Clinical case studies in heart failure management

Robert J. MacFadyen,1,2 Paul Shiels1 & Allan D. Struthers1

1 2
Departments of Clinical Pharmacology and Cardiology, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY,
United Kingdom

Keywords: aetiologies, case studies, clinical cardiac failure, diagnosis, diastolic failure,
dysrhythmia, management issues, optimal treatment, systolic failure, trial evidence

unremarkable. Echocardiography showed a dilated heart

Therapeutic aspects of heart failure management
(left ventricular end diastolic distension (LVEDD)
The outlook for patients with cardiac failure has improved 650 mm) with anterior and septal hypokinesis and apical
substantially in the last 15 years. This is largely due to dilatation compatible with previous anterior infarction.
the application of the results of multicentre clinical trials The posterior wall was contracting vigorously. A high
of new and older drugs and a better understanding of velocity jet (4.7 m s−1 ) of mitral regurgitation was noted
outcomes for individual patients. Interest has focused on but the left atrial size was normal.
systolic dysfunction in both symptomatic and asympto-
matic patients. Less is known about the definition and
Comments
management of diastolic dysfunction.
The following case studies have been chosen to This is a common clinical presentation of progressive
illustrate the basis for therapeutic management of systolic systolic dysfunction after unheralded myocardial infarc-
heart failure and outline the remaining gaps in knowledge, tion. A number of therapeutic and general management
of which there are several. The issues apply across the steps should be considered for all such patients. Whereas
spectrum of patients seen in clinical practice. in stable patients clinical identification or grading of the
severity of heart failure is unreliable [1], recent studies
suggest that in acute heart failure clinical diagnosis is
Acute stabilization and chronic management of
much more secure [2]. Any abnormality of the ECG in
systolic failure
a breathless patient is supportive evidence for a cardiac
Case history cause of dyspnoea. A normal ECG usually suggests
another diagnosis [3]. Radiological cardiomegaly is also
A 74-year-old female patient was admitted from home
supportive of a diagnosis of heart failure [4]. This is not
with progressive increase in breathlessness, orthopnoea
the case for more subtle radiological signs, even in the
and ankle oedema over the previous 3 weeks. Her general
hands of experienced radiological staff [5] where the
practitioner had prescribed oral coamoxiclav and coamilo-
clinical context can significantly affect the interpretation.
fruse (substituting the latter for bendrofluazide). She had
Radiological cardiomegaly most often represents either
suffered from dyspepsia, increasing over recent weeks,
significant ventricular dilatation or hypertrophy ( provided
and the general practitioner had noted a new murmur.
−1 that there is no suspicion of pericardial fluid). This, in
She was apyrexial yet tachypnoeic (25 beats min );
conjunction with an abnormal ECG, almost rules out a
with a low volume pulse. Sitting blood pressure was
noncardiac cause of breathlessness.
110/70 mm Hg. The apex beat was in the anterior
Echocardiography provides definitive diagnosis.
axillary line and a parasternal lift was prominent. A
Although a lack of quantitative images is a frequent
pansystolic murmur was audible and late inspiratory
practical problem, this may not be of importance to
crackles were heard throughout both lung fields. There
clinical management [6].
was sacral oedema.
The ECG confirmed sinus tachycardia (110
beats min−1 ) with antero-lateral Q waves of previous Immediate therapeutic strategies
infarction and the chest X-ray confirmed cardiomegaly
+ While there is a lack of controlled clinical trial evidence
and interstitial oedema. Routine chemistry showed Na
−1 + −1 −1 to support the use of diuretics as initial therapy, effective
128 mmol l ; K 5.8 mmol l ; urea 9 mmol l ;
−1 diuresis and consequent adjustment of the loading
creatinine 155 mmol l . A creatine kinase series was
conditions of the failing heart is generally regarded as
Correspondence: Dr Robert J. MacFadyen, Cardiac Unit (7th floor), Raigmore
essential [7]. Immediate empirical management is with
Hospital, Inverness IV2 3UJ. supplementary oxygen, opiates and diuretics. Vaso-
Received 14 April 1998, accepted 23 April 1998. dilatation appears to be an important effect of intravenous

© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247 239

R. J. MacFadyen et al.
diuretics although clear evidence for this is scant.
However, relief of symptoms appears to precede diuresis
and natriuresis.
Intravenous nitrate infusion provides balanced arterio-
venous dilatation and is widely employed, supported by
beneficial central haemodynamic changes in small studies
[8], although little is known about its effects on either
morbidity or mortality [9]. Intravenous ACE inhibitors
also produce beneficial haemodynamic effects [10]. These
drugs are not used routinely intravenously due to
difficulties with appropriate dosage regimens, unpredict-
able and protracted hypotensive effects and concerns over
an adverse effect on survival in haemodynamically
unstable patients in the early stages after myocardial
infarction [11]. More recent data suggest that there may
yet be a role for intravenous administration of ACE
inhibitors in unstable patients [12].
Long-term therapeutic issues
ACE inhibitors It is now clear that patients with either
symptomatic or asymptomatic left ventricular dysfunction
benefit from ACE inhibitor drugs. Morbidity is reduced
with symptomatic improvement, improved exercise dur-
ation and improved quality of life indices. Mortality is
reduced at all stages of the illness with greater absolute
benefit the greater the degree of left ventricular impair-
ment. Treatment is effective regardless of age, gender or
aetiology of cardiac impairment. Further coronary events
are also reduced in patients with ischaemic cardiomyopa-
thy [13] although the reasons for this are obscure.
