• Scenario: Suspected angina: covers the management of people with suspected stable angina.
• Scenario: New diagnosis (confirmed): covers the management of people with a newly-confirmed diagnosis of stable angina.
• Scenario: Routine review: covers the management of people with angina whose symptoms are currently stable on treatment.
• Scenario: Poor control on treatment: covers the management of people with angina for whom existing treatment is not adequately controlling their symptoms.

• Consider hospital admission for people with the following symptoms, as they may have unstable angina:
• Pain at rest (which may occur at night).
• Pain on minimal exertion.
• Angina that seems to be progressing rapidly despite increasing medical treatment.
• Refer urgently all people with suspected angina to a chest pain evaluation service, for confirmation of the diagnosis and assessment of the severity of coronary heart disease.

In depth

• Provide the person with glyceryl trinitrate (sublingual spray or tablets) to use for the relief of symptoms while they are waiting for specialist referral.
• Instruct the person that if they experience chest pain they should:
• Stop what they are doing and rest.
• Use their glyceryl trinitrate spray or tablets as instructed.
• Take a second dose after 5 minutes if the pain has not eased.
• Take a third dose after another 5 minutes if the pain still has not eased.
• Call 999 for an ambulance if the pain has not eased after another 5 minutes, or earlier if the pain is intensifying or the person is unwell.
• If clinically confident of the diagnosis, start aspirin.

In depth

• For symptom relief:
• Sublingual glyceryl trinitrate should be used for the rapid relief of the symptoms of angina and before performing activities known to cause symptoms of angina.
• Prescribe a beta-blocker as first-line regular treatment to reduce the symptoms of stable angina.
• If a beta-blocker is contraindicated or not tolerated, prescribe a calcium-channel blocker (CCB), a nitrate (such as isosorbide mononitrate), or nicorandil.
• Ivabradine is an alternative to a CCB, a nitrate, or nicorandil if a beta-blocker is contraindicated or not tolerated. However, there is less experience with its use in primary care, and it is significantly more expensive than alternative anti-anginal drugs. Primary care prescribers may wish to consider seeking advice from a specialist before initiating ivabradine in primary care, particularly if they are not familiar with its use.
• To improve prognosis:
• All people with stable angina should be taking low-dose aspirin and a statin unless these are contraindicated or not tolerated.
• All people with stable angina should be considered for treatment with an angiotensin-converting enzyme (ACE) inhibitor.
• For people with stable angina and coexisting hypertension, diabetes, heart failure, asymptomatic left ventricular dysfunction, or previous myocardial infarction, an ACE inhibitor should be prescribed unless this is contraindicated or not tolerated.
• For people with stable angina and no coexisting indications for treatment with an ACE inhibitor, any anticipated benefit of treatment should be considered, alongside the costs and potential risks, on an individual basis.

In depth

• Consider hospital admission for people with the following symptoms, as they may have unstable angina:
• Pain at rest (which may occur at night).
• Pain on minimal exertion.
• Angina that seems to be progressing rapidly despite increasing medical treatment.
• Indications for early referral to a cardiologist include:
• Previous myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty and development of angina.
• Electrocardiographic evidence of previous myocardial infarction or other significant abnormality.
• Newly diagnosed atrial fibrillation.
• Heart failure and angina.
• An ejection systolic murmur suggesting aortic stenosis.
• Any suggestion of hypertrophic cardiomyopathy (for example by family history, physical examination, or electrocardiographic abnormality).
• Refer for prognostic exercise testing if this has not been done as part of the diagnostic process.
• Further reasons to refer people to a cardiologist include:
• Doubt about the diagnosis.
• The presence of several risk factors or a strong family history.
• The person's preference for referral.
• Problems with employment, life insurance, or unacceptable interference with lifestyle.
• Significant comorbidity (such as diabetes).

In depth

All people with angina are assumed to be at high risk for cardiovascular events, and their cardiovascular risk factors should be managed accordingly.

• Optimize the management of comorbid conditions that give an increased risk of cardiovascular events (such as hypertension, diabetes mellitus, and hyperlipidaemia).
• Advise and assist all people who smoke to stop (see the CKS topic on Smoking cessation).
• Encourage people to eat a cardioprotective diet (see the section on Cardioprotective diet in the CKS topic on CVD risk assessment and management).
• Offer advice and support, to achieve and maintain a healthy weight, to people who are overweight or obese (see the CKS topic on Obesity).
• Encourage people to increase their physical activity levels within the limits set by their symptoms. For a detailed discussion on recommended levels of physical activity for cardiovascular protection, see the section on Physical activity in the CKS topic on CVD risk assessment and management.
• Encourage people to limit their alcohol consumption.
• Advise men to limit their alcohol intake to 3–4 units a day, with at most 21 units a week.
• Advise women to limit their alcohol intake to 2–3 units a day, with at most 14 units a week.
• For more information, see the CKS topic on Alcohol - problem drinking.

