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Although the most widely indicated medication for cardiovascular disease,

?-blockers are significantly underused by GPs ­

Dr Rubin Minhas makes

an evidence-based case

for their use

While there are many general concerns about ?-blockers there is little evidence to support these. Indeed our increasing understanding of ?-blockers means the Nobel Prize statement that they are 'the greatest discovery against heart illness' (see box right) is more true today than it was then, despite the advent of several other classes of treatment.

Clinical trial evidence does not support the notion that ?-blockers are associated with substantial risks of side-effects, including depressive symptoms or sexual dysfunction. Trial data indicates there is no significant increased risk of depressive symptoms and only a minor increase in sexual dysfunction (one additional report for every 199 patients treated per year)3. It is therefore important to review the characteristics of these drugs in light of their significant potential benefits.

Yet audits have shown ?-blockers remain underused in clinical practice and this underuse has been associated with general concerns. Low levels of discharge medication from hospital have also been identified as a key influence that inhibits greater community-based prescribing of ?-blockers4.

Differences in class

?-blockers are traditionally classified by the specific site of their antagonist effects on the sympathetic nervous system. Some ?-blockers block both the B1 receptors (found mainly in the heart) and B2 receptors (found in heart, arteries and bronchi) while others are more selective for the ?1 receptor ­ these are termed cardioselective ?-blockers (see table right).

In practice, cardioselectivity is dose dependent and can decrease or disappear as the dose is increased. Some agents also exhibit peripheral vasodilator activity due to effects on alpha 1 receptors (eg carvedilol), stimulation of ?2

receptors (eg celiprolol) or via novel mechanisms that may involve the nitrous oxide pathway (eg nebivolol).

The lipid solubility of ?-blockers is a factor that influences the likelihood of both therapeutic and adverse effects and it is worthwhile being aware of the common lipophilic drugs (ie propranolol and metoprolol) and hydrophilic drugs (ie atenolol, esmolol, nebivolol). Lipophilic ?-blockers are more likely to enter the central nervous system and produce CNS side-effects.

?-blockers act through numerous mechanisms to reduce heart rate, including via reducing AV

nodal conduction and reducing myocardial contractility, which is in addition to their peripheral effects.

Where there is a degree of pre-existing heart disease affecting the conduction system some patients may demonstrate an exaggerated reduction in heart rate ­ for this reason it is important to check the patient's pulse rate when these drugs are initiated or patients are reviewed.

Increasing indications

?-blockers are now the mostly widely indicated class of medication in the treatment of cardiovascular disease as they are recommended in the treatment of hypertension, following myocardial infarction, in stable angina, heart failure and also in the treatment of particular arrhythmias.


When treating hypertension, in the absence of compelling indications for specific therapy, GPs should adopt a cost minimisation approach and use the least-cost therapy as efficacy is broadly similar between different classes of agent5,6.

?-blockers are among the first-line drugs for hypertension according to the ABCD rule and more suited to younger, non-black patients where the renin angiotension system is more likely to be a factor in their hypertension5.

Co-existing conditions such as stable angina or previous MI are a compelling indication for

?-blockers in the absence of an absolute contraindication5.

The use of ?-blockers in treating hypertension demonstrates a linear and increasing relationship between dose and response which is mirrored by a similar increase in side-effects. Reduction in blood pressure is only about 20 per cent less at half standard dose than at standard dose, but adverse effects are much less common ­ in one meta-analysis ?-blockers caused symptoms in 5.5 per cent of patients at half standard dose and in 7.5 per cent at standard dose while adverse metabolic effects (such as changes in cholesterol or potassium) were negligible at half standard dose.


NICE guidance specifies ?-blockers among the first drugs that patients should receive following an MI ­ the sequence being ?-blockers and aspirin and then ACE inhibitors and statins7. Controlled trials have demonstrated a 20-25 per cent improvement in survival for patients given chronic ?-blocker therapy post-MI compared with placebo8,9.

At this level of benefit GPs need to treat 84 patients for one year to prevent one death8. Of all the therapies currently available for the prevention of sudden cardiac death, none is more established or more effective than ?-blockers.

Patients with angina are an obvious group at risk of MI and for this reason clinical guidelines also specify ?-blocker use in patients with angina where possible10.

Heart failure

NICE guidance for treating confirmed heart failure recommends patients with left ventricular systolic dysfunction be initiated on ?-blockers after diuretic and ACE inhibitor therapy and regardless of whether symptoms persist11.

Patients should be stable and already taking initial therapy such as diuretics and ACE inhibitors. Up to a third of patients will report feeling worse during the first three months of treatment but it is worth encouraging them to persevere as the eventual benefits are considerable.

