• 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 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.
• For people with a confirmed diagnosis of angina:
• Treat the symptoms.
• Give a short-acting nitrate for rapid symptom relief, and a beta-blocker (unless contraindicated).
• If additional treatment is required to control symptoms, consider adding a second anti-anginal drug.
• If symptoms are not controlled with optimum use of two drugs, refer for consideration of revascularization.
• Ensure that all people with angina are taking aspirin and a statin (unless contraindicated or not tolerated), and consider an angiotensin-converting enzyme inhibitor.
• Give advice on managing cardiovascular risk, driving, work, and sexual activity.
• Give education about myocardial infarction (heart attack) and the need to seek help rapidly by phoning for an ambulance if symptoms develop.
• Review the person every 6 months to 1 year depending on the stability of their angina and their comorbidities.

• 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.

• This recommendation is based on expert consensus in the National Service Framework for coronary heart disease [DH, 2000] and guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2001; SIGN, 2007].

• Provide the person with sublingual glyceryl trinitrate 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.

• CKS found no evidence or guidelines regarding what treatment to start whilst the person is waiting for specialist assessment. The recommendation to prescribe sublingual glyceryl trinitrate is based on the assumption that the working diagnosis of angina is correct.
• The recommendation for instructions on how to use glyceryl trinitrate (GTN) is based on expert opinion and local guidelines.
• CKS expert reviewers suggested that aspirin can also be started if angina is likely on the basis of clinical assessment. Opinion was divided on whether to start a beta-blocker, so this has not been recommended in primary care before the diagnosis is confirmed.

• For symptom relief:
• Sublingual glyceryl trinitrate (GTN) should be used for the rapid relief of symptoms of angina and before performing activities known to cause symptoms of angina.
• A beta-blocker should be prescribed 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.
• Ranolazine is not recommended for initiation in primary care.
• To improve the person's prognosis:
• All people with stable angina should be taking low-dose aspirin and a statin unless these are contraindicated or not tolerated.
• For information on antiplatelet prophylaxis, including advice on what to do if the person is allergic to aspirin or is at risk of gastrointestinal adverse effects, see the CKS topic on Antiplatelet treatment.
• For further information on prescribing a statin for the prevention of cardiovascular events, see the CKS topic on Lipid modification - CVD prevention.
• 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.
• For more information, see the CKS topics on Diabetes type 2, Heart failure - chronic, Hypertension - not diabetic, and MI - secondary prevention.

These recommendations are based on guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2007] and the European Society of Cardiology [Fox et al, 2006a].

Drugs for symptom control

• Sublingual glyceryl trinitrate (GTN)
• Weak evidence from a small trial indicates that sublingual GTN is effective in relieving the symptoms of angina compared with placebo [Parker et al, 1983]. In practice, sublingual GTN seems to rapidly relieve angina symptoms in most people.
• Beta-blockers
• The evidence for the efficacy of beta-blockers in treating the symptoms of angina is generally poor; however, they are widely recommended first-line for the treatment of angina [Fox et al, 2006a; SIGN, 2007]. Beta-blockers appear to have similar efficacy to calcium-channel blockers (CCBs).
• Beta-blockers are recommended first-line because good evidence indicates that they reduce mortality after myocardial infarction (MI) and in people with heart failure. There is also weak evidence that they reduce all-cause mortality in people with stable angina (and no prior MI or heart failure).
• They may be better tolerated and have fewer adverse effects than calcium-channel blockers or nitrates [DH, 2000].
• Calcium-channel blockers (CCBs)
• Evidence from meta-analyses and subsequent randomized controlled trials (RCTs) suggests that CCBs have similar efficacy to beta-blockers at reducing the symptoms of angina. CCBs are widely recommended for the treatment of stable angina as an alternative first-line treatment in people who cannot take a beta-blocker [Fox et al, 2006a; SIGN, 2007].
• Nitrates
• There is limited evidence on the efficacy of nitrates in the treatment of angina compared with either placebo or a comparator drug. Available data suggests that nitrates have similar efficacy to CCBs and beta-blockers.
• Some evidence from one RCT suggests that amlodipine is more effective than a nitrate in controlling exercise-induced angina in elderly people with coronary heart disease.
• Nitrates are recommended as an alternative to CCBs in people who cannot take a beta-blocker, on the basis of expert consensus [Fox et al, 2006a; SIGN, 2007].
• Nicorandil
• There is consensus that nicorandil is an effective treatment for angina [Fox et al, 2006a; SIGN, 2007]. Although data evidence from one study suggest that nicorandil may have prognostic benefits, further trials are needed to confirm this.
• Ivabradine
• Some evidence from RCTs indicates that ivabradine monotherapy improves symptoms in people with angina. Available evidence indicates that it does not affect prognosis.
• Some CKS expert reviewers recommend that ivabradine is suitable for initiation in primary care. Other CKS reviewers recommend that primary health care professionals seek advice from a specialist before initiating ivabradine in primary care. CKS recommends that 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 ivabradine.
• Ivabradine is a black triangle drug — data on its long-term safety are limited, and it is being monitored intensively by the Commission on Human Medicines and the Medicines and Healthcare products Regulatory Agency [ABPI Medicines Compendium, 2010].
• Visual disturbances were commonly reported in people taking ivabradine in clinical studies. These were generally reported to be mild-to-moderate and resolved either during, or after stopping, treatment.
• Cardiovascular adverse effects have been noted in people taking ivabradine in clinical studies. Bradycardia has been noted in 3.3% of people taking ivabradine, particularly within the first 2 to 3 months of treatment. Only 0.5% of people have been reported to experience a severe bradycardia below or equal to 40 beats per minute.
• Psychiatric adverse effects (including one suicide) were reported in people taking ivabradine in two clinical studies.

