practical recommendations for the use of ace inhibitors, beta-blockers and spironolactone in heart...

Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure:

Putting Guidelines into Practice

— INTRODUCTION —

McMurray J, Cohen-Solal A, Dietz R, Eichhorn E, Erhardt L,

Hobbs R, Maggioni A, Pina I, Soler-Soler J, Swedberg K

Eur J Heart Failure 2001;3:495–502

Practical Recommendations for Heart Failure Treatment: Putting Guidelines into Practice


• A number of large, carefully designed clinical outcome trials have been

conducted in patients with chronic heart failure

• The trials were sufficiently powered to allow unequivocal interpretation

of the results

• Consequently, there now exists robust safety and efficacy information

on a number of therapeutic interventions

• The translation of these results into clinical prescribing has been

slow and incomplete

• Patients may therefore be denied the full benefit of proven

therapeutic interventions



Development of Recommendations• The speed and extent of update of evidence-based therapies (particularly ACE

inhibitors and beta-blockers) for the treatment of heart failure has been disappointing in hospital practice and primary care

• This may reflect a lack of practical advice regarding dosing issues and the management of associated adverse events

• Consequently, a group of eminent clinicians with expertise in the management of heart failure met during 2000

• The remit of the faculty was to review all the relevant published clinical trials and produce a set of clinical recommendations independent of any other interests

Practical Recommendations for in Heart Failure Treatment: Putting Guidelines into Practice


Advisory GroupJohn McMurray Glasgow, UK

Alain Cohen-Solal Clichy, France

Rainer Dietz Berlin, Germany

Eric Eichhorn Dallas, USA

Leif Erhardt Malmö, Sweden

Richard Hobbs Birmingham, UK

Aldo Maggioni Florence, Italy

Ileana Pina Cleveland, USA

Jordi Soler-Soler Barcelona, Spain

Karl Swedberg Göteborg, Sweden



Output• The output from discussions was a step-wise, concise set of clinical recommendations

concentrating on three key therapies for the management of heart failure

• These recommendations are not meant to replace existing guidelines, but rather provide a tool to facilitate their implementation

• The opinions expressed are those of the faculty members and do not necessarily reflect the views of AstraZeneca or the manufacturers of the products mentioned

• Prescribers need to be aware of the relevant product prescribing information which applies in their country

• The costs associated with the Advisory Group meetings were met by an educational grant from AstraZeneca



FormatThe practical recommendations for treatment are reviewed under the

following headings: Why? – what evidence exists to support the use of these treatments In whom and when? – which patients, what contra-indications, what cautions and

drug interactions Where? – hospital or primary care setting Which agent and what dose? – options offered based on

outcome evidence How to use – titration and monitoring information Advice to patient – expected benefits and drawbacks Problem solving – management of adverse events and concomitant medications



Practical Recommendations

These recommendations start from the assumption that the physician has made

a clinical diagnosis of heart failure and may have initiated diuretic treatment for

treating the symptoms and signs associated with fluid overload

• STEP 1

- Confirm left ventricular systolic dysfunction (LVSD) by echocardiography, radionuclide ventriculography or radiological left ventricular angiography. [These investigations are regarded as definitive and must be regarded as representing the minimum standard of care.]



Practical Recommendations• STEP 2

- Initiate first-line therapy in all patients with heart failure due to LVSD with an ACE inhibitor for NYHA class I-IV and a beta-blocker for NYHA class II-III, unless

these are contra-indicated.- Initiate ACE inhibitor first, followed by beta-blocker, both initially at low doses and

then up-titrate slowly to the target doses used in the clinical trials, check tolerability and blood chemistry.

• STEP 3 - Initiate second-line therapy in patients with persistent signs and symptoms

of heart failure (NYHA class III/IV) with spironolactone and digoxin; contra-indications and cautions should be observed. - Initiate spironolactone first followed by digoxin, both at a low dose and then up-

titrate, check tolerability and blood chemistry.



