European Heart Journal Supplements (2002) 4 (Supplement D), D59-D65
How do heart failure patients die?
S. Orn and K. Dickstein
University of Bergen and Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway
Approximately 90% of heart failure patients die from
cardiovascular causes. Fifty per cent die from progressive heart
failure, and the remainder die suddenly from arrhythmias and
ischaemic events. Autopsy reveals the presence of an acute
ischaemic event in approximately 50% of sudden deaths and in
35% of all deaths among patients with ischaemic heart failure.
An accurate description of the cause and mode of death is
important if we are to elucidate the mechanisms that are
operative in the heart failure population. At present, the most
accurate data on mode of death are obtained from large
randomized heart failure trials. They indicate that current
Introduction
The heterogeneity of the heart failure population is reflected
in the different ways in which these patients die. Some
deteriorate progressively, whereas others die after acute
episodes of decompensation. Others die suddenly and
unexpectedly, and some (relatively few) die from noncardiac causes. Before the angiotensin-converting enzyme
(ACE) inhibitor era, it was estimated that 90% of the total
deaths in heart failure patients were from cardiovascular
causes, 49% were related to worsening heart failure, 22% to
arrhythmias and 11% to acute myocardial infarction[S].
Classification of cause and
mode of death
It is conventional to categorise death according to mode
and cause o f death. Cause o f death addresses the
mechanisms by which death occurs, such as arrhythmia,
acute myocardial infarction or progressive heart failure
(Table 1). Mode of death is perhaps easier to categorise,
Correspondence:Dr Stein Orn, University of Bergen and Cardiology
Division, Central Hospital in Rogaland, Stavanger, Norway.
1520-765X/02/0D0059 + 07 $35.00/0
treatment strategies for heart failure prolong life expectancy,
but have relatively little impact on the proportion of heart
failure patients who die from cardiovascular causes. The
ultimate goal of intervention is to shift the balance toward more
deaths from non-cardiovascular causes.
(Eur Heart J Supplements 2002; 4 (Suppl D): D59-D65)
© 2002 The European Society of Cardiology
Key Words: Autopsy, cause of death, classification of death,
heart failure, mode of death.
reflects how patients die and is described as sudden or nonsudden. Mode and cause of death are not the same,
although they are often used interchangeably. Sudden death
has various underlying causes, such as arrhythmia, acute
myocardial infarction, pulmonary embolism, myocardial or
aortic rupture, and stroke. Sudden cardiac death is defined
as natural death due to cardiac causes, heralded by abrupt
loss of consciousness within 1 h of the onset of acute
symptoms[2]. In order to avoid confusion in terminology,
some clinical trials subclassify death without using the
term 'cause of death' and end-point committees focus
instead on mode and place of death (Table 1)[31. However,
although it is more difficult to classify cause of death than
mode of death, it is nevertheless productive to examine the
causes of death among heart failure patients. The cause of
death reflects the underlying pathophysiology of the
disease, and helps us to understand the mechanisms
responsible for its progression. Unravelling the
mechanisms that lead to death is clinically relevant and
may reveal potential new treatment targets. Effective
treatment may alter the cause of death, and should ideally
shift the operative mechanism from cardiovascular to noncardiovascular.
Most of our loaowledge of the cause and mode of death in
heart failure comes from the large randomized mortality
trials and from official death registries. However, both of
these sources of information have their problems.
© 2002 The European Society of Cardiology
D60
S. Orn and K. Dickstein
Table 1 A simplified classification o f h e a r t f a i l u r e
deaths
•
SOLVD treatment ACE inhibitor
[] MERITplacebo
Cardiovascular
Cardiac
Myocardial infarction
Progressive heart failure
Other cardiac
Sudden death
Non-cardiac
Stroke
Other
Procedure-related
Non-cardiovascular
100
90
80
70
60
.g 50
40
30
20
Death registries
The advantage of official death registries lies in the large
amount of data available on a non-selected population
exposed to various treatment strategies. However, even
though data on total mortality is fairly reliable, official
death registries make it difficult to analyse the cause of
death. Data are often scarce or biased, and the clinical basis
of the diagnosis may be absent or inadequate.