Research now focuses on the reasons why ACE
inhibitors remain under used in the management of heart
failure [14]. They are cost-effective in comparison with
other cardiovascular treatments [15] (e.g. lipid lowering
in patients with ischaemic heart disease; control of mild
hypertension) even when used for treatment of mild
(NYHA Grade I/II) heart failure. The reasons why
individual patients do not receive an ACE inhibitor need
to be clearly defined but may relate to unfounded
concerns about side effects. The implications for such
patients are a significantly worse prognosis for symptom
control, repeated hospitalization and survival.
The degree of neurohormonal suppression by the ACE
inhibitor is linked to survival in individual patients [16].
Some patients taking long-term ACE inhibitor therapy
still have normal or elevated levels of the key mediator
hormones aldosterone and angiotensin II. The reasons for
this are unclear. It may be due to the secondary rise in
active renin in response to treatment, failure of com-
pliance, the use of short-acting agents (although these are
undoubtedly better than placebo) or to alternative control
pathways for generating angiotensin II (the tissue chymase
+
system) and aldosterone (K or ACTH).
240
Despite 20 years of study the minimum effective dose
of an ACE inhibitor to treat heart failure remains
unknown [17]. It is possible that the symptomatic and
mortality benefits occur at different doses and are achieved
through a combination of haemodynamic, hormonal or
structural effects on the heart and/or the kidneys. One
large but short-duration study of enalapril (NETWORK)
[18] has suggested that high dosages may be unnecessary
to reduce mortality. The results of a larger study with
lisinopril (ATLAS) [19] suggest high doses may provide
additional benefits.
The need for long-term loop diuretic treatment in
stable patients taking an ACE inhibitor is unclear and has
received little attention. Few studies address the effects
of ACE inhibition alone compared with those of an ACE
inhibitor plus diuretic, either in the short or long-term.
Patients treated with and without a loop diuretic after
myocardial infarction in the SAVE study appeared to
benefit from captopril [20]. Those requiring a loop
diuretic might have more significant impairment of left
ventricular systolic function but this is by no means
always the case. Although the left ventricular ejection
fraction is an accurate predictor of mortality, it is poorly
correlated with exercise capacity. Discontinuation of
frusemide in patients with stable heart failure appears to
be feasible in a minority of patients, usually those with
lesser degrees of impairment of left ventricular function
[21]. In practice this is rarely attempted and chronic
diuretic therapy is usual for patients who have had one
episode of overt heart failure requiring hospital admission.
Newer agents to suppress the renin angiotensin aldosterone
system
Other agents that block the tissue and circulating RAS
have been widely studied. Inhibitors of renin have been
available for many years but there are few published data
from controlled trials [22]. Low oral bioavailability has
seriously compromised the value of this drug class
although they are undoubtedly active biochemically and
haemodynamically after intravenous administration [23].
More promising are the selective orally active non-
peptide antagonists of the angiotensin II AT1 re-
ceptor (ARAs) of which there are now several [24].
Haemodynamic activity is predictable and all produce
prolonged hormone suppression. These drugs have a
significant advantage for some patients, since they do not
produce the dry cough which results from potentiation
of kinins during treatment with an ACE inhibitor [25].
A recent trial has shown a useful improvement in
short-term survival with the AT1 ARA losartan compared
with thrice daily captopril in elderly patients with grade
II/III heart failure [26]. This study was designed to
examine the safety of losartan with respect to renal
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247

function. The reasons for reduced mortality in the group
receiving losartan are unclear. The large body of
experimental work suggesting that potentiation of the
effects of kinins by ACE inhibitors has an important
adjuvant role in the therapeutic effects of ACE inhibitors
in heart failure [27] now appears to be in doubt. Before
the use of ARAs can be recommended in preference to
ACE inhibitors for the management of heart failure, this
result must be confirmed in outcome trials. At present,
ARAs are a useful alternative for patients intolerant of
ACE inhibitors.
Other therapeutic options in systolic heart failure Combination
high dose oral nitrate and hydralazine therapy was shown
in the mid 1980s to be effective in relieving symptoms
of heart failure [28] although the impact on survival was
less than that achieved by an ACE inhibitor [29]. The
efficacy of nitrates or hydralazine alone has not been
tested. The combination should be considered when an
ACE inhibitor is contraindicated, e.g. in bilateral reno-
vascular stenosis. The main limitation to this therapy is
intolerable vasodilator side-effects in a substantial pro-
portion of patients. Nitrate tolerance must be avoided by
ensuring an 8 h wash-out phase overnight.
Management and course of the illustrative case
The patient was symptomatically improved by initial
intravenous diuretics and supplemental oxygen correction
of the fluid imbalance (1.5 l fluid restriction; oral
coamilofruse twice daily) resulted in a weight loss of
4.5 kg over 5 days. Although supine blood pressure
remained low (#100 mmHg ), an ACE inhibitor ( perin-
dopril 2 mg daily) was introduced without difficulty and
she experienced no postural symptoms. Renal function
improved in response to the changes in therapy. No
other therapy was required long-term and diuretic dose
was subsequently reduced to coamilofruse one daily).
While remaining functionally limited at discharge, she
was able to live independently. Having remained well
during out-patient review and with no further cardiac
admissions, she died suddenly at home some 18 months
after presentation.
Optimization of therapy in established cardiac
failure
Case history
A 53-year-old man who had sustained previous inferior
and anterior myocardial infarctions presented with gradu-
ally increasing fatigue and oedema despite increasing
diuretic therapy. He was being treated with frusemide
80 mg three times daily, captopril 50 mg three times
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247
Heart failure management
daily, aspirin 150 mg once daily, isosorbide mononitrate
SR 60 mg once daily and amlodipine 10 mg once daily.