‘The preparation of these concise and practical clinical recommendations for the prescribing of ACE inhibitors and beta-blockers should provide doctors with the

confidence to practise evidence-based medicine in their patients with chronic heart failure. This would improve not only the outcomes for the individual

patient but also reduce the burden on healthcare systems.’






— ACE INHIBITORS —






ACE Inhibitors – Why?• CONSENSUS I, the SOLVD-treatment study and a meta-analysis of smaller trials

showed conclusively that ACE inhibitors increase survival, reduce hospital admissions and improve NYHA class and quality of life in patients with all grades of symptomatic heart failure

• ATLAS showed clinically important advantages with higher doses of ACE inhibitors in heart failure

• SAVE, AIRE and TRACE showed that ACE inhibitors increase survival in patients with systolic dysfunction after acute myocardial infarction

• SOLVD-prevention study showed that ACE inhibitors delay or prevent the development of symptomatic heart failure in patients with asymptomatic LVSD



Co-operative North SScandinavian Enalapril Survival SStudy I – CONSENSUS I

CONSENSUS Trial Study Group N Engl J Med 1987;316:1429–1435

80

70

10

20

30

40

50

60

0 1 2 3 4 5 6 7 8 9 10 11 12

Follow-up (months)

Mortality

(%)

Enalapril

Placebo

Riskreduction40%p=0.002



Studies of Left Ventricular Dysfunction – SOLVD (Treatment Study)

SOLVD Investigators N Engl J Med 1991;325:293–302

0

10

20

30

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50

0 6 12 18 24 30 36 42 48

PlaceboEnalapril

Follow-up (months)

Mortality(%)

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0 6 12 18 24 30 36 42 48

PlaceboEnalapril

Follow-up (months)

Mortality(%)




Assessment of Treatment with Lisinopril and Survival Study ATLAS

Event- free* survival High-dose %

Low-dose

0 6 12 18 24 30 36 42 48

0

25

50

75

100

Follow-up (months)

*Combined all-cause mortality plus all-cause hospitalisations

Risk reduction 12% p=0.002



ACE Inhibitors – In Whom and When?Indications:

• Potentially all patients with heart failure• First-line treatment (along with beta-blockers) in NYHA class I–IV heart failure

Contra-indications:• History of angioneurotic oedema

Cautions/seek specialist advice:• Significant renal dysfunction (creatinine >2.5 mg/dL or 221 µmol/L) or

hyperkalaemia (K+ >5.0 mmol/L)• Symptomatic or severe asymptomatic hypotension (SBP <90 mmHg)

Drug interactions to look out for:• K+ supplements/ K+ sparing diuretics (including spironolactone)• NSAIDs*

• AT1-receptor blockers *avoid unless essential



ACE Inhibitors – Where? In the community for most patients

Exceptions – see CAUTIONS/SPECIALIST ADVICE



ACE Inhibitors – Which and What Dose?

Starting dose Target dose

• captopril 6.25 mg tds 50–100 mg tds

• enalapril 2.5 mg bd 10–20 mg bd

• lisinopril 2.5–5 mg od 30–35 mg od

• ramipril 2.5 mg od 5 mg bd/10 mg od

• trandolapril 1 mg od 4 mg od

od = once daily; bd = twice daily; tds = thrice daily



ACE Inhibitors – How to Use• Start with a low dose

• Double dose at not less than two weekly intervals

• Aim for target dose or, failing that, the highest tolerated dose

• Remember some ACE inhibitor is better than no ACE inhibitor

• Monitor blood chemistry (urea, creatinine, K+) and blood pressure

• When to stop up-titration/down-titration – see PROBLEM SOLVING



ACE Inhibitors – Advice to Patient• Explain expected benefits (see WHY?)