In most countries, official death certificates discourage
terms such as 'sudden death' and 'worsening heart failure'.
Aetiological diagnoses, such as arrhythmia and myocardial
infarction, are encouraged. However, most of these
diagnoses are based on the judgement of the physician
signing the death form, which may be arbitrary. Autopsy
data has demonstrated the limited reliability of death
certificates, medical records and interviews as sources of
mortality statistics in cardiovascular epidemiology[41.
Moreover, most death registries use World Health
Organization International Classification of Diseases
coding. The current trend toward linking payment for health
services to International Classification of Diseases codes
threatens to create bias and renders the use of these codes
unreliable in epidemiological research.
Randomized trials
The most accurate data on cause of death is obtained from
large randomized trials. However, several issues complicate
their interpretation. Classification of cause of death appears
to differ between trials. Comparison of two large
randomized trials - the ACE inhibitor treated arm of the
Studies of Left Ventricular Dysfunction (SOLVD) treatment
trial[ 1] and the Metoprolol CR/XL Randomized Intervention
Trial in Congestive Heart Failure (MERIT-HF)[5] - reveals
wide variations in cause of death between the trials, despite
nearly identical selection criteria (Fig. 1).
Furthermore, classification problems may arise when
death is not witnessed or information is scarce. In the
Cardiac Insufficiency Bisoprolol Study (CIBIS) II[6], for
example, 30% of deaths in the placebo group and 20% in
the bisoprolol group were classified as of un!mown cause.
Eur Heart J Supplements,VoI.4 (Suppi D) April 2002
10
Total
Worsening Sudden/
cardiovascular heart failure arrhythmic
deaths
Other
Figure 1 Modes and causes of death in patients treated
with angiotensin-converting enzyme inhibitors in the
Studies of Left Ventricular Dysfunction (SOLVD)
treatment trial[tl and patients treated with placebo in
Metoprolol CR/XL Randomized Intervention Trial in
Congestive Heart Failure (MERIT-HF)[S]. In SOLVD the
term 'arrhythmic death' was used to describe presumed
arrhythmic death in patients dying suddenly, whereas a
broader definition of sudden death was used in
MERIT-HE
The inconsistency in interpretation of death narratives
among centres is another major problem. Ziesche et al.[7]
reported agreement only in 50% of cases when 21 SOLVD
investigators independently classified 10 death narratives
from the Valsartan Heart Failure Trial (V-HeFT) trial. Much
of the inconsistency between centres can be reduced,
however, if deaths are evaluated by end-point committees
according to well-defined guidelines. However, many large
trials, such as SOLVD, the Digitalis Investigative Group
(DIG) trial[S], the U.S. carvedilol trials[9] and the Survival
and Ventricular Enlargement (SAVE) trial[l°l, did not use
end-point committees.
In most trials, records are provided for cardiovascular
death, sudden death, myocardial infarction and death caused
by worsening heart failure. As with official death registries,
the classification of death according to clinical records
shows considerable discordance with autopsy data. In the
Assessment of Treatment with Lisinopril and Survival
(ATLAS) trial[111, autopsy revealed acute coronary findings
(myocardial infarction) in 54% of heart failure patients with
known coronary artery disease who died suddenly. That trial
found myocardial infarction at autopsy in 27-5% of all heart
failure patients who died during the study.
The high incidence of myocardial infarction
demonstrated by autopsy in heart failure patients who die
suddenly is in sharp contrast to death records based on
clinical data alone; on the basis of clinical judgement, the
ATLAS trial recorded the occurrence of fatal myocardial
How do heart failure patients die?
D61
extrapolate it to the general heart failure population, we need
to know more about the impact of treatment: its relationship
with the severity of heart failure, its effects on cause of death
and mode of death over time, and its interactions with sex
and the underlying aetiology of heart failure.