On examination he had dependent oedema to the mid
thigh and basal fine crepitations. He had a resting
−1
tachycardia of 105 beats min in sinus rhythm. Mitral
and tricuspid regurgitation were evident and the supine
blood pressure was low at 95/48 mmHg. Laboratory
investigation revealed a reduced serum sodium
−1
(125 mmol l ) with impaired renal function (urea
−1 −1
12.8 mmol l ; creatinine 189 mmol l ). The chest
radiograph showed minimal interstitial oedema, a right
sided pleural effusion and marked cardiomegaly. A 24-h
ECG shows repetitive but nonsustained ventricular
tachycardia (4 episodes of 10–20 beats with rate >150
−1
beats min ) and multifocal ventricular ectopy (>15 000
aberrant beats/24 h). Repeat echocardiography revealed
poor left ventricular contractility with global impairment,
marked dilatation (LVEDD 750 mm) and functional
mitral regurgitation. Radionuclide scintigraphy indicated
a left ventricular ejection fraction of 11%.
Comments
The prospects for improving symptom control rely on
optimising current treatment. Multiple drug therapy
involves the risk of patient confusion over the medicines
and a failure of compliance. This is a neglected area in
the care of patients with heart failure [30] yet well known
to be associated with poor clinical outcome in cardiac
patients [31]. Most decompensated patients require
hospital admission for assessment and observation although
community based care is increasingly being studied to
reduce costs (see below).
Isolated dependent oedema may be drug-related.
Although amlodipine does not appear to cause deterior-
ation in heart failure [32] unlike some calcium antagonists
[33], marked oedema can occur in some patients. Unless
active myocardial ischaemia is present and there are no
other management options, withdrawal should be
considered.
Diuretic resistance and optimising diuretic therapy
Initiating more effective diuresis and overcoming diuretic
resistance is the first goal. Increasing the dosage or
frequency of dosing with an oral loop diuretic has limited
value for diuretic resistance. Improved efficacy can be
achieved by a variety of means [34]. Oral combination
diuretic therapy with the addition of a thiazide drug such
as bendrofluazide is one option. Although metolazone is
often used, it offers no greater benefit and may cause a
greater incidence of adverse effects [35]. The combination
of a loop diuretic with a potassium sparing diuretic is
another possibility. If the patient is taking an ACE
241
R. J. MacFadyen et al.
inhibitor, such an approach is not generally advised but
can be used with success given careful control (see
below). Combination diuretic treatment requires close
monitoring. Once a diuresis is established, it may be
possible to stop the additional drug. Long-term combi-
nation therapy has not been shown to be beneficial and
the risks of electrolyte depletion and induction of
dysrhythmia (although this remains controversial) raises
concerns. If a combination of diuretics is continued,
regular biochemical monitoring is desirable.
Another method to overcome resistance to loop
diuretic therapy is intravenous administration either by
bolus dosing or by continuous infusion [36]. The latter
is particularly effective as it delivers a constant efficient
concentration of frusemide at the tubular lumen. Careful
monitoring of renal function and the extent of the
diuresis are desirable.
Diuresis can also be enhanced by the addition of low-
dose dopamine infusion to facilitate renal vasodilatation
[37]. This may be used in combination with intravenous
or oral loop diuretic. Oral dopamine agonist drugs have
not been demonstrated to be useful [38].
Improving neurohormonal blockade of aldosterone and
angiotensin II
Failure to suppress plasma angiotensin II and/or aldos-
terone concentrations may be associated with an adverse
outcome in heart failure [39]. Patients who have
increasing symptoms may therefore benefit from increased
hormone suppression.
The short-acting agent captopril provides incomplete
hormone suppression over 24 h unless used in multiple
daily doses. Nevertheless, it is widely used in heart failure.
The case for using a longer-acting ACE inhibitor in
preference is poorly documented. Comparative studies of
long and short-acting ACE inhibitors are few and do not
address improvement in symptoms or mortality. Short-
acting drugs are sometimes used on the pretext of a
lower risk of producing significant biochemical renal
dysfunction [40]. However, adverse renal effects induced
by the combination of loop diuretic and ACE inhibitor
are generally predictable, minor and are probably unre-
lated to the duration of action of the ACE inhibitor
selected [41]. Increased dosage or increased dose frequency
of the ACE inhibitor might be useful for some patients,
although the optimal dose of ACE inhibitor remains
uncertain.
Due to the strength of the evidence suggesting that
neurohormonal activation in heart failure is integral both
to the progression of symptoms and pathology [42] the
combination of ACE inhibitor and ARA is being
examined as an option. By blocking the negative feedback
loop promoting renin release following treatment with
242
an ACE inhibitor and in addition by providing receptor
blockade, levels of bioactive angiotensin II are markedly
reduced [43]. This strategy is currently under investigation
using enalapril and valsartan in a multicentre outcome
study (ValHeFT).
As aldosterone has control systems independent of the
renin-angiotensin axis and since it may be independently
detrimental in heart failure, the use of additional
aldosterone blockade may have a role. Spironolactone
has a variety of beneficial effects on surrogate markers of
prognosis in heart failure [44]. Whether this can be
translated to an improved outcome will be demonstrated
by the multicentre RALES study [45]. Preliminary reports
of this study suggest that mortality is significantly reduced
by this combination. The combination of loop diuretic,
ACE inhibitor and spironolactone increases the risk of
renal dysfunction and significant electrolyte imbalance,
particularly potassium retention. In small trials it is not
possible to assess the frequency of such potential adverse
events in routine clinical practice, since treatment and
biochemical changes are closely monitored.