In depth

• Advise the person that it is their responsibility to inform the Driver and Vehicle Licensing Agency (DVLA) of any condition that may affect their ability to drive.
• The DVLA's medical rules regarding angina are:
• For group 1 entitlement (cars, motorcycles):
• Driving must cease when symptoms occur at rest, with emotion, or at the wheel.
• Driving may recommence when satisfactory symptom control is achieved.
• The DVLA need not be notified.
• For group 2 entitlement (lorries, buses):
• Refusal or revocation of a driver's license may occur if symptoms (treated or untreated) continue.
• Re-licensing may be permitted thereafter provided that the person has been free from angina for at least 6 weeks, exercise or other functional test requirements can be met, and there is no other disqualifying condition.
• The person should check with their insurer that they are still covered for driving.
• The latest information from the DVLA regarding medical fitness to drive can be obtained at www.dvla.gov.uk/medical/ataglance.

In depth

• Advise the person that, if they can briskly climb up and down two flights of stairs without any symptoms of angina, sexual activity is unlikely to precipitate an episode of angina.
• If sexual activity does precipitate an episode of angina, sublingual glyceryl trinitrate taken immediately before intercourse may help prevent subsequent attacks.
• The concomitant use of nitrates or nicorandil with phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil), often used in the treatment of erectile dysfunction, is contraindicated.
• Advise people with angina who take a phosphodiesterase inhibitor that:
• They should not use glyceryl trinitrate (GTN) for at least 24 hours before taking sildenafil or vardenafil and for at least 48 hours before taking tadalafil.
• They should not use GTN for at least 24 hours after taking sildenafil or vardenafil and for at least 48 hours after taking tadalafil.
• If they have an episode of angina during sexual intercourse, they must not use GTN. They should stop sexual activity and, if their pain does not resolve, they should call for an ambulance.

In depth

• Advise people with angina that:
• Many people with angina can continue to work as before.
• If their job involves heavy manual work, they may need to alter their work practices.
• If their job involves driving, they should consult the Driver and Vehicle Licensing Agency.
• If the person's employer has an occupational health department, they should be encouraged to discuss the options.

In depth

• Beta-blockers are contraindicated in people with:
• A history of asthma or bronchospasm (beta-blockers can be used in people with chronic obstructive pulmonary disease, but caution should be used if disease is severe).
• Second- or third-degree heart block (in the absence of a permanent pacemaker).
• Sick sinus syndrome.
• Sinus bradycardia (heart rate less than 50 beats per minute at the start of treatment).
• Severe hypotension.
• Severe peripheral arterial disease (pain at rest and sometimes intermittent claudication) — the blood pressure-lowering properties of beta-blockers can exacerbate symptoms.
• Uncontrolled heart failure.
• Seek specialist advice before starting a beta-blocker in people with a current or recent exacerbation of heart failure.

In depth

• CKS recommends atenolol, bisoprolol, or metoprolol as first-choice beta-blockers for the management of angina.
• For people who have had a previous myocardial infarction, metoprolol (standard release), propranolol (standard release), timolol, or atenolol may be preferred.
• For more information, see the CKS topic on MI - secondary prevention.
• For people with angina and heart failure, bisoprolol, carvedilol, or nebivolol may be preferred.
• For more information, see the CKS topic on Heart failure - chronic.

In depth

• Titrate the dose of beta-blocker to the target dose (or maximum tolerated dose), according to the person's response and heart rate control (at rest and during exercise).
• Recommended target doses are:
• Atenolol 100 mg once a day or 50 mg twice a day (twice-daily dosing may provide better symptom control).
• Bisoprolol 10 mg once a day.
• Metoprolol 100 mg three times a day (standard-release) or 200 mg once a day (modified-release).

In depth

• Cold extremities, paraesthesiae, and numbness can occur, and beta-blockers can worsen symptoms in people with peripheral vascular disease — use a cardioselective beta-blocker (such as atenolol, bisoprolol, and metoprolol).
• Sleep disturbance or nightmares can occur — use a water-soluble beta-blocker (such as atenolol).
• Fatigue and sexual dysfunction can occur but do not usually necessitate stopping the beta-blocker.
• Ask people taking a beta-blocker whether they are having sexual problems.
• Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers — use a cardioselective beta-blocker in people with diabetes.

