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How Do Patients With Heart Failure With Preserved Ejection Fraction Die?
Michelle M.Y. Chan, Carolyn S.P. Lam Eur J Heart Fail. 2013;15(6):604-613.

Abstract and Introduction

Abstract

Understanding how patients with heart failure with preserved ejection fraction (HFPEF) die provides insight into the natural history and pathophysiology of this complex syndrome, thereby allowing better prediction of response to therapy in designing clinical trials. This review summarizes the current state of knowledge surrounding mortality rates, modes of death, and prognostic factors in HFPEF. Despite the lack of uniform reporting, the following conclusions may be drawn from previous studies. The mortality burden of HFPEF is substantial, ranging from 10% to 30% annually, and higher in epidemiological studies than in clinical trials. Mortality rates compared with heart failure with reduced ejection fraction (HFREF) appear to be strongly influenced by the type of study, but are clearly elevated compared with age- and co-morbidity-matched controls without heart failure. The majority of deaths in HFPEF are cardiovascular deaths, comprising 51 60% of deaths in epidemiological studies and ~70% in clinical trials. Among cardiovascular deaths, sudden death and heart failure death are the leading cardiac modes of death in HFPEF clinical trials. Compared with HFREF, the proportions of cardiovascular deaths, sudden death, and heart failure deaths are lower in HFPEF. Conversely, non-cardiovascular deaths constitute a higher proportion of deaths in HFPEF than in HFREF, particularly in epidemiological studies, where this difference may be related to fewer coronary heart deaths in HFPEF. Key mortality risk factors, including age, gender, body mass index, burden of co-morbidities, and coronary artery disease, offer some explanation for the differences in mortality rates observed across studies.
Introduction

The importance of understanding how patients with heart failure with preserved ejection fraction (HFPEF) die goes far beyond morbid fascination. Epidemiological trends show that the prevalence of HFPEF relative to heart failure with reduced ejection fraction (HFREF) is increasing over time; yet at the same time survival in HFPEF has remained dismal, whereas prognosis has improved in HFREF.[1,2] In fact, all outcome trials in HFPEF to date have failed to demonstrate survival benefit, despite robust evidence of prognostic benefit using the same agents in HFREF. The continued absence of guideline-recommended proven therapies for HFPEF may directly impact outcomes in patients with HFPEF,[3] but also importantly points to large gaps in knowledge of therapeutic targets and raises the issue of whether we are measuring the right outcomes in HFPEF trials. Do we really understand how patients with HFPEF die? What is their risk of death in absolute terms, as well as relative to age- and co-morbidity-matched adults or patients with HFREF? Do these elderly patients die of the disease itself (i.e. heart failure), related cardiovascular causes (e.g. myocardial infarction) or age-associated non-cardiovascular causes (e.g. cancer)? In other words, do they die with or of HFPEF (analogous to the case with prostate cancer in elderly men, who often die with, but not of, prostate cancer)? What are the factors that contribute to death in HFPEF? Can we expect targeted therapies to influence all-cause mortality, and, if not, what cause-specific outcomes are most appropriately studied? We aim to explore these issues in this review, using available data to date.

What Is the Risk of Death in Heart Failure With Preserved Ejection Fraction?
Several studies have examined mortality in HFPEF, usually in comparison with HFREF ( ).
Table 1. Characteristics and mortality rates of recent studies reporting outcomes in heart failure with preserved ejection fraction Study (study period) HFPEF LVEF Inclusion criteria no. criteria Approximate Key exclusion follow-up criteria duration (years) Average annual mortality rate (%)

Setting

Population-based studies

Adabag et al. 29 22 hospitals, 787 (19952000) USA Owan et al. 2 (19872001) Bhatia et al. 15 (19992001) Mayo Clinic Hospital, USA 103 hospitals, Canada 2167

45% 50%

Index HF hospitalization Index HF hospitalization + echo in 30 days Index HF hospitalization 70 years, index HF hospitalization, clinical and radiographic diagnosis of HF

10

10

13

880

>50%

22.2

Perez de Isla et Single-centre al. 53 (2002 hospital, 679 2003) Spain

50%

1.5

25.4

Randomized clinical trials

9

I-PRESERVE (20022005)

25 Countries, Europe, USA, South 4128 Africa, and Australia USA (186 centres), 988 Canada (116 centres) 618 centres in 26 countries