• Diagnosisbased on clinical information
[] Diagnosisbased on autopsy
100
90
8O
Impact of treatment
70
60
50
~3
4O
30
20
10
Total
Worsening Sudden death
cardiovascular heartfailure
deaths
Other
Figure 2 Data from a cohort of 171 patients included in
the A s s e s s m e n t of Treatment with Lisinopril and
Survival (ATLAS) triali221, comparing cause and mode
of death based on clinical information alone with that
based on autopsy results. The difference between the two
groups is almost entirely due to an underestimation of
acute myocardial infarction by clinical judgement alone
(represented by an increase in the 'other' column for
autopsy results).
infarction as only 5.8%. Thus, clinical records appear to
underestimate considerably the incidence of acute
myocardial infarction as a cause of death (Fig. 2). Notably,
none of the patients classified in the ATLAS trial as having
died of non-cardiovascular causes had acute coronary
findings at autopsy.
It is clear, therefore, that comparison of the cause or mode
of death between trials is not meaningful. The steering or
end-point committee of each individual trial defines its own
rules, making it difficult to assess differences between trials.
There is no universally accepted system that takes into
account the problems in classifying cause of death in clinical
trials. In order to overcome this problem, working groups
have been established that are attempting to standardize
classification. The Task Force on Sudden Death of the
European Society of CardiologyE21 recently published its
recommendations for the definition of sudden cardiac death.
Within trials, however, definitions of the cause or mode of
death are consistent, albeit subject to systematic error.
Within-trial data may therefore be used to evaluate the effect
of intervention. However, it is important to recognize that
clinical trials are not conducted in populations that are
representative of heart failure patients in the community. The
typical trial population is highly selected. It consists mainly
of men who are, on average, younger than the typical heart
failure patient, and without serious comorbidities. Women,
the elderly and patients with other chronic diseases are not
adequately studied. To evaluate the existing data and
Improvements in treatment have significantly increased the
life expectancy of heart failure patients, but have done little
to reduce the proportion of patients who die from
cardiovascular causes. The percentage of patients who die
from cardiovascular causes was 88% in the SOLVD
treatment trial[i], 88% in the metoprolol-treated patients in
MERIT-HF[51 and 87% in the spironolactone-treated
patients in the Randomized Aldactone Evaluation Study
(RALES)[12]. It is true that, in MERIT-HF, significant
reductions in both worsening heart failure deaths and
sudden deaths in metoprolol-treated patients accounted for
a significant reduction in overall cardiovascular deaths, as
compared with placebo. However, in RALES there was no
reduction in the proportion of patients who died from
cardiovascular causes. Rather, the highly significant
reduction in total mortality was mostly attributable to a
reduction in non-cardiovascular deaths.
It might be argued that modes of death compete, and that
a treatment that reduces one mode or cause of death will
increase the frequency of another. 'Therapeutic conversion'
may therefore be taken as evidence of benefit. The most
reliable measure of the real efficacy of cardiovascular
treatments may be a reduction in the proportion of
cardiovascular deaths within the context of an overall
reduction in mortality. A failure to reduce cardiovascular
deaths may be recorded due to fundamental problems of
classification, or may occur because the underlying
pathophysiological processes are slowed but not terminated.
Severity of heartfailure
Patients with heart failure are readily classified according to
the severity of their symptoms, and most clinicians are
experienced in the use of the New York Heart Association
(NYHA) classification. The SOLVD treatment[11 and
prevention[ 131 trials allow a comparison of causes and
modes of death in patients with left ventricular dysfunction
(with and without overt symptoms of heart failure). In the
SOLVD prevention trial 67% of patients were classified as
NYHA class I and 33% as NYHA class II. In the SOLVD
treatment trial 11% were classified as NYHA class I, 57%
as NYHA class II, 30% as NYHA class III and 2% as
NYHA class IV[~4]. There were other significant differences
in the baseline characteristics o f the patients; more
prevention trial patients had a history of myocardial
infarction and revascularization procedures, but they were
less likely to have a history of diabetes mellitus, systemic
hypertension and chronic lung disease.
Eur Heart J Supplements,Voh 4 (Suppl D) April 2002
D62
S. Orn and K. Dickstein
• TreatmentACEinhibitor
[] PreventionACE inhibitor
10090"
80
~3
70.