In depth

• Verapamil and diltiazem
• The combination of a beta-blocker and verapamil must not be prescribed.
• The combination of a beta-blocker and diltiazem should only be prescribed on specialist advice.
• Class I antiarrhythmics (such as quinidine, disopyramide, flecainide, lidocaine)
• The combination of a beta-blocker and a class I antiarrhythmic is not recommended.
• Amiodarone
• The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse and blood pressure, and check for signs of worsening heart failure, as there is an increased risk of bradycardia, atrioventricular (AV) block, and myocardial depression. Amiodarone should not be initiated in primary care unless on specialist advice.
• Digoxin
• Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia — monitor pulse.
• Other drugs that reduce blood pressure
• An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

In depth

• Monotherapy (when a beta-blocker is contraindicated or not tolerated): a rate-limiting calcium-channel blocker (CCB) may be preferred.
• Combination therapy
• People taking a beta-blocker: prescribe a dihydropyridine (amlodipine, felodipine, or modified-release nifedipine).
• People not taking a beta-blocker: a rate-limiting CCB may be preferred.
• If the person has concomitant heart failure: prescribe a amlodipine or felodipine.

In depth

• Rate-limiting calcium-channel blockers (verapamil and diltiazem) are contraindicated in people with:
• Heart failure.
• Bradycardia or atrioventricular block.
• Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy): vasodilatation may result in reduced cardiac output.
• Dihydropyridine calcium-channel blockers should not be started in people with uncontrolled heart failure (but amlodipine and felodipine can be used if heart failure is stable).

In depth

• Vasodilatory adverse effects (facial flushing, headaches, postural hypotension, and ankle swelling) can occur; they are more common with dihydropyridine calcium-channel blockers (CCBs) than rate-limiting CCBs.
• Vasodilatory effects usually reduce in severity with continued treatment, although ankle swelling often persists.
• Diuretics should not be routinely prescribed for ankle oedema, as they only partially reduce ankle oedema caused by CCBs.
• Verapamil commonly causes constipation.
• Advise the person to eat more fibre (such as fruit, vegetables, cereals, and wholemeal bread), to try to drink at least 12 cups (equivalent to eight glasses or eight mugs) of liquid a day, and to avoid drinks with a high caffeine content (because these can make constipation worse).

In depth

• Beta-blockers
• The combination of a beta-blocker and verapamil should not be prescribed.
• The combination of a beta-blocker and diltiazem should only be prescribed on specialist advice.
• Digoxin
• Verapamil and verapamil: reduce the digoxin dose by one-third to one-half and monitor digoxin concentrations.
• Diltiazem and digoxin: monitor for signs of digoxin toxicity.
• Grapefruit
• Advise the person to avoid grapefruit juice, whole grapefruit, and grapefruit products.

In depth

• Nitrates should be used with caution in people with:
• Left ventricular outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy).
• Closed-angle glaucoma.
• The combination of a nitrate and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

In depth

• Short-acting, sublingual glyceryl trinitrate should be used for immediate relief of an episode of angina, or before activities that are likely to precipitate angina.
• Long-acting oral nitrates should be used regularly to decrease the frequency and severity of anginal symptoms.
• Isosorbide mononitrate is generally preferred to isosorbide dinitrate.

In depth

• Standard-release nitrate preparations: use an asymmetric dosing interval to minimize nitrate tolerance.
• For mononitrate preparations, this can be achieved with twice-daily dosing, for example at 8 a.m. and 3 p.m., or 2 p.m. and 10 p.m.
• For dinitrate preparations, dosing may be more complicated because dinitrate requires more frequent administration than mononitrate.
• Modified-release nitrate preparations: use a once-daily dose to maintain a nitrate-low period and thus minimize tolerance.
• Modified-release preparations are significantly more expensive than standard-release preparations, but they may be useful for people who find it difficult to comply with an asymmetric dosing regimen.

In depth

• Transient hypotension that manifests as dizziness, weakness, and palpitations has been reported with isosorbide mononitrate. Hypotension often presents as postural hypotension occurring shortly after drug administration.
• Headache occurs in more than 60% of people receiving glyceryl trinitrate (GTN) and 25–40% of people receiving isosorbide dinitrate or mononitrate. In addition, GTN may precipitate a migraine headache in people with a history of migraine.
• Tolerance to headache usually occurs over 1–2 weeks, although 10–20% of people cannot tolerate nitrates because of headache.
• To minimize the risk of headache, start at a low dose (for example 10 mg twice a day) and titrate up.
• Burning, stinging, or tingling of the mouth is experienced by some people taking sublingual GTN tablets.
• If this is bothersome, consider using a lower dose of GTN tablets, or a GTN sublingual spray.

In depth

• The concurrent use of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil) with nitrates is contraindicated.
• A nitrate should not be given for at least 24 hours after the last dose of sildenafil or vardenafil, and for at least 48 hours after the last dose of tadalafil.
• Sildenafil and vardenafil should not be used for at least 24 hours after the last dose of a nitrate, and tadalafil should not be used for at least 48 hours after the last dose of a nitrate.
• Advise people with angina who are taking a phosphodiesterase inhibitor that they must not use glyceryl trinitrate if they have an angina attack during sexual intercourse. Advise them to stop sexual activity and, if their pain does not resolve, they should call for an ambulance.

