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Family Practice Vol. 18, No. 2, 217-222
© Oxford University Press 2001

Guidelines

Evidence-based guideline for the primary care management of stable angina

Martin Eccles, Nikki Rousseau, Phil Adams,a, Lois Thomas and for the North of England Stable Angina Guideline DevelopmentGroup

Centre for Health Services Research, University of Newcastle Upon Tyne, 21 Claremont Place, Newcastle Upon Tyne NE2 4AA and
a Royal Victoria Infirmary, Newcastle Upon Tyne, UK.

Professor Martin Eccles.

Eccles M, Rousseau N, Adams P and Thomas L for the North of England Stable Angina Guideline Development Group. Evidence-based guideline for the primary care management of stable angina. Family Practice 2001; 18: 217–222.

Received 19 April 2000; Accepted 30 October 2000.

Keywords. Angina, clinical guideline, ischaemic heart disease.


   Introduction
Top
 Introduction
Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
This is an updated version of the first North of England Stable Angina Guideline1,2 and summarizes the full guideline.3 This paper presents all the recommendations within the guideline; and where these are new or substantially altered from the original version, it also presents a summary of the supporting evidence.

The aims and methods of development (summarized in Box 1Go) of this guideline are unchanged from the original version, to which readers are directed for more detail. The research questions raised during the development of this guideline are shown in Box 2.Go


BOX1 The search strategy, categories of evidence and strength of recommendations

The search strategy and synthesizing the literature

We searched the electronic databases MEDLINE, EMBASE and the Cochrane Database of Reviews (1994–1997) using a combination of subject heading and free text terms aimed at locating systematic reviews, meta-analyses and randomized trials. The search was backed up by the expert knowledge and experience of group members. The quality of relevant studies retrieved was assessed and, from relevant papers, the information was synthesized qualitatively. The studies on drug use were categorized against explicit criteria into two groups. The first group comprised studies that had high internal and external validity, reported exercise test results and which measured the outcomes that were likely to be available to a GP (GTN use, anginal frequency). In addition, studies which did not fulfil all these criteria were used provided they had high internal and external validity and reported exercise duration. The second group comprising studies that did not fulfil these criteria were cited as ‘supporting papers’ only and are reported in the full version of the guideline only.

Categories of evidence

I: evidence from meta-analysis of randomized controlled trials or from at least one randomized controlled trial
II: evidence from at least one controlled study without randomization or at least one other type of quasi-experimental study
III: evidence from non-experimental descriptive studies, such as comparative studies, correlation studies and case–control studies
IV: evidence from expert committee reports or opinions and/or clinical experience of respected authorities

Strength of recommendation

  1. A directly based on category I evidence
  2. B directly based on category II evidence or extrapolated recommendation from category I evidence
  3. C directly based on category III evidence or extrapolated recommendation from category I or II evidence
  4. D directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence

 

BOX2 Research questions

There are few cost-effectiveness data available for any of the strategies recommended within the guideline; such analysis would be valuable.

Investigation of angina: what is the role of routine biochemical testing in the investigation of patients with stable angina?

Exercise testing: what are the indications for repeating an exercise test in a patient with stable angina?

Diet: what is the cost-effectiveness of a Mediterranean style diet and an increased fatty fish diet in patients with stable angina?

Secondary prophylactic treatment: what is the cost-effectiveness of other anti-platelet drugs in those patients who cannot take low dose aspirin?

Choosing a second drug: what is the most appropriate choice of second line drug?

Non-drug treatment: is there a role for complementary therapies in the treatment of stable angina?

 


   Initial assessment
Top
 Introduction
 Initial assessment
Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
This guideline requires that the following should be known: precipitants of anginal attacks; smoking history; occupation; amount of exercise taken; drug history; weight; and blood pressure. A blanket chronological age limit for investigation or referral was not felt to be appropriate; functional status was felt to be more appropriate.


   Precipitating factors
Top
 Introduction
 Initial assessment
 Precipitating factors
Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
Recommendation:

  • Factors that precipitate angina should be enquired about and their management discussed (D).


   Investigation of angina
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
Recommendations:

Patients being investigated for angina should have the following investigations:

  • Haemoglobin, thyroid function and blood glucose measured (D)
  • Serum lipids measured in accordance with local guidelines (see risk factor management) (A).


   Resting 12-lead electrocardiogram (ECG)
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
Recommendation:

  • All patients with angina should have a resting 12-lead ECG (B) and it should be interpreted by someone who is competent to do so (D).