45%

60 years, NYHA II, HF hospitalization 6 mths

SBP <100 or >160 mmHg, DBP >95 mmHg, Hb <11g/dL

5.2

DIG-PEF8 (19911993)

>45%

Clinical diagnosis of HF, sinus Cor pulmonale 3 rhythm at baseline 18 years, NYHA IIIV 4 weeks, previous hospitalization for cardiac reason Persistent systolic or diastolic hypertension

7.6

CHARMPreserved10 (19992000)

3023

> 40%

PEP-CHF7 (20002003)

53 centres in 846 8 countries

>40%

70 years, clinical and echo diagnosis of HF, Significant treated with valve disease, 2.2 diuretics, HF stroke history hospitalization 6 months 60 years, NYHA II, hospitalization 1 year, NTproBNP level 2 ULN

5.9

TIME-CHF (2004)

19

15 hospitals, Switzerland 123 and Germany

>45%

1.5

14

National Heart Failure Registries Heart Failure Survey in Israel 25 hospitals, 1364 (HFSIS)16 Israel (2003) Japanese Cardiac 164 Registry of hospitals, Heart Failure in Japan Cardiology (JCARE40% Clinical diagnosis of HF, confirmed by echo and radiography

22

429

50%

HF as primary cause of hospitalization

2.4

11.6

CARD)14 (2009) DBP, diastolic blood pressure; echo, echocardiography; Hb, haemoglobin; HF, heart failure; HFPEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association Class; NT-proBNP, N-terminal pro B-type natriuretic peptide; SBP, systolic blood pressure; ULN, upper limit of normal.
Effect of the Type of Study

Depending on the study design [randomized controlled trials (RCT) vs. population-based studies] and selection criteria [left ventricular ejection fraction (LVEF) critena, hospitalized patients vs. outpatients, number of comorbidities], different HFPEF populations have been sampled, potentially explaining some of the discrepancies amongst reported outcomes.[46] In epidemiological community-based studies, the 1-year mortality rate of HFPEF was almost 30%.[2] In RCTs, mortality rates 23 times lower have been reported (1-year mortality ~10%),[710] a difference that may be partially attributed to selection bias (younger population, better compliance with therapy, and lower burden of co-morbidities in RCTs). In terms of absolute mortality rates, a recent metaanalysis of 31 studies (both observational studies and RCTs) showed that the pooled death rate in HFPEF was 121 [95% confidence interval (CI) 117126] deaths per 1000 patient-years in all the studies; 146 (95% CI 138 154) deaths per 1000 patient-years in non-RCTs alone; and 101 (95% CI 96107) deaths per 1000 patientyears in the RCTs alone.[11] In aggregate, it is clear that the mortality burden of HFPEF is substantial regardless of setting, but has been reported to be higher in 'real world' compared with clinical trial settings.
Effect of Hospitalization

Studies have also examined short- and long-term mortality rates following hospitalization for HFPEF. Inhospital mortality rates have ranged from 2.5% to 6.5%, with similar or lower risks compared with HFREF.[1214] Short-term mortality ranged from 30-day rates of 5.3%,[15] to 60- to 90-day rates of 9.5%,[12] and to 6-month rates of 14.2% to 16%.[16,17] Published long-term 5-year mortality rates varied from 22% to 65%.[2,18] The over-riding message from these studies is that the mortality rate in hospitalized HFPEF is high. There appear to be similar mortality rates between HFPEF and HFREF up to 6 months following hospitalization, after which HFPEF patients may display a better survival probability.
Comparison With Heart Failure With Reduced Ejection Fraction

Reported mortality rates in comparison with HFREF are strongly influenced by the type of study from which mortality data are derived. Epidemiological community-based studies demonstrated a similar prognosis in both patient groups,[2,15] whereas a meta-analysis inclusive of RCTs showed ~32% higher survival in HFPEF than in HFREF (pooled hazards ratio 0.68; 95% CI 0.640.71).[11] Of note, there was a highly significant interaction between type of heart failure (HFPEF vs. HFREF) and the type of study (RCT vs. non-RCT) on risk of death, where survival was ~39% higher in HFPEF than in HFREF in the RCTs, but only ~24% higher in HFPEF than in HFREF in the non-RCTs. Interestingly, the mortality gap between HFPEF and HFREF appeared to be diminished among the very elderly.[19]
Comparison With Age- and Co-morbidity-Matched Patients