?-blocker prescribing in heart failure is suboptimal and concerns regarding tolerability in the elderly have been cited3. The two licensed

?-blockers for treating heart failure are carvedilol and metoprolol.

The results of the SENIORS study now demonstrate beneficial effects in the elderly population using nebivolol. ?-blocker initiation should be undertaken by GPs who are experienced in their use in heart failure.

Initial doses should be low and titrated slowly upwards at no more than fortnightly intervals.

Carvedilol is licensed for use in the hospital setting while bisoprolol has a licence for use in primary care. The licence for bisoprolol stipulates a four-hour period of monitoring following the initial dose (1.25mg). Patients arriving for an early (or first) morning appointment can have their blood pressure and pulse rate monitored on hourly intervals by the practice nurse after having taken the first dose.

If patients with heart failure experience tolerability issues (as around 20-30 per cent of patients will) then any dose of ?-blocker is preferable to none at all. In practice it is worth spending more time explaining the potential benefits of these drugs to patients as they are more effective than ACE inhibitors at reducing mortality in heart failure and early counselling helps to improve concordance.

Important considerations apply to initiating ?-blockers in heart failure and the NICE guidance provides a useful review of their use.

Atrial fibrillation

?-blockers may be useful in slowing heart rate in sinus tachycardia particularly where anxiety, hyperthyroidism or heart failure are present. They are also useful in suppressing SVTs, including atrial flutter and atrial fibrillation (AF).

The incidence of AF is also reduced in patients who receive ?-blockers, pointing to a preventive role. Where patients with AF are not rate controlled, a combination of ?-blocker and digoxin appears to be more effective than either drug alone ­ atenolol and sotalol appear to be the most effective drugs at reducing heart rate in this situation.


Asthma and COPD

Asthma or bronchospastic COPD is a contraindication to the use of ?-blockers. It is important to be aware that COPD is not itself a contraindication to ?-blockers but only when there is significant reactive airways disease component12.

If a reactive component has been excluded (through spirometry) these patients may benefit from the use of low-dose cardioselective (?1)

?-blockers such as atenolol or nebivolol.


Contrary to popular belief, diabetes is not a contraindication to the use of ?-blockers3,12. As diabetes is a risk factor for heart disease and the two conditions often co-exist, there may be situations as with the post-MI patient where the clinical benefit outweighs the risk. Trial evidence indicates that post-MI diabetic patients may actually benefit more than non-diabetic patients.

In type 1 diabetes, non-selective ?-blockers may mask some of the warning signs of hypoglycaemia such as tremor or tachycardia. But studies have shown that hypoglycemic unawareness to a dangerous extent is only a problem in a minority of type 1 diabetes patients and is not encountered in the vast majority of type 2 diabetes patients13.

Adverse effects

?-blockers are generally well tolerated; however, tiredness (5 per cent), bronchospasm (4 per cent), cold extremities (2 per cent), and diarrhoea (2 per cent) have been reported significantly more often than with control patients during clinical trials. Side-effects are more common when these drugs are used in large doses. However, serious complications of

?-blockers are relatively rare.

Symptoms such as sweating are unaffected and can be enhanced by both non-selective and selective

?-blockers14. In diabetic patients a selective ?-blocker such as atenolol or nebivolol should be considered in preference to a non selective ?-blocker.

Blockade of vascular ?2 receptors can give rise to symptoms of cold extremities, Raynaud's phenomenon and worsen symptoms in patients with peripheral vascular disease. In practice patients with mild to moderate peripheral vascular disease can probably be given ?-blockers safely12.

In this scenario a selective ?1 ?-blocker such as atenolol is obviously preferable. Alternatively, one that has vasodilating properties, such as nebivolol, may offer additional reassurance and tolerability. Patients with severe PVD (pain at rest, ischemic ulcers) should not receive ?-blockers.

?-blockers have been reported to have an adverse effect on serum lipids. Non-selective ?-blockers tend to decrease HDL levels by about 10 per cent and increase triglyceride levels by 25-30 per cent while cardioselective ?-blockers have a less pronounced effect.

Even for patients who experienced the adverse effects on lipids, mortality after MI was reduced by 20 per cent in a large controlled tria · 13.

Considerations for clinical use

Consideration must be given to the relative benefit of treatment where there may be a relative contraindication ­ particularly with patients

with heart disease and a single relative contraindication.

Examination of the patient should include a comprehensive cardiorespiratory check. An ECG should also be undertaken to exclude heart block and pulse rate checked regularly at each review in addition to blood pressure.

