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European Journal of Heart Failure 2008 10(11):1108-1116; doi:10.1016/j.ejheart.2008.09.004
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© 2008 European Society of Cardiology

Mode of death in patients with newly diagnosed heart failure in the general population

Paresh A. Mehtaa, Simon W. Dubreyb, Hugh F. McIntyrec, David M. Walkerc, Suzanna M.C. Hardmand, George C. Suttona, Theresa A. McDonagha and Martin R. Cowiea,*

a Imperial College London, UK
b The Hillingdon Hospital London, UK
c The Conquest Hospital East Sussex, UK
d The Whittington Hospital & University College London, UK

* Corresponding author. National Heart & Lung institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. Tel.: +44 207 351 8856; fax: +44 207 351 8148. E-mail address: m.cowie{at}imperial.ac.uk (M.R. Cowie)


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 
Background: Early prognosis for incident (new) heart failure (HF) patients in the general population is poor. Clinical trials suggest approximately half of chronic HF patients die suddenly but mode of death for incident HF cases in the general population has not been evaluated.

Aims: To describe mode of death in the first six months after a new diagnosis in the general population.

Methods: Two-centre UK population-based study.

Results: 396 incident HF patients were prospectively identified. Overall mortality rates were 6% [3–8%], 11% [8–14%] and 14% [11–18%] at 1, 3 and 6months respectively. There were 59 deaths over a median follow-up of 10months; 86% (n = 51) were cardiovascular (CV) deaths. Overall, the mode of death was progressive HF in 52% (n = 31), sudden death (SD) in 22% (n = 13), other CV death in 12% (n = 7), and non-CV death in 14% (n = 8). On multivariable analysis, progressive HF deaths were associated with older age, lower serum sodium, systolic hypotension, prolonged QRS duration at baseline and absence of ACE inhibitor therapy at the time of discharge or death.

Conclusion: Early prognosis after a new diagnosis of HF in the general population is poor and progressive HF, rather than sudden death, accounts for the majority of deaths.

Key Words: Heart failure • Mode of death • Mortality • Prognosis

Received March 19, 2008; Revised July 28, 2008; Accepted September 16, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 
The prognosis following a new diagnosis of heart failure in the general population is poor. The risk of mortality is particularly high in the early period after diagnosis with approximately 25-30% not surviving six months [1-3]. Maximising duration and quality of life while preventing progression of heart failure are goals of heart failure management [4,5]. Describing and understanding the mode (or mechanism) of death in heart failure may enable identification of high-risk individuals and provide insight into the clinical course of the syndrome, and the appropriate targeting of therapeutic interventions, such as drugs or electrical devices, including implantable-cardioverter defibrillators.

Several clinical trials in patients with heart failure or left ventricular systolic dysfunction after acute myocardial infarction [6-10], and in patients with prevalent (established) heart failure [11-15], have reported that dying suddenly is the single most common mode of death accounting for approximately 50% of all deaths. Progressive heart failure death appears to account for about 30% of deaths, although the literature is not entirely consistent [16-18].

The variation in published reports is in part due to the use of differing definitions of heart failure, a lack of uniformity in classification of mode of death [19,20], and the methods used to adjudicate the mode of death [21].

Clinical trial data are based on highly selected series. Study patients are often established cases of heart failure, consisting of the ‘natural survivors’ of the early high-risk period. The mode of death of such selected patients may differ from that in unselected newly diagnosed heart failure patients. In addition, a considerable increase in the use of neurohormonal antagonists, such as beta-blockers and aldosterone antagonists, and more recently electrical device therapies, may influence the mode of death.

There are no population-based data on the mode of death in patients with heart failure in the early period after diagnosis. The Hillingdon and Hastings Heart Failure study prospectively evaluated the mode of death and associated clinical factors in a cohort of incident heart failure patients in the UK general population.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 
2.1. Study population and identification of cases
The study population consisted of two geographically defined but distinct populations in the United Kingdom. The populations consisted of 243,006 people in Hillingdon, West London and 170,457 from Hastings and Rother, East Sussex. All inpatient care and the majority of outpatient care for the respective study populations are provided by The Hillingdon Hospital and The Conquest Hospital, respectively.

