or buccal spray is the initial treatment for acute ischaemic discomfort.
In acute coronary syndromes, the cited dosing regimen is:
Nitroglycerin 0.3–0.6 mg sublingually or by buccal spray
If symptoms persist, repeat at 5-minute intervals for up to three doses
If symptoms continue after three doses, intravenous nitroglycerin may be started at 5–10 µg/min
The infusion may be increased by 10 µg/min every 3–5 minutes
Titration should stop if symptoms resolve, systolic blood pressure falls below 90 mmHg, or the infusion reaches 200 µg/min
Intravenous nitrates are particularly considered for recurrent angina, uncontrolled hypertension, or signs of heart failure. They may also be used in vasospastic angina.
Short-acting nitrates should be used cautiously in heart failure because hypotension may occur.
Long-acting nitrates
Long-acting nitrates are useful for persistent symptoms despite beta-blocker and/or CCB therapy and may be used as part of initial treatment in appropriately selected patients. They can be combined with a beta-blocker or CCB, or used when these agents are contraindicated or poorly tolerated.
A nitrate-free or low-nitrate interval should be incorporated into the dosing schedule to reduce nitrate tolerance. Long-acting oral or transdermal nitrates may be introduced after intravenous nitroglycerin has controlled symptoms, including when the patient has remained symptom-free for 12–24 hours.
Contraindications and precautions
Nitrates should not be administered in:
Hypotension
Recent phosphodiesterase-5 inhibitor use
Right ventricular infarction
Severe aortic stenosis
The specified phosphodiesterase-5 inhibitor intervals are:
Sildenafil or vardenafil within the preceding 24 hours
Tadalafil within the preceding 48 hours
Nitrates are also not recommended in hypertrophic cardiomyopathy or in combination with phosphodiesterase inhibitors.
Ranolazine
Clinical role
Ranolazine is an antianginal option that can be used as add-on therapy when symptoms remain inadequately controlled with beta-blockers and/or CCBs. It may also be selected early in appropriately chosen patients.
A particular practical advantage is its usefulness when escalation of heart-rate- or blood-pressure-lowering treatment is limited by:
Bradycardia
Low blood pressure
Left ventricular dysfunction
Intolerance of beta-blockers or CCBs
Ranolazine is therefore a reasonable component of combination therapy in patients with a low heart rate and/or low blood pressure. It may also be considered in microvascular angina.
The cited material describes ranolazine as reducing myocardial ischaemia at the cellular level. It has additionally been associated with a modest reduction in glycated haemoglobin, with preliminary evidence suggesting that its antianginal effect may be somewhat greater in individuals with higher HbA1c. These metabolic observations do not establish a prognostic indication.
Evidence in non-obstructive disease
In patients with symptoms and signs of ischaemia but no obstructive CAD, responses to antianginal therapy are variable. A small pilot study in women with documented microvascular angina reported improved functional status and quality of life with ranolazine, but a subsequent placebo-controlled study in patients with angina and impaired coronary flow reserve on magnetic resonance imaging did not demonstrate benefit.
Accordingly, ranolazine may be tried in selected patients, but the response should be assessed individually.
Combination therapy
Ranolazine can be combined with a beta-blocker, CCB, or long-acting nitrate. It is especially useful when further dose escalation of these agents is constrained by hypotension, bradycardia, left ventricular dysfunction, or adverse effects.
Other antianginal agents
Although the focus of this chapter is beta-blockers, CCBs, nitrates, and ranolazine, other agents may have a role:
Ivabradine: May be considered as add-on therapy in patients with LVEF <40% and inadequate symptom control. It may also be used as an alternative to beta-blockers in HFrEF when beta-blockers are contraindicated, in patients in sinus rhythm with a heart rate >70 beats per minute. It is not recommended as add-on therapy in patients with LVEF >40% and no clinical heart failure. It should not be combined with verapamil, diltiazem, or other strong CYP3A4 inhibitors.
Nicorandil: May be considered as add-on therapy or, in selected patients, as initial therapy. It may be particularly relevant in coronary artery spasm.
Trimetazidine: May be considered as add-on therapy or in selected patients as part of initial treatment. It is a reasonable option when heart rate or blood pressure limits other therapies and may have additive effects in patients with HFrEF and CCS already receiving beta-blockers.
Patient-specific treatment considerations
| Clinical circumstance | Preferred or potentially useful strategy |
|---|---|
| Most patients with CCS | Beta-blocker and/or CCB |
| Low heart rate or low blood pressure | Ranolazine or trimetazidine; avoid unnecessary escalation of rate- or pressure-lowering drugs |
| Tachycardia or hypertension | Beta-blocker; CCB may be added |
| Coronary vasospasm | CCB; nicorandil or nitrates may be considered |
| Suspected microvascular angina | Ranolazine or trimetazidine may be considered |
| HFrEF and CAD | Beta-blocker as prognostic therapy; consider ivabradine when appropriate |
| HFrEF with persistent angina | Consider additional antianginal therapy; avoid verapamil and diltiazem |
| Bradycardia or atrioventricular conduction disease | Avoid or use beta-blockers and non-dihydropyridine CCBs with great caution; consider ranolazine |
| Chronic obstructive pulmonary disease with bronchospasm | Avoid non-cardioselective beta-blockers; CCBs may be suitable |
| Diabetes | Beta-blockers require caution; vasodilating beta-blockers may be preferred; ranolazine may modestly reduce HbA1c |
| Severe hypertension with angina | Amlodipine plus carvedilol may be effective |
| Anticipated or acute anginal episode | Sublingual or buccal nitroglycerin |
| Recent phosphodiesterase-5 inhibitor use | Avoid nitrates |
Acute anti-ischaemic treatment in non-ST-segment elevation acute coronary syndrome
Initial treatment of ischaemic discomfort includes bed rest and anti-ischaemic medication. Oxygen is used in patients with hypoxaemia, defined in the cited material as arterial oxygen saturation <90%, and/or in those with heart failure and pulmonary rales.