60
50
40
30
20
10
0
Total
Worsening Arrythmia Myocardial
cardiovascular heart failure
infarction
deaths
heart failure (46% versus 31%; Fig. 3). The same tendency
was noted in post-hoc analyses of data from the MERIT-HF
trial[51, which assessed total mortality and mode of death in
relation to NYHA class at randomization. The proportion of
sudden deaths generally decreased with increasing severity
of heart failure according to NYHA functional class.
Conversely, the proportion of patients who died from
worsening heart failure increased with increasing severity of
heart failure (Fig. 4).
These intriguing results from SOLVD and MERIT-HF
provide data that are central to our understanding of the
mechanisms of death and progression of heart failure. One
may speculate that many patients who die suddenly may do
so because of underlying ischaemic disease before the
process of remodelling has caused deterioration in NYHA
class. These questions may be answered by looking at the
mode and cause o f death in patients whose N Y H A
classification improves after treatment.
Gender
Figure 3
Relationship between cause of death and
clinical status in the Studies of Left Ventricular
Dysfunction (SOLVD) trial: patients with asymptomatic
left ventricular dysfunction (SOLVD prevention)J131
compared with patients with symptomatic left
ventricular dysfunction (SOLVD treatment)Iq. In the
symptomatic group, more patients died from worsening
heart failure. In the asymptomatic group, more patients
died as a result of arrhythmias. ACE=angiotensin converting enzyme.
The mortality data showed that fewer SOLVD treatment
trial patients died from acute myocardial infarction (9%
versus 15%) and arrhythmias (23% versus 31%) than in the
SOLVD prevention group, but more died from worsening
Experimental and clinical studies have suggested the
presence of gender-specific differences in left ventricular
remodellingE~5,161. There are also data that suggest genderrelated differences in the cause of death in the heart failure
population. The Framingham Heart Study[ 171 reported that
women with heart failure were 36% less likely to die than
were men. A post-hoc analysis of the CIBIS II trial[ 18]
attempted to evaluate gender-related differences in survival
by analysing data from the 515 women in the trial
(n = 2647). A total of 53 women died during follow-up. In
women as compared with men, the relative risk for
cardiovascular death was 0.64 ( P = 0.013) and for noncardiovascular causes it was 0.11 (P = 0.005). Male patients
[] NYHAII
[] NYHAIII
[] NYHAIV
70
60
50
40
30
~-
2O
Figure 4 Severity of heart failure
10
Worsening heart
failure
Sudden death
Eur Heart J Supplements,Vol. 4 (Suppl D) April 2002
Other
and mode of death in Metoprolol
CR/XL Randomized Intervention
Trial in Congestive Heart Failure
(MERIT-HF)ISl. NYHA=New York
Heart Association.
How do heart failure patients die?
•
D63
Ischaemiccardiomyopathy
[] Non-ischaemiccardiomyopathy
35
30
25
~z
2
20
~
15
Sudden
Myocardial
failure
Myocardial
infarction
Other
Noncardiovascular
Figure 5 Assessment of Treatment with Lisinopril and Survival (ATLAS) triali221: comparison of mode and cause
of death in autopsied patients diagnosed as having ischaemic or non-ischaemic dilated cardiomyopathy.
were also more likely to die suddenly. These results are
consistent with the findings of the Framingham Heart
Study[~7], the first National Health and Nutrition
Examination Survey (NHANES-1)[191 and the Flolan
International Randomized Survival Trial (FIRST)E20]. Those
studies included only a limited number of women, however,
and further studies are needed in populations that include
larger numbers of female patients.
Aetiology of heart failure
In the Metoprolol in Dilated Cardiomyopathy (MDC)
trial[a1], 383 patients with idiopathic dilated cardiomyopathy
and symptomatic heart failure were studied. Only 42 patients
died during the trial. As compared with patients receiving
metoprolol, more patients receiving placebo underwent
cardiac transplantation (19 versus 2; P = 0-0001). Sudden
death occurred in 78% of patients receiving metoprolol and
in 63% of patients receiving placebo. Death from
progressive heart failure occurred in 22% of patients
receiving metoprolol versus 26% of those receiving placebo.