This study includes 396 patients diagnosed with incident heart failure from these two hospitals serving a combined population of 413,463. This study included all individuals within the Hillingdon study population in whom the diagnosis of heart failure had been made for the first time between January 2004 and October 2005, and all individuals within the Hastings and Rother study population in whom the diagnosis of heart failure had been made for the first time between June 2004 and October 2005.

The methodology for case identification has been used in previous population-based studies of heart failure [1,2,22]. All new cases of suspected heart failure were identified from daily surveillance of general practitioner referral, acute hospital admissions, echocardiography lists, and in-patient cardiology referral by a cardiologist (PM) or a research nurse. Patients with suspected heart failure underwent routine clinical assessment, chest radiography, electrocardiography and echocardiography where possible. Echocardiography was performed to a standard protocol and according to accepted guidelines by experienced cardiac technicians [23,24].

2.2. Case definition
A clinical diagnosis of heart failure was defined according to accepted guidelines at the time of the current study [25]. To meet the case definition of heart failure (‘definite’ cases) patients were required to have symptoms of heart failure and the presence of an underlying abnormality of cardiac structure or function. In cases where the diagnosis was in doubt (‘possible’ cases), a favourable response to treatment for heart failure was taken as confirmation of diagnosis.

All data regarding ‘possible’ cases and a random sample of ‘definite’ cases were presented to a panel of three cardiologists (MRC, TM and GS) to determine, on the basis of a majority decision, whether the case definition for heart failure had been met and the underlying aetiology. All patients' medical notes and details from primary care were scrutinised to ensure that only new (incident) cases of heart failure were included in the study.

2.3. Follow up
The date of death was ascertained by ‘flagging’ each patient's record at the Office of National Statistics using their unique National Health Service number. Follow up for death was 100% complete to the end of January 2006 representing a median follow-up (excluding mortality cases) of 370days (range 100 to 814days). Of the 398 patients recruited with newly diagnosed heart failure, two patients (< 1%) withdrew from the study due to personal reasons and their data were excluded from the analysis.

2.4. Mode of death
The present study has employed a classification system for the mode of death derived from the ‘ACME’ system for death in heart failure, taking account of (A) activity and place of death, (C) cause of death, (M) mode of death and (E) events associated with death [19].

A panel of three cardiologists (MRC, TM, GCS) reviewed all patients that had died and assigned a mode of death. Determination of the mode of death was made on the basis of all available information from hospital medical notes, general practitioner records, and communication with next of kin/family. In the case of a non-unanimous panel decision, the majority decided the final adjudication.

Mode of death was classified as cardiovascular or non-cardiovascular. Cardiovascular modes of death were sub-classified as sudden death, progressive heart failure death, and ‘other’ cardiovascular death (which included stroke, vascular disease, pulmonary embolism, cardiac procedural complication and other cardiovascular event not otherwise specified).

Sudden death included observed instantaneous deaths (occurring within 24h of acute symptoms) or unobserved deaths, but assumed to be instantaneous due to the clinical setting. Information regarding the patient's clinical status (within the week preceding his/her death) was required to be present with confirmation that there had been no prior worsening of heart failure symptoms, no increase in heart failure medications and no heart failure related hospitalisations. Patients with abrupt loss of consciousness who underwent resuscitation that was unsuccessful or who were initially successfully resuscitated but died later were labelled as sudden death.

Progressive heart failure death was defined as worsening heart failure, manifest by an increase in symptoms and heart failure medications and usually including hospitalisation, in the week preceding death. Progressive heart failure deaths included cardiogenic shock, pulmonary oedema, heart failure symptoms and/or signs requiring intravenous therapy or O2, confinement at home due to heart failure, cases described as end stage heart failure in which therapy was felt to be futile and progressive heart failure cases in which terminal arrhythmias were documented.