Nitrates
Sublingual or intravenous nitrates may be used for angina. Intravenous therapy is particularly appropriate for recurrent symptoms, uncontrolled hypertension, or signs of heart failure. Treatment must be avoided in hypotension, right ventricular infarction, severe aortic stenosis, or recent phosphodiesterase-5 inhibitor use.
Beta-blockers
Beta-blockers should generally be initiated early for ischaemic symptoms and continued as chronic therapy when appropriate. Oral therapy is ordinarily targeted to a heart rate of 50–60 beats per minute in the acute coronary syndrome setting.
They should be avoided in:
PR interval >0.24 seconds
Second- or third-degree atrioventricular block
Heart rate <50 beats per minute
Systolic blood pressure <90 mmHg
Shock
Killip class III or IV heart failure
Severe reactive airway disease
Acute or severe heart failure
Low cardiac output
Intravenous initiation may be considered in severe ischaemia, but only in the absence of these contraindications.
Calcium channel blockers
Verapamil or diltiazem may be considered when symptoms or electrocardiographic evidence of ischaemia persist after full-dose nitrates and beta-blockers, or when either class is contraindicated. They may also be considered in vasospastic angina.
They should be avoided in hypotension, pulmonary oedema, and left ventricular dysfunction. Short-acting nifedipine should not be used.
Analgesia for refractory pain
When severe chest pain continues despite three sublingual nitroglycerin doses or when recurrent ischaemia persists despite adequate anti-ischaemic treatment, intravenous morphine may be used in the absence of contraindications. The cited dose is 1–5 mg every 5–30 minutes. It should be avoided in hypotension, respiratory depression, confusion, or obtundation. Concomitant administration may delay absorption and blunt the antiplatelet effect of oral P2Y12 inhibitors.
Guideline recommendations
The principal recommendations for antianginal therapy in CCS are summarized below.
| Recommendation | Class | Level |
|---|---|---|
| Tailor antianginal therapy to clinical characteristics, comorbidities, concomitant drugs, tolerability, underlying pathophysiology, availability, and cost | I | C |
| Use short-acting nitrates for immediate relief of angina | I | B |
| Begin most patients with a beta-blocker and/or CCB to control heart rate and symptoms | I | B |
| Consider beta-blocker plus dihydropyridine CCB when monotherapy is inadequate, unless contraindicated | IIa | B |
| Consider long-acting nitrates or ranolazine as add-on therapy when symptoms persist on beta-blocker and/or CCB therapy, or as initial therapy in selected patients | IIa | B |
| Use a nitrate-free or low-nitrate interval with long-acting nitrates to reduce tolerance | IIa | B |
| Consider ivabradine in LVEF <40% with inadequate symptom control, or initially in selected patients | IIa | B |
| Consider nicorandil or trimetazidine as add-on therapy, or initially in selected patients | IIb | B |
| Do not use ivabradine as add-on therapy in CCS with LVEF >40% and no clinical heart failure | III | B |
| Do not combine ivabradine with non-dihydropyridine CCBs or other strong CYP3A4 inhibitors | III | — |
| Do not use nitrates with phosphodiesterase inhibitors or in hypertrophic cardiomyopathy | III | — |
In patients with HFrEF and CAD, beta-blockers are central because of their prognostic benefit. Diltiazem and verapamil are contraindicated in HFrEF. In HFpEF, beta-blockers, long-acting nitrates, CCBs, ivabradine, ranolazine, trimetazidine, and nicorandil may be considered for angina relief, but no benefit on heart-failure or coronary endpoints is expected from these antianginal agents.
Monitoring and follow-up
Follow-up should assess:
Frequency, duration, severity, and triggers of angina
Exercise tolerance and functional limitation
Use of rescue nitroglycerin
Resting heart rate and blood pressure
Symptoms of hypotension or bradycardia
Adherence and tolerability
Evidence of heart failure
Development of conduction disease or bronchospasm where relevant
The need for escalation to combination therapy or revascularization
Treatment should be modified when symptoms remain inadequately controlled or adverse effects develop. Particular attention is required when combining agents that slow heart rate or atrioventricular conduction, such as beta-blockers with verapamil or diltiazem.
Patients with new or worsening symptoms should undergo risk stratification, preferably with stress imaging. Persistent symptoms despite medical therapy, particularly in patients with suspected angina or ischaemia with non-obstructive coronary arteries, may warrant invasive coronary functional testing to identify treatable endotypes and improve symptoms and quality of life.
Prognosis
The prognostic implications of antianginal therapy depend on the underlying cardiac condition. Beta-blockers improve prognosis in HFrEF and in selected post-MI patients, particularly when LVEF is reduced. Their long-term benefit after uncomplicated acute coronary syndrome with preserved LVEF remains uncertain, and the appropriate duration of treatment is unresolved.
For most other antianginal drugs, including CCBs, nitrates, and ranolazine, the principal established benefit is symptomatic. In patients with diabetes and CAD who are not candidates for revascularization, beta-blockers, CCBs, nitrates, ranolazine, and ivabradine may relieve symptoms, but these agents do not improve mortality or the rate of ischaemic events in the cited material.
Accordingly, symptom improvement should not be conflated with modification of coronary risk. Long-term management must continue to address established atherosclerosis and associated risk factors, including high-intensity lipid-lowering therapy and appropriate antithrombotic treatment, while persistent or refractory angina should trigger reassessment of diagnosis, mechanism, treatment adherence, and the potential role of revascularization.