Additional therapies
Digoxin The role of digoxin in patients with heart failure
already treated with an ACE inhibitor and diuretics and
who are in sinus rhythm has been a matter of controversy
for many years. However, digoxin withdrawal was
demonstrated to be detrimental in the PROVED trial
[46]. Recent studies have confirmed that there is no
adverse effect on mortality in heart failure [47] when
digoxin is added to patients on diuretics and ACE
inhibitors. However, there were useful reductions in
recurrent hospitalization after the addition of digoxin.
Digoxin should be considered in patients with persistent
symptoms despite optimal dosage of a diuretic and an
ACE inhibitor. Care should be exercised when there is
impairment of renal function and/or suspicion of impaired
AV conduction or sinus node disease, in view of the
effects of digoxin on cardiac conduction.
b-adrenoceptor blockade More recently considerable interest
has arisen in the use of b-adrenoceptor blockade in heart
failure. Importantly these studies have been conducted in
patients who were already receiving an ACE inhibitor
and diuretic. The combination of data from several
studies using carvedilol, a non selective b-adrenoceptor
antagonist with additional a1-adrenoceptor blocking
effects, show its efficacy in unselected patients with heart
failure. Carvedilol improves survival in patients already
receiving an ACE inhibitor and diuretic [48]. Worsening
heart failure was not more frequent in the b-adrenoceptor
blocker treated patients and benefits only emerge over
weeks, with a vaguely defined period of increased
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247

symptoms during the early phase of treatment.
Cardioselective (b1 )-adrenoceptor blockade has been
studied for some years in the management of idiopathic
dilated cardiomyopathy. Recently preliminary data from
a multicentre trial of bisoprolol in unselected heart failure
have shown unequivocal evidence of further reductions
in mortality. Although the overall mortality reductions
appear small, significant reductions in symptomatic
decompensation were evident [49]. A retrospective
(though nonrandomised) analysis of the SAVE study
database [50] suggested that in patients with asymptomatic
left ventricular dysfunction after myocardial infarction
there is a 30% reduction in cardiovascular death and
a 21% reduction in the development of heart failure
with the addition of any b-adrenoceptor blocker to
captopril.
Small scale studies suggest greater improvements
in central haemodynamics and a more significant
impact on cardiac adrenergic tone with carvedilol in
comparison with metoprolol [51]. Overall the
impact of b-adrenoceptor blockade on exercise capacity
is variable, positive in some studies but negative or
insubstantial in others dependent on the method of
testing [52].
If b-adrenoceptor blockade is to be widely accepted as
a treatment for heart failure, significant practical issues
remain to be addressed. There is no clear definition of
those patients who stand to benefit most. The treatment
appears to be well tolerated in small studies (7–8%
intolerance for cardioselective and/or vasodilating b-
adrenoceptor blockers; [53]) but many patients in routine
clinical practice will have occult peripheral vascular
disease or airways obstruction related to smoking which
may complicate the use of these drugs.
The best methods for initiation of treatment is
uncertain. Large doses of a b-adrenoceptor bocker can
induce hypotension, bradycardia and shock due to the
withdrawal of myocardial adrenergic support. As the
benefits of b-adrenoceptor blockade appear to emerge
gradually during chronic therapy [54] slow dosage titration
is desirable. In most instances weekly medical reviews
including daily weight records and regular blood pressure
and renal function assessment are recommended for safe
treatment [53]. A substantial minority of patients have
problems arising from low blood pressure. As with the
ACE inhibitors the optimal dose of b-adrenoceptor
blockers is unknown and titration to the ‘maximum
tolerated’ dose is currently recommended.
The mechanism of action of b-adrenoceptor blockers
in heart failure is unclear. As many patients have overt
or covert coronary disease they may simply reduce the
impact of ischaemia in otherwise stable cardiac failure.
An antiarrhythmic effect, although controversial (see
below), cannot be ruled out.
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247
Heart failure management
Balanced vasodilator therapy The use of diuretics can be
guided by clinical assessment and body weight. For other
treatments, the use of invasive pressure measurements can
be valuable. Optimal use of vasodilator/vasoconstrictor
agents and inotropic drugs in conjunction with diuretics
can sometimes be guided by readings from a central
haemodynamic monitoring catheter. This is particularly
helpful for patients who have uncontrolled breathlessness
and oedema or as a prelude to cardiac transplantation
[55]. This approach can be effective in restoring a
compensated state to an otherwise decompensated and
deteriorating patient. Most patients who develop major
haemodynamic and symptomatic decline despite an ACE
inhibitor and effective diuresis are in an almost intractable
position. Intensive intravenous therapy, more commonly
employed in North America and in younger patients, is
not widely used in Europe. Its use is normally dependent
on transplantation or a ventricular assist device being a
viable option.
Anti-arrhythmic therapy Control of dysrhythmia in heart
failure remains a major concern. Many patients die
suddenly, usually attributed to some form of dysrhythmia
(both tachydysrhythmias and bradydysrhythmias are
common). The numbers who die in this way may be
increasing with the increasing use of therapies that reduce
uncontrolled pump failure as the mode of death.
The use of antiarrhythmic therapy in left ventricular
dysfunction is restricted following the results from the
CAST studies which demonstrated increased mortality
with some treatments in patients with coexistent left
ventricular (LV) dysfunction [56]. A particular concern
reflects the use of potent drugs with the potential for
pro-arrhythmic effects in patients who had minimal
levels of electrical instability. Amiodarone appears to
be an exception. Although results from four major trials
have not shown consistent improvement in survival
in established LV dysfunction [57, 58], amiodarone
is the best available drug for overt dysrhythmia
in the face of impaired LV function. In general it can
be used without preliminary electrophysiological testing
[59].