Sudden and progressive heart failure deaths were both further subdivided into whether or not death had occurred following (defined as within 14days) an acute myocardial infarction (AMI), defined according to accepted guidelines at the time of the current study [26].

2.5. Data analysis
Continuous variables with a normal distribution were described using mean and standard deviation (SD). If the distribution was not normal, median and 90% range were used as descriptors. Comparisons of variables with a normal distribution were by Student's t-test, and for non-normal distributed variables that could not be transformed to a normal distribution, by log-rank test. Comparisons of proportions were performed using a {chi}2 test or Fisher's exact test.

Survival was estimated using the Kaplan-Meier method. The estimated survival probabilities and 95% confidence intervals at one, three and six months were calculated. The association between clinical and investigative findings and adjudicated mode of death were examined by Cox proportional hazards regression modelling [27]. All covariates associated with survival in the Cox univariate regression (p < 0.15) were then entered into a multivariable Cox regression analysis and discarded in a step-wise manner provided they did not significantly (p < 0.05) improve the fit of the model. Non-cardiovascular deaths were censored at the time of death.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 6. Limitations
 References
 
During the study period, 396 incident cases of heart failure were identified within the study population. Table 1 gives the baseline characteristics recorded at the time of first presentation with heart failure.


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  		Table 1 Baseline characteristics of 396 cases of incident heart failure

 
Overall mortality rates were 6% [95% confidence interval (CI) 3-8%] at 1month, 11% [8-14%] at 3months and 14% [11-18%] at 6months (Fig. 1).


Figure 01
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  		Fig. 1 Overall survival of 396 patients with incident heart failure in the Hillingdon/Hastings heart failure study.

 
3.1. Mode of death
Overall, there were 59 deaths during the follow-up period (Fig. 2). Of these deaths, 51 were cardiovascular deaths and 8 non-cardiovascular deaths. Of the 51 cardiovascular deaths, 13 (25%) occurred following an acute myocardial infarction.


Figure 02
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  		Fig. 2 Mode of death. Peripheral vascular disease (3), cerebrovascular disease (1), pulmonary embolus (1), cardiac procedure (1) and undetermined (1). PHF = progressive heart failure.

 
Non-cardiovascular deaths were due to cancer (3), bronchopneumonia (3), renal failure (1) and suicide (1).

Overall, the mode of death was progressive heart failure in 31 (52%), sudden death in 13 (22%), other cardiovascular death in 7 (12%) and non-cardiovascular death in 8 (14%). Other cardiovascular deaths were due to peripheral vascular disease (3), cerebrovascular disease (1), pulmonary embolus (1), cardiac procedure (1), and undetermined (1).

3.2. Place of death
Of the 59 deaths, 41 (69%) occurred in hospital and 18 (31%) out of hospital. Deaths occurring out of hospital accounted for all 13 (100%) sudden deaths vs. 5 (11%) of 46 non-sudden deaths (p < 0.0001).

3.3. Survival and mode of death
Of the 396 patients with incident heart failure, the mortality rate due to progressive heart failure was 5% [95% confidence interval (CI) 3-7%] at 1month, 7% [4-9%] at 3months and 8% [5-11%] at 6months. The mortality rate due to sudden death was 1% [0-2%] at one month, 2% [0-3%] at three months and 3% [1-5%] at six months.

Fig. 3 shows the mortality curves for all-cause mortality, progressive heart failure deaths and sudden deaths.


Figure 03
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  		Fig. 3 Kaplan-Meier mortality curves for all-cause mortality, progressive heart failure death and sudden death.

 
3.4. Predictors of cardiovascular mortality
On multivariable Cox regression analysis (Table 2), five variables were independently associated with cardiovascular mortality: increasing age of patients, lower serum sodium and higher serum urea (≥ 10mmol/l vs. rest), longer QRS duration (≥ 100ms vs. rest) and lower systolic blood pressure (< 115mm Hg vs. rest).