The lower mortality of HFPEF compared with 'conventional' heart failure (i.e. HFREF) in controlled trials, the presence of multiple age-related co-morbidities, and the non-specificity of symptoms of HFPEF have given rise to two controversies. First, do patients enrolled in HFPEF trials truly have the syndrome of HFPEF, or are they misdiagnosed cases (of, for example, lung disease, obesity, or myocardial ischaemia)?[20] Secondly, is HFPEF a distinct disease entity, or does it merely represent a collection of co-morbidities in an elderly breathless patient?[21] The potential for misdiagnosis of HFPEF is clinically relevant and an important consideration particularly in earlier trials such as CHARM-Preserved, where patients were enrolled solely on the basis of symptoms and signs of heart failure (and normal EF), with or without a history of recent heart failure hospitalization, and in the absence of additional echocardiographic or biomarker criteria.[10] In fact, Caruana et al. [20] showed that alternative non- heart failure diagnoses were available that could explain patients' symptoms and signs in the majority of cases in their cohort of suspected HFPEF from general practice. A misdiagnosis of HFPEF would be expected to contribute to a lower proportion of cardiovascular deaths. [22] However, when Campbell et al.[23] compared mortality in patients from RCTs of HFPEF (including CHARMPreserved, DIG-PEF, and I-PRESERVE) with patients of similar age, gender, and co-morbidity distribution in

other cardiovascular trials of hypertension (ALLHAT, LIFE, ANBP-2, VALUE, and HYVET), coronary heart disease (ACTION), and diabetes mellitus (ACCORD), patients with HFPEF were found to have a significantly higher proportion of cardiovascular deaths compared with non-HFPEF patients. Furthermore, overall mortality rates were found to be strikingly higher in HFPEF trial patients (5376 per 1000 patient-years) compared with non-HFPEF trial patients (1147 per 1000 patient-years), despite a lower co-morbidity burden in HFPEF than in non-HFPEF trial patients. Thus, even acknowledging the potential for misdiagnosis, the substantially worse prognosis of patients with HFPEF compared with patients with hypertension and other cardiovascular risk factors but without heart failure suggests that HFPEF is not merely about old age and co-morbidities; instead, HFPEF is an entity in itself that identifies patients at an elevated risk of death. In the community-based setting, Mohammed et al.[24] compared survival, as well as cardiovascular parameters adjusted for co-morbidities and scaled for body size and age, in patients with HFPEF, age-/gender-matched healthy controls, and hypertensive controls without heart failure. While each co-morbidity was associated with a unique ventricularvascular profile and impacted survival in HFPEF, the presence of HFPEF itself was associated with further cardiovascular changes that could not be accounted for by co-morbidities alone. These findings thus supported the conclusion that HFPEF was a distinct disease rather than an amalgamation of comorbidities, and provided a basis to understand the worse survival in patients with HFPEF compared with ageand comorbidity-matched patients without heart failure.

How Do Patients With Heart Failure With Preserved Ejection Fraction Die?
Importance of Defining how Patients With Heart Failure With Preserved Ejection Fraction Die

Although several studies have examined outcomes in HFPEF, few have reported specific causes or modes of death. Why is it important to drill down to specifics? As discussed above, multiple age-related co-morbidities may co-exist in patients with HFPEF, and each co-morbidity may impart a mortality risk. Knowledge of allcause mortality alone will not allow discernment of risk related to the co-morbidity vs. risk associated with HFPEF itself. Knowledge of cause-specific mortality, on the other hand, will aid our understanding of the pathophysiology and natural history of HFPEF as a distinct syndrome, and allow better discernment of risk that may be prevented or treated, vs. that which cannot. This knowledge then forms the basis for planning and predicting the impact of interventional strategies. Take, for instance, a patient with HFPEF who suffers an acute myocardial infarction [cause of death (COD)] leading to sudden death [mode of death (MOD)], vs. one with severe infective exacerbation of concomitant chronic lung disease (COD) leading to respiratory collapse (MOD). An intervention such as an implantable cardiac defibrillator would be expected to prevent death in the former, but not the latter, and knowledge of the relative proportions of deaths from each cause/mode in HFPEF would guide decisions on whether defibrillators should be considered or tested as a therapeutic strategy in this patient population.
Challenges in the Classification of Death in Heart Failure With Preserved Ejection Fraction