Nonsustained ventricular tachycardia (VT) is common
in symptomatic heart failure and is an independent marker
of increased risk of sudden death in severe heart failure
[60]. Whether amiodarone should be prescribed in all
patients with heart failure who have non sustained and
asymptomatic VT is not yet clear.
The role of drug therapy in comparison with electrical
devices allowing sophisticated pacing detection and
including the implantable cardioverter/defibrillator
remains an important area for study [61]. At present these
devices are generally restricted to patients with docu-
mented syncopal dysrhythmia or resuscitated arrest.
243
R. J. MacFadyen et al.
Patients who survive arrhythmogenic cardiac arrest
generally have significant pre-existent heart failure and
structurally abnormal hearts. In Europe the application of
such technology remains relatively limited and adequate
trials comparing this therapy with drug treatments,
although underway, are not yet available for guidance.
These devices may play a significant role in heart failure
in the management of selected patients.
Pulsed inotropic therapy and inotropic-vasodilator drugs The
use of inotropic agents in heart failure has encountered
many problems. In the 1980s and early 1990s many
agents were developed with effects on the heart and
vascular tree combining a central inotropic stimulus with
peripheral arterial vasodilatation. These have been uni-
formly unsuccessful during chronic dosing and often
result in increased mortality [62–64] (e.g. flosequinan;
ibopamine) As a result, the development of new drugs in
this class has been all but halted. The major problems
have been selection of appropriate patients and the narrow
therapeutic index for such treatments. However, these
drugs may have a role in the short term to relieve
symptoms without the increase in mortality that occurs
during protracted use [65].
In a different approach to inotropic therapy,
Adamopoulos and colleagues employed intermittent
dobutamine infusion in 20 patients with severe heart
failure in an attempt to up-regulate myocardial b1-
adrenoceptors [66]. In the short term, there were no
clinical complications of treatment, but also no increase
in diuresis. Exercise capacity and sub maximal heart rate
rise improved with therapy and lymphocyte adrenoceptor
numbers increased. This result is in contrast to the adverse
effects of chronic inotropic therapy [64]. A fine balance
may have be struck to improve adrenoreceptor responsive-
ness but to avoid excessive stimulation or adrenoceptor
down-regulation.
Multidisciplinary care and hospitalization Despite high
annual mortality rates a substantial proportion of patients
with heart failure face an uncertain yet chronic illness.
Many patients are elderly and need repeated hospital
admission. These admissions are both psychologically and
financially taxing. In common with many chronic
diseases, management of these patients can be improved
by contact with many varied health professionals con-
cerned not only with cardiac care but social circumstances;
promotion of drug compliance and psychological support
[67, 68]. Non-pharmacological approaches such as
increased exercise and training within limits has important
and demonstrable physical [69] as well as psychological
effects [70]. There are few instances where a supervised
increase in physical exercise is not of benefit to the
patient with heart failure.
244
Surgical management Surgical treatment need not be
considered as a final line of therapy. Increasingly important
is the application of surgical revascularization for occult
or overt ischaemia in patients with heart failure. This is
often the best way to improve contractility although
the operative management may be complicated and
associated with increased perioperative mortality. Less
well demonstrated are the benefits of scar reduction;
cardiomyoplasty or the most recent and most dramatic
innovation of ventricular reduction/ventriculotomy.
As yet these procedures are limited in their application
to a few selected patients and with generally no agreed
role.
Cardiac transplantation is a proven therapy but restric-
ted by organ availability and delay prior to intervention.
Assessment is usually based on the severity of cardiac
impairment on objective testing during treatment with
maximal therapies. It is increasingly recognized that many
patients with very poor left ventricular function can
survive for many years without transplant. Functional
exercise capacity is seen as the main delineator of those
patients who should be entered onto an urgent trans-
plantation waiting list or those who can safely remain
on drug therapy [71, 72]. The long-term problems
of rejection and accelerated atherosclerosis and their
effects on survival after transplantation will not be
considered here. The outlook for the transplanted patient
is dramatically better than those who await transplantation.
Management and course of the illustrative case
Following emergency admission, initiation of diuresis
required bolus doses of intravenous frusemide combined
with continuous intravenous infusion of dopamine and
fluid and sodium restriction. Although he was considered
a good candidate for invasive pulmonary pressure moni-
toring, this proved unnecessary. Following temporary
withdrawal of captopril during stabilisation of renal
function and diuresis, an ACE inhibitor was subsequently
reintroduced without difficulty (lisinopril 10 mg daily).
Renal function improved and blood pressure stabilised.
Following discharge he remained symptomatic. Oral
digoxin was introduced with only modest benefit. Repeat
outpatient ambulatory ECG recording confirmed persist-
ent episodes of non-sustained ventricular tachycardia. He
was treated with prophylactic oral amiodarone despite his
lack of symptoms. Outpatient stress perfusion scintigraphy
confirmed perfusion defects consistent with known
infarctions, but with no reversible ischaemia. Maximal
cardiopulmonary exercise testing confirmed severe func-
tional incapacity and very poor maximal oxygen consump-
tion at peak exertion (13 ml kg−1 min−1 ). He was
therefore referred for consideration of orthotopic cardiac
transplantation.
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247

Key therapeutic points
Case 1 Acute stabilization and chronic management of
systolic failure
$ Establishing aetiology must be part of diagnosis but
does not importantly affect therapeutic strategies
$ Diuretic therapy is a key element although formally
untested in symptomatic patients. Diuretics were given
to nearly all the patients in trials assessing the efficacy of
ACE inhibitors.
$ ACE inhibition must be considered in all patients and
failure to provide this treatment requires clear justification.