In the ATLAS trial[22], a specific analysis was made of
mode of death in patients with ischaemic and non-ischaemic
cardiomyopathy. The total number of deaths analysed was
substantially larger than in the MDC trial (950 deaths in the
ischaemic and 394 deaths in the non-ischaemic group).
Cardiovascular mortality was generally higher in the
ischaemic subgroup (41.9% versus 29.5% in patients with
non-ischaemic heart disease). However, there was no
difference in the relative proportions of sudden deaths,
which accounted for 44% of deaths in both groups.
In the same trial, death from worsening heart failure
occurred in 31% of patients with ischaemic cardiomyopathy
and in 29% of those with non-ischaemic cardiomyopathy.
There were more deaths from non-cardiovascular causes
among patients with non-ischaemic heart disease. Not
surprisingly, there was a difference between the groups in
deaths clinically reported as related to myocardial infarction
(8% in the ischaemic subgroup versus 5% in the nonischaemic subgroup). Interestingly, however, autopsy
revealed the number of fatal myocardial infarctions in both
subgroups to be much higher than estimated on clinical
grounds (31.7% ischaemic and 17-6% non-ischaemic;
Fig. 5). This clearly indicates that there may be underlying
ischaemic disease even in heart failure patients diagnosed as
having non-ischaemic cardiomyopathy.
Time and place of death
In recent years there has been a trend toward fewer patients
dying from cardiac causes outside the hospital setting[231.
This trend also applies to the heart failure population. In a
Scottish study based on a national database including
12,640 patients and 4877 deaths during a 3-year period[24],
73% of all heart failure deaths occurred in hospital. Median
time from hospitalization until death was less than 10 days,
and 45% of patients died within 90 days of discharge. Most
deaths following discharge from hospital occurred within
Eur Heart J Supplements, Vol. 4 (Suppl D) Apr/1 2002
D64
S. O r n a n d K. D i c k s t e i n
Pump failure I
death
I Arrhythmic
death
Ischaemic
death
I
Figure 6 Interaction between underlying mechanisms
and cause of death in heart failure.
the first year. Patients hospitalized with an acute myocardial
infarction subsequent to a heart failure admission had a
particularly poor prognosis. Once a patient had been
admitted with an acute ischaemic event, this remained the
dominant reason for later readmission.
Conclusion
A n intricate interplay of underlying pathophysiological
m e c h a n i s m s determines the progression and clinical
presentation of heart failure (Fig. 6). The process of
remodelling and neurohumoral activation, through central
and peripheral mechanisms, increases susceptibility to
arrhythmias and exacerbates the progression of ischaemic
disease. Ischaemia induces arrhythmias and myocardial
infarction, which in turn may cause increased neurohumoral
activation and cardiac remodelling. Tailored heart failure
therapy requires the identification and treatment of the
detrimental pathophysiological factors in each individual
patient.
The goal of therapy in this large and heterogeneous
population should be both to prolong survival and to
increase the percentage of patients dying from noncardiovascular causes.
While non-cardiovascular death is a robust parameter,
subclassification of cardiovascular death is highly
complicated because of the complex variation in clinical
presentation of death in the heart failure population. We do
know, however, that there is a strong relationship between
mode of death and severity of heart failure, with patients in
lower N Y H A classes being more likely to die suddenly.
This observation may well be due to the underestimated
effects of underlying ischaemic disease. In fact, according
to autopsy data, ischaemia is the single most important
cause of death in patients with heart failure. Ischaemia may
cause arrythmias, worsening heart failure and sudden death.
However, the role of stunning and hibernation is difficult to
quantify. Aggressive treatment of underlying coronary
Eur Heart J Supplements, Vol. 4 (Suppl D) April 2002
artery disease as well as supraventricular arrhythmias is
therefore essential in the heart failure population.
In conclusion, it is not possible to separate cause from
simple association accurately in the pathophysiological
maze of heart failure. In spite of major advances in the
treatment of heart failure, the distribution between the
modes of death remains largely unchanged. The
understanding of how heart failure patients die requires an
accurate description of the mode and cause of death. A
simple and clinically relevant classification system is
required if current controversies are to be resolved.
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