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  		Table 2 Cox proportional hazards multivariable analysis: final model for overall cardiovascular mortality

 
3.5. Predictors of progressive heart failure death
On univariable Cox modelling, progressive heart failure death (n = 31) was associated with several clinical factors during the follow up period (Table 3).


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  		Table 3 Cox regression analysis for progressive heart failure death

 
On multivariable Cox modelling (Table 3) five features were independently associated with progressive heart failure death: increasing age, lower serum sodium, longer QRS duration, lower systolic blood pressure and absence of treatment with an angiotensin converting enzyme inhibitor.

3.6. Mode of death and aetiology of heart failure
Of the 95 patients with incident heart failure post-acute myocardial infarction, there were 21 (22.1%) deaths over the study period. Of these 21 deaths, 12 (57%) were due to progressive heart failure, 5 (24%) were sudden deaths and 4 (19%) non-cardiovascular deaths.

Of the 301 patients with incident heart failure not due to acute myocardial infarction, there were 38 deaths. Of these 38 deaths, 19 (50%) were due to progressive heart failure, 8 (21%) were sudden deaths, 7 (18%) other cardiovascular deaths and 4 (11%) non-cardiovascular deaths.

Overall, patients with incident failure due to acute myocardial infarction (vs. all other aetiologies of heart failure) were more likely to die from progressive heart failure (12/95 [12.6%] vs. 19/301 [6.3%]; p = 0.032). There was no association of aetiology of heart failure with risk of sudden death (8/301 [2.7%] vs. 5/95 [5.3%]; p = 0.2), albeit with a low total number of sudden deaths. Fig. 4 depicts the survival curve for progressive heart failure death by aetiology of heart failure.


Figure 04
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  		Fig. 4 Cumulative survival curve (Kaplan-Meier method) for progressive heart failure death, by aetiology of incident heart failure.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 6. Limitations
 References
 
The prognosis after a new diagnosis of heart failure in the general population is poor with a particularly high risk of mortality in the first few months after diagnosis. The most common mode of death in this early high-risk period is progressive heart failure, accounting for over half of all deaths. Progressive heart failure related deaths are likely to occur in hospital. Such deaths are independently associated with older age, lower serum sodium, systolic hypotension, prolonged QRS duration at baseline and absence of angiotensin converting enzyme inhibitor therapy.

In contrast, dying suddenly accounts for less than one quarter of all deaths and is likely to occur out-of-hospital. Due to the small number of sudden deaths (n = 13) we have not reported associations with clinical variables.

In this study, approximately 40% of incident heart failure cases were attributed to coronary artery disease, consistent with findings from earlier epidemiological studies [22,28,29]. Acute myocardial infarction is associated with sudden cardiac death and is also likely to precipitate a worsening in progressive heart failure and subsequent death [30-32]. Prevention, or delay, of such acute events is likely to improve prognosis. In the current study, patients with incident heart failure due to acute myocardial infarction were significantly more likely to die from progressive heart failure during the first few months after diagnosis compared with heart failure due to other aetiologies.

The risk of dying from progressive heart failure was particularly high in the early period after diagnosis with over half of all progressive heart failure deaths in the first six months occurring within one month after diagnosis. The pattern of risk for sudden death appears to be more uniform with a similar mortality rate during the first six months after diagnosis.