In depth

• Instruct the person in the correct use of their sublingual glyceryl trinitrate (GTN), and what to do if their angina attack does not respond to sublingual GTN.
• Key points for discussion include:
• Why GTN has been prescribed (it helps the heart work better, but it is not a painkiller).
• How to use the spray or tablets.
• When to use GTN to treat chest pain and to prevent pain if it can be precipitated.
• Likely adverse effects.
• What to do if pain persists after two doses or beyond 15 minutes.
• The short shelf-life of GTN tablets once opened (8 weeks), and how to obtain further supplies.

In depth

• Nicorandil is contraindicated in people with:
• Left ventricular failure.
• Hypotension.
• The concomitant use of nicorandil and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

In depth

• Headache is usually seen during the first 2 weeks of treatment; it is dose related and tends to diminish with continued use. Careful dose titration can reduce the incidence of headache and the number of people who stop treatment because of it.
• Hypotension may occur, especially after high starting doses; it can be minimized by careful dose titration.
• Gastrointestinal ulceration (including aphthous ulcers and anal ulceration) has been reported with nicorandil.
• Consider nicorandil treatment as a possible cause in people who present with symptoms of gastrointestinal ulceration.
• Ulcers that result from nicorandil are usually refractory to treatment; they respond only to withdrawal of nicorandil.
• Nicorandil withdrawal should take place only under the supervision of a cardiologist.

In depth

• The concomitant use of nicorandil and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

In depth

• Advise people taking nicorandil that they should not drive or operate machinery until it is established that nicorandil does not impair their performance.
• Advise the person that if they develop symptoms suggestive of gastrointestinal ulceration, they should seek medical advice. Although these adverse effects are rare, they are frequently missed.

In depth

• Ivabradine is contraindicated in:
• Acute myocardial infarction or unstable angina.
• Severe hypotension (blood pressure less than 90/50 mmHg).
• Heart failure (New York Heart Association class III or IV).
• Sino-atrial block or 3rd degree AV block.
• Severe hepatic insufficiency.
• Ivabradine should not be started in anyone with a resting heart rate less than 60 beats per minute.
• Ivabradine is contraindicated in women who are pregnant or breastfeeding because data are lacking to support its use in these women.

In depth

• Visual disturbances, including luminous phenomena (phosphenes) and blurred vision, have been commonly reported in people taking ivabradine.
• Luminous phenomena occur in about 15% of people taking ivabradine, usually starting within the first 2 months of treatment and resolving either on continued treatment or on stopping treatment.
• People taking ivabradine should be advised to be careful when driving or using machines at times when there could be sudden changes in light intensity (especially when driving at night) if they experience luminous phenomena.
• Bradycardia is noted in about 4% of people taking ivabradine. Monitor heart rate closely within the first 2–3 months of treatment.
• Headache is a common adverse effect experienced by people taking ivabradine. This is usually transient and resolves within the first month of treatment.

In depth

• CYP3A4 enzyme inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors) should not be given concomitantly with ivabradine. Concomitant administration of a CYP3A4 enzyme inhibitor may increase the plasma concentration of ivabradine, increasing the risk of bradycardia.
• Drugs which prolong the QT interval (such as quinidine, amiodarone, and erythromycin) should not be given concomitantly with ivabradine. QT prolongation may be exacerbated by the heart rate reduction experienced with ivabradine.
• Grapefruit can increase the plasma concentration of ivabradine up to two-fold. People should be advised not to eat grapefruit or drink grapefruit juice whilst taking ivabradine.
• Rate-limiting calcium-channel blockers: concomitant use of ivabradine with verapamil or diltiazem is not recommended, because it can result in excessive reduction of heart rate.

In depth

• Review the person every 6 months to 1 year depending on the stability of their angina and their comorbidities.
• Check for ongoing symptoms of angina (at rest or with exercise).
• If the person is taking anti-anginal treatment but has persistent symptoms, see Poor control on treatment for advice on further treatment and referral.
• Assess cardiovascular disease risk and identify any modifiable cardiovascular risk factors:
• For information on cardiovascular risk factors, see Managing cardiovascular risk.
• Check for any complications of angina or treatment.
• Check the person's heart rate and blood pressure.
• Check for signs and symptoms of heart failure (for example breathlessness, fatigue, or ankle swelling).
• Screen for low mood or depression using the two questions:
• During the past month, have you often been bothered by feeling down, depressed, or hopeless?
• During the past month, have you often been bothered by having little interest or pleasure in doing things?
• Check compliance, and identify and manage drug interactions and complications of treatment (see Prescribing information).
• Review the person's medication.
• If the person is taking treatment for symptom control, ensure that they are taking a beta-blocker (unless this is contraindicated or not tolerated).
• Ensure that the person is taking aspirin and a statin (unless these are contraindicated or not tolerated).
• Consider whether an angiotensin-converting enzyme inhibitor is indicated.
• See Drug treatment for further information.
• Provide information on angina.
• Provide written information (if this has not already been given).
• Explain when to seek further medical advice (such as worsening symptoms).
• For more information on patient education, see www.bhf.org.uk.