• Treatment is given to improve symptoms, to prevent worsening of heart failure and to increase survival

• Symptoms improve within a few weeks to a few months

• Advise patients to report principal adverse effects

(i.e. dizziness/symptomatic hypotension, cough)



ACE Inhibitors – Problem SolvingAsymptomatic low blood pressure:

• Does not usually require any change in therapy

Symptomatic hypotension:

• If dizziness, light-headedness and/or confusion and low blood pressure occur, reconsider need for nitrates, calcium channel blockers* and other vasodilators

• If no signs/symptoms of congestion, consider reducing diuretic dose

• If these measures do not solve the problem, seek specialist advice

*calcium channel blockers should be discontinued unless absolutely essential (e.g. for angina or hypertension)



ACE Inhibitors – Problem Solving (continued)Cough:

• Cough is common in patients with heart failure, many of whom have smoking-related lung disease

• Cough is also a symptom of pulmonary oedema, which should be excluded if a new or worsening cough develops

• ACE inhibitor-induced cough rarely requires treatment discontinuation

• If a very troublesome cough develops (e.g. one stopping the patient sleeping) and can be proven to be due to ACE inhibition (i.e. it recurs after ACE inhibitor withdrawal and rechallenge), substitution with an AT1-receptor blocker can be considered



ACE Inhibitors – Problem Solving (continued)Worsening renal function:• Some increase in urea (blood urea nitrogen), creatinine and K+ is to be expected after

initiation; if the increase is small and asymptomatic no action is necessary• An increase in creatinine of up to 50% above baseline, or 3 mg/dL (266 µmol/L),

whichever is the smaller, is acceptable• An increase in K+ 6.0 mmol/L is acceptable• If urea, creatinine or K+ rise excessively, consider stopping concomitant nephrotoxic

drugs (e.g. NSAIDs), other K+ supplements/ K+ retaining agents (triamterene, amiloride) and, if no signs of congestion, reducing the dose of diuretic

• If greater rises in creatinine or K+ than those outlined above persist, despite adjustment of concomitant medications, halve the dose of ACE inhibitor and recheck blood chemistry; if there is still an unsatisfactory response, specialist advice should be sought



ACE Inhibitors – Problem Solving (continued)Worsening renal function (cont.):

• If K+ rises to >6.0 mmol/L, or creatinine increases by >100% or to above 4 mg/dL (354 µmol/L), the dose of ACE inhibitor should be stopped and specialist advice sought

• Blood chemistry should be monitored serially until K+ and creatinine have plateaued

NOTE: it is very rarely necessary to stop an ACE inhibitor and clinical deterioration is likely if treatment is withdrawn; ideally, specialist advice should be sought before treatment discontinuation


— AT1-RECEPTOR BLOCKERS —

AT1-Receptor Blockers

• At present, position is unclear due to inconclusive evidence from clinical trials (ELITE I, ELITE II, Val-HeFT)

• Currently, prescribing AT1-receptor blockers in heart failure should be confined to patients who are unable to tolerate ACE inhibitors

• Results from the ongoing CHARM study programme, involving candesartan, should provide a clearer picture of their role in heart failure management



— BETA BLOCKERS —






Beta Blockers – Why? USCP, CIBIS II, MERIT-HF and COPERNICUS have shown conclusively that

beta-blockers increase survival, reduce hospital admissions and improve NYHA class and quality of life when added to standard therapy (diuretics, digoxin and ACE inhibitors) in patients with stable mild and moderate heart failure and in some patients with severe heart failure

• One trial (BEST) did not show a reduction in all-cause mortality but did report a reduction in cardiovascular mortality



United States Carvedilol Program (USCP)

Packer M et al. N Engl J Med 1996;334:1349–1355

556065707580859095

100

Carvedilol

Placebo

Duration of therapy (days)


Survival(%)

0 50 100 150 200 250 350 400300



Cardiac Insufficiency Bisoprolol Study II ( (CIBIS II)

CIBIS II Investigators, Lancet 1999;359:9–13

0

60

80

100

0 200 400 600 800Time after inclusion (days)

Survival(%)