Comprehensive clinical data are needed for the accurate classification of death in HFPEF. A previously published ACME system for death in heart failure is a useful guideline for the extent of information required to draw meaningful inferences:[25] A for activity and place of death (outpatient or in-hospital), C for COD (e.g. myocardial infarction, ventricular dysfunction, or pneumonia), M for MOD (e.g. sudden death or circulatory failure), and E for events associated with death (e.g. recent hospitalizations or de-compensations). Without a priori planning, such detailed information is rarely available to allow accurate classification of death. Causes of death are more commonly reported in epidemiological studies, where data are extracted from death certificates, medical records, and autopsy findings. Reliability of the data is increased when death ascertainment is carried out by autopsy findings or a chief medical examiner; however, this is available on a large scale in only few communities.[26] MODs are more readily available in RCTs, where there is regular surveillance and formal adjudication of deaths by appointed outcome review committees using pre-specified criteria. There is a lack of uniformity in definitions used to classify deaths in HFPEF in previous publications. To illustrate, mortal events have been grouped under subheadings of sudden death (MOD) and acute myocardial infarction (COD) within the same table, without distinguishing MOD vs. COD.[9,27] Some other studies have also reported events according to the underlying vs. immediate causes of death, rather than COD and MOD.[28]
Cardiovascular vs. Non-cardiovascular Deaths in Heart Failure With Preserved Ejection Fraction

Notwithstanding the variability of definitions used in different studies, the following conclusions can be derived from published outcomes studies in HFPEF (Figure 1). First, the majority of deaths in HFPEF across all studies are cardiovascular deaths. Secondly, the proportion of cardiovascular deaths varies with the type of study, ranging from 5160% in epidemiological studies to ~70% in RCTs. The only exception was the study by Adabag et al. [29] of HF hospitalizations in St Paul, MN, where 5-year post-discharge mortality in HFPEF was classified based on death certificates as non-cardiovascular deaths in 61% of cases. Lack of autopsy data and selection bias due to large amounts of missing EF data may have influenced these results. Nonetheless, the higher proportion of non-cardiovascular deaths in this observational study is consistent with the trend for more non-cardiovascular deaths in epidemiological studies, compared with RCTs, in HFPEF.

Figure 1.

Distribution of mortal events in studies of heart failure with preserved ejection fraction. Bars and numbers indicate the approximate percentage of total deaths.
Mode of Death in Heart Failure With Preserved Ejection Fraction

Specific MODs in HFPEF have been examined in the CHARM-Preserved and I-PRESERVE clinical trials (Figure 2).[27,30] Despite some differences in the populations studied, remarkable consistency was observed in MODs reported: among the ~70% majority of cardiovascular deaths, sudden death was the most common cardiac MOD (2628% of all deaths), followed by heart failure deaths (1421% of all deaths).

Figure 2.

Distribution of modes of death of patients with heart failure with preserved ejection fraction from the IPRESERVE trial30 (top) and CHARM-Preserved trial27 (bottom). Pie charts on the left display the proportion of CV, non-cardiovascular (non-CV), and unknown deaths with the respective percentages of total death. Further breakdown of CV deaths into sudden cardiac death, heart failure deaths, stroke, myocardial infarction, and other CV deaths are shown in a separate pie chart on the right with the respective percentages of CV death.

Cause of Death in Heart Failure With Preserved Ejection Fraction

In epidemiological studies, CODs are described albeit inconsistently. In the large Olmsted County cohort, COD was ascertained from death certificates (>75% of which were completed by a coroner or Mayo staff) and reported under the categories of non-cardiovascular deaths, coronary heart deaths and other cardiovascular deaths. Results showed that the predominant single COD in this study was non-cardiovascular death. However, cardiovascular CODs as a group were more common than non-cardiovascular CODs, and the most prominent cardiovascular COD was coronary heart disease (29% of all deaths).[26]
Cause of Death vs. Mode of Death in Heart Failure With Preserved Ejection Fraction

Both COD and MOD were specifically reported and directly compared in the recent TIME-CHF study, where outcomes were classified according to the ACME criteria after an 18-month follow-up.[19] Analysis of COD vs. MOD in TIME-CHF showed differences in the proportions of cardiovascular-related events when classified by COD (~40%) vs. MOD (~66%) (Figure 3). Careful inspection of the data revealed that this difference was primarily attributed to a larger proportion of 'unknown' assignments for COD, with less 'unknown' and more frequent assignment of 'cardiovascular' for MOD, and otherwise comparable classification of noncardiovascular events by COD or MOD. These results highlight the challenges in classification of death and the limitations of comparisons across studies using different methods, and provide a possible source of discordance between observational studies (mainly reporting COD) and clinical outcome trials (mainly reporting MOD).