In depth

All people with angina are assumed to be at high risk for cardiovascular events, and their cardiovascular risk factors should be managed accordingly.

• Optimize the management of comorbid conditions that give an increased risk of cardiovascular events (such as hypertension, diabetes mellitus, and hyperlipidaemia).
• Advise and assist all people who smoke to stop (see the CKS topic on Smoking cessation).
• Encourage people to eat a cardioprotective diet (see the section on Cardioprotective diet in the CKS topic on CVD risk assessment and management).
• Offer advice and support, to achieve and maintain a healthy weight, to people who are overweight or obese (see the CKS topic on Obesity).
• Encourage people to increase their physical activity levels within the limits set by their symptoms. For a detailed discussion on recommended levels of physical activity for cardiovascular protection, see the section on Physical activity in the CKS topic on CVD risk assessment and management.
• Encourage people to limit their alcohol consumption.
• Advise men to limit their alcohol intake to 3–4 units a day, with at most 21 units a week.
• Advise women to limit their alcohol intake to 2–3 units a day, with at most 14 units a week.
• For more information, see the CKS topic on Alcohol - problem drinking.

In depth

• Advise people with angina that:
• Many people with angina can continue to work as before.
• If their job involves heavy manual work, they may need to alter their work practices.
• If their job involves driving, they should consult the Driver and Vehicle Licensing Agency.
• If the person's employer has an occupational health department, they should be encouraged to discuss the options.

In depth

• Advise the person that it is their responsibility to inform the Driver and Vehicle Licensing Agency (DVLA) of any condition that may affect their ability to drive.
• The DVLA's medical rules regarding angina are:
• For group 1 entitlement (cars, motorcycles):
• Driving must cease when symptoms occur at rest, with emotion, or at the wheel.
• Driving may recommence when satisfactory symptom control is achieved.
• The DVLA need not be notified.
• For group 2 entitlement (lorries, buses):
• Refusal or revocation of a driver's license may occur if symptoms (treated or untreated) continue.
• Re-licensing may be permitted thereafter provided that the person has been free from angina for at least 6 weeks, exercise or other functional test requirements can be met, and there is no other disqualifying condition.
• The person should check with their insurer that they are still covered for driving.
• The latest information from the DVLA regarding medical fitness to drive can be obtained at www.dvla.gov.uk/medical/ataglance.

In depth

• Advise the person that, if they can briskly climb up and down two flights of stairs without any symptoms of angina, sexual activity is unlikely to precipitate an episode of angina.
• If sexual activity does precipitate an episode of angina, sublingual glyceryl trinitrate taken immediately before intercourse may help prevent subsequent attacks.
• The concomitant use of nitrates or nicorandil with phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil), often used in the treatment of erectile dysfunction, is contraindicated.
• Advise people with angina who take a phosphodiesterase inhibitor that:
• They should not use glyceryl trinitrate (GTN) for at least 24 hours before taking sildenafil or vardenafil and for at least 48 hours before taking tadalafil.
• They should not use GTN for at least 24 hours after taking sildenafil or vardenafil and for at least 48 hours after taking tadalafil.
• If they have an episode of angina during sexual intercourse, they must not use GTN. They should stop sexual activity and, if their pain does not resolve, they should call for an ambulance.

In depth

• If the person has poorly controlled angina symptoms, see Referral.
• If the person is stable on treatment, referral to a cardiologist is not usually required. However, refer promptly if:
• Stress testing (for example exercise tolerance testing) has not been done as part of the diagnostic process.
• The result of stress testing was highly abnormal, but the person has not been reviewed by a specialist.
• A murmur is detected that has not been assessed by a specialist.
• Also consider referral if:
• There are several risk factors or a strong family history.
• The person requests it.
• There are problems with employment or life insurance.
• A significant comorbidity (such as diabetes) is present.

