European Heart Journal (2002) 23, 13221323

doi:10.1053/euhj.2002.3225, available online at http://www.idealibrary.com on

Optimization of ACE inhibitor therapy in heart failure

See doi:10.1053/euhj.2001.3112 for the article to which
this Editorial refers
The clinical syndrome of heart failure results in
impaired quality of life, exercise intolerance, frequent
hospital admissions and high mortality. Each of these
can be of importance for a patient with heart failure.
Ideal drug treatment for heart failure should result in
improvement in all of these end-points. However, it is
now well established that there can be dissociation
between short- and long-term eects of pharmacological agents. For example, both enoximone and
milrinone can improve symptoms in the short term
but result in increased mortality, mainly due to an
increase in sudden presumed arrhythmic death[1,2]. As
a result of this and the dominance of survival data for
drug regulatory requirements, the eects of many
drugs on end-points other than survival are relatively
unstudied. However, improvement in symptoms,
quality of life and ability to exercise rather than
survival, may be a higher priority for heart failure
patients, particularly the elderly.
ACE inhibitor therapy provides a good example of
this data disparity, with clear evidence of survival
benefit but conflicting information on the eects on
exercise. The study in this edition by Cooke et al.
again raises the issue of the optimal dose of ACE
inhibitor therapy in heart failure[3]. The study relates
the pathophysiology of exercise intolerance in heart
failure to vasodilator therapy with ACE inhibitors.
The study was performed with a small sample of 12
heart failure patients in a crossover design, testing the
eects of 5 mg and 20 mg of lisinopril on exercise
capacity. The low-dose of lisinopril had more favourable eects on aerobic exercise capacity than the
20 mg dose. Although this is an elegant study, several
issues relevant to the application of these findings to
heart failure patients remain uncertain. For example,
although the study demonstrated beneficial eects on
aerobic exercise capacity, there were no data to
support extension of these benefits to overall improvements in quality of life. Many heart failure
patients are severely limited by concomitant conditions and thus data on exercise capacity alone are
not convincing enough to mandate this dose. In
addition, how the eects observed in this study will
translate to the patient receiving standard betablocker therapy is uncertain.
Other studies have compared dierent doses of
ACE inhibitors in heart failure patients. A recent
comparison of low (5 mg . day
1) and high dose

enalapril (40 mg . day
1) in heart failure patients

demonstrated no greater suppression of angiotensin
II, aldosterone or catecholamines with the high dose
compared with the low dose[4]. There were no dierences in exercise duration or VO2 between the two
groups. However, there was a trend for a reduction in
a pre-specified clinical composite end-point (hospital
admission, emergency room visit, death, sustained
increase in diuretic) in the high-dose group. The
ATLAS trial compared (very) low-dose lisinopril (25
to 5 mg . day
1) with (very) high-dose lisinopril
(35 mg . day
1) in 3614 patients with heart failure[5].
There was no statistically significant dierence in
survival (primary end-point) between the two groups
although there was a significant reduction in hospital
admissions for heart failure and the combined endpoint of death or hospital admission with the high
dose. These data support a beneficial eect on clinical
outcome with higher dose ACE inhibitor therapy but
do not preclude a similar advantage with an intermediate dose which may be more practical and
ecient.
Thus, while it is clear that ACE inhibitor therapy
should be used to treat patients with heart failure,
uncertainty remains regarding the optimal dose. How
do we incorporate this information into the clinical
decision making for individual patients? A fundamental concept of evidence-based medicine is that we
should take the overall clinical trial results obtained
from various heterogeneous patient groups and apply
these to individual patients. There are many circumstances where we must make assumptions beyond
the available evidence until such time as (hopefully)
further evidence gaps are filled. One argument is to
assume that the apparent beneficial eects of high
dose ACE inhibitor therapy on expensive hospital
readmissions should outweigh any lesser eect on
aerobic exercise capacity and be justified on the
basis of cost eectiveness. Worsening heart failure
occurs commonly in heart failure patients and will
contribute to the impaired quality of life for these
individuals. Thus, this argument for higher-dose
therapy is reasonable. No clear evidence-based recommendations can be made regarding the eects of
ACE inhibitors at dierent doses on survival alone.
The practical reality though is that many patients
with heart failure may not tolerate the high doses of
ACE inhibitor required to achieve these benefits.
Thus, we may end up with many patients receiving intermediate doses, such as the equivalent of
lisinopril 20 mg daily, where the eects on hospital

 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.