   Exercise testing
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
Recommendations:

  • All patients with clinically certain angina should have an exercise test; this will mean referral to an open access service where this is available and referral to a cardiologist where it is not (B).
  • If a patient who requires an exercise test cannot physically perform the test they should be referred to a cardiologist for consideration of other forms of investigation (D).
  • Patients having an exercise test for prognostic investigation and treatment should have the test performed while taking their normal medication (B).
  • Whether or not a patient has diabetes and the oestrogen status of women should be recorded on a request form as it will influence the performance and interpretation of the test (B).

Patients who should not have an exercise test are:

  • Those whose symptoms are uncontrolled on maximal medical therapy (they should be referred to a cardiologist for consideration of angiography, not exercise testing) (D).
  • Those who are physically incapable of performing the test for reasons other than their angina (see above) (D).
  • Those with co-morbid illness that is currently more important (D).
  • Those who decline to have the test (D).


   Risk factor modification
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
Drug treatment
 Review of patients with...
 Referral of patients
 References
 
Assessing risk factors
Recommendations:

  • The majority of patients with stable angina will be at increased risk of subsequent cardiovascular events or death; the assessment of a patient's absolute risk of subsequent cardiovascular events or death should be based upon an assessment of all of their risk factors. As well as their modifiable risk factors, this will include their age, sex, whether or not they have diabetes and their family history of premature coronary heart disease (A).

A patient's absolute risk of subsequent cardiovascular events or death is related to their underlying risk factors, both modifiable and non-modifiable (I).4

Cholesterol
Recommendations:

  • All patients with angina should have their serum lipids measured (A).
  • The management of serum cholesterol should be considered along with the management of other modifiable risk factors (A).
  • A patient with a raised serum cholesterol should be offered treatment to lower their serum cholesterol (A).
  • The use of statins for lowering cholesterol has economic consequences that are still the subject of debate and disagreement; details of lipid management should be addressed in local guidelines (D).

Most (but not all) patients with stable angina are at high risk of subsequent cardiovascular events or death (I), and patients at high risk of subsequent cardiovascular events or death benefit from having a raised serum cholesterol lowered (I). Cholesterol-lowering using statins is effective at reducing subsequent coronary heart disease mortality and morbidity (I). In patients with ischaemic heart disease, there is no good evidence to support the effectiveness of a range of ‘diet alone’ interventions (low fat diets; garlic, oats and soy protein) in lowering total mortality, or fatal or non-fatal coronary events (I). In patients at high risk of ischaemic heart disease (>3% annual CHD death rate), fibrates are, on balance, beneficial in reducing CHD event rates. Not all patients with stable angina will be at such risk (I).4,5

Blood pressure
Recommendations:

  • All patients should have their blood pressure measured and, if it is consistently raised, should be offered treatment to lower it (A).
  • The management of raised blood pressure should be considered along with the management of other modifiable risk factors (A).

For patients with high blood pressure, anti-hypertensive medication reduces the risk of cardiovascular and all cause mortality (I).6 The details of levels of intervention, target levels of control and appropriate drugs vary between published guidelines.

Smoking and smoking cessation
Recommendations:

  • The current smoking status of all patients should be known so that patients with angina who smoke should be advised to stop (A).
  • While there is no one strategy that is effective for all patients, strategies should be centred on both advice and support from a health professional and nicotine replacement therapy in those who are motivated to quit (A).
  • Nicotine patches can safely be used to help patients with coronary artery disease stop smoking (A).

Both brief advice from a health professional and nicotine replacement therapy can help patients stop smoking (I).7,8 Transdermal nicotine is safe to use with patients with ischaemic heart disease (I),9,10 although the BNF11 recommends caution when using nicotine products in patients with cardiovascular disease.

Exercise
Recommendations:

  • Moderate exercise within a patient's capabilities should be recommended to improve general fitness and well-being (C).
  • Training packages may help improve exercise capacity but the important constituents of such packages are not clear (C).

Training packages may help improve exercise capacity, but the important constituents of such packages are not clear (I).12,13

Weight reduction and dietary management
Recommendations:

  • Hypertensive (A) and normotensive (C) patients with a body mass index above the normal range should be encouraged to reduce their body weight until their BMI is as close to normal as is achievable.
  • Patients with stable angina who have survived a myocardial infarction should be advised to eat a ‘Mediterranean diet’ and oily fish twice a week (A).

Weight-reducing diets in overweight hypertensive persons can affect modest weight loss and may decrease dosage requirements of persons taking anti-hypertensive medications (I).14 Patients who have survived a myocardial infarction and take a ‘Mediterranean diet’ or increase their intake of fatty fish have a lower rate of subsequent cardiovascular events (I).15,16 In one randomized controlled trial, supplemental vitamin E reduced non-fatal myocardial infarction rates (I).17


   Drug treatment
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
Review of patients with...
 Referral of patients
 References
 
Recommendations:

  • It is important to ensure that patients are complying with treatment and that any side effects they are experiencing are known about (D).
  • Within any drug class, patients should be treated with the cheapest preparation that they can tolerate, comply with and that controls their symptoms (D).