In depth

People currently on monotherapy:

• Ensure that the person is taking the maximum licensed or highest tolerated dose.
• If the person is taking a beta-blocker:
• Add a long-acting dihydropyridine calcium-channel blocker (CCB), such as amlodipine, modified-release nifedipine, or modified-release felodipine.
• If a dihydropyridine CCB is contraindicated or not tolerated, add a nitrate; nicorandil; or ivabradine (if their heart rate is > 60 bpm).
• If the person is taking an anti-anginal drug other than a beta-blocker, and is not known to be intolerant of a beta-blocker and has no contraindications:
• Consider adding a beta-blocker.
• Do not combine a beta-blocker with a rate-limiting CCB (diltiazem or verapamil).
• If the person is taking an anti-anginal drug other than a beta-blocker, and a beta-blocker is contraindicated or not tolerated:
• If taking a CCB, add a nitrate or nicorandil.
• If taking a nitrate, add a CCB or nicorandil.
• If taking nicorandil, add a CCB or a nitrate.
• If taking ivabradine, add a dihydropyridine CCB, a nitrate, or nicorandil (consider seeking specialist advice).

For people on dual therapy:

• Ensure that the person is taking the maximum licensed or highest tolerated dose of each drug.
• If symptom control is poor on the maximum licensed or tolerated doses of two drugs, refer to a cardiologist (for advice on further drug management and assessment for revascularization).
• Consider starting a third anti-anginal drug while awaiting referral.

In depth

• Consider hospital admission for people with the following symptoms, as they may have unstable angina:
• Pain at rest (which may occur at night).
• Pain on minimal exertion.
• Angina that seems to be progressing rapidly despite increasing medical treatment.
• Indications for early referral to a cardiologist include:
• No previous stress test (such as exercise tolerance test).
• Failure to respond to medical treatment (maximum therapeutic doses of two drugs).
• A highly abnormal exercise tolerance test.
• Previous myocardial infarction, coronary artery bypass graft, or percutaneous transluminal coronary angioplasty.
• Newly diagnosed or uncontrolled atrial fibrillation.
• Electrocardiographic evidence of a previous myocardial infarction or other significant abnormality.
• Ejection systolic murmur suggesting aortic stenosis.
• Further reasons to refer to a cardiologist include:
• The presence of several risk factors or a strong family history.
• The person's preference for referral.
• Problems with employment, life insurance, or unacceptable interference with lifestyle.
• Significant comorbidity (such as diabetes).

In depth

• Beta-blockers are contraindicated in people with:
• A history of asthma or bronchospasm (beta-blockers can be used in people with chronic obstructive pulmonary disease, but caution should be used if disease is severe).
• Second- or third-degree heart block (in the absence of a permanent pacemaker).
• Sick sinus syndrome.
• Sinus bradycardia (heart rate less than 50 beats per minute at the start of treatment).
• Severe hypotension.
• Severe peripheral arterial disease (pain at rest and sometimes intermittent claudication) — the blood pressure-lowering properties of beta-blockers can exacerbate symptoms.
• Uncontrolled heart failure.
• Seek specialist advice before starting a beta-blocker in people with a current or recent exacerbation of heart failure.

In depth

• CKS recommends atenolol, bisoprolol, or metoprolol as first-choice beta-blockers for the management of angina.
• For people who have had a previous myocardial infarction, metoprolol (standard release), propranolol (standard release), timolol, or atenolol may be preferred.
• For more information, see the CKS topic on MI - secondary prevention.
• For people with angina and heart failure, bisoprolol, carvedilol, or nebivolol may be preferred.
• For more information, see the CKS topic on Heart failure - chronic.

In depth

• Titrate the dose of beta-blocker to the target dose (or maximum tolerated dose), according to the person's response and heart rate control (at rest and during exercise).
• Recommended target doses are:
• Atenolol 100 mg once a day or 50 mg twice a day (twice-daily dosing may provide better symptom control).
• Bisoprolol 10 mg once a day.
• Metoprolol 100 mg three times a day (standard-release) or 200 mg once a day (modified-release).

In depth

• Cold extremities, paraesthesiae, and numbness can occur, and beta-blockers can worsen symptoms in people with peripheral vascular disease — use a cardioselective beta-blocker (such as atenolol, bisoprolol, and metoprolol).
• Sleep disturbance or nightmares can occur — use a water-soluble beta-blocker (such as atenolol).
• Fatigue and sexual dysfunction can occur but do not usually necessitate stopping the beta-blocker.
• Ask people taking a beta-blocker whether they are having sexual problems.
• Warning signs of hypoglycaemia (such as tremor and tachycardia) can be masked by non-selective beta-blockers — use a cardioselective beta-blocker in people with diabetes.