Bisoprolol

Placebo

Riskreduction34%p<0.0001



Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF)

Hjalmarson A et al. Lancet 1999;353:2001–2007

0

5

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0 3 6 9 12 15 18 21Follow-up (Months)

Mortality(%)

Placebo

Metoprolol

Risk reduction 34%p=0.0062



Beta Blockers – In Whom and When?Indications:

• Potentially all patients with stable mild and moderate heart failure; patients with severe heart failure should be referred for specialist advice

• First-line treatment (along with ACE inhibitors) in patients with stable NYHA class II–III heart failure; start as early as possible

Contra-indications:

• Asthma



Beta Blockers – In Whom and When? (continued)Cautions/seek specialist advice:

• Severe (NYHA Class IV) heart failure

• Current or recent (<4 weeks) exacerbation of heart failure (e.g. hospital admission with worsening heart failure)

• Heart block or heart rate <60 beats/min

• Persisting signs of congestion – raised jugular venous pressure, ascites, marked peripheral oedema

Drug interactions to look out for:• verapamil/diltiazem (should be discontinued)• amiodarone



Beta Blockers – Where? In the community in stable patients (NYHA class IV/severe heart failure patients

should be referred for specialist advice) Not in unstable patients hospitalised with worsening heart failure Other exceptions – see CAUTIONS/SEEK SPECIALIST ADVICE



Beta Blockers – Which and What Dose?

Starting dose Target dose bisoprolol 1.25 mg od 10 mg od carvedilol 3.125 mg bd 25–50 mg bd metoprolol CR/XL 12.5–25 mg od 200 mg od od = once daily; bd = twice daily



Beta Blockers – How to Use • Start with a low dose

• Double dose at not less than two-weekly intervals

• Aim for target dose or, failing that, the highest tolerated dose

• Remember some beta-blocker is better than no beta-blocker

• Monitor HR, BP, clinical status (symptoms, signs – especially signs of congestion, and body weight)

• Check blood chemistry 1–2 weeks after initiation and 1–2 weeks after final dose titration

• A specialist heart failure nurse may assist with patient education, follow-up (in person/by telephone) and dose up-titration

• When to down-titrate/stop up-titration – see PROBLEM SOLVING



Beta Blockers – Advice to Patient • Explain expected benefits (see WHY?)

• Emphasise that treatment given as much to prevent worsening of heart failure as to improve symptoms; beta-blockers also increase survival

• If symptomatic improvement occurs, this may develop slowly, 3–6 months or longer

• Temporary symptomatic deterioration may occur (estimated 20–30% of cases) during initiation/up-titration phase



Beta Blockers – Advice to Patient (continued)• Advise patient to report deterioration (see PROBLEM SOLVING) and that

deterioration (tiredness, fatigue, breathlessness) can usually be easily managed by adjustment of other medication; patients should be advised not to stop beta-blocker therapy without consulting their physician

• Patients should be encouraged to weigh themselves daily (after waking, before dressing, after voiding, before eating) and to increase their diuretic dose should their weight increase, persistently (>2 days), by >1.5–2.0 kg



Beta Blockers – Problem SolvingWorsening symptoms/signs (e.g. increasing dyspnoea,

fatigue, oedema, weight gain):

• If increasing congestion, double the dose of diuretic and/or halve the dose of beta-blocker (if increasing diuretic does not work)

• If marked fatigue (and/or bradycardia – see below), halve the dose of beta-blocker (rarely necessary)

• Review patient in 1–2 weeks; if not improved, seek specialist advice

• If serious deterioration, halve the dose of beta-blocker or stop this treatment (rarely necessary); seek specialist advice



Beta Blockers – Problem Solving (continued)Low heart rate:

• If <50 beats/min and worsening symptoms – halve the dose of beta-blocker or, if severe deterioration, stop beta-blocker (rarely necessary)

• Review need for other heart-rate slowing drugs (e.g. digoxin, amiodarone, diltiazem)