Editorials

readmissions and worsening heart failure may be less

pronounced. This moderate approach is more in
keeping with the average dose actually achieved in the
large-scale ACE inhibitor survival trials[6,7] and in our
view is a reasonable target.
A more attractive future option would be to tailor
therapy to the individual patient. This would allow
optimization of drugs and dosage to achieve the
optimal outcomes for that individual patient. Tailoring therapy to achieve a desired neurohormonal
response and improve outcomes has been demonstrated[8] and further large-scale clinical trials are
ongoing in this area. In the meanwhile we should
ensure that evidence-based therapies are more widely
applied in general to all patients with heart failure,
continue to debate dosage while supporting
additional more definitive studies.
R. N. DOUGHTY
N. SHARPE
Division of Medicine,
Faculty of Medical and Health Sciences,
The University of Auckland,
Auckland,
New Zealand

1323

References
[1] Cowley AJ, Skene AM on behalf of the Enoximone Investigators. Treatment of severe heart failure: quantity or quality of
life? A trial of enoximone. Br Heart J 1994; 72: 22630.
[2] Packer M, Carver JR, Rodeheer RJ et al. for the PROMISE
Study Research Group. Eect of oral milrinone on mortality in
severe heart failure. N Engl J Med 1991; 325: 146875.
[3] Cooke GA, Williams SG, Marshall P et al. A mechanistic
investigation of ACE inhibitor dose eects on aerobic exercise
capacity in heart failure patients. Eur Heart J 2002; 23:
135866.
[4] Tang WHW, Vagelos RH, Yee Y-G et al. Neurohormonal and
clinical responses to high-versus low-dose enalapril therapy in
chronic heart failure. J Am Coll Cardiol 2002; 39: 708.
[5] Packer M, Poole-Wilson Armstrong PW et al. Comparative
eects of low and high doses of the angiotensin-converting
enzyme inhibitor, lisinopril, on morbidity and mortality in
chronic heart failure. ATLAS Study Group. Circulation 1999;
100: 23128.
[6] The CONSENSUS Trial Study Group. Eects of enalapril on
mortality in severe congestive heart failure. Results of the
Cooperative North Scandinavian Enalapril Survival Study
(CONSENSUS). N Engl J Med 1987; 316: 142935.
[7] The SOLVD Investigators Eect of enalapril on survival in
patients with reduced left ventricular ejection fractions and
congestive heart failure. N Engl J Med 1991; 325: 293302.
[8] Troughton RW, Frampton CM, Yandle TG, Espiner EA,
Nicholls MG, Richards AM. Treatment of heart failure guided
by plasma aminoterminal brain natriuretic peptide (n-BNP)
concentrations. Lancet 2000; 355: 112630.

European Heart Journal (2002) 23, 13231325

doi:10.1053/euhj.2002.3178, available online at http://www.idealibrary.com on

Home-based management of patients with chronic heart

failure focus on content not just form!
See doi:10.1053/euhj.2001.3114 for the article to which
this Editorial refers
Chronic heart failure is common, costly, dangerous
and treatable, and is a syndrome mainly found
among elderly patients. Its management is often
complex and involves the use of several pharmacological agents, in particular, neurohormonal antagonists. The significance of lifestyle modifications has not
been studied carefully, but is recognised to be important. The value of chronic heart failure management
has been outlined in several recent Guidelines[1,2].
Treatment of chronic heart failure, as transmitted
by these documents, shows the need for monitoring
of patients during initiation of therapy as well as
during follow-up. With modern therapy, prognosis
has improved markedly with reduction of mortality,
morbidity and improved quality of life.

How do we implement treatment as outlined in

these Guidelines? Unfortunately, many patients with
chronic heart failure are not oered optimal treatment. In Euro-HF, primary care physicians from six
European countries were asked about chronic heart
failure treatments[3]. Knowledge of ACE-inhibitors
was wide, but perceived dose levels were lower than
recommended. The beneficial eects of beta-blockers
were not familiar. In IMPROVEMENT, primary
care physicians from 24 countries were also asked
about chronic heart failure treatment[4]. The use of
ACE-inhibitors and beta-blockers were more common in this study than in Euro-HF. However, their
prescription varied widely and were mostly initiated
other than by primary care physicians. The limited
take-up of these beneficial therapeutic options may
be explained by the complexity of their use. Neurohormonal blockers, for example ACE-inhibitors and

 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.