Morbidity and mortality benefits are unequivocal and
generally greater the more significant the impairment of
LV function. Minor or relative contraindications to use
(e.g. asymptomatic hypotension; minor pretreatment renal
impairment) should be weighed against the significant
consequences of failure to treat.
$ Angiotensin receptor antagonists may be an effective
substitute for patients unable to tolerate an ACE inhibitor.
Case 2 Optimization of therapy in established heart failure
$ In-hospital stabilization is usually necessary if the
patient is already taking diuretics and an ACE inhibitor.
$ Optimising diuretic therapy may involve:
$ high doses;
$ intravenous treatment;
$ combination therapy
$ and/or haemodynamic (Swan Ganz catheter)
monitoring
$ Consider adjuvant digoxin for symptom control
even in sinus rhythm
$ Consider adjuvant b-adrenoceptor blockade
$ dose titration may be protracted and complex
$ the effects of selection bias ( patient tolerance to
treatment) on clinical trial results is unclear and may be
important when considering treatment in routine practice
$ Pulsed inotropic therapy or balanced vasodilator/
inotropic therapy may be useful in selected patients
$ Surgical revascularization or myocardial reconstruction
may be feasible and useful options but are unproven in
formal clinical trials
$ Transplantation is effective when available but
‘survivors’ live to receive transplants
References
1 Remes J, Miettinen H, Reunanen A, Pyorala K. Validity of
diagnosis of heart failure in primary health care. Eur Heart J
1991; 12: 315–321.
2 Gillespie ND, McNeill GP, Pringle TH, Ogston S, Struthers
AD, Pringle SD. Cross sectional study of contribution of
clinical assessment and simple cardiac investigations to
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247
Heart failure management
diagnosis of left ventricular systolic dysfunction in patients
admitted with acute dyspnoea. Br Med J 1997; 314 936–940.
3 Davie AP, Francis CM, Love MP, et al. Value of the
electrocardiogram in identifying heart failure due to left
ventricular systolic dysfunction. Br Med J 1996; 312:
222–224.
4 Dargie HJ, McMurray JVV. Diagnosis and management of
heart failure. Br Med J 1994; 308: 321–328.
5 Badgett RG, Mulrow CD, Otto PM, Ramirez G. How well
can the chest radiograph diagnose left ventricular
dysfunction? J Gen Int Med 1996; 11: 625–634.
6 Choy AM, Darbar D, Lang CC, et al. Detection of left
ventricular dysfunction after myocardial infarction:
comparison of clinical, echocardiographic and
neurohormonal methods. Br Heart J 1994; 72: 16–22.
7 Raftery EB. Haemodynamic effects of diuretics in heart
failure. Br Heart J 1994; 72:(suppl) S44–S47.
8 Verma SP, Silke B, Hussain M, et al. First line treatment of
left ventricular failure complicating acute myocardial
infarction: a randomised evaluation of immediate effects of
diuretic, venodilator, arteriodilator and positive inotropic
drugs on left ventricular function. J Cardiovasc Pharmacol
1987; 10: 38–46.
9 Collins R, Peto R, Flather M, for the ISIS4 Study Group. A
randomised factorial trial assessing early oral captopril,
mononitrate or intravenous magnesium sulphate in 58 050
patients with suspected acute myocardial infarc 321–328tion.
Lancet 1995; 345: 669–685.
10 Flynn K, Coughlan MG, Phelan DM, Luke D, Neligan M,
Wood AE. Intravenous captopril in acute heart failure. Lancet
1988; 301: 173–174.
11 Swedberg K, on behalf of the CONSENSUS Trial
investigators. Effects of early administration of enalapril on
mortality in patients with acute myocardial infarcation—
results of the cooperative new scandinavian study II
(CONSENSUS II). N Engl J Med 1992; 327: 678–684.
12 Annane D, Bellisant E, Pussard E, et al. Placebo controlled,
randomized double blind study of intravenous enalaprilat
efficacy and safety in acute cardiogenic pulmonary edema.
Circulation 1996; 94: 1316–1324.
13 Garg R, Yusuf S. Overview of randomized trials of
angiotensin converting enzyme inhibitors on mortality and
morbidity in patients with heart failure. J Am Med Ass 1995;
273: 1450–1456.
14 Hillis GS, Trent RJ, Winton P, MacLeod AM, Jennings KP.
Angiotensin converting enzyme inhibitors in the
management of cardiac failure: are we ignoring the
evidence? Quart J Med 1995; 89: 145–150.
15 Hart W, Rhodes G, McMurray J. The cost effectiveness of
enalapril in the treatment of chronic heart failure. Br J Med
Econ 1993; 6: 91–98.
16 Benedict CR, Francis GS, Shelton B, et al. Effect of long
term enalapril therapy on neurohormones in patients with
left ventricular dysfunction. Am J Cardiol 1995; 75:
1151–1157.
17 Cleland JGF, Poole-Wilson PA. ACE inhibitors for heart
failure a question of dose. Br Heart J 1994; 72: s106–s110.
18 Poole Wilson PA, The NETWORK Study—The effect of
dose of an ACE inhibitor on outcome in patients with heart
failure. Heart 1996; 75(s1): 95.
245
R. J. MacFadyen et al.
19 Packer M. Do angiotensin converting enzyme inhibitors
prolong life in patients with heart failure treated in clinical
practice. J Am Coll Cardiol 1996; 28: 1323–1327.
20 Pfeffer MA, for the SAVE Study Investigators. Effect of
captopril on mortality and morbidity in patients with left
ventricular dysfunction after myocardial infarction. N Engl
J Med 1992; 327: 669–677.
