European Journal of Heart Failure

European Journal of Heart Failure 2001 3(4):495-502; doi:10.1016/S1388-9842(01)00173-8

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© 2001 European Society of Cardiology

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

John McMurray^a,*, Alain Cohen-Solal^b, Rainer Dietz^c, Eric Eichhorn^d, Leif Erhardt^e, Richard Hobbs^f, Aldo Maggioni^g, Ileana Pina^h, Jordi Soler-Solerⁱ and Karl Swedberg^j

^a Clinical Research Initiative in Heart Failure Glasgow, Scotland G11 6NT, UK
^b L'Hôpital Beaujon Clichy, France
^c Franz-Volhard-Klinik Berlin, Germany
^d VA Hospital Dallas, TX, USA
^e University Hosptial Malmo, Sweden
^f Department of Primary Care and General Practice Birmingham, UK
^g Research Centre Anmco Florence, Italy
^h University Hospital Cleveland, USA
ⁱ Vall d'Hebron University Barcelona, Spain
^j Department of Medicine, Sahlgrenska Hospital/Östra Goteborg, Sweden

^* Corresponding author. Tel.: +44-141-330-6588; fax: +44-141-330-6588. E-mail address: j.mcmurray{at}bio.gla.ac.uk (J. McMurray).

	Abstract

Top Abstract 1. Introduction 2. Development of... 3. Practical recommendations 4. Conclusions References

 
Surveys of prescribing in both hospitals and primary care have shown delays in translating improved survival data from clinical trials into clinical practice thereby denying patients the benefits of proven treatments, such as the angiotensin converting enzyme inhibitors. This may be due to unfamiliarity with clinical guidelines and concerns about adverse events. Recent trials have shown that substantial improvements in survival are associated with spironolactone and beta-blocker therapy. In order to accelerate the uptake of these treatments, and to ensure that all eligible patients should receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of heart failure. The objective of these recommendations is to provide practical guidance for non-specialists in order to support the implementation of evidenced-based therapy for heart failure. These practical recommendations are meant to supplement rather than replace existing guidelines.

Key Words: Clinical recommendations • Beta-blockers • Angiotensin converting enzyme inhibitors • Spironolactone • Heart failure

Received June 1, 2001; Accepted June 25, 2001

	1. Introduction

Top Abstract 1. Introduction 2. Development of... 3. Practical recommendations 4. Conclusions References

 
Evidence-based medicine is the accepted goal to which doctors should aspire in their clinical practice. In the past two decades, large, placebo controlled, double-blind trials have been conducted in patients with chronic heart failure (CHF) using clinically important outcome measures, such as mortality and major morbid events. The trials were designed with adequate patient numbers and length of follow-up to provide the required number of events to ensure the necessary statistical power for unequivocal interpretation of the results. Consequently, there is now evidence for the safety and efficacy, or otherwise, of a number of medical interventions. It has, nevertheless, become apparent that, in spite of the publication of the results of such clinical trials, the translation of the results into clinical prescribing has been slow and incomplete. Patients are thus denied the benefits of proven interventions, which would increase both the quality and quantity of life.

In spite of a number of trials showing significant improvements in survival and reductions in hospitalisations for patients with chronic heart failure who received angiotensin converting enzyme inhibitors (Table 1) [1,2], a number of clinical surveys conducted in different countries both in primary care [3,4] and in hospital practice [5–7] revealed that substantial proportions of patients who should have been treated with an angiotensin converting enzyme inhibitor were not receiving the treatment. It is not entirely clear what the reasons are for the reluctance of doctors to prescribe angiotensin converting enzyme inhibitors to all patients who should receive them but there does seem to be unreasonable concern about possible adverse effects, such as hypotension or renal insufficiency [4,8]. Furthermore, the doses of angiotensin converting enzyme inhibitors used in clinical practice has been lower than the doses used in the clinical trials which were shown to have survival benefits. Whether or not these lower doses would have the same benefits as the higher doses can only be the subject of speculation but the results of the Assessment of Treatment with Lisinopril and Survival (ATLAS) trial which compared low and high doses of an angiotensin converting enzyme inhibitor showed that the high dose was significantly better than the low dose in reducing the combined end-point of mortality and hospitalisation [9]. In addition to the under-prescribing and under-dosing of angiotensin converting enzyme inhibitors having unfavourable consequences for the patients, there is also an unfavourable impact on the costs incurred in managing heart failure [10].

View this table: [in this window] [in a new window]   Table 1 Events prevented per 1000 patients years of treatment

 
A large trial of spironolactone vs. placebo in patients with moderate to severe heart failure, already receiving diuretic and angiotensin converting enzyme inhibitor therapy, showed improved survival and reduced hospitalisation in the group treated with spironolactone (Table 1) [11] but no information is available at present as to the uptake of spironolactone into prescribing practice.