Figure 3.

Effect of classification by causes (left) vs. modes (right) of death in heart failure with preserved ejection fraction (adapted from TIME-CHF19). All numbers represent the approximate percentage of total deaths. Under causes of death, cardiac deaths are further separated into acute myocardial infarction (AMI) and LV dysfunction. Under modes of death, cardiac deaths are further separated into sudden cardiac death or circulatory failure.
Classification of Death in Heart Failure With Preserved Ejection Fraction vs. Heart Failure With Reduced Ejection Fraction

Cardiovascular deaths constitute the majority of deaths in both HFPEF and HFREF (Figure 4). However, the proportion of total deaths that are cardiovascular related is higher in HFREF than in HFPEF, whether considering data from RCTs (~80% vs. ~70%)[27,30] or from community-based studies (~60% vs. ~50%).[26,29,31]

Conversely, non-cardiovascular deaths constitute a larger proportion of deaths in HFPEF than in HFREF (~30% vs. ~15% from RCTs; ~50% vs. ~30% in community-based studies).

Figure 4.

Distribution of deaths in heart failure with preserved ejection fraction (HFPEF) vs. heart failure with reduced ejection fraction (HFREF) from studies examining outcomes in HFPEF and HFREF. Specific MODs differ in their distribution between HFPEF and HFREF (). Sudden death and heart failure deaths constitute a larger proportion of deaths in HFREF compared with HFPEF. In fact, the leading single MOD in HFREF RCTs was sudden death (~42%), whereas that in HFPEF was non-cardiovascular death (~30%) followed closely by sudden death (2628%).[30] In epidemiological studies from Olmsted County, the proportion of deaths attributed to coronary heart deaths was larger in HFREF (43%) than in HFPEF (29%).[26] Of note, the lower proportion of coronary heart deaths in HFPEF appeared to account for the lower proportion of cardiovascular deaths, or the higher proportion of non-cardiovascular deaths, in HFPEF compared with HFREF. The Olmsted County study also showed that the proportion of cardiovascular deaths decreased from 69% in 19791984 to 40% in 19972002 (P = 0.007) in HFPEF, in contrast to a modest trend in HFREF (from 77% to 64%, P = 0.08). These observations raise the intriguing notion that HFPEF patients may be increasingly spared from coronary deaths, only to succumb eventually to non-cardiovascular deaths. The role of coronary artery disease (CAD) as a risk factor for death is discussed in further detail later.
Table 2. Distribution of deaths in studies with both heart failure with preserved ejection fraction and heart failure with reduced ejection fraction HFPEF Henkel Adabag JCAREet al. 26 et al. 29 CARD31 CHARM27 DIG8,54 HFREF Henkel Adabag JCAREet al. 26 et al. 29 CARD31 CHARM27 DIG54,55

Total deaths (n) 476

411

169

481

231

441

817

154

1350

2373

Cardiovascular

51

39 11 7 NR NR NR NR NR 61 0

58 11 35 5 4 0 1 2 28 14

71 28 21 4.4 6.9 2.7 7.3 NR 29 0

70 NR 28 NR NR NR 35 7 24 6

64 NR NR 43 NR NR NR NR 36 0

60 24 6 NR NR NR NR NR 40 0

68 23 37 2 3 1 1 1 18 14

83 38 27 6.7 4.1 1.6 5.5 NR 17 0

80 NR 36 NR NR NR 40 4 15 5

Sudden cardiac NR death Heart failure death Coronary heart death Stroke Cardiovascular procedure Other cardiac Other vascular Noncardiovascular Unknown NR 29 NR NR NR NR 49 0

Numbers represent percentages of total deaths unless otherwise stated. HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction; NR, not reported. In summary, cardiovascular-related deaths comprise the majority of mortality events in HFPEF patients, with greater predominance seen in RCTs compared with epidemiological studies. Among cardiovascular deaths, sudden death and heart failure death are the leading cardiac MODs in HFPEF clinical trials. Compared with HFREF, the proportions of cardiovascular deaths, sudden death, and heart failure deaths are lower in HFPEF. Conversely, non-cardiovascular deaths constitute a higher proportion of deaths in HFPEF than in HFREF, particularly in epidemiological studies, where this difference appears to be primarily related to fewer coronary heart deaths in HFPEF.