Clinical trial data, in contrast to the current study, have suggested that it is sudden rather than progressive heart failure death which accounts for most deaths in patients with heart failure [6-13,15]. Such studies do not represent the generality of heart failure patients due to both selection and survival bias. The former is well recognised, with clinical trials tending to recruit patients that are more likely to be younger and male than the generality of patients. In addition, selection bias in clinical trials has led to the exclusion of severely symptomatic (New York Heart Association class (NYHA) IV) heart failure cases and may explain the relatively lower frequency of reported progressive heart failure related deaths. Two clinical trials [16,17] have reported the mode of death in patients with severely symptomatic chronic heart failure. The CONSENSUS-I trial [16] enrolled established heart failure patients with NYHA class IV symptoms and reported progressive heart failure as the mode of death in 65% of cases. Similarly, the RALES study [17], recruited patients with severe symptoms in the prior six months, although only 27% were in NYHA class IV at the time of recruitment. In this study, approximately 50% of all deaths were due to progressive heart failure. These two studies demonstrated that the single most common mode of death was progressive heart failure and reported rates were higher than other clinical trials but similar to the findings in the present study.

Survival bias is less often discussed: the vast majority of clinical heart failure trials recruit prevalent (established) cases of heart failure. Such cases are identified later in the time course of heart failure, and are the ‘natural survivors’ of the early high-risk period with regard to both overall prognosis and progressive heart failure related death. This may account for the relatively higher proportion of sudden deaths observed in clinical trials.

Although clinical trials demonstrate that neurohormonal antagonists influence mortality, the effect on mode of death is not entirely consistent [19]. The use of angiotensin converting enzyme inhibitors in patients with heart failure is associated with a reduction in deaths due to progressive heart failure [33]. This effect is consistent across several clinical trials, but there are also some data to support a reduction in sudden death [6,7]. A reduction in both sudden death [12,14], and deaths from progressive heart failure, has been reported from randomised trials of β-blockade in heart failure [14]. Similarly, aldosterone antagonists have been reported to reduce both progressive heart failure death [17] and sudden death [10]. The frequency of use of treatments may therefore alter the relative likelihood of death being sudden or due to progressive heart failure [20].

In this population-based study, 79% of patients were prescribed an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, 31% a β-blocker and 20% an aldosterone antagonist prior to discharge/death. Only 28% received the combination of β-blocker and angiotensin converting enzyme inhibitor or angiotensin receptor blocker during the first six months of follow-up. In contrast to the clinical trial setting, treatment was not driven by a study protocol but was solely at the discretion of the physician caring for the patient. The low rates of early use of β-blocker therapy are similar to those reported in primary and secondary care heart failure surveys across Europe [34,35], and more recently in a national audit of heart failure care in England, Wales and Northern Ireland [36]. Although sub-optimal it represents the true situation within an elderly study population.

The use of device therapies such as implantable-cardioverter defibrillators have been reported to reduce the risk of sudden deaths in selected heart failure patients [37-39]. Cardiac resynchronisation therapy reduces the incidence of both sudden death and progressive heart failure deaths [40]. The use of such devices in this population-based study was low (n = 4; [< 1%]) reflecting the incident nature of the population and the low implant rates in the UK at the time of the study.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
6. Limitations
 References
 
The early prognosis after a new diagnosis of heart failure in the general population is poor and progressive heart failure, rather than sudden death, account for the majority of deaths. This observation suggests that the focus of early heart failure management should be the initiation and up-titration of neurohormonal antagonists known to retard the progression of heart failure. Optimisation of pharmacological therapy prior to hospital discharge, rather than a strategy of early hospital discharge and out patient drug up-titration, may be advisable in order to avoid any delay.


   6. Limitations
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
References
 
This study was limited by the number of deaths, and in particular the low number of sudden deaths. Analyses have therefore focused on the associations with progressive heart failure as a mode of death. By design, our study only addressed deaths within the first six months after diagnosis, and we cannot comment on mode of deaths after that period. In addition, the use of β-blocker therapy was relatively low, albeit similar to data from recent European surveys and recent audits from the United Kingdom. The number of patients receiving an implantable defibrillator was low, but in keeping with the low implant rates in the United Kingdom at the time of this study.


   Acknowledgements
 
This work was supported by British Heart Foundation Project grant PG/03/097 & by the Royal Brompton & Harefield Trustees. We are grateful to Tina Chan and Lorraine Dunne for collection of medical data.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 6. Limitations
 References
 

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