Secondary prophylactic treatment Recommendations:

  • Patients who have stable angina should be treated with aspirin 75 mg daily for four years (A).
  • After four years, aspirin should be continued long term at a dose of 75 mg daily (D).

Aspirin given to patients with stable angina lowers their risk of suffering a subsequent vascular event (I).18

Initial symptomatic treatment Recommendations:

  • Patients should be treated with short-acting nitrates as required in response to pain and before performing activities that are known to bring on pain (A).
  • For all but minimal symptoms, patients should be started on regular symptomatic treatment (D).

Regular symptomatic treatment
First line monotherapy: beta-blockers Recommendations:

  • All patients who require regular symptomatic treatment should be treated with a beta-blocker (B).
  • The dose should be increased to the maximum tolerated; this will involve adjusting the dose according to the patient's response (D).
  • Patients should be warned not to stop beta-blockers suddenly nor to allow them to run out (B).
  • If beta-blockers need to be stopped, they should be tailed off over a period of four weeks (D).

First line monotherapy: verapamil for patients who cannot take beta-blockers Recommendation:

  • Patients intolerant of beta-blockers should be treated with verapamil (C).

First line monotherapy for patients who cannot take beta-blockers or verapamil Recommendations:

  • If a patient cannot tolerate a beta-blocker or verapamil, then there is no clear basis from the evidence for choosing substitution monotherapy. They should therefore be given the cheapest drug with which they can comply and that controls their symptoms (D).
  • If nitrates are to be used, they should be used in a way that avoids nitrate tolerance (A), and nitrate patches, if used, should be used in dosages of at least 10 mg (A).

Choosing a second anti-anginal drug Recommendations:

  • In patients taking beta-blockers, add a dihydropyridine or diltiazem (B).
  • In patients taking beta-blockers who cannot tolerate dihydropyridines or diltiazem, add isosorbide mononitrate (B).
  • In patients taking verapamil, add isosorbide mononitrate (D).
  • In patients taking dihydropyridines, add isosorbide mononitrate (D).
  • In patients taking nitrates, add any calcium channel blocker (B).

In six studies, adding dihydropyridines to beta-blockers produces an improvement in a range of parameters (I).19–24 In three studies, adding dihydropyridines to beta-blockers produces no additional effect across a range of parameters (I).25–29

Adding diltiazem to beta-blockers produces a dose-dependent improvement in symptom control and exercise tolerance (I).30 If this combination is used, the cautions in the BNF should be observed.

The effectiveness of adding nitrates to beta-blockers or calcium channel blockers may be determined by the preparation used. Adding isosorbide dinitrate to beta-blockers or calcium channel blockers produces no additional benefit. Nitrate patches added to beta-blockers produce no additional benefit. Adding isosorbide mononitrate to beta-blockers is effective (I).31–33 In patients taking nitrates, add any calcium channel blocker (I).34

Choosing a third drug Recommendations:

  • In patients who are not adequately controlled on maximal therapeutic doses of two drugs, then the remaining evidence-based therapeutic options are very limited. Such patients should be referred rather than given a third drug (D).
  • If a third drug is introduced, for instance, while awaiting an out-patient appointment, its effect should be monitored and, if it has no effect, it should be stopped (D).


   Review of patients with stable angina
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
Referral of patients
 References
 
Recommendation:

  • Patients should be reviewed at least annually (D).


   Referral of patients
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
References
 
Recommendations:

  • All patients in whom the diagnosis is uncertain should be considered for referral for clarification of the diagnosis (D).
  • All patients in whom management is currently suboptimal, as judged by symptoms, should be considered for referral for further treatment or investigation (D).
  • Patients whose symptoms are uncontrolled on maximal medical therapy should be referred to a cardiologist for angiography not exercise testing (D).
  • For patients who are not adequately controlled on full doses of two drugs, the remaining evidence-based therapeutic options are very limited. Such patients should be referred rather than given a third drug (D).
  • Reasons for not referring are: patients declining referral; patients currently having a more significant condition (D).

See referral for an exercise test above.