In depth

• Verapamil and diltiazem
• The combination of a beta-blocker and verapamil must not be prescribed.
• The combination of a beta-blocker and diltiazem should only be prescribed on specialist advice.
• Class I antiarrhythmics (such as quinidine, disopyramide, flecainide, lidocaine)
• The combination of a beta-blocker and a class I antiarrhythmic is not recommended.
• Amiodarone
• The combination of a beta-blocker and amiodarone should be prescribed with caution — monitor pulse and blood pressure, and check for signs of worsening heart failure, as there is an increased risk of bradycardia, atrioventricular (AV) block, and myocardial depression. Amiodarone should not be initiated in primary care unless on specialist advice.
• Digoxin
• Concomitant administration of a beta-blocker and digoxin can reduce heart rate and prolong AV conduction time, increasing the risk of AV block and bradycardia — monitor pulse.
• Other drugs that reduce blood pressure
• An additive hypotensive effect may occur — monitor for signs of hypotension (such as dizziness, light-headedness, and confusion).

In depth

• Monotherapy (when a beta-blocker is contraindicated or not tolerated): a rate-limiting calcium-channel blocker (CCB) may be preferred.
• Combination therapy
• People taking a beta-blocker: prescribe a dihydropyridine (amlodipine, felodipine, or modified-release nifedipine).
• People not taking a beta-blocker: a rate-limiting CCB may be preferred.
• If the person has concomitant heart failure: prescribe a amlodipine or felodipine.

In depth

• Rate-limiting calcium-channel blockers (verapamil and diltiazem) are contraindicated in people with:
• Heart failure.
• Bradycardia or atrioventricular block.
• Cardiac outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy): vasodilatation may result in reduced cardiac output.
• Dihydropyridine calcium-channel blockers should not be started in people with uncontrolled heart failure (but amlodipine and felodipine can be used if heart failure is stable).

In depth

• Vasodilatory adverse effects (facial flushing, headaches, postural hypotension, and ankle swelling) can occur; they are more common with dihydropyridine calcium-channel blockers (CCBs) than rate-limiting CCBs.
• Vasodilatory effects usually reduce in severity with continued treatment, although ankle swelling often persists.
• Diuretics should not be routinely prescribed for ankle oedema, as they only partially reduce ankle oedema caused by CCBs.
• Verapamil commonly causes constipation.
• Advise the person to eat more fibre (such as fruit, vegetables, cereals, and wholemeal bread), to try to drink at least 12 cups (equivalent to eight glasses or eight mugs) of liquid a day, and to avoid drinks with a high caffeine content (because these can make constipation worse).

In depth

• Beta-blockers
• The combination of a beta-blocker and verapamil should not be prescribed.
• The combination of a beta-blocker and diltiazem should only be prescribed on specialist advice.
• Digoxin
• Verapamil and verapamil: reduce the digoxin dose by one-third to one-half and monitor digoxin concentrations.
• Diltiazem and digoxin: monitor for signs of digoxin toxicity.
• Grapefruit
• Advise the person to avoid grapefruit juice, whole grapefruit, and grapefruit products.

In depth

• Nitrates should be used with caution in people with:
• Left ventricular outflow obstruction (significant aortic stenosis or obstructive hypertrophic cardiomyopathy).
• Closed-angle glaucoma.
• The combination of a nitrate and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

In depth

• Short-acting, sublingual glyceryl trinitrate should be used for immediate relief of an episode of angina, or before activities that are likely to precipitate angina.
• Long-acting oral nitrates should be used regularly to decrease the frequency and severity of anginal symptoms.
• Isosorbide mononitrate is generally preferred to isosorbide dinitrate.

In depth

• Standard-release nitrate preparations: use an asymmetric dosing interval to minimize nitrate tolerance.
• For mononitrate preparations, this can be achieved with twice-daily dosing, for example at 8 a.m. and 3 p.m., or 2 p.m. and 10 p.m.
• For dinitrate preparations, dosing may be more complicated because dinitrate requires more frequent administration than mononitrate.
• Modified-release nitrate preparations: use a once-daily dose to maintain a nitrate-low period and thus minimize tolerance.
• Modified-release preparations are significantly more expensive than standard-release preparations, but they may be useful for people who find it difficult to comply with an asymmetric dosing regimen.

In depth

• Transient hypotension that manifests as dizziness, weakness, and palpitations has been reported with isosorbide mononitrate. Hypotension often presents as postural hypotension occurring shortly after drug administration.
• Headache occurs in more than 60% of people receiving glyceryl trinitrate (GTN) and 25–40% of people receiving isosorbide dinitrate or mononitrate. In addition, GTN may precipitate a migraine headache in people with a history of migraine.
• Tolerance to headache usually occurs over 1–2 weeks, although 10–20% of people cannot tolerate nitrates because of headache.
• To minimize the risk of headache, start at a low dose (for example 10 mg twice a day) and titrate up.
• Burning, stinging, or tingling of the mouth is experienced by some people taking sublingual GTN tablets.
• If this is bothersome, consider using a lower dose of GTN tablets, or a GTN sublingual spray.