What Are the Risk Factors for Death in Heart Failure With Preserved Ejection Fraction?
Multiple variables are associated with survival in HFPEF. Key risk factors include age, gender, body mass index, burden of co-morbidities, and CAD.
Age

Increasing age is associated with higher mortality in HFPEF,[32] in a variety of clinical settings.[13,33] Increasing age is also associated with higher burden of cardiovascular co-morbidities in HFPEF (ischaemic heart disease, hypertension, diabetes, and atrial fibrillation), at least up to the seventh decade.[34] While age-associated comorbidites confound the risk of death in HFPEF, age alone remains independently predictive of mortality. [29,35] The TIME-CHF study, which included the oldest cohort of HFPEF to date (mean age 80 years), showed that the increase in mortality with age applies even to those aged 75 years compared with those aged 6074 years.[19] This study further showed that MODs were similar in the two age groups, which goes against the perception that greater age-associated non-cardiac co-morbidity burden may lead to more non-cardiac deaths in the very elderly.
Sex

Women have consistently been shown to have better survival than men with HFPEF. This advantage is observed in both epidemiological studies[36] and RCTs,[37,38] all of which analysed long-term follow-up data for at least 2 years. Interestingly, short-term survival odds appear to be non-discriminatory between the sexes, as demonstrated in the Get With The Guidelines-Heart Failure multicentre registry.[39] This study found similar risks of in-hospital mortality in both sexes, and extends previous findings of similar risks in short-term outcomes for both groups up to 6 months, after which women displayed better survival probablities.[40]

Although it has been postulated that the premise for better survival in women is due to a lower proportion of heart failure with ischaemic origins or a higher LVEF in this group, a recent study comprising a larger HFPEF population has shown no interaction between LVEF or heart failure aetiology and outcomes.[38] In the large IPRESERVE HFPEF trial (60% women),[41] the lower risk of death in women was shown to apply not only to allcause deaths but also to both cardiovascular and non-cardiovascular deaths. The latter runs contrary to the hypothesis that women with HFPEF, being older than men with HFPEF, may have more non-cardiac comorbidities contributing to more non-cardiovascular deaths. Most notably, the I-PRESERVE study showed that the association between sex and mortality risk was significantly modified by four risk factors (AF, renal dysfunction, angina, and NYHA status), such that the sex difference was ameliorated in the presence of AF or renal dysfunction, or in the absence of angina or NYHA class 3 symptoms.
Obesity

The obesity paradox refers to a U-shaped relationship of body mass index (BMI) with mortality, with the highest hazards in groups with the lowest and highest BMI. Although earlier studies of BMI in undifferentiated heart failure showed increased risk only with lower BMI,[42] the U-shaped relationship was observed in recent studies of chronic heart failure patients[43] and, specifically, the HFPEF population.[44,45] In I-PRESERVE, BMI at extreme quintiles of <23.5 kg/m2 and 35 kg/m2 were associated with increased risk of the primary composite outcome (death or cardiovascular hospitalization), as well as all-cause deaths alone.[45] Mortality risk was highest in the lowest BMI quintile. The association between BMI and mortality risk varied with the MOD: heart failure deaths demonstrated the U-shaped relationship with BMI, whereas the rates of both sudden death and noncardiovascular death declined linearly with increasing BMI. Heart failure-related inflammation, stress hormone activation, and excessive catabolism leading to muscle wasting may explain the excess heart failure mortality in the lowest BMI group. Greater metabolic reserve and lipoprotein pools to neutralize circulating lipopolysaccharide endotoxins may explain the lower sudden death and non-cardiovascular death in more obese patients, but does not explain the higher heart failure mortality in the severely obese.
Non-cardiac Co-morbidities