Drugs for prognostic benefit

• Aspirin
• Strong evidence indicates that antiplatelet treatment reduces serious vascular events, non-fatal myocardial infarction, non-fatal stroke, and vascular mortality in people with cardiovascular disease [SIGN, 2007]. For a discussion of the evidence on antiplatelet treatment in people with previous MI, see the CKS topic on MI - secondary prevention.
• There is also evidence from one randomized placebo-controlled trial that in people with angina who are also taking a beta-blocker, aspirin reduces MI and sudden death [Juul-Möller et al, 1992].
• Statins
• Guidelines from the National Institute for Health and Clinical Excellence on lipid modification for the secondary prevention of cardiovascular disease [NICE, 2008] recommend that for secondary prevention, lipid modification therapy should be offered and should not be delayed by management of modifiable risk factors.
• For a full discussion of the use of statins for the secondary prevention of cardiovascular disease, see the CKS topic on Lipid modification - CVD prevention.
• Angiotensin-converting enzyme (ACE) inhibitors
• The benefits of ACE inhibitors after MI or in people with heart failure are well established. For further details, see the CKS topics on MI - secondary prevention and Heart failure - chronic.
• It is uncertain whether people with angina, but no other cardiovascular risk factors (for example previous MI, hypertension), are likely to benefit from taking an ACE inhibitor because evidence from large trials is conflicting [Fox et al, 2006b; SIGN, 2007].
• The European Society of Cardiology recommends that, in people with angina without coexisting indications for an ACE inhibitor (for example hypertension, heart failure, diabetes, or history of MI), the possible absolute benefits of treatment (which are greater in high-risk people with angina) should be weighed against the costs and risks of adverse effects [Fox et al, 2006a]. However, the view from the Joint British Societies is that ACE inhibitors are unlikely to offer any special benefit beyond that which can be attributed to reduction of blood pressure [British Cardiac Society et al, 2005].

Drugs that are not recommended

• Ranolazine
• Until further evidence of benefit and safety is available, ranolazine should only be initiated by a cardiologist.
• Some evidence from RCTs indicates that ranolazine improves symptoms in people with angina. Available evidence indicates that it does not affect prognosis.
• Ranolazine is a black triangle drug — data on its long-term safety are limited, and it is being monitored intensively by the Commission on Human Medicines and the Medicines and Healthcare products Regulatory Agency [ABPI Medicines Compendium, 2010].
• In clinical trials, the most common adverse effects were dizziness, nausea, asthenia, and constipation.
• There are concerns regarding QT prolongation noted in people taking ranolazine, and the increased likelihood of drug interactions.

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 conditions include 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.

• Comorbidities that are associated with an increased risk of new cardiovascular events are covered in the following CKS topics:
• Atrial fibrillation
• Chronic kidney disease - not diabetic
• Diabetes type 2
• Heart failure - chronic
• Hypertension - not diabetic
• Lipid modification - CVD prevention
• MI - secondary prevention
• Obesity
• Rheumatoid arthritis
• Stroke and TIA

• These recommendations are in line with those made by the National Institute for Health and Clinical Excellence in the guideline Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease [National Collaborating Centre for Primary Care, 2008].

• 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 licence 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.

• This information on medical rules is from the Driver and Vehicle Licensing Agency's guidance for medical practitioners, At a glance guide to the current medical standards of fitness to drive [DVLA, 2010].

• Reassure the person that, if they can briskly climb up and down two flights of stairs without any angina symptoms, sexual activity is unlikely to precipitate an episode of angina.
• If sexual activity does precipitate an episode of angina, sublingual glyceryl trinitrate (GTN) 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.