In depth

• The concurrent use of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil) with nitrates is contraindicated.
• A nitrate should not be given for at least 24 hours after the last dose of sildenafil or vardenafil, and for at least 48 hours after the last dose of tadalafil.
• Sildenafil and vardenafil should not be used for at least 24 hours after the last dose of a nitrate, and tadalafil should not be used for at least 48 hours after the last dose of a nitrate.
• Advise people with angina who are taking a phosphodiesterase inhibitor that they must not use glyceryl trinitrate if they have an angina attack during sexual intercourse. Advise them to stop sexual activity and, if their pain does not resolve, they should call for an ambulance.

In depth

• Instruct the person in the correct use of their sublingual glyceryl trinitrate (GTN), and what to do if their angina attack does not respond to sublingual GTN.
• Key points for discussion include:
• Why GTN has been prescribed (it helps the heart work better, but it is not a painkiller).
• How to use the spray or tablets.
• When to use GTN to treat chest pain and to prevent pain if it can be precipitated.
• Likely adverse effects.
• What to do if pain persists after two doses or beyond 15 minutes.
• The short shelf-life of GTN tablets once opened (8 weeks), and how to obtain further supplies.

In depth

• Nicorandil is contraindicated in people with:
• Left ventricular failure.
• Hypotension.
• The concomitant use of nicorandil and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

In depth

• Headache is usually seen during the first 2 weeks of treatment; it is dose related and tends to diminish with continued use. Careful dose titration can reduce the incidence of headache and the number of people who stop treatment because of it.
• Hypotension may occur, especially after high starting doses; it can be minimized by careful dose titration.
• Gastrointestinal ulceration (including aphthous ulcers and anal ulceration) has been reported with nicorandil.
• Consider nicorandil treatment as a possible cause in people who present with symptoms of gastrointestinal ulceration.
• Ulcers that result from nicorandil are usually refractory to treatment; they respond only to withdrawal of nicorandil.
• Nicorandil withdrawal should take place only under the supervision of a cardiologist.

In depth

• The concomitant use of nicorandil and a phosphodiesterase inhibitor (sildenafil, tadalafil, or vardenafil) is contraindicated.

In depth

• Advise people taking nicorandil that they should not drive or operate machinery until it is established that nicorandil does not impair their performance.
• Advise the person that if they develop symptoms suggestive of gastrointestinal ulceration, they should seek medical advice. Although these adverse effects are rare, they are frequently missed.

In depth

• Ivabradine is contraindicated in:
• Acute myocardial infarction or unstable angina.
• Severe hypotension (blood pressure less than 90/50 mmHg).
• Heart failure (New York Heart Association class III or IV).
• Sino-atrial block or 3rd degree AV block.
• Severe hepatic insufficiency.
• Ivabradine should not be started in anyone with a resting heart rate less than 60 beats per minute.
• Ivabradine is contraindicated in women who are pregnant or breastfeeding because data are lacking to support its use in these women.

In depth

• Visual disturbances, including luminous phenomena (phosphenes) and blurred vision, have been commonly reported in people taking ivabradine.
• Luminous phenomena occur in about 15% of people taking ivabradine, usually starting within the first 2 months of treatment and resolving either on continued treatment or on stopping treatment.
• People taking ivabradine should be advised to be careful when driving or using machines at times when there could be sudden changes in light intensity (especially when driving at night) if they experience luminous phenomena.
• Bradycardia is noted in about 4% of people taking ivabradine. Monitor heart rate closely within the first 2–3 months of treatment.
• Headache is a common adverse effect experienced by people taking ivabradine. This is usually transient and resolves within the first month of treatment.

In depth

• CYP3A4 enzyme inhibitors (such as azole antifungals, macrolide antibiotics, and protease inhibitors) should not be given concomitantly with ivabradine. Concomitant administration of a CYP3A4 enzyme inhibitor may increase the plasma concentration of ivabradine, increasing the risk of bradycardia.
• Drugs which prolong the QT interval (such as quinidine, amiodarone, and erythromycin) should not be given concomitantly with ivabradine. QT prolongation may be exacerbated by the heart rate reduction experienced with ivabradine.
• Grapefruit can increase the plasma concentration of ivabradine up to two-fold. People should be advised not to eat grapefruit or drink grapefruit juice whilst taking ivabradine.
• Rate-limiting calcium-channel blockers: concomitant use of ivabradine with verapamil or diltiazem is not recommended, because it can result in excessive reduction of heart rate.

In depth

Prescription details for the initiation of new drugs only are included. Prescription details for dose increases are not included, although this may be a more appropriate action to take. See the relevant Clinical summary for details of recommendations.