Where indicated, a selective ?1 receptor blocker (eg atenolol) is preferable to a non-selective

?-blocker (eg propranolol). If patients complain of peripheral side-effects a vasodilating ?-blocker such as nebivolol can be useful and if CNS side-effects are reported hydrophilic agents such as atenolol or nebivolol can be considered.

Treatment should begin with a low dose and be increased gradually every four weeks. If patients complain of mild side-effects they should be encouraged to persevere where possible or a dose reduction might be attempted.

If patients are unable to tolerate any dose of a

?-blocker the medication should be stopped gradually over a period of weeks as upregulation of receptors during ?-blockade means that patients may experience withdrawl effects if treatment is stopped suddenly.

The specific quality target for using ?-blockers in CHD patients will award seven points, worth around £525 to the average practice, for establishing treatment in 50 per cent of patients.

Rubin Minhas is a GP in Medway, Kent, and a NICE Appraisal Committeee member ­ hs is also a board member of the Primary Care Cardiovascular Society

The shifting ground on ?-blockers

When the Nobel Prize in Medicine was awarded to Sir James Black in 1988 for his role in the development of ?-blockers, his discovery was heralded as 'the greatest breakthrough against heart illness since the discovery of digitalis 200 years ago'.

Yet fears have grown among GPs over the years regarding

side-effects, contraindications and co-morbidities.

GPs have also traditionally lacked experience in initiating ?-blockers.

In September 2004 a major report by the European Society of Cardiology1 said GPs were over-estimating the risk of side-effects from ?-blockers.

The consensus report backed greater use in hypertension, non-ST-segment elevation acute coronary syndromes, heart failure, myocardial infarction and secondary prevention of coronary heart disease.

It added GPs should consider using the drugs even when they were apparently contraindicated, arguing that diabetes, peripheral vascular disease and chronic obstructive pulmonary disease were 'not absolute contraindications' and the benefits could outweigh the risks.

Weeks later a University of Dundee study2 said GPs should

trial patients with ?-blockers

for secondary MI prevention,

even if they have 'relative' contraindications.

It concluded those with the

most to gain ­ post-MI, heart failure, obstructive pulmonary disease, aged >80 ­ were the most neglected.

2 Summary of current

recommendations on

?-blocker therapy

·Co-therapy in hypertensive patients receiving a diuretic at low risk of new onset diabetes1,2

·?-blockers, aspirin, then ACE inhibitors/ statins are recommended following MI3

·?-blockers have been shown to reduce mortality when prescribed to patients before or following a myocardial infarction6

·?-blockers indicated in NYHA II-IV heart failure7

·GMS contract: GPs must determine the percentage of their patients with known coronary heart disease receiving

?-blocker therapy


01 Expert consensus document on ?-adrenergic receptor blockers.

European Heart Journal (2004) 25, 1341-1362

02 MWei L et al. Use and adherence to ?-blockers for secondary prevention of MI: who is not getting the treatment? Pharmacoepidemiology and drug safety, April 2004, Volume 13, issue 11, 761-6

03 ?-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. Ko DT et al. JAMA. 2002 Jul 17;288(3):351-7

04 The Euro Heart Failure Survey programme ­ a survey on the quality of

care among patients with heart failure in Europe. Part 2: treatment. Komajda M et al. Eur Heart J. 2003 Mar;24(5):464-74

05 Williams B et al. Guidelines for the management of hypertension: report of the fourth working party of the British Hypertension Society ­ BHS IV:

J Hum Hypertens 2004;18:139-85

06 Management of hypertension in adults in primary care

07 NICE guideline on prophylaxis for patients who have experienced an MI

08 Yusuf S et al. Primary and secondary prevention of myocardial

infarction and strokes. An update of randomly allocated clinical trials.

J Hypertens 1993; (Suppl. 4):S61-S73

09 Freemantle N et al. ?-blockade after myocardial infaction. Systematic review and metaregression analysis. BMJ 1999:1730-7

10 Joint British recommendations on the prevention of coronary heart disease in clinical practice. Heart 1998;80:1-29 (December)

11 Management of chronic heart failure in adults in primary and secondary care

12 Expert consensus document on ?-adrenergic receptor blockers.

European Heart Journal(2004) 25, 1341-62

13 ?-blockers for the Treatment of Hypertension in Patients with Diabetes: Exploring the Contraindication Myth. Majumdar SR.

Cardiovascular Drugs and Therapy 1999; 13: 435-439

14 Tse WY, Kendall M. Is there a role for ?-blockers in hypertensive diabetic patients? Diabetic Medicine 1994; 11: 137-144

15 GMS contract.

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