The recent publications of four large clinical trials of beta-blockers in patients with chronic heart failure [12–16] have shown that when the beta-blocker therapy was added to standard therapy which included both diuretic and angiotensin converting enzyme inhibitor, significant improvements in survival and reductions in hospitalisations were achieved (Table 1).

1.1. Need for practical guidance
The speed and extent of uptake of angiotensin converting enzyme inhibitors as a treatment for chronic heart failure has been repeatedly shown to be disappointing in many countries [3–7]. Beta-blockers usage after myocardial infarction is similarly unsatisfactory and this is also likely to be the case in chronic heart failure [17–19]. There does, therefore, appear to be the need for a practical tool to facilitate the implementation of evidence based therapy.

	2. Development of recommendations

Top Abstract 1. Introduction 2. Development of... 3. Practical recommendations 4. Conclusions References

 
On the assumption that the reluctance of doctors to prescribe the angiotensin converting enzyme inhibitors and beta-blockers reflects a lack of practical, easy-to-follow advice on dosing, both initiation and maintenance and identification of potential problems, with clear recommendations on how to handle these if they should arise, a group of clinicians with expertise in the diagnosis and management of heart failure met recently. The output of this meeting was a step-wise, concise set of clinical recommendations for each of beta-blockers, angiotensin converting enzyme inhibitors and spironolactone based on the questions which a physician is likely to ask when considering treatment options: why should the treatment be given; in whom and when; where (in which setting); which agent and what dose; how to use; advice to patient; and problem solving. These practical recommendations are not meant to replace existing guidelines [20–31], but rather offer a tool to facilitate their implementation.

	3. Practical recommendations

Top Abstract 1. Introduction 2. Development of... 3. Practical recommendations 4. Conclusions References

 
The 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 salt and water overload.

Step 1 requires that the presence of left ventricular systolic dysfunction is confirmed using 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.

Step 2 requires the initiation of first-line therapy which, for all patients with heart failure due to left ventricular systolic dysfunction, consists of an angiotensin converting enzyme inhibitor (for New York Heart Association classes I–IV) and a beta-blocker (for New York Heart Association classes I–IV), unless these are contra-indicated. It is important that contra-indications and cautions are observed. It is recommended that the angiotensin converting enzyme inhibitor is initiated first, followed by the beta-blocker, that both are initially introduced at low doses and then up-titrated slowly, and that both are titrated to the target doses used in the clinical trials checking tolerability and blood chemistry. The objective is to treat patients with both an angiotensin converting enzyme inhibitor and a beta-blocker, both, ideally given at the target doses used in the large randomised trials. It was, however, the panel's view that lower doses of both treatment were still likely to be of value and should be used if larger doses are not tolerated. These recommendations are set out in more detail in Table 2 for angiotensin converting enzyme inhibitors and Table 3 for beta-blockers.

View this table: [in this window] [in a new window]   Table 2 Practical guidance on the use of ACE inhibitors in patients with CHF due to left ventricular systolic dysfunction

 

View this table: [in this window] [in a new window]   Table 3 Practical guidance on the use of beta-blockers in patients with CHF due to left ventricular systolic dysfunction

 
Step 3 requires the addition of second-line therapy for those patients in whom there are persisting signs and symptoms of heart failure (New York Heart Association class III/IV), consisting of spironolactone and digoxin. Again, it is important that contra-indications and cautions are observed, that spironolactone is initiated first followed by digoxin, that both are initiated at a low dose and then up-titrated checking tolerability and blood chemistry. The recommendations for spironolactone are set out in Table 4. Digoxin is included in this summary as one large trial showed that it reduced the need for hospital admission, particularly for worsening heart failure, though this treatment had no effect on survival, either positive or negative (Table 1) [32]. Digoxin may still have a special role in the patient with atrial fibrillation when rapid control of the ventricular rate is needed (which cannot be achieved with cautious introduction and up-titration of a beta-blocker). Initial treatment with digoxin should not preclude subsequent introduction of a beta-blocker. Digoxin can be withdrawn if an excessive bradycardia develops during combined digoxin beta-blocker treatment although combined use of digoxin and beta-blockers may be required for optimal ventricular rate control [35].

View this table: [in this window] [in a new window]   Table 4 Practical guidance on the use of spironolactone in patients with CHF due to left ventricular systolic dysfunction

 

	4. Conclusions

Top Abstract 1. Introduction 2. Development of... 3. Practical recommendations 4. Conclusions References

 
Under-prescribing and under-dosing of therapeutic interventions which have significantly reduced both mortality and morbidity in patients with chronic heart failure in controlled clinical trials is a persisting problem. Consequently, this under-treatment denies patients the benefits of these interventions and has an adverse health economic effect in terms of increased hospitalisations. The preparation of these concise and practical clinical recommendations for the prescribing of angiotensin converting enzyme 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 health care systems.

	References

Top Abstract 1. Introduction 2. Development of... 3. Practical recommendations 4. Conclusions References

 

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