The information on angina and sexual activity is in line with that from the British Heart Foundation and guidelines from the European Society of Cardiology [BHF, 2006; Fox et al, 2006a].

Interaction between nitrates/nicorandil and phosphodiesterase inhibitors

• The combination of a phosphodiesterase inhibitor and a nitrate (including amyl nitrite) or nicorandil can result in excessive hypotension and possibly precipitate myocardial infarction [Baxter, 2008].
• The interaction with phosphodiesterase inhibitors is well established and clinically significant.
• It is not yet established whether nicorandil interacts with phosphodiesterase inhibitors to the same extent, but the manufacturers recommend that its use is contraindicated with all phosphodiesterase inhibitors.
• The duration between taking a nitrate or nicorandil and a phosphodiesterase inhibitor is based on expert consensus and information from the manufacturers of sildenafil, tadalafil, and vardenafil.

• 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.

• Information for patients is available from the British Heart Foundation (www.bhf.org.uk).
• See the BHF booklet HIS21 - Returning to work with a heart condition.

• The information on angina and work is based on advice and information from the British Heart Foundation [BHF, 2008a].

• Give the person the following advice depending on the severity of their angina symptoms:
• Chest pain on considerable exertion with no recent change in symptoms or medication: no restriction on flying.
• Chest pain on minimal exertion with no recent change of symptoms or medication: consider airport assistance and possible in flight oxygen.
• Chest pain at rest or a change in symptoms and/or medication: defer travel until stable or travel with a medical escort and ensure in flight oxygen is available.

• These recommendations are based on the British Heart Foundation Factfile: Fitness to fly for passengers with cardiovascular disease, which is based on the British Cardiovascular Society Working Group's expert guidance [BHF, 2010].

• 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 electrocardiography).
• Refer for prognostic exercise testing 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).

• This recommendation is based on expert consensus in the National Service Framework for coronary heart disease [DH, 2000] and guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2001; SIGN, 2007].

• 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 symptom 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.

• CKS found no evidence or guidelines on either the frequency or format of follow up and review for people with stable angina.
• Recommendations for the frequency of review are based on the opinion of CKS expert reviewers.

• 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.

• This recommendation is based on expert consensus in the National Service Framework for coronary heart disease [DH, 2000] and guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2001; SIGN, 2007].

People 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), as severe bradycardia and heart failure can occur.
• 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).

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.
• Do not combine a beta-blocker with a rate-limiting CCB (diltiazem or verapamil) as severe bradycardia and heart failure may occur.
• Do not combine a rate-limiting CCB with ivabradine, as severe bradycardia and heart failure may occur.

These recommendations are based on guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2007] and the European Society of Cardiology [Fox et al, 2006a].

Combining two drugs

• Evidence on combining two drugs for symptomatic relief of angina is limited.
• An industry-sponsored meta-analysis found that a beta-blocker combined with a calcium-channel blocker (CCB) is more effective at improving exercise tolerance than monotherapy [Klein et al, 2002], but other randomized controlled trials (RCT) found that the combination of CCBs and beta-blockers only provided small, if any, benefit in relief of anginal symptoms.
• There is weak evidence that isosorbide mononitrate combined with a beta-blocker improves symptoms of angina.
• Evidence from one large RCT supports the effectiveness of nicorandil plus either a beta-blocker or a CCB in reducing cardiovascular endpoints.
• Evidence from one randomized controlled trial suggests that, in people already taking a beta-blocker, the addition of ivabradine appears to provide increased control of angina symptoms. This combination has recently been licensed for use in the UK.
• CKS found no further RCTs of ivabradine in combination with other treatments for the symptomatic control of angina; however, several expert reviewers recommend their combination with a dihydropyridine CCB or a nitrate.
• Because of the limited evidence and experience of using ivabradine in combination with other anti-anginal drugs, CKS recommends that primary care prescribers consider seeking specialist advice before adding a second anti-anginal drug (other than a beta-blocker) to ivabradine.

Combining three drugs

• Evidence from an RCT found that a nitrate plus amlodipine or atenolol was as effective as the combination of all three in terms of symptomatic outcome measures [Pehrsson et al, 2000].
• Despite the lack of evidence, European guidelines suggest triple therapy as an option if optimal two-drug regimens are not effective, although careful evaluation of the effects and assessment for revascularization is advised [Fox et al, 2006a]. Triple therapy is used in clinical practice, although it increases the risk of adverse effects [Thadani, 2006].
• CKS expert reviewers suggest starting a third drug while awaiting referral.

• 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 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).

• This recommendation is based on expert consensus in the National Service Framework for coronary heart disease [DH, 2000] and guidelines from the Scottish Intercollegiate Guidelines Network [SIGN, 2001; SIGN, 2007].