Since HFPEF is a disease syndrome of the elderly, age-associated non-cardiac co-morbidities are highly prevalent in these patients. A greater co-morbidity burden, indexed by the Charlson score, is known to be associated with reduced short- and long-term survival in heart failure regardless of LVEF.[6] [,19] Specifically in HFPEF, non-cardiac co-morbidities have been shown to be related to increased incidence of future HFPEF, [47] reduced functional status,[48] and increased risk of hospitalizations.[49] In fact, compared with HFREF, noncardiac co-morbidities were found to impact functional status to a greater extent in HFPEF,[48] and potentially accounts for more non-heart failure hospitalizations in HFPEF than in HFREF.[49] A greater non-cardiac co-morbidity burden in HFPEF, particularly in community-based HFPEF, offers a potentially simple explanation for the mortality differences between epidemiological studies and RCTs, or between HFPEF and HFREF. However, the extent to which non-cardiac co-morbidities predict death in HFPEF remains unclear, and non-cardiac co-morbidities alone do not explain mortality differences between different heart failure cohorts. For example, in Olmsted County, the burden of non-cardiac co-morbidities was similar between HFPEF and HFREF groups, yet the percentage of non-cardiovascular deaths was higher in the former.[26] Nonetheless, recent mortality risk scores in HFPEF have attempted to quantify the risk associated with non-cardiac factors in HFPEF.[32,50] While more research is needed to define this risk fully, it is clear that attention must be paid to non-cardiac co-morbidities in the optimal management of HFPEF.
Coronary Artery Disease

Coronary artery disease plays an important role in the pathophysiology of HFPEF,[51] and coronary heart deaths constitute the chief cardiovascular COD in HFPEF from epidemiological studies.[26] Whereas differences in prevalence of non-cardiac co-morbidities do not fully account for the contrasting burden of non-cardiovascular deaths between cohorts, the extent of CAD appears to be inversely related to the the burden of noncardiovascular deaths in different heart failure cohorts. Using the Olmsted County community-based cohort and the RCT population from TIME-CHF as representative studies investigating COD in both HFPEF and HFREF, a lower baseline proportion of CAD was related to a higher proportion of non-cardiovascular deaths, in both study designs and heart failure groups (Figure 5).[19,26]

Figure 5.

Inverse relationship between prevalence of CAD and percentage non-cardiovascular deaths. Comparison of baseline burden of CAD and percentage of non-cardiovascular-related deaths (% total deaths) from similar heart failure populations (Olmsted26 and TIME-CHF19) shows an inverse relationship regardless of LVEF. HFPEF, heart failure with preserved ejection fraction; HFREF, heart failure with reduced ejection fraction. A potential explanation for these observations is that patients with HFPEF 'escape' coronary heart deaths, only to die subsequently from their non-cardiac co-morbidities. Alternatively, patients with CAD may have been more likely to 'transition' to HFREF following their myocardial infarctions, thus enriching the HFREF population eventually with more coronary heart deaths. Indeed, a recent study of longitudinal changes in LVEF over time in patients with heart failure showed that CAD was a major determinant of change in LVEF: over 5 years, ~39% of HFPEF patients transitioned to HFREF (LVEF <50%), whereas a similar percentage of HFREF patients transitioned to HFPEF (LVEF 50%).[52] The presence of CAD was associated with greater reduction of LVEF in HFPEF, and, conversely, the absence of CAD was associated with a greater improvement of LVEF in HFREF.

Conclusion
Our review of how patients with HFPEF die provides the following insights: the mortality burden of HFPEF is substantial, ranging from 10% to 30% annually, and higher in epidemiological studies than in clinical trials. Mortality rates compared with HFREF appear to be strongly influenced by the type of study, but are clearly elevated compared with age- and co-morbidity-matched controls without heart failure. The majority of deaths in HFPEF are cardiovascular deaths, comprising 5160% of deaths in epidemiological studies and ~70% in clinical trials. Among cardiovascular deaths, sudden death and heart failure death are the leading cardiac

modes of death in HFPEF clinical trials. Compared with HFREF, the proportions of cardiovascular deaths, sudden death, and heart failure deaths are lower in HFPEF. Conversely, non-cardiovascular deaths constitute a higher proportion of deaths in HFPEF than in HFREF, particularly in epidemiological studies, where this difference may be related to fewer coronary heart deaths in HFPEF. Other key mortality risk factors include age, gender, BMI, and burden of co-morbidities. These previous studies provide some guidance for better prediction of response to therapy in designing clinical trials, but also highlight the urgent need for more consistent reporting of COD/MOD in future studies.
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Funding The National Medical Research Council (a Clinician Scientist Award to C.S.P.L.). Eur J Heart Fail. 2013;15(6):604-613. 2013 Oxford University Press