   Acknowledgments
 
We thank the following people for reviewing the full version of the guideline: Dr R Baker, Director, Eli Lilly National Clinical Audit Centre, University of Leicester, Dr TA Carney, General Practitioner, Hexham, Northumberland, Professor S Cobbe, Walton Professor of Medical Cardiology, University of Glasgow, Dr JA Hall, Consultant Cardiologist, Cardiothoracic Unit, South Cleveland Hospital, Middlesbrough, Dr G Jackson, Consultant Cardiologist, St Thomas' Hospital, London, Dr JMH Jackson, General Practitioner, Newcastle upon Tyne, and Dr JS Skinner, Consultant Community Cardiologist, Royal Victoria Infirmary, Newcastle upon Tyne. We are grateful to Maureen Craig, Linda Duckworth and Liz Wood for their skilled secretarial work on the guideline. The updating of the guideline was funded by the Department of Health of England and Wales. The Centre for Health Services Research is a member of the Medical Research Council Health Services Research Collaboration.

Guideline development group: Dr P Adams (consultant cardiologist and specialist resource), Professor M Eccles (small group leader, guideline methodologist), Dr H Geoghegan (GP), Ms C Frizelle (nurse), Dr J Harley (GP), Dr K Kunti (lecturer in general practice), Dr J Mason (health economist), Dr J Myers (GP), Dr B Penney (GP), Ms N Rousseau [research associate (from 1st May 1998)], Dr E Selby (GP), Dr L Thomas [research associate (until 30th April 1998)].


   References
Top
 Introduction
 Initial assessment
 Precipitating factors
 Investigation of angina
 Resting 12-lead...
 Exercise testing
 Risk factor modification
 Drug treatment
 Review of patients with...
 Referral of patients
 References
 
1 North of England Evidence Based Guideline Development Project. Evidence Based Clinical Practice Guideline: The Primary Care Management of Stable Angina. Report 74. Newcastle upon Tyne: Centre for Health Services Research, 1996.

2 North of England Stable Angina Guidelines Development Group. Evidence based guideline for the primary care management of stable angina: summary version. Br Med J 1996; 312: 827–832.[Free Full Text]

3 North of England Evidence Based Guideline Development Project. The Primary Care Management of Stable Angina. 98. Newcastle upon Tyne: Centre for Health Services Research, 1999.

4 NHS Centre for Reviews and Dissemination. Cholesterol and coronary heart disease: screening and treatment. Effect Health Care 1998; 4: 1–16.

5 Davey Smith G, Song F, Sheldon TA. Cholesterol lowering and mortality: the importance of considering initial level of risk. Br Med J 1991; 306: 1367–1373.

6 Mulrow C, Lau J, Cornell J, Brand M. Antihypertensive drug therapy in the elderly (Cochrane Review). In The Cochrane Library, Issue 2. Oxford: Update Software, 1998.

7 Lancaster T, Silagy C, Fullerton D. Tobacco addiction module of the Cochrane Database of Systematic Reviews. In The Cochrane Library, Issue 4. Oxford: Update Software, 1998.

8 NHS Centre for Reviews and Dissemination. Smoking cessation: what the health service can do. Effectiveness Matters 1998; 3.

9 Working Group for the Study of Transdermal Nicotine in Patients with Coronary Artery Disease. Nicotine replacement therapy for patients with coronary artery disease. Working group for the study of transdermal nicotine in patients with coronary artery disease. Arch Intern Med 1994; 154: 989–995.[Abstract]

10 Joseph AM, Norman SM, Ferry LH et al. The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 1996; 335: 1792–1798.[Abstract/Free Full Text]

11 British Medical Association. British National Formulary. Bath: BMA, The Pharmaceutical Press, 1998.

12 Lewin B, Cay EL, Todd I et al. The Angina Management Programme: a rehabilitation treatment. Br J Cardiol 1995; 2: 221–226.

13 Cupples ME, McKnight A. Randomised controlled trial of health promotion in general practice for patients at high cardiovascular risk. Br Med J 1994; 309: 993–996.[Abstract/Free Full Text]

14 Brand MB, Mulrow CD, Chiquette E et al. Weight reduction through dieting for control of hypertension in adults. In The Cochrane Library, Issue 4. Oxford: Update Software, 1998.

15 de Lorgeril M, Salen P, Martin J-L et al. Effect of a mediterranean type of diet on the rate of cardiovascular complications in patients with coronary artery disease. Insights into the cardioprotective effect of certain nutriments. J Am Coll Cardiol 1996; 28: 1103–1108.[Abstract]

16 Burr ML, Gilbert JF, Holliday RM et al. Effects of changes in fat, fish and fibre intakes on death and myocardial reinfarction: Diet And Reinfarction Trial (DART). Lancet 1989; 30 September: 757–761.