• Arrange ECG to exclude heart block

• Seek specialist advice



Beta Blockers – Problem Solving (continued)Asymptomatic low blood pressure:

• Does not usually require any change in therapy

Symptomatic hypotension:

• If dizziness, light-headedness and/or confusion and a low blood pressure occur, reconsider need for nitrates, calcium channel blockers and other vasodilators

• If no signs/symptoms of congestion, consider reducing diuretic dose

• If these measures do not solve problem, seek specialist advice

NOTE: Beta-blockers should not be stopped suddenly unless absolutely necessary (there is a risk of a ‘rebound’ increase in myocardial ischaemia/infarction and arrhythmias); ideally specialist advice should be sought before treatment discontinuation



— SPIRONOLACTONE —





— SPIRONOLACTONE—







Spironolactone – Why?

The RALES study showed that low-dose spironolactone increased survival, reduced hospital admissions and improved NYHA class when added to standard therapy (diuretic, digoxin, ACE inhibitor and, in a minority of cases, a beta-blocker) in patients with severe (NYHA class III or IV) heart failure



Pitt B et al. N Engl J Med 1999;10:709–717

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Spironolactone

Placebo

Probabilityof survival

Months

Randomized AldactoneEvaluationStudy(RALES)

Risk reduction 30%p<0.001



Spironolactone – In Whom and When?

Indications:

• Potentially all patients with symptomatically moderately severe or severe heart failure

• Second-line therapy (after ACE inhibitors and beta-blockers) in patients with NYHA class III–IV heart failure

Cautions/seek specialist advice:

• Significant renal dysfunction (creatinine >221 µmol/L or 2.5 mg/dL)

• Significant hyperkalaemia (K+ >5.0 mmol/L)



Spironolactone – In Whom and When? (Continued)

Drug interactions to look out for:• ACE inhibitors, AT1-receptor blockers, other K+ sparing diuretics (beware

combination preparations, e.g. frusemide plus amiloride or triamterene), K+ supplements (e.g. KCl)

• NSAIDs• ‘Low salt’ substitutes with high K+ content



Spironolactone – Where?• In the community or in hospital

• Exceptions – see CAUTIONS/SEEK SPECIALIST ADVICE

Spironolactone – Which Dose?• Starting dose: 25 mg od or on alternate days

• Target dose: 25–50 mg od



Spironolactone – How to Use• Start at 25 mg once daily

• Check blood chemistry at 1, 4, 8 and 12 weeks; 6, 9 and 12 months; 6 monthly thereafter

• If K+ rises to between 5.5 and 6.0 mmol/L, or creatinine rises to 2.5 mg/dL (221 µmol/L), reduce dose to 25 mg on alternate days and monitor blood chemistry closely

• If K+ rises to >6.0 mmol/L, or creatinine to >4.0 mg/dL (354 µmol/L), stop spironolactone and seek specialist advice



Spironolactone – Advice to Patient• Explain expected benefits (see WHY?)

• Treatment is given to improve symptoms, prevent worsening of heart failure and to increase survival

• Symptom improvement occurs within a few weeks to a few months of starting treatment

• Avoid NSAIDs not prescribed by a physician (self-purchased ‘over the counter’ treatment, e.g. ibuprofen)

• Temporarily stop spironolactone if diarrhoea and/or vomiting occur and contact

physician



Spironolactone – Problem SolvingWorsening renal function/hyperkalaemia:

• See HOW TO USE section

• Major concern is hyperkalaemia (K+ >6.0 mmol/L) though this was uncommon in RALES; a high-normal K+ may be desirable in heart failure patients, especially if taking digoxin

• It is important to avoid other K+ retaining drugs (e.g. K+ sparing diuretics) and nephrotoxic agents (e.g. NSAIDs)

• Some ‘low salt’ substitutes have a high K+ content

• Male patients may develop breast discomfort and/or gynaecomastia

practical recommendations for the use of ace inhibitors, beta-blockers and spironolactone in heart...

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