21 Grinstead WC, Francis MJ, Marks GF, Tawa CB, Zoghbi
WA, Young JB. Discontinuation of chronic diuretic therapy
in stable congestive heart failure secondary to coronary artery
disease or to idiopathic dilated cardiomyopathy. Am J Cardiol
1994; 73: 881–886.
22 Rongen GA, Lenders JWM, Smits P, Thein T. Clinical
pharmacokinetics and efficacy of renin inhibitors. Clin
Pharmacokin 1995; 29: 6–14.
23 MacFadyen RJ, Jones CR, Doig JK, Birnbock H, Reid JL.
Responses to an orally active renin inhibitor remikiren
(Ro-42-5892) after controlled salt depletion in humans.
J Cardiovasc Pharmacol 1995; 25: 347–353.
24 MacFadyen RJ. Angiotensin receptor antagonists from
theory to practice. In Current issues in cardiovascular therapy ed
Elliott HL. Martin Dunitz London 1997; chapter 3:
pp. 35–51.
25 Lacourciere Y, Brunner HR, Irwin R, et al. Effects of
modulators of the renin angiotensin system on cough.
J Hypertension 1994; 12: 1387–1393.
26 Pitt B, Segal R, Martinez FA, et al. Randomized trial of
losartan versus captopril in patients over 65 with heart failure
(Evaluation of losartan in the elderly Study, ELITE). Lancet
1997; 349: 747–752.
27 Gohlike P, Linz W, Scholkens BA, et al. Angiotensin
converting enzyme inhibition improves cardiac function: role
of bradykinin. Hypertension 1994; 23: 411–418.
28 Cohn JN, Archibald DG, Ziesche S, et al. Effect of
vasodilator therapy on mortality in chronic congestive heart
failure: results of a Veterans Administration Cooperative
Study. N Engl J Med 1986; 314: 1547–1552.
29 Cohn JD, Johnson G, Ziesche S, et al. A comparison of
enalapril with hydralazine-isosorbide dinitrate in the
treatment of chronic congestive heart failure. N Engl J Med
1991; 325: 303–310.
30 Rich MW, Vinson JM, Sperry JC, et al. Prevention of
readmission in elderly patients with congestive heart failure:
results of a prospective randomized pilot study. J Gen Int
Med 1993; 8: 585–590.
31 Monane M, Bohn R, Gurwitz JH, Glynn
RJ. Noncompliance with congestive heart failure therapy in
the elderly. Arch Int Med 1994; 154: 433–437.
32 Packer M, O’Connor CM, Ghali JK, et al. Effect of
amlodipine on morbidity and mortality in severe chronic
heart failure. N Engl J Med 1996; 335: 1107–1114.
33 The Multicenter Diltiazem Postinfarction Trial Research
Group. The effect of diltiazem on mortality and re-infarction
after myocardial infarction. N Engl J Med 1988; 319:
385–395.
34 Cohn JN. Physiological rationale for co-treatment with
diuretics in heart failure. Br Heart J 1994; 72(suppl 2):
s63–s67.
35 Channer KS, McLean KA, Lawson-Matthew P, Richardson
M. Combination diuretic therapy in severe heart failure a
randomized controlled trial. Br Heart J 1994; 71: 146–150.
246
36 Dormans TP, et al. Diuretic efficacy of high dose furosemide
in severe heart failure: bolus injection versus continuous
infusion. J Am Coll Cardiol 1996; 28: 376–382.
37 Vargo DL, Brater DC, Rudy DW, Swan SK. Dopamine
does not enhance furosemide induced natriuresis in patients
with congestive heart failure. J Am Soc Neph 1996; 7:
1032–1037.
38 Van veldhuisen DJ, Man Int Veld AJ, Dunselman PHJM,
et al. Double blind placebo controlled study of ibopamine
and digoxin in patients with mild to moderate heart failure:
results of the Dutch Ibopamine multicenter study (DIMT).
J Am Coll Cardiol 1993; 22: 1564–1573.
39 Struthers AD. Aldosterone escape during ACE inhibitor
therapy in chronic heart failure. Eur Heart J 1995; 16:
103–106.
40 Packer M, Lee WH, Medina N, Yushak M, Kessler PD.
Functional renal insufficiency during long term therapy with
captopril and enalapril in severe chronic heart failure. Ann
Int Med 1987; 106: 346–354.
41 Gottlieb SS, Robinson S, Weir MR, Fisher ML, Krichen
CM. Determinants of the renal response to ACE inhibition
in patients with congestive heart failure. Am Heart J 1992;
124: 131–136.
42 Packer M. The neurohormonal hypothesis: a theory to
explain the mechanisms of disease progression in heart
failure. J Am Coll Cardiol 1992; 20: 248–254.
43 Azizi M, Chatellier G, Guyene TT, Murieta-Geoffrey D,
Menard J. Additive effects of combined angiotensin
converting enzyme inhibition and angiotensin II antagonism
on blood pressure and renin release in sodium depleted
normotensives. Circulation 1995; 92: 825–834.
44 MacFadyen RJ, Barr CS, Struthers AD. Aldosterone
blockade reduces vascular collagen turnover, improves heart
rate variability and reduces early morning rise in heart rate in
heart failure patients. Cardiovasc Res 1997; 35: 30–34.
45 Pitt B. ACE inhibitor co-therapy in patients with heart
failure: rationale for the randomized aldactone evaluation
study (RALES). Eur Heart J 1995; 16: 107–110.
46 Uretsky BF, Young JB, Shahidi FE, Yellen LG, Harrison
MC, Jolly MK. Randomized study assessing the effect of
digoxin withdrawal in patients with mild to moderate
chronic congestive heart failure: Results of the PROVED
trial. J Am Coll Cardiol 1993; 22: 955–962.