17 Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS) [see comments]. Lancet 1996; 347: 781–786.[ISI][Medline]

18 Eccles M, Freemantle N, Mason J, North of England Aspirin Guideline Development Group. North of England Evidence Based Guideline Development Project: evidence based guideline for the use of aspirin for the secondary prophylaxis of vascular disease in primary care. Br Med J 1998; 316: 1303–1309.[Free Full Text]

19 Uusitalo A, Arstila M, Bae EA et al. Metoprolol, nifedipine, and the combination in stable effort angina pectoris. Am J Cardiol 1986; 57: 733–737.[ISI][Medline]

20 DiBianco R, Schoomaker FW, Singh JB et al. Amlodipine combined with beta blockade for chronic angina: results of a multicenter, placebo-controlled, randomized double-blind study. Clin Cardiol 1992; 15: 519–524.[ISI][Medline]

21 Foale RA. Atenolol versus the fixed combination of atenolol and nifedipine in stable angina pectoris. Eur Heart J 1993; 14: 1369–1374.[Abstract/Free Full Text]

22 Dunselman P, Liem AH, Verdel G, Kragten H, Bosma A, Bernink P. Addition of felodipine to metoprolol vs replacement of metoprolol by felodipine in patients with angina pectoris despite adequate beta-blockade. Results of the Felodipine ER and Metoprolol CR in Angina (FEMINA) Study. Eur Heart J 1997; 18: 1755–1764.[Abstract/Free Full Text]

23 Ronnevik PK, Silke B, Ostergaard O. Felodipine in addition to beta-adrenergic blockade for angina pectoris: a multicentre, randomized, placebo-controlled trial. Eur Heart J 1995; 16: 1535–1541.[Abstract/Free Full Text]

24 Davies RF, Habibi H, Klinke WP et al. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. J Am Coll Cardiol 1995; 25: 619–625.[Abstract]

25 Dargie HJ, Ford I, Fox KM. Total Ischaemic Burden European Trial (TIBET). Effects of ischaemia and treatment with atenolol, nifedipine SR and their combination on outcome in patients with chronic stable angina. The TIBET Study Group. Eur Heart J 1996; 17: 104–112.[Abstract/Free Full Text]

26 Fox KM, Mulcahy D, Findlay I, Ford I, Dargie HJ. The Total Ischaemic Burden European Trial (TIBET). Effects of atenolol, nifedipine SR and their combination on the exercise test and the total ischaemic burden in 608 patients with stable angina. The TIBET Study Group. Eur Heart J 1996; 17: 96–103.[Abstract/Free Full Text]

27 Ardissino D, Savonitto S, Egstrup K et al. Selection of medical treatment in stable angina pectoris: results of the International Multicenter Angina Exercise (IMAGE) study. J Am Coll Cardiol 1995; 25: 1516–1521.[Abstract]

28 Savonitto S, Ardissiono D, Egstrup K et al. Combination therapy with metoprolol and nifedipine versus monotherapy in patients with stable angina pectoris. Results of the International Multicenter Angina Exercise (IMAGE) study. J Am Coll Cardiol 1996; 27: 311–316.[Abstract]

29 Madjlessi-Simon T, Fillette F, Mary-Krause M, Lechat P, Jaillon P. Effects of amlodipine on transient myocardial ischaemia in patients with a severe coronary condition treated with a beta-blocker. Amlor-Holter Study Investigators [see comments]. Eur Heart J 1995; 16: 1780–1788.[Abstract/Free Full Text]

30 Heller GV, Sridharan M, Morse J et al. Antianginal response to once-daily diltiazem CD in patients receiving concomitant beta-blockers, long-acting nitrates, or both. Pharmacotherapy 1997; 17: 760–766.[ISI][Medline]

31 Uusitalo A, Keyrilainen O, Harkonen R et al. Anti-anginal efficacy of a controlled-release formulation of isosorbide-5-mononitrate once daily in angina patients on chronic beta-blockade. Acta Med Scand 1988; 223: 219–225.[ISI][Medline]

32 Thadani U, Maranda CR, Amsterdam E et al. Lack of pharmacologic tolerance and rebound angina pectoris during twice-daily therapy with isosorbide-5-mononitrate. Ann Intern Med 1994; 120: 353–359.[Abstract/Free Full Text]

33 Parker JO, Amies MH, Hawkinson RW et al. Intermittent transdermal nitroglycerin therapy in angina pectoris: clinically effective without tolerance or rebound. Circulation 1995; 91: 1368–1374.[Abstract/Free Full Text]

34 Cutler NR, Eff J, Fromell G et al. Dose-ranging study of a new, once-daily diltiazem formulation for patients with stable angina. J Clin Pharmacol 1995; 35: 189–195.[Abstract]


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