47 The Digitalis Investigation Group. The effect of diogoxin on
mortality and morbidity in patients with heart failure. N Engl
J Med 1997; 336: 525–533.
48 Packer M, Colucci WS, Sackner-Bernstein JD, for the
PRECISE Study Group. Double blind placebo controlled
study of the effects of carvedilol in patients with moderate to
severe heart failure—The PRECISE Trial. Circulation 1996;
94: 2793–2799.
49 Waagstein F, Bristow MR, Swedberg K, for the Metoprolol
in Dilated Cardiomyopathy Trial Study Group. Beneficial
effects of metoprolol in idiopathic dilated cardiomyopathy
Lancet 1993; 342: 1441–1446.
50 Vantrimpoint P, Rouleau JL, Wun CC, et al. Additive
beneficial effects of beta blockers to angiotensin converting
enzyme inhibitors in the survival and ventricular
enlargement (SAVE) study. J Am Coll Cardiol 1997; 29:
229–236.
51 Gilbert EM, Abraham WT, Olsen S, et al. Comparative
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247

hemodynamic, LV functional and anti-adrenergic effects of
chronic treatment with metoprolol vs carvedilol in the failing
heart. Circulation 1996; 94: 2817–2825.
52 Doughty RN, Sharpe N. Beta adrenergic blocking agents in
the treatment of congestive heart failure: mechanisms and
clinical results. Ann Rev Med 1997; 48: 103–114.
53 Eichorn EJ, Bristow MP. Practical guidelines for initiation of
beta adrenergic blockade in patients with chronic heart
failure. Am J Cardiol 1997; 79: 794–798.
54 Hall SA, Cigarroa CG, Marcoux L, Risser RC, Grayburn
PA, Eichorn EJ. Time course of improvement in left
ventricular function, mass, and geometry in patients with
congestive heart failure treated with beta adrenergic
blockade. J Am Coll Cardiol 1995; 25: 1154–1161.
55 Stevenson LW, Dracup KA, Tillisch JH. Efficacy of medical
therapy tailored for severe congestive heart failure in patients
transferred for urgent cardiac transplantation. Am J Cardiol
1989; 63: 461–464.
56 The Cardiac Arrhythmia Suppression Trial II Investigators.
Effect of the antiarrhythmic agent moricizine on survival
after myocardial infarction. N Engl J Med 1992; 327:
227–233.
57 Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman
GR, Curiel R. Randomized trial of low dose amiodarone in
severe congestive heart failure. Lancet 1994; 344: 493–498.
58 Singh SN, Fletcher RD, Fisher SG, for the CHF STAT
Investigators. Amiodarone in patients with congestive heart
failure and asymptomatic ventricular arrhythmia. N Engl
J Med 1995; 333: 77–82.
59 Stevenson WG, Ridker PM. Should survivors of myocardial
infarction with low ejection fraction be routinely referred to
arrhythmia specialists. J Am Med Ass 1996; 276: 481–485.
60 Doval HC, Nul DR, Grancelli HO, et al. Nonsustained
ventricular tachycardia in severe heart failure—independent
marker of increased mortality due to sudden death.
Circulation 1996; 94: 3198–3203.
61 AVID Trial Executive Committee. Are implantable
© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 47, 239–247
Heart failure management
cardioverter-defribillators or drugs more effective in
prolonging life. Am J Cardiol 1997; 79: 661–663.
62 Curfman GD. Inotropic therapy for heart failure—an
unfulfilled promise. N Engl J Med 1991; 325: 1509–1510.
63 Dies F, Krell MJ, Whitlow P, et al. Intermittent dobutamine
in ambulatory outpatients with chronic cardiac failure.
Circulation 1986; 74: 38.
64 Packer M, Carver JR, Rodeheffer RJ, for the PROMISE
Study Research Group. Effect of oral milrinone in severe
chronic heart failure. N Engl J Med 1991; 325: 1468–1475.
65 Poole Wilson PA. Heart failure. Unfinished business—a
possible role for vasodilators. Int J Cardiol 1993; 40: 1–6.
66 Adamopoulos S, Piepoli M, Qiang F, et al. Effects of pulsed
beta stimulant therapy on beta receptors and chronotropic
responsiveness in chronic heart failure. Lancet 1995; 345:
344–349.
67 Hunn D, Pedersen WR, Beccker R, et al. Benefits of
attending a heart failure clinic. Circulation 1990; 82: 609.
68 West JA, Miller NH, Parker KM, et al. A comprehensive
management system for heart failure improves clinical
outcomes and reduces medical resource utilization. Am
J Cardiol 1997; 79: 58–63.
69 McKelvie RS, Teo KK, McCartney N, Humen D,
Montague T, Yusuf S. Effects of exercise training in patients
with congestive heart failure: a critical review. J Am Coll
Cardiol 1995; 25: 789–796.
70 Jenkinson C, Jenkinson D, Shepperd S, Layte R, Petersen S.
Evaluation of treatment for congestive heart failure in
patients aged 60 years and older using generic measures of
health status (SF36 and COOP charts). Age and Ageing 1997;
26: 7–13.
71 Myers J, Gullestad L, Vagelos R, Bellin D, Do D, Ross H,
Fowler M. Clinical, hemodynamic and cardipulmonary
exercise test predictors of outcome in patients referred for
heart failure evaluation. J Am Coll Cardiol 1997; 29: 98 160.
72 Chomsky Lang CC, Rayos GH, Shyr Y, et al.
Hemodynamic exercise testing—a valuable tool in the
selection of cardiac transplantation candidates. Circulation
1996; 94